CH637384A5 - FLUOROMETHYL DERIVATIVES OF HISTAMINE AND RELATED COMPOUNDS. - Google Patents

Description

The present invention relates to new pharmaceutically useful halomethyl derivatives of histamine and related compounds.

Most mammalian tissues contain histamine, the concentration of which is particularly high in the skin, intestinal mucosa and lungs. Any histamine-containing mammalian tissue, including white blood cells, appears to be able to synthesize the amine from histidine. The main enzyme that catalyzes the conversion of histidine to histamine in vivo is histidine decarboxylase, which is specific for the substrate L-histine 5. In many tissues, the main site of histamine is the mast cell or, in the case of blood, the basophilic cell, which is the circulating counterpart of the mast cell fixed in the tissue.

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

Histamine is involved in various physiological processes. Histamine is released during the antigen-antibody reaction and is largely responsible for the hypersensitivity reaction, which is characterized by vasodilation, itching and edema formation. The type of antigen-antibody reaction, the main cells involved being the mast cells and basophilic cells from which 20 histamine is released, is often referred to as an immediate hypersensitivity reaction. In addition to antigens or allergens, histamine is released by many chemical substances, macromolecules, animal toxins, physical insults, such as heat and other harmful stimuli. Gastric acid secretion is known to be stimulated by histamine. Histamine is also known to be often involved in inducing pain and itching sensory impulses. It has also been found that histamine levels in many rapidly growing tissues, e.g. embryonic tissue, regenerating liver growth and malignant growth are high.

Correlations between histamine level and histidine decarboxylase activity in tissues were examined. In the brain, which contains histamine and histidine decarboxylase, the conversion of histamine, which is increased by stress stimuli, which also increase histidine decarboxylase activity, is rapid. Inhibitors of L-histidine decarboxylase, such as a-hydrazinohistidine, are known to reduce histamine concentrations. In rat fetal tissue where histamine is present in high concentrations, inhibition of L-histidine decarboxylase has been shown to inhibit fetal development.

The effects of histamine and its mode of action are well documented. The amine is believed to exert its effect through at least two receptors classified as Ht and H2 receptors. Various agents are known to counteract the effects of histamine, but not all of the 50-like agents prevent the formation of histamine. E.g. Classic antihistamines that are useful in the treatment of allergic reactions are believed to be useful by disrupting the binding of histamine to Hr receptors. Similar agents that are useful to counteract the stimulatory effect of histamine on gastric acid secretion are believed to work by disrupting the binding of histamine to H2 receptors.

Agents that are able to block Hr receptors are 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 the control of cough and have some use in the treatment of systemic anaphylaxis and bronchial asthma. Antihistamines, which act via Hr receptors, are also used in the treatment of all

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allergic dermatoses such as acute and chronic urticaria, vascular edema, tingling itchy skin, e.g. atopic dermatitis and contact dermatitis, useful in the treatment of urticarial and edematous damage to serum disease, in the control of blood transfusion reactions and drug reactions attributable to allergic phenomena. Agents that block the H2 receptors are useful in the treatment of gastric ulcers, Zollinger-Ellison syndrome and other gastric hypersecretory conditions.

Agents which block the formation of histamine by inhibiting the activity of histamine decarboxylase, e.g. a-Methylhistidine and a-hydrazinohistidine are reported to be useful in the same manner as antihistamines that block Hr and H2 receptors. In addition, the histidine decarboxylase inhibitors are useful in the control of certain tumors that have a high histamine content.

The compounds of the invention inhibit histamine formation by inhibiting the action of histidine decarboxylase, which makes the compounds valuable in the treatment of pathophysiological conditions resulting from histamine. The compounds according to the invention can be used in the same manner and for the same purposes as the compounds which antagonize Hj and H2 receptors.

The compounds according to the invention have the general formula I:

2 ~ tnh r

ch2-ch-nhr

Ri in which Y is a radical of the formula FCH2, F2CH or F3C, R is a hydrogen atom, an alkylcarbonyl radical in which the alkyl part has 1 to 4 carbon atoms and is straight or branched chain, an alkoxycarbonyl radical in which the alkoxy part has 1 to 4 carbon atoms and is straight or branched chain, or a radical of the formula

O

II

—C — CH — R3

nh2

wherein R3 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 Rj and R2, which may be the same or different, a hydrogen atom or a straight- or branched chain lower alkyl radical having 1 to 4 carbon atoms or Rj is a hydrogen atom and R2 is a fluorine atom.

The compounds of formula I according to the invention can be present as salts, in particular as pharmaceutically acceptable salts.

Formula I also includes the individual optical isomers.

The term alkylcarbonyl group used in the above general formula means a group of the formula

O

II

—C — alkyl,

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

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

O

II

—C — O — alkyl wherein the alkoxy group, i.e. the -O-alkyl radical has 1 to 4 carbon atoms and is straight or branched, e.g. the methoxy radical, ethoxy radical, n-propoxy radical, isopropoxy radical, n-butoxy radical and tert-butoxy radical.

Examples of pharmaceutically acceptable salts of the compounds according to the invention include, in particular, non-toxic acid addition salts which are reacted with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids, such as methanesulfonic acid, salicylic acid, maleic acid, cyclamic acid, malonic acid, tartaric acid, citric acid and Ascorbic acid are formed. The salts can be prepared in the usual way.

Preferred compounds according to the invention are those compounds of the general formula I in which R represents a hydrogen atom or an alkylcarbonyl radical, in which the alkyl part is straight or branched chain and has 1 to 4 carbon atoms, with compounds in which R represents a hydrogen atom being particularly preferred.

A further preferred embodiment relates to compounds of the general formula I, in which each of the radicals R2 and R2 denotes a hydrogen atom or a methyl radical. Compounds of the general formula I in which R, is a hydrogen atom and R3 is a fluorine atom are also preferred. Particularly preferred compounds according to the invention are those of the general formula I in which Y is a radical of the formula FCH2- or F2CH-.

Illustrative examples of compounds according to the invention are as follows:

l-fluoromethyl-2- (5-imidazolyl) ethylamine,

l-fluoromethyl-2- [5- (2-fluorine) imidazolyl] ethylamine,

l-trifluoromethyl-2- [5- (4-methyl) imidazolyl] ethylamine,

l-fluoromethyl-2- [5- (2,4-dimethyl) imidazolyl] ethylamine,

l-difluoromethyl-2- [5- (2,4-diethyl) imidazolyl] ethylamine,

l-trifluoromethyl-2- [5- (2,4-diisopropyl) imidazolyl] ethylamine,

l-fluoromethyl-2- [5- (2,4-di-tert-butyl) imidazolyl] ethylamine,

l-difluoromethyl-2- [5- (2-n-butyl) imidazolyl] ethylamine,

N- {l-difluoromethyl-2- [5- (2-fluoro) imidazolyl] ethyl} acetamide,

N- [1-fluoromethyl-2- (5-imidazolyl) ethyl] methyl carbamate,

N- {l-fluoromethyl-2- [5- (2-ethyl) imidazolyl] ethyl} -2-amino-

propionamide and N- [l-difluoromethyl-2- (5-imidazolyl) ethyl] -2-amino-3-phenyl-propionamide.

The compounds of the formula I according to the invention are irreversible inhibitors of histidine decarboxylase, the enzyme which converts histidine to histamine in vivo. Thus, 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 of the invention are useful in the same manner as known antihistamines, whether such compounds exert their activity by blocking the Hx and H2 receptors or by other means.

The compounds of the invention are useful in the treatment of pathophysiological conditions due to histamine. Thus, the compounds of general formula I according to the invention are valuable in

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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 bronchodilators. The compounds of general formula I are also useful in the treatment of 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 urticarial and edematous damage to serum disease, blood transfusion reactions, which are attributable to the allergic phenomenon and vomiting. The compounds of general formula I are also useful in the treatment of gastric ulcer, Zollinger-El-lison syndrome and other gastric hypersecretion conditions. As described above, it has been found that histamine concentrations are high in rapidly growing tissues such as tumors, therefore the compounds of formula I according to the invention can be used by inhibiting the formation of histamine to control the growth of certain tumors, e.g. Walker breast cancer and Ehrlich ascites tumors.

The compounds according to the invention can be administered in various ways in order to achieve the desired effect. The compounds according to the invention, alone or in the form of pharmaceutical preparations, can be administered to the patient to be treated either orally, parenterally, i.e. administered subcutaneously, intravenously or intraperitoneally, or topically. The compounds can be administered intranasally or by application to the mucous membranes, e.g. those of the nose, throat and trachea, e.g. in an aerosol spray which contains small particles of a compound according to the invention in a spray solution or in dry powder form.

The amount of new compound administered varies and can be any effective amount. Depending on the patient, the condition being treated, and the mode of administration, the amount of new compound administered can vary over a wide range to an effective amount in the form of a unit dose of about 0.1 to 500 mg / kg of body weight of the patient per dose, and preferably from about 50 to 200 mg / kg body weight to achieve the desired effect. E.g.

the desired effect can be achieved by administering a dosage unit, e.g. a tablet containing from 10 to 500 mg of a new compound according to the invention can be obtained one to four times a day.

The term patient as used herein means warm-blooded animals such as birds and mammals, e.g. Cats, dogs, rats, mice, guinea pigs, sheep, horses, cattle and humans.

The solid dosage unit forms can be of the usual type. Thus the solid form may be a capsule which corresponds to the usual gelatin capsule which contains a compound according to the invention and a carrier, e.g. Contains lubricants and inert fillers such as lactose, sucrose and corn starch. According to another embodiment, the compounds according to the invention can be tableted with conventional tablet bases, such as lactose, sucrose or corn starch, in combination with binders, such as acacia gum, corn starch or gelatin, disintegrating agents, such as corn starch, potato starch or alginic acid and a lubricant, such as stearic acid or magnesium stearate.

For parenteral administration, the compounds can be administered as injectable doses of a solution or suspension of the

Compound can be administered in a physiologically acceptable diluent with a pharmaceutically acceptable carrier, such as a sterile liquid, such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Examples of oils that can be used in these preparations are those of crude oil, animal, vegetable or synthetic origin, e.g. Peanut oil, soybean oil and mineral oil. In general, water, common salt, aqueous dextrose and related sugar solutions, ethanols and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, especially for injectable solutions.

The compounds can be administered in the form of a depot injection or an implant preparation, which can be formulated in such a way that they allow delayed release of the active ingredient. The active ingredient can be pressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implantation. Implants can be inert materials, such as biodegradable polymers or synthetic silicones, e.g. Use silicone rubber (Silastic, Dow-Corning Corporation).

For use as aerosols, the compounds according to the invention can be used 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, are packed in a pressurized aerosol container. The compounds can also be administered in a non-pressurized form, such as in a nebulizer or atomizer.

The usefulness of the compounds of the general formula I according to the invention as irreversible inhibitors of histidine decarboxylase can be demonstrated as follows: A compound of the general formula I is administered either orally or parenterally as an aqueous solution or suspension to rats or acids. At various time intervals after administration of the test compound, the animals are administered intraperitoneally 2 (xCi 2-14C-L-histidine. Two hours after the injection of labeled histidine, the animals are sacrificed and the amount of radioactive histamine that is in the glandular part of the stomach is present, is determined as described by KM Mole and DM Shepherd, J. Pharm. Pharmac. 25, 609-613 (1937).

In addition to being useful as pharmacological agents, the compounds of the invention wherein R is hydrogen atom are useful as intermediates for the preparation of cephalosphorin derivatives of general formula II

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-CH2-CHNHCH £ - ^ - CHa-C-NH

Ri 0

-N-Nj ^ -CHSX

COOM

(il)

wherein X represents a hydrogen atom or an acetoxy radical and M represents a hydrogen atom or a negative charge and Rj, R2 and Y have the meaning given above for the general formula I, which are useful as antibiotics.

The compounds of general formula II and the pharmaceutically acceptable salts and individual optical isomers thereof are new compounds which are useful as antibiotics and in a manner similar to that of many well known cephalosporin derivatives, e.g. Cephalexin, cephalothin or cephaloglycin can be administered. The compounds of general formula II and pharmaceutically acceptable salts and isomers thereof, alone or in the form of pharmaceutical preparations, can be administered either orally or parenterally and topically to warm-blooded animals, i.e. Birds and mammals, e.g. Cats, dogs, cattle, sheep, horses and humans can be administered. For oral administration, the compounds can be formulated in the form of tablets, capsules or pills or in the form of elixirs or suspensions. For parenteral administration, the compounds can best be used in the form of a sterile aqueous solution containing other solutes, e.g. contain enough table salt or glucose to make the solution isotonic. 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 pharmaceutically acceptable salts and individual optical isomers thereof are active 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 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- (4-imidazolyl) ethylaminomethyl] phenyl] acetyl] amino] -3-acetyloxy-methyl-8- oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, 7 - [[2- [4- [l-difluoromethyl-2- [5- (2-fluoro) -imidazolyl] -ethylaminomethyl] phenyl] acetyl] amino] -3-acetyloxymethyl - 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 7 - [[2- [4- [1-fluoromethyl-2- [4- (2,5-dimethyl) imidazolyl] ethyl-aminomethyl] phenyl] acetyl] amino] -3-acetyloxymethyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid.

The compounds of general formula II can be prepared by using a compound of general formula III

0

'"" -o -'-'- TCL »

wherein X and M are as defined above for General Formula II, which is prepared as described in U.S. Patent No. 3,919,206, incorporated herein by reference, with a compound of General Formula I, wherein R is a Hydrogen atom means. The reaction is generally carried out in a solvent such as a lower alcohol, e.g. Methanol, ethanol or 15 isopropyl alcohol or dimethyl sulfoxide, dimethylformamide or aqueous mixtures of these solvents. The reaction temperature can vary from about 0 to 125 ° C and the reaction time from about% hour to 24 hours. Following the solvolysis reaction, the amino-20 protecting group is usually removed by acid hydrolysis and the cephalosporin products can be isolated by conventional techniques.

The compounds of general formula I, in which R represents a hydrogen atom, are e.g. by making a suitably substituted 5-imidazolyl halo genomethyl ketone derivative, as described below by Formula IV, to the corresponding alcohol which is dissolved in a solvent such as ethers, e.g. Di-ethyl ether, tetrahydrofuran or p-dioxane, benzene or di-30 methoxyethane under an inert atmosphere, e.g. Nitrogen or argon, at about 0 to 100 ° C, preferably about 25 ° C, about x / 2 hours to 24 hours with one equivalent of an imide such as phthalimide, succinimide or maleimide, 1.1 equivalents of a phosphine, e.g. Triphenylphosphine, 35 or a trialkylphosphine, such as tri-n-butylphosphine, and 1.1 equivalents of diethyl azodicarboxylate. The imido derivative obtained can then be hydrolyzed to the free amine.

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R

2 yy N-S02 -— Ç ~ /) CH:

N

ch2-c-y

(IV)

> X (in)

c00m

In this general formula IV, Y, Rx and R2 have the meaning given above for the general formula I.

The reduction of the ketones of general formula IV so to the corresponding alcohol is preferably carried out chemically using e.g. 1 to 10 equivalents of a metal hydride reducing agent, e.g. Lithium borohydride, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride, borane or dimethylthioborane, or catalytically using e.g. Raney nickel, rhodium, palladium on carbon or platinum oxide reached. The total reaction time generally varies from about 10 minutes to 24 hours and the temperature varies from about -40 ° C to 100 ° C, depending on the reducing agent used. With chemical reduction, the reaction time generally varies from about 10 minutes to 24 hours, with temperatures varying from about -40 ° C to 65 ° C. 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 a preferred catalytic reduction, the reaction time varies from about 1 hour to 24 hours, the reaction temperature

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• Doors from about 25 to 100 ° C and the pressure varies from 1 atmosphere to 120 atmospheres. Suitable solvents for the catalytic reduction of the compounds of general formula IV include lower alcohols, e.g. Methanol or ethanol, acetic acid or ethyl acetate. Chemical reduction is preferred.

Hydrolysis to the amine and removal of any ring protecting groups can be accomplished using a strong 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 e.g. 1 to 3 equivalents of hydrazine, methylhydrazine or methylamine at a temperature from about 25 ° C. to the reflux temperature within about 1 hour to 12 hours, followed by treatment with a strong mineral acid or organic acid, as described above, or by hydrogenolysis of the protective group, if appropriate, be achieved.

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

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

O

II

R4-C-Halo wherein halo is a halogen atom, e.g. is a chlorine atom or a bromine atom, and R4 denotes a straight-chain or branched-chain alkyl radical having 1 to 4 carbon atoms.

The compounds of the general formula I in which R is an alkoxycarbonyl radical, in which the alkoxy part is straight-chain or branched-chain and has from 1 to 4 carbon atoms, are preferably prepared by adding the corresponding derivative, in which R is a hydrogen, to water in Presence of a base such as sodium hydroxide or sodium borate for about an hour to 6 hours at a temperature of about 0 ° C to 25 ° C with an alkyl haloformate of the formula

0

II

Halo-C-ORs,

wherein halo represents a halogen atom, such as a chlorine atom or a bromine atom, and R5 denotes a straight or branched chain alkyl radical having 1 to 4 carbon atoms.

The compounds of general formula I, wherein R is a radical of the formula

O

II

—C — CH — R3

1

nh2

in which R3 is a hydrogen atom, a straight-chain or branched-chain lower alkyl radical having 1 to 4 carbon atoms,

represents a benzyl radical or a p-hydroxybenzyl radical, can be prepared by reacting the corresponding derivative, in which R represents 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 0 ° C to 35 ° C for about 1 hour to 12 hours with an acid of the formula

HOOC-CH-R3,

I.

NHa wherein R3 has the meaning given above and the amino group is suitably protected, e.g. treated with a tert-butoxycarbonyl radical or a benzyloxycarbonyl radical, or an anhydride thereof and then hydrolyzed acidic or basic.

The compounds of the general formula IV, in which Y is a radical of the formula FCH2-, are generally obtained by reacting an appropriately substituted 5-imidazolylmethyl-substituted methyl ketone of the formula V

ri Ii -so2- (T) - ch3

U \ fi w i xch2-c-ch2r6 Ri in which Rj and R2 have the meanings given above for the compounds of the formula I and R6 is a suitable leaving group, such as a halogen atom, e.g. is a chlorine atom, a bromine atom or an iodine atom, a mesylate residue, a tosylate residue, a triflate residue or a trifluoroacetate residue, in a suitable solvent, such as dimethoxyethane, dimethyl sulfoxide, dimethylformamide, ethylene glycol, acetonitrile, acetone, benzene or hydrogen fluoride in one Temperature from about 0 to 200 ° C for about 2 to 48 hours with a suitable fluorinating agent, such as Potassium fluoride, silver fluoride, cesium fluoride, thalium fluoride or tetrabutylammonium fluoride treated. The leaving group R6 in the formula V can also be a diazo group, in which case the fluorinating agent used is hydrogen fluoride / pyridine. Suitable solvents for the reaction in which R6 is a diazo group are aprotic solvents such as diethyl ether, tetrahydrofuran and pentane. The reaction time generally varies from about 30 minutes to 24 hours at a temperature of about -20 to 65 ° C. A suitable diazoketone derivative, i.e. a compound of formula V, wherein R6 represents a diazo group, in a suitable aprotic solvent e.g. added to a solution of hydrogen fluoride / pyridine cooled to -10 ° C. The reaction mixture is preferably stirred vigorously at -10 ° C. for 1 hour, then vigorously at about 25 ° C. for 2 hours and then poured into ice. The organic phase can be separated, with base, e.g. Sodium bicarbonate, washed, dried over magnesium sulfate and concentrated in vacuo to give an appropriately substituted 5-imidazolyl-methyl-fluoromethyl-ketone derivative of the formula IV.

The diazoketone derivatives, i.e. the compounds of formula V, wherein R6 represents a diazo group, can be derived from the corresponding acid halide, i.e. an appropriately substituted 2- (5-imidazolyl) acetyl halide, the halide, e.g. Can be chloride by slowly adding the acid halide in an aprotic solvent such as diethyl ether, tetrahydrofuran, pentane, hexane, benzene, dimethoxyethane or dioxane to a solution of di-

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Azomethane, which was cooled to about -40 to 20 ° C, is obtained in ether and then vigorously stirred at about 25 ° C for about 1 hour to 24 hours. The diazoketone derivative thus obtained can be obtained by standard methods, e.g. Evaporation of the solvent can be isolated with purification by crystallization or chromatography or can be treated without isolation with a suitable fluorinating agent as described above.

The correspondingly substituted diazoketone derivative described above can also be used to prepare compounds of formula V wherein R6 e.g. a halogen atom means a mesylate residue, a tosylate residue, a triflate residue or a trifluoroacetate residue by methods well known in the art. In order to obtain compounds of the general formula V in which R6 is a halogen atom, such as a chlorine atom, a bromine atom or an iodine atom, the corresponding compound of the formula V in which R6 is a diazo group can be dissolved in an appropriate aprotic solvent with aqueous hydrogen chloride, Hydrogen bromide or hydrogen iodide can be treated. For the preparation of compounds of formula V, in which R6 is a mesylate residue, tosylate residue, triflate residue or trifluoroacetate residue, e.g. the corresponding diazoketone derivative, i.e. a compound of formula V, wherein R6 is a diazo group, is treated with dilute sulfuric acid in a suitable aprotic solvent to give the corresponding 5-imidazolylmethyl-methanol ketone derivative which is obtained with a suitable acid chloride or anhydride of methanesulfonic acid, p- ToluoIsuIfonic acid, trifluoromethylsulfonic acid or trifluoroacetic acid is esterified.

The correspondingly substituted 2- (5-imidazolyl) acetyl halide, which is used to prepare the diazoketone derivatives of the formula V, i.e. Compounds in which R6 represents a diazo group are preferably used, can be obtained from the corresponding acids, e.g. by treatment with thionyl chloride in an aprotic solvent such as diethyl ether, tetrahydrofuran, benzene or dichloromethane at temperatures ranging from about 0 ° C to the reflux temperature of the solvent for about 1 to 24 hours. Alternatively, 1 equivalent of the corresponding acid can be treated with 1 equivalent of oxalyl chloride in an aprotic solvent as indicated above at a temperature of about 0 ° C to 40 ° C for about 1 hour to 24 hours. The correspondingly substituted 2- (5-imidazolyl) acetic acid derivatives used as described above are preferably obtained by reacting the corresponding acid in the presence of a base for about 4 to 20 hours at about 25 ° C with p-toluenesulfonyl halide, e.g. p-toluenesulfonyl chloride treated. These acids are known in the art or can be obtained by acidic or basic hydrolysis of an appropriately substituted 5-imidazolylaceto-nitrile by methods known in the art. The corresponding substituted 5-imidazolylaceto-nitriles are known in the art or can be obtained by treating the corresponding 5-imidazolylmethyl halide, e.g. of 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, hexamethylphosphorotriamide, dimethyl sulfoxide, dimethylformamide, acetamide or dimethylacetamide in a period from about 1 hour to 48 hours at a temperature of about 0 to 150 ° C. The appropriately substituted 5-imidazolylmethyl halides are known in the art or can be prepared from the corresponding suitably substituted 5-imidazolyl-methanol 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.

The compounds of general formula IV, wherein Y is a radical of formula F2CH-, can be prepared by using [[(methylsulfinyl) methyl] thio] methane or [[(EthyIsulfinyI) methyl] thio] ethane with a suitable strength Base treated and then the product obtained with a suitably substituted 5-imidazolylmethyl derivative of the formula VI

r-jpjj n-soa — çj) - * - ^ 3

f (v «

j ch2occh3

wherein Rj and R2 have the meaning given above for formula IV, alkylated, the correspondingly substituted 5-imidazolylmethyl-substituted sulfinyl derivative thus obtained treated with a suitable strong base, the product thus obtained with a halomethylhalogenation alkylating agent such as chlorodifluoromethane, bromodifluoromethane or Difluoromethane, alkylated, the product thus obtained hydrolysed with aqueous acid and the R ^ R2-substituted 5-acetoxymethylimidazole derivative thus obtained 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, for example p-toluenesulfonyl chloride treated.

Suitable strong bases which can be used in the preparation of the difluoromethyl-substituted ketone derivatives described above are, for example, sodium hydride, dilithium acetylide, lithium diisopropylamide, butyllithium, potassium tert-butoxide, sodium tert-butoxide, lithium tert . -butoxide, phenyllithium, methyllithium, sodium amide, lithium amide or potassium hydride.

The alkylation reactions described in the preparation of the difluoromethyl ketone derivatives can be 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 e.g. prepared by quenching with saturated saline and then using e.g. Extracted diethyl ether, dichloromethane or benzene.

The hydrolysis of the alkylated sulfinyl derivatives to the ketone is preferably accomplished 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 . Generally 0.3 equivalent mineral acid in 1.5% water is used. The preparation of the difluoromethyl ketone derivatives of the formula IV is explained in more detail by the specific examples.

The compounds of the formula VI can be prepared by reacting the correspondingly substituted imidazol-5-ylmethanol derivatives of the formula VII

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where R! and R2 have the meaning given above in formula VI, in the presence of a base at about 25 ° C for about 4 to 20 hours with a p-toluenesulfonyl halide, e.g. p-Toluenesulfonyl chloride, treated to give the corresponding l-tosylimidazol-5-ylmethanol, 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 general formula IV, wherein Y is a radical of formula F3C-, can be prepared by a compound of 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 in hydrocarbons, e.g. Benzene or toluene, or lower alcohols, such as methanol or ethanol, or acetonitrile, tetrahydrofuran, diethyl ether or dimethoxyethane, treated with triphenylphosphine. After cooling, a precipitate usually forms which is washed with solvent and washed using e.g. Ethyl acetate, acetonitrile or a lower alcohol is recrystallized, whereby the correspondingly substituted 5-imidazolylmethyl-phosphonium salt can be obtained. The appropriately substituted 5-imidazolylmethylphosphonium salt can also be obtained by treating an appropriately substituted 5-imidazolylmethanol with a triphenyl-prosphonium salt such as triphenylphosphonium bromide using generally the same reaction conditions as set forth above -Imidazolylmethyl-triphenylphosphonium salt can be added to excess (up to 25%) sodium or lithium metal dissolved in liquid ammonia, which contains a catalytic amount of ferric nitrate with stirring over a period of about 10 minutes to 3 hours is added, after which the ammonia is evaporated off under an inert atmosphere, such as nitrogen or argon. A suitable solvent such as benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane is preferably added and the resulting 5-imide-azolylmethylidene phosphorane can be collected. The 5-imidazolylmethylidene phosphorane is usually heated for about 30 minutes to 24 hours under an inert atmosphere such as nitrogen or argon at a temperature from about 0 ° C to the reflux temperature of the solvent in a solvent such as benzene, toluene, diethyl ether, tetrahydrofuran or dimethoxyethane. with an ester, such as a lower alkyl ester, e.g. Methyl ester, ethyl ester, n-propyl ester, isopropyl ester or n-butyl ester of trifluoroacetic acid, treated, after which the reaction mixture can be concentrated and distilled to give the olefin, preferably with aqueous mineral acid, such as hydrochloric acid or hydrobromic acid, or an organic acid, such as Trifluoroacetic acid or p-toluenesulfonic acid is treated 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 used can vary from a catalytic amount to a concentrated acid. The chemistry used in the preparation of the compounds of formula IV, wherein Y is a radical of formula F3C-, as described above, is generally described by P. H. Betmann, Ang. Chem. Int. Ed. 1966, p. 308.

The following examples serve to further explain the present invention.

Application example 1

7 - ((4- (l-difluoromethyl-2- (5-imidazolyl) ethyl) aminomethyl) ~ phenyl) acetylamino) -3-acetyloxymethyl-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid

A mixture of 1 g of 3-acetyloxymethyl-7 - [[2- [4- (chloromethyl) phenyl] acetyl] amino] -8-oxo-5-thia-l-azabicyclo- [4.2.0] oct-2 -en-2-carboxylic acid and 1 g of l-fluoromethyl-2- (5-imidazolyl) etliylamine in 50 ml of ethanol was stirred at 25 ° C. for 24 hours, after which the solvent was removed and a residue was obtained, which was dissolved in silica gel Chromatographed using benzene-acetone as eluent to give the title compound.

Use Example 2 An illustrative composition for hard gelatin capsules is as follows:

(a) 1-difluoromethyl-2- (5-imidazolyl) -

-ethylamine 20 mg

(b) Talc 5 mg

(c) Lactose 90 mg

The formulation was prepared by driving the dry powders of (a) and (b) through a fine mesh sieve and mixing them well together. The powder was then filled into hard gelatin capsules with a filling weight of 115 mg per capsule.

Use Example 3 An illustrative composition for tablets is as follows:

(a) l-fluoromethyl-2- (5-imidazolyl) -

-ethylamine 20 mg

(b) Strength 43 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 was dried, sieved and mixed with magnesium stearate. The mixture was pressed into tablets, each weighing 110 mg.

Use Example 4 An illustrative composition for an injectable suspension is the following 1 ml ampoule for an intramuscular injection:

Weight-%

(a) 1-difluoromethyl-2- (5-imidazolyl) -

ethylamine 1.0

(b) Polyvinyl pyrrolidone 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 at 121 ° C for 20 minutes. Each ampoule contained 10 mg of the new compound (a) per ml.

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example 1

l-fluoromethyl-2- (5-imidazolyl) ethylamino hydrobromide

(A) A solution of 29 mmol of diazomethane in 84 ml of ether, which was cooled to 0 ° C. and magnetically stirred, was added dropwise with a solution of 4.32 g (14.5 mmol) of 1-tosyl- within 45 minutes. 5-imidazolyl-acetyl chloride in 60 ml ether. After stirring for 1.5 hours at 25 ° C, the reaction mixture was added to a solution of hydrogen chloride / pyridine, pre-cooled to 0 ° C. 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, washed with sodium bicarbonate (pH 8) and then with brine and dried over magnesium sulfate. After concentration of the mixture under reduced pressure, 1-tosyl-5-imidazolylmethylfluoromethyl ketone was obtained.

(B) A solution of 20 mmol of l-tosyl-5-imidazolylmethylfluoromethyl ketone in 25 ml of methanol, cooled to -10 ° C., was treated with 30 mg of sodium borohydride. After 2 hours at - 10 ° C to 0 ° C, the reaction mixture with

6 M HCl neutralized and concentrated under vacuum. The residue was extracted several times with chloroform. After evaporation of the solvent, an oil was obtained which was purified by distillation under high vacuum to give 3-fluoro-l- (l-tosyl-5-imidazolyl) propan-2-ol. A solution of 2 g of 3-fluoro-1- (l-tosyl-5-imidazolyl) propan-2-ol, 1.37 g of phthalimide, 1.74 g of diethyl azodicarboxylate in 2.4 g of triphenylphosphine and 25 ml of tetrahydrofuran was used for 20 hours Stirred at 25 ° C under nitrogen, after which the solvent was evaporated under reduced pressure and the residue obtained was taken up in benzene. The insoluble material was discarded and the semisolid residue obtained after concentrating the filtrate under vacuum was recrystallized using dichloromethane / diethyl ether to give the fluorophthalimide derivative. A solution of 1.12 g of fluorophthalimide derivative in 0.18 g of hydrazine hydrate in 42 ml of absolute ethanol was heated under reflux for 5 hours. After cooling, the solution was concentrated under vacuum to a volume of 15 ml, turned off at 0 ° C. overnight and then filtered. The filtrate was concentrated and distilled under high vacuum to give l-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 ° C was heated. It was then concentrated under reduced pressure to obtain a solid residue. The residue was recrystallized from ethanol-diethyl ether to give l-fluoromethyl-2- (5-imidazolyl) ethylaminohydrobromide.

Example 2 5-A cetoxymethyl-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-yl-methanol hydrochloride and then with a solution of 0.025 mol of tosyl chloride in 30 ml of ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. The organic phase was separated, washed with sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-tosyl-imidazol-5-ylmethanol.

(B) A solution of 10 mmol of l-tosylimidazol-5-ylmethanol in 10 ml of chloroform was added dropwise with 20 mmol of triethylamine and then over a period of

13 mmol of acetic anhydride were added for 2 hours. The

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 washed with sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gave 5-acetoxymethyl-l-tosylimidazole.

Example 3

Difluoromethyl-l-tosylimidazol-5-ylmethyl ketone

(A) A solution of 10 mmol of [[(ethylsulfinyl) methyl] thio] ethane in 20 ml of dry tetrahydrofuran was prepared at 0 ° C. with 10 mmol of lithium diisopropylamine, prepared from a solution of M diisopropylamine in tetrahydrofuran and 2 M buptyllithium in hexane , treated. 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, whereby

[[(Ethylsulfinyl) -1-tosylimidazol-5-ylmethyl] methylthio] ethane was obtained. A solution of 20 mmol [[(ethylsulfinyl) -1-tosylimidazol-5-ylmethyl] thio] ethane in 20 ml of dry tetrahydrofuran was prepared at 0 ° C. and under nitrogen with a solution of 20 mmol of lithium diisopropyl amide, prepared from a solution of M diisopropylamine in tetrahydrofuran and 2 M butyllithium in hexane.

Stirring was continued at 25 ° C for 30 minutes after which a stream of chloride fluoromethane was blown into the reaction mixture for H hour. The reaction mixture was kept at 40 ° C. for 3 hours, 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 - ((di-fluoromethyl) -l-tosylimidazol-5-ylmethyl) methylthio] ethane. A solution of 30 ml [[(ethylsulfinyl) ((di-fluoromethyl) -l-tosylimidazol-5-ylmethyl)] thiop] ethane in 33 ml of acetonitrile was mixed with a 70% aqueous solution of perchloric acid (1.1 ml) at 0 ° C. 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, with difluoromethyl-5-imidazolyl methyl ketone was obtained.

(B) In the procedure of Example 2 (A), an appropriate amount of difluoromethyl-5-imidazolyimethyl ketone hydrochloride made from the free base obtained above was used instead of imidazol-5-ylmethanol hydrochloride, and an appropriate amount of triethylamine was used for the sodium bicarbonate used , Difluor-methyl-l-tosylimidazol-5-ylmethyl ketone was obtained.

Example 4

Trifluoromethyl-l-tosylimidazol-5-ylmethyl ketone

A mixture of 20 mmol of 5-acetoxymethyl-l-tosylimidazole and 22 mmol of triphenylphosphine in 100 ml of benzene was heated under reflux for 4 days. The solid separated after cooling was filtered, washed with benzene, dried under reduced pressure and then slowly with a solution of 20 mmol sodium amide in 100 ml liquid ammonia (produced by Zu5

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put 0.46 g of sodium into liquid ammonia in the presence of a catalytic amount of iron (III) nitrate) added. After stirring for 10 minutes, the ammonia was evaporated under nitrogen. 100 ml of anhydrous benzene was added to the residue and the heterogeneous mixture was refluxed for 10 minutes. The solid residue was filtered and the filtrate, which contained salt-free 1-tosyl - 5-imidazolylmethylidene triphenylphosphorane, was mixed with 5. 10 2M ethyl trifluoroacetate was added. The reaction mixture was heated at reflux temperature under nitrogen for 12 hours. When the solvent was concentrated, a residue remained, which was distilled under high vacuum to give 2-ethoxy-1,1,1-trifluoro-3- (l-tosyl-5-imidazolyl) prop-2-ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-3- (l-tosyl-5-imidazolyl) prop-2-ene in 50 ml of ether was added with a solution of 1 M sulfuric acid in 50 ml of water treated. The reaction mixture was stirred at 25 ° C for H hour. The ether phase was separated, washed with brine, dried over magnesium sulfate and concentrated to give trifluoromethyl-1-tosyl-imidazol-5-yimethyl ketone.

Example 5

2-isopropyl-1-losylimidazol-5-ylmethyl fluoromethyl ketone

200 ml of cold thionyl chloride were mixed with 0.1 mol of 2-iso-propylimidazol-5-ylmethanol. After stirring at 25 ° C for 1 hour, excess thionyl chloride was evaporated under reduced pressure to obtain crude 5-chloromethyl-2-isopropylimidazole hydrochloride. An ice-cold solution of 5 mmol of 5-chloromethyl-2-isopropyl-imidazole hydrochloride in 25 ml of dry dimethylformamide was mixed with 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 was saturated with sodium chloride and extracted with ethyl acetate (5 X 50 ml). The organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure 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 obtain 2-isopropylimidazol-5-yleslacetic acid hydrochloride. An ice-cold solution of 0.08 mol of sodium carbonate in 40 ml of water was mixed with 2-isopropyl-imidazol-5-ylacetic acid hydrochloride and then with 0.025 mol of tosyl chloride, dissolved in 30 ml of ethyl acetate. 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 concentrated under reduced pressure to give 2-isopropyl-1-tosyiimidazol-5-ylacetic acid. A suspension of the sodium salt of 2-isopropyl-l-tosylimid-azol-5-ylacetic acid in 100 ml of benzene was mixed with 1 equivalent of oxalyl chloride. 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-l-tosylimidazol-5-ylacetyl chloride. A solution of 29 mmol of diazomethane in 84 ml of ether, which was cooled to 0 ° C. and stirred mechanically, was added dropwise over a period of 45 minutes with a solution of 14.3 mmol of 2-isopropyl-1-tosyl-imidazole-5 -ylacetyl chloride in 60 ml ether. After stirring for 1.5 hours at 25 ° C, the reaction mixture was added to a solution of hydrogen fluoride / pyridine, pre-cooled to 0 ° C. The resulting heterogeneous solution was stirred at 25 ° C. for 1.5 hours and then poured into 150 g of ice. The organic phase was separated off, washed with sodium bicarbonate (pH 8) and then with brine and dried over magnesium sulfate. Concentration of the mixture under reduced pressure gave 2-isopropyl-l-tosylimidazol-5-ylmethyl fluoromethyl ketone.

Example 6

In the process of Example 2, the imidazol-5-yl-methanol was replaced by a suitable amount of 2-fluorimidazol-5-yl-methanol, 2,4-dimethyl-imidazol-5-ylmethanol, 2,4-isopropyl-imidazol-5- ylmethanol, 2-isopropyl-5-ethylimidazol-5-ylme-methanol or 2-fluorimidazol-5-ylmethanol, the following corresponding compounds were obtained: 5-acetoxymethyl-2-fluoro-l-tosylimidazole, 5-acetoxymethyl-2 , 4-dimethyl-1-tosylimidazole, 5-acetoxymethyl-2,4-diisopropyl-1-tosylimidazole, 5-acetoxymethyl-2-isopropyl-1-tosylimidazole and 5-acetoxymethyl-2-f luor-1-tosylimidazole.

Example 7

In the procedure of Example 3 (A), when the 5-acetoxymethyl-1-tosylimidazole was replaced with an appropriate amount of the imidazole compounds obtained in Example 6, the following ketones were obtained: 2-fluorimidazol-5-ylmethyl-difluoromethyl-ketone , Difluoromethyl-2,4-dimethylimidazol-5-ylmethyl-ketone, difluoromethyl-2,4-diisopropylimidazol-5-ylmethyl-ketone, difluoromethyl-2-isopropylimidazol-5-ylmethyl-ketone and 2-fluorimidazol-5-ylmethyl-dif -ketone.

Example 8

In the procedure of Example 2 (A), when the imidazol-5-ylmethanol was replaced with an appropriate amount of the hydrochloride salt of the ketones obtained in Example 7, the following compounds were obtained: 2-fluoro-1 -tosylimidazol-5-ylmethyl-difluoromethyl-ketone, difluoromethyl-2,4-dimethyl-l-tosylimidazol-5-ylmethyl-ketone, difluoromethyl-2,4-diisopropyl-1-tosylimidazoI-5-ylmethyl-ketone,

Difluoromethyl-2-isopropyl-l-tosylimidazol-5-ylmethyl ketone and

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

Example 9

When in the procedure of Example 4 the 5-acctoxy-methyl-1-tosylimidazole was replaced by a suitable amount of the imidazole compounds obtained in Example 6, the following compounds were obtained: 2-fluoro-1-tosylimidazol-5-ylmethyl-trifluoromethyl- ketone, 2,4-dimethyl-1-tosylimidazol-5-yimethyl-trifluoromethyl-ketone, 2,4-diisopropyl-l-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone,

2-isopropyl-1-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone and

2-Fiuor-l-tosylimidazol-5-ylmethyl-trifluoromethyl-ketone.

Example 10

In the procedure of Example 5, the 2-isopropylimidazol-5-yimethanol was replaced by an appropriate amount of 2-fluororidimol-5-ylmethanol, 2,4-dimethylimidazol-5-ylmcthanol, 2,4-diisopropylimidazol-5-ylmethanol , 2-isopropyl-4-ethyl-imidazol-5-ylmethanol or 2-fluorimidazol-5-yImethanol, the following ketone derivatives were obtained: 2-fluoro-l-tosylimidazoi-5-ylmethyI-fluoromethyl-ketone,

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2,4-dimethyl-l-tosylimidazol-5-ylmethyl-fluoromethyl-ketone, 2,4-diisopropyl-l-tosylimidazol-5-ylmethyl-fluoromethyl-ketone,

2-isopropyl-4-ethyl-l-tosylimidazol-5-ylmethyl-fluoromethyl - ketone and

2-fluoro-l-tosyimidazol-5-ylmethyl-fluoromethyl-ketone.

Example 11

In the procedure of Example 1 (B), when the 1-tosyl-5-imidazolylmethyl-fluoromethyl-ketone was replaced with an appropriate amount of the ketone compounds obtained in Examples 8, 9 and 10, the following corresponding compounds were replaced obtained: 2- (2-fluorimidazol-5-yl) -1-dif hiormethyl-ethylamine hydrobromide,

l-difluoromethyl-2-, 2,4-dimethylimidazol-5-yl) ethylamine - hydrobromide,

l-difluoromethyI-2- (2,4-diisopropylimidazol-5-yI) ethylamine - hydrobromide,

1-difluoromethyl-2- (2-isopropylimidazol-5-yl) ethylamine - hydrobromide,

2- (2-fluorimidazol-5-yl) -l-difluoromethylethylamine hydrobromide,

2- (2-fluorimidazol-5-yl) -l-trifluoromethylethylamine hydrobromide,

2- (2,4-dimethylimidazol-5-yl) -1-trifluoromethylethylamine - hydrobromide,

2- (2,4-diisopropylimidazol-5-yl) -l-trifluoromethylethylamine - hydrobromide,

2- (2-isopropylimidazol-5-yl) -1-trifluoromethylethylamine hydrobromide,

2- (2-fluorimidazol-5-yl) -1-trif luormethylethylamine hydrobromide,

l-fluoromethyl-2- (2-fluorimidazol-5-y]) ethylamine hydrobromide,

l-fluoromethyl-2- (2,4-dimethylimidazol-5-yl) ethylamine hydrobromide,

l-fluoromethyl-2- (2,4-diisopropylimidazol-5-yl) ethylamine-

-hydrobromide, l-fluoromethyl-2- (2-isopropyl-4-ethylimidazol-5-yl) -ethyl-

amine hydrobromide and l-fluoromethyl-2- (2-fluorimidazol-5-yl) ethylamine hydrobromide.

Example 12

N- [l-fiormethyl-2- (5-imidazolyl) ethyl] acetcimide

A solution of 10 mmoles of 1-fluoromethyl-2- (5-imide-azolyl) ethylamine hydrobromide in 26 ml of 2 M sodium Hy637384

hydroxide solution was cooled to 5 ° C. This solution was simultaneously added dropwise with 13 mmol of acetyl chloride and 5 ml of 2 M sodium hydroxide solution from 2 syringes. After 2 hours the solution was neutralized by adding 16 ml of 1 M hydrochloric acid and then evaporated to dryness. The residue was triturated with dichloromethane, filtered and evaporated to give N- (l-difluoromethyl - 2- (5-imidazolyl) ethyl] acetamide, which was recrystallized from ethyl acetate.

When the acetyl chloride was replaced with an appropriate amount of benzyl chloroformate in the above-described process, benzyl-N- [l-fluoromethyl-2- (5-imid-azolyl) ethyl] carbamate was obtained.

Example 13

N- [l-fluoromethyl-2- (5-imidazolyl) ethyl] -2-aminopropionamide

A solution of 10 mmol of benzyl-N- [l-fluoromethyl-2 - (5-imidazolyl) ethyl] carbamate in 20 ml of methylene chloride, which contained 1.1 g of triethylamine, was mixed with 10 mmol of benzyl chloroformate. After 2 hours at 25 ° C., the solution was washed with water and 1 N hydrochloric acid and then evaporated to give the dicarbobenzoxy derivative. This residue was mixed with 30 ml of 100% (weight / weight) hydrogen bromide in dioxane and the mixture was switched off at 25 ° C. for 30 minutes, after which 150 ml of ether were added. The resulting precipitate was filtered off and cold bicarbonate solution was added and then quickly extracted with dichloromethane. The dried organic phase was concentrated to give l-carbobenzoxy-5- [2-fluoromethyl-2-aminoethyl] imidazole, which was dissolved in 10 ml dichloromethane for about 16 hours at 25 ° C. with 1.6 g (7 mmol) N -Carbobenzoxyalanin and 1.45 g (7 mmol) of N, N-dicyclo-hexylcarbodiimide was treated. The mixture was then cooled to 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% (weight / weight) hydrogen bromide in dioxane at 25 ° C. for 30 minutes. The addition of 150 ml of ether led to a precipitate of the hydrobromide, which was filtered off and treated at 25 ° C. for about 16 hours with 50 ml of 1 N sodium hydroxide. The resulting solution was adjusted to neutral pH and the product was isolated from amberlite 120 H + resin by elution with 2 M ammonia, giving N- [l - fluoromethyl-2- (5-imidazolyl) ethyl] -2-aminopropionamide was obtained.

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Claims (10)

637384 2. A compound according to claim 1, characterized in that R is a hydrogen atom or an alkylcarbonyl radical, the alkyl part having 1 to 4 carbon atoms and being straight or branched chain. 2nd 1. A compound of the general formula ch2-ch-nhr cd in which Y is a radical of the formulas FCH2, F2CH or F3C, R is a hydrogen atom, an alkylcarbonyl radical, the alkyl part having 1 to 4 carbon atoms and being straight-chain or branched-chain , an alkoxycarbonyl radical, where the alkoxy part has 1 to 4 carbon atoms and is straight or branched chain, or a radical of the formula O —C — CH — R, NH, wherein R3 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 Rj and R2 each represent a hydrogen atom, a straight or branched chain lower alkyl radical having 1 to 4 carbon atoms, wherein Rj and R2 may be the same or different, or Ri is a hydrogen atom and R2 is a fluorine atom, and the salts thereof. 3. A compound according to claim 1, characterized in that R represents a hydrogen atom. 4. A compound according to claim 1, characterized in that each of the radicals Rj and R2 represents a hydrogen atom or a methyl radical. 5. Compounds according to claim 1, characterized in that each of the radicals Rj and R2 represents a hydrogen atom. 6. A compound according to claim 1, characterized in that Y is a radical of the formula FCH2- or F2CH-. 7. A compound according to claim 6, characterized in that each of the radicals R, Rj and R2 represents a hydrogen atom. 8. l-fluoromethyl-2- (5-imidazolyl) ethylamine or a pharmaceutically acceptable salt thereof, as a compound according to claim 1. 9. l-difluoromethyl-2- (5-imidazolyl) ethylamine or a pharmaceutically acceptable salt thereof, as a compound according to claim 1. 10. l-trifluoromethyl-2- (5-imidazolyl) ethylamine or a pharmaceutically acceptable salt thereof, as a compound according to claim 1.