DE2844104A1 - HALOGENMETHYL DERIVATIVES OF HISTAMINE AND RELATED COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

_ 5 -
our no. 22 157 Ka / Hs

Merrell Tcraude et Compagnie 67OOO Strasbourg, France

Halomethyl derivatives of histamine and related compounds and processes for their preparation

The present invention relates to new pharmaceuticals useful halomethyl derivatives of histamine and related compounds and processes for their preparation.

Most mammalian tissues contain histamine, its Concentration is particularly high in the skin, intestinal mucosa and lungs. Each Histamine containing mammalian tissues including white blood cells appear to be able to get out Histin to synthesize the amine. The main enzyme that In vivo, the conversion of histine to histamine catalyzes, histine decarboxylase is responsible for the substrate L-histine is specific. In many tissues, the main source of histamine is the mast cell or, in the case of Blood, the basophil cell, which is the circulating counterpart of the mast cell fixed in the tissue.

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Mast cells are not the only tissue source of histamine, which is found in substantial quantities in the human epidermis, the central nervous system and the gastrointestinal mucosa is present.

Histamine is involved in various physiological processes. Histamine is released during the antigen-antibody reaction released and is largely responsible for the hypersensitivity reaction - caused by vasodilation, Characterized itching and edema formation are responsible. The type of antigen-antibody reaction that is involved Major cells are the mast cells and basophils from which histamine is released often referred to as an immediate hypersensitivity reaction. In addition to antigens or allergens is histamine through many chemical substances, macromolecules, animal poisons, physical insults (physical insult), how heat and other harmful stimuli are released. The gastric acid secretion is known to be through Histamine is stimulated. Histamine is also known to be involved in the initiation of pain and itching evoking sensory impulses is involved. It was also found that histamine levels in many tissues subject to rapid growth, e.g., embryonic Tissue, regenerative liver growth, and malignant growth are high.

Correlations between histamine levels and histidine decarboxylase activity in tissues were investigated. In the brain, which contains histamine and histidine decarboxylase, the conversion of histamine takes place through Stress stimuli, which also increase histidine decarboxylase activity, are increased rapidly. Inhibitors of L-histidine decarboxylase, such as a-hydrazinohistidine,

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are known to reduce histamine levels to decrease. In rat fetal tissue where histamine is present in high concentrations, it has been shown that the Inhibition of L-histidine decarboxylase fetal development inhibits.

The effects of histamine and its mode of action are good documented. It is believed that the amine works through at least two receptors, called Hv and H ^ receptors are classified, exerts. Different Agents are known to counteract the effects of histamine, but not all prevent such Means the formation of histamine. For example, it is believed that classic antihistamines that are useful in the treatment of allergic reactions are useful by disrupting the binding of histamine with ^ receptors exercise. Of Similar Agents That Are Useful To The Stimulatory Effect Of Histamine On Gastric Acid Secretion To counteract this, it is believed that they act by preventing histamine from binding to Hp receptors disturb.

Agents capable of blocking H ^ receptors, found in the treatment of acute exudative types of allergies, such as seasonal rhinitis, hay fever, hay fever with sneezing (pollinosis relieving the sneezing), runny nose, itchy eyes, nose and throat, use. Such agents are also useful in controlling coughs and have some use in the treatment of systemic anaphylaxis and bronchial asthma. Antihistamines, which have H receptors are also effective in treating allergic

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Dermatoses such as acute and chronic urticaria, vascular edema, tingling itchy skin, e.g. atopic dermatitis and contact dermatitis, in the treatment of urticarial cells and edematous harm of serum sickness, in combating of blood transfusion reactions and drug reactions, attributable to allergic phenomena are useful. Agents that block the Hp receptors, are used in the treatment of gastric ulcer, Zollinger-Ellison syndrome and other gastric hypersecretory States useful.

Agents which block the formation of histamine by inhibiting the activity of histamine decarboxylase, e.g. α-methyl histidine and α-kydrazinohistidine are, as reported becomes useful in the same way as antihistamines that block H ^ and Hp receptors. Additionally are the histidine decarboxylase inhibitors in the fight against certain tumors that are high in histamine exhibit, valuable.

The compounds of the present invention inhibit the formation of histamine by inhibiting the action of histidine decarboxylase, which makes the compounds useful in the treatment of pathophysiological conditions resulting from histamine. The compounds of the invention can be used in the same manner and for the same purposes as the compounds H-- and H ₂ ^- receptors antagonize be used.

The compounds of the invention have the general Formula IJ

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CH ₂ -CH-NHR (D.

wherein Y is a radical of the formula PCHp-, PpCH- or F-rC-, R is a hydrogen atom, an alkyl carbonyl radical, in which the alkyl part has from 1 to 4 carbon atoms and is straight or branched, an alkoxycarbonyl radical, the alkoxy part having 1 to 4 carbon atoms and is straight or branched, or a radical of the formula |

-C-CH-R,

I ³

NH ₂

wherein R, represents a hydrogen atom, a straight or branched chain lower alkyl radical having 1 to 4 carbon atoms, a benzyl radical or a p-hydroxybenzyl radical, and each of the radicals R ₁ and Rp, which can be the same or different, represents a hydrogen atom or a straight or branched-chain lower alkyl radical having 1 to 4 carbon atoms or R _{1 is} a hydrogen atom and R _{2 is} a fluorine atom.

The present invention also encompasses pharmaceutical acceptable. Salts and individual optical isomers of the compounds of the general formula I.

Illustrative examples of straight or branched chain lower alkyl radicals having 1 to 4 carbon atoms, such as they are used in the above formula I are the / ethyl radical ', n-propyl radical, isopropyl radical, n-butyl radical and the tert-butyl radical.

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The term alkylcarbonyl used in the above general formula means one Radical of the formula 0, in which the alkyl radical

-C alkyl

is straight or branched and has 1 to 4 carbon atoms, e.g. the methyl radical, ethyl radical, n-propyl radical, Isopropyl radical, n-5utyl radical and tert-butyl radical.

The term alkoxycarbonyl radical used in the general formula I denotes a radical of the formula j

-C-O-alkyl

wherein the alkoxy radical, i.e. the -O-alkyl radical from 1 to Has 4 carbon atoms and is straight or branched chain is, such as the methoxy radical, ethoxy radical, n-propoxy radical, Isopropoxy, n-butoxy and tert-butoxy.

Examples of pharmaceutically acceptable salts of the invention Compounds include non-toxic acid addition salts with inorganic acids such as hydrochloric acid, hydrogen bromide acid, sulfuric acid and phosphoric acid, and organic acids such as kethanesulfonic acid, salicylic acid, Maleic acid, cyclamic acid, malonic acid, tartaric acid, citric acid and ascorbic acid are formed. The salts are produced in the usual way.

Preferred compounds of the invention are those compounds of the general formula I, in which R is a hydrogen atom or an alkylcarbohyl radical, in which the alkyl moiety straight or branched chain and 1 to 4 carbon

represents
having atoms, compounds in which R is a hydrogen atom are particularly preferred. Another preferred embodiment relates to compounds of the general formula I in which each of the radicals R ″ and Rp denotes a hydrogen atom or a methyl radical. Compounds of the general formula I in which R _{1 denotes}

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- ii -

Hydrogen atom and R-, meaning a fluorine atom, are also preferred. Particularly preferred according to the invention Compounds are those of the general formula I in which Y is a radical of the formula FCHp- or FpCH-.

Illustrative examples of compounds according to the invention are the following:

l-fluoromethyl-2- (5-imidazcly1) ethylamine, l-fluoromethyl-2- [5 "(2-fluoro) imidazolyl methylamine, 1-trifluoromethyl-2- [5 - (^ - methyl) imidazolylethylamine, l-fluoromethyl- 2- [5- (2, M-dimethyl) imidazolyl-ethylamine, 1-difluoromethyl-2- [5- (2, ^ - diethyl) imidazolyl-ethylamine, 1-trifluoromethyl-2- [5- (2, k -diisopropy1) imidazolyl-ethylamine, l-fluoromethyl-2- [5- (2,4-di-tert-butyl) imidazolylethylamine, 1-difluoromethyl-2- [5- (2-η-butyl) imidazolyl3ethylamine, N- [1-difluoromethyl-2- [5- (2-fluoro) imidazolyl-ethyl-acetamide, N- [1-fluoromethyl-2- (5-ircidazolyl) ethyl] -methyl-carbamate, N- [1-fluoromethyl-2- [5- (2-ethyl) imidazolyl-3-ethyl 3 -2-aminopropionamide and

N- [1-Difluoromethyl-2- (5-imidazolyl) ethyl3-2-amino-3-phenylpropionamide.

The compounds of the formula I according to the invention are irreversible inhibitors of histidine decarboxylase, the enzyme that converts histidine into histamine in vivo. So the compounds block the formation of histamine, which is known to play an important role in certain pathophysiological conditions. As inhibitors of histidine decarboxylase, the compounds according to the invention are of the same type and Way like well-known antihistamines whether such compounds increase their effectiveness by blocking the H ^ and Hg receptors or wield other smocks, useful.

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The compounds of the invention are useful in Treatment of histamine-related pathophysiological conditions. So are the inventive Compounds of general formula I valuable in the treatment of acute exudative types of allergy, such as seasonal rhinitis, hay fever and hay fever with sneezing, runny nose, itchy eyes, itchy nose, and itchy throat. The compounds of general formula I. are also useful in the treatment of cough and systemic anaphylaxis and bronchial asthma and are also valuable as eronchodilators. The compounds of general formula I are also in the treatment allergic dermatoses such as acute urticaria, chronic urticaria, tissue edema, tingling itchy skin, e.g. atopic dermatitis and contact dermatitis, valuable. The compounds of general formula I are also useful in the treatment of urti ° .arial and edematous damage to serum sickness, blood transfusion reactions, attributable to the allergic phenomenon and vomiting. The connections of the general Formula I are also used in the treatment of gastric ulcer, Zollinger-Eliison syndrome and others gastric hypersecretion. As described above, it was found that histamine concentrations are high in rapidly growing tissues such as tumors, so the compounds of the invention of the formula I by inhibiting the formation of histamine in combating the growth of certain tumors, e.g., Walker's mammary carcinoma and Ehrlich's ascites tumors.

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The compounds according to the invention can be used to achieve the desired effect can be administered in various ways. The compounds according to the invention can alone or in the form of pharmaceutical preparations to the patient to be treated either orally, parenterally, i.e. administered subcutaneously, intravenously or intraperitoneally .. or topically. The connections can be made by intranasal Instillation or application to the mucous membranes such as those of the nose, throat and trachea, e.g. in an aerosol spray, the small particles of an inventive Compound in a spray solution or in dry powder form, are administered.

The amount of new compound administered will vary and can be any effective amount. Depending on the patient, the condition being treated and the mode of administration, the amount of the new compound administered can vary over a wide range to an effective amount in unit dosage form of about 0.1 to 500 mg / kg of patient body weight per dose and preferably mg of about 50 to 200 / kg body weight to achieve the desired effect bereitzu- / ^e Z.§? ', the desired effect can be obtained by administration of a dosage unit such as a tablet of 10 to 500 mg of a novel compound of the invention, one to be obtained four times a day.

As used herein, the term "patient" means Warm-blooded animals such as birds and acid animals, e.g. cats, dogs, rats, mice, guinea pigs, sheep, horses, cattle and people.

The solid dosage unit forms can be of the usual type. So the solid form can be a capsule that corresponds to the usual gelatin capsule, which is an inventive

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appropriate compound and a carrier, e.g., lubricants and inert fillers such as lactose, sucrose and corn starch contains. According to another embodiment can the erfindungsgeir.äSen compounds with customary Tablet bases such as lactose, sucrose or corn starch in combination with binding agents such as acacia gum, Corn starch or gelatin, disintegrating agents such as corn starch, potato starch or alginic acid, and one Lubricants such as stearic acid or magnesium stearate can be tabletted.

For parenteral administration, the compounds as injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutically acceptable carrier such as a sterile liquid such as water and oils or administered without the addition of a surfactant and other pharmaceutically acceptable adjuvants will. Examples of oils that can be used in these preparations are those made from crude oil, animal, of vegetable or synthetic origin, e.g. peanut oil, soybean oil and mineral oil. In general are water, Table salt, aqueous dextrose and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol preferred liquid carriers, especially for injectable solutions.

The compounds can be in the form of a depot injection or an implant preparation that can be formulated to provide a delayed release of the Allow active ingredient to be administered. The active ingredient can be pressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injection or implantation. Implants can be inert

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Materials, such as biodegradable polymers or use synthetic silicones, e.g. silicone rubber (Silastic, Dow-Corning Corporation).

For use as aerosols, the inventive Compounds in solution or suspension together with a gaseous or liquefied propellant, e.g. dichlorodifluoromethane, dichlorodifluoromethane with dichlorodifluoroethane, carbon dioxide, nitrogen or Propane with the usual adjuvants such as cosolvents and wetting agents, if necessary or desired, packaged in a pressurized aerosol container will. The compounds can also be in a non-pressurized form, such as in a nebulizer or an atomizer.

The utility of the compounds of the general formula I according to the invention as irreversible inhibitors of Hydroxide decarboxylase can be demonstrated as follows: A compound of the general formula I becomes administered either orally or parenterally as an aqueous solution or suspension to rats or mice. At different Time intervals after administration of test compound are given intraperitoneally to animals 2 / µCi

2- C-L-histidine administered. Two hours after the injection of labeled histidine, the animals are killed and the amount of radioactive histamine that is in the glandular part of the stomach is present, as described by K.M. Mole and D.M. Shepherd, J. Pharm. Pharnac. 25, 609-613 (1973) described, certainly.

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In addition to having utility as pharmacological agents, the compounds of the invention are wherein R is Hydrogen atom means useful as intermediates for the preparation of cephalosphorine derivatives general formula II

Y
CH ₂ -CHNHCH ₂ ,.,. _(ΙΙ)

COOM

wherein X is a hydrogen atom or a / jicetoxy radical and M represents a hydrogen atom or a negative charge and R ^, Rp and Y are those above for the general Formula I have the meaning given as antibiotics

are useful.

The compounds of general formula II and the pharmaceutically acceptable salts and individual optical Isomers of these are new compounds that are useful as antibiotics and in some manner similar to that of many well-known cephalosporin derivatives, e.g. cephalexin, cephalothin or cephaloglycine can be administered. The compounds of general formula II and pharmaceutically acceptable salts and isomers thereof can be used alone or in the form of pharmaceutical preparations either orally or parenterally and topically to warm-blooded animals, i.e. birds and mammals, e.g. cats, dogs, cattle, sheep, horses and humans, administered. For oral administration, the compounds can be in the form of tablets, capsules, or pills

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or be formulated in the form of elixirs or suspensions. For parenteral administration, the compounds of a sterile aqueous solution can best be in the form used, the other solutes, for example, contain sufficient saline or glucose to make the solution isotonic to. For topical administration, the compounds of general formula II, salts and isomers thereof can be incorporated into creams or ointments.

Illustrative examples of bacteria against which the compounds of general formula II and the pharmaceutical acceptable salts and individual optical isomers thereof are effective are Staphylococcus aureus, Salmonella schotmuehleri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyogenes.

Illustrative pharmaceutically acceptable non-toxic inorganic Acid addition salts of the compounds of the formula II are mineral acid addition salts, e.g. hydrochlorides, Hydrobromides, sulfates, sulfamates, phosphates, and organic Acid addition salts, e.g. maleates, acetates, citrates, oxalates, succinates, benzoates, tartrates, fumarates, malates and ascorbates. The salts can be prepared in the usual way.

Illustrative examples of cephalosporin derivatives of the general formula II are 7 - [[2- [4- [l-fluoromethyl-2- ( ² l-imidazolyl) ethylaminomethyl3-3phenyl3-acetyl3amino3-3-acetyloxymethyl- & - oxo-5-thia-1 -azabicyclo [ ¹ <.2.03oct-2-en-2-carboxylic acid, 7 - [[2- [4- [l-difluoromethyl-2- [5- (2-fluoro) -imidazolyl3ethylaminomethyl3phenyl3acetyl3amino3 "3- acetyloxymethyl-8- oxo-5-thia-l-azabicycloC ⁱ t.2.Q3oct-2-en-2-carboxylic acid and 7 - [[2- [4- [l-fluoromethyl-2- [4- (2,5-dimethyl) -imidazolyl3ethylaminomethyl3-phenyl3acetyl3amino3-3-acetyloxymethyl-8-oxo-5-thia-1-azabicycloj. " ⁱ {.2.03oct-2-en-2-carboxylic acid.

817 / 0S92

The compounds of the general formula II are prepared by a compound of the general Formula III

C! CH ₂ -O- CH ₂ -C-HN

ti

CH ₂ X

I COOM

wherein X and M have the meanings given above for the general formula II, which are as in US-PS 3,919,206, incorporated herein by reference, with a compound of the general Formula I in which R is a hydrogen atom. The reaction is generally carried out in a solvent such as a lower alcohol such as methanol, ethanol or isopropyl alcohol or dimethyl sulfoxide, dimethylformamide or aqueous mixtures of these solvents ". The reaction temperature can be from about 0 to 125 C and the reaction time from about 1/2 hour to Vary 24 hours. Following the solvolysis reaction the amino protecting group is removed by acid hydrolysis and the cephalosporin products are removed by customary Techniques isolated.

The compounds of the general formula I in which R is a hydrogen atom are prepared by that a suitably substituted 5-imidazolyl halomethyl ketone derivative, as described below by formula IV, reduced to the corresponding alcohol, that in a solvent such as ethers, e.g. diethyl ether, tetrahydrofuran or p-dioxane, benzene or dimethoxyethane

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under an inert atmosphere, for example nitrogen or argon, at about 0 to ICO ⁰ C, preferably about 25 ° C, for about 1/2 hour to 2 hours J ¹ with one equivalent of an imide, such as phthalimide, succinimide, or maleimide, 1.1 Equivalents of a phosphine, for example triphenylphosphine, or of a trialkylphosphine, such as tri-n-butylphosphine, and 1.1 equivalents of diethylazodicarbxylate is treated. The imido derivative obtained is then hydrolyzed to the free amine.

[■ · «= Ii It -I ^ α - ^ jj - (IV)

^Rl

In this general formula IV, Y, R ₁ and Rp have the meaning given above for general formula I.

The reduction of the ketones of the general formula IV to the corresponding alcohol is carried out chemically using, for example, 1 to 10 equivalents of a metal hydride reducing agent, such as lithium borohydride, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride, borane or dimethylthioborane, or catalytically using, for example, Raney Nickel, rhodium, palladium on carbon or platinum oxide achieved. The total reaction time varies from about 10 minutes to 2k hours and the temperature varies from about -kō ° C to 100 ⁰ C, depending on the applied reducing agent. The reaction time varies with chemical reduction

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generally from about 10 minutes to 2 hours, ¹ I, wherein the temperatures of about -40 ° C to 65 C vary. Suitable solvents for the chemical reduction of compounds of the general formula IV include lower alcohols such as methanol or ethanol or ethers such as diethyl ether or tetrahydrofuran. In the case of catalytic reduction, the reaction time varies from about 1 hour to 24 hours, the reaction temperatures varying from about 25 to 100 ° C. and the pressure varying from 1 atmosphere to 120 atmospheres. Suitable solvents for the catalytic reduction of the compounds of the general formula IV include lower alcohols, for example methanol or ethanol, acetic acid or ethyl acetate. Chemical reduction is preferred.

The hydrolysis to the amine and removal of any ring protecting groups is carried out using a strong one Mineral acid, e.g. hydrochloric acid, hydrobromic acid, or sulfuric acid, or an organic acid, e.g. Toluenesulfonic acid or trifluoroacetic acid in water at reflux temperature within about 4 to 48 hours or using, for example, 1 to 3 equivalents. Hydrazine, methylhydrazine or methylamine at a temperature of about 25 ° C to reflux of about 1 hour to 12 hours followed by treatment with a strong mineral acid or organic acid such as described above, or by hydrogenolysis of the protecting group as appropriate.

As indicated above, tri-alkylphosphines such as tri-n-butylphosphine can be used in the reaction will. The term "alkyl" means an alkyl radical having 1 to 10 carbon atoms. The tri-alkylphosphines are known in the art or can be made by methods known in the art.

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The compounds of the general formula I in which R is an alkylcarbonyl radical, the alkyl moiety being straight or branched-chain and having 1 to 4 carbon atoms, are prepared by the corresponding derivatives in which R is a hydrogen atom in water in the presence of a base such as sodium hydroxide or sodium borate, 1/2 hour to 6 hours at a temperature of ⁰ ° C. to 25 ° C. with an acid halide of the formula 11

R ₁₁ -C Halo

wherein Halo is a halogen atom, for example a chlorine atom or a bromine atom, and R _{1 is} a straight or branched chain alkyl radical having 1 to 4 carbon atoms.

The compounds of general formula I in which R is an alkoxycarbonyl radical in which the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms are prepared by reacting the corresponding derivative in which R is hydrogen in the presence of water a base, such as sodium hydroxide or sodium borate, from about 1/2 hour to 6 hours at a temperature of about O ⁰ C to 25 ° C with a

Alkyl haloformate of the formula? _{wherein Ha} io

naJ.o — L'— UJt _{1 -}

a halogen atom, such as a chlorine atom or a bromine atom, and R ₁ - denotes a straight or branched-chain alkyl radical having 1 to * J carbon atoms.

The compounds of the general formula I in which R is a radical of the formula υ

-C-CH-R,

NH ₂

wherein R, a hydrogen atom, a straight or branched chain means lower alkyl radical with 1 to 4 carbon atoms, a benzyl radical or a p-hydroxybenzyl radical, representi

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are prepared by the corresponding derivative, in which R is a hydrogen atom, in a solvent such as tetrahydrofuran, dioxane or other ethers or methylene chloride or chloroform _; and in the presence of a dehydrating agent, if the free acid is used, at a temperature of about O ⁰ C to 35 C for about 1 hour to 12 hours with an acid of the formula HOOC-CH-R,,

. NH ₂

wherein R, has the meaning given above and the amino group is suitably protected, e.g. with a tert.-butoxycarbonyl radical or a benzyloxy

carbonyl radical, or an anhydride thereof, and then treated acidic or basic hydrolysed.

The compounds of the general formula IV in which Y is a radical of the formula FCH ₂ - are prepared by adding a suitably substituted 5-imidazolylmethyl-substituted methyl ketone of the formula V

- (Z)) - CH ₃

(V)

wherein R ₁ and Rp have the meanings given above for the compounds of the formula I and Rg is a suitable leaving group, such as a halogen atom, for example a chlorine atom, a bromine atom or an iodine atom, a mesylate radical, a tosylate radical, a triflate radical or a prifluoroacetate radical , in a suitable solvent such as direthoxyethane, dimethyl sulfoxide, dimethylformamide, ethylene glycol, acetonitrile, acetone, benzene or hydrogen fluoride at a temperature of about 0 to 200 ⁰ C for about 2 to 48 hours with a suitable

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Fluorinating agents, such as potassium chloride, silver fluoride, cesium fluoride, thallium fluoride or / butylammonium fluoride. The Laaving group Rg in formula V can likewise be a diazo group, in which case the fluorinating agent used is hydrogen fluoride / pyridine. Suitable solvents for the reaction in which Rg is a diazo group are aprotic solvents such as diethyl ether, tetrahydrofuran and pentane. The reaction time varies from about 30 minutes to 2k hours at a temperature of about -20 to 65C ⁰ C. A suitable diazoketone derivative, ie a compound of formula V where Rg represents a diazo group, in a suitable aprotic solvent is a solution of Hydrogen fluoride / pyridine cooled to -10 ° C was added. The reaction mixture is stirred vigorously for 1 hour at -10 ° C., then for 2 hours at about 25 ° C. and then poured into ice. The organic phase is separated off, washed with base, for example sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo, a suitably substituted 5-imidazolylmethyl-fluoromethyl-ketone derivative of the formula IV being obtained.

The diazoketone D.erivate, ie the compounds of the formula V in which Rg is a diazo group, are converted slowly from the corresponding acid halide, ie from a suitably substituted 2- (5-imidazolyl) acetyl halide, the halide being, for example, chloride adding subsequently the acid halide in an aprotic solvent such as diethyl ether, tetrahydrofuran, pentane _s hexane, benzene, dimethoxyethane or dioxane to a solution of diazomethane, which was cooled to about -40 to 20 ^0C in ether and about 1 hour to 2i »-Hour vigorous stirring at about 25 ° C obtained. The diazoketone derivative thus obtained can be prepared by standard methods, eg Verdampfenjdes Lösungsmittelß be with purification by crystallization or chromatography can be isolated or without isolation with a suitable fluorinating agent, as described above, ■ - '■ -----

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be treated.

The appropriately substituted diazoketone derivative described above can also be used to prepare compounds of the formula V ₃ wherein Rg is, for example, halogen, mesylate, tosylate, triflate or trifluoroacetate, by methods generally known in the art. To obtain compounds of the general formula V in which Rg is an Ealogenatom, such as a chlorine atom, a bromine atom or an iodine atom, the corresponding compound of the formula V, in which Rg is a diazo group, in a suitable aprotic solvent with aqueous hydrogen chloride, hydrogen bromide or Treated hydrogen iodide. To obtain compounds of the formula V in which Rg is a mesylate, tosylate, triflate or trifluoroacetate radical, the corresponding diazoketone derivative, ie a suitable compound of the formula V in which Rg is a diazo group, is treated with dilute sulfuric acid in a suitable aprotic solvent , the corresponding 5-iniidazolylmethyl-methanol ketone derivative being obtained which is esterified with a suitable acid chloride or anhydride of methanesulfonic acid, p-toluenesulfonic acid, trifluoromethylsulfonic acid or trifluoroacetic acid.

The suitably substituted 2- (5-imidazolyl) acetyl halide, which is used for the preparation of the diazoketone derivatives of the formula V ,. ie compounds in which Rg is a diazo group is used, is converted from the corresponding acids ^ for example by treatment with thionyl chloride in an aprotic solvent, such as diethyl ether, tetrahydrofuran, benzene or dichloromethane, at temperatures in the range from about ⁰ ° C. to the reflux temperature of the solvent obtained for about 1 to 2k hours. Alternatively can

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Are treated at a temperature of about ⁰ ° C to 4O ⁰ C for about 1 hour to 24 hours, 1 equivalent of the corresponding acid with 1 equivalent of oxalyl chloride in an aprotic solvent, as indicated above. The appropriately substituted 2- (5-imidazolyl) acetic acid derivatives used as described above are obtained by treating the appropriate acid in the presence of a base for about 4 to 20 hours at about 25 ° C. with p-toluenesulfonyl halide, for example p-toluenesulfonyl chloride. The appropriate acids are known in the art or can be obtained by acidic or basic hydrolysis of an appropriately substituted 5-imidazolylacetronitrile by methods known in the art. The appropriately substituted 5-imidazolylacetonitriles are known in the art or can be obtained by treating the corresponding 5-imidazolylmethyl halide, e.g. the chloride, with potassium cyanide or sodium cyanide in a protic solvent such as ethanol, dimethoxyethane, water or glycol, or an aprotic solvent such as diethyl ether , benzene, hexamethylphosphoric triamide, dimethyl sulfoxide, dimethylformamide, acetamide or dimethylacetamide are produced in a period of about 1 hour to 48 hours at a temperature of about 0 to 150 ⁰ C. The appropriately substituted 5-imidazolylmethyl halides are known in the art or can be prepared by methods well known in the art from the corresponding, appropriately substituted 5-imidazolylmethanol derivatives known in the art, e.g., by treating the appropriate methanol with hydrohalic acids, e.g., hydrogen bromide, Hydrogen iodide or hydrogen chloride, or by treatment with thionyl chloride, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride.

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The compounds of the general formula IV, wherein Y denotes a radical of the formula FpCH- are prepared by adding [[(methylsulfinyl) methyl3thio3-methane or [[(Ethylsulfinyl) methyl3thio3ethane treated with a suitable strong base and then the obtained product with a suitably substituted 5-imidazolylmethyl derivative of the formula VI

in which R ₁ and Rp have the meaning given above for formula IV, alkylated, the suitably substituted 5-imidazolylmethyl-substituted sulfinyl derivative obtained in this way is treated with a suitable strong base, the product thus obtained is alkylated with a suitable halomethylhalogenoalkylating agent, such as chlorodifluoromethane, bromodifluoromethane or difluoromethane , hydrolyzed the product thus obtained with aqueous acid and the so obtained, suitably R ₁ , Rp-substituted 5-acetoxymethylimidazole derivative in the presence of a base such as sodium carbonate or an organic amine, for about 4 to 20 hours at about 25 ° C with a p-toluenesulfonyl halide, e.g. p-toluenesulfonyl chloride, treated,

Suitable strong bases, which are used in the above-described, benen production of the difluoromethyl-substituted ketone derivatives can be used, for example Sodium hydride, dilithium acetylide, lithium diisopropylaniid, butyllithium, potassium tert-butoxide, sodium tert-butoxide, Lithium tert-butoxide, phenyllithium, methyllithium,

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Sodium amide, lithium amide or potassium hydride.

The alkylation reactions described in the preparation of the difluoromethyl ketone derivatives are carried out in a suitable solvent such as tetrahydrofuran, diethyl ether, hexamethylphosphoric triamide, dimethyl sulfoxide or benzene at a temperature in the range from about -78 to 65 ^° C. within 30 minutes to 24 hours. A preferred temperature for the difluoromethyl alkylation step is about 40 ° C. The alkylated sulfinyl intermediates are prepared by quenching with saturated sodium chloride solution (brine) and then extracting with, for example, diethyl ether, dichloromethane or benzene.

The hydrolysis of the alkylated sulfinyl derivatives to the ketone is effected using aqueous mineral acid such as hydrochloric acid, hydrobromic acid, perchloric acid or sulfuric acid in a solvent such as tetrahydrofuran, acetonitrile, diethyl ether or benzene at about -20 to 105 ° C, preferably in about 2 hours. In general, 0.3 equivalents of mineral acid in 1.5 % water are used. The preparation of the difluoromethyl ketone derivatives of the formula IV is illustrated in more detail by the specific examples.

The compounds of the formula VI are prepared by using the appropriately substituted imidazol-5-ylmethanol derivatives of formula VII

NH

CH ₂ OH

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-28- 284410

wherein R ₁ and R _{2 have} the meaning given above in formula YI, treated in the presence of a base at about 25 ° C for about 4 to 20 hours with a p-toluenesulfonyl halide, for example p-toluenesulfonyl chloride, the corresponding l-tosylimidazole-5 -ylmethanol is obtained, which is treated with acetic anhydride in the presence of an organic base such as triethylamine for about 2 to 6 hours at about 25 ° C.

The compounds of the general formula IV, in which Y is a radical of the formula F, C-, are prepared by reacting a compound of the formula VI for about 10 minutes to 96 hours at about 25 ° C to the reflux temperature of the solvent in a solvent such as treated with triphenylphosphine in hydrocarbons, for example benzene or toluene, or lower alcohols, such as methanol or ethanol, or acetonitrile, tetrahydrofuran, diethyl ether or dimethoxyethane. After cooling, a precipitate forms, which is washed with solvent and recrystallized using, for example, ethyl acetate, acetonitrile or a lower alcohol to give the appropriately substituted 5-imidazolylmethylphosphine salt. The appropriately substituted 5-imidazolylmethyl phosphonium salt can also be obtained by treating an appropriately substituted 5-imidazolylmethanol with a triphenylphosphonium salt such as triphenylphosphonium bromide using generally the same reaction conditions as given above. The appropriately substituted 5-imidazolylmethyl-triphenylphosphonium salt is added to excess (up to 25 %) sodium or lithium metal, which is dissolved in liquid ammonia, to which a catalytic amount of iron (III) nitrate is added over a period of about 10 minutes with stirring · 3 hours is added, after which the ammonia under an inert atmosphere, such as nitrogen or

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Argon, is evaporated. A suitable solvent such as benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane is added and the resulting 5-imidazolylmethylidene phosphorane is collected. The 5-Imidazolylmethylidenphosphoran is about 30 minutes to 24 hours under an inert atmosphere, such as nitrogen or argon, at a temperature of about 0 C to the reflux temperature of the solvent in a solvent such as benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane, with a Treated esters, such as a lower alkyl ester, e.g. methyl ester, ethyl ester, n-propyl ester, isopropyl ester or n-butyl ester of trifluoroacetic acid, after which the reaction mixture is concentrated and distilled, the olefin being obtained, which is obtained with aqueous mineral acid such as hydrochloric acid or hydrobromic acid, or an organic acid such as trifluoroacetic acid or p-toluenesulfonic acid using a co-solvent such as tetrahydrofuran, diethyl ether or benzene, for about 30 minutes to 24 hours at a temperature of about ⁰ ° C. to the reflux temperature of the solvent. The amount of acids employed can vary from a catalytic amount to a concentrated acid. The chemistry employed in the preparation of the compounds of the formula IV in which Y is a radical of the formula F, C-, as described above, is generally used by PH Betmann, Ang. Chem. Int. Ed. 1966, p. 308.

The following examples serve to further illustrate the present invention.

909817/0892

example 1

7- (( ¹ J- (1-difluoromethyl-2- (5-imidazolyl) ethyl) aminome thy 1) phenyl) ace ty laF.ino) -3-acetyloxymet hy 1-8-0 XO-5-thia-1-azabicycloC ¹ * .2.0 ioct-2-en-2-carboxylic acid

A mixture of 1 g of 3-acetyloxymethyl-7 - [[2- [ ^f l- (chloromethyl) phenyljacetyl3ar.ino3-8-oxo-5-thia-1-azab] cycloid. 2.COoct ^ -en ^ -carboxylic acid and 1 g of l-fluoromethyl-2- (5-imidazolyl) ethylamine in 50 ml of ethanol was stirred for 24 hours at 25 ° C, after which the solvent was removed and a residue was obtained chromatographed on silica gel using benzene-acetone as the eluant to give the title compound.

Example 2

An illustrative composition for hard gelatin capsules is the following:

(a) l-Difluoromethyl-2- (5-imidazolyl) - 20 mg ethylamine

(b) Talc 5 mg

(c) lactose 90 mg

The formulation was prepared by passing the dry powders of (a) and (b) through a fine mesh Sieve floated and mixed them well together. The powder was then placed in hard gelatin capsules filled in a filling weight of 115 mg per capsule.

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28441

Example 5

An illustrative composition for tablets is the following:

(a) l-Fluoromethyl-2- (5-inudazolyl) - 20 mg ethylamine

(b) Strength * H 3 mg

(c) lactose 45 mg

(d) Magnesium stearate 2 mg

The granulation obtained after mixing the lactose with the compound (a) and part of the starch and granulated with starch paste, dried, sieved and mixed with magnesium stearate. The mixture was compressed into tablets weighing 110 mg each.

example H

An illustrative composition for an injectable suspension is the following 1 ml ampoule for one intramuscular injection:

Weight- ^

(a) 1-Difluoromethyl-2- (5-imidazolyl) -1.0 ethylamine

(b) polyvinyl pyrrolidone x 0.5

(c) Lecithin 0.25

(d) water for injection ad 100.0

The materials (a) - (d) were mixed, homogenized and filled into 1 ml ampoules. “The ampoules were sealed and ^{treated in an autoclave for 20 minutes at 121 °} C. Each ampoule contained 10 mg of the new compound (a) per ml .

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284410A

Example 5 l-fluoroethyl-2- (5-imiGazolyl) ethylamine hydrobromide

(A) A solution of 29 mmoles of diazomethane in 84 ml of ether, which was cooled to 0 ° C. and stirred magnetically, was added dropwise within 45 minutes with a solution of ¹ 1.32 g (14.5 mmoles) of l-tosyl- 5-imidazolylacetyl chloride in 60 ml of ether was added. After 1.5 -stündigem stirring at 25 ° C the reaction mixture a solution of hydrogen chloride / pyridine, pre-cooled to 0 ⁰ C, was added. The resulting heterogeneous solution was stirred at 25 ° C. for 1.5 hours and then poured onto ice (150 g). The organic phase was separated off, washed with sodium bicarbonate (pH 8) and then with sodium chloride solution and dried over magnesium sulfate. After the mixture was concentrated under reduced pressure, 1-tosyl-5-imidazolylmethyl fluoromethyl ketone was obtained.

(B) A solution of 20 μl of 1-tosyl-5-imidazolylmethylfluoromethyl ketone in 25 μl of methanol, cooled to -10 ° C., was treated with 30 mg of sodium borohydride. After 2 hours at -10 ° C to 0 ⁰ C, the reaction mixture was neutralized with 6 M HCl and concentrated under vacuum. The residue was extracted several times with chloroform. After evaporation of the solvent gave a oil which was purified by distillation under high vacuum to give 3-fluoro-l '- (l-tosyl-5-imidazolyl) was obtained propan-2-ol. A solution of 2 g of 3-fluoro-l- (l-tosyl-5-imidazolyl) propan-2-ol, 1.37 g of phthalimide, 14 g of diethylazodicarboxylate in 2.4 g of triphenylphosphine and 25 ml of tetrahydrofuran was 20 hours at 25 stirred ° C under nitrogen, after which the solvent was evaporated under reduced pressure and the residue was taken up in benzene. The insoluble material

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was discarded and the semi-solid residue obtained after concentrating the filtrate in vacuo was recrystallized using dichloromethane / diethyl ether to give the fluorophthalimide derivative. A solution of 1.12 g of the fluorophthalimide derivative in 0.18 g of hydrazine hydrate in 42 ml of absolute ethanol was refluxed for 5 hours. After cooling, the solution was concentrated to a volume of 15 ml under vacuum, ^{stored at 0 °} C. overnight and then filtered. The filtrate was concentrated and distilled under high vacuum, to give 1-fluoromethyl-2- (1-tosyl-5-imidazolyl) -ethylamine which was combined with 6 ml of 47? Hydrogen bromide and under nitrogen for 4 hours at 100 ⁰ C was heated. Then, it was concentrated under reduced pressure to obtain a solid residue. The residue was recrystallized from ethanol-diethyl ether, whereby 1-fluoromethyl-2- (5-imidazolyl) ethylamine hydrobromide was obtained.

Example 6 5-Ethoxymethyl-1-tosylimidazole

(A) An ice cold solution of 0.08 mol of sodium bicarbonate in 40 ml of water was mixed with 0.02 mol of imidazol-5-ylmethanol hydrochloride and then a solution of 0.025 mol of tosyl chloride in 30 ml of ethyl acetate is added. The reaction mixture was 5 hours at room temperature touched. The organic phase was separated off, washed with sodium bicarbonate and dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate, whereby 1-tosylimidazol-5-y! methanol was obtained.

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(B) A solution of 30 in Mcl of 1-tosylimidazol-5-ylmethanol in 10 ml of chloroform was added dropwise with 20 nmol Triethylamine and then added over a period of 2 hours with 13 mmol acetic anhydride. Stirring at 25 ° C was continued for 5 hours after which the solvent was removed under reduced pressure, The residue was partitioned between ethyl acetate and water. The organic phase was made with sodium bicarbonate washed, dried over magnesium sulfate and taken under Evaporated in vacuo. The recrystallization of the residue from ethyl acetate gave 5-acetoxymethyl-1-tosylimidazole.

Example 7 Difluoromethyl-1-tosyliinidazol-5-ylmethyl ketone

(A) A solution of 10 mmol [[(ethylsulfinyl) -methylI-thio3 ^ethane i * ¹ 20 ml of dry tetrahydrofuran was prepared at 10 ° C. with 10 mmol of lithium diisopropylamide, prepared from a solution of M diisopropylamine in tetrahydrofuran and 2 M butyllithium in eexane , heated. After 30 minutes at 0 C, a solution of 12 mmol of 5-acetyloxymethyl-1-tosylimidazole in 10 ml of tetrahydrofuran was added. The reaction mixture was stirred at 25 ° C. overnight and then quenched with brine and extracted with ether. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give [[(ethylsulfinyl) -1-tosylimidazol-5-ylmethyl] thiffiJethane. A solution of 20 mmol [[(ethylsulfinyl) -l-tosylimidazol-5-ylmethyl3thio3ethane in 20 ml of dry tetrahydrofuran was at 0 ⁰ C and under nitrogen with a solution of 20 mmol of lithium diisopropylamide, prepared from a solution of M diisopropylamine in tetrahydrofuran and 2 M butyllithium in hexane, added.

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_ 35-28441Oi

Stirring was continued for 30 minutes at 25 ° C after which time a stream of chlorodifluoromethane was bubbled into the reaction mixture for 1/2 hour. The reaction mixture was kept at ⁰ C for 3 hours JLO, then quenched with brine and extracted with ether. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give [[(ethylsulfinyl) - ((difluoromethyl) -l-tosylimidazol-5-ylmethyl)] thi © jethane. A solution of 30 ml of [[(ethylsulfinyl) - ((difluoromethyl) -l-tosylimidazol-5-ylniethyl) 3thi © 3ethane in 33 ml of acetonitrile was treated at ⁰ ° C. with a 70% aqueous solution of perchloric acid (1.1 ml) added. After stirring for 2 hours at 0 ^° C., the reaction mixture was poured into 60 ml of water and then extracted with difluoromethane. The organic phase was washed with sodium bicarbonate and then with water, dried over magnesium sulfate and concentrated under reduced pressure to give difluoromethyl-5-imidazolylmethy! Ketone.

(B) In the procedure of Example 6 (A), when an appropriate amount of difluoromethyl-5-itnidazolylmethyl ketone hydrochloride, prepared from the free base obtained above instead of imidazol-5-ylmethanol hydrochloride and a suitable amount of triethylamine for the sodium bicarbonate used was used Difluonethyl-1-tosyfi.midazol-5-ylniethy! Ketone obtained.

909817/0692

Example 8 Trifluoromethyl-1-tosylimidazol-5-ylmethyl ketone

A mixture of 20 mmol of 5-acetoxymethyl-1-tosyliniidazole and 22 mmoles of triphenylphosphine in 100 ml of benzene was Heated under reflux temperature for 4 days. The one after cooling separated pesticides were filtered, washed with benzene, dried under reduced pressure, and then slowly add a solution of 20 mmol sodium amide in 100 ml liquid ammonia (prepared by adding 0.16 g of sodium to liquid ammonia in the presence of a catalytic amount of iron (III) nitrate) was added. After stirring for 10 minutes, the ammonia was evaporated under nitrogen. The residue became anhydrous with 100 ml Benzene was added and the heterogeneous mixture was refluxed for 10 minutes. The solid residue was filtered and the filtrate, the salt-free 1-tosyl-5-imidazolylmethylidene-triphenylphosphorane contained, 5 · 10 Μ ethyl trifluoroacetate was added. The reaction mixture was refluxed for 12 hours heated under nitrogen. Concentration of the solvent left a residue, which was kept under high vacuum was distilled, 2-ethoxy-l, l, l-trifluoro-3- (l-tosyl-5-imidazolyl) prop-2-ene was obtained. A solution of 3 g of 2-ethoxy-l, l, l-trifluoro-3- (l-tosyl-5-imidazolyl) prop-2-ene in 50 ml of ether was treated with a solution of 1 M sulfuric acid in 50 ml of water. The reaction mixture was stirred at 25 ° C for 1/2 hour. The ether phase was separated, washed with brine, over magnesium sulfate dried and concentrated, with trifluoromethyll-tosylimidazol-5-ylmethy! ketone was obtained.

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Example 9 2-Isopropyl-1-tosylimidazol-5-ylmethyl-fluoromethyl-ketone

200 ml of cold thionyl chloride were mixed with 0.1 mol of 3-isopropylimidazol-5-ylmethanol. After stirring at 25 ° C. for 1 hour, excess thionyl chloride was evaporated under reduced pressure to give crude S-chloromethyl-isopropylimidazole hydrochloride. An ice-cold solution of 5 mmol of 5-chloromethyl-2-isopropylimidazole hydrochloride in 25 ml of dry dimethylformamide was added to a cold solution of powdered sodium cyanide (18 mmol) in 30 ml of dimethylformamide. The reaction mixture was stirred at 25 ° C. overnight, then diluted with 200 ml of water and neutralized with sodium bicarbonate, the solution saturated with sodium chloride and extracted with ethyl acetate (5 x 50 ml), the organic extracts washed with water, dried over magnesium sulfate and evaporated in vacuo to give a solid residue which was sublimed to give 5-cyanomethyl-2-isopropylimidazole. 5-cyanomethyl-2-isopropylimidazole (10 mmol) was heated at reflux temperature with 10 ml of concentrated hydrochloric acid for 12 hours and then concentrated under reduced pressure to give 2-isopropylimidazole. 5-ylacetic acid hydrochloride, an ice-cold solution of 0.08 mol of sodium carbonate in HO m 2-isopropyl-imidazol-5- • ylacetic acid hydrochloride and then 0.025 mol of tosyl chloride, dissolved in 30 ml of ethyl acetate, were added to water. After stirring at 25 ° C. for 5 hours, the reaction mixture was neutralized with M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and reduced under reduced pressure

90 9 817/0692

Pressure concentrated to give 2-isopropyl-1-tosylimidazol-5-yl acetic acid. 1 equivalent of oxalyl chloride was added to a suspension of the sodium salt of 2-isopropyl-1-tosylimidazol-5-ylacetic acid in 100 ml of benzene. The reaction mixture was stirred at 25 ° C. for 12 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure to give 2-isopropyl-1-tosylimidazol-5-ylacetyl chloride. A solution of 29 mmol diazomethane in 8 * 1 ml ether, which was cooled to 0 ⁰ C and mechanically stirred, was added dropwise over a period of 45 minutes with a solution of 14.3 mmol 2-Isopropyll-tosylimidazol-5-ylacetyl chloride in 60 ml of ether are added. After stirring for 1.5 hours at 25 ° C, the reaction mixture was a solution of hydrogen fluoride / pyridine,

O
cools to OC, added. The resulting heterogeneous solution was stirred for 1.5 hours at 25 ° C. and then poured into 150 g of ice. The organic phase was separated off, washed with sodium carbonate (pH 8) and then with sodium chloride solution and dried over magnesium sulfate. Concentration of the mixture under reduced pressure gave 2-isopropyl-1-tosylimidazol-5-ylmethyl fluoromethyl ketone.

Example 10

In the procedure of Example 6, the imidazol-5-ylmethanol by a suitable amount of 2-fluoroimidazol-5-ylmethanol, 2,4-dimethyl-imidazol-5-ylmethanol, 2,4-isopropylimidazol-5-ylmethanol, 2-isopropy1-5-ethylimidazol-5-ylmethanol or 2-fluorimidazol-5-ylmethanol, the following corresponding compounds were obtained:

909817/0692

- 39 -. .28UK

S-acetoxymethyl-Z-fluor-1-tosylimidazole, 5 _{-acetoxymethyl-S-isopropyl-1, 5-acetoxymethyl-2 3} ¹ -diisopropyl-1-tosyliinidazole, 5-acetoxymethyl-S-isopropyl-1 -fcosylimidazole and S-acetoxymethyl ^ -fluoro-1-tosylimidazole.

Example 11

In the procedure of Example 7 (A), the 5-acetoxymethyl-1-tosylimidazole replaced by a suitable amount of the imidazole compounds obtained in Example 10, the following ketones were obtained: 2-fluorimidazol-5-ylπlethyl-difluoromethyl-ketone, Difluoromethyl ^ j ^ -dimethylimidazol-S-ylniethyl-ketone, Difluoromethyl-2,4-diisopropylimidazol-5-ylmethyl-ketone, Difluoromethyl-2-isopropyliInidazol-5-ylπlethyl-ketön and 2-fluoroimidazol-5-ylmethyl-difluoromethyl-ketone.

Example 12

In the procedure of Example 6 (A), the imidazol-5-ylmethanol by an appropriate amount of the hydrochloride salt of the ketones obtained in Example 11, replaced, the following compounds were obtained ;.

a-fluoro-l-tosylimidazol-S-ylmethyl-difluoromethyl-ketone, Difluoromethyl-2, ^ - dimethyl-1-tosylimidazol-S-ylmethy1-ketone,

Difluoromethyl-2,4-diisopropy 1-1-t osy limidazol-5-ylniethyl ketone,

Difluoromethyl-2-isopropyl-1-tosylimidazol-5-yl methyl ketone

2-fluoro-1-tosylimidazol-5-ylmethyl-difluoromethyl-ketone.

909817/0692

- * o - 2844 10A

Example 1?

In the procedure of Example 8, when the 5-acetoxymethyl-1-tosylimidazole was replaced by an appropriate amount of the imidazole compounds obtained in Example 10, the following compounds were obtained: 2-fluor-1-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone, 2, ⁱ } -Dimethyl-l-tosylimidazol-5-ylmethyl-trifluoromethyl ketone,

2, ¹ l-diisopropyl-l-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone,

2-IsopΓopyl-l-tosylimidazol-5-ylmethyl-trifluoromethyl ketone and
2-Pluoro-1-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone.

Example l * t

In the procedure of Example 9, the 3-isopropylimidazol-5-ylmethanol with a suitable amount of 2-fluorimidazol-5-ylmethanol, 2,4-dimethylimidazol-5-ylmethanol, 2, ^ - Diisopropylimidazol-S-ylmethanol, 2-isopropyl - ^ - ethylimidazol-5-ylniethanol or 2-fluorimidazol-5-ylmethanol replaced, the following ketone derivatives were obtained:

2-fluoro-l-tosylimidazol-5-ylπιethyl-fluoromethyl-ketone, 2, ί | -Dimethyl-l-t6sylimidazol-5-yl-methyl-fluoromethyl-ketone, 2, ^ - Diisopropyl-l-tosylimidazol-5-ylmethyl-fluoromethyl ketone,

2-Isopropyl- ¹ } -ethyl-1-tosylimidazol-5-ylmethyl-fluoromethyl-ketone and
2-Fluoro-1-tosylimidazol-5-yl-methyl-fluoromethyl-ketone.

909817/0692

- 41 example

In the procedure of Example 5 (B), the l-tosyl-5-imidazolylmethyl-fluoromethyl-ketone was made by replacing an appropriate amount of the ketone compounds obtained in Examples 12, 13 and 14, thus the following corresponding compounds were obtained:

2- (2-fluorimidazol-5-yl) -1-difluoromethyl-ethylamine hydrobromide, 1-Difluormethy1-2-C2,4-dimethylimidazül-5-yl) ethylamine hydrobromide, 1-difluoromethyl-2- (2,4-diisopropylimidazol-5-yl) ethylamine hydrobromide, 1-difluoromethyl 1-2- (2-isopropylimidazol-5-ydethylamine hydrobromide, 2- (2-fluorimidazol-5-y1) -1-difluoromethylethylamine hydrobromide, 2- (2-fluorimidazol-5-yl) -1-trifluoromethylethylamine hydrobromide, 2- (2,4-Dimethylimidazol-5-yl) -l-trifluoromethylethylamine hydrobromide, 2- (2,4-Diisopropylimidazol-5-y1) -1-trifluoromethylethylamine hydrobromide, 2- (2-isopropylimidazol-5-y1) -1-trifluoromethylethylamine hydrobromide, 2- (2-fluoroimidazol-5-yl) 1-trifluoromethylethylamine-

hydrobromide, -

l-fluoromethyl-2- (2-fluoroimidazol-5-ydethyamine hydrobromide, 1-fluoromethyl 1-2- (2,4-dimethylimidazol-5-y1) ethylamine hydrobromide, l-fluoromethyl-2- (2,4-diisopropylimidazole-5 ' ^f -yl) ethylamine hydrobromide,

909817/0692

l-fluoromethyl-2- (2-isopropyl- ⁱ -ethylimidazol-5-yl) -ethylamine-hydrobromide and

1-fluoromethyl-2- (2-fluoroimidazol-5-yl) ethylamine hydrobromide.

Example 16 N- [1-Fluoromethyl-2- (5-iiriidazolyl) ethyl acetate amide

A solution of 10 mmol of 1-fluoromethyl-2- (5-imidazolyl) -ethylamine-hydrobromide in 26 ml of 2 M sodium hydroxide solution was cooled to 5 ° C. This solution was simultaneous from 2 syringes dropwise with 13 mmol acetyl chloride and 5 ml of 2 M sodium hydroxide solution are added. After 2 hours the solution was neutralized by adding 16 ml of 1 M hydrochloric acid and then to dryness evaporated. The residue was triturated with dichloromethane, filtered and evaporated, whereby N- (1-difluoromethyl-2- (5-iniidazolyl) ethyl3acetamide which was recrystallized from ethyl acetate.

In the procedure described above, the acetyl chloride was replaced by an appropriate amount of benzyl chloroformate replaced, so was benzyl N- [1-fluoromethyl-2- (5-imidazolyl) ethyl carbamate obtain.

Example 17 N- [1-Fluoromethyl-2- [5-imidazolyl3ethylI2-aminopropionamide

A solution of 10 mmoles of benzyl-N- [1-fluoromethyl-2- (5-imidazolyUethyljcarbamat in 20 ml of methylene chloride, which contained 1.1 g of triethylamine, was 10 mmol of benzyl chloroformate offset. After 2 hours at 25 ° C, the

909817/0692

The solution was washed with water and 1 U hydrochloric acid and then evaporated to give the dicarbobenzoxy derivative. 30 ml of 100% strength (weight / weight) hydrogen bromide in dioxane were added to this residue, and the mixture was turned off for 30 minutes at 25 ° C., after which 150 μl of ether were added. The resulting precipitate was filtered off and cold bicarbonate solution was added, followed by rapid extraction with dichloromethane. The dried organic phase was concentrated, l-carbobenzoxy-5- [2-fluoromethyl-2-aminoethyl3inidazole being obtained, which was dissolved in 10 ml of dichloromethane for about 16 hours at 25 ° C. with 1.6 g (7 mmol) of N-carbobenzoxyalanine and 1.45 g (7 mmol) of NjN-dicyclohexylcarbodiimide treated vmrde. The mixture was then ^{cooled to Q 0} C and filtered. The organic solution was washed with 1N hydrochloric acid and bicarbonate solution, and then dried and concentrated. The residue was treated with 30 ml of 100 # (w / w) hydrogen bromide in dioxane at 25 ° C for 30 minutes. The addition of 150 ml of ether resulted in a precipitate of the hydrobromide, which was filtered off and treated with 50 ml of 1N sodium hydroxide at 25 ° C. for about 16 hours. The resulting solution was adjusted to neutral pH and the product was isolated from Amberlite 120 H resin by elution with 2 M ammonia, N- [1.- ^J? fluoromethyl 2- (5-iniidazolyl) ethyl3-2-aminopropionamide was obtained.

For: Merrell Toraude et Compagnie 67000 Stnestooijtfg, France

Lawyer

909817/0 692

BATH ORIGINAL

Claims (11)

sit, WOLFF A ESIL 09. OHt. REOHTSA t: Y ^f X.SrJ 6230 FRANZJ ⁷ URT, \. M MAIN 80 Claims Compound of the general formula CH ₂ -CH-NHR wherein Y is a radical of the formulas FCH ₂ -, F ₂ CH- or F-, C-, R is a hydrogen atom, an alkylcarbonyl radical, wherein the alkyl part has from 1 to 4 carbon atoms and is straight or branched chain, an alkoxycarbonyl radical, where the alkoxy part has 1 to 4 carbon atoms and is straight or branched chain, or one Remainder of formula 0 I!
-C-CH-R, I ³ NH ₂ wherein R, a hydrogen atom, a straight or branched chain lower alkyl radical with 1 to ² J carbon. atoms, a benzyl radical or a p-hydroxybenzyl radical, and R ^ and Rp each represents a hydrogen atom, a straight or branched chain lower alkyl radical having 1 to 4 carbon atoms, where R ₁ and Rp can be the same or different, or R _{1 is} a hydrogen atom and R ₉ a Fluoratonf DeÖeuten, and the pharmaceutical 909817/0692 • acceptable salts and. individual optical isomers the same. 2. A compound according to claim 1, characterized in that R of the general formula is a hydrogen atom or an alkylcarbonyl radical, the alkyl part having from 1 to if Kchlenstoffarcrse and straight or is branched., means. 3. A compound according to claim 1, characterized in that R of the formula is a V.'asserst off atom. ¹ I. A compound according to claim 1, characterized in that each of the radicals R. and R _{2 of} the formula is a hydrogen atom or a methyl radical. 5. A compound according to claim 1, characterized in that each of the radicals R ₁ and R "of the formula is a hydrogen atom. 6. A compound according to claim 1, characterized in that Y of the formula is a radical of the formula FCH ₂ - or F ₂ CH-. 7. A compound according to claim 6, characterized in that each of the radicals R, R ₁ and R _? of the formula represents a hydrogen atom. 8. l-fluoromethyl-2- (5-ii-thiidazolyl) ethylamine or a pharmaceutically acceptable salt thereof as a compound according to claim 1. 9. l-difluoromethyl-2- (5-yne: idazolyl) ethylamine or a pharmaceutically acceptable salt thereof as a compound according to claim 1. 909817/0692 28441OA 10. l-trifluoromethyl-2- (5-imidazolyl) ethylamine or a pharmaceutically acceptable salt thereof as a compound according to claim 1. 11. Process for the preparation of a compound according to claim 1, characterized in that one (a) when R of the formula is a hydrogen atom, a suitably substituted 5-imidazoyl halomethyl ketone derivative the general formula chemically or catalytically reduced and the resulting alcohol in a suitable solvent 1/2 hour to 2k hours under an inert atmosphere at a temperature of about 0 ⁰ C to 100 ⁰ C. with one equivalent of a suitable imide, 1.1 equivalents of one treated suitable phosphines and 1.1 equivalents of diethylazodicarboxylate and then subjected the product obtained to hydrolysis, (b) when R of the formula is an alkylcarbonyl radical, where the alkyl part has 1 to 4 carbon atoms and is straight or branched, the corresponding derivatives, in which R is a hydrogen atom, in a suitable solvent in the presence of a base means about 1 / 2 hours to 6 hours at a temperature of about 0 ⁰ C to 25 ° C with an acid halide of the formula 909817/0692 R ^ -C-Halo, in which Halo is a halogen atom and R ₁ J is a straight or branched-chain alkyl radical having 1 to 4 carbon atoms, treated, (c) when R of the formula is an alkoxycarbonyl radical, the alkoxy part having from 1 to 4 carbon atoms and is straight or branched chain, denotes the corresponding derivative in which R is a hydrogen atom means, in water / water in the presence of a base at a temperature of about 0 to 25 ° C about 1/2 Hour to 6 hours with a haloalkyl formate the formula
O Halo-CR ₁ -, wherein Halo is a halogen atom and R ₁ - is a "straight or branched-chain alkyl radical with 1 to carbon atoms, treated, (d) when R of the formula is a radical of the formula -C-CH-R,, NH ₂ wherein R, which has the meaning given in claim 1, is the corresponding derivative, wherein R represents a hydrogen atom, in a suitable solvent and in the presence of a dehydrating agent, if the free acid is used, at a temperature of about 0 to 35 ° C for about 1 hour up to 12 hours with an acid of the general formula HOOC-CH-R-, or an anhydride thereof, in which NH ₂ R, has the meaning given above and the amino group is suitably protected, treated and the product obtained thereby subjected to acidic or basic hydrolysis, and (e) in the case of a pharmaceutically acceptable salt, the compound thus obtained with a pharmaceutically converts acceptable acid. 909817/0692