NO149546B - ANALOGUE PROCEDURE FOR THE PREPARATION OF A NEW THERAPEUTIC ACTIVE AMINOALKYLFURAN DERIVATIVE - Google Patents

Description

This invention relates to the production of a new amino-alkyl-furan derivative which has a selective effect on histamine receptors.

A division of histamine receptors (H receptors) i

two groups designated H^ and I^ receptors have been proposed by Ash and Schild (Brit. J. Pharmacol. Chemother, 1966, !27, 427) and Black et al (Nature 1972, 236, 385). Stimulation of bronchial

and gastrointestinal smooth muscles are produced by means of H^ receptors, and these effects can be prevented by means of common histamine antagonists such as mepyramine. Stimulation of gastric acid secretion and heart rate is produced by means of f^ receptors. These effects are not modified by mepyramine, but are prevented or abolished by means of I^-antagonists so

as methiamide. Histamine stimulates H^ and I^ receptors.

We have found that a new aminoalkylfuran derivative is a selective H2-antagonist, in that it exhibits inhibition of gastric acid secretion when this is stimulated via histamine Hj receptors (Ash and Schild loe. eit.). Its ability to prevent gastric acid secretion when stimulated via histamine H 2~ receptors can be demonstrated on the perfused rat stomach using the method described by Ghosh and Schild (Brit.

J. Pharmacol. 1958, 13^, 54), modified as described below, and in conscious dogs fitted with Heidenhain pouches using the same method as Black et al (Nature 1972 236 385). The compound produced according to the invention does not modify histamine-induced contraction of isolated gastro-intestinal smooth muscle.

A compound with histamine I^-blocking action can be used to treat conditions where there is a hypersecretion of gastric acid, e.g. in gastric and peptic ulcer formation, and for the treatment of allergic conditions where histamine is a known inducing agent. It can be used either alone or together with other active ingredients in the treatment of allergic and inflammatory conditions such as hives.

According to the invention, the compound N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl-N'-methyl-2-nitro-1,1-ethenediamine is prepared with formula (I) :

and physiologically acceptable salts thereof.

DOS 2,423,813 relates to connections with the general

formula Het(CH„) Z(CH0) NHC(=CXY)NHR. These compounds separate

to m zn

differs from the compound produced according to the invention in that the group Het is a nitrogen-containing heterocyclic ring selected from imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,

triazole or thiadiazole, the ring possibly being substituted with lower alkyl, hydroxy, halogen or amino. The compound produced according to the invention differs from these known compounds in that, instead of the group Het as indicated above, a furan group is present which is substituted with a substituted aminoalkyl group at the carbon atom adjacent to the oxygen atom in the furan ring. There is no indication in the literature that such an aminoalkylfuran group is equivalent to the group Het as stated in DOS 2,423,813.

DAS 2,211,454 concerns urea, thiourea and guanidine derivatives, but not 1,1-diaminoethylene derivatives, and is thus even further from the present invention than is the case with DOS 2,423,813. According to both of these known literature sources, these are compounds where it is an essential feature that the compound contains a nitrogen-containing heterocyclic group. There is nothing in the literature that suggests replacing such a heterocyclic group with an aminoalkyl-substituted furan group.

DAS 2,211,454 and DOS 2,423,813 describe compounds

with the general formula A

and a clinically used compound is cimetidine (A; X=NCN) covered by DAS 2,211,454. The compound described in DOS 2,423,813 in example 2 and in claim 6 is the compound where the group X in the above formula A means CHN02, i.e. the nitrovinyl compound.

In each case, it can be shown that the compound according to the invention is better than the known compounds. In the following, experimental details and results are given with regard to the ability to inhibit histamine-induced gastric acid secretion in rats. For the compound produced according to the invention, an ED^Q value of 0.18 mg/kg was found. Under the same experimental conditions, cimetidine (A; X=NCN) has an ED5Q value of 1.12 mg/kg, and the nitrovinyl derivative (A; X=CHN02) has an ED^Q value of 1.75 mg/kg . The more active a compound is, the lower the ED^ value, and it is therefore clear that the compound produced according to the invention is significantly better than both of these known compounds.

The compound produced according to the invention

has, among other things, the advantage that it can be easily produced from readily available starting materials.

The compound of formula (I) may exhibit tautomerism,

and the formula shall be understood to include all tautomers.

The compound prepared according to the invention readily forms physiologically acceptable salts. Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulphates. Particularly suitable salts of organic acids are formed with aliphatic mono- or di-carboxylic acids. Examples of such salts are acetates, maleates and fumarates. The hydrochloride salt is particularly preferred because this salt is particularly suitable for being incorporated into pharmaceutical preparations. This salt is physiologically acceptable and can be easily obtained in crystalline form. Also, the melting point of the salt is such that the salt has no tendency to flow under compression to make tablets.

The compound produced according to the invention can be administered orally, topically or parenterally or by suppositories, the preferred route of administration being the oral one. The compound can be used in the form of the base or as a physiologically acceptable salt. It will usually be used in admixture with a pharmaceutically acceptable carrier or diluent to provide a pharmaceutical preparation.

The new compound can be administered in combination with other active ingredients, e.g. regular antihistamines if desired. For oral administration, the pharmaceutical preparation can most conveniently be in the form of capsules or tablets, which can be slow-release tablets. The preparation can also be in the form of a dragon or in the form of a syrup. Suitable topical preparations include ointments, liquids, creams, powders and spray preparations.

A suitable daily dose by oral administration would be

in the order of 100 mg to 1.2 g per day, in the form of dose units containing from 20 to 200 mg per dose unit. An appropriate administration in the case of a slow-release tablet would be two to three times a day.

Parenteral administration can be carried out by injections at intervals, or as a continuous infusion. Injection solutions can contain from 10 to 100 mg/ml active ingredient.

For topical application, a spray preparation can be used,

an ointment, cream or liquid. These preparations may contain an effective amount of the active ingredient, e.g. in the order of 1.5 to 2% by weight of the total preparation.

According to the invention, the new compound with the general formula I can be prepared by a primary amine with the formula:

reacted with a compound which can introduce the group The amine can be used as a free base or in the form of a salt with a weak acid, e.g. acetic acid. Compounds that can introduce the group are compounds with the formula where P is a leaving group. Reaction with is carried out by melting the reaction components at an elevated temperature, e.g. 100-120°C. Alternatively, the amine (II) and the compound can be stirred in aqueous solution at room temperature. Examples of leaving groups are halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, preferably thiomethyl. Introduction of the group can also be carried out by first reacting the amine (II) with a compound of the formula:

, where P is a leaving group as indicated above.

This reaction can be carried out in a solvent, e.g. ether or acetonitrile at a temperature from room temperature to reflux temperature. Treatment of the resulting compound of formula (III):

with a primary amine CH3NH2 at a temperature from room temperature to reflux temperature gives the desired end product. In another method, the compound of formula I can be prepared by starting with a starting material of formula (IV)

where R_ can be hydrogen or an acyl group such as acetyl or p-nitrobenzoyl.

The above compounds can be reacted with a thiol of the formula (V):

The reaction is preferably carried out at 0°C in concentrated hydrochloric acid.

In the above description of the methods which can be used for the preparation of the new compound of formula I, reference has been made to the primary amine of formula II. This intermediate can be prepared by a number of different methods which are described below.

The amine of formula (II) can be prepared from a furfuryl thiol of formula (VI):

by reaction with a u-bromoalkylphthalimide (VII): The group can be introduced into the resulting compound of formula (VIII):

by e.g. a Mannich reaction.

Removal of the protecting group by reaction with e.g. hydrazine hydrate, gives the amine of formula (II).

In an alternative method for preparing the amine of formula (II), 2-furfuryl chloride can be used as starting material. Reaction of furfuryl chloride with tu-aminoethylthiol where the amine group is protected, e.g. as the phthalimide (IX):

gives the intermediate of formula (VIII). This is treated as be-

written above to form the amine of formula (II).

In another method for producing the amine (II), a starting material of formula (X) is used:

This compound can be treated under acidic conditions with oo-aminoethylthiol in which the amine group can optionally be protected. Alternatively, the compound of formula (X) can be converted to the corresponding acetate before the reaction, under basic conditions with u-aminoethylthiol.

The primary amine of formula II can be prepared by reacting furan with butyllithium to form a lithium derivative (XI): which is then reacted sequentially with (i) an a,w-dihalogen compound Hal-CH2~S(CH2)2 ~Hal (where Hal is chlorine, bromine or iodine), and (ii) potassium phthalimide. The reaction product of formula (VIII)

is then subjected to e.g. a Mannich reaction and the protecting group is removed by reaction with e.g. hydrazine hydrate.

The intermediate of formula II can also be prepared using ethyleneimine. This compound is reacted with the isosteric thiol of the compound of formula X.

The amine of formula II can also be prepared by starting

with a compound of formula (XII):

A Mannich reaction is performed on this nitrile compound, followed by reduction with lithium aluminum hydride, to form the compound

with formula II.

When a Mannich reaction is used the group can

introduced at any suitable step, but the reaction is preferably carried out on compounds of formula (XIII) or

(VIII):

using formaldehyde and dimethylamine.

In an alternative method, furan-2-carboxylic acid is used as starting material. This is reacted with the amine of the formula (CH-j^NH to form an amide of formula (XIV), which is then reduced with, for example, lithium aluminum hydride to form a compound of formula (XV):

To convert the compound of formula XV to the compound of formula X, the hydroxymethyl group can be introduced using formaldehyde and acetic acid. Alternatively, the hydroxymethylation can be carried out using butyllithium, followed by formaldehyde.

When preparing the compound of formula I, one can react a compound of formula IV with the thiol of formula V. The compound of formula V can be prepared from a thiazolidine intermediate with the formula: by reaction with an amine CH3NH2- The thiazolidine (XVI) can be prepared from cysteamine and a bis-methylthio compound (XVII):

The following examples shall serve to further illustrate the invention. Examples A to D illustrate the preparation of the amine of formula II and related intermediates, and Examples 1-5 illustrate the present process for the preparation of the compound of formula I.

Example A

2-[[[ 5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine

5-(Dimethylamino)methyl-2-furanmethanol (15.5 g) was added dropwise to a stirred, ice-cold solution of cysteamine hydrochloride (11.36 g) in concentrated hydrochloric acid (40 ml). After standing at 0°

for 18 hours, excess anhydrous sodium carbonate was added,

and the resulting solid was extracted with diethyl ether. Removal of solvent followed by distillation of the residue gave 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine

(11.6 g), b.p. 104-106° (0.1 mm), picrate salt, m.p. 142-144°.

Example B

2-[ 2-[[( 2- furanyl) methyl] thio] ethyl]- 1H- isoindole- 1, 3( 2H)-dione

80% sodium hydride (1.58 g) was added portionwise to a solution of furfuryl mercaptan (6 g) in dry dimethylformamide

(50 ml). After 30 minutes, a solution of 2-bromomethyl-

phthalimide (16.71 g) was added in dry dimethylformamide (65 ml), and the solution was heated at 110° for 2 days. After removal of solvents, the residue was washed with water and extracted with ethyl acetate. The ethyl acetate extracts were combined, the solvent was removed, and the residue was recrystallized from cyclohexane to give 2-[2-[[(2-furanyl)methyl]thio]ethyl]-1H-isoindole-1,3(2H) -dione, sm.p. 62-63° (7.8 g).

Example C

2-[ 2-[[[ 5-( dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl] - 1H-isoindole- 1, 3( 2H)-dione

A mixture of 2-[2-[ [ (2-furanyl)methyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione (10 g), dimethylammonium chloride (3.1 g) and 36% formaldehyde solution (3 ml) in acetic acid (50 ml) was heated on a steam bath for 9 hours. The solution was cooled and the solvent was removed in vacuo. The residue was basified with 5N sodium hydroxide and extracted with ethyl acetate. The organic phase was treated with charcoal, dried and evaporated to give an oil which was purified by column chromatography (silica/ethanol: ethyl acetate 1:1) (5.7 g) Rf 0.4.

NMR (CDCl 3 /DMSO) : 7.71 s (6H), 7.22 s (2H), 6.52 s (2H), 6.2 s (2H), 6.1 t (2H), 3.8 m (2H), 2.2m (4H).

Example D

2-[[[ 5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine

2-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]-ethyl-1H-isoindole-1,3(2H)-dione (5.3 g) and hydrazine hydrate (0 .85 g) was refluxed in ethanol for 30 hours. Evaporation of the solvent gave the phthalhydrazine salt of 2-[[[5-(dimethylamino)-methyl-2-furanyl]methyl]thio]ethanamine.

Example 1

N-[ 2-[[[ 5-(dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]-N1- methyl- 2- nitro- 1, 1- ethenediamine

N-methyl-1-(methylthio)-2-nitroethenamine (230 g) in water (400 ml) was stirred and heated at 45-50°. 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (321 g) was added dropwise over 4 hours, and the resulting solution was stirred for an additional 3.5 hours. The solution was then heated under reflux for 1/2 hour, cooled to 70°, and 4-methylpentan-2-one (2 L) was added. The water was removed by azeotropic distillation under reduced pressure (260 torr),

and the resulting solution was treated with charcoal (10 g) at 50°. The solution was filtered and cooled to 10°. N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N1-methyl-2-nitro-1,1-ethenediamine (380 g) was filtered off and dried, sm. p. 69-70°.

Example 2

N-[ 2-[[[ 5-(dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]- N- methyl-2- nitro- 1, 1- ethenediamine

2-nitromethylenethiazolidine

A mixture of cysteamine hydrochloride (11.36 g), potassium hydroxide (5.61 g) and 1,1-bis(methylthio)-2-nitroethylene (16.52 g)

in water (30 ml) and ethanol (100 ml) was heated under reflux for 1 hour. The suspension was evaporated to dryness, the residue was suspended in water, filtered, and the residue was crystallized from methanol to give 2-nitromethylenethiazolidine (9.2 g), m.p. 141-142°.

Analysis:

C4H6N202S requires: C 32.87, H 4.14, N 19.17%

found: C 32.91, H 4.13, N 19.10%.

N-(2- mercaptoethyl)- N'- methyl- 2- nitro- 1, 1- ethenediamine

A solution of 2-nitromethylene-thiazolidine (5 g) in a

A 33% solution of methylamine in ethanol (40 ml) was kept at room temperature for 65 hours. The solid which separated was filtered, washed with ethanol and dried to give N-(2-mercapto-ethyl)-N'-methyl-2-nitro-1,1'-ethenediamine (4.98 g), sm.p. 174-175°, split. 209-211°.

Analysis:

C5H11N3°2S requires: c 33.88, H 6.26, N 23.71%

found: C 34.05, H 5.87, N 23.85%.

N-[ 2-[[[ 5-(dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]- N'-methyl- 2- nitro- 1, 1- ethenediamine

N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg)

in concentrated hydrochloric acid (2 ml) was added dropwise to 5-(dimethylamino)methyl 1-2-furan methanol (428 mg) at 0°. After standing at 0° for 7 days, the reaction mixture was diluted with water

(3 mL), excess potassium carbonate was added, and the solid was extracted with ethyl acetate (50 mL).

The solvent was evaporated and the residue was purified by preparative layer chromatography to give the title compound

(100 mg) as Example 1.

Example 3

N-[ 2-[[[ 5-(dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]-N'-methyl- 2- nitro- 1, 1- ethenediamine

N,N-dimethyl-2-furanmethanamine (125 mg) was dissolved in glacial acetic acid (1 ml) and paraformaldehyde (30 mg) was added. A resolution

of N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine (354 mg)

in concentrated hydrochloric acid (1 ml) and glacial acetic acid (1 ml) were added dropwise, and the mixture was allowed to stand at room temperature for 5 days. The solution was diluted with water (30 mL), saturated with potassium carbonate and extracted with ethyl acetate. The combined extracts were purified by preparative layer chromatography to give the title compound as Example 1 (89 mg).

Example 4

N-[ 2-[[[ 5-(dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]- N'-methyl- 2- nitro- 1, 1- ethenediamine

2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (4.25 g) and 1,1-bis(methylthio)-2-nitroethylene (3.3 g) were refluxed in acetonitrile (50 mL) for 14 h. Solvent was removed and the residue was dissolved in 36% methanolic methylamine (50 mL) and the solution was refluxed for 8 hours. Solvents were removed and the residue in methanol was treated with charcoal. Filtration and evaporation of the solvent gave the title compound as Example 1 (5.0 g).

Example 5

N- [ 2- [ [ [ 5-( dimethylamino) methyl- 2- furanyl] methyl] thio] ethyl]- N'- methyl-2- nitro- 1, 1- ethenediamine hydrochloride

N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (50 g, 0.16 mol) was dissolved in industrial denatured alcohol 74° o.p. (200 ml) containing 0.16

of an equivalent of hydrogen chloride. Ethyl acetate (200 mL) was slowly added to the solution. The hydrochloride crystallized out and was filtered off, washed with a mixture of industrial denatured alcohol 74° o.p. (50 ml) and ethyl acetate (50 ml) and was dried at 50°C. The product (50 g) was obtained as a whitish solid, m.p. 133-134°.

The compound of formula (I) has been found to be an inhibitor

for gastric acid secretion induced by histamine. This has been shown in rats using a modification of the method described by M.N. Ghosh and H.O. Schild in the British Journal of Pharmacology 1958, vol. 13, page 54.

Female rats weighing 150 g are starved overnight and

gets 8% sucrose in normal saline instead of drinking water.

The rats are anesthetized with a simple intraperitoneal injection

of 25% weight/volume urethane solution (0.5 ml/100 g), and in trachea-

and jugular veins are inserted cannulas.

A midline incision on the abdominal wall is made to expose the stomach which is separated from the liver and spleen by cutting open the connective tissue. A small opening is made in the fundus area of the stomach, and the stomach is washed with a 5% dextrose solution. A cannula with a rubber tube is inserted into the oesophagus, and the esophagus and vagus are then cut above the cannula.

A small opening is then made in the pylorus area i

the stomach. A large perspex cannula is inserted into the stomach via the opening

in the fundus area, in such a way that the inlet end of the cannula comes out of the stomach through the opening in the pyloric area. The cannula is of such a shape that it reduces the effective volume of

the stomach and induces a turbulent flow of the perfusion fluid over the mucosal surface. A drainage cannula is then inserted through the opening in the fundus area of the stomach. Both cannulas are tied in place using a ligature around the abdomen, positioned to avoid the main blood vessels. Puncture wounds are then made in the body wall, and the needles are passed through. The stomach is perfused through the esophagus and

the pylorus cannulae with 5% dextrose solution at 39°C in a quantity of 1.5 ml/minute for each cannula. The flowing liquid is passed over a microcurrent pH electrode and recorded via a pH meter and a so-called "flat bed recorder" .

The basal production of acid secretion from the stomach is controlled by measuring the pH of the perfusion outflow, and then increased acid secretion is induced by means of a continuous intravenous infusion of a sub-maximal dose of histamine. This induces a stable level of acid secretion, and the pH of the perfusion effluent is determined when this condition is achieved.

The test compound is then administered to the rat

by an intravenous injection, and the change in "stomach" acid secretion is monitored by measuring the change in pH in the perfusion outflow.

From the change in pH in the perfusion outflow,

the difference in acid secretion between basal production and the histamine-stimulated level is calculated as hydrogen ion concentration in mol/litre. The reduction in acid secretion caused by the administration of the test compound is also calculated as the change in hydrogen ion concentration in mol/liter from the difference in pH of the perfusion effluent. The percentage reduction in acid secretion caused by administration of the test compound can then be calculated on the basis of the two values obtained.

EDc-Q values for inhibition of acid secretion are determined by

administering one dose of the test compound to one rat and repeating this in at least four rats for each of three or more dose levels. The results obtained are then used to calculate the ED(-0 value by the standard least square method, as used for any dose-response line.

Using the method described above, an ED5Q value of 0.18 mg/kg was obtained for the compound of formula I.

Claims (2)

1. Analogy method for the preparation of a therapeutically active aminoalkylfuran derivative of formula I and physiologically acceptable salts thereof, characterized in that (a) the compound of formula II: is traded with a compound that is capable of introducing the group or (b) a compound of formula III: where P is a leaving group, is reacted with the primary amine of the formula CH^NP^; or (c) a compound of the formula: where R 7 is hydrogen or an acyl group, is reacted with a thiol of formula V: or (d) 2-nitromethylenethiazolidine is reacted with methylamine followed by reaction with 5-(dimethylamino)methyl-2-furan-methanol in the presence of an acid; then, for the preparation of physiologically compatible salts, the compound of formula I or a salt thereof is treated with a suitable inorganic or organic acid. 2. Method according to claim 1 for producing the hydrochloride of the compound of formula I, characterized in that a compound of formula I or a salt thereof is reacted with hydrochloric acid.