DE2505415C3 - Phosphinylanthranilic acid or aminonicotinic acid derivatives, processes for their production and preparations containing them - Google Patents

Description

Some aminocarboxylic acid esters, such as the water-insoluble 2,3-dihydroxypropyl-N- (7-chloro-4-quinolyl) -anthranilate and the 2,3-dihydroxypropyl-N- (7- or 8-trifluoromethyl-4-quinolyl) anthranilate are used as analgesic agents in pharmaceutical preparations has been used, difficulties in application arose due to poor solubility (FR-PS 14 21 229 and CH-PS 5 02 340).

The subject matter of the invention is defined in more detail in the claims

The anthranilic acid or 2-amino-nicotinic acid derivatives according to the invention are notable for their favorable properties therapeutic properties. They show analgesic, anti-inflammatory and anti-rheumatic effects without undesirable side effects. They also have favorable water solubility; they are therefore superior to comparable products.

The implementation according to embodiment b) of the claimed process is particularly smooth. the Implementation c) will generally be preferred if you are relatively good at organic Solvent-soluble esters as starting material produce phosphinyl derivatives of a carboxylic acid (H) which is less readily soluble in organic solvents want.

In general, one takes the reactions a) to d) at a temperature of up to 200, preferably from 20 to 180 ° C. You can also in the presence of an inert gas under the reaction conditions, for. B. Nitrogen, work.

The reaction a) expediently takes place in the presence of agents which promote the elimination of water, for example acidic catalysts such as hydrochloric acid, hydrobromic acid, sulfuric acid, toluenesulfonic acid or cation exchangers in the hydrogen form, with the water formed during the esterification optionally being distilled with an entrainer, for example benzene or Toluene, is removed as an azcotropic mixture. However , it is also possible to work without a catalyst.

The splitting off of water according to embodiment a) can also be carried out with I lilfc of carbodiimides ^ for example dicyclohexylcarbodiimide I -dycloxyl-3- (2-niorpholinomethyl) -carbodiimide, 1- (3-dimethylammopropyl) -3-ethyl-carbodiimide hydrochloride, di -p-tolyl-carbodiimide or diisopropylcarbodiimide as well as with the help of Ν, Ν'-carbonyldiitnidazole.

The reaction a) can be carried out, for example, with the aid of dicyclothoxylcarbodiimide in a carboxylic acids: alcohols ratio of about 1: 1 to 1.5: 1 in an inert solvent. The temperatures can be varied depending on the selected solvent or catalyst. For example, in the presence of the diimulus mentioned in ren / ol or toluene, it is particularly advantageous to work at temperatures between 70 and 110 "C, while the I ι; ι <,; · ι / ιιιΐ" ι ·! Ϊ́ in the presence of carbonyldiimidazole are usually advantageously carried out even at low temperatures between 20 ° and 60 ⁰ C.

Suitable phosphinyl alcohols are those in the S main chain between the alcoholic OH group

andthephosphinyl group have 1 to 4 carbon atoms:

O CFi ₃

II /

HO-A-P

CH ₃

(HD

Suitable reactive carboxylic acid derivatives of the form in Ha to lic are e.g. B. the anhydrides, I lalogenidc and lower alkyl esters with 1 to 6, preferably 1 to 3

C atoms in the alkyl radical. Also the implementation of acid derivatives will

expediently carried out in the presence of catalysts or auxiliaries. So when implementing

Carboxylic acid halides advantageously in the presence

an alkali carbonate or a tertiary amine, e.g. B.

Pyridine or picoline, usually in an inert one

Solvent, such as benzene or toluene, at a temperature of 15 to 90 ⁰ C, preferably at 20 to

40 ° C, worked. Assuming acid anhydrides, so can

for example also cyclic anhydrides of the formulas

(Via)

(VIb)

(VIc)

can be used. The desired INier is formed advantageous in the presence of catalytic amounts of an alkali hydroxide, such as sodium or potassium hydroxide, with the release of carbon dioxide in the event of Teinperaliiren around 65 to 100 "C.

The alkyl group of those used as starting materials Carboxylic acid esters according to formulas

(VlIa)

C-O-alkyl O

(VIIb)

C — O — alkyl -

expediently has a maximum of 3 carbon atoms, so that the alcohols released from z. B. by acids or bases, such as mineral acids, ion exchangers, sodium or potassium metal, sodium hydride or sodium amide catalyzed transesterification easily from the reaction mixture can be removed.

For example, alkali, alkaline earth or tertiary ammonium salts are suitable for reaction b). When tertiary amines for the ammonium salts are z. B. ethyl bis (isopropyi) amine, ethyl bis (cyclohexyl) amine, Tris- [2-hydroxypropyl- (l) -] - amine and 1,8-bis- (dimethylamino) -naphthalene called. The required halogen Nide correspond to the alcohols for reaction a), where in place of the terminal hydroxyl groups each 1 halogen atom, such as chlorine or bromine, is arranged.

Reaction c) proceeds in such a way that the N atom is linked directly to the quinolyl radical. For this too Reaction is the presence of a catalyst, e.g. B. a mineral acid, appropriate.

When implementing d), the z. B. takes place in the range from 40 to 180 ⁰ C, the addition of the dimethylphosphinyloxyds on the double bonds in the presence of radical formers and / or take place under UV light. Suitable radical formers are, for. B. «/ x azo-bis-isobutyronitrile, azo-bis-isobutanol diacetate, phenylazotriphenylmethyl, tetraphenyl succinic acid dinitrile and di-tert-butyl-pcroxyd (cf. DT-OS 19 12 708).

Suitable alkenyl esters are, for example, the compounds of the form!

HN

C-O- (CH ₂ ), -CH = CH ₂

I η = 0-2

^υ (VIII)

especially an allyl ester.

Most of the compounds obtained in crystalline form are well tolerated and so stable that the manufacture of pharmaceutical preparations is possible.

The pharmaceutical processing of the invention Anthranilic acid derivatives for the customary use forms such as solutions, suspensions, powders. Tablets, coated tablets, suppositories, granules or Dcpotiormcn takes place in the usual way with the help of the usual aids for this. 10

Bet games

Anthranilic acid 1 a) 6.1 g (0.02 mole) of the sodium salt of N- (3-TnRuormethylphenyl) and 3.2 g (0.025 mol) Chlormethyldimcthyl-phosphine oxide with stirring at 150 ⁰ C in 100 ml of dimethylformamide - advantageously under a nitrogen atmosphere - implemented. After the sodium chloride and solvent have been separated off, the ester is taken up in methanol. A small amount of contamination can be column chromatographically or by recrystallization, e.g. B. from ether, separate. (VlIc) One uses for thin layer chromatography

Silica gel F254 prefabricated sheets from Finna Merck. Eluent: chloroform-methanol-30% aqueous ammonia caustic solution (volume ratio 85: 14: 1). Detection: UV light.

6.8 g (92% of theory) of N- (3-trifluoromethylphenyl) anthranilic acid dimethylphosphinyl methyl ester are obtained. Melting point: 85 ° C; R ₁ value: 035.

Ib) The same compound is obtained in the reaction of N '- {3-trifluoromethylphenyl) -anthranilic acid with Hydroxymethyldimethylphosphinoxyd at 110 ⁰ C, with toluene as entraining center! serve as a catalyst to remove the water of reaction and gaseous hydrogen chloride.

Ic) The analogously obtained N- {2,3-dimethylphenyl) anihranilic acid dimethylphosphine) 1-methyl ester melts at 177 ° C. its R, value is 0.80.

Id) to If) obtained Analog N- (23-DtmethyI-phenyl) -anthranilic acid-dimethylphosphinyl-propyl ester and N- (3-trifluoromethylphenyl) -anthranilic acid-dimethylphosphinyl-propyl or melt at i31 ° C 102 ⁰ N-ie -TrifluoromethyM-quinolylJ-anthranilic acid-3- (dimethyl-phosphinyl) -propyl ester melts at 122 ° C

2a) A mixture of 7.1 g (0.02 mol) of N- (8-trifluoromethyl-4-quinolyl) -anthranilic acid, sodium salt, 33 g, is heated under inert gas (nitrogen) while stirring (0.03 mol) chloromethyl-dimethyl-phosphine oxide and 100 ml of dimethylformamide at 120 ° C. for 15 hours is separated from crystalline sodium chloride and the N-te-trifluoromethyM-quinolylJ-anthranilic acid-dimethylphosphinyl-methyl-ester after concentration of the Reaction solution isolated. The crystals obtained can be stirred up in ether. Melting point: 176 ° C. Yield: 8.0 g (95% of theory).

2b) to 2e) The esters N (7-chloro-4-quinolyl) anthranic acid 3- (diinethylphosphinyl) propylsler (melting point 165 "C),

N- (7-chloro-4-quinolyl) -anthr3niisäure- (dimethylphosphiny l) -methylester (melting point 164 ° C), 2- {3-Trifluoromethylanilino) -nicolinic acid- (dimethylphosb.s phinyl) -methylcstcr (melting point 124 ° C) and

2- (3-Trifluoromethylanilino) -ninic acid-3- (dimethylphosphinyl-propylic acid (melting point 165 ° C) get.

3) 4.6 g (0.02 mole) of anth-tunilic acid c-dimethylphosphinyl-nicthylic acid and 4.6 g (0.02 mole) of 4-chloro-8-irifluoromethylquinoline will be in 15 m! Isopropanol in the presence held by 2.3 ml of concentrated aqueous hydrochloric acid for about 3 1/2 hours at 80 "C. After removal of Solvent and excess hydrochloric acid, the base of the Elster is released at 0 ° C. The received

N-iS-trifluoroniethyl-quinolyl-anthranilic acid diniethylphosphinyl methyl ester is identical to the preparation obtained according to example 2a)
Yield 7.6 g (90% of theory).

4) A mixture of 3.37 g (0.01 mol) of 7-chloro-4-quinolyl-anthranilsäureallylcster (melting point 112 ° C) "dissolved in 60 ml of toluene and 1.17 g (0,015MoI) Dimethylphosphinoxyd is heated to 100 ⁰ C. Then 30 mg of Λ, Λ'-azo-bis-isobutyronitrile in 10 ml of toluene are slowly added dropwise in order to catalyze the addition of the dimethylphosphine oxide to the allyl double bond. The N- (7-chloro-4-quinolyl ) -anthranilic acid c-3-dimethylphos
Isolate phynyl propyl ester, which after recrystallization from acetone melts at 162 ° C:
Yield: 3.58 g (86% of theory).

5) The N- (3-trifluoromethylphenyl) anthrunilic acid-diniethylphosplimyl-pm obtainable according to Example Ic) pylester is also formed if 5.9 g (0.02 mol)

ίο N- (3-trifluoromethylphenyl) -anthranilic acid-nicthylestcr transesterified with an equivalent amount of 3-dimethylphosphinylpropanol boiling point 157 ° C at 0.3 Torr in the presence of 400 mg of a cation exchanger containing sulfonic acid groups in the hydrogen form under reduced pressure at 6O ⁰ C. The product obtained has a melting point of 102 ^° C.

Claims (3)

Patent claims: 1. Phosphinylanthranilic acid or aminonicotinic acid derivatives of formulas (Ia) to (Ic) 5 O CH ₃ II / COO -A-P (Ia) α \ ίο CH ₃ NH R ¹ O CH ₃ II / COO -A -P (Ic) CH, NH 3 ° 35 where 40 R ^{1 is} chlorine, trifluoromethyl, 1 or 2 methyl groups and A is an alkylene group with 1 to 5 carbon atoms, of which 1 to 4 carbon atoms are between the alcoholic OH group and the phosphinyl group, 45 mean.
2. Process for making the compounds according to claim 1, characterized in that one in a manner known per se
a) Carboxylic acids of formula 50 COOH NH (Ha) X ₊ / R ¹ COOH NM 55 6o (Hb) 2
COOH (Mc) R ¹ or one of their reactive derivatives with phosphinyl alcohols of the formula O CH ₃ II / HO-A-P X
CH ₃ (III) or b) Salts of the carboxylic acids of the formulas (Ha) to (lic) with phosphinyl alkyl chlorides of the formula O CH ₃ II / Cl-A-P CH ₃ (IV) or
c) esters of the formula COO-A-PO (CH ₃ ) ₂ NH ₂ (V) with the corresponding 4-chloroquinolines or d) esters of the formula R 'H (IXa) (IXb) II " R ¹ H ■■ - <> (IXc) COR ² Il ο where R ^! ΛI k l- 11 ν I with 2 to 5 C atoms means with dimethylphosphine oxide of the formula HPO (CHj) ₂ (X) implements 3. Pharmaceutical preparation, characterized in that it contains a compound of the formula (I) in addition to a conventional carrier or additive.