DE1233404B - Process for the preparation of new 2,6-dialkoxy-4-sulfanilamidopyrimidine derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Int. Cl .:

C07d

GERMAN

PATENT OFFICE

EDITORIAL

German class: 12p-7 / oil

Number: 1233 404

File number: G 36745IV d / 12 ρ

Filing date: December 28, 1962

Opened on: February 2, 1967

The invention relates to a process for the preparation of new antibacterially active 2,6-dialkoxy-4-sulfanilamidopyrimidine derivatives of the general formula q ^

H ₂ N-

SO ₂ -NH

N (I)

wherein Ri and R _{2 are} lower alkoxy groups, preferably methoxy, n-propoxy or isopropoxy groups, also z. B. ethoxy residues.

One of the two manufacturing processes for these new compounds is characterized by that in a manner known per se, an alkali metal salt of a compound of the general formula

SO ₂ - NH ₂

(II)

wherein x is the amino group or a nitrogen-containing group which can be converted into the free amino group Rest means with a pyrimidine derivative of the general formula q ^

N = T ⁷

(III)

Ri

wherein Ri and Ra have the meaning given above and Y is a halogen atom, in particular a Means chlorine atom, a lower alkyl mercapto or alkyl sulfonyl radical, and one in Any present in the reaction product obtained can be converted into an amino group Rest x converted into the free amino group by hydrolysis or reduction. The implementations are in a suitable organic solvent, e.g. B. in dimethylformamide, acetamide, Ν, Ν-dimethylacetamide or dimethyl sulfoxide carried out with heating. As nitrogenous, in the Free amino group convertible residues come by hydrolysis into the amino group convertible Remnants, e.g. B. acylamino radicals, such as the acetamino radical, or lower carbalkoxyamino radicals, or substituted Imino groups, such as the benzylideneamino radical or the p-dimethylamino-benzylideneamino radical, or radicals which can be converted into the amino group by reduction, e.g. B. the phenylazo or p-dimethylaminophenylazo radical, further z. B. the Carbobenzyloxyaminorest or the Benzylidenaminorest in question.

Method of making new

2,6-dialkoxy-4-sulfanilamidopyrimidine

Derivatives

Applicant:

JR Geigy AG, Basel (Switzerland)
Representative:

Dr. F. Zumstein, Dr. E. Assmann

and Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Named as inventor:

Dr. Markus Zimmermann, Riehen (Switzerland)

Claimed priority:

Switzerland of December 29, 1961 (15 122)

Starting materials of the general formula III are known and others in a manner known per se manufacturable.

Another process for the preparation of compounds of general formula I consists in that in a manner known per se, a reactive functional derivative, in particular that Chloride or bromide, a sulfonic acid of the general formula

x '

SO ₂ - OH

where x 'is a nitrogen-containing group which can be converted into the amino group, in particular an acylamino group or nitro group, with a substituted aminopyrimidine of the general formula

Cl R ₂

H ₂ N-

"n

Ri

in which Ri and R _{2 have} the meaning given above, optionally reacted in the presence of an acid-binding agent, and any radical x 'which may be present in the reaction product obtained and which can be converted into an amino group

709 507/395

Hydrolysis or reduction converted into the free amino group.

The implementation of reactive functional derivatives of sulfonic acids of the general formula IV with substituted aminopyrimidines of the general formula V takes place in suitable inert ones organic solvents such as methylene chloride, acetone, tetrahydrofuran, as acid-binding Means z. B. N, N-diisopropylethylamine, trieth \! - amine, pyridine or collidine can be added. These Implementation can also be carried out using sodium hydroxide solution as an acid-binding agent a single-phase system, such as aqueous acetone, or a two-phase system, such as water-ether, be performed.

The subsequent hydrolysis to release the p-position amino group is preferably acidic, z. B. using dilute hydrochloric acid with moderate heating. The reduction of the above-mentioned reducible or reductively cleavable groups can generally be catalytic, eg. B. by means of Hydrogen in the presence of Raney nickel in an inert organic solvent; however, there are also non-catalytic processes, such as the reduction of nitro groups or azo groups using iron in acetic acid or hydrochloric acid. A radical that can be reducible to an amino group is also the nitrile radical N - bonded to the benzene ring with one of its three valences.

The aminopyrimidines of the general formula V required as starting materials are z. B. by Reaction of 2,4,5,6-tetrachloropyrimidine with 1 mol of ammonia and further reaction of the resulting 4-Amino-2,5,6-trichloropyrimidine with 2 mol of an alkali metal alkoxide available.

The new process products of the general formula I are suitable for the preparation of medicaments for internal or external use, optionally in the form of their salts.

The following is the chemotherapeutic effect in vivo of the compounds

I 2,6-dimethoxy-4-sulfanilamido-5-chloropyrimidine II 2,6-dimethoxy-4-sulfanilamido-pyrimidine (according to French patent 1 265 553)

examined and compared. Five white mice each are at different time intervals before the Infection treated therapeutically once. Was infected with

1. Streptococcus haemolyticus K 113: infection with a 10 ³ -diluted suspension. According to the germ count, this dose contained about 20,000 living germs and corresponded to about 1,000 times the lethal dose;

2. Diplococcus pneumoniae NTC 7465: infection with a 10 ⁴ -diluted suspension. According to the germ count, this dose contained about 12,800 living germs and corresponded to about 1,000 times the lethal dose;

3. Escherichia coli K 309: infection with a 10 ³ -diluted suspension. According to the germ count, this dose contained about 200,000 living germs and corresponded to about 10 to 100 times the lethal dose.

The test substances suspended in carboxymethyl cellulose are either 24, 20, 16, 12, 8, 4 or Administered once perorally with a gastric tube 1 hour before infection. The one-time applied Dose was 500 mg / kg.

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Dose: once 500 mg'kg po Number of surviving animals on the 2nd or 5th day of infection
(1st digit 2nd day, 2nd digit 5th day)
Treated therapeutically once hours before infection 24 20th 16 12th 8th 4th 1 Strep infection
I.
II 4/2
0/0 5/1
i / o 5/2
i / o 4/3
3/0 5/2
2/0 5/2
1/1 5/3
5/1 Pneumococcal infection
I.
II 4/0
0/0 4/0
0/0 5/0
0/0 5/1
i / o 5/1
0/0 5/5
1/0 5/5
4/0 Coli infection
I.
II 3'3
3/3 3/3
2/2 2'2
3/3 2/2
5/5 5/5
5/5 2/1
5/5 5/5
5/5

The substances to be tested were used to determine the lethal dose (DLöo) for 50% of the animals administered orally in various single doses to white mice and the results

evaluates.

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Results

DL- , 11 mouse
per os

5000 mg kg
5000 mg / kg

DLsn rat
per os

'5000 mg / kg
5000 mg / kg

The investigated process product shows in comparison to the best, previously known compound more similar Constitution and the same indication a significantly higher chemotherapeutic activity.

The following examples are intended to explain the preparation of the new compounds in more detail.

example 1

2.1 g of 2,6-dimethoxy-4,5-dichloropyrimidine and 5.8 g of sulfanilamide sodium are added with 6 g of acetamide 100 C for 2 hours. The reaction mixture is then allowed to cool and mixed with it a little water and acidify it with 2η hydrochloric acid. The precipitate is filtered off with suction and stirred for 1 to 2 hours with 10% sodium carbonate solution. Undissolved substance is sucked off

Claims (1)

and the filtrate is brought to pH 3 with hydrochloric acid. The precipitated crude 2,6-dimethoxy-4-sulfanilamido-5-chloropyrimidine is recrystallized from isopropanol and then melts at 202 to 203 ° C. B e i s ρ i e 1 2 a) 2.8 g of 4- (N ⁴ -Acetylsulfanilamido) -2,5,6-trichloropiperimidine, which has been obtained by reacting N ⁴ -Acetylsulfanilamid-sodium with 2,4,5,6-tetrachloropyrimidine, with a Solution of 1 g of sodium in 70 ml of absolute methanol refluxed for 18 hours. The solvent is distilled off, the residue is dissolved in water and the aqueous solution is adjusted to pH 5 with glacial acetic acid. The precipitate is filtered off and recrystallized from isopropanol, giving 2,6 - dimethoxy - 4 - (N ⁴ - acetylsulfanilamido) - 5 - chloropyrimidine which, after crystallization from dimethylformamide / water, melts at 229 to 230 ° C. with decomposition. b) 3.86 g of the 2,6-dimethoxy-4- (N ⁴ -acetylsulfanilamido) -5-chloropyrimidine obtained according to a) are boiled in a mixture of 30 ml of methanol and 5 ml of concentrated hydrochloric acid for 1 hour and then concentrated in vacuo . 2N soda solution is added to the residue until the pH is between 4 and 5. The precipitate is filtered off and recrystallized from isopropanol, after which the 2,6-dimethoxy-4-sulfanilamide-5-chloropyrimidine with a melting point of 202 to 203 ° C. is obtained. Example 3 a) By reacting 4-nitrobenzenesulfonamide sodium with 2,4,5,6-tetrachloropyrimidine, the 4- (4-Nitrobenzenesulfonamido) -2,5,6-trichloropyrimidine obtained after crystallization from ethyl acetate — hexane melts at 199 to 200 "C. This compound is treated analogously to the procedure described in Example 2, a) with sodium in absolute methanol, the 2,6-dimethoxy-4- (4-nitrobenzenesulfonamido) -5-chloropyrimidine obtained, which melts at 212 to 214 ° C after crystallization from acetone. b) 2.55 g of the 2,6-dimethoxy obtained according to a) 4- (4-nitrobenzenesulfonamido) -5-chloropyrimidines are in 100 ml of methanol with 1 g of Raney nickel as Catalyst hydrogenated at room temperature and normal pressure. The catalyst is dissolved in 30 ml of 2N hydrochloric acid dissolved, and after a short time the crystalline hydrochloride of 2,6-dimethoxy-4-sulfanilamido- 5-chloropyrimidine precipitates and after crystallization from methanol-isopropanol at 194 to 195 ° C melts with decomposition. The hydrochloride is dissolved in 2N soda solution and the free base is precipitated with acetic acid at pH 5. After crystallization from isopropanol, the pure 2,6-dimethoxy-4-sulfanilamide-5-chloropyrimidine is obtained (identical to example 2). The hydrochloride is dissolved in 2N soda solution and the free base is precipitated with acetic acid at pH 5. After crystallization from isopropanol, pure 2,6-dimethoxy-4-sulfanilamido-5-chloropyrimidine is obtained (identical to example 2). B is ρ ie 1 4 _6s ^{2.4 g of N 4} -acetylsulfanilic acid chloride are added in small portions to 1.90 g of 2,6-dimethoxy-4-amino-5-chloropyrimidine in 5 ml of pyridine, while cooling with ice and while stirring. After standing for 3 days at room temperature, the suspension is concentrated in vacuo and the residue is triturated with 15 ml of 2N sodium hydroxide solution. It is filtered and the filtrate is heated on a water bath for 2 hours. The solution obtained is adjusted to a pH of about 5 with 1: 1 dilute hydrochloric acid. The product is identical to 2,6-dimethoxy-4-sulfaniI-amido-5-chloropyrimidine (identical to Example 2). Example 5 1.35 g of 2,6-dimethoxy-4-methylsulfonyl-5-chloropyrimidine are dissolved in 12 ml of dimethylformamide, then 2.08 g of sulfanilamide sodium are added and stirred for 1 hour at room temperature, Maintained bath temperature for 2 hours at 40.degree. C. and 15 hours at 80.degree. It is then concentrated in vacuo and the residue taken up in water. With carbon dioxide the pH of the solution becomes set to 8. The reaction mixture is cooled with ice for 2 hours and excess sulfanilamide sucked off. The filtrate is acidified to pH 4 to 5 with 1: 1 dilute hydrochloric acid, cooled and the Sucked off precipitate. After crystallization from methanol, the 2,6-dimethoxy-4-sulfanilamido-5-chloropyrimidine melts at 202 to 203 C (see example 2). Claim: Process for the preparation of new 2,6-dialkoxy-4-sulfanilamidopyrimidine derivatives the general formula Cl R ₂ H ₂ N- SO ₂ - NH wherein Ri and R _{2 are} lower alkoxy radicals, characterized in that one e'ntweder in a manner known per se a) an alkali metal salt of a compound of the general formula SO ₂ - NH ₂ wherein X denotes the amino group or a nitrogen-containing group which can be converted into this, with a pyrimidine derivative of the general formula Cl R ₂ Y ^ f ^ N (III) N = Ri wherein Y is a halogen atom or a lower alkyl mercapto or alkylsulfonyl radical, implements or b) a reactive functional derivative of a sulfonic acid of the general formula X ' SO ₂ - OH where X 'is a nitrogen-containing, into the amino