DE1768787C3 - (o-Carboxy-phenyl) -acetamidine, process for their preparation and (o-CarboxyphenyO-acetamidine-containing preparations - Google Patents

Description

Ν 'CH ₃ R ²

in which R ^{1 is} hydrogen or a methyl group, R ^{2 is} hydrogen, a straight-chain or branched alkyl group with 1 to 4 carbon atoms, optionally substituted by a phenyl or methoxyphenyl group, or one, optionally with one or more halogen atoms and straight-chain or branched alkyl groups or alkylaminoalkyl groups I to 5 carbon atoms substituted phenyl and R ^{3 is} hydrogen or a nitro group.

2. N'-Phenyl-N ² - (o-carboxy-phenyl) -acetamidine.

3. N ¹ - [p - (2-methylamino-propyl) -phenyl] -N ² - (o-carboxy-phenyl) -acetamidine.

4. N ¹ - (phenyl - isopropyl) - N ¹ - methyl - N ² - (o-carboxy-phenyl) -acetamidine.

5. Process for the preparation of (o-carboxyphenyl) acetamidines of the general formula ... in the presence of an inert solvent or a Anthranilic acid derivative (IV) with imidic acid derivatives (V) of the following general formula

COOH

and

XC = NR ²

CH ₃

(IV)

wherein X is halogen, the alkoxy-. Aryloxy-. Acyloxy group means, implements.

"6 pharmaceutical preparations, characterized in that that they are an (o-CarboxyphenyO-acetamidine according to claim I. 7 Pharmaceutical preparations according to claim 6, characterized in that they are an active ingredient of the following compounds:

N'-phenyl-NMo-carboxy-phenyll-acctami-

din,
N ¹ [p- (2-methylamino-propyl) -phenyl] -N--

(o-carboxy-phenyl) -acetamidine. N ¹ - (phenyl - isopropyl) - N ¹ - methyl - N ² -

(o -carboxy-phenyl) -acetamidine.

COOH

R ¹

35 (I) The invention relates to new (o-carboxy-phenyl) -acetamidines of the general formula

40

in which R ^{1 is} hydrogen or a methyl group, R ^{2 is} hydrogen, a straight-chain or branched alkyl group with 1 to 4 carbon atoms, optionally substituted by a phenyl or methoxyphenyl group, or one, optionally with one or more halogen atoms and straight-chain or branched alkyl groups or alkylaminoalkyl groups 1 to 5 carbon atoms substituted phenyl radical and R ³ denotes hydrogen or a nitro group, characterized in that either a 3,1-benzoxazin-4-one (II) with an amine (III) of the following general formulas

-CH ₃

(II)

HN

R ¹

R ²

(HD

55

60

65 COOH

R ¹

C-N

H CH ₃ R ²

in the range from room temperature to 60 ° C. in Gein where R ^{1 is} hydrogen or a methyl group, R ^: hydrogen, a straight-chain which is optionally substituted by a phenyl or methoxyphenyl group! or branched alkyl group with 1 to 4 carbon atoms or one, optionally by one or more halogen atoms and straight or branched! Alkyl groups or alkylaminoalkyl groups with I bi: 5 carbon atoms substituted phenyl radical unc R ^{3 is} hydrogen or a nitro group.

The (o-carboxy-phenyO-acetamidines of the formula have valuable pharmaceutical, especially psy choslimulating, anorcxigenic and spasmolytic Properties.

The following derivatives are particularly valuable compounds of the formula:

N'-phenyl-N ² - (o-cart) oxy-phenyl) -acctamidine. N ¹ - [p- (2-methylaminopropyl) phenyl] - N ²

(o-carboxy-phenylj-acetamidine, N '- (phenyl-isopropyl) -N'-methyl-N ² - (o-carb oxy-phynyl) -acetamidine.

The invention also relates to a method / ur Preparation of (o-carboxy-phenyl) -acetamidines of the general formula

COOH

(D

in which R ^{1 is} hydrogen or a methyl group. R ^{2 is} hydrogen, a straight-chain or branched alkyl group with 1 to 4 carbon atoms, optionally substituted by a phenyl or methoxyphynyl group, or a phenyl radical optionally substituted by one or more halogen atoms and straight-chain or branched alkyl groups or alkylaminoalkyl groups with 1 to 5 carbon atoms, and R ³ Means hydrogen or a nitro group, which is characterized in that either a 3,1-benzoxazin-4-one! Ll) is used with an amine (HI) of the following general formulas

(H)

R ¹

HN

(IH)

in the range from room temperature to 60 C in the presence of inert solvents or an anthranilic acid derivative (IV) with imidic acid derivatives (V) represented by the following general formulas

³ 4 Il

COOH

NH,

XC = NR ²
CH ₃

(IV)

(V)

wherein X is halogen, the alkoxy, aryloxy, acyloxy group, converts.

According to one embodiment of the process of the invention there is a 3,1-benzoxazinone-4 of the formula II, e.g. B. 2-methyl-3, l-benzoxazinone-4 with amines of the general formula III in the presence of an inert one Solvent implemented. Aliphatic or aromatic hydrocarbons, such as benzene, toluene, hexane, gasoline; Alcohols. Ethers, esters or ketones can be used. The implementation can be carried out at room temperature. For connections with less reactivity, can the reaction can be accelerated by heating up to 60 C. The (o-carboxy-phenyl) -amidines obtained of the formula I often crystallize out of the reaction mixture and can be filtered off isolate. In other cases they can be isolated by distilling off the solvent. One can but also proceed in such a way that they are first extracted from the reaction mixture with an alkali and then precipitates from the alkaline solution by adjusting the pH. Should be the final product contain a free amino group, it can be extracted from the reaction mixture with an acid. In most cases, the end products obtained in this way have a sufficient degree of purity; she however, they can be further purified by recrystallization or other methods if necessary.

According to another embodiment of the method according to the invention, anthranilic acid derivatives of the formula IV with imidic acid derivatives of the formula V reacted. The reaction will be beneficial in one inert solvent, but can also be carried out in the absence of a solvent. Examples for solvents are: aliphatic or aromatic hydrocarbons, halogenated hydrocarbon derivatives, Alcohols, ethers, esters, etc.

You can also proceed in such a way that the aqueous alkaline solution of the anthranilic acid derivative of Formula IV with the imidic acid derivatives of the formula V is reacted. The o-carboxy-phenyl-amidines obtained are isolated by filtration, concentration of the reaction mixture or alkaline or acidic extraction.

The structure of (o-carboxy-phcnyl) -amidine was proven by its production method and by the IR spectrum. In the IR spectrum, the characteristic carbonyl band of the carboxylate anion appears in the range of 1575 cm ^ ¹ . At the height of 2600 to 2700 cm 'one finds the characteristic bands of the ammonium ions, which indicate that the compounds are in the zwitterion form of the formula

N CHj R ²
are present.

The structure of the compounds of the invention is also confirmed by the fact that they diluted in.

dissolve in aqueous bases. This speaks for the presence of the carboxyl group.

From Beilstein, Hauptwerk, Vol. 27, p. 207. Paragraph 1, it is known by the action of amines Benzoxazinone Chinazolone Manufacture. Compared to this previously known effect of aniline on Benzoxazin-inone differs from the reaction of 1,3-benzoxazin-4-one with an amine according to the Erlindun « in that they under milder reaction conditions than in the previously known process, namely is preferably carried out at room temperature and in dilute solution.

The (o-carboxy-phcnyl) -acctamidine derivatives obtained according to the invention formula 1 can then under more energetic or milder process conditions, depending on the structure of the reacting amines into the 4-oxo-3,4-dihydrodiinazoline rivals of the cited references.

The invention also relates to the pharmaceuticals characterized in claims 6 and 7 Preparations.

The compounds of the formula I have valuable pharmaceutical properties. The N'-fo-carboxyphynyl) -N ² -pheny! -Acctamidine-Dcriva: c exert a strong spasmolytic effect. It is known that the most effective antispasmodics, such as phenylethylbarbituric acid or diphenylhydanloin, have an important hypnotic effect in addition to the spasmolytic effect. The hypnotic effect of the compounds of the invention of the formula I, on the other hand, is many times less than that of the previously known products, while their spasmolytic effect is of the same order of magnitude. As a result, the o-carboxyphenylamidines of the formula / are excellent for the treatment of epilepsy.

Another group of the (o-carboxy-phenyl) -acetamidines of the formula I, in which R- ^{1 is} a 2-aminopropyl-phenyl or phenyl-isopropyl group, has important psychostimulic and anorexigenic properties. An advantage of these compounds over the previously known derivatives with anorxigenic properties is that the compounds of the invention have no acute stimulating effect and hardly increase the motility of the test animals, while the previously known anorexigenic agents have a significant motility-increasing effect. The compounds of the formula I can be used in pharmacy in the form of pharmaceutical preparations which, in addition to the active ingredient, are inert, solid or liquid carriers. z. B. starch, magnesium stearate, talc, stearin. Contain water, polyalkylene glycols, magnesium carbonate, etc. The pharmaceutical preparations can optionally contain other auxiliaries, e.g. B. emulsifiers, wetting agents, etc. and, if desired, contain other therapeutically active compounds.

Further details of the process can be found in the examples.

Example I.

4.83 g of 2-methyl-3, l-benzoxazin-4-one are dissolved in 10 ecm of anhydrous ethanol, then 2.8 g Aniline was added, after which the mixture was heated to 55 to 60 C and the Knstallabscheidung in a few minutes. After one hour the precipitated crystals are filtered off with ethanol washed and dried under reduced pressure to constant weight. Melting point: 121 up to 123 C.

Analysis for C ₁₅ H ₁₄ H ₂ O ₂ :

Calculated ... C 70.9, H 5.15, N 11.05%; "

found .... C 71.0, H 5.2, N 11.1%.

Yield: 84% of theory.

The following information is to be given regarding the pharmacological effect of the N'-phenyl-N ² - (o-rarboxy-phenyl) -acetamidine obtained: Inhibition of spasms produced by 1,5-pentamethylentelrazole in mice po ED ₅₀ = 65 mg / kg.

Antagonism of 1,5-pentamethylenetetrazole toxicity in mice po ED ₅₀ = 170 mg'kg.

Inhibition of electric shock spasms in mice po ED ₅₀ = 92 mg kg.

Inhibition of electric shock spasms in rough po ED ₅₀ = 136 mg kg.

Inhibition of Slrvehninspasmen in Mice p. O. 200 mg kg. "

Hmmuni! the nicotine toxicity in mice ρ ο. ED ,,, = 94 mg kg.

Anesthesia in mice po ED ₅ ,, = 244 mg kg.

Anesthesia in rats po ED ₅₀ = 250 mg kg.

Toxicity in mice DL ₅ ,, = 905 mu kg.

The spasmolylic effect of this compound is illustrated in the following table:

HD ₅₁₁ -WeH in mice
po

Verbin- Phenyl- Dipher.yl-

duny iithylhydantoin

after barbilur-

Example I acid

3KO

244

100

Opposite through
1,5-pentamethyl-octrazo! generated
Spasms

Hypnotic Act
(Quantities with which
an undesirable one
hypnotic side effect is achieved)

This table shows that although the spasmolylic effect of the compound of the invention is somewhat less, at the same time, however, its undesirable side effects, and indeed significantly, are lower.

Example 2

8 g of 2-methyl-3.1-benzoxazin-4-one are dissolved in 30 ecm of anhydrous benzene, then 7.06 g of 2-methyl-4-chloro-aniline are added to the solution, after which the mixture warms to 40 to 45.degree. After 15 minutes the precipitated crystals are filtered off, washed with benzene and dried under reduced pressure. The melting point of the N ¹ - (4 - chloro - 2 - methyl - phenyl) - N ² - (ο - carboxyphenyD-acetamidine) obtained in this way is 122 to 124 C.

Analysis for C ₁₆ H ₁₅ ClN ₂ O ₂ :

Calculated ... C 63.4. H 4.95. Cl 11.73. N 9.26%: found .... C 63.7. H 5.1, Cl 12.0. N 9.19%.

Yield: 57% of theory.

Example 3

The N ¹ - (5 - bromo - 2 - methyl - phenyl) - N ² - (ο - carboxy-phcnyl) -acclamidine is prepared in the manner described in Example 2. Melting point: 116 to 118 C. The product is soluble in 5% aqueous lye.

Analysis for C ₁₆ H ₁₅ BrN ₂ O ₂ :

Calculated ... C 55.8. H 4.32, Br 23.0, N 8.02%: found .... C 55.8, H 4.4. Br 23.1, N 8.2%.

Yield: 98% of theory.

Example 4

16.1 g of 2-methyl-3, l-benzoxazin-4-one are dissolved in 60 ecm of benzene, then 9.84 ecm of isobiitylamine added, the mixture heats up and the crystal separation begins. After half a sense

de the precipitated crystals are filtered off, washed with benzene and dried. The product is first dissolved in alcohol, then with lissigestcr added, the resulting mixture filtered clear and after cooling to -5 ^C C precipitated crystals were filtered off, using a 1: 3 mixture of ethanol washed and Essigester and dried under reduced pressure. The melting point of the N ¹ - isobutyl - N ² - (o - carboxy - phenyl) - acetamidine obtained in this way is 158 to 160 ° C. The white crystals can be dissolved in 5% strength aqueous alkali.

Analysis door C ₁₃ H ₁₂ N ₂ O ₂ :

Calculated ... C 66.9, H 7.7, N 11.95%:

found .... C 67.2, H 7.9, N 11.6%. ^

Yield: 50% of theory.

Example 5

1.61 g of 2-methyl-3, l-benzoxazin-4-one are reacted in 3 ecm of benzene with 0.83 ecm of n-propylamine. The product isolated in the manner described in Example 4 is dissolved in ethanol and precipitated with ether. The N ¹ -propyl-N ² thus obtained - (o-carboxyphenyl) acetamidine melts at 152 to 154 ^C and C is aqueous alkali soluble in 5%.

Analysis for C ₁₂ H ₁₆ N ₂ O ₂ :

Calculated ... C 65.5. H 7.28,
found .... C 65.5, H 7.5.

Yield: 52% of theory.

N 12.7%:
N 12.6%.

Example 6

2.06 g of 2-methyl-7-nitro-3, l-benzoxazin-4-one are dissolved in 20 ecm warm benzene, then the solution is cooled and 1 ecm aniline is added for precipitation. The initially resinous, but later crystallizing product is filtered off and washed well with benzene and ethanol. The N'-phenyl-N ² - (2 - carboxy - 5 - nitro - phenyl) - acetamidine obtained in this way melts at 194 to 196 ° C. and is soluble in 5% aqueous alkali.
Analysis for C ₁₅ Hi ₃ NjO ₄ :

Calculated .. C 60.1, H 4.38, N 14.0%;

found .... C 59.6. H 4.9. N 13.7%.

Yield: 70% of theory.

Example 7

2.06 g of 2 - methyl - 7 - nitro - 3,1 - benzoxazol - 4 - one are reacted with 0.73 g (1 ecm) of isobutylamine, as described in Example 6, and the precipitated crystalline product is nitrated and removed from ethanol recrystallized. The N ¹ -isobutyl-N ² - <2-carboxy-5-nitrophenyl) -acetamidine thus obtained melts at 160 to 161 ° C. and is soluble in 5% aqueous alkali.

Analysis for Ci ₃ H _n N ₃ O ₄ : Calculated ... C 56.1, H 6.1, N 15.1%; found .... C 55.7, H 6.3, N 15.2%.

Yield: 45% of theory.

The mixture was left to stand for 3 days, a resinous precipitate forming as the reaction progressed. The benzene solution is poured off, the resin is washed with benzene, then mixed with 40 ecm of ethanol, the crystalline product is filtered off, washed with ethanol and dried. The melting point of the N '- [p- (2-methyl-aminopropyl) -phenyl] -N ² - (o-carboxy-phenyl) -acetamidine obtained in this way is 169 to 172 ° C. After recrystallization

ίο 50% ethanol, the melting point remains unchanged. The product can be dissolved in 5% lye.

Analysis for C ₁₉ H ₂₃ N ₃ O ₂ :

Calculated ... C 70.3. H 7.08. N 12.9%;
found .... C 69.9. H 7.24. N 12.7%.

Yield: 50% of theory.

The product obtained in this way has the following pharmacological properties:

The psychostimulating effect of the product is enhanced by antagonizing the effect of 15mg / kg 1,2,3,4,6,7-hexahydro-3-isobutyl-9,10-dimethoxy-11bH-benzo- [a] -quinolizin-2-one on rats by means of of the modified jump test measured (Arch. Int.

Pharmacodyn 148, 200 [1964]). The product inhibits the depressive effects of 1,2,3,4,6,7-hexahydro-3-isobutyl-9,10-dimethoxy-l 1 bH-benzo- [a "] - quinolizin-2-one in a dose of 10 mg / kg by 60% and at a dose of 20 mg / kg by 100%.

The metabolism-increasing effect of the product is determined by measuring the oxygen consumption in rats. In a subcutaneous dose of 6.9 mg / kg the product increases the metabolism of the animals by 50%. The subcutaneous toxicity is 360 mg kg. The product does not affect the motility of the animals. The OL- / i-phenyl-isopropylamine exerts such an effect in a subcutaneous dose of 2 mg / kg, but the toxicity of this known compound is LD ₅₀ = 35 mg kg, and it increases in a dose of 5 mg / kg Motility of the animals by about 50%

When administered orally, the product increases permanently the metabolic level I ¹ I ₁ hours, however, takes the effect of the known DL - ^ - phenyl-isopropylamins already one hour after the application from. The product obtained thus has a greater range of activity than the known DL - /? - phenyl-isopropylamine (the toxicity is V, _o that of DL - /? - phenyl-isopropylamine). Other advantages of the product obtained domestic product are that it exerts a longer lasting effect and the undesirable primary motility-enhancing effect of DL - not having phenyl-isopropylamins - ^.

55

in

Example 8

9.55 g of 2-methyl-3.1-benzoxazm-4-one become Dissolved 35 ecm of benzene, then added 9.55 g of p-amino-phenylisopropyl-methylamine and the resulting

Example 9

90 g of 2-methyl-3, l-benzoxazin-4-one and 90 g of ρ - aminophenyl - isopropyl - methylamine are stirred in 900 ecm of benzene for 10 hours and the reaction mixture obtained is further worked up as indicated in Example 8. The resulting Ν * - [ρ- (2 - methylaminopropyl) - phenyl] - N ² - (ο - carboxyphenyiy-acetamidine melts at 169 to 172 ° C.

Yield: 50% of theory. 05

The properties of the crystalline product obtained agree with those of the compound prepared according to Example 8.

609618/92

Example 10

37.32 g of phenyl-isopropyl-triethylamine and 40.2 g of 2-methyl-3,1-benzoxazin-4-one are left to stand at 25 ° C. for 20 days, after which the reaction mixture is shaken thoroughly with 5% sodium hydroxide solution and the two phases separated. The pH of the aqueous alkaline layer is adjusted to 6.5 with acetic acid. The precipitated crystals are filtered off, washed with water and dried. After recrystallization from water, the N '- (phenylisopropyl) - N ¹ - methyl - N ² - 2 - (ο - carboxyphenyl) acetamidine melts at 74 to 75 ° C. According to the analysis, the product contains 5 mol of crystal water. It can be dissolved in 5% aqueous alkali.

Analysis for C _n H ₂₂ N ₃ O ₂ · 5H ₂ O:

Calculated ... C 56.0. H 7.78. N 7.25%:
found .... C, 55.7. H 8.02. N 7.4%.

Yield: 30% of theory.

20th

In a 100 mg / kg dose administered subcutaneously the product increases the metabolism in rats by 55%. Antagonized at a 100mg / kg subcutaneous dose the product the depressive effect of 15 mg / kg 1,2,3,4,6,7 - hexahydro - 3 - isobutyl - 9,10 - dimcthoxy -11 bH - benzo - [a] - quinolizin - 2 - one (tested according to the modified jump test. Arch. Int. Pharmacodyn. 148, 200 [1964 "J).

Example 11

28.6 g of (p-methoxy-phenyl-isopropyl) -methylamine are reacted with 25.8 g of 2-methyl-3,1-benzoxazin-4-one in 170 ecm of benzene in the manner described in Example 8, and the reaction mixture obtained is concentrated, the residue is mixed with 25 ecm of benzene and the precipitated crystals are filtered off, washed with benzene and dried. After recrystallization from anhydrous ethanol, the obtained N ¹ - (p - methoxyphenyl) - isopropyl - N ¹ - methyl - N ² - (o-carboxy-phenyl) -acetamidine at 147 to 148 C. The product is in 5% igcr aqueous alkali dissolvable.

Analysis for C ₂₀ H ₂₄ N ₂ O ₃ :

Calculated ... C 70.5. H 5.05. N 8.24%:
found .... C 70.8. H 7.00. N 8.4%.

Yield: 30% of theory.

Example 12

13.7 g of anthranilic acid are dissolved in 70 cc of anhydrous tetrahydrofuran, it g under stirring at 30 to 35 C 14.9 N-phenyl-acetimidsäuremethylester added, the reaction mixture was stirred for 5 hours at 30 to 35 ⁰ C, then filtering off the precipitated product, with Washed tetrahydrofuran and dried. The melting point of the N ¹ - phenyl - N ² - (ο - carboxy - phenyH-acetamidine) obtained in this way is 122 to 123 ° C.

Yield: 60% of theory.

Claims (1)

Patent claims: I. (o-Carboxy-phenyl) -acetamidine of the general formula COOH R ¹ C-N (D