JPH05504968A - Glycinamide derivatives, their production and pharmaceuticals containing them - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Glinonamide derivatives, their production and pharmaceuticals containing the same The present invention relates to the following formula: derivatives, their production methods, and pharmaceuticals containing them.

In formula (1), -R, ha・ ・Phenyl group or halogen atom and alkyl, alkoxy, alkylthio, di Fe substituted with one or more substituents selected from tro and cyano groups Nyl group, ・41　CH(R4)　-CO-Rs, where R4 is a hydrogen atom, furkyl, or an alkoxycarbonyl group, or (optionally a halogen atom and an alkyl, alkoxycarbonyl group) substituted by one or more substituents selected from xy, alkylthio and nitro groups (optionally substituted) phenyl group, R6 is alkoxy, (optionally at least (optionally substituted with one alkyl group) cycloalkyloxy, cycloalkyl Alkyloxy, phenylalkyloxy, polyfluoroalkyloxy or nanamyloxy group, or residue -N Ra R7, where R6 and R7 can be the same or different, and hydrogen atoms or alkyl, (optionally halogen) One or more atoms selected from alkyl, alkoxy, and alkylthio groups phenyl, cycloalkylalkyl, cyclo is an alkyl, indanyl or phenylalkyl group, or otherwise R6 and R7 together with the nitrogen atom to which they are bonded are saturated or unsaturated single or It forms a polycyclic heterocycle, which has 4 to 9 carbon atoms and has a ring length of 1 m or more. It has elementary atoms (0, N, S) and 1. Optionally one or more alkyl, alkyl substituted by xy, alkoxycarbonyl, dialkylcarbamoyl or phenyl group optionally 1m or more in combination with the carbon atoms of the heterocycle. Optionally substituted in a 4- or 5-membered spiro-ring system containing the above heteroatoms (0, S, N) may be replaced, -R, is pyridyl, isoquinolyl, quinolyl, quinoxalinyl (these complexes The ring contains one or more alkyl and phenyl groups or halogen atoms. optionally substituted with a substituent), alkyl, phenylalkyl, naphthi Le, 5. 6. 7. 8-tetrahydronaphthyl, 1, 2. 3. 4-te trahydronaphthyl, alkoxycarbonylalkyl or cycloalkyl group the law of nature, -R3 is (optionally a halogen atom and an alkyl, alkoxy and alkylthio group) phenyl, naphyl, which may be substituted with one or more substituents selected from a thyl, indolyl or quinolyl group, or a phenyl ring optionally containing a halogen atom, and alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbony hydroxyl, nitro, amino, acyl, cyano, sulfamoyl, carba Moyl, benzoyl, phenylhydroxymethyl, piperidino, hydroxyimine Noalkyl, Alcoquiniminoalkyl, Hydroxyaminocarbonyl, Alco xyaminocarbonyl, 5-tetrazolyl, 5-tetrazolylalkyl, triph fluoromethylsulfonamide, alkylsulfinyl, mono- or polyhydroxy Alkyl, sulfo, -a I k-0-Co-a l k, -a 1 k-C 00X, -a]] k-0-aI, ni, a I k' -COOX, -0 -a Jk -COOX, -CH=CH-COOX, -Co-COOX, - a 1 k-5OsH, -CH=CH-a] k', -C (=NOH) C0 to one or more substituents selected from 0X and -3-a Ik-COOX groups -X is a phenylamino group which may be substituted by a hydrogen atom or an alkyl group, -alk is an alkyl or alkylene group, -alk' is a It is a droxyalkylene or hydroxyalkyl group.

In the definitions mentioned above and below, unless stated otherwise, alkylene and alkoxy groups and alkyl, alkylene and alkoxy The moieties contain 1-4 carbon atoms in a straight or branched chain and include cycloalkyl groups and moieties. Minutes contain 3-6 carbon atoms and acyl groups contain 2-4 carbon atoms.

In formula (1), the halogen atom is preferably a chlorine, bromine or fluorine atom. Yes.

When R6 and Ry together with the nitrogen atom to which they are attached form a heterocycle, the latter (optionally at least one alkyl, phenyl, alkoxycarbonyl or (optionally substituted with a dialkylcarbamoyl group) piperidino ring 1, or perhydro-1-azepinyl, 1.2.3.6-tetrahydro-1-pyridyl, 1. 2. 3. 4-tetrahydro-1-quinolyl, 1-pyrrolidinyl, 3. 4-dihydro-2H-1,4-benzoxazin-4-yl, 3,4-dihydro- 2H-1,4-benzothiazin-4-yl, N-alkyl-1,2,3,4-te trahydro-1-quinoxalinyl, perhydro-1-quinolyl, 1. 2. 3 ．． 4-tetrahydro-2-isoquinolyl, 8-azaspiro-[4,5]decane -8-yl, 2- or 3-phenyl-1-pyrrolidinyl, 8-aza-1,4-di oxaspiro[4,5]decane-8-yl, (with optionally less than one alkyl thiomorpholino or l-indolinyl (which may be substituted by a group) is preferable.

Compounds of formula (1) containing one or more asymmetric centers have isomeric forms . Racemates and enantiomers of these compounds also form part of the invention.

In formula (I), R8 is a phenyl ring optionally a halogen atom, alkyl, or Koxy, alkylthio, nitro, acyl, cyano, sulfamoyl, benzoyl , alkoxycarbonyl, -a 1 k-0-a 1 k.

5-tetrazolyl, 5-tetrazolylalkyl and trifluoromethylsulfone Phenyl optionally substituted with one or more substituents selected from amide groups A compound that is an amino group has the following formula (0 formula%) [In the formula, R3 is optionally a halogen atom and alkyl, alkoxy, alkylthio, Nitro, acyl, cyano, sulfamoyl, benzoyl, alkoxycarbonyl , -alk-0-alk, 5-tetrazolyl, 5-tetrazolylalkyl and by one or more substituents selected from the fluoromethylsulfonamide group. is an optionally substituted phenyl group] to an isocyanate using the following formula: Produced by the action of a derivative of [wherein R1 and R2 have the same meanings as in formula (1)] can be built.

This reaction is commonly performed using tetrahydrofuran, dimethylformamide, chlorinated solvents (e.g. e.g. chloroform, l,2-dichloroethane) or aromatic solvents (e.g. benzene). in an inert solvent such as zene, toluene) at a temperature between 10°C and the boiling point of the solvent. cormorant.

Isocyanates of formula (III) are available from R, RICHTER et al., TheChem istry of Cyanate [sic] and their th io derivatives, S, PATAI.

Part2. Apply the method described in WiIey New-York (1977). It can be obtained by using or applying.

Derivatives of formula (II) are derived from T, WIELAND et al., Justus Liebig s Ann, Chem, 613.84 (1958). or by the Gabriel method (M, S, GIBSON, etc., Angew, Che m, Int, Ed., 7.919 (1968)). , Gabriel method is the following formula 0 formula % () [In the formula, R9 is a hydrogen atom or a methyl group] hydrazine, and the following formula [In the formula, R, and R2 include a reaction with a derivative of co having the same meaning as in formula (1).

This reaction can be performed using alcohols (e.g. methanol, ethanol) or chlorinated solvents (e.g. in an inert solvent such as chloroform, dichloromethane) from 0°C to the boiling point of the solvent. It is preferred to carry out at temperatures up to the point.

The derivative of formula (V) is expressed by the following formula To the derivative of [wherein R2 has the same meaning as in formula (1)], the following formula Ha I - R+ (VI) [In the formula, R1 has the same meaning as in formula (1), and Hal is a halogen atom (preferably (or chlorine or bromine)].

This reaction is generally performed using acetonitrile, dimethylformamide or tetrahydrofuran. at 0°C in the presence of a base such as an alkyl metal hydride in an inert solvent such as and the reflux temperature of the reaction medium.

Derivatives of formula (VII) can be converted to 2-phthalimidoacetyl chloride by the following formula: %formula%) [In the formula, R7 has the same meaning as in formula (I)] can be obtained by the action of an amine. can.

This reaction is generally performed using chlorinated solvents (e.g. chloroform, 1,2-dichloroethane). ) in an inert solvent such as tertiary amines such as trialkylamines or alkaline It is carried out at a temperature around 20°C in the presence of a base such as potassium metal carbonate or bicarbonate. cormorant.

2-phthalimide acetyl chloride is W, GRASSMANN, etc.

Applying the method described in Chem, Ber, 83.244 (1950) It can be manufactured by

Derivatives of formula (V) can also be converted to 2-phthalimidoacetyl chloride by the following formula R, -NH- R, (IX) [In the formula, R1 and R2 are obtained by the action of the same amine as in the case of formula (I)] can be done.

This reaction is carried out under the conditions described above for the preparation of compounds of formula (VII). .

Amines of formula (IX) are commercially available or can be obtained by application of the methods described in the Examples. Or it can be obtained by application.

In particular, these compounds have the following formula E, R and R2 have the same meanings as in formula (1)] by hydrolysis of a derivative of can be obtained.

This hydrolysis is generally carried out using an inert solvent such as water, alcohol, or a mixture of these solvents. In the compound, alkali metal hydroxide (sodium hydroxide, potassium hydroxide) or using a base such as ammonium hydroxide to reduce the reflux temperature of the reaction medium from 20°C. Do it between degrees.

The derivative of formula (X) is converted to the derivative of formula (VI) by the following formula Rt-NHC0CF! ( XI) [Formula thR, can be obtained by the action of a derivative of Can be done.

This reaction is generally carried out using tetrahydrofuran, dimethylformamide or acetonitrile. alkali metal hydride or alkali metal carbonate in an inert solvent such as in the presence of a base such as, between 10° C. and the reflux temperature of the reaction medium.

The derivatives of formula (ON) are prepared by the action of trifluoroacetic anhydride on the amine of formula (VIII). can be obtained.

This reaction is generally carried out in an inert solvent such as pyridine at temperatures between -25°C and 10°C. Do it with

In formula (1), R8 is a phenylamino group in which the phenyl ring is optionally substituted; A compound has the following formula %formula%) [In the formula, R1° is optionally a halogen atom, alkyl, alkokene, alkylthio , carboxyl, alkoxycarbonyl, hydroxyl, nitro, amino, acyl cyano, sulfamoyl, carbamoyl, benzoyl, phenylhydroxy Methyl, piperidino, hydroxyiminoalkyl, alkinoiminoalkyl, Hydroxyaminocarbonyl, alkoxyaminocarbonyl, 5-tetrazolyl , 5-tetrazolylalkyl, trifluoromethylsulfonamide, alkyls rufinyl, mono- or polyhydroxyalkyl, sulfo, -a I k-0- Co-a] k, -alk-COOX, -a 1k-0-a lk, a I k'-COOX, -0-a] k C00X, CH=CH-C00X, a l k-5O3H1-co-coox, -CH=CH-a lk', -C(= NOH)-Co.

by one or more substituents selected from X and -Sa l k-COOX groups is an optionally substituted phenyl group] to a derivative of the following formula 5 [wherein R1 and and R2 can also be produced by the action of a derivative of the same meaning as in the case of formula (I). I can do it.

This reaction is generally performed using tetrahydrofuran, dimethylformamide, chlorinated solvents or is carried out in an inert solvent such as an aromatic solvent at a temperature between 20° C. and the boiling point of the solvent.

Substituted anilines of formula (Xllll) are commercially available or R95CHRQ TER, Methoden der Organischen Chemie, Houben Weil, Volume X/l.

It can be obtained by application or adaptation of the method described in p., 360.

Derivatives of formula (Xll) are derivatives of formula (I It can be obtained by the action of a derivative of I).

This reaction is generally performed using tetrahydrofuran, dimethylformamide, chlorinated solvents or is carried out in an inert solvent such as an aromatic solvent at a temperature between 20° C. and the boiling point of the solvent.

In formula (1), R8 is phenylamine whose phenyl ring may be optionally substituted. Compounds having the following formula [wherein R1 and R1 are , can also be produced by the action of a derivative of the same meaning as in the case of formula (I). Ru.

This reaction is commonly performed using tetrahydrofuran, dimethylformamide, chlorinated solvents ( e.g. chloroform, 1,2-dichloroethane) or aromatic solvents (e.g. benzene). in an inert solvent such as chlorine, toluene) at a temperature between 10°C and the boiling point of the solvent. .

Isocyanate of formula (XIV) can be converted to isocyanate acetyl chloride by formula (I It can be obtained by the action of X) with an amine.

This reaction is generally performed in an ether (e.g. diethyl ether) or an aromatic solution (e.g. amines, e.g. triethyl alcohol, in an inert solvent such as benzene, toluene). It is carried out at a temperature of about 5°C to 30°C in the presence of an acid acceptor such as amine or pyridine.

In formula (1), R3 optionally represents a halogen atom, alkyl, alkoxy, or Lukylthio, nitro, acyl, cyano, sulfamoyl, benzoyl, alkoxy cyclocarbonyl, -al to -0-alk15-tetrazolylalkyl, 5-tetra one or more selected from zolyl and trifluoromethylsulfonamide groups A compound that is a phenylamino group substituted with a substituent has the following formula: %formula%() [Formula (IX) in which R3 is the same acid as defined above or an active derivative of this acid] It can also be produced by the action of amines.

When an acid is used, the reaction is performed with an ether (e.g. tetrahydrofuran, dioxane), amides (dimethylformamide) or chlorinated solvents (e.g. methylene chloride, 1 , 2-dichloroethane, chloroform). (e.g. dicyclohexylcarposiimide) or N,N'-carbonyldiimide from 0 °C to the reflux temperature of the reaction mixture in the presence of a peptide condensing agent such as midazole. I will do it.

When using active derivatives of acids, anhydrides, mixed anhydrides, acid halides or esters ( (can be selected from activated or deactivated esters of acids) Wear.

The reaction is carried out in an organic medium with a nitrogenous organic base (e.g. trialkylamine, pyridine). , 1,8-diazabicyclo[5,4,0]-7-undecene or 1,5-dia in the presence of an acid acceptor such as zabicyclo[4,3,0]-5-nonene). or mixtures thereof, between 0°C and the reflux temperature of the reaction medium; alkaline metal or alkaline earth metal base (sodium hydroxide, potassium hydroxide) or two-phase water in the presence of alkali metal or alkaline earth metal carbonates or bicarbonates. - Carry out in an organic medium at a temperature of 0 to 40°C.

The acid of formula (XV) is obtained by the action of an isocyanate of formula (III) on glycine. can be done.

This reaction is generally carried out in aqueous solution in the presence of a base such as an alkali metal bicarbonate. It is carried out at a temperature in the range of 0°C.

In formula (I), R2 is carboxyl having at least one phenyl ring, -a 1 k-COOHl-0-a l k-COOHl-a 1 k’-C0OH , -CH=CH-C0OH, -Co-COOH, -9-a 1k-C00X or A compound that is a phenylamino group substituted by a -C(=NOH)-COOH group can also be prepared by hydrolysis of the corresponding ester.

This hydrolysis is generally performed using an inert solvent such as tetrahydrofuran, dioxane, or water. , or in a mixture of these solvents, such as sodium hydroxide or potassium hydroxide. It is carried out using a base at a temperature of 20°C to 40°C or using a chlorinated solvent (e.g. dichloromethane). in an inert medium such as chloromethane, chloroform, l,2-dichloroethane). It is carried out using fluorinated acetic acid at a temperature from 20° C. to the boiling point of the solvent.

In formula (I), R3 is an optionally substituted phenyl group, or naphthyl, Compounds with indolyl or quinolyl group have the following formula % formula % () to an acid of the formula (I in which R3 has the same meaning as above) or an active derivative of this acid. It can be produced by the action of a derivative of I).

This reaction is described above for the reaction of an amine of formula (IX) and an acid of formula (XV). carried out under the following conditions.

For those skilled in the art, in order to carry out the method of the invention described above, a group protecting the amine function can be added. It will be appreciated that it is necessary to avoid side reactions by introducing these The functional group can be protected, for example in the form of trifluoromethylacetamide, and then It can be regenerated by the action of ammoniacal methanol after performing the method described above. Ru.

At least 1! An enantiomer of a compound of formula (I) having an asymmetric center of, for example W, H, PIRCKLE, etc., Asymmetric 5ynthesis, vo l, 1. Chiral column according to Academic Press (1983) by chromatographic resolution of the racemate or from chiral precursors. It can be obtained by the synthesis of

Compounds of formula (I) can be prepared by conventional methods such as crystallization, chromatography, extraction, etc. It can be purified by the following method.

Compounds of formula (I) exhibit advantageous pharmacological properties. These compounds Strong affinity for tokinin (CCK) receptors and gastrin receptors and thus the disease associated with CCK and gastrin at the nervous and gastrointestinal level. Useful for treatment and prevention.

Therefore, these compounds may be used to treat psychosis, depression, Parkinson's disease, tardive movement disorder, Irritable bowel syndrome, acute pancreatitis, ulcers and poor intestinal motility, as well as lower esophagus and large intestine and for the treatment and prevention of certain types of tumors, as well as for use as an appetite regulator. I can do it.

These compounds also have a boosting effect on the pain activity of narcotic and non-narcotic drugs. has.

The affinity of the compound of formula (1) for the CCK receptor is determined by A, 5AITO, etc., (J , Neuro, Chem, 37.483-490 (1981)). Then, it was determined at the cerebral cortex level and pancreatic level.

In these tests, the cso of compounds of formula (I) is generally 1,000 nM That's not all.

In addition, products that recognize central CCK receptors have been shown to react with gastrin in the gastrointestinal tract. are known to have similar specificity (BOCK et al.

J, Med, Chem, 32.16-23 (1989); REYFELD et al. , Am, J, Phys iol, , 240. G25, 5-266 (1981) : BEINFELD et al., Neuropeptides, 3.411-427 ( 1983)).

Compounds of formula (I) have low toxicity. When administered subcutaneously to mice, the LDs o is generally 40 mg/kg or more.

Of particular interest is the formula (I) 11m~cRJ<chain-CH(R4)-COR.

, where R4 is a hydrogen atom and R3 is alkoxy, preferably tert -butoxy group, or the residue -NRaRT, where R6 is an alkyl group. and R7 is a phenyl group, or R1 and R7 are bonded together. 1. 2. 3. 4-tetrahydro-1-quinolyl group R2 is a quinolyl or isoquinolyl group, and R2 is a phenyl ring selected from Kyl, carbonyl, hydroxyiminoalkyl or hydroxyalkyl group Compounds that are phenylamino substituted with one or more substituents It is.

The following compounds are particularly advantageous: -(E)-2-+3- [3-'(Hydroxyiminomethyl)phenylcolare -N-(8-quinolyl')-N-[(1,2,3,4-tetrahydro- 1-quinolyl)-carponylmethylcoacetamide-2-[3-(3-methylphenyl) (enyl) ureidoco N-[2-(1,2゜3.4-tetrahydro-1-quinolinyl) )-2-oxoethyl]-N-(8-quinolyl)acetamide -3-13-IN-(8-quinolyl)-N-[2-(1,2,3,4-tetrahydryl) Dolo-1-quinolyl)-2-oxoethyl)carbamoylmethyl)ureido)an Zozoic acid -tert-butyl 2- +2- [3-(3-methylphenyl)ureido] -N-(4-inquinolyl)acetamido)acetate-2-+3- [3- (hydroxymethyl)phenylcolaleido)-N-(8-quinolyl')-N-[ 2-(1,2,3,4-tetrahydro-1-quinolyl)-2-oxoethyl]a Cetamido-tert-butyl 2-[2-[3-(3-methylphenyl)u Reid]-N-(5-quinolyl)acetamide]acetate-tert-butyl 2-[2-[3-(3-methylphenylinureidoco N-(8-quinolyl ) Acetamide] Acetate-tert-butyl 2- + 2- [3-[3- (1-Hydroxyethyl)phenylchoraleido)-N-(8-quinolyl)acetate amide) acetate -tert-butyl 2-[2-+3-[3-(hydroxymethyl)phenylene Lucolarade 1-N(4-isoquinolyl)acetamide]acetate -3-+3- [N-(N-methyl-N-phenylcarbamoylmethyl)-N- (8-quinolyl)carbamoylmethyl]ureido)benzoic acid-3-(3-[N- t e r t-butoxycarbonylmethyl-N-(8-quinolyl)-carbamo ylmethylcoureide) benzoic acid.

The following examples illustrate, but do not limit, the invention.

Example 1 tert-butyl 2-[2-phthalimide in dichloromethane (90c) In a solution of -N-(3-pyridyl)acetamido]acetate (6.1 g), 0! Add methylhydrazine (2.13 g) at a similar temperature. The reaction mixture was heated to 20°C. Stir for 30 minutes at ambient temperature and then for 1 hour under reflux. After cooling, water (100cc) was added, the mixture was stirred and after the onset of precipitation the aqueous phase was separated and dichloromethane (2x6 0cc). Combine the organic phases, wash with water (2 x 15 cc), and add sulfuric acid. Dry over magnesium, filter and then concentrate under reduced pressure (2,7 kPa) at 40°C. dry.

This results in tert-butyl 2-[2-amino-N-(3-pyridyl)acetate. toamide] acetate (3.75 g) was obtained as a yellow oil, which was poured into anhydrous tetra Dissolve in hydrofuran (40cc). Add 3-methylphenylisisosil to this solution. Anate (1,9 g) was added and the reaction mixture was then stirred for 1 hour at a temperature around 20°C. Stir and concentrate to dryness under reduced pressure (2.7 kPa) at 40°C. Residue in ethyl acetate After recrystallizing with ) ureido]-N-(3-pyridyl)acetamitocoacetate (2.25g) , a melting point of 173°C is obtained.

tert-butyl 2-[2-phthalimido-N-(3-pyridyl)acetamide Tocoacetate can be produced in the following way: kept under an argon atmosphere. 2-phthalimide-N-(3 -pyridyl)acetamide (11.4 g) at a temperature around 10°C. An oily suspension of lium hydride (50% by weight) (2.13 g) was added, and the obtained The suspension is stirred for 1 hour at a temperature around 20°C. Then anhydrous tetrahydrofuran (20c) A solution of tert-butyl bromoacetate (9.5g) in and continued stirring at a temperature of around 20°C for 3 hours, then at a temperature of around 40°C for 45 minutes. Let's go. The reaction mixture was then cooled to a temperature around 0°C and then heated to 0°C with water (150c Pour into a mixture of c) and ethyl acetate (200c). After the start of settling, the aqueous phase Separate and re-extract with ethyl acetate (2x40cc). Combine organic phases and wash with water (3x50cc), dried over magnesium sulfate, filtered and dried under reduced pressure (2,7k Pa) Concentrate and dry at 40°C. After recrystallization in ethyl acetate, tert-butyl 2-[2-phthalimido-N-(3-pyridyl)-acetamitocoacetate ( Obtain 7.8 gL melting point 154°C.

2-phthalimido-N-(3-pyridyl)acetamide is produced by the following method. 3 in dichloromethane (80 cc) kept under an argon atmosphere. - Add triethylamine (5.6 g) to a solution of aminopyridine (4.7 g) , then 2- in dichloromethane (70 cc) while keeping the temperature around 20°C. A solution of phthalimide acetyl chloride (11.2 g) is added. The obtained solution Stir for 3 hours at a temperature around 20° C. and treat with water (300 cc). solid to form was separated by filtration and diisopropyl ether (3xlOcc) and water (3x2 0 CC) and air dry. After the onset of sedimentation, the organic phase of the filtrate is separated and mixed with water ( 2 x 20 cc), dried over magnesium sulfate, filtered and washed under reduced pressure (2, 7kPa) Concentrate and dry at 40°C. Combine the obtained solid with the above solid and is recrystallized in ethyl acetate. Thereby, 2-phthalimido-N-(3-pyridi ) acetamide (11.4 g), melting point 229°C.

2-phthalimidoacetyl chloride, W, GRASSMAN et al., Ber, 8 3.244 (1950). Using a method analogous to tert-butyl 2-C2-phthalimide-N- (8-quinolyl)acetamitocoacetate (9.3g), methylhydrazine (2,9 g) and 3-methylphenylisocyanate (2,8 g) and after recrystallization in ethyl acetate, tert-butyl 2-[2-[3-(3-methyl tylphenyl)ureido] -N-(8-quinolyl)acetamitocoacetate (5.6 g), melting point 131°C.

tert-butyl 2-[2-phthalimido-N-(8-quinolyl)acetamide Tocoacetate is 2-[2-phthalimide-N-(3-pyridyl) in Example 1. ) using a method similar to that described for the production of acetamitocoacetamide; , 2-phthalimido-N-(8-quinolyl)acetamide (12,3g), Nato Oily suspension (50% by weight) of lithium hydride (2 g) and tert-butyl Starting with bromoacetate (8.8 g). of recrystallization in ethyl acetate Then, tert-butyl 2-[2-phthalimido-N-(8-quinolyl)aceto Amitocacetate (12.3 g), melting point 196° C., is obtained.

2-phthalimido-N-(8-quinolyl)acetamide is 8-aminoquinoline (5,8g), triethylamine (4,4g) and 2-phthalimide acetylamine 2-phthalimide- Produced in a similar manner as described for the production of N-(3-pyridyl)acetamide can do. Thereby, 2-phthalimido-N-(8-quinolyl)acetyl Toamide (4.3 g) is obtained, melting point 224°C.

Example 3 Using a method similar to that described in Example 1, but using tert-butyl 2-[2-phenyl Talimide-N-(2-pyridyl)acetamitocoacetate (3.45gL Meth) Chylhydrazine (1,2 g) and 3-methylphenylisocyanate (1,16 g), diisopropyl ether and ethyl acetate (95:5 volume ratio) ) in a mixture of tert-butyl 2-[2-[3-(3-methyl phenyl)ureidoco-N-(2-pyridyl)acetamitocoacetate (0, 45 g), melting point 112°C.

tert-butyl 2-[2-phthalimido-N-(2-pyridyl)acetamide Tocoacetate is 2-[2-phthalimide-N-(3-pyridyl) in Example 1. ) using a method similar to that described for the production of acetamitocoacetamide; , 2-phthalimido-N-(2-pyridyl)acetamide (4.3gL sodium Oily suspension (50% by weight) of muhydride (0.8 g) and tert-butyl Start with chill bromoacetate (3.5 g). Recrystallization in ethyl acetate After that, tert-butyl 2-[2-phthalimido-N-(2-pyridyl)acetate Obtain toamitocoacetate (3.5 gL melting point 120°C).

2-phthalimido-N-(2-pyridyl)acetamide is 2-aminopyridine (2,4g), triethylamine (2,8g) and 2-phthalimide acetylamine 2-phthalimide- Produced in a similar manner as described for the production of N-(3-pyridyl)acetamide can do. Thereby, 2-phthalimido-N-(2-pyridyl)acetate Toamide (4.3 g) is obtained, melting point 193°C.

Example 4 3-Methylphenyl isocyanate (0.72 g) was added to the tube at a temperature around 20°C. tert-Butyl 2-(2-amino-N- Add to a solution of (8-isoquinolyl)acetamitocoacetate (1.6 g).

The resulting solution was stirred for 4 hours at a temperature around 20°C, and then stirred under reduced pressure (2,7kP a) Concentrate to dryness at 40°C.

The residual oil was poured into a 2 cm diameter column packed with silica (0,063-0 mm) (1 50 g) (eluent dichlorohexa/ethyl acetate (75: 25 volume ratio)] and collect a 20 cc fraction. Contains only the desired product The fractions were combined and concentrated to dryness under reduced pressure (2.7 kPa at 40°C. In ethyl acetate. After recrystallization, tert-buty2-[2-[3-(3-methylphenyl)ureido ]-N-(8-tsuquinolyl)acetamido]acetate) (0.85g), Melting point 170゛tert-butyl 2-[2-amino-N-(8-inquinolyl) 'cetamido]acetate is tert-butyl 2-[2-phthalide-N- (8-Inquinorinori Z cetamide coacetate (2.6g) and hydrazine ha tert-butyl 2-C except starting with idlate (0,93 g) Regarding the production of 2-amino-N-(3-pyridyl)acetamitocoacetate It can be prepared by Method 1 analogous to the method described in Example 1. Thereby, ter t-Butyl 2-[2-amino-N-(8-isoquinolyl)acetamitocoacetate tate (1,75) was obtained in oil form and used for subsequent synthesis without further treatment. Tert-butyl used 2-[2-phthalimide-N-(8-isoquinolyl) ) acetamitocoacetate is 2-phthalimido-N-(8-inquinolyl) Acetamide (4.3 gL oily suspension of sodium hydride (501% by weight) (0.76g) and tert-butyl bromoacetate (2.65g). tert-butyl 2 can be used. Thereby, te rt-Butyl 2-[2-phthalimido mido-N-(8-isoquinolyl)acetate Toamitocoacetate (2.6 g) was obtained in the form of an oil, which could be further processed. used for subsequent synthesis.

) 2-phthalimido-N-(8-isoquinolyl)acetamide is 8-' Aminoisoquinoline (3.4gL) Triethinogenine (2.63g) and I and 2 - Starting with phthalimide acetyl chloride (5,75 g) Example 1 for the production of 2-phthalimido-N-(3-pyridyl)acetamide It can be manufactured by a method similar to that described in . Due to this, 2-phthal Imido-N-(8-inquinolyl)acetamide (4.3 g) is obtained.

) Example 5 tert-butyl 2-[2-amino-N-(5-quinolyl)acedoamide ] acetate (3,3 g) and 3-methylphenylisocyaner (1,3 Using a method similar to Example 4, except using di-isopropyl ether After recrystallization in chill, tert-butyl 2-[2-[3g’)-(3-methyl ruphenyl)ureido]-N-(5-quinolyl)acetate. Mido] acetate (3.9 g), melting point 121°C.

Tert-butyl 2-[2-amino-N-(5-quinolyl)acetone a tert-butyl 2-[2-phthalimide-raw N-( 5-quinolyl) acetamitocoacetate (5,5 g) and human e radin high tertj-butyl 2 except starting with drate (1,85 g) Regarding the production of -[2-amino-N-(3-pyridyl)acetamitocoacetate] It can be produced by a method similar to that described in Example 1. Thereby, t ert-butyl 2-[2-amino-N-(5-quinolyl)acetamitocoacetate Tate (3.3 g) was obtained as an oil, which was subjected to subsequent synthesis without further treatment. used for.

tert-butyl 2-[2-phthalimido-N-(5-quinolyl)acetamide Tocoacetate is 2-phthalimido-N-(5-quinolyl)acetamide (8 Oily suspension (50% by weight) of gL sodium hydride (1,16 gL and t except starting with ert-butyl bromoacetate (47 g). t-Butyl 2-[2-phthalimido-N-(3-pyridyl)acetamitocore Produced by a method similar to that described in Example 1 for the production of cetate. Can be done. 1, tert-butyl 2-C after recrystallization in diisopropyl ether 2-phthalimido-N-(5-quinolyl)acetamitocoacetate (5°5g ), giving a melting point of 168°C.

2-phthalimido-N-(5-quinolyl)acetamide is 5-aminoquinoline (3,6g), triethylamine (2,8g) and 2-phthalimide acetylamine 2-phthalimide- Produced in a similar manner as described for the production of N-(3-pyridyl)acetamide can do. Thereby, 2-phthalimido-N-(5-quinolyl)acetyl Toamide (8 g) is obtained.

Cetamide coacetate (1,95g) and 3-methylphenylisonanate Using a method similar to Example 4 except using diisopropyl After recrystallization in ether, tert-butyl 2-[2-[3-(3-methylphenyl) [phenyl)ureido]-N-(5-isoquinolyl)acetamitocoacetate (1 , 3g), melting point 188°C.

tert-butyl 2-[2-amino-N-(5-quinolyl)acetamito Coacetate is tert-butyl 2-[2-phthalimido-N-(5-iso quinolyl)acetamido]acetate-h (3.65g) and hydrazine hydrate tert-butyl 2-[2-aryl, but starting with Example 1 for the production of mino-N-(3-pyridyl)acetamitocoacetate It can be produced by a method similar to that described in . Thereby, the tert-button Chil 2-[2-amino-N-(5-inquinolyl)acetamitocoacetate (1,95 g) was obtained in the form of an oil, which was used in the subsequent synthesis without further treatment. tert-butyl 2-[2-phthalimido-N-(5-isoquinolyl)acetate Toamitocoacetate is 2-phthalimido-N-(5-isoquinolyl)acetate. amide (6.15 g), oily suspension of sodium hydride (50% by weight) ( using tert-butyl bromoacetate (1,07 g) and tert-butyl bromoacetate (3,6 g) tert-Butyl 2-[2-phthalimido-N-(3-pyridi l) A method similar to that described in Example 1 for the production of acetamitocoacetate. It can be manufactured by the method. 1, tert-butyl after recrystallization in acetic acid amide 2-[2-phthalimido-N-(5-inquinolyl)acetamitocoacetate (3.65 g), melting point 176°C.

2-phthalimido-N-(5-inquinolyl)acetamide is 5-aminoiso Quinoline (3,6 g), triethylamine (2,8 g) and 2-phthalimidore 2-phthal as in Example 1 except starting with cetyl chloride (5,6 g). Similar to the one described regarding the production of imido-N-(3-pyridyl)acetamide It can be manufactured by the method. Thereby, 2-phthalimido-N-(5-isoqui Noryl)acetamide (6.2 g) is obtained.

Example 7 tert-butyl 2-[2-amino-N-(4-phenyl-8-quinolyl)a Cetamitocoacetate (1,8g) and 3-methylphenylisocyanate ( 0.67 g) in acetonitrile using a method similar to Example 4, except that After recrystallization of tert-butyl 2-[2-[3-(3-methylphenyl)ure ]-N-(4-phenyl-8-quinolyl)acetamitocoacetate (0 , 95 g), melting point 228°C.

tert-butyl 2-[2-amino-N-(4-phenyl-8-quinolyl)a Cetamitocoacetate is tert-butyl 2=[2-phthalimide-N -(4-phenyl-8-quinolyl)acetamitocoacetate (2,5g) and tert-build except starting with hydrazine hydrate (0,77 g). Production of chill 2-[2-amino-N-(3-pyridyl)acetamitocoacetate Regarding the structure, it can be manufactured by a method similar to that described in Example 1. in addition tert-butyl 2-[2-amino-N-(4-phenyl-8-quinolinyl) l) acetamitocoacetate (1,9+g) was obtained in the form of an oil, which was further processed. Kotona (Used for subsequent synthesis.

tert-butyl 2-[2-phthalimido-N-(4-phenyl-8-quinoli) ) acetamitocoacetate is 2-phthalimido-N-(4-phenyl-8 -quinolyl)acetamide (4.9gL sodium hydride oily suspension ( 50% by weight) (0,7 g), and tert-butyl bromoacetate (2,4 tert-butyl 2-[2-phthalimide- Described in Example 1 for the production of N-(3-pyridyl)acetamitocoacetate It can be manufactured by a method similar to that of . Thereby, tert-buti 2-[2-phthalimido-N-(4-phenyl-8-quinolyl)acetamide Tocoacetate (2.6 g) was obtained in the form of an oil, which was processed without further treatment. Used for later synthesis.

2-phthalimido-N-(4-phenyl-8-quinolyl)acetamide is 8- Amino-4-phenylquinoline (5g), triethylamine (3,05g) and Performed except starting with 2-phthalimidoacetyl chloride (5,4 g) Regarding the production of 2-phthalimido-N-(3-pyridyl)acetamide in Example 1 It can be produced in a similar manner to that described. Thereby, 2-phthalimide -N-(4-phenyl-8-quinolyl)acetamide (5 g), melting point 200°C obtain.

Example 8 1. tert-Butyl 2-[2-amidine in 2-dichloroethane (50c) A solution of nor-N-(8-quinolyl)acetamide acetate (4.8 g) was added to 20 N, N'-cal in 1,2-dichloroethane (40 cc) at a temperature around °C. Add to a solution of bonyldiimidazole (2,7 g) and heat the mixture at a temperature around 20°C. Stir for 2 hours. Then 3-(1- A solution of hydroxyethyl)aniline (2.1 g) was added and the mixture was brought to the reflux temperature of the solvent. Heat for 6 hours to ℃. The reaction mixture was cooled to a temperature around 10°C and submerged in water (1 00cc). After the onset of sedimentation, the aqueous phase was separated and dichloromethane (2x8 0CC). Combine the organic phases and add water (50 cc) then 0.5 Wash with N hydrochloric acid aqueous solution (100 cc) and water (2 x 80 cc), and rinse with magnesium sulfate. The mixture is dried over a vacuum tube, filtered and concentrated to dryness under reduced pressure (2,7 kPa) at 40°C. profit Silica (0,063-0,2m) packed with oil in a column with a diameter of 2.5cm m) Chromatography on (150 g) [eluent dichloromethane/methanol (98:2 volume ratio) and collect 30 cc fraction. desired product The fractions containing only the above-mentioned components were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. a After recrystallization in setonitrile, tert-butyl 2- + 2- + 3- [3- (1-hydroxyethyl)phenyl]ureido l -N-(8-quinolyl)acetate toamide) acetate (0.4 g), melting point 200°C.

tert-butyl 2-[2-amino-N-(8-quinolyl)acetamitocore Cetate can be produced by the following method: hydrazine hydrate (4 , 8 g) in methanol (300 cc). In a solution of limido-N-(8-quinolyl)acetamitocoacetate (15 g) Add. The reaction mixture was stirred for 4 hours at a temperature around 20°C and then stirred under reduced pressure (2,7 kPa) Concentrate and dry at 40°C. Dissolve the residual oil in ethyl acetate (400cc) and treat the resulting solution with water (100 cc). After the start of sedimentation, separate the aqueous phase , then re-extracted with ethyl acetate (2x50cc). Combine organic phases and wash with water (2x60cc), dried over magnesium sulfate, filtered and dried under reduced pressure (2,7 kPa) Concentrate and dry at 40°C. Thereby, tert-butyl 2-[2- Amino-N-(8-quinolyl)acetamido]acetate-4 (10.2 g) in oil form , and use it for further processing (subsequent synthesis).

Example 9 3-Methylphenyl isocyanate (1.2 g) was anhydrous at a temperature around 20°C. tert-butyl 2-[2-amino-N in tetrahydrofuran (30 cc) -(5-chloro-8-inquinolyl)acetamitocoacetate solution . The resulting solution was stirred for 4 hours at a temperature around 20°C and then stirred under reduced pressure (2.7 kPa). Concentrate and dry at 40°C. The residual oil was removed using silica (0 ,063-0,2 mm) (75 g) [eluent dichloro Purify by methane/methanol (98:2 volume ratio) and collect 20cc fraction. . The fractions containing only the desired product were combined and concentrated under reduced pressure (2.7 kPa) at 40°C. Reduce to dryness. After recrystallization in ethyl acetate, tert-butyl 2-IN-(5- Chloro-8-isoquinolyl)-2-[3-(3-methylphenyl)ureido]a Cetamido)acetate (2.1 g), melting point 160° C., is obtained.

tert-butyl 2-[2-amino-N-(5-chloro-8-isoquinolyl) Acetamitocoacetate can be produced by the following method: hydrazine The hydrate (0.54 g) was dissolved in tert-butyl in methanol (80 cc). 2-[N-(5-chloro-8-isoquinolyl)-2-phthalimide acetate [mido]acetate) (4.0 g). Heat the reaction mixture to reflux for 3 hours Then, it is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Remove residual oil with ethyl acetate (150 cc) and treat the resulting solution with water (50 cc). of sedimentation After initiation, the aqueous phase is separated and then re-extracted with ethyl acetate (2 x 30 cc). organic Combine the phases, wash with water (3 x 15 cc), dry over magnesium sulfate and filter. and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. Thereby, tert- Butyl 2-E2-amino-N-(5-chloro-8-isoquinolyl)acetamide Acetate (3.0 g) was obtained in the form of an oil, which was then processed without further treatment. used in the synthesis of

tert-butyl 2-[N-(5-chloro-8-isoquinolyl)-2-phthal [imidoacetamide] acetate can be produced by the following method =lO An oily suspension (50% by weight) of sodium hydride (1,3 g) in anhydrous tetrahydrofuran (150 cc) kept under an argon atmosphere. N-(5-chloro-8-isoquinolyl)-2-phthalimidoacetamide (7, 8 g) and the resulting suspension is stirred for 2 hours at a temperature around 20°C. Nothing tert-butyl bromoacetate in water tetrahydrofuran (10c) Add a solution of (5.5 g) and continue stirring at a temperature around 20° C. for 16 hours. after that The reaction mixture was poured into water (50 c) and evaporated at 40 °C under reduced pressure (2,7 kPa). to remove the solvent and add a mixture of ethyl acetate (500 cc) and water (100 cc). Add. After the onset of precipitation, the aqueous phase was separated and re-extracted with ethyl acetate (2x100cc). put out The organic phases were combined, washed with water (3 x 80 cc) and poured over magnesium sulfate. Dry, filter and concentrate to dryness under reduced pressure (2,7 kPa) at 40°C. the resulting oil Silica (0,063-0,2 mm) packed in a column with a diameter of 2.5 cm (20 0g) Upstream 07 Tographie [Eluent dichloromethane/methanol (98: 2 volume ratio)] and collect 30 cc of fraction. Contains only the desired product The fractions are combined and concentrated to dryness at 40'C under reduced pressure (2,7 kPa). Ethyl acetate After recrystallization in tert-butyl 2-[N-(5-chloro-8-isoquinolyl )-2-phthalimidoacetamide] acetate (4.7 g), melting point 200°C obtain.

N-(5-chloro-8-inquinolyl)-2-phthalimidoacetamide is It can be manufactured by the method below. While keeping the temperature around 20℃, of 2-phthalimidoacetyl chloride (7.4g) in lomethane (50c) The solution was diluted with 8-aminoamide in dichloromethane (130 cc) kept under an argon atmosphere. Solution of nor-5-chloroisoquinoline (5°4g) and triethylamine (3g) Add to. The resulting solution was stirred at a temperature around 20°C for 4 hours and then diluted with water (50cc). Process. The insoluble product was separated by filtration and diisopropyl ether (2x 25cc) and its drained water (5x50cc) and air dry. Thereby N-(5-chloro-8-isoquinolyl)-2-phthalimidoacetamide (7, 9g) is obtained.

8-Amino-5-chloroisoquinoline was prepared by J, H, H, FRAENKEL, an d E, 5CHROEDER, Liebigs, Ann, Chem,, 396. 53-75 (1913).

Example 10 tert-butyl 2-[2-amino-N-(5-quinoxalinyl)acetamide acetate (2,6 g) and 3-methylphenylisocyanate (1,2 g) ) was used, but after recrystallization in ethyl acetate, t ert-butyl 2- + 2- [3= (3-methylphenyl)ureido]- N-(5-quinoxalinyl)acetamido]acetate (1,1gL melting point 132 Get ℃.

tert-butyl 2-[2-amino-N-(5-quinoxalinyl)acetamide [de]acetate is tert-butyl 2-[2-phthalimido-N-(5-butyl Noxalinyl)acetamide]acetate (7.4g) and hydrazine hydrate tert-butyl 2-[2-aminobutyl For the production of no-N-(5-chloro-8-inquinolyl)acetamido]acetate can be produced in a similar manner to that described in Example 9. Thereby , tert-butyl 2-[2-amino-N-(5-quinoxalinyl)acetoacetate Mido]acetate (2.6 g) was obtained in the form of an oil, which was processed without further treatment. Used for later synthesis.

tert-butyl 2-[2-phthalimido-N-(5-quinoxalinyl)acetate 2-phthalimido-N-(5-quinoxalinyl)acetate toamide (8.7 g), oily suspension of sodium hydride (50% by weight) ( 1.3 g) and tert-butyl bromoacetate (5.1 g). tert-butyl 2-[2-phthalimide-N-(5-chloro- As described in Example 9 for the preparation of 8-isoquinolyl)acetamido]acetate. It can be manufactured by a method similar to the above method. Thereby, tert-butyl 2-[2-phthalimido-N-(5-quinoxalinyl)acetamide]acetate (7.4 g), melting point 195°C.

2-phthalimido-N-(5-quinoxalinyl)acetamide is 5-7 Noxaline (5,6 g), triethylamine (3,9 g) and 2-phthalimide 2-phthalate as in Example 9 except starting with acetyl chloride (8.6 g). Regarding the production of limido-N-(5-chloro-8-isoquinolyl)acetamide It can be produced in a similar manner to that described. Thereby, 2-phthalimide -N-(5-quinoxalyl)acetamide (10.8 gL melting point 261°C is obtained.

5-Aminoquinoxaline is PLATT B, C, and 5HARPT, M, J , Chem, Soc, 2129-2134 (1948). It can be manufactured using

Example 11 N-methyl-N-phenyl-2-[N-(8-quinolyl) at a temperature around 20°C. - incyanatoacetamitocoacetamide (3 g) under an argon atmosphere. 3-(1-hydroxyethyl) in anhydrous tetrahydrofuran (30 cc) kept Add to the solution of aniline (0.41 g).

The resulting solution was stirred for 16 hours at a temperature around 20°C and then stirred under reduced pressure (2,7 kPa). Concentrate and dry at 40°C. Silica packed with residual oil in a column with a diameter of 2.5 cm Chromatography on (0,063-0,2 mm) (75 g) [eluent Nijik Purified by lolomethane/methanol (98:2 volume ratio) and collected 20cc fraction. Melt. The fractions containing only the desired product were combined and heated to 40 °C under reduced pressure (2,7 kPa). Concentrate and dry. After recrystallization in ethyl acetate, 2- Droxyethyl) phenylcoralide l -N-(8-quinolyl)acetamide 1-N-methyl-N-phenylacetamide (0.80 g), melting point 188°C was obtained. Ru.

N-methyl-N-phenyl-2-[N-(8-quinolyl)-isocyanatoacetate [Tamide] Acetamide can be produced by the following method. Temperature around 5℃ N-Methyl-N-phthalate in anhydrous diethyl ether (200 cc) while maintaining temperature. phenyl-2-[(8-quinolyl)aminocoacetamide (2,9 g) and pyridine A solution of (0.8 g) in anhydrous diethyl ether (2 5c Add to the solution of isonoanatoacetyl chloride (1.6 g) in c).

The reaction mixture was stirred for 4 hours at a temperature around 20°C, and the insoluble product was removed! It's too late Separate and wash with anhydrous tetrahydrofuran (3xlOcc). Combine the filtrates , concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Thereby, N-methyl-N -phenyl-2-[N-(8-quinolyl)-isocyanatoacetamitocoacetate The toamide (2,3 g) was obtained in the form of an oil, which was then processed without further treatment. Use for synthesis.

Isocyanate acetyl chloride is YO5HTOIWAKURA.

KEIKICHI UNO, SANAM KANG, J Org, Chem, 30.1158-1161 (1965). Wear.

N-methyl-N-phenyl-2-CC8-quinolyl) aminocoacetamide is It can be produced by the following method: ・2N hydrochloric acid aqueous solution (at a temperature around 20℃) 6,2c c) in ethanol (40c c) with N-methyl-N-phenyl-2 -[N-(8-quinolyl)trifluoroacetamitocoacetamide (2,4g ) to the solution. The reaction mixture was heated to reflux for 30 minutes, then the ethanol was removed under reduced pressure. It is removed by evaporation at 40° C. (2.7 kPa). Water the residue (50 c) The insoluble product is separated by filtration and recrystallized in ethanol.

Thereby N-methyl-N-phenyl-2-[(8-quinolyl)aminocoacetate Obtain amide (1.6 gL melting point 169°C.

N-Methyl-N-phenyl-2-[N-(8-quinolyl)trifluoroacetoa Mitocoacetamide can be produced in the following way: at a temperature around 10°C. An oily suspension (50% by weight) (0.25 g) of sodium hydride was added to the alkaline solution. 8-(trifluor) in anhydrous tetrahydrofuran (20 cc) kept under a nitrogen atmosphere. Add the resulting suspension to a solution of (1,2 g) quinoline (oacetylamino) Stir for 30 minutes at a temperature around 0°C. Then anhydrous tetrahydrofuran (15c) c) of 2-bromo-N-methyl-N-phenylacetamide (1,8 g) in and heat the mixture to reflux for 5 hours. The reaction mixture was then heated to a temperature around 20°C. Cool and pour into a mixture of water (25 cc) and ethyl acetate (50 cc). sedimentation After initiation of the reaction, the aqueous phase is separated and re-extracted with ethyl acetate (2x25 cc). organic phase Combine, wash with water (3x20cc), dry over magnesium sulfate, filter, Concentrate and dry under reduced pressure (2.7 kPa) at 40°C. The obtained oil is 2.5cm in diameter. Chromatography on silica (0°06370.2 mm) (75 g) packed in a column of Purify by chromatography (eluent: dichloromethane) and collect 10 cc of fractions.

The fractions containing only the desired product were combined and concentrated under reduced pressure (2,7 kPa) at 40°C. dry. Thereby N-methyl-N-phenyl-2-[N-(8-quinolyl) Trifluoroacetamitocoacetamide (0.7 g) was obtained as an oil and further purified. used for subsequent synthesis without further processing.

2-Bromo-N-methyl-N-phenylacetamide is produced by the following method. be able to. Triethylamine (11,1 g) and dichloromethane were added at a temperature around -5°C. A solution of bromoacetyl bromide (20.4 g) in lolomethane (10 c) , to a solution of N-methylaniline (10,7 g) in dichloromethane (65 cc) Add continuously. The suspension was stirred for 2 hours at a temperature around 20°C and its condensate (25c Process in c). After the onset of sedimentation, the aqueous phase was separated and dichloromethane (2x15c Re-extract in c).

Combine the organic phases, wash with water (3 x 25 cc) and dry over magnesium sulfate. , filter, and concentrate and dry at 40° C. under reduced pressure (2,7 kPa). Anhydrous diester to remove residual oil Treatment with methyl ether (100 CC), separation of the insoluble product by filtration and diethyl ether (100 CC). Wash with thyl ether (3x15cc). The filtrates were combined and heated under reduced pressure (2.7 kP a) Concentrate and dry at 40°C. Thereby, 2-bromo-N-methyl-N-phenylene Ruacetamide (20,5 g) was obtained as an oil, which was used for subsequent treatment without further treatment. Use for synthesis.

8-(trifluoroacetylamino)quinoline can be produced by the following method. Trifluoroacetic anhydride (4°2g) was added to pyridine at a temperature of around 20°C. Add to a solution of 8-aminoquinoline (2.9 g) in (25 CC). reaction mixture Stir at a temperature around -20℃ for 30 minutes, then stir at a temperature around 0℃ for 1 hour, and then stir at a temperature around 0℃. Pour into water (150 cc) cooled to a similar temperature. Separate insoluble products by filtration Wash with water (5xlOcc) and air dry. As a result, 8-(trifluoro) This yields 4.7 g of loacetylamino)quinoline, melting point 84°C.

Example 12 3-(Hydroxymethyl)aniline (0,37 g) and N-methyl-N-phenylene Ru-2-[N-(5-quinolyl)isocyanatoacetamitocoacetamide ( Using a method similar to that described in Example 11, but starting with After recrystallization in ethyl acetate, 2-12-f3-[3-(hydroxymethane) thyl)phenyl]ureido)-N-(5-quinolyl)acetamido]-N-methy LeuN-phenylacetamide (0.80 g), melting point 205° C., is obtained.

N-methyl-N-phenyl-2-[N-(5-quinolyl)isocyanatoacetate Amitocacetamide is made from isocyanatoacetyl chloride (1,7g), N- Methyl-N-phenyl-2-E(5-quinolyl)aminocoacetamide (3,5 g) and pyridine (0,96 g). phenyl-2-[N-(8-quinolyl)isocyanatoacetamitocoacetamide It can be produced by a method similar to that described in Example 11 regarding the production of Ru. Thereby, N-methyl-N-phenyl-2-[N-(5-quinolyl)yn Cyanatoacetamitocoacetamide (2,3 g) was obtained in the form of an oil, which was further Used for later synthesis without processing.

N-methyl-N-phenyl-2-[(5-quinolyl)aminocoacetamide is Can be produced by the following method = 2N sodium hydroxide at a temperature around 20℃ Aqueous solution (16c) of N-methyl-N- in ethanol (20c) Phenyl-2-[N-(5-quinolyl)trifluoroacetamitocoacetamide Add to the solution of (6.2 g). The reaction mixture was stirred for 1 hour at a temperature around 20°C. , the ethanol is removed by evaporation under reduced pressure (2,7 kPa) at 40°C. residue was stirred with water (75cc), the insoluble product was separated by filtration, and the ethanol recrystallize in a glass bottle. Thereby, N-methyl-N-phenyl-2-[(5-quinoli ) Aminocoacetamide (3.6 g), melting point 165°C.

N-methyl-N-phenyl-2-CN-(5-quinolyl)trifluoroacetoa Mido]acetamide can be produced in the following way: at a temperature around 0°C. An oily suspension (50% by weight) (1.0 g) of sodium hydride was heated with argon. 5-(trifluoro) in anhydrous tetrahydrofuran (60 cc) kept under atmosphere. acetylamino)quinoline (4 g) and the resulting suspension was heated at around 0°C. Stir at temperature for 30 minutes. Then 2-butyl in anhydrous tetrahydrofuran (30 cc) Add a solution of lomo-N-methyl-N-phenylacetamide (5.7 g) and mix. The mixture is heated to reflux with stirring for 5 hours. The reaction mixture was then brought to a temperature around 20°C. Cool and pour into a mixture of water (30 cc) and ethyl acetate (200 cc). Shen After the onset of precipitation, the aqueous phase is separated and re-extracted with ethyl acetate (2 x 20 cc). organic phase Combine, wash with water, dry over 5x25ccL magnesium sulfate, filter, Concentrate and dry under reduced pressure (2.7 kPa) at 40°C. Pour the obtained oil into a 3 cm diameter Chromatog on silica (0,063-2 mm) (125 g) packed in a column Purify with a roughy (eluent dichloromethane) and collect 20 cc of fraction. place The fractions containing only the desired product were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. dry

Thereby N-methyl-N-phenyl-2-[N-(5-quinolyl)trifluoro roacetamide] Acetamide (6.2 g) was obtained as an oil, which was further processed. used in subsequent synthesis without

5-(trifluoroacetylamino)quinoline is produced by the following method. Trifluoroacetic anhydride (4.2 g) was mixed with pyridine (25 c ) to a solution of 5-aminoquinoline (2.9 g) in ). The reaction mixture was heated to -20°C. Stir for 30 minutes at a temperature around 0°C, then stir for 1 hour at a temperature around 0°C, and then stir at a temperature around 0°C. Pour into chilled water (200cc).

The insoluble product is separated by filtration, washed with water (5xlOcc) and air dried. . Thereby 5-(trifluoroacetylamino)quinoline (4,7 g), m.p. 124°C is obtained.

) Example 13 3-(Hydroxymethyl)aniline (0,31 g) and N-methyl-N-phenylene Ru-2-[N-(8-quinolyl)isocyanatoacetamide]acetamide ( Using a method similar to that described in Example 11, except that 1.0 g) was used, After recrystallization in nitrile, 2-[2-(3-[3-(hydroxymethyl) phenylcoralide]-N-(8-quinolyl)acetamide]-N-methyl-N -Phenylacetamide (0°47 g), melting point 190°C is obtained.

Example 14 tert-butyl 2-+2-[(1-imida) in toluene (25 cc) zolyl)carboxamide] -N-(4-isoquinolyl)acetamido)ace A solution of tate (1,5 g) and 3-aminobenzyl alcohol (0,9 g) was Heat under reflux for 4 hours and concentrate and dry the reaction medium at 70°C under reduced pressure (2,7 kPa). . The residue was treated with ethyl acetate (150 cc) and the resulting solution was dissolved in water (100 cc). ), dried over magnesium sulfate, filtered and dried under reduced pressure (2,7 kPa) 7 Concentrate and dry at 0°C. The obtained product was sized to have a diameter of 1. Packed into gcm column Chromatography on silica (0°063-0.200mmM30g) [elution agent: dichloromethanemethanol (98:2 volume ratio)], and 15 cc of the fraction was collect. Fractions 54 to 60 were combined and concentrated and dried at 60°C under reduced pressure (2.7 kPa). dry After recrystallization in diisopropyl ether, tert-butyl 2-[2 -(3-[3-(hydroxymethyl)phenylcoralide I -N-(4-yne Quinolyl) acetamitocoacetate (0°17 g), melting point 153°C, is obtained.

tert-butyl 2-(2-[(1-imidazolyl)carboxamide EN- (4-isoquinolyl)acetamido)acetate can be manufactured by the following method. can be made: tert-butyl 2-[2- in tetrahydrofuran (25 cc) Amino-N-(4-isoquinolyl)acetamitocoacetate) (2.7g) and and N,N’-carbonyldiimidazole (1.4 g) at a temperature around 20°C. Stir for 24 hours at 30°C. The insoluble product was separated by filtration and washed with anhydrous tetrahydrofuran. Wash with run (5c). Thereby, tert-butyl 2-(2-[( 1-imidazolyl)carboxamide]-NL-(4-isoquinolyl)acetate Amido)acetate (1.4 gL melting point 130° C. is obtained.

tert-butyl 2-[2-amino-N-(4-isoquinolyl)acetamito Coacetate can be produced in the following way: under heat at a temperature around 20°C. Drazine hydrate (1.3 g) was dissolved in tert in methanol (100 cc). -Butyl 2-[2-phthalimido-N-(4-isoquinolyl)-acetamito Add to the solution of Coacetate (3.9 g). The reaction mixture was heated at 20°C for 24 hours. Stir and then add water (30 cc). The mixture was heated under reduced pressure (2,7 kPa) 60 Concentrated to dryness at ℃, diluted with water (100cc), dichloromethane (2xlOO Extract with cc). Combine the phases, wash with water (100 cc), and add magnesium sulfate. The mixture is dried on top, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. in addition tert-butyl 2-[2-amino-N-(4-inquinolyl)acetoacetate Mitocoacetate is obtained in the form of an oil, which can be used for subsequent synthesis without further processing. use

tert-butyl 2-[2-phthalimido-N-(4-inquinolyl)-acetate Toamitocoacetate can be produced in the following way: at a temperature around 20°C. An oily suspension (50% by weight) of sodium hydride (0.73 g) at 2-lid in anhydrous tetrahydrofuran (150 cc) kept under argon atmosphere. Add to a solution of limido-N-(4-isoquinolinel)acetamide (8 g).

The resulting suspension is stirred at this temperature for 3 hours. Then tert-butyl bromo Acetate (4°7 g) is added and stirring is continued for 18 hours at a temperature around 20°C. So Add water (10cc) then pour the reaction mixture into water (400cc) .

The mixture is extracted with ethyl acetate (2x250cc). Combine organic phases and wash with water 100 cc), dried over magnesium sulfate, filtered and dried under reduced pressure (2,7 kP). a) Concentrate and dry at 70°C. By recrystallization in diisopropyl ether, te rt-Butyl 2-[2-phthalimido-N-(4-isoquinolyl)-aceto Amitocoacetate (6.1 g), melting point 183° C., is obtained.

2-phthalimido-N-(4-isoquinolyl)acetamide is produced by the following method. Nitriethylamine (4.85 g), which can be prepared by dichloromethane Dissolution of 2-phthalimide acetyl chloride (10,9 g) in tan (70 c) The solution was diluted with 4-aminoisoquinoline (7.0 g) in dichloromethane (80 cc). Add to suspension. The resulting suspension was stirred at a temperature around 20°C for 18 hours, and water (6 00cc). The solid formed was separated by filtration and water (3xlOOcc) Wash with 2-phthalimido-N-(4-isoquinolyl)acetamide (8, 0g), melting point 260°C.

Example 15 N-methyl-N-phenyl-2-[N-(8-quinolyl)-isocyanatoacetate toamide] acetamide (2,9 g) and ethyl 3-aminobenzoate (1 ,0g) in isopropanol using the method described in Example 11 except that After recrystallization, 313EN-(N-methyl-N-phenylcarbamoylmethyl)- N-(8-quinolyl)carbamoylmethyl]ureido)benzoate (1,05 g), melting point 173°C region IN sodium hydroxide aqueous solution (10cc), 1.4 -Ethyl in dioxane (10cc) and tetrahydrofuran (10cc) 3-+3- [N-(N-methyl-N-phenylcarbamoylmethyl)-N-( A solution of 8-quinolyl)carbamoylmethyl]ureido)benzoate was heated at 20°C. Stir for 46 hours at around temperature. The reaction medium was heated to around 45°C under reduced pressure (2°7 kPa). Concentrate to a volume of 10 cc at ambient temperature. The resulting residue is separated by filtration, 0. Treat with IN aqueous sodium hydroxide solution (10cc) and water (10cc). Ru. The aqueous phases were combined, washed with ethyl acetate (2xlocc), and aqueous solution of IN hydrochloric acid ( Acidify to pH around 3 with 2cc) and extract with dichloromethane (3x20cc) do. Combine the organic extracts and wash with saturated aqueous sodium chloride solution (25cc). Ru. Filter the solid and wash with dichloromethane (2x5cc) and water (30cc). Resuspend in water, filter, and rinse with water (3xlOcc). As a result, 3-+3-[N -(N-methyl-N-phenylcarbamoylmethyl)-N-(8-quinolyl)ka Rubamoylmethyl]ureido)benzoic acid (0.26 g), melting point 180° C., is obtained.

Example 17 2-Isocyanato N-(8-quinolyl)-N-r2- (1,2゜3.4- Tetrahydro-1-quinolyl)-2-oxoethyl)acetamide (2.0g> and 3-aminobenzyl alcohol (0.61 g). Using the method described in Example 11, 2-(3-[3-(hydroxymethyl)phenylene ] ureido l -N-, (8-quinolyl) -N-[2-(1,2,3,4- Tetrahydro-1-quinolyl)-2-oxoethyl]acetamide (0,13g ), giving a melting point of 125°C.

2-Isonoanato-N-(8-quinolyl)-N-[2-(1,2°3.4-te trahydro-1-quinolyl)-2-oxoethyl)acetamide is an isonoana acetyl chloride (2.0 g) and 1−+2. -[(8-quinolyl)amino Using coacetyl l-1,2,3,4-tetrahydroquinoline (5,3 g) N-methyl-N-phenyl-2-EN-(8-quinolyl)iso Cyanatoacetamide] Those described in Example 11 regarding the production of acetamide It can be manufactured by a method similar to the method. Thereby, 2-incyanato-N-( 8-Bovinenoryl)-N-[2-(1,2,3,4-tetrahydro-1-quinolyl) -2-oxoethyl)acetamide (6.6 g) was obtained as an oil and could be further processed. Tona (Used for later synthesis.

1-[2-[(8-quinolyl)aminocoacetyl-1,2,3,4-tet Lahydroquinoline was prepared using 2N aqueous sodium hydroxide solution (65cc) and N-(8 -quinolyl) -N-[2-(1,2,3,,4-tetrahydro-1-quinolyl) )-2-oxoethylcotrifluoroacetamide (27 g) N-methyl-N-phenyl-2-[(8-quinolyl)aminocoacetate The amide can be produced by a method similar to that described in Example 11. Ru. Thereby, 1-(2-[(8-quinolyl)aminocoacetyl-1,2 , 3,4-tetrahydroquinoline (17 g), melting point 134°C.

N-(8-quinolyl)-N-[2-(1,2,3,4-tetrahydro-1-quino Lyru)-2-oxoethylcotrifluoroacetamide is produced by the following method. Can: Potassium carbonate (12, g) and its IN,N-dimethylform 1-Bromoacetyl-1,2,3,4-tetrahydro in Muamide (80cc) A solution of quinoline (22 g) was added continuously to N,N-dimethylformamide (210 g). cc) to a solution of 8-(trifluoroacetylamino)quinoline (21 g) in I can do it. The resulting suspension is stirred for 18 hours at a temperature around 20°C. So The post-reaction mixture was poured into water (11) and the mixture was diluted with diethyl ether (3x500 Extract with cc). The organic phases were combined, dried over magnesium sulfate, filtered and reduced. Concentrate and dry under pressure (2.7 kPa) at 50°C. Re-in diisopropyl ether After crystallization, N-(8-quinolyl)-N-[2-(1,2,3°4-tetrahydro- 1-quinolyl)-2-oxoethylcotrifluoroacetamide (22.6g ), giving a melting point of 132°C.

1-Bromo-1,2,3,4-tetrahydroquinoline is 1. 2.　3゜4- Using tetrahydroquinoline (40g) and bromoacetylbromide (64g) For the production of 2-bromo-N-methyl-N-phenylacetamide, except starting with It can be produced by a method similar to that described in Example 11. Thereby , 1-bromo-1,2,3,4-tetrahydroquinoline (67 g) was obtained as an oil, It is used for later synthesis without further processing.

Example 18 2-Isocyanato-N-(8-quinolyl)-N-[2-(1,2°3.4-te trahydro-1-quinolyl)-2-oxoethyl]acetamide (4.5 g) and The procedure was as follows, except starting with ethyl 3-aminobenzoate (1,9 g). Using a method analogous to that described in Example 11, ethyl 3-[3-(N-(8-key) Noryl)-N-[2-(1,2,3゜4-tetrahydro-1-quinolyl)-2- Oxoethylcocarbamoylmethyl 1ureido)benzoate (0.7g), fused Obtain a point of 140°C.

Example 19 Tert-butyl 2-[2-amino-N-(8-quinolyl) ) acetamide] acetate (2.7 g) and N, N'-carbonyldiimide A solution of dazole (1.5 g) and 1,2-dichloroethane (30 cc) was added for 30 minutes. Stir for a while. Then 3-aminobenzyl alcohol (1.1g) was added and the mixture Heat to reflux for 8 hours. The reaction medium is then cooled to a temperature around 20°C and dichloro Dilute with methane (150 cc). Wash the organic phase with water (2x80cc)''C' dried over magnesium sulfate, filtered and dried under reduced pressure (2,7 kPa) at 60°C. Concentrate and dry. The obtained residue was packed in a column with a diameter of 2.2 cm using silica ( 0,063-0,200 mm) (90 g) [eluent: di Pour chlormethane/methanol (99.5:0.5 volume ratio) into 10 cc distillate. Collect. Combine fractions 40-60 and concentrate and dry at 60°C under reduced pressure (2.7 kPa). dry After recrystallization in ethyl acetate, ethyl 3-(3-[N-tert-but- (xycarbonylmethyl-N-(8-quinolyl)carbamoylmethylchoralide) Obtain benzoate (0.65 g), melting point 200°C.

Example 20 tert-butyl 2-[amino-N-(8-quinolyl)acetamide 3-acetate N, N'-carbonyldiimidazole (1,5 g) and 3-aminoben The method described in Example 19, but starting with dial alcohol (1.1 g) tert-butyl 2-[2-+3-[3-(hydroxy cymethyl)phenyl]ureido)-N-(8-quinolyl)acetamitocoacetate (0.85 g), melting point 115°C.

Example 21 Ethyl 3- +3- (N-(8-quinolyl)-N-[2-(1,2゜3.4 -tetrahydro-1-quinolyl)-2-oxoethylcocarbamoylmethyl) Reid) benzoate (1.0 g) and aqueous sodium hydroxide solution (1.0 g) of O, IN 3- + using the method described in Example 16, but starting with 8 cc) 3-iN-(8-quinolyl)-N-[2-(1,2,3,4-tetrahydro -1-quinolyl)-2-oxoethylcocarbamoylmethyl)ureido)an, Mt. , number (0.81 g), melting point 164°C.

2-Incyanato-N-(8-quinolyl)-N-[2-(1,2゜3.4- Tetrahydro-1-quinolyl)-2-oxoethyl]acetamide (2,75g ) and 3-aminobenzaldehyde (0,93 g). Using the method described in Example 11, (E)-2-+3-[3-(hydroxyi (minomethyl)phenyl]ureido 1-N-(8-quinolyl)-N-[(1,2 ,3,4-tetrahydro-1-quinolyl)carbamoylmethylcoacetamide ( 0.76 gL melting point 221°C is obtained.

3-Aminobenzaldehyde, S. Gabriel, Chem.

It can be produced according to the method described in Ber., 16.1997 (1883). can.

Example 23 Methyl 3-[3-[N-t e r t-butoxycarbonylmethyl-N- (8-quinolyl)carbamoylmethylchoralide)benzoate (0°4g) and and 0. Except starting with an aqueous solution of sodium hydroxide (5,8 cc) in Using the method described in Example 16, 3-+3-[N-tert-butoxyca Rubonylmethyl-N-(8-quinolyl)carbamoylmethylchoralide)benzoin Acid (0.04 g), melting point 180° C. is obtained.

Methyl 3-(3-IN-tert-butoxycarbonylmethyl-N-(8- Quinolyl)carbamoylmethylchoralide)benzoate is N-tert-butyl Toxycarbonylmethyl-2-isocyanato-N-(8-quinolyl)acetoa Derived using amide (4.2g) and methyl 3-aminobenzoate (1.9g). 2-+2-+3-[3-(1-hydroxyethyl)phenyl] Ureido l -N-(8-quinolyl)acetamide l -N-methyl-N-phene Produced in a similar manner to that described in Example 11 for the production of nylacetamide be able to.

Thereby, methyl 3-(3-[N-tert-butoxycarbonylmethyl -N-(8-quinolyl)carbamoylmethylchoralide 1 benzoate (1,8 g), a melting point of 96°C is obtained.

N-tert-butoquinocarbonylmethyl-2-iso/ana-)-N-(8-key Noryl)acetamide is tert-butyl 2-[(8-quinolyl)amino coacetate (3,2 g), isocyanatoacetyl chloride (1,5 g) and N-methyl-N-phenyl-2 but starting with pyridine (1,0 g) -[N-(8-quinolyl)isocyanatoacetamitocoacetamide production It can be produced by a method similar to that described in Example 11. Thereby , N-tert-butoxycarbonylmethyl-2-isocyanato-N-(8- Quinolyl)acetamide (4-4 g) was obtained as an oil, which was obtained without further treatment. used for subsequent synthesis.

tert-butyl 2-[(8-quinolyl)aminocoacetate is tert-butyl Butyl 2-[N-(8-quinolyl)trifluoroacetamitocoacetate Starting with (18.7g) and 2N aqueous sodium hydroxide solution (53cc) N-methyl-N-phenyl-2-[(8-quinolyl)bumino]acetate Regarding the production of toamide, it can be produced by a method similar to that described in Example 11. Wear. Thereby, tert-butyl 2-[(8-quinolyl)aminocoacetate (3.5 g), melting point 62°C.

tert-butyl 2-[N-(8-quinolyl)trifluoroacetamitoco Acetate can be produced by the following method = carbonic acid at a temperature around 20°C. Potassium (8.6 g) and then in anhydrous dimethylformamide (50 c) A solution of tert-butyl bromoacetate (12 g) was added continuously to anhydrous dimethylene. 8-(trifluoroacetylamino)quinolin in diformamide (150 cc) (15 g).

The reaction mixture is stirred for 17 hours at a temperature around 20°C and poured into water (1 liter). . The aqueous phase is extracted with ethyl diacetate (3x250cc). Combine the organic phases and add sodium chloride. Wash with saturated aqueous thorium solution (100 cc), dry over magnesium sulfate, and filter. The mixture is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. The obtained solid is diiso suspended in propyl ether (30cc) and separated the insoluble product by filtration; Wash with pentane (2x30cc) and dry at 25°C under reduced pressure (+0kPa) . Thereby, tert-butyl 2-[N-(8-quinolyl)trifluoroacetate Toamitocoacetate (18.7 g) is obtained, melting point 98°C.

Example 24 At a temperature around 20°C, 2-incyaner)-N-C2-(3,3-dimethylpipe lysino)-2-oxoethyl]-N-(8-quinolyl)acetamide (2,3 g) in anhydrous tetrahydrofuran (25c) kept under an argon atmosphere. Add to a solution of 3-methylaniline (1,07 g). The obtained solution was heated to around 20℃. The mixture was stirred for 2 hours at a temperature of . The residual oil was packed with silica (0,063-0,2 m) in a column with a diameter of 2,5 cm. Chromatography on m) [eluent dichloromethane/methanol (98:2 volume ratio)] and collect a 20 cc fraction. A fraction containing only the desired product are combined and concentrated and dried at 40° C. under reduced pressure (2.7 kPa). in acetonitrile After recrystallization of 2-[3-(3-methylphenyl)ureido]-N-[2-(3 ,3-dimethylpiperidino)-2-oxoethyl]-N-(8-quinolyl)acetate Toamide (1.2 g) is obtained, melting point 180°C.

2-Isocyanato N-[2-(3,3-dimethylpiperidino)-2-oxo Ethyl]-N-(8-quinolyl)acetamide can be produced by the following method. Can be done. 8-1 [2-(3,3-dimethylpyri) from anhydrous dioxane (25 cc) peridino)-2-oxoethylcoamino)quinoline (1,8 g) and pyridine ( A solution of 0.48 g) was kept under an argon atmosphere while keeping the temperature around 5 °C. Incyanate acetyl chloride (0,8 4g) of the solution. The reaction mixture was stirred for 2 hours at a temperature around 20°C, until the insoluble The product is separated by filtration and washed with anhydrous dioxane (2 x 5 cc). filtrate The mixture is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Thereby, 2-iso Cyanato-N-[2-(3,3-dimethylpiperidino)-2-oxoethyl] -N-(8-quinolyl)acetamide (2.35 g) was obtained as an oil, which was further used for later synthesis without further processing.

8-f [2-(3,3-dimethylpiperidino)-2-oxoethyl]amino ) Quinoline can be produced in the following way: at a temperature around 20°C, N-r2-(3,3-dimethylpiperidino)-2-o in alcohol (50cc) xoethyl]-N-(8-quinolyl)trifluoroacetamide (3 g) Add 2N aqueous sodium hydroxide solution (7°5 cc) to the liquid. 2 of the reaction mixture Stir for 3 hours at a temperature around 0°C, then evaporate at 40°C under reduced pressure (2.7 kPa). to remove ethanol. The residue was dissolved in water (50 c) and ethyl acetate (1 50 cc) of the mixture. After the onset of precipitation, the aqueous phase was separated and treated with ethyl acetate (2 x25cc). The organic phases were combined and washed with water (3x150cc); Dry over magnesium sulfate, filter and concentrate under reduced pressure (2,7 kPa) at 40°C. dry. Thereby, 8-1 [2-(3,3-dimethylpiperidino)-2- Oxoethyl]amyl quinoline (2.1 g) was obtained as an oil, which was further processed. Use it for later synthesis without any trouble.

N-[2-(3,3-dimethylpiperidino)-2-oxoethyl]-N-[8- Quinolyl trifluoroacetamide can be produced by the following method : An oily suspension of sodium hydride (50% by weight) (0.6g) was heated at 10°C. Anhydrous tetrahydrofuran (40 cc. ) of 8-(trifluoroacetylamino)quinoline (2.4 g) in The resulting suspension is stirred for 30 minutes at a temperature around 20°C. Then anhydrous tetrahydride 2-bromo-1-(3,3-dimethylpiperidino) in lofuran (30c) A solution of -1-ethanone (3.5 g) was added and the mixture was heated under stirring for 5 hours. Flow.

The reaction mixture was then cooled to a temperature around 20°C and mixed with water (25cc) and ethyl acetate. (100 cc) of the mixture. After the start of precipitation, separate the aqueous phase and add ethyl acetate (2x25cc). Combine the organic phases and wash with water (3x20cc) , dried over magnesium sulfate, filtered and concentrated under reduced pressure (2,7 kPa) at 40°C. Shrink dry. The obtained oil was packed in a column with a diameter of 2.5 cm using silica (0,0 63-0,200 mm) (100 g) [eluent Nijichrome The fractions containing only the desired lomethane/meta product were combined and Concentrate and dry at 0°C. Thereby, N-[2-(3,3-dimethylpiperidino )-2-oxoethyl]-N-(8-cow-noryl)trifluoroacetamide ( 3.0 g) is obtained in the form of an oil, which is used in the subsequent synthesis without further treatment.

2-Bromo-1-(3,3-dimethylpiperidino)-1-ethanone is suitable for the following people. dichloromethane (65 c ) to a solution of 3,3-dimethylpiperidine (11,3 g) in triethylamine (11,1 g) and bromoacetyl bromide in dichloromethane (10c) A solution of (20.4 g) is added continuously.

The resulting suspension was stirred for 2 hours at a temperature around 20°C and treated with its condensate (25CC). Understand. After the onset of sedimentation, the aqueous phase was separated and diluted with dichloromethane (2 x 15 c). Re-extract. The organic phases were combined, washed with water (3 x 25 cc) and treated with magnesium sulfate. Dry on top, filter and concentrate to dryness under reduced pressure (2,7 kPa) at 40°C. residual oil was treated with anhydrous diethyl ether (100 cc) and the insoluble product was separated by filtration. Remove and wash with diethyl ether (3 x 15 c). Combine the filtrates and reduce pressure AVA dry at 40° C. (2,7 kPa). Thereby, 2-bromo-1- (3,3-dimethylpiperituno)-1-ethanone (6,5 g) was obtained as an oil; used in subsequent synthesis without further processing.

8-Trifluoroacetylaminoquinoline can be produced by the following method. - At a temperature around -20°C, add trifluoroacetic anhydride (4.2 g) to pyridine (2 5c Add to the solution of 8-aminoquinoline (2.9 g) in c). reaction mixture Stir at a temperature around -20℃ for 30 minutes, then stir at a temperature around 0℃ for 1 hour, and then stir at a temperature around 0℃ for 30 minutes. Pour into water (150 cc) cooled to ambient temperature. Insoluble products are separated by filtration. , water (5xlOcc) and air dry. Thereby, 8-(trifluoro Acetylamino)quinoline (4.7 gL melting point 84° C. is obtained.

Example 25 At a temperature around 20°C, N-methyl-N-phenyl-2-[N-(8-quinolyl) Isocyanate acetamitocoacetamide (1.5 g) was added under an argon atmosphere. 3-Methylthioaniline (0 cc) in anhydrous tetrahydrofuran (10 cc) kept at , 56 g). The resulting solution was stirred at a temperature around 20°C for 16 hours. , and then concentrated and dried under reduced pressure (2.7 kPa) at 40°C. in acetonitrile After recrystallization, N-methyl-2-[2-[3-(3-methylthiophenyl)ureido ]-N-(8-quinolyl)acetamide]-N-phenylacetamide (0, 65 g), melting point 174°C.

N-methyl-N-phenyl-2-[N-(8-quinolyl)isocyanatoacetate Amitocoacetamide can be produced by the following method: at a temperature around 5°C. N-Methyl-N-phenylene in anhydrous diethyl ether (200 cc) while maintaining Ru-2-[(8-quinolyl)aminocoacetamide (2.9 g) and pyridine ( 0.8 g) in anhydrous diethyl ether (25 c) kept under an argon atmosphere. Add to the solution of isocyanate acetyl chloride (1.6 g) in c). reaction mixture The mixture was stirred for 4 hours at a temperature around 20°C, after which the insoluble mixture was separated by filtration. and wash with anhydrous tetrahydrofuran (3×10 CC). Combine the filtrates and reduce pressure Concentrate and dry at 40° C. (2.7 kPa). Thereby, N-methyl-N-phene Nyl-2-[N-(8-quinolyl)isocyanatoacetamitocoacetamide (2.3 g) was obtained in the form of an oil, which was used without further processing (for later synthesis).

N-methyl-N-phenyl-2-[(8-quinolyl)aminocoacetamide is It can be produced in the following way: 2N sodium hydroxide at a temperature around 20°C. N-methyl-N- in ethanol (40c) Phenyl-2-[N-(8-quinolyl)trifluoroacetamitocoacetamide Add to the solution of (2.-4 g). The reaction mixture was stirred under reflux for 30 min and then reduced under reduced pressure. Ethanol is removed by evaporation at 40° C. (2.7 kPa). Dip the residue in water ( 50c), the product is separated by filtration and recrystallized in ethanol. do. Thereby, N-methyl-N-phenyl-2-[(8-quinolyl)aminoco Obtain acetamide (1.6 gL melting point 169°C).

N-Methyl-N-phenyl-2-[N-(8-quinolyl)trifluoroacetoa Mitocoacetamide can be produced by the following method: Sodium Hyde An oily suspension (50% by weight) (0.25 g) of Ride was added at a temperature of around 10°C. 8-( Add the resulting suspension to a solution of trifluoroacetylamino)quinoline (1.2 g). The suspension is stirred for 30 minutes at a temperature around 20°C. Then anhydrous tetrahydrofuran (1 2-bromo-N-methyl-N-phenylacetamide (1,8 g) in 5 cc) A solution of is added and the mixture is heated to reflux with stirring for 5 hours. Then the reaction mixture Cool to a temperature around 20℃ and mix with water (25cc) and ethyl acetate (50cc). Pour into the mixture. After the onset of precipitation, the aqueous phase was separated and reconstituted with ethyl acetate (2X25cc). Extract. The organic phases were combined, washed with water (3x20cc) and dried on magnesium sulfate. It is dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. obtained Oil packed in a column with a diameter of 2.5 cm (063-0.200 mm) ) (75 g) [eluent: dichloromethane] , collect a 10 cc fraction.

The fractions containing only the desired product were combined and a-condensed at 40°C under reduced pressure (2.7 kPa). dry. Thereby, N-methyl-N-phenyl-2-[N-(8-quinolyl ) Trifluoroacetamitocoacetamide (1.7 g) was obtained in the form of an oil, which was Used in subsequent synthesis without further processing.

2-Bromo-N-methyl-N-phenylacetamide is produced by the following method. N-Methyl in dichloromethane (65CC) at a temperature around 5°C. In a solution of luaniline (10.7 g), triethylamine (11.1 g) and A solution of bromoacetyl bromide (20.4 g) in lolomethane (10 c) Add it as a continuous read. Got it! Stir the turbid liquid for 2 hours at a temperature around 20°C, and collect the condensate. (25cc).

After the onset of sedimentation, the aqueous phase is separated and re-extracted with dichloromethane (2x15 cc).

The organic phases were combined, washed with water (3x25cc), dried over magnesium sulfate, Filter and concentrate to dryness under reduced pressure (2.7 kPa) at 40°C. Remove residual oil with anhydrous diethyl the insoluble product was separated by filtration, and the insoluble product was separated by filtration. Wash with thyl ether (3x15cc). The filtrates were combined and heated under reduced pressure (2.7 kP a) Concentrate and dry at 40°C.

Thereby, 2-bromo-N-methyl-N-phenylacetamide (20,5 g ) is obtained as an oil, which is used in the subsequent synthesis without further treatment.

Example 26 3-methylphenylisocyanate (0.34 g) at a temperature around 20°C, anhydrous 2-[2-amino-N-(5-quinolyl) in tetrahydrofuran (70 cc) acetamide]-N-methyl-N-phenylacetamide (0.8 g) Add. The resulting solution was stirred for 3 hours at a temperature around 20°C and then heated under reduced pressure (2.7kP a) Concentrate and dry at 40°C. Silica packed with residual oil in a 2cm diameter column Chromatography on (0,063-0,2 mm) (60) [eluent: acetic acid ethyl chloride] Purify by Chilco and collect 20cc fraction. Combine the fractions containing only the desired product The mixture was concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Recrystallized in ethyl acetate Then, N-methyl-2-[2-[3-(3-methylphenyl)ureido]-N-( 5-quinolyl)acetamitoco-N-phenylacetamide (0°67g), melted A point of 206°C is obtained.

2-[2-amino-N-(5-quinolyl)acetamide 1fN-methyl-N-ph Phenylacetamide can be produced by the following method: Hydrazine Hyde (0°72 g) was dissolved in N-methyl-N-phthalate in methanol (100 c). Phenyl-2-[2-phthalimido-N-(5-quinolyl)acetamitocoacetate Add to the solution of amide (2.3 g).

The reaction mixture was stirred for 3 hours at a temperature around 20°C and then under reduced pressure (2,7 kPa). Concentrate and dry at 40°C. Thereby, 2-[2-amino-N-(5-quinolyl) acetamide]-N-methyl-N-phenylacetamide (1.3 g), melting point 1 Obtain 57°C.

N-methyl-N-phenyl-2-[2-phthalimido-N-(5-quinolyl)a Cetamitocoacetamide can be produced by the following method: Sodium An oily suspension of hydride (50% by weight) (0.72 g) was added at a temperature of around 10°C. 2 in anhydrous tetrahydrofuran (10 c) kept under an argon atmosphere at -Phthalimide-N-(5-quinolyl)acetamide (5 g) and the obtained The resulting suspension is stirred for 1 hour at a temperature around 20°C. Then anhydrous tetrahydrof 2-bromo-N-methyl-N-phenylacetamide ( Add a solution of 5.1 g) and continue stirring at a temperature around 20° C. for 3 hours. then react Water (60 cc) and ethyl acetate (20 cc) cooled the mixture to a temperature around 0°C. Pour into the mixture. After the onset of precipitation, the aqueous phase was separated and ethyl acetate (2x20cc) Re-extract with . The organic phases were combined, washed with water (3 x 50 cc) and treated with magnesium sulfate. The mixture is dried on a vacuum sieve, filtered, and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). acetic acid After recrystallization in ethyl, N-methyl-N-phenyl-2-[2-phthalimide-N -(5-quinolyl)acetamitocoacetamide (3.4g), melting point 208°C obtain.

2-phthalimide-N-(5-quinolyl)acetamide is produced by the following method. in dichloromethane (60cc) kept under an argon atmosphere. Triethylamine (3.9 g) was added to a solution of 5-aminoquinoline (4.3 g). Then, while keeping the temperature around 20℃, 2 in dichloromethane (60℃) was added. - Add a solution of phthalimide acetyl chloride (8°1 g). the resulting suspension Stir for 1 hour at a temperature around 20°C. The generated solid was separated by filtration and water ( 3x50cc) and air dry. Thereby, 2-phthalimide-N-( 5-quinolyl)acetamide (9.9 g) is obtained.

tert-butyl in 1,2-dichloroethane (30 cc) at a temperature around 20°C. 2-[2-amino-N-(8-quinolyl)acetamitocoacetate (3,2 g) in 1,2-dichloroethane (25c). Add to a solution of bonyldiimidazole (1.8 g) and store the resulting solution at around 20°C. Stir at temperature for 2 hours. Then 3- in 1,2-dichloroethane (10c) Add a solution of methylthioaniline (1.4 g) and stir for 5 hours under reflux of the solvent. continue. The reaction mixture was then cooled to a temperature around 10°C and treated with water (100cc). Understand. After the onset of sedimentation, the aqueous phase was separated and re-extracted with dichloromethane (2x80cc). put out

The organic phases were combined and added with water (50 ccL followed by 0.5N aqueous hydrochloric acid solution (100 cc) and Wash with water (2 x 80 cc), dry over magnesium sulfate, filter and remove under reduced pressure. (2,7 kPa) Concentrate and dry at 40°C. The obtained oil was poured into a tube with a diameter of 2.5 cm. Chromatog on silica (0,063-0゜2mm) (200g) packed in a column Purified by roughy [eluent dichloromethane/methanol 9822 volume ratio] and collect 30cc fraction. The fractions containing only the desired product were combined and purified under reduced pressure (2 , 7kPa) Concentrate and dry at 40°C. After recrystallization in acetonitrile, tert -Butyl 2- [2-[3-(3-methylthiophenyl)ureidoco N-( 8-quinolyl)acetamitocoacetate (3.0 g), melting point 165° C. is obtained.

Example 28 3-Methylaniline (4,4 g) and 2-isocyanato-N-[2-oxo- 2-(1-pyrrolidinyl)ethyl]-N-(8-quinolyl)acetamide (4 Using a method similar to that described in Example 24, but starting with After recrystallization in setonitrile, 2-[3-(3-methylphenyl)ureido] -N-[2-oxo-2-(1-pyrrolidinyl)ethyl] -N-(8-quinoli ) acetamide (0.7 g), melting point 227°C.

2-Isocyanato-N-[2-oxo-2-(1-pyrrolidinyl)ethyl] -N-(8-quinolyl)acetamide is isocyanatoacetyl chloride (0 , 65g), 8-([2-oxo-2-(1-pyrrolidinyl)ethylcoami N-[2 -(3,3-dimethylpiperidino)-2-oxoethyl]-2-isocyaner) -The method described in Example 24 for the production of N-(8-quinolyl)acetamide and It can be manufactured by similar methods. Thereby, 2-isocyanate-N- [2-oxo-2-(1-pyrrolidinyl)ethyl]-N-(8-quinolyl)a Cetamide (1.4 g) was obtained as an oil without further treatment (used in subsequent synthesis). Ru.

8-([2-oxo-2-(1-pyrrolidinyl)ethylkoamino)quinoline is N-(2-oxo-2-(1-pyrrolidinyl)ethyl]-N-(8-quinolyl) Trifluoroacetamide (1.9 g) and 2N aqueous sodium hydroxide solution 8-(,C2-(3,3-dimethylpipe Described in Example 24 for the production of lysino)-2-oxoethylcoamica quinoline It can be manufactured by a method similar to that of . Thereby, 8-([2-oxo -2-(1-pyrrolidinyl)ethylcoamino)quinoline (1,1 g), melting point 17 Obtain 8°C.

N-(2-oxo-2-(1-pyrrolidinyl)ethyl-N-(8-quinolyl) Trifluoroacetamide is 2-(trifluoroacetylamino)quinoline ( Oily suspension (50% by weight) of 2,5 gL sodium hydride (0,6 g) and and 2-bromo-1-(1-pyrrolidinyl)-1-ethanone (2.4 g). N-[2-(3゜3-dimethylpiperidino)-2-oxoethyl Example regarding the production of -N-(8-quinolinolidofluoroacetamide) It can be produced by a method similar to that described in 24. Thereby, N-(2- Oxo-2-(1-pyrrolidinyl)ethyl]-N-(8-quinolyl)trifluoro Roacetamide (1,9 g) was obtained as an oil, which was used for subsequent synthesis without further treatment. used for construction.

2-Bromo-1-(l-pyrrolidininoly-1-ethanone is pyrrolidine (7,1 g), triethylamine (11,1 g) and bromoacetyl bromide (20,4 g) except starting with 2-bromo-1-(3,3-dimethylpiperidino ) Regarding the production of ethanone, it can be produced by a method similar to that described in Example 24. can. Thereby, 2-bromo-1-(1-pyrrolidinyl)-1-ethanone ( 9.1 g) is obtained in the form of an oil, which is used in the subsequent synthesis without further treatment.

Example 29 3-methylphenylisocyaner h (0.4 g) was added to the water at a temperature of around 20°C. tert-butyl 2-[2-amino Add to the solution of -N-(7-quinolyl)acetamitocoacetate (0°6g) . The resulting solution was stirred for 3 hours at a temperature around 20°C and then heated under reduced pressure (2,7kP a) Concentrate and dry at 40°C. Silica packed with residual oil in a 2cm diameter column Chromatography on (0,063-0,2 mm) (4Og) [eluent: acetic acid ethyl] and collect a 20 cc fraction. the fraction containing only the desired product The mixture is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Reconsolidate in ethyl acetate After crystallization, tert-butyl 2-[2-13-(3-methylphenyl)ureido ]-N-(7-quinolyl)acetamitocoacetate (0.37g), melting point 1 Obtain 65°C.

tert-butyl 2-[2-amino-N-(7-quinolyl)acetamitocore Cetate can be produced by the following method: hydrazine hydrate (0 , 6g) in methanol (40c). Solution of limido-N-(7-quinolyl)acetamitocoacetate (1,3g) Add to. The reaction mixture was heated to reflux for 3 hours, then under reduced pressure (2,7 kPa) for 40 Concentrate and dry at °C. Dissolve the residual oil in water (50 cc). After the start of sedimentation, the aqueous phase Separate and re-extract with ethyl acetate (2 x 30 cc). Combine the organic phases and add water (3 x 15 cc), dried over sodium sulfate, filtered and washed under reduced pressure (2,7 k Pa) Concentrate and dry at 40°C. Thereby, tert-butyl 2-[2-amino No-N-(7-quinolyl)acetamitocoacetate (0°65g) was obtained in the form of an oil. , and use it in later synthesis without further processing.

tert-butyl 2-[2-phthalimido-N-(7-quinolyl)acetamide Tocoacetate can be produced by the following method: Sodium hydride An oily suspension (50% by weight) (0.53 g) of 2-phthalate in anhydrous tetrahydrofuran (100 cc) kept under a nitrogen atmosphere. Added to a solution of mido-N-(7-quinolyl)acedeamide (3°4 g), the obtained The suspension is stirred for 2 hours at a temperature around 20°C. Then anhydrous tetrahydrofuran ( 10c Add a solution of tert-butyl bromoacetate (2.1 g) in c) Continue stirring at a temperature around 20°C for 16 hours. The reaction mixture was then diluted with water (50 c c) and remove the solvent by evaporating under reduced pressure (2,7 kPa) at 40 °C. and add a mixture of ethyl acetate (100 cc) and water (50 cc). opening of rain After starting, the aqueous phase is separated and re-extracted with ethyl acetate (2xlOcc). Combine the organic phases washed with water (3 x 80 cc), dried over magnesium sulfate, filtered and dried under reduced pressure. Concentrate and dry at 40° C. (2.7 kPa). After recrystallization in ethyl acetate, ter t-Butyl 2-[2-phthalimido-N-(7-quinolyl)acetamitocore Cetate (1.4 g), melting point 213° C., is obtained.

2-phthalimide-N-(7-quinolyl)acetamide is produced by the following method. can be done. in dichloromethane (80cc) kept under an argon atmosphere. Triethylamine (2.1 g) was added to a solution of 7-aminoquinoline (3.0 g). Then, while keeping the temperature around 20℃, 2- in dichloromethane (50cc) Add a solution of phthalimide acetyl chloride (4.7 g). The obtained solution is 2 Stir for 4 hours at a temperature around 0° C. and treat with water (50 cc). Filter the formed solid. Diisopropyl ether (2x25cc) and its condensate (4x 50cc) and air dry. Thereby, 2-phthalimide-N-(7- Quinolyl)acetamide (3.5 g), melting point 259° C., is obtained.

7-Aminoquinoline is F, LINSKERand R, L, EVANS, J , Amer, Chem, Soc, 68.149-150 (1946). can be manufactured according to the method.

Example 30 tert-butyl 2-F2-amino-N-(6-quinolyl)acetamitocore Cetate (3, Og) and 3-methylphenylisocyaner) (1,06g) Using a method similar to that described in Example 29, but starting with After recrystallization in propyl ether, tert-butyl 2-[2-[3-(3-methane) tylphenyl)ureido] -N-(6-quinolyl)acetamitocoacetate (0.9 g), melting point 105°C.

tert-butyl 2-[2-amino-N-(6-quinolyl)acetamitocore Cetate is tert-butyl 2-[2-phthalimido-N-(6-quinolyl ) acetamitocoacetate (3,3 g) and hydrazine hydrate (1,2 tert-butyl 2-[2-amino-N-(7 - those described in Example 29 for the production of quinolyl) acetamitocoacetate. It can be manufactured by a method similar to the method. Thereby, tert-butyl 2-[2 -Amino-N-(6-quinolyl)acetamitocoacetate (3.0g) in oil form and used in the subsequent synthesis without further processing.

tert-butyl 2-[2-phthalimido-N-(6-quinolyl)acetamide Tocoacetate is 2-phthalimido-N-(6-quinolyl)acetamide (9 , 7 g), oily suspension of sodium hydride (50% by weight) (1,55 g) and tert-butyl bromoacetate (6°05 g). , tert-butyl 2-[2-phthalimido-N-(7-quinolyl)acetoacetate Produced in a similar manner to that described in Example 29 for the production of mitocoacetate can do.

As a result, tert-butyl 2-[2-phthalimido-N'-(6-quinolinide) ) acetamitocoacetate (3.4 g) is obtained.

2-phthalimido-N-(6-quinolyl)acetamide is 6-aminoquinoline (4,35g), triethylamine (3,3g) and 2-phthalimidoacetyl 2-phthalimide-N-(7- In a method analogous to that described in Example 29 for the preparation of quinolyl)acetamide. It can be manufactured more easily. Thereby, 2-phthalimide-N-(6-quinoli ) acetamide (9.8 g) is obtained.

Example 31 3-Methylaniline (0.64 g) and 2-isocyanato-N-F2- (1 ,2,3,4-tetrahydro-1-quinolyl)-2-oxoethyl] -'N- As described in Example 24, but starting with (8-quinolyl)acetamide. 2-[3-(3-methyl phenyl)ureido] -N-[2-(1゜2, 3.4-tetrahydro-1 -quinolyl)-2-oxoethyl]-N-(8-quinolyl)acetamide (1, 6 g), melting point 187°C.

2-Incyanato-N-[2-(1,2,3,4-tetrahydro-1-quinoli) )-2-oxoethyl]-N-(8-quinolyl)acetamide is Natoacetyl chloride (0.85g), 8-([2-(x, 2. a, 4 -tetrahydro-1-quinolyl)-2-oxoethyl]aminoquinoline (1,9 g) and pyridine (0,48 g). -N-[2-(3,3-dimethylpiperidino)-2-oxoethyl] -N-( A method analogous to that described in Example 24 for the production of 8-quinolithuriacetamide It can be manufactured in Thereby, 2-isocyanato-N-[2-(1, 2,3゜4-tetrahydro-1-quinolyl)-2-oxoethyl] -N-(8 -quinolyl)acetamide (2,6 g) was obtained as an oil, which was further processed. used for later synthesis.

8- + [2-(1,2,3,4-tetrahydro-1-quinolyl)-2-oxo Ethylcoamino)quinoline is N-(8-quinolyl)-N-[2-(1,2,3 ,4-tetrahydro-1-quinolyl)-2-oxoethyl)trifluoroacetate Using amide C2.8g) and 2N aqueous sodium hydroxide solution (6.7c) 8-([2-(3,3-dimethylpiperidino)-2-oxo By a method similar to that described in Example 24 for the production of [ethyl]amyl quinoline. can be manufactured by After recrystallization in ethyl acetate, 8-1 [2-(1,2, 3,4-tetrahydro-1-quinolyl)-2-oxoethyl]amihaquinoline ( Obtain 2.0 gl, melting point 128°C.

N-(8-quinolyl)-N-[2-(1,2,3,4-tetrahydro-1-quinolyl) noryl)-2-oxoethyl)trifluoroacetamide is 8-(trifluoroacetamide). loacetylamino)quinoline (2.4 g), oily suspension of sodium hydride liquid (50% by weight) (0,6 gL and 2-bromo-1-(1,2,3,4-tetra except starting with hydro-1-quinolyl)-1-ethanone (3,75 g) , N-[2-(3,3-dimethylpiperidino)-2-oxoethyl] -N-( The method described in Example 24 for the production of 8-quinolyl) trifluoroacetamide It can be manufactured by a method similar to the method. Thereby, N-(8-quinolyl)-N -[2-(1,2,3,4-tetrahydro-1-quinolyl)-2-oxoethyl ) Trifluoroacetamide (2.8 g) was obtained as an oil, which could be further processed. Tona (Used for later synthesis.

2-Bromo-1-(1,2,3,4-tetrahydro-1-quinolyl)-1-etha Non is 1. 2. 3. 4-tetrahydroquinoline (13.3g), Torie using thylamine (11,1 g) and bromoacetyl bromide (20,4 g) 2-bromo-1-(3,3-dimethylpiperidino)-1-eth It can be produced by a method similar to that described in Example 24 regarding the production of non. . Thereby, 2-bromo-1-(1,2,3,4-tetrahydro-1-quinolinyl )-1-ethanone (20,3 g) was obtained in the form of an oil, which was obtained without further treatment. Used for later synthesis.

Example 32 3-Methylaniline (0.43 g) and 2-isocyanato-N-(2-piperi Dino-2-oxoethyl)-N-(8-quinolyl)acetamide (1.5 g) Using a method similar to that described in Example 24, but starting with acetonitrile After recrystallization in Ril, 2-[3-(3-methylphenyl)ureido]-N-( 2-Piperidino-2-oxoethyl)-N-(8-quinolyl)acetamide (0 , 8g), melting point 183°C.

2-Isocyanato-N-(2-piperidino-2-oxoethyl)-N-(8- Quinolyl)acetamide is isocyanatoacetyl chloride (0.75g) , 8-[(2-piperine-no-2-oxoethyl)aminocoquinoline (1,4g ) and pyridine (0,42 g). N-c2-(3,a-dimethylpiperidino)-2-oxoethyl] -N-( Method i Similar method described in Example 24 for the preparation of 8-quinolyl)acetamide It can be manufactured in

Thereby, 2-isocyanato-N-(2-piperidino-2-oxoethyl) -N-(8-quinolyl)acetamide (1,5 g) was obtained as an oil, which was further processed. used for later synthesis without processing.

8-[(2-piperidino-2-oxoethyl)aminocoquinoline is N-(2- Biheridino-2-oxoethyl)-N-(8-quinolyl)trifluoroacetoa Using Mido (2.55 g) and 2N aqueous sodium hydroxide solution (7.0 cc) 8-(E2-(3,3-dimethylpiperidino)-2-ox A method similar to that described in Example 24 for the preparation of soethylcoamino)quinoline It can be manufactured by

After recrystallization in ethyl acetate, 8-[(2-piperidino-2-oxoethyl)amino Coquinoline (1.5 g) is obtained, melting point 135°C.

N-(2-piperidino-2-oxoethyl)-N-(8-quinolyl)-triflu Oroacetamide is 8-()lifluoroacetylamino)quinoline (2.4 g ), an oily suspension of sodium hydride (50% by weight) (0,6 g), and 2 - except starting with bromo-1-piperidino-1-ethanone (3,1 g) , N-[2-(3,3-dimethylpiperidino)-2-oxoethyl] -N-( The method described in Example 24 for the production of 8-quinolyl) trifluoroacetamide It can be manufactured by a method similar to the method. Thereby, N-(2-piperidino-2 -oxoethyl)-N-(8τquinolyl)trifluoroacetamide (2,55 g) is obtained in the form of an oil, which is used in the subsequent synthesis without further treatment.

2-Bromo-1-piperidino-1-ethanone was prepared using piperidine (8.5 g), tri- Using ethylamine (11.1 g) and bromoacetyl bromide (20.4 g) 2-bromo-1-(3,3-dimethylpiperidino)-1-ethyl Tanone can be produced by a method similar to that described in Example 24. Ru. Thereby, 2-bromo-1-piperidino-1-ethanone (7 g) was prepared as an oil. obtain.

Example 33 The method uses tert-butyl 2-[2-phthalimide-N-(4-isoquinolyl ) acetamitocoacetate (2.25g), hydrazine/X idlate (0 , 75 g) and 3-methylphenylisocyanate (0°68 g). The method is similar to that described in Example 1, except that.

The obtained crude product was packed with silica (0°063 -0.2mm) (25g) 07 tographie (eluent dichloromethane) and collect 10 cc fraction. Fractions 48-97 were combined and heated under reduced pressure (2.7 kP a) Concentrate and dry at 50°C. After recrystallization in petroleum ether, tert-butyl 2-(2-[3-(3-methylphenyl)ureido]-N-(4-isoquino tate (0.35 g), melting point 100° C., was obtained with (Ryl)acetamide.

tert-butyl 2-[2-phthalimido-N-(4-isoquinolyl)aceto Amitocacetate is N-(4-isoquinolyl)-2-phthalimide acetate. Mido (1.3 g), oily suspension of sodium hydride (50% by weight) (0. (24 g) and tert-butyl bromoacetate (0.78 g). tert-butyl 2-[2-phthalimide-N-(3-pyridinol) Produced by a method similar to that described in Example 1 for the production of acetamitocoacetate. can be built. Thereby, tert-butyl 2-[2-phthalimide -N-(4-isoquinolyl)acetamitocoacetate (0.85g) in oil form obtained and used for subsequent synthesis without further processing.

2-phthalimido-N-(4-isoquinolyl)acetamide is 4-aminoiso Quinoline (1,45 g), triethylamine (1,0 g) and 2-phthalimide 2-phthalimide- but starting with acetyl chloride (2,25 g) Similar to the method described in Example 1 for the preparation of N-(3-pyridyl)acetamide It can be manufactured by the method. Thereby, 2-phthalimido-N-(4-iso Quinolyl)acetamide (1.6 g), melting point >260°C, is obtained.

Example 34 tert-butyl 2-[2-amino-N-(8-quinolyl)acetamitocore Cetate (4,45g) and 3-methoxyphenylisocyanate (1,37g) ) using a method similar to that described in Example 1, but starting with tert -Butyl 2-(2-[3-(3-methoxyphenyl)ureidoco N-(8 -quinolyl)acetamitoneacetate-) (1.6g), melting point 149°C. .

Example 35 tert-butyl N-benzyl-N-(isocyanate) at a temperature around 20°C. Cetyl)glycinate (3.5 g) was added to anhydrous tetrahedron under an argon atmosphere. Add to a solution of 3-methylaniline (1,1 g) in Dorofuran (100 cc) . The resulting solution was stirred at a temperature around 20°C for 3 hours and then heated under reduced pressure (2,7 kPa) 4 Concentrate and dry at 0°C. After recrystallizing the residue in ethyl acetate, tert-butyl 2-[2-[3-(3-methylphenyl)ureido]-N-benzylacetate toamide] acetate (2.2 gL melting point 117° C. is obtained.

tert-butyl N-benzyl-N-(isocyanatoacetyl)glycine can be produced by the following method: anhydrous diethyl ether (25 cc) tert-butyl 2-(benzylamino)acetate (2.21 g) and A solution of pyridino (8 g) was dissolved in anhydrous diethyl ether kept under an argon atmosphere. of isonoanatoacetyl chloride (1.2 g) in Ru. The reaction mixture was stirred for 2 hours at a temperature around 20°C and the insoluble products were removed by filtration. Separate and wash with anhydrous diethyl ether (15cc). Combine the filtrates and reduce pressure Concentrate and dry at 40°C (2°7 kPa). Thereby, tert-butyl N -Benzyl-N-(isocyanatoacetyl)glycine-) (3.5g) in oil and is used in the subsequent synthesis without further treatment.

Tert-butyl 2-(benzylamino)acetate is produced by the following method. You can add tert-butyl bromoacetate (19.5g) to the Add to a solution of benzylamine (21.4 g) in setonitrile (200 cc) . The resulting solution is heated to reflux for 4 hours. After cooling, insoluble products are separated by filtration. and wash with acetonitrile (3x20cc). The filtrates were combined and heated under reduced pressure (2, 7kPa) Concentrate and dry at 40°C. Thereby, tert-butyl 2-(ben dylamino)acetate (44,7 g) was obtained as an oil, which was further processed. used for later synthesis.

Isocyanate acetyl chloride, YO5HIOIWAKtJRA.

KEIKICHI UNO and SANAM KANG, J, Org, Che M, 30.1158 (1965). Ru.

Example 36 Hydrazine hydrate (2.17 g) was mixed with methanol (1 00cc) of tert-butyl 2-[2-phthalimide-N-(1-phenyl) acetamitocoacetate (6 g). 2 of the reaction mixture Stir at a temperature around 0°C for 3 hours, then concentrate and dry at 40°C under reduced pressure (<2.7 kPa). Ru. The residual oil was dissolved in ethyl acetate (50cc) and the resulting solution was dissolved in water (50cc). ). After the onset of precipitation, the aqueous phase was separated and reconstituted with ethyl acetate (2x25cc). Extract. The organic phases were combined, washed with water (2x15cc) and dried on magnesium sulfate. It is dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. residue Dissolved in tetrahydrofuran (30cc) and added 3-methylphenyl to this solution. Add isocyanate (1.89 g). The resulting solution was kept at a temperature of 20°C for 1 hour. Stir and concentrate to dryness under reduced pressure (2.7 kPa) at 40°C. Remove the residue with a diameter of 2 Chromatogram on silica (0,063-0,2 mm) (150 g) packed in a cm column. Matography C eluent dichlorohexane/ethyl acetate (50:50 volume ratio)] and collect 20 cc fraction. Combine the fractions containing only the desired product, Concentrate and dry under reduced pressure (2.7 kPa) at 40°C. in diisopropyl ether After recrystallization, tert-butyl 2-[2-[3-(3-methylphenyl)ure ido]-N-(1-phenylethyl)acetamitocoacetate (1,7 g), A melting point of 120°C is obtained.

tert-butyl 2-[2-phthalimido-N-(1-phenylethyl)acetate Toamitocoacetate can be produced by the following method. argon atmosphere tert-Butyl 2- in 1,2-dichloroethane (60cc) kept under [(To a solution of 1-phenylethynolyaminocoacetate (4.2 g), Add thylamine (2.15 g) and then add 1,2-dichloro at a temperature around 20°C. A solution of 2-phthalimidoacetyl chloride (4g) in ethane (20CC) was added dropwise. down. The resulting solution was stirred for 3 hours at a temperature around 20°C and treated with water (50cc). Understand. After the onset of precipitation, the aqueous phase was separated and 1,2-dichloroethane (2x50cc ) to re-extract. The organic phases were combined, washed with water (2xlOcc) and diluted with magnesium sulfate. The mixture is dried over vacuum, filtered and concentrated to dryness under reduced pressure (2,7 kPa) at 40°C. Jii After recrystallization in sopropyl ether, tert-butyl 2-[2-phthalimide- N-(1-phenylethyl)acetamitocoacetate (6g), melting point 131°C get.

tert-butyl 2-[(1-phenylethyl)aminocoacetate is as follows: It can be produced by the following method: Acetonitrile (60cc ) to a solution of 1-phenylethylamine (6.1 g) in sodium bicarbonate (2 , 1 g) and then add tert-butyl bromoacetate (4,9 g). . The reaction mixture is heated to reflux for 48 hours and cooled to a temperature around 20°C. insoluble substances is separated by filtration and washed with acetonitrile (50 cc). Combine the filtrates, Concentrate and dry at 40° C. under reduced pressure (2.7 kPa). Thereby, tert-butyl 2-[(1-phenylethyl)aminocoacetate (1), 5 g) was obtained as an oil, It is used for later synthesis without further processing.

Example 37 tert-butyl 2-(isopropylamino)acetate at a temperature around 20°C (2g) was mixed with 1,2-dichloroethane (230c) kept under argon atmosphere. ) of 2-[3-(3-methylphenyl)ureido]acetic acid (2,6 g) in Add to liquid. The reaction mixture is heated with stirring and the solvent is refluxed. Then reflux Sulfinyl chloride (2.12 g) was added dropwise while maintaining the temperature. After addition, add Thermal reflux was continued for 10 minutes, after which the reaction mixture was cooled to a temperature around 10°C and added with water (3 Pour into a solution of sodium bicarbonate (15 g) in 00 cc). After the start of settling, Separate the aqueous phase and re-extract with 1,2-dichloroethane (2 x 50 cc). organic Combine the phases, wash with water (3 x 20 cc), dry over magnesium sulfate and filter. The mixture is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Remove the residue with a diameter of 3.5 Chromatography on silica (0,063-0,2 mm) (200 g) packed in a cm column. Matography [eluent dichlorohexane/ethyl acetate (50:50 volume ratio)] and collect 30 cc fraction. Combine the fractions containing only the desired product, Concentrate and dry under reduced pressure (2.7 kPa) at 40°C. After recrystallization in ethyl acetate, t ert-butyl 2-[2-[3-(3-methylphenyl)ureido]-N-y Sopropylacetamitocoacetate (0.8 g), melting point 143° C., is obtained.

Tert-butyl 2-(isopropylamino)acetate is produced by the following method. It can be prepared by adding tert-butyl bromoacetate (7.3 g) to Added to a solution of inpropylamine (4,4 g) in setonitrile (60 c) Ru. The resulting solution is stirred under reflux for 4 hours.

After cooling, the insoluble product was separated by filtration and washed with acetonitrile (30cc). Purify. The filtrates are combined and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). residual oil Dissolve in dichloromethane (150cc) and wash the solution with water (4x15cc) Ru. The organic phase was dried over magnesium sulphate, filtered and dried under reduced pressure (2,7 kPa) 4 Concentrate and dry at 0°C. Thereby, tert-butyl 2-(isopropyl amide (4.1 g) was obtained in the form of an oil, which was used in the subsequent synthesis without further treatment. used for construction.

2-[3-(3-methylphenyl)ureido]acetic acid is produced by the following method. Can: At a temperature around 20°C, 3-methylphenylisocyanate (13 , 3 g) in water (250 cc) and glycine (7.5 g) and sodium bicarbonate. (8.4 g). Stir the reaction mixture for 18 hours at a temperature around 2 cm and the insoluble product was separated by filtration, water (2 x 30 cc) and then ethyl acetate. (2x30cc). The filtrates were combined and after the onset of sedimentation, the aqueous phase was separated and 5 Acidify with an aqueous solution of N hydrochloric acid to bring the pH to around 1. Separate the generated solid by filtration. Remove, wash with water (2 x 30 cc) and then ethyl acetate (2 x 30 cc) and empty. Air dry. 2-[3-(3-methylphenyl)ureido]acetic acid (16°3g ), giving a melting point of 225°C.

Example 38 At a temperature of around 2 cm, 3-methylphenylisocyanate-1- (0.6 g) was tert-butyl 2-[2-amino in water tetrahydrofuran (100 cc) Add to a solution of -N-(1-naphthyl)acetamido]acetate (8 g). profit The resulting solution was stirred at a temperature of around 2 cm for 4 hours, and then heated at 40°C under reduced pressure (2.7 kPa). Concentrate and dry. The residual oil was collected using silica (0,0 63-0,2 mm) (400 g) [eluent dichlorohexyl 20cc fraction was collected. . The fractions containing only the desired product were combined and concentrated under reduced pressure (2.7 kPa) at 40°C. Shrink dry. After recrystallization in acetonitrile, tert-butyl 2-[2-[ 3-(3-methylphenyl)ureido]-N-(1-naphthyl)acetamide ] Acetate (3.4 g), melting point 156° C. is obtained.

tert-butyl 2-[2-amino-N-(1-naphthyl)acetamido]a Cetate can be produced by the following method: hydrazine nozodrate (3 g) in methanol (100 cc) as tert-butyl 2-[N-(1- Naphthyl)-2-phthalimidoacetamido]acetate (8.9 g) Add. The reaction mixture was stirred for 3 hours at a temperature around 2 cm and then stirred under reduced pressure (2,7 kPa) Concentrate and dry at 40°C. The residue was mixed with diethyl ether (400cc). Stir together and separate the insoluble product by filtration. The filtrate was heated under reduced pressure (2,7 kPa ) Same dry at 40°C. Thereby, tert-butyl 2-[2-amino No-N-(1-naphthyl)acetamido]acetate (8 g) was obtained as an oil and further used for later synthesis without further processing.

tert-butyl 2-[N-(1-naphthyl)-2-phthalimide acetate Mido]acetate can be produced in the following way: at a temperature around 10°C. , an oily suspension (50% by weight) (2.4 g) of sodium hydride was added to the Argo N-(1-naphthyl) in anhydrous tetrahydrofuran (1000°C) kept under -2-phthalimideacetamide (14.9g) and the resulting suspension Stir for 1 hour at a temperature of around 2 cm. Then anhydrous tetrahydrofuran (40c Add the solution of tert-butyl bromoacetate (9.75 g) in c), Stirring is continued for 3 hours at a temperature around 2 cm. The reaction mixture was then cooled to 0°C. Pour into a mixture of water (80cc) and ethyl acetate (800cc). After the start of settling, Separate the aqueous phase and re-extract with ethyl acetate (2x8Qcc). Combine the organic phases and add water (3xlOOcc), dried over magnesium sulfate, filtered and under reduced pressure ( 2,7 kPa) Concentrate and dry at 40°C. Thereby, tert-butyl 2-[ N-(1-naphthyl)-2-phthalimidoacetamido]acetate (20g) is obtained in the form of an oil, which is used in the subsequent synthesis without further treatment.

N-(1-naphthyl)-2-phthalimide acetamide is produced by the following method. In dichloromethane (100cc) kept under an argon atmosphere To a solution of 1-naphthylamine (7.15 g) was added triethylamine (5.56 g). ) in dichloromethane (75cc) while maintaining the temperature around 20℃. A solution of 2-phthalimidoacetyl chloride (11.2 g) is added. obtained The solution is stirred for 3 hours at a temperature around 2 cm and treated with water (75 cc). generated The solid was separated by filtration, dichloromethane (3x15cc) and water (3x30cc). c) and air dry. After the onset of sedimentation, the organic phase of the filtrate was separated and diluted with water (2x 30cc), dried over magnesium sulfate, filtered and washed under reduced pressure (2,7k Pa) Concentrate and dry at 40°C. The resulting solid is combined with the above solid. That's it N-(1-naphthyl)-2-phthalimidoacetamide (16 g) was obtained.

2-phthalimide acetyl chloride is W, GRASSMANN, etc.

B, er, 83, 244 (1950). can.

Example 39 Methylhydrazine (2.8 g) was dissolved in dichloromethane (100 tert-butyl 2-C2-phthalimide-N-(t e r t -butoxycarbonylmethyl)acetamide]acetate CM, 9 g) in a solution of Add. The reaction mixture was heated at a temperature of around 2 cm for 30 hours, and then for 1 hour under reflux. Stir. After cooling, water (100 cc) was added, the mixture was stirred, and after the start of settling, Separate the aqueous phase and re-extract with dichloromethane (2x80cc). Combine the organic phases , washed with water (2X15CC), dried over magnesium sulfate, filtered and under reduced pressure. Concentrate and dry at (2,7 kPa,) 40°C. The oil thereby obtained is anhydrous. Dissolve in lahydrofuran (60cc). Add 3-methylphenyliso to this solution. Cyanate (2.7 g) was added and the reaction mixture was stirred for 1 hour at a temperature of around 2 cm. , concentrated and dried under reduced pressure (2.7 kPa) at 40°C. A yellow oil (9 g) was obtained, Silica (0°・063-0.2mm) (2 Chromatography on 50 g) [eluent dichlorohexane/ethyl acetate (50 g) :50 volume ratio) and collect a 40cc fraction. Contains only the desired product The fractions are combined and concentrated and dried at 40° C. under reduced pressure (C2, 7 kPa). the residue obtained The distillate was packed into a 2 cm diameter column of silica (0,063-0,2 mm) (7 5 g) [eluent dichlorohexane/ethyl acetate ( 60:40 volume ratio)] and collect a 15 cc fraction. desired product only The fractions containing are combined and concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Diiso Twice consecutively in a mixture of propyl ether and ethyl acetate (90:10 body/m ratio) After recrystallizing, 2-[3-(3-methylphenyl)ureido]-N,N -bis(tert-butoxycarbonylmethyl)acetamide (2gL melting point 11 Obtain 9°C.

tert-butyl 2-[2-phthalimido-N-(tert-butquin carbo Nylmethyl) acetamitocoacetate can be produced by the following method - tert-butyl in acetonitrile (40 cc) kept under argon atmosphere Add sodium hydrogen carbonate to a solution of glycinate (7.9 g) at a temperature of around 20°C. Add (2.5g) and add acetonitrile (80c) while keeping the temperature around 20℃. Add a solution of tert-butyl bromoacetate (5.85 g) in c). anti The reaction mixture is stirred for 2 hours at a temperature around 20°C and then for 1 hour at a temperature of 40°C. . The product is separated by filtration and washed with acetonitrile (15cc). filtrate are combined and concentrated and dried at 40° C. under reduced pressure (2.7 kPa). Diisoprop the residue Stir with lopyl ether (100cc) and separate the insoluble product by filtration. The filtrate is concentrated and dried under reduced pressure (2.7 kPa) at 4'O<0>C. Residual oil 1.2 -Dissolved in dichloroethane (120 cc) and added sodium bicarbonate to the resulting solution. (2.5g), then keep the temperature around 20℃ and add 1,2-dichloroether. A solution of 2-phthalimido acetyl chloride (6.7 g) in tank (20 cc) Add. The resulting suspension was stirred at a temperature around 20°C for 16 hours and water (50c ).

After the onset of sedimentation, the aqueous phase was separated and reconstituted with 1,2-dichloroethane (2xlOOCC). Extract. The organic phases were combined, washed with water (2 x 100 cc) and treated with magnesium sulfate. Dry on top, filter and concentrate to dryness under reduced pressure (2,7 kPa) at 40°C. acetic acid After recrystallization in ethyl, tert-butyl 2-[2-phthalimide-N-(te rt-butoxycarbonylmethyl)acetamitocoacetate (8,9gL melting point Obtain 150'C.

Example 40 tert-butyl 2-[2-amino-N-(1,2,3,4-tetrahydrona phthyl) acetamitocoacetate (6,4 g) and 3-methylphenylis Similar procedure to that described in Example 38, but starting with ananate (2°26 g). Using a similar method, after recrystallization in diisopropyl ether, 2-[2-[3-(3 -methylphenyl)ureido-N-(1,2,3,4-tetrahydro-5-naph (chill) acetamitocoacetate (3; 8 gL melting point 146° C. is obtained.

tert-butyl 2-[2-amino-N-(1,2,3,4-tetrahydrona phtyl)acetamitocoacetate is tert-butyl 2-[2-phthalimide Do-N-(1,2,3,4-tetrahydro-5-naphthyl)acetamitocoacetate Starting with tate (7,9 g) and hydrazine hydrate (2,7 g) tert-butyl 2-[2-amino-N-81-naphthyl)aceto Produced in a similar manner to that described in Example 38 for the production of mitocoacetate. be able to.

Thereby, tert-butyl 2-[2-amino-N-(1,2,3°4-te Trahydronaphthyl) acetamitocoacetate (6.5 g) was obtained as an oil; used in subsequent synthesis without further processing.

tert-butyl 2-[2-phthalimido-N-(1,2,3,4-tetrahyde Dro-5-naphthyl) acetamitocoacetate is 2-phthalimide-N-( 1,2,3,4-tetrahydro-5-naphthyl)acetamide (10g), Nato Oily suspension of lium hydride (50% by weight) (1,6 g) and tert- tert-butyl bromoacetate (6.05 g) Butyl 2-[N-(1-naphthyl)-2-phthalimide acetamitocoacetate Regarding the production of tate, it can be produced by a method similar to that described in Example 38. Ru. After recrystallization in diisopropyl ether, tert-butyl 2-[2-phenyl Thalimide-N-(1,2,3,4-tetrahydro-5-naphthyl)acetamide Obtain 9 gL of dotacetate, melting point 144°C.

2-phthalimido-N-(1,2,s,4-tetrahydro-5-naphthyl)acetate Toamide is 1. 2. 3. 4-tetrahydro-5-naphthylamine (5, 9g), triethylamine (4,4g) and 2-phthalimidoacetyl chloride N-(1-naphthyl)-2-phthalimide except starting with (9,6 g) Doacetamide can be produced by a method similar to that described in Example 38. I can do it. Thereby, 2-phthalimide-N-(1,2,3,4-tetrahyde Dro-5-naphthyl)acetamide (13 g) is obtained.

Example 41 Hydrazine hydrate (2.3 g) was mixed with methanol (80 g) at a temperature around 20°C. tert-butyl 2-(N-cyclopropyl-2-phthalimidore in cc) Add to a solution of cetamido)acetate (5.5 g). The reaction mixture at this temperature Stir for 1 hour. The formed insoluble substances were removed by filtration, and diethyl ether ( The filtrate was concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Ru. The residual oil is treated with a mixture of water (40 cc) and ethyl acetate (40 cc). Shen After the onset of precipitation, the aqueous phase is separated and re-extracted with ethyl acetate (2 x 20 cc). organic phase were combined, washed with water (2x20cc), dried over magnesium sulfate, filtered. , concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Thereby, the tert-button Chil 2-(2-amino-N-cyclobropylacetamide) acetate (3, 2g) was obtained as a yellow oil, which was dissolved in anhydrous tetrahydrofuran (50cc). do. Add 3-methylphenylisocyanate (1.9 g) to this solution and react. The mixture was stirred for 1 hour at a temperature around 20°C and then heated at 40°C under reduced pressure (2,7 kPa). Concentrate and dry. After recrystallizing the residue in ethyl acetate, tert-butyl N- cyclopropyl-2-[3-(3-methylphenyl)ureidogo-2-acetoa Midacetate (2.0 g), melting point 128° C., is obtained.

tert-butyl 2-(N-cyclopropyl-2-phthalimidoacetamide ) Acetate can be produced in the following way: kept under an argon atmosphere. tert-Butyl 2-(cyclopropyl) in dichloromethane (50cc) Triethylamine (2.9 g) was added to a solution of amino) acetate (4.1 g). Then, 2-phthalimide in dichloromethane (50 cc) at a temperature around 20°C. A solution of doacetyl chloride (5.4 g) was added dropwise. The obtained solution was heated to around 20℃. Stir for 1 hour at a temperature of and treat with water (+01 cc). After the start of settling, separate the aqueous phase. Remove and re-extract with dichloromethane (2x25c, c). Combine the organic phases and add water ( 2 x 20 cc), dried over magnesium sulfate, filtered and washed under reduced pressure (2, 7 kPa) Concentrate and dry at 40°C. After recrystallization in ethyl acetate, tert-butyl Chil 2-(N-cyclopropyl-2-phthalimidoacetamide) acetate (5.5 g), melting point 167°C.

Tert-butyl 2-(cyclopropylamino)acetate can be prepared by the following method. Can be prepared: in acetonitrile (100 cc) at a temperature around 20°C. Sodium bicarbonate (2.1 g) is added to a solution of cyclopropylamine (2.9 g). and then tert-butyl bromoacetate in acetonitrile (50c) Add a solution of salt (4.9 g).

The reaction mixture is heated to reflux for 4 hours and then cooled to a temperature around 20°C.

The insoluble product was separated by filtration, washed with acetonitrile (50 cc), and the filtrate are combined and concentrated and dried at 40° C. under reduced pressure (2.7 kPa).

The residual oil was treated with a mixture of water (50cc) and ethyl acetate (100cc) and precipitated. After the onset of precipitation, the aqueous phase is separated and re-extracted with ethyl acetate (2 x 25 cc). organic phase were combined, washed with water (2x20cc), dried over magnesium sulfate, filtered. , concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Thereby, the tert-button Chil 2-(cyclopropylamino)acetate (4.1 g) was obtained as an oil; used in subsequent synthesis without further processing.

Example 42 3-Methylphenyl isocyanate (3.1 g) was added to anhydrous solution at a temperature around 20°C. tert-butyl 2-[2-amino-N in trahydrofuran (15c) -(1,2,3,4-tetrahydro-1-naphthyl)acetamitocoacetate (7.6 g). The resulting solution was stirred at a temperature around 20°C for 16 hours. The mixture is concentrated and dried under reduced pressure (2.7 kPa) at 40°C. Remove residual oil with a diameter of 5 cm. Chromatography on silica (0,063-0,2 mm) (450 g) packed in a column of Purify by chromatography (eluent: ethyl acetate) and collect a 20 cc fraction. desired The fractions containing only the product were combined and concentrated and dried at 40°C under reduced pressure (2.7 kPa). do. After recrystallization in ethyl acetate, tert-butyl 2-[2-[3-(3- methylphenyl)ureidoco N-(1,2,3,4-tetrahydro-1-naph (3.7 gL melting point 144° C.) obtained.

tert-butyl 2-[2-amino-N-(1,2,3,4-tetrahydro- 1-naphthyl)acetamitocoacetate can be produced by the following method. Hydrazine hydrate) (3.2 g) in methanol (150 c) tert-butyl 2-[2-phthalimido-N-(1,2,3,4-tetra Add to the solution of hydro-1-naphthyl)acetamitocoacetate (9.5 g) . The reaction mixture was stirred for 3 hours at a temperature around 20°C and then stirred under reduced pressure (2,7 kPa ) Concentrate and dry at 40°C. Treat the residue with diethyl ether (200cc) and the insoluble product was separated by filtration and washed with ethyl acetate (2xlOOcc). The filtrates are combined and concentrated and dried at 40° C. under reduced pressure (2.7 kPa). Thereby , tert-butyl 2-[2-amino-N-(1,2,3,4-tetrahydro -1-naphthyl)acetamitocoacetate (6.8 g) was obtained as an oil and further processed. used in later synthesis without processing.

tert-butyl 2-[2-phthalimido-N-(1,2,3,4-tetrahyde Dro-1-naphthyl)acetamitocoacetate can be produced by the following method. = 1,2-dioxtan (6 0c c) tert-butyl 2-[(1゜2, 3. 4-tetrahydro -1-Naphthyl) aminocoacetate (7゜2g) in a solution of triethylamine. (3,4 g) and then 2-phthal in 1,2-dichloroethane (60 c) Add imidoacetyl chloride (6°8g). The resulting solution was heated to a temperature around 20°C. Stir at 30°C for 16 hours and treat with water (150cc). After the start of settling, separate the aqueous phase. Separate and re-extract with 1,2-dichloroethane (2 x 50 cc). Combine the organic phases , washed with water (2xlOcc), dried over magnesium sulfate, filtered and dried under reduced pressure. (2,7 kPa) Concentrate and dry at 40°C. After recrystallization in ethyl acetate, tert -Butyl 2-[2-phthalimido-N-(1,2,3゜4-tetrahydro-1 -naphthyl) acetamitocoacetate (10°1 g), melting point 176°C.

tert-butyl 2-[(1,2,3,4-tetrahydro-1-naphthyl) Aminocoacetate can be produced by the following method = temperature around 20°C 1. in acetonitrile (100cc). 2. 3゜4-tetrahydro- To a solution of 1-naphthylamine (14.2 g) was added sodium bicarbonate (4.2 g). and then tert-butyl bromoacetate in acetonitrile (50c) Add a solution of salt (9.8 g).

The reaction mixture is heated to reflux for 4 hours and cooled to a temperature around 20°C. insoluble products It was separated by filtration, washed with acetonitrile (50 c), and the filtrate was purified under reduced pressure (2 , 7kPa) Concentrate and dry at 40°C. Pack the residue into a column with a diameter of 5 cm. Chromatography on Tanori force (0,063-1200 mm) (700 g) ( [Purified with eluent dichlorohexane/ethyl acetate (70:30 volume ratio), Collect 50 cc of fraction.

The fractions containing only the desired product were combined and concentrated under reduced pressure (2,7 kPa) at 40°C. dry. As a result, tert-butyl 2-[(1,2,3゜4-tetrahydryl Dro-1-naphthyl) aminocoacetate (7.3 g) was obtained as an oil, which was further purified. used for later synthesis without further processing.

Example 43 3-Methylaniline (0.54 g) and tert-butyl N-cyclohequine Starting with -N-(isocyanatoacetyl)glycinate (1', 5g) Using a method similar to that described in Example 35, except that diisopropyl ether After recrystallization of tert-butyl 2-[2-[3-(3-methylaniline) ureido] -N-(cyclohexyl)acetamitocoacetate (0.53g ), giving a melting point of 73°C.

tert-butyl N-(incyanatoacetyl)-N-cyclohexyl glycerin Cinate is incyanato acetyl chloride (1.2g), tert-butyl 2-(cyclohexylamino)acetate (2,13g) and pyridine (0, tert-butyl N-benzyl-N-(in A method similar to that described in Example 35 for the production of cyanatoacetyl)glycinate. It can be manufactured in a similar manner. Thereby, tert-butyl N-(isosil anatoacetyl)-N-cyclohexylglycinate (1,5gL melting point 135 Get ℃.

Tert-butyl 2-(cyclohexylamino)acetate can be prepared by the following method. Can be produced: tert-butyl bromoacetate (19,5g) of cyclohexylamine (19.8 g) in acetonitrile (100 cc) Add to solution. The resulting solution is heated to reflux for 4 hours. After cooling, filter the insoluble product. Separated by filtration, washed with acetonitrile (3 x 30 cc), and the filtrate was purified under reduced pressure (2 x 30 cc). , 7kPa) Concentrate and dry at 40°C. Transfer the residual oil to a column with a diameter of 3.5 cm. Chromatograph on packed silica (0,063-0,200 mm) (350 g) Eluent (C eluent; cyclohexane/ethyl acetate (70:30 volume ratio)) and collect 20 cc of fraction. Combine the fractions containing only the desired product and evaporate under reduced pressure. (2,7 kPa) Concentrate and dry at 40°C. Thereby, tert-butyl 2- (Cyclohexylamino)acetate (11.8 g) was obtained as an oil, which was further Used for later synthesis without processing.

Example 44 The method involves the preparation of N-methyl-N-phenyl-2-[N-(8-quinolyl) isocyaner. Toacetamitocoacetamide (0,5 g) and 3-methylaniline (0,16 Similar to the method described in Example 11, except starting with g). Acetoni After recrystallization in tolyl, 2-(2-[3-(3-methylphenyl)ureido] -N-(8-quinolyl)acetamide 1-N-methyl-N-phenylacetamide Obtain 0.25 gL melting point 206°C.

The present invention provides at least one compound of formula (I) in pure form or in an inert form. in combination with other pharmaceutically compatible products that can be both biologically active and physiologically active. It also relates to pharmaceutical products, including in the form of combined compositions.

The medicament of the present invention can be used orally, parenterally, rectally, or topically. Can be done.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, wafer capsules) or granules can be used. In these compositions, The active ingredients of the invention may be combined with one or more diluents such as starch, cellulose, sugar, etc. Mix with loin, lactose or silica.

These compositions may contain substrates other than diluents, such as magnesium stearate or tar. may contain one or more lubricants, colorants, coatings (sugar coatings) or varnishes, such as I can do it.

Liquid compositions for oral administration include water, ethanol, glycerol, vegetable oil or is a pharmaceutically acceptable solution, suspension, containing an inert diluent such as liquid paraffin. Emulsions, 70 tubes and elixirs can be used. These compositions Contains substances other than diluents, such as wetting agents, sweeteners, thickeners, flavoring agents or stabilizers. Can be done.

Sterile compositions for parenteral administration include solutions, aqueous or non-aqueous suspensions or milk. Preferably, it is a liquid. Water, propylene glycol as solvent or vehicle , polyethylene glycols, vegetable oils, especially olive oil, injectable organic liquids, e.g. For example, ethyl oleate or other suitable organic solvents can be used. this Their compositions contain adjuvants, especially wetting agents, tonics, emulsifiers, dispersants and stabilizers. can also be included. Sterilization can include, for example, sterile filtration, the inclusion of disinfectants in the composition, and release. This can be done by several methods, such as irradiation or heating. It may also be prepared in the form of a body composition and dissolved in a sterile injectable medium at the time of use. Wear.

Compositions for rectal administration contain, in addition to the active product, cocoa butter, semi-synthetic glycerin. suppositories or rectal capsules containing excipients such as polyester or polyethylene glycol .

Compositions for topical administration include, for example, creams, ointments, lotions, eye drops, mouthwashes, etc. It can be a liquid, a drop, or an aerosol.

For the treatment of humans, the compounds of the invention may inhibit CCK and gas at the level of the nervous and gastrointestinal systems. It is particularly useful in the treatment and prevention of diseases associated with strins.

Therefore, these compounds may be used to treat psychosis, depression, Parkinson's disease, tardive movement disorder, Irritable bowel syndrome, acute pancreatitis, ulcers, abnormalities in intestinal motility, and lower esophagus, large intestine and For the treatment and prevention of certain tumors of the intestines, as well as sedatives of narcotic and non-narcotic analgesics. It can be used as a pain booster and as an appetite regulator.

The dosage depends on the desired effect, the duration of treatment and the route of administration used. Orally administered Generally, 0.00 ml per day for adults. 05g-1g, one dose Amounts range from 10 mg to 500 mg of active substrate.

The physician will generally consider age and weight as well as any other factors specific to the patient being treated. Determine the appropriate dosage accordingly.

The following examples illustrate compositions of the invention: Example A Tablets containing 50 mg of active substance and having the following composition are prepared in the usual way: tert-butyl 2-(2-[3-(3-methylphenyl)-ureidoco- N-(4-isoquinolyl)acetamido)-acetate...50mg Lactose...104mg Cellulose...40mg Bolividone...10mg Sodium carboxymethyl starch...22mg Talc...1 0mg Magnesium stearate...2mg Colloidal silica...2m g hydroxymethylcellulose Mixture of glycerol and titanium oxide (72:3.5:24.5) ...The weight of one film-coated completed tablet is 245 amount in mg Example B Hard gelatin capsules containing 50 mg of active substance and having the following composition are added to the usual Prepared by method・ tert-butyl 2-(2-[3-(3-1-hydroxy-ethyl)phenylene ]Ureido 1-N-<g-quinolyl)-acetamido)acetate... 50mg cellulose...18mg Lactose...55mg Colloidal silica...1mg Sodium carboxymethyl starch...10mg Talc...1 0mg Magnesium stearate...1mg Example C Prepare an injectable solution containing 10+H active substance and having the following composition = (E)- 2-(3-[3-(hydroxyiminomethyl)phenylcoraleide l -N- (8-quinolyl)-N-[(1,2,3,4-tetrahydro-1-quinolyl)ka Rubamoylmethyl]-acetamide...10mg Benzoic acid...80mg Benzyl alcohol...-0,06cc Sodium benzoate...8 Q mg ethanol, 95%...0.4cc sodium hydroxide...24 mg Propylene glycol...1.6cc Water...until it becomes 4cc summary The following formula [In the formula, R is an optionally substituted phenyl group or chain -CH(R4)- Co-R1, R4 is pyridyl, isoquinolyl, quinolyl, quinoxalyl , alkyl, phenylalkyl, naphthyl, 5,6゜7.8-tetrahydronaph Chill, 1. 2. 3. 4-tetrahydronaphthyl, alkoxycarbonyl alkyl or cycloalkyl group, and R3 is an optionally substituted phenol group. nyl, naphthyl, indolyl or quinolyl, or optionally substituted Compounds with a good phenylamino group, their production methods, and pharmaceuticals containing them .

Copy and translation of amendment) Submission (Article 184-8 of the Patent Law) Plain! August 17, 4th year

Claims (11)

[Claims] 1. The following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [in the formula -R1 is: ・Phenyl group or halogen atom and alkyl, alkoxy, alkylthio, di Fe substituted with one or more substituents selected from tro and cyano groups Nyl group, ・Chain -CH(R4)-CO-R5, where R4 is a hydrogen atom, alkyl or alkyl koxycarbonyl group, or (optional halogen atom and alkyl, alkoxy , alkylthio and nitro groups. R5 is a phenyl group (optionally at least one), and R5 is alkoxy, (optionally at least one (optionally substituted with an alkyl group) cycloalkyloxy, cycloalkylalk Kyloxy, phenylalkyloxy, polyfluoroalkyloxy or thinner a miloxy group or a residue -NR6R7, where R6 and R7 are the same or can be different, including hydrogen atoms or alkyl atoms (optionally halogen atoms and one or more substituents selected from alkyl, alkoxy and alkylthio groups phenyl, indanyl, cycloalkylalkyl, chloroalkyl or phenylalkyl group, or otherwise R6 and R7 are saturated or unsaturated single or polycyclic complexes together with the nitrogen atom to which they are attached. form a ring, which has 4-9 carbon atoms and one or more heteroatoms ( O, S, N), optionally one or more alkyl, alkoxy, alkyl Even if substituted by koxycarbonyl, dialkylcarbamoyl or phenyl group optionally one or more heterocycles, often or in combination with the carbon atoms of the heterocycle Optionally substituted with a 4- or 5-membered spirocar ring system containing atoms (O, S, N) -R2 is pyridyl, isoquinolyl, quinolyl, quinoxalinyl (these The heterocycle includes one or more atoms selected from alkyl and phenyl groups or halogen atoms. optionally substituted with the above substituents), alkyl, phenylalkyl , naphthyl, 5,6,7.8-tetrahydronaphthyl, 1,2.3,4-tetra a hydronaphthyl, alkoxycarbonylalkyl or cycloalkyl group, -R3 is (optionally a halogen atom and an alkyl, alkoxy and alkylthio group) phenyl, optionally substituted with one or more substituents selected from A naphthyl, indolyl or quinolyl group or a phenyl ring is optionally a halogen radical. children, and alkyl, alkoxy, alkylthio, carboxyl, alkoxycar Bonyl, hydroxyl, nitro, amino, acyl, cyano, sulfamoyl, carbonyl Rubamoyl, benzoyl, phenylhydroxymethyl, piperidino, hydroxy iminoalkyl, alkoxyiminoalkyl, hydroxyaminocarbonyl, rukoxyaminocarbonyl, 5-tetrazolyl, 5-tetrazolylalkyl, Lifluoromethylsulfonamide, alkylsulfinyl, mono or polyhydro xyalkyl, sulfo, -alk-O-CO-alk, -alk-COOX, - alk-O-alk, alk'-COOX, -O-alk-COOX, -CH= CH-COOX, -CO-COOX, -alk-SO3H, -CH=CH-al k', 1 selected from -C(=NOH)-COOX and -S-alk-COOX groups a phenylamino group optionally substituted with one or more substituents, -X is a hydrogen atom or an alkyl group, -alk is an alkyl or alkylene group, and -alk' is a hydroxyalkylene or hydroxyalkyl group. is represented by alkyl, alkylene and alkoxy groups, as well as alkyl, alkyl and alkoxy groups. The kylene and alkoxy moieties contain 1-4 carbon atoms in a straight or branched chain and are chloroalkyl groups and moieties contain 3-6 carbon atoms, acyl groups contain 2-4 compounds containing carbon atoms, and if it has at least one asymmetric center If so, its racemate and enantiomer. 2. In formula (I), R6 and R7 together with the nitrogen atom to which they are bonded (optional) at least one alkyl, alkoxycarbonyl, phenyl or dialkyl piperidino ring (optionally substituted with carbamoyl group), or perhydride rho-1-azevinyl, 1,2,3,6-tetrahydro-1-pyridyl, 1,2, 3,4-tetrahydro-1-quinolyl, 1-pyrrolidinyl, 3,4-dihydro- 2H-1,4-benzoxazin-4-yl, 3,4-dihydro-2H-1,4- Benzothiazin-4-yl, N-alkyl-1,2,3,4-tetrahydro-1 -quinoxalinyl, perhydro-1-quinolyl, 1,2,3,4-tetrahydro -2-isoquinolyl, 8-azaspiro-[4,5]decane-8-yl, 2- or 3-phenyl-1-pyrrolidinyl, 8-aza-1,4-dioxaspiro[4,5 ]decane-8-yl, (optionally substituted by at least one alkyl group) may form a heterocyclic ring system selected from thiomorpholino or 1-indolinyl ring systems. The compound according to claim 1. 3. In formula (I), R1 is the chain -CH(R4)-CO-R5, where R 4 is a hydrogen atom, R5 is an alkoxy group or a residue -NR6R7, where R6 is an alkyl group, R7 is a phenyl group, or R6 and R7 are together with the nitrogen atom to which they are bonded, 1,2,3,4-tetrahydro-1-quinolyl group, R2 is quinolyl or isoquinolyl group, and R3 is phenylamino group, where the phenyl ring is an alkyl, carboxyl, or hydroxyiminoalkyl group. Substituted with one or more substituents selected from Kyl or hydroxyalkyl groups The compound according to claim 1 or 2, which is 4. The following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1 and R2 are within the scope of claims. [synonymous with 1] and the following formula OCN-R8 (III) [In the formula, R8 is optionally a halogen atom and alkyl, alkoxy, alkylthio, Nitro, amino, acyl, cyano, sulfamoyl, benzoyl, alkoxyca rubonyl, -alk-O-alk, 5-tetrazolyl, 5-tetrazolylalkyl and one or more substitutions selected from trifluoromethylsulfonamide groups isocyanate which is a phenyl group which may be substituted with , by isolating the product, in formula (I) where R3 is optionally the phenyl ring Halogen atoms and alkyl, alkoxy, alkylthio, nitro, cyano, acyl , sulfamoyl, benzoyl, alkoxycarbonyl, -alk-O-al k, 5-tetrazolyl, 5-tetrazolylalkyl and trifluoromethylsul Optionally substituted with one or more substituents selected from honamido groups A method for producing the compound according to claim 1, which is a phenylamino group. 5. The following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XII) [In the formula, R1 and R2 are as requested. By reacting a compound with the following formula and isolating the product. , in formula (I), R3 is phenyl, the phenyl ring of which may be optionally substituted. A method for producing the compound according to claim 1, which is an amino group. 6. The following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIV) [In the formula, R1 and R2 are derivatives of [synonymous with Box 1] and the following formula H2N-R10 (XIII) [In the formula, R10 is optionally a halogen atom, alkyl, alkoxy, alkylthio , carboxyl, alkoxycarbonyl, hydroxyl, nitro, amino, acyl cyano, sulfamoyl, carbamoyl, benzoyl, phenylhydroxy Methyl, piperidino, hydroxyiminoalkyl, alkoxyiminoalkyl, Hydroxyaminocarbonyl, alkoxyaminocarbonyl, 5-tetrazolyl , 5-tetrazolylalkyl, trifluoromethylsulfonamide, alkyls rufinyl, mono- or polyhydroxyalkyl, sulfo, -alk-O-CO -alk, -alk-COOX, -alk-O-alk, alk'-COOX, -O-alk-COOX, -CH=CH-COOX, -CO-COOX, -al k-SO3H, -CH=CH-alk', -C(=NOH)-COOX and -S -alk-COOX substituted with one or more substituents selected from the group by reacting a derivative of [which may be a phenyl group] and isolating the product. , in formula (I), R3 is phenyl, the phenyl ring of which may be optionally substituted. A method for producing the compound according to claim 1, which is an amino group. 7. The following formula R1-NH-R2 (IX) The amine [wherein R1 and R2 have the same meanings as in claim 1] is converted into the following formula HOOC -CH2-NH-CO-NH-R3 (XV) [wherein R3 has the same meaning as above ] in formula (I), R3 is Optionally halogen atoms and alkyl, alkoxy, alkylthio, nitro, acyl , cyano, sulfamoyl, benzoyl, alkoxycarbonyl, 5-tetrazo lyl, 5-tetrazolylalkyl, trifluoromethylsulfonamide and -a substituted with one or more substituents selected from the lk-O-alk group; A method for producing the compound according to claim 1, which is a phenylamino group. 8. In formula (I), R3 is carboxyl having at least one phenyl ring, - alk-COOH, -O-alk-COOH, -alk'-COOH, -CH= CH-COOH, -CO-COOH, -S-alk-COOX or -C(=NO H) is a phenylamino group substituted with a -COOH group according to claim 1. production of a compound by hydrolysis of the corresponding ester and isolation of the product Law. 9. The following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R1 and R2 are within the scope of claims. 1] and the following formula HOOC-R3 (XVI) The acid [wherein R3 has the same meaning as above] or an active derivative of this acid is reacted to produce a product. In formula (I), R3 is (optionally a halogen atom and and one or more substitutions selected from alkyl, alkoxy and alkylthio groups. optionally substituted with phenyl, naphthyl, indolyl or quinolyl A method for producing the compound according to claim 1, which is a group. 10. At least one compound of formula (I) according to claim 1 as active ingredient medicines, including products. 11. Treatment of abnormalities linked to CCK and gastrin at the level of the nervous and gastrointestinal systems The pharmaceutical according to claim 10 for treatment or prevention.