WO2003075922A1

WO2003075922A1 - Nitrogen monoxide synthase inhibitors

Info

Publication number: WO2003075922A1
Application number: PCT/JP2002/002392
Authority: WO
Inventors: Hideo Terauchi; Shigeo Ueda; Motoharu Ido; Akihiro Yano; Masashi Matsumoto; Junichi Tsuji
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 2002-03-14
Filing date: 2002-03-14
Publication date: 2003-09-18
Also published as: AU2002238889A1

Abstract

Nitrogen monoxide synthase (NOS) inhibitors comprising as the active ingredient 2-aminothiazoline or oxazoline derivatives represented by the following general formula (I) or physiologically acceptable acid addition salts thereof: (I) wherein R1 and R2 are the same or different and each represents hydrogen or lower alkyl; X represents oxygen or sulfur, provided that R1 and R2 represent hydrogen atoms at the same time; and each &ast; stands for an asymmetric carbon atom in case where R1 or R2 is not hydrogen. These compounds have an extremely high inhibitory activity on iNOS and have a high selectivity, which makes them useful as NOS inhibitors with little side effects.

Description

Description Nitric oxide synthase inhibitor Technical field

The present invention relates to 2-aminothiazoline or oxazoline derivatives useful as nitric oxide synthase inhibitors. Background art

In vivo, nitric oxide (NO) is an endothelium-derived vasorelaxant in the vascular system (Moncada, S., et al., Pharmacol. Rev., 1991, 43, 109), and the nervous system. It is believed that they have important physiological activities as neurotransmitters (Edelman, GM, et al., Proc. Natl. Acad. Sci., USA., 1992, 89, 11651). On the other hand, in leukocytes, NO is considered to play a role as a biological defense factor due to bactericidal action (Nathan C.F., et al., Curr. Opin. Immunol., 1991, 3, 65). These NOs are produced by nitric oxide synthase (NOS) using L-arginine as a substrate. To date, two major types of NOS have been reported. One is called constitutive NOS (hereinafter abbreviated as “cNOS”), and cNOS is further referred to as endothelial NOS (abbreviated as “eNOS”) and nervous NOS. S

(neuronal NOS: hereinafter abbreviated as “nNOS”), all of which are constantly expressed and are temporarily active depending on intracellular calcium that is increased by physiological stimulation. To produce small amounts of NO. The other is called inducible NOS (inducible NOS), and its expression is induced in various cells, including macrophages, by stimulation of endotoxins and various cytokines. Once induced, cNOS, unlike cNOS, produces persistent and large amounts of NO independent of intracellular calcium. Therefore, it has been reported that N〇 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., Circ. Res., 2000, 86, 774), suggesting that NO 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). It has also 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; van't Hof, RJ, et. Al., Proc. Natl. Acad. Sci., USA., 2000, 97, 7993).

As the NOS inhibitor, a compound represented by the following general formula (a) is described in a patent gazette (WO 95/11231, JP-T-Hei 9-504028).

(Where R ¹ and R ² represent a hydrogen atom, a lower alkyl group, etc., R ³ represents a hydrogen atom, etc., R ⁴ represents a hydrogen atom, etc., X represents an oxygen atom, a sulfur atom, etc. Means n means 0-7)

Further, a compound represented by the following general formula (b) is also described in the patent gazette as a NOS inhibitor (WO 96/35677, JP-T-11-511741).

(Wherein, R ¹ represents a hydrogen atom, etc., R ⁵ , R ⁶ and R ⁷ represent C 1-10 -alkyl etc., R ⁸ and R ⁹ represent a hydrogen atom etc., X, A And B represent NR ² , oxygen atom, sulfur atom, (CH ₂ ) _P, etc., p represents 0-6, and R ² represents hydrogen atom etc.

These patent publications disclose structures including the compounds of the present invention, but do not specifically disclose the compounds of the present invention. Furthermore, it is described in a patent publication that a compound represented by the following general formula (C) can be used as an antihypertensive agent, diuretic agent or anti-inflammatory agent (US Pat. No. 3,931,214, JP-A-49-76867). However, it does not describe nitric oxide synthase inhibitory action.

(In the formula, R ¹ ′ means an alkyl having 1 to 6 carbon atoms, R ² ′ and R ³ ′ represent a hydrogen atom, an alkyl having 1 to 3 carbon atoms, and the like, ⁽⁴ means hydrogen atom, methyl, ethyl, etc.)

Further, compounds represented by the following formulas (d) and (d ') are described in the literature (J. Org. Chem., 1972, 37, 4401). However, this document does not describe any pharmacological effects.

》 ~ NH ₂ (d) (d ')

Disclosure of the invention

As mentioned above, NOS has cNOS and iNOS, so N

In order to develop OS inhibitors, ones that exhibit high selective inhibitory activity against iNOS are required. Accordingly, an object of the present invention is to inhibit NOS, which has a high inhibitory activity and high selectivity for iNOS, which is useful for treating and / or preventing diseases caused by excessive NO production of iNOS. To provide an agent.

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 having high power and selectivity.

The present invention is useful for treating and / or preventing a disease caused by excessive NO production of iNOS, and more specifically, 2-aminothiazoline or a compound represented by the following general formula (I). The present invention relates to a NOS inhibitor comprising, as an active ingredient, an oxazoline derivative or a physiologically acceptable acid addition salt thereof (hereinafter, also referred to as “the compound of the present invention”).

That is, the present invention

(1) The following formula (1)

(Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and X represents an oxygen atom or a sulfur atom. However, R ¹ and R ² are not hydrogen atoms at the same time. "*" Indicates an asymmetric carbon atom when R ¹ or R ² is not a hydrogen atom.)

A 2-aminothiazoline or oxazoline derivative represented by the formula or a physiologically acceptable acid addition salt thereof as an active ingredient;

(2) The nitric oxide synthase inhibitor according to the above (1), wherein X is a sulfur atom,

(3) The nitric oxide synthase inhibitor according to the above (1) or (2), wherein the configuration of the carbon atom at the 4-position and the 5-position is both R-type.

(4) R ¹ and R ² are identical or different, a methyl group or Echiru group wherein

(1 g (3) described nitric oxide synthase inhibitor,

(5) The monoacid nitrogen synthase inhibitor according to the above (1), wherein X is an oxygen atom, and

(6) The nitric oxide synthase inhibitor according to the above (1) or (5), wherein R ¹ and R ² are the same or different and each is a methyl group or an ethyl group.

The present invention also provides

(7) The following general formula (Ia)

(Wherein, R ¹ ′ and R ² , are the same or different and represent a lower alkyl group. R ¹ ′ and R ² ′ are not methyl groups at the same time. “*” Indicates an asymmetric carbon atom.) Do) A 2-aminothiazoline derivative represented by or a physiologically acceptable acid addition salt thereof, and

(8) The following general formula (Ib)

_R 2

(In the formula, R and R ² ″ are different and represent a lower alkyl group, and “*” represents an asymmetric carbon atom.)

A 2 -aminooxazoline derivative represented by the formula: or a physiologically acceptable caro salt with acid.

The 2-aminothiazoline or oxazoline derivative represented by the general formula (I) may be referred to as a 4,5-dihydro-1,3-thiazole (or oxazole) -12-ylamine derivative.

The compound of the present invention is preferably a compound represented by the general formula (I), wherein X is a sulfur atom in the general formula (I), and the carbon atoms at the 4-position and the 5-position are both R-type. Compound.

More preferred specific examples include the following compounds or their physiologically acceptable acid addition salts.

• (4R, 5 R) —5-Ethyl-4—Methyl_4,5-Dihydro-1,3,3-Thiazol-1-2-ylamine,

• (4 S, 5 S) —4,5-dimethyl-1,4,5-dihydro-1,3-thiazole-2-ylamine,

• (4 R, 5 R) —4-Ethyl-5-Methyl-4,5-Dihydro-1,3-thiazol-Lu-2-ylamine,

• (4R, 5R) -4,5-dimethyl-4,5-dihydrido1,3-thiazole-2-ylamine,

· (4R, 5R) —4,5-Jetyl-4,5-Dihidro 1,3-Thiazol-2-ylamine, • (4 S, 5 S) —4-Ethyl-5-methyl-4,5-dihydro_1,3_thiazono-2-ene-2-amine

• (4 R, 5 S) —4,5-diethyl-1,4,5-dihydro-1,3-thiazole-12-ylamine,

· (4 S, 5 S) —4-Ethyl-1-5-Methynole-4,5-Dihydro-1,3-oxazolu-Ru 2-Yilamine,

• (4 R, 5 R) _ 5—Ethyl-4—Methyl-4,5-dihydro-1,3—oxazo mono-l 2 _ylamine,

• (4R, 5 S) — 5-Ethyl — 4-Methyl-4,5-dihydro-1,3-thiazolone 1-2-Inoleamine,

• (4 S, 5 S) —5-Ethyl — 4-Methyl-1, 4,5-Dihydro-1,3-thiazolyl 2-ylamine,

• (4R, 5S) —4-ethyl-5_methyl-1,4,5-dihydro_1,3_thiazole 2--2-ylamine,

· (4 R, 5 R) —4—n—Propyl-5-methyl-1-dihydro—1,3 _thiazole-12-ylamine,

• (4R, 5 S) _ 4— n-propyl-15-methyl-1-dihydro 1,3-thiazole-12-ylamine,

• (4 S, 5 S) —4—n—Propyl-5-methyldihydro 1,3-thiazole—2-ylamine,

• (4 S, 5R) — 4-n-Propyl-5-methyl-1-hydro-1,1,3-thiazonole-2-ylamine,

• (4 R, 5 R) —4-n-butyl-5-methyldihydro-1,3-thiazole-1-ylamine,

· (4 S, 5 S) — 4 _n-butyl-5-methynole-dihydro _ 1,3-thiazolone

2—Ilamine,

• (4 R, 5 S) —4-n-butyl-5-methyl-1-dihydro-1,3-thiazole-12-ylamine,

• (4 R, 5 S) —4—n—propinole-5—methinole 4,5—dihydro-1,3— Oxazoline 21- ^ f / reamine,

• (4S, 5S) —4-n-Propyl-5-methinolay 4,5-Dihydro-1,1,3-oxazole-12-ylamine, and

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

The compound of the present invention represented by the general formula (I) may form a physiologically acceptable acid addition salt. Examples of the acid addition salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid. , Phosphoric acid, nitric acid and other salts with inorganic acids, or acetic acid, oxalic acid, fumaric acid, maleic acid, malonic acid, lactic acid, malic acid, succinic acid, citric acid, tartaric acid, benzoic acid, methanesulfonic acid, p- Salts with organic acids such as toluene sulfonic acid are mentioned.

As used herein, the term "lower alkyl group" means a linear or branched C1-6 alkyl group, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a —Butynole group, isobutyl group, sec-butynole group, tert-butynole group, n-pentyl group and the like. Among them, C 1-3 alkyl group is particularly preferable.

In the general formula (I), when one asymmetric carbon atom is present, the configuration is R type or S type. When two asymmetric carbon atoms are present, the configuration is There are RR type, RS type, SR type and SS type, and these optically active substances are all included in the compound of the present invention. The compound represented by the general formula (I) may exist as an imino tautomer represented by the following formula (式), and these tautomers are also included in the compound of the present invention. included.

[In the formula, RR ² , X and “* J” are the same as in the above-mentioned general formula (I).

Further, the compound represented by the general formula (I) or a physiologically acceptable acid addition salt thereof may exist as a hydrate or a solvate, and these compounds are also included in the compounds of the present invention. included.

Next, a method for producing the compound of the present invention will be described. —The compound of the present invention represented by the general formula (I) can be produced by the following production method 1 or 2.

(Production method 1)

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

[In the formula, X ¹ represents a leaving group such as a halogen atom, p-toluenesulfonyloxy, and methanesulfonyloxy, and RR ² , X, and the symbol “*” are the same as described above.) ) Can be converted to an isothiocyanate or an isocyanate derivative (II) according to the method described in the literature (J. Chem. Soc. Perkin Trans 1, 1979, 3, 765; Justus Liebigs Ann. Chem., 1974, 593). It can be produced by reacting ammonia, ammonia gas or aqueous ammonia solution.

The reaction temperature varies depending on the type of the starting compound used and the like, but is usually from 10 to 150 ° C, preferably from 10 to 100 ° C. The reaction time is usually about 30 minutes to 24 hours, preferably about 1 to 10 hours.

(Production method 2)

The compound (I ") of the present invention in which X is an oxygen atom in the general formula (I) can also be produced by the method shown in the following reaction formula.

(In)

[Wherein X ² represents a halogen atom, and RR ² and “*” mark are the same as described above.] That is, the compound (1 ″) of the present invention can be prepared by the method described in the literature (J. Org. Chem., 1996, 61, 4210; synthesized according to Angew. Chem. Int. Ed. Engl., 1987, 26, 1141). The compound (III) can be produced by reacting a cyanogen halide with or without a base in a suitable solvent.

The reaction temperature varies depending on the type of the starting material to be used and the like, but is usually from 10 to 100 ° C, preferably from 0 to 70 ° C. The reaction time is generally about 1-20 hours, preferably about 1-5 hours.

When the reaction is carried out in the presence of a base, the base may be sodium acetate, sodium acetate, such as sodium acetate acetate, sodium hydrogen carbonate, sodium hydrogen carbonate, such as sodium hydrogen carbonate, or sodium carbonate. Examples include sodium carbonate, potassium carbonate such as potassium carbonate, and organic bases such as pyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine.

Reactions used in the above Process 1 and 2 is usually carried out in a suitable solvent inert to the reaction. As the solvent, methanol, ethanol, isopropyl Nono ⁰ Nord, Arukonore such as tert- butanol, Examples include acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, dioxane, and water. These solvents may be used alone or as a mixed solvent of two or more.

The compound of the present invention produced by the above production method 1 or 2 can be isolated and purified by ordinary chemical operations such as chromatography and recrystallization. The compound of the present invention represented by the general formula (I) can be obtained in the form of a free base or an acid addition salt, and both can be converted into each other by a usual method.

The compound (II) used in the production method 1 can be synthesized according to the method shown in the following reaction formula according to the method described in the literature. i) MsCI or PPh ₃ · ΒΓ ₂

ii) TFA or HCI

(IV)

(V) (ID

(In the formula, x ¹ represents a leaving group such as a halogen atom, p-toluenesulfonyloxy, methanesulfonyloxy, etc., and Ri, R ² , X and `` * '' are the same as described above.) Chem., 1996, 61>4210; Angew. Chem. Int. Ed. Engl., 1987, 26, 1141). According to a conventional method, carbonate (Boc ₂ 〇) is allowed to act in a solvent in the presence or absence of a base to obtain a compound (IV) in which the amino group is protected, and then the compound (IV) Sulfonylation of the hydroxy group with tosinolectide or methanesulfonyl chloride, or nitrogenation with triphenylphosphine dihalogenide, followed by deprotection of the amino group under acidic conditions such as trifluoroacetic acid (TFA). Compound (V), and then described in the literature Hohi. Org. Chem., 1993, 58, 5192) to analogously can be synthesized compound is reacted with phosgene or Chiohosugen to 該I 匕合 compound (V) and (II).

Hereinafter, pharmacological tests for investigating the NOS inhibitory activity of the representative compounds of the present invention and comparative compounds are shown.

Test Example 1: Inhibitory activity on inducible NO synthase (iNOS)

(1) Preparation of iNOS crude enzyme preparation

A crude enzyme sample of iNOS was prepared by the following procedure. Mouse macrophage cell line RAW264.7 (3-4x10 ⁶ cells / culture dish) is carbon dioxide ink in D-MEM (Dulbecco-Minimum Essential Medium) medium containing 10% FBS (fetal calf serum). : The cells were cultured in the タ. Next, LPS (lipopolysaccharide) and mouse IFN-γ (interferon-gamma) were added to this medium to a final concentration of 0.2 μg Zm1 and 100 U / m1, respectively. Furthermore the Chi cells were collected to that over晚culture was homogenized by adding 2x1 0 ⁷ cells / ml and so as to 5 Omm Tris monohydrochloride / 1 00 μ M DTT (dithiothreitol) (ρΗ 7. 5), This one

Centrifuged at 00, 000xg for 30 minutes. Dowe X HCR-W2 was added to the soluble cytoplasmic fraction of the obtained supernatant and stirred at 4 ° C for 30 minutes, and the obtained supernatant was used as a crude enzyme sample of iNOS.

(2) Measurement of i NO SP and harmful activity

i NOS inhibitory activity L_ ^[3 H] - it has been conducted under measurement to quantify the amount of conversion from § / Reginin to L one ^[3 H] over citrulline. The crude enzyme preparation (701) contains 1 mM N ADPH (reduced nicotinamide adenine dinucleotide phosphate) in 5 OmM Tris-HCl buffer (pH 7.5) (20 µl), test compound (1 0 1), 1 0 μ C i / m 1 L- ^[3 H] one arginine (20 μ 1) and 5 Omm tris monohydrochloride buffer solution (p H7. 5) (80 1) was added, at 37 Incubated for 30 minutes. This contains 2 mM EDTA (ethylenediaminetetraacetic acid) and 2 mM EGTA [ethylene glycol bis (-aminoethyl ether) -N, N, N, N-tetraacetic acid] in 0.1 M sodium acetate buffer (pH 5. 0) (200 μl) was added to stop the reaction. The reaction solution was stirred for 30 minutes with Dowe X 50W-X 8 calorie, and allowed to stand for 30 minutes. Then, a liquid scintillation cocktail was added to the supernatant, and the radioactivity was measured. As the iNOS inhibitory activity value of each compound, the concentration (IC ₅ ) at which the production inhibition rate of L- [ ³ H] -citrulline was 50% was calculated. The results are shown in Table 1.

Test Example 2: Inhibitory activity on rat brain-derived constitutive NO synthase (nNOS) (Preparation of crude DnNOS enzyme preparation)

A crude enzyme preparation of nNOS was prepared by the following procedure. An untreated female Wistar rat (body weight 150-: L 70 g) was decapitated and the whole brain was quickly removed and mixed with 5 volumes of 0.1 mM PMS F (phenylmethylsulfonyl fluoride) on ice. 5 OmM HEP ES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) buffer containing 12.5 mM 2-mercaptoethanol and 0.5 mM EDTA The mixture was homogenized by adding a liquid (pH 7.1) and centrifuged at 100,000 xg 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, and the obtained supernatant was used as a crude enzyme sample of nNOS.

(2) Measurement of nNOS inhibitory activity

11 ^^ Rei_3 inhibitory activity have been conducted under measurement to quantify chromatography ^[3 H] amount of conversion from a arginine to L one ^[3 H] over citrulline. Crude enzyme preparation (1 00/1) to 1 mM NADPH, 2mM C a C 1 2 and 3 0 0 nM including calmodulin 5 0 m M Tris monohydrochloride buffer (pH7. 5) (6 0 μ 1), test compound (1 0 1), 1 0 ^ C i / m 1 L- ^[3 H] one arginine (20 μ 1) and 5 Omm tris monohydrochloride buffer (pH7. 5) added (1 0 μ 1) And incubated at 37 ° C for 30 minutes. A 0.1 M sodium acetate buffer solution (pH 5.0) (200 1) containing 2 mM EDTA and 2 mM EGTA was added to stop the reaction, and Dowe X 50W-X8 was added to the reaction solution, followed by stirring for 30 minutes. After allowing to stand for 30 minutes, a liquid scintillation cocktail was added to the supernatant, and the radioactivity was measured. The concentration (IC ₅ ) at which the production inhibition rate of L- [ ³ H] -citrulline was 50% was calculated as the nNOS inhibitory activity value of each compound. The ratio between the obtained nNOS inhibitory activity value and the iNOS inhibitory activity value obtained in Test Example 1 was calculated, and the selectivity for iNOS was expressed as “dissociation degree” (dissociation degree = nNOS / iNOS). Shown in 1.

In the above pharmacological test, the following known compounds were used as the compounds of the present invention together with the compounds of the examples shown in Table 1.

Comparative compound 1:

Trans-1,4-dimethinolate 4,5-dihydro-1,3-thiazole_2-inoleamine · 3/2 fumarate (racemic)

Comparative compound 2:

2-iminothiazolidine hydrochloride (purchased from Aldrich Chemical Co.) HCI

Comparative compound 3:

2-iminooxazolidine (purchased from Tokyo Chemical Industry Co., Ltd.)

i NOS inhibitory activity and divergence

From Table 1, it can be seen that the compound of the present invention has an iNOS inhibitory activity equal to or higher than that of a known compound with respect to iNOS and also has excellent selectivity for iNOS. It is clear that there is.

As is clear from the test examples described above, the compound of the present invention has excellent iNOS inhibitory activity and high selectivity for iNOS, so that safe NOS for humans and mammals can be used. It is expected to be used as SP and harmful agent. Therefore, the NOS inhibitor of the present invention is useful for NO-induced diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic disorder, Alzheimer's disease, multiple sclerosis, sepsis, hypotension, rheumatoid arthritis, and deformation. Osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, uvea It is useful as a prophylactic and / or therapeutic agent for inflammation, osteoporosis, pneumonia, hepatitis, ischemia-reperfusion injury, transplant rejection, pain, pruritus (itch) and the like.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of the compound, the administration method, the symptom-age of the patient, etc. However, for example, in the case of oral administration, usually about 0.001 to 100 mg, more preferably about 0.01 to 50 mg per lkg body weight of human or mammal is divided into 1 to several portions. Can be administered. For parenteral administration, such as intravenous injection, usually, for example, it may be administered to humans or mammals lkg body weight per about 1 μ _§ ~1 0 πΐ 8, preferably from about 1 0 g to 5 mg in further.

When the compound of the present invention is used for the above-mentioned pharmaceutical uses, it is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a non-toxic substance which is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, cunic acid, glutamic acid, glycine, lactose, inositol, dextrose, mannitol, dextran, sorbitole, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, methyl paraoxybenzoate, propyl methacrylate Magnesium aluminate, synthetic aluminum silicate, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropynole starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropyl senorelose, low substitution degree Hydroxypropylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, polybutylalcohol, algi Acids, sodium alginate, light acid anhydride, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin Glycerose gelatin, polysorbate, macrogol, 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 are always It can be prepared according to the 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, aqueous solvents (eg, distilled water, saline, Ringer's solution, etc.), tonicity agents (eg, glucose, D-sorbitol, D-mannitol, salt) Sodium hydroxide, etc.), stabilizers (eg, human serum albumin), preservatives (eg, benzyl alcohol, chlorobutanol, methyl parahydroxybenzoate, propyl paraoxybenzoate, phenol), buffers (eg, phosphorus) Salt buffers, sodium acetate buffers, etc.) and soothing agents (eg, benzanolecone chloride, proforce hydrochloride, etc.) can be added as appropriate. In addition, these preparations may contain other therapeutically valuable ingredients. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Formulation Examples, but these do not limit the present invention. The compounds were identified by elemental analysis, mass spectrum, IR spectrum, ifi-NMR spectrum, high performance liquid chromatography (HPLC), and the like. The configuration of the compound of the present invention was determined according to the method described in the literature (J. Org. Chem., 1972, 37, 4401).

The following abbreviations may be used in the tables to simplify the description of the specification.

Symbols used as substituents are: Me is a methyl group, Et is an ethyl group, n

— Pr represents a normal propyl group, and n-Bu represents a normal butyl group. The symbols used as recrystallization solvents are E for getyl ether, T for toluene, AC for acetonitrile, CF for chromatoform, ET for ethanol, HX for _n- hexane, and IP for isopropanol. .

As symbols used in NMR, s is a singlet, d is a doublet, td is a triplet, t is a triplet, q is a quadruple, (111 is a quintuple | , Br are broad, and J means the binding constant.

(2 S, 3 S) — 2 _amino-3-pentano JH ₂

OH

Using the known (2S) -2-amino-11-propanol, the desired product was obtained according to the method described in the literature (J. Org. Chem., 1996, 61. 4210).

The corresponding aminoalcohols were used in place of (2S) -2-amino-1-propanol in Reference Example 1, and the method described in Reference Example 1 or the literature (Angew. Chem. Nt. Ed. Engl. , 1987, 26, 1141) to obtain the following compounds.

(1) (2 R, 3 S) —2-amino-1-3-pentano-

(2) (2 S, 3 R) — 2 × 5 · No 3 —Pentano

(3) (2 R, 3 R) — 2 — No 3

10 (.4; (2 R, 3 R) —3-amino-1-2-pentano-

(5) (2 R, 3 S) —3 1 2

(6) (2 S, 3 R) — 3 1 ^ No 2 — Hentano 1

(7) (.2 S, 3 S) —3 ゾ ^ No 2 — No No ¹ to No,

— To>

(8) (2 S, 3 R) — 3 —

1 It) C 9 (2 R, 3 S J— 3 1) No 1 2 — No

(10) (3S, 4R) 4-amino 3-hexanol,

(1 1) (3 R, 4 S) 4-amino3_hexanol,

(12) (2R, 3 S) 2-amino-3-hexanol,

(13) (2 S, 3R) 3-amino 2-hexanol,

20 (14) (2R, 3 R) 3-amino2 hexanol,

(15) (2R, 3 S) 3-amino 2-hexanol,

(16) (2 S, 3 S) 3-amino 2-hexanol,

(17) (2 S, 3 R) 3-amino 2-heptanol,

(18) (2R, 3R) 3-amino 2-heptanol,

25 (19) (2R, 3 S) 3-Amino 2-Heptanol,

(20) (2 S, 3 S) 3-amino 2-heptanol, and

(21) (2R) -2- -Amino-1--hexanone Reference example 2:

(S, 2 'R) —2,1-Amino-Ethylpropynole methylsulfonate salt

To a solution of (2 R, 3 S)-2-amino-3-pentanol 0.47 g in dioxane 1 Oml at room temperature was added di-tert-butyl dicarbonate 1.05 g dioxane solution 2 ml, and the mixture was stirred at the same temperature for 2 hours. . After the solvent was distilled off, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate-n-hexane (2: 1), purified, and tert-butyl (1R, 2S) -2-H 0.80 g of droxy-11-methinolevbutinorecanolenomate was obtained as crystals. To a solution of 0.80 g of the obtained compound and 0.60 ml of triethylamine in 8 ml of methylene chloride was added a solution of 0.47 g of methanesulfuryl chloride in 1 ml of methylene chloride while stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. 10 ml of water was added, and the mixture was extracted with 10 ml of black-mouthed form. The extract was dried over magnesium sulfate and concentrated, and 1.03 g of (1 'S, 2' R) -2 '-[(tert-butoxy) -propionylamino] 1,1-ethylpropyl methylsulfonate was converted to an oily substance. Obtained. To an ethanol solution (5 ml) of 1.03 g of the obtained compound was added 5 ml of a 30% hydrochloric acid-ethanol solution under ice-cooling and stirring, and the mixture was stirred at the same temperature for 1 hour. After evaporating the solvent, 0.80 g of the desired product was obtained as crude crystals.

The same reaction and treatment were carried out using the corresponding starting compounds to obtain the following compounds.

(1) (1 'R, 2' R) -2, -amino-1'-ethylpropyl methylsulfonate ■ hydrochloride,

(2) (S, 2, S) —2, —amino-ethylpropylmethylsulfonate

(3) (1 'R, 2' S) -2'-Amino-1'-Ethylpropyl methylsulfonate hydrochloride, (4) (S, 2'R) -2'-amino-1,1-methylbutyl methylsulfonate hydrochloride,

(5) (1 'R, 2, R)-2'-amino 1'-methinolevbutinole methylsulfonate hydrochloride,

(6) (S, 2'S) -2, -amino-1'-methinolebutynole methylsulfonate hydrochloride,

(7) (1 'R, 2' S) _2'-amino 1,1, methinolevbutinole methylsulfonate hydrochloride,

(8) (1, S, 2 'R) —2, _amino-1,1-methinolepropynole methinolesulfonate hydrochloride,

(9) (R, 2'S) —2, _amino-1,1-methylpropinole methinolesulfonate hydrochloride,

(10) (1, S, 2 'R) — 2'-Amino-1,1-ethylbutyl methylsulfonate · (11) (1'R, 2, S) —2'-Amino-1'-ethylbutyl methinolate Sulfonate hydrochloride,

(12) (2 'R)-2'-aminopropyl methylsulfonate hydrochloride,

(13) (1'S, 2, R) -2'-amino-1'-propylpropylmethylsulfonate hydrochloride

(14) (S, 2'R) -2, -Amino-1,1-methinolespentinole methinolesnolefonate hydrochloride,

(15) (R, 2'R) -2, -amino-1'-methinolepentinole methinoresnolehonate.hydrochloride,

(16) (1, R, 2'S) —2, -amino-1, -methylpentinole methinolesulfone mono-hydrochloride,

(17) (1 'S, 2, S) -2'-Amino-1, -methinolepentinole methinolesulfonate hydrochloride,

(18) (1, S, 2 'R) —2,1-amino-1,1-methinolehexinole methinolesulfonate.hydrochloride, (19) (R, 2, R) -2'-amino-methinolehexynolemethylsulfonate.hydrochloride,

(20) (R, 2'S)-2, _ amino-methylhexyl methylsulfonate hydrochloride,

(21) (1 'S, 2, S) —2,1-amino-1-methylhexyl methylsulfonate hydrochloride, and

(22) 2, R-2, -aminohexyl methylsulfonate hydrochloride

Reference example 3:

(3 S, 4 S) —Preparation of 4-bromohexan-3-isothiocyanate:

Add 21.0 g of dibromotriphenylphosphorane to 10 Om1 of acetonitrile, and add dropwise a solution of 10.3 g of acetonitrile solution of 10.3 g of tert-butyl (1S, 2R) -1-1-propyl_2-hydroxypropylcarbamate with stirring. Then, the mixture was stirred at room temperature for 12 hours, and further heated under reflux for 1 hour. The reaction solution was concentrated, 15 Oml of water and 15 Oml of ether were added to the residue, and the aqueous layer was further washed with 7 Oml of ether. To this aqueous layer, 14.0 g of calcium carbonate and 5.34 ml of thiophosgene are added while stirring, and stirred at room temperature for 2 hours. After filtering off the insolubles, the extract was extracted twice with 20 mL of chloroform. The extract was dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and then extracted with chloroform-hexane (1: 1). Elution and purification gave 3.09 g of the desired product as an oil.

Using the corresponding starting compounds, the same reaction and treatment are performed to obtain the following compounds.

(1) (3R, 4R) — 4-Bromohexane-3-isothiocyanate

Example 1:

(4 R, 5 R) —5-Ethyl 4-Methyl-1,4,5-Dihydro 1,3-Thiazo-Nor-1-2-Inoleamine '1/2 fumarate —M ₂ ■ 1 no 2 fumaric acid

,,

(1) 0.80 g of (1 'S, 2' R) -2'-amino-1, _ethylpropylmethylsulfonate hydrochloride obtained in Reference Example 2 was mixed with water and chloroform (water: chloroform = 1: 1) In addition to 22 ml, under ice-cooled stirring, 1.10 g of calcium carbonate and 0.42 ml of thiophosgene were added, followed by stirring at the same temperature for 30 minutes. After the temperature was raised to room temperature, the mixture was further stirred for 1 hour. The organic layer was dried over magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography, eluted with ethyl acetate- _n- hexane (1: 5) and purified, and (1, S, 2'1) _1 0.52 g of 1,2-ethyl-1,2-isothiosiana monopropyl methylsulfonate was obtained as an oil.

(2) The above-obtained (S, 2'R) _1, 1-ethyl-2'-isothiocyanato-top pill methylsulfonate 0.52 g of acetone 5 ml solution was added under ice-cooling and stirring with 28% ammonia. After adding 5 ml of water, the mixture was stirred at the same temperature for 30 minutes. Further, the mixture was heated and stirred at 80 ° C for 3 hours. After the acetone was distilled off under reduced pressure, 20 ml of a 50% aqueous sodium hydroxide solution was added under ice-cooling, and the mixture was extracted three times with 20 ml of a mouth opening form. The extract was dried over sodium sulfate and concentrated, and the residue was subjected to silica gel column chromatography, eluted and purified with silica gel column form, treated with fumaric acid, and recrystallized from ethanol-n-hexane to obtain the desired product 0.19 g was obtained. Melting point 158—164 ° C

-NMR (DMSO- d ₆ ) δ: 0.93 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H), 1.56 (m, IH), 1.76 (m, IH), 3.50 ( td, J = 4.8Hz, J = 8.6Hz, IH), 3.94 (qu, J = 6.3Hz, IH), 6.42 (s, IH).

(4R, 5S) —5-Ethyl-4,1-methyl-1,4,5-dihydro 1,3-thiazono-nor- _2- inoleamine. 1/2 fumarate ■ 1 2 Fumaric acid

Instead of (1, S, 2'R) -2'-amino-ethylpropylmethylsulfonate hydrochloride in Example 1, the corresponding (R, 2'R) _2 'obtained in Reference Example 2 (1) —Amino-ethylpropylmethylsulfonate hydrochloride, The reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from ethanol to obtain 0.23 g of the desired product. Melting point 193_ 195 ° C

NMR-NMR (DMS0-d ₆ ) δ 0.92 (t, J = 7.46Hz, 3H), 1.12 (d, J = 6.6Hz, 3H), 1.4 (m, 1H), 1.71 (m, 1H), 3.84 (qu, J = 5.3Hz, 1H), 4.13 (qu, J = 6.6Hz), 6.45 (s, 1H).

Example 3:

(4S, 5S) -4,5-Detyl-1,4,5-dihydro-1,3-thiazole-2-inoleamine.0.3-2 Fumarate

■ 32 fumaric acid

(1) Instead of (1'S, 2'R) -2, -amino-ethylpropylmethylsulfonate hydrochloride in Example 1, the corresponding (R,

The reaction and treatment were carried out in the same manner as in Example 1 using 2 ′S) —2,1-amino-ethylethylsulfonate′hydrochloride, and (4S, 5S) -4,5-Jetyl_4,5-dihidro 1,3-Thiazol-2-ylamine was obtained as an oil.

¾— 丽 R (CDC1 ₃ ) 8: 0.97 (t, J = 7.32Hz, 3H), 0.99 (t, J = 7.35Hz, 3H), 1.45- 2.17 (m, 4H), 3.53 (ra, 1H), 3.83 (m, 1H).

(2) The above oil was treated with fumaric acid and recrystallized from ethanol-n-hexane to obtain the desired product. 141-144 ° C

Examples 4 to 23:

Reference Example 2 (2) -2 (10), 2 (12) -2 (21) Instead of (1, S, 2, R) -2'-aminoaminopropylmethylsulfonate.hydrochloride in Example 1 The corresponding starting compounds obtained from (2) and (2) were subjected to a reaction * treatment in the same manner as in Example 1 to obtain a compound shown in Table 2 below. Table 2

4R, 5R

19 n-Bu Me 120-124 1 Fumarate E-ET

(Trance)

4R, 5S

20 n-Bu Me 111-115 1 Fumarate E-ET

(Cis)

4S, 5S

21 n-Bu Me 123-126 1 Nomalic acid;

(Trance)

4S, 5R 6/5

22 n-Bu Me 115-119 E-ET

(Cis) fumarate

4R

23 n-BuH 125-126 1 fumarate E-ET Example 24:

(4S, 5R) -4,5-Detyl-1,4,5-dihydro-1,3-thiazole-1-ylamine'3Z2 fumarate

3/2 fumaric acid

(1) To a solution of 4.0 g of (3S, 4S) _4-bromohexane-1-3-isothiocyanate obtained in Reference Example 3 in 30 ml of acetone, 28% ammonia water 2 was added under ice-cooling and stirring.

After adding 0 ml, the mixture was heated to room temperature and stirred for 30 minutes. The mixture was further refluxed for 2 hours. After evaporating the solvent, 20 ml of a 50% aqueous sodium hydroxide solution was added under ice cooling, and the mixture was extracted three times with 10 Om1 of chloroform. The extract was dried over magnesium sulfate and concentrated, and the residue was subjected to silica gel gel chromatography, eluted with chlorophonolem n-hexane (1: 1), purified and purified (4S, 5R). —4,5-Jetyl-1,4,5-dihydro-1,3-thiazol-2-ylamine was obtained as an oily substance in an amount of 2.1 g.

_{- NMR (CDC1 3) δ:} 0.96 (t, J = 7.4Hz, 3H), 1.05 (d, J = 6.4Hz, 3H), 1.44-2.17 (m, 4H), 3.65 (m, 1H), 3.88 ( m, 1H).

(2) The above oil was treated with fumaric acid and recrystallized from ethanol-n-hexane to obtain 1.5 g of the desired product. Melting point 153-155 ° C

Example 25:

(4R, 5S) -4,5-Detyl-1,4,5-dihydro_1,3-thiazol-2-ylamine 3/2 fumarate

'' 3-2 fumaric acid

Instead of (3S, 4S) -4-promohexane-3- (3 ^^ f sothiocyanate in Example 24, the (3R, 4R) _4-promo obtained in Reference Example 3 (1) The reaction and treatment were carried out in the same manner as in Example 24 using xanth-3-isothiocyanate to obtain the desired product. Melting point 121- 126 ° C

Example 26:

(4 R, 5 R) —5-Ethyl-14-methyl-1,4,5-dihydro-1,3-oxazole—2-ylamine

Reference Example 1 0.98 g of (2R, 3R) _2-amino-3-pentanol obtained in (3) was added to 20 ml of a mixed solution of methanol and water (methanol: water = 1: 1). Under ice cooling and stirring, 1.42 g of cyanogen bromide and 2.34 g of sodium acetate were added. After the temperature was raised to room temperature, the mixture was stirred overnight. The reaction solution was added with 5 ml of 28 ° / ₀ aqueous ammonia and concentrated, and acidified with hydrochloric acid with 2 Oml of an aqueous hydrochloric acid solution (6 mol / L). After washing with black-mouthed form, 20 ml of a 50% aqueous sodium hydroxide solution was added under ice-cooling, and the mixture was extracted three times with 20 ml of black-mouthed form. The extract was dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-n-hexane (3: 1), and crystallized from acetonitrile to obtain 0.25 g of the desired product. Melting point 103- 105 ° C

_{¾-NMR (CDC1 3) δ} : 0.97 (t, J = 7.4Hz, 3H), 1.19 (d, J = 6.4Hz, 3H), 1.54-1.75 (m, 2H), 3.64 (qu, J = 6.5Hz , 1H), 3.94 (q, J = 6.6Hz, 1H), 4.43 (br, 2H).

Example 27:

(4R, 5S) —5-Ethyl-1-4-methyl-4,5-dihydro-1,3-oxazole-1-2-ylamine

Instead of (2R, 3R) -2-amino-3-pentanol in Example 26 the corresponding (2R, 3S) -2-amino-3-pentanol obtained in Reference Example 1 (1) The reaction and treatment were carried out in the same manner as in Example 26 using 0.50 g, and crystallized from getyl ether to obtain 0.12 g of the desired product. Melting point 101-105 ° C

_{¾-NMR (CDC1 3) δ} : 1.02 (t, J = 7.4Hz, 3H), 1.08 (d, J = 6.8Hz, 3H), 1.48-1.76 (m, 2H), 3.84 (br, 2H), 4.01 (qu, J = 6.8Hz, 1H), 4.40 (td, J = 4.4Hz, J = 8.5Hz).

Examples 28 to 32:

Correspondence obtained from Reference Examples 1, 1 (2), 1 (4), 1 (6) and 1 (12) instead of (2 R, 3 R) -2-amino-3-pentanol in Example 26 The reaction and treatment were carried out in the same manner as in Example 26 using the starting compound to obtain the compounds shown in Table 3 below. Table 3

Example 33:

(4 S, 5 R) — 4-ethyl-5-methyl-4,5-dihydro-1,3-oxazole _2-ylamine

I NH ₂

,,, ''.

1.40 g of cyanogen bromide was added to a 20 ml ethanol solution of 0.60 g of (2R, 3S) -3-amino-2-pentanol obtained in Reference Example 1 (5) under ice-cooling and stirring. After the temperature was raised to room temperature, the mixture was stirred for 30 minutes. Further, the mixture was heated and stirred at 80 ° C for 3 hours. Dissolution After the solvent was distilled off, 2 Oml of a 50% aqueous sodium hydroxide solution was added under ice-cooling, and the mixture was extracted three times with 20 ml of chloroform at the outlet. The extract was dried over magnesium sulfate and concentrated, and the residue was crystallized from n-hexane to obtain 0.36 g of the desired product. 87-90 ° C

Examples 34 to 44:

Instead of (2R, 3S) -3-amino-2-pentanol in Example 33 Reference Examples 1 (7) to 1 (9), 1 (13) to 1 (19) and 1 (20) Using the corresponding starting material obtained in the above, the reaction and treatment were carried out in the same manner as in Example 33 to obtain the compounds shown in Table 4 below.

Table 4

Three-dimensional rooster

Example R ¹ R ² (cis or melting point (° c) Recrystallization solvent

Trance)

4R, 5S

34 Me Me 110-115 CF-HX

(Cis)

4S, 5R

35 Me Me 100-106 3/20 hydrate ΗΧ

(Cis)

4S, 5S

36 Et Me 76-80 3/20 hydrate Ε-ΗΧ

(Trance)

4R, 5R

37 n-Pr Me 67-70 ΗΧ

(Trance)

4R, 5S

38 n-Pr Me 74-75 ΗΧ

(Cis)

4S, 5S

39 n-Pr Me 71-73 ΗΧ

(Trance)

4S, 5R

40 n-Pr Me 74-79 ΗΧ

(Cis)

4R, 5R 5/4 fumaric acid

41 n-Bu Me 137-141 Ε-ΕΤ

(Trance)

4R, 5S

42 n-Bu Me 155-156 2 Fumarate Ε-ΕΤ

(Cis) 5/4 fumaric acid

4S, 5S

43 n-Bu Me 145-148 ¥ Ξ Ε-ΕΤ

(Trance)

1/4 hydrate

4S, 5R

44 n-Bu Me 55-59 ΗΧ

(Cis)

Comparative compound 1:

Trans-1,4,5-dimethyl-4,5-dihydro-3-thiazonore-2-inoleamine. 3/2 fumarate (racemic)

(1) Erythro 2'-amino-1'-methinolepropyl methylsulfonate 'hydrochloride, which is a raw material compound, was prepared using a known 2-amino-1-propanol by a method described in the literature (J. Org. Chem., 1996). , 61, 4210) and the method of Reference Example 2 described above.

(2) Instead of the (S, 2'R) _2, _amino-1,1-ethylpropylmethylsulfonate hydrochloride in Example 1 described above, the starting material lysroe 2 obtained in (1) above was used. The reaction was carried out in the same manner as in Example 1 described above, and the product was recrystallized from ethanol / hexane to obtain the desired 3/2 fumarate. I got 128-130 ° C

Formulation Example 1: Production of tablets (5 mg tablets)

(4 R, 5 R) - 5-Echiru 4-methyl-4, 5 Jihi mud one 1, 3-Chiazo Le -. ₂ one Iruamin hemifumarate (compound of Example 1) (5 g), lactose ( 80 _g ), corn starch (30 g), microcrystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) in a conventional manner. The mixture is then granulated and tableted at 145 mg per tablet to produce 1 000 tablets. Industrial applicability

The NOS inhibitor of the present invention containing a 2-aminothiazoline or oxazoline derivative represented by the general formula (I) as an active ingredient has excellent iNOS inhibitory activity and i The high selectivity of NOS allows it to be used as a safe NOS inhibitor for humans and mammals.NO-related diseases such as arteriosclerosis, myocarditis, cardiomyopathy, cerebral ischemic injury, Alzheimer's disease, Multiple sclerosis, sepsis, hypotension, rheumatoid arthritis, osteoarthritis, gastric ulcer, duodenal ulcer, ulcerative colitis, diabetes, glomerulonephritis, pud's meningitis, osteoporosis, pneumonia, hepatitis, ischemic reperfusion injury Useful as a prophylactic and / or therapeutic agent for transplant rejection, pain, pruritus (itch), etc.

Claims

The following general formula (I)

(Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group.

And X represents an oxygen atom or a sulfur atom. However, R ¹ and R ² are not simultaneously hydrogen atoms. The asterisk (*) indicates an asymmetric carbon atom when R ¹ or R ² is not a hydrogen atom.

Means atom)

2-aminothiazoline or oxazoline derivative represented by

A nitric oxide synthase inhibitor comprising a chemically acceptable acid addition salt as an active ingredient.

2. The nitric oxide synthase inhibitor according to claim 1, wherein X is a sulfur atom.

3. The nitric oxide synthase inhibitor according to claim 1 or 2, wherein the configuration of the carbon atom at position 4 and position 5 are both R-type.

4. R ¹ and R ² are identical or different, nitric synthase inhibitor according to請any one of determined ranging first term to third term is a Mechinore group or Echinore group.

5. (4 R, 5 R)-5-Ethyl _ 4 _ methyl _ 4, 5-dihydro-1, 3-thiazoneno 1-2-ylamine or a physiologically acceptable acid addition salt thereof as an active ingredient Nitric oxide synthase inhibitor.

6. The monoacid nitrogen synthase inhibitor according to claim 1, wherein X is an oxygen atom.

7. R ¹ and R ² are identical or different, nitric synthase inhibitor according to the first or ⁶ wherein the range of billed a methyl group or Echiru group.

8. Use of the compound according to any one of claims 1 to 7 or a physiologically acceptable acid addition salt thereof for the production of a monoacid nitrogenase inhibitor.

9. An effective amount of the compound according to any one of claims 1 to 7 or a physiologically acceptable acid addition salt thereof is used for a disease requiring a monoacid nitrogen synthase inhibitor. A method for preventing and / or treating a disease caused by nitric oxide production in a mammal, which comprises administering to a mammal in need of the prevention and / or treatment.

10. The prophylactic and / or therapeutic method according to any one of claims 1 to 9, wherein the mammal is a human.

1 1. The following general formula (Ia)

(In the formula, R ¹ ′ and R ² ′ are the same or different and represent a lower alkyl group, provided that R ¹ ′ and R ² ′ are not methyl groups at the same time. “*” Indicates an asymmetric carbon atom ) A 2-aminothiazoline derivative represented by the formula or a physiologically acceptable caro salt with an acid.

12. The following general formula (lb) (lb)

(In the formula, R ¹ , 'and R ² ', mean differently lower alkyl groups, and “*” means an asymmetric carbon atom.)

A 2-aminoxazoline derivative represented by the formula or a physiologically acceptable acid addition salt thereof.