WO2004106312A1

WO2004106312A1 - Novel 2-aminoselenazoline derivative and use thereof

Info

Publication number: WO2004106312A1
Application number: PCT/JP2004/007547
Authority: WO
Inventors: Shigeo Ueda; Hideo Terauchi; Akihiro Yano; Masashi Matsumoto; Taeko Kubo
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 2003-05-29
Filing date: 2004-05-26
Publication date: 2004-12-09
Also published as: TW200504039A; JP2006232671A

Abstract

A novel 2-aminoselenazoline derivative represented by the following general formula (I), which has excellent inhibitory activity against a nitric oxide synthase, or a physiologically acceptable acid addition salt thereof. (In the formula, R1 and R2 are the same or different and each means hydrogen or C1-10 alkyl, provided that not both of R1 and R2 are hydrogen.) The compound has extremely high inhibitory activity against and/or high selectivity for inducible NOS (iNOS) and hence is useful as an NOS inhibitor reduced in side effects.

Description

Description New 2-aminoselenazoline derivatives and their technical fields

The present invention relates to 2-aminoselenazoline derivatives useful as nitric oxide synthase inhibitors and uses thereof. Background art

In vivo, nitric oxide (NO) 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. Immunol., 1991, 3, 65.) These NOs are composed of nitric oxide synthase (Nitric Oxide Synthase (hereinafter abbreviated as “NOS”) is produced using L-arginine as a substrate.To date, NOS has been roughly classified into two types: one is constitutive NOS (constitutive NOS: In the following, cNOS is referred to as “cNOS”, and cNOS further includes endothelial N0S: Below, referred to as "eNOS") and neuronal NO S

(neuronal 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. Once induced, 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. (Hollenberg, SM, et al., Circulation Research, 2000, 86,

774), and it has been suggested that N 2 O produced by iNOS during cerebral ischemia-reperfusion may cause neuronal cell death (Parmentier-Batteur S., et al., J. Cereb.

Blood Flow Metab., 2001, 21, 15). —In addition, it has been suggested that chronic diseases such as autoimmune diseases, insulin-dependent diabetes mellitus, and osteoarthritis may be caused by cytotoxicity caused by NO produced from macrophages in which iNOS expression is induced. (Corbett, JA, et al., Diabetes, 1992, 41 »897 and van t Hof, R.

J "et. Al., Proc. Natl. Acad. Sci., USA., 2000, 97, 7993).

A compound represented by the following formula (A) has been reported as a compound having NOS inhibitory activity (see Le Sciences, 1996, 58, 1139).

Further, a compound represented by the following general formula (B) is also described as a NOS inhibitor (WO 01/94325; see JP-T-2003-535853).丄-H ₂ (B)

(In the formula, R ¹ is a hydrogen atom or an alkyl group, R ² denotes an alkyl group, one alkyl Le one NH _2, etc.)

Further, compounds represented by the following general formula (C) are also described as NOS inhibitors (W095 / 1 1231; see Japanese Patent Application Laid-Open No. 9-504028). (C)

(Wherein X represents nitrogen, oxygen, sulfur, etc., R ¹ and R ² represent hydrogen, lower alkyl, etc., R ³ , R ⁴ represent hydrogen, hydroxy, etc., and n = 0 Up to 7)

These documents and publications do not describe or disclose the 2-aminoselenazoline derivative of the compound of the present invention represented by the following general formula (I) at all. Disclosure of the invention

As mentioned above, NOS is roughly divided into cNOS and iNOS.However, in order to develop a NOS inhibitor as a therapeutic agent, a drug that exhibits a selectively high inhibitory activity against iNOS is required. . Therefore, 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. To provide an S inhibitor. 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.

That is, the present invention provides the following various aspects of the invention.

(1) The following general formula (I)

(Wherein, 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.

(2) The 2-aminoselenazoline derivative according to the above (1), wherein R ¹ and R ² are an alkyl group having 1 to 6 carbon atoms, or a physiologically acceptable acid addition salt thereof.

(3) The following general formula ()

(Wherein, 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)

Or a physiologically acceptable acid addition salt thereof.

(4) The 2-aminoselenazoline derivative according to the above (3), wherein R ¹ and R ² are an alkyl group having 1 to 6 carbon atoms, or a physiologically acceptable acid addition salt thereof.

(5) 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).

(6) administering the 2-aminoselenazoline derivative or the physiologically acceptable acid addition salt thereof described in any one of the above (1) to (4) to a subject in need thereof. A method for treating and / or preventing a disease caused by nitric oxide.

(7) treatment of a disease caused by nitric oxide of the 2-aminoselenazoline derivative or the physiologically acceptable acid addition salt thereof according to any one of (1) to (4) and / or Or use for the manufacture of a prophylactic medicament.

In the present specification, 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.

Specific examples include the following compounds, or physiologically acceptable acid addition salts thereof.

• 4-methyl-1,4,5-dihydro-1,3-selenazole-12-ylamine, .4-ethyl-4,5-dihydro-1,3-selenazole-12-ylamine,

■ 4-n-propizolee 4,5-dihydro-1,3-selenazonol-2-inolenamine,

• 4,5-dimethyl-4,5-dihydro-1,3-selenazole-2-ylamine, 5-ethyl-4-methyl-1,4,5-dihydro-1,3-selenazol-2-inoleamine,

• 4-ethyl-5-methyl-4,5-dihydro-1,3-selenazole-12-ylamine,

• 5-Methyl-14-n-Propyl-4,5-dihydro-1,3-selenazole-2 —Ilamine,

■ 4-Pininole-5-Methyl-4,5-dihydro-1,3-Selenazonol-1-inoleamine,

• 5-methinolay 4-pentinole 1,5-dihydro-1,3-selenazonol-2-yneoleamine, and

• 4- (3-ethyl) pentyl-5-methyl-4,5-dihydro-1,3-selenazo-1-ru 2-ylamine

More preferably, the following compounds, or physiologically acceptable acid addition salts thereof, can be mentioned.

· (4R) —4-methyl-4,5-dihydro-1,3-selenazole-2-ylamine,

■ (4R) —4-ethyl-1,4,5-dihydro-1,3-selenazole-12 f-lumina,

'' (4 R) — 4-n-propyl-1,4,5-dihydro-1,3-selenazole-2-ylamine,

. (4R, 5S) -4,5-dimethyl-1,4,5-dihydro-1,3-selenazole-12-ylamine,

-(4 S, 5 R) -4,5-dimethinolee 4,5-dihydro-1,3-selenazonole 1 2-ylamine,

· (4R, 5 S) —4,5-Getinolae 4,5-dihydro_1,3-Selenazone 2

—Ilamine,

• (4 R, 5 R) —5-Ethyl-4-methyl-1-4,5-Dihydro_1,3-Selenazo-l-2-ylamine

• (4 S, 5 S) —4-Ethyl-1-5-methyl-4,5-dihydro-1,3-Selenazo-1-ru-2-ylamine,

• (4 S, 5 S) —5-Ethyl-4-methyl-4,5-dihydro-1,3-Selenazo-1-ru-2-ylamine,

• (4R, 5R) —4-Ethyl-5-Methyl-1,4,5-dihydro-1,3-Selenazol-12-ylamine, ■ (4R, 5 S) —5-Echinolé 4-Methinole _ 4,5-Dihydro-1,3-Selenazo 1-Ru 2-Ilamine,

■ (4R, 5 S) —4-ethyl-5-methyl-4,5-dihydro 1,3-selenazo 1-ru 2-ylamine,

· (4 S, 5 R) — 4—Ethyl 1—5—Methinole 4,5—Jihi Draw 1, 3—Serenazo 1-Ru 2-Ilamine

• (4R, 5 S) — 5—methinole 4—n—propinole 1,5—dihidro 1,3—Serenazono 1—2-inoleamine,

• (4 S, 5 R) —5—methinole 4—n—propinole 4,5—dihydro 1,3-selenazole-2-ylamine,

• (4 S, 5R) —4-butyl-5-methyl-1,4,5-dihydro_1,3-selenazole-12-ylamine,

• (4 R, 5 R) —5—methinole 4—n—propinolee 4,5—dihydro 1,3—selenazonole 1—inoleamine,

· (4 R, 5 R) —4-butyl-1-5-methyl-1,4,5-dihydro-1,3-selenazole-1-ylamine,

• (4 S, 5 S) —4—butyl-5-methyl-4,5-dihydro-1,3-selenazo—1—2-ylamine

• (4 R, 5 S) —5-Methyl-1-pentyl-4,5-dihydro 1,3-Selena Zonore 2-Inoleamine, and

■ (4R, 5 S) — 4- (3-ethyl) pentyl-5-methyl-4,5-dihydro-1,3-selenazonol 2-amine

The compound of the present invention represented by the general formula (I) or () (simply represented by the general formula (I) throughout the present specification, unless otherwise specified) is a physiologically acceptable caro salt with acid. May be formed as acid addition salts, for example, salts with 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, citric acid, tartaric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid. In the present invention, “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.

(1'-1)

(Where RR ² and “*” are the same as above)

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.

Next, a method for producing the compound of the present invention will be described below.

The compound of the present invention represented by the general formula (I) can be produced by the following production methods 1 to 3.

(Production method 1)

The compound of the present invention represented by the general formula (I) can be produced according to the following reaction formula.

(II) (')

(Where Y is a halogen atom, ρ-toluenesolephonyloxy, methanesolephoninole M means an alkali metal, and R ¹ and R ² are the same as described above.)

That is, 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.

(Production method 2)

Further, the compound of the present invention represented by the general formula (I) can be produced according to the following reaction formula.

(I)

(In the formula, X represents a halogen atom, and R ¹ and R ² are the same as described above.)

That is, 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. Examples of the solvent 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.

(Production method 3)

(IV) (I)

(Where RR ² and Y are the same as above)

That is, 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. Examples of the solvent 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.

Next, the production of the compounds (I 1), (II I) and (IV) used in the production methods 1 to 3 will be described below.

Compound (II) used in Production Method 1 can be produced, for example, according to the method shown in the following reaction formula.

(II)

(In the formula, R represents a methyl group, a tolyl group, etc., and I ¹ , R ² , X and Y are as defined above. J)

That is, 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. Then, 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.

(VIII) (III)

(Where I ¹ , R ² and X are the same as above)

That is, 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.

(Where RR ² , R, X and Y are the same as above)

That is, 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). (IX), and then the ability of the compound (IX) to sulfonylate the hydroxy group with (i) a tosinolec or a mesylc by a conventional method, or (ii) a triphenylphosphine dihalide by a conventional method. According to the method described in the literature (Tetrahedron Lett., 1981, 22, 3759; J. Chem. Res. Miniprint, 1984, 12, 3655). ) Is reacted with a phosgene equivalent or phosphorus oxychloride to form isotril, and then reacted with selenium. The compound (V) used in the production of the compounds (II) and (IV) described above can also be produced, for example, according to the method shown in the following reaction formula.

(V)

(Wherein, R ^a represents an alkyl group having 1 to 8 carbon atoms, B n represents a benzyl group, and RR ² and X are the same as described above.)

That is, 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). Next, the compound (XIV) is treated under acidic conditions, and then the amino group is removed using a benzyl halide. 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).

When the compound (I) of the present invention produced by the above production methods 1 to 3 is obtained as a mixture of isomers, the compound (I) of the present invention, which is a single isomer, is separated and purified by ordinary chemical operations A compound can be obtained.

In addition, 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.

Since the compound of the present invention has excellent iNOS inhibitory activity, such as high Z selectivity or high iNOS selectivity, it is expected that it can be used as a safe NOSP inhibitor for humans and mammals. In addition, 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 causes; rheumatoid arthritis, osteoarthritis; alcohol, chemicals, etc. Useful as a prophylactic and / or therapeutic agents such as toxins.

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. In the case of 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. Can be administered. In the case of 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 μg to 5 mg Can be.

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. As the carrier for pharmaceutical preparations, non-toxic substances which do not react with the compound of the present invention are commonly used in the field of pharmaceutical preparations. Specifically, cunic acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially alpha-starched starch, sucrose, methyl paraoxybenzoate, methyl paraoxybenzoate, propyl methacrylate Magnesium aluminate, synthetic aluminum silicate, Microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone , Polybutyl alcohol, alginic acid, sodium alginate, light caffeic anhydride, magnesium stearate, tanolek, tragacanth, bentonite, veegum, carboxyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid Glycerin ester, purified lanolin, glycerinated gelatin, polysorbate, macrogo Oil, vegetable oil, mouth, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the like.

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. When preparing parenteral preparations, for example, injections, 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.) and soothing agents (eg, benzalcoium chloride, proforce hydrochloride, etc.) can be added as appropriate. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Test Examples, but these do not limit the present invention. The compounds were identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC), and the like. The configuration of the compound (trans configuration and cis configuration) The arrangement was determined with reference to the method described in the literature (J. Org. Chem., 1972, 37, 4401). The following abbreviations may be used in the examples and tables to simplify the description of the specification.

Abbreviations used as substituents are: 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 and n-Pn Represents a normal pentyl group.

Abbreviations used as recrystallization solvents include ET for ethanol, HX for n-hexane and IP for isopropanol.

Abbreviations used in NMR are: s is a singlet, d is a double / line, dd is a doublet, t is a triplet, q is a quadruple, m is a multiplet, br is broad and J Means the coupling constant.

Reference example 1

(1) (2 S, 3 R) — 3-amino-2-butano

(2R)-Using 2-amino-1-propanol, literature (J. Org. Chem. 1996,

61, 4210) to give the desired product.

Reference Example 1 (1) or literature (Angew. Chem., Int. Ed. Engl., 1987, 26, 1141) using the corresponding amino alcohols instead of (2R) -2-amino-1-propanol. The following compounds were obtained by the same reaction and treatment according to the method described.

(2) (2 R, 3 S) — 3-amino-2-butanol

(3) (3 S, 4 R) — 4-Amino-3-Hexanol

(4) (3R, 4 S) — 4-amino-3-hexanonone

(5) (2R, 3 R) — 2-amino-3-pentanol

(6) (2 S, 3 S) — 2-amino-3-pentanol

(7) (2 R, 3 R) —3-amino-1-2-pentanol

(8) (2 S, 3 S) — 3-amino-2-pentanol

(9) (2R, 3 S) — 2-Amino-3-pentano Reference example 2

(1) (1 S, 2 R) — 2-Amino-1-methylpropyl methylsulfonate · 1 HCI: 'HCI

0.22 g of (2S, 3R) -3-amino-2-butanol was added to 5 ml of dioxane, and 2 ml of a dioxane solution of 0.54 g of di-tert-butyldicarbonate was added at room temperature, followed by stirring at the same temperature for 2 hours. did. After evaporating the solvent, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (2: 1), purified, and purified with tert-butynole (1R, 2S) -2-hydroxy-1-methynolepropyl 0.40 g of zolecanorebamate was obtained as crystals. To a solution of 0.40 g of the obtained tert-butyl (1R, 2S) -2-hydroxy-1-methylpropyl carbamate and 0.36 ml of triethylamine in 5 ml of methylene chloride was stirred methanesulfochloride at 0 ° C. 0.27 g of methylene chloride solution (1 ml) was added, and the mixture was stirred at the same temperature for 1 hour. 5 ml of water was added, and the mixture was extracted with 5 ml of black-mouthed form. The extract was dried over magnesium sulfate and concentrated to give (1S, 2R) -2-[(tert-butoxy) potanol-amino] -1-methylpropyl methylsulfonate 0.55 g as an oil. The obtained (1S, 2R)-2-[(tert-butoxy) carbonylamino] 1-1-methylpropylmethylsulfonate 0.55 g of ethanol solution 5 ml in 0 ml under stirring at 0 ° C was added with 30% 5 ml of a hydrochloric acid-ethanol solution was added, and the mixture was stirred at the same temperature for 1 hour. After evaporating the solvent, 0.35 g of the desired product was obtained as crude crystals.

The corresponding compounds were used in place of (2 S, 3R) -3-amino-2-butanol in the same manner as in Reference Example 2 (1), and the following compounds were obtained. (2) (1 R, 2 S) — 2-amino-1-methylpropyl methylsulfonate ■ 1 salt

(3) (1 S, 2R) — 2-Amino-1-ethylbutyl methylsulfonate salt (4) (1 R, 2 S) —2-Amino-1-ethylbutyl methylsulfonate salt

(5) (1R, 2R) — 2-amino-1-ethylpropyl methylsulfonate monosalt

(6) (1 S, 2 S) —2-Amino-Echi / Reb Mouth Pill Mechi / Resnorefonate Salt

(7) (1 R, 2 R) — 2-amino-1-methylbutyl methylsulfonate

(8) (1 S, 2 S) — 2-amino-1 monomethylbutyl methylsulfonate salt

(9) (1 S, 2 R) — 2-amino-1-ethylpropyl methylsulfonate salt

10) 2R-1 2-aminopropyl methylsulfonate

11) 2 S—2-Aminopropyl methylsulfonate

12) 2R-2-aminobutyl methylsulfonate monohydrochloride

13) 2S-I-2-aminobutylmethylsulfonate

14) 2 R 1 2—Aminopentisole Mechinoreshonorehonate

15) 2 S —2—Amino pliers / Lemethinolesnoleshonate

16) 2 R — 2-Amino-3-methylbutyl methylsulfonate hydrochloride 1) 2 S-12-Amino-3-methylbutylmethylsulfonate

18) 2 R — 2-aminohexyl methylsulfonate

19) 2 S —2-Aminohexyl methylsulfonate

Reference example 3

(1) (2 S, 3R) — 3-amino-2-otatanol:

(S) —4— (2-Oxazolidinonyl) monomethyltriphenylphosphonium disulfide 37 g was added to 756 ml of tetrahydrofuran, and the solution was added at 178 ° C under 149 ° C. A 1.6 M hexane solution of m 1 normal butyl lithium was added and stirred at the same temperature for 1 hour. 6. Normal pressure 6.5 ml was added to the mixture [J, and the mixture was stirred at the same temperature for another 2.5 hours. After the temperature was raised to room temperature, saturated aqueous ammonium chloride solution 378m1 was added, and ethyl acetate 378m3 was added. Extracted in step 1. The extract was dried over magnesium sulfate, subjected to column chromatography, eluted with ethyl acetate-hexane (2: 1), purified, and purified with (R)-4- (1,1-pentenyl) 6. O g of 2-oxazolidinone was obtained as an oily product, and the obtained (R) -4- (1, unenyl) -2-oxazolidinone 6.0 g in ethanol solution 50% in 10 ml of 10% palladium-carbon 0.5 g was added, and the mixture was stirred for 3 hours under a hydrogen atmosphere, and the catalyst was removed by filtration and concentrated to obtain (R) _4-pentyl-1-oxazolidinone as an oil (5.7 g). (R) —4-pentyl-2-oxazolidinone 5.7 g of methylene chloride solution in 10 Om 1 at room temperature Notate 16.6 ml, triethylamine 1 01111 4_1 ^, ^^-dimethylaminopyridine 0.4 g, stirred at the same temperature for 3 hours 5% aqueous solution of citric acid 100 m After washing with 1, dry over magnesium sulfate, concentrate, apply to column chromatography, elute and purify with ethyl acetate-hexane (1: 4), and (R) -N-tert-butoxycarbonyl

8.3 g of 4-pentyl-1-oxazolidinone was obtained as an oil. 3.25 g of cesium carbonate was added to 100 ml of a methanol solution of 8.3 g of the obtained (R) -N-tert-butoxycarbo-norethone-41-pentynole-2-oxazolidinone, and the mixture was stirred at room temperature overnight. did. After distilling off the solvent, 100 ml of chloroform in the mouth was collected, washed with 100 ml of a 5% aqueous solution of citric acid, dried over magnesium sulfate and concentrated, and then subjected to column chromatography. Elution with 1: 1) was followed by purification to obtain 6.5 g of (R) -N-tert-butoxycarbonyl 2-amino-11-heptanol as an oil. To a solution of 5.5 g of the obtained (R) -N-tert-butoxycarbonyl 2-amino-1-heptanol in 24 ml of ethanol at room temperature was added 3 Oml of a 30% hydrochloric acid-ethanol solution at room temperature. The mixture was stirred at the same temperature for 2 hours. After evaporating the solvent, 4.7 g of (R) -2-amino-11-heptanol monohydrochloride was obtained as crude crystals. The obtained (R) -2-2-amino-1-heptanol 'monohydrochloride (4.7 g) in a mixed solution of acetonitrile (19 Oml) and ethanol (27 ml) at room temperature was added with 13 g of potassium carbonate and room temperature. After adding benzyl bromide (8.2 g), the mixture was heated to 60 ° C and stirred overnight. Insoluble salt After filtration, concentrate, add 50 ml of chloroform, wash with 50 ml of water, dry over magnesium sulfate, concentrate, apply to column chromatography, elute and purify with ethyl acetate hexane (2: 3). 6.6 g of (R) -N, N-dibenzyl-1-amino-1-heptanol were obtained as an oil. Using the obtained (R) -N, N-dibenzyl-l-amino-l-heptano monole, according to the method described in the literature (Angew. Chem., Int. Ed. Engl., 1987, 26, 1141). Reaction ■ treatment gave the desired product.

Reference Example 3 using the corresponding aldehyde instead of normal ptanal

The reaction and treatment were carried out in the same manner as in (1) to obtain the following compound.

(2) (2 S, 3 R) _ 3-amino-1 7-methyl-1-octanol

(3) (2 S, 3 R) — 3-amino-1 6-ethynole 2-octanol

Example 1

(4R) —4-Methyl-4,5-dihydro-1,3-selenazole_2-ylamine

~ ΝΗ ₂ ■ 1 2 Fumaric acid

And Se Reference Example 2 1.42 g of (2R) -2-aminopropylmethylsulfonate monohydrochloride obtained in (10) and 2.70 g of potassium selenocyanate at room temperature in 30 m of water In addition to 1, the mixture was stirred at the same temperature for 15 minutes. After the temperature was raised to 100 ° C, the mixture was further stirred for 3 hours. After cooling to room temperature, the mixture was cooled under ice, 1 Oml of a 25% aqueous sodium hydroxide solution was added, and the mixture was extracted three times with 20 ml of chloroform. The extract was dried over sodium sulfate and concentrated, and the residue was treated with fumaric acid in ethanol and recrystallized from ethanol-n-hexane to obtain 0.113 g of the desired product. Melting point: 160-163 ° C

¾-丽 R (DMSO-de) δ: 1.21 (d, J = 6.4Hz, 3H), 3.08 (dd, J = 7.4Hz, J = 10.1Hz, 1H), 3.56 (dd, J = 6.7Hz, J = 10.1Hz, 1H), 4.15 (ra, 1H), 6.46 (s, 1H)

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. The compounds shown in Table 1 below were obtained. table 1

Examples 15 and 16

Example 15

(4R, 5 R) — 5-Ethyl-4,5-Methyl-1,5-dihydro-1,3-Selenazo'-l-2-ylamine fumarate 1 no 2 fumaric acid

Example 16

(4 S, 5 S) —4-Ethyl-1-5-methyl-4,5-dihydro_1,3-Selenazol-1-2-ylamine 1/2 fumarate ■ 1 2 Fumaric acid

[Step 1] Reference Example 2 25.5 g of (1R, 2R) -2-amino-1-ethylpyruluyl methylsulfonate monohydrochloride obtained in (5) and 25.4 g of potassium selenocyanate were added to 350 ml of water. After stirring at room temperature for 15 minutes, the mixture was stirred at 100 for 3 hours, and further stirred at room temperature overnight. Under ice-cooling, 100 ml of a 25% aqueous sodium hydroxide solution was added, and the mixture was extracted three times with 100 ml of a black hole form. The extract was dried over sodium sulfate and concentrated, and (4R, 5R) -5-ethyl-14-methyl-1,4,5-dihydro-1,3-selenazole-12-ylamine and (4S, 5S) -4 Thus, 14 g of a mixture of —ethyl-5-methyl-4,5-dihydro-1,3-selenazole-1-ylamine was obtained.

[Step 2] The (4R, 5R) -5-ethyl-14-methyl-1,4, obtained in the above step 1

Mixture of 5-dihydro-1,3-selenazole-1-ylamine and (4S, 5S) -4-ethyl-5-methyl-1,4-dihydro-1,3-selenazole-2-ylamine 1.00 g of chloride To a methylene solution (15 ml) were added 0.65 ml of triethylamine and 0.385 ml of methyl chloroglyoxylate under ice-cooling, followed by stirring for 30 minutes. The 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. Was.

■ N- (4 R, 5 R) — (5-Echinol 4- 4-methynole 1,5-dihydro-1,3-selenazole-1-yl) -oxamic acid methyl ester 0.30 g

-删_{R (CDC1 3) δ: 1.03} (t, J = 7.3Hz, 3H), 1.31 (d, J = 6.4Hz, 3H), 1.72- 1.99 (m, 2H), 3.25 (m, 1H), 3.87 (s, 3H), 4.00 (m, 1H)

• N— (4S, 5S) — (4-Ethyl-5-methyl-1,4,5-dihydro-1,3-selenazol-1-yl) -oxamic acid methylesterol 0.50 g

_{¾-NMR (CDC1 3) δ} : 0.91 (t, 1 = 7.3Hz, 3H), 1.61 (. D, J = 7 OHz, 3H), 1.62 (ra, 2H), 3.45 (ra, 1H), 3.77 ( m, 1H), 3.88 (s, 3H)

(Step 3)

(a) N— (4R, 5R) — (5-ethyl-4-methyl_4,5—dihydro-1,3-selenazol-2-yl) -oxamic acid methyl ester obtained in step 2 above To a solution of 0.30 g of methanol in 0.1 ml of methanol was added 0.15 g of lithium carbonate, followed by stirring at room temperature overnight. After methanol was distilled off under reduced pressure, 30 ml of dichloromethane and 9 ml of an aqueous sodium hydroxide solution (2 mo 1ZL) were added, and the mixture was stirred. The dichloromethane layer was separated, dried over sodium sulfate, concentrated, and the residue was subjected to an amine-treated silica gel column chromatography. After elution with chromatographic form, purified and purified (4R, 5R) —5—Ethynole-1—4-Methinole-1,4,5-dihydro-1,3-Selenazonole1-2—Inoleamine 0.18 g as an oil Obtained.

One _{NMR (CDC1 3) δ: 0.99} (t, J = 7.2Hz, 3H), 1.25 (d, J = 6.4Hz, 3H), 1.68-1.97 (m, 2H), 3.85 (m, 1H), 3.96 ( m, 1H), 4.63 (br, 2H)

Obtained above (4 R, 5 R) - 5- Echiru 4-methyl-4, was treated with 5-dihydro one 1, ₃ Serenazoru-2-^ f Noreamin 0. 18 g of ethanol fumarate, ethanol one n —Recrystallized from hexane to obtain 0.18 g of the target compound of Example 15. 145-152 ° C

(b) In the same manner as in (a) above, 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.

¾-NMR (CDCI3) δ: 1.01 (t, J = 7.4 Hz, 3H), 1.50—1.59 (m, 2H), 1.56 (d, J = 7. OHz, 3H), 3.66 (tn, 1H), 4.01 (m, 1H)

(4S, 5S) —4-ethyl-5-methyl-4,5-dihydro-1,4 obtained above 0.21 g of 3-selenazole-l-ylamine was treated with fumaric acid in ethanol and recrystallized from ethanol-n-hexane to obtain 0.18 g of the target compound of Example 16. . Melting point 1 6 0— 1 6 4 ° C

Examples 17 to 22

The corresponding starting compounds obtained in Reference Example 2 were used instead of (1R, 2R) -2-amino-1-ethylpropyl methylsulfonate monohydrochloride in Examples 15 and 16 respectively. The reaction and treatment were carried out in the same manner as in 15 and 16, to obtain the compounds shown in Table 2 below.

Table 2

Example 2 3

(4R, 5R) —5-Ethyl-1-methyl 4-, 5-dihydro-1,3-selenazo'Ru-2-ylamine 'fumarate -1 2 fumaric acid

[Step 1] Reference example 1 To 5 ml of a ethanol solution of 2.0 g of (21,3S) -2-amino-13-pentanol obtained in (9), 16 ml of ethyl formate was added, and the mixture was heated at 90 ° C. Stirred overnight. After cooling to room temperature, the mixture was concentrated, and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (10: 1). 1.38 g of 3-pentanol were obtained.

[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. After adding 10 ml of water and washing with water, the methylene chloride layer was dried over sodium sulfate and concentrated to obtain 0.21 g of (1S, 2R) -1-ethyl-12-formylaminopropylmethylsulfonate. .

[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 4] Without further purification, the (1 S, 2R) -1-ethyl-2-isocyanopropyl methylsulfonate obtained in the above step 3 was obtained in the form of 10 m

To 1 solution, 0.9 g of selenium and 0.45 ml of triethylamine were added, and the mixture was stirred at 60 ° C overnight. The reaction solution was filtered through celite and concentrated to obtain (1S, 2R) -1-ethyl-2-isoselenocyanocyanatopropyl 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. The extract was dried over sodium sulfate and concentrated, and the residue was subjected to silica gel gel chromatography treated with amide, eluted with a chromatographic form, purified, treated with fumaric acid, and then diluted with ethanol. Recrystallization from xane gave 0.035 g of the compound of Example 23 (same as the compound of Example 15).

Examples 24 to 26

The corresponding starting compounds obtained in Reference Example 3 were used instead of (2R, 3S) -2-amino-3-pentanol in Example 23, and the reaction-treatment was performed in the same manner as in Example 23. The compounds shown in Table 3 below were obtained.

Table 3

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)

(Essential Medium) medium and cultured in a carbon dioxide gas incubator. Next, LPS (lipopolysaccharide) and mouse IFN-v (interfacial gamma) were added to the medium to a final concentration of 0.2 g / m1 and 10 OUZm1, respectively. After further culturing the cells for 1 B, the cells were collected and homogenized by adding 5 OmM Tris-monohydrochloride Zl 0 ΟμΜ DTT (dithiothreinone) (pH 7.5) to 2 × 10 ⁷ cells / m 1, Centrifuge at 100, OO OXg for 30 minutes Was. Dowe X HCR-W2 was added to the soluble cytoplasmic fraction of the obtained supernatant, and the mixture was stirred at 4 ° C for 30 minutes, and the obtained supernatant was used as a crude enzyme sample of iNOS.

i NOS activity L- ^[3 H] - have been conducted under measurement to quantify the variable replacement amount of arginine to L one ^[3 H] over citrulline.

5 OmM Tris-monohydrochloride buffer (pH 7.5) containing 1 mM NAD PH (reduced nicotinamide adenine dinucleotide phosphate) in crude enzyme preparation (70 μl), test compound (1 0 μ 1), 10 Ci / m 1 L— [ ³ H] monoarginine (20 μ 1) and 5 OmM Tris-hydrochloride buffer (pH 7.5) (80 μ 1) And incubated at 37 ° C for 30 minutes. This contains 2 mM EDTA (ethylene diamine tetraacetic acid) and 2 mM EGTA [ethylene glycol bis (6-aminoethyl ether) mono-, di-, tri-, tetra-acetic acid] 0.1 M sodium acetate buffer (ρΗ5.0 ) (200 μl) was added to stop the reaction. Dowex 50W-X8 was added to the reaction solution, stirred for 30 minutes, allowed to stand for 30 minutes, and then liquid scintillation force was added to the supernatant to measure radioactivity. The concentration (IC ₅₀ ) at which the inhibition rate of the production of L- [ ³ H] -citrulline was 50% was calculated as the iNOS P and harmful activity value of each compound, and the results are shown in Table 4.

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.

An untreated female Wistar rat (weighing 150-170 g) was decapitated and the whole brain was quickly removed, to which 5 volumes of 0.1 lmM PMS F (phenylmethylsulfonyl fluoride), 12. A 5 OmM HEPE S (N-2-hydroxyethylpiperazine-N, 12-ethanesulfonic acid) buffer (pH 7.1) containing 5 mM 2-mercaptoethanol and 0.5 mM EDTA was added and homogenized. This was centrifuged at 100,000 × g for 60 minutes. Dowe X HCR-W2 was added to the soluble cytoplasmic fraction of the obtained supernatant, and the mixture was stirred at 4 ° C for 30 minutes.

A crude enzyme preparation of S was used.

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.

1 mM NAD PH to crude enzyme preparation (1 00 μ 1), 2mM C a C 1 2 and 30 OnM calmodulin 5 Omm tris monohydrochloride buffer containing (p H 7.5) (60 1 ), test compound (1 1), 10 μ C i / m 1 L one ^[3 H] one arginine (2

0 μ1) and 5 OmM Tris-HCl buffer (pH 7.5) (10 ^ 1)

Incubated at 37 ° C for 30 minutes. The reaction was quenched with 0.1M sodium acetate buffer (pH 5.0) (200 1) containing 2mM £ 0 ぉぴ 2111] ^ E GTA, and the reaction solution was added to Dowe X 50W- X8 was added, the mixture was stirred for 30 minutes, and allowed to stand for 30 minutes. Then, a liquid scintillation cocktail was added to the supernatant, and the radioactivity was measured. The concentration (IC ₅₀ ) at which the production inhibition rate of L- [ ³ H] -citrulline was 50% was calculated as the nNOS inhibitory activity value of each of the conjugates.

Using iNOS and nNOSP and the harmful activity values obtained in Test Examples 1 and 2,

Table 4 shows the results with the selectivity for 1 NOS as “deviation” (deviation = nNOSZ-iNOS).

The following compound (A) described in the above-mentioned document (Life Sciences, 1996, 58, 1139):

Was used as a comparative compound, and tested in the same manner as in Test Examples 1 and 2 above, and the results are shown in Table 4.

Table 4

Industrial potential

As is clear from the test examples described above, 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., and useful as Z or therapeutic agents.

Claims

Scope of claim General formula (I) below

(Wherein, 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) —Aminoselenazoline derivatives or physiologically acceptable acid addition salts thereof.

2. The 2-aminoselenazoline derivative according to claim ^{1, wherein} R ¹ and R ² are an alkyl group having 1 to 6 carbon atoms, or a physiologically acceptable acid addition salt thereof.

3. The following general formula ()

(Wherein, 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. And R ¹ and R ² are not simultaneously hydrogen atoms)

2. The 2-aminoselenazoline derivative according to claim 1, represented by the formula: or a physiologically acceptable acid addition salt thereof.

4. The 2-aminoselenazoline derivative according to claim 3, wherein R ¹ and R ² are an alkyl group having 1 to 6 carbon atoms, or a physiologically acceptable acid addition salt thereof.

5. Nitrogen monosulfide synthesis comprising the 2-aminoselenazoline derivative according to any one of claims 1 to 4 or a physiologically acceptable acid addition salt thereof as an active ingredient.

6. Administering a 2-aminoselenazoline derivative or a physiologically acceptable acid addition salt thereof according to any one of claims 1 to 4 to a subject in need thereof. A method for treating or preventing a disease caused by nitrogen oxide.

7. Treatment and treatment of a disease caused by nitric oxide of the 2-aminoselenazoline derivative or a physiologically acceptable acid addition salt thereof according to any one of claims 1 to 4. / Or use for the manufacture of a prophylactic medicament.