JPS603060B2 - Method for producing organic compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a compound represented by the following general formula or a pharmaceutically suitable acid addition salt thereof.

, and [in each formula, each group and ' group may be localized on any carbon atom, but one group cannot be in an ortho positional relationship with the other group: R is hydrogen, selected from the group consisting of lower alkyl and pharmaceutically suitable metal or amine ions; R is a lower alkyl group; x and Y are the same or different and consist of hydrogen, lower alkoxy, halogen, and carboxy groups; selected from the group.

] The term "halogen" herein refers to fluor, chlor, bromine, and iodo.

``Pharmaceutically suitable metals'' refers to alkali metals such as sodium and potassium, alkali metals such as calcium and magnesium, and other suitable metals such as aluminum.

The amine ion r refers to ammonia, tris-(hydroxymethyl)-aminomethane (THAM), D-threo-2-amino-1-pnitrophenyl-1,3-propanediol, N,N-bis(hydroxyethyl)-
Piverazine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-furopanediol and pi-2,2-bis(hydroxymethyl)-2,2
',〆,--trosotriethanol and day2NR',
All pharmaceutically suitable compounds derived from amines such as HNR'2 and NR'3 (wherein R' is selected from the group consisting of alkyl having 1 to 3 carbon atoms and -CH2CH20) It is an ion. Pharmaceutically suitable acid addition salts are salts that can be formed with the residual nitrogen atom of pyridine.

These salts include hydrochloride, bromate, sulfate, nitrate, sulfate, postaltate, cyclohexane sulfamate, salicylic acid, and the like. *The compounds of this invention can be produced by known methods.

Suitably substituted dianopyridines (0) are suitable starting materials. These compounds are reacted with an alkyl oxalyl halide, preferably ethyl oxalyl chloride (ma) in a suitable solvent and base to form the dioxamate (
N) is generated. At this point in the synthetic route, the oxamate can be converted to the diacid by hydrolysis and converted to the metal or amine salt by conventional methods. N-oxide derivatives of pyridyl dioxamate esters or salts can be readily prepared by oxidizing the gester with an oxidizing agent such as m-chlorberoxybenzoic acid. Suitably X and Y substituted diaminopyridine starting materials are prepared by conventional substitution methods well known in the art.

These methods involve the substituents themselves, the substitution of substituents and the substitution of oxamine groups. * Carboxy substituents can be prepared by converting the corresponding diamino or dinitropyridine carboxylic acids to eg esters, amides, etc. by standard methods.

This can be done before making the dioxamate from the substituted diaminole starting material. Another route to producing the starting material (m) is to react a substituted dihalopyridine, e.g. dichloropyridine (V), with ammonia under pressure and at elevated temperature to produce the substituted diaminopyridine starting material (0).
It consists of generating.

Once starting material D has been prepared, it is reacted with an alkyl oxalyl halide or dialkyl oxalate.

When using an alkyl oxalyl halide, the reaction is carried out under standard conditions in base and solvent. Examples of suitable solvents are dimethylformamide (DMF), dioxane, and tetrahydrofuran. Suitable bases are triethylamine, NH methylmorpholine, dimethylpiverazine and N-methylpiverizine. If a dialkyl oxalate is used, starting material D or a substituted homologue thereof is heated with the addition of the dialkyl oxalate or, if desired, a solvent such as chirecine or diphenyl ether to form the dioxamate. The temperature at this time is approximately 25
qo to the reflux temperature of the system, preferably between about 100°C and the reflux temperature. The dioxamate is then readily converted to dioxamic acid by using a dilute base such as sodium hydroxide, potassium hydroxide or potassium carbonate at a temperature of about 25 to about 100 oo, followed by addition of acid.

The alkali metal salt of the oxamate may be soluble or relatively insoluble in the hydroxyl medium. If soluble in the aqueous medium, the pH is adjusted with acid and the resulting precipitate is collected. If the alkali metal salt is insoluble in the aqueous medium, the desired diacid can be isolated by collecting the precipitate itself and heating the mixture to an appropriate temperature in an aqueous acid solution.
This acid can be readily converted to a metal or amine salt by contacting it with two equivalents of the desired amine or metal hydroxide and heating in sufficient water to effect solubilization. This crystalline salt can be precipitated by addition of an organic solvent, such as methanol. Table 0 A specific example of a compound of this invention is dioxamic acid prepared from the starting materials of Table 1 by the method of this invention,
It is considered that it was manufactured and is described as Table D.

The dioxamic acids in Table m are converted by standard methods into pharmaceutically suitable salts, such as metal and amine salts and especially tris(hydroxymethyl)methylammonium salts.

Table N The dioxamic acid of Table 0 was prepared using a standard method with R having 1 carbon number.
~6 alkyl and phenyl compounds.

Table V The compounds of Table N are converted to pyridine N-oxide oxamates by standard methods.

The compound of Nagato's Table V is converted to pyridyl N.-oxidodioxamic acid by standard methods.

Table W The dioxamic acids of Table W are converted by conventional methods into pharmaceutically acceptable salts, such as metal and amine enteric ions and especially tri(hydroxymethyl)methylammonium salts.

Table D~Fields are not presented in the same manner as Table 1 for simplicity, but are intended to cover the same range.

The examples below are compounds according to this invention. These compounds are illustrative rather than limiting to the invention. Example 1 Pyridine-2,6-diyldioxamic acid a N,N'
-2,6-pyridinediyldi-oxanoate diethyl 2,
6-Diaminopyridine (13.6 minutes) was dissolved in anhydrous DMFIOO containing triethylamine (21 hours).

The cooled reaction mixture was cooled to ice bath temperature and treated with ethyl oxalyl chloride (30 min) dropwise. Stirring was continued for 1 hour at room temperature and the reaction mixture was poured into water.
The product was built up by filtration, washed with water and dried under vacuum at 60q0. . Recrystallized from acetone, melting point 179
-18 pi○ material (150 yen) was obtained. b Product The above gelatin ester (13.0 ml) was stirred in IM sodium hydroxide (250 ml) for 1 hour at room temperature.

, this solution was acidified with MHCI to give the desired acid as a white solid. The product was collected by filtration, washed with water and dried under reduced pressure at 60°C. Yield 7.3mm, melting point >31pp0 Infrared spectrum (nujol): 3190
172 165 162 157 735 Example 2 Pyridine-2,5-diyldioxamic acid a 2,5-diaminopyridine 2-amino-5 nitropyridine (10 evenings, 0.071
A mixture of 5% palladium on charcoal (1.0 molar), and methanol (200 molar) was treated with hydrogen (4 molar) in a Pal hydrogenator until hydrogen consumption ceased.

The catalyst was filtered off and the solvent removed leaving a red oil.
When this was left to stand, it crystallized. b Jetyl N,N'-2,5-pyridinediyldioxamate Diamine obtained above, triethylamine (14th night, 0.14 mol)
and anhydrous dimethylformamide (125') of ethyl oxalyl chloride (18.4 min, 0.1
4 mol) was added slowly.

The reaction mixture was stirred overnight at room temperature and then poured into water.
The resulting solid was collected, treated with Darco, and recrystallized from methanol to give a pale red solid (5.5% yield, 26% yield, melting point 178-18 pi). A small sample was recrystallized. c The product N,N'-jetyl 2,5-pyridinediyldioxanoate (1.0 min, 0.0032 mol) was added to 1.0 min. The mixture was concentrated in sodium hydroxide (25°C) at 70-85°C until complete solution.

The reaction mixture was diluted with water (25 kg) and acidified with concentrated hydrochloric acid (
pH=3). The desired product was collected. (0.35
analysis nuclear magnetic resonance (D20 containing THAM): 5.956 (double line, IH
, 3-proton, J3,4=pine ps): 6956 (singlet, IH, 4-proton, J4,3=pillow pS, J4 pair=
Phantom ps): 7.356 (double line, IH, 6-proton,
J6 Basaps) Infrared Spectrum (Nujol) 350
31302650 (Hirochu), 170016101 $1200 Other examples 32,6-dimethoxy3,5-pyridinediyldioxamic acid disodium salt a N,N'
-(2,6-dimethoxy-3,5-pyridinediyl)dioxamate diethyl 3,5-diamino-2,6-dimethoxypyridine dihydrochloride in DMF (50') and triethylamine (83 min, 0.28 mol) Ethyl oxalyl chloride (571 min, 0.0418 mol) was slowly added to a solution of (50 min, 0.027 mol) at 0°C while stirring.

. The reaction mixture was incubated at 0 °C for 1 h, then at room temperature for 18 h.
I worshiped time. Dilution with water (500w') gave a dark colored product. This was collected using rotary koji, washed with water, and dried (38 days, melting point: 170-173°C). Recrystallization from ethanol and treatment with Oarco gave a pale green product (1.9 pm, mp 173-174.5°C, 25% yield). Analysis C is calculated as day, 906N3: C, 4878; H: 519:N, 11. Actual measurement value of spots: C, 49.06: Sun, 518: N, 11.36 Ultraviolet spectrum (EtOH) input max; Z2 (10
300), 316 (14600) Infrared spectrum (Nujol): NH powder 9 Li = CH3 Female 0, C Ni 0 173
0, 1710, CniC/CniN/amide 11161〇1
53F1515CH/C-0ノC-N/Ether 147
51405136fuC=0/C-N/ether 1290
, 123, 117, 1115, 1020, 100 ○ Grass spectrum: Molecular ion compromise b Product 1.75 mol (0.0048 mol) of the above product was dissolved in 1 at room temperature.
．． I worshiped the state NaOH (25 [)].

The sodium salt precipitated out as an off-white mass, which was left behind and dissolved in water (400 g). This solution was acid-oxidized with SuHCl (pH=4). passed.
The filtrate was concentrated under reduced pressure to 200°C and its sodium dioxide salt precipitated out as a white solid. (75 evening, melting point >3
100) Analysis C,. Calculated value assuming day 9N306N: C, 3699: day, 2. String; N, 11.76:
Na, 12.88 Actual value: C, 37.55: Day, 2.5
4:N, 12.05:Na, 11.95 Ultraviolet spectrum (QO)^mne x (f): 21$h (11600),
3M (9400) Infrared Spectrum (Nujol): N
H/OH3 section u 340 3350, C ni 0 no CQ no C
= N no C: H/C in CI muscle 5, 1610, 1 spot: 0/C
-N13951 Private 1015 Example 4 In the method of Example 1(b), an appropriate amount of 4-methoxy-2,6-diaminopyridine or 4-carpoxy-2,6-diaminopyridine was used instead of 2,5-diaminopyridine. and 4-chloro-2,6-diaminobiridine to obtain the following compound.

N,N'-(4-methoxy-2,6-pyridinediyl)
Jetyl dioxamate m. P. 243-245°C (decomposition); N,N'-(4-carboxy-2,6-pyridinediyl)jetyl dioxamate m. P. 255-2
570; and N,N'-(4-chloro-2,6-pyridinediyl)jetyl dioxamate m. p. IM~
1660○.

Example 5 The compound of Example 1(A), ie, jetyl N,N'-2,6-pyridinediyldioxamate, is mekted.

Oxidized with roberoxybenzoic acid, N,N'-2,6-pyridinediyldioxamate diethyl N-oxide m
．． p. 225~Nebio (decomposed) was obtained. The compositions of this invention may be prepared in unit dosage forms, such as tablets, capsules, pills, powders, tablets, sterile parenteral solutions or suspensions, eye drops, oral solutions or suspensions, containing a suitable amount of a compound of formula 1. It is formulated for administration to humans and animals as suspensions and oil-in-water and water-in-oil emulsions.

. A preferred means of administration is intravenous inhalation via an aerosol solution or powder for inhalation. For oral administration, either solid or liquid unit dosage forms can be prepared.

For preparing solid compositions such as tablets, the compound of formula 1 may be combined with a conventional compound such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, gum arabic, methylcellulose. ingredients and a material that has a similar function as a pharmaceutical diluent or carrier. Capsules are prepared by mixing the above compound with an inert pharmaceutical diluent and filling the resulting mixture into suitable size gelatin. European gelatin capsules are prepared by mechanically encapsulating a slurry of the above three compounds and a suitable vegetable oil, light liquid paraffin or other inert oil.
. Liquid dosage forms for oral administration, e.g. syrup 3,
Can produce elixirs and suspensions.

A syrup is made by dissolving the compound in water-soluble form in an aqueous medium along with sugar, flavoring agents and preservatives. Elixir is prepared by using a hydroalcoholic (ethanol) vehicle, a suitable sweetening agent such as sucrose and saccharin, and flavoring agents. Suspensions are prepared in aqueous media with suspending agents such as gum arabic, tragacanth, methylcellulose, and the like.

For parenteral administration, liquid unit dosage forms can be prepared utilizing the compound and a sterile vehicle, preferably water.
The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved in Water for Injection and filter sterilized before filling into a suitable vial or ampoule or ampoules and sealing. Adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To increase stability, the composition is frozen after filling and the water is removed under vacuum. The lyophilized powder is then sealed in a vial and provided with a vial of water for injection to reconstitute it before use.
Parenteral suspensions are prepared in the same manner as described above, except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. In this case, the compound can be sterilized by exposure to ethylene oxide prior to suspension in a sterile medium. It may be advantageous to include a surfactant or wetting agent in the composition to promote uniform distribution of the compound.
Additionally, rectal suppositories can be used to administer the active compound. This dosage form is of particular interest when the corneal mammal is difficult to treat by other dosage forms such as oral or inhalation, such as in debilitated young children. The active compounds can be incorporated into known suppository bases by methods known in the art. Examples of such bases include coconut oil, polyethylene glycols (carbo waxes),
Examples include polyethylene sorbitan monostearate and those mixed with other compatible materials to change the melting point or dissolution rate. These armpit suppositories are about 1-2.
It can be 5 yen's weight. Preferred compositions are those that are applied for pulmonary inhalation and contain the water-dissolving compounds of this invention.

Compositions suitable for administration to the nasal cavity for the treatment of nasal allergic conditions such as rhinitis are preferred. Compositions for inhalation are of three basic types: 1) preferably micronized powder mixtures with particle sizes preferably from about 1 to about 5 microns; 2) dispersed by a nebulizer. and 3) an aqueous solution containing a volatile propellant in a pressurized container.

Powders are prepared quite simply by mixing a compound of the above formula with a solid base compatible with arm tissue, preferably lactose.

The powder is placed in a device suitable for ejecting a metered amount of powder when inhaled through the mouth. Aqueous solutions are prepared by dissolving the compound of Formula 1 in water and adding salt to provide an isopplexic solution and buffering to a pH suitable for inhalation.

These aqueous solutions are placed in a morning dispenser or nebulizer and misted into the mouth during inhalation.
Z aerosols are made by dissolving the compound of Formula 1 in water or ethanol, mixing with a volatile propellant, and placing in a pressurized container with a metering valve to release a predetermined amount of material. The liquefied propellant used has a boiling point below 18yo (65Z.F) at atmospheric pressure. For use in compositions for producing medical aerosols, liquefied propellants must be non-toxic. Suitable liquefied propellants that can be used include carbon atoms
and lower alkanes such as methyl, ethyl or propyl chloride. Further suitable liquefied propellants are fluorinated and chlorochlorinated lower alkanes such as those sold under the trademarks "Freon" and "Qnetron". Mixtures of the abovementioned propellants can be suitably used. Examples of these propellants are dichlorodifluoromethane (Freon 12), dichlortetrafluoroethane (Freon 114), trichlormonofluoromethane (Freon 11), dichloromonofluoromethane (Freon 21), monochlordifluor These are ormethane (Freon 22), trichlorotrifluoroethane (Freon 113), difluoroethane (Genetron 1421A) and monochlorotrifluoromethane (Freon 13). As used herein, the term "unit dosage form" refers to a physically indivisible unit suitable as a unit dosage for humans and animals.

Each unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect as well as the required pharmaceutical diluent, carrier or vehicle. The novel unit dosage forms of this invention are characterized by (a) the unique properties of the active ingredients and the particular action to be achieved, and (b) the limitations inherent in the techniques of formulating active ingredients as described above for use in humans and animals. It is influenced by and directly dependent on the These new unit dosage forms are embodiments of the present invention. Examples of suitable unit dosage forms of this invention are tablets, capsules, pills,
Suppositories, powder sachets, wafers, tablets, cashews, teaspoons, spoonfuls, dropper pins, ampoules, vials, aerosols with measuring devices, and divided portions of any of the above dosage forms are included in this specification. Other dosage forms mentioned. It is to be understood that composition herein refers to the groups and structures of compounds A to G, each of which is pyridine and a pharmaceutically suitable acid addition salt thereof, as well as the exemplified compounds.

Effective but non-toxic amounts of the compounds are used in treatment. The dosage of a therapeutic compound will depend on the route of administration and efficacy of the particular compound. A dosing regimen of about 0.05 to 20 9 compounds administered parenterally or by inhalation in a single administration of the compositions of this invention is effective in preventing allergic attacks. About 0.2 to about 2 at a time
Preferably, 0 of the compound is administered.

A single oral and rectal dose is about 1 to about 60 o.

Preferably, from about 3 to about 30 o of compound are administered in a single dose.

This dose can be repeated up to 4 times per day. However, when repeated treatments are necessary, a preferred dosing regimen is to increase the dose for the second treatment to about 0% of the first dose.
．． 5 to about 20%, more specifically about 1 to about 10%. In this way, a state of allergy prevention can be maintained. This reduced dosage is maintained until no longer effective protection is obtained. If this dose is no longer effective, a higher dose (initial dose) is repeated and then the dose is lowered. An example of such a dosing regimen is as follows: an asthma patient was inhaled with 0.5 doses of the tris(hydroxymethyl)aminomethane salt of pyridine-2,6-diyldioxamic acid.

Four hours later, the patient inhaled 0.005 o of the same compound;
This reduced dose was continued every 4-6 hours until no effective allergy prophylaxis was obtained.

When the effect disappeared, administer 0.5 of the compound in 2;
Another reduced dose is then repeated every 4-6 hours. Continue the dosing regimen in this manner. Administration of the compositions of this invention to humans and animals provides a method of prophylactic treatment of reagin or non-reagin mediated allergic or all anaphylactic reactions.

That is, if these compositions are administered to a sensitized patient before the patient comes into contact with the substance (antigen) to which the patient is allergic, allergic reactions may be prevented. For example, this method can be used for the preventive treatment of chronic conditions such as bronchial asthma, allergic rhinitis, food allergies, hay fever, urticaria, autoimmune diseases, linked-induced asthma, stress-induced asthma, and systemic anabraxis. Can be used for In the examples below, compounds are used in the salt form and the weight of the compound is given in its acid form.

Reference Example 1 From the following composition, each tablet contains 1 ton of pyridine.
1 lot containing 2,6-diyldiaxamic acid 10
00 fake rhombus was manufactured.

Pyrin-2,6-diyldioxamic acid 10 dicalcium phosphate 1000 methylcellulose US Pharmacopoeia (1&ps) 60 tatarc
150 Corn starch 200 Magnesium stearate 5 The above compound and dicalcium phosphate were thoroughly mixed and granulated with a 7.5% aqueous solution of methyl cellulose. Extruded through 8 screens and carefully dried.

The dried chin grains were placed in No. It was extruded through 12 screens, mixed thoroughly with talc, starch and magnesium stearate and compressed into tablets. These tablets were useful in preventing attacks of hay fever at a dosage of 1 tablet every 4 to 6 hours.

Reference Example 2 From the following composition, each capsule contains 20% of pyridine-2,5-diyldioxamic acid.
Two hard gelatin capsules were manufactured: 3
Pyridine-2,5-diyldioxamic acid 20% milk
Sugar 400 talc
1.5 mg Magnesium stearate 1. Each component was thoroughly mixed and filled into capsules 4 of appropriate size.

The capsules so produced were useful in preventing bronchial asthma attacks at a dosage of 1 capsule every 4 to 6 hours.

Reference Example 3 From the following composition, each tablet contains 100% of the four secret 2,66-dimethoxypyridine-3,5-diyldioxamic acids.
Tablets were prepared around 2,6-dimethoxypyridine-3,5-diyldioxamic acid.
4-Year Microcrystalline Cellulose NF 41
0 evening meal 10
Each component was tested, mixed thoroughly, and compressed into 516 female tablets.

This tablet was useful in protecting against food allergies in one pre-meal dose.

Reference example 4 Suitable for intramuscular injection, 0.1 pyridine-2 per person
, 6-diyldioxamic acid was prepared from the following composition: Pyridine-2,6-diyldioxamic acid 0.1 Penzyl benzoate
200 0 Methylparaben
1.5 Tapropylbaraben
This sterile preparation, made up to a total volume of 1000 by adding a sufficient amount of 0.5 tang oil, is injected for the prophylactic treatment of allergic rhinitis.

Reference Example 5, Tris(hydroxymethyl)amine/methane (TH) of pyridine-2,6-diyldioxamic acid
Tris,(hydroxymethyl)amino methane of pyridine-2,6-diyldioxamic acid was prepared as follows:
HAM) Salt 1.8 t Sodium chloride 5 t Add water for injection to make a total volume of 600 m.

The above THAM salt and sodium chloride were dissolved in a sufficient amount of water to make 600 ml of water and passed through a sterilized oven. This solution was placed in a nebulizer designed to deliver 0.25' of solution per mist.

This solution was inhaled into the arm every 4 to 6 hours to prevent asthma attacks.

Reference Example 6 A powder mixture consisting of 0.2 g of tris(hydroxymethyl)aminomethane salt of pyridine-2,6-diyldioxamic acid and an amount of lactose sufficient to strain the mixture by 5 g was pulverized and administered for each dose. I put it in an inhaler designed to emit 5 ounces of powder.

. The powder was inhaled into her sister every 4 to 6 hours to prevent asthma attacks. This powder was inhaled into the nasal cavity every 4 to 6 hours to prevent rhinitis.

. Reference Example 7 A 12-day aerosol composition was prepared from the following ingredients: Tris(hydroxymethyl)aminomethane salt of pyridine-2,6-diyldioxamine salt 0.10 Tafreon 1
2 1.440 Taffleon 114 2.160 Tafwater
7.700 t Sorbicun monooleate 0.600 t The above THAM salt was dissolved in water, cooled to 130 qo, and added to the cooled Freon.

12 batches of the composition was added to a 13 cc plastic coated bottle and filled with a metering valve.

The metering valve releases 80 secret compositions in one shot.
This aerosol was inhaled every 4 to 6 hours to prevent asthma attacks. . EXAMPLE 8 In cases 4 to 10 of patients requiring continued treatment, each dose was given first and then continued at a dose 1/50 of the original dose.

This maintenance dose was continued until no effective allergy prophylaxis was obtained. The original dose of Examples 4-10 is then administered once more, followed by the maintenance dose described above. Reference Example 9 Appropriate amounts of each of the compounds in Tables 0 to W and Examples 1 to 3 were added to Examples 7 to 10, taking into account the differences in solubility of the compounds and the activity of the particular compound as measured by an invipot passive dermal anaphylaxis assay, etc. It was used in place of the active compound used in the compositions and applications.

Results showing antiallergic activity were obtained. Reference Example 10 A rat passive cutaneous anaphylaxis test was conducted as follows: Female Sprague-Dawley rats (250 m) were unstable to heat and had a passive cutaneous anaphylaxis value of 1:1.
The skin was sensitized with 28 rat anti-ovalbumin allogeneic cell affinity antibodies.

After a 7-hour incubation period, animals were exposed to 4 layers of egg albumin (O
A) Fifteen females were injected intravenously with Evans blue dye and the saponified compound.

After 30 minutes, blue coloration outside the veins resulting from antigen binding occurring in the skin area was measured.

using antibody dilutions such that 4 skin spots are the smallest detectable spots in control animals;
Each animal received a range of antibodies using 4- or 5-fold dilutions. . Four to five animals were used for each concentration of antibody. Percent inhibition of the PCA test was calculated by comparing spot scores of treated and control rats. The spot score is the total number of detectable spots divided by the number of animals. Pyridine-2,6-
The tris(hydroxymethyl)aminomethane salt of diyldioxamic acid was prepared by dissolving the dicarboxylic acid in an equal weight of an aqueous solution of tris(hydroxymethyl)aminomethane and was tested in the rat passive cutaneous anaphylaxis assay as described above. Ta.

The 50% inhibitory dose of the tris(hydroxymethyl)aminomethane salt of pyridine-2,6-diyldioxamic acid was an o/k9 of 0.01.

Mugihata Table 0 and W compounds were converted to pharmaceutically suitable acid addition salts by conventional methods.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In each formula, there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ The group may be localized on any carbon atom. , one group cannot be in an ortho position with another; R is selected from the group consisting of hydrogen, lower alkyl and a pharmaceutically suitable metal or amine cation; X and Y are the same or different; selected from the group consisting of hydrogen, lower alkoxy, halogen, and carboxy groups. ] A method for producing a compound with the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [X and Y are as defined above, NH_2 is at the same position as the oxamine group above] It is in. ] X and Y substituted pyridyldiamine and general formula ▲ mathematical formula,
Chemical formulas, tables, etc. are available▼ [In the formula, R' is lower alkyl, and Halo is fluoro, chloro, bromo, or iodo. ] with the alkyl oxalyl halide in molten soot and a base to form the corresponding dioxamate ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ When producing a compound where R is hydrogen, the dioxamate is hydrolyzed, and when producing a compound where R is a metal or an amine cation, after hydrolyzing the dioxamate, each A method characterized in that it consists of converting into a cation of. 2 General formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In each formula, there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ Groups may be localized on any carbon atom, but if one group is cannot be in ortho position with one group; R' is lower alkyl; X and Y are the same or different;
selected from the group consisting of hydrogen, lower alkoxy, halogen, and carboxy groups. [X and Y are as defined above, and NH_2 is at the same position as the oxamine group. ] X and Y substituted pyridyldiamine and general formula ▲ mathematical formula,
Chemical formulas, tables, etc. are available▼ [In the formula, R' is lower alkyl, and Halo is fluoro, chloro, bromo, or iodo. ] with the alkyl oxalyl halide in molten soot and a base to form the corresponding dioxamate ▲ mathematical formula, chemical formula,
A method consisting of producing ▼ and oxidizing it with a suitable oxidizing agent.