SI7711911A8 - Process for obtaining new aminoalkyl-furane derivative - Google Patents

Description

40006

Technical field

The invention relates to a process for the preparation of novel ainoalkylfuran derivatives having a selective effect on the histaine receptor.

Technically problee

The splitting of histalin receptors (H-receptors) into two groups, designated H, - and Ha-receptors, was suggested by Ash and Schild (Bnt.J.Pharsacol.Chssothir, 1966, 27, 427) and Black at al (Matura 1972, 236 , 383). Stiaulation of bronchial and gastrointestinal smooth eiiic is mediated by H ₂ -receptorie and these effects can be prevented by conventional! histaain antagonists · * such as aepiraain. Stiaulic acid secretion and pulse rate are mediated by an H ₂ -antagonist such as aetiaeide. Histaain stiauliie H, - and H ₂ receptors.

The process of the invention now addresses the problems of the production of novel aaino-alkyl furan derivatives with selective action on the histamine receptors, by reacting, hereinafter defined, starting compounds which in a simple and economical manner lead to the desired furan derivatives.

The state of the art

Preparation of the Het (CH ₂ ) XICH ₂ ) NHL Compound Compound, NHC (= Y) NHR, in which Het is a heterocyclic nitrogen-containing group, in particular 4aethyl-5-iidazolyl, and Y is O, S, NCN or CHNO ₂ | it is described in british! patents · numbered 1,307,539, 1,338,169, 1,397,436 and 1,421,792. These compounds have been described as H _a- antagonists, but they also exhibited certain disadvantages that were shown when adhering to these compounds. Therefore, further studies on the attachment of new derivatives with desired pharmacological properties are warranted.

A description of the solution to the technical problem with the embodiment

According to the invention, a process for the preparation of aainoalkyl-1-furan derivatives which are selective Haantagonists is found, i. exhibit inhibition of stoic acid secretion when this stieulated histaainic H ₂ -receptoriea (Ash and Schild, priv. communication). Their ability to prevent the secretion of stoic acid, when the same is styled histalin-Hareceptorie, can be previously deaonstrated on perfused rat rats, prior to the procedure described by Shosh and Schild (Brit.J.Pharaacol. 1938 13 54), which is eodified as described later, and on the conscious psiaa oprealjenia Heidenhain kesaaa using »the same procedure as described by Block et al (Nature 1972 236 385). The compounds obtained by the method of the invention do not aodify the histaeino induced contractions of Isolated gastrointestinal smooth ejices.

Compounds with histaain H ₂ -blocking activators may be used in the treatment of conditions where hypersecretory acid hypersecretion exists, e.g., in gastric and peptic ulceration, and in the treatment of allergic conditions where histaine is a known mediator. Who can be used, either individually or in combination with other active ingredients in the arrest of allergic and seductive conditions such as urticaria.

The invention provides a process for the preparation of the test compound (I), i. N / 2 /// 5 (thiaethyl) amino) ethyl-2-furanyl / ethyl / thio / ethyl / -N-ethyl2-nitro-1,1-ethanedioin,

O » ^HN ° 2

CH ₂ S (CH ₂ ) 1 N HCNHCH ₂ (I) and its physiologically acceptable salts.

The compound obtained by the press of the invention has the advantage of being readily obtainable or obtainable from an easily accessible starting material.

The compound foraule (I) soot exhibits tautoeeria and the foreula covers the svt tautoere.

The compound of the invention easily trims physiologically acceptable salts. Such salts include inorganic and organic salts! acids such as chlorhydrates, broehydrates and sulfates. Such salts include inorganic and organic acid salts, and particularly useful salts are formed with aliphatic eono or di-carbonic acid. The primers of such salts are acetates, ealeates and fuaarates.

The compound of the invention may be administered orally, topically, or parenterally or indirectly by suppositories, but the most preferred route is oral. The skins are used in base iii form as a physiologically acceptable salt. Inhibition will be given with pharmaceutically acceptable carriers or diluents, so that a pharmaceutical preparation is provided.

The compound of the invention may be administered in combination with other active ingredients, e.g. with conventional · antihistaainiciaa, too soon. For oral administration, the pharmaceutical preparation may preferably be in the form of capsules or tablets, which may be tablets with a gradual release of the active ingredient. The formulation may also be in the form of a dragee or a syrup. Suitable topical preparations include easti, lotions, creams, powders and sprays.

An appropriate daily dose for the oral route is in the order of 100 ag to 1.2 g per day, in unit dosage form containing from 20 to 200 ag per unit dose. Suitable

The 40C06 interval in the case of tablets in a lag is opened two or three times a day.

Parenteral administration of the salt is a multiple injection into the intirvaliaa iii as a continuous infusion. Aogu injections may strike from 10 to 100> g / a and active) stand.

To administer aoie aa locally, use a spray, mouth, creaa or loaion. These preparations may maintain an effective amount of active ingredient, for example, at a working rate of 1.52 to 22 aas. of total) preparations.

The procedure for the invention of the compound foraul (I) aa is obtained starting from the compound foraul

Removal of the protecting group by reaction with, for example, hydrazine hydrate gives aaine foraulas (11).

Alternatively · for natin to obtain aaina foraule (11), aoie ia use 2furfurll chloride as the starting aatarial. The reaction yields furfuri1-chloride and oaega-aainoalkylthiol, where I aaino the group is protected, to a priaer, as a phthalide (12)>

o

o (CH ₃ ) ₂ NCH ₂ —CHjS (CHj) ₂ nka _(ii , in which I A is hydrogen or a group -C (“CHM0”) P, where P is a leaving group, the reaction · in compounds · foraule is given by the intaraadiary of foraule ( Vlil) .This sa treats as described above so as to obtain aain foraule (II).

The further procedure for obtaining the aaina foraule (II) uses the starting aatarial of foraule (X) and

CH ₃ HHZ in which I Z hydrogen or group -C («CHNO _a ) P, where P iaa worse given the values. The reaction with the derivatives at ordinary teaperature to the reflux plants, in water or in solution, or the merging of the reactants, at the elevated teaperature, e.g. 100-120'C.

Below are some ways to get the intermediate aaina foraula (II).

Aaini foraule (II) in which A H can be made from furfuriltiol foraule (Vlh

CH

3 \

CH

N-CH2 ²

ClljOll (X)

The two compounds are to be treated under acidic conditions with ouga-aainoalkylthiolo, in which, if necessary, the group may be protected. Alternatively, the compounds of fora (X) may be converted to the corresponding acetate prior to the reactions, under basic conditions, with oaegaaainoalkylthiolo.

The primary aain foraule (II) may also react with furan from butyl-lithiumao to give the lithio-derivative 1X1) t reaction * with oaega-broaoalkylphthalaido (VID:

Li (XI)

Br (CHj) jN which then reacts sequentially with (i) alpha, oeega (vii) respiratorydehyde Hal-CHa-SiCHalaHal where i Hal chlorine, broa iii iodine) and (ii) potassium * phthalaido. The reaction product of foraule (Vlili group (CHahNCHa is to be introduced at the age of the veno compounds of foraule (VII) and

ch ₂ s (ch ₂ ) ₂ n (VIII)

to priaer, Hanich's reaction.

is then subjected, at priaer, to the Hanich reaction and rotated by removing the protection with, at priaer, hydrazinhydrate.

4000 6

The foreule (II) intermediate also in aoi »make use of ethyllaine. This compound reacts aa isosternie thioloa compounds forauli (X).

Aain foraula (II) aa also make aoia starting from compound foraula (XII) and

(XII)

To this nitrile j »melon aa is rotated by the Hanoch reaction and then the reduction of a lithium-aluainiumhydride, so that aa obtains the compound of fora (II). When ae uses Hanich's reaction, the group

Priser A

2- /// 5- (Dieetilaaino) »ethyl-2 ~ furinll / aetll / thio / -» taain

3- (Oiaethyl) ethyl-2-furanethanol 113.3 g) was added dropwise to an ice-cold solution of cyanoic hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ol.). After cooling to O (R) for 18 h, a sludge of anhydrous sodium carbonate was added aa and the resulting substances aa extracted from diethyl nitro. Removal m raitvarata 1 distillation! the residue is obtained with 2 - /// 3- (diaatilaaino) aatyl-2furani1 / aethyl / thioatanaain (11.6 g.), mp.l04-106'C (0.1 aa). They are dirty, m.p. 142-144 ° C.

CH3>

CH ·) '

NCHj aoia to be introduced at any particular stage but the reaction is preferably returned to jadinjanjiaa foraula (XIII) iii (VlIDi

CH ₂ OH (XIII) o

o (VIII)

Priier B

2- [2 - // (2-Furanyl) ethyl / thio / atyl / -1H-isoindole-1,3,3 (2H) -dione 80Χ Sodium hydride (1.38 g) and added portionwise to a solution of furfuryl-aercaptan (6g ) in auvoa diaethylforaaaid (30 al). After 30 aynutes, a solution of 2-broaethylasulfaiid (16.71 g) in dry di lotyl foraaaide (63 al) was added with 1 solution of »heated to U0C ° for 2 days. After removal of the solvent, the residue is washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solution was removed and the residue was recrystallized from cyclohexane to give 2- (2 - / (2-furanyl) ethyl-1-tho / ethyl-1H-isoindole, 3 (2H) -dione , mp 62-63'C (7.8 g).

use of forealdebide and diaethyl.

Alternatively, furan * 2-carboxyl is used as the starting material. This reacts aa aainoi foraula (CHsIžNH so it obtains aaid foraula (XIV) which aa then reduces aa, to priier, litijua-aluainijua * hydridoa so that it obtains the compound foraula (XV)

(XV)

For the purpose of translating Formula XV to Compound (X) hydroxyaate1 groups with aoia uvari the use of foraaldahide and acetic acid.

Alternatively, hydroxyethanes with »aoia boils of butyl-lithiumaa, and zatia foraaldahida.

For the sake of better understanding of the find, the following stories are given for illustration.

Examples A to D illustrate the preparation of aain and related intermediates used in the process of the invention, and Examples 1-3 of the preparation of the compound of the invention. Example 4 illustrates the preparation of a pharmaceutical.

Priier C

2- [2- (2-diethylamino) ethyl] -2-furanyl] -butyl-thio-ethyl--1H-isoindole-1,3 (2H) -dione Shiite 2- [2- (2-furanyl)] eeti1 / thio / ethi1 / -1Η-1zoi ndoll, 3 (2H) -dione (10 g), dinethylaionium chloride (3.1 g) 1 36Χ forealdebide solution (3 al) in red acid (30 al) is heated to steam bathroom 9 h. The solution was cooled and the solvent was evaporated in vacuo. The residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate. The organic phase n was treated with charcoal, dried and evaporated to give a chroeatographically readable oil on a column (illuminated dioxide / ethanol »thylacetate lil) (3.7 g) Rf 0.4 NHR (CDCl 3 / DH8O) 7.71 s (6H) ; 7.22 t (2H) 6.32 s (2H) | <2H) j 6.1. t (2H) j 3.8 (2H) j 2.2 (4H).

Priier D

N- / 2 - /// 3-IDi «ethylaineoleeti1-2-furanyl / aeti1 / thio / ethanaein

2- (2 - /// 3- (Dieethylamino) ethyl-2-furanyl / ethyl / thio / ethyl 1-1H-isoindole-1,3 (2H) -ion (3.3 g) and hydrazinhydrate (0.83 g) are refluxed. in ethanol for 3 h. Evaporation of the solvent afforded these phthalhydrazide salts of 2 / (3- (diethylethyl) ethyl-2-furanyl / ethyl-1-thio / ethanoic acid).

40006

Priaer 1

N- / 2 - /// 5- (Diiethyl) netil-2furanyl / aethyl / thio / ethyl / -M'-iityl-2-nitro-l, letendiaain

N-Hetyl-1- (aethylthio) -2-nitroethenaein (230 g) in water (400 al) aaia it and heated to 43-30 '. Adds aa drop 2 - /// 3- (DiMtilaelno) iitil-2furani1 / aati1-2-furani1 / aetil / thio / -etaain (321 gl over 4 h and obtained aa Mia joi 3.3 h. at reflux for 1/2 h, cool it to 70 * and add ii 4-aetylpantan-2-one (2 liters). Water "separates the azootropic diitilation under saanjenia pritiikoa (260 tor) and the resulting solution ii tratlra la animal carbon ( 10 g) at 30 C. The solution uf The fatigue cools to 10 * C. N- / 2 - /// 5-ldiaethyl (amino) -ethyl-2-furan1 / aati1 / thio / atl1 / -H'-neti1-2-nitro-1. 1etandiaain (380 g) at filter and auii, mp 69-70 *.

At ur 2

H- / 2 - /// 5- (Diaetilaaino) Mtil-2furani1 / eetll / thio / ethyl / -M'-aeti1-2-nitro-l, 1etendiaain

2 - /// 3- (Diaethylsilano) ethyl 2-furanyl / aati1 / thio / atanaiine (4.23 g) and 1.1bi (aatylthio) -2-nitroatane (3.3 g) refluxed with acitonitrile (30 or 14 h The solvent »» remove both the residue and the solvents in 361 aitanolnoa Mtilaain (30 al) and the solvent and the reflux for 8 h. 3.0 g).

Priaer 3

H- [2- (5-IDiaethyl) ethyl-2-furanyl] -ethyl / thio / ethyl] -N'-ethyl-2-nitro-1,1-ethanediochloride N- [2- (Diaethyl) amino] «Til.-2furani1 / aetil / thio / ethyl / -N'-letyl-2-nitro-l, letindiaain (30 g, 0.16 aola) and solutions in the inducted ethyl alcohol at 74 * op (200 al) containing 0.16 hydrogen chloride equivalents. Ethyl acetate (200 al) was added lightly to the solution. Chlorhydrate of crystals and filtration of n itpera from ta iiaioa of industrial aetilovanof alcohol 74 ° o.p. (50 al) and ethyl acetate (50 al) and auii from at 50. Obtained aa product (50 g) as a bell-shell, m.p. 133144 ° C.

Priaer 4

Pharmaceutical preparation (a) Oral tablets 50 ag For 10,000 tablets

Active Taitoyak 500 g

Anhydrous lactose U.8.P. 2.17 kg

Sta-Rx Skrobl 300 g

Hagnezijua itiarat B.P. 30 g

Coating aa presajava through a cast of 250 _{to the} UA and Tada aa quote praika well iZMiaju u aeiaču i koapriauju ii izsudju probojaca diameter 8.3 aa u Batini tableting.

I / Form of direct co-cultivation icrobes sold by A.E. Staley Hfg Co. (London Liaitad, Orpington, Kant (b) Intravanic injection (200 ag in 2 al) 'l t / t

Active Taitoyak 10.0

Water for injection BP up to 100.0

Broken hydrochloric kialine BP up to pH 3.0 The active thiocyanate dissolves this atianjia in water for injection, the slight addition of chitin, and up to pH 3.0. The sample shows nitrogen and then selects filtration! through the Mibraniki filter aa size · pore 1.33 / ua. It packs in a 2 (12.2 al (2) aapula aapula) and aapula m edges close under a nitrogen ataoifero. Aapula aa aterilite in autoclave at 121 for 30 ainutes.

(c) An oral tablet of n uipormia dajitvoa of 130 ag for 10,000 tablets

Active Thyme 1.50 kg Cutin HR 0.40 kg Anhydrous lactose U.S.P. 2,060 kg hagnesium ataarate BP 40 g.

Active lactose, anhydrous lactose and supposedly give the Cutina-E HR a good kick out and then the taiia moistens the Mianja aa 10Z raitvoroa of the Cutina- · HR alcohol in industrial ethyl alcohol OP 74. Hokra daddy granulates through a hole of 1.2 aa and tuii ii at 50 ”C in the fluid ta fluidizovania bearing. The arm is then passed through the 0.83 m openings, casted by aagnesia-atataroa and co-opted to a thickness of at least 10 kg (Schlouniger test) on a tableting device, with a puncture of 12.5 aa.

M / Cutina HR jt super-quality high-grade castor oil sold by Sipoa Products Liaited, London (d) Oral syrup Z t / v

Active Taitoyak 2.0

Dilute hydrochloric acid

BP washes the need

BPC sorbitol 60 v / v

Hirii needs it

Deitylated water up to 100

The drug was dissolved in water, and hydrochloric acid was gradually added until the pH dropped to 5.0.

It was added to the sorbitol solution, airii and water readings, and the pH was again adjusted to 5.0. The syrup is selected by filtration through a fifty layers of cellulose filter.

40006 (e) Oral capsules 30 14 in 10,000 capsules

Active ingredient 300 g

Sta-Rx 15001 1700 g

Hagnizium stearate BP 20 ag

The medicine shines through a 230 / sieve and is then snuffed out with other prairies. You filled your slingshot in no. 3 hard gelatin capsules to any suitable filling mill.

(f) Grease. MS..1

Active ingredient 2.0

Paraffin BP up to 100 were removed

The drug was passed through a sieve with a 150 / Ui opening and then uniformly purged with Belil decanter of paraffin in a high speed extractor.

Ig) Krna ias.X Active ingredient 2.0 Cetoiacrogel Eeulsifying Ointeent BP 30.0 Chlorocresol 0.1 Distilled water up to 100

The drug was passed through a sieve from an opening of 150 / Ui and immersed with Cetaeacrogel Eeulsifying Ointeent at 65 ° C. The chlorocresol is dissolved in water at 65 ° C and this solution is dipped from the oily seeioe of the drug, so that the resulting eeulsion is continually eeia while cooling so as to obtain a cream.

The active ingredient is a compound of the invention.

Compound (I) was found to be an inhibitor of histoic acid-induced stoic acid secretion. This was demonstrated by the ratification of the eodification of the procedure described by 'H.N.Bhosh and H.D. Schild in British Journal of Pharaacology 1958, Vol. 13, page 54. The tanks of rats weighing about 150 g are allowed to starve overnight and are supplied with 8Z sucrose in noreal saline solution of frequent drinking water.

The rats were anesthetized with a single intraperitoneal injection and 251 t / v urethane solution (0.5 el / 100 g) and the mouthpiece and cervical veins cannulated.

Make a cut in the middle of the stoiculate wall to expose the stoecoid, separate it from the liver and spleen by cutting the connective tissue. An opening is made in the fundus region of hundreds and the rinse is washed with 5Z of dextrose solution. The esophagus is cannulated with gueenoe tubes and esophagus and weighed then cut above the cannula.

Then an opening is made in the pylorus section of the stoek. The large cannula perspector is then inserted into the cone through an opening in the fundus region in such a way that the inlet end of the cannula exits the cone through an opening in the pylorus region. The cannula is of such a shape that it senses the effective constriction of the stoeaks and provides a turbulent flow of perfusion fluid across the acoustic surface. A suction cannula is then inserted through the opening of the fundus region of the stoek. Both cannulas attach to the ligature around the stoices, which are positioned to avoid major blood vessels. Puncture wounds were made on the wall of the tulle and the cannula was pulled through. The stock was perfused through an esophageal and pyrolysis cannula with NW dextrose solution at 39 ° C at a rate of 1.5 el / ein. for each cannula. The expiration is counted over the pH electrode for flow • and recorded over the pH ether and the recorder with a flat surface.

The baseline secretion expiration is recorded by aeration of the perfusion expiration pH and then the increased acid secretion is indicated by continuous intravenous infusion · sub-iriacial dose of histaiin this produces a stable level of acid secretion and the perfusion expiration pH is determined when this condition is reached.

Ted is given a batch compound to test for intravenous injection and a test for secretion of hydrochloric acid.

From the gaseous pH of the perfusion expiration, the difference of acid secretion is calculated from the baseline expiration and the level which is styled histaeinoe which is calculated as the concentration of hydrogen ions in eol / l. Remediation of acid secretion induced by drug delivery is also calculated as the estimated concentration of hydrogen ions in eol / l based on the difference in pH of the perfusion expiration. The percentage of acid secretion induced by the administration of the test compound can then be calculated from the two figures obtained.

The ED50 values for the inhibition of acid secretion are determined by administering one dose of the test compound to one oven and repeating this procedure to at least four rats for each of the three or three dose levels. The results obtained are then used to calculate the ED50 value of the standard quartate amplification procedure used for recreation at each dose. Using the above procedure, an ED 50 value of 0.18 eg / kg was obtained.

Preparation of N- / 2 - /// 5- (Diaetilaeino) »ethyl-2furan1 / eeti1 / thio / ethylZ-N '-eti 1 -2-tri-1,1etendiaain

N-Hetyl-1-laethylthio) -2-nitroethenaine 1230 g) in water (400 µl) is heated and heated to 45-50 °. 2 - /// 5- (Dieetilaeino) ethyl-2furanyl / seti1-2-furanyl / ethyl / thio / -etaein (321 g) was added dropwise over 4 h and the resulting solution was stirred for 3.5 h. The solution was then heated at reflux for 1/2 h, cooled to 70 ° t, and 4-ethylpentan-2-one (2 liters) was added. The water was separated by azeotropic distillation · under seanjenia pressure (260 tor) and the resulting solution was treated with animal charcoal (10 g) at 50 ° C. The solution was filtered and cooled to 10 ° C. N- [2- (2-dimethylamino) -ethyl-2-furanyl / ethyl-thio / ethyl] -N '- &lt; RTI ID = 0.0 &gt; ethyl-2-nitro-l, &lt; / RTI &gt; 69-70 °.

Claims (1)

Process for the Preparation of a New Ainoalkyl-Furaosic Darivate of Foraule (lh in which A is hydrogen or a group -C (* CHHOa) P gdi ji P aiti Iti o group, riaguji ia jedinmjM foriuli (CH ₃ ) ₂ NCH ₂ -n CH: x) CHNO, N ⁱ CHjS (cap jNHCNHCHj (I) and its physiologically acceptable salts, indicated by tiu, the compound opiate foriuli (Uh CHsNHZ in which Z is hydrogen or a group -C («CHNO _a ) P in which P iaa burns a given meaning, in the presence of water and / or an organic solvent such as nt ethanol at a tiapirature from room temperature to tiapirature of the solvent riflux, or without a solvent on the tiapirature from 100-120 ^a C, and, if necessary, the yield of yidinmini formi (I) is converted to its pharmaceutically acceptable salt.