WO1993003011A1 - Urea derivative - Google Patents

Abstract

A novel urea derivative represented by general formula (I) or a salt thereof, having a λ-receptor activator activity and being useful as a centrally acting analgesic.

Description

 Specification

 ゥ Layer guide

 Technical field

 The present invention relates to a perrea derivative or a salt thereof useful as a medicament having an analgesic action or the like. Background art

 In clinical pain treatment, analgesics are used gradually from weak agonists, and finally morphine, a strong agonist, is used. It is well known that morphine forms dependence.

 In recent years, with the progress of research on the subtypes of the obioid receptor, //, many subtypes such as κ, δ, and σ have become known. The action of a strong agonist such as morphine activates the ζ (mu) -receptor to exert an analgesic effect, but it is difficult for this receptor agonist to exhibit dependence. (Kappa-1) Drugs that selectively activate one receptor are expected to be independent, central analgesics. Conventionally, as a c-receptor agonist, for example, a 2-aminoethylamine derivative is described in Japanese Patent No. 261,842.

 The general description of a wide range of compounds in the publication discloses certain urea compounds, but no specific disclosure is made of the urea compounds. Disclosure of the invention

 Thus, the present inventors have conducted intensive studies and as a result have shown a potent analgesic activity comparable to that of morphine, and can achieve a clinical purpose as a selective Λ-receptor agonist with no dependence and low toxicity. This led to the completion of the present invention.

The compound of the present invention is clearly distinguished from the above-mentioned known compounds in chemical structure. It is low-toxic without the dependence observed for highly potent drugs such as morphine. In addition, it is a novel compound that has good oral absorption and long-lasting activity—it has receptor agonist activity.

 That is, the present invention relates to a novel urea derivative represented by the general formula (I) or a salt thereof.

(The groups in the formula mean the following groups.

R ^l , R ² : lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, or a group in which R ¹ and R ² can form a ring together with a nitrogen atom.

R ³ , is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, or R ³ and R <are taken together as a lower alkylene group, a lower alkenylene group, or represented by the formula i. Base

 II

— C— (CH ₂ ) n

 (In the formula, represents an oxygen atom or a sulfur atom, and n represents an integer of 1 to 5.)

 An optionally substituted carbocyclic group or a heterocyclic group containing one or two oxygen atoms and Z or sulfur atoms condensed with an optionally substituted benzene ring

R ⁶ optionally substituted phenyl group

 X oxygen atom or sulfur atom

Provided that when X is an oxygen atom, R ³ and R ⁴ may be taken together to form a lower alkylene group, a lower alkenylene group or a lower alkylene group which may have a substituent;

It means a group represented by the formula: Hereinafter the same)

 II

—C- (CH ₂ ) n BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a graph comparing the duration of the analgesic effect of the compound of the present invention (the compound of Example 21) and the comparative compound (the compound of EP261, 842 Example 1) in the acetic acid writhing method.

 Compound of the present invention; = 〇 = Comparative compound; one square (20 mg / kg) (1 mg / kg) The compound of the present invention is further described as follows.

 Unless otherwise specified in the definition of the general formulas herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the “lower alkyl group”, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group Group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ethylbutyl group, 2-Ethylbutyl group, 1,1,2-Trimethylpropyl group, 1,2,2-Trimethylpropyl group, 1-Ethyl-1-Methylpropyl group Building group, 1 one Echiru - 2 Mechirupuropi Le group and the like, preferably a methyl group, Echiru group, a propyl group, isopropoxy port propyl group, a butyl group.

The “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-probenyl group, an isopropenyl group, a 1-butenyl group. 1,2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1,1-dimethylvinyl group, 1-pentenyl group , 2—pentenyl group, 3— Pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl 3-butenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethylaryl group, 1,2-dimethyl-1-propenyl group, 1, 2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl 2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4 1-hexenyl group, 5-hexeninole group, 1,1-dimethyl-1-butenyl group, 1,1-dimethyl-2-butenyl group, 1,1-dimethyl-3-butenyl group, 3,3-dimethyl-1-butenyl Group, 1-methyl-one-pentenyl Group, 1-methylenol 2-pentenyl group, 1-methyl-3-pentenyl group, 1-methyl-11-pentenyl group, 4-methyl-11-pentenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, and the like are preferable. Examples include vinyl, aryl, 1-propenyl, 1-butenyl and the like.

 A "lower alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, an I-butynyl group, a 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, I-hexynyl group, 2-hexynyl group, 3-hexynyl group, A hexynyl group, a 5-hexynyl group and the like are preferable, and an ethynyl group is a 1-propynyl group and a 1-butynyl group.

The “lower alkylene group” is a straight or branched carbon chain having 2 to 6 carbon atoms, and specifically includes, for example, an ethylene group, a propylene group, a tetramethylene group, a 2-methyltrimethylene group, -Echillechille Pentamethylene group, 1,2-getylethylene group and the like.

 The “lower alkenylene group” is a straight or branched carbon chain having 2 to 6 carbon atoms, and specific examples thereof include a vinylene group, a propenylene group, a butenylene group, a 1-methylvinylene group, — A methylpropylenylene group and the like.

 The “cycloalkyl group” includes those having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

Examples of the group in which R ¹ and R ² can form a ring together with a nitrogen atom include 5- to 7-membered nitrogen-containing saturated groups such as a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, and a thiomorpholino group. And a heterocyclic group.

 Examples of the “carbocyclic group” include a phenyl group, a naphthyl group, an indenyl group, a fluorenyl group, an indanyl group, a biphenylenyl group, an ant'racenyl group, a phenanthrenyl group and the like.

As the "heterocyclic group containing one or two oxygen atoms and / or sulfur atoms condensed with a benzene ring", the following can be mentioned as typical ones.

 Substituents which may be substituted on the benzene ring of these "carbocyclic group" or "heterocyclic group" include halogen atom, hydroxyl group, lower alkyl group, lower alkenyl group, lower alkoxy group, lower alkenyl oxy group. Group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfinyloxy group, lower alkylsulfonyloxy group, lower alkylsulfonamide group, nitro group, amino group, cyano group, trifluoro group Romethyl group, lower acylamide group, carboxy group, lower alkoxycarbonyl group, aryl group, aralkyl group, carbamoyl group, sulfonyl group, lower alkenyl group, lower acylmethylamino group, monono or zirky R-substituted amino group, mono or aralkyl Substituted Aminokarubo two group, mono- mono- or di-alkyl-substituted Aminosuruhoniru group der o

Here, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and the “lower alkoxy group” is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group. , Sec —butoxy group, tert —butoxy group, ぺ Examples include benzyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, and hexyloxy group. Can be The "lower alkenyloxy group" is a linear or branched alkenyloxy group having 2 to 6 carbon atoms. Specific examples include a group in which a hydrogen atom of a hydroxyl group (OH group) is substituted with the above-mentioned lower alkenyl group.

 The “lower alkylthio group” is specifically a group in which a hydrogen atom of a thiol group (SH group) is substituted with the above-mentioned lower alkyl group. For example, a methylthio group, an ethylthio group, a propylthio group, a butylthio group A "lower alkylsulfinyl (oxy) group" such as a methylsulfinyl (oxy) group, an ethylsulfinyl (oxy) group, a propylsulfinyl (oxy) group, or an isopropylsulfinyl (oxy) group; Group, butylsulfinyl (oxy) group, isobutylsulfinyl (oxy) group, sec-butylsulfinyl (oxy) group, tert-butylsulfinyl (oxy) group, pentylsulfinyl (oxy) group, hexylsulfinyl (oxy) group, etc. To " Examples of the “quaternary alkylsulfonyl (oxy) group” include a methylsulfonyl (oxy) group, an ethylsulfonyl (oxy) group, a propylsulfonyl (oxy) group, an isopropylsulfonyl (oxy) group, and a butylsulfonyl (oxy) group. Groups, isobutylsulfonyl (oxy) group, sec-butylsulfonyl (oxy) group, tert-butylsulfonyl (oxy) group, pentylsulfonyl (oxy) group, hexylsulfonyl (oxy) group, and the like.

The “lower alkylsulfonamide group” includes methylsulfonamide group, ethylsulfonamide group, propylsulfonamide group, isopropylsulfonamide group, butylsulfonamide group, isobutylsulfonamide group, sec—butylsulfonamide group, tert Butylsulfonamide group, pentylsulfonamide group, etc., and “lower acylamido group” include acetamide group, propionylamide group, butyrylamide group, valerylamide group, isovalerylamide group, etc .; Examples of the "alkyl group" include acetyl, propionyl, butyryl, valeryl, and isovaleryl groups. Examples of the "lower acylmethylamino" group include acetylmethylamino, propionylmethylamino, and butyrylmethylamino. , Valerinolemethylamino group, isovalerylmethylamino group and the like.

 Examples of the "lower alkoxycarbonyl group" include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group and the like. Examples of the alkyl group in the "amino group", the "mono- or di-alkyl-substituted aminocarbonyl group", or the "mono- or di-alkyl-substituted aminosulfonyl group" include the aforementioned lower alkyl groups. Examples of the “aryl group” include a phenyl group and a naphthyl group, and examples of the “aralkyl group” include a benzyl group, a phenyl group, a benzhydryl group and a trityl group.

 One or more, preferably one to three, of these substituents can be substituted at any position of the benzene ring of the “carbocyclic group” or “heterocyclic group”.

Examples of the substituent that can be substituted on the phenyl group represented by R ⁶ include the above-mentioned substituents on a carbocyclic group or a heterocyclic group, and preferably a nitro group or an amino group. , A hydroxyl group, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a trifluoromethyl group, a cyano group and a lower alkoxy group.

Among the compounds of the present invention, preferred are compounds in which R ¹ and R ² are a lower alkyl group or a combination of a saturated monocyclic nitrogen-containing heterocyclic ring together with a nitrogen atom. R ³ and R ⁴ are a hydrogen atom, a lower alkyl group, and R ³ and R ⁴ are united by a lower alkylene group or a group represented by the formula

— C— (CH ₂ ) n—

R ⁶ is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfonyloxy group, a lower acylamino group, A carbocyclic group which may be substituted by a lower alkylsulfonamide group, a nitro group, an amino group, a cyano group or an aryl group, or a heterocyclic ring containing 1 to 2 oxygen atoms fused to a benzene ring; Or a salt thereof, wherein R ⁶ is a phenyl group which may be substituted with a nitro group or an amino group, or more preferably, R ¹ and R ² are combined to form a ring together with a nitrogen atom. a radicals, R ^3, R ⁴ are the same or different represent a hydrogen atom, a lower alkyl group or together with a connexion lower alkylene group, R ^s is lower alkyl , Halogen atom, triflate Ruo b Fuweniru group substituted with a methyl group or a 3, 4-methylenedioxy O carboxymethyl off We sulfonyl group, R ⁶ is a compound or a salt thereof Fuweniru group.

The compound (I) of the present invention includes optical isomers and diastereomers based on asymmetric carbon atoms. In addition, there are geometric isomers, tautomers, and the like, depending on the type of the substituent. In some cases, various hydrates and solvates also exist. The compounds of the present invention include all compounds such as isolated forms of these isomers and mixtures thereof. Incidentally, the shape of the preferred stereo Isomers in formula (I), a compound where the carbon atom (S) coordinating substituents R ^6.

 The compound (I) of the present invention has optical isomers based on asymmetric carbon atoms. Geometric isomers exist depending on the type of substituent.

The compound of the present invention includes an isolated form of these isomers and a mixture thereof.

The compound (I) of the present invention forms a salt. Such salts include salt Mineral acids such as acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, ^ acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Acid addition salts with organic acids such as malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid. Among them, preferred salts are salts with hydrochloric acid, oxalic acid, maleic acid and fumaric acid. Depending on the type of the substituent, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as magnesium, and salts with organic bases such as ammonia and trimethylamine are exemplified.

 The compound (I) of the present invention can be produced by various synthetic methods utilizing the characteristics of the basic skeleton and the substituent. The typical production method is shown below. First manufacturing method

(Wherein, R ¹ , R ² , R ³ , R ⁵ , R ⁶ and X have the same meanings as described above.) The compound (la) of the present invention comprises an amine represented by the general formula (II) and a compound represented by the general formula (III) ) Can be produced by reacting the compound with

This reaction is carried out by mixing compound (II) with a corresponding amount of isocyanate or isothiocyanate in an inert solvent. Examples of the inert solvent include dimethylformamide, dimethylacetamide, tetrachloroethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethyloxetane, ethyl ethoxide, benzene, acetonitrile, and dimethyl sulfoxide. Etc. These include mixed solvents. The medium is appropriately selected according to the method to be applied.

 This reaction proceeds easily from room temperature to cooling.

Second manufacturing method ''

R ⁵ and R ⁶ have the same meanings as defined above. )

 The compound (la) of the present invention can be produced by reacting an amine represented by the general formula (II) with an amine represented by the general formula (IV) and a carbonyl dihalide represented by the general formula (V). .

 This reaction is carried out by reacting the compound (II) with a corresponding amount of the compound (IV) and the compound (V) in the above inert solvent at room temperature or under heating.

Third manufacturing method

(Wherein, R ¹ , R ² , R ³ , RR ⁵ , R ⁶ and X have the same meanings as described above.) The compound (la) of the present invention comprises an amine represented by the general formula (II) and an amine represented by the general formula (IV) Can be produced by reacting an amine represented by the following formula with carbon dioxide or carbon disulfide represented by the general formula (VI).

In this reaction, compound (II) is reacted with a corresponding amount of compound (IV) and compound (IV). (VI) is carried out in the above-mentioned inert solvent, preferably under heating.

(In the formula, R ¹ , R ² , R ³ , R ⁵ , and R ⁶ have the above-mentioned meanings. R ⁷ means the above-mentioned lower alkyl group.)

 The compound (lb) of the present invention can be produced by reacting an amine represented by the general formula (II) with an aminoformate represented by the general formula (VII). This reaction is carried out by reacting compound (II) with a corresponding amount of compound (VII) in the presence of a Lewis acid in the above-mentioned inert solvent, preferably under heating.

Fifth manufacturing method

(In the formula, Z means a halogen atom means a sulfonyl group, and R ¹ , R: R ³ .R ⁵ , and R ⁶ have the above-mentioned meaning.)

This production method is a method for producing a target compound in which R ⁴ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a cycloalkyl group in the general formula (I). The reaction of this production method is a substitution reaction with a halide or a sulfonate represented by the formula (VIII). A reaction-corresponding amount of the starting compound is usually prepared in a suitable inert solvent in the presence of a base such as sodium hydride. The reaction is carried out under cooling or at room temperature and optionally under heating.

6th manufacturing method

 (Id) (K) (Ie)

(In the formula, A represents an alkylene group having 2 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms. In addition, R ¹ , R ² , R ⁵ , R ⁶ and Z have the same meanings as described above. )

This production method is a method for producing a target compound in which R ³ and R ⁴ in Formula (I) are an alkylene group or an alkenylene group formed in a form. This reaction is carried out by reacting a compound represented by the general formula (Id) with a corresponding amount of ω, —dihalogen (or disulfonyl) alkyl (or argen). The reaction conditions are the same as in the fifth production method. 0

7th manufacturing method

 (X) (Ie)

(In the formula, X, Y, R ¹ , R ² , R ⁵ , R ⁶ and A have the above-mentioned meanings.) The compound (Ie) of the present invention is a compound represented by the formula (X): General It can be produced by reacting phosgene (thiophosgene) represented by the formula (XI), carbonyldiimidazole (CDI) or thiocarbonyldiimidazole. '

 In this reaction, compound (X) and a corresponding amount of the compound are reacted in the above inert solvent under ice-cooling or at room temperature or under heating.

 8th manufacturing method

 (I c)

(P ₂ S ₅ or Lawesson's reagent)

 (If)

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6, and Ar have the above meanings.)

Another method for producing the target compound, which is a thiourea derivative, is to convert a urea derivative into a thiourea derivative.

This conversion reaction can be easily carried out by heating the urea derivative (Ic) with phosphorus pentasulfide or Lawesson's reagent.

9th manufacturing method

(Ig) (I) The production method comprises reducing the compound represented by the general formula (ig) to obtain the compound represented by the general formula (I) Is a method for producing a compound represented by the formula: The reduction is carried out with lithium aluminum hydride, borante-tetrahydrofuran complex, etc. The reaction solvent is getyl ether, tetrahydro cifuran, benzene or the like.

 The compound of the present invention thus produced can be isolated or purified as it is, or as a salt thereof by a conventional salt-forming treatment. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of mouth chromatography. The racemic compound can be converted to a diastereomer salt with a general optically active acid (such as tartaric acid) by using an appropriate starting compound or by a general racemic resolution method. Etc.] can lead to stereochemically pure isomers. Industrial applicability

 The compound (I) of the present invention shows good oral absorption and has a selective and long-lasting c-receptor activating activity. And, because of its extremely low affinity for other obioid receptors, it is expected that the formation of dependence on morphine, etc. based on the receptor, and the occurrence of side effects such as discomfort and hallucinations based on the sigma-receptor will be small. You.

 Therefore, the compounds of the present invention are extremely useful as independent central analgesics. The compounds (I) of the present invention also include compounds that exhibit pharmacological effects such as an anti-inflammatory effect, a diuretic effect, and a neuroprotective effect in addition to analgesic activity. It is also useful as an anti-inflammatory, diuretic, and neuroprotective agent. The pharmacological activity of the compound of the present invention was confirmed using the following test method.

 (1) tail pinch test in mice

 Ίτ according to the method of Takagi et al. (Japan J. Pharmacol., 16, 287, 1966).

Male ICR mice (SLC) weighing about 25 g were ~ 12 animals were used. The tail of the mouse tail (anal side) is pinched with crenne adjusted to 500 g pressure. The analgesic effect is determined using the bite reaction to the ridge and Klemme caused by this as an index. This method was performed in advance, and mice that did not show a biting response within 2 seconds were excluded. The test compound was dissolved in physiological saline and injected subcutaneously or orally, and the analgesic effect was evaluated at 15 and 30 minutes. Judgment criteria are as follows: Complete analgesia (+): A chewing reaction does not occur even after 6 seconds or more after application of Klemme. In order to prevent organizational damage, the application of Klemme was limited to 15 seconds.

 Partial pain relief (P): The one that bites in 2 to 6 seconds after applying Klemme. No analgesia (1): Those that bite within 2 seconds.

For each dose, to calculate the indicated complete analgesia [animal number Z number of animals used], ED _S by probit preparative method. I asked.

(2) Receptor affinity test

 a. Preparation of brain membrane preparation

Brain membrane specimen, line of One according to a general method for preparing the ₂ fractions crude P / <-!

After removing the cerebellum of Hartley male guinea pig (SLC) weighing around 350 g, the whole brain was homogenized in 10 volumes of ice-cooled 0.32 M sucrose solution, and then at 900 Xg for 10 min. Centrifuge. The supernatant was centrifuged at 11,500 X g for 20 minutes, and the resulting pellet was suspended in 0.05 M Tris buffer (pH 7.4). After centrifugation at 11,500 X g for 20 minutes, the pellet was resuspended in 0.05 M Tris buffer (pH 7.4). After incubation at 37 ° C for 30 minutes, the mixture was centrifuged at 1,500 × g for 20 minutes. The pellet obtained here was suspended in 0.05 M Tris buffer (pH 7.4) and incubated at 180 ° C. saved. It was melted at the time of use and used for experiments.

b. «—Binding to receptor

 The receptor binding test was performed according to the method of Gillan & Kosterlitz (Br. J. Pharmacol., 77, 461, 1982).

 Using 5 η 9 U-695993 labeled with tritium as a ligand, its binding to brain membrane preparations and the binding inhibitory activity of the test compound were examined. For non-specific binding, a large excess

(10 βΜ) It was determined by adding Dynorphin (1-17).

 After incubating the brain membrane sample, labeled, unlabeled ligand and test compound in 0.5 ml of 0.05 M Tris buffer (pH 7.4) at 37 ° C for 30 minutes, 5 ml An ice-cold 0.05 M Tris knofer (pH 7.4) was added, and the mixture was filtered under reduced pressure using a Wattman GFZB filter, and washed three times. The radioactivity of the labeled ligand bound to the filter paper was measured with a liquid scintillation counter. The affinity of the compound of the present invention for the Λ-receptor was determined by the K i (nM) value calculated from the concentration that inhibited the binding of the labeled ligand by 50%.

c Binding to one receptor

_Λ was also described above for binding experiments to chromatography receptor - it was carried out according to the method of the receptor binding experiment. Ligands were used D AG 0 of 3 nM was tritium labeled ^{([D-Ala 2, Gly} -ol 5] enk).

d. σ—binding to receptor

The experiment for binding to the σ-receptor was carried out at an incubation temperature and time of 25 ° C. and 45 minutes in the above-mentioned / one receptor binding experiment. The ligand used was tritium-labeled 3 nm DTG (1,3-Di (tolyl) guanidine). The results of the above experiments are summarized in the table below. It is clear from this result As is evident, the compound of the present invention had an analgesic activity equal to or higher than that of morphine hydrochloride or the comparative compound, and showed excellent A: —selectivity. '

化合物 I : US 4, 145, 435 に記載の （一） 一 trans - 2— （3, 4

Compound I: (1) one trans-2— (3, 4) described in US 4,145,435

 N-methyl-N- [2- (1-Pyrrolidinyl) cyclohexyl] acetamide maleate

 (3) Sustainability test

 齚 acid rising method

A group of 69 I male mice weighing 2731 g was used. The test compound was orally administered 50 minutes, 110 minutes or 1 0 minutes before the administration of acetic acid. In the control group, distilled water was used instead of the test compound. Was orally administered. Inject 0.1 ml of 0.6% WZV acetic acid solution per 10 g body weight intraperitoneally. The number of writhing episodes between 5 and 15 minutes after acetic acid administration was measured. The rising suppression rate of each individual was calculated according to the following formula, and the average value and standard error were calculated for each group. The significance test of the drug administration group was performed by Wilcoxon U-Test. The result is shown in FIG.

^ Ha ha Measured value of test drug-administered individual, 、 _η inhibition rate (%) = (1) _× 100

 Average measured value of control group As is clear from these results, the comparative compound showed a remarkable tendency to eliminate the analgesic effect 180 minutes after oral administration, whereas the compound of the present invention showed a sustained Showed analgesic effect.

 (4) Locomotor activity test

 Twenty-five male (6 Weeks) ICR mice weighing 28 to 35 g were used per group. The test compound was administered subcutaneously immediately before measuring the locomotion with an experimental animal locomotion measuring device (ANIMEX IIIA; manufactured by SHIMADZU). For the control group, physiological saline containing 10% DMS0 was subcutaneously administered instead of the test compound. Spontaneous locomotor activity for 10 to 20 minutes after administration of the test compound was measured.

From the measured values, the locomotor activity suppression rate of each administration group was calculated according to the following formula, and the average value and standard error were calculated for each. Furthermore, a 50% inhibitory dose (ID ₅ ) was calculated from the dose of the test compound and the locomotor activity inhibition rate using the Probit method. η _/ . _平均 Average measured value of test drug administration group, Yield ( ^{%) = α} — Measured value of contrast ~) X ¹⁰⁰ (result)

 Comparative compound (EP261,842 Compound of Example 1)

 Performing this experiment suggests whether or not the test compound has a sedative effect in mice and its strength.

 From these results, it was suggested that the compound of the present invention had less effect of suppressing the spontaneous movement than the comparative compound.

 Formulations containing the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared by using tablets, buccals, and the like, using commonly used pharmaceutical carriers, excipients and other additives. It is prepared into powders, fine granules, granules, capsules, pills, oral liquids (including syrups), injections, suppositories, etc., and is administered orally or parenterally.

 Pharmaceutical carriers and excipients include solid or corrugated non-toxic pharmaceutical substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones. .

The clinical dose of the compound of the present invention is appropriately determined in consideration of the disease, body weight, age, sex, administration route, etc. of the patient to which the compound is applied. mg, preferably 0.5 to 50 mg, intravenously, for adults, 0.01 to 100 mg / day, preferably 0.1 to: LO mg, divided into single doses or 2 to 4 doses Administration. BEST MODE FOR CARRYING OUT THE INVENTION

 (Example)

 The compound of the present invention and the method for producing the compound have been described above, and will be described in more detail with reference to examples.

The starting compounds of the present invention include novel compounds, and their production methods are shown in Reference Examples.

 Among the symbols indicating the physicochemical properties, IR is an infrared absorption spectrum, MS is a mass spectrum, mp is a melting point, An al.

¹ HNMR means nuclear magnetic resonance spectrum.

Reference example 1

(S) 12-Phenyl-2-benzyloxycarbonylamino, N, N-dimethylacetamide 10.0 g of ethyl acetate in a solution of 200 ml of 10% palladium-carbon 1 Then, 0 g was added and the contact reduction was performed under normal temperature and normal pressure. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 5.56 g of (S) -2-phenyl-2-amino-N, N-dimethylacetamide. Its physical and chemical properties are as follows.

Physicochemical properties

 MS (FAB): 1 79 (M ++ 1)

IR (KBr) cm " ¹ : 3 488, 1 642

 »HNMR (CDC1a, TMS internal standard)

 δ: 2.04 (2Η, s), 2.85 (3Η, s),

 2.99 (3 H, s), 4.72 (1 H, s),

7.3.3 (5 H, s) Reference example 2

トリェチルァミン 7. 0 & g及び 3, 4—ジクロロア二リン 1 1. 3 g "のジクロロメタン 1 0 Om l溶波に一 1 0°Cにて トリメチルク ロロシラン 8. 9 m 1を滴下して 3 0分撹拌後， 一 1 0°Cでメルド ラム酸 7. 9 9 gを加えて室温で 3時間撹拌した。 溶媒を減圧下濃 縮後， 残渣にクロ口ホルムを加え， 1 N塩酸で洗浄後， 有機層を無 水硫酸マグネシウムで乾燥した。

Triethylamine 7.0 & g and 3,4-dichloroaniline 11.3 g "in dichloromethane 10 Oml solution wave at 110 ° C trimethylchlorosilane 8.9 ml 1 was added dropwise 30 After stirring for 1 min, add 9.99 g of meldulmic acid at 110 ° C and stir at room temperature for 3 hours After concentrating the solvent under reduced pressure, add chloroform to the residue and wash with 1N hydrochloric acid The organic layer was dried over anhydrous magnesium sulfate.

 After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-form-Z methanol = 10/1) to obtain N- (3,4-dichloromethylphenyl) power. 8.23 g of rubamoyl acetic acid was obtained. Its physical and chemical properties are as follows.

¹ HNMR (DMS 0-d _fi , TMS internal standard)

 δ: 3.38 (2Η, s), 7.35-7.65 (2Η, m), 7.98 (1H, d, J = 2Hz),

 1 0, 42 (1 H, s), 1 2.70 (1 H, b rs) Reference example 3

(S) 12-phenyl-2-amino-N, N-dimethylacetamide 5.34 g, N- (3,4-dichlorophenyl) -potamoyl acetic acid 8.12 g and 1-hydroxy Benzotriazole 4.45 g of dichloromethane 200 ml in a solution of N, Ν'dicyclo 6.74 g of hexylcarpoimide was added, and the mixture was stirred at room temperature for 26 hours.

 After filtering off the insoluble matter, ethyl acetate was added, and the insoluble matter was filtered off again. The ethyl acetate layer was washed with 1N hydrochloric acid and 1N aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform methanol = 100Z1) to give (S) -N- (3,4-dichlorophenyl) -N ' — (1.1-Fu-2-ru 2-oxo-12-dimethylamino) ethylmalonamide (1.135 g) was obtained as a colorless amorphous. Its physical and chemical properties are as follows.

Physicochemical properties

MS (FAB): 408, 4 10 (M ⁺ + 1)

IR (KB r) cm " ¹ : 3320, 1648, 1596, 1532,

 1 480

'HNMR (CDC 1 _3, TMS internal standard)

 6 2.91 (3 H, s), 2.99 (3 H, s)

 3.37 (2 H, d d, J = 27, 17 H z) 5.83 (1 H, d, J = 7 H z),

 7.25-7.40 (7 H, m),

 7.77 (1 H, d, J = 2 H z),

 7.95 (1 H, d, J = 7 H z),

 9.95 (1 H, s)

Reference example 4

(S) —N— (3,4 pages) N- (1-phenyl-2-oxo-2-dimethylamino) ethylmalonamide 5. OO g was added, and the mixture was heated under reflux for 7.5 hours. After adding 35 ml of methanol and heating to reflux for 30 minutes, 35 ml of concentrated hydrochloric acid was added and the mixture was heated to reflux for 30 minutes.

 The solvent was concentrated under reduced pressure, the residue was washed with ether, 1N aqueous sodium hydroxide was added, and the mixture was extracted with ethyl acetate. ^ After drying the acid ethyl layer with anhydrous magnesium sulfate, the magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform Z methanol = 20/1), and (S) —N— (3,4-dichlorophenyl) 1— (1-phenyl-2-dimethylaminoethyl) propanediamine 3.05 g was obtained as a yellow oil. The physicochemical properties of this product are as follows.

Physicochemical properties

 MS (FAB): 3 6 6, 3 6 8 (M ++ 1)

IR (Ne at) cm " ¹ : 3448, 3328, 1604, 1500,

 1 4 7 6, 1 3 5 0, 1 1 5 4

lHNMR (CD C 1 _3, TMS internal standard)

 δ: I. 6-2.3 (2 H, m),

 1. 9 9 (1 H, b r s),

 2.28 (6 H, s),

 2. 4-2.7 (2 H, m),

 3.0-3.2 (2 H, m),

 3.5.3.8 (2H, m), 4.54 (1 H, b rs), 6.37 (1 H, d d, J = 9, 2 H z),

6.60 (1 H, d, J = 3 H z),

 7.14 (1 H, d, J = 9 H z),

 7.2-7.4 (1 H, m),

7.31 (5 H, s) Reference example 5

N sodium hydride (60%) 0. 7 1 g , N- Jimechiruhoru Muami de 50 m 1 suspension 1 it (5-benzofuranyl) Single 2 O key Sopahai de port pyrimidine _3. The 25 g was added After stirring at 45 ° C for 1.5 hours, a solution of α- (1-1-pyrrolidinylcarbonyl) benzyl bromide 4.53 in 1 ^, Ν-dimethylformamide 10 ml was added dropwise over 30 minutes. After stirring at room temperature for 2.5 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1- (5-benzofuranyl) -12-oxo-1 3- [2-oxo-11- 1-Fe-2- (1-pyrrolidinyl) ethyl] perpyi) bpyrimidi 3.23 g were obtained as a yellow oil. Its physicochemical properties are as follows.

Physicochemical properties

 MS (FAB): 404 (M ++ 1)

 333, 305

 I R (Ne a t) cwf ';

1 636, 1 438, 1 206 'HNMR (CDC 1 3, TMS internal standard)

 5: 1.70-1.95 (5 H, m),

 2.13-2.19 (1 H, m),

 2.87-3.02 (2 H, m),

3.46-3.85 (6 H, m), 6.50 (1 H, s), 6.73 (1 H, s), 7.22-7 62 (9 H, m) Reference example 6

 (S) -a- (1-Pyrrolidinylcarbonyl) benzylamine 6.

90 g and 7.40 g of N- (4-212 trophenyl) acrylamide were stirred at 115 ° C in 5 Om1 of toluene at once. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 491) to give (S) 1 ′ 1-oxo-1 N— (412 trophenyl) 1 N '— La-(1-pyrrolidinylcarbonyl) benzyl] 1, 1-3-propanediamine 10.02 g was obtained as a yellow oil. Its physicochemical properties are as follows.

Physicochemical properties

MS (FAB): 3 97 ( M + + 1), 298

'HNMR (CDC 1 _3, TMS internal standard)

 5: 1.73-1.96 (4 H, m),

 2. 5 1-2.69 (2 H, m),

 2, 80 (1 H, b r s),

 2.88—3.1 2 (3H, m),

 3, 44-3.62 (3 H, m) 4.44 (1 H, s), 7.33-7.44 (5 H, m),

 7.67 (2 H, d, J = 8.8 Hz),

 8.1 3 (2 H, d, J = 9.3 H z),

1 1.1 (1 H _f s) Reference Example 7

N0 ₂

1 Mボラン— TH F溶液 8 0 m 1に （S) — 1一ォキソ一 N— (4 一二トロフヱニル） 一 N' — [a- ( 1一ピロリジニルカルボニル） ベンジル ] ー 1 , 3—プロパンジァミン 8. 7 0 gのテトラヒ ドロ フラン 6 Om 1溶液を室温にて 3 0分で滴下した後， 6時間加熱還 流した。 反応液にメタノール 1 O Om lを加えて 1時間加熱還流し た後， 1 N—塩酸 1 0 Om 1を加えさらに 1時間加熱還流した。 溶 媒を減圧濃縮後， 1 N—水酸化ナトリウム水溶液を加え， クロロホ ルムで抽出した後， 水洗した。 有機層を無水硫酸マグネシウムで乾 燥後， 硫酸マグネシウムを濾去し， 濾液を減圧濃縮した。 残渣をシ リ力ゲル力ラムクロマトグラフィー （クロ口ホルム/メタノ一ル= 4 9 / 1 ) にて精製することにより （S) — N— （4一二トロフエ ニル） — N' — [ 1—フヱニルー 2— （1一ピロリジニル） ェチル] - 1 , 3—プロパンジァミ ン 7. 0 5 gを黄色油状物として得た。 このものの理化学的性状は以下のとおりである。

1 M borane-THF solution in 80 m 1 (S) — 1-oxo-1 N— (4,2-trophenyl) 1 N ′ — [a- (1-pyrrolidinylcarbonyl) benzyl] ー 1,3— A solution of 8.70 g of propanediamine in 6 Om1 of tetrahydrofuran was added dropwise at room temperature over 30 minutes, and the mixture was heated under reflux for 6 hours. The reaction mixture was mixed with 1 O Oml of methanol and heated under reflux for 1 hour, and then added with 1 N-hydrochloric acid 10 Om 1 and further heated under reflux for 1 hour. After concentrating the solvent under reduced pressure, a 1N aqueous solution of sodium hydroxide was added, extracted with chloroform, and washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel gel column chromatography (chloroform / methanol = 49/1) to give (S) — N— (412-trophenyl) — N '— [1— [Phenyl-2- (1-pyrrolidinyl) ethyl] -1, 3-propanediamine (7.05 g) was obtained as a yellow oil. Its physical and chemical properties are as follows.

Physicochemical properties

MS (FAB): 3 6 9 (M + + 1), 1 7 4

 ! HNMR (CDC lo, TMS internal standard)

 δ: 1.72-1.86 (6H, m),

 3.00 (1 H, d d, J = 12, 2, 3.3.4 H z)

2.42-2.92 (9 H, m),

 3. 1 2— 3. 3 5 (2 H, m),

 3.68 (1 H, d d, J = 1 2.4, 3.4 Hz) 5.98 (1 H, b rs),

6.45 (2 H, d, J = 9.3 H z) 7. 21 -7. 35 (5 H, m),

 8, 05 (2H, d, J = 8.8 Hz)

 Reference Example 8

 4.5 ml of concentrated nitric acid was added dropwise to 30.Og of concentrated sulfuric acid at room temperature, and the mixture was stirred at room temperature for 1 hour. The obtained mixed acid was added to a solution of 12.1 g of concentrated sulfuric acid (60.0 g) containing 12.1 g of (S)-(1-pyrrolidinylcarbonyl) benzylamine under ice cooling, followed by stirring for 30 minutes under ice cooling. The reaction solution was poured into ice water, sodium hydroxide was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (formaldehyde Z methanol = 40Z1) to give 6.41 g of (S) -3-3-nitro-1 <<-'(1-pyrrolidinylcarbonyl) benzylamine in pale orange oil Obtained as a product. Its physical and chemical properties are as follows.

Physicochemical properties

 MS (FAB): 250 (M ++ 1)

IR (Ne at) cm " ¹ :

 3400, 1 6 44, 1 53 4, 1448, 1354

lHNMR (CDC 1 _3, TMS internal standard)

 5: 1.76-2.04 (4 H, m),

 2.60 (2 H, b r s),

 3. 05-3.12 (1 H, m),

 3.40-3.52 (1 H, m),

3.53-3.64 (2H, m), 4.78 (1 H, brs), 7.55 (1 H, t, J = 7.9 H z)

 7.77 (1 H, d, J = 7.3 Hz)

 8.16 (1 H, d, J = 7.9 Hz)

 8.25 (1 H, d, J = 1.2 H z)

Reference Example 9

無水コハク酸 5. 00 g, 3, 4—ジクロロア二リン 8. 00 g, リン酸 1滴のベンゼン 50 m 1溶液を 3時間加熱還流した。 リン酸 2滴及びベンゼン 5 Om 1を加え， さらに 5. 5時間加熱還流した 後， 析出した結晶を濾取し， N— （3, 4—ジクロロフヱニル） ス クシンアミ ド酸 1 0. 6 gを得た。 このものの理化学的性状は以下 のとおりである。

A solution of 5.00 g of succinic anhydride, 8.00 g of 3,4-dichloroaniline and 1 drop of phosphoric acid in 50 ml of benzene was heated under reflux for 3 hours. Two drops of phosphoric acid and 5 Om 1 of benzene were added, and the mixture was further heated under reflux for 5.5 hours. The precipitated crystals were collected by filtration to obtain 10.6 g of N- (3,4-dichlorophenyl) succinamide. Was. Its physical and chemical properties are as follows.

Physicochemical properties

 MS (EI): 26 1, 263 (M +)

IR (N eat) (KB r) cm " ¹ :

3308, 1 708, 1 668 nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard)

 δ: 2.56 (4 Η, s),

 7.26-8.00 (3 Η, m),

 1 0.24 (1 H, b r s),

1 1.5 (1 Η, brs) Reference example 10

 (S)--(1-Pyrrolidinylcarbonyl) benzylamine 6.

1 3 g, N— (3,4-dichlorophenyl) succinamic acid 8.65 g, 1-hydroxybenztriazole 4.45 g dichloro-mouth methane 20 Oml solution under ice-cooling N, N 'Dicyclohexylcarbodiimide 6.74 g was added, and the mixture was stirred at room temperature for 3 hours. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the insoluble matter was removed by filtration. The ethyl acetate layer was washed sequentially with 1N hydrochloric acid and 1N sodium hydroxide, and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform Z methanol = 50Z1) to give (S) -N- (3,4-dichlorophenyl). 1N ′ — [Na-1 (1-pyrrolidinylcarbonyl) benzyl] succinamide (10.5 g) was obtained as a pale yellow oil. Its physical and chemical properties are as follows. Physicochemical properties

 MS (FAB): 449

IR (N eat) cm ' ¹ :

 3 43 2, 3 3 2 0, 1 6 3 4 1 5 9 4, 1 53 2, 1 47 8

 JHNMR (TMS internal standard)

 5: 1.73-1.93 (4 H, m),

 2 5 5-2.75 (4 H, m),

 3.00-3.07 (1 H, m),

 3.37-3.58 (3 H, m),

5.69 (1 H, d, J = 6.8 H z), 7.2 2-7.40 (7 H, m),

 7. 4 8 (1 H, d, J = 6.8 H z),

 9.20 (1 H, b r s)

Reference example 1 1

 To 100 ml of 1 M borane-THF solution, 5.39 g of (S) -N- (3,4-dichlorophenyl) —N '— [a- (1-pyrrolidinylcarbonyl) benzyl] succinamide In addition, the mixture was heated under reflux for 8 hours. 35 ml of methanol was added to the reaction solution, and the mixture was heated under reflux for 1 hour. Then, 35 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 1 hour. After concentrating the solvent under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. After drying the form layer with anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20Z1) to give (S) —N— (3,4-dichlorophenyl) -1-N ′ — [1-phenyl-2- (1-pyrrolidinyl) Ethyl] 1,4-butanediamine (4.45 g) was obtained as a pale yellow oil. Its chemical structural formula and physicochemical properties are as follows. '

Physicochemical properties

 MS (FAB): 400, 4 08 (M ++ 1)

IR (N eat) cm— ¹ :

 3 4 4 8, 3 3 2 4 1 6 0 8, 1 4 7 6, 1 3 2 4, 1 1 3 4

• HNMR (CDC1a, TMS internal standard)

 (5: 1.52-1.73 (4 H, m),

1.75-1.85 (4 H, m), 2.28 (1H, dd, J = 12.0, 3.2Hz), 2.42-2.58 (4H, m),

 2.59-2, 68 (2 H, m), '

 2.85 C 1 H, t, J = 1 1.5 Hz),

 2.96-3.07 (2 H, m),

 3.68-3.74 (1 H, m),

6.38 (1 H, dd, J = 8.8, 2.9 Hz) _f

6.6 1 (1 H, d, J = 2.9 H z),

 7.14 (1 H, d, J = 8.8 H z),

 7.23-7.38 (5 H, m)

 Example 1

 (S) — 1 [(2-Methylamino-2-phenyl) ethyl] 1.50 g of pyridine and 2-chlorophenyl isothiocyanate 1.30 are stirred in 1,51111 1,2-dichloroethane at room temperature for 1 hour. did. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 49Z1) to give (S) -1-1 (2-chlorophenyl) -13-methyl-3- [ 1-Phenol 2- (1-pyrrolidinyl) ethyl] thiourea 1.88 g was obtained as a pale yellow oil.

 (S) 1-11 (2-chlorophenyl) 1-3-methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea 1.88 g of 4 N-hydrogen chloride / ethyl acetate solution 2m After the treatment with 1, the obtained crystals are recrystallized from ethanol monoluethyl ether to give (S) -1- (2-chlorophenyl) 13-methyl-3- [1-phenyl-2--2- (1 1.Pyrrolidinyl) ethyl] thiourea hydrochloride 1.90 g was obtained as colorless needles. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 2

Instead of 2-chlorophenyl isothiocyanate described in Example 1 (S) -1- (4-chlorophenyl) -13-methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl, treated in the same manner as in Example 1 using 4-monochlorothiocyanate. ] Thiourea 'hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 3

 (S) -1-Methyl-3- (4-methylphenyl) 1-111 was treated in the same manner as in Example 1 using 4-methylphenyl isothiocyanate instead of 2-chlorophenyl isothiocyanate described in Example 1. 1- [1-Phenyl-2- (1-pyrrolidinyl) ethyl] thiourine · hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 4

 (S) -11- (4-Promophenyl) -13-methyl-3- was treated in the same manner as in Example 1 except that 2-chlorophenyl isothiocyanate described in Example 1 was used in place of 4-chlorophenyl isothiocyanate. [1-Phenyl-1- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5

The same treatment as in Example 1 was conducted using 3-chlorophenyl isothiocyanate in place of 2-chlorophenyl isothiocyanate described in Example 1, and treated in the same manner as in Example 1. (S) -11- (3-chlorophenyl) -3-methyl 3- [1 -Phenyl-2- (1 -pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below. Example 6

 The same treatment as in Example 1 was carried out using 4-methoxyphenyl isothiocyanate instead of 2-chlorophenyl isothiocyanate described in Example 1, and treated in the same manner as in Example 1. (S) ′ — I- (4-methoxyphenyl) 1-Methyl 3- (1-phenyl-2- (1-pyrrolidinyl) ethyl) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 7

 (S) —1-Methyl-3- (4-nitrophenyl) —11 was treated in the same manner as in Example 1 except that 4-chlorophenyl isothiocyanate was used instead of 2-chlorophenyl isothiocyanate described in Example 1. [(1-Phenyl-2- (1-pyrrolidinyl) ethyl] thiourine hydrochloride was obtained, whose chemical structural formula and physicochemical properties are as shown in the table below.

Example 8

 The same treatment as in Example 1 was repeated, except that 1-naphthyl isothiocyanate was used instead of 2-chlorophenyl isothiocyanate described in Example 1, to give (S) -1-methyl-3- (1-naphthyl) 111 [1-Phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below. Example 9

 The same treatment as in Example 1 was performed using 4-fluorophenyl isothiocyanate instead of 2-chlorophenyl isothiocyanate described in Example 1, and treated with (S) -1- (4-fluorophenyl) -13-methyl-3 — [1-Fuen 2- (1-pyrrolidinyl) ethyl] Thiourea and hydrochloride were obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 10

Instead of 2-chlorophenyl isothiocyanate described in Example 1 And treated with phenyl isothiocyanate in the same manner as in Example 1 to obtain (S) —1-methyl-3-phenyl-2- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride. Obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 1 1

 (S) -1-1- (3,4-dimethylphenyl) -I was treated in the same manner as in Example 1 by using 3,4-dimethylphenyl isothiocyanate in place of 2-chlorophenyl isothiocyanate described in Example 1. 3-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 1 2

 Using 4-methylphenyl isothiocyanate in place of 2-chlorophenyl isothiocyanate described in Example 1, and (S) —in place of (S) —11-[(2-methylamino-2-phenyl) ethyl] pyrrolidine Treatment with N, N, N * —trimethyl-2-phenylethanediamine in the same manner as in Example 1 to give (S) —1— (2-dimethylamino 1-phenylethyl) 1-1—methyl-3- (4 -Methylphenyl) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 13

a) (S) — 1 — [(2-Methylamino-2-phenyl) ethyl] 0.61 g of pyrrolidine and 0.55 g of 3,4-methylenedioxyphenyl isothiocyanate in 1, 1, 2, 2, The mixture was stirred at room temperature in 10 ml of 2-tetrachloroethane for one day. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform Z methanol = 49/1) to give (S) 1-1-methyl-3- (3,4-methylenedioxane). Xiphenyl) 1 1 1 [1 1-Phenyl-2— (1. 1-Pyrrolidinyl) ethyl] 1.01 g of thiourea was obtained as a pale brown oil.

 b) (S) 1-1-Methyl-3- (3,4-methylenedioxyphenyl) 1-1-1 [1-phenyl-2- (1-pyridinyl) ethyl] thiourea 1.01 g was treated with a 4N hydrogen chloride-ethyl acetate solution, and the obtained crystals were recrystallized from water-ethanol to give (S) -1-methyl-3- (3,4-methylenedioxyphenyl) -1 [111-2- (1-pyrrolidinyl) ethyl] 0.52 g of thiourea · hydrochloride was obtained as colorless needles. Its chemical structural formula and chemical formula are as shown in the table below.

 Example 14

 (S) —11- (5-Indanyl) 1 was treated in the same manner as in Example 13 except that 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 was replaced with 5-indanyl isothiocyanate. 3-methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 15

 (S) -1-Methyl-3- (2-naphthyl) was treated in the same manner as in Example 13 by using 2-naphthyl isothiocyanate instead of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. 1) I-I- [I-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 16

(S) -1-Methyl-3- (2-methylphenyl) was treated in the same manner as in Example 13 except that 2-methylphenyl isothiocyanate was used instead of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. ) 1 1 1 [1 1 2 1-1 (1 pyrrolidinyl) Ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 17

 (S) -1-Methyl-3- (3-methylphenyl) was treated in the same manner as in Example 13 except that 3-methylphenyl isothiocyanate was used in place of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. ) — 1— [1 —Phenyl-2-((1-pyrrolidinyl) ethyl) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 18

 (S) -111 (4-ethylphenyl) was treated in the same manner as in Example 13 except that 4-ethylphenylisothiocyanate was used instead of 3,4-methylenedioxyphenylisothiocyanate described in Example 13 1-Methyl-3- [1-phenyl-1- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 19

 (S) —1-Methyl-11- [1-phenylene] was treated in the same manner as in Example 13 except that 4,4-methylenedioxyphenylisothiocyanate described in Example 13 was replaced with 4-propylphenylisothiocyanate. 2- (1-Pyrrolidinyl) ethyl] 1-3- (4-Propirfuunil) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 20

(S) -11- (4-butylphenyl) 1-S- (4-butylphenyl) 1-Sulfonyl-1-thiocyanate was treated in the same manner as in Example 13 except that 3,4-methylenedioxyphenyl-isothiocyanate described in Example 13 was replaced with 4-butylphenyl-isothiocyanate. 3-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea maleate was obtained. The chemical structural formula and The physicochemical properties are as shown in the table below.

 Example 2 1

 The same treatment as in Example 13 was carried out except that 4,3 sec-butylphenyl isothiocyanate was used instead of the 3,4 "methylenedioxyphenyl isothiocyanate described in Example 13 to obtain 11 (41 sec-butyl phenylene). 3-Methyl-3-[(1S) -phenyl-2- (1-1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained, whose chemical structural formula and physicochemical properties are as shown in the table below.

 Example 22

 (S) -I- (3,4-) was treated in the same manner as in Example 13 except that 3,4-dimethoxyphenyl isothiocyanate was used in place of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. Dimethoxyphenyl) -1-methyl-3-[[1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea fumarate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 2 '3

 The same treatment as in Example 13 was repeated, except that 3,4,5-trimethoxyphenyl isothiocyanate was used in place of the 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to give (S) —1-methylethylene 1 1- [1-phenyl-2- (1-pyrrolidinyl) ethyl] 1-3-1 (3,4,5-trimethoxyphenyl) thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 24

 The same procedure as in Example 13 was repeated, except that 3,4-methylenedioxyphenylisothiocyanate described in Example 13 was replaced by 3,4-dichloromethaneisothiocyanate to obtain (S) —11 ( 3,4-Dichloro mouth phenyl) 1-3-methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained.

Its chemical structural formula and physicochemical properties are as shown in the table below. Example 25

 (S) -11- (41-cyanophenyl) 1- (4-cyanophenyl) -treated by the same manner as in Example 13 except for using 4-cyanophenyl isothiocyanate instead of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 3-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 26

 Treatment was carried out in the same manner as in Example 13 except that 4,1-tert-butylphenyl isothiocyanate was used in place of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to give (S) -11- (4-tert-butylphenyl) 1-Methyl-3-[[1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea maleate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 2 7

 The same treatment as in Example 13 was performed using 5-benzofuranyl isothiocyanate instead of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to obtain (S) -11- (5-benzofuranyl). ) — 3-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 28

Treatment was carried out in the same manner as in Example 13 except that 2,3-dihydro-5-benzofuranyl isothiocyanate was used in place of the 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. , 3-Dihydro-5-benzofuranyl) -1-methyl-3-[[1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structure, formula and physicochemical properties are shown in the table below. Example of Yeouido 29

 The same treatment as in Example 13 was repeated, except that 4-benzofuranyl isothiocyanate was used in place of 3,4-methylenedioxyphenyl isothiocyanate described in Example 13 to give (S) -11- (4-benzofuranyl). 1-Methyl-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 30

 The same treatment as in Example 13 was performed using 2-fluorenyl isothiocyanate instead of the 3,4-methylenedioxyphenyl isothiocyanate described in Example 13. (S) -11- (2-fluorenyl) -13-methyl-3 — [1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 31

 (S) — N— (3,4-dichloromouth phenyl) 1 N ′ — (1 phenyl 2-methylaminoethyl) 1.0 g of propanediamine and 0.8 ml of triethylamine in 15 ml of dichloromethane in 28 ml of triphosgene 28 Omg Was added and stirred at room temperature for 3 hours. Again, 27 Omg of triphosgene was added, and the mixture was stirred at room temperature for 2 hours. Then, a 1N aqueous solution of sodium hydroxide was added to the reaction solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform Zmethanol = 50Z1). (S) — 11 (3,4-Dichloromouth phenyl) 12-oxo 13- (1-phenyl 2-dimethylaminoethyl) ) 0.86 g of pyrimidine in the mouth was obtained as a pale yellow oil.

(S) 1 1 1 (3,4-dichloro phenyl) 1 2 -oxo 1 3-(1 phenyl 2 -dimethylaminoethyl) After dissolving 0.886 g of gin in ethanol, adding 254 mg of maleic acid and concentrating under reduced pressure, the resulting crystals were recrystallized from ethanol and ether to give (S) -1-(3,4- There was obtained 659 mg of dichlorophenyl-1-2-oxo-3--3- (1-fluoro-2-dimethylaminoethyl) perhydropyrimidine'maleate.

 Its chemical structural formula and physicochemical properties are as shown in the table below. Example 3 2

 Sodium hydroxide (60%) 0.36 g ON, 85 ml of N-dimethylformamide in ice-cold suspension, (S) —1— (3,4-dichlorophenyl) 1-3— [1-phenyl 2- — (1-Pyrrolidinyl) ethyl] urea 3.46 g ON, N-dimethylformamide 3 ml solution was added dropwise, and the mixture was stirred at 5 for 30 minutes, and then 1,3-dibromopropane 2.00 Of 1 ^, N-dimethylformamide was added dropwise over 30 minutes. After stirring at room temperature for 1.5 hours and at 60 ° C for 1 hour, 0.36 g of sodium hydride (60%) was added again under ice cooling, and the mixture was stirred at room temperature for 5 days. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform Z methanol = 24 1) to give (S) -1-1 (3,4-dichlorophenol). Nore) 12-oxo 13- [1-phenyl-2- (1-pyrrolidinyl) ethyl] Perhydropyrimidine 0.46 g was obtained as a pale yellow oil.

(S) 1-11 (3,4-dichloromouth phenyl) 1-2-oxo 3- (1-phenyl-2- (1-pyrrolidinyl) ethyl) perhydropyrimidine 0.46 g ethanol 5 m After dissolving in 1 and adding 0.13 g of fumaric acid, the solvent was concentrated under reduced pressure. The obtained residue was crystallized from acetonitrile and then recrystallized from acetonitrile to give (S) -111 (3,4-dichloromethylphenyl) -12-oxo-1-3- 31 1-Phenyl-2- (1-pyrrolidinyl) ethyl] 0.41 g of a pyrimidine / fumarate salt having a mouth opening was obtained as colorless crystals. Its chemical structural formula and physicochemical properties are as shown in the table below. '

 Example 33

 Lithium aluminum hydride 68 mg of tetrahydrofuran 8 ml suspension in a suspension of 1- (5-benzofuranyl) 1-2-oxo-1-3- [2-oxo-1 1-phenyl-2- (1-pyrrolidinyl) ethyl] An 8 mg solution of Omg in tetrahydrofuran was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 1.5 hours. After a saturated sodium hydrogen carbonate solution was added to the reaction solution, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. After adding 2 Om 1 of water to the residue, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Recrystallize 1- (5-benzofuranyl) 1-2-oxo 3- 3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] Pyrididine 18-mg of colorless needles I got it. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 34

 1- (5-benzofuranyl) 1-2-oxo-1 3- [2-oxo-1 I-phenyl-2- (2-pyrrolidinyl) ethyl] described in Example 33 instead of pyrimidine (4-Benzofuranyl) 1-2-oxo-3-[2-oxo-11-phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 33 using pyrimidine in the form of a peridotide, and then fumar By treatment with an acid, 1- (4-benzobenzofuranyl) -12-oxo-13- [1-phenyl-2- (1-pipiridinyl) ethyl] perhydropyrimidine 'fumarate was obtained.

Its chemical structural formula and physicochemical properties are as shown in the table below. Example 3 5

 (S) One N— (4-12 Trophenyl) One N '

2-((1-Pyrrolidinyl) ethyl) To a solution of 6.50 g of 1,1,3-propanediamine and 1.1.6 g of triethylamine in 65 ml of dichloromethane was added 1.9 g of triphosgene under ice-cooling, and the mixture was stirred for 40 minutes. Again, triphosgene (1.50 g) was added and the mixture was stirred at room temperature for 1 hour. 100 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, extracted with a black hole form, washed with water and dried over anhydrous magnesium sulfate. After the magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (formaldehyde methanol: 49Z1) to obtain 4- (4-nitrophenyl). —Oxo-1 3— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] perhydropyrimidine 4.85 g was obtained as a yellow oil. 1- (4-1-2trophenyl) -2-oxo-3-[1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydropyrimidine 1.20 g is dissolved in 20 ml of ethanol, and oxalic acid is added. After adding 27 g, the solvent was concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol / water to give 1- (4-112-trophenyl) -12-oxo-1-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] pyrimidine. 0.75 g of the acid salt was obtained as pale yellow needles. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 3 6

 In place of (S) —N— (412-trophenyl) -N ′-[1-phenyl-2-((1-pyrrolidinyl) ethyl) 1-1,3-propanediamine described in Example 35 S) -N- (4-Ethylphenyl) 1 N '— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] 1 1,

Treated in the same manner as in Example 35 using 3-propanediamine, and treated with (S) 111- (4-ethylphenyl) 1-2-oxo-1-3- [1-1phenyl-2--2- (1-pyrrolidinyl) ethyl 1 Droppyrimidine The oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 37

 (S) —N— (412-trophenyl) —N ′-[1-Phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 and (S) —N instead of 1,1,3-propanediamine — (4-Methylphenyl) -Ν ′-[1-Phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 35 using 1,1,3-propanediamine (S) —

1-1 (4-methylphenyl) 1-2-oxo 3-[1-1 2

2- (1-pyrrolidinyl) ethyl] perhydropyrimidine 'oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 38

 (S) -Ν- (4-112-trophenyl) -1-N '-[1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 (S) -instead of 1,3-propanediamine Ν— (4-methylsulfonylphenyl) -N ′ — [I-phenyl-2- (1-pyrrolidinyl) ethyl] Using 1,1,3-propanediamine, the same treatment as in Example 35 was performed (S) -1 -(4-Methylsulfonylphenyl) -l-oxo-l3-[-l-phenyl-2-(-l-pyrrolidinyl) ethyl] permidopyrimidine oxalate ethanolate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 3 9

(S) —Ν ((412-trophenyl)) 1 N ′ 1 [1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 (S) — instead of 1,1,3-propanediamine Ν- (4-Methylsulfonyloxyphenyl) -1-N '— [1-phenyl-2- (1-pyrrolidinyl) ethyl] Using 1,1,3-propanediamine, the same treatment as in Example 35 was carried out. (S) — 1- (4-methylsulfonyloxyphenyl) 1-2-oxo-1-3- (1-phenyl-2-yl)-(1-pyrrolidinyl) ethyl] perhydropyrimidine / oxalate ethanolate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below. Example 40

 (S) —N— (4-Trotropinyl) -N ′ — [1-phenyl-2--2- (1-pyrrolidinyl) ethyl] described in Example 35 and (S) —N instead of 1,1,3-propanediamine — [1-Phenyl-2- (1-pyrrolidinyl) ethyl] -1-N '— (2,3,4-trifluorophenyl) treated with 1,1,3-propanediamine in the same manner as in Example 35. (S) — 2-oxo-1 1- [1-phenyl-2-yl (1-pyrrolidinyl) ethyl] -3--3- (2,3,4-trifluorophenylperhydropyrimidine. Oxalate Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 4 1

 In place of (S) —N— (4-12-trophenyl) -1-N ′-[1-phenyl-2- (1-pyrrolidinyl) ethyl] 1-1, .3-propanediamin described in Example 35 S) — N— (4-Methoxycarboxylphenyl) 1 N ′ — [1-Phenyl-2- (1-pyrrolidinyl) ethyl] Using 1,1,3-propanediamine in the same manner as in Example 35, (S) —11- (4-methoxycarbonyldiphenyl) -12-oxo-3- (1-phenyl-2- (1-pyrrolidinyl) ethyl) perhydridopyrimidine. Fumarate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 4 2

(S) -N- (4-12-trophenyl) -N '-[1-phenyl-2-((1-pyrrolidinyl) ethyl) -11,3- (1), 3-propanediamine described in Example 35 — N— (1-naphthyl) 1 N ′ 1- [1-phenyl 2- (1-pyrrolidinyl) ethyl] 1 1, 3-Treatment with propanediamine in the same manner as in Example 35, (S) — 1 —Naphthyl) 1—2-oxo 3 —— (1—Fe2—2— (1—pyrrolidinyl) ethyl) Its chemical structural formula and physicochemical properties are as shown in the table below. '

 Example 43

 (S) -N- (4-12-trophenyl) 1 N '1 [I-Phenyl-2- (I-pyrrolidinyl) ethyl] described in Example 35 Instead of 1,1,3-propanediamine, (S) —N— (3-Ditrophenyl) — N ′ — [1-Phenyl-2- (1-pyrrolidinyl) ethyl] — treated with 1,3-propanediamine in the same manner as in Example 35 to give (S) 1 1 1 (3— (2-Trophanyl) -12-oxo-1-3- [1-Phenyl-12- (1-bilolidinyl) ethyl] Perhydropyrimidine 'oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 44

 (S) —N— (4-112 trofurdinyl) 1-1ST-1- [1-fluoro-2 -— (1-pyrrolidinyl) ethyl] described in Example 35 Instead of (1,3-) propanediamine, (S) —N— (2-naphthyl) 1 N '1 [1-phenyl 2- (1 -pyrrolidinyl) ethyl] — 1; 3-treated with propanediamine in the same manner as in Example 35, and (S) — 1 1 (2— Naphthyl) 1-2-oxo-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydropyrimidine was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 45

(S) -N- (4-nitrophenyl) -1-N '-[1-phenyl-2- (1-pyrrolidinyl) ethyl] -1-1,3-propanediamine as described in Example 35 (S)- N— (4-chlorophenyl) 1 N ′ — [I-phenyl-2- (1-pyrrolidinyl) ethyl] 1,3-propanediamine was treated in the same manner as in Example 35, and (S) 1-11 (4— 1-phenyl- (2-phenyl) 3- [1-phenyl I 2-(-I-pyrrolidinyl) ethyl] perhydropyrimidine / fumarate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below. ·

Example 46

 (S) -N- (4-12-trophenyl) -N '-[1-phenyl-2-((1-pyrrolidinyl) ethyl)-(S)-in place of (1-1,3-propanediamine) described in Example 35 N- (3,4-difluorophenyl) -N '-[1-phenyl-2-((1-pyrrolidinyl) ethyl]]-treated in the same manner as in Example 35 using 1,3-propanediamine. , (S) —1- (3,4-difluorophenyl) -12-oxo-1-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydridopyrimidine oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 47

 In place of (S) —N— (412-tropinyl) -1-N ′-[1-phenyl-2-((1-pyrrolidinyl) ethyl) 1-1,3-propanediamin described in Example 35 S) -N- (3,4-Dimethoxyphenyl) 1 N '— [1-phenyl-2- (1-pyrrolidinyl) ethyl] As in Example 35 using 1,1,3-propanediamine To give (S) -1- (3,4-dimethoxyphenyl) 1-2-oxo-13- [1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydridopyrimidine 'oxalate. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 48

(S) -N— (4-Trotropinyl) — [1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 and (S) —N— (4-1) instead of 1,1,3-propanediamine Fluorophenyl) 1 N '_ [1-Phenyl-2- (1-pyrrolidinyl) ethyl] — 1,3-propanediamine was treated in the same manner as in Example 35, and (S) 11- (4-Fluorophenyl) 1-2-oxo-1-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] Hydropyrimidimidine oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 49

 (S) -N- (4-212-trophenyl) 1 N '1 [1-phenyl-1-(1-pyrrolidinyl) ethyl] described in Example 35 Instead of (1,3) -propanediamine, (S) -N- (4-Methoxyphenyl) — N ′ — [1-Phenyl-2- (1-pyrrolidinyl) -ethyl] —1,3-propanediamine treated in the same manner as in Example 35, and (S) 2-methoxy-1-3-[1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydridopyrimidine 'oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 50

 (S) —N— (4-212-trophenyl) -1-N ′-[1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 Instead of (1,3-propanediamine) ) — N— (4-phenol) -N ′-[1-Phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 35 using 1,1,1-propanediamine. (4-iodophenyl) 1-2-oxo-3-([1-phenyl-12- (1-pyrrolidinyl) ethyl]) perhydropropyrimidine 'fumarate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 1

(S) -N- (4-112-trophenyl) -N '-[1-1-Phenyl-2-((1-pyrrolidinyl) ethyl) -1-1,3- described in Example 35 Instead of (1,3-) propanediamine, (S) -N- (4-Methylthiophenyl) 1 N '— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] — 1, 3-Propanediamine was treated in the same manner as in Example 35, and (S) 111- (4-methylthiophenidyl) -12-oxo-1-3 -— [1-phenyl--2 -— (1 1-pyrrolidinyl) ethyl] perhydropyrimidine / oxalate / ethanol solvate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 2

 (S) -Ν- (4-212-trophenyl) 1 N ′ — [1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35. Instead of 1,1,3-propanediamine, (S) —Ν— (4-Phenylphenyl) —N ′ — [1-Phenyl—2- (1-pyrrolidinyl) ethyl] Using 1,3-propanediamine, the same treatment as in Example 35 was carried out, and (S) —2-oxo-one 1- (4-phenylphenyl) -1-3- (1-phenyl-2- (1-pyrrolidinyl) ethyl] perhydropyrimidine ♦ Oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 3

 In place of (S) —Ν— (4-12 trophenyl) 1 N ′ 1 [1-phenyl 2- (1-pyrrolidinyl) ethyl] described in Example 35, instead of 1,1,3-propanediamine ( S) — Ν— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] 1 N '— (4-trifluoromethylphenyl) 1 1,3-propanediamine (S) — 2-oxo-1 1 [1-phenyl 2- (1-pyrrolidinyl) ethyl] 1-3— (4-trifluoromethylphenyl) per-Hydropyrimidine 'Fumar The acid salt was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 4

(S) — Ν-(4,2-trophenyl) 1 N '1 [1-phenyl-2- (1 -pyrrolidinyl) ethyl] described in Example 35 5. Instead of 1,1,3-propanediamine, (S)-ミ— (3,4-Dimethylphene Nyl) —N, — [1-Phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 35 using 1, 1, 1 -propanediamine to give (S) -1-(3,4-dimethyl Phenyl) —2-oxo-1-3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] pyrimidine oxalate having a mouth opening was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 5 5

 (S) —N— (4-12-trophenyl) 1 N ′ 1 [1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 5. Instead of 1,1,3-propanediamine, (S) -N- (3,4-Methylenedioxyphenyl) — [1-phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 35 using 1,1,3-propandiamine, and (S) — 1- (3,4-methylenedioxyphenyl) -l-l-oxo-l 3-[-l-l-phenyl-2-((l-pyrrolidinyl) ethyl] perhydropyropyrimidine was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 6

 (S) -N- (4-112-trophenyl) 1 N '1 [1-phenyl-2-yl (1-pyrrolidinyl) ethyl] described in Example 35 and (S) in place of 1,1,3-propanediamine — N— (4-Promopropynyl) 1 N ′ — [1-Fen-2-u (1-pyrrolidinyl) ethyl] 1,3-propanediamine, treated in the same manner as in Example 35, and (S) 1-11 (4-bromophenyl) 1-2-oxo-13- [1-phenyl-12- (1-pyrrolidinyl) ethyl] perhydropropyrimidine 'fumarate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 7

(S) -N- (4-12-trophenyl) 1-N'-1 [1-phenyl-2- (1-pyrrolidinyl) ethyl] as described in Example 35; I, 3- Same as Example 35 using (S) —N— [1-phenyl-2- (1-pyrrolidinyl) ethyl] —N ′ — (4-propylphenyl) —1,3-propanediamine instead of propanediamine To give (S) 12-oxo-1- [1-phenyl-2- (1-pyrrolidinyl) ethyl] -13- (4-propylpropyl) perhydropyrimidine oxalate. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 8

 (S) —N— (412-trophenyl) —N ′-[1—phenyl—2-((1-pyrrolidinyl) ethyl) described in Example 35 and N— (instead of propanediamine) 4 1 sec—butylphenyl) 1 N ′ — [(1 S) 1 1-phenyl 2-— (1 —pyrrolidinyl) ethyl] Using 1,1,3-propanediamine in the same manner as in Example 35. , 11- (4-sec-butylphenyl) -l-oxo-3-[(1S) -l-phenyl-2- (l-pyrrolidinyl) ethyl] perhydropyrimidine oxalate was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 5 9

 (S) -N- (4-212-trophenyl) -1-N '-[1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 instead of 1,1,3-propanediamine (S) — N— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] 1 N ′ — (3,4,5-trichlorophenyl) 1-, 3-propanediamine Treated in the same manner (S) — 2-oxo-1-1- [1-phenyl-2- (1-pyrrolidinyl) ethyl] -13- (3,4,5-trichlorophenyl) perhydropyrimidine · Obtained oxalate. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 6 0

(S) —N— (4-12-trophenyl) -1-N ′ described in Example 35 1 [1-phenyl 2 -— (1-pyrrolidinyl) ethyl] 1 I, 3—Instead of propanediamine (S) —N— (3,4-dichlorophenyl) 1 N '-[1 ( 3- (2-trophenyl) -1-Z- (1-1-pyrrolidinyl) ethyl] The same treatment as in Example 35 was performed using 1,1,3-propanediamine. (S) —11- (3,4-dichloromethyl) phenyl 3- [1- (3-Ditrophenyl) -1-2- (1-1-pyrrolidinyl) ethyl]-2-oxoperhydropyrimidine / fumarate was obtained. Its chemical structural formula and physical and chemical properties are as shown in the table below.

 Example 6 1

 Lithium aluminum hydride 1-4 g suspension in tetrahydrofuran 50 ml at-20 ° C (S) — N— (5-benzofuranyl) -11-oxo N '— [-(-1-pyrrolidinylcarbonyl) benzyl A solution of 6.9 g of 1,3-propanediamine in 40 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution were added a saturated aqueous solution of sodium hydrogencarbonate and a 1N aqueous solution of sodium hydroxide, and the insoluble material was removed by filtration. The filtrate was extracted with chloroform. After drying the form layer at the mouth with anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol = 40 1) to give crude (S) -N- (5-benzofuranyl) -l-oxo-l] ST-la- (l-pyrrolidinylbenzyl) 1. 1,3-propanediamine 2. lg was obtained as a pale yellow oil. This was used for the next reaction as it was.

Crude (S) —N— (5-benzofuranyl) 1-1'-oxo-N'-la- (1-pyrrolidinyl) benzyl] 1,1,3-propanediamine 2.Ig and triethylamine 1.6 ml of dichloromethane in 20 ml solution To the mixture was added 1.28 g of triphosgene under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After adding 6 ml of triethylamine to the reaction wave, 1.28 g of triphosgene was added under ice cooling, followed by stirring at room temperature for 2 hours. A 1N aqueous solution of sodium hydroxide was added to the reaction solution, and the mixture was extracted with a black form. Chloropho After drying the layer over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol = 40-1) to give (S) -3- (5-benzofuranyl) -1,2,4-dioxo-1

 [1-Phenyl-2- (1-pyrrolidinyl) ethyl] 0.53 g of perhydropyrimidine was obtained as colorless crystals.

 Its chemical structural formula and physicochemical properties are as shown in the table below. Example 6 2

(S) -N- (3,4-dichroic phenyl) 1 N '— [1 — phenyl 2 — (1 — pyrrolidinyl) ethyl] — 1,4 butanediamin 1.10 g and triethylamine 0.8 ml Triphosgene (28 Omg) was added to a solution of dichloromethane (15 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Again, triphosgene (28 Omg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a 1N aqueous solution of sodium hydroxide, and the mixture was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, magnesium sulfate was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form-form Z-methanol = 401) to give (S) -1-1 (3,4-dichlorophenyl) 1-2-oxo-1-3- [1-phenyl Lou 2— (1-Pyrrolidinyl) ethyl] no, ⁰ —Hydro 1,3—Dazepine 1.19 g as a pale yellow oil

(S) — 1- (3, 4-diphenyl phenyl) 1 2-oxo-1 3—

[1-Phenyl-2-(. 1-pyrrolidinyl) ethyl] 1.19 g of perhydro-1,3-diazepine is dissolved in ethanol, 30 mg of fumaric acid is added, and the mixture is concentrated under reduced pressure. The recrystallized crystals are recrystallized from ethanol-ether. (S) — 1- (3,4-dichloromethane) 12-oxo-1 3— [1-phenyl-2- (1-pyrrolidinyl) ethyl] There were obtained 479 mg of per-high draw 1,3-dazepine fumarate. Its chemical structural formula and physicochemical properties are as shown in the table below. A << ₀

 Example 63

 (S) —N— (4-12-trophenyl) -1-N ′ — [1-phenyl-2- (1-pyrrolidinyl) ethyl] described in Example 35 (S) — instead of 1,3-propanediamine N- (3,4-dichlorophenyl) 1 N '— [1-phenyl-2- (1-pyrrolidinyl) ethyl] Treated in the same manner as in Example 35 using ethylenediamine to obtain (S) —1 1-1 (3, 4-Dichloro mouth phenyl-2-1-2-oxo-3- (1-phenyl-2- (1-1-pyrrolidinyl) ethyl) imidazolidin hydrochloride was obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

 Example 64

 (S) — 11- (4-nitrophenyl) 1-2-oxo-3- 3- [1-phenyl-2- (1-pyrrolidinyl) ethyl] pyrimidine, 5.30 g in 50 ml of ethanol, 0 80 g of 10% no. Catalytic reduction was carried out at room temperature and normal pressure in the presence of radium carbon powder. After filtering the palladium carbon powder, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (cloform form Z methanol = 19/1) to obtain (S) -I- (4-aminophenyl) 2-—Kiso 3 -— [1-phenyl-2- (1-pyrrolidinyl) ethyl] pyridine at the mouth opening 2.77 g was obtained as a yellow amorphous.

(S) 1-11 (4-aminophenyl) 1-2-oxo 3- 3- [1-phenyl 2- (1-pyrrolidinyl) ethyl] Pyrimidine (0.64 g) dissolved in 10 ml of ethanol Then, 0.20 g of fumaric acid was added, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from acetonitrile, and then recrystallized from acetonitrile-ethanol to give (S) -1-1 (4-aminophenyl) 1-2-oxo-13- [11-phenyl-2- (1-1. Pyrrolidinyl) ethyl] no, ^β- hydrid pyrimidine / fumarate (0.41 g) was obtained as yellow crystals. This one The chemical structural formula and physicochemical properties of Nono are as shown in the table below.

Example 6 5

 (S) 1-11 (3,4-dichlorophenyl) 13- [11- (3-nitrophenyl)-2- (1-pyrrolidinyl) ethyl] 12-oxoperhydric pyrimidine 3.25 g A solution of 3.42 g of water in 30 ml of methanol was added to a solution of 30 ml of methanol, and then 4.18 g of zinc powder was added under ice-cooling. Stirred for hours.

 After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with a mouth-mouth form. After drying the form layer over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform methanol = 10/1) to give (S) — 1— [1- (3-aminophenyl) 1-2 — (11-hydroxylidinyl) ethyl] 1-3 — (3,4-Dichlorophenyl) -12-oxo perhydrid pyrimidine 50 Omg was obtained as a pale yellow oil.

 (S)-1-[1-(3-Aminophenyl) 12-(1-pyrrolidinyl) ethyl] 13-(3, 4-dichlorophenyl) 12-Oxo perhydropyrimidine 422 mg dissolved in methanol After adding 87 mg of oxalic acid, the mixture was concentrated under reduced pressure, and the substituted crystals were recrystallized from acetonitrile to obtain (S) -1-1 [3- (3-aminophenyl) 1-2- (1-Pyrrolidinyl) ethyl] -3- (3,4-dichlorophenyl) -12-oxoperhydropyrimidine ′ oxalate (263 mg) was obtained.

 Its chemical structural formula and physicochemical properties are as shown in the table below. Example 6 6

(S) 1-11 (4-aminophenyl) 1-2-oxo-3- (1-phenyl-2- (1-pyrrolidinyl) ethyl) perhydropropyrimidine 1.60 g is dissolved in concentrated hydrochloric acid 3m1 and ice-M e Under cooling with OH, An 8 ml aqueous solution of 0.336 g of sodium nitrite was added dropwise in 5 minutes. After stirring at 15 for 15 minutes, adjust the pH of the reaction solution to 8 with a saturated aqueous solution of sodium bicarbonate, and add 1.08 g of cuprous chloride and 2.28 g of potassium cyanide under ice-cooling. Was added dropwise to a mixed solution of water and ethyl acetate in 15 minutes. After stirring for an additional 15 minutes, the mixture was stirred at room temperature for 2.5 hours, and the organic layer was separated. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (formanol methanol = 9/1) to give (S) -1-(4-cyanophenyl) -2-oxo-l3- [1 —Feniru 2- (1-pyrrolidinyl) ethyl] 1.41 g of perhydropyrimidine was obtained as a red oil.

(S) — 1- (4-Cyanophenyl)-2-oxo-1 3 — [1-Fuen 2- (1-pyrrolidinyl) ethyl] Pyrimidine 1.4-g in ethanol 30 m 1 After dissolution and addition of 0.33 g of oxalic acid, the solvent was concentrated under reduced pressure. The obtained residue was crystallized with acetonitrile-dimethyl ether, and then recrystallized from acetonitrile to give (S) -1-1 (4-cyanophenyl) 1-2-oxo-3-[1-phenyl-2-ol — (1-Pyrrolidinyl) ethyl] 0.58 g of perhydropyrimidin oxalate was obtained as pale red crystals. Its chemical structural formula and physicochemical properties are as shown in the table below. Example 6 7

(S) — I — (4-aminophenyl) 1 2 —oxo 1 3 — [1 1 2 1 2-pyrrolidinyl) ethyl] Pyrimidine with perhydric opening 0.85 g pyridine 8 m 0.2 ml of methanesulfonyl chloride was added to 1 solution under ice-cooling, and the mixture was stirred for 1.7 hours. After the reaction solution was concentrated under reduced pressure, 30 ml of chloroform-form and 3 O ml of saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred vigorously. After separating the organic layer, it was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was reduced. The residue was purified by silica gel column chromatography (chloroform Z methanol = 49: 1) to give (S) -14-methanesulfonamidophenyl) 1-2-oxo-13- [ 1-Phenyl-2- (1-1-pyrrolidinyl) ethyl] 0.83 g of perhydropyrimidine was obtained as a yellow oil.

 (S) — 1- (4-Methanesulfonamide) 2- 2-oxo 3 -— [1-Phenyl-2- (1-pyrrolidinyl) ethyl] 0.81 g of pyrimidine It was dissolved in 15 ml of ethanol and 0.22 g of fumaric acid was added. The precipitated crystals are collected by filtration and recrystallized from ethanol / water to give (S) -1— (4-methanesulfonamide phenyl) -12-oxo-13- [1-phenyl-2- (1-1) 0.51 g of pyrrolidinyl) ethyl] perhydropyrimidine 'fumarate was obtained as pale yellow crystals. Its chemical structural formula and physicochemical properties are as shown in the table below.

Example 6 8

(S) -11- (4-Acetamidophenyl) -12-oxo was treated in the same manner as in Example 67, using acetyl chloride instead of the methanesulfonyl chloride described in Example 67. 1- [1-Phenyl-2- (1-pyrrolidinyl) ethyl] perhydropyrimidine hydrochloride and hydrate were obtained. Its chemical structural formula and physicochemical properties are as shown in the table below.

CO

en Example ¹

Ν Structural chemical properties mp: 195-199 ΐ (decomposition) (EtOH EtjtO), MS (FAB): 374, 376 ( ⁺ + 1) IR (KBr) cm " ¹ : 1488, 1326

Anal. (As CwI ^ s SCl _a )

 c H N S Cl mvkttL.%) 58.53 6.14 10.24 7,81 17 ^ 8

Me

 HCl Yi sm (w) 58.28 6,19 10.03 7,64 17

mp: 200 - 202 (decomposition) (EtOH-Et, 0) , MS (FAB) 374, 376 (M + + I) IR (KBr) cm "1: 1510, 1330

 Anal. (As CJORMNISCI :)

Cl C H N S CI

 Reason

 Me Mfi (JO 58.53 6.14 10.24 7.81 17 ^ 8

HCl real Kit (90 58.42 6.10 10.11 7.90 17 ^ 5 mp: 190-192Ό (^ solution) (EtOH-Et, 0), MS (FAB) 354 (M ++ 1) BR (KBr) cm— ¹ : 1522, 1370, 1338

 Anal. CHeN.SClO.lHxO)

 Me c H N S Cl

 Tttt (i 64.38 7.25 10.73 8.18 9.05

HCl real key («) 64.2 & 7.04 10.62 8.12 927

t

 cn n

CO

C

 cn C7I

CN3 n

t

en cn

Five CO

 en

05

CO en

CO

 n Example

Να-named physicochemical properties mp: 203-206 (decomposed) (MeOH-Et ₂₀ ). MS (FAB): 382 ( ¹ "+1) 00 IR (KBr) cm" ¹ : 1496, 1340 , 1228

Anal. (As C ₂₂ H _M N ₃ 0SC1)

 28

 C H N S CI

 1 H HCl

 Me logic »« (%) 63.22 6.75 10.05 7.67 8.48

Real ttft <%) 63.15 6.81 10.02 7.52 8.34 mp: 224- by _{225 (MeOH - Et z 0)} MS (FAB):. 380 (M + + 1)

 IR (KBr) cm "': 1506, 1332

Anal. (As C _a H ₂ , N _a OSCI)

 29

 C H N S CI

理 M (%) 63.52 6.30 10.10 7.71 8.52

Process M (%) 63.52 6.30 10.10 7.71 8.52

Actual tt »(%) 63.41 6.26 10.13 7.77 8.58 mp: 206-208lC (decomposition) (EtOH-Η, Ο), MS (FAB): 428 (M ⁺ +1)

IR (KBr) cm ¹ : 1458, 1308 · Anal. (As C „Hj ₀ N _s SCl)

 30

 C H N S CI

 Me

 ¾ (S (%) 69.88 6.52 9.05 6.91 7.64

Actual ft® (%) 69.97 6.56 8.95 6.89 7.64

C

 cn

 Penn

CD

1)

 + 1)

CO en

CO

J1

021 CO

cm

Three CO

 n

01 ^ CO n

tND

n en cn

61 CO

1 >>

7 CO I— *

 cn

Prescription example

 Next, examples of the formulation of the compound of the present invention as a medicine will be described.

 (1) Tablets ''

 Compound of Example 13 5.Omg

 (Hereinafter referred to as Compound A)

 Lactose 1 0 6.mg

 Corn starch 43.0 mg

 Hydroxypropyl cellulose 5. Omg

 Magnesium stearate 0.6 mg

 160.0 mg / tablet Compound A5.0, lactose106.4 g and cornstarch 43 g were mixed uniformly, and to this was added 43 ml of a 10% aqueous solution of hydroxypropylcellulose and granulated using a granulator. I do. Add 0.6 g of magnesium stearate to the granulated granules and tablet into 16 Omg tablets (1 000 tablets). Example 3 Compound of 2 1.Omg

 (Hereinafter referred to as Compound B)

 Lactose 1 06. 4 mg

 Corn starch 48.0 mg

 Hydroxypropyl cellulose 4. Omg

 Magnesium stearate 0.6 mg

1 60. OmgZ tablet Compound Bl.Og, lactose 106.4 _g and corn starch 48 g are mixed uniformly, and to this is added 40% hydroxypropylcellulose 10% aqueous solution and granulated using a granulator. Add 0.6 g of magnesium stearate to the granulated granules and compress into 16 Omg tablets (1 000 tablets). (2) powder

 Compound A 50 mg

 Mannit 7 70 0 'mg

 Cornstarch 1 95 0 mg

 Polyvinyl pyrrolene 300 mg_

 1 0 0 0.0.0 mg

 Compound A (5.0 g), Mannit (770 g), and Corn Starch (1.95 Og) are mixed uniformly, added with 300 ml of a 10% aqueous solution of polyvinylpyrrolidone, granulated with a granulator, and used as a powder. (1 kg). Compound 1.1.0 mg

 Mannit 7 7 0.0 mg

 Corn starch 1 9 1.1 mg

 Polyvinylpyrrolibin 30.0 m

 1 0 0 0.0.0 mg

 Compound B 1.0 g, mannite 770 g and corn starch 19 1. Og were mixed uniformly, added with 10% aqueous polyvinylpyrrolidone 300 ml, granulated with a granulator, and used as a powder. 1 kg).

(3) Capsules

 Compound A 5.0 mg

 Cornstarch 1 95.0 mg

 Lucium stearate 1-Omg

 2 0 0.0 mg

Mix 5.0 g of Compound A, 15.0 g of corn starch, and 15.0 g of calcium stearate uniformly, and fill No. 3 capsules to 20 mg to make capsules (100 capsules). Compound B 1.Omg

 Corn starch 1 9 1.0 mg

 Calcium stearate 1. mg

 2 0 0.0 mg

 Compound B 1.0 g, corn starch 191.0 g, and calcium stearate 1 g are mixed uniformly, and filled into a No. 3 capsule at 20 Omg to prepare a capsule (100 capsules).

(4) Injection for intravenous injection

 Compound A 0.2 mg

 Sodium chloride 9 mg

 Add distilled water for injection to 1. Oml

 Dissolve compound A20 Omg and sodium chloride 9 g in distilled water for injection and adjust to 100 Oml. After filtration, fill the ampoule with lml to obtain injection. At this time, the space in the ampoule is replaced with nitrogen gas.

 The sample is then heat-sterilized with autocrepe (100 samples).

(4) Injection for intravenous injection

 Compound B 0.2 mg

 Sodium chloride 9 mg

 Add distilled water for injection to 1. Oml

 Dissolve Compound B (20 mg) and sodium chloride (9 g) in distilled water for injection and adjust to 100 Oml. After filtration, fill this solution into an ampoule and use it for injection. At this time, the space in the ampoule is replaced with nitrogen gas.

 Then, the ampoule is heat-sterilized with an autoclave (100 samples).

Claims

The scope of the claims 1. A novel urea derivative represented by the following general formula (I) or a salt thereof

(The groups in the formula mean the following groups. R ¹ , R ² : lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, or group in which R ¹ and R ² are united to form a ring together with a nitrogen atom R ³ , R ⁴ : a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkylene group, a cycloalkyl group, or R ³ and R ⁴ are in the form of a lower alkylene group, a lower alkenylene group or a formula Group (where X, '— C— (CH ₂ ) n—  Represents an oxygen atom or a sulfur atom, and n represents an integer of 1 to 5. ) R ⁵ : a heterocyclic group containing one or two oxygen atoms and one or two sulfur atoms condensed with an optionally substituted carbocyclic group or an optionally substituted benzene ring R ⁶ : substituted Remoyl phenyl group  X: oxygen atom or sulfur atom Provided that when X is an oxygen atom, R ₃ and R ₄ may be taken together to form a lower alkyl group, a lower alkenylene group or a lower alkenylene group which may have a substituent;  Xi -C— means a group represented by (CH ₂ ) n—. ) 2. X is an oxygen atom, and R ³ and R ⁴ are taken together to form a lower alkylene group, a lower alkenylene group, or represented by the formula ι — The compound according to claim 1, which is a C— (CH ₂ ) n— group, or a salt thereof. 3. X is a compound or a salt thereof as set forth in claim 1, wherein the claims is a sulfur atom 4. Substituent R ⁵ is a halogen atom, a hydroxyl group, a lower alkyl group, lower alkenyl group, a lower alkoxy group, a lower Arukeniruokishi Group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfinyloxy group, lower alkylsulfonyloxy group, lower alkylsulfonamide group, nitro group, amino group, cyano group, trifluoro Methyl group, lower acylamide group, carboxy group, lower alkoxycarbonyl group, aryl group, aralkyl group, carbamoyl group, sulfonyl group, lower alkanoyl group, lower acetylmethylamino group, mono- or di-alkyl substitution Amino group,, mono or dialkyl-substituted aminocarbon 2. The compound according to claim 1, which is a mono- or di-alkyl-substituted aminosulfonyl group, or a salt thereof. R ¹ and R ² are a lower alkyl group or a group which together form a saturated monocyclic nitrogen-containing heterocyclic ring with a nitrogen atom, and R ³ , is a hydrogen atom, a lower alkyl group, R ³ And R <are together a lower alkylene group or a group represented by the formula Xi, wherein R ⁵ is halo. — C— (CH ₂ ) n— Gen atom, trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylsulfonyloxy group, lower acylamino group, lower alkylsulfonamide group, 1 to 2 oxygen atoms condensed with a carbocyclic group or a benzene ring which may be substituted by a nitro group, amino group, cyano group or aryl group 2. The compound according to claim 1, wherein R ⁶ is a heteroaryl group optionally substituted with a nitro group or an amino group, or a salt thereof. 6. A group in which R ¹ and R ² form a ring together with a nitrogen atom to form a ring, and R ³ and R ⁴ are the same or different and each have a hydrogen atom, a lower alkyl group, or a substituent in combination. R ⁵ is a lower alkyl group, a halogen atom, a phenyl group substituted with a trifluoromethyl group or a 3,4-methylenedioxyphenyl group, and R ⁶ is a phenyl group. 2. The compound according to claim 1 which is a group or a salt thereof. 7. R ¹ and R ² are a pyrrolidinyl group together with a nitrogen atom, R ³ and R ⁴ are a trimethylene group and R ⁵ is a phenyl group substituted with a halogen atom or a trifluoromethyl group. 3. The compound according to claim 2, wherein R ⁶ is a phenyl group, or a salt thereof. 8. R ¹ and R ² are in the form of a pyrrolidinyl group together with a nitrogen atom, R ³ and R ⁴ are different hydrogen atoms or lower alkyl groups, and R ⁵ is a phenyl group or a lower alkyl group substituted with a lower alkyl group. 4. The compound according to claim 3, which is a 1,3-methylenedioxyphenyl group and R ⁶ is a phenyl group, or a salt thereof.  9. (S) — 1- (3,4-dichlorophenyl) 1-2-oxo-1 3-1-1 [1-phenyl-2- (1-pyrrolidinyl) ethyl] pyramide or salt thereof  10. (S) — 2-oxo-1- 1- [2-phenyl-2-ethyl (1-pyrrolidinyl) ethyl] — 3- (4-trifluoromethylphenyl) perhydropyrimidine or its salt 11. (S) — 1-Methyl-3— (3,4-Methylenedioxyphenyl) 1- [1-1-Phenyl-2- (1-pyridinyl) ethyl] thiourine or its salt 12. 1- (4-sec-butylphenyl) — 3-methyl-3 — [(1S) 1-phenyl-2- (1-pyrrolidinyl) ethyl] thiourea or salt thereof —  13. In a method for producing a novel urea derivative represented by the following general formula (I) or a salt thereof,

(The groups in the formula mean the following groups. R ¹ , R ² : lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, or a group in which R ¹ and R ² can form a ring together with a nitrogen atom. R ³ , R ⁴ : a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, or a combination of R ³ and R ⁴ which may have a substituent; Lower alkenyl

 (Wherein X represents an oxygen atom or a sulfur atom, and n represents an integer of 1 to 5.) R ⁵ : an optionally substituted carbocyclic group or a heterocyclic group having one or two oxygen atoms and Z or sulfur atoms condensed with an optionally substituted benzene ring R ⁶ : a phenyl group which may be substituted  X: oxygen atom or sulfur atom However, when X is an oxygen atom, R ³ and R ⁴ together represent a lower alkylene group, a lower alkenylene group or a group represented by the formula which may have a substituent. ) — C— (CH ₂ ) n— 1) General formula (II)

And an amine compound represented by the general formula (III) X-CNR ⁵ (III)  React with the compound shown by  2) —Amine compound represented by general formula (II) and general formula (IV) R ⁵ -NH ₂ (IV)  And a compound represented by the general formula (V) CX Υ ₂ (V)  (Where 式 represents a halogen atom.)  3) The amine compound represented by the general formula (II), the compound represented by the general formula (IV) and the compound represented by the general formula (VI) CX ₂ (VI)  React with carbon dioxide or carbon disulfide shown in 4) — Among the compounds represented by the general formula (I), the compounds represented by the following general formula (lb)

Is represented by an amine compound represented by the general formula (II) and a compound represented by the general formula (VII) R ⁵ -NHCOOR ⁷ (VII)  Reacting with the amino formate represented by 5) — Among the compounds represented by the general formula (I), the compounds represented by the following general formula (Ic) R ⁶ 0  (I c) Is represented by a compound represented by the general formula (lb) and a compound represented by the general formula (VIII) R: Z (VIII)  (Wherein, Z represents a halogen atom or a sulfonyl group.)  ) Among the compounds represented by the general formula (I), the compounds represented by the following general formula (Ie)

(In the formula, A means an alkylene group or an alkenylene group having 2 to 6 carbon atoms.) Is given by the general formula (I d)

And a compound represented by the general formula (IX)  Z—A-Z (IX) Reacting a compound represented by the general formula (X)

And a compound represented by the general formula (XI) CXY ₂ (XI)  Reacting halide or carbonyldiimidazole represented by  7) Among the compounds represented by the general formula (I), the compound represented by the following general formula (If)

About the ability to react phosphorus pentasulfide or Lawesson's reagent with the compound represented by the general formula (Ic),  8) General formula (Ig)

A method comprising reducing the compound represented by the formula:  14. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.  15. A compound as claimed in claim 1 or a salt thereof as an active ingredient / c-receptor activator 16.Central analgesic containing the compound described in claim 1 or a salt thereof as an active ingredient Claims captured [November 23, 1992 (23.11.92) Accepted by the International Bureau; Claim 1 at the time of filing was captured; other claims unchanged. (1 page)] I. Novel urea derivative represented by the following general formula (I) or a salt thereof

(The groups in the formula mean the following groups. R ¹ , R ² : lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, or group in which R ¹ and R ² are united to form a ring together with a nitrogen atom R ³ , R ⁴ : hydrogen atom, lower alkyl group, lower alkenyl group, lower alkylene group, cycloalkyl group, or R ³ and R ⁴ —A lower alkylene group, a lower alkenylene group or a group represented by the formula (wherein, X: — C— (CH ₂ ) n—  Represents an oxygen atom or a sulfur atom, and n represents an integer of 1 to 5. ) R ⁵ : a heterocyclic group containing one or two oxygen atoms and one or two sulfur atoms condensed with an optionally substituted carbocyclic group or an optionally substituted benzene ring R ⁶ : substituted Remoyl phenyl group  X: oxygen atom or sulfur atom Provided that when X is an oxygen atom, R ₃ , a lower alkyl group, a lower alkenylene group or a lower alkenylene group which may have a substituent together;  ι  II -Means a group represented by C— (CH ₂ ) n—. ) Instructions under Article 19 It is clear from the specification and the claims that the carbonyl group in the general formula (I) in claim 1 is simply a clerical error, and does not exceed the scope of disclosure at the time of filing a face-to-face application .  Therefore, this amendment rectifies this mistake and clarifies that it is significantly different in structure and effect from the example cited in the international search report.