JP2003503489A - N-imidazolylmethylcarboxamides as nitric oxide production inhibitors - Google Patents

Abstract

(57) [Summary] The present invention provides a compound represented by the following formula: Wherein each symbol is as described herein, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and a pharmaceutically acceptable salt thereof have a strong inhibitory activity on nitric oxide (NO) production, and are useful for the prevention and / or treatment of NO-mediated diseases in humans and animals. is there.

Description

Detailed Description of the Invention

[0001] The present invention relates acceptable salt thereof as useful novel amide compounds and pharmaceutically pharmaceutical.

[0002] Some peptide compounds were known as described, for example, EP 0 394 989 A2.

DISCLOSURE OF THE INVENTION The present invention relates to novel amide compounds. One of the objects of the present invention is to provide a novel and useful amide compound having a strong inhibitory activity on the production of nitric oxide (NO) and a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a method for producing the amide compound and its salt.

A further object of the present invention is to provide a pharmaceutical composition containing the amide compound or a pharmaceutically acceptable salt thereof.

A still further object of the present invention is respiratory diseases such as adult respiratory distress syndrome (ARDS) and asthma; cardiovascular ischemia, myocarditis, heart failure, cardiovascular system such as hypotension and atherosclerosis. Diseases; diabetes (eg, insulin-dependent diabetes mellitus), complications of diabetes (eg, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.) and endocrine diseases such as gout; glomerulonephritis and renal failure Kidney diseases such as; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (eg, ulcerative colitis and chronic colitis); pancreatic diseases such as pancreatitis; liver diseases such as hepatitis and cirrhosis; synovitis, Bone and joint diseases such as arthritis, osteoarthritis, and osteoporosis; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; skin diseases such as dermatitis and eczema; cancer such as solid tumors and transfer Of the amide compound or a pharmaceutically acceptable salt thereof as a medicament for the prevention and treatment of NO-mediated diseases including sepsis-induced systemic inflammatory response syndrome; Is to provide use.

[0006]   The amide compounds for the purposes of the present invention are new and have the general formula (I)

[0007]

[Chemical 11]

[Wherein, R ¹ is benzofuranyl substituted with halogen or styryl substituted with halogen, R ² is hydrogen or lower alkyl, R ³ is pyridyl, optionally protected hydroxy or lower alkyl Sulfonylamino, R ⁴ is lower alkyl, R ⁵ and R ⁶ are the same or different, each is hydrogen or lower alkyl, X is CH or N, provided that (i) R ² is Hydrogen, R ³ is pyridyl, R ⁵ and R ⁶ are each hydrogen, and X is CH, R ¹ is styryl substituted by halogen; (ii) R ¹ is benzofuranyl substituted by halogen; X is N when ³ is pyridyl and R ⁵ and R ⁶ are each hydrogen].

Suitable pharmaceutically acceptable salts of the object compound (I) are the usual non-toxic salts, eg salts with inorganic bases, eg alkali metal salts (eg sodium salts,
Potassium salt etc.), alkaline earth metal salt (eg calcium salt, magnesium salt etc.), ammonium salt; salt with organic base, eg organic amine salt (eg,
Triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salt (for example, hydrochloride, hydrobromide, Sulfates, phosphates, etc.); Organic carboxylic acid addition salts or organic sulfonic acid addition salts (eg formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methane) Sulfonates, benzenesulfonates, toluenesulfonates, etc.); salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.); and salts with bases or acid addition salts.

In the above and subsequent descriptions of the present specification, suitable examples and explanations of the various definitions included within the scope of the present invention are described in detail as follows.

The term “lower”, unless stated otherwise, is used to indicate a group having 1 to 6, preferably 1 to 4 carbon atoms.

Suitable “halogen” includes, for example, fluorine, bromine, chlorine, iodine.

Suitable “lower alkyl” and “lower alkyl moieties” of the term “lower alkylsulfonylamino” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert. −
Mention may be made of straight or branched chains having 1 to 6 carbon atoms such as pentyl and hexyl, more preferably C ₁ -C ₄ alkyl.

“Optionally protected hydroxy” includes hydroxy and protected hydroxy. Suitable examples of "hydroxy protecting group" in the term "protected hydroxy" include acyl such as lower alkanoyl (eg acetyl, trichloroacetyl etc.) optionally substituted by 1 to 3 halogen atoms, 1 1 or more suitable substituents (or di or tri) phenyl (lower) alkyl (eg, benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl (eg, tri (lower) alkyl) Silyl (eg trimethylsilyl, tert
-Butyldimethylsilyl, etc.), tetrahydropyranyl and the like.

“Styryl substituted by halogen” means styryl having a halogen atom as a substituent on the benzene ring. Suitable examples of "styryl substituted by halogen" include 2- (2-chlorophenyl) ethenyl, 2- (3-chlorophenyl) ethenyl, 2- (4-chlorophenyl) ethenyl, 2- (2-bromophenyl). Ethenyl, 2- (3-bromophenyl) ethenyl, 2- (4-bromophenyl) ethenyl, 2- (2-fluorophenyl) ethenyl, 2- (3-
Examples thereof include fluorophenyl) ethenyl and 2- (4-fluorophenyl) ethenyl.

[0016]   The object compound (I) of the present invention can be produced by the following method.

Method (1)

[0018]

[Chemical 12]

Method (2)

[0020]

[Chemical 13]

Method (3)

[0022]

[Chemical 14]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are each as defined above,
R ⁷ is lower alkyl and R ⁸ is a hydroxy protecting group.

The starting compounds may be prepared by the methods of preparation described below, or by methods known in the art for the preparation of their structurally similar compounds.

[0025]   The method for producing the target compound is described in detail below.

Method (1) Compound (1) or a salt thereof comprises compound (II) or its reactive derivative at an amino group or a salt thereof, and compound (III) or a reactive derivative at a carboxy group or a salt thereof. Can be produced by reacting with.

Suitable reactive derivative of the compound (II) includes a Schiff base type imino formed by the reaction of the compound (II) with a carbonyl compound such as an aldehyde or a ketone, or a tautomeric enamine type isomer thereof. Compound (II) and N, O-bis (
A silyl derivative formed by a reaction with a silyl compound such as trimethylsilyl) acetamide or N-trimethylsilylacetamide; a derivative formed by a reaction between compound (II) and phosphorus trichloride or phosgene.

Suitable reactive derivatives of compound (III) include acid halides, acid anhydrides, and activated esters. Suitable examples are acid chlorides; acid azides; substituted phosphoric acids (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, Thiosulfuric acid, alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), Mixed acid anhydrides with acids such as aromatic carboxylic acids (eg, benzoic acid); symmetrical acid anhydrides; activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, or tetrazole; activated esters ( For example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [( H _{3) 2} N ⁺ = CH-
] Ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p -Cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); or N-
Hydroxy compound (eg, N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H -Benzotriazole and the like). These reactive derivatives may optionally be selected from those mentioned above, depending on the type of compound (III) used.

The reaction may be performed with water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, or any other organic compound that does not adversely affect the reaction. It is usually performed in a conventional solvent such as a solvent or a mixture thereof.

When compound (III) is used in the free acid form or a salt form thereof during the reaction, preferably the reaction is N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(
4-diethylaminocyclohexyl) carbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N-carbonyl-bis- (2-methylimidazole); pentamethyleneketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; Oxalyl chloride; triphenylphosphine; 2
-Ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m
-Sulfophenyl) isoxazolium hydroxide inner salt; 1- (p
-Chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; the presence of a conventional condensing agent such as the so-called Vilsmeier reagent produced by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like. Done below.

The reaction is also carried out in the presence of an organic or inorganic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. Done in.

[0032]   The reaction temperature is not important. The reaction is usually performed under cooling or heating conditions.

Method (2) Compound (I) -1 or a salt thereof is prepared by converting Compound (IV) or a salt thereof into Compound (V).
Can be produced by reacting with. This reaction can be carried out in the same manner as in Example 5, or in a similar manner.

Method (3) Compound (I) -3 or a salt thereof can be produced by protecting compound (I) -2 or a salt thereof with a hydroxy group. This reaction can be carried out in the same manner as in Example 7, or in a similar manner.

For the suitable salts of the starting compounds and their reactive derivatives in methods (1)-(3), see those exemplified for compound (I).

The compound obtained by the above method can be isolated and purified by a usual method such as pulverization, recrystallization, column chromatography or reprecipitation.

It should be noted that compound (I) and other compounds may contain one or more stereoisomers such as optical isomers and geometric isomers due to the asymmetric carbon atom and double bond. All such isomers, and mixtures thereof, are included within the scope of the present invention.

The target compound (I) and pharmaceutically acceptable salts thereof include solvates (
For example, an inclusion compound (for example, a hydrate etc.) is mentioned.

The target compound (I) and pharmaceutically acceptable salts thereof have a strong inhibitory activity on nitric oxide (NO) production.

Therefore, the target compound (I) and a pharmaceutically acceptable salt thereof are expected to have nitric oxide synthase (NOS) inhibitory activity or NOS production inhibitory activity.

Therefore, the compound of interest (I) and pharmaceutically acceptable salts thereof can be used as a respiratory disease such as adult respiratory distress syndrome (ARDS) and asthma; cardiovascular ischemia, myocarditis, heart failure, hypotension and atherogenicity. Cardiovascular diseases such as arteriosclerosis; diabetes (eg, insulin-dependent diabetes mellitus), complications of diabetes (eg, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.) and endocrine system such as gout Diseases; renal diseases such as glomerulonephritis and renal failure; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (eg, ulcerative colitis and chronic colitis); pancreatic diseases such as pancreatitis; hepatitis and cirrhosis Diseases of the bones; synovitis, arthritis, osteoarthritis, osteoporosis and other bone and joint diseases; rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; autoimmune diseases; skin such as dermatitis and eczema Skin diseases; cancers such as solid tumors and metastases; rejection due to organ transplantation; shock (for example, septic shock); NO including sepsis-induced systemic inflammatory response syndrome
It is useful for prevention and / or treatment of mediated diseases.

The target compound (I) and a pharmaceutically acceptable salt thereof are CNS disorders, cerebrovascular diseases (eg, cerebral infarction, cerebral ischemia, cerebral hemorrhage, etc.), migraine, central nervous system diseases such as Alzheimer's disease; nerves. Such as inflammation, pain (eg, postherpetic neuralgia, reflex sympathetic dystrophy (RSD), causalgia, deafferentative pain syndrome, neuropathic pain, etc.), abnormal hyperalgesia, hyperalgesia, neurological disorders and neuroprotection It is also useful for the prevention and / or treatment of NO-mediated neurological disorders including peripheral nervous system disorders; Parkinson's disease; amyotrophic lateral sclerosis.

Further, the object compound (I) and a pharmaceutically acceptable salt thereof are sexual dysfunctions such as male sexual dysfunction including erectile dysfunction, and female sexual dysfunction including orgasmic dysfunction associated with clitoral disorders. It is useful for the treatment of

Further, the object compound (I) and a pharmaceutically acceptable salt thereof are conjunctival diseases such as conjunctivitis (eg, allergic conjunctivitis, spring catarrhal, keratoconjunctivitis sicca, viral conjunctivitis, bacterial conjunctivitis, etc.); uveal membrane. Flames (eg Behcet's disease, Harada's disease,
Uveal diseases such as sympathetic ophthalmitis, sarcoidosis, diabetic iritis, etc .; scleral diseases such as scleritis; corneal neovascularization, cornea, corneal edema, corneal opacity, corneal dystrophy, keratoconus and neuroparesis Corneal diseases such as keratitis; diabetic retinopathy, retinal artery occlusion, retinal vein occlusion, central serous chorioretinopathy, central hemorrhagic chorioretinitis, macular degeneration (eg age-related macular degeneration) ), Retinal detachment, retinitis pigmentosa;
Neovascular macular disease, macular hole, proliferative vitreoretinopathy, retina such as vitreous hemorrhage and vitreous opacity, vitreous diseases; cataracts (eg senile cataract, traumatic cataract, diabetic cataract, atopic cataract) , Etc .; primary open-angle glaucoma, primary angle-closure glaucoma, glaucoma such as normal tension glaucoma and neovascular glaucoma; ocular hypertension; amblyopia, color blindness and night blindness; astigmatism, hyperopia, NO including refractive errors such as myopia and presbyopia; lacrimal diseases such as dry eye syndrome, lacrimal duct obstruction and lacrimal cystitis
It is useful for prevention and / or treatment of mediated eye diseases.

In order to explain the usefulness of the target compound (I), the results of the pharmacological test of the compound (I) are shown below.

Test Compound Compound (a): (2E) -3- (4-chlorophenyl) -N-[(1S) -1
-[1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazole-2
-Yl] -2- (2-pyridyl) ethyl] -2-propenamide

Test 1: Assay of inhibitory activity on nitric oxide production In this study, mouse macrophage cell line RAW264.7 (American Typ) was used.
e Culture Collection, No. TIB71) was used. RAW264.7 cells were grown at 37 ° C. in F75 plastic culture flasks in 5% Dulbecco's Modified Eagle Medium (DMEM) supplemented with L-glutamine, penicillin, streptomycin and 10% heat-inactivated calf serum. The cells were removed from the culture flask with a rubber cell scraper, centrifuged and resuspended in DMEM without phenol red. Cells were plated in 96-well microtiter plates (10 ⁵ cells / well) and allowed to attach for 2 hours. Test samples were added and cells were preincubated for 1 hour. Then, the cells were treated with lipopolysaccharide (LPS) (1 μg / ml) and interferon γ (IFNγ) (3 U / ml).
Both were activated for 18-24 hours. An equal volume of Griess reagent (1% sulfanilamide /0.1%N- naphthylethylenediamine dihydrochloride /2.5%H ₃ PO _4), the cells were incubated at room temperature for 10 minutes. The absorbance at 570 nm was read using a microplate reader, and Na _{2 —} was used as a standard to measure NO ₂ ⁻ .

[0048]   Test results:

[0049]

[Table 1]

Test 2: Protective effect of compound (I) in combination with FK506 on rat heart allograft

The experiments were carried out on male Lewis and ACI rats weighing 175-200 g. Rats were treated with sodium pentobarbital (50 mg / kg, i.
． p. ), And the mice underwent an allogeneic (Lewis donor to ACI recipient) ectopic intraabdominal heart transplant. The experimental group was divided into a single drug group and a concomitant drug group. The single dose of FK506 (prepared in a manner similar to that disclosed in EP-0184162) was 0.32 mg / kg. Concomitant drug dosage is FK506 (0.32 mg / kg) + Compound (I) (10 mg / kg)
Met. The transplanted hearts were monitored by daily palpation and complete rejection was defined as palpable arrest of contractile activity. Suspend each drug in 0.5% methylcellulose solution,
The dose was 5 ml per kg body weight and was administered by daily gastric intubation for 14 days.

[0052]   The combination of compound (I) and FK506 dramatically prolonged survival by transplantation.

The activity and / or potency of the immunosuppressive agent in transplant rejection is remarkably increased by co-administration of the compound (I) having a strong inhibitory activity on nitric oxide production,
And the above experimental results show that it can be synergistically increased.

For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are organic or inorganic, solid or liquid forms suitable for oral, parenteral or external administration. It is used in the form of a usual pharmaceutical preparation, mixed with a usual pharmaceutically acceptable carrier such as an agent. Pharmaceutical formulations include solid forms such as granules, capsules, tablets, dragees, suppositories, or ointments, or solutions, suspensions or emulsions for injection, intravenous drip,
It can be formulated as a liquid form for oral ingestion, eye drops and the like. If necessary, in the above formulation,
Auxiliary substances such as stabilizers, wetting or emulsifying agents, buffering agents, or any other commonly used additives can also be included.

Usually, the active ingredient is a unit dose of 0.001 mg / kg to 500 mg / kg,
The dose may be preferably 0.01 mg / kg to 10 mg / kg, and may be administered 1 to 4 times a day. However, the above dosage depends on the age, weight and symptoms of the patient or the administration method.
It can be increased or decreased.

Preferred embodiments of the amide compound of the present invention represented by the general formula (I) are as follows. 1) A compound of the formula (I), wherein R ¹ is benzofuranyl substituted with halogen, R ³ is optionally protected hydroxy or lower alkylsulfonylamino, or a pharmaceutically acceptable salt thereof. 2) A compound of the formula (I), wherein R ¹ is styryl substituted with halogen, R ³ is pyridyl, optionally protected hydroxy, or lower alkylsulfonylamino, or a pharmaceutically acceptable salt thereof. . 3) A compound of the formula (I), wherein R ¹ is styryl substituted with halogen, R ³ is pyridyl, or optionally protected hydroxy, or a pharmaceutically acceptable salt thereof. 4) A compound of the formula (I), wherein R ¹ is benzofuranyl substituted with halogen, R ³ is pyridyl, X is N] or a pharmaceutically acceptable salt thereof.

[0057]   The following preparations and examples are described in order to illustrate the invention in detail.

Preparation Example 1 1- [4- (morpholin-4-yl) phenyl] ethane-1-one 1- (4-fluorophenyl) ethane-1 in N, N-dimethylformamide (DMF) (1 L) A mixture of -one (100 g), morpholine (126 ml) and potassium carbonate (95 g) was heated at 150 ° C (bath temperature) for 48 hours. Thin layer chromatography showed that the starting material had disappeared. The reaction mixture was poured into water (2 L), the precipitate was collected and washed with water. The residue was then dissolved in ethyl acetate, dried over magnesium sulfate and filtered. After removing the solvent, 1- [4- (morpholin-4-yl) phenyl] ethan-1-one (81.5 g) was obtained as a tan powder. ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (3H, s), 3.30 (4H, dd, J = 4Hz, J = 5Hz), 3.72 (4 H, dd, J = 4Hz, J = 5Hz), 6.98 (2H, d, J = 9Hz), 7.83 (2H, d, J = 9Hz).

Preparation Example 2 2-Bromo-1- [4- (morpholin-4-yl) phenyl] ethan-1-one 48% 1- [4- (morpholin-4-one in hydrobromic acid (340 ml). 48% hydrobromic acid (60 ml) in a solution of (yl) phenyl] ethan-1-one (170 g).
A solution of bromine (43 ml) in) was added dropwise at 65-75 ° C over 0.5 h.
The mixture was stirred for an additional hour at 65 ° C. The reaction mixture was cooled to 10 ° C. and the resulting precipitate was collected by filtration. The solid obtained (hydrobromide salt) was carefully basified with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform (500 ml). The organic layer was dried over magnesium sulfate and filtered. After removing the solvent, 2-
Bromo-1- [4- (morpholin-4-yl) phenyl] ethan-1-one (2
00g) was obtained as a greenish-yellow powder. No further purification was attempted. ¹ H-NMR (DMSO-d ₆ ) δ 3.30-3.34 (4H, dd, J = 4Hz, J = 5Hz), 3.34-3.43 (4H, m), 6.99 (2H, d, J = 9Hz), 7.86 ( 2H, d, J = 9Hz).

PREPARATION 3 2- [2- [4- (morpholin-4-yl) phenyl] -2-oxoethyl] isoindoline-1,3-dione 2-bromo-1- [4 in DMF (1500 ml). -(Morpholin-4-yl) phenyl] ethan-1-one (200 g) and potassium phthalimido (137 g
The mixture of 1) was stirred at 90 ° C. for 1 hour. After cooling to 10 ° C, the precipitate is collected and cold DM
It was washed successively with F (150 ml) and water (250 ml × 2). 2- [2- [4- (
Morpholin-4-yl) phenyl] -2-oxoethyl] isoindoline-1,
3-dione (186 g) was obtained as a pale yellow wet solid. This compound was used in the next step without further drying or purification. ¹ H-NMR (DMSO-d ₆ ) δ 3.34 (4H, dd, J = 4Hz, J = 5Hz), 3.72 (4H, dd, J = 4Hz, J = 5Hz), 5.10 (2H, s), 7.04 ( 2H, d, J = 9Hz), 7.86-7.97 (6H, m).

Preparation 4 2-Amino-1- [4- (morpholin-4-yl) phenyl] ethan-1-one dihydrochloride 2- [2- [4- (morpholin- A slurry of 4-yl) phenyl] -2-oxoethyl] isoindoline-1,3-dione (185 g) was heated to reflux for 8 hours. As a result, the slurry gradually dissolved to give a clear pale yellow solution. After removing the solvent under reduced pressure, the residual oily solid was converted to methanol (400 m
Trituration with l). The obtained precipitate was collected by filtration, washed with methanol (100 ml), and 2-amino-1- [4- (morpholin-4-yl) phenyl] ethane-1-
On dihydrochloride (125 g) was obtained as a white powder. ¹ H-NMR (DMSO-d ₆ ) δ 3.35 (4H, dd, J = 4Hz, J = 5Hz), 3.73 (4H, dd, J = 4Hz, J = 5Hz), 4.45 (2H, d, J = 4.5 Hz), 7.03 (2H, d, J = 9Hz), 7.87 (2H, d, J = 9Hz).

Production Example 5 (2S) -2- (tert-butoxycarbonylamino) -N- [2
-[4- (morpholin-4-yl) phenyl] -2-oxoethyl] -3- (2
-Pyridyl) propanamide 2-amino-1- [4- (morpholin-4-yl) phenyl] ethan-1-one dihydrochloride (3.71 g), (2S) -2- (in DMF (70 ml). tert
-Butoxycarbonylamino) -3- (2-pyridyl) propanoic acid (5.73 g
) And diphenylphosphoryl azide (3.48 g) were added dropwise to N, N-diisopropylethylamine (4.41 ml) at 0 ° C. and the mixture was stirred for 20 minutes. The mixture was heated to ambient temperature and stirred for 8 hours. The resulting mixture was diluted with ethyl acetate (200 ml) and washed successively with water, saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was triturated with ethyl acetate-diisopropyl ether (1: 2), (2S) -2.
-(Tert-Butoxycarbonylamino) -N- [2- [4- (morpholine-
4-yl) phenyl] -2-oxoethyl] -3- (2-pyridyl) propanamide (2.06 g) was obtained as off-white crystals. ESI-MS: 469 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.46 (9H, s), 3.20-3.38 (6H, m), 3.82-3.88 (4H, m), 4.60 (2H, d, J = 5Hz), 4.64-4.74 (1H, br), 6.37-6.45 (1H, br), 6.86 (2H, d, J = 9Hz), 7.14 (1H, dd, J = 5Hz, J = 8Hz), 7.21 (1H, d, J = 8Hz), 7.59 (1H, t, J = 8Hz), 7.82-7.90 (3H, m), 8.56 (1H, d, J = 5Hz).

Production Example 6 1- (tert-butoxy) -N-[(1S) -1- [1-methyl-
5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2-
(2-Pyridyl) ethyl] formamide (2S) -2- (tert- in acetic acid (4.0 ml) and xylene (60 ml).
Butoxycarbonylamino) -N- [2- [4- (morpholin-4-yl) phenyl] -2-oxoethyl] -3- (2-pyridyl) propanamide (2.0 g
) Was added methylamine (40% in water, 4.0 ml) and the mixture was Dea.
Reflux for 3 hours in a round bottom flask equipped with an n-Stark apparatus. The mixture was cooled to ambient temperature and acetic acid (4.0 ml) and methylamine (40% in water, 4.0 ml).
Was added to the solution. The solution was refluxed for 2 hours and cooled to ambient temperature. 1 solution
It was extracted with N hydrochloric acid (100 ml), and the aqueous layer was washed with ethyl acetate (50 ml). The aqueous layer was made basic with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (100 ml). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine,
It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 2% methanol in chloroform), 1- (tert.
-Butoxy) -N-[(1S) -1- [1-methyl-5- [4- (morpholine-
4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl]
Formamide (1.45 g) was obtained as yellow crystals. ESI-MS: 464 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.37 (9H, s), 3.17-3.23 (4H, m), 3.40 (3H, s), 3.41-3.47 (2H, m), 3.83-3.92 (4H, m), 5.33-5.47 (2H, m), 6.93 (1H, s), 6.94 (2H, d, J = 9Hz), 7.08-7.16 (2H, m), 7.21 ( 2H, d, J = 9Hz), 7.56 (1H, t, J = 8Hz), 8.55 (1H, d, J = 5Hz).

Production Example 7 (1S) -1- [1-Methyl-5- [4- (morpholin-4-yl)
Phenyl] imidazol-2-yl] -2- (2-pyridyl) ethylamine 1- (tert-butoxy) -N-[(1S) in dichloromethane (25 ml).
) -1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl] formamide (1.43 g)
To the above solution was added trifluoroacetic acid (5.0 ml) at 0 ° C. and the mixture was stirred at ambient temperature for 2.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in water (20 ml). The aqueous layer is basified with saturated aqueous sodium hydrogen carbonate solution and chloroform (
80 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with ethyl acetate-diisopropyl ether (1: 2), (1S) -1-
[1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2
-Yl] -2- (2-pyridyl) ethylamine (1.02 g) was obtained as yellow crystals. ESI-MS: 364 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 3.17-3.23 (4H, m), 3.27-3.47 (2H, m), 3.49 (3H, s), 3.84-3.91 ( 4H, m), 4.58 (1H, dd, J = 5Hz, J = 8Hz), 6.95 (2H, d, J = 9 Hz), 6.97 (1H, s), 7.11-7.18 (2H, m), 7.23 ( 2H, d, J = 9Hz), 7.59 (1H, t, J = 8Hz), 8.58 (1H, d, J = 5Hz).

Example 1 (2E) -3- (4-chlorophenyl) -N-[(1S) -1- [1
-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl] -2-propenamide 4-chlorocinnamic acid (in dichloromethane (90 ml) ( To a solution of 9.04 g) was added oxalyl chloride (6.48 ml) and 1 drop of DMF and the mixture was stirred at ambient temperature for 2 hours. After removal of the solvent by evaporation, the residual acid chloride was washed with dichloromethane (
50 ml). This solution was added to (1S) -1- [1-methyl-5- [4- (morpholin-4-yl) phenyl] in dichloromethane (150 ml) at 0 ° C.
Imidazol-2-yl] -2- (2-pyridyl) ethylamine (18 g) was added to the solution. After stirring the mixture at ambient temperature for 4 hours, the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried over sodium sulfate. The solvent was removed by evaporation and (2E) -3- (4-chlorophenyl) -N-[(1S) -1- [1
-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl] -2-propenamide (26g) was obtained. ¹ H-NMR (300MHz, CDCl ₃ ) δ 3.21 (4H, t, J = 7Hz), 3.46-3.64. (5H, m), 3.88 (4H, t, J = 7Hz), 3.83 (1H, q, J = 7Hz), 6.31 (1H, d, J = 15Hz), 6.89-6. 97 (3H, m), 7.08-7.22 (4H, m), 7.23-7.33 (3H, m), 7.43 (1H, d, J = 15Hz), 7.55 (1H, m), 7.68 (1H, d, J = 8Hz), 8.54 (1H, m).

Production Example 8 (2R ^* , 6S ^* )-4 '-(2,6-dimethylmorpholin-4-yl) acetophenone 4-fluoroacetophenone (40 g), cis-2 in DMF (400 ml).
A suspension of 6,6-dimethylmorpholine (66.7 g) and potassium carbonate (38 g) was stirred at 120 ° C. for 65 hours. Dilute the resulting mixture with water (800 ml),
It was extracted with ethyl acetate (800 ml). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residual solid was triturated with n-hexane (200 ml) and (2R ^* , 6S ^* )-4 '-(2,6
-Dimethylmorpholin-4-yl) acetophenone (45.5 g) was obtained as brown crystals. ESI-MS: 234.2 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.28 (6H, d, J = 6Hz), 2.47-2.52 (2H, m), 2.53 (3H, s), 3.58-3.66 (2H, m), 3.70-3.83 (2H, m), 6.86 (2H, d, J = 9Hz), 7.88 (2H, d, J = 9Hz).

Production Example 9 2-Bromo-[(2R ^* , 6S ^* )-4 '-(2,6-dimethylmorpholin-4-yl)] acetophenone 47% (2R ^* ) in hydrobromic acid (40 ml) ^. , 6S ^* )-4 ′-(2,6-dimethylmorpholin-4-yl) acetophenone (20.8 g) was added to a solution of bromine in 47% hydrobromic acid (5.0 ml) at 55 ° C. It was added dropwise over 45 minutes and the mixture was stirred at 65 ° C. for 1.5 hours. The resulting mixture was cooled to 10 ° C. and the solid collected by filtration. The solid was dissolved in water and the aqueous solution was made basic with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform (100 ml), the organic layer was washed with brine, then dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was treated with cold ethyl acetate-diisopropyl ether (1: 5, 18 ml) and collected by filtration, then washed sequentially with ethyl acetate-diisopropyl ether (1:10, 11 ml) and diisopropyl ether (5.0 ml). , 2-bromo-[(2R ^* , 6S ^* )-
4 '-(2,6-dimethylmorpholin-4-yl)] acetophenone (9.54
g) was obtained as slightly green crystals. ESI-MS: 312.0 (M +) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.28 (6H, d, J = 6Hz), 2.52-2.63 (2H, m), 3.61-3.69 (2H, m), 3.70- 3.82 (2H, m), 4.37 (2H, s), 6.86 (2H, d, J = 9Hz), 7.90 (2H, d, J = 9Hz).

Preparation Example 10 [(2R ^* , 6S ^* )-4 '-(2,6-Dimethylmorpholin-4-yl)]-2-phthalimidoacetophenone 2-Bromo-[(2R ^* ) in DMF (140 ml) ^. , 6S ^* )-4 '-(2,6
A mixture of -dimethylmorpholin-4-yl)] acetophenone (13.8g) and potassium phthalimide salt (8.6g) was stirred at 100 ° C for 30 minutes. The resulting mixture was cooled to 5 ° C and diluted with water (300ml). The solid was collected by filtration, washed with water (40 ml × 2), and [(2R ^* , 6S ^* )-4 ′-(2,6-dimethylmorpholin-4-yl)]-2-phthalimidoacetophenone (17.5 g ) Was obtained as yellow crystals. ESI-MS: 379.2 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.29 (6H, d, J = 6Hz), 2.57 (2H, dd, J = 10Hz, J = 12Hz), 3.65 (2H , dd, J = 2Hz, J = 10Hz), 3.72-3.84 (2H, m), 5.07 (2H, s), 6.88 (2H, d, J = 9Hz), 7.70-7.79 (2H, m), 7.85- 7.94 (4H, m).

Production Example 11 2-Amino-[(2R ^* , 6S ^* )-4 '-(2,6-dimethylmorpholin-4-yl)] acetophenone dihydrochloride [(2R ^* ) in concentrated hydrochloric acid (170 ml) ^. , 6S ^* )-4 ′-(2,6-dimethylmorpholin-4-yl)]-2-phthalimidoacetophenone (17.5 g) was stirred at 120 ° C. for 20 hours. The resulting clear solution was concentrated under reduced pressure and the residue was diluted with water (80 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residual solid was treated with cold methanol (15 ml) and the mixture was stirred at 0 ° C. for 45 minutes. The solid was collected by filtration, washed with cold methanol-ethyl acetate (1: 2, 24 ml), 2-amino-[(2R ^* , 6S ^* )-4 ′-(2,6-dimethylmorpholin-4-yl).
] Acetophenone dihydrochloride (10.13 g) was obtained as colorless crystals. ESI-MS: 249.1 (M + H) ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.17 (6H, d, J = 6Hz), 2.44 (2H, dd, J = 11Hz, J = 13Hz), 3.58 -3.72 (2H, m), 3.87 (2H, dd, J = 2Hz, J = 13Hz), 4.42 (2H, d, J = 4Hz), 7.05 (2H, d, J = 9Hz), 7.85 (2H, d , J = 9Hz), 8.27-8.41 (2H, br s).

Production Example 12 (2S) -2-[(tert-butoxy) carbonylamino] -N- [
2-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] -2-oxoethyl] -3- (2-pyridyl) propanamide 2- in DMF (30 ml). Amino-[(2R ^* , 6S ^* )-4 '-(2,6-
Dimethylmorpholin-4-yl)] acetophenone dihydrochloride (1.50 g), (
2S) -2-[(tert-Butoxy) carbonylamino] -3- (2-pyridyl) propanoic acid (1.31 g) and diphenylphosphoryl azide (1.11 ml).
) Was added dropwise to N, N-diisopropylethylamine (2.44 ml) at 0 ° C. and the mixture was stirred for 30 minutes. The temperature of the reaction mixture was gradually raised to ambient temperature and the mixture was stirred under a nitrogen atmosphere for 15 hours. The resulting mixture was diluted with ethyl acetate (75 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (40 ml). The organic layer was extracted with 1N hydrochloric acid (60 ml), the aqueous layer was made basic with saturated aqueous sodium hydrogen carbonate solution, and then extracted with chloroform (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was triturated with ethyl acetate-diisopropyl ether (1: 3, 20 ml) and (2S) -2-[(tert-butoxy) carbonylamino] -N- [2-[(2R ^* , 6S ^* )-. 4- (2,6-
Dimethylmorpholin-4-yl) phenyl] -2-oxoethyl] -3- (2-
Pyridyl) propanamide (1.66 g) was obtained as off-white crystals. ESI-MS: 497.4 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.28 (6H, d, J = 6Hz), 1.46 (9H, s), 2.55 (2H, dd, J = 11Hz, J = 13Hz), 3.26 (1H, dd, J = 7Hz, J = 15Hz), 3.31-3.43 (1H, m), 3.63 (2H, dd, J = 2Hz, J = 13Hz), 3.69-3.82 (2H, m ), 4.59 (2H, d, J = 4Hz), 4.63-4.74 (1H, m), 6.34 (1H, m), 6.85 (2H, d, J = 9Hz), 7.14 (1H, dd, J = 5Hz, J = 8Hz), 7.21 (1H, d, J = 8Hz), 7.59 (1H, dt, J = 2Hz, J = 8Hz), 7.79-7.88 (1H, m), 7.84 (2H, d, J = 9Hz) , 8.54 (1H, d, J = 5Hz).

Production Example 13 1- (tert-Butoxy) -N-[(1S) -1- [1-methyl-
5-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl] formamide acetic acid (9.7 ml) And (2S) -2-[(tert
-Butoxy) carbonylamino] -N- [2-[(2R ^* , 6S ^* )-4- (2,
6-Dimethylmorpholin-4-yl) phenyl] -2-oxoethyl] -3- (
To a solution of 2-pyridyl) propanamide (2.80 g) was added methylamine (4 in water).
0%, 4.1 ml) was added and the mixture was refluxed for 1.5 hours in a round bottom flask equipped with a Dean-Stark apparatus. The mixture was cooled to 50 ° C. under nitrogen atmosphere and then acetic acid (9.7 ml) and methylamine (40% in water, 4.1 ml) were added to the mixture. The mixture was refluxed for 1.5 hours. The mixture was extracted with 1N hydrochloric acid (85 ml), the aqueous layer was basified with saturated aqueous sodium hydrogen carbonate solution, then ethyl acetate (10
It was extracted with 0 ml × 2). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 2-5% methanol in chloroform).
, 1- (tert-butoxy) -N-[(1S) -1- [1-methyl-5-[(
2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl] formamide (2.37)
g) was obtained as a brown amorphous solid. ESI-MS: 492.4 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.27 (6H, d, J = 6Hz), 1.37 (9H, s), 2.45 (2H, dd, J = 11Hz, J = 13Hz), 3.37 (3H, s), 3.39-3.53 (4H, m), 3.75-3.87 (2H, m), 5.32-5.42 (1H, m), 5.47-5.53 (1H, m), 6.92 (1H , s), 6.93 (2H, d, J = 9Hz), 7.07-7.15 (2H, m), 7.18 (2H, d, J = 9Hz), 7.55 (1H, dt, J = 2Hz, J = 8Hz), 8.54 (1H, d, J = 5Hz).

Production Example 14 (1S) -1- [1-Methyl-5-[(2R ^* , 6S ^* )-4- (2
6-Dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2-
(2-Pyridyl) ethylamine 1- (tert-butoxy) -N-[(1S) in methanol (5.0 ml).
-1- [1-Methyl-5-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethyl ] To a suspension of formamide (2.36 g) was added 4 in ethyl acetate (20 ml).
N hydrogen chloride was added at 0 ° C. and the solution was stirred at 0 ° C. for 10 minutes. The temperature of the reaction mixture was raised to ambient temperature and the suspension was stirred for 1.5 hours. Mix the mixture with water (80 ml)
It was diluted with and the organic layer and the aqueous layer were separated. The aqueous layer was made basic with sodium hydrogen carbonate (3.0 g) and then extracted with chloroform (30 ml x 2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 2-10% methanol in chloroform), (1S) -1-
[1-Methyl-5-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholine-
4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethylamine (1.70 g) was obtained as a pale yellow syrup. ESI-MS: 392.3 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.28 (6H, d, J = 6Hz), 2.46 (2H, dd, J = 11Hz, J = 13Hz), 3.32 (1H , dd, J = 8Hz, J = 14Hz), 3.41 (1H, dd, J = 6Hz, J = 14Hz), 3.47 (3H, s), 3.49 (2H, dd, J = 2Hz, J = 13Hz), 3.75 -3.88 (2H, m), 4.57 (1H, dd, J = 6Hz, J = 8Hz), 6.94 (2H, d, J = 9Hz), 6.96 (1H, s), 7.10-7.18 (2H, m), 7.21 (2H, d, J = 9Hz), 7.59 (1H, dt, J = 2Hz, J = 8Hz), 8.57 (1H, d, J = 4Hz).

Example 2 1-[(2E) -2- (4-chlorophenyl) ethenyl] -N-[(
1S) -1- [1-Methyl-5-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl ) Ethyl] formamide (1S) -1- [1-methyl-5-[(2R ^* , in 20.0 ml) DMF (20.0 ml).
6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl) ethylamine (1.02 g), 4-chlorocinnamic acid (500 mg) and 1-hydroxybenzotriazole (387 mg
) Was added at 0 ° C. to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (549 mg), then the mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water (40 ml) and extracted with ethyl acetate (40 ml). The organic layer was extracted with 1N hydrochloric acid (25 ml), the aqueous layer was made basic with saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate (40 ml). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residual syrup was purified by silica gel column chromatography (eluent; 5% methanol in chloroform). The syrup obtained was solidified with diisopropyl ether and the solids were collected by filtration, 1-[(2E) -2- (4-chlorophenyl) ethenyl] -N-[(1
S) -1- [1-Methyl-5-[(2R ^* , 6S ^* )-4- (2,6-dimethylmorpholin-4-yl) phenyl] imidazol-2-yl] -2- (2-pyridyl ) Ethyl] formamide (1.05 g) was obtained as an off-white powder. ESI-MS: 556.2 (M +) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.27 (6H, d, J = 6Hz), 2.46 (2H, dd, J = 11Hz, J = 13Hz), 3.47 (3H, s ), 3.48-3.69 (4H, m), 3.74-3.88 (2H, m), 5.83 (1H, q, J = 8Hz), 6.37 (1H, d, J = 16Hz), 6.92 (1H, s), 6.94 (2H, d, J = 9Hz), 7.0 9-7.20 (4H, m), 7.25-7.37 (4H, m), 7.46 (1H, d, J = 16Hz), 7.52-7.60 (2H, m), 8.54 (1H, d, J = 4Hz).

Production Example 15 (2S, 3R) -2-[(tert-butoxy) carbonylamino]
-N- [2- [4- (morpholin-4-yl) phenyl] -2-oxoethyl]
-3- (Phenylmethoxy) butanamide To a stirred solution of (2S, 3R) -2-[(tert-butoxy) carbonylamino] -3- (phenylmethoxy) butanoic acid (3g) in DMF (25ml), 4
Diphenylphosphoryl azide (2.2 ml) and 2-amino-1- [4- (morpholin-4-yl) phenyl] ethan-1-one dihydrochloride (2.83 g) were added at ° C. N, N-Diisopropylethylamine (5.6 ml) was added dropwise at 0 ° C (orange-yellow suspension). After removing the ice bath, the reaction mixture was stirred at room temperature for 8 hours (change from orange-yellow suspension to yellow solution). After evaporation of the solvent, the residue was diluted with a mixture of ethyl acetate and tetrahydrofuran, washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate and n-hexane to give (2S, 3R) -2-[(tert-butoxy) carbonylamino] -N- [2- [4- (morpholin-4-yl) phenyl] -2-.
Oxoethyl] -3- (phenylmethoxy) butanamide (4.60 g) was obtained as pale yellow crystals. MS (m / z) 511 (M ⁺ +1), 131 (bp) ¹ H-NMR (CDCl ₃ ) δ 1.22 (3H, d, J = 7Hz), 1.48 (9H, s), 3.34 (4H, d , J = 5Hz), 3.86 (4H, d, J = 5Hz), 4.22-4.35 (2H, m), 4.59 (2H, AB, J = 10.5Hz, J = 10 Hz), 4.68 (2H, d, J = 7Hz), 5.52 (1H, d, J = 7Hz), 6.89 (2H, d, J = 8Hz), 7.2 4-7.33 (5H, m), 7.55 (1H, s), 7.90 (2H, d, J = 8Hz).

Production Example 16 1- (tert-Butoxy) -N-[(1R, 2R) -1- [1-methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazole-2
-Yl] -2- (phenylmethoxy) propyl] formamide (2S, 3R) -2-[(tert-butoxy) carbonyl in acetic acid (12 ml) and xylene (72 ml) in a flask equipped with a Dean-Stark trap. Amino] -N- [2- [4- (morpholin-4-yl) phenyl] -2-
Oxoethyl] -3- (phenylmethoxy) butanamide (3.58 g) and 40
A mixture of% methylamine solution (12 ml) was refluxed for 2 hours and cooled to ambient temperature under a nitrogen atmosphere. Acetic acid (12 ml) and 40% methylamine solution (12 ml) were added to the mixture and the mixture was again refluxed for 4 hours. The mixture was concentrated, neutralized with aqueous sodium hydrogen carbonate solution and extracted 3 times with ethyl acetate. The combined extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate,
Filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform / methanol = 70/1) and 1- (tert-butoxy) -N-[(1
R, 2R) -1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazol-2-yl] -2- (phenylmethoxy) propyl] formamide (830 mg) was washed with light. Obtained as a yellow amorphous solid. MS (ESI) m / z 507 (M + H) ^{+ 1} H-NMR (300MHz, CDCl ₃ ) δ 1.18 (3H, d, J = 6Hz), 1.45 (9H, s), 3.15-3.25 (4H, m ), 3.51 (3H, s), 3.82-3.92 (4H, m), 4.01 (1H, qd, J = 6Hz, J = 5Hz), 4.58 (1H, A of AB, JAB = 12Hz, OCH ₂ Ph), 4.65 (1H, B of AB, JAB = 12Hz, OCH ₂ Ph), 5.02 (1H, dd, J = 8Hz, J = 5Hz), 5.70 (1H, br d, J = 8Hz), 6.94 (2H, d, J = 9Hz), 6.96 (1H, s), 7.17-7.36 (7H, m).

Production Example 17 1- (tert-Butoxy) -N-[(1R, 2R) -2-hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl) phenyl] -1H
-Imidazol-2-yl] propyl] formamide 1- (tert-butoxy) -N-[(1R, 2R) -1 in acetic acid (4 ml).
-[1-Methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazol-2-yl] -2- (phenylmethoxy) propyl] formamide (80
A solution of 8 mg) was hydrogenated at 40 ° C. over 20% palladium hydroxide on carbon (173 mg) for 10 hours (3.5 atm). After removing the catalyst by filtration, the filtrate was concentrated, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloroform / methanol = 50/1), 1- (tert-butoxy) -N-[(1R, 2R) -2-hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl) phenyl]
-1H-Imidazol-2-yl] propyl] formamide (413 mg) was obtained as a white amorphous solid. MS (ESI) m / z 417 (M + H) ^{+ 1} H-NMR (300MHz, CDCl ₃ ) δ 1.28 (3H, d, J = 6Hz), 1.45 (9H, s), 3.19-3.24 (4H, m ), 3.59 (3H, s), 3.85-3.91 (4H, m), 4.44 (1H, qd, J = 6Hz, J = 2Hz), 4.74 (1H, dd, J = 10Hz, J = 2Hz), 5.35 ( 1H, br d, J = 10Hz), 6.88 (1H, s), 6.96 (2H, d, J = 9Hz), 7.27 (2H, d, J = 9Hz).

Production Example 18 (1R, 2R) -2-Hydroxy-1- [1-methyl-5- [4- (
Morpholin-4-yl) phenyl] -1H-imidazol-2-yl] propylamine trihydrochloride 1- (tert-butoxy) -N-[(1R, 2R) -2-hydroxy-1-
[1-Methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazol-2-yl] propyl] formamide (403 mg) and methanol (0.8 mg).
ml) in ice-cooled mixture was added 4N hydrogen chloride in ethyl acetate (3.2 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated, the residue was dried under reduced pressure, (1R, 2
R) -2-Hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazol-2-yl] propylamine trihydrochloride (411
mg) was obtained as a pale yellow amorphous solid. MS (ESI) m / z 317 (M-3HCl + H) ^{+ 1} H-NMR (300MHz, DMSO-d ₆ ) δ 1.17 (3H, d, J = 6Hz), 3.15-3.30 (4H, m), 3 .70-3.82 (4H, m), 3.83 (3H, s), 4.41 (1H, qd, J = 6Hz, J = 6Hz), 4.87 (1H, br d, J = 6Hz), 7.13 (2H, d, J = 9Hz), 7.41 (2H, d, J = 9Hz), 7.85 (1H, s), 9.20 (3H, br s).

Example 3 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1R, 2R
) -2-Hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl)
Phenyl] -1H-imidazol-2-yl] propyl] formamide (1R, 2R) -2-hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl) in DMF (1.7 ml). ) Phenyl] -1H-imidazole-2-
Il] propylamine trihydrochloride (213 mg), 5-chlorobenzo [b] furan-2-carboxylic acid (109 mg), 1-hydroxybenzotriazole (68 m
g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (120 mg) in an ice-cooled mixture, N, N-diisopropylethylamine (0
． 28 ml) was added dropwise. The mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with chloroform three times. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (
Silica gel, chloroform / methanol = 50/1). The eluate was evaporated, triturated with ethyl acetate-hexane and 1- (5-chlorobenzo [b] furan-2-yl).
-N-[(1R, 2R) -2-hydroxy-1- [1-methyl-5- [4- (morpholin-4-yl) phenyl] -1H-imidazol-2-yl] propyl] formamide (159 mg) Was obtained as a white powder. mp 188-189 ℃ MS (ESI) m / z 495 (M + H) ^{+ 1} H-NMR (300MHz, CDCl ₃ ) δ 1.33 (3H, d, J = 6Hz), 3.15-3.26 (4H, m), 3.66 (3H, d, J = 1Hz), 3.82-3.92 (4H, m), 4.55 (1H, qd, J = 6Hz, J = 2Hz), 5.30 (1H, dd, J = 10Hz, J = 2Hz ), 6.94 (1H, s), 6.95 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz), 7.34-7.50 (4H, m), 7.62-7.68 (1H, m).

Example 4 1-[(E) -2- (4-chlorophenyl) ethenyl] -N-[(1
R, 2R) -2-Hydroxy-1- [1-methyl-5- [4- (morpholine-4
-Yl) phenyl] -1H-imidazol-2-yl] propyl] formamide The title compound was obtained from the compound of Preparation 18 in a manner substantially similar to Example 3. White powder mp 218-219 ℃ MS (ESI) m / z 481 (M + H) ^{+ 1} H-NMR (300MHz, CDCl ₃ ) δ 1.30 (3H, d, J = 6Hz), 3.14-3.29 (4H, m ), 3.64 (3H, s), 3.80-3.94 (4H, m), 4.49 (1H, qd, J = 6Hz, J = 2Hz), 5.25 (1H, dd, J = 10Hz, J = 2Hz), 6.43 ( 1H, d, J = 16Hz), 6.52 (1H, br d, J = 10Hz), 6.91 (1H, s), 6.96 (2H, d, J = 9Hz), 7.26 (2H, d, J = 9Hz), 7.35 (2H, d, J = 8Hz), 7.43 (2H, d, J = 8Hz), 7.62 (1H, d, J = 16Hz).

Production Example 19 (2S) -2-benzyloxycarbonylamino-N- [2- [4-
(Morpholin-4-yl) phenyl] -2-oxoethyl] -3- (tert-
Butoxycarbonylamino) propanamide The title compound and (2S) -2-benzyloxycarbonylamino-3- (tert-butoxycarbonylamino) propane were prepared in substantially the same manner as in Production Example 12 and the compound of Production Example 4 was used. Obtained from the acid. ESI-MS: 541.0 (M + H) ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.36 (9H, s), 3.14-3.25 (1H, m), 3.28-3 .35 (5H, m), 3.70-3.77 (4H, m), 4.14-4.24 (1H, m), 4.47-4.54 (2H, m), 5.02 (1H, d, J = 14Hz), 5.06 (1H, d, J = 14Hz), 6.73 -6.79 (1H, m), 7.01 (2H, d, J = 9Hz), 7.28-7.39 (6H, m), 7.85 (2H, d, J = 9Hz), 8.11-8.17 (1H, m).

Production Example 20 1-Benzyloxy-N-[(1S) -1- [1-methyl-5- [4
-(Morpholin-4-yl) phenyl] imidazol-2-yl] -2- (ter
t-Butoxycarbonylamino) ethyl] formamide The title compound was obtained from the compound of Preparation 19 in much the same manner as in Preparation 13. ESI-MS: 536.5 (M + H) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.42 (9H, s), 3.18-3.25 (4H, m), 3.54-3.7 2 (2H, m), 3.58 (3H , s), 3.85-3.92 (4H, m), 5.05-5.16 (1H, m), 5.13 (2H, s), 5.43-5.52 (1H, m), 5.66-5.74 (1H, m), 6.91 (1H , s), 6.96 (2H, d, J = 9Hz), 7.24 (2H, d, J = 9Hz), 7.30-7.39 (5H, m).

Production Example 21 (1S) -1- [1-methyl-5- [4- (morpholin-4-yl)
Phenyl] imidazol-2-yl] -2- (tert-butoxycarbonylamino) ethylamine 1-benzyloxy-N-[(1S) -1- [1 in methanol (30 ml).
-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (tert-butoxycarbonylamino) ethyl] formamide (3
． A stirred solution of 37 g) was hydrogenated over palladium hydroxide (1.2 g) at 35 ° C. for 4.5 hours under 4 atmospheres. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and (1
S) -1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (tert-butoxycarbonylamino) ethylamine (2.52 g) as brown amorphous Obtained as a solid. ESI-MS: 402.2 (M + H) ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 1.34 (9H, s), 3.14-3.21 (4H, m), 3.28-3 .53 (2H, m), 3.60 (3H, s), 3.72-3.79 (4H, m), 4.64-4.71 (1H, m), 7.02- 7.10 (3H, m), 7.27 (2H, d, J = 8Hz), 8.55-8.68 (2H , br).

Production Example 22 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1S)-
1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2- (tert-butoxycarbonylamino) ethyl] formamide The title compound was prepared in the same manner as in Example 2. By method, obtained from the compound of Preparation 21. mp 214-217 ℃ ESI-MS: 580.2 (M +) ¹ H-NMR (300MHz, CDCl ₃ ) δ 1.40 (9H, s), 3.18-3.25 (4H, m), 3.59-3.6 8 (1H, m), 3.65 (3H, s), 3.75-3.83 (1H, m), 3.85-3.92 (4H, m), 5.53-5.62 (2H, m), 6.96 (2H, d, J = 9Hz), 6.97 (1H , s), 7.25 (2H, d, J = 9Hz), 7.34 -7.45 (3H, m), 7.61 (1H, d, J = 8Hz), 7.64 (1H, d, J = 2Hz).

Production Example 23 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1S)-
1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2-aminoethyl] formamide The title compound was prepared in the same manner as in Production Example 14 in Production Example 22. From the compound of. mp 184-188 ℃ ESI-MS: 480.1 (M +) ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 3.04 (1H, dd, J = 6Hz, J = 14Hz), 3.11-3.20 (5H, m), 3.57 (3H, s), 3.70-3.78 (4H, m), 5.18-5.26 (1H, m), 6.90 (1H, s), 7.01 (2H, d, J = 9Hz), 7.29 (2H, d, J = 9Hz), 7.49 (1H, dd, J = 2Hz, J = 8Hz), 7.65 (1H, s), 7.71 (1H, d, J = 8Hz), 7.88 (1H, d, J = 2Hz).

Example 5 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1S) -1
-[1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazole-
2-yl] -2-methylsulfonylaminoethyl] formamide 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1S) -1- [1-methyl-5] in dichloromethane (3 ml). -[4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2-aminoethyl] formamide (12
0 mg) and N, N-diisopropylethylamine (0.48 ml) in a solution of 0
Methanesulfonyl chloride (30 mg) was added at ° C. The reaction mixture at room temperature was 1.
It was stirred for 5 hours and diluted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was washed with ethyl acetate and 1- (5-chlorobenzo [b] furan-2-yl) -N-[(1
S) -1- [1-Methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] -2-methylsulfonylaminoethyl] formamide (87
mg) was obtained as colorless crystals. mp 231-234 ℃ ESI-MS: 558.2 (M +) ¹ H-NMR (300MHz, DMSO-d ₆ ) δ 2.91 (3H, s), 3.12-3.20 (4H, m), 3.53-3.70 (2H, m), 3.57 (3H, s), 3.71-3.78 (4H, m), 5.40-5.50 (1H, m), 6.92 (1H, s), 7.01 (2H, d, J = 9Hz), 7.23-7.34 ( 3H, m), 7.50 (1H, dt, J = 2Hz, J = 8Hz), 7.65 (1H, s), 7.71 (1H, d, J = 8Hz), 7.90 (1H, d, J = 2Hz), 9.19 (1H, d, J = 8Hz).

Production Example 24 (1R) -1- [1-methyl-5- [4- (morpholin-4-yl)
Phenyl] imidazol-2-yl] -2- (phenylmethoxy) ethylamine trihydrochloride The title compound was obtained from the compound of Preparation 4 in much the same manner as in Preparations 15, 16, 18.

Production Example 25 (2R) -2-Amino-2- [1-methyl-5- [4- (morpholin-4-yl) phenyl] imidazol-2-yl] ethane-1-ol triacetate acetic acid (1R) -1- [1-methyl-5- [4- (morpholine-in 5 ml).
To a solution of 4-yl) phenyl] imidazol-2-yl] -2- (phenylmethoxy) ethylamine trihydrochloride (500 mg) was added palladium hydroxide (200 mg) and the mixture was added under hydrogen atmosphere (4 atm), The mixture was stirred at 45 ° C for 4 hours. After removing the catalyst, the solvent was removed under reduced pressure to give (2R) -2-amino-2- [1-methyl-5- [4
-(Morpholin-4-yl) phenyl] imidazol-2-yl] ethan-1-ol triacetate (370 mg) was obtained as a brown amorphous solid. No further purification was attempted.

Example 6 1- (5-chlorobenzo [b] furan-2-yl) -N- [2-hydroxy- (1R) -1- [1-methyl-5- [4- (morpholine-4- Il) phenyl] imidazol-2-yl] ethyl] formamide The title compound was obtained from the compound of Preparation 25 in much the same manner as in Example 3. mp 188-190 ℃ MS 481 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.18-3.24 (4H, m), 3.65 (3H, s), 3.85-3.90 (5H, m), 4.01 (1H, dd, J = 13.5Hz, J = 3.0Hz), 4.34 (1H, dd, J = 13.5Hz, J = 1.5Hz), 5.45-5.51 (1H, m), 6.94-6.97 (2H, m), 7.23-7.27 ( 2H, m), 7.35-7.46 (3 H, m), 7.62-7.65 (2H, m). [Α] D 25 ° = + 247.2 ° (c 1.04, CHCl ₃ : MeOH = 10: 1)

Example 7 (2R) -2-[(5-chlorobenzo [b] furan-2-yl) carbonylamino] -2- [1-methyl-5- [4- (morpholin-4-yl) phenyl] ] Imidazol-2-yl] ethyl acetate 1- (5-chlorobenzo [b] furan-2-yl) -N- [2-hydroxy- (1R) -1- [1-methyl-5] in pyridine (120 ml). -[4- (morpholin-4-yl) phenyl] imidazol-2-yl] ethyl] formamide (3
Acetic anhydride (20 ml) was added to the solution of 1 g) at room temperature. After 1 hour, pyridine was removed under reduced pressure. Water (200 ml) was added to the residual oil and the resulting precipitate was collected by filtration and washed with water (100 ml). The wet solid was recrystallized from ethanol (150 ml), washed with ethanol (50 ml), (2R) -2-[(5-chlorobenzo [b] furan-2-yl) carbonylamino] -2- [1- Methyl-5- [
4- (morpholin-4-yl) phenyl] imidazol-2-yl] ethyl acetate (27 g) was obtained as white crystals. mp 163-164 ℃ ¹ H-NMR (CDCl ₃ ) δ 1.65 (3H, s), 3.20-3.24 (4H, m), 3.65 (3H, s), 3.85 -3.90 (4H, m), 4.53-4.57 ( 1H, m), 5.70-5.77 (1H, m), 6.93-7.00 (3H, m), 7.24-7.28 (2H, m), 7.35-7.65 (5H, m). [Α] _D 24 ° = +162.72 ° (c 1.14, CHCl ₃ )

Production Example 26 6-Chloro-N-methoxy-N-methylnicotinamide 6-chloronicotinic acid (29 g), N, O-dimethylhydroxylamine hydrochloride (26.9 g), 1 in DMF (300 ml). To a mixture of -hydroxybenzotriazole (36.6 g) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (42.3 g) and N, N-diisopropylethylamine (48 ml) at 5 ° C. . The reaction mixture was stirred at 5 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (300 ml) and ethyl acetate (300 ml) were added to the reaction mixture.
Was added. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. After removing the solvent under reduced pressure, 6-chloro-N-methoxy-N-methylnicotinamide (33.3 g) was obtained as a pale brown oil. MS 200.99 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.40 (3H, s), 3.56 (3H, s), 7.40 (1H, d, J = 7.5Hz), 8.03 (1H, dd, J = 7.5Hz, J = 1Hz), 8.78 (1H, d, J = 1Hz).

Production Example 27 1- (6-Chloro-3-pyridyl) ethan-1-one 6-chloro-N-methoxy-N-methylnicotinamide (33 g) was placed in a 3-necked flask. Tetrahydrofuran (300 ml) was added to it and the mixture was -3.
Cooled to 0 ° C. To the mixture was added a solution of 1.1 M methyllithium in diethyl ether (165 ml) dropwise over 10 minutes. After 5 minutes, the reaction mixture was poured into saturated brine. The organic layer was separated, washed with saturated aqueous ammonium chloride solution, and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residual solid was triturated with a mixed solution of diisopropyl ether and n-hexane to obtain 1- (6-chloro-3-pyridyl) ethan-1-one (16 g) as a yellowish brown powder. . MS 155.94 (ES +) ¹ H-NMR (CDCl ₃ ) δ 2.65 (3H, s), 7.45 (1H, d, J = 7.5Hz), 8.20 (1H, dd, J = 7.5Hz, J = 1Hz), 8.93 (1H, d, J = 1Hz).

Preparation Example 28 1- [6- (4-morpholinyl) -3-pyridyl] ethan-1-one 1- (6-chloro-3-pyridyl) in dimethylsulfoxide (100 ml).
Ethan-1-one (5 g), morpholine (8.4 g), potassium carbonate (4.4 g
) Was heated at 130 ° C. (bath temperature) for 2 hours. Thin layer chromatography showed that the starting material (1- (6-chloro-3-pyridyl) ethan-1-one) was completely consumed. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate solution (2
00 ml) and the mixture was extracted with ethyl acetate (200 ml). The organic layer was concentrated. The residue was dissolved in diethyl ether (200 ml) and washed with saturated aqueous ammonium chloride solution (100 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residue was triturated with diisopropyl ether (50 ml) and 1- [6- (4-morpholinyl) -3-pyridyl] ethan-1-one (5.9
9 g) was obtained as a pale yellow powder. MS 207.05 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.64-3.89 (4H, m), 3.80-3.84 (4H, m), 6.62 (1H, d, J = 7.5Hz), 8.04 (1H, dd, J = 7.5Hz, J = 1Hz), 8.77 (1H, d, J = 1Hz).

PREPARATION 29 2-Bromo-1- [6- (4-morpholinyl) -3-pyridyl] ethan-1-one 1- [6- (4-morpholinyl) -3 in 48% HBr (5 ml). To a solution of -pyridyl] ethan-1-one (3g) was added a solution of bromine in 48% HBr (2ml) (
0.75 ml) was added dropwise at 65 ° C. The mixture was heated at 65 ° C. for 0.5 hours. After cooling on an ice bath, the resulting precipitate was collected by filtration and washed with a small amount of HBr. The light brown solid obtained was made basic with saturated aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration and washed with water. The wet solid was dried under reduced pressure to give 2-bromo-1- [6-
(4-morpholinyl) -3-pyridyl] ethan-1-one (3.6 g) was obtained as a brown solid. MS 285.10 & 287.10 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.70-3,74 (4H, m), 3.80-3.84 (4H, m), 6.63 (1H, d, J = 7.5Hz), 8.07 ( 1H, dd, J = 7.5Hz, J = 1Hz), 8.80 (1H, d, J = 1Hz).

Preparation 30 2- [2- {6- (4-morpholinyl) -3-pyridyl} -2-oxoethyl] -1H-isoindole-1,3 (2H) -dione 2 in DMF (40 ml). -Bromo-1- [6- (4-morpholinyl) -3-
Pyridyl] ethan-1-one (3.6 g) and potassium 1H-isoindole-
A mixture of 1,3 (2H) -dione (2.5g) was heated at 130 ° C for 15 minutes.
After cooling, the obtained precipitate was collected by filtration, washed successively with DMF (4 ml) and water (10 ml), and then 2- [2- {6- (4-morpholinyl) -3-pyridyl} -2-oxoethyl]-. 1H-isoindole-1,3 (2H) -dione (2.7 g) was obtained as a pale yellow powder. MS 352.12 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.70-3.74 (4H, m), 3.80-3.84 (4H, m), 5.03 (2H, s), 6.63 (1H, d, J = 7.5Hz) , 7.72-7.77 (2H, m), 7.87-7.92 (2H, m), 8.04 (1H, dd, J = 7.5Hz, J = 1Hz), 8.83 (1H, d, J = 1Hz).

Preparation 31 2-Amino-1- [6- (4-morpholinyl) -3-pyridyl] ethan-1-one trihydrochloride 2- [2- {6- (4 -Morpholinyl) -3-pyridyl} -2-oxoethyl] -1H-isoindole-1,3 (2H) -dione (
A solution of 2.7 g) was heated to reflux for 8 hours. After removal of the solvent under reduced pressure, the residual oily solid was triturated with methanol (5 ml), collected by filtration, washed with methanol, and 2-amino-1- [6- (4-morpholinyl) -3-pyridyl] ethane-1. -One trihydrochloride (0.34 g) was obtained as a brown powder. MS 222.1 (ES +) (free mw 221) ¹ H-NMR (DMSO-d ₆ ) δ 3.68 (8H, br-s), 4.42-4.48 (2H, m), 6.98 (1H, d, J = 7.5Hz) , 8.06 (1H, dd, J = 7.5Hz, J = 1Hz), 8.75 (1H, d, J = 1Hz).

Production Example 32 tert-butyl 2-[[2- {6- (4-morpholinyl) -3-]
Pyridyl} -2-oxoethyl] amino] -2-oxo- (1S) -1- (2-
Pyridylmethyl) ethylcarbamate 2-Amino-1- [6- (4-morpholinyl) -3-pyridyl] ethan-1-one trihydrochloride (1.5 g) and (2S) -2-[(tert To a mixture of -butoxycarbonyl) amino] -3- (2-pyridyl) propanoic acid (1.2g), diphenylphosphoryl azide (1.3g) and N, N-diisopropylethylamine (3.5ml) were added at 5 ° C. It was The reaction mixture was stirred at 5 ° C. for 0.5 hours and room temperature for 1.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution (50 m
1) was added and the mixture was extracted with ethyl acetate. The organic layer was separated and extracted with 1N hydrochloric acid. The aqueous layer was washed with ethyl acetate, basified with aqueous sodium hydrogen carbonate solution and extracted with diethyl ether-ethyl acetate (10: 1). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residual solid was triturated with diisopropyl ether and tert-butyl 2-[[2- {6- (4-morpholinyl) -3-].
Pyridyl} -2-oxoethyl] amino] -2-oxo- (1S) -1- (2-
Pyridylmethyl) ethyl carbamate (1.42 g) was obtained as a white powder. MS 470.31 (ES +) ¹ H-NMR (CDCl ₃ ) δ 1.45 (9H, s), 3.19-3.43 (2H, m), 3.66-3.70 (4H, m), 3.77-3.81 (4H, m), 4.54- 4.58 (2H, m), 4.67 (1H, m), 6.40 (1H, br-s), 6.58 (1H, d, J = 7.5Hz), 7.10-7.13 (2H, m), 7.55-7.63 (1H, m), 7.87 (1H, br-s), 7.97 (1H, dd, J = 7.5Hz, J = 1Hz), 8.52-8.56 (1H, m), 8.73 (1H, d, J = 1Hz).

Production Example 33 (1S) -1- [1-methyl-5- {6- (4-morpholinyl) -3]
-Pyridyl} -1H-imidazol-2-yl] -2- (2-pyridyl) ethylamine tert-butyl 2-[[2- {6- (4-morpholinyl) -3-pyridyl} -2-oxoethyl] amino] 2-oxo- (1S) -1- (2-pyridylmethyl) ethyl carbamate (0.2 g) was dissolved in hot methanol (1 ml) and the solution was charged with 4N hydrogen chloride in ethyl acetate (5 ml). added. After 0.5 hours, the solvent was removed under reduced pressure. The residual solid was treated with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer is separated, dried over magnesium sulfate,
Filtered. The filtrate was concentrated under reduced pressure, and (1S) -1- [1-methyl-5- {6- (4-
Morpholinyl) -3-pyridyl} -1H-imidazol-2-yl] -2- (2-
Pyridyl) ethylamine (0.15 g) was obtained as a brown oil. MS 365.21 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.38-3.43 (2H, m), 3.48 (3H, s), 3.53-3.57 (4H, m), 3.79-3.84 (4H, m), 4.63- 4.68 (1H, m), 6.67 (1H, d, J = 7.5Hz), 6.97 (1H, s), 7.1-7.19 (2H, m), 7.44 (1H, dd, J = 7.5Hz, J = 1Hz) , 7.56-7.63 (1H, m), 8.14 (1H, d, J = 1Hz), 8.55-8.57 (1H, m).

Example 8 5-Chloro-N-[(1S) -1- [1-methyl-5- {6- (4-
Morpholinyl) -3-pyridyl} -1H-imidazol-2-yl] -2- (2-
Pyridyl) ethyl] benzo [b] furan-2-carboxamide (1S) -1- [1-methyl-5- {6- (4-morpholinyl) -3-pyridyl} -1H-imidazole- in DMF (3 ml). 2-yl] -2- (2-pyridyl) ethylamine (140 mg), 5-chlorobenzo [b] furan-2-carboxylic acid (76 mg) and 1-hydroxybenzotriazole (62 mg) in a mixture of 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (
81 mg) and N, N-diisopropylethylamine (0.08 ml) were sequentially added at 5 ° C. The reaction mixture was stirred at room temperature for 1 hour. Water (10 ml) in the reaction mixture
Was added and the mixture was extracted with ethyl acetate (10 ml). The organic layer was added to 1N HCl (
5 ml). The aqueous layer was washed with ethyl acetate, made basic with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate,
Filtered. The filtrate was concentrated and the residual oily solid was purified by thin layer chromatography (chloroform: methanol = 20: 1). The obtained solid was triturated with diethyl ether to give 5-chloro-N-[(1S) -1- [1-methyl-5- {6- (4-morpholinyl) -3-pyridyl} -1H-imidazole- 2-yl] -2- (2-pyridyl) ethyl] benzo [b] furan-2-carboxamide (45 mg) was obtained as a pale yellow powder. mp 128-130 ℃ MS 543.25 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.45 (3H, s), 3.51-3.57 (4H, m), 3.58-3.62 (2H, m), 3.80-3.84 (4H, m), 5.88-5.96 (1H, m), 6.67 (1H, d, J = 7.5Hz), 6.98 (1H, s), 7.10-7.15 (2H, m), 7.34-7.46 (3H, m), 7.52 -7.58 (1H, m), 7.63 (1 H, d, J = 1Hz), 7.73 (1H, dd, J = 7.5Hz, J = 1Hz), 8.12 (1H, d, J = 1Hz), 8.52- 8.55 (1H, m).

Example 9 (2E) -3- (4-chlorophenyl) -N-[(1S) -1- [1
-Methyl-5- {6- (4-morpholinyl) -3-pyridyl} -1H-imidazol-2-yl] -2- (2-pyridyl) ethyl] -2-propenamide (1S in DMF (3 ml). ) -1- [1-Methyl-5- {6- (4-morpholinyl) -3-pyridyl} -1H-imidazol-2-yl] -2- (2-pyridyl) ethylamine (100 mg), (2E)- 3- (4-chlorophenyl) -2
-Propenoic acid (50 mg) and 1-hydroxybenzotriazole (45 mg)
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (58 mg) and N, N-diisopropylethylamine (0.08 ml) were sequentially added to the mixture of 5 ° C. The reaction mixture was stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (10 ml). The organic layer is 1N H
Extracted with Cl (5 ml). The aqueous layer was washed with ethyl acetate, made basic with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residual oily solid was purified by thin layer chromatography (chloroform: methanol = 20: 1). The solid obtained was triturated with a mixture of diethyl ether and ethyl acetate to give (2E) -3- (4-chlorophenyl)-
N-[(1S) -1- [1-Methyl-5- {6- (4-morpholinyl) -3-pyridyl} -1H-imidazol-2-yl] -2- (2-pyridyl) ethyl] -2
-Propenamide (27 mg) was obtained as a white solid. mp 172-173 ℃ MS 529.25 (ES +) ¹ H-NMR (CDCl ₃ ) δ 3.44 (3H, s), 3.47-3.52 (2H, m), 3.52-3.56 (4H, m), 3.80-3.84 (4H, m), 5.78-5.85 (1H, m), 6.35 (1H, d, J = 15Hz), 6.76 (1H, d, J = 7.5Hz), 6.93 (1H, s), 7.08-7.15 (2H, m) , 7.26-7.58 (7H, m), 8.11 (1H, d, J = 1Hz), 8.52-8.54 (1H, m).

This application is based on the patent application No. No. 1 filed in Australia on July 5, 1999. P
Based on Q1425. The contents of which are incorporated herein by reference.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 3/10 A61P 3/10 9/04 9/04 9/10 9/10 101 101 11/00 11 / 00 11/06 11/06 13/02 13/02 13/12 13/12 15/10 15/10 17/00 17/00 19/02 19/02 19/08 19/08 19/10 19/10 25 / 00 25/00 25/06 25/06 25/16 25/16 25/28 25/28 27/02 27/02 27/04 27/04 27/06 27/06 27/10 27/10 27/12 27/12 29/00 29/00 101 101 31/04 31/04 35/00 35/00 35/04 35/04 37/06 37/06 43/00 43/00 C07D 401/06 C07D 401/06 401 / 14 401/14 405/12 405/12 405/14 405/14 413/14 413/14 (72) Inventor Tatsuya Yoshimitsu 3-4-7 Doshomachi, Chuo-ku, Osaka-shi, Osaka Prefecture Fujisawa Pharmaceutical Co., Ltd. (72) Inventor Kentaro Sato 3-4-7 Doshomachi, Chuo-ku, Osaka-shi, Osaka Prefecture F-term inside Fujisawa Pharmaceutical Co., Ltd. (reference) 4C063 AA01 AA03 AA05 BB04 BB06 BB09 CC25 CC54 CC76 DD12 DD25 EE01 4C086 AA01 AA02 AA03 AA04 BC73 GA02 GA07 GA08 GA09 MA01 MA04 NA14 ZA02 ZA08 ZA15 ZA15 B75 ZABZ17B15 ZB17B15 ZA45B15 ZA45B15 ZA45B15 ZA45B16 ZA45B16 ZA45B15 ZA16B

Claims (10)

[Claims] 1. Formula (I): [Wherein R ¹ is benzofuranyl substituted with halogen or styryl substituted with halogen, R ² is hydrogen or lower alkyl, R ³ is pyridyl, optionally protected hydroxy or lower alkylsulfonylamino, R ⁴ is lower alkyl, R ⁵ and R ⁶ are the same or different, each is hydrogen or lower alkyl, X is CH or N, provided that (i) R ² is hydrogen, R ^{When 3} is pyridyl, R ⁵ and R ⁶ are each hydrogen, and X is CH, R ¹ is styryl substituted by halogen, (ii) R ¹ is benzofuranyl substituted by halogen, and R ³ is pyridyl. , X is N when R ⁵ and R ⁶ are each hydrogen, or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ¹ is benzofuranyl substituted with halogen, and R ³ is optionally protected hydroxy or lower alkylsulfonylamino, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein R ¹ is styryl substituted with halogen, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim ³ , wherein R ³ is pyridyl or optionally protected hydroxy, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, wherein R ¹ is benzofuranyl substituted with halogen, R ³ is pyridyl, and X is N, or a pharmaceutically acceptable salt thereof. 6. The formula: [Wherein R ¹ is benzofuranyl substituted with halogen or styryl substituted with halogen, R ² is hydrogen or lower alkyl, R ³ is pyridyl, optionally protected hydroxy or lower alkylsulfonylamino, R ⁴ is lower alkyl, R ⁵ and R ⁶ are the same or different, each is hydrogen or lower alkyl, X is CH or N, provided that (i) R ² is hydrogen, R ^{When 3} is pyridyl, R ⁵ and R ⁶ are each hydrogen, and X is CH, R ¹ is styryl substituted by halogen, (ii) R ¹ is benzofuranyl substituted by halogen, and R ³ is pyridyl. , R ⁵ and R ⁶ are each hydrogen, X is N], or a salt thereof. [Wherein each of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and X is as described above], or a reactive derivative thereof at an amino group, or a salt thereof; 4] [Wherein R ¹ is as defined above] or a reactive derivative thereof at the carboxy group, or a salt thereof, [Wherein ^each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X is as defined above] or a salt thereof, or a compound of the formula (2) [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and X are as described above] or a salt thereof, and a compound of the formula: A compound of the formula: wherein R ⁷ is lower alkyl, [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X are as described above] or a salt thereof, or a compound of the formula (3) [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and X are as described above] or a salt thereof is subjected to a protection reaction of a hydroxy group and represented by the formula: [Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and X are as described above, and R ⁸ is a hydroxy protecting group], or a salt thereof. Method. 7. A pharmaceutical composition containing the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier. 8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as a medicine. 9. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as a medicament for preventing or treating NO-mediated diseases. 10. Adult respiratory distress syndrome (ARDS); asthma; cardiovascular ischemia; myocarditis; heart failure; hypotension; atherosclerosis; diabetes including insulin-dependent diabetes mellitus; diabetic nephropathy, diabetic retina. And diabetic complications including diabetic neuropathy; gout; glomerulonephritis; renal failure; peptic ulcer; inflammatory bowel disease including ulcerative colitis and chronic colitis; pancreatitis; hepatitis; cirrhosis; synovitis Arthritis; Osteoarthritis; Osteoporosis; Autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; Dermatitis; Eczema; Cancer; Solid tumors; Metastases; Organ transplant rejection; Sepsis shock Shock; sepsis-induced systemic inflammatory response syndrome; CNS disorders; cerebral infarction; cerebral ischemia; cerebral hemorrhage; migraine; Alzheimer's disease; neuritis; postherpetic neuralgia; reflex sympathetic neuropathy (R) SD); causalgia; deafferentative pain syndrome;
Neuropathic pain; abnormal hyperalgesia; hyperalgesia; neurological disorders; neuroprotection; Parkinson's disease; amyotrophic lateral sclerosis; male sexual dysfunction including erectile dysfunction; including orgasmic dysfunction associated with clitoral disorders Female sexual dysfunction; conjunctivitis including allergic conjunctivitis, spring catarrhal, keratoconjunctivitis sicca, viral conjunctivitis and viral conjunctivitis; Behcet's disease, Harada's disease, sympathetic ophthalmitis, uveitis including diabetic iritis. Scleritis; corneal neovascularization; keratitis; corneal edema; corneal opacity; corneal dystrophy; keratoconus; neuroparetic keratitis; diabetic retinopathy; retinal artery occlusion; retinal vein occlusion; central serous choroid retina Disease; central hemorrhagic chorioretinitis; macular degeneration including age-related macular degeneration; detachment of the retina; retinitis pigmentosa; neovascular macular disease; macular hole; proliferative vitreoretina Vitreous hemorrhage; vitreous opacity; cataracts including senile cataract, traumatic cataract, diabetic cataract, atopic cataract; primary open-angle glaucoma, primary closed-angle glaucoma, normal tension glaucoma and neovascular glaucoma Glaucoma; ocular hypertension;
For the prevention of NO-mediated diseases selected from the group consisting of amblyopia, color blindness and night blindness; refractive errors including astigmatism, hyperopia, myopia and presbyopia; dry eye syndrome; lacrimal duct obstruction; lacrimal cystitis Or the use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as a therapeutic medicament.