KR800001678B1 - Process for the preparation of benzylaminesl - Google Patents

Abstract

Benzylamines(I, R1 = H; R2 = H, Cl or Br; R3 = F, methyl, C2-4 straight of branched alkyl, trifluoromethyl, l-hydroxy ethyl, alkoxy or aminomethyl; R4, R5 = C1-5 straight or branched alkyl, C2-4 alkenyl, C5-7 cycloalkyl), useful as antitussives, as tested on guinea pigs, were prepd. by reduction of compd. (II). LD50 data and pharmaceutical formulations were given.

Description

Method for preparing benzylamine

The present invention relates to a process for preparing benzylamine of the following formula (I).

In the common sense,

R ₁ is a hydrogen atom,

R ₂ is hydrogen, chlorine or bromine atom,

R ₃ is a fluorine atom: methyl group (located at the 3-, 4- or 5-position,

의 아미노메틸기(여기서 R₆와 R₇은 동일하거나 상이한 것으로서 각각 알킬, 사이클로알킬 또는 하이드록시 사이클로알킬기를 나타내거나, 질소원자와 함게 피롤리딘, 또는 모르폴린환을 나타낸다)이며,When R ₂ is a chlorine or bromine atom, it may be in the 2- or 6-position): C ₂ ~ C ₄ straight or branched alkyl group: trifluoromethyl group or 1-hydroxyethyl group: alkoxy group In the 3-, 4- or 5-position, where R ₂ is a chlorine or bromine atom, or in the 2- or 6-position):

Wherein the aminomethyl group of R ₆ and R ₇ is the same or different and represents an alkyl, cycloalkyl or hydroxy cycloalkyl group, or a pyrrolidine or morpholine ring together with a nitrogen atom,

R ₄ and R ₅ are the same or different and are a hydrogen atom, a C ₁ -C ₅ straight or branched alkyl group, which may be substituted with one or two hydroxy groups, an alkenyl group of C ₂ -C ₄ , one or two A pyrrolidine, ciperidine, hexamethyleneamine, morpholine, N-methyl-piperazine or campydine ring together with a C ₅ -C ₇ cycloalkyl group, benzyl or nitrogen atom optionally substituted with a hydroxy group.

Compounds of formula (I) have valuable pharmacological properties and, in particular, have anti-ulcer activity, secretory and antitussive effects, and irritant effects on the production of surfactant or dilated insufficiency factors of the alveoli.

The novel compounds of the present invention are prepared by reducing the compound of formula II.

In the common sense,

R ₂ , R ₃ , R ₄ and R ₅ are as described above.

The reduction reaction is carried out in the presence of a solvent by generator hydrogen, for example sodium in ethanol, catalytically activated hydrogen or metal complex hydride, for example sodium borohydride in pyridine or advantageously in ether or tetrahydrofuran With lithium aluminum hydride, it is convenient to carry out at a slightly higher temperature, for example 30-70 ° C. or at the boiling point of the solvent used.

By the above method, when R ₁ is a hydrogen atom and R ₂ , R ₃ , R ₄ and R ₅ are the same as those described above except for the group containing a reactive hydrogen atom, the compound of formula (I) is obtained. Acylation is then carried out as necessary. This reaction is conveniently carried out by reactive acid derivatives such as acid halides, acid anhydrides or mixed acid anhydrides in the presence of dehydrating agents such as NN'-dicyclohexylcarbodiimide.

The compound of formula (I) obtained is converted into its acid addition salt with its physiologically mild inorganic or organic acid using 1,2 or 3 equivalents of the corresponding acid as required. As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, maleic acid tartaric acid or fumaric acid are suitable.

The compounds of the formula (II) used as starting materials are prepared by known methods, for example by reacting the corresponding isatosan anhydride with the corresponding amine.

As mentioned above, the novel compounds of formula (I) have valuable pharmacological properties and, more specifically, have anti-ulcer activity, secretory and antitussive effects, stimulating effects on the production of surfactant or dilated factors of alveoli. .

As examples, the following compounds were investigated for their physiological action.

A = N-ethyl-2-amino-5-bromo-N-cyclohexyl-3-chloro-benzylamine-hydrochloride,

B = N- (2-amino-5-bromo-3-methyl-benzyl) -hexamethyleneamine-dihydrochloride,

C = N- (2-amino-5-bromo-4-tert-butylbenzyl) -morpholine-dihydrochloride,

D = 2-amino-3-bromo-N, N-dimethyl-5-fluoro-benzylamine-hydrochloride,

1. Secretion effect

Anesthetic tests were performed on anesthetized mormot or anesthetized rabbit.

Six to eight animals were orally administered 8 mg / kg each. It was calculated by comparing the increase in secretion within 2 hours after administration of the test substance.

The circulatory effect was measured by intravenously administering the test substances 2,4 and 8 mg / kg to three rats anesthetized with chloralose-urethane.

Test for Mormot:

Test for the rabbit:

2. Antiulcer activity

The action of the test substance on ulceration was determined by the method of Takagi et al. (Jap. J. Pharmac. 19,418 (1969)). The embryos of female rats weighing 220-250 g, anesthetized with eterl, split off and protruded over the stomach. Next, 0.05 ml of 5% acetic acid solution was injected between the gastric mucosa and the submucosal tissue. Two times after the injections were recommended again. After 3-5 days, the ulcers formed on the mucosa were treated for 3 weeks by administering 50 and 100 mg / kg of test substance (6 mice / dose) mixed with food. Control rats were fed only ground food.

After treatment for 3 weeks, rats were killed and stomachs were taken to measure the length and width of the ulcers. The activity of the test substance was compared with the control value (100%). Intensive administration of Test Substance A at a dose of 5 mg / kg resulted in a 52% reduction in ulcers compared to the control, and 79% reduction in ulcers at a dose of 100 mg / kg.

3. Acute Benefit

Five rats were orally administered 1000 or 2000 mg / kg (one time) of test substance, respectively, to determine the acute toxicity of the test substance.

The novel compounds of formula (I) may be combined with other active ingredients, optionally in combination with other active ingredients, in conventional dosage forms such as tablets, coated tablets, capsules, suppositories, ampoules and solutions in a single dosage of 1-100 mg. Is 4-60 mg, and the daily dose is 2-300 mg, preferably 4-2000 mg. In the case of a compound having a secretory activity, the dosage is 1-20 mg, preferably 4-15 mg, and in the case of a compound having antiulcer activity, 25-100 mg, preferably 30 60 mg.

The following examples are intended to illustrate the present invention.

Example 1

2-Amino-3-chloro-N-cyclohexyl-5-fluoro-N-methyl-benzylamine

A solution containing 9.1 g of 2-amino-3-chloro-N-cyclohexyl-5-chloro-N-methyl-benzamide dissolved in 300 ml of anhydrous ether was stirred while stirring a suspension of 3.8 g of lithium aluminum hydride suspended in 200 ml of anhydrous ether. I dropped it. This was then heated to reflux for 1 hour and then cooled in an ice bath. Excess lithium hydride aluminum was carefully decomposed as water under nitrogen as a protective gas. The organic solution was decanted from the precipitate and dried over sodium sulfate. Acidified with etheric hydrochloric acid, 2-amino-3-chloro-N-cyclohexyl-5-chloro-N-methyl-benzylamine precipitated as hydrochloride. This was recrystallized from ethanol anhydride.

Melting Point: 190-192 ℃

Example 2

N- (2-Amino-5-fluoro-benzyl) -hexamethyleneamine

Boiling Point: 96-100 ℃

Prepared according to a method similar to Example 1 from 2-amino-5-fluoro-N-hexamethyleneamino-benzamido and lithium aluminum hydride.

Claims (1)

A method for producing benzylamine of formula (I) by reducing the compound of formula (II) as described above in the text.

R ₁ is a hydrogen atom, R ₂ is hydrogen, chlorine or bromine atom, R ₃ is a fluorine atom: a methyl group (located at the 3-4- or 5-position, When R ₂ is chlorine or bromine atom, it may be located in 2- or 6-position): C ₂ ~ C ₄ straight or branched alkyl group: trifluoromethyl group or 1-hydroxyethyl group: alkoxy group (phenyl nucleus Is located at the 3-, 4- or 5- position of and may be at the 2- or 6-position when R ₂ is chlorine or bromine)

Amino methyl group wherein R ₆ and R ₇ are the same or different and represent an alkyl, cycloalkyl or hydroxycycloalkyl group or a pyrrolidine, piperidine or morpholine ring together with a nitrogen atom, R ₄ and R ₅ are the same or different and are hydrogen atom, C ₁ -C ₅ straight or branched alkyl group, which may be substituted with one or two hydroxy groups, C ₂ ~ C ₄ alkenyl group, one or two hydride A pyrrolidin, piperidine, hexamethyleneamine, morpholine, N-methyl-piperazine or campidine ring together with a C ₅ to C ₇ cycloalkyl group, benzyl, or nitrogen atom optionally substituted with an oxy group.