KR830002276B1 - Method for preparing 4- (2'-pyridyl amino) phenyl acetic acid derivative - Google Patents

Abstract

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Description

Method for preparing 4- (2'-pyridyl amino) phenyl acetic acid derivative

Graph showing the protective effect of test compounds on arthritis in rats.

The present invention provides a novel 4- (2'-pyridyl amino) phenyl acetic acid derivative having antiseptic and analgesic action and a process for producing the same. And it is related with the usage method of this and this composition.

General formula (Ⅱ):

Compounds are disclosed in US Pat. No. 3,766,260.

Wherein R ' ₁ is hydrogen or lower alkyl, R' ₂ is hard, lower alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl or cycloalkenyl-alkyl, Ph is 1,3- or 1, 4-phenylene group, R ' ₃ is lower alkyl, alkenyl, hydrooxy alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl or cycloalkenyl-alkyl wherein the heteroatom is at least 2 Carbon atoms are separated. R ' ₄ is an aryl group, which is useful as an anti-inflammatory agent. In US Patent No. 2, lines 59 to 62, the aryl group R ' ₄ is preferably a monocyclic iso or heterocyclic aryl group, that is, an unsubstituted or substituted phenyl, pyridyl, furyl or thiophenyl group, and the substituent is It is reported that the flag indicated in Ph. However, R ' ₄ did not specifically disclose a compound of formula (II) which is an unsubstituted or pyridyl group.

In addition, in Japanese Patent Publication (Unexamined) No. 149, 668/1975, the general formula (III):

Compounds have been published.

는 피리딜, 피리미디닐, 이미다졸릴, 테트라졸릴 또는 티아졸릴, R은 탄화수소, A는 산호, 황, 이미노, 또는 이미노기로 치환된 탄화수소기이며, 상기의 일반식(Ⅲ)의

및 벤젠고리는 반응에 영향을 주지 않는 1 내지 3치환기를 가지고 있으며, 또는 붙은 벤젠고리 또는 붙은 지방족 단환식고리를 가지고 있고, 그리고 기

는 붙은 벤젠고리에 위치하고 있는데,

이 티아졸릴이 아닌 경우에는 A는 산소 또는 황이며, 우수한 항염 및 진통작용이 있다.here

Is a pyridyl, pyrimidinyl, imidazolyl, tetrazolyl or thiazolyl, R is a hydrocarbon, A is a hydrocarbon group substituted with a coral, sulfur, imino, or imino group, and

And the benzene ring has 1-3 substituents which do not affect the reaction, or has a benzene ring or an aliphatic monocyclic ring attached, and

Is located in the attached benzene ring,

When not thiazolyl, A is oxygen or sulfur, and has excellent anti-inflammatory and analgesic action.

Anti-inflammatory and analgesics typically have the undesirable side effect of Ulcerogenicity in gastrointestinal light.

The present inventors have intensively studied the desired compounds with good anti-inflammatory and analgesic effects while having mild and low alserogenity side effects in the gastrointestinal tract.

As a result, it was found that the desired compound can be obtained by replacing one hydrogen atom of the amino group of the P-aminophenyl acetic acid derivative with a 2-pyridyl group.

It is an object of the present invention to provide 4- (2'-pyridylamino) phenylacetic acid derivatives which have good anti-inflammatory and analgesic action but in the gastrointestinal tract, with weak and low alserogenity side effects.

Another object of the present invention is to provide a method for preparing a cyclic compound, and another object of the present invention is to provide the use of the compound of the present invention as an anti-inflammatory and analgesic agent. Another object of the present invention is to provide a composition of the active compound.

These and other objects and advantages of the present invention will become apparent to those skilled in the art by the following description.

The compound of the present invention is represented by the following general formula (I):

Is displayed.

Wherein R ₁ is hydrogen, halogen, lower alkyl having 1 to 3 carbon atoms, or nitro, R ₂ is hydrogen, halogen, or lower alkyl having 1 to 3 carbon atoms, R ₃ is hydrogen, halogen, or 1 to lower alkyl having from 3 carbon atoms, R ₄ is lower alkyl having from hydrogen, lower alkyl, R ₅ is hydrogen or R ₆ 2 or 3 carbon atoms with from 1 to 3 carbon atoms, R ₁ or R ₂ is 4- If not halogen, -CH ₂ CH ₂ OR ₆ substituted with 1 or 2 hydroxy group.

The compounds of the present invention also include salts which can be used as medicaments. Salts usable as medicaments represent salts of compounds of formula (I) wherein R ₅ is hydrogen with an inorganic or organic base. Bases with inorganic bases include sodium, potassium, magnesium, aluminum and ammonium salts. Salts with organic bases include isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, lysine or the like.

Compounds of general formula (I) wherein R ₄ is lower alkyl contain asymmetric carbon and are therefore racemic compounds and optical isomers.

The present invention includes such racemic compounds and optical isomers. In general formula (I), halogen represents a fluorine, a chlorine, and a bromine atom. Lower alkyl denotes methyl, ethyl, propyl and isopropyl, preferably methyl. The group -CH ₂ CH ₂ OR _{6 preferably} includes 2- (2-2-hydroxyethoxy) ethyl, 2- (2,3-dihydroxypropoxy) ethyl or the like.

Compounds of general formula (I) and salts which can be used as medicaments thereof have excellent anti-inflammatory and analgesic effects with mild alserogenity side effects in the gastrointestinal tract, and have an extremely high safety margin. Certain compounds of the present invention have an inhibitory effect on chronic inflammation caused by cellular immunity, and also have an antiallergic effect with extremely mild allerogenicity side effects in the gastrointestinal tract.

Suitable compounds of the present invention are compounds of formula (I) wherein R ₁ is hydrogen, halogen or nitro and R ₂ is hydrogen or halogen.

More suitable compounds are those in which R ₁ and R ₂ are both hydrogen, R ₃ is hydrogen, 3-halogen or 3-methyl, R ₄ is methyl, R ₅ is hydrogen or 2- (2-hydroxyethoxy) ethyl Phosphorus is a compound of the general formula (I). Particularly suitable compounds are as follows.

2- [4 (2'-pyridylamino) phenyl] propionic acid, 2- [3-chloro-4- (2'-pyridylamino) phenyl] propionic acid, and 2- [3-methyl-4- ( 2'-pyridylamino) phenyl] propionic acid.

Compound of general formula (I) is represented by general formula (IV):

The compound of formula (ⅴ):

React with general formula (I '):

The compound of can be obtained, optionally hydrolyzed and prepared by decarboxylation reaction.

또는 임의로 탈카르복시 반응이 수반되는 가수분해로

로 전환이 가능한 기이다.)Wherein R ₁ , R ₂ , R ₃ are as defined above, X is halogen (eg chlorine or bromine), and Z is

Or optionally by hydrolysis accompanied by a decarboxylation reaction.

Can be switched to.)

로 전환이 가능한 기는

및

를 포함한다.Of general formula (IV) above

Can be switched to

And

It includes.

(Wherein R ₅ is alkyl having 1 to 6 carbon atoms or phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety.)

인데, 여기서는 1 내지 3탄소원자를 가진 알킬이다.Among these lifts, suitable groups

Where alkyl is one to three carbon atoms.

Condensation reactions of compounds (IV) and (V) are usually carried out in the presence or absence of a base. Catalysts such as equal parts or cuprous oxide may also be used in the reaction. The reaction can be carried out without using any solvent, but may be carried out with a solvent that does not participate in the reaction, such as toluene, xylene, pyridine or dimethylformamide. Bases used in the reaction include alkali metal carbonates (eg sodium carbonate or potassium carbonate), alkali bicarbonate metals (eg sodium bicarbonate or potassium bicarbonate) and organic bases (eg triethylamine or tri-n-propylamine) .

로 전환할 수 있는 기인 화합물(Ⅰ')을 상기의 반응으로 얻고져 할때는, 화합물(Ⅰ')을 종래의 방법으로 가수분해하여 R₅가 수소인 화합물(Ⅰ)을 얻는다. 예컨대, Z가

로 전환할 수 있는 기인 화합물(Ⅰ')은 실은 내지 약 100℃의 온도에서 열기예컨데, 수산화나트륨, 수산화칼륨, 탄산나트륨, 또는 칼륨)의 존재하에 물 또는 알코올을 함유한 물(예컨대, 에탄올 또는 이소프로판올)과 접촉시킨다. 가수분해는 대체로 약 10분에서 약5시간에 완료된다.Compound (IV) uses about 1 to 1.2 molar amount per 1 mole of compound (V). The reaction temperature is usually in the range of about 100 to 180 ° C., and the reaction time is usually about 30 minutes to about 20 hours. Z is hydrolysis

When compound (I ') which is a group which can be converted into is obtained by the above reaction, compound (I') is hydrolyzed by a conventional method to obtain compound (I) wherein R ₅ is hydrogen. For example, Z

Compounds (I ′) which can be converted to are actually hot water at temperatures of about 100 ° C., for example water containing alcohol or water (eg ethanol or isopropanol) in the presence of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium. ). Hydrolysis is usually completed in about 10 minutes to about 5 hours.

로 전환할 수가 있는 기인 화합물(Ⅰ')을 상기의 반응으로 얻고져 할 경우에는, 화합물(Ⅰ')을 가수분해하고, 그리고 종래의 방법으로 탈카르복시 반응을 시켜서 R₅가 수소인 화합물(Ⅰ)을 얻는다. 보통, Z가

로 전환할 수 있는 기인 화합물(Ⅰ')은 물 또는 알코올을 함유한 물(예컨대, 에탄올 또는 이소프로판올)에서 약 50 내지 100℃온도로 약 10분 내지 약8시간 약 2 내지 3당량의 염기의 존재하에 가열하면 가수분해와 탈카르복시 반응이 동시에 진행된다. 상기의 반응으로 얻어지는 일반식(Ⅰ)의 화합물은 통상의 방법으로 단리시키고, 그리고 정제한다.Z is hydrolysis and decarboxylation

When compound (I ') which is a group which can be converted to is obtained by the above reaction, compound (I') is hydrolyzed, and decarboxylation is carried out by a conventional method to give R ₅ as hydrogen. Get) Usually, Z is

The compound (I ′) which is a group which can be converted into the presence of about 2 to 3 equivalents of base in water or alcohol-containing water (eg ethanol or isopropanol) at a temperature of about 50 to 100 ° C. for about 10 minutes to about 8 hours. Under heating, hydrolysis and decarboxylation proceed simultaneously. The compound of general formula (I) obtained by said reaction is isolated and refine | purified by a conventional method.

Racemic mixtures of compound (I) in which R ₄ is lower alkyl and R ₅ is hydrogen are broken down into conventional optically active bases (i.e. disintegrating agents), ie cicononidine or d or Each optically active isomer is obtained.

Compound (II) wherein R ₅ is hydrogen is sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonium hydroxide, isopropylamine, diethyl amine, ethanol amine, piperidine, tromethamine, lysine or the like. And salts with inorganic or organic bases.

The conversion to salt is usually carried out at a temperature of about 0 to 100 ° C. with a suitable solvent such as water, lower alcohols (eg methanol, ethanol, or isopropanol), toluene, or mixtures thereof. The calcium or magnesium salt of compound (I) is suitably obtained by treating the corresponding sodium or potassium salt with calcium chloride or magnesium chloride.

Starting compounds of the general formula are commercially available or published in 1961 by New York's "Interscience Publishers, Inc." by E. Elingsberg (ed) "Heterocyclic Compound Chemistry" ; Pyridine and its derivatives, Part Two, can be prepared by the known methods described on pages 299 to 383.

In addition, other starting compounds of the general formula (IV) are commercially available or can be prepared by the known method described in Experientia, published in 1973, Vol. 29, page 938.

The pharmacological test data of certain representative compounds of the present invention are shown below, along with the data of commercial drugs and certain cognate complexes. The compound used for a test is as follows.

(Compound of the present invention):

A: 2- [4- (2'-pyridylamino) phenyl] propionic acid

B: 2- [3-chloro-40 (2'-pyridylamino) phenyl] propionic acid.

(Control compound)

1: Ibuprofen whose chemical name is a 2- (4-isobutylphenyl) propionic acid which is a well-known anti-inflammatory agent.

2: 2- [4-N-methyl-N- (2'-pyridyl) amino] phenyl] propionic acid which is new but which comes within the general formula defined in US Pat. No. 3,766,260.

3: 2-[-(2'-pyridyloxy) phenyl] propionic acid published in the specification of Japanese Patent Publication (Unexamined) 1975, 149,668.

10-15 animals were used to test anti-inflammatory and analgesic for each dose of test compound, and 4-6 dose levels were used to calculate individual ED ₅₀ (50% effective). For each dose 6-15 rivers and 4-6 dose levels were used to calculate the individual UD ₅₀ (50% Ulcer Formation) or LD ₅₀ (50% Formation).

Test 1. Anti-inflammatory action (effect on acute inflammation)

a) hindlimb edema in rats induced by terazinin (CAR method)

The test was published in 1962. Soc. Exp. Biol. It carried out according to the method described in Med., 111,544.

b) Vascular Penetration in Rats Induced by Acetic Acid (CAP Method)

The test was published in 1964 Brit. J. Pharm. It carried out according to the method described in Cehmother., 22,246.

Test 2. Pain Relief

a) Phenylquinone-induced pain (PQW method) in rats was tested in Proc. Soc. Exp. Biol. It carried out according to the method described in Med., 95, 729.

b) Pain in rats induced by acetic acid (ACWR method) The test was conducted according to the method published in Arzneim, Forsch., 25 1505, 1975.

The results of tests 1 and 2 are shown in Table 1.

[Table 1]

Anti-inflammatory and analgesic action

1) CAR: Leg edema in rats induced with carrageenan.

2) CAP: Vascular penetration of rats induced by acetic acid.

3) PQW: Pain in rats induced by phenylquinone.

ACWR: Pain in rats induced by acetic acid.

As apparent from the above results,

(1) Compounds A and B of the present invention have superior anti-inflammatory and analgesic effects to ibuprofen (Compound 1), which is a known anti-inflammatory agent.

(2) Compounds A and B have significantly greater anti-inflammatory and analgesic activity than known compound 2.

(3) Compounds A and B are superior to known compounds 3 in anti-inflammatory action and have significantly greater analgesic action.

Test 3. Effect on Chronic Inflammation Induced by Cellular Immunity Preventive Effect on Arthritis in Rats Induced by Adjuvant.

Testing was conducted according to the method published in Brit, J. Pharmcol., 21, 127, published in 1963.

Adjuvant (M in transit oil, tuberculosis H ₃₇ R _V 0.6 mg / 0.06 ml; Bayol F / rat) was inoculated intradermally into the tail of a female rat of JCL: SD strain on day 0.

Each compound was administered orally at a dose of 80 mg / kg / day once every 3.5 hours before adjuvant (0-20 days) and 20 days after adjuvant occupation. Only excipients were administered orally (0.5% tragacanth rubber solution) to the rats of the control group, and the results are shown in the second table and the attached table. In the table, the prophylactic effect of the test compound on adjuvant-induced arthritis of rats is indicated based on hindlimb swelling, and lines (1), (2) and (3) are control body shapes, compounds 1 and Display the data of Compound A, respectively.

[Table 2]

Preventive Effect on Adjuvant-induced Arthritis in Rats

**: There is a remarkable difference from the control excipient. P <0. 01

As apparent from the above results, the compound A of the present invention is significantly larger than the known ibuprofen (Compound 1) in suppressing action against chronic inflammation caused by cellular immunity. In addition, Compound A shows anti- analgesic action, but known ibuprofen does not show such action.

Trial 4. Gastrointestinal Alserogenity

The test was issued in 1969 by Arzneim. Forch., 19 36 was performed using mice fasted by the method disclosed in.

Test 5. Acute lethal toxicity

Mortality was observed 7 days after the single oral administration of test compounds to rats. LD ₅₀ was then calculated based on the Litchfield and Wilcoxon methods.

The results of the above tests 4 and 5 are shown in Table 3.

[Table 3]

Alserogenity, Safety Index and Acute Toxicity

As apparent from the above results, the safety factor of Compound A of the present invention is much larger than the safety index of known ibuprofen, and its toxicity is weaker than that of the latter. In addition, it was noted that Compound A has extremely weak alserogenis in the gastrointestinal tract.

Therefore, the compounds of the present invention have excellent anti-inflammatory action with extremely weak alserogenis in the gastrointestinal tract and at the same time excellent analgesic action. Thus, the above compounds have a large safety margin. On top of that, there is an excellent inhibitory effect on elastic inflammation caused by cellular immunity.

Therefore, compound (I) and salts usable as medicaments thereof may be used for the musculoskeletal system, skeletal joints, skeletal tissues such as rheumatism, shaking, laceration, arthritis, fracture, wound state, and ferritindine in animals including humans. It is useful as an anti-inflammatory and analgesic agent for the treatment of various inflammatory conditions of periendinitls.

When such inflammatory conditions include pain associated with inflammation, the compounds of the present invention are useful for removing pain along with inflammation.

Compound (I) of the present invention and salts usable as medicaments thereof can be administered to a patient orally, by injection, rectally, or transdermally. The dosage of compound (I) and salts thereof may vary depending on the compound, the route of administration, the age of the patient, the type and severity of the disease to be treated, or the like, but may range from 1 to 60 mg, preferably 2 to 30 mg per kilogram of body weight per day. It must be within range.

The dose may be divided into two to several times a day. Compound (I) and salts usable as medicaments thereof are usually administered to a patient in the form of a pharmaceutical composition containing an undesired and effective amount of the compound. Pharmaceutical compositions are usually prepared by combining compound (I) or a salt thereof with conventional pharmaceutical weight substances that do not react with compound (I) or salts thereof.

Examples of suitable weight materials include lactose, starch, sucrose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, methylcellulose, gelatin, acacia, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylfitpolydon , Light silicic anhydride, magnesium stearate, talc, tragacanth, bentonite, beegum, carboxyvinyl polymer, titanium dioxide, sorbitan fatty acid, sodium lauryl sulfate, cacao oil, saturated fatty acid glyceride, anhydrous lanolin, glycerol gelatin , Macrogol, vegetable oil, wax, cetyl alcohol, oleyl alcohol, propylene glycol, ethanol, isopropanol, water or the like.

The pharmaceutical composition may be in the form of tablets, capsules, granules, granules, powders, syrups, suppositories, ointments, creams, gels, injections or other forms. Such preparations can be formulated by conventional methods. Pharmaceutical preparations may be prepared by dissolving or suspending the active compound in water or other suitable excipients when in use. Tablets can be coated by conventional methods.

The pharmaceutical composition may contain, as an active ingredient, a compound (I) or a salt usable as a medicament thereof in a proportion of 0.5% or more by weight to the total weight of the composition, and preferably 3 to 70% by weight. have.

The present invention is illustrated by the following examples but not limited thereto. In the Examples, the compounds were evaluated by elemental analysis, mass spectrum, IR spectrum, NMR and the like.

Example 1

4- (2'-pyridyl amino) phenylacetic acid:

A mixture of 3.0 g p-aminophenyl acetic acid, 3.2 g 2-bromopyridine and 4.3 g tri-n-propylamine was heated at 170 ° C. for 3 hours. The reaction mixture was diluted with dilute ammonia and treated with activated carbon and filtered.

The filtrate was made acidic with acetic acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from acetone and a mixture of acetone and ethanol to give the title compound (1.5 g, 33%). Melting point 167-170 ℃

Example 2

2- [4- (2'-pyridylamino) phenyl] propionic acid:

A mixture of 2.1 g of methyl 2- (4-aminophenyl) propionate and 1.33 g of 2-chloropyridine was heated at 160 ° C. for 3.5 hours and dissolved in 12 ml of methanol. To this solution was added 12 ml of 10% aqueous sodium hydroxide solution, and the solution was stirred at room temperature for 30 minutes. After methanol was evaporated, the solution was adjusted to pH 5 with dilute hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized with methanol to give the title compound (2.0 g, 72%). Melting Point: 188-190 ℃

Example 3

2- (2-hydroxy ethoxy) ethyl 2- [4- (2'-pyridylamino) phenyl] propionate:

4.4 g of 2- (2-hydroxyethoxy) ethyl 2- (4-aminophenyl)

Propionate and 2.75 g of 2-bromopyridine were heated at 160 ° C. for 1 hour. Then, it was dissolved in a small amount of methanol.

Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to this solution. The organic layer was separated, washed, dried over sodium sulfate and concentrated. The residue was chromatographed with silica gel (60 g) using chloroform as eluent.

The part containing the title compound was pooled and concentrated to give the title oil compound (4.3 g, 75%).

Analytical Theory: (of C ₁₈ H ₂₂ N ₂ O ₄ ), C, 65. 44; H, 6.71; N, 8. 48

Found: C, 65. 31; H, 6. 79; N, 8. 22

Mass spectrum m / e: 330 (M ⁺ )

Example 4

Various compounds of were prepared by reacting the corresponding pyridine compounds with the corresponding propionic acid or propionate compounds in the same manner as in Examples 1-3.

[Table 4]

Example 5

Calcium 2- [4- (2'-pyridylamino) phenyl] propionate:

2- [4- (2'-pyridyl amino) phenyl] propionic acid (1.21 g) was dissolved in 20 ml of water containing 0.2 g of sodium hydroxide. The solution obtained by adding 0.368 g of calcium dichloride solution in 10 ml of water to the solution cooled in the bath was stirred for 1 hour.

After filtering off a very small amount of insoluble material, the filtrate was concentrated to a volume of about 10 ml and cooled. The precipitated crystals were collected, washed with water and dried to afford the title compound (1.05 g, 74%), melting point, 210-220 ° C.

Reference Example 1

2- (2-hydroxy ethoxy) ethyl 2- (4-amino phenyl) propionate (starting material used in Example 3)

i) A mixture of 5. 0 g of 2- (4-nitrophenyl) propionic acid, 20 ml of diethylene glycol and 0.5 ml of concentrated sulfuric acid was heated at 100 ° C. for 1 hour. It was then poured into ice water. The resulting solution was extracted with ethyl acetate.

The organic layer was washed with dilute aqueous sodium carbonate solution and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed with silica gel (50 g) using chloroform as eluent. The portion containing 2- (2-hydroxy ethoxy) ethyl 2- (4-nitrophenyl) propionate was concentrated by pooling.

ii) The ester compound obtained as above was dissolved in 30 ml of ethanol containing 0.1 g of platinum oxide. The solution was hydrogenated until the theoretical amount of hydrogen was absorbed. The residue was chromatographed with silica gel (40 g) using chloroform methanol (100: 1) as the solvent.

The part containing the title compound was concentrated by pooling to give the title oil compound (yield, 4. 6 g, 70%).

Reference Example 2

2- [4- [N-methyl-N- (2'-pyridyl) amino] phenyl] (propionic acid (Compound No. 2 used in pharmacology test)):

5. A mixture of 93 g of 2-bromopyridine and 90 g of methyl 2- (4-methylaminophenyl) propionate (prepared by the method described in US Pat. No. 3, 957, 850) was 160 ° C. for 1 hour. Heated at.

The reaction mixture was dissolved in 20 ml of methanol and 40 ml of 5% aqueous sodium hydroxide solution was added. The resulting solution was stirred for 30 minutes at room temperature, washed with chloroform, adjusted to pH 5 with dilute hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and thus chromatographed with silica gel (100 g) using chloroformmethanol (100: 2) as eluent. The portion containing the title compound was concentrated by pooling. The residue was recrystallized from ethanol to obtain the title compound (yield, 3. 60 g, 55%), melting point 120-121 ° C

Example 6

1. About 000 tablets

The above components and the like were mixed to form granules, and the tablets were prepared in a conventional manner to prepare 1,000 tablets each weighing 200 mg.

Example 7

About 1,000 tablets

The above ingredients and the like were mixed to form granules and put into 1,000 capsules by a conventional method.

Example 8

About 1,000 seats

(Glycerides of saturated fatty acids, products of Dynamit Nobel Chemicals)

The above components and the like were prepared in a conventional manner for 1,000 suppositories each weighing 1,500 mg.

Claims (1)

General formula:

Compound of general formula:

A general formula characterized by reacting with a compound of:

Method for preparing 4- (2'-pyridylamino) phenylacetic acid derivative of. In the above formula, R ₁ is hydrogen, halogen, lower alkyl or nitro having 1 to 3 carbon atoms, R ₂ is hydrogen, halogen or lower alkyl having 1 to 3 carbon atoms, R ₃ is hydrogen, halogen or 1 Lower alkyl having from 3 to 3 carbon atoms, R ₄ is hydrogen or lower alkyl having from 1 to 3 carbon atoms, R ₅ is hydrogen or —CH ₂ CH ₂ OR ₆ , wherein R ₆ is a carbon source substituted with 1 or 2 hydroxy groups Embroidered from 2 to 3 lower alkyl groups), X is halogen, Z is

Or by hydrolysis optionally accompanied by a decarboxylation reaction.

It can be converted into a group. Provided that R ₁ or R ₂ means halogen above 4.

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