HU210346A9 - 5-(1-(imidazol)methyl)-3,3-disubstituted-2(3h)furanone derivatives - Google Patents

Description

BACKGROUND OF THE INVENTION

A) FIELD OF THE INVENTION

This invention relates to novel 5- [1- (imidazole) methyl] -3,3-diphenyl-2 (3H) -furanone and 3-cycloalkyl-5- [1- (imidazole) methyl] -3-phenyl-2 (3H) -. refers to furanone derivatives, their pharmaceutically acceptable quaternary alkyl and acid addition salts, and users of disorders in which anticholine agents are effective.

B) State of science

Antagonizing the action of acetylcholine on muscarinic cholinergic receptors to antagonize its action on different receptors in various tissues has anticonvulsant, antitumoural, and pupil dilating activity. As a result, such compounds have wide therapeutic applications, namely as anticonvulsants, as an adjuvant in the treatment of gastric ulcer, as adjuvants in the treatment of bowel or bladder functional disorders such as irritable bowel syndrome, colonic ulcer, ulcerative colitis, -inflammation and neurogenic bladder disorders (V. V. Rama Sastry, in "Buerger's Medical Chemistry", Part III, Chapter 44, p. 361; ed. Μ E. Wolff, 4th ed.).

Furanones have long been known in the realm of natural compound chemistry. Pilocarpine, a 4-l-imidazole-methyl] -2 (3H) -furanone, is a naturally occurring muscarinic active ingredient (LS Goodman, A. Gilman, "The Pharmacological Basis of Therapeutics", 6th edition, 1980). p.87). 5 - [(Diethylamino) -methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone is a furan which has been described as having an antiarrhythmic (but not anticholinergic) effect on mammalian heart tissue. A. Pohland, South Africa Patent 6,805,631, March 2, 1970; Eli Lilly et al., U.S. Patent Application, November 13, 1967. Another phyranone, an antispasmodic that inhibits isolated guinea-pig gut contraction, is 3 - [(dimethylamino) methyl] -4,5-dihydro-5,5-diphenyl-2- (3H) -furanone [N . Kolokouris, G. Eytas, C. Brunet, M. Luyckx, Ann. Pharm. Fr. 43 (3): 257 (1985)].

Most of the currently known antimuscarinic agents are structurally similar to potato alkaloids, such as anthropin, or to a diverse group of compounds that include hydroxy esters, such as oxybutynin, amides, such as tropicamide, and amino alcohols, such as procyclidine. These groups of compounds inhibit the action of acetylcholine on the cholinergic receptor. The use of anthropin isopropyl quaternary bromide, ipratropium bromide, is particularly well-known as a bronchodilator in the treatment of respiratory disorders such as asthma and chronic bronchitis. [G. E. Pakes, R. N. Brodgen, R. C. Heel, T. M. Speight, G.

S. Avery, Drugs, 20, 237-266 (1980)].

The present invention relates to 5- [1- (imidazole) methyl] -3,3-diphenyl-2- (3H) -furanone and 3-cycloalkyl-5- [1- (imidazole) methyl] -3-phenyl. It provides a new class of -2 (3H) -furanone derivatives which have anticholinergic activity.

Summary of the Invention

The present invention provides novel compounds of the formula:

in which:

the dashed line represents either the 4,5-unsaturated or 4,5-dihydrofuranone ring;

R 1 and R ₂ may be the same or different and represent hydrogen, thienyl, furanyl or C 3 -C 6 cycloalkyl, benzyl, phenyl, substituted phenyl or substituted benzyl, wherein the phenyl or benzyl is halogen, trifluoromethyl, , may be substituted by lower alkyl, lower alkoxy or hydroxy;

R _{3 is} hydrogen, lower alkyl, lower alkyl, lower alkyl, alkoxy, amino, carboxylic acid, ester or amide substituted with one halogen, benzyl, phenyl, nitro, trifluoromethyl, cycloalkyl, 3-6. a carbon atom, a halogen atom, or a portion of an alkene bridge which forms a quaternary salt with a double bonded imidazole nitrogen, substituted phenyl or substituted benzyl having the same substituents as those for R ₁ and R ₂ substituted benzyl or phenyl;

R ₄ and R ₅ may be the same or different and represent (R) as described for R ₃ or form an alkylene bridge;

Rg is hydrogen or lower alkyl (a

4,5-dihydrofuranone series) and pharmaceutically acceptable salts of such compounds, in particular quaternary alkyl (C 1 -C 4) and acid addition salts thereof. (The formula above is hereinafter referred to as Formula I.).

As used herein, lower alkyl or lower alkoxy (term) refers to groups having one to six carbon atoms and C 3-6 cycloalkyl (term) refers to cycloalkyl (groups) having three to six carbon atoms in the cyclic group, alone including cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The alkylene bridges which are illustrated for R ₃ , R ₄ and R ₅ may have one, two, three, four or more carbon atoms. Each R group may be different from the other groups, i.e., each R group

Group A9 is independently selected. The present invention includes lower alkyl quaternary salts of the aforementioned compounds. The invention also encompasses pharmaceutical compositions and therapeutic methods which are effective as anticholinergics using such compounds in disorders where the efficacy of anticholinergic agents, including neurogenic bladder disorders, is recognized.

Detailed Description of the Invention

The present invention provides 5- [1-imidazole-methyl] -3,3-diphenyl-2 (3H) -furanone and 3-cycloalkyl-5- [1- (imidazole) -methyl] -3- [5 phenyl-2- (3H) -furanone derivatives. The compounds of the present invention include those wherein R 1 and R ₂ are independently selected from phenyl, thienyl, furanyl and substituted phenyl, and R ₃ , R 4 and R ₅ are each independently lower alkyl. Preferred compounds include those wherein R 1 and R _{2 are} phenyl and R ₃ , R ₄ and R ₅ are each independently lower alkyl. Preferred compounds of the invention are those wherein R and R _{2 is} phenyl or substituted phenyl. Most preferred R ₃ groups are hydrogen and lower alkyl groups. Preferred R ₄ and R ₅ groups are both (at position) hydrogen or methyl. Preferred compounds include 5- [1- (2-ethylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone, 5- [1- (2- propylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone, 5- [1- (2-methylimidazo) methyl] -4,5-dihydro- 3,3-diphenyl-2 (3H) -furanone and 5- [1- (2-isopropylimidazolyl) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone. Other preferred compounds include (R) - (+) - 5- [1- (2-ethylimidazolyl) methyl] -4,5-dihiro-3,3-diphenyl-2 (3H) -furanone; - [1- (2-n-Propylimidazole) methyl-4,5-dihydro-3,3-diphenyl-2 (3 H) -furanone, 5- [2-ethylimidazole] methyl] -3,3 -diphenyl-2- (3H) -furanone, 5- [1- (2-ethyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2) 3H) -furanone bromide , 5- [1- (2-tert-butylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2- (3H) -furanone, 6,7-dihydro-1 [2,3 , 4,5-Tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] 5H-pyrrolyl (1,2-a) -imidazolium chloride, 5- [1- (2-isopropyl) - imidazole) methyl-3,3-diphenyl-2 (3H) -furanone, (R) - (+) - 5- [1- (2-isopropylimidazole) methyl] -4,5-dihydro-3,3 - diphenyl-2 (3H) -fyranone.

The compounds of the invention act as antagonists of cholinergic prescription and have (a range) of various antimuscarinic therapeutic uses, particularly in the treatment of neurogenic bladder and respiratory disorders. Due to their action on bladder contraction, anticonvulsant and antisecretory activity, they are particularly useful in the treatment of urinary incontinence (incontinence). The compounds are also expected to exhibit anticonvulsant, antisecretory, and pupil dilating activity which may be used in other disorders, namely as anticonvulsants, as an adjuvant in the treatment of gastric ulcer, and as adjuvants in the treatment of functional disorders of the gut or bladder, such as irritable bowel syndrome, spastic colitis, ulcerative colitis, and diverticulitis. The quatemeric salts of this invention are particularly useful as bronchodilators, particularly in the treatment of asthma and chronic bronchitis.

To some extent, the compounds of the invention may exist as optical or geometric isomers, so that all isomers and racemic mixtures are, of course, within the scope of the invention. In addition, all possible other isomeric forms of the compounds of the invention are within the scope of the invention.

The compounds of the invention may be used in the form of a non-toxic pharmaceutically acceptable acid addition salt (which) has the utility of the free base. Such salts, prepared by methods well known to those skilled in the art, may be prepared from both inorganic and organic acids, such as maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, [4,4'-methylene-bis (3-hydroxy-2 naphthyl acid), emboic acid], succinic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citric acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, benzenesulfonic acid, hydrogen chloride, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid.

The compounds of the invention may be administered orally, parenterally or by inhalation in conventional dosage units such as tablets, capsules, injections, aerosols or the like, by combining the appropriate doses of the compounds of Formula I with carriers in accordance with standard pharmaceutical practice.

Preferably, a compound or an acid addition salt thereof can be orally administered to an animal in a tablet or capsule or aerosol (which) contains sufficient amount to produce the desired effect of a cholinergic antagonist. Each dosage unit will contain from about 0.1 mg to about 40 mg of active ingredient. Preferably, equal doses will be administered three to four times a day (thus) in a daily dosage regimen of from about 1 mg to about 160 mg, preferably from about 6 mg to about 80 mg.

For example, the pharmaceutical carrier used may be either solid or liquid. Exemplary solid carriers include lactose, gypsum, sucrose, talc, gelatin, agar, petkin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, and the like. The carrier or diluent may include any time delay material which is well known in the art, such as glycerol monostearate or glycerol distearate alone or with a wax.

A wide variety of pharmaceutical forms can be used. Thus, when a solid carrier is used, the composition may be tableted into a hard gelatin capsule

It may be presented as a powder or granules, or may be cylindrical or diamond-shaped (tablet). The amount of solid carrier can vary widely but is preferably from about 25 mg to about 1 g. When a liquid carrier is used, it may be in the form of a syrup, emulsion, soft gelatin capsule, aerosol, sterile injectable liquid such as an ampoule, or an aqueous or non-aqueous liquid suspension.

The compounds of the invention may be prepared by alkylation of substituted acetic acids. For example, diphenylacetic acid is doubly lithiated and treated with allyl bromide to give 2,2-diphenyl-4-pentenoic acid. This acid is cyclized to a phranone by treatment of its sodium salt with bromine. The resulting 5- (bromomethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone is allowed to react with the substituted imidazole under warm conditions (which ultimately yields the compounds of the invention). Alternatively, a 2,2-disubstituted-4-pentenoic acid is oxidized to an epoxide which is treated with alkali to give 5-hydroxymethyl-4,5-dihydro-3,3-disubstituted-2 (3H) -furanone, which is converted stepwise the corresponding 5-bromomethyl or triflate derivative. This is used, in its salt, to alkylate the corresponding imidazole, prepared from an alkyl cyanide through an imidate and condensed with aminoacetaldehyde dimethylacetate to give a 5- [1- (imidazole) methyl] -4,5-dihydro-3, 3-disubstituted-2 (3H) -furanone. Stereoselective synthesis of the compounds of this invention proceeds from (R) and (S) -2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane via the corresponding 4-iodomethyl derivative to alkylate a phenylacetic acid. Hydrolysis of dioxolane yields a diol which, after lactonization to the corresponding 5- (hydroxymethyl) -4,5-dihydro-3,3-disubstituted -2 (3H) -furanone, is used to alkylate an imidazole as indicated above. Base-induced dehydrohalogenation of 5- (bromomethyl) -4,5-dihydro-3,3-disubstituted-2 (3H) -furanones yields 4,5-dehydro-5-methyl derivatives which, after bromination, imidazole can be used to give the unsaturated (4,5-dehydro) -2 (3H) -furanones of this invention. Quaternary alkyl derivatives are obtained from 5- [1- (imidazole) methyl] -3,3-disubstituted 2- (3H) -furanones by treatment with an alkyl halide or by appropriate alkylation of a quaternary alkyl imidazole.

The following examples illustrate the invention. The temperature is given in degrees Celsius; NMR signals are reported in ppm down from an internal standard of Me ₄ SI.

Examples

Example I 1- (Dimethylamino) methylimidazole

Imidazole (20.4 g, 0.3 mol) and dimethylamine hydrochloride (26 g, 0.3 mol) were mixed with water (50 ml) and the cooled solution was adjusted to pH 4.97 with concentrated hydrochloric acid. A 37% formaldehyde solution (27 g, 0.33 mol) was added and the mixture allowed to stand for three days. ApH was adjusted to 14 with 20% aqueous potassium hydroxide before salting the product with solid K ₂ CO ₃ . The organic material is extracted with methylene chloride (dichloromethane), dried (K ₂ CO ₃ ) and evaporated under reduced pressure. The residue is distilled in a Kugelrohr apparatus at 0.1 mm and 95 ° C and

30.8 g (83%) of pure product are obtained.

2-Butyl-imidazole

1- (Dimethylamino) methylimidazole (5.0 g, 40 mmol) was stirred in tetrahydrofuran (80 mL) under argon (gas) at 78 ° C and 2.4 mL of n-butyllithium (20 mL, 48 mmol) in hexane is added dropwise. After 1 hour

8.8 g (48 mmol) of 1-iodobutane were added and the mixture was stirred at -78 ° C for 1 hour before being removed from the cooling bath and stirred overnight. The reaction was acidified by the addition of 60 ml of 2N hydrochloric acid and evaporated under reduced pressure as the organic solvent. Solid NaHCO ₃ was added to the aqueous residue before the mixture was extracted with methylene chloride. The extract was dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil. Kugolrohr distillation gave 2.1 g (43%) of product at 0.1 mm and 125-120 ° C. The following imidazoles were prepared by an analogous method

2-isobutylimidazole (m.p. 125-126 ° C)

2-benzylimidazole (m.p. 123-124,5 ° C).

Example IL

2- tert -butylimidazole

Tert-butyl nitrile (25 g, 0.3 mol) and 17.4 ml (0.3 mol) absolute ethanol were stirred at 25 ° C under argon (g) and gaseous hydrogen chloride was slowly bubbled into the solution. After 5 days, ether (200 mL) was added at 25 ° C to give 18.6 g (37%) of a solid, which was found to be ethyl tert-butyl imidate. This product (18.6 g, 0.11 mol) was stirred in methanol (20 mL) and 13.0 g (0.123 mol) of aminoacetaldehyde dimethylacetal was added and the mixture was allowed to stand at 25 ° C for 3 days. The solution was concentrated in vacuo at 88 ° C to give 26.6 g of a residual liquid, to which 30 ml of concentrated hydrochloric acid and 20 ml of water were added. The mixture was concentrated in vacuo at 88 ° C to give 20 g of a dark viscous liquid. A suspension of this residue in 10 mL of water was adjusted to pH 10 with solid K ₂ CO ₃ . After removing the water in vacuo, the residue was stirred with 200 mL of ethanol. The resulting mixture (obtained) is filtered and the filtrate is concentrated under reduced pressure to give a solid residue. Sublimation of this solid gave 9.0 g of crystalline product, m.p. 224-225 ° C.

The following imidazoles were prepared analogously;

2-Isobutylimidazole (m.p. 125-126,5 'C)

2-Benzylimidazole (m.p. 123-124 'C)

2- (2-methoxyethyl) imidazole (Kugelrohr bp 90-95 'C at 0.1 mm)

2- (2-hydroxyethyl) imidazole (m.p. 128-129 'C)

2- (4-chlorobutyl) imidazole (identified by oil chromatography and 1 H NMR)

2- (3-chloropropyl) imidazole [hygroscopic solid

EN 210 346 A9 (which was used for the next reaction without purification).

III. example

5.6.7.8- Tetrahydro-imidazo [1,2-a] pyridine

To a solution of 11.0 g (69.3 mmol) of 2- (4-chlorobutyl) imidazole in 90 ml of methyl ethyl ketone and 10 ml of dioxane was added 12.0 g (80.0 mmol) of sodium iodide and 5.0 ml. g (36.2 mmol) of potassium carbonate was added. After stirring and refluxing for 20 hours, the mixture was cooled to 25 ° C and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in methanol (40 ml), propylene oxide (10 ml) was added and the solution was stirred at 25 ° C for 20 hours. Concentration of the solution in vacuo afforded a liquid which was applied to 300 g of silica gel and eluted with 2% methanol in methylene chloride; 2.2 g of a colorless liquid are obtained which are identified by 1 H NMR. THE

6,7-Dihydro-5H-pyrrolyl- [1,2-a] imidazole was prepared in a similar manner from 2-chloropropylimidazole; A hygroscopic white solid was obtained at 80 ° C and 0.1 Torr.

ARC. example

8-Methylimidazo [1,2-a] pyridine

To a mixture of chloroacetaldehyde (25.4 mL (0.2 mol) in 50% aqueous solution) and 18.8 g (0.2 mol) of 2-amino-3-methylpyridine in 150 mL of water were added 16.8 g ( Sodium bicarbonate (0.2 mol) was added. After stirring for 3 days at 25 ° C, the mixture was acidified with concentrated hydrochloric acid and stirred for an additional 30 minutes. After adjusting the pH to 10 by the addition of sodium hydroxide, the mixture was saturated with sodium chloride and extracted with ether. The ether extract was dried and concentrated; 16.3 g (62%) of a liquid residue (m.p. 6870 DEG C. at 0.1 Torr) are obtained. Imidazo- [1,2-a] pyridine, fp. 6166 ° C was prepared in an analogous manner at 0.1 Torr.

Example V

5.6.7.8- Tetrahydro-8-methylimidazo [1,2-a] pyridine

A mixture of 2.0 g (15.1 mmol) of 8-methylimidazo [1,2-a] pyridine and 2 teaspoons of Raney Nickel 2800 was hydrogenated in 40 ml of n-butanol at 55 psi initial hydrogen pressure at 65 ° C for 24 hours. over. The mixture was filtered and the filtrate concentrated in vacuo. The resulting liquid was chromatographed (silica gel, 40 g, 98: 2 methylene chloride: methanol) to give 1.1 g of an oil.

1 H NMR (CDCl ₃ ) δ 1.32 (d, J = 7.4 Hz, 3H), 1.42-1.58 (m, 1H), 1.82-2.0 (m, 1H), 2.0-2.12 (m, 2H), 2.822.99 (m, 1H), 3.80-4.02 (m, 2H), 6.74 (d, J = 1.5 Hz,

1H), 6.97 (d, J = 1.5 Hz), 1H); analytical TLC (silica gel, 95: 5 methylene chloride: methanol) Rf. 0.46.

VI. example

2-Ethyl-1-methylimidazole g (0.52 mol) 2-ethylimidazole, 104 g (0.78 mol) potassium carbonate, 1.4 g (5.2 mmol) [18] A mixture of 6 and 260 ml of dimethyl carbonate was stirred and refluxed for 3 days. The mixture was then filtered and the filter cake washed with ether. The filtrate and washings (liquids) were concentrated in vacuo and the resulting residue was partitioned between water and ether. After the ether layer was separated, dried over MgSO ₄ , concentrated and distilled to give 17 g (30%) of a colorless liquid, m.p. 65-75 ° C at 0.1 Torr.

2-Isopropyl-1-methylimidazole is a colorless liquid, m.p. 70 DEG C. at 0.1 Torr, analogously.

VII. example

1-Trityl-itnidazol

To a stirred solution of imidazole (23.5 g, 0.35 mol) in ethyl acetate (425 ml) was added triphenylmethyl chloride (triphenyl chloromethane) (48.0 g, 0.32 mol). The mixture was stirred for 20 hours and then water (500 mL) was added. After stirring for another two hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO ₄ ), and concentrated. Recrystallization of the remaining xylene gave 41 g of white crystals, m.p. 222-225 ° C.

2-carbomethoxy-l-trityl-imidazole

To a stirred solution of 1-tritylimidazole (12.4 g, 40 mmol) in tetrahydrofuran (250 mL) under argon (gas) was added n-butyllithium (20 mL, 48 mmol) in hexane. After the solution was allowed to warm to ambient temperature, it was stirred for 1 hour then

Methyl chloroformate (methyl chloroformate) (3.4 mL, 50 mmol) was added dropwise. The mixture was stirred for 20 hours at 25 ° C, 100 ml of water was added and then the mixture was concentrated in vacuo. The residue was extracted with ether. After the extract was dried (MgSO ₄ ) and concentrated, the residue was chromatographed on 200 g of silica gel with 1: 3 ethyl acetate: hexane followed by 1: 1 ethyl acetate: hexane and finally ethyl acetate to give 3.2 g of a colorless product.

2-Carbomethoxy-imidazole

After a solution of 3.2 g (8.7 mmol) of 1-trityl-2-carbomethoxyimidazole in 40 ml of 5% methanolic acetic acid solution was refluxed for 30 minutes and concentrated in vacuo. Recrystallization from ethanol gives colorless needles, m.p. 187-188 “C.

VIII. example

2,2-diphenyl-4-pentenoic acid

A solution of diphenylacetic acid (250 g, 1.17 mol) was stirred in 2.4 L of tetrahydrofuran at 0 ° C under argon while 0.94 L of a 2.5 molar solution of n-butyllithium in hexane was added. add drop by drop. After 1 hour, allyl bromide (142.5 g, 1.17 mol) was added in one portion. After 15 minutes, 500 ml of 10% hydrochloric acid was added together with ether (2 L). The layers were separated, the aqueous layer was extracted with ethyl ether (1 x 250 mL), the organic layers were combined, washed with brine, dried (MgSO ₄ ) and filtered. Concentration gave 296 g (99%) of an off-white solid, m.p. 134-137 “C.

1 H NMR (CDCl 3) δ 7.3 (m, 10H), 5.6 (m, 1H), 4.9 (bs,

2H), 3.2 (d, 2H).

5- (Bromomethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone

To a mixed mixture of tetrahydrofuran: water (9: 1,

HU 210 346 A9

1.65 L 2,2-Diphenyl-4-pentenoic acid (296 g, 1.17 mol) and sodium bicarbonate (98.85 g, 1.17 mol) were added. After the mixture became homogeneous, bromine (188 g, 1.17 mol) was added dropwise. After 1 hour, a solution of sodium thiosulfate (10 g in 250 mL of water) was added and the mixture was stirred for 10 minutes. Ether (1 L) was added and the layers were separated. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered. Concentration gave 364 g of an oil which crystallized on standing. Recrystallization from ether gave 230 g (59%) of a white crystalline solid, m.p. 84-85'C. IR (KBr) 1766 ^cm-first

1 H NMR (CDCl 3) δ 7.45-7.27 (m, 10H), 4.5 (Μ, 1H),

3.5 (m, 2H), 3.2 (dd, 1H, J = 13.1), 2.8 (dd, 1H, J =

10, 13.1)

5- [l- (imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) jurand

5- (Bromomethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (1.5 g, 4.5 mmol) and imidazole (2 g) were dissolved in dimethylformamide ( 6 ml). This solution was heated under argon (gas) at 100 ° C for 20 hours. After cooling, the mixture was partitioned between saturated sodium bicarbonate solution (25 mL) and methylene chloride (200 mL) and the layers were separated. The organic layer was washed with water (2 x 50 mL), then washed with brine and dried (MgSO ₄ ). Filtration, after concentration, gives a solid. Recrystallization from ether gave a white solid (0.7 g, 50%), m.p. 146-148'C. Irish (KBr) 1777 cm ^-1 .

1 H NMR (CDCl ₃ ) δ 7.5-7.1 (m, 13H), 4.55 (m, 1H),

4.3 (dd, 1H), 4.16 (dd, 1H), 2.99 (dd, 1H), 2.5 (dd,

IH).

Calcd for C ₂₀ H ₁₈ N ₂ O ₂ (C): C, 75.45; H, 5.69; N, 8.79. Found: C, 75.31; H, 5.76; N, 8.71.

IX. example

5- [1- (3-Methylimidazolyl) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone bromide hydrate

5- (Bromomethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (1.35 g, 4.07 mmol), 1-methylimidazole (0.35 g, (07 mmol) and ether (5 ml) were placed in a sealed tube. The tube was filled with argon, sealed and heated at 110 ° C for 18 hours. After the solution was cooled, the resinous residue was removed and triturated with acetone (which) ad. recrystallization from acetone gives a white hygroscopic solid, mp. 148-152 ° C (0.70 g, 42%). IR (KBr) 1758 ^cm-1.

1 H NMR (DMSO-d ₆ ) 9.1 (s, 1H), 7.7 (dd, 2H), 7.4-7.4 (m, 10H), 4.6 (m, 1H), 3 , 86 (s, 3H), 3.3 (dd, 1H),

2.8 (dd, 1H).

Analysis calculated for C ₂₁ H ₂₁ N ₂ O ₂ Br.H ₂ O (%): C, 58.47; H, 5.37; N, 6.49; Br, 18.52. Found: C, 57.91; H, 5.40; N, 6.40; Br, 18.41.

The following compounds (m.p. in parentheses) are also available from Vili. and IX. The reaction sequence was prepared according to the reaction sequence given in Example 1A.

5 - [(1-Imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) furanone (146-148 ° C),

5- [1- (2-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone (106-108 ° C), 5- [1- (2-ethyl) - imidazole-methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (265-268 ° C), 5- [1- (3-methylimidazole) methyl] -4, 5-dihydro-3,3-diphenyl-2 (3H) -furanone bromide hydrate (148-152 ° C), 5- [1- (2,3-dimethylimidazole) methyl] -4,5-dihydro- 3,3-diphenyl-2 (3H) -furanone bromide (240-243 ° C),

5- [1- (2-Methyl-3-benzylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone bromide (218-220 ° C), 5- [1 - (2-isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (108-109 ° C),

5- [1- (2-Butylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone (134-135 ° C), 5- [1- (Propylimidazole) -methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (168-169 ° C),

5- [1- (3-ethylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (155-160 ° C).

Example X.

5- (Hydroxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone

2,2-Diphenyl-4-pentenoic acid (5.0 g, 20 mmol) was mixed with 20 mL of formic acid and 2.4 mL (22 mmol) of 30% hydrogen peroxide at 70 ° C for 25 hours at ambient temperature. The solvents are removed under reduced pressure, the residue is taken up in 20 ml of methanol and a solution of 750 mg of solid sodium hydroxide in 10 ml of water (prepared) is added. The mixture was heated to 70 ° C to dissolve before cooling for about 1 hour and acidifying with 6N hydrochloric acid. The product was extracted with ether, the organics dried (MgSO ₄ ) and evaporated under reduced pressure to give an oil in quantitative yield, H NMR indicated a pure reaction product which was carried on without further purification. Analytical TLC (silica gel, 9: 1, methylene chloride: ethyl acetate) Rf. 0.35; IR (neat) 3419, 3060, 2936, 1763, 1177, 766, 763, 699 cm ^-1 ;

1 H NMR CDCl ₃ δ 2.5-, 2.65 (bs, 1H), 2.84-3.02 (m,

2H), 3.64-3.72 (m, 1H), 3.92-4.00 (m, 1H), 4.414.51 (m, 1H), 7.2-7.4 (m, 10H). .

5- (Trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone

5.5 ml of Trifluoromethanesulfonic anhydride (32.5 mmol) are added to 14 ml of dry methylene chloride under argon at room temperature. The solution was cooled to -40 ° C and 2.3 g (22 mmol) of finely powdered, oven-dried Na ₂ CO ₃ was added. To the stirred mixture was added dropwise 5- (hydroxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (6.7 g, 25 mmol) in methylene chloride (15 mL), stirred for 2 hours at -40 '. C before heating to 0 ° C for 0.5 hour. The reaction was stopped at 0 ° C by the dropwise addition of 10 ml of water under vigorous stirring. The layers are separated, the organic material is washed with brine, dried (MgSO ₄ ) and evaporated under reduced pressure to a solid, which is used as it is obtained and usually contains 5-15% unreacted alcohol.

HU 210 346 A9 1 H NMR (CDCl 3) δ 2.77-2.83 (m, 1H), 3.05-3.14 (m, 1H), 4.51-4.71 (m, 2H), 4.70-4.75 (m, 1H), 7.257.45 (m, 10H).

5- [1- (2n-Propyl-imidazole) -methyl-4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride

5- (Trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (5.2 g, 13 mmol) and 3.0 g (28 mmol) of 2-n- propylimidazole was stirred in 15 mL of methylene chloride under argon in a sealed tube and 120 ° C of methylene chloride under argon in a sealed tube and heated at 120 ° C overnight. After the cooled solution is poured into water, the organics are washed with dilute aqueous K ₂ CO ₃ , brine and dried (MgSO ₄ ) before evaporation under reduced pressure to give an oil. The residue was chromatographed (silica gel, 98: 2, methylene chloride: methanol) to give 3.0 g (64%) of product. This material was dissolved in warm isopropanol, an equivalent of 1 N hydrochloric acid in ether was added and the product was allowed to crystallize, m.p. 232-234 ° C.

1 H NMR (DMSO-d ₆ ) δ 0.905 (t, J = 7.4 Hz, 3H), 1.631,79 (m, 2H), 2.79-2.89 (m, 1H), 2.95 ( t, J =

7.5 Hz, 2H), 3.23-3.33 (m, 1H), 4.48 ^ 1.70 (m, 3H), 7.23-7.34 (m, 10H), 7.61 (d, J = 1.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H);

IR (KBr) 3062, 2957, 2933, 2872, 1761, 1493,

1445,1277,1169,1069,696 cm ^-1 ; analytical TLC (silica gel, 95: 5, methylene chloride: methanol) Rf. 0.39. Calcd for C ₂₃ H ₂₅ ClN ₂ O ₂ (C): C, 69.60; H, 6.35; Cl, 8.93; N, 7.06. Found: C, 69.62; H, 6.37; Cl, 8.97; N, 7.04.

The following compounds were prepared analogously.

5- [1- (2-Isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (m.p. 250.5-252.5 ° C), 5- [1- (2-Isobutylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (m.p. 223-227 ° C), 5- [l - (2-tert-Butylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride hydrate (m.p. 118-

130 'C),

5- [1- (2-Phenylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride (m.p. 189-190.5 ° C), 5- {1 - [2- (2-methoxyethyl) imidazole] methyl} -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (m.p. 236237 ° C).

XI. example

5- [1- (2-Ethyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone chloride hydrate 1-Methyl-2-ethylimidazole 2 5 g (22 mmol) and 8.0 g (20 mmol) of 5- (trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone are mixed with 15 ml of methylene chloride. chloride under argon in a sealed tube and heated for 1.2 hours at 100 ° C. During cooling, a solid is formed which is filtered off. The solvents were evaporated under reduced pressure and the residue and solid were recrystallized from isopropanol (6.5 g, 61%), the pure triflate salt. The solid was taken up in 180 mL of methanol and passed through 180 mL of Amberlite IRA-100 (Cl) (ion exchange resin). The resulting solid was recrystallized from acetone to give 4.8 g of product, m.p. 243245 'C.

1 H NMR (CDCl ₃ ) δ 1.17 (t, J = 7.5 Hz, 3H), 2.81-2.91 (m, 1H), 3.03-3.14 (m, 2H), 3.26-3.34 (m, 1H), 3.80 (s, 3H), 7.21-7.43 (m, 10H), 7.66 (d, J = 2.0 Hz, 1H). , 7.71 (d, J = 2.0 Hz, 1H);

IR (KBr) 3478, 3409, 3108, 3077, 1769, 1531,

1447, 1159, 1061, 964, 753, 704 cm -1; analytical TLC (silica gel, 95: 5, methylene chloride: methanol) Rf. 0.26. Calcd for C ₂₃ H ₂₅ ClN ₂ O ₂ .0.05H ₂ O (%): C, 68.05; H, 6.46; N, 6.90; Cl, 8.73. Found: c, 68.24; H, 6.45; N, 7.10; Cl, 8.97. 5- [1- (2-Isopropyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2- (3H) furanone chloride hydrate was prepared analogously, m.p. 156-159'C.

XII. example

5- [l- (2-carbomethoxy-imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -juranon hydrochloride

To a solution of 2-carbomethoximidazole (0.11 g, 0.87 mmol) in dimethylformamide (5 mL) was added sodium hydride (34 mg, 1.5 mmol) under argon. The mixture was stirred until dissolution was complete (about 1 hour) and then 0.5 g (1.2 mmol) of 5- (trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl -2- (3H) -furanone is added. After stirring for 20 hours, the solution was concentrated in vacuo. The remaining semi-solid was partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried over MgSO ₄ , and concentrated in vacuo. The residue was applied to a preparative TLC plate (silica gel, 2 mm x 20 cm x 20 cm), methanol: methylene chloride (5:95) (mixture). Dissolution of the main spot gave a base of 300 mg (91%). To a solution of this material in ethyl acetate is added an equivalent of 1 N hydrochloric acid in ether to give a colorless crystal, m.p. 151-152 'C.

1 H NMR (CDCl ₃ ) δ 2.62-2.76 (m, 1H), 3.20-3.28 (m,

2H), 4.07 (s, 3H), 4.65-4.77 (m, 2H), 5.14-5.23 (m, 1H), 7.22-7.40 (m, 10H). , 7.56 (s, 1H), 7.63 (s, 1H); IR (KBr) 3432, 2519, 1765, 1745, 1460, 1447,

1270, 1172, 960, 699 cm ''; analytical TLC (silica gel, 96: 4, methylene chloride: methanol) Rf. 0.55. Analysis calculated for C ₂ H ₂₁ ClN ₂ O ₄ (C 64.00): C, 64.00; H, 5.13; Cl, 8.59: N, 6.78. Found: C, 64.29; H, 5.24; Cl, 8.43; N, 6.56.

The following compounds were prepared analogously.

5 - [(2-Nitro-imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (m.p. 190-205 ° C), 5- [1- (2- benzylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride (m.p. 256-260 ° C).

XIII. example

6,7-dihydro-1 - [(2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] -5-pyrrolyl [I, 2-a] - imidazolium chloride

2.0 g (18.5 mmol) of 6,7-dihydro-5H-pyrrolyl- [1,2-a] imidazole and 5.0 g (12.5 mmol) of 5- (trifluoromethylsulfo)

A9 Nyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone in 20 ml of methylene chloride was heated under argon in a sealed tube at 100 ° C for 20 hours. over. After cooling to 25 ° C, the reaction mixture was washed successively with brine and water, dried over MgSO ₄ , and concentrated. The residue was chromatographed on silica gel (135 g) eluting with 98: 2 followed by 96: 4 methylene chloride: methanol; 4.0 g (63%) of product are obtained. This triflate salt was passed through 60 mL of methanol over a 150 mL Amberlite IRA-400 (chloride anion exchange resin) column. The eluate was concentrated to give 2.6 g of colorless crystals, m.p. 245-246 ° C.

1 H NMR (CDCl ₃ ) δ 2.67 (dd, J = 10.3 Hz, J = 13.4 Hz,

1H), 2.78-2.91 (m, 2H), 3.42-3.66 (m, 3H), 4,244.36 (m, 2H), 4.37-4.48 (m, 1H). , 4.82-4.93 (m,

1H), 5.41 (dd, J = 1.7 Hz, J = 14.6 Hz, 1H), 7.217.43 (m 1H), 8.21 (d, J = 1.8 Hz, 1H);

IR (KBr) 3484, 3399, 3093, 3062, 1764, 1553, 1447, 1164, 964, 709 cm ^-1 ; analytical TLC (silica gel, 9: 1, methylene chloride: methanol) Rf. 0.14. Analysis calculated for C 3 H ₂₃ CLN ₂ O ₂ 0.75H ₂ O ₂ + (calcd): C, 67.64; H, 6.05; N, 6.86; Cl, 8.68. Found: C, 67.71; H, 6.06; N, 6.92; Cl, 8.69.

The following compounds were prepared analogously.

5.6.7.8- Tetrahydro-1 - [(2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] imidazole [1,2-a] pyridinium chloride hydrate (m.p. 235.5-237 ° C),

5.6.7.8- Tetrahydro-8-methyl-1 - [(2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] imidazo [1,2-a] - pyridinium chloride (m.p. 220-225 ° C),

1 - ((2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] -8-methylimidazo [1,2-a] pyridinium chloride) hydrate (m.p. 232.5-234.5 ° C),

1 - ((2,3,4,5-Tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] imidazo [1,2-a] pyridinium chloride hydrate (m.p. 266268 ° C).

XIV. Example 391 To a stirred solution of (S) - (+) - 2,2-Dimethyl-1,3-diaxolane-4-methyl-p-toluenesulfonate in methylene chloride, 491 g (2.57 mol) of p-toluenesulfonyl chloride was added dropwise to 391 ml. Triethylamine (2.81 mol) was added. The stirred solution was cooled to 0 ° C and (R) -glycerol acetonide (338.2 g, 2.56 mol) was added dropwise. The reaction mixture was stirred at 0 ° C for 2 hours and at 25 ° C for 20 hours. After filtration of the solution, the filtrate was washed successively with 1N hydrochloric acid, water and saturated sodium bicarbonate solution. The methylene chloride solution was then dried over MgSO ₄ and concentrated to give 610 g (83%) of a pale yellow liquid. GC analysis PH5-crosslinked 5% toluene silicone, 25 m x 0.2 mm x 0.01 mm film thickness, Ti 100 ° C for 3 min then 15 ° C / min up to 300 ° C, Tr 11.83 min (100%). Optical rotation of 0.171 g (material) to 1.0 mL with 95% ethanol at 22 ° C [α] D + 4.11 '. IR (neat) 2992, 1594.1356, 1182, 1090.977, 825 cm in ^{the first}

1 H NMR (CDCl ₃ ) δ 7.79 (d, 2H), 7.35 (d, 2H), 4.27 (m,

1H), 4.06-3.97 (m, 3H), 3.78-3.73 (m, 1H), 2.45 (s,

3H), 1.31 (s, 3H).

Calculated for C ₁₃ H ₁₈ O ₅ S (C): C,

54.53; H, 6.34; S, 11.20. Found: C, 54.51; H, 6.35; And,

11.14.

(S) - (-) - 2,2-dimethyl-4-iodomethyl-1,3-dioxolane in 9.6 g (33.4 mmol) of (S) - (+) - 2 in dimethylformamide, Sodium iodide (5.0 g, 33.4 mmol) was added portionwise at 45 ° C to 2-dimethyl-1,3-dioxolane-4-methyl-toluenesulfonate. The reaction mixture was stirred at 78 ° C for 20 hours. After cooling to 25 ° C, the mixture is filtered. Water (200 mL) and ether (250 mL) were added to the filtrate. The ether layer was separated and washed successively with 1 N hydrochloric acid, water, aqueous sodium bicarbonate and brine. After the solution is dried over _MgSO4, concentrated (and) 2.9 (83%) of an orange liquid. TLC (silica gel, ethyl acetate: hexane, 1: 9) Rf. 0.38. GC anise PH5-crosslinked 5% toluene silicone, 25 mx0.2 mm x 0.13 film thickness, Ti 100 ° C min then 15 ° C / min up to 300 ° C, Tr 4.13 min (100%). Optical rotation of 0.036 g of iodide diluted to 2.0 ml with 95% ethanol at 22 ° C [α] D-27.0 °. IR (swam) 2987, 2869, 1450, 1378, 1252, 1218, 1149, 1059, 845 ^cm-first

1 H NMR (CDCl ₃ ) δ 4.35-1.23 (m, 1H), 4.17-4.12 (m,

1H), 3.81-3.76 (m, 1H), 3.28-3.23 (m, 1H), 3.173.11 (m, 1H), 1.15 (s, 3H), 1.34 (s, 3H).

(R) - (+) - 3 - [(2,2-Dimethyl-1,3-dioxolanyl) methyl] -2,2-diphenylpropionic acid

To 39.2 g (0.185 mol) of diphenylacetic acid in 100 ml of terahydrofuran was added 309 ml (0.463 mol) of 1.5 mol lithium diisopropylamide mono (tetrahydrofuran) in 300 ml of cyclohexane at 0 ° C. The resulting mixture was stirred at 25 ° C for 30 minutes and then at 70 ° C for 1 hour. After cooling to 0 ° C, (S) - (-) - 2,2-dimethyl-4-iodomethyl-1,3-dioxolane (67.1 g, 0.227 mol) was added dropwise and stirring continued at 0 ° C. 30 minutes, then at 25 ° C for 20 hours. The reaction mixture was poured into 800 ml of ice water and extracted with ethyl acetate. The aqueous portion was acidified (pH 4) with 2.5 N hydrochloric acid and saturated with sodium chloride. The mixture was extracted with ethyl acetate. After the organic extract was washed with brine, dried (MgSO ₄ ) and concentrated,

44.5 g (74%) of a red oil are obtained.

1 H NMR (CDCl ₃ ) δ 7.38-7.25 (m), 3.95-3.85 (m 1H),

3.30-3.15 (m, 1H), 2.95-2.90 (m, 1H), 2.35-2.30 (m, 1H), 1.23 (s, CH ₃ ), 1 , 25 (s, CHJ.

(R) - (+) - 5-Hydroxymethyl-4,5-dihydro-3,3-diphenyl-2 (3) phytranone

(R) - (+) - 3- [2,2-Dimethyl-1,3-dioxolanyl) methyl] -2,2-diphenylpropionic acid (44.5 g, 0.136 mol) in methanol (300 ml) and water (300 ml). acid) (pH 1) with 6N hydrochloric acid. After stirring the reaction mixture at 25 ° C for 2.5 hours, concentrate in vacuo. The residue was extracted with ether. The ether extracts were washed successively with 10% sodium bicarbonate and dried over brine (MgSO ₄ ) and concentrated to give 29.1 g (80%) of a yellow liquid. TLC (silica gel, ethyl acetate: methylene chloride, 1: 9) Rf. Optical rotation of 0.40, 0.038 g (material) diluted to 2.0 ml

HU 210 346 A9

95% ethanol at 23 ° C [α] D + 54.63 °. IR (neat) 3420, 2972, 2860, 1746, 1498, 1448, 1177, 1110, 699, 675 cm ^-1 .

Ή NMR (CDCl ₃ ) δ 7.37-7.24 (m, 1H), 4.52-4.42 (m,

1H), 3.98 (dd, J = 2.80 Hz, 1H), 3.69 (dd, J =

4.56 Hz, 1H), 3.01-2.85 (m, J = 4.13 Hz, J =

2.88 Hz, 2H), 2.30 (brs, 1H).

(R) - (+) - 5-Trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone g (0.177 mol) trifluoromethanesulfonic anhydride in 50 ml of methylene chloride ) under argon at -60 ° C was added 10.1 g (0.095 mol) of sodium carbonate, which was dissolved in (R) - (+) - 5 (29 g, 0.11 mol) in 100 ml of methylene chloride. followed by the dropwise addition of hydroxymethyl-3,3-diphenyl-4,5-dihydro-2 (3H) -furanone. After stirring for 2 hours at -60 ° C and for 1 hour at 0 ° C, 35 ml of water are slowly added. The organic layer was separated, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give 37.8 g (88%) of a liquid product. TLC (silica gel, hexane: ethyl acetate, 7: 3) Rf. Optical rotation of 0.51, 0.185 g of product diluted to 1.0 mL in chloroform at 23 ° C [α] D + 48.64 °.

1 H NMR (CDCl ₃ ) δ 7.39-7.24 (m, 10H), 4.71 (dd, J =

2.19 Hz, 1H), 4.64-4.60 (m, 1H), 4.59 ^, 53 (m,

1H), 3.05 (dd, J = 5.10 Hz, 1H), 2.81 (dd, J =

10.14 Hz, 1H).

(R) - (+) - 5- [1- (2-Isopropyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone

(R) - (+) - 5- (Trifluoromethanesulfonyloxymethyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone (4.33 g, 11 mmol) in methylene chloride (30 mL) 2-isopropylimidazole (2.2 g, 20 mmol) was added. The mixture was placed under argon (gas) in a sealed tube and heated at 110 ° C for 20 hours. After cooling to 25 ° C, the mixture was washed with 5% aqueous potassium carbonate and brine. The methylene chloride solution was dried (MgSO ₄ ) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 100 g, 40-60 mesh, methanol: dichloromethane 2:98) to give 3.2 g (82%) of a slightly pale yellow foam. TLC (silica gel, methanol: dichloromethane, 1: 9) Rf. Optical rotation of 0.76.0.0156 g (material) diluted to 2.0 ml with 95% ethanol at 23 [deg.] C. [a] D + 36.15 [deg.]. IR (KBr) 3400, 2975, 2918, 1760, 1495, 1447, 1275, 1170, 962,699 cm ^-1 .

Ή NMR (CDCl ₃ ) δ 7.38-7.18 (m, 10H), 6.92 (d, J =

1.2 Hz, 1H), 6.70 (d, J = 1.2 Hz, 1H), 4.58-4.52 (m,

1 H), 4.28-4.12 (m, 2H), 3.06-2.92 (m, 2H), 2,652.54 (m, 2H), 1.34-1.23 (m, 6H). .

(R) - (+) - 5- [1- (2-Isopmpyl-imidazole) -methyl) -4,5-dihydro-3,3-diphenyl-2 (3) -furanone hydrochloride

2.05 g (5.7 mmol) of (R) - (+) - 5- [1- (2-isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) To a solution of furanone in 200 mL of ethyl acetate (prepared) was added 5.7 mL (5.7 mmol) of 1N hydrochloric acid in ether. The (formed) crystalline solid (1.92 g, 85%) was filtered off, m.p. 233-234 'C. Optical rotation of 0.0150 g (material) 2.0 m diluted with 95% ethanol at 21 ° C [α] D + 20.27 °, IR (KBr) 3435, 2499, 1767, 1600, 1180, 753, 700 cm ^-1 .

Ή NMR (CDCl ₃ ) δ 7.43 (d, J = 1.6 Hz, 1H), 7.37-7.20 (m, 11H), 4.73-4.62 (m, 2H), δ , 38 ^ 1.28 (m, 1H), 3.413.33 (m, 2H), 2.72-2.68 (m, 1H), 1.58-1.47 (m, 6H).

Calcd. For C ₂₃ H ₂₄ N ₂ O ₂ + HCl (formula); C, 69.60; H, 6.35; N, 7.06; Cl, 8.93. Found: C, 69.40; 6.31; N, 6.85; Cl, 8.72.

(S) - (-) - 5- [1- (2-Isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride is prepared from (S) -glycerol. was prepared from acetonide by an analogue (reaction) series.

XV. example

2,2-diphenyl-4-methyl-4-pentenoic acid

To 150 ml of diphenylacetic acid in tetrahydrofuran (14 g, 66 mmol) at 0 ° C under argon was added dropwise a solution of 55.5 ml of 2.5 M N-butyllithium in hexane. After 15 minutes, 3-chloro-2-methylpropene (6.51 mL, 66 mmol) was added in one portion. After 10 minutes, 25 mL of 4N hydrochloric acid was added along with ether (250 mL). The layers were separated and the organic layer was washed with water (2 x 100 mL), brine. water (2 x 100 mL), dried (MgSO ₄ ) and filtered. Concentration gave 20.2 g (99%) of a yellow oil.

1 H NMR (CDCl ₃ ) δ 7.4-7.2 (m, 10H), 4.7 (s, 1H), 4.6 (s, 1H), 3.2 (s, 2H), 1, 4 (s, 3H).

5- (Bromomethyl) -4,5-dihydro-3,3-diphenyl-5-methyl-2 (3H) fitranon

To a stirred mixture of tetrahydrofuran: water (5: 1,100 mL) was added 2,2-diphenyl-4-methyl-4-pentenoic acid (19.5 g, 73 mmol) and sodium bicarbonate (6.15 g, 73 mmol). After 30 minutes, bromine (3.7 mL, 73 mmol) was added dropwise. After stirring for 40 min, a solution of sodium thiosulfate (3 g) in water (50 mL) was added. Ether (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried (MgSO ₄ ) and filtered. Concentration gave a yellow solid. Recrystallization from ethyl acetate gave 15 g (60%) of a white solid, m.p. 146-148 ° C. IR (KBr) 1766 mc ^-1 .

1 H NMR (CDCl ₃ ) δ 7.4-7.2 (m, 10H), 3.4 (m, 3H), 2.9 (d, 1H), 1.5 (s, 3H).

5- [1- (2-Methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl5-methyl-2 (3H) -furanone

5- (Bromomethyl) -4,5-dihydro-3,3-diphenyl-5-methyl-2- (3H) furanone (3.0 g, 8.7 mmol), 2-methylimidazole (1, 5 g (18 mmol) and dimethylformamide (6 mL) were placed in a sealable tube. The tube was filled with argon, sealed, and heated at 150 ° C for 65 hours. After the solution was cooled, the mixture was partitioned between saturated sodium bicarbonate solution (20 mL) and methylene chloride (100 mL) and the layers were separated. The organic layer was washed with water (2 x 50 mL), then washed with brine and dried (MgSO ₄ ). Filtration followed by concentration gives a solid. Recrystallization from ethyl acetate-hexane gave 1.70 g (57%) of a white crystalline solid, m.p. 166-167'C. IR (KBr) 1758 'Cm ^first

1 H NMR (CDCl ₃ ) δ 7.05-6.55 (m, 12H), 3.59 (AB q,

HU 210 346 A9

J = 15.12 Hz, 2H), 2.59 (AB q, J = 13.68 Hz, 2H),

2.01 (s, 3H), 0.84 (s, 3H).

Calcd. For C22 H20 N2 O2 0.25 H2 O: C, 75.28; H, 6.47; N, 7.97. Found: C, 75.30; H, 6.50; N, 7.52.

XVI. example

5-Methyl-3,3-diphenyl-2 (3H) -furanone and

5-Methylene-4,5-dihydro-3,3-diphenyl-2 (3H) -furanone g (66 mol) 5-bromomethyl-4,5-dihydro-3,3-diphenyl-2 (3H) - A solution of furanone and 10.47 mL (70 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) in 65 mL of benzene was heated to reflux under argon for 20 h. The resulting mixture was cooled to 25 ° C and filtered. To the filtrate was added 150 ml of 10% hydrochloric acid and 200 ml of ether. The organic layer was separated and washed successively with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. After drying over sodium sulfate, the solution was concentrated to give 16.12 g (97%) of a crude liquid. TLC (silica gel, ethyl acetate) Rf. 0.64.

1 H NMR (CDCl ₃ ) δ 7.34-7.08 (m), 5.69 (br s, 1H),

4.78 (s), 4.41 (m), 3.64 (d), 3.54 (s), 2.08 (s), 2.02 (s).

An overview of the NMR spectrum and a comparison between the resonances of 5.69 (vinyl H) and 4.78 (methylene H) show that the product has a ratio of unsaturated methyl lactone to methylene lactone of 70:30.

5-Bromomethyl-3,3-diphenyl-2 (3H) -furanone and

4-bromo-5-methylene-4,5-dihydro-3,3-diphenyl-2 (3) -furanone

To a crude mixture of 4.30 g (1.7 mmol) of 5-methyl3,3-diphenyl-2- (3H) -furanone and 5-methylene-4,5-dihydro-3,3-diphenyl-2 (3H) -furanon mixed with it

(2.6 mmol) of N-bromosuccinimide and 4.62 g of 0.05 g of 2,2 -azobisz- ¹ (2-methylpropionitrile) was heated to reflux under argon and 40 mL of carbon tetrachloride for 20 hours. After cooling to 25 ° C, the mixture was poured into water (200 mL) and extracted with ether. The ether extract was washed with water, dried over sodium sulfate and concentrated to give 6.57 g of crude liquid.

Ή NMR (CDCl 3) δ 7.4-7.05 (m), 6.26 (s), 6.25 (2),

6.09 (s), 5.9 (s), 4.5 ^, 2 (m), 4.13 (s), 3.62 (d), 2.77 (s), 2.05 (s) ), 1.72 (2), 1.5 (brm).

Analysis of the NMR spectrum showed a ratio of 60:40 between the bromomethyl product and a secondary bromomethylene lactone.

5- [1- (2-Isopropylimidazole) methyl] -3,3-phytranone hydrochloride hydrate

A crude mixture of 6.5 g (19 mmol) (60:40) of 5-bromomethyl-3,3-diphenyl-2 (3H) -furanone and 4-bromo-5-methylene-4,5-dihydro-3,3 a mixture of diphenyl-2 (3H) -furanone, 3.25 g (29 mmol) of 2-isopropylimidazole and 1.0 g (9 mmol) of sodium carbonate in 25 mL of dimethylformamide under argon in a sealed tube at 115 ° C. is heated for 7 hours and at 80 ° C for 20 hours. The mixture was then stirred at 25 ° C for 2 days. The mixture was poured into saturated aqueous sodium bicarbonate (solution) (75 mL) and extracted with ether. The combined organic layers were washed with saturated sodium bicarbonate, water, and dried over sodium sulfate. Filtration and removal of solvent

It gives 4.95 g of a dark foamy semi-solid. TLC (silica gel, ethyl acetate) Rf. 0.1, Rf. 0.26, Rf. 0.35, Rf. 0.8 with the desired lactone imidazole Rf. At 0.26. Column chromatography on Merck (230-400 mesh) silica gel 9: 1 hexane: ethyl acetate to 100% ethyl acetate (gradient elution) gave 0.88 g (13%) of the free base as a sticky brown residue.

Ή NMR (CDCl ₃ ) δ 7.33-7.20 (m, 10H), 7.02 (d, 1H),

6.89 (d, 1H), 5.71 (t, J = 1.5, 1H), 4.83, (d, 2H),

3.02-2.97 (m, 1H), 1.79 (s), 1.35-1.21 (m, 6H).

The free base (0.85 g, 2.3 mmol) was dissolved in hot methanol (10 mL) and diluted with ether (50 mL). To the warm mixture was added 1N hydrochloric acid (2.3 mL, 2.3 mmol) in ether. The mixture was allowed to cool and then placed in a freezer overnight. The solids are filtered off and washed with food. The tan solid was dried under vacuum at 100 ° C to give 0.700 g (1.7 mmol) of hydrochloride, m.p. 209-211.5 'C. Solubility (> 1 mg / ml in 0.5 N hydrochloric acid with one Tween 80).

1 H NMR (DMSO-d ₆ ) 7.69 (d, 2H), 7.39-7.21 (m,

10H), 6.64 (s, 1H), 5.41 (s, 2H), 3.56-3.44 (m, 1H),

3.36 (brs, H ₂ O), 1.26 (d, 6H).

IR (KBr) 3412, 3055, 2980, 2936, 2697, 1797, 1600, 1500, 1494, 1448, 1134, 1085, 949, 763, 699 cm ^-1 . Calculated Analysis a

C ₂₃ H ₂₂ N ₂ O ₂ .HCl 1.0.75H ₂ O (requires) C, 69.95; H, 5.87; N, 7.09; Cl, 8.98. Found: C, 67.66, 67.60; H, 6.02, 6.02; N, 6.91. Cl, 8.70. TLC (silica gel, ethyl acetate) Rf. 0.40.

5- [1- (2-Ethylimidazole) methyl] -3,3-diphenyl-2 (3 H) furanone was prepared analogously from 2-ethyl imidazole and a mixture of bromo-lactone. The base is a tan solid, m.p. 102-103 ° C, after rubbing with ether.

Ή NMR (CDCl ₃ ) 7.4-7.2 (m, 10H), 7.01 (d, 1H), 6.95 (d, 1H), 5.7 (s, 1H), 4.8 ( s, 2H), 2.6 (q, 2H), 1.4 (t,

3H)

IR (KBr) 2975, 1794, 1687 cm ^-1 . Analysis calculated for C22 H20 N2 O2: C, 76.72; H, 5.85; N, 8.13. Found: C, 76.47; H, 5.89; N, 8.09.

XVII. example

5- [l- (3-Methyl-2-n-propyl) imidazole] methyl-4,5-dihydro-3,3-diphenyl-2 (3H) -fiiranon iodide

2.75 g (7.6 mmol) of 5- [1- (2-n-propyl) imidazole] methyl-4,5-dihydro-3,3-diphenyl-2 (3H) -furanone and 10 ml of iodomethane (methyl iodide) mixture was heated in a sealed tube for 20 minutes at 120 ° C. After cooling to 25 ° C, the excess iodomethane is evaporated under a stream of nitrogen. Trituration of the remaining solid with acetone

3.5 g (92%) of quaternary salt, m.p. Mp 207-210 ° C.

Ή NMR (CDCl ₃ ) δ 0.954 (t, J = 7.2 Hz, 3H), 1.521.68 (m, 2H), 2.82-2.94 (m, 1H), 2.95-3.08 (m,

2H), 3.26-3.36 (m, 1H), 3.80 (m, 3H), 4.48-4.70 (m, 3H), 7.24-7.44 (s, 10H). 7.64-7.70 (m, 2H).

IR (KBr) 3090, 3059, 2982, 2933, 1756, 1226, 1175, 1154, 707, 696 cm ^-1 . Analytical TLC (silica gel,

HU 210 346 A9

95: 5, methylene chloride: methanol) Rf. 0.15. Analysis calculated for C94H27IN2O2: C, 57.38; H, 5.41; I, 25.25; N, 5.57. Found: C, 57.46; H, 5.43; I. 25.16; N, 5.56.

The following quatemeric salts were prepared analogously.

5- [1- (2-Isopropyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone iodide hydrate (m.p. 216217 'C),

5- [1- (2-Ethyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2- (3H) -furanone iodide hydrate (m.p. 219.5-

221 'C),

5- [1- (2-tert-Butyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone iodide hydrate (m.p. 213-

214.5 'C),

5- {1- [2- (2-Methoxy-ethyl) -3-methyl-imidazole] -methyl} -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone dihydrate (m.p. 179-183 ° C).

XVIII. example

Screening for a carcinogenic (effect) of animus

This assay is designed to determine compounds that exhibit antagonistic activity at the postsynaptic muscarinic cholinergic receptors on the small intestine (longitudinal) smooth muscle and the bladder evacuation muscle.

Preparation of the ileum for examination

Male albino guinea pigs are killed by decapitation or dissection of the cervical vertebrae. The abdominal cavity is opened and the small intestine is removed and discarded about 10 cm from the terminal iliac. The intestine is placed in a Petri dish containing Tyrode's solution (137 mmol NaCl, 2.7 mmol KCl, 1.8 mmol CaCl _2. 2H ₂ O, 1.1 glucose) and cut into 3-4 cm sections. The sections are preferably taken from the tail end of the hip. Carefully stretch each section on a glass rod 6 mm in diameter and cut off the drip tissue remaining on it. The longitudinal muscle layer is separated from the underlying circumferential muscle layer by a gentle stroke of a cotton ball impregnated with Tyrode solution from the shallow annular filament (Auerbach's plaque) downward from the shallow longitudinal incision made by joining the drip. Using gentle pulling and making sure that the intestinal tract is kept wet throughout the procedure, the tissue is pulled along the entire length of the section [Paton and Zar, J. Physiol. 194, 13, (1968)].

The tissues were suspended on a 5-0 silk suture in a 10 ml water jacketed glass tissue bath containing Tfyrode solution at 37 ° C and aerated with 95% O ₂ /5% CO ₂ (gas mixture). The suture connects each tissue to an isometric force displacement sensor (Grass or Gould) connected to a physiograph. Each preparation was suspended at 0.3 g at rest and allowed to equilibrate for 36 minutes. During this time, the bath is emptied every 12 minutes and filled with 10 ml of warm Tyrode solution. At the end of the equilibration time, the muscle strips are conditioned by adding 10 pmoles of carbachol (carbamylcholine chloride) to the bath. The drug is contacted with the tissue for 1-2 minutes and then removed from the bath by 4 rinses with 10 ml of warm Tyrode solution (done). The preparations are allowed to recover for 12 minutes before being used in the experiment.

Preparation of the bladder for examination

Male albino guinea pigs are killed by decapitation or dissection of the cervical vertebrae. The abdominal cavity is opened and the bladder is lightly grasped at the apex, gently tightened, and the fat is lifted with a fine tweezer and trimmed with a blunt-pointed scissor in situ as close as possible to the bladder surface. The tissue was placed in a Petri dish of rubber bottom containing modified Krebs solution (133 mmol NaCl, 1.3 mmol NaH ₂ PO ₄ , 16.3 mmol NaHCO ₃ ,

Containing 4.7 mmol KCl, 0.6 mmol MgSO ₄ .7H ₂ O, 2.5 mmol CaCl _2. 2H ₂ 0.7,7 mmol glucose) and cut over the neck. The bladder collapses into a flat pouch, which is opened by two lateral incisions and spread on a rectangular tissue sheet (about 2 cm long and 1 cm wide). Gently tighten the plate and strain it onto the bottom of the Petri dish. The mucous membrane, which is visible as a loose, superficial, pink layer, is bluntly removed at one end (by) carefully inserting the edges of a micro-scissor scissor between the mucous membrane and the muscle layer, with a gentle opening of the edges, with constant tweezing pull the two layers apart. Clean removal of the mucous membrane can generally be accomplished without undermining or wrinkling the underlying muscle layer. Mucosal removal is considered essential to enhance the oxygen supply of the preparation and to achieve better access to both sides of the thin muscle plate by the active ingredients used [Ambeche and Zar, J. Physiol. 210: 671 (1970)]. The plates are cut into shape if necessary and cut lengthwise into 4 strips.

The strips were anchored with 5-0 silk suture and suspended in a 10 mL, water jacketed glass tissue bath containing 35 ° C Krebs solution and aerated with 95% O ₂ /5% CO ₂ (gas mixture). The suture connects each tissue to an isometric force displacement sensor (Grass or Gould) connected to a physiograph. Each preparation was suspended at a resting voltage of 0.5 g and allowed to equilibrate for 36 minutes. During this time, the bath is emptied every 12 minutes and filled with 10 ml of warm Krebs buffer. After this time, the muscle strips were conditioned by adding 10 pmoles of carbachol to the bath. The drug remains in contact with the tissue for 1-2 minutes and then removed from the bath by four fast washes with 10 ml of warm Krebs buffer. The preparations are allowed to recover for 12 minutes before being used in the experiment.

Preparation of the agonist

Carbachol (carbamylcholine chloride) is a physiological salt11

Dissolved in EN 210 346 A9 solution prepared 2xl0 ^2M stock solution. Serial dilutions (1:10) of the stock solution are made in physiological saline or water. The appropriate volumes of these solutions are added cumulatively to the 10 mL tissue bath to achieve the desired bath concentration.

Preparation of test compounds

The water-soluble or physiological saline-soluble compounds are dissolved in these solvents to produce 2x10 ^-2 or 2x10 ^-3 molar stock solutions. Small amounts of 1N hydrochloric acid, sodium hydroxide, or 95% ethanol may be added to compounds which are insoluble in water or physiological saline alone. Serial dilutions (1:10) are made from the stock solution in physiological saline or water. Compounds that are insoluble in aqueous solvents are dissolved in dimethylsulfonoxide (DMSO) to make a 4x10 ^-2 molar stock solution. Other solvents may be used provided they are suitable and are specifically described in the experimental procedure. The appropriate volumes are then added to the baths to achieve the desired bath concentrations.

Experimental procedure

Appropriate volumes of carbachol solutions are added to the 10 ml tissue baths in a summation manner to increase the concentration of carbachol in the bath step by step without being washed (after each dose). The tissue isometrically contracted at each concentration step. The next concentration is known only when the previous contraction has reached a constant value. If the next step of concentration does not cause a further decrease in contraction, then it is considered that the maximum effect is achieved. At this time, the tissue was washed with 4 fast rinses of 10 ml of warm Tyrode solution (allowed) and allowed to recover for 12 minutes [Van Rossum et al., Arch. Int Pharmacodyn. 143, 240 (1963) and 143, 299 (1963)]. Inhibition of the carbachol response in the presence of an antagonist is determined by repeating the cumulative dosing procedure after treatment of the tissue with the agonist for 5 minutes.

Three or four different concentrations of the antagonist were tested on the same formulations. Responses are expressed relative to the maximum contraction induced by carbachol in the absence of the antagonist. Data were collected through a Buxco Data Logger and analyzed with the Branch Technology software package to obtain Kb values for the antagonists.

XIX. example

Primary in vivo determination of bronchodilator effects of muscarinic antagonists Hun guinea pigs are anesthetized with urethane. Cannulas were introduced into the trachea, carotid artery (A. carotis) and varicose vein (V. jugularis). The animals are ventilated with room air, constant speed and volume. Respiratory pressure is measured at a lateral opening of the tracheal catheter and blood pressure and heart rate are also monitored.

After a stable baseline period, carbachol is added with an ultrasonic nebulizer. When the bronchoconstrictor response peaks, the test compound is administered intravenously in increasing doses to induce a gradual, cumulative decrease in airway pressure. When more than 50% of bronchoconstriction is achieved, the ED _{50 of} the bronchodilator effect is calculated by probit analysis. The ED ₅₀ is defined as the cumulative IV dose that causes 50% dissolution of bronchoconstriction.

Compound Muscarinic antagonist activity Bronchodilator effect ED ₅₀ Mg / kg iv ileal bladder Kb (nmole) 5- [l- (imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -fura- non 373 - - 5- [l- (2-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone 107 238 5.5 5- [l- (2-ethyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) - furanone hydrochloride 68 86 4.0 5- [l- (3-methyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone bromide hydrate 322 151 1.0 5- [l- (2,3-dimethyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone bromide 71 0.85 5- [1- (2-Isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 30 33 0.83 5- [l- (2-n-propyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 21 70 1.3 5- [1- (2-Methyl-3-benzylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3 H) -furanone bromide 544 - - 5- [l- (2-n-butyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -ftiranon 113 - > 10

HU 210 346 A9

Compound Muscarinic antagonist activity Bronchodilator effect ED ₅₀ Mg / kg iv ileal bladder Kb (nmole) 5 - [(l-benzimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) - -furanone 1281 - - 5- [l- (ethyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -fu- Rano bromide 229 - - 5- [l- (2-ethyl-imidazole) -3,3-diphenyl-2 (3H) -fiiranon 8.2 - 1.9 5- [1- (2-Ethyl-4-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrobromide 86 - - 5- [l- (3-methyl-2-n-propyl-imidazole) methyl] -4,5-dihydro-3,3- diphenyl-2 (3H) -furanone iodide 23 11 0.11 5- [l- (3-methyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrate 370 317 - 5- [l- (2-isopropyl-3-methyl-imidazole) methyl] -4,5-dihydro-3,3- diphenyl-2 (3H) -furanone bromide 2.9 0.7 0,007 5- [l- (2-ethyl-3-methyl-imidazole) methyl] -4,5-dihydro-3,3-dife- phenyl-2 (3H) -furanone bromide 8 5 0.13 (S) - (-) - 5- [l- (2-ethyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -ftiranon hydrochloride 169 350 - (R) - (-) - 5- [1- (2-Ethylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -pyranone hydrochloride 21 129 - 5- [l- (2-isobutyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 489 - > 10 5- [l- (2-tert-butyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 3.3 - 0.14 5- [l- (4-phenyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride hydrate 140 - not solved. 5- [l- (2-phenyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone 5920 - > 6 5- {1- [2- (2-Methoxymethyl) imidazole] methyl} -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone hydrochloride hydrate 67 > 10 6,7-Dihydro-1 - [(2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] -5H-pyrrolyl- [1,2-a ] imidazolium chloride hydrate 33 - 0.7 5- [l- (2-ethoxy-methyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone > 1000 - > 10 5 - [(1,8-diazabicyclo [5.4.0.] - undec-7-en-8-yl) methyl] -4,5-dihydro-3,3-diphenyl-2 (3 H) -furanone- hydrochloride hydrate > 1000 - > 10 5- [l- (2-isopropyl-3-methyl-imidazole) methyl] -4,5-dihydro-3,3- diphenyl-2 (3H) -furanone iodide 4 2.4 0.06 5- [l- (ethoxy-methyl-3-methyl-imidazole) methyl] -4,5-dihydro-3,3- diphenyl-2 (3H) -furanone iodide 253 339 > 10 5- [l- (2-isopropyl imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride hydrate 31 - - 5- [l- (2-methoxy-ethyl imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 638 - > 10 5- [l- (2-methoxymethyl-3-methyl-imidazole) methyl] -4,5-dihydro- 3,3-diphenyl-2 (3H) -furanone iodide 40 - - 5- [1- (2-Methoxyethyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone iodide hydrate 39 - - 5- [l- (2-carbomethoxy-imidazole) methyl] -4,5-dihydro-3,3-dife- phenyl-2 (3H) -furanone hydrochloride 435 - - 1 - [(2,3,4,5-Tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methylimidazo [1,2-a] pyridinium chloride hydrate 45 - -

HU 210 346 A9

Compound Muscarinic antagonist activity Bronchodilator effect EDjo Mg / kg i. v. ileal bladder Kb (nmole) (R) - (-) - 5- [l- (2-isopropyl imidazole) methyl] -4,5-dihydro-3,3- diphenyl-2 (3H) -furanone hydrochloride 10 15 - 1 - ((2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] -8-methyl-imidazo [l, 2-a [pyridinium chloride hydrate 74 - - 5- [l- (2-benzyl-imidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone hydrochloride 223 - - 5,6,7,8-Tetrahydro-1 - [(2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanyl) methyl] imidazo [1,2-a] pyridinium chloride hydrate - - -

PATENT CLAIMS

Claims (30)

1. A compound according to the formula: R or a pharmaceutically acceptable salt thereof, wherein the dotted line represents a 4,5-unsaturated or 4,5-dihydrofuranone ring; R 1 and R ₂ are independently selected from the group consisting of hydrogen, thienyl, furanyl, C3-6cycloalkyl, benzyl, phenyl and substituted benzyl and substituted phenyl, wherein the phenyl or benzyl substituents are halogen, trifluoromethyl, hydroxy, lower alkoxy and lower alkyl; (groups) are selected; R ₃ , R 4 and R _5, which may be the same or different, are independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, nitro, lower alkyl, lower alkyl substituted with one halo, lower alkoxy, amino, or a carboxyl group, an alkylene bridge between R ₄ and R ₅ or R ₃ and the ring-N, a C 3 -C 6 cycloalkyl group, benzyl, phenyl, substituted benzyl and substituted phenyl, wherein benzyl and phenyl substituents are selected from halogen, trifluoromethyl, hydroxy, lower alkoxy or lower alkyl. For the dihydrofuranone series, R is hydrogen or lower alkyl. The compound of claim 1, wherein R 1 is R 1; and R _{2 is} independently selected from phenyl, thienyl, furanyl, substituted phenyl, and R ₃ , R ₄ and R ₅ are each independently lower alkyl. The compound of claim 1, wherein R 1 and R _{2 are} phenyl and R ₃ , R ₄ and R ₅ are each independently lower alkyl. The compound of claim 1, wherein R 1 and R _{2 are} phenyl and R ₃ is lower alkyl and R ₄ and R _{5 are} hydrogen. The compound of claim 1 which is 5- (1- (2-ethylimidazole) methyl) -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone. The compound of claim 1 which is (R) - (+) 5- [1- (2-ethylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) - mi. The compound of claim 1 which is 5- [1- (2-propylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -furanone. The compound of claim 1 which is 5- (1- (2-propylimidazole) methyl) -4,5-dihydro-3,3-diphenyl-2 (3H) furanone. The compound of claim 1 which is 5- [1- (2-npropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) furanone. The compound of claim 1 which is 5- [1- (2-ethylimidazole) methyl] -3,3-diphenyl-2 (3H) -furanone. The compound of claim 1 which is 5- [1- (2-ethyl-3-methylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone bromide. The compound of claim 1 which is 5- [1- (2-tert-butylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone. The compound of claim 1 which is 6,7-dihydro-1 - ((2,3,4,5-tetrahydro-5-oxo-4,4-diphenyl-2-furanylmethyl) -5H-pyrrolyl [ 1,2a] imidazolium chloride. The compound of claim 1 which is 5- [1- (2-isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone. The compound of claim 1 which is (R) (+) - 5- [1- (2-isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl-2 (3H) -phyranone. The compound of claim 1 which is 5- [1- (2-isopropylimidazole) methyl] -4,5-dihydro-3,3-diphenyl 2 (3H) -furanone. A pharmaceutical composition for use as a cholinergic receptor antagonist (comprising) an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of neurogenic bladder disorders (which) comprises an amount of a compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for use as an anticonvulsant (comprising) an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. HU 210 346 A9 A pharmaceutical composition for use as an antisecretory agent, comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for use as a pupil dilator (comprising) an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. A method for treating a disorder responsive to an anticholinergic agent, which comprises administering to a patient an effective amount of a compound according to claims 1 to 10. A method of treating a neurogenic bladder disorder, comprising administering to a subject an effective amount of a compound according to claim 1. A method for treating irritable bowel syndrome, comprising administering to a patient an effective amount of a compound according to claim 1. A method of treating colitis, which comprises administering to a patient an effective amount of a compound according to claim 1. A method of treating ulcerative colitis (comprising) administering to a patient an effective amount of a compound according to claim 1. A method of treating diverticulitis which comprises administering to a patient an effective amount of a compound according to claim 1. A method of treating diarrhea comprising administering to a patient an effective amount of a compound according to claim 1. A method of treating hypertension (hypertension) comprising administering to a patient an effective amount of a compound according to claim 1. A method of treating chronic obstructive airways diseases, comprising administering to a patient an effective amount of a compound according to claim 1.