PH26028A - A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles - Google Patents

Description

A PROCESS FOR PREPARING (ARYL OR :

HETEROAROMATIC METHYL)-2,2'-BI-1H- :

IMIDAZOLES

This invention relates to novel (aryl or heteroaromatic methyl)-2,2'~-bi-1H-imidazoles, to a process for their production, to pharmaceutical com-

Co positions of said compounds, and to methods of treat- ing hypertension with such compounds.

More specifically, this invention relates to methylated 2,2'~bi-1H-imidasoles of the general formula

N N

~~

N\ / v N

CH, (1)

X wherein X is 2~ or 3-thienyl, 2- or 3-furyl, 2- or b= thiasolyl or phenyl with each of said groups optionally being substituted; the optional substitution on said thienyl, furyl or thiasolyl groups being 1 or 2 moieties selected from the group -2 a.

consisting of chloro, fluoro, bromo and lower alkyl of from 1 to 6 carbon atoms; the optional substitution on said phenyl group being 1 or 2 moieties selected from the group consisting of chloro, bromo, fluoro, lower 9 alkyl of from 1 to 6 carben atoms, alkoxy of from 1 to 6 carbon atoms, trifluoromethyl, amino, sulfhydryl, and 8(0) _R wherein m is O, or 2 and R is lower alkyl of from 1 to 6 carbon atoms; the therapeutically acceptable acid addition salts thereof, and a process for preparing these compounds.

The compounds of this invention are dopamine p hydroxylase inhibitors, and as such are useful as antihypertensive agents. This invention also relates to a process for preparing imidazole compounds,

The tera "C,~Ce lower alkyl" means a straight or branched-chain alkyl group containing from one to six carbon atoms, and includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups. The term "Cy =C¢ alkoxy" refers to an -OR' group where R' is C,~Cg lower alkyl as above. 20: When X is a mono-substituted group, the substituent can be located at any of the available positions on the aroma- tic or heteroaromatic ring. When X is a disubstituted group, the substituents can be the same or they oan be - 3a a —— TTT 26028 different and they can be located at any of the avail- able positions on the ring and oriented in any manner with respect to each other. Preferably, X is an unsube- tituted group or is a monosubstituted group. Preferred 3 substituents include chloro, fluoro and methoxy. The :

X-CH,- moiety can be located at either the 1- or l= posi- tion of the imidazole ring and both positions are encom- passed by fhe present invention.

Illustrative examples of compounds of this invention include: 1-(3-thienylmethyl)-2,2'-bi-1H-imidazole h/T4-methoxyphenyl)methyl/-2,2'~bi-1H-1inidasole . 4=(3-thienylmethyl)-2,2'~bi-1H-imidasole 1-(2-thienylmethyl)-2,2'-bi=1H-imidasocle l-(2-furylmethyl)-2,2'=bi-1H-imidazole h-(3-furylmethyl)=2,2'=bi-1H-imidaxole 1-(2-thiazolylmethyl)-2,2'~bi~1H-imidazole . 4-(4=thiugolylmethyl)=2,2'~bi-1H-imidasole : 4-/U3-3-dichlorophenyl)methyl/-2,2'-bi-1H-inidasole 1-(2,fluoro-3-thienylmethyl)-2,2'~bi-1li-1inidazole h-(2-f1uoro-b=thienylmethyl)-2,2'~bi-1ii-imidagole b(3-chloro-5-thienylmethyl)~2,2'=bi-1H-4nidasole " he(3-ohloro-5%-furylmethyl)-2,2'-bi-1H-imidasole 1-(2-methoxy-li-thienylmethyl)-2,2'~bi-1li-imidasole 2s 4o(2-methoxy~5~furylmethyl)-2,2'=bi-1H-imidasole 4~(4~chloro-2-thiazolylmethyl)-2,2'-bi-1li-inidazole ll and the therapeutically acceptable acid addition salts thereof.

Representative salts are those salts formed with non-toxic organic or inorganic acids, such as, for example, 9 those formed from the following acids: hydrochloric, hydrobromio, sulfonic, sulfurio, phosphoric, nitria, maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic, benzenesulfonic and toluenesulfonic,

The biimidasoles of this invention can readily be prepared by the resction depicted in reaction Scheme I:

REACTION SCHEME I

N

CN N N NC

\ BassjEtOHjreflux ( / X-CH «Bp or X«CH A / J . : 2 2 N 8

H H 111 [he

I X

II vherein X is as defined above,

In easence, Reaction Scheme I illustrates that the biimidasoles of formula I can be prepared by reacting the appropriate d- bromo or chloro compounds (III) with 2,2'- bi-1H-imidazole (II) in a solvent such as ethanol (EtOH) 5S and in the presence of a base such as sodium hydroxide (NaOH) under reflux conditions. The biimidasole starting material (II) can be obtained by a method of Matthews,

D.P,y Whitten, J.P., and McCarthy, J.R., set forth in

Synthesis, 4, 336, (1986).

When the desired product contains X as amino ; substituted phenyl, (IXI) would include the smino group : protected by a silyl protecting group or protected as a phthalimide, and the resulting silylated compound or bi- inidagole~phthalimide would be appropriately deprotected to obtain the desired final product (I). Appropriate deprotecting agents for the silyl-protected compound would be, for example, ethanolic hydrochloric acid, or sodium fluoride. The phthalimide compound would be deprotected by means of hydrazine and alcohol,

Examples 1 through 5 are illustrations of Reaction . Scheme I.

The process described above can also be used for the novel synthesis of known imidazole compounds wherein a readily available 2-substituted imidazole (IV) (wherein Y 2% can be alkyl, aryl or trialkylsilyl, with the alkyl groups being straight- or branched-chain and containing up to - tent carbon atoms, and the aryl groups being phenyl or naphthyl optionally substituted with groups such as alkyl of from 1 to 6 oarbon atoms, halo, or alkoxy of from 1 to 6 carbon atoms) is reacted with the appropriate o- bromo, or chloro compound (III), wherein X is as defined above, in a solvent such as ethanol (EtOH) in the presence of a base such as sodium hydroxide under reflux conditions to readily yield a mixture of 1- and 4= and 4,5-bis- (X- methyl)-1H-imidasoles (V) which can be separated by flash chromatography. This reaction ie depicted in Reaction

Scheme II, :

REACTION SCHEME 11

N

\ ~ base;EtoH;reflux N

Y XeCBp-Br or Kehp.gy (X=CHp) Y ~CHo=Br or X.CHy-C1 2°n /

N

B H

(111) (V) : (1v) i wherein X and Y are as defined above and n is 1 or 2

Hd . -7 a

Examples 6 is f11lustrative of Reaction Scheme II.

The following examples are present to illustrate the present invention, but they should not be construed as limiting it in any way. | a

EXAMPLE 1 4o/Tb=Nethoxyphenyl)methyl7-2,2"-bi-1H-aidasole (1) and 1-/Us-Methoxyphenyl)methyl7=2,2"-bi-1H-inidasole (2) 2,2'-1H~Biimidazole was prepared by the pethod of

Matthews, D.P., Whitten, J.P. and McCarthy, J.R., in

Synthesis, 4, 336 (1986). A mixture of 10 g (0.75 mol) biimidasole, 17 m1 3 N sodium hydrokide, and 150 ml ethanol was refluxed for one hour. After the mixture was cooled to room temperature, 8.6 g (0.055 mol) be methoxybenzyl chloride was added and the reaction was refluxed for 24 hours. The mixture vas cooled to room : temperature and was filtered to remove any unreacted 2,2'~ biimidazole solid. The filtrate was concentrated under reduced pfessure to yield 14.7? g orude (1) and (2).

Purification by flash ohromatography (35% ace tone/CH, C1, then 50% acetone ) yielded 3.0 g (31%) (1) and 2.0 g (20%) (2). (1): mp 204-205 (1sopropanol) s 14 nmr (DMSO-d.) 3.71 (s, 3), 3.95 (8, 2), 6.77-7.26 (m, 7); HS BI at. 70EV 254(48) (M*), 147(100), 121(81). Anal. Caled. for

C,H N,08 Co 66.133 H, 5.55; N, 22.03. Founds C, 66.03;

H, 5.6%; N, 21.73. : (2): mp 138-140°C (toluene/hexane); 1H NMR (DMSO-d) 3.75 (8, 3), 5.85 (8, 2), 6.71-7.43 (m, 8)3 MS (EI at 70e V) s a/s 254(6) (n%), 147(3), 121(100).

EXAMPLE 2 4=(Phenylmethyl)=2,2'=bi-1H-imidasole (3) and 1~ (Phenylaethyl)=2,2'~-bi-1li~imidazole (4)

The procedure described in Example 1 was followed, substituting benzyl bromide for the 4-methoxybenzyl chloride used in Example 1, to produce 16% (3), 23% (4) and 17% 1,1'dialkylated biimidarzole. (3): mp 208-210°C (isopropanol); 14 NMR (DH8O-dg) 3.94 (ey 2), 6.81<7.34 (m, 8); MB (EI at 70 eV) m/z 224 (30) (M*) 147(100), 91(33), 77(48). Anal. Caled for C,4H, Ny: GC, : 69.62; He 5.39. Founds C, 69.673 H, 5.54, (4)s =p 138-140°C (toluene/hexane) 14 nur (DMBO-d) S.84 (8, 2), 6.99-7.28 (m, 9); MS (EI- at 70eV) m/s 224(13) (M*), 147(40), 91(100), 77(9). Anal. Caled for

Cy 3M? c, 69.62; H, 9.39. Found C, 70.003 H, 5.49. The dibenzylated material had md 132-134°C; MS (EI at 70 eV) m/s 314(41) (M%), 237(23), 223(60), 91(100),

EXAMPLE 3 lw(2-Furylmethyl)-2,2'=bi-1H-imidasole (5) and he(2- furylmethyl)=2,2'=bi-1li-isidasole (6)

If the procedure of Example 1 is repeated using 2-

S | bromomethylfuran rather than 4-methoxybenazyl chloride of

Example 1, the products obtained are title compounds (5) and (6).

EXAMPLE U4 1-(2-Thiazolylmethyl)-2,2'~-bi~1H-imidagole (7?) and 4-(2-

Thiasolylmethyl)=2,2'bi-1H-imidazole (8)

If the procedure of Example 1 is repeated using 2- bromomethylthiazole rather than 4-methoxybenzyl chloride © of Example 1, the products obtained are title compounds : (7) and (8).

Similarly, if an appropriate halo- or methyl substituted (bromomethyl) thiazole is used in the above procedure, the cofresponding halo- of methyl-substituted thiazole product is obtained,

An alternate route for making a compound of this : 20 invention is presented in Example 5.

EXAMPLE $ 1-(2-Thienylmethyl)=2,2'=bi~1H=imidasole (9)

Under nitrogen, a solution of 6.1 g (0,03 mol) he dimethylaminopyridine in 100 ml dimethyl formamide vas 23 cooled to 10°C and 5.3 g (0.05 mol) cyanogen bromide was :

added. The reaction was warmed to 20°C and a precipitate of cyanogen bromide-dimethylaminopyridine complex formed.

Upon cooling to 10°C. 3.3¢ (0.02 mol) 1-(2-thienyl- methyl)=lH=imidazole (which may be produced in a manner set forth in Gernan patent application 3,228,266, 29 July 1982) was added. The reaction was stirred at room temperature for 6 hours and then guenched with 600 ml dilute sodium carbonate, The product was washed with water, dried (sodium sulfate) and concentrated under reduced pressure to yield 3.7 g crude 1-(2-~thienylmethyl)- 1H-imidazole-2-carbonitrile a which was purified by flash chromatography (5% ethyl acetate/dichloromethane).

A mixture of 4.7 g (0.025 mol) a, 0.5 g sulfur, 20 ml methoxyethanol and 1.7 g (0.029 mol) ethylenediamine was stirred at room temperature under nitrogen for 15 minutes.

The reaction was then heated and maintained at 120°C for 6 " hours, after which it was cooled to room temperature,

After the addition, with stirring, of 300 ml water, 5.33 g (92%) off-white solid was collected and recrystallised (isopropanol) to yield 4% ,5'=dihydro-1-(2-thienyluethyl)~ 2,2'-bi-1H-imidasole b (mp 101-103°C; Anal. Calcd for: N, 24,123 Found: N, 24.20). : A mixture of 3.0 g (0.0129 mol) of b, 7.2 g (0.083 mol) activated manganess oxide, and 200 ml dry 2% dichloromethane was stirred at room temperature for 13

' 26028 . days. The reaction was filtered hot and the solids washed again with hot dichloromethane. Concentration under reduced pressurs yielded 4.0 g orude (9). Purification by flash chromatography (dthyl acetate) resulted in 1.26 g (b2%) of the title product (9). mp 153-155°C; Anal Caled for C,H, N81 C, 57.37; H, 4.384 Ny 24,33; Founds C, 57.25; H, b.45; N, 24.30.

EXAMPLE 6 oo | © 2-Phenyl-4-(3-thienylmethyl)-1H-inidagole (10), 2-Phenyl- 4,5-bis-(3-thienylmethyl)-1li~inidazole (11) and 2-phenyle 1-(3-thienylmethyl)-1H-imidazole (12).

A mixture of 7.2 g (0.05 mol) 2-phenylimidazole, 12 nl

SM NaOH, and 100 ml ethanol was refluxed for 1 hour.

After cooling to room temperature, 7.1 g (0.04 mol) 3- thienylmethyl bromide was added and the reaction vas again heated to reflux. After 24 hours, the reaction was cooled and concentrated to give 23 g brown residue. The products were sepapated by flash chromatography (10% acetone/CH,C1,) to yield 3.1 g (10), 2.6 g (11), 0.3 g (12) and also 3.0 g 2-phenylimidarole. : } (10): wp 166-168°c; IR (KBr) 3100 at br} 1 NMR (DM30- dg) 3.90 (8, 2), 6.85-7.96 (mw, 9), 12.37 (br a, 1)y HS (EX at 70 eV) m/s 240(100) (N'), 157(9), 136(62), 97(8). Anal.

Caled for C,H; ,N,3¢ Cc, 69.973 H, 5.033 N, 11.66. Found c, 69.831 H, 5.133 N, 11.58.

(11): mp 163-165°Cs IR (KBr) 3100 om br; YH NMR (DMSO- ds) 3.88 (a, 4), 6.93-7.98. (iy £315 12580 (br 8, 1); M8 (EX at 70 eV) w/z 336 (87) (M.*), 239(%0, 97(100). Anal.

Calcd for CygliygNa8, Co 67.821 H, 4.79; Wt; 8.32. Founds C, 67.60; H, 4.85; N, 8.35, (12)s lu NMR (DM30-dg) S.b2 (8, 2), 6.95-7.90 (m, 10); M3 (EI at 70 eV) m/z 240(53) (M.%), 157(1), 136(2), 97(100).

The compounds of this invention inhibit the enzyme depamine B-hydroxylase (DBH and therefore are useful in the treatment of hypertension. An embodiment of this invention is a method of treating hypertension in a mammal : which comprises administering to said mammal an effective antihypertensive amount of compound of formula I. Since

DBH is a major enzyme in the synthetic pathway of 1s norepinephrine (NE), the presence of an inhibitor should decrease the amount of NE produced, and thereby have gn antihypertensive effect,

The DBH inhibitory properties of the compounds of this - invention can readily be determined by standard and well- known procedures. For example, inhibition of DBH was determined by a procedure wherein enzymatic activity was ascertained in aqueous solution in the presence of molecular oxygen, an electron donor such as ascorbate, a substrate such as tyramine, an inhibitor, and the 2% necessary cofacgors for the enzyme at a pH of 4.5 to 5.5,

———————— roo ttt mmr | ee preferably pH 5.0, and at a temperature of 20% to 4o°c, preferably 37%. The inhibitor was assayed over a range of concentrations. Each reaction was followed by measuring oxygen uptake as an indication of encyme activity using a polarographic electrode and an oxygen : monitor, following the method of S. May, et al., J. Biol,

Chem., 256, 2258 (1981). The DBH inhibitory activity of ’ compounds of this invention is indicated in Table I.

TABLE I

DBH INHIBITORY ACTIVITY

Compound ICe0e l=(3-thienylmethyl)- 29.0 pM +/-6.0pM 2,2'=bi-lH=imidazole 4~(3-thienylmethyl)e 8.8 pM +/=1.8pM 2,2'-bi=1H-inidasole l-(2-thienylmethyl)=- 65.5 pM +/-4.3pN 2,2'=bj-1lH-imidazole *Concentration at which the reaction ia inhibited by 50%.

Thus, based on this and other standard laboratory techniques used to evaluate DBH inhibitors, by standard toxicity tests and pharmacological assays for the determination of antihypertensive activity in mammals, and by comparison of these results with the results of known antihypertensive agents, the effective antihypertensive - 1b -

P¢oog dosdge of the compounds of this invention can readily be determined. In general, effective antihypertensive results can be achieved at a dose of about 5 to about 100 mg per kilogram body weight per day. Of course, the specific initial and ccntinuing dosage regimen for each patient will vary according to the nature and severity of the hypertension as determined by the attending diagnostician,

In their function as therapsutically useful compounds, it is advantageous to administer the compounds to the host animal in admixture with an acceptable and suitabld pharsaceutical carrier. Such preparations may be in such : forms as, for example, tablets, ocaplets and suppositories, or in liquid forms, as for example, elixirs, emulsions, sprays and injectables. In the formulation of pharmaceutical preparations, such substances can be employed which do not react with active substances as, for example, water, gelatin, lactose, starches, nmagnesiun sterate, talo, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and the lile,

Claims (1)

1. 0265 CLAIMS . 26 © ‘ls A process for preparing a compound of the formula

   N N. oy N “Nea «X H 2 . wherein X is 2-~ or 3-thienyl, 2- or 3-furyl, 2- or L- thiaegolyl or phenyl, with each of said groups optionally . being substituted; the optional substitution on said thienyl, furyl or thiazolyl groups being 1 or 2 moieties selacted from the group consisting of chloro, fluoro, bromo sind lower alkyl of from 1 to 6 carbon atoms; the optional substitution on said phenyl group being 1 or 2 . moleties selected from the group consisting of chloro, bromo, fluoro, lower alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, trifluoromethyl, amino, sulfhydryl, and 8(0) R wherein m is O, 1 or 2 and R is lower alkyl of from 1 to 6 carbon atomsj which comprises reacting an appropriate d-brominated or d~ chlorinated methylated, subskituted or non-substituted,

   monoaromatic ring of the formula X-CH,~Br or X=-CH,-C1 wherein X is as defined above, with 2,2'-bi-1H~imidagole in ethanol and in the presence of sodium hydroxide under reflux conditions.

   DONALD P.

   MATTHEWS JEFFREY P., WHITTEN JAMES Re.

   McCARTHY Inventors p17 =