WO1998046569A1 - Benzene derivatives - Google Patents

Abstract

Benzene derivatives represented by general formula (1) or pharmaceutically acceptable salts thereof, which are useful as growth hormone liberation promoters, etc. wherein ring A represents an optionally substituted benzene ring, etc.; X represents -CO- or -SO2-; Y represents oxygen or a single bond; R3 represents a single bond or C¿1-3? alkylene; R?4¿ represents a single bond or C¿1-2? alkylene; R?5¿ represents hydrogen, optionally hydroxylated alkyl, etc.; and R6 represents an optionally substituted, saturated nitrogen-containing heterocycle, etc.; or R?1 and R2¿ may form together with the nitrogen atom (a), wherein E represents optionally substituted ethylene, optionally substituted vinylene, -CH¿2NR?9- or -NR9CH2- (wherein R9 represents hydrogen, lower alkyl, lower alkanoyl or lower alkylsulfonyl); and R8 represents a substituent.

Description

 Description Benzene derivative Technical field

 The present invention relates to a benzene derivative or a pharmaceutically acceptable salt useful as a growth hormone release enhancer or the like. Landscape technology

 Various factors are involved in the growth of an individual, but growth hormone is the most important for growth, since excessive growth hormone secretion causes giantosis and acromegaly, and growth hormone deficiency causes dwarfism. It is clear that this is a factor. In addition, growth hormone is known to have basic effects on the body's metabolic processes, such as increasing the rate of protein synthesis, decreasing the rate of carbohydrate utilization, increasing the distribution of free fatty acids, and increasing fatty acid utilization.

 Various substances having an action of releasing growth hormone are known, such as arginine,

Examples include L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopretinsin, and insulin that induce hypoglycemia. In addition, activities such as sleep and movement are known to have the effect of releasing growth hormone. These substances and activities act in the hypothalamus by a variety of mechanisms, such as decreasing somatostatin secretion and increasing secretion of known growth hormone-releasing factor (GRF) or unknown endogenous growth hormone-releasing factor. It is also known to cause growth hormone to be indirectly released from the pituitary gland.

As a method of increasing the growth hormone concentration in the body, a method of exogenously administering growth hormone is known. Growth hormone is derived from pituitary pituitary gland or used recombinantly, but these are very expensive, and pituitary gland extract is a source-related disease that causes growth hormone acceptance. With the danger of transmission to the elderly. Because growth hormone is difficult to administer orally, it is administered by injection or nasal spray. Was needed.

 A second method for increasing the concentration of growth hormone in the body is to use GRF or its derivatives (そ の choen WR et al., “Growth hormone secretagogues” m Annual Reports in Medicinal Chemistry; Academic Press, Vol. 28, Chapter 19, 1993) or a method of administering a peptide that stimulates growth hormone production and release (US Pat. No. 4,411,890) is known. Although these peptides are quite small compared to growth hormone, they are still poorly bioavailable on oral administration because they are degraded by various proteases.

 UK Patent 2,297,972 describes non-peptidic compounds useful as growth hormone release enhancers. The compound is stable in various physiological environments and can be administered by parenteral, nasal, or oral routes, but has not reached clinical application.

Disclosure of the invention

 The problem to be solved by the invention is to provide a non-peptidic compound which is useful as a growth hormone release enhancer applicable as a pharmaceutical.

 The present inventors have studied various non-peptidic compounds and have found that a benzene derivative or a pharmaceutically acceptable salt thereof is useful as a growth hormone release enhancer applicable as a pharmaceutical. The present invention has been completed.

 That is, the present invention relates to the following [1] to [13].

 [1] Equation 1:

. ¹

. No R ^{6 R}

[In the formula, ring A represents an optionally substituted benzene ring or an optionally substituted naphthalene ring. Represents —CO— or one S 0 ₂ —. Y represents an oxygen atom or a single bond You.

R ³ represents a single bond or alkylene having 1 to 3 carbon atoms. R ⁴ represents a single bond or an alkylene having 1 to 2 carbons. R ⁵ represents a hydrogen atom, an alkyl group optionally substituted with a hydroxyl group, an alkenyl group optionally substituted with a hydroxyl group, or an alkynyl group optionally substituted with a hydroxyl group.

R ⁶ is an optionally substituted amino group, an optionally substituted aminoalkyl group, an optionally substituted, saturated nitrogen-containing heterocyclic group, or an optionally substituted saturated nitrogen-containing heterocyclic group. Represents a substituted alkyl group.

R ¹ and R ² are as described in (1), (2) or (3) below.

(1) R ¹ represents a group represented by the formula: Ar—R ⁷ —, and R ² represents a hydrogen atom or a lower alkyl group.

Ar represents an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted indenyl group, an optionally substituted indanyl group or an optionally substituted Represents a good benzoheterocyclic group. R ⁷ represents unsubstituted or good having 1 to 4 carbon atoms in the alkylene, substituted carbon atoms which may be 2-4 alkenylene, alkynylene or cycloalk Kanjiiru of optionally substituted carbon atoms 2 be 4.

(2) R ¹ and R ^{2 taken} together with a nitrogen atom represent a saturated nitrogen-containing heterocyclic group substituted with an optionally substituted phenyl group.

(3) R ¹ and R ² together form a nitrogen atom with the formula:

(E represents an optionally substituted ethylene, an optionally substituted vinylene, _CH ₂ NR ⁹ — or —NR ⁹ CH ₂ —. R ⁸ represents a substituent. R ⁹ represents a hydrogen atom, Represents a lower alkyl group, a lower alkanol group or a lower alkylsulfonyl group. ) Represents a group represented by ]

Or a pharmaceutically acceptable salt thereof.

 [2] The benzene derivative according to [1], wherein ring A is a benzene ring which may be substituted, or a pharmaceutically acceptable salt thereof.

[3] R ¹ and R ² are joined together with a nitrogen atom, optionally substituted spiro (indane-1,4′-piperidine) monoyl group, optionally substituted 1,2-dihydrospiro (3 H —Indole—3,4,1-piperidine) 1-yl group, optionally substituted 4-1-phenylbiperazine-11-yl group, optionally substituted 4-phenylphenylperidine—1-yl group, Optionally substituted 3-phenylpropyl group, optionally substituted 1-naphthylmethyl group, optionally substituted 2-naphthylmethyl group, optionally substituted 2- (2,3-dihydro- The benzene derivative according to [1] or [2], which is a 2-indolyl) ethyl group or an optionally substituted 2- (1,2,3,4-tetrahydro-2-quinolyl) ethyl group, or a pharmaceutically acceptable salt thereof; Salt.

 [4]-The benzene derivative according to any one of [1] to (: 3), wherein Y is a single bond, or a pharmaceutically acceptable salt thereof.

[5] The benzene derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R ³ is methylene or ethylene.

[6] The benzene derivative according to any one of [1] to [5], wherein R ⁴ is a single bond, or a pharmaceutically acceptable salt thereof.

 [7] Formula:

[Wherein, X, R ⁵ and R ⁶ are as defined above.

W is an optionally substituted indanilidene group, an optionally substituted phenylimino Represents a phenylmethylene group or an optionally substituted phenylmethylene group. n represents 1 or 2. ] The benzene derivative according to [1] or a pharmaceutically acceptable salt thereof.

 [8] The benzene derivative according to any one of [1] to [7], wherein X is —CO—, or a pharmaceutically acceptable salt thereof.

[9] The benzene derivative according to any one of [1] to [8], wherein R ⁶ is an optionally substituted saturated nitrogen-containing heterocyclic group or an optionally substituted aminoalkyl group, or a pharmaceutically acceptable salt thereof. .

[10] The benzene derivative according to any one of [1] to [9], wherein R ⁶ is 3-piperidyl which may be substituted or 2_amino 2_propyl which may be substituted, or a pharmaceutically acceptable salt thereof. Salt.

 [11] A medicament comprising the benzene derivative according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof.

 [12] The medicament according to [11], which is a growth hormone release enhancer.

 [13] A method for enhancing the release of growth hormone comprising the benzene derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [10].

 [14] Use of the benzene derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [10] for producing a growth hormone release enhancer. Examples of the aryl group include an aryl group having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, and 2-naphthyl.

Examples of the heterocyclic group include a monocyclic or bicyclic 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms, and sulfur or a sulfur atom. Can be Specific examples of such a saturated heterocyclic group include piperidyl, piperazinyl, morpholyl, piperidyl, pyrazolidyl, tetrahydrofuryl and the like. Specific examples of such unsaturated heterocyclic groups include pyridyl, virazyl, indolyl, isoindolyl, isothiazolyl, isobenzofuranyl, chromenyl, pyrrolyl, furyl, phenyl, quinolyl, isoquinolyl, thiazolyl, imidazolyl, pyrimidinyl, and thiaziridyl. Azozolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl, isothiazolyl, triazolyl, imidazolone-1-yl, oxazadiazolyl, benzimidazoyl-2-yl, triazolinone-yl — 5-yl and the like.

 The saturated nitrogen-containing heterocyclic group includes, for example, one nitrogen atom, and may further contain one or two nitrogen atoms, oxygen atoms and / or sulfur atoms. And a 7-membered saturated heterocyclic group. Preferably, a monocyclic or bicyclic saturated heterocyclic group containing 1 to 3 nitrogen atoms is exemplified. More preferred saturated nitrogen-containing heterocyclic groups include a 5- to 7-membered monocyclic saturated heterocyclic group containing one nitrogen atom, more preferably piperidyl, and particularly preferably 3- And piperidyl.

The benzoheterocyclic group refers to a heterocyclic group in which a benzene ring is condensed, and includes, for example, a monocyclic heterocyclic group in which a benzene ring is condensed. Specifically, for example, a monocyclic 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 3 nitrogen, oxygen, Z or sulfur atoms condensed with a benzene ring may be mentioned. Can be Preferred benzo heterocyclic groups include one or two nitrogen atoms in which a benzene ring such as 2,3-dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxanyl, and tetrahydrophthalazyl is fused. 5-7 membered monocyclic saturated heterocyclic group containing 1 to 5 nitrogen atoms containing 1 or 2 nitrogen atoms fused with a benzene ring such as indolyl, isoindolyl, quinolyl, isoquinolyl, etc. And unsaturated heterocyclic groups. Substituted benzene, substituted naphthalene, substituted saturated nitrogen-containing heterocyclic group, substituted phenyl, substituted naphthyl, substituted tetrahydronaphthyl, substituted indenyl, substituted indanyl and substituted benzoheterocyclic group, and the substituent represented by R ⁸ Examples thereof include the following substituents, which may be substituted with any one or more of these substituents.

 Substituent:

Hydroxyl group, halogen atom, cyano group, nitro group, amino group, alkyl group, alkenyl group, Alkynyl group, cycloalkyl group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, aryl group, aryloxy group, heterocyclic group, complex ring oxy group, alkamoyl group, sulfamoyl group, alkanoyl group , Alkanoyloxy group, alkanoylamino group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylamino group, alkylsulfonyl group, alkylsulfinyl group, alkylthio group, perido group, etc.

 In addition, these substituents may be substituted by other substituents described herein. Preferred examples of the substituent include a hydroxyl group, an amino group, an alkyl group, a heterocyclic group, a carbamoyl group, a carboxyl group, an alkylsulfonyl group, a hydroxyalkyl group, a dihydroxyalkyl group, a trihydroxyalkyl group, and a carbamoylalkyl group. Group, carboxyalkyl group, alkylsulfonylamino group and the like.

 Examples of more preferred substituents include a hydroxyl group, a 1 H-tetrazol-5-yl group, a carboxyl group, a hydroxyethyl group, a hydroxypropyl group, a dihydroxypropyl group, a methylsulfonylamino group and the like. Can be

Preferred examples of the substituent in substituted benzene and substituted naphthalene include, for example, chlorine atom, bromine atom, methylenedioxy, methoxy, ethoxy, benzyloxy, phenyl and the like. In Formula 1, examples of the substitution position of Y and R ^{4 in} the optionally substituted benzene represented by ring A include 1, 2, 1, 3, and 1, 4, and preferably 1, 2, and 1, 3, and particularly preferably 1. Examples of the substitution position of Y and R ^{4 in} the optionally substituted naphthalene represented by ring A include 1, 2, 2, 3, 1, 3, 1, 4, and the like, and preferably 2, 3 and the like. Can be Examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, and 1,1-dimethylethyl. , Pentyl, 3-methylbutyl, hexyl, 4-methylpentyl and the like. Examples of the lower alkyl group include a linear or branched alkyl group having 1 to 3 carbon atoms.

 Examples of the alkenyl group include a linear or branched alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include vinyl, aryl, crotyl, methacryl, butadienyl, 2-pentenyl, and 3-hexenyl. .

 Examples of the alkynyl group include a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl and 1-propynyl.

 In the alkyl group which may be substituted with a hydroxyl group, the alkenyl group which may be substituted with a hydroxyl group, and the alkynyl group which may be substituted with a hydroxyl group, one or more hydroxyl groups may be replaced. Examples of the alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, pentoxy, 3-methylbutoxy, hexoxy, 4-methylpentoxy and the like.

 Examples of the alkanoyl group include a linear or branched alkanol group having 1 to 6 carbon atoms, and specific examples include formyl, acetyl, propanol, butanol, pentanol, hexanoyl, and the like. Examples of the lower alkanoyl group include a straight or branched alkanoyl group having 1 to 3 carbon atoms.

Examples of the cycloalkyl group include a cycloalkyl group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of the alkylene having 1 to 4 carbon atoms include linear or branched alkylene having 1 to 4 carbon atoms, and specific examples thereof include methylene, ethylene, ethylidene, propylene, trimethylene, tetramethylene, and 2-methyltrimethylene. And the like. Examples of the alkylene having 1 to 3 carbon atoms include linear or branched alkylene having 1 to 3 carbon atoms. Is mentioned. Examples of the alkylene having 1 to 2 carbon atoms include linear or branched alkylene having 1 to 2 carbon atoms.

 Examples of C 2-4 alkenylene include straight-chain or branched-chain alkenylene having 2 to 4 carbon atoms, and specific examples thereof include vinylene, vinylidene, propenylene, butenylene and the like. No.

 Examples of the alkynylene having 2 to 4 carbon atoms include straight-chain or branched alkynylene having 2 to 4 carbon atoms, and specific examples include ethinylene, propynylene, and petinylene.

 Examples of the cycloalkanediyl include cycloalkanediyl having 3 to 7 carbon atoms, and specifically, 1,2-cyclopropanedyl, 1,3-cyclobutanedyl, 1,3-cyclopentanedyl, 1, 3-cyclohexanediyl, 1,4-cyclohexanediyl, 1,4-cycloheptandiyl and the like.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Substituted amino group, substituted aminoalkyl group, alkylene group having 1 to 4 carbon atoms, alkenylene having 2 to 4 carbon atoms, alkynylene having 2 to 4 carbon atoms, substituted ethylene, substituted vinylene, substituted spiro (indan 1, 4'-piperidine) — 1 ^ Tyl group, substituted 2-dihydrospiro (3H-indole-3,4'-piperidine) -1'-yl group, substituted 4-phenylbiperazine-1 4-substituted 4-phenylbiperidine-1-yl-substituted 3-phenylpropyl-substituted 1-naphthylmethyl-substituted 2-naphthylmethyl-substituted 2- (2,3-dihydro-2--substituted) Indolyl) ethyl, substituted 2- (1,2,3,4-tetrahydro-2-quinolyl) ethyl, substituted 1-indanilidene, substituted phenylimino, and substituted phenylmethylene The same group as substituent in the substituted benzene. The substituted aminoalkyl group also includes, for example, a residue obtained by removing a carboxyl group from amino acid. When the benzene derivative of the present invention has one or more asymmetric centers, the present invention provides a method for separating the same as a pure optical isomer, a partially purified optical isomer, a racemic mixture, or a diastereomer. Any of the mixtures thereof includes all such optical isomers.

 Pharmaceutically acceptable salts of the benzene derivatives include, for example, salts with inorganic or organic acids. Examples of the inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid, and examples of the organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, citric acid, malonic acid, and methanesulfonic acid. . When an acidic functional group such as a carboxyl group is present in the benzene derivative of the present invention, a salt with a base can be used. Examples of the salt with a base include a salt with a basic amino acid such as arginine and lysine, an alkali metal salt such as a sodium salt and a potassium salt, and an alkaline earth metal such as a calcium salt and a magnesium salt. The present invention also includes solvates such as hydrates of benzene derivatives or pharmaceutically acceptable salts thereof. The benzene derivative of the present invention can be produced, for example, as follows.

[Wherein, X, Y, RR ² , R ³ , R ⁴ , R ⁵ , R ⁶ and A are as defined above. The compound of formula 4 can be obtained by reacting the compound of formula 3 with the amine of formula 2. Examples of the method for reacting the compound of Formula 3 with the amine of Formula 2 include a conventional peptide bond formation method (for example, “Peptide Synthesis” Maruzen Co., Ltd. 1975; “Basic and Experimental Peptide Synthesis” Maruzen Co., Ltd.) 1985). In the case where X is —SO ₂ — in Formula 3, it is preferable to induce the compound to react with sulfonyl chloride or the like. For example, a sulfonyl chloride or the like and an amine of the formula 2 can be reacted in an inert solvent such as acetonitrile in the presence of an aprotic organic base such as triethylamine. The amine of formula 2 can be produced, for example, in the same manner as described in British Patent 2,297,972.

By reducing the compound of Formula 4, the compound of Formula 5 can be produced. Examples of the reduction method include a hydrogenation reaction (for example, a hydrogenation reaction using a palladium catalyst in a solvent such as methanol) and a hydride reduction reaction (for example, sodium borohydride and a chloride in a solvent such as ethanol). Hydride reduction reaction using tin). When X is —S 0 ₂ — in Formula 4, a hydride reduction reaction is preferable.

The benzene derivative of the present invention can be produced by reacting the compound of the formula 5 with the compound of the formula 6 according to a general peptide bond formation method and, if necessary, introducing a substituent as R ^5. it can. Examples of the method for introducing a substituent include a reductive amination reaction and the like. The compound of formula 6 is commercially available or can be prepared by a known method (Williams RM "Synthesis of Optically Active a-ammo Acids" Pergamon Press, Vol. 7, 1989).

In the present production method, the functional group can be protected if necessary. Examples of the protecting group include known groups, which can be protected and deprotected by a known method (Greene T., Wuts PGM "Protective Groups in organic synthesis" John Wiley & Sons Inc., 1991). Since the benzene derivative of the present invention can enhance endogenous growth hormone release, it has the same effects and uses as growth hormone. Uses for growth hormone For example, the following may be mentioned.

Increased growth hormone release in the elderly Z Treatment of adults with growth hormone deficiency / prevention of anabolic side effects of dalcocorticoid Z Treatment of osteoporosis Enhancement of the immune system Promotion of wound healing Promotion of fracture repair / treatment of growth delay Acute Or treatment of chronic renal dysfunction or renal failure Treatment of physiological short stature, especially in children with growth hormone deficiency / Treatment of short stature associated with chronic diseases Treatment of obesity and growth retardation associated with obesity / P rader—Treatment of growth retardation associated with Wi11i syndrome and Turner's syndrome Enhanced recovery and reduced hospital stay in burn patients Enhanced recovery and hospital stay after major surgery such as gastrointestinal surgery Treatment of reduced / intrauterine growth, skeletal dysplasia, cortisone hyperplasia and C ushings syndrome Growth hormone substitution in patients with stress Osteochondrodysplasia, Noon an s syndrome, sleep disorders Treatment of Alzheimer's disease and delayed wound healing Treatment of pulmonary insufficiency and ventilator-dependent conditions Treatment of impaired protein anabolic response after major surgery and treatment of malabsorption syndrome Chronic such as Z cancer or AIDS Reduced weight loss and protein loss / increased weight gain and increased protein gain in patients receiving total parenteral nutrition (TPN) Treatment of insulin hypersecretion, including puberty islet cellosis Ovulation Adjuvant treatment for induction Adjuvant treatment for prevention and treatment of gastric and duodenal ulcers Increased thyroid development Prevention of age-related hypothyroidism / For patients undergoing chronic blood analysis Treatment of patients with immunosuppression Treatment for enhancing antibody response after vaccination Improving muscle strength and mobility in frail elderly people Skin thickness, metabolic homeostasis in frail elderly people Osteoblasts, bone regeneration, and cartilage growth in frail elderly people Peripheral and drug-induced neuropathy, Gu illi an-Barre syndrome, muscular atrophic side Treatment of chorionic sclerosis, multiple sclerosis, cerebrovascular disorders, and demyelinating diseases / enhancement of the immune system in pets Treatment of age-related diseases in pets / promotion of growth in livestock Enhancement of wool growth The benzene derivative of the present invention can be applied not only to humans but also to various mammals such as mice, rats, dogs, horses, horses, goats, sheep, horses, and pigs. The benzene derivative or the like of the present invention can be administered by a usual administration route, for example, oral, intramuscular, intravenous, subcutaneous, intraperitoneal, intranasal or intracerebral administration.

 The dose and frequency of administration vary depending on the animal species, administration route, severity of the symptoms, body weight, etc., and are not particularly limited.In humans, however, usually about 1 μg to 1 g per adult day, preferably about l ~ 500 mg is administered once or more times a day.

 Examples of the dosage form include powders, fine granules, granules, tablets, capsules, suppositories, injections, nasal preparations and the like. At the time of formulation, it can be manufactured by a usual method using a usual formulation carrier. When preparing oral preparations, excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, etc. are added to the active ingredient, and then tablets, granules, dispersion II are prepared in the usual manner , Capsules and the like. When preparing an injection, a pH adjuster, a buffer, a stabilizing agent, a solubilizing agent, and the like can be added as necessary, and the injection can be prepared by a conventional method. Example

 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

 In the present specification, amino acids, protecting groups, active groups, solvents and the like may be represented by abbreviations based on IUPAC-IUB and commonly used abbreviations in the art.

For example, B oc means t-butyroxycarbonyl.

The HPLC conditions used in the following examples are as follows.

 Column YMC-ODS A-211 (JMSC Inc.)

 Solution A water / 0.1% trifluoroacetic acid

 Solution B acetonitrile 1 0.1% trifluoroacetic acid

 B%: 10% → 35min → 80%

 Detection wavelength: 254 nm

Flow rate: 1. Oml / mm Example 1

Piperidine—3-Rubonic acid (2- (2-oxo-1-2-spiro (indane-1,4-piperidine) —1-yl-ethyl) -phenyl) —amide hydrochloride (1 1)

 20.14 g of commercially available dipecotinic acid (12) is suspended in Dioxane-¾0 = 2: 1 (180 ml), and 172 ml of IN aqueous sodium hydroxide solution and 37.43 g of di-tert-butyl dicarbonate are added under ice-cooling and overnight. Stirred. The reaction solution was washed twice with getyl ether, acidified by adding citric acid, and then extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the obtained residue, and the precipitated crystals were collected by filtration and washed with hexane to obtain 34.91 g (98%) of intermediate (13).

-丽_{R (CDC1 3, 270MHz) δ} 1.45 (9H, s), 1.74-1.58 (2H, m), 2.06 (lH, m), 2.48 (lH, ra), 2.85 (lH, t, J = 10.9Hz ), 3 · 04 (1H, brs), 3.88 (1H, d, J = 13.5Hz), 4. ll (lH, brs), 7.5 (lH, brs) Chambers MS et al., J. Med. Chem., 35, 2033 (1992) Compound (14) 0.07 g was dissolved in 20 ml of acetonitrile, and 0.236 g of methanesulfonic acid was added under ice cooling. After stirring for 1 hour, the reaction solution was neutralized by adding 0.248 g of triethylamine. 0.052 g of 1-hydroxybenzotriazole (HOBt), 0.049 g of 2-nitrophenylacetic acid, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimid hydrochloride (EDC HC1) 0.052 _g was added and stirred overnight. After the solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with saturated saline, 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified on a silica gel column (25 g, Hexane: ethyl acetate = 1: 1) to yield 80.6 mg of the intermediate (15)

(95%).

 -NMlUCDCls, 270MHz) δ 1.41 (2H, m), 2.06 (1H, td, J = 13.2, 4.3Hz), 2.18 (lH, td, J = 12.8, 4.3Hz), 3.06 (1H, td, J = 12.8 , 2.6Hz), 3.52 (1H, td, J = 14.5, 2.3Hz), 4.07 (lH, d, J = 16.2Hz), 4.15-4.05 (lH, m), 4.23 (1H, d, J = 15.8Hz) ), 4.65 (lH, d, J = 13.5Hz), 6.82 (lH, d, J = 5.9Hz), 6.89 (1H, d, J-5.6Hz), 7.29-7.20 (2H, m), 7.39-7.31 (3H, m), 7.46 (lH, m), 7.60 (lH, m), 8.12 (lH, d, J = 7.9Hz)

80.6 mg of the intermediate (15) was dissolved in 20 ml of ethanol, 50 mg of 10% Pd-C was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The catalyst was filtered off through a membrane filter, and the residue was washed with ethanol. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in 30 ml of dimethylformamide, and 31 mg of HOB t, 58 mg of the intermediate (13), 149 mg of EDC / HC, and 31 mg of 4- (dimethylamino) pyridine were added overnight. Stirred. Ethyl acetate was added, and the mixture was washed successively with saturated saline, 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified on a silica gel column (20 g, Hexane: ethyl acetate = 3: 1 → 1: 1), followed by preparative TLC (20 X 20 cm, 1 mm, CHC1 _3: methanol = 20: 1) to give the intermediate (1 6) 32.3mg (26% ).

-Gut (CDCl ₃ , 270MHz) δ 1.25 (3H, m), 1.47 (9H, s), 1.86-1.56 (4H, m), 2.08 (2H, t, J = 7.2Hz), 2.15 (lH, m) , 2.55 (lH, m), 3.09-2.79 (4H, m), 3.37 (1H, t, J = 12.2Hz), 3.77 (2H, s), 4.23-4.07 (2H, m), 4.34 (1H, d , J = 13.5Hz), 4.58 (1H, d, J = 13.2Hz), 7.09-7.03 (2H, m), 7.31-7.15 (5H, m), 8.06 (1H, d, J = 6.2Hz), 10.32 (1H, brs) Intermediate (16) 32.3 _mg of 4N HCl in dioxane 5 ml Was added and the mixture was stirred for 1.5 hours under ice cooling. To the mixture was added Jethyl ether, and the mixture was further stirred for 1 hour. The precipitated white precipitate was collected by filtration, the residue was washed with Jethyl ether, and dried under reduced pressure to obtain 22.1 mg of compound (11). 77%).

_{- NMR (DMS0-d 6,} 300MHz) δ 1.89-1.37 (7H, m), 2.15-1.99 (3H, m), 3.16-2.71 (9H, m), 3.83-3.67 (2H, m), 3.93 (1H , brd, J = 12.6Hz), 4.40 (1H, brd, J = 13.3Hz), 7.30-7.08 (7H, m), 7.50 (lH, m), 8.72 (1H, brs), 10.03 (1H, d, J = 9.5Hz)

 HPLC retention time: 28.9 1 min Example 2

Piperidine-3-carboxylic acid (3- (2-oxo-2-spiro (indane-14-piperidine)-1-yl-ethyl) -phenyl) monoamide hydrochloride (17)

 In the same manner as in Example 1, 100.2 mg of compound (17) was obtained using 3-nitrophenylphenylacetic acid instead of 2-nitrophenylacetic acid.

 ^ -NMR DMSO-de, 300ΜΗζ) δ 1.90-1.33 (7H, m), 2.02-1.98 (3H, m), 3.20-2.72 (9H, m), 3.80-3.65 (2H, m), 3.85 (lH, m), 4.45 (lH, m), 6.96 (1H, d, J = 7.7Hz), 7.26-7.09 (5H, m), 7.57-7.43 (2H, m), 8.75 (1H, brs), 10.25 (1H , Brs)

 HPLC retention time: 2 8.0 7 minutes Example 3

Piperidine-1-3-carboxylic acid (4- (2-oxo _2-spiro (indane-1,4_ (Piperidine)-1-yluetyl)-phenyl) monoamide hydrochloride (18)

 83.1 mg of compound (18) was obtained in the same manner as described in Example 1, except that 4-nitrophenylacetic acid was used instead of 2-nitrophenylacetic acid.

 'H-NMRCDMSO-dg, 300MHz) δ 1.89-1.34 (7H, m), 2.03-1.97 (3H, m), 3.26-2.68 (9H, m), 3.73-3.60 (2H, m), 3.90 (1H, brd, J = 13.9Hz), 4.39 (1H, brd, J = 13.6Hz), 7.19-7.06 (6H, m), 7.54 (2H, d, J = 8.4Hz), 9.20-8.80 (2H, m), 10.26 (lH, s)

 HPLC retention time: 2 7.99 minutes Example 4

Piperidine-3-carboxylic acid (2 (3-oxo_3-spiro (indane-1,4 piperidine) _1-loop pill) monophenyl) -amide hydrochloride (19)

 52.6 mg of compound (19) was obtained in the same manner as described in Example 1, except that 2-nitrocinnamic acid was used instead of 2-nitrophenylacetic acid.

] _{H-NMR (DMS0 - d 6} , 300MHz) 81.89 - 1.40 (7H, m), 2.10 - 1.98 (3H, m), 3.25-2.55 (13H, m):

3.80 (lH, brd, J = 13.4Hz), 4.41 (1H, brd, J = 13.OHz), 7.19- 7.07 (6H, m), 7.27 (1H, dd, J = 6.9,1.8Hz), 7.36 ( lH, m), 9.15- 8.75 (2H, m), 9.95 (lH, s) HPLC retention time: 29.98 minutes Example 5

Piperidine—3-Rubonic acid (3- (3-oxo-1-spiro (indane-1,4-piperidine) -11-yl-propyl) -phenyl) -amide hydrochloride (20)

59.6 mg of compound (20) was obtained in the same manner as in Example 1, except that 3-nitrobutanoic acid was used instead of 2-nitrophenylacetic acid.

- thigh _{(DMS0- d 6, 300MHz) δ} 1.89 - 1.35 (7H, m), 2.03- 1.98 (3H, m), 3.25-2.56 (13H, m),

3.80 (lH, brd, J = 13.0Hz), 4.40 (lH, brd, J = 12.8Hz), 6.96 (1H, d, J = 7.7Hz), 7.23-

7.09 (5H, m), 7.45 (2H, m), 9.10-8.70 (2H, m), 10.22 (lH, s)

 HPLC retention time: 28.80 minutes Example 6

Piperidine—3-Rubonic acid (4- (3-oxo-3—spiro (indane and 4-piperidine) —1-loop pill) —phenyl) —amide hydrochloride (2 1)

In the same manner as described in Example 1, 4-nitrophenylacetic acid 60.5 mg of the compound (21) was obtained using cinnamate.

 "H-NMRCDMSO-dg, 300MHz) δ 1.89-1.36 (7H, ra), 2.03-1.98 (3H, m), 3.25-2.55 (13H, m), 3.81 (lH, brd, J = 12.4Hz), 4.39 (1H, brd, J = 13.1Hz), 7.19-7.08 (6H, m), 7.50 (2H, d, J = 8.4Hz), 9.15-8.70 (2H, m), 10.19 (lH, s)

 HPLC retention time: 28. 18 minutes Example 7

Piperidine-1-3-rhubonic acid (2- (spiro (indane-1,4-piperidine) _-sulfonylmethyl) -phenyl) -amide hydrochloride (22)

In a manner similar to that described in Example 1, 2-nitrophenylacetic acid, HOBt, and EDC · HC1 were replaced with 2-nitro-ci-toluenesulfonyl chloride to give 20.4 mg of the compound (22). Obtained.

'H-NMR (DMS0-d 6, 300ΜΗζ) δ 2.10- 1.45 (10H, m), 3.17- 2.82 (9H, m), 3.69-3.48 (3H, m), 4.63- 4.59 (lH, m), 7.26 -7.12 (5H, m), 7.36 (1H, t, J = 7.5Hz), 7.51-7.45 (2H, m), 8.65 (lH, brs), 9.77 (lH, s)

 HPLC retention time: 30. 75 minutes Example 8

Piperidine-1-carboxylic acid (2- (spiro (indan-1,4-piperidine) _1-carbonyl) -phenyl) -amide hydrochloride (23)

 In the same manner as in the method described in Example 1, 49.9 mg of compound (23) was obtained by using 2-2 dibenzobenzoic acid instead of 2-ditrophenylacetic acid.

- Awakening: _{R (DMS0-d 6, 300MHz} ) δ 1.34 (1H, brd, J = 12.3Hz), 1.89-1.52 (6H, m), 2.03 (3H, m),

3.60-2.84 (10H, m), 4.48 (1H, brd, J = ll.5Hz), 7.27-7.10 (5H, m), 7.42-7.35 (3H, m), 8.60 (lH, m), 9.88 (1H , d, J = 12.6Hz)

 HPLC retention time: 27.99 minutes Example 9

Piperine ^-3-carboxylic acid (3- (spiro (indane-1,4-piperidine) -1 carbonyl) -phenyl) -amide hydrochloride (24)

 In the same manner as described in Example 1, 88.Img of the compound (24) was obtained by using 3-nitrobenzoic acid instead of 2-nitrophenylacetic acid.

 'H-NMRCDMSO-dg, 300ΜΗζ) δ 1.89-1.30 (7H, m), 2.06 (3H, m), 3.35-2.84 (9H, m), 3.63-3.50 (lH, m), 4.46 (lH, m) , 7.25-7.10 (5H, m), 7.37 (1H, t, J = 7.7Hz), 7.62 (lH, m), 7.74 (lH, m), 9.20-8.75 (2H, m), 10.47 (lH, s )

HPLC retention time: 28. 14 minutes Example 10

Piperidine-1-3-carboxylic acid (2- (4-oxo_4-spiro (indane-1,4_piperidine) _1_yl-butyl) -phenyl) -amide 'trifluoroacetate (25)

10.446 g of the compound (14) described in Example 1 was dissolved in 250 ml of 4N dioxane hydrochloride and stirred at 0 ° C. for 2 hours. After concentration under reduced pressure, 1000 ml of getyl ether was added, and the mixture was stirred for 30 minutes, filtered, washed with ether and dried to obtain 7.999 g (98%) of intermediate (26).

 ^ -NM! DMSO-ds, 300MHz) δ 1.28 (2H, d, J = 14.3Hz), 2.35 (2H, td, J = 13.5, 3.8Hz), 3.21 (2H, td, J = 12.8, 2.8Hz) , 3.40 (2H, ra), 6.84 (1H, d, J = 5.7Hz), 7.13 (lH, d,

J = 5.7Hz), 7.40-7.19 (4H, m), 9.29 (2H, brs)

 1.46 g of commercially available tetralone (27), 15 g of trichloroacetic acid, and l.Og of sodium azide were mixed and stirred at 60 ° C for 8 hours. After cooling, 75 ml of water was added, and the precipitated crystals were collected by filtration, washed with water and hexane, and dried to obtain 0.878 g (55%) of intermediate (28).

'H-NM (DMS0-d 6, 300MHz) δ 2.17-2.02 (4H, m), 2.66 (2H, t, J = 6.8Hz), 6.94 (lH, d, J = 7.9Hz), 7.06 (lH, td, J = 7.3, 1.1 1), 7.24-7.17 (2H, m), 9.50 (lH, s)

0.854 _g of the intermediate (28) was dissolved in 10 ml of acetic acid and 10 ml of concentrated hydrochloric acid, and the mixture was refluxed for 11 hours. After allowing to cool, the mixture was concentrated under reduced pressure, and the obtained residue was dissolved by adding 30 ml of water, 30 ml of dioxane, and 0.636 g of sodium hydroxide, and 1.156 g of di-tert-butyldicarbonate was added, followed by stirring overnight. The reaction solution was acidified by adding citric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Again, the residue was dissolved in ethyl acetate, and 0.496 ml of cyclohexylamine was added dropwise, and the precipitated crystals were collected by filtration. Further, the crystals were dissolved using ethyl acetate and an aqueous solution of 10 citric acid, the layers were separated, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.835 g (56%) of intermediate (29).

0.835 g of the intermediate (29) was dissolved in 30 ml of dimethylformamide, 0.669 g of the intermediate (26), 0.404 g of HOBt, 0.573 g of EDC-HC1 and 0.42 ml of triethylamine were added, and the mixture was stirred overnight. Ethyl acetate was added, and the mixture was washed successively with a saturated saline solution, an aqueous solution of 10 citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (50 g, Hexane: ethyl acetate = 2: 1) to give 0.720 g (54%) of the intermediate (30). ).

δ 1.45-1.33 (2H, m), 1.54 (9H, s), 2.08-1.83 (4H, m), 2.46- 2.42 (2H, m), 2.66-2.60 (2H, m), 3.03 (1H, td, J = 13.2, 2.6Hz), 3.36 (lH, td, J = 13.2, 2.6Hz), 3.93 (lH, d, J = 14.1Hz), 4.75 (1H, d, J = 13.6Hz), 6.81 (lH, d, J = 5.7Hz), 6.86 (lH, d, J = 5.7Hz), 6.97 (1H, td, J = 7.3, 0.9Hz), 7.35-7.10 (6H, m), 8.01 (lH, brd, J = 8.1Hz), 8.36 (lH, brs)

 0.720 g of the intermediate (30) was dissolved in 50 ml of methanol, 0.40 g of 10% Pd-C was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. After filtering off the catalyst, the solvent was concentrated under reduced pressure to give the intermediate (31).

0.647 g (89%) was obtained.

^] H-NMR (CDCl3, 300 MHz) δ 1.54 (9H, s), 1.60-1.49 (2H, m), 1.85-1.65 (4H, m), 2.08 (2H, t, J = 6.9Hz), 2.40 (2H , m), 2.61 (2H, m), 2.82 (1H, brt, J = 12.5Hz), 2.94 (2H, t, J = 7.3Hz), 3.20 (lH, brt, J = 12.8Hz), 3.79 (lH , brd, J = 12.3Hz), 4.69 (lH, brd,

J = 13.0Hz), 6.95 (lH, t, J = 7.3Hz), 7.23- 7.09 (6H, m), 8.00 (1H, brd, J = 8.0Hz), 8.41 (lH, brs)

 0.647 g of the intermediate (31) was dissolved in 40 ml of 4N dioxane hydrochloride, and the mixture was stirred under ice cooling for 3 hours. The residue obtained after concentration under reduced pressure was dissolved in 50 ml of dimethylformamide, and 0.481 g of the intermediate (13) described in Example 1, 0.284 g of HOBt, 0.604 g of EDC-HC1, 0.256 g of dimethylaminopyridine, 0.44 ml of triethylamine was added and stirred overnight. Ethyl acetate was added, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue obtained was purified on a silica gel column (30 g, Hexane: ethyl acetate = 2: 1) to obtain 0.592 g (73%) of the intermediate (32) I got

_{- NMR (CDC1 3, 300MHz)} δ 1.44 (9H, s), 1.90- 1.40 (10H, m), 2.20-2.04 (3H, m), 2.46 (2H, ra), 2.60 (2H, m), 2.84 ( 1H, t, J = 13.0Hz), 2.96 (2H, t, J = 7.1Hz), 3.15-2.55 (2H, m), 3.26 (lH, t, J = 13.1Hz), 3.85 (1H, brd, J = 14.3Hz), 4.40-3.95 (2H, m), 4.63 (lH, brd, J = 11.7Hz), 7.01 (1H, t, J = 7.3Hz), 7.26-7.ll (6H, m), 8.25 (lH, m), 9.72 (lH, m)

0.190 g of the intermediate (32) was dissolved in 30 ml of 4N hydrochloric acid-dioxane and stirred at room temperature for 1.5 hours. The residue obtained after concentration under reduced pressure was dissolved in water and purified by HPLC (using a ₃ cm0 column, water-CH ₃ CN-TFA system) to obtain 0.129 g (77%) of compound (25). ^{] H-NMR (DMS0-d} 6, 300MHz) δ 1.95-1.40 (9H, m), 2.08-2.03 (3H, m), 2.41 (2H, m), 2.55 (2H, m), 2.77 (lH, t , J = 13.0Hz), 2.87 (3H, m), 3.04 (2H, m), 3.19 (2H, m), 3.34 (1H, brd, J = 10.8Hz), 3.83 (1H, brd, J = 13.4Hz) ), 4.48 (lH, brd, J = ll.9Hz), 7.23-7.07 (7H, m), 7.60 (lH, d, J = 7.9Hz), 8.61 (2H, brs), 9.82 (1H, d, J = 5.3Hz)

 HPLC retention time: 3 1.98 minutes

Example 1 1

Piperidine-3-carboxylic acid 2- (2-oxo-2-spiro (indane-1,4-piberidine) -1-yl-ethyl) benzylamide hydrochloride (33)

oc

 I.568 g of the compound (14) described in Example 1 was dissolved in 100 ml of ethanol, 0.412 g of 10% Pd-C was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After the catalyst was filtered off and washed with ethanol, the solvent was concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of 4N hydrochloric acid // dioxane and stirred at 0 ° C. for 2.5 hours. After concentrating under reduced pressure, getyl ether was added to the obtained residue, and the precipitated crystals were filtered and washed with getyl ether. Drying under reduced pressure gave 1.269 g (quantitative) of the intermediate (34).

, 2.08-1.97 (4H, m), 2.86 (2H, t, J = 7.3Hz), 2.99 (2H, td, J = 13.0, 2.4Hz), 3.25 (2H, m), 7.23- 7.10 (4H, m ), 9.07 (2H, brs)

5.00 g of commercially available 1,3-phenylenediacetic acid (35) was dissolved in 50 ml of methanol, and 4.94 g of EDC-HCl and 0.63 g of dimethylaminopyridine were added, followed by stirring overnight. Ethyl acetate and 1N hydrochloric acid were added to the reaction solution, and the mixture was separated. The organic layer was washed successively with IN hydrochloric acid and saturated saline. After drying over anhydrous magnesium sulfate, and concentrated under reduced pressure, the resulting residue was obtained intermediate was purified on a silica gel column (100 g, CHC1 ₃₎ a (36) 2.204g (41%) .

 'H-NMR (CDCl, 300MHz) 53.62 (2H, s), 3.63 (2H, s), 3.68 (3H, s), 7.23-7.17 (3H, m), 7.32-7.25 (lH, m)

1.126 g of the intermediate (36) was dissolved in 50 ml of benzene, 0.657 g of triethylamine and 1.786 g of diphenylphosphoryl azide were added, and the mixture was heated under reflux for 3 hours. After cooling, 30 ml of tert-butanol was added, and the mixture was heated and refluxed for another 24 hours. After the solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified on a silica gel column (50 g, Hexane: ethyl acetate = 2: 1) to give 0.540 g (36%) of the intermediate (37). Obtained.

_{¾ - NMR (CDC1 3, 300MHz} ) δ 1.46 (9H, s), 3.62 (2H, s), 3.69 (3H, s), 4.30 (2H, d,

J = 5.9Hz), 4.86 (lH, brs), 7.22-7.15 (3H, m), 7.33-7.26 (lH, m)

 0.520 g of the intermediate (37) was dissolved in 30 ml of methanol, and 2.31 ml of 4N NaOH was added thereto, followed by stirring overnight. After the reaction solution was acidified by adding citric acid, ethyl acetate and water were added to separate the solution, and the organic layer was washed successively with a 10% aqueous solution of citric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.493 g (quantitative) of the intermediate (38).

 'H-NMRCCDCla.SOOMHz) δ 1.45 (9H, s), 3.62 (2H, s), 4.31-4.20 (2H, m), 4.88 (1H, brs), 7.32-7.18 (4H, m)

0.172 g of the intermediate (38) was dissolved in 50 ml of dimethylformamide, and 0.145 g of the intermediate (34), 0.087 g of HOBt, 0.124 g of EDC-HC1, and 0.065 g of triethylamine were added, followed by stirring overnight. Ethyl acetate was added, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (15 g, Hexane: ethyl acetate = 2: 1—1: 1) to yield 0.254 _{g of the} intermediate (39) (90%).

 ^ -NMRCCDCla ^ OOMHz) 8 1.45 (9H, s), 1.60-1.40 (3H, m), 1.76 (1H, dt, J-13.0, 4.8Hz), 2. ll-1.96 (2H, m), 2.80 ( 1H, td, J = 13.0, 2.9Hz), 2.91 (2H, t, J-7.4Hz), 3.17 (lH, m), 3.76 (2H, s), 3.85 (lH, m), 4.30 (2H, d , J = 5.9Hz), 4.64 (lH, m), 4.95 (lH, brs), 7.06-7.02 (lH, ra), 7.22-7.13 (6H, m), 7.32-7.27 (1H, m)

 0.254 g of the intermediate (39) was dissolved in 20 ml of 4N hydrochloric acid dioxane and stirred at 0 ° C. for 2 hours. After concentrating under reduced pressure, dimethyl ether was added to the obtained residue, and the precipitated crystals were filtered and washed with dimethyl ether. Drying under reduced pressure gave 0.170 g (78%) of intermediate (40).

0.081 g of the intermediate (40) was dissolved in 30 ml of dimethylformamide, and 0.065 g of the intermediate (13) described in Example 1, 0.039 g of HOBt, 0.055 g of EDC-HC1, and 0.040 ml of triethylamine were added, followed by stirring overnight. . Add ethyl acetate and add saturated saline, 10% aqueous citric acid, and saturated The extract was washed successively with aqueous sodium chloride solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (20 g, Hexane: ethyl acetate = 1: 3) to obtain 0.119 g (99%) of the intermediate (41). I got

_{H- NMR (CDC1 3, 300MHz)} 5 1.42 (9H, s), 1.95-1.40 (6H, m), 2.12-1.97 (2H, m), 2.31 (2H, brs), 2.80 (lH, td, J- 13.0, 2.9Hz), 2.91 (2H, t, J = 7.4Hz), 3.06- 2.75 (lH, m), 3.23-3.09 (2H, m), 3.74 (2H, s), 4.00-3.69 (3H, m ), 4.40 (2H, brs), 4.63 (lH, m), 6.62 (lH, brs), 7.07-7.03 (IH, m), 7.22-7.13 (6H, m), 7.31-7.26 (1H, m)

0.119 _g of the intermediate (41) was dissolved in 20 ml of 4N hydrochloric acid / dioxane, and the mixture was stirred at 0 ° C for 2 hours. The residue obtained after concentration under reduced pressure was dissolved in water and freeze-dried to obtain 0.098 g (93%) of compound (33).

300MHz) δ 1.80-1.35 (7H, m), 1.98-1.87 (lH, m), 2.00 (2H, t, J-7.3Hz), 2.98-2.68 (6H, m), 3.22-3.09 (3H, m) , 3.78- 3.66 (2H, m), 3.91 (lH, brd, J = 13.2Hz), 4.32-4.18 (2H, m), 4.40 (1H, brd, J = 12.8Hz), 7.19-7.08 (7H, m ), 7.26 (lH, t, J = 7.8Hz), 8.72 (1H, t, J = 5.6Hz), 9.08-8.92 (2H, m)

 HPLC retention time: 28. 28 minutes Example 1 2

Piperidine-3-carboxylic acid 2- (2-oxo-12-spiro (indane-1.4-piperidine) -1-Iluethyl) -benzylamide hydrochloride (42)

Example 11 In the same manner as described in 11, instead of 1,3-phenylenediacetic acid, 1 Using 2-phenylenediacetic acid, 0.053 g of compound (42) was obtained.

 ^ -NMRCDMSO-de ^ OOMHz) δ 1.74-1.42 (7H, m), 1.94- 1.89 (lH, m), 2.05 (2H, t, J = 6.8Hz), 2.95-2.73 (6H, m), 3.24- 3.10 (3H, m), 3.80 (2H, s), 3.91 (lH, brd, J = 12.6Hz), 4.31- 4.17 (2H, m), 4.41 (1H, brd, J = 12.5Hz), 7.24-7.09 (8H, m), 8.55 (lH, m), 8.95-8.82 (2H, m)

 HPLC retention time: 29.10 minutes Example 13

Piperidine-3-carboxylic acid 4- (2-oxo-2-spiro (indan-1,4 piperidine) -1-yl-ethyl) -benzylamide hydrochloride (43)

 In the same manner as in Example 11, using 1,4-phenylenediacetic acid instead of 1,3-phenylenediacetic acid, 0.095 g of compound (43) was obtained.

_{- NMR (DMS0-d 6,} 300MHz) δ 1.46-1.37 (2H, m), 1.62-1.52 (4H, m), 1.82-1.70 (lH, m), 1.95- 1.87 (lH, m), 2.01 (2H , t, J = 7.1Hz), 2.76-2.65 (2H, m), 2.86-2.81 (3H, m), 3.03-2.96 (1H, in), 3.24-3.09 (3H, m), 3.78-3.65 (2H , M), 3.96-3.91 (lH, m), 4.32-4.16 (2H, m), 4.39 (1H, brd, J = 13.6Hz), 7.22-7.06 (8H, m), 8.65-8.56 (3H, m )

HPLC retention time: 28. 22 minutes Example 14

Piperidine-3-carboxylic acid 2- (spiro (gondane-1,4-piperidine) di-sulfonylmethyl) -benzylamide hydrochloride (44)

I

 10.09 g of commercially available 2-cyanobenzyl bromide (45) and 6.48 g of sodium sulfite were dissolved in 50 ml of water and heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was recrystallized from water to obtain 3.906 g (35%) of intermediate (46).

- Awakening: _{(DMS0-d 6, 300MHz)} 53.92 (2H, s), 7.40 (lH, ra), 7 · 63-7.56 (2H, m), 7.72 (lH, d, J = 7.5Hz)

 0.653 g of the intermediate (46) and 0.873 g of phosphorus pentachloride were mixed under ice cooling, and the mixture was stirred as it was overnight. Water and chloroform were added to the reaction mixture, and the mixture was separated, and extracted twice with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.572 g (89%) of the intermediate (47).

 'H-NMRiCDC ^ .SOOMHz) δ 5. ll (2H, s), 7.67-7.60 (lH, m), 7.74-7.72 (2H, m), 7.82

(lH, dt, J = 7.5, 0.9Hz)

0.563 g of the intermediate (47) and 0.292 g of the intermediate (34) described in Example 11 were dissolved in 30 ml of dimethylformamide, and 0.54 ml of triethylamine was added in 5 portions under ice-cooling (2 hours). ). After stirring overnight, ethyl acetate was added to the reaction solution, and the mixture was washed successively with saturated saline, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and is dried under reduced pressure. The residue obtained by concentration was purified by a silica gel column (10 g, Hexane: ethyl acetate = 2: 1) & (10 g, toluene → toluene: ethyl acetate = 1: 1), and the intermediate (48) 0.128 g (27 %).

Negation _{R (CDC1 3, 300MHz) δ} 1.53 (2H, d, J = 13.9Hz), 1.88 (2H, td, J = 12.6, 4.0Hz), 2.01 (2H, t, J = 7.3Hz), 2.90 (2H , t, J = 7.3Hz), 2.99 (2H, td, J = 12.6, 2.4Hz), 3.67 (2H, d, J = 12.6Hz), 4.46 (2H, s), 7.26-7.ll (4H, m), 7.49 (1H, td, J = 7.5, 1.3Hz), 7.64

(1H, td, J = 8.0, 0.9Hz), 7.76- 7.71 (2H, m)

 0.021 g of the intermediate (48) was dissolved in 10 ml of methylene chloride, 0.137 g of tetrabutylammonium borohydride was added, and the mixture was heated under reflux for 29 hours. After allowing to cool, the mixture was concentrated under reduced pressure, 10 ml of 1N hydrochloric acid was added to the residue, and the mixture was further heated under reflux for 1 hour. After adding sodium hydroxide to the reaction solution to make it alkaline, the mixture was extracted three times with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

 The obtained residue was dissolved in dimethylformamide (20 ml), and 0.013 g of the intermediate (13) described in Example 1, 0.008 g of HOBt, and EDC'HCl 0.1 Olg were added, followed by stirring overnight. 4- (3-Aminopropyl) morpholine was added to the reaction solution, and the mixture was further stirred for 1 hour. Ethyl acetate was added, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative silica gel TLC (1 thigh, 20 × 20 cm, Hexane: ethyl acetate = 1: 1) and purified as an intermediate. (49) 0.022 g (66%) was obtained.

 ^ -NMRCCDC ^ .SOOMHz) 81.42 (9H, s), 2.06-1.45 (10H, m), 2..26 (1H, m), 3.08-2.75 (6H, m), 3.77 (2H, d, J = 12.5Hz), 3.95-3.65 (1H, m), 4.03 (lH, d, J = 11.4Hz), 4.36

(2H, s), 4.54 (2H, d, J = 5.5Hz), 6.77 (lH, brs), 7.24-7.13 (4H, m), 7.42-7.30 (4H, m)

 0.022 g of the intermediate (49) was dissolved in 10 ml of 4N nodioxane hydrochloride and stirred at 0 ° C for 2 hours. <The residue obtained after concentration under reduced pressure was dissolved in water, and lyophilized to give 0.020 g of the compound (44) ( Quantitative).

_{- NMR (DMS0 - d 6,} 300MHz) δ 2.02-1.51 (10H, m), 3.30-2.71 (9H, m), 3.60 (2H, brd, J = 11.7Hz), 4.45 (2H, d, J = 5.7 Hz), 4.55 (2H, s), 7.40-7.14 (8H, m), 8.85-8.65 (3H, m)

 HPLC retention time: 3 1.3 1 minute Example 15

Piperidine-3-carboxylic acid 2- (dioxo-1-spiro (indane 4-piperidine) -1-yl-propyl) -benzylamide 'trifluoroacetate (5_0)

 (Carbmethoxymethyl) triphenylphosphonium bromide 2.808 g in anhydrous THF

The mixture was dissolved in 20 ml, and 4.58 ml of n-butyllithium (n-hexane solution, 1.59 mol / l) was added dropwise under ice cooling, followed by stirring for 1 hour. To the reaction solution was added a solution of commercially available 3-cyanobenzaldehyde (51) (0.887 g) in anhydrous THF (5 ml) at room temperature. After stirring overnight, 1N hydrochloric acid was added to stop the reaction, and ethyl acetate was added, and the mixture was washed with saturated saline, 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified on a silica gel column (50 g, Hexane: ethyl acetate = 3: 1), and the intermediate (52) 0.77 g (61% ). ^! H-NMR (CDC 13 ₍ 300MHz) δ 3.83 (3H, s), 6.50 (1H, d, J = 16.1Hz), 7.52 (1H, t, J = 7.7Hz),

7.66 (lH, d, J = 15.9Hz), 7.68-7.60 (lH, m), 7.83-7.73 (2H, m)

 0.043 g of the intermediate (52) was dissolved in 10 ml of methanol, and 1.39 ml of an aqueous IN sodium hydroxide solution was added thereto, followed by stirring overnight. After the reaction solution was acidified with IN hydrochloric acid, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid and saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.036 g (90%) of the intermediate (53).

_{- NMR (DMS0-d 6,} 300MHz) 86.68 (1H, d, J = 16.1Hz), 7.60 (1H, d, J = 16.1Hz), 7.59 (1H, t, J = 7.5Hz), 7.83 (lH, d, J = 7.5Hz), 8.02 (1H, d, J = 7.7Hz), 8.20 (lH, s), 12.56 (1H, brs)

 0.036 g of the intermediate (53) was dissolved in 30 ml of dimethylformamide, and 0.046 g of the intermediate (26) described in Example 10, 0.028 g of HOBt, 0.040 g of EDC-HC1, and 0.029 ml of triethylamine were added, followed by stirring overnight. Ethyl acetate was added, and the mixture was washed sequentially with saturated saline, 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative silica gel TLC (lmm, 20 × 20 cm, Hexane: ethyl acetate = 1: 1) to give the intermediate (54) 0.034 g (49%) was obtained.

-丽₃ , 300 Hz) δ 1.48 (2H, m), 2.09 (2H, td, J = 12.6, 4.2Hz), 3.15 (lH, t, J-12.1Hz), 3.54 (lH, t, J = 12.5Hz), 4.23 (1H, d, J = 13.9Hz), 4.79 (1H, d, J = 13.4Hz), 6.84 (lH, d, J = 5.7Hz), 6.90 (1H, d, J = 5.7Hz) ), 7.05 (1H, d, J = 15.4Hz), 7.37-7.19 (4H, ra), 7.50 (lH, t, J = 7.7Hz), 7.63 (1H, dt, J = 7.9, 1.5Hz), 7.69 (1H, d, J = 15.4 Hz), 7.75 (1H, dt, J = 7.9, 1.6Hz), 7.84 (lH, s)

 0.034 g of the intermediate (54) was dissolved in 30 ml of ethanol, 0.030 g of 10% Pd-C and 0.03 ml of 4N hydrochloric acid / dioxane were added, and the mixture was stirred under a hydrogen atmosphere for 18 hours. After the catalyst was filtered off and washed with ethanol, the solvent was concentrated under reduced pressure.

The obtained residue was dissolved in dimethylformamide (20 ml), and 0.024 g of the intermediate (13) described in Example 1, 0.014 g of HOBt, 0.020 g of EDC-HC1, and 0.014 ml of triethylamine were added, followed by stirring overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer is dried over anhydrous magnesium sulfate and is dried under reduced pressure. The residue obtained by concentration was purified by preparative silica gel TLC (1 thigh, 20 × 20 cm, Hexane: ethyl acetate = 1: 4) to obtain 0.035 g (66%) of the intermediate (55).

 ! H-NMR ^ DClg, 300MHz) δ 1.41 (9H, s), 2.14-1.43 (10H, m), 2.29 (lH, m), 2.67 (2H, td, J = 8.2, 3.8Hz), 2.78 (lH , Td, J = 13.0, 2.9Hz), 3.08-2.90 (5H, m), 3.18 (1H, td, J = 12.6, 2.9Hz), 3.23-3.13 (lH, m), 3.80 (1H, d, J = 13.9Hz), 3.83- 3.60 (lH, m), 3.93 (lH, d, J = 12.7Hz), 4.40 (2H, d, J = 4.6Hz), 4.63 (lH, m), 6.43 (1H, brs ), 7.29- 7.07 (8H, m)

0.035 g of the intermediate (55) was dissolved in 10 ml of 4N dioxane hydrochloride, and the mixture was stirred for 2 hours under ice cooling. The residue obtained after concentration under reduced pressure was dissolved in water and purified by HPLC (using a ₃ cm0 column, water-CH ₃ CN-TFA system) to obtain 0.019 g (62%) of compound (50).

δ 1.45-1.40 (2H, m), 1.63-1.50 (4H, m), 1.75 (lH, m), 1.91 (lH, m), 2.02 (2H, t, J = 7.1Hz), 2.75-2.56 (4H , M), 2.87-2.79 (5H, ra), 3.04-3.00 (lH, m), 3.23-3.09 (3H, m), 3.82 (1H, brd, J = 13.9Hz), 4.25 (2H, qd, J = 16.5, 5.9Hz), 4.40 (lH, brd, J = 13.4Hz), 7.05 (1H, d, J = 7.5Hz), 7.28-7.08 (7H, m), 8.49 (2H, brs), 8.6K1H, (t, J-5.9Hz)

 HPLC retention time: 29. 16 minutes Example 16

 (R) —Piperidine-1-carboxylic acid (2- (2-oxo-2-spiro (indane. 1,4-piperidine) —— 1-yl-ethyl) —phenyl) —amide hydrochloride (56 )

NH HCI

 Intermediate (58) was prepared with reference to the method described in Akkerman A. M. et al., Reel. Trav. Chim. Pays-Bas, 70, 913 (1951). That is, 21.0 g of commercially available ethyl ester of dipecotinate (57) and 20.0 g of d-tartaric acid were dissolved in 110 ml of ethanol, and left at 4 ° C overnight. The precipitated crystals were collected by filtration and washed sequentially with ethanol and ethanol-ethyl acetate = 1: 1. 34.48 g of the crude intermediate (58) obtained by drying was recrystallized three times from ethanol to obtain 12.07 g (29%) of the intermediate (58).

 [^] 23 + 51.8 ° (c = 2.07, 0.2% ammonium molybdate aqueous solution)

Literature value: [α] ³ + 51 ° (c = 2, 0.2% aqueous solution of ammonium molybdate)

 Melting point 155-156 ° C (Literature: 155-156 ° C)

 6.17 g of the intermediate (58) was suspended in 100 ml of dioxane / aqueous solution (2: 1), 6.75 g of sodium hydroxide and 4.82 g of di-tert-butyl dicarbonate were added under ice cooling, and the mixture was stirred for 4 hours. The reaction solution was acidified by adding citric acid, and then extracted twice with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added to the obtained residue, and the precipitated crystals were collected by filtration and washed with hexane to obtain 4.60 g (quantitative) of the intermediate (59).

^ -NMRiCDCl ₃ , 300 MHz) δ 1.45 (9H, s), 1.53-1.35 (lH, m), 1.75-1.58 (2H, m), 2.08-2.04 (lH, m), 2.48 (lH, m), 2.85 (lH, m), 3.03 (lH, brs), 3.88 (lH, m), 4.ll (lH, brs) In the same manner as described in Example 1, the intermediate (13) is replaced with an intermediate (13). Using the compound (59), 0.014 g of the compound (56) was obtained.

 'H-NMR DMSO-dg, 300MHz) δ 1.80-1.37 (7H, m), 2.02 (2Η, t, J = 7.1Hz), 2.11-2.06 (1H, m), 3.20-2.72 (9H, m), 3.83-3.67 (2H, m), 3.91 (1H, brd, J = 13.0Hz), 4.40 (lH, brd, J = 13.0Hz), 7.29-7.09 (7H, m), 7.49-7.45 (lH, m) , 9.12-8.95 (2H, m), 10.05 (lH, d, J = 7.9Hz)

HPLC retention time: 29. 28 minutes Example 17

Piperidine-4-carboxylic acid (2- (2-oxo-1-2-spiro (indane-1,4-piperidine) -11-yl-ethyl) -phenyl) -amide hydrochloride (60)

 2.58 g of commercially available isodipecotinic acid was suspended in 40 ml of dioxane / aqueous solution (1: 1), 0.80 g of sodium hydroxide and 4.80 g of d-butyldicarbonate were added under ice cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to about half the volume, made acidic by adding a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.32 g (94%) of the intermediate (62).

_{'H-NMR (CDC1 3,} 300MHz) δ 1.45 (9H, s), 1.73-1.56 (2H, m), 1.98-1.85 (2H, m), 2.49

(lH, m), 2.85 (2H, m), 4.04 (2H, m)

 Using a method similar to that described in Example 1 and using intermediate (62) instead of intermediate (13), 0.082 g of compound (60) was obtained.

- thigh _{(DMS0 - d 6, 300MHz)} δ 1.65-1.38 (4H, m), 1.88-1.74 (2H, m), 2.07-1.99 (4H, m), 3.01-2.64 (6H, m), 3.18 (1H , t, J = ll.0Hz), 3.33 (2H, brd, J = 12.4Hz), 3.75-3.68 (2H, m), 3.96 (lH, brd, J-14.1Hz), 4.39 (1H, brd, J = 12.8Hz), 7.30-7.06 (7H, m), 7.53 (1H, d, J = 7.1Hz), 8.62-8.34 (2H, m), 9.93 (lH, s)

 HPLC retention time: 28. 70 minutes Example 18

3-amino-1 3-methyl-N_ (2-(2-oxo1-2-spiro (indane-1,4 —Piperidine) —1-yl-ethyl) —phenyl) monobutylamide hydrochloride (63)

7.06 g of commercially available diacetoneamine oxalate (64) is suspended in 150 ml of dioxane / aqueous water (2: 1), and 3.03 g of sodium hydroxide and 8.25 g of dibutylbutylcarbonate are added under ice cooling. Stirred overnight. The reaction solution was acidified by adding citric acid and extracted with ethyl acetate. The organic layer was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an intermediate (65) 6.67 g (90%) I got

 ^ -NMRCCDCU, 300MHz) δ 1.35 (6H, s), 1.42 (9H, s), 2.14 (3H, s), 2.87 (2H, s), 4.84 (lH, brs)

 8.85 g of sodium hydroxide was dissolved in 75 ml of water, and 4.15 ml of bromine was added dropwise over 10 minutes while cooling with ice. Further, 5.78 g of the intermediate (65) was added in 10 minutes, 35 ml of dioxane was added, and the mixture was stirred overnight. The reaction solution was acidified by adding citric acid and extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of citric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and 3.07 ml of cyclohexylamine was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried.

 The obtained crystals were dissolved in ethyl acetate and a 10% aqueous solution of citric acid, and separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.313 g (40%) of intermediate (66).

 -NM! CDClg, 300MHz) δ 1.40 (6H, s), 1.45 (9H, s), 2.73 (2H, s)

In a similar manner to that described in Example 1, using intermediate (66) instead of intermediate (13), 0.049 g of compound (63) was obtained. 'H-NMRCDMSO-de, 300MHz) δ 1.36 (6H, s), 1.64-1.42 (4H, m), 2.02 (2H, t, J = 7.4Hz),

2.70 (2H, s), 2.80-2.75 (lH, m), 2.84 (2H, t, J = 7.1Hz), 3.17 (1H, t, J = ll.7Hz), 3.79 (2H, s), 3.92 ( lH, brd, J = 13.7Hz), 4.40 (1H, brd, J = 13.2Hz), 7.29-7.07 (7H, m), 7.52-7.49 (lH, m), 8.25-8, 00 (3H, m) , 10.14 (lH, s)

 HPLC retention time: 29.10 minutes Example 19

 2-Amino-N- (2- (2-oxo-1-2-spiro (indan-1,4-piberidine) -11-yl-ethyl) -phenyl) monoisobutylamide hydrochloride (67)

In the same manner as in the method described in Example 1, 0.017 g of the compound (67) was obtained using a commercially available Nt-butoxycarbonyl 2-aminoisobutyric acid instead of the intermediate (13).

δ 1.65-1.44 (10H, m), 2.09-2.00 (2H, m), 2.89-2.73 (3H, m), 3.22 (lH, t, J = 11.9Hz), 3.80 (2H, m), 4.04-4.00 (lH, m), 4.40 (1H, brd, J = 13.0Hz), 7.35-7.05 (7H, m), 7.49-7.45 (lH, m), 8.43-8.22 (3H, m), 10.37 (lH, s ) HPLC retention time: 29.66 minutes Example 20

1- (2-Hydroxy-propyl) piperidine-1-3-carboxylic acid (2- (2-oxo-1-spiro (indane-1,4-piperidine) -11-yluetyl) 1-phenyl) — Amido trifluoroacetate (68)

 6.3 mg of the compound (11) described in Example 1 was dissolved in 1 ml of propylene oxide, a very small amount of activated alumina (neutral) and 0.002 ml of triethylamine were added, and the mixture was allowed to stand at room temperature overnight. After propylene oxide was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue, alumina was separated by filtration, washed with 1N hydrochloric acid, and the filtrate was combined and freeze-dried. The obtained powder was dissolved in 0.1% TFA water, desalted using Sep-Pak C18 manufactured by Waters, and lyophilized to obtain 9.0 mg (quantitative) of compound (68).

300MHz) δ 1.10 (3H, d, J = 6.06Hz), 2-17-1.30 (10H, m), 3.65-2.70 (llH, m), 3.85-3.70 (2H, m), 4.00- 3.87 (lH, m), 4.16—4.05 (lH, m), 4.45-4.35 (1H, m), 5.48 (lH, brs), 7.31-7.07 (7H, m), 7.52-7.45 (lH, m), 9.23 (1H, brs), 10.08- 10.03 (lH, m)

 HPLC retention time: 30. 30 minutes Example 21

Piperidine-3-carboxylic acid (2- (3-phenylopen-mouthed pill force rubamoylmethyl) -phenyl) -amide hydrochloride (69)

 Dissolve 10.28 g of commercially available 2-ditrophenylacetic acid (70) in 100 ml of chloroform, add 23 ml of methanol, 6.93 g of dimethylaminopyridine and 16.23 g of EDC-HC1 and stir at 0 ° C for 30 minutes. The mixture was further stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate was added, and the mixture was washed with a saturated saline solution, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated saline solution in that order. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 12.16 g (quantitative) of the intermediate (71).

 ^ -NMRCCDC ^, 300ΜΗζ) δ 3.72 (3H, s), 4.03 (2H, s), 7.36 (1H, dd, J = 7.5, 1.3Hz), 7.48 (lH, td, J = 7.9, 1.5Hz), 7.60 (1H, td, J = 7.5, 1.5Hz), 8.12 (1H, dd, J = 8.0, 1.3Hz)

 7.51 g of the intermediate (71) was dissolved in 100 ml of methanol, 10% Pd-Cl.OOg was added, and the mixture was stirred under a hydrogen atmosphere for 6 hours. After the catalyst was separated by filtration, the catalyst was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was dissolved by adding 15 ml of 4N nodoxane hydrochloride, and the mixture was evaporated under reduced pressure, benzene was added, azeotroped twice, and dried to obtain 6.40 g (82%) of intermediate (72).

_{- NMR (DMS0-d 6,} 300MHz) 53.62 (3H, s), 3.88 (2H, s), 7.41-7.26 (4H, m)

6.4 g of the intermediate (72) was dissolved in 500 ml of dimethylformamide, and 4.29 g of HOBt, 7.28 g of the intermediate described in Example 1 (13), 6.08 g of EDC-HC1, dimethylaminopyridine 3.88 g, and triethylamine 3.21 g was added under ice cooling, and the mixture was stirred overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with saturated saline, aqueous solution of 10 citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column (50 g, hexane: ethyl acetate = 2: 1 & 50 g, toluene: ethyl acetate = 2: Purification was carried out twice in 1) to obtain 2.00 g (17%) of the intermediate (73).

_{- NMR (CDC1 3, 300MHz)} δ 1.47 (9H, s), 1.54-1.40 (1H, m), 1.83-1.68 (2H, m), 2.17- 2.03 (lH, m), 2.48 (lH, m), 2.80 (1H, brs), 3.07 (lH, m), 3.60 (1H, d, J = 14.1Hz), 3.65 (lH, d, J = 14.2Hz), 3.72 (3H, s), 4.02 (1H, brs ), 4.27 (lH, m), 7.10 (lH, t, J = 7.3Hz), 7.20 (lH, d, J = 7.7Hz), 7.29 (1H, t, J = 7.3Hz), 7.80 (1H, d , J = 7.1Hz),

8.86 (lH, brs)

 1.052 g of the intermediate (73) was dissolved in 20 ml of methanol, and 1.68 ml of a 4N aqueous sodium hydroxide solution was added under ice cooling, followed by stirring at the same temperature for 2 hours and further at room temperature for 2 hours. After adding 10% aqueous citric acid to make it acidic, ethyl acetate was added, and the mixture was washed sequentially with 10% aqueous citric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and 0.333 g of cyclohexylamine was added dropwise at room temperature. After stirring for 30 minutes, the precipitated crystals were collected by filtration and washed with ethyl acetate. The filtered product was dissolved in 10% aqueous citric acid and ethyl acetate, and washed sequentially with 10% aqueous citric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.008 g (99%) of the intermediate (74).

^ -NMR CDCl ₃ , 300 MHz) 51.46 (9H, s), 1.54-1.35 (lH, m), 1.75-1.66 (lH, m), 2.09-1.80 (2H, m), 2.50 (lH, m), 2.93 (lH, brs), 3.15 (1H, dd, J = 13.4, 9.9Hz), 3.56 (1H, d, J = 14.8Hz), 3.62 (lH, d, J = 14.8Hz), 3.88 (1H, brs) , 4.16 (lH, m), 7.14 (lH, m), 7.30-7.20 (2H, m), 7.48 (lH, m), 8.57 (lH, s)

 Intermediate (74) lOOmg was dissolved in dimethylformamide 20ml, HOBt 44.7mg, EDO HC1 63.5mg, and phenylpropylamine 44.8mg were added under ice-cooling and stirred overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with saturated saline, 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 125.3 mg (95%) of the intermediate (75).

-NMR (CDCl ₃ , 300MHz) δ 1.46 (9H, s), 1.60-1.40 (lH, m), 1.83-1.71 (4H, m), 2.14 (lH, m), 2.65-2.45 (3H, m), 2.90-2.60 (lH, m), 3.04 (1H, dd, J = 13.0,11.0Hz),

3.18 (2H, m), 3.36 (2H, m), 4.05 (1H, brs), 4.31 (lH, m), 6.85 (1H, t, J = 5.5Hz), 7.30-6.97 (8H, m), 7.82 (lH, brs), 10.3 (lH, m) Under ice-cooling, 125.3 mg of the intermediate (75) was dissolved in 4N nodioxane hydrochloride 2 (dissolved in # 1 and stirred at 0 ° C for 2 hours. After concentration under reduced pressure, dioxane and water were added, dissolved, and lyophilized. 86.9 mg (80%) of the compound (69) was obtained.

Thigh _{R (DMSO-d 6, 300MHz} ) δ 1.89 - 1.63 (5H, m), 2.07 (lH, m), 2.56-2.49 (2H, m), 2.87 (2H, m), 3.04 (3H, m), 3.17 (lH, m), 3.51 (2H, m), 3.72-3.62 (1H, m), 7.27-7.08 (9H, m), 7.60 (lH, d, J = 7.3Hz), 8.95-8.40 (2H, m), 10.42 (lH, s)

 HPLC retention time: 25.80 minutes Example 22

Pyridine-1-3-Rubonic acid (2 (3-Furou '

Phenyl) monoamide hydrochloride (76)

84.6 _mg of compound (76) was obtained in the same manner as in Example 21 except that cinnamylamine was used instead of phenylpropylamine.

^{J H - NMR (DMS0-d} 6, 300MHz) δ 1.89-1.60 (3H, m), 2.15-2.04 (lH, m), 3.08-2.77 (3H, m), 3.16 (lH, m), 3.58-3.33 (3H, m), 3.90-3.83 (2H, m), 6.22 (1H, dt, J = 15.9, 5.7Hz), 6.43 (lH, d, J = 15.9Hz), 7.12 (1H, td, J = 7.5 , 1.3Hz), 7.37-7.19 (8H, m), 7.59 (1H, m), 9.10-8.63 (2H, m), 10.35 (lH, s)

 HPLC retention time: 25. 42 minutes Example 23

Piperidine-1,3-dicarboxylic acid _ (2- _ (3,3-diphenyl loop mouth pill force rubamoylmethyl. Tyl)-phenyl) monoamide hydrochloride (77)

 136.6 rag of compound (77) was obtained in the same manner as in Example 21 except that 3,3-diphenylpropylamine was used instead of 3-phenylpropylamine.

δ 1.86-1.62 (3H, m), 2.10-2.00 (lH, m), 2.15 (2H, m), 3.06-2.77 (5H, m), 3.16 (lH, m), 3.34 (lH, m), 3.67 (2H, m), 3.93 (lH, m), 7.37-7.08 (14H, m), 7.59 (lH, m), 9.10-8.47 (2H, m), 10.38 (lH, s)

 HPLC retention time: 30. 14 minutes Example 24

4-phenyl-2 (2- (2-((piperidine-3-carbonyl) -amino) -phenyl) -acetylamino) -ethyl butyrate hydrochloride (78)

 In the same manner as in Example 21, the compound (78) 92.8 was used in place of 3-phenylpropylamine, using DL-homophenylphenylalanineethyl ester'p-toluenesulfonate. mg was obtained.

- thigh _{(DMS0-d 6, 300MHz)} δ 1.13 (1.5H, t,

, 2.15- 1.60 (6H, m), 2.67-2.50 (2H, m), 2.93-2.80 (2H, m), 3,02 (lH, m), 3.16 (lH, m), 3.38- 3.27 (lH, m), 3.64-3.53 (2H, m), 4.17-3.99 (3H, m), 7.27-7.09 (8H, m), 7.32 (lH, d, J-7.5Hz), 7.56 (lH, m), 8.74 (1H, brs), 8.86 (0.5H, m), 10.07 (0.5H, d, J = 4.2Hz)

 1 ^ Retention time: 27.88 minutes & 28.02 minutes Example 25

 T-phenyl-2- (2- (2-((piperidine-3-carbonyl) -amino) -phenyl) -acetylamino) dipropionic acid ethyl ester hydrochloride (79)

 In a manner similar to that described in Example 21, 18.2 g of the compound (79) was obtained by using DL-phenylalanineethyl ester'p-toluenesulfonate instead of 3-phenylpropylamine. Obtained.

- thigh _{(DMS0-d 6, 300MHz)} δ 1.06 (3H, t, J-7.1Hz), 1.89- 1.65 (3H, m), 2.04 (lH, m), 3.06-2.80 (5H, m), 3.16 ( lH, m), 3.49 (2H, m), 3.74-3.63 (lH, m), 4.02 (2H, q, J = 7.1Hz), 4.44 (lH, m), 7.27-7.03 (9H, m), 7.53 -7.49 (lH, m), 8.84 (lH, m), 8.82 (0.5H, m), 10.00 (0.5H, s)

 HPLC retention time: 26. 18 minutes & 26. 28 minutes Example 26

Piperidine-3-carboxylic acid (2- (trans-1-phenyl-cyclopropylcarbamoylmethyl) -phenyl)-amide hydrochloride (80)

In a manner similar to that described in Example 21, instead of 3-phenylpropylamine, Using Lance_2-phenylcyclopropylamine hydrochloride, 60.5 mg of compound (80) was obtained.

^{] H-NMR (DMS0-d} 6, 300MHz) 81.22-1.06 (2H, m), 1.87-1.63 (3H, m), 1.94 (lH, m), 2.07 (lH, m), 2.93-2.77 (3H, m), 3.01 (1H, t, J = 12.3Hz), 3.16 (1H, d, J = l 1.2Hz), 3.49 (2H, m), 3.67 (lH, m), 7.25-7.06 (9H, m) , 7.57 (lH, m), 8.73 (lH, m), 8.81 (lH, m), 10.31 (lH, m)

 HPLC retention time: 24.88 minutes Example 27

Piperidine—3-Rubronic acid (2- (2-oxo—2_ (4—o toluyl piperazin—1-yl) —ethyl) —phenyl) —amide hydrochloride (8 1)

72.7 mg of compound (81) was obtained in the same manner as in Example 21 except that tri (0-tolyl) pidazine hydrochloride was used instead of phenylpropylamine.

_{- NMR (DMS0-d 6,} 300MHz) δ 1.87- 1.58 (3H, m), 2.13- 2.03 (lH, m), 2.26 (3H, s), 3.07-2.70 (7H, m), 3.22-3.12 (lH , m), 3.90-3.25 (7H, m), 6.99-6.96 (2H, m), 7.26-7.12 (5H, m), 7.44 (1H, d, J = 7.7Hz), 9.00-8.86 (2H, m ), 9.96 (lH, s)

 HPLC retention time: 26. 88 minutes Example 28

Piperidine-1-3-Rubonic acid (2- (2-oxo-1-_2- (1,2-dihydro-1-1-methanesulfonylspiro) (3H-indole-3-, 4-piperidine) 1-1-1 Le) Chill) monophenyl) monoamide hydrochloride (82)

 83 84

 To 3.0 g of thionyl chloride, 1.37 g of 2,2′-methyliminodiethanol (83) was added dropwise under ice-cooling, and 2 ml of chloroform was added, followed by stirring at room temperature for 40 minutes. After heating to 60 ° C, ethanol was added and the mixture was further stirred for 15 minutes. After standing overnight, dimethyl ether was added, and the precipitated white precipitate was collected by filtration, washed with ether and dried to obtain 1.99 g (90%) of intermediate (84).

 ! H-NMI ^ DMSO-ds, 270MHz) δ 2.83 (3H, s), 3.6-3.4 (4H, m), 4.02 (4H, t, J = 6.9Hz), 11.0 (lH, brs)

A solution of 1.58 g of 2-fluorophenylacetonitrile (85) in dimethylsulfoxide (20 ml) was added dropwise over 20 minutes to 1.28 g of sodium hydride that had been washed and dried with hexane and stirred for 40 minutes. Then, a solution of 1.99 g of the intermediate (84) in dimethyl sulfoxide (20 ml) was added, and the mixture was stirred at 75 ° C for 3 hours. After standing overnight, water was added, and the mixture was extracted five times with Jetyl ether. The ether layer was separated with 2N hydrochloric acid (300 ml). After the hydrochloric acid layer was adjusted to pHIO with potassium hydroxide, it was extracted again with jetiethyl ether. The obtained ether layer is dried over anhydrous sodium sulfate. And dried under reduced pressure to obtain 2.02 g (89%) of an intermediate (86).

δ 2.26-2.21 (4Η, m), 2.38 (3H, s), 2.57-2.47 (2H, m), 2.99-

2.94 (2H, m), 7.21-7.08 (2H, m), 7.39-7.30 (lH, m), 7.45 (1H, td, J = 7.6,2.2Hz) 1.40g of lithium aluminum hydride and 43ml of glyme In addition, 3.5 ml of anhydrous ethanol was added dropwise under ice cooling. After heating under reflux for 30 minutes, a solution of intermediate (86) in 2,01 g of glyme (23 nU) was added dropwise over 30 minutes, and the mixture was further heated under reflux for 40 hours. After allowing to cool, 1.5 ml of water, 1.5 ml of 15% sodium hydroxide aqueous solution and 5 ml of water were sequentially added to stop the reaction. The precipitated insoluble matter was filtered off, and the filtrate was washed twice with chloroform. After washing the filtrate with saturated saline, the organic layer was dried over anhydrous potassium carbonate and concentrated under reduced pressure to obtain 1.79 g (96%) of the intermediate (87).

'H-NMR (CDCl ₃ , 300MHz) δ 1.77-1.72 (2H, m), 2.12-1.90 (4H, m), 2.33 (3H, s), 2.86-2.80 (2H, m), 3.43 (2H, s ), 3.68 (1H, brs), 6.64 (lH, d, J = 7.6Hz), 6.74 (1H, td, J = 7.3, 1.0Hz), 7.09-7.00 (2H, m)

GC-MS: 202CM ⁴ ), 203 (M + H)

 1.79 g of the intermediate (87) was dissolved in chloroform, 1.07 g of triethylamine and 1.22 g of methanesulfonyl chloride were added at 0 ° C., and the mixture was stirred for 1 hour. Further, 0.45 g of triethylamine and 0.51 g of methanesulfonyl chloride were added, and stirring was continued at room temperature for 1 hour. After evaporating the solvent, ethyl acetate and saturated aqueous sodium bicarbonate were added to carry out liquid separation, and the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the residue obtained by concentration under reduced pressure was dissolved in 1N hydrochloric acid, and washed with ethyl ether. After adding sodium bicarbonate to the hydrochloric acid layer to make it alkaline, the mixture was extracted with ethyl acetate and washed with saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.38 g (56%) of the intermediate (88).

_{Ή-NMR (CDC1 3, 300MHz} ) δ 1.79- 1.68 (2H, m), 2.13-1.96 (4H, m), 2.34 (3H, s), 2.90 (3H, s), 2.90-2.86 (2H, m) , 3.80 (2H, s), 7.06 (1H, td, J = 7.3, 1.0Hz), 7.25-7.17 (2H, m), 7.40-7.37 (lH, m)

1.21 g of the intermediate (88) was dissolved in 80 ml of 1,2-dichloroethane, and 0.56 ml of 1-chloroethyl chloroformate was added dropwise under ice-cooling, followed by heating under reflux for 4 hours. After allowing to cool, the mixture was concentrated under reduced pressure, 100 ml of methanol was added to the residue, and the mixture was further heated under reflux for 1 hour. The solvent is distilled off under reduced pressure A methyl form was obtained.

 The obtained demethylated product was dissolved in 30 ml of dioxane / aqueous solution (2: 1), 5.6 ml of 1N aqueous sodium hydroxide solution and 1.036 g of di-tert-butyldicarbonate were added under ice cooling, and the mixture was stirred overnight. The reaction solution was acidified by adding citric acid, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (25 g, hexane: ethyl acetate = 2: 1) to obtain 0.79 g (50%) of intermediate (89). Was.

-Thigh (CDCl ₃ , 300MHz) δ 1.49 (9H, s), 1.71-1.61 (2H, m), 1, 89-1.81 (2H, m), 2.92 (3H, s), 2.96-2.83 (2H, m ), 3.85 (2H, s), 4.15-4.09 (2H, m), 7.07 (1H, dt, J = 7.4, l, lHz), 7.16 (lH, dd, J = 7.5,1.3Hz), 7.24 (1H , dt, J = 7.9, 1.5Hz), 7.40 (lH, d,

(J = 8.0Hz)

97.7 mg of the intermediate (89) was dissolved in 20 ml of acetonitrile, and 256 mg of methanesulfonic acid was added under ice-cooling, followed by stirring for 1 hour. To the reaction mixture were added 269 _mg of triethylamine, 20 ml of dimethylformamide, 39.6 mg of HOBt, 106.3 mg of the intermediate (74) described in Example 21 and 56.2 mg of EDC-HCl, and the mixture was stirred overnight. After the solvent was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed successively with saturated saline, 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by a silica gel column (20 g, hexane: ethyl acetate = 1: 2).

 The resulting residue was dissolved in 20 ml of 4N hydrochloric acid-dioxane under ice-cooling and stirred at 0 ° C for 2 hours. After concentration under reduced pressure, dioxane and water were added to dissolve and freeze-dried to obtain 64.2 mg (44%) of compound (82).

'H-NMR (DMS0-d 6, 300ΜΗζ) δ 1.90-1.43 (7H, m), 2.07 (lH, m), 2.95- 2.70 (3H, m), 3.03 (3H, s), 3.50- 3.00 (4H , m), 4.00-3.68 (5H, m), 4.39 (lH, m), 7.04 (1H, t, J = 6.2Hz), 7.31-7.14 (6H, III), 7.46 (1H, d, J = 7.7 Hz), 8.70 (2H, m), 9.97 (1H, d, J = 9.5Hz) HPLC retention time: 25.70 minutes Example 29 Pyrididine-3-cal /; ^ Acid 2- (spiro (1H-^-p-dene-_1,41-pyridin) -11-carbonyl) 1-Benzilamide hydrochloride (90)

 Commercially available phthalide (91) 2. OOOg and phthalimide potassium (92) 3.000 g were dissolved in dimethylformamide (10 ml) and heated under reflux for 5 hours. After cooling, 6 ml of acetic acid and 10 ml of water were further added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and recrystallized (ethanol / water) to obtain 3.384 g (81%) of the intermediate (93).

'H-MRiCDCla ^ OOMHz) δ 5.14 (s, 2H), 7.15 (d, 1H, J = 7.5Hz), 7.38 (dt, 1H, J = 0.9Hz, 7.5Hz), 7.47 (dt, lH, J = (1.5 Hz, 7.5 Hz), 7.84-7.95 (m, 5H), 13.23 (s, 1H) Intermediate described in Example 1 (14) Dissolve 4 mg of U in 20 ml of acetonitrile, and add 260 μl of methanesulfonic acid under ice cooling. after stirring for 2 hours was added, Toryechiruamin 585Myu1, intermediate (93) 135mg, EDC-HCl 92m g, successively added HOBt 65 mg, and stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, 204 mg of the intermediate (94) was obtained as a crude product using a silica gel column chromatography (chloroform).

-NMR (CDCl ₃ , 300MHz) δ 1.24-1.68 (m, 2H), 1.98-2.32 (m, 2H), 3.14-3.48 (m, 2H), 3.64-3.86 (m, 2H), 4.80-5.28 (m , 2H), 6.81-6.95 (m, 2H), 7.23-7.48 (m, 8H), 7.73-7.76 (m, 2H), 7.87-7.90 (m, 2H) 204 mg of the crude product of the intermediate (94) was dissolved in 20 ml of ethanol, and 200 μl of hydrate was added under ice cooling, followed by stirring for 3 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in 10 ml of dimethylformamide, 184 _mg of the intermediate (13) described in Example 1 (157 mg) of EDC.HC1 and HOBtllmg were added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, 115 mg of intermediate (95) (54%, two steps from intermediate (93)) were obtained by silica gel column chromatography (form of chloroform: methanol = 100: 1). Was.

 'H-NMRCCDClg, 300MHz) δ 1.25-1.54 (m, 13Η), 1.84-2.32 (m, 4H), 2.62-3.02 (m, 3H), 3.20-3.48 (m, 2H), 3.68-3.78 (m, 1H), 3.84-4.26 (m, 3H), 4.77-4.87 (m, 2H), 6.75-6.93 (m, 3H), 7.22-7.47 (m, 8H)

 10 ml of 4N nodoxane hydrochloride was added to 53 mg of the intermediate (95), and the mixture was stirred for 2 hours under ice cooling. The reaction solution was concentrated under reduced pressure, and the residue was lyophilized to obtain 49.5 mg (100%) of compound (90).

 ^ -NMRCDMSO-de, 300ΜΗζ) δ 1.03-1.20 (m, 1H), 1.22-1.39 (m, 1H), 1.53-1.80 (m, 3H), 1.83-2.33 (m, 3H), 2.66-3.00 (m , 3H), 3.11-3.28 (m, 2H), 3.55-3.72 (m, 2H), 4.13-4.38 (m, 2H), 4.54-4.66 (m, 2H), 6.83 (d, 1H, J = 5.5Hz ), 7.07-7.52 (m, 11H), 8.67 (m, 1H)

 HPLC retention time: 20.85 minutes Example 30

 Piperidine-13-carboxylic acid 2- (spiro (indane-1,4-piperidine) -11-carbonyl) monobenzylamide hydrochloride (96)

NBoc NH HCI

95 52 mg of the intermediate (95) described in Example 29 was dissolved in 20 ml of ethanol, 40 mg of 10% Pd-C was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The catalyst was separated by filtration, and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure to obtain 54 mg (100%) of the intermediate (97).

_{^ -NMR (CDC1 3, 300MHz)} δ 1.44 (s, 9H), 1.46- 1.51 (m, 2H), 1.64-1.78 (m, 4H), 1.84 - 1.98 (m, 2H), 2.03-2.24 (m, 3H), 2.64-3.12 (m, 5H), 3.18-3.32 (m, 1H), 3.55-3.63 (m, 1H), 3.84- 4.16 (m, 3H), 4.64-4.93 (m, 2H), 6.79 ( br, 1H), 7.16-7.47 (m, 8H) To 54 mg of the intermediate (97), 10 ml of 4N hydrochloric acid dioxane was added, and the mixture was stirred under ice cooling for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was freeze-dried to obtain 40.2 mg (85%) of compound (96).

300ΜΗζ) δ 1.34- 1.40 (m, 1Η), 1.54-1.81 (m, 6H), 1.90-2.15 (m, 3H), 2.69-3.00 (m, 6H), 3.11-3.30 (m, 3H), 3.45- 3.58 (m, 1H), 4.15-4.43 (m, 2H), 4.51-4.62 (m, 1H), 7.11-7.34 (m, 8H), 8.60-8.91 (m, 3H)

 HPLC retention time: 23. 93 minutes Example 31

Piperidine-3-carboxylic acid 3- (spiro (1H-indene-1,4-piperidine) -11-carbonyl) -benzylamide hydrochloride (98)

NH HCI

1.0514 g of commercially available m-cyanobenzoic acid (99) and 5.3178 g of tetra-n-butylammonium borohydride were dissolved in 50 ml of dichloromethane, and the mixture was heated under reflux for 10 hours. After the reaction solution was concentrated under reduced pressure, 4N hydrochloric acid (60 ml) was added thereto, and the mixture was further heated under reflux for 1 hour. After allowing to cool, 10.02 g of sodium hydroxide was added under ice cooling to make the mixture basic, to which 1.8385 g of di-tert-butyl dicarbonate and 60 ml of dioxane were added, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, adjusted to pH = 2 to 3 with 5% aqueous potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.886 g (22%) of the intermediate (100).

δ 1.47 (s, 9H), 4.38 (s, 2H), 4.96 (sbr, 1H), 7, 42-7.53 (m, 2H), 8.00-8.02 (m, 2H)

 In the same manner as in the synthesis of the intermediate (94) described in Example 29, 209 mg of the intermediate (101) was obtained as a crude product from 121 mg of the intermediate (100).

 -NM! KCDClg, 300MHz) δ 1.25-1.38 (m, 2H), 1.46 (s, 9H), 1.91-2.20 (m, 2H), 3.18-3.48 (m, 2H), 3.82-3.96 (m, 1H) , 4.32--4.48 (m, 2H), 4.72-5.02 (m, 2H), 6.82 (d, 1H, J = 5.7Hz), 6.88 (d, lH, J = 5.7Hz), 7.21-746 (m, 8H )

 Intermediate (101) (crude product) 197 mg was dissolved in acetonitrile (20 ml), methanesulfonic acid (260 µl) was added in an ice bath, and the mixture was stirred for 3 hours. Triethylamine (585 µ585) 13) 110 mg, EDC-HCl 92 mg, and HOBt 65 mg were sequentially added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, 173 mg of intermediate (102) (two steps from 821 intermediate (100)) was obtained by silica gel column chromatography (chloroform: methanol = 100: 1). .

-NMR (CDCl ₃ , 300MHz) δ 1.25-1.57 (m, 13H), 1.60-1.68 (m, 2H), 1.84-2.18 (m, 4H), 2.28-2.36 (m, 1H), 2.98- 3.44 (m , 3H), 3.82- 4.98 (m, 2H), 4.40-4.67 (m, 2H), 4.72- 4.84 (m, lH), 6.82 (d, 1H, J = 5.8 Hz), 6.89 (d, 1H, J = 5.8 Hz), 7.21-7.40 (m, 8H) Intermediate (102) 70 _{mg from} compound (98) 61.9 mg (100%) in the same manner as in the synthesis of compound (90) described in Example 29 I got _{- NMR (DMS0-d 6,} 300MHz) δ 1.16 - 1.30 (m, 2H), 1.53- 1.82 (m, 3H), 1.90-2.13 (in, 3H), 2.65-3.03 (m, 3H), 3.10-3.28 (m, 2H), 3.41-3.72 (m, 3H), 4.32 (m, 2H), 4.54-4.66 (m, lH), 6.84 (d, IH, J = 5.6Hz), 7.13 (d, lH, J = 5.6Hz), 7.16-7.51 (m, 9H), 8.60- 9.00 (m, 2H)

 HPLC retention time: 23. 20 minutes Example 32

Piperidine-3-carboxylic acid 3- (spiro (indane-1,4-piperidine) monocarbonyl) -benzylamide hydrochloride (103)

 In the same manner as in the synthesis of the intermediate (97) described in Example-30, the intermediate (102) 100mg was obtained from the intermediate (102) 100mg described in Example 31 (100%). Was.

_{^{] H-NMR (CDC1 3,}} 300MHz) δ 1.42 (s, 9H), 1.39- 1.47 (m, 2H), 1.60-1.96 (m, 6H), 2.04-

2.17 (m, 2H), 2.28-2.36 (m, IH), 2.90-3.28 (m, 6H), 3.70-3.98 (m, 3H), 4.37-4.55

(m, 2H), 4.66- 4.76 (m, 1H), 6.57 (br, lH), 7.17-7.40 (m, 8H)

 In a similar manner to the synthesis of the compound (96) described in Example 30, 78.7 mg (89%) of the compound (103) was obtained from 10 mg of the intermediate (104).

 'H-NMRCDMSO-dg, 300ΜΗζ) δ 1.35-1.80 (m, 7H), 1.9-1.96 (m, 1H), 2.03-2.12 (m, 2H),

2.72 (m, IH), 2.84-3.01 (m, 5H), 3.10-3 · 23 (m, 3H), 3.45-3.51 (m, IH), 4.26 (dd, lH, J = 5.9Hz, 15.6Hz) , 4.36 (dd, lH, J = 5.9Hz, 15.6Hz), 4.48-4.62 (m, IH), 7.11-

7.42 (m, 8H), 8.71-8.87 (m, 3H)

HPLC retention time: 23.54 minutes Example 33

Piperidine: 3-carboxylic acid 4- (spiro (1 H-indene-1,4-piberidine: n) -1-1-carbonyl) monobenzylamide hydrochloride (105)

 459 mg of the intermediate (13) described in Example 1, 351.3 mg of commercially available N-hydroxysuccinimide, 383.EDC.HCl 383. (kg was dissolved in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 hours, and then commercially available. 334.5 mg of P-aminomethylbenzoic acid (106) and 306 μl of triethylamine were added, and the mixture was stirred overnight at room temperature, water and 1N aqueous hydrochloric acid were added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. By silica gel column chromatography (hexane: ethyl acetate: acetic acid = 300: 200: 1), 618 mg (85%) of the intermediate (107) was obtained.

_{^ -NMR (CDC1 3, 300MHz)} δ 1.44 (s, 9H), 1.41-1.55 (m, IH), 1.65-1.72 (m, IH), 1.90- 1.98 (m, 2H), 2.53 (br, IH) , 2.94-3.02 (m, IH), 3.15 (dd, 1H, J = 9.9Hz, 13.4Hz), 3.80-3.88 (m, 1H), 4.10-4.20 (m, IH), 4.29-4.41 (m, IH ), 4.56-4.65 (m, IH), 7.14

(br, lH), 7.23-7.28 (m, 2H), 7.75-7.83 (m, 2H)

 In the same manner as in the synthesis of the intermediate (94) described in Example 29, 235 mg (100%) of the intermediate (108) was obtained from 157 mg of the intermediate (107).

_{! H- NMR (CDC1 3, 300MHz} ) δ 1.30- 1.55 (m, 13H), 1.60 - 1.68 (m, 2H), 1.83-2.17 (m, 4H), 2.30- 2.40 (m, 1H), 3.00-3.42 (m, 3H), 3.80-3.96 (m, 2H), 4.40-4.52 (m, 2H), 4.73-4.85 (m, IH), 6.82 (d, IH , J = 5.7Hz), 6.88 (d, 1H, J = 5.7Hz), 7.21-7.27 (m, 2H), 7.29-7.36 (m, 4H), 7.43-7.46 (m, 2H)

 By a method similar to that for synthesizing compound (90) described in Example 29, 84.8 mg (100%) of compound (105) was obtained from 91 mg of intermediate (108).

^] H-NMR (DMS0-d ₆ , 300ΜΗζ) δ 1.06-1.33 (m, 2Η), 1.53-1.80 (m, 3H), 1.90-2.10 (m, 3H), 2.63-3.03 (m, 3H) , 3.08-3.28 (m, 3H), 3.66-3.81 (m, 2H), 4.27 (dd, lH, J = 5.9Hz, 15.8Hz), 4.34 (dd, lH, J = 5.9Hz, 15.8Hz), 4.49 -4.65 (m, IH), 6.83 (d, IH, J = 5.5Hz), 7.12 (d, IH, J = 5.5Hz), 7.15-7.52 (m, 8H), 8.72-8.95 (m, 3H)

 HPLC retention time: 23.00 minutes Example 34

Piperidine-3-carboxylic acid 4 _ (spiro (indane-1,4-piperidine) monocarbonyl) -benzylamide hydrochloride (109)

 In a similar manner to the synthesis of the intermediate (97) described in Example 30, 123 mg (100%) of the intermediate (110) was obtained from 122 mg of the intermediate (108) described in Example 33.

'H-NMR (CDCl ₃ , 300 MHz) 8 1.42 (s, 9H), 1.38-1.51 (m, 2H), 1.59-1.99 (m, 6H), 2.04- 1.17 (m, 2H), 2.33-2.38 (m , IH), 2.81-3.27 (m, 6H), 3.68-4.00 (m, 3H), 4.38-4.44 (m'2H), 4.63-4.75 (m, IH), 6.89 (br, IH), 7.16-7.27 (m, 6H), 7.36-7.38 (m, 2H) In the same manner as in the synthesis of compound (96) described in Example 30, compound (109) (93 () was obtained from 123 _{mg of} intermediate (110). ).

'Eta - thigh (Como _{0 - d 6, 300MHz) δ} 1.34-1.84 (m, 7Η), 1.90-1.98 (m, IH), 2.01-2.13 (m, 2H), 2.72 (m, lH), 2.82-3.01 (m, 5H), 3.10-3.29 (m, 3H), 3.48-3.60 (m, 1H), 4.26 (dd, lH, J = 6.2Hz, 15.9Hz), 4.34 (dd, lH, J = 6.2Hz, 15.9Hz), 4.40-4.58 (m, 1H), 7.12-7.41 (m, 8H), 8.71-8.91 (m, 3H)

 HPLC retention time: 23. 39 minutes Example 35

Piperidine-3-carboxylic acid (2_ (2- (spiro (indane-1,1, -pyridin) -1-1-carbonyl) -1-phenyl) -ethyl) -amide hydrochloride (111)

 1.96 g of commercially available phthalide (111) and 0.951 g of potassium cyanide were mixed and stirred at 180 ° C for 4 hours. After allowing to cool, 20 ml of water was added, and the insolubles were filtered off. The filtrate was acidified with 6N hydrochloric acid, neutralized with saturated aqueous sodium hydrogen carbonate, and decolorized with activated carbon. The filtrate was acidified again with concentrated hydrochloric acid, and then allowed to stand at 4 ° C overnight. The precipitated crystals were collected by filtration and dried to obtain 1.209 g (51%) of an intermediate (113).

_{^{! H-NMR (CDC1 3,}} 300MHz) δ 4.27 (2H, s), 7.52- 7.47 (lH, m), 7.69-7.62 (2H, m), 8.23 - 8.21 (lH, m)

0.216 g of the intermediate (113) was dissolved in 30 ml of dimethylformamide, and 0.300 g of the intermediate (26) described in Example 10, 0.181 g of HOBt, 0.257 g of EDC-HC1, and 0.187 ml of triethylamine And stirred overnight. Ethyl acetate was added, and the mixture was washed sequentially with saturated saline, 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (20 g, hexane: ethyl acetate = 1: 1), and the intermediate (114) 0.281 g (64 %).

_{Ή-NMR (CDC1 3, 300MHz} ) δ 1.30-1.20 (1H, m), 1.49 (lH, brd, J = 13.2Hz), 2.30-1.97 (2H, m), 3.25 (1H, td, J = 13.6, 3.lHz), 3.42 (1H, t, J = l 1.9Hz), 4.30-3.60 (3H, m), 4.83 (lH, m), 6.81 (1H, d, J = 5.7Hz), 6.87 (1H, d, J = 5.7Hz), 7.48-7.18 (8H, ra) Dissolve 0.281 g of the intermediate (114) in 50 ml of ethanol, add 0.172 g of 10% Pd-C and 0.214 ml of 4N dioxane hydrochloride, and add hydrogen The mixture was stirred under an atmosphere for 56 hours. After the catalyst was filtered off and washed with ethanol, the solvent was concentrated under reduced pressure.

The obtained residue was dissolved in dimethylformamide (30 ml), and 0.164 _g of the intermediate (13) described in Example 1, 0.096 _g of HOBt, 0.137 g of EDC-HC1, and 0.099 ml of triethylamine were added, followed by stirring overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified on a silica gel column (20 g, hexane: ethyl acetate = 1: 2) to give 0.268 g of the intermediate (115). 69%).

 ! H-NMlUCDClg, 300MHz) δ 1.44 (9H, s), 1.96-1.41 (8H, m), 2.21-2.00 (3H, m), 3.29-2.65 (8H, m), 3.55-3.52 (3H, m) , 4.13-3.96 (2H, m), 4.79 (1H, t, J = 13.5Hz), 7.79- 7.15 (9H, m)

 0.267 g of the intermediate (115) was dissolved in 30 ml of 4N dioxane hydrochloride, and the mixture was stirred for 2 hours under ice cooling. The residue obtained after concentration under reduced pressure was dissolved in water and freeze-dried to obtain 0.217 g (92%) of compound (111).

 ^ -NMRCDMSO-de, 300MHz) δ 1.84-1.38 (8H, m), 2.05 (2H, m), 3.00-2.53 (8H, m), 3.40-3.05 (6H, in), 4.57 (lH, m), 7.37-7.10 (8H, m), 8.38-8.26 (1H, m), 9.09-8.92 (2H, m)

HPLC retention time: 29.86 minutes Example 36

Pyridine-1-3-rhubonic acid (2 (3- (spiro (indane-1,4-piberidine) -11-carbonyl) -phenyl) -ethyl) -amide hydrochloride (116)

 1.325 g of commercially available methyl 3- (bromomethyl) benzoate (117) was dissolved in 10 ml of dimethyl sulfoxide, and 0.283 g of sodium cyanide was added thereto, followed by stirring overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was further washed with saturated saline, 1N hydrochloric acid, and saturated saline in this order. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column (50 g, hexane: ethyl acetate = 2: 1) to obtain intermediate (118) 0.772 g (76%) was obtained.

_{- NMR (CDC1 3, 300MHz)} δ 3.83- 3.81 (2H, m), 3.93 (3H, s), 7.51- 7.44 (lH, m), 7.58-

7.54 (lH, m), 8.03-8.00 (2H, m)

 0.746 g of the intermediate (118) was dissolved in 40 ml of methanol, and 2.13 ml of a 4N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 6 hours. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.657 g (96%) of the intermediate (119).

300MHz) δ 3.84 (2H, s), 7.56-7.51 (1H, m), 7.65- 7.61 (lH, m), 8.11- 8.07 (2H, m)

 0.198 g of the intermediate (119) was dissolved in 30 ml of dimethylformamide, and 0.275 g of the intermediate (26) described in Example 10, 0.166 g of HOBt, 0.236 g of EDC-HC1, and 0.344 g of triethylamine were added overnight. Stirred. Ethyl acetate was added, and the mixture was washed sequentially with saturated saline, 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified on a silica gel column (30 g, hexane: ethyl acetate = 1: 1) to give 0.190 g (47%) of the intermediate (120). %).

 'H-NMRCCDC ^ .SOOMHz) δ 1.49-1.27 (2H, m), 2.13-1.99 (2H, m), 3.40-3.23 (2H, m), 3.78 (2H, s), 3.95-3.75 (lH, m ), 4.78-4.75 (lH, m), 6.81 (1H, d, J = 5.7Hz), 6.87 (lH, d, J = 5.7Hz), 7.47-7.19 (8H, m)

 0.190 g of the intermediate (120) was dissolved in 50 ml of ethanol, 0.20 g of 10% Pd-C and 0.145 ml of 4N dioxane hydrochloride were added, and the mixture was stirred under a hydrogen atmosphere for 40 hours. After the catalyst was filtered off and washed with ethanol, the solvent was concentrated under reduced pressure.

 The obtained residue was dissolved in 30 ml of dimethylformamide, and 0.091 g of the intermediate (13) described in Example 1, 0.054 g of HOBt, 0.076 g of EDC-HC1, and 0.055 ml of triethylamine were added, followed by stirring overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed successively with a saturated saline solution, a 10% aqueous solution of citric acid, a saturated sodium bicarbonate solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified on a silica gel column (10 g, hexane: ethyl acetate = 1: 3) to give 0.166 g of the intermediate (122). 77%).

_{'H-NMR (CDC1 3,} 300MHz) δ 1.44 (9H, s), 1.99- 1.32 (8H, m), 2.22-2.03 (3H, m), 2.82 (2H, t, J = 7.1Hz), 2.94 ( 2H, t, J = 5.9Hz), 3.24-2.65 (4H, m), 3.47 (2H, m), 3.93-3.72 (3H, m), 4.80-4.65 (lH, m), 6.53 (lH, brs) , 7.37-7.14 (8H, ra)

 0.166 g of the intermediate (121) was dissolved in 30 ml of 4N nodioxane hydrochloride, and the mixture was stirred for 2 hours under ice cooling. The residue obtained after concentration under reduced pressure was dissolved in water and lyophilized to give 0.136 g (93%) of compound (116).

^ -NMRCDMSO-de ^ OOMHz) δ 1.76― 1.35 (8H, m), 2.07-2.05 (2H, m), 2.59 (lH, m), 3.00-2.72 (7H, m), 3.15-3.04 (2H, m ), 3.50-3.20 (3H, m), 3.62-3.52 (lH, m), 4.55-4.40 (lH, m), 7.38-7.09 (8H, m), 8.25 (1H, t, J = 5.1 Hz), 9.01-8.81 (2H, m) HPLC retention time: 29.26 minutes Example 37

Piperidine-3-carboxylic acid (2 (4- (spiro (indane-1,4-piberidine) -11-carbonyl) -phenyl) -ethyl) -amide hydrochloride (122)

In a similar manner to that described in Example 36, 0.187 g of compound (122) was obtained using methyl 4- (bromomethyl) benzoate instead of methyl 3- (bromomethyl) benzoate.

300MHz) δ 1.81-1.30 (8H, m), 2.06 (2H, brs), 2.62 (lH, m), 3.40-2.71 (12H, m), 3.65-3.45 (lH, m), 4.58-4.38 (1H, m), 7.20-7.09 (3H, m), 7.27-7.23 (3H, m), 7.36-7.33 (2H, m), 8.28 (1H, t, J = 5.3 Hz), 9.12-8.92 (2H, ra)

 HPLC retention time: 28.90 minutes Other preferable benzene derivatives include, for example, the following compounds or pharmaceutically acceptable salts thereof.

NCO— R ¹⁰ —Y ¹ NHCO NH R ^{1 0} -Y-Ring A

Example 3 8

Measurement of biological activity

 The effect of the benzene derivative of the present invention to enhance the release of growth hormone was measured with reference to the method described by Smith R. G. et al., Science, 260, 1640 (1993).

That is, the pituitary gland excised from a 7-week-old male Wistar / ST rat was washed three times with HBSS (-), and then the tissue was minced with scissors so as to be about one thigh angle. The tissue was transferred to a 15 ml round-bottom centrifuge tube and washed three times with 10 ml HBSS (-). After washing, 0.1 ml of the enzyme solution per pituitary gland was added, and enzyme digestion was started in a 37 ° C water bath. Pipetting was performed every 5 minutes on the way, and the cells were treated for about 20 to 30 minutes until they became dispersed cells. The mixture was centrifuged at 1200 rpm for 2 to 3 minutes at room temperature, the supernatant was removed, and 8 m of the culture solution was added. The same operation was repeated twice to wash the dispersed cells. 96 well plate - with bets on 1 X 10 ⁴ cells number / ΙΟΟμ Ι / wel l in narrowing the cells were plated 37 ° C, 5% C0 ₂ culture was started. After 3 days from the start of the culture, discard the culture supernatant, add the Acetate solution, and incubate for 1.5 hours. After washing once, a test compound solution was added and reacted at 37 ° C. in a 5% CO ₂ incubator for 15 minutes. After collecting the supernatant, the GH concentration in the supernatant was measured by the RIA method.

Sample diluted with RIA buffer 1 (1% BSA, 0.1% NaN ₃ , 25 mM EDTA / PBS (pH = 7.6)) 50 1 and ¹²⁵ 1 Labeled GH (about 10, OOOcpm) 50 μl and 1,000 times dilutedゥ 50 501 of rabbit-derived anti-rat GH serum (manufactured by Biogenesis) was added to a 96-well RIA plate (Coster) and reacted at 4 ° C for 3 days. The protein A-containing cell membrane fraction was added, left for 20 minutes, centrifuged, and the supernatant was collected. After the precipitate was washed with RIA buffer were measured ¹²⁵ 1 volume. A standard curve was prepared using standard GH, and the GH concentration in the sample was calculated.

The _EC5Q value (B) was determined by regression calculation by substituting the compound concentration XnM used in the test and the measured GH concentration Yng / ml in the test supernatant into the following formula. A and C both represent the values obtained from the regression calculation, C represents the GH concentration in the supernatant when no compound was added, and A represents the value in the culture supernatant when the compound concentration X was infinite. The difference between the GH concentration and C in Fig. 3 is shown.

 Y = AX / (B + X) + C

However, the composition of the culture solution was 10% serum serum, 2.5% fetal serum, 1% non-essential amino acids, 1% antibiotic / DMEM, and the composition of the Atsey solution was 25 mM HEPES / culture solution (ρΗ7.3) Met. The test compound solution was prepared by adding 1 n1 of the compound solution prepared at a 1000-fold concentration using DMS0 to 1 ml of Atsushi solution. Further enzyme solution, Collagenase 400mg, DNase type I lmg , HEPES and BSA lg - Buffer (0.8% NaCl , 0.037¾ KC1, 0.9% Glucose, 1% streptomycin _{'penicillin, 0.7mM Na 2 HP0 4, 25mM} HEPES (pH7. 4)) Dissolved in 40 ml, added lmg / ml CaCl ₂ 226 µl, added HEPES-Buffer to a final volume of 50 ml, sterilized by filtration through a 0.22 µm filter, and used.

When the biological activity of the compound (11) of Example 1 was measured by the above measurement method, the EC ₅₀ value was 34 nM. Industrial applicability

 According to the present invention, a novel benzene derivative useful as a growth hormone release enhancer can be provided.

Claims

Scope of Claim [wherein ring A represents an optionally substituted benzene ring or an optionally substituted naphthalene ring. Represents one CO—or —SO 2—. Y represents an oxygen atom or a single bond. R3 represents a single bond or alkylene having 1 to 3 carbon atoms. R4 represents a single bond or an alkylene having 1 to 2 carbons. R5 represents a hydrogen atom, an alkyl group optionally substituted with a hydroxyl group, an alkenyl group optionally substituted with a hydroxyl group, or an alkynyl group optionally substituted with a hydroxyl group. R6 is an optionally substituted amino group, an optionally substituted aminoalkynole group, an optionally substituted, saturated nitrogen-containing heterocyclic group, or an optionally substituted saturated nitrogen-containing heterocyclic group. Represents a substituted alkyl group. ? ^^ ^^ Well, it is the following (1), (2) or (3).

(1) R ¹ represents a group represented by the formula: Ar—R ⁷ —, and R ² represents a hydrogen atom or a lower alkyl group.

Ar represents an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted indenyl group, an optionally substituted indanyl group or an optionally substituted Represents a good benzoheterocyclic group. R ⁷ represents an optionally substituted alkylene having 1 to 4 carbon atoms, an alkenylene having 2 to 4 carbon atoms, an alkynylene or a cycloalkanediyl having 2 to 4 carbon atoms which may be substituted.

(2) a phenyl group which may be substituted together with R ¹ and R ² together with a nitrogen atom Represents a saturated nitrogen-containing heterocyclic group substituted with

(3) R ¹ and R ² together form a nitrogen atom with the formula

(Ε represents an optionally substituted ethylene, an optionally substituted vinylene, one CH ₂ NR ⁹ — or — NR ⁹ CH ₂ —. R ⁸ represents a substituent. R ⁹ represents a hydrogen atom, Represents a lower alkyl group, a lower alkanol group or a lower alkylsulfonyl group). ]

Or a pharmaceutically acceptable salt thereof.

 2. The benzene derivative according to claim 1, wherein ring A is an optionally substituted benzene ring, or a pharmaceutically acceptable salt thereof.

3. R ¹ and R ² are joined together with a nitrogen atom, optionally substituted spiro (indane-1,4'-piperidine) 1 1'-yl group, optionally substituted 1,2-di- Hydrospiro (3H-indole-1,4'-piperidine) — 1'-yl, optionally substituted 4-phenylbiperazine-1-yl, optionally substituted 4-phenylpiperidine 1-yl group, optionally substituted 3-phenylpropyl group, optionally substituted 1-naphthylmethyl group, optionally substituted 2-naphthylmethyl group, optionally substituted 2- ( 3. The benzene derivative according to claim 1 or 2, which is a 2,3-dihydro-2-indolyl) ethyl group or an optionally substituted 2- (1,2,3,4-tetrahydro_2-quinolyl) ethyl group. Its pharmaceutically acceptable salts.

 4. The benzene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Y is a single bond.

5. The benzene derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ³ is methylene or ethylene.

6. The benzene derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁴ is a single bond.

 7. Formula:

[Wherein, X, R ⁵ and R ⁶ have the same meanings as in claim 1.

 W represents an optionally substituted 1-indanilidene group, an optionally substituted phenylimino group or an optionally substituted phenylmethylene group. n represents 1 or 2. The benzene derivative according to claim 1, which is represented by the formula: or a pharmaceutically acceptable salt thereof.

 8. The benzene derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein X is —CO—.

9. R ⁶ is Yo Le substituted, saturated nitrogen-containing heterocyclic group or benzene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 which is optionally substituted amino Noarukiru group.

10. The benzene derivative according to any one of claims 1 to 9, wherein R ⁶ is an optionally substituted 3-piperidyl or an optionally substituted 2-amino-2-propyl, or a pharmaceutically acceptable salt thereof. salt.

 11. A medicament comprising the benzene derivative according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

 12. The medicament according to claim 11, which is a growth hormone release enhancer.

 13. A method for enhancing the release of growth hormone, comprising the benzene derivative according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

 14. Use of the benzene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for producing a growth hormone release enhancer.