MXPA98007897A - Derivatives of 4 [(tien-2-il) methyl] imidazole that have agronistic activity of adrenoceptor alf - Google Patents

Abstract

The 4 [(thien-2-yl) methyl] imidazoles of formula I, wherein R is hydrogen or methyl, X is hydrogen, C 1-4 alkyl, bromo or chloro, and Y is hydrogen, C 1-4 alkyl, bromine or chlorine, with the proviso that X and Y are not both simultaneously hydrogen, have analgesic activity except

Description

DERIVATIVES OF 4- [(TIEN-2-IL) METHYL] IMIDAZ0L THAT HAVE AGONISTA ACTIVITY OF ADRENOCEPTOR ALPHA-2 The present invention relates to receptor agonists having analgesic activity. More in paragraph r, the present invention relates to 4- [(thien-2-yl) methyl] imidazoles having improved analgesic activity.

BACKGROUND OF THE INVENTION Clonidine is a centrally acting receptor receptor-reactive agonist with broad clinical utility as an antihypertensive agent. It is believed that clonidine acts to inhibit the release of noropinephrine from the terminals of the sympathetic nerve, through a negative feedback mechanism involving the 2 adrenorrocoptors located on the presynaptic nerve terminal. It is believed that this action occurs both in the central nervous system (CNS) and in the peripheral nervous system (SNP) More recently, the role of a2-adrenoreceptor agonists as analgesic agents in humans, and as agents has been demonstrated. antinociceptive in animals. It has been shown that clonidine and other oc2-adrenoreceptor agonists produce analgesia through a non-opioid mechanism and, thus, without the addition of opiates. However, there were also other behavioral and physiological effects, which included sedation and cavitation surgery. clonidine Edetomidine and detomidine are adrenoreceptor agonists widely used in clinical veterinary medicine as sedatives / hypnotics for proanesthesia. These compounds are hypotensive in animals and humans, but the magnitude of this cardiovascular effect is relatively insignificant. medetomidine U.S. Patent No. 3,574,844 to Gardocki and coinventores teaches the 4- [4- (or 5) -imidazolylmethyl] -oxazoles as effective analgesics. The disclosed compounds have the general formula.

Compounds of this type are insufficiently active and suffer from undesirable side effects. U.S. Patent No. 4,913,207 to Nagel and co-inventors teaches arylthiazolylimidazoles as effective analgesics. The compounds described are of the general formula: Compounds of this type are insufficiently active and suffer from undesirable side effects. W092 / 14453, by Campbell and co-inventors, teaches 4 - [(aryl or heteroaryl) methyl] imidazoles as effective analgesics. The disclosed compounds have the general formula: R is H or aryl A is aryl or heteroaryl Compounds of this type are insufficiently active and suffer from undesirable side effects.

Kokai No. 1-242571 of Kihara and co-inventors, describes a method for producing imidazole derivatives for use, among others, as antihypertensive agents. or halogen X is S u 0 As reported, by the method of the invention, a single mixture of compounds satisfying the above formula was produced. This was a mixture of 4- (2-thienyl) -methylimidazole and 4- (3-thienyl) methyl-imidazole represented by the following formula: The described compounds are insufficiently active and suffer from undesirable side effects. It is an object of the present invention to produce 4- C (thien-2-yl) methyl] imidazoles having improved analgesic activity.

It is another objective of the present invention to produce analgesics of 4- [(thien-2-yl) methyl] imidazole that have reduced side effects. BRIEF DESCRIPTION OF THE INVENTION Briefly, compounds which have improved analgesic activity of the formula are provided by the present invention: wherein: R is hydrogen or methyl; X is hydrogen, alkyl of 1 to 4 carbon atoms, bromine or chlorine; and Y is hydrogen, alkyl of 1 to 4 carbon atoms, bromine or chlorine; provided that X and Y are not simultaneously both hydrogen.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be prepared basically in a two step process. In the first step, an appropriately substituted thiophene precursor is obtained, having substituents hydrogen, alkyl of 1 to 4 carbon atoms, bromine or chlorine, as desired, and in the required positions. This thiophene precursor will have an electrophilic carbon substituent at position 2. In the second step, an imidazole precursor having an anion in position 4, reacted with the electrophilic carbon of the thiophene precursor, is reacted to leave a residue of carbon bridge, with the thiophene precursor to produce the desired skeleton, and then it is followed by deoxygenation of the bridge residue. Of course, many variations are possible. It may be convenient to initially replace the thiophene, as described, or modify the substitution in the thiophene after the base structure is formed in the final compound. In addition, in the compounds where it is convenient to have methyl substitution in the carbon bridge residue, additional steps will be necessary. Here a Grignard reaction is favored for use in the second step, in order to bind the thienyl portion and the imidazolyl portion. Thus, it is preferred that the imidazole precursor be substituted at the 4-position, as a Grignard reagent, and that the thiophene precursor be substituted at the 2-position, with a carbonyl, such as formyl or an N, 0-dimethylcarbo group? iamido. The preferred imidazole precursor has the formula: ^ MQX 'where X1 is iodine, bromine or chlorine. This compound is prepared by methods well known in the art, ie, by reaction between the alkyl or magnesium Grignard and imidazolyl halide in alcohol free, dry, or THF or dichloromethane. Preferred precursor thiophenes have the formula: AA BB where X and Y are as defined above. As starting materials for forming the preferred precursor thiophenes AA and BB, the preparation of various brominated and methylated thiophenes is well known from the literature. The thiophenes precursors of type AA can be produced from 3,4-disubstituted thiophenes or 3-substituted thiophenes, by the use of a Vilsmeier formylation. Vilsmeier formylation is carried out by simple heating of the thiophene substituted in DMF or POCI3. The resulting compound is thiophene-2-carboxyaldehyde-3-substituted or thiophene-2-carboxyaldehyde-4-substituted, or thiophene-2-carboxyaldehyde-3,4-disubstituted. When the starting material is a thiophene-3-substituted, these resulting compounds can be produced, in some cases, as thiophene mixtures (2 and 5) -carboxyaldehydes. Of course, thiophenes-5-carboxyaldehyde-3-substituted are thiophene-2-carboxyaldehyde-4-substituted. In the case of a mixture, the desired pure compound can be recovered by standard techniques, including chromatography and recrystallization. Alternatively, certain thiophenes precursors of the AA type can be produced from 2-bromo-3,4-disubstituted-thiophenes or from 2-bromo-3-substituted-thiophenes or 2-bromo-4-substituted-thiophenes, by use of halogen-metal exchange. In a first step, the compound is treated with an organoalkali compound, such as n-butyllithium, whose product is reacted, in a second step, in situ. with DMF. The reaction is quenched with aqueous ammonium chloride. The resulting compound is 2-carboxyaldehyde-3,4-disubstituted-thiophene or 2-carboxyaldehyde-3-substituted-thiophene or 2-carboxyaldehyde-4-substituted-thiophene. Thiophenes precursors of type BB can be produced from 2-carboxylate 3- (methyl or chloro or bromo) -4- (methyl or chloro or bromo) thiophene or 2-carboxylate of 4- (methyl or chloro or bromo) - thiophene, by two methods. In the first method, the carboxylate starting material is converted to the acid chloride and reacted with N, 0-dimethylhydroxylamine to produce the Weinreb amide, thiophene of the BB type. In the second method, the carboxylate is reacted with N, 0-dimethylhydroxylamine and an appropriate coupling agent, such as DCC or CDI to produce the Weinreb amide. The precursor imidazole can be reacted with any of the precursor thiophenes of types AA or BB, by use of the Grignard reaction. When the thiophene precursor is of the AA type, a solution of the thiophene precursor is combined with a solution of the imidazole precursor at room temperature, and the reaction is quenched with aqueous solution of ammonium chloride to produce an imidazothienylmethanol. Carbinol is deoxygenated to the final product, wherein R is hydrogen, by the use of a reducing agent, such as borane ethylsulfide, in combination with TFA. Alternatively, methanol is catalytically deoxygenated to a final product, wherein R is hydrogen, heating with Pearlman's catalyst and one equivalent of acid. To produce the final product wherein R is methyl, the methanol is oxidized to the corresponding ketone with an oxidizing agent, such as MnO or a Jones reagent, and the resulting ketone is reacted with the methyl Grignard, to produce a carbinol which it is deoxygenated as described immediately above. When the thiophene precursor is of the BB type, a solution of the thiophene precursor is combined with a solution of the imidazole precursor at room temperature, and the reaction is quenched with aqueous ammonium chloride solution to produce an i idazothienyl ketone. To produce the final product, wherein R is hydrogen, the ketone is reduced to carbinol by the use of a reducing agent, such as sodium borohydride or lithium aluminum hydride and, subsequently, carbinol is deoxygenated as described immediately above. Generally, to produce the final product in which R is methyl, the imidazothienyl ketone is reacted with the methyl Grignard reagent to produce a carbinol which is deoxygenated as described above. The protecting group in the imidazole precursor is exemplified herein as trityl, which is preferred. However, a person skilled in the art will readily recognize that other protective groups are suitable. Suitable protecting groups include dimethylsulphamoyl or methoxymethyl. The trityl group is removed in the deoxygenation to final product or by heating in a dilute acid and alcohol solvent. The most preferred compounds of the present invention are shown in Table I: The activity of the compounds of the invention as analgesics can be demonstrated by the in vivo and viral analyzes described below.

ANALYSIS OF UNION TO THE ADRENERGIC RECEIVER ALPHA 3 Male Wistar rats (150 to 250 g, VAF, Charles River, Kingston, NY, USA) are sacrificed by cervical dislocation and the brain is removed and immediately placed in HEPES-regulated sucrose, cooled with ice. The bark is dissected and homogenized in 20 volumes of sucrose with HEPES in a Teflon (R) -green glass homogenizer. The homogenate is centrifuged at 1000 g for 10 minutes and the resulting supernatant is centrifuged at 42,000 g for 10 minutes. The resulting pellet is resuspended in 30 volumes of 3-iliolar potassium phosphate buffer, pH 7.5, preincubated at 25 ° C for 30 minutes and recentrifuged. The resulting pellet is again suspended as described above and used for receptor binding analysis. Incubation is carried out in test tubes containing phosphate buffer, 2.5 mmol of MgCl, aliquots of the synaptic membrane fraction, the 3 H-para-aminoclonidine ligand, and the drug is tested at 25 ° C for 20 minutes. The incubation is terminated by filtering the contents of the tube through glass fiber filter sheets. After washing the sheets with 10 mmoles of HEPES regulator, i: quantifies adhesion radioactivity by liquid flash spectrometry. The binding of the test drug to the receptor is determined by comparing the amount of radiolabelled ligand bound in the control tubes without drug, with the amount of radiolabelled ligand bound in the presence of the drug. The dose response data are analyzed with LIGAND, a non-linear curve fitting program, designed specifically for the analysis of ligand binding data. This analysis is described by Simmons, R.M. ?, and Jones, D.J., Binding of [3H-] prazosin and [3H-] p-aminoclonidine to ot-Adreceptors in Rat Spinal Cord, Brain Research 445: 338-349, 1988.

ANALYSIS OF ABDOMINAL CONSTRICTION INDUCED BY ACETYLCOLINE BROMIDE IN MICE The analysis of abdominal constriction induced by acetylcholine bromide on mice, which was described by Collier and co-authors, was used in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minimal modifications to determine the analgesic potency of the compounds herein. The test drug or appropriate vehicle was administered orally (po), and 30 minutes after the animal received an intraperitoneal (ip) injection of 5.5 mg / kg of aceticum bromide (Matheson, Cole an and Bell, East Rutherford, New Jersey). , USA). The mice were then placed in groups of three, in glass jars, and observed for a ten-minute observation period for abdominal constriction response (defined as a constriction and elongation wave that passes in a caudal direction along the abdominal wall, accompanied by trunk cramps and followed by extension of the front legs). The percentage inhibition of this response to the nociceptive stimulus (equal to the percentage of analgesia) was calculated as follows: The percentage of inhibition of response, that is, the percentage of analgesia, is equal to the difference between the response number of the control animals and the response number of the animals treated with the drug, multiplied by 100, divided by the number of control animals that respond. At least 15 animals were used for control and in each of the drug-treated groups. At least three doses were used to determine each dose response curve and ED50 (that dose that would produce 50% analgesia). The ED50 values and their 95% safety limits were determined by a probit analysis (of percentage units), aided by a computer.

IT BOX Abdominal constriction in mouse Compound Ki (nm)% DE50 inhibition Cp-1 0.45 0.94 mpk / po Cp-2 2.1 1.4 mpk / po Cp-3 0.35 1.7 mpk / po Cp-4 0.96 2.1 mpk / po Cp-5 0.17 100% at 30 pk / po Cp-6 0.75 87% a 30 mpk / po Cp-7 0.43 80% at 30 mpk / po Cp-8 0.7 5.7 mpk / po Cp-9 1.4 80% at 30 mpk / po 3. 6 33% at 30 mpk Based on the above results, the compounds of the present invention can be used for mild to moderately severe pain in warm-blooded animals, such as humans, by administering an analgesically effective dose. The dose scale would be between about 10 to 3000 mg, in particular about 25 to 1000 mg or about 100 to 500 mg of active ingredient, from one to four times per day for an average human (70 kg) although it is evident which activity of the individual compounds of the invention will vary as well as the pain that is being treated. The pharmaceutical compositions of the invention comprise the compounds of the formula (I) as defined above, particularly in admixture with a pharmaceutically acceptable carrier. To prepare the pharmaceutical compositions of the invention, one or more compounds of the invention or their salts, as an active ingredient, is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, and said carrier can take a variety of forms , depending on the form of preparation desired for administration, for example, oral or parenteral, such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugar, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent a more advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be sugar coated or enteric coated, by common and current techniques. For parenteral applications, the carrier will usually comprise sterile water, although other ingredients may be included, for example, for purposes such as to aid solubility or for preservation. Injectable suspensions may also be prepared, and in that case the appropriate liquid carriers that would be employed would be suspending agents and the like. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of active ingredient necessary to deliver an effective dose, as described above. The pharmaceutically acceptable salts referred to above, generally adopt a form in which the imidazolyl ring is protonated with an inorganic or organic acid. Representative organic or inorganic acids include: hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethane sulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexansulfamic, salicylic or saccharic. The following examples illustrate the invention: EXAMPLE 1 10 CHLORHYDRATE OF -? I3-METTLTIEN-2-IL-METHYL-lH-IMIDAZ0L PftSQ A I »21.4 g, 0.18 mol, of thionyl chloride were added to a solution of 21.3 g, 0.15 mol of 3-methylthiophen-2-carboxylic acid in 100 ml of chloroform. The reaction mixture was refluxed for 2 hours and then allowed to cool. In a separate flask, a solution of 21.9 g, 0.225 mol, of N, 0-dimethylhydroxylamine hydrochloride in 300 ml of chloroform was cooled in ice. Then 56 ml, 0.4 mole, of triethylamine, followed by a solution of 3-methylthiophen-2-carboxylic acid chloride. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into a separatory funnel and washed with dilute aqueous hydrochloric acid and then with water. The organic layer was dried over magnesium sulfate and concentrated to give a yellow oil. The distillation produced 19.0 g (68%) of N, 0-dirnethyl-3-methylthiophen-2-carboxyamide,.., As a colorless liquid, bp 91-93 ° C (0.05 mm Hg). The NMR with 1H in CDCI3 confirmed the assigned structure.

STEP B fil To a solution of 32.7 g, 0.075 mol, of 4-iodo-l-trityl imidazole in 300 ml of dry dichloromethane, under nitrogen, a solution of 25.0 ml, 3.0 mol, of ethyl agnesium bromide in diethyl ether was added dropwise. . When the addition was complete, the reaction mixture was stirred for 1 hour at 25 ° C. TLC analysis indicated that the starting material had disappeared, so 13.9 g, 0.075 mol, of N, 0-dimethyl-3-methylthiophen-2-carboxyamide, ____, was added dropwise, over 2 hours, as a solution in tea rahidrofurano.

After stirring overnight at room temperature, the reaction is quenched with saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The residue was recrystallized from acetone to give (3-methylthien-2-yl) -l-trityl-imidazol-4-yl-methanone, B, as an off-white solid. NMR with ^ H in CDCI3 confirmed the assigned structure.

STEP C A solution of 7.7 g, 0.018 mol, of (3-methylthien-2-yl) -imidazol-2-yl-methanone and 1.03 g, 0.027 mol of sodium borohydride in 50 ml of 2-C was heated at reflux for 2 hours. propanol After cooling, a 3N solution of hydrochloric acid was added to the reaction mixture, followed by a 10% aqueous solution of sodium carbonate. The mixture was concentrated under reduced pressure and the resulting solution was extracted twice with chloroform. The organic extracts were combined, dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate with a small amount of chloroform, to give a white solid. The mother liquor was concentrated to give a second crop of the desired (3-methylthien-2-yl) -l-trityl-imidazol-4-yl-methanol. The total yield of both crops was 7.2 g (92%). NMR with ^ H in CDCI3 confirmed the assigned structure. 2É _____ J_ CP-1 A solution of 40 ml, 1.0 mol, of BH3-THF was added dropwise to a solution of 9.1 g, 0.80 mol, of TFA in 20 ml of dry dichloromethane, which was cooled in an ice bath. When the addition was completed the alcohol was added in portions (2.8 g, 0.0066 mol). The reaction mixture was stirred at 0 ° C for 3 hours. The reaction was quenched by the careful addition of water and the resulting solution made basic with solid sodium carbonate. This solution was extracted twice with dichloromethane. The organic extracts were combined and dried over potassium carbonate. It appeared that a precipitate formed from the solution that was filtered and the residue was washed with 10% methanol-dichloromethane solution. The organic layers were combined and evaporated. The resulting residue was dissolved in methanol and the insoluble material was filtered off. To this solution was added 10 ml of 3M HCl. This solution was stirred for 2 days. TLC analysis indicated that some of the starting material was still present, so the reaction mixture was heated to reflux. After 2 hours the starting material had disappeared, so that the mixture was cooled and the solution was concentrated in vacuo. The residue was dissolved in water. This solution was washed twice with ether, made basic with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated to give 1.1 g of an amber syrup. This material was passed through a column of rapid silica gel using 98: 2 chloroform: 10% ammonium hydroxide, in methanol. The separation was very poor so the material was re-purified in rapid silica gel with 98: 1: 1 ethyl acetate: methanol: ammonium hydroxide, as eluent. The fractions containing the product were combined to give 0.25 g of material which was again purified on flash silica gel using 98: 1: 1 ethyl acetate: methanol: ammonium hydroxide. The fractions containing the product were combined and concentrated. The residue was dissolved in ethyl acetate and heated with ethereal HCl. The solid that precipitated was collected and recrised in acetone with a drop of water. The collected solid was vacuum dried to give 0.060 g of white needles, £ ßl, mp 127.5-129 ° C. The NMR with XH in DMS0-d6 confirmed the assigned structure; __ 2.15-2.25 (d, 3H, Me), 4.10-4.20 (s, 2H, CH2), 6.85-6.95 (d, 1H), 7.30-7.40 (d, 1H), 7.40-7.50 (s, 1H), 8.95-9.05 (s, 1H), 14.35-14.5 (broad s, 2H). Elemental analysis: calculated for CgH] _g S "HCl: C, 50.35; H, 5.16; N, 13.05, Found C, 50.50; H, 5.15; N, 13.07.

EXAMPLE 2 1H-CLOLRHTD TO OF 4-ri-f3-METTI TTEN-2-IL ETTLQl STEP A ?2 A solution of 9.0 ml, 3.Q mol, of methylmagnesium bromide at 10.1 g, 0.024 mol, of an ice-cooled solution of (3-methylthien-2-yl) -l-trityl-imidazol-4-yl was added. -methanone, EL, in 25 ml of rahydrofuran tea. After 1 hour the TLC analysis indicated that some unreacted starting material was present, so an additional 1.5 ml of methylmagnesium bromide was added. After 30 minutes of shaking, the TLC analysis indicated that the starting material had disappeared. The reaction was quenched with aqueous ammonium chloride solution and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water and with brine, dried over sodium sulfate and concentrated. The crude product was recrystallized from acetone to give the carbinol, A2, which was used directly in the next step.

STEP B Cp-2 A solution of 380 ml, 1.0 mole, of BH3-THF in THF, was added dropwise, over 2.5 hours, to a solution of 86.8 g, 0.76 mol, of TFA in 75 ml of dry dichloromethane, maintained below -10. ° C during the addition. When the addition was complete, the reaction mixture was stirred for 10 minutes. Then 8.6 g, 0.019 mol, of carbinol Z, in dry dichloromethane was added in one portion. The reaction mixture was stirred on ice for 90 minutes. The reaction was quenched by the careful addition of 150 ml of 3N HCl. Then an equivalent volume of water was added. Most of the THF was evaporated in vacuo and then the mixture was made basic with solid sodium carbonate. This solution was extracted twice with ethyl acetate. The organic extracts were combined, washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in 100 ml of methanol and 25 ml of 3N HCl was added, and the mixture was allowed to reflux for 2.5 hours. The solution was allowed to cool overnight and then concentrated in vacuo to give an amber colored syrup. This material was dissolved in water and extracted twice with diethyl ether, then made basic and extracted with ethyl acetate. The organic extracts were dried over potassium carbonate and filtered. The filtrate was treated with ethereal HCl solution and 2.3 g of the resulting precipitate was collected. More ethereal HCl was added to the filtrate to give a second crop of crystals containing an impurity. These were recrystallized from acetone with filtration through Dicalite to give the purified material which was combined with the first crop. Recrystallization from acetone yielded 2.2 g of 4-Cl- (3-methylthien-2-yl) ethyl] -lH-imidazole hydrochloride, Cp-2. as a white solid, mp 164-166 ° C. NMR with ^ H in DMS0-d¿ confirmed the assigned structure; __ 1.55-1.65 (d, 3H, Me), 2.15-2.25 (s, 3H, Me), 4.55-4.65 (c, 1H, CH), 6.85-6.95 (d, 1H), 7.30-7.35 (d, 1H ), 7.40-7.50 (s, 1H), 9.05-9.10 (s, 1H), 14.6-14.8 (s broad, 2H). Elemental analysis: calculated for C10H12N2S-HC1: C, 52.51; H, 5.73; N, 12.25. Found C, 52.56; H, 5.65; N, 12.27.

EXAMPLE 3 CHLORHYDRATE OF 4-f r3-BR0M0TTEN-2-ILLMETILl-lH-IMTDA70L STEP A ?2 To a solution of 24.2 g, 0.10 mol, of 2,3-bromothiophene in 200 ml of anhydrous diethyl ether, cooled to -78 ° C, was added a solution of 66 ml, 1.6 moles, of n-BuLi in hexanes. When the addition was complete, the solution was stirred for 30 minutes. Then a solution cooled to -78 ° C of 18.3 g, 0.25 mol, of DMF in 50 ml of anhydrous ether was added by means of cannulation to the thiophene mixture. When the addition was complete, the reaction mixture was allowed to warm to room temperature and then allowed to stir overnight. The reaction was quenched with water and the mixture was transferred to a separatory funnel and the aqueous layer was extracted with ether. The organic layers were combined, washed with water and brine, dried over magnesium sulfate and concentrated to give an oil. Distillation through a Vigreux column produced 3-bromothiophen-2-carboxyaldehyde, &, as a yellow oil, bp 108-109 ° C. NMR with ^ H in DMS0-d¿ confirmed the assigned structure.

STEP B fia To a solution of 10.9 g, 0.025 mol, of 4-iodo-l-t-rityl-imidazole in 75 ml of dry dichloromethane, under nitrogen, a solution of 8.5 ml, 3.0 mol, of ethylmagnesium bromide in diethyl ether was added dropwise. After 1 hour another 1.5 ml of Grignard reagent was added to complete the exchange. The reaction mixture was stirred for 1 hour at 25 ° C. TLC analysis indicated that the starting material had disappeared, so 4.8 g, 0.025 mol, 3-bromothiophen-2-carboxyaldehyde, Q3., Was added as a solution in dry dichloromethane. After stirring overnight at room temperature, the reaction is quenched with saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. The residue was recrystallized from acetone to give 8.4 g of (3-bromothien-2-yl) -l-trityl-imidazol-4-yl-methanol, B3., As a crude colored solid. A second crop was collected which was recrystallized twice from ethyl acetate to give 0.4 g more of product. NMR with ^ H in CDCI3 confirmed the assigned structure.

STEP C Q 3.

A solution of 90 ml, 1.0 mol, of BH3-THF in THF was added dropwise over 2.5 hours to a solution of 18.2 g, 0.16 mol of TFA in 25 ml of dry dichloromethane, maintained at 10 ° C for the addition. When the addition was complete, the reaction mixture was stirred for 15 minutes. It was then added in a 2.0 g solution, 0.040 mol, of carbinol E3., In dry dichloromethane, in one portion and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water and then 20 ml of 3N HCl was added. Most of the THF was evaporated in vacuo and then the mixture was made basic with solid sodium carbonate. This solution was extracted twice with ethyl acetate. The organic extracts were combined, washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in 100 ml of methanol and 25 ml of 3N HCl was added, and the mixture was allowed to reflux for 2.5 hours. The solution was allowed to cool overnight and then concentrated in vacuo to give an amber colored syrup. This material was dissolved in water and extracted twice with diethyl ether, then made basic and extracted with ethyl acetate. The filtrate was treated with ethereal HCl solution and the resulting precipitate was collected as a white solid. This material was recrystallized with filtration through Dicalite in acetonitrile, with the addition of a little methanol. A second recrystallization was carried out to give 0.49 g of 4 - [(3-bromothien-2-yl) methyl] -lH-imidazole hydrochloride, Cp-3. as a white solid, mp 211.5-213.5 ° C. The NMR with 1H in DMS0-d¿ confirmed the assigned structure; .._ 4.25 (s, 2H), 7.10 (d, 1H), 7.45 (s, 1H), 7.60 (d, 1H), 9.00 (s, 2H). Elemental analysis: calculated for C8H7BrN S-HCl: C, 34.37; H, 2.88; N, 10.02. Found C, 34.35; H, 2.86; N, 10.07.

CHLORHYDRATE OF? -T __- (3-BROMOTIEN-2-IL ^ -ETILl-lH-TMIDAZQL STEP A To a solution of 17.3 g, 0.00345 mol, of (3-bromothien-2-yl) -l-t-ritylimidazol-4-yl-methanol, B3., In 300 ml of dichloromethane, 17.2 g of Mn0 was added. The TLC analysis indicated that the release material had disappeared after 2 hours . The reaction mixture was filtered and the filtrate was concentrated to give 4- (3-bromothiophen-2-yl) -l-trityl-imidazol-4-yl-methanone, which was used directly in the next step. .

STEP B A solution of 2.0 ml, 3.0 moles, of methylmagnesium bromide in diethyl ether was added to a solution of 2.0 g, 0.0045 mol, of 4- (3-bromothien-2-yl) -lt-rityl-imidazol-4-yl- methanone, ___., in 40 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride solution and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated to give a light yellow solid. The residue was recrystallized to give 1.75 g (84%) of l - [(3-bromothien-2-yl) -l-trityl-imidazol-4-yl] -ethanol, e.g., as a white solid. NMR with ^ H in CDCI3 confirmed the assigned structure.

STEP C A solution of 413 ml, 1.0 mol, of BH3-Me S in dichloromethane, was added dropwise, over 2.5 hours, to a solution of 62.8 g, 0.65 mol, of TFA in 200 rnl of dry dichloromethane, maintained at 0 ° C. during. When the addition was complete, the mixture was stirred for another 2 hours, then a 7.1 g solution, 0.014 mol, of l - [(3-bromothien-2-yl) -l-trityl-imidazole- was added in one portion. 4-yl] ethanol, ___., In dry dichloromethane and the reaction mixture was warmed to room temperature overnight. The reaction was quenched by the addition of 250 ml of MeOH / 3N HCl (4: 1) and the mixture was allowed to reflux for 2 hours. After cooling to room temperature, most of the MeOH was evaporated in vacuo and the mixture was diluted with water and washed twice with Et 0. The aqueous layer was made basic with sodium carbonate and extracted with EtOAc. The extracts were combined dried over potassium carbonate and filtered. The solvent was evaporated in vacuo to give a light yellow syrup which was purified on flash silica gel with 98: 1: 1 EtOAc / MeOH / NH4.0H to give 3.2 g of the free base which was converted to its hydrochloride salt. This material was recrystallized from acetonitrile to yield 2.6 g of the desired product, Cp-4. as a light yellow solid. mp 184-188 ° C. The NMR with! H in DMS0-d¿ confirmed the assigned structure; "" 1.65 (d, J = 7.1 Hz, 3H, Me), 4.60 (c, 1H, CH), 7.10 (d, J = 5.3 Hz, 1H), 7.60 (s, 1H), 7.68 (d, 1H) , 9.10 (s, 1H), 14.50 (s, broad, 1H). Elemental analysis: calculated for C9H9BrN2S-HCl: C, 36.82; H, 3.43; N, 9.54. Found C, 36.98; H, 3.29; N, 9.62.

EXAMPLE 5 FUMARATE OF -t (3,4-DIMETTLTIEN-2-IL-> METIL1-lH-TMIDAZOL ?5 To a solution of 12.36 g, 0.0671 mol, of ethyl 3,4-dimethylthiophen-2-carboxylate (Wynberg, H., S anenburg, DJ, J. Ora, Chem-- 1964, 29, 1919; Chadwick, DJ, Chambers, J .; Meakins, GD; Sno den, RL, J. Chem. S .. Perkin Trans. __, 1972, 2079) in 15 ml of ethanol and 5 ml of water, 5.64 g, 0.1 mol, of potassium hydroxide was added. The solution was stirred in a steam bath until the reaction mixture became homogeneous. The reaction was heated for 1.5 hours, cooled and acidified with 6N HCl. The suspension was filtered to give . 97 g (quantitative yield) of 3,4-dimethylthiophen-2-carboxylate, ____, which was taken directly to the next step. STEP B To a solution of 21.3 g, "0.070 mol, of 3,4-dimethylthiophen-2-carboxylic acid, thionyl chloride was added, the reaction mixture was allowed to reflux overnight and then allowed to cool. In a separate flask, a solution of 8.7 g, 0.089 mol of N, 0-dimethylhydroxylamine hydrochloride and 10.1 g, 0.1 mol of triethylamine in 100 ml of chloroform was added to the solution 3,4-dimethylthiophen-2-carboxylic acid. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured into a separatory funnel and washed with dilute aqueous hydrochloric acid, with water, with dilute sodium hydroxide and then with water. The organic layer was dried over magnesium sulfate and concentrated. By means of TLC some 3,4-thiophene-2-carboxylic acid was present, so the product was dissolved in diethyl ether and this solution was washed with 3N NaOH, with water and with brine, and then dried over magnesium sulfate and He concentrated. The crude product was distilled under vacuum to give 6.4 g (52%) of N, 0-dimethyl-3,4-dimethylthiophen-2-ca rboxamide E =., As a clear liquid, bp 85-86 ° C ( 0.1 mm Hg). NMR with 1H in CDCI3 confi rmed the assigned structure.

STEP C To a solution of 10.5 g, 0.024 mol, of 4-iodo-l-trityl-imidazole in 100 ml of dry dichloromethane, under nitrogen, was added dropwise a solution of 8.0 ml, 3.0 moles, of ethylmagnesium bromide in diethyl ether . When the addition was complete, the reaction mixture was stirred for 1 hour at 25 ° C. The TLC analysis indicated that the starting material had disappeared, so that 4.78 g, 0.024 mol, of N, 0-dimethyl-3,4-dimethylthiophen-2-carboxyamide, BU, was added as a solution in dichloromethane. After stirring overnight at room temperature, the reaction is quenched with saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated. Diethyl ether was added to the residue and the solution was cooled in ice. A white solid was obtained from the solution. Filtration yielded 8.2 g of the (3,4-dimethylthien-2-yl) -l-trityl-imidazol-4-yl-methanone, £ 5., As a white solid, NMR with ^ H in CDCI3 confirmed the structure assigned.

STEP D The solution was heated at reflux for 2 hours. 3. 4 g, 0.0075 mol, of (3,4-dimethylthien-2-yl) -l-trityl-imidazol-4-yl-methanone, < ___, in 50 ml of 2-propanol. After cooling, a 3N solution of hydrochloric acid was added to the reaction mixture, followed by a 10% aqueous solution of sodium carbonate. The mixture was concentrated under reduced pressure and the resulting solution was extracted twice with chloroform. The chloroform extracts were combined, dried over sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate with a small amount of chloroform to give a white solid. The mother liquor was concentrated to give a second crop of (3,4-dimethylthien-2-yl) -l-trityl-imidazol-4-yl-methanol,] ___, as desired. The NMR with 1H in CDCI3 confirmed the assigned structure.

STEP E Qsü A solution of (3,4-dimethylthien-2-yl) -l-trityl-imidazole-4-yl) solution was shaken with hydrogen at 4.2 kg / cm2 at 50 ° C in a Parr hydrogenator for 40 hours. methanol,] ___, in 50 ml of ethanol, containing 4.0 ml of normal hydrochloric acid and 1. 0 g of palladium hydroxide. The solution was cooled and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted twice with diethyl ether, then made basic with sodium carbonate. This solution was extracted twice with ethyl acetate. The organic layers were combined, dried over potassium carbonate and concentrated. The residue was dissolved in diethyl ether and ethereal hydrogen chloride was added. A precipitate formed which was collected by suction filtration and then crystallized from acetonitrile to give 0.21 g of 4 - [(3,4-dimethylthien-2-yl) methyl] -lH-imidazole hydrochloride, Cp-5. as a white solid, mp 180-182 ° C. NMR with ΔH in DMS0-d confirmed the assigned structure; "2.00 (s, 3H, Me), 2.20 (s, 3H, Me), 4.15 (s, 2H, CH2), 6.95 (S, 1H), 7-40 (s, 1H), 9.00 (s, 1H) , 14.42 (broad s, 2H). Elemental analysis: calculated for C? GH? N S-HCl: C, 52.51; H, 5.72; N, 12.25. Found C, 52.54; H, 5.79; N, 12.28.

EXAMPLE 6 FUMARATE OF 4-f (3,4-DIMETILTIEN-2-IL ^ ETIL ~ l-lH-IMTDAZQL STEP A To a solution of 2.0 g, 0.0045 mol, of (3,4-dimethylthien-2-yl) -l-trityl-imidazol-4-yl-methanone, < ___, in 20 ml of tetrahydrofuran, a 1.5 ml solution, 3.0 moles, of methylmagnesium bromide, The reaction mixture was stirred overnight at room temperature. The reaction was quenched with aqueous ammonium chloride solution and the resulting mixture was extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated. The residue was recrystallized to give 1.75 g (84%) of the desired carbinol, £ ___, as a white solid. NMR with ^ H in CDCI3 confirmed the assigned structure.

STEP B Q ___ £ A solution of the above carbinol M_ in 50 ml of ethanol, containing 3.9 ml of hydrochloric acid, was shaken with hydrogen at 4.2 kg / cm2 at 50 ° C in a Parr hydrogenator for 24 hours. normal and 0.9 g of palladium hydroxide. After cooling, the solution was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted twice with diethyl ether, then made basic with sodium carbonate. He extracted two times this solution with ethyl acetate. The organic layers were combined, dried over potassium carbonate and concentrated. The residue was absorbed on 5 g of a flash silica gel column, which was eluted with 97.5: 2.5 chloroform, 10% NH 4 OH in methanol. The fractions containing the product and were concentrated to give 0.46 g (59%) of the desired product as a free base. A solution of this material in 2-propanol was heated with 260 mg of fumaric acid. The solvent was evaporated and the residue was recrystallized from acetone to give 0.36 g of a white solid, Cp t mp 127-129 ° C. The NMR with ^ H in DMSO-d ^ confirmed the assigned structure; "1.65 (d, J = 7.1 Hz, 3H, Me), 2.00 (s, 3H, Me), 2.10 (s, 3H, Me), 4.37 (c, 1H, CH), 6.65 (s, 2H, fumaric acid) ), 6.77 (s, 1H), 6.87 (s, 1H), 7.55 (s, 1H). Elemental analysis: calculated for C11H14N2S "C4H404: c» 55.89; H, 5.63; N, 8.69, Found C, 55.99; H, 5.74; N, 8.38.

EXAMPLE 7 FUMARATE OF 4-f f 3.4-DTBR0M0TTEN-2-IL ^ METTLl-lH-TMIDAZ0L PASQ A ? Z A solution of 2.46 g, 0.0076 mol, 2, 3, 4-ribosulphiofen in 20 ml of tetrahydrofuran was cooled to -78 ° C, and then a solution cooled to -78 ° C was added by cannulation. 4. 75 ml, 2.5 moles, of n-butyl lithium. This solution was stirred for 20 minutes and then a solution of 4.4 g, 0.76 mol, l-trityl-imidazole-4-carboxyaldehyde in 100 ml of THF was added by cannula. When the addition was complete, the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with aqueous ammonium hydroxide and extracted with ethyl acetate to give a brown semi-solid. This material was chromatographed on flash silica gel using 1% methanol / chloro as an eluent. The fractions containing the impure product were combined and concentrated, and the residue was recrystallized from ethyl acetate. The recrystallization was not satisfactory so the collected solid and the mother liquor were combined and chromatographed on flash silica, as before. The fractions containing the crude product were concentrated and combined with the pure product obtained from the previous column. These products were combined and recrystallized from ethyl acetate to give the desired carbinol __J_, as a white solid which was carried directly into the next step.

STEP B A solution of 44 ml, 1.0 mol, of BH3-e2S in dichloromethane was added dropwise to a solution of 6.5 g, 0.152 mol, of TFA in 25 ml of dry dichloromethane at 0 ° C. When the addition was complete, the reaction mixture was stirred for 90 minutes. 0.84 g, 0.00144 mol, of carbinol __1_ was added in one portion and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 75 ml of 3N HCl, which was added cautiously at the beginning. The mixture was then allowed to reflux in a steam bath for 2 hours. The solution was cooled and concentrated in vacuo to give a brown oil. The residue was dissolved in water. This solution was washed twice with ether, made basic with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate and concentrated. The residue was dissolved in ether, filtered to remove a small amount of insolubles and treated with 1.0 equivalent of ethereal HCl. A white solid was collected which was recrystallized from acetonitrile with a small amount of methanol with filtration through Dicalite to give 0.35 g of fumarate of 4- [(3,4-dibromothien-2-yl) methyl 3-lH- imidazole, Cp-Z, as a white solid, mp 224-227 ° C. The NMR with XH in DMS0-o_, confirmed the assigned structure; "4.30 (s, 2H, CH), 7.50 (s, 1H), 7.90 (s, 1H), 9.05 (s, 1H). Elemental analysis: calculated for CgH6N S "HCl: C, 26.80; H, 1.97; N, 7.81, Found C, 26.86; H, 1.96; N, 7.79.

EXAMPLE 8 FUMARATE OF 4-f r3.4-DIBR0M0TIEN-2-IL ^ ETILl-lH STEP A? D A solution of 2.56 g, 0.0080 mol, 2, 3, 4 trib tribothiophene in 20 ml of diethyl ether was cooled to -78 ° C and then 5.0 ml, 1.6 mol, from a funnel was added slowly from an addition funnel. n-butyl lithium in hexanes. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then 0.88 g, 1.2 moles, of DMF was added in one portion. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small portions of water and with brine and dried over magnesium sulfate. The solution was filtered and concentrated and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes to give 1.1 g of 3,4-dibromothiophen-2-carboxyaldehyde as a white, off-white solid. The above sequence was repeated as before, except that n-butyllithium was cooled to -78 ° C and then added to the thiophene solution by cannulation. The reaction mixture was stirred for 2 hours before adding DMF. The reaction was worked up as before and the crude product was recrystallized from ether to give 0.9 g of product. A third preparation was also made. A solution of 4.8 g was cooled to -78 ° C., 0.015 mol, of 2,3,4-tribro otiofen in 20 ml of diethyl ether, and then 10.0 ml, 1.6 mol, of n-butyllithium was slowly added from an addition funnel. When the addition was complete, the reaction mixture was stirred for 15 minutes. Then 1.82 g, 0.025 mol, of DMF was added in one portion. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with two small reactions of water and then with brine and dried over magnesium sulfate. The solution was filtered and the residue was purified on flash silica gel with 2.5% diethyl ether-hexanes. The product was combined with the previous charges of 3,4-dibromothiophene-2-carboxyaldehyde and recrystallized from diethyl ether to give 3.7 g of 3,4-dibromothiophene-2-carboxyaldehyde, [, whose NMR in CDCI3 confirmed the structure of the desired product.

STEP B fifi To a solution of 5.8 g, 0.0133 mol, of 4-iodo-l-trityl imidazole in 75 ml of dry dichloromethane under nitrogen, a 4.4 ml, 3.0 mol solution of ethyl agnesium bromide in diethyl ether was added dropwise. When the addition was complete, the reaction mixture was stirred for 45 minutes at 25 ° C. The TLC analysis indicated that some of the starting material remained, so 1.0 ml more of the Grignard reagent was added. After stirring for 1 hour the TLC analysis indicated that the starting material had disappeared and 3.6 g, 0.0133 mol, of 3,4-dibromothiophen-2-carboxyaldehyde, was added. { ___, co or a solution in dichloromethane. After stirring overnight at room temperature, the reaction mixture is quenched with saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated to give a white, off-white solid. This material was recrystallized from ethyl acetate and a small amount of chloroform was added in solution. Filtration afforded 5.3 g (69%) of 4- (3,4-dibromothien-2-yl) methanol-l-trityl-imidazole, BS., As a white solid. 1 H NMR in CDCl 3 confirmed the structure of the desired product.

STEP C QS To a solution of 3.5 g, 0.0006 mol, of carbinol in 100 ml of dichloromethane, 2.0 g, 0.0230 mol, of Mn0 was added. TLC analysis indicated that the starting material had disappeared after 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give (3,4-dibromothien-2-yl) -l-trityl-imidazol-4-yl-methanone &, which was used directly in the next step. STEP D YOU. A solution of 0.55 ml, 3.0 moles, of methylmagnesium bromide in diethyl ether was added to an ice-cooled solution of 0.88 g, 0.0015 mol, of (3,4-dibromothien-2-yl) -l-trityl-imidazole- 4-yl-methanone S, in 20 ml of THF. After stirring for 30 minutes, the reaction was quenched with aqueous ammonium chloride solution and the resulting reaction mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed with water and with brine, dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from diethyl ether to give the carbinol SO, as an ante-colored solid, which was used directly in the next step.

PftSQ E A solution of 30 ml, 1.0 mol, of BH3"Me S in dichloromethane, was added dropwise to a solution of 4.56 g, 0.040 mol of TFA in 20 ml of dry dichloromethane at 0 [deg.] C. When the addition was complete, The reaction mixture was stirred for 60 minutes, 0.60 g, 0.0010 mol, of carbinol HQ was added .. After stirring for 2 hours, the reaction mixture was warmed to room temperature and stirred overnight. 50 ml of 4: 1 MeOH: 3N HCl, and the resulting mixture was refluxed for 2 hours.The solution was cooled and concentrated in vacuo.The residue was dissolved in water and washed with ether twice, it was made basic With sodium carbonate, it was extracted twice with ethyl acetate, the ethyl acetate extracts were combined, dried over potassium carbonate and concentrated, and the residue was purified three times on rapid silica gel with 99: 0.5: 0.5. of ethyl acetate: methanol: ammonia to give 100 mg of the free base, which is It was combined with 0.32 mg of fumaric acid in acetone-ethanol. This solution was concentrated in vacuo and the residue was triturated with ether. Filtration yielded 0.066 g of 4 - [(3,4-dibromothien-2-yl) ethyl] -lH-imidazole fumarate, Cp-8. as a white solid, mp 128-130 ° C. NMR with ^ H in DMS0-d¿ confirmed the assigned structure; "1.60 (d, 3H, Me), 4.42 (c, 1H, CH), 6.60 (s, 2H, fumaric acid), 7.02 (s, 1H), 7.60 (s, 1H), 7.75 (s, 1H). Elemental analysis: calculated for C9HgBr S-0 ^ 0: C, 34.54; H, 2.68; N, 6.20. Found C, 35.08; H, 2.74; N, 6.20.

EXAMPLE 9 CHLORHYDRATE OF 4-rr¿-BR0M0TIEN-2-TL METTILl-lH-IMIDAZ0L STEP A ? S To a solution of 4.36 g, O.OIO mol, of 4-iodo-l-trityl-imidazole in 20 ml of dry dichloromethane, under nitrogen, was added dropwise a solution of 3.5 ml, 3.0 moles, of ethylmagnesium bromide in THF When the addition was complete, the reaction mixture was stirred for 45 minutes at 25 ° C. TLC analysis indicated that the starting material had disappeared, so that 1.9 g, 0.010 mol, of 4-bromothiophen-2-carboxyaldehyde was added as a solution in dichloromethane. After stirring overnight at room temperature, the reaction is quenched with saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted again with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated to give a white, off-white solid. This material was triturated with diethyl ether. Filtration yielded 4, (4-bromothien-2-yl) methanol-1-trityl-imidazole Q2., As a white solid. The NMR with 1H in CDCI3 confirmed the assigned structure.

STEP B Q? _3.

A 50 ml solution, 1.0 mol, of BH3"Me S in dichloromethane, was added dropwise to a solution of 9.1 g, 0.080 mol of TFA in 25 ml of dry dichloromethane at 0 ° C. When the addition was complete, The reaction mixture was stirred for 60 minutes.Add 1.0 g, 2.0 mmol, of carbinol ___., after stirring, the reaction mixture was heated at room temperature for one hour, the reaction was quenched with MeOH, followed by addition of 20 ml of 3N HCl The solution was made basic with sodium carbonate and extracted twice with dichloromethane, the organic layers were combined, dried over sodium sulfate, filtered and concentrated, the residue was triturated with ether. treated the ethereal extracts with charcoal, filtered through Dicalite and treated with Et 0: HCl to give a white solid which was recrystallized from MeOH: MeCN to give the title compound, CP-9 .pf ~ 186-186- 5 ° C. The NMR with 1 in DMS0-d¿ confirmed the assigned structure; "4.30 (s 2H), 7. 53 (s, 1H), 7.58 (s, 1H), 9.05 (s, 1H), 14.75 (s broad, 1H). Elemental analysis: calculated for CgHgBrN ^ -HCl: C, 34.37; H, 2.88; N, 10.02. Found C, 34.88; H, 2.75; N, 9.93.

Claims (2)

NOVELTY DF THE INVENTION CLAIMS

1. - A compound of the formula: wherein R is hydrogen or methyl, X is hydrogen, alkyl of 1 to 4 carbon atoms, bromine or chlorine; and Y is hydrogen, alkyl of 1 to 4 carbon atoms, bromine or chlorine; provided that X and Y are not simultaneously both hydrogen.

2. The compound in accordance with the claim 1, further characterized in that it is selected from the group consisting of: -