GB2144408A - Imidazole derivatives - Google Patents

Imidazole derivatives Download PDF

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GB2144408A
GB2144408A GB08321000A GB8321000A GB2144408A GB 2144408 A GB2144408 A GB 2144408A GB 08321000 A GB08321000 A GB 08321000A GB 8321000 A GB8321000 A GB 8321000A GB 2144408 A GB2144408 A GB 2144408A
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phenyl
thienyl
chlorophenyl
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Kazuo Matsumoto
Yoshio Iwasawa
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Tanabe Seiyaku Co Ltd
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Tanabe Seiyaku Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

Imidazole derivatives of the formula: <IMAGE> (wherein R<1> is furyl, thienyl, phenyl, halogenophenyl, alkylphenyl or alkoxyphenyl, R<2> is fury, thienyl, phenyl, halogenophenyl, alkylphenyl or (trifluoroalkyl)phenyl, and Y is monofluoromethyl, difluoromethyl or trifluoromethyl) and their salts are analgesic, anti-inflammatory and/or antipyretic agents.

Description

SPECIFICATION Novel imidazole derivative and a process for preparing same This invention relates to a novel imidazole derivative and a process for preparing same. More particularly, it relates to an imidazole derivative of the formula:
wherein R1 is furyl, thienyl, phenyl, halogenophenyl, alkylphenyl or alkoxyphenyl, R2 is furyl, thienyl, phenyl, halogenophenyl, alkylphenyl or (trifluoroalkyl)phenyl, and Y is monofluoromethyl, difluoromethyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
U.S. Patent No. 3707475 discloses that a class of 2-phenyl-4,5-disubstituted-imidazole derivatives such as 2-(4-chlorophenyl)-4-phenyl-5-trifluoromethylimidazole have an anti-inflammatory activity. However, said 2-(4-chlorophenyl)-4-phenyl-5-trifluoromethylimidazole is still unsatisfactory for use as an anti-inflammatory agent because of poor therapeutic effects thereof.
As a result of investigations, we have now found that the imidazole derivative (I) of the present invention shows potent anti-inflammatory, analgesic, and anti-pyretic activities. For example, when the antiinflammatory activity is estimated by the preventive effect against carrageenin-induced paw edema in rats, the 30 % effective dose (ED30) of 2-(4-chlornphenyl)-4-phenyl-5-(2-fluornethyl)imidazole and 2-(4chlorphenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole of the present invention are 2.2 mg/kg and 2.0 mg/kg, respectively.
When the analgesic activity is estimated according to Randall Selitto's method (Arch. int. Pharmacodyn., 1957, CXI, No. 4, 409), 2-(4-chlorophenyl)-4-phenyl-5-(2-fluoroethyl)-imidazole of the invention shows the 50 % effective dose (EDso) of 11 mg/kg.
The compound (I) of the present invention also shows anti-pyretic activity. For example, when the anti-pyretic activity is estimated by preventive effect against carrageenin-induced pyrexia in rats, the 50 % effective dose (ED50) of 2-(4-ch lorophenyl ienyl )-4-(3-thienyl )-5-(2,2,2-trifluoroethyl)-imidazole of the present invention is 2.0 mg/kg.
Moreover, the compound (I) of the present invention is quite characteristic in that it is low in toxicity or side effects such as ulcerogenicity in gastro-intestinai organs and therefore has great safety for use as an anti-inflammatory, analgesic and/or anti-pyretic agent. For example, when 2-(4-chlorophenyl)-4-phenyl-5 (2,2,2-trifluoroethyl)-imidazole of the invention is administered orally to rats at dose of 10 mg/kg once a day for 35 consecutive days, no substantial change in weight of the body and organs (i.e., adrenals, kidneys, liver, spleen and thymus) was observed during the experiments.
Representative examples of the imidazole derivative of the invention include those of the formula (I) in which R1 is furyl e.g. 2furyl or 3-furyl; thienyl e.g. 2-thienyl or 3-thienyl; phenyl; halogenophenyl e.g.
chlorophenyl, fluorophenyl, bromophenyl or iodophenyl; alkylphenyl e.g. methylphenyl or ethylphenyl; alkoxyphenyl e.g. methoxyphenyl orethoxyphenyl, R2 is fury e.g. 2-furyl or or3-furyl; thienyl e.g. 2-thienyl or 3-thienyl; phenyl; halogenophenyl e.g. chlorophenyl, fluorophenyl, bromophenyl or iodophenyl; alkylphenyl e.g. methylphenyl or ethylphenyl; (trifluoroalkyl)phenyl e.g. trifluoromethylphenyl, and Y is monofluoromethyl, difluoromethyl or trifluoromethyl.Among them, a preferred subgenus includes the compound of the formula (I) in which R1 is 24uryl, 3-furyl, 2-thienyl, 3-thienyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl, R2 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl or 4-trifluoromethylphenyl, and Y is monofluoromethyl or trifluoromethyl. Further preferred subgenus includes the compound of the formula (I) in which R1 is 3-thienyl or phenyl, R2 is 3-chlorophenyl, 4-chlorophenyl or 4-fluorophenyl and Y is monofluoromethyl ortrifluoromethyl.
According to the present invention, the imidazole derivative (I) can be prepared for example by reacting a methylamine compound of the formula:
wherein R1, R2 and Y are the same defined above, with ammonia or a salt thereof.
The cyclization reaction of the methylamine compound (II) with ammonia or a salt thereof can be readily accomplished. For example, it is preferably carried out in a solvent under heating. Any ammonium salts which release ammonia in a solvent can be used as the starting material of the invention. Representative examples of such ammonium salts include the corresponding organic or inorganic acid addition salts e.g.
ammonium carbonate, ammonium formate, ammonium acetate, ammonium propionate, ammonium benzoate and ammonium picolinate. Acetic acid, propionic acid, dioxane, toluene, xylene, chlorobenzene, n-butanol are examples of suitable solvents. It is preferred to carry out the reaction at a temperature of 100 to 150"C, especially 120 to 140"C. If ammonia is used as the starting material, the reaction is preferably carried out under 5 to 120 atmospheres in a sealed vessel.
As shown in the following formulae, the imidazole derivative (I) of the present invention has two tautomeric structures which are mutually convertible from one to another. Both of these isomers are included in the present invention.
wherein R1, R2 and Y are the same as defined above.
As described hereinbefore, the imidazole derivative (I) of the present invention is useful as an anti-flammatory, analgesic and/or anti-pyretic agent. Said derivative (I) may be used for the therapeutic treatment or alleviation of a variety of inflammatory diseases in skeletal muscles, joints (e.g., knee joint, shoulder joint, elbow joint, ankle joint) and other organs, for example, for the treatment or alleviation of rheumatism, gout and arthritis or of inflammation caused by bone fracture, lesion, trauma and the like. It may also be used for alleviation of pain, pyrexia and other symptons usually associated with these various inflammatory diseases.
The imidazole derivative (I) of the present invention can be used for pharmaceutical use either as the free base or a salt thereof. Pharmaceutically acceptable salts of the imidazole derivative (I) are, for example, inorganic acid addition salts e.g. hydrochloride, phosphate, nitrate and sulfate; organic acid addition salts e.g. acetate, lactate, citrate, tartarate, fumarate, maleate, glycinate, aspartate, methanesulfonate and benzoate; and salts thereof with metals (e.g., sodium, potassium, lithium) or amines. These salts may be prepared by, for example, neutralizing the compound (I) with an acid, a metal hydroxide or hydride or an amine. The imidazole derivative (I) or a salt thereof can be administered either orally or parenterally.Further, the imidazole derivative (I) or its salt may be used in the form of a pharmaceutical preparation containing the same derivative in conjunction or admixture with a pharmaceutical excipient suitable for oral or parenteral administration. Suitable excipients are, for example, mannitol, lactose, magnesium stearate, starch, talc, cellulose, sugar, glucose, magnesium carbonate, polypropyleneglycol, water, a saline solution, ethanol, glycerin, sodium acetate, sorbitan monolaurate, ortriethanolamine oleate. The pharmaceutical preparation may be in solid forms e.g. tablets, powder, capsules or granules; or in liquid forms e.g. solutions or suspensions. Further, when administered parenterally, the pharmaceutical preparation may be used in the form of injection.
The daily dose of the compound (I) or a salt thereof may vary depending on the administration route, the age, weight or conditions of patients, and the severity of diseases to be treated. In general, however, a preferred daily dose of said compound (I) or a salt thereof may be 25 to 100 mg, especially 0.5 to 2.0 mg, per kilogram of body weight per day.
Concomitantly, the starting compound (II) of the invention is a novel compound and may be prepared by, for example, according to the method shown in the following reaction scheme:
wherein X is halogen, R3 is an ester residue and R' and R2 are the same as defined above.
The reaction of the compound (III) with the isocyanoacetate compound (IV) is carried out in a solvent (e.g., tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide) in the presence of a base e.g. triethyla mine, potassium t-butoxide or 1 ,8-diazabicyclo[5,4,0] undecene-7 at -50" to 500C. The oxazole derivative (V) thus obtained is treated with a mineral acid (e.g., 3 to 6N-hydrochloric acid) at 40 to 1 000C to give the aminoketone compound (VI). Then, the condensation of the aminoketone compound (IV) with the compound (VII) is conducted at a temperature below 1 0 C in the presence of an acid acceptor (e.g., sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate) in a solvent (e.g., water, ethyl acetate, methylene chloride, benzene, dioxane or a mixture thereof).The subsequent condensation of the resulting compound (VIII) with a halide compound is carried out at a temperature of -50" to 300C in the presence of an acid acceptor (e.g., sodium hydride, potassium t-butoxide, alkyl lithium) in a solvent (e.g., tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, dimethylsulfoxide). Alternatively, the compound (VI) in which R1 is phenyl or substituted phenyl may be prepared by the method described in Organic Synthesis Vol. 41, page 82.
Practical and presently-preferred embodiments of the present invention are illustratively shown in the following examples. Throughout the specification and claims, the term "alkyl" and "alkoxy" should be interpreted as referring to alkyl of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms and alkoxy of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms.
Experiment 1 (Anti-inflammatory activity) A test compound suspended in a 0.25 % carboxymethyl-cellulose solution was administered orally to Sprague-Dawley male rats (body weight: 160 - 180 g) fasted overnight. One hour after the administration, 0.05 ml of a 1 % carrageeninsaline solution was injected into the plantar surface of either one of the hind feet.
Then, the volume of both hind feet were measured 4 hours after administration of carrageenin, and the preventive effect (%) of the test compound against carrageenin-induced paw edema was estimated by comparing the volume of both hind feet. The anti-inflammatory activity of the test compound was expressed in term of 30 % effective dose (ED20), i.e., a dose which would produce 30 % decrease in carrageenin-induced paw edema. The results are shown in the following Table 1.
TABLE 1
Test compounds Anti-inflammatory Activity R1 R2 Y ED30 (mg/kg) phenyl 4-chlorophenyl monofluoromethyl 2.2 3-thienyl 4-chlorophenyl monofluoromethyl 4.2 phenyl 4-chlorophenyl trifluoromethyi 2.0 phenyl 3-chlorophenyi trifluoromethyl 5.0 3-thienyl 4-chlorophenyl trifluoromethyl 2.8 Experiment2 (Analgesic activity) A test compound suspended in a 0.25 % carboxymethyl-cellulose solution was administered orally to Sprague-Dawley male rats (body weight: 60 - 90 g) fasted overnight. Immediately after administration of the test compound, 0.1 ml of 20 % dried yeast suspended in a physiological saline solution was injected into the plantar surface of either one of the hind feet.Then, pain threshold of both hind feet were measured by Analgesy Meter (Ugo Basile co.) 2 hours after injection of yeast, and the analgesic activity of the test compound was estimated by comparing the pain threshold of the inflamed foot with that of the control foot.
As a result, the 50 % effective dose (ED50) (i.e., a dose which would produce 50 % reduction in said pain threshold) of 2-(4-chlorophenyl)-4-phenyl-5-(2-fluoroethyl)-imidazole was 11 mg/kg.
Experiment 3 (Anti-pyretic activity) 0.1 ml of a 2 % carrageenin-saline solution was injected into the plantar surface of the hind foot of Sprague-Dawley male rats. Three hours after the injection, a test compound suspended in a 0.25 % carboxymethylcellulose solution was administered orally to said rats. The temperature of the rectum of the rats were measured by Thermister Thermomater two hours after administration of the test compound, and the anti-pyretic activity of the test compound was estimated therefrom. The 50 % effective dose (ED50) (i.e., a i dose which would produce 50 % reduction in carrageenin-induced hyperthermia) was estimated by the dose-response curve obtained in the experiments. The results are shown in the following Table 3.
TABLE 3
Test compounds Anti-pyretic activity R1 R2 Y ED30 (mg/kg) phenyl 4-chlorophenyl monofluormethyl 3.0 phenyl 4-chlorophenyl trifluoromethyl 2.2 3-thienyl 4-chlorophenyl trifluoromethyl 2.0 Experiment 4 (Ulcerogenicity) Immediately after oral administration of a test compound, male ddY mice weighing 22 to 25 g were kept in a restraint-cage and immersed into a water bath (24 + 0.5 C) upto their neck for 15 min. Then they were returned to their home cage in the animal room 22 + 1"C). Two hours after the administration, mice were sacrificed by dislocation of their neck. The stomach was isolated from each animal and opened for microscopic examination and scoring of ulcers.
As a result,2-(4-chlorphenyl)-4-phenyl-5-(2-fluoroethyl)imidazole,2-(4-chlorophenyl)-4-phenyl-5-(2,2,2,- trifluoroethyl)imidazole,2-(4-chlorophenyl)-4-(3-thienyl)-5-(2-fluoroethyl)imidazole,2-(3-chlorophenyl)-4- phenyl-5-(2,2,2-trifluoroethyl)imidazole and 2-(4-chlorophenyl)-4-(3-thienyl)-5-(2,2,2-trifluoroethyl)imidazole when administered at a dose of 30 mg/kg were found to induce no substantial ulceration.
Example 1 (1) 7.0 g of 4-fluorobenzoyl chloride are added dropwise to a mixture of 7.2 g of benzoylmethylamine hydrochloride, 10 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water at a temperature below 10 "C under stirring. The mixture is stirred at room temperature for 3 hours. Then, the ethyl acetate layer is collected, washed with water and dried. Said ethyl acetate layer is evaporated under reduced pressure to remove solvent. 10.3 g of N-(4-fluorobenzoyl)-benzoylmethylamine are thereby obtained.
Yield: 95% M.p. 138-139 IR vnUlol (cm~1): 3380,1693, 1650, 1600 (2) 0.94 g of sodium hydride (61 % oil dispersion) is suspended in 25 ml of dimethylformamide, and 5.14 g of N-(4-fluorobenzoyl)-benzoylmethylamine are added to the suspension at -40 to -50 C under stirring, The mixture is stirred at -40 to -50"C for 5 minutes. 2.54 g of 2-fluoroethyl bromide are added to said mixture, and the mixture is stirred at the same temperature for one hour and then at O"C for one hour. The reaction mixture is neutralized with acetic acid, water is added thereto, and said mixture is extracted with ethyl acetate.The extract is washed with an aqueous sodium bicarbonate solution and water, respectively. Then, the extract is dried and evaporated under reduced pressure to remove solvent. The residue thus obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 4.38 g of N-(4-fluorobenzoyl)-1-benzoyl-3- fluoropropylamine are obtained.
Yield: 72.2 % M.p.103-105 C IR VmflUaIxO (cm~1): 3380, 1680, 1640, 1660 (3) 3.03 g of N-(-4-fluorobenzoyl)-1 -benzoyl-3-fluoropropylamine are added to 2 ml of acetic acid, and the mixture is heated at 120 to 140 C to dissolve said propylamine therein. 20 g of ammonium acetate are added gradually to the mixture for 2 hours under stirring. After cooling the mixture, 100 ml of water and 100 ml of ethyl acetate are added thereto, and the mixture is neutralized with sodium bicarbonate. The ethyl acetate layer is collected from the mixture, washed with water and dried. Then, the ethyl acetate layer is condensed under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent:chloroform) and then recrystallized from a mixture of ethylacetate and isopropyl ether. 1.25 g of 2-(4-fiuorophenyl)-4-phenyl-5-(2-fluoroethyl)imidazole are thereby obtained.
Yield: 43.9 % M.p. 127-128C IR VmUE;XI (cm-1): 1650,1608,1590 Example 2 (1) 7.0 g of 3-fluorobenzoyl chloride, 7.2 g of benzoylemethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 10.2 g of N-(3-fluorobenzoyl)-benzoyl)methylamine are obtained.
Yield: 94% M.p. 130-1320C IR #max. nujol (cm-1): 3170,1687,1635,1595 (2) 5.14 g of N-(3-fluorobenzoyl)-benzoylmethylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1-(2), whereby 5.09 g of N-(3-fluorobenzoyl)-1-benzoyl-3-fluoropropylamine are obtained.
Yield: 84% M.p. 73750C IR #max. nujol (cm-1): 3125,1685,1640,1585 (3) 3.03 g of N-(3-fluorobenzoyl)-1-benzoyl-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.99 g of 2-(3-fluorophenyl)4-phenyl-5-(2-fluorethyl)imidazole are obtained.
Yield: 35 % M.p. 133-1350C IR #max. nujol (cm-1): 3040, 1620, 1590 Example 3 (1) 7.7 g of 4-chlorobenzyoi chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1 -(1), whereby 9.4 g of N-(4-chlorobenzyl)-benzoylmethylamine are obtained.
Yield: 82 % M.p. 155-1560C IR #max. nujol (cm-1): 3360,1690,1645,1595 (2) 5.47 g of N-(4-chlorobenzoyl)-benzoylmethylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluroethyl bromide are treated in the same manner as described in Example 1 -(2), whereby 4.83 g of N-(4-chlorobenzoyl)-1 -benzoyl-3-fluoropropylamine are obtained.
Yield: 75.6 % M.p. 105-1060C IR #max. nujol (cm-1): 3350, 1690, 1640, 1595 (3) 3.2 g of N-(4-chlorobenzoyl)-1 -benzoyl-3-fluoropylamine, 2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 1.12 g of 2-(4-chlorophenyl)4-phenyl-5-(2-fluroethyl)imidazole are obtained.
Yield: 37.2 % M.p.164 - 165 C IR #max. nujol (cm-1): 1600,1595 Example 4 (1) 7.7 g of 3-chlorobenzoyl chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 10.8 g of N-(3-chlorobenzoyl)-benzoylmethylamine are obtained.
Yield: 94 % M.p.136-137 C IR #max. nujol (cm-5): 3180, 1685, 1640, 1595 (2) 5.47 g of N-(3-chlorobenzoyl)-benzoyl methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1-(2), whereby 5.63 g of N-(3-chlorobenzoyl)-1-benzoyl-3-fluoropropylamine are obtained.
Yield: 88 % M.p. 82-84'C IR #max. nujol (cm-1): 3145,3020, 1690, 1635, 1595 (3) 3.2 g of N-(3-chlorobenzoyl)-1-benzoyl-3-fluropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.96 g of 2-(3-chlorophenyl)4-phenyl-5-(2-fluoroethyl)imidazole are obtained.
Yield: 32 % M.p. 141 -1430C IR #max. nujol (cm-1): 3040,1604,1590 Example 5 (1) 6.8 g of 4-methylbenzoyl chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1 ), whereby 10.1 g of N-(4-methylbenzoyl)-benzoylmethylamine are obtained.
Yield: 95 % M.p.109-110 C IR #max. nujol (cm-1): 3370,1690,1630 (2) 5.07 g of N-(4-methylbenzoyl)-benzoylmethylamine,0.94g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1-(2), whereby 4.89 g of N-(4-methylbenzoyl)-1-benzoyl-3-fluoropropylamine are obtained.
Yield: 81.6 % M.p. 83-85 C IR VmUE]xl (cm-1): 3360,1690, 1640, 1610, 1600 (3) 2.99 g of N-(4-methylbenzoyl)-1-benzoyl-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.77 g of 2-(4-methylphenyl)-4-phenyl-5-(2-fluoroethyl)imidazole are obtained.
Yield: 27.6 % M.p. 150-1510C IR #max. nujol 1610,1590 Example 6 (1) 6.5 g of 3-thienylcarbonyl chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 9.6 g of N-(3-thienylcarbonyl)benzoylmethylamine are obtained.
Yield: 93 % M.p. 128-1290C IR mTh0x. (cm-1): 3380,3120,1690,1633,1595 (2) 4.91 g of N-(3-thienylcarbonyl)-benzoylmethylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1-(2), whereby 4.25 g of N-(3-thienylcarbonyl)-1-benzoyl-3-fluoropropylamine are obtained.
Yield: 72.9 % M.p. 126-128 C IR #max. nujol (cm-1): 3360,1690,1630,1598 (3) 2.91 g of N-(3-thienylcarbonyl)-1 -benzoyl-3-fluoropropylamine, 2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 1.33 g of 2-(3-thienyl)-4-phenyl-5-(2-fluoroethyl)imidazole are obtained.
Yield: 49 % M.p.149-151 C IR #max. nujol (cm-1): 1610,1595 Example 7 (1) 5.60 g of N-(3-chlorobenzoyl)-3(3-thienylcarbonyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethylbromide are treated in the same manner as described in Example 1-(2), whereby 5.67 g of N-(3-chlorobenzoyl)-1-(3-thienyl-carbonyl)-3- fluoropropylamine are obtained.
Yield: 87 % M.p.106-108 C IR #max. nujol (cm-1): 3170,3050, 1680, 1642 (2) 3.26 g of N-(3-chlorobenzoyl)-1-(3-thienylcarbonyl)-34luoropropylamine, 2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1 -(3), whereby 0.89 g of 2-(3-chlorobenzoyl)-4-(3-thienyi)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 29 % M.p. 123-126C IR #max. nujol (cm-1): 1620, 1600 Example 8 (1) 5.26 g of N-(4-fluorobenzoyl )-(3-thienylcarbonyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1 -(2), whereby 4.21 g of N-(4-fluorobenzoyl)-1-(3-thienylcarbonyl)-3- fluoropropylamine are obtained.
Yield: 68% M.p.100-102 C IR #max. nujol (cm-1): 3390,3100,1680,1640,1605 (2) 3.09 g of N-(4-fluorobenzoyl)-1-(3-thienylcarbonyl)-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.78 g of 2-(4-fluorophenyl)-4-(3-thienyl)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 26.7 % M.p. 149- 1500C IR #max. nujol (cm-1): 1610,1600 Example 9 (1) 5.60g of N-(4-chlorobenzoyl)-(3-thienylcarbonyl)-methylamine, 0.94 of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1 -(2), whereby 3.94 g of N-(4-chlorobenzoyl)-1-(3-thienylcarbonyl)-3- fluoropropylamine are obtained.
Yield: 60.5% M.p.123-124 C IR #max. nujol (cm-1): 3350,3100,1665,1630,1600 (2) 3.26 g of N-(4-chlorobenzoyl)-1 -(3-thienylcarbonyl)-3-fiuoropropylamine 2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 1.25 g of 2-(4-chlorophenyl)-4-(3-thienyl)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 40.7% M.p.173-174 C IR #max. nujol(cm-1): 1610,1595 Example 10 (1) 5.9 g of 3-thnyl chloride, 7.5 g of (3-thienylcarbonyl)methylamine hydrochloride and 10.0 g of sodium biocarbonate are treated in the same manner as described in Example 1-(1), whereby 9.8 g of N-(3-thienylcarbonyl)-(3-thienylcarbonyl)methylamine are obtained.
Yield: 93 % M.p. 125-1260C IR #max. nujol (cm-1): 3370,3100,1685,1630 (2) 5.03 of N-(3-thienylcarbonyl)-(3-thienylcarbonyl)-methylamine, 0.94g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyi bromide are treated in the same manner as described in Example 1 -(2), whereby 3.94 g of N-(3-thienylcarbonyl)-1 -(3-thienylcarbonyl)-3fluoropropylamine are obtained.
Yield: 72 % M.p.116-117 C IR VmflUaxO. (cm-1): 3350,3100,1680,1630 (3) 2.97 g of N-(3-thienylcarbonyl)-1-(3-thienylcarbonyl)-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.88 g of 2-(3-thienyl )-4-(3-thienyl)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 31.7 % M.p.184-186 C IR #max. nujol(cm-1): 1610 Example ii (1) 6.0 g of potssium tert.-butoxide are dissolved in 60 ml of tetrahydrofuran, and 4.4 g of methyl a-isocyano-acetate are added dropwise thereto at -500C under stirring. The mixture is stirred at the same temperature for one hour. Then, 5.8 g of 2-furylcarbonyl chloride are added dropwise to the mixture at -50 C under stirring, and said mixture further stirred for 2 hours. After the reaction is completed, the mixture is adjusted to a pH of 3 to 4 with acetic acid and then evaporated under reduced pressure to remove solvent.
The residue is extracted with ethyl acetate, and the extract is washed with water and an aqueous sodium bicarbonate solution, successively. Said extract is dried and evaporated under reduced pressure to remove solvent. The residue is washed with isopropyl ether, whereby 6.5 g of methyl 5-(2-furyl)-oxazole-4- carboxylate are obtained.
Yield: 75 % M.p. 93-940C IR #max. nujol (cm-1): 3140,3120, 1720, 1605 (2) A mixture of 3.0 g of methyl 5-(2-furyl)oxazole-4 carboxylate and 50 ml of 6N hydrochloric acid is stirred at 80 to 90 C for 6.5 hours. Then, the mixture is condensed under reduced pressure, and the residue is crystallized with acetone. The precipitated crystals are collected by filtration, whereby 2.2 g of (2-furylcarbonyl)methylamine hydroloride are obtained.
Yield :80 % M.p. 211 - 2130C IR #max. nujol (cm-1): 1730, 1680, 1584 (3) 23.4 g of (2-furylcarbonyl)methylamine hydrochloride, 29.3 g of sodium bicarbonate and 23.0 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Example 1-(1), whereby 24.0 g of N-(4-fluorobenzoyl)-(2-furylcarbonyl)methylamine are obtained.
Yield: 66.8 % M.p. 153-1550C IR #max. nujol (cm-1): 3410,3100,1680,1655 (4) 4.94 of N-(4-fluorobenzoyl)-(2-furylcarbonyl)-methylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1-(2), whereby 4.11 g of N-(4-fluorobenzoyl)-1-(2-furycarbonyl)-3-fluoropropylamine are obtained.
Yield: 70 % M.p.97- 101 C IRvnmuaixo.I(cml): 3410,3390,3110,1679,1650,1600 (5) 2.93 g of N-(4-fluorobenzoyl)-1-(2-furylcarbonyl)-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3), whereby 0.77 g of 2-(4-fluorophenyl)-4-)2-furyi)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 28 % M.p. 144- 146 C IR #max. nujol (cm-1): 1635, 1608 Example 12 (1) 12.0 g of 4-chlorobenzoyl chloride, 10 g of (2-furylcarbonyl)methylamine hydrochloride and 12.5 of sodium bicarbonate are treated in the same manner as described in Example 1 -(1), whereby 16.0 g of N-(4-chlorobenzoyl)-(2-furylcarbonyl)methylamine are obtained.
Yield: 98 % M.p.138-139 C #max. nujol (cm- ): 3400,1680,1660,1595 (2) 5.27 g of N-(4-chlorobenzoyl)-(2-furycarbonyl)-methylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 2.54 g of 2-fluoroethyl bromide are treated in the same manner as described in Example 1 -(2), whereby 3.9 g of N-(4-chlorobenzoyl)-1-(2-furylcarbonyl)-3-fluoropropylamine are obtained.
Yield: 63 % M.p.99- 102 C IR #max. nujol (cm-1): 3400,3320,3140, 1680, 1630, 1597 (3) 3.1 g of N-(4-chlorobenzoyl)-1-(2-furylcarbonyl)-3-fluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 1-(3),whereby 0.93 g of 2-(4-chlorophenyl)-4-(2-furyl)-5-(2-fluoroethyl)imidazole are obtained.
Yield: 32 % M.p.133-136 C #max. nujol (cm-1): 1630,1605 Example 13 (1) 0.94 g of sodium hydride (61 % oil dispersion) is suspended in 25 ml of dimethylformamide, and 5.14 g of N-(4-fluorobenzoyl)-benzoylmethylamine are added to the suspension at -40 to -50 C under stirring. The mixture is stirred at -40 to -500C for 5 minutes. 4.2 g of 2,2,2-trifluoroethyl iodide are added to said mixture, and the mixture is stirred at the same temperature for one hour and then at 0 C for one hour. The reaction mixture is neutralized with acetic acid, water is added thereto, and said mixture is extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution and water, respectively.Then, the extract is dried and evaporated under reduced pressure to remove solvent. The residue thus obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 5.94 g of N-(4-fluorobenzoyl)-1-benzoyl-3,3,3- trifluoropropylamine are obtained.
Yield: 87.6 % M.p.111-112 C IR #max. nujol (cm-1): 3300,3080,1685,1640,1600 (2) 3.39 g of N-)4-fluorobenzoyl)-1-benzoyl-3,3,3-trifluoropropylamine are added to 2 ml of acetic acid, and the mixture is heated at 120 to 140 C to dissolve said propylamine therein. 20 g of ammonium acetate are added gradually to the mixture for 2 hours under stirring. After cooling the mixture, 100 ml of water and 100 ml of ethyl acetate are added thereto, and the mixture is neutralized with sodium bicarbonate. The ethyl acetate layer is collected from the mixture, washed with water and dried. Then, the ethyl acetate layer is condensed under reduced pressure to remove solvent.The residue is purified by silica gel chromatography (solvent: chloroform) and then recrystallized from a mixture of ethyl acetate and isopropyl ether. 2.18 g of 2-(4-fluorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are thereby obtained.
Yield: 68.1 % M.p.170-171 C IR #max. nujol (cm- ): 1612,1595 Example 14 (1) 5.14 g of N-(3-fluorobenzoyl)-benzoylmethylamine 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.42 g of N-(3-fluorobenzoyl)-1-benzoyl-3,3,3-thifluoropropylamine are obtained.
Yield: 80 % M.p.115-116 C IR #max. nujol (cm-1): 3160,1687,1643,1600,1593 (2) 3.39 g of N-(3-fluorobenzoyl)-1-benzoyl-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 13-(2), whereby 3.04 g of 2-(3-fluorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 95 % M.p. 156-157 C IR #max. nujol (cm-1): 1620,1593 Example 15 (1) 5.47 g of N-(4-chlorobenzoyl)-benzoylmethylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.44 g of N-(4-chlorobenzoyl)-1 -benzoyl-3,3,3-trifluoropropylamine are obtained.
Yield: 76.5 % M.p. .p.138 - 139 C IR #max. nujol (cm-1): 3240,3080, 1690,1640,1600 (2) 3.55 g of N-(4-chlorobenzoyl)-1-benzoyl-3,3,3-trifluropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 13-(2), whereby 3.32 g of 2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 98.7 % M.p. 173-174 IR #max. nujol(cm-1): 1610, 1590 Example 16 (1) 5.47 g of N-(3-chlorobenzoyl)-benzoylmethylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.41 g of N-(3-chlorobenzoyl)-1 -benzol-3,3,3-trifluoropropylamine are obtained.
Yield: 76% M.p. 121 - 1200C IR #max. nujol(cm-1): 3145,3025,1690,1685, 1640,1595 (2) 3.55 g of N-(3-chlorobenzoyl)-1-benzoyl-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 13-(2), whereby 3.34 g of 2-(3-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 94 % M.p. 180-1810C IR VrnnUaxl (cm- ): 3030,1590 Example 17 (1) 9.7 g of 3-trifluoromethylbenzoyl chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 9.6 g of N-(3-trifluoromethylbenzoyl)-benzoylmethylamine are obtained.
Yield: 74% M.p. 127-1280C IR #max. nujol (cm-1): 3170,1685,1635 (2) 6.14 g of N-(3-tifluoromethylbenzoyl)-benzoyl-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.06 g of N-(3-trifluoromethylbenzoly)-1-benzoyl-3,3,3- trifluoropropylamine, are obtained.
Yield: 65% M.p. 107-1080C IR #max. nujol (cm-1): 3100,3030,1695,1637, 1615 (3) 3.89 g of n-(3-trifluoromethylbenzoyl)-1-benzoyl-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 13-(2), whereby 3.07 g of 2-(3-trifl uoromethyl phenyl )-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 83 % M.p.187-188 C IR #max. nujol(cm-1): 1610,1590 Example 18 (1) 9.7 g of 2-trifluoromethylbenzoyl chloride, 7.2 g of benzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1 -(1), whereby 11,1 g of N-(2-trifluoromethyl benzoyl )-benzoylmethylamine are obtained.
Yield: 86 % M.p.110-111 C IR #max. nujol (cm-'): 3135,3070, 1700, 1640 (2) 6.14 g of N-(2-trifluoromethylbenzoyl)-benzoyl-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4,2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1),whereby 5.29 g of N-(2-trifluoromethylbenzoyl)-l -benzoyl-3,3,3- trifluoropropylamine are obtained.
Yield: 68% M.p. 135-1370C IR #max. nujol (cm-1): 3125,3030,1690, 1650, 1600 (3) 3.89 g of N-(2-trifluoromethylbenzoyl)-1-benzoyl-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described in Example 13-(2), whereby 2.11 g of 2-(2-trifluormethylphenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 57 % M.p. 161 -1620C IR vnUax (cm-'): 1610,1590 Example 19 (1) 3.0 g of methyl a-isocyanoacetate and 4.76 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Example 11-(1), whereby 5.71 g of methyl 5-(4-fluorophenyl)oxazole-4-carboxylate are obtained.
Yield: 80 % M.p. 99- 1000C IR #max. nujol (cm-1): 3145,1713,1613,1600, 1587 (2) 4.42 g of methyl 5-(4-fluorophenyl)oxazole-4-carboxylate and 50 ml of 6N hydrochloric acid are treated in the same manner as descrribed in Example 1 1-(2), whereby 2.28 g of 4-fluorobenzoylmethylamine hydrochloride are obtained.
Yield: 60 % M.p. 237-240'C IR #max. nujol (cm-1): 1690,1605,1513 (3) 7.7 g of 4-chlorobenzoyl chloride, 8.0 g of 4-fluorobenzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1 -(1), whereby 9.9 g of N-(4-chlorobenzoyl)-(4-fluorobenzoyl)methylamine are obtained.
Yield: 81 % M.p. 176-178 C IR VflmUaOx.I (cm-1): 3350,1685,1640,1600 (4) 5.83 g of N-(4-chlorobenzoyl)-(4-fluorobenzoyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 6.13 g of N-(4-chlorobenzoyl)-1-(4-fluorobenzoyl)-3,3,3 trifluoropropylamine are obtained.
Yield: 82 % M.p. 145-1460C IR #max. nujol (cm-1): 3300,1695,1650,1600 (5) 3.73 g of N-(4-chlorobenzoyl)-1-(4-fluorobenzoyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 3.19 g of 2-(4-chlorophenyl)-4-(4-fluorophenyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 90 % M.p. 196- 197'C IR #max. nujol (cm-1): 3060,1615, 1600 Example 20 (1) 7.7 g of 4-chlorobenzoyl chloride, 8.7 g of 4-chlorobenzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 12.2 g of N-(4-chlorobenzoyl)-(4-chlorobenzoyl)methylamine are obtained.
Yield: 94% M.p.177-179 C IR vmUaxl (cm-1): 3300, 1690, 1640, 1590 (2) 6.16 g of N-(4-chlorobenzoyl)-(4-chlorobenzoyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.31 g of N-(4-chlorobenzoyl)-1 -(4-chlorobenzoyl)-3,3,3trifluoropropylamine are obtained.
Yield: 68% M.p. 173-174 C IR #max. nujol (cm-1): 3300,3050,1690,1645,1593 (3) 3.9 g of N-(4-chlorobenzoyl)-1-(4-chlorobenzoyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 3.38 g of 2-(4-chlorophenyl)-4-(4-chlorophenyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 91 % M.p. 239 - 240 C IR #max. nujol (cm-l): 3050,1615,1600 Example 21 (1) 7.7 g of 4-chlorobenzoyl chloride, 7.8 g of 4-methylbenzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same mannaer as described in Example 1 -(1), whereby 10.3 g of N-(4-chlorobenzoyl)-(4-methylbenzoyl)methylamine are obtained.
Yield: 85% M.p. 133-135 C IR #max. nujol (cm-1): 3390,3270,1687,1650, 1605 (2) 5.75 g of N-(4-chlorobenzoyl)-(4-methylbenzoyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 6.06 g of N-(4-chlorobenzoyl)-1-(4-methylbenzoyl)-3,3,3- trifluoropropylamine are obtained.
Yield: 82 % M.p. 132-134 C IR #max. nujol (cm-1): 3310,1686,1645,1610 (3) 3.7 g of N-(4-chlorobenzoyl)-1-(4-methylbenzoly)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.28 g of 2-(4-chlorophenyl)-4-(4-methylphenyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 65 % M.p.233-234 C IR #max. nujol (cm-1): 1620,1607, 1595 Example 22 (1)7.7 g of 4-chlorobenzoyl chloride, 8.5 g of 4-methoxybenzoylmethylamine hydrochloride and 10 g of sodium bicarbonate are treated in the same manner as described in Example 1-(1), whereby 9.8 g of N-(4-chlorobenzoyl)-(4-methoxybenzoyl)methylamine are obtained.
Yield: 77 % M.p. 175-1760C IR #max. nujol(cm-1): 3350, 1683, 1640, 1602 (2) 6.08 g of N-(4-chlorobenzoyl)-(4-methoxybenzoyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1 ), whereby 6.02 g of N-(4-chlorobenzoyl)-1-(methoxybenzoyl)-3,3,3- trifluoropropylamine are obtained.
Yield: 78 % M.p. 137-139'C IR #max. nujol (cm-1): 3300,1680,1648,1605 (3) 3.86 g of N-(4-chlorobenzoyl)-1-(4-methoxybenzoyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.42 g of 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-5-(2,2,2-trifluorophenyl)imidazole are obtained.
Yield: 66% M.p. 215-2160C IR vmUlxl (cm-1): 1620,1610 Example 23 (1) 5.60 g of N-(4-chlorobenzoyl)-(2-thienylcarbonyl)-methylamine, 0.94g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 15-(1), whereby 5.13 g of N-(4-chlorobenzoyl)-1 -(2-thienylcarbonyl)-3,3,3trifluoropropylamine are obtained.
Yield: 71 % M.p.175-177 C IR #max. nujol (cm-1): 3270,3050,1660,1637,1597 (2) 3.62 g of N-(4-chlorobenzoyl)-1-(2-thienylcarbonyl)-3,3,3-trifluroropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.43 g of 2-(4-chlorophenyl)-4-(2-thienyl)-5-(2,2,2-trifluorethyl)imidazole are obtained.
Yield: 71 % M.p.165-166 C IR max. nujol (cm-1): 3070,1610 Example 24 (1) 5.27 g of N-(4-fluorobenzoyl )-(3-thienylcarbonyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 5.66 g of N-(4-fluorobenzoyl)-1-(3-thienylcarbonyl)-3,3,3- trifluoropropylamine are obtained.
Yield: 81.9 % M.p. 139-1410C IR #max. nujol (cm-1): 3300,3100,1678,1640, 1605 (2) 3.45 g of N-(4-fluorobenzoyl)-1-(3-thienylcarbonyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.68 g of 2-(4-fluorophenyl)-4-(3-thienyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 82.2 % M.p.150-151 C IR vmyexl (cm-1): 1619,1598 Example 25 (1) 5.6 g of N-(4-chlorobenzoyl)-(3-thienylcarbonyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 6.56 g of N-(4-chlorobenzoyl)-1-(3-thienylcarbonyl)-3,3,3- trifluoropropylamine are obtained.
Yield: 90.7 M.p.150 - 152 C IR UflmUaOx.I (cm-5): 3300,3100,1680,1640,1595 (2) 3.62 g of N-(4-chlorobenzoyl)-1-(3-thienylcarbonyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.36 g of 2-(4-chlorophenyl)-4-(3-thienyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 18.8% M.p. 171 - 1720C IR #max. nujol (cm-1): 1619, 1600 Example 26 (1) 5.6 g of N-(3-chlorobenzoyl)-(3-thienylcarbonyl)-methylamine, 0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 6.73 g of N-(3-chlorobenzoyl)-1 -(3-thienylcarbonyl)-3,3,3trifluoropropylamine are obtained.
Yield: 93 % M.p. 141 - 1420C IR #max. nujol (cm-1): 3150,3050,1675,1640 (2) 3.62 g of n-(3-chlorobenzoyl)-1-(3-thienylcarbonyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 2.87 g of 2-(3-chlorophenyl)-4-(3-thienyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 84% M.p. 185-1860C IR #max. nujol(cm-1): 1620, 1600 Example 27 (1) 9.7 g of 4-trifluoromethylbenzoyl chloride, 7.5 g of (3-thienylcarbonyl)methylamine hydrochloride anc 10.0 g of sodium bicarbonate are treated in the same manner as described in Example 1(1), whereby 12.6 c of N-(4-trifluoromethylbenzoyl)-(3-thienylcarbonyl)methylamine are obtained.
Yield: 95 % M.p. 180 1820C IR #max. nujol 3350, (cm-1): 3350,3110,1687,1640 (2) 6.3 g of N-(4-trifluoromethylbenzoyl)-(3-thienylcarbonyl)methylamine,0.94 g of sodium hydride (61 /c oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1),whereby 6.48 g of N-(4-trifluoromethylbenzoyl)-1-(3- thienylcarbonyl)-3,3,3-trifluoropropylamine are obtained.
Yield: 82 % M.p.148-149 C IR #max. nujol (cm-1): 3155,3050, 1680,1645 (3) 3.95 g of N-(4-trifluoromethylbenzoyl)-1-(3-thienylcarbonyl)-3,3,3-trifluoropropylamine,2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 3.23 g of 2-(4-trifluoromethylphenyl)-4-(3-thienyl)-5-(2,2,2-trifluoroethyl)-imidazole are obtained.
Yield: 86% M.p. 163-1650C IR vmuaxol (cm-1): 1620,1610 Example 28 (1) 5.27 g of N-(4-chlorobenzoyl)-(2-furylcarboneyl)-methylamine,0.94 g of sodium hydride (61 % oil dispersion), 25 ml of dimethylformamide and 4.2 g of 2,2,2-trifluoroethyl iodide are treated in the same manner as described in Example 13-(1), whereby 4.63 g of N-(4-chlorobenzoyl)-1 -(2-furylcarbonyl)-3,3,3trifluoropropylamine are obtained.
Yield: 67 % M.p.175-177 C IR #max. nujol (cm-1): 3300, 1685,1643,1597 (2) 3.45 g of N-(4-chlorobenzoyl)-1-(2-furylcarbonyl)-3,3,3-trifluoropropylamine, 2 ml of acetic acid and 20 g of ammonium acetate are treated in the same manner as described Example 13-(2), whereby 0.62 g of 2-(4-chlorophenyl)-4-(2-furyl)-5-(2,2,2-trifluoroethyl)imidazole are obtained.
Yield: 19% M.p. 169- 170"C IR unnUaxl (cm-1): 1640, 1605

Claims (11)

1. An imidazole derivative of the formula:
wherein R1 is furyl, thienyl, phenyl, halogenophenyl, alkylphenyl or alkoxyphenyl, R2 is furyl, thienyl, phenyl, halogenophenyl, alkylphenyl or (trifuoroalkyl)phenyl, and Y is monofluoromethyl, difluoromethyl or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
2. An imidazole derivative as claimed in claim 1 in which R' is furyl, thienyl, phenyl, chlorophenyl, fluorophenyl, methylphenyl or methoxyphenyl, R2 is furyl, thienyl, phenyl, chlorophenyl, fluorophenyl, methylphenyl, or trifluoromethylphenyl, and Y is monofluoromethyl or trifluoromethyl.
3. An imidazole derivative as claimed in claim 2 in which R1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl or 4-methoxyphenyl, R2 is 2furyl, 3-furyl, 2-thienyl, 3-thienyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 34luorophenyl, 4- fluorophenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethyiphenyl or 4-trifluoromethylphenyl.
4. An imidazole derivative as claimed in claim 3 in which R' is 3-thienyl or phenyl, and R2 is 3-chlorophenyl, 4-chlorophenyl or 4-fluorophenyl.
5. An imidazole derivative of the formula given in claim 1 substantially as herein described with reference to and as illustrated in any of the examples.
6. A process for preparing an imidazole derivative of the formula given in claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting a methylamine compound of the formula:
dose which would produce 50 % reduction in carrageenin-induced hyperthermia) was estimated by the dose-response curve obtained in the experiments. The results are shown in the following Table 3.
Example 3 acetate. The extract is washed with an aqueous sodium bicarbonate solution and water, respectively. Then, wherein R', R2 and Y have the meanings given in claim 1, with ammonia or salt thereof, and if required, further converting the product into a pharmaceutically acceptable salt thereof.
7. A process according to claim 6, wherein the ammonium salt is ammonium acetate.
8. A process for preparing an imidazole derivative of the formula given in claim 1, or a pharmaceutically accepable salt thereof, substantially as before described with reference to and as illustrated in any of the examples.
9. A pharmaceutical composition which comprises a therapeutically effective amount of an imidazole derivative as claimed in any of claims 1 to 5, or of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
10. An imidazole derivative as claimed in any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as an analgesic, anti-inflammatory and/or anti-pyretic agent.
11. A methylamine compound oftheformula
wherein R1, R2 and Y have the meanings given in claim 1.
GB08321000A 1983-08-04 1983-08-04 Imidazole derivatives Withdrawn GB2144408A (en)

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Publication number Priority date Publication date Assignee Title
WO1995017390A1 (en) * 1993-12-21 1995-06-29 Bayer Aktiengesellschaft N-substituted aryl trifluoromethyl imidazoles

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WO1995033730A1 (en) * 1994-06-09 1995-12-14 Nippon Soda Co., Ltd. Imidazole derivative, production process, and herbicide
JP5858884B2 (en) * 2012-08-16 2016-02-10 四国化成工業株式会社 Imidazole compounds having a thiophene ring
KR102253652B1 (en) * 2019-08-19 2021-05-18 주식회사 셀젠텍 Novel compound with cancer metastasis inhibiting activity, method for preparing the same and pharmaceutical composition for inhibiting cancer metastasis and invasion or treating cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995017390A1 (en) * 1993-12-21 1995-06-29 Bayer Aktiengesellschaft N-substituted aryl trifluoromethyl imidazoles

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