KR840001070B1 - Process for the preparation of phenyl alkyl amine derivation - Google Patents

Abstract

The title compds. I≮n=1,2,3; R1=H, aliph. acyl,benzoyl, R3C6H4CO-; R2=H, C1-C4 aliph. alkyl, C2-C5 aliph. acyl, benzoyl, R4C6H4CO-; R3=H, Me; R4=H, Me≉and their pharmaceutically acceptable salts, which showed bronchodilating, α-spasmolytic, and uterus-relaxing activity in tests on animals, were prepd. Thus, 3.0g 1,1-dimethyl -3- (2-methoxyphenyl)propyl amine in 40mL EtOH was treated with 4.0g 4-benzyloxy- phenyloxalate and reduced to give 1-(4-hydroxyphenyl)-2-≮1,1-dimethyl-3-(2-meth- oxyphenyl)propylamino≉-ethanol.

Description

Process for preparing phenylalkylamine derivative

The present invention relates to a process for the preparation of compounds which are effective in treating the symptoms of the lungs in reversible atresia in various causes, in particular asthmatic conditions, but which exhibit reduced cardiac stimulation and reduced tremor.

Sympathetic excitatory amines are commonly used as bronchodilators to treat transpiration in the lungs of reversible atresia, such as asthma. However, sympathetic excitatory amines such as adrenaline and isoprenin have side effects that cause strong cardiac irritation. Continuously available bronchial anticonvulsants, such as turbutalin, act selectively on the bronchus, which means much less cardiac irritation, in addition to their bronchodilating effects. However, they still have side effects, such as occasional tremors, which can naturally cause major disabilities in patients. The forward effects of β-stimulants are described, for example, in Marsoln et al., Clinical Sciences 1967, 33 53-65 and Marsoln and Meadows, Physiology. Reviewed 1970,207 429-448.

As such, there is a need for an anticonvulsant of bronchus that exhibits a low cardio-stimulatory effect and a low tremor effect, and especially has significant bronchial dilatation effects in oral administration.

The present invention provides a method for preparing a new compound, which exhibits a low cardiac stimulatory effect and a low tremor effect and has a significant bronchial dilatation effect.

The compounds of the present invention also proved to have an α-receptor blocking effect. The invention can also be used as α-receptor blockers in mammals, including humans as well. Drugs that combine α-adrenoceptor blockers and β-adrenocepti stimulants are beneficial in treating specific diseases such as asthma. Agerbeck et al., Pharmacy Handbook (1979) 65. 155-159: Nussian et al., Pharmacy (1979) 15 1169-477.

Another property of the present invention is that the compound is also effective in relaxing the uterus of a human.

The present invention relates to novel compounds of formula (I) and to therapeutically suitable salts thereof.

In formula (I), n is 1,2 or 3: R ¹ is selected from the group constituting H, an aliphatic acyl group containing 2-5 carbon atoms and an unsubstituted or substituted of the following general formula: It is a benzoyl group.

(Wherein R ³ is hydrogen or methyl group) In formula (I), R ² is selected from the group constituting H, an aliphatic alkyl group containing 1-4 carbon atoms, containing 2-5 carbon atoms Aliphatic acyl group and unsubstituted or substituted benzoyl group of the following general formula.

R ⁴ in the general formula is selected from the groups constituting hydrogen and methyl. R ³ and R ⁴ groups may be located at any of positions 2, 3 and 4 on the phenyl ring. Illustrative groups of R ¹ and R ² are as follows.

Alkyl group (R ² only): -CH ₃ , -C ₂ H ₅ , γ-C ₃ H ₇ , iC ₃ H ₇ , nC ₄ H ₇ , sec-C ₄ H ₇ , iso-C ₄ H ₇

Illustrative compounds of the present invention are as follows.

Examples of preferred groups of the general formula I compound are as follows.

1. A compound wherein R ¹ is hydrogen.

2. A compound wherein R ² is an aliphatic acyl group containing 2-5 carbon atoms.

3. A compound wherein n is 2.

4. Compounds wherein n is one.

5. A compound wherein R ² is an alkyl group having 1-4 carbon atoms.

6. A compound wherein n is 2, R ¹ is hydrogen and R ² is an alkyl group having 1-4 carbon atoms.

7. A compound wherein n is 2, R ¹ is an aliphatic acyl group having 2-5 carbon atoms or an unsubstituted or substituted benzoyl group of the following general formula.

In the general formula above, R ³ is H or CH ₃ , and R ² is an alkyl group containing 1-4 carbon atoms.

8. n is 1, R ¹ is hydrogen and R ² is an alkyl group containing 1-4 carbon atoms.

9. A compound wherein n is 1 and R ¹ is an aliphatic acyl group containing 2-5 carbon atoms or an unsubstituted or substituted benzoyl group of the following general formula.

In the general formula above, R ³ is H or CH ₃ , and R ² is an alkyl group containing 1-4 carbon atoms.

Preferred compounds of the present invention are compounds of the formula

Since the compounds of the present invention of general formula I have at least one member carbon atom, the present invention includes all possible optically active forms and racemic mixtures of the compounds. The racemic mixture can be separated by conventional methods, for example by forming salts with optically active acids followed by fractional crystallization.

In clinical applications, the present invention is a pharmaceutical compound which optionally contains the active ingredient in the form of the original compound or in the form of its pharmaceutically suitable salts together with a pharmaceutically suitable carrier such as solid, semi-solid or diluent or ingestible capsule. It may be administered normally orally or by injection or inhalation in the form of a suitable formulation. Such formulations also include another aspect of the present invention. The compounds can also be used without a carrier. Examples of pharmaceutical preparations include tablets, drops, and inhalation aerosols. Usually the active ingredient will contain 0.05-99 or 0.1-99% of the formulation weight, eg 0.5-20% for injectable preparations and 0.1-50% for oral preparations.

The novel compounds prepared according to the invention can be administered in the form of salts with physiologically suitable acids. Suitable acids that may be used are, for example, hydrochloric acid, hydrochloric acid, sulfuric acid, fumaric acid, citric acid, maleic acid or succinic acid.

Pharmaceutical compositions containing at least one active ingredient of one of the compounds according to the invention can be adapted for oral, bronchial, rectal or parenteral administration.

The compounds of the present invention, in the form of free bases or pharmaceutically suitable salts thereof, contain the active ingredient as a solid powder carrier, e.g. lactose, to prepare a pharmaceutical formulation in dosage unit form for oral administration. , Starch such as sucrose, solititol, mannitol, potato starch, corn starch, or mixed with amylopectin, cellulose derivatives or gelatin, etc., may also contain magnesium or calcium stearate, or carbowax or other polyethylene glycol wax and Or compressed to produce dragees. If you need a party, you can coat the center of Bunte. For example, it may be coated with a concentrated sugar solution containing gum arabic, talc and / or titanium dioxide, or may be coated as a lacquer dissolved in an easily evaporated organic solvent or a mixture of organic solvents.

Pigments may also be added to these coatings. Soft gelatinboxes composed of gelatin, for example glycerol, or similar enclosed capsules, may contain lactose derivatives or gelatin with lactose, sucrose, solitol, malitol, starch (eg potato starch, corn starch or amylopectin). It may contain granules other than the active substance together with a carrier of the same solid powder. And may also contain magnesium stearate or stearic acid.

Rectal dosage forms may be in the form of preparations containing the active substance mixed with triglycerides or in the form of gelatin rectal capsules containing the active substance mixed with carbowax or other polyethylene glycol waxes. And may also contain magnesium stearate or stearic acid.

Rectal dosage forms may be in the form of preparations containing the active substance mixed with triglycerides or in the form of gelatin rectal capsules containing the active substance mixed with carbowax or other polyethylene glycol waxes. The dosage unit of each dosage form preferably contains 0.5-50 mg of active ingredient.

Liquids for oral administration are, for example, in the form of syrups, suspensions or emulsions containing from about 0.1-20% by weight of the active substance and, if desired, auxiliaries such as stabilizers, suspensions, diffusion agents, flavoring and / or sweetening agents. It may contain. Pharmaceutical compositions containing the active ingredient may be suitably formulated to provide doses within these ranges, whether in single or multiple dose units.

The compound of formula (I) wherein R ¹ and R ² are an aliphatic acyl group or an unsubstituted or substituted benzoyl has the same fast effect as the compound of which R ¹ and / or R ² is hydrogen and has a continuous pharmacological effect. This is probably due to better absorption due to hydrolysis of ester bonds in vivo.

Compounds in which R ¹ and R ² are aliphatic acyl groups or unsubstituted or substituted benzoyl serve as prodrugs for those compounds in which R ¹ and / or R ² are hydrogen.

The compound of the present invention is prepared by the following method.

That is, A. A compound of the following formula (III) is reacted with a compound of the following formula (IV) to form a compound of formula (V).

의 비치환 또는 치환벤조일기(R³은 수소 또는 메틸); 또는 1-5개의 탄소원자를 포함하고 있는 알킬기와 같은 하이드록시보호기, 또는 벤질이나 나프틸메틸처럼 11개이하의 탄소원자를 갖는 모노-또는 비시클릭 아랄킬기와 같은 하이드록시보호기이다.R in the formula (III) is hydrogen; aliphatic acyl group having 2-5 carbon atoms;

Unsubstituted or substituted benzoyl group (R ³ is hydrogen or methyl); Or a hydroxyprotecting group such as an alkyl group containing 1-5 carbon atoms, or a hydroxyprotecting group such as a mono- or bicyclic aralkyl group having 11 or less carbon atoms, such as benzyl or naphthylmethyl.

의 비치환 또는 치환벤조일(본 일반식에서 R⁴은 수소 또는 메틸); 구조식(Ⅳ)에서 R⁵는 수소 또는 벤질과 같은 N-보호기이다. 상기 구조식(Ⅴ)의 화합물을 형성시킨 다음 필요하다면 보호기 R 및 R⁵를 제거한다.N in the formula (IV) is 1,2 or 3; R ² is selected from the group formed as hydrogen; Aliphatic alkyl groups having 1-4 carbon atoms; Aliphatic acyl groups and general formula containing 2-5 carbon atoms

Unsubstituted or substituted benzoyl in which R ⁴ is hydrogen or methyl; R ⁵ in formula (IV) is an N-protecting group such as hydrogen or benzyl. The compounds of formula (V) are formed and then the protecting groups R and R ⁵ are removed if necessary.

B. The compound of formula (IV) is prepared by reducing the compound of formula (IV).

In the compound of formula VI, n, R and R ² have the meanings defined in the above-mentioned A.

The compound of formula (V) is formed and then the protecting group R is removed if necessary. If desired, the compound of formula (I) thus obtained is then converted to a pharmaceutically suitable salt or to its optical isomer.

The starting material used in the A-B reaction is a known compound that can be prepared by a known method.

The following examples illustrate the invention.

Example 1

Method B: Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyoxphenyl) propylamino] -ethanol.

a) Preparation of 1- (4-benzyloxyphenyl) -2 [1,1-dimethyl-3- (2-methoxyphenyl) -propylamino] -ethanol.

A solution of 4.0 g (0.0155) of 4-benzyloxyphenyloxal in 3.0 g (0.0155 mol) of 1,1-dimethyl-3- (2-methoxyphenyl) propylamine in 40.0 ml of ethanol was boiled under reflux for 1 hour and 20 hours Stir at room temperature. Thereafter, intermediate intermediate noketone was directly reduced by adding 1.5 g of NaBH _4, and then the solution was further stirred for 1 hour. The reaction mixture was evaporated to dryness in vacuo and then the residue was partitioned between Et ₂ O and water. The ether phase was washed with water, dried over MgSO ₄ and evaporated. The crystalline residue was recrystallized from ethanol.

Yield: 3.1 g

NMR for intermediate iminoketone: (CDCl 3) δ (ppm): 1.25 (6H, s), 1.82 (2H, m), 2.60 (2H, s), 3.75 (3H, s), 5.10 (2H, s) , 7.18 (11H, m), 8.10 (2H, d), 8.35 (1H, s).

b) Preparation of 1- (4-hydroxyphenyl) -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] -ethanol.

The compound obtained in step a) was hydrogenated in the same manner as described in Example 1b to obtain the target compound.

Example 2

Method B: Preparation of 1-4-pivaloyloxyphenyl-2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulfate.

A solution of 2 g of 1,1-dimethyl-3- (2-methoxyphenyl) -propylamine and 2.9 g of 4-pivaloyloxyphenyl glyoxal monoethyl acetal in 100 ml of ethanol was refluxed for 2 hours and left at room temperature for 20 hours. It was.

B ₂ H ₆ prepared from ₂₃ ml of BF ₃ ether salt and 3.4 g of NaBH ₄ in 110 ml of diglyme was introduced by inflow of N ₂ . Water was added carefully when the reaction was complete. The reaction mixture was then evaporated to dryness. The residue was extracted with ethanol and then washed with water, dried and evaporated. The residue was dissolved in ethanol and neutralized with ethanol sulfuric acid. The crystalline residue obtained after evaporation was recrystallized from ethanol.

Yield: 1.6g 100% Neutral Sulfate

NMR: (CDCl ₃ , CF ₃ COOH) δ (ppm): 1.10 (9H, s), 1.52 (6H, s), 2.00 (2H, m), 2.10 (2H, m), 3.25 (2H, m), .90 (3H, s), 5.25 (1H, m), 7.18 (8H, m).

Example 3

Method B: Preparation of 1- [4- (4-methylbenzoyloxy) -phenyl] -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulfate.

This target compound was prepared in the same manner as described in Example 2 for 1- [4-pivaloyloxyphenyl] -2- [1,1-dimethyl-3- (2-methoxyphenyl) propylamino] ethanol sulfate To 6.0 g of 1,1-dimethyl-3- (2-methoxyphenyl) -propylamine and 9.8 g of 4- [4-methylbenzoyloxyphenylglyoxalmono] ethylacetal in 200 ml of ethanol. Recrystallization with i-PrOH gave the following target compound.

Yield: 1.3g 99.4% Neutral Sulfate

NMR: (CDCl ₃ , CF ₃ COOH) δ (ppm): 1.52 (6H, s), 2.02 (2H, m), 2.50 (3H, s), 2.75 (2H, m), 3.15 (2H, m), 3.85 (3H, s), 5.25 (1H, m), 7.20 (12H, m).

Example 4

Spray for inhalation

Example 5

Quantity per tablet:

Example 6

Suppository

Impairment of bank account:

Example 7

Injection

Example 8

Inhalation solution

Example 9

Liquids for rectal administration (rectal vials)

Example 10

Sublingual tablet

Example 11

Drops

A. Initiation and Duration of Bronchial Anticonvulsant Activity After Oral Administration

Tests for the initiation and persistence of bronchial anticonvulsant action of the compounds according to Examples 1 and 2 of the original application were conducted. Such compounds have the structure

Way

This bronchial spasm effect was tested as a deterrent effect on histamine-induced bronchial stenosis in non-anaesthesia geuinea-pigs. Test animals were exposed to histamine mist generated by Roth-Petersen nebulizer from a solution of 0.3 mg / ml of salted histamine. Positive guinea-pigs, Strain Dunkin-Hartley 160-230 g were used. Physiologically treated control animals were exposed to aerosols in less than 4 minutes and then strengthened and irregular breathing began. Pharmaceutical animals that hold histamine aerosol for 4 minutes without affecting breathing are considered protected.

The animals were fasted for 15 hours with water and libitum prior to administration of the test compounds into the gastrointestinal tract. Each test substance was administered in an amount of ^4.10-6 mole / kg body weight. 8-10 animal roots were tested in aerosol every 7,15,30,60 and 120 minutes after administration of the test substance. Percentages of animals that could resist the aerosol for 4 and 10 minutes were obtained. The test results are shown in Table 3.

TABLE 3 Initiation and Duration of Bronchial Anticonvulsant Activity in Oral Administration

The potency of both tested compounds is shown in Table 3. The persistence of the compound of Example 4 was significantly extended compared to the persistence of the compound of Example 1.

B. Testing for α-Receptor Blocking

The α-receptor blocking action of the two compounds of the present invention was studied. This effect is associated with the treatment of asthma. Compounds having an α-therapeutic effect have been suggested by Nuxiandon, Pharmacy 15 , 469-477 (1977), for example, to enhance the effect of β-receptor stimulants such as terbongtalin. In this test, α-receptor blocker thioxamine was used as the reference material.

Way

Positive white rabbits (2-3 kg) were used. Approximately 5 cm of the aorta was dissected from the root of the arch as much as possible and transferred to a dish containing Kneb's solution to develop a spiral. Usually three restraints were received from the dissected front of the vessel.

Each unit was bathed in an organ in a Kneb solution at 37 ° C. and ventilated with cartbogen. The load for this formulation was 2 g and the change in tension was recorded as isotonic on Grass transducer FRO ₃ and polygraph 95.

Noradrenaline, a potent α-receptor stimulant, has a hydrophilic effect on the medium when added to the baths described above. Noradrenaline solutions were used at concentrations ranging from 70-80 maximal shrinkage (0.03-0.06 μg / ml). This test compound was added in long-term use 10 minutes before the addition of noradrenaline.

This test score is determined by the concentration of the test compound that inhibits noradrenaline-induced contraction by 50% (EC 50).

Test score

The test results are shown in Table 4 below.

TABLE 4 Receptor Blocking Actions of Compounds of the Invention

Based on testing of six formulations from three animals of this EC50 rich

Findings on test scores

It is shown in Table 4 that Compound D 2343 of the present invention has a higher α-receptor blocking activity than the α-blocking effect of thymoxamine.

The α-blocking effect of D2343 also indicates that it can be obtained in the same range of dosage as the flux in its β-stimulating effect. As already pointed out above, the complex of α-adrenoceptor blocking properties and β-adrenoceptor stimulating properties is beneficial in treating asthma.

C. Suppresses the contraction of the rat uterus in in vitro tests induced by oxycytocin and carbacol

The relaxation effect of the compound of the present invention was tested. Terbutalin was used as standard.

Way

Sprauge-Dawley rats, females 150-200 g body weight, were used. 0.25 mg / 100 g of estrogen steroid (Estradurin, Leo) was administered subcutaneously for 4-6 days prior to testing to cause Desterus.

The uterine angle was developed as a bell and attached to a long-term bath in a Locke solution at 33 ° C. And aerated with carbogen. Shrinkage of this formulation was manifested by oxytocin (Partocen, Ferring) or carbagol and exhibited 70-80% of the largest shrinkage, or 0.005-0.021E / ml of oxytocin and 0.2-0.6 µg / ml of cinecarbaline Was administered in the bath 3 minutes after administration of the test substance.

The inhibitory effect exhibited by the test substance was raised by propanolol (0.4 × 10 ⁻⁵ M or 1 μg / ml administered in the bath 15 minutes prior to administration of this drug).

The change in tension was recorded as dynamic (transduce FP03 and Grass Polygraph P5).

Test score

The test results are shown in Table 5. The results are expressed as the concentration of the test compound which reduces the contraction induced by oxytocin and carbacol by 50% (EC50), respectively.

[Table 5] Inhibitory effect on the induced contraction of rat uterus

* P = 0.01 ** P = 0.001

Oxytocin crab: 10 preparations from 6 animals

Carbacol series: 9 preparations from 5 animals

Findings about this test score

It is shown in Table 4 that Compound D2343 of the present invention is more potent as a diastolic agent than terbutalin.

For example, Andersson et al., Acta Obstet Gynec. Scand. Terbutalin was tested by 1974 as a uterine morbidity agent to inhibit preterm delivery. The test results in Table 4 indicate that compound D2343 of the present invention is at least as effective as terbutalin in use as a uterine relaxant. Of particular interest is the contact with compounds with reduced tremor for use as uterine relaxants. This is because medications in such cases are administered only for a limited time. In treatment with turbutalin, it has been found that the progress that occurs at the onset of treatment decreases the procedure when treatment continues for a short time. Such degeneration of tremor effects cannot be obtained in treatments for uterine relaxation. Because in such cases the dosing time is short. Accordingly, the compounds of the present invention present important improvements in the treatment of the purpose of relaxing the uterus of humans in this respect.

C. Acute Toxicity in Mice

The acute toxicity of compound D2343 of the present invention was studied. 20-25 g of male mice (NMRI) were used. The test compound was administered intravenously (microvenously), subcutaneously, intraperitoneally and orally (into the gastrointestinal tract to fasted animals) at which 10 or more test animals were used at each eluent level to determine LD50. Six levels of elution in the log-sequence were administered. The animals began to die within the first hour after subcutaneous and intraperitoneal administration of toxic solvents, and the first three hours after oral administration. There was no mortality for the animals over the next five days. The test results are shown in Table 6.

TABLE 6 Acute Toxicity of Compound D 2343 of the Invention

Claims (1)

A method for preparing a compound of formula (I) and a therapeutically suitable salt thereof by reducing the compound of formula (IV):

In which n is 1,2 or 3; R ¹ is hydrogen, an aliphatic acyl group containing 2-5 carbon atoms or a substituted or unsubstituted benzoyl of the formula wherein R ³ is hydrogen or a methyl group

R ² is hydrogen, an aliphatic alkyl group containing 1-4 carbon atoms, benzyl, an aliphatic acyl group containing 2-5 carbon atoms or substituted or unsubstituted benzoyl of the following formula: wherein R ⁴ is hydrogen or methyl

R is R^OneEqual to or Or a hydroxy protecting group such as an alkyl group containing 1-5 carbon atoms, or a hydroxy protecting group such as a mono or bicyclic aralkyl group having up to 11 carbon atoms, such as benzyl or naphthylmethyl.