DE1645988C3 - 23-Dihydro-1H-pyrido [2,3-b] [1,4] -thiazines and processes for their preparation - Google Patents

Description

HS — CH-COOR '

(H)

wherein R 'denotes a hydrogen atom or a lower alkyl radical, with a compound of the general formula

(HD

40

COOR '

CH-R

(IV) optionally the carbonyl compounds thus obtained reduced with a metal hydride in an inert reaction medium and / or the obtained The compound is stirred into a salt with an acid.

The invention relates to 2,3-DihydrolH-pyrido [2,3-b] [1,4] -thiazines the general formula

(D

a, where Z is a methylene or carbonyl group, R and R are hydrogen atoms or methyl groups and R _{2 is} a hydrogen atom or a methyl or propargyl group, and the salts of these compounds with acids. .

The new compounds as well as their non-toxic acid addition salts have after oral administration an anti-inflammatory activity. In particular The new compounds and their non-toxic acid salts reduce edema in warm-blooded animals by at least 25% of the infected area after a single application of 10 to 100 mg / kg of the active ingredient. The new compounds and their non-toxic acid addition salts have also has antipyretic activity in warm-blooded animals. In this respect the activity is new Compounds comparable to that of acetyl

salicylic acid. - ,,, ·.

According to the invention, the new compounds obtained by making a compound of the general formula

in which R "denotes a nitro group or the group —NHR ₂ , heated in the presence of a polar solvent and a base, where in case a) that R" denotes a nitro group, a compound of the general formula IV

HS — CH-COOR '

(H)

wherein R 'denotes a hydrogen atom or a lower alkyl radical, with a compound of the general formula

for ^R "

(III)

is obtained, which is catalytically hydrogenated to the corresponding amino compound and then heated, resulting in a compound of the general formula I in which Z is the carbonyl group and R _{2 is} a hydrogen atom, and in case b) that R "is the group -NHR ₂ means in which R _{2 has} the meaning given in claim 1, a compound of the general formula I is formed immediately, in which Z is the carbonyl group, optionally compounds obtained in this way in which R _{2 is} a hydrogen atom, with a halide of the general formula R ₂ - Hai substituted in the 1-position and where R "denotes a nitro group or the group -NHR ₂ , heated in the presence of a polar solvent and a base, where in case a) that R" denotes a nitro group, a compound of the general formula IV

NO ₂

(IV)

is obtained, which is catalytically hydrogenated to the corresponding amino compound and then

is heated to form a compound of the general formula I in which Z stands for the carbonyl group and R ₂ for a hydrogen atom, and in case b) that R "denotes the group —NHR ₂ , in which R _{2 has} the meaning given in claim I. possesses, immediately a compound of the general formula I is formed, in which Z is the carbonyl group, any compounds obtained in this way in which R _{2 is} a hydrogen atom, substituted with a halide of the general formula R ₂ -Hai in the 1-position and optionally the carbonyl compound thus obtained reduced with a metal hydride in an inert reaction medium and / or the compound obtained is converted into a salt with an acid.

Suitable polar solvents are, for example, water, ethanol, methoxyethanol or mixtures of these and suitable bases are, for example, potassium bicarbonate. Sodium carbonate or sodium hydroxide.

Of particular interest are the non-toxic acid addition salts of the new compounds because these are more soluble in the usual pharmaceutically acceptable vehicles. Preferred salts are the hydrochlorides, sulfates, phosphates, acetates and citrates.

To demonstrate the pharmacological superiority of the new compounds according to the invention, the following comparative experiment was carried out: 30 minutes from the subplantar injection of 0.1 ml of a 1.5% suspension of carrageenan into a paw, rats were given the test conditions listed in the table below, the oral were administered. 3 hours after the injection of carrageenan, the injected paws were measured volumetrically. The results obtained were compared with those measured on rats that had received no medication but only the subplantar injections of carrageenan. The LD ₅₀ was determined orally in mice.

? 5

connection LD ₅₀ ED ₂₅ Edema reduction at
at 50
100 mg / kg
mg / kg of the example (mg / kp) (mg / kg p. 0.) at 50 mg / kg Acetylsalicylic
acid > 1600 100 16%
30% at 50 mg / kg (Comparative at 50 mg / kg connection) yeh 100 mg / kg example 1 1600 40 36% at 100 mg / kg Example 2 1500 6th 41% at 100 mg / kg Example 4 1500 30th 32% Example 5 ' > 1000 40 53% Example 6 1500 80 43% Example 8 1000 70 38% B. e i s pi el 1 Method a

40

45

A solution of 37.9 g of ethyl mercaptoacetate in 50 ml of ethanol slowly becomes a solution 27.7 g of sodium bicarbonate in 300 ml of water were added. The clear solution is 30 minutes at room temperature stirred, after which the slow addition of 50 g of 2-chloro-3-nitropyridine in 100 ml of ethanol connects. After the addition is complete, the mixture is refluxed for 12 hours. whereupon 150 ml of water are added. After cooling the mixture in an ice bath, precipitates Solid off. The crude reaction product formed in this way is filtered and extracted from ethanol and Recrystallized water, with 48.5 g of 2-carbethoxymethylthio-3-nitropyridine (F. 56-57 ° C).

The new intermediate is in 300 ml of 2-methoxyalhanol dissolved and placed in a Parr shaker in the presence of Raney nickel under a Hydrogen pressure of 2 to 3 atmospheres hydrogenated. After absorption of 3 moles of hydrogen will the catalyst was removed by filtration and the resulting filtrate was concentrated. It will get an oil. This oil is dissolved in 500 ml of xylene and the solution is refluxed for 12 hours and then concentrate to give a dark residue. The recrystallization the residue from methanol gives 17.4 g of 2,3 - dihydro - 1 H - pyrido [2,3 - b] [1,4] - thiazinon- (2) (F. 209-21 TC).

In the procedure described above, the ethyl mercaptoacetate is replaced by thioacetic acid replaced, then essentially the same result is obtained. The corresponding 2-carboxymethylthio derivative melts at 133-134 ° C

Method B.

A solution of 24 g of ethyl mercaptoacetate in 50 ml of 2-methoxyethanol is used for a period of time of 20 minutes of a solution of 11.2 g of potassium hydroxide pellets in 100 ml of water in an ice bath admitted. After the addition is complete, the mixture is left at room temperature for 15 minutes stirred, whereupon a solution of 25.6 g of 3-amino-l-chloropyridine in 300ml of 2-methoxyethanol is added in a single serving. The mixture is refluxed for 16 hours and then concentrated in vacuo to give a solid residue. The solid residue is another hour in an oil bath at 150 "C heated, whereupon the product obtained is triturated with 100 ml of water. The solid will then through Filtration isolated and recrystallized from methanol. 17.5 g of 2,3-dihydro-l H-pyrido [2,3-b] - [1,4] -thiazinon- (2) on. This substance shows no melting point depression in combination with the compound of method A.

The 3-amino-2-chloropyridine used above is made from 3-nitro-2-chloropyridine by hydrogenation in the presence of catalytic amounts of Raney nickel or by chlorination of 3-aminopyridine manufactured.

Example 2

A suspension of 5.7 g of lithium aluminum hydride in 800 ml of dry ether is placed in an ice bath Cooled 0-5 ° C, whereupon 16.6 g of 2,3 - dihydro-1 H - pyrido [2,3 - b] [1,4] - thiazinon - (2) in small Portions are added over a 30 minute period. After the addition is complete the mixture was refluxed for 48 hours and then cooled in an ice bath. the The hydride complex and the excess hydride are then removed by careful addition of 3.6 ml of water ser and subsequent addition of 3.6 ml of a

55

60

[1,4] -thiazinone- (2) (m.p. 186-187 C
Example 7

15% strength aqueous sodium hydroxide solution decomposes. Another portion of 10.8 ml of water is added, whereupon the new mixture is stirred for 3 hours at room temperature. The unusual one Salt is removed by filtration, followed by a few portions of warm methylene chloride on the filter cake is washed. The one with the washing liquid

The combined filtrate is evaporated, whereby (F. 175-176 "C).

white crude 2,3-dihydro-l H-pyrido [2,3-b] [1,4] -thi-

azine, which after recrystallization from ethyl

acetate and pentane 9.3 g of the pure compound

(F. 127-128 "C) results. The corresponding hydro-

chloride salt melts at 135-137 C.

Example 3 '5

In compliance with that in Example 1, Method A, procedure described, except that 3-methylamino-2-chloropyridine is used as starting material, one obtains 2,3-dihydro-I-methyl-ze lH-pyrido [2,3-b] [1,4] -thiazinone- (2) (m.p. 91-93 "C).

Example 4

If the 25 g procedure described in Example 2 is adhered to using the 150-152 ° C. in Example 3. The compound described is obtained 2,3-dihydro-1-methyl-1 H-pyrido [2,3-b] [1,4] thiazine.

The free base is dissolved in ether, whereupon a compliance

alcoholic solution of sulfuric acid to precipitate the sulfate salt of the base. The

Sulphate melts at 139-142 ° C and has the

empirical formula C ₈ H ₁₂ N ₂ O ₄ S ₂ . [1,4] thiazino

V t

B e i s ρ i e I 5

1, method B.

Example 6

α r described in Example 1

If the J Be J ^,

Working method, wöbe, jedot, _{nd is}

one obtains 2,3-1

\ m Reisrjiel 5 u bSriebencn method described hyd o-3-methyl-l H-pyrido [2,3-b] - ^η ^ _{bi dung w} j _r d in ether dissolved. hydrogen solution for

Example 8
Here in the presence

described _{by 3} -Prop-

Claims (6)

Patent claims: 1. 2,3-Dihydro-1 H-pyrido [2,3-b] [1,4] -thiazines of the general formula (D IO where Z is a methylene or carbonyl group, R and R _{1 are} hydrogen atoms or methyl groups and R _{2 is} a hydrogen atom or a methyl or propargyl group, and the salts of these compounds with acids. 2. 2,3 - Dihydro - 1 H - pyrido [2,3 - b] [1,4] - thiazinone- (2). 3. 2,3-Dihydro-1 H -pyrido [2,3-b] [1,4] -thiazine. 4. 2,3 - Dihydro - 3 - methyl -1 H - pyrido [2,3 - b] - [1,4] -thiazinone- (2). 5. 2,3-Dihydro-1-propargyl-1H-pyrido [2,3-b] - [1,4] -thiazinone- (2). 6. A method for the preparation of compounds according to claim 1, characterized in that one is a compound of the general formula