JPS60123472A - Aminopyridinecarboxylic acid derivatives and pharmaceutical compositions - 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 The present invention relates to dipeptidyl carboxypeptidase (D 1
The present invention relates to a novel aminopyridinecarboxylic acid derivative that inhibits 1 CP ), a method for producing the same, and a pharmaceutical composition containing the compound. More specifically, the present invention is based on the general formula %, where Z is hydrogen, an alkyl group having 1 to 3 carbon atoms, halogen or an alkoxy group having 1 to 3 carbon atoms; R1 is hydrogen, an alkyl group having 1 to 6 carbon atoms, Aryl alkyl group having 7 to 12 carbon atoms, aryl group having 6 to 15 carbon atoms; In and 11 are 0
an integer of ~4, provided that m+n is 5 or less iR2 is hydrogen, an alkyl group having 1 to 6 carbon atoms, or an arylalkyl group having 7 to 12 carbon atoms; R3 is hydrogen or an acyl group having 1 to 8 carbon atoms; R4 is hydrogen or The present invention relates to a compound represented by an alkyl group having 1 to 3 carbon atoms, and a pharmaceutically acceptable salt of the compound and an organic or inorganic acid.

The novel derivatives of the present invention can be synthesized according to a number of acylation methods, more specifically those developed for the synthesis of peptide bonds, to compounds represented by the general formula (wherein Z, R, and R4 are as previously described) or reactions thereof. (in the formula, m, n, R2, I<3 are respectively as described above)
It is produced by reacting the compound represented by or its reactive derivative.

Examples of useful reactive derivatives of compounds of formula (III) are symmetrical anhydrides, mixed anhydrides, halides.

When protecting either a carboxy or thiol group that does not participate in the condensation reaction, the protection or deprotection reaction is also carried out by techniques commonly used in peptide chemistry.

When a reactive derivative is not used, a compound of formula (IT) and a compound of formula (
The reaction of the compound m) is carried out using a suitable condensing agent such as N,N-dicyclohexylcarbodiimide or it together with N.
-Hydroxysuccinimide, N-hydroxybenzotriazole, pentachlorophenol, α-chlorovinylethyl ether, ethoxyacetylene, cyanamide,
It is carried out by a conventional method in the presence of ketene imine, ketene, triphenylphosphite l- or imidazole.

The reaction is preferably carried out in the presence of a suitable diluent such as te-1-rahydrofuran, dume-1-xyethane, N,N-dimethylformamide, methyleneprolite or acetinitrile at a temperature of -30°C to the boiling point of the reaction mixture. It will be implemented.

The reaction of a reactive derivative of a compound of formula (III) with a compound of formula (II) is also carried out in a conventional manner.

Examples of reactive derivatives of compounds of formula (1) are acyl halides, mixed or symmetrical anhydrides, hydroxybenzos such as N-hydroxysuccinimide, N-hydroxybenzo-1-lyazole, pentachlorophenol or 2,4 - Gini 1 - Conister of lophenol. The reaction can also be carried out in the presence of catalysts F, such as 4-N,N-dimethylaminopyridine or 4-pyrrolidinepyridine.

This reaction is preferably carried out in the presence of a suitable diluent such as te-1-rahidofuran, di-1-xyethane, N,N-dimethylborumamide or ace]-21-lyl.
It is carried out at temperatures between 0°C and the boiling point of the reaction mixture.

[(When 2 is not hydrogen, the 1L compound of formula (III) is optically active, therefore, the R and S forms of the compound of general formula (1) as well as any racemic mixture thereof are also the object compounds of the present invention. be.

A preferred method for preparing the optically active compound of formula (1) is a method using the corresponding optically active compound of formula (III) as a starting material. However, it is also possible to prepare a racemic compound of formula (1) and resolve it into optically active isomers according to conventional methods.

Pharmaceutically acceptable salts of compounds of general formula (1) are also made in conventional manner.

Preferred compounds of the present invention are formula (1), where 2 is hydrogen, R1 is an alkyl group having 1 to 3 carbon atoms, R2 is H, methyl or benzyl, R3 is acetyl or benzoyl, 1+4
is 11 or methyl, m is 0, and n is 1.

It has been found that the compounds of general formula (I) are active as inhibitors of leaf CP, which involves the metabolic deactivation of enkephalins (enkephalinase), and that this action is highly specific. This is because compounds of general formula (1) have been found to be inactive as inhibitors of other peptidases such as aminopeptidases.

Since the compounds of the present invention act as opcp inhibitors, they are useful as analgesics, antihypertensive agents, and antipsychotic agents.

The inhibitory effect on enkephalinase and aminopeptidase activities was evaluated as follows.

a) Enkephalinase: Brumbelb et al. Life Science 2g (1,98])
An enzyme preparation extracted and purified from ratte striae particulate 1~ fraction described in 301 was used, and the enzyme activity was evaluated using 311-thyl-leucine-enkephalin as a substrate (Bogel, Alstein, F.
EBS Letters 80, (1,977) 332).

b) Aminopeptidase: The soluble fraction of a) above was used as the enzyme source and "I+-thyl-leucine-enkephalin" as the substrate (Bogel, Alstein FIEBS Letter 80 (1977) 332).

The results were as follows.

(Left below) Table 1 Drug concentration that inhibits 50% of enzyme activity (IC50 (M)) Compound Enkephali Aminopepti (Example number) Nase Dase 8. 5X10-7) 10= 31 5 X 10-7>10”" 23 2 X 10-7> 10-6 14 5 -6 17 1 X 10-7 >10-' 16 7X10-7 > 10-6 28 1.8 The strength of the analgesic effect induced by intracerebral administration of methionine-enkephalin (Met-EnK) to Met-EnK was determined using a hot plate test method (Eddie et al., Journal of Pharmacology 108 (1950021)). The intracerebral administration (IC) was carried out by Barley and Matriculation (Pritessch Journal of Pharmacology 12 (1957) 12).The results were as follows. Ta.

Table 2 Effect on MeS EnK analgesia in Mice Compound Dose Latency time (Example number) (μg/IC) X+SE (sec) -1
0.7±0.8 Met-E EnK 50 1'1.7±1.3Met-E
nK+8 50-1-12.5 19.6±2.1*M
et EnK+31 50+ 12.5 15.4±1
, 2Me and +23 50+25 26.1±2
．． 1*Met-EnK+1.4 50+25 27.7
±1.5*Met-EnK+18a 50+50 13
．． 1±0.9Met-EnK+], 7 50+50 1
3.8±1.4Met -EnK+16 50+5 1
4.8±1.1Met-EnK+28 50+50 2
7.0±1.6** Po, 05 ("L" test) for the MeL-EnK alone treatment group Acute toxicity of the compounds of the invention was evaluated by gavage administration to mice.

Table 3 Acute toxicity in Mice after oral administration (mg/Kg) Compound LD50 Confidence limit (Example number) (mg/g in) (95%) 24 3
90 361-421 25 329 244-444 26 421, 369-480 The present invention also relates to a pharmaceutical composition comprising a compound of general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

These compositions contain the active ingredient together with an organic or inorganic liquid or solid carrier and may be administered orally, parenterally or rectally.

The pharmaceutical compositions of the present invention contain a sufficient amount of a compound of formula (1) to produce an inhibitory effect on enkephalinase.

Preferably, each dosage unit contains from 30 mg to 300 mB of active ingredient, calculated as base, of effective and non-toxic groups.

The daily dosage is determined by various factors such as age, body weight, symptoms, method of administration, and the relative potency of the active ingredient compared to the activity of Kab 1 Hepril and Bestatin in the test method described above.

Preferably the daily dose is 60 mg of base nail;
It is preferable to administer the same amount of 30 to 300 mg 1 to 5 times a day.

The final dosage form is a solid dosage form such as a tablet, dragee, capsule, powder, or granule, or a liquid dosage form such as a solution, suspension, or emulsion.

It is also formulated so that its efficacy lasts for a long time after administration.

In addition to the carrier, it may contain preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting permeation pressure, buffers, colorants, and fragrances. They may be made by known methods and may incorporate other therapeutic agents.

The present invention will be explained below with reference to Examples.

Example 1 To 7.6 g (50 mmol) of methyl 2-amino-nicotine 1, 8.9 g (55 mmol) of 2-acetylthiomethylpropionic acid, 12.4E (60 mmol) of N,N-dicyclo 150+n hexylcarbodiimide
The solution in 1 ml of dry methylene chloride was heated to reflux for 10 hours. It was evaporated to dryness in vacuo, the residue was taken up in 100 ml of a 1-7:3 mixture of petroleum ether/ethyl acetate, and the insoluble dicyclohexylurea was removed by filtration.

The filtrate was evaporated under reduced pressure and purified by chromatography on a silica gel column eluting with petroleum ether/ethyl acetate 8:2. Methyl 2-(2-acetylthiomethyl-propionamido)nicotinate was thus obtained as a chromatographically pure oil in a yield of 71%. (Thin layer chroma 1-graph method with silica gel, eluent 1-luene/ethyl acetate-1-; U, V, detection J2; purity confirmed by H at quality nail spectrum 296 m/e) Example 2 Example 1 Methyl 2-(2-acetylthiomethyl-propionamide)-nicotine h obtained as described in
4 g (13.5 mmol) was dissolved in 100 ml of 50% methanol water under a nitrogen stream, and 2.73. (27
The reaction mixture was made acidic by adding 5 mmol of triethylamine, then evaporated in vacuo and the residue was purified by chromatography on a silica gel column eluting with methylene chloride to give methyl 2-(2-mercaptomethyl-propionamide). )-Nicotine-1 (recrystallized from petroleum ether, melting point 50-52°C, yield 29%) was obtained.

Example 3 Methyl 2-(2-acetylthiomethyl-
A solution of 4 g (13.5 mmol) of nicotine (propionamide) and 1.62 g (40.5 mmol) of caustic soda dissolved in 20 m of water and 1.00 m of methanol was stirred at room temperature under a nitrogen stream for 2 hours. p1 with hydrochloric acid
14, the methanol was evaporated under reduced pressure and the residue was diluted with 70 ml of water and chloroform/methanol 7:
Extracted with a mixture of 3.

The extract was dried over 1-lium sulfate, filtered and evaporated. The residue was crystallized with acetone/petroleum ether to give 2-(2-mercaptothiomethyl-
Propionamide) nicotinic acid was obtained. Yield: 40% Example 4 The same method as in Example 1 was used, except that an equivalent amount of methyl 4-aminonicotinate was used instead of methyl 2-aminonicotinate, and methylene chloride was used as the eluent for column chromatography. 4-(2-acetylthiomethyl-propionamide)-nicotinate was obtained. Melting point of the product recrystallized from petroleum ether 55-57°C Example 5 Similar procedure as Example 2, but instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1. Using an equivalent amount of methyl 4-(2-acetylthiomethyl-propionamide)-nicotine-1- obtained in step 4, methyl 4-(2-mercaptomethyl-propionamide)-nicotinate was obtained. Recrystallized from petroleum ether. Melting point 54-56°C Example 6 The reaction mixture was prepared in the same manner as in Example 1, but using an equivalent amount of ethyl 6-aminonicotinate instead of methyl 2-aminonicotinate 1-, and using pyridine as the reaction solvent. The mixture was kept at 50 to 60°C for 5 hours to obtain ethyl 6-(2-acetyldiomediylpropionamide)-nicotine-1. Is this the ether of hydrochloric acid? I2' was added to the corresponding hydrochloride. Repurified from ethyl alcohol.

Melting point: 176-178°C Example 7 The same method as in Example 2, except that ethyl 6-(2-acetylthiomethyl-propionamide obtained in Example 6) was used instead of methyl 2 (2,7 cetylthiomethyl-propionamide). )-Nicotine~1・noゝ1F
Re-harvested from petroleum ether using A. Quality. Melting point 58-6
1°(2-ethyl 6-(2-mercaptomethyl-pro1
pionamide)-nicotine-1-(a.

Example 8 Same method as Example 3, except that methyl Z-(2-acefalthiomethyl-propionamide)-nicotine-1-
Recrystallized from absolute ethanol (-, fused) using the equivalent of ethyl f; 6-(2-Mercaptomethyl-propionamido)-nicotinic acid was obtained at a temperature of 22°C to 222°C.

Example 9 Methyl 6-aminonicotinate 5 g (33 mmol) and 2-acetylthiomethyl-propionyl chloride 6,
A solution of 55 g (36.3 mmol) of 100 g (36.3 mmol) dissolved in 50 ml of pyridine was stirred for 1 hour.

The reaction mixture was poured into water, extracted with ethyl acetate,
The extract was washed with water, dried over sodium sulfate, evaporated and the residue was taken up in ethyl acetate/petroleum ether and dissolved in methyl 6-(2-acetylthiomethyl-
Propionamide)-picolinate was obtained. Yield 84% Example 10 Same method as in Example 2, except that instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1~, equivalent amount of methyl 6-( obtained in Example 9) was used. 2-acetylthiomethyl-propionamide)-picoline 1-, chromatographically pure (silica gel with methylene chloride/toluene/methanol as eluent 25
: Thin layer chromatography using 5:3: U.
V.

Detection J2; 1 addition to methyl 6-(2-mercapunamide)-picolina 1 as M+) oil at mass spectrum 254 m/e.

Example 11 In the same manner as in Example 3, except that instead of methyl 2-(2-acetylthiomethyl-propionamide)nicotine-1, an equivalent amount of methyl obtained in Example 9 was converted to -(2-acetylthiomethyl-propionamide). Using methyl-propionamide) picoline-1-, acetone/ethyl acetate-1- Example 12 Acid was obtained in the same manner as in Example 1, except that an equivalent amount of methyl 5-aronicotine-1 was used instead of methyl 2-aminonicotine-1, and pyridine was used as the solvent. The heart mixture was kept at room temperature for 7 hours and rethreaded from ethyl acetate. +1
Methyl 5(2--,)' with a melting point of 88-90°C
Hytyldiomethyl-propionamide)-Nicogne-1
Example 13 In the same manner as in Example 2, but instead of methyl 2-(2-7cetylthiomethyl-propionamide)-nicotine-1., an equivalent amount of the methyl obtained in Example 12 was used. 5-(2-acetylthiomethyl-propionamide)-nicotine-1-
was recrystallized from ethyl acetate-I using a mixture of methylene chloride/methanol 99:1 as the solvent for Chroma 1 to Grafcolor 11 to obtain methyl 5-(2-mercaptomethyl-propion) with a melting point of 96-97°C. amide)
-Nicogene-1 was obtained.

Example 14 In the same manner as in Example 3, except that instead of ethyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1-, an equivalent amount of methyl 5-(2-acetylthiomethyl) obtained in Example 12 was used. Methyl-propionamide) nicotine-1-, using an equivalent amount of potassium carbonate instead of caustic soda, the reaction mixture was stirred at room temperature for 6 hours and purified on a silica gel column (elution with ethylene chloride/methanol 99:1). 5-(2-Mercaptomethyl-propionamide crystals, melting point 160-165°C.

Example 15 The same procedure as in Example 9, except that instead of methyl 6-aminopicolinate, an equivalent amount of 5-amino-nicotin>'s.
7, the reaction time was extended to 4 hours using
5-(2--17 cetylthiomethyl-propionamido)-nicotinic acid was recrystallized from tate at 15 Il to 158°C.

Example 16 Methyl 5-methylamino nicotinate 111; (24 mmol) and 4-dimethylaminopyridine 029 di(21
5.2 g (28.8 mmol) of 2-methyl-3-thioacedelpropionic acid chloride was added to a solution of 1 mmol) in 50 ml of pyridine under 1'1'' at room temperature. After 1 hour, the reaction mixture was poured into water, extracted with 7I-1-1-1-ethyl ethyl, and the organic phase was diluted with 1-1-1-100% sulfuric acid and evaporated in vacuo twice. was converted from ethyl acetate-1- to <A Mr to form methyl 5(7.-'-', /
'Cetyldiomethyl-N-methylpropio()'amide)-2-21za1'.-1- was obtained. The intermediate methyl 5-methylamino-nicotine-1 was obtained in the following manner with a yield of 90%.

Methylamine (40% aqueous solution) and 5-B-L1monicotinic acid were reacted at 140°C for 7 hours in an O-1-crepe.
Methylamino-nicotinic acid was obtained. It was recrystallized from ethanol/water and had a melting point of 239-242°C. This acid was heated to reflux with SOCI in methanol for 7 hours (recrystallized from petroleum ether, showing a melting point of 113-115°C) with methyl 5
-Methylaminonicotine 1- was obtained.

Example 17 In the same manner as in Example 3, except that instead of methyl 2-(2-acetylthiomethyl-propionamide)nicotine-1-, an equivalent amount of methyl 5-(2-acetylthiomethyl-N-1-) obtained in Example 1G was used. 5-(2-Mercaptomethyl-N-methyl-propionamido)-nicotinic acid was obtained using 1-methyl-propionamide)-nicotinic acid.It showed a melting point of 190-192°C by recrystallization from methanol. .

Example 18 (a) 0.98 g (8.95 mmol) of ethyl chloroformate was mixed with 2 g (8.95 mmol) of S(-)-2-benzoylthiomethylpropion r'[f) and 1-ethylamine. 0. ! lla (8.!15 mmol) in N
, N-dimethylpolamide (7IOml) was added to the solution at -12°C under a nitrogen stream. After keeping at −12° C. for 2 minutes, 1.23 g (8.95 mmol) of 5-aminonicotinic acid was added and after keeping at room temperature for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate.

The organic phases were combined, washed with water, dried over sodium sulphate and evaporated to dryness in vacuo.

The resulting residue was adsorbed onto a silica gel column and purified by chromatography, eluting with methylene chloride/methanol 95:5. The obtained product was recrystallized from acetone to obtain S(-)-5-(2-penzoylthiomethylpropionamito)nicotinic acid. Yield 49%, melting point 213-215°C; [α]” = -153° (c-1
, 95% methanol) (b) In the same manner as above, but using R(+)-2-benzoylthiomethylpropionic acid, the corresponding tautomer R(+)-5-(2-benzoylthiomethyl- Propionamide) nicotinic acid was obtained.

A racemic compound was obtained in the same manner starting from (C)(±)-2-benzoylthiomethylpropionic acid. It was recrystallized from acetone and had a melting point of 202-204°C.

Example 19 (a) Methyl 5(-)-5-(2-benzoylthio Methyl-propionamide) nicotinate was obtained. Recrystallized from ace-1-nitrile, melting point 140-142°C; (
a) 20-186.3° (c = 1.95% methanol) (b) Same method as Example 18(b), but using an equivalent amount of methyl 5-aminonicotinate instead of 5-aminonicotinic acid. , the corresponding optical isomers were obtained.

Example 20 (a) Same method as Example 3, except that 5(-)-5-(2
-Mercaptomethyl-propionamide Instead of equivalent amount of methyl S obtained in Example 19 (-)
- S(-)-5-(2-
Mercaptomethyl-propionamide)-nicotinic acid was obtained. Recrystallized from ethanol/ethyl acetate, melting point 232-233°C, [α)%' T69.27° (
c=1, 95% ethanol) (b) Methyl R(+)-5
Starting from -(!-mercap 1-methyl-propionamide)-nicotine-1-, the corresponding optical isomer was obtained in the same manner.

(c) The racemic product was obtained starting from methyl (±)-5-(2-benzoylthiomethyl-propionamido)-nicotine-1- by the l distribution method or the method described in Example 19.

Example 21 In the same manner as in Example 1, except that instead of methyl 2-aminonicotine 1-, an equivalent amount of methyl 5-aminonicotine-1-
and using pyridine as the solvent, the reaction mixture was heated to 40
C. for 7 hours and methylene chloride was used to elute the chromatographic column to give methyl 5-(2-acetylthiomethyl-propionami 1-)-picolina 1-. The melting point of recrystallized from ethyl acetate is 16
The temperature was 9-171°C.

Example 22 In the same manner as in Example 2, except that instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1-, an equivalent amount of methyl 5-(2-acetylthiomethyl) obtained in Example 21 was used. -Propionami 1-) -Picoline 1-
It was recrystallized from methyl 5-(2-mercaptomethyl-propionamidotate) with a melting point of 140-142°C.

Example 23 In a similar manner to Example 3, but instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotinate, an equivalent amount of methyl 5-(2-acetylthiomethyl-propionamide) obtained in Example 21 was used. ) - using picolinate,
5-(2-mercaptomethyl-propionamido)-picolinic acid was obtained. Recrystallized from acetone, melting point 175~
The temperature was 177°C.

Example 24 In the same manner as in Example 1, but instead of methyl 2-aminonicotinate, hexamethylphosphoramide was used with an equivalent amount of methyl 3-aminovicorine-1- as the solvent, and the reaction mixture was kept at 60°C for 8 hours. , recrystallized from ethyl ether/petroleum ether to give methyl 3-(2
-acetylthiomethyl-propionamide) picolinate was obtained.

Example 25 In the same manner as in Example 2, but instead of methyl 2-(2-acetylthiomethyl-propionamide, an equivalent amount of methyl 3-(2-acetylthiomethyl-propionamide)-Vicoline 1 obtained in Example 24 was used. Recrystallized from petroleum ether using ethyl acetate and a glass of ethyl acetate, melting point 55.
Methyl 3-(2-mercaptomethyl-propionamide)-picoline 1 at ~56°C is <:ノ.

Example 26 In the same manner as in Example 3, but instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1-, an equivalent amount of methyl 3-(2-acetylthiomethyl) obtained in Example 24 was prepared. -Propionamide)-Vicoryne 1-, recrystallized from acetin, melting point 162-164°C
2-(2-acetylthiomethyl-propionamide)
-Picolinic acid was obtained.

Example 27 The same method as in Example 1, except that instead of methyl 2-aminoisonicotine-1- and 2-acetylthiomethyl-3-phenyl-propionic acid, equivalents of methyl 2-aminoisonicotine-1- and 2-acetylthiomethyl-3-phenyl-propionic acid were used. Using 2-acetylthiomethyl-3-phenylpropionic acid and pyridine as the reaction solvent, the reaction mixture was kept at 50-60 °C for 5 hours and purified on a silica gel column (eluent: petroleum ether/ether 7:3). Purification by chroma 1 to graph method gave methyl 2-(2-acetylthiomethyl-3-phenylpropionamide)-isonicotinate as an oil. This was converted to the corresponding hydrochloride salt with alcoholic hydrogen chloride solution. Recrystallization from acetone/ether gave a melting point of 137-139°C.

Example 28 In the same manner as in Example 3, but instead of methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate, an equivalent amount of methyl 2-(2-acetylthiomethyl-3) obtained in Example 27 was used. 2-(2-mercaptomethyl-3-phenylpropionamide) was purified by chroma 1 to chroma 1 adsorbed on a silica gel column and eluted with methylene chloride/methanol 95:5 using 2-(2-mercaptomethyl-3-phenylpropionamide)-isonicotinate. -Isonicotinic acid was obtained. Recrystallized from absolute ethanol, melting point 234-23
It was 6°C.

Example 29 In the same manner as in Example 1, but instead of methyl 2-aminonicotinate, an equivalent amount of methyl 2-aminoisonicotine 1 was prepared.
~, using pyridine as the reaction solvent, and converting the reaction mixture to 5
The mixture was kept at 0-60°C for 5 hours and recrystallized from ethyl acetate-1- to give methyl 2-(2-acetylthiomethyl-propionami-1-)-isonicotine-1. with a melting point of 105-106°C.

Example 30 In the same manner as in Example 2, but instead of methyl 2-(2-acetylthiomethyl-propionamide)nicotine-1-, an equivalent amount of methyl 2-(2-acetylthiomethyl) obtained in Example 29 was prepared. -propionamide)-isonicotinate and a 99:1 methylene chloride/methanol mixture as the eluent for the chromatographic column to give methyl 2-(2-mercaptomethyl-propionamide)-isonicotinic acid l-. , which was converted to the corresponding hydrochloride with ethereal hydrogen chloride. It was recrystallized from acetone/ethyl ether and had a melting point of 90-95°C.

Example 31 In the same manner as in Example 3, except that instead of methyl 2-(2-acetylthiomethyl-propionamide)-nicotine-1-, an equivalent amount of methyl 2-(2-acetylthiomethyl) obtained in Example 29 was used. 2-(2-mercaptomethyl-propionamido)-isonicotinic acid was obtained using methyl-propionamido)-isonicotinate. Recrystallized from ethanol/water, melting point 247-248°C.

Patent application agent B1 Physician Takeo Ito Procedural amendment January 24, 1980 Director of the Japan Patent Office Indication of 'Hariri' I case 1981 Patent application No. 232 GO/' I No. 2 Name of invention Aminopyridine Carboxylic acid derivatives, their manufacturing process, and their relationship to the Pharmaceutical Composition 3 Amendment Case Patent Applicant Address Italy 2016+ Milanovia Bellerio 41 Name Siemes, Società Italiana Medicinari
Representative Albert 1 - Zampon Nationality Italian 4 Agent Address 6th Floor, Building River Center, 57, Kyobashi 3, Higashi-ku, Osaka, IO Name Patent Attorney (6871) Convenience Takeo 5 Amended Order Number of inventions increased by daily amendment 6. Subject of 7th amendment Miscellaneous book

Claims (4)

[Claims] (1) General formula (in the formula, Z is hydrogen, an alkyl group having 1 to 3 carbon atoms, a halogen, or an alkoxy group having 1 to 3 carbon atoms; R1 is hydrogen,
an alkyl group having 1 to 6 carbon atoms, an arylalkyl group having 7 to 12 carbon atoms, or an aryl group having 6 to 15 carbon atoms; m
and n are integers from 0 to 4, provided that m+n is 5 or less; R2
is hydrogen, an alkyl group having 1 to 6 carbon atoms, or 7 to 6 carbon atoms
12 arylalkyl groups; R3 is hydrogen or an acyl group having 1 to 8 carbon atoms; 1 (4 is hydrogen or an acyl group having 1 to 8 carbon atoms;
~3 alkyl group) and pharmaceutically acceptable salts thereof with organic or inorganic acids. (2) z is hydrogen, R1 has 1-3 carbon atoms Noah /[/
g) Li, j, I;, 1 (dihydrogen, methyl or benzyl, R3 is acetyl or benzoyl, R4 is hydrogen or methyl, Ill is 0, ■) is 1 according to claim 1; Compounds and their pharmaceutically acceptable salts with organic or inorganic acids. (3) General formula (in the formula, Z is hydrogen, an alkyl group having 1 to 3 carbon atoms, a halogen, an alkoxy group having 1 to 3 carbon atoms; R'' is hydrogen, a carbon number 1
-6 alkyl group, C7-12 arylalkyl group. Aryl group having 6 to 15 carbon atoms;
an alkyl group or an arylalkyl group having 7 to 12 carbon atoms; 1, hydrogen or an acyl group having 1 to 8 carbon atoms; I
i is hydrogen or an alkyl group having 1 to 3 carbon atoms. (4) Z is hydrogen, R1 is an alkyl group having 1 to 3 carbon atoms, R
2 is hydrogen, methyl or benzyl, 113 is acetyl or benzoyl, R4 is hydrogen or methyl, 1
The composition according to claim 3, wherein is 0 and [1 is 1].