PH26027A - A process for preparing (aryl or heteroaromatic methyl)-2,2'-bi-1H-imidazoles - Google Patents

Description

A PROCESS FOR PREPARING ARYL OR HETERO-

AROMATIC METHYL)=2,2'~Bl~1H-IMIDAZOLES

This invention relates to novel {aryl or hetero- aromatic methyl)-2,2'-bi-lH-imidazoles, to a process for their production, to pharmaceutical compositions of said compounda, and to methods of treating hypertension with such compounds,

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

N

~~ N

B ‘H fe (1) X wherein X is 2- or 3-thienyl, 2- or 3-furyl, 2- or 4 thiasolyl or phenyl with each of said groups optionally being substituted; the optional subatitution on said thienyl, furyl or thiaszolyl groups being 1 or 2 moieties selected from the group 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 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 s of from 1 to 6 carbon atoms; : the therapsutically scceptable 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,=C¢ lower alkyl!" means a straight or branched-chain alkyl group containing from one to six carbon atoms, and includes methyl, ethyl, propyl, butyl, 18 pentyl and hexyl groups. The term "C,=C¢ alkoxy" refers to an -OR' group where R' is GC -C¢ lower alkyl as above.

When X is a mono-substituted group, the substituent oan be located at any of the available positions on the aro- matic or heteroaromatic ring. When X is a disubstituted group, the substituents can be the same or they can be different and they can be located at any of the available positions on the ring and oriented in any manner with } respect to each other, Preferably, X is an unsubstituted group or is a monosubstituted group. Preferred substituents 2% include chloro, fluoro and methoxy. The X-CH,~ moiety can - 3 a :

located at either the 1- or U- position of the imidasole ring and both positions are encompassed by the present invention,

Illustrative examples of compounds of this invention includes 1=(3-thienylmethyl~2,2'=bi-1H-imidazole 4-/Th-methoxyphenyl)methyl/-2,2'-bi-1H-imidasole be(3-thienylmethyl)=2,2'-bi-1H-imidaszole 1-(2-thienylmethyl)-2,2'<bi-1H-inidazole 1-(2-furylmethyl)=2,2'~bi-1H-inidazole b-(3-furylmethyl)=2,2'~bi-1H-imidasole l-(2-thiazolylmethyl)-2,2'-bi~1H-imidasole bo(4=thiasolylmethyl)=-2,2'-bi-1H-imidasole 4 /(3-5-dichlorophenyl)methyl/-2,2'~bi-1H-imidasole 1-(2,fluoro=%-thienylmethyl)=2,2'-bi-1H-imidasole ho(2-fluoro-t-thisenylmethyl)=2,2%=bi-1H-inidasole 4~(3~chloro-%-thienylmethyl)=2,2'~bi-1H-inidasole 4e(3-chloro-%-furylmethyl)-2,2'-bi-1H~imidasole 1-(2-methoxy=l-thisnylmethyl)-2,2'~bi-1H-imidasole : 20 4u(2-methoxy=5-furylmethyl)-2,2'-bi-1H-imidazole h=(b-chloro-2-thiazolylmethyl)-2,2'~bi-1H-4inidasole and the therapeutically acceptable acid addition salts thereof, oh a Representative salts are those salts formed with non-toxic organic or inorganic acids, such as, for example, those formed from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitrio, maleic, fumaric, benzoic, ascorbic, sucdinic, methanesul- fonic, ascetic, propionic, tartaric, citric, lactic, malic, mandelio, cinnamic, palmitic, itaconioc, bensenesulfonic and toluenesulfonic, ~ The biimidazoles of this invention can readily de prepared by the reaction depicted in reaction Scheme I:

REACTION SCHEME I

N

N N SL pa ~~ \ / NN base; st0ll; reflux \ /4 r——

XaCH, «By or Xe-CH_ =C1 i

N N— 2 2 ~~ vx : CH >: H H H 2 11

I X

11 : §

Sb : wherein X is as defined above, “5 a

In essence, Reaction Scheme I illustrates that the biimidazoles of formula I can be prepared by reacting the appropriate ot bromo or chloro compounds (III) with 2,2'~bi-1H-imidazole (II) in a solvent such as ethanol (EtOH) and in the presence of a base such as sodium hydro- xide (NaOH) under reflux conditions. The biimidasole starting aaterial (11) oan be obtained by a method of

Matthews, D.P., Whitten, J.P., and McCarthy, J.R., set forth in Synthesis, 4, 336, (1986).

When the desired product contains X as amino substituted phenyl, (III) would include Ahe amino group protected by a silyl protecting group or protected as a : phthalimide, and the resulting silylated compound or bi- imidasole-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 Resction

Scheme I.

The process described above can also be used for the . novel synthesis of known imidazole compounds wherein a readily available 2-substituted imidasole (IV) (wherein Y can be alkyl, aryl or trialkylsiyl, with the alkyl groups

\ . being straight- or branched-chain and containing up to ten carbon atoms, and the aryl groups being phenyl or naphthyl optionally substituted with groups such as alkyl of from 1 to 6 carbon atoms, halo, or alkoxy of from 1 to 6 carbon atoms) is reacted with the appropriate of 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 1l- and b= and 4,%5-big- (X- : 10 sethyl)-1H-imidasoles (V) which can be separated by flash chromatography. This reaction is depicted in Reaction

Scheme II.

REACTION SCHEME II

A b EtOH3rafl N ase; EtOH raflux \ \ i > > (XaCH } / ¥

X-CH,-Br or X-CH_«C1 2'n 2 2 N

H H

111 v (1V) (111) (vX

I. . wherein X and Y are as defined above and n is 1 or 2 sad

: Example 6 isa 11lustrative of Reaction Scheme II.

The following examples are present to illustrate the present invention, but: they should not be constructed as limiting it in any way. 3 EXAMPLE 1 : 4={Tl-Methoxyphenyl) methy17-2,2"-bi-1H-iuidasole (1) and 1-/T4-Methoxyphenyl)methyl/-2,2'-bi-1H-imidazole (2) 2,2'-1H-Biimidazole was prppared by the method of

Matthews, D.P., Whitten, J.P., McArthy, J.R., ida . 10° Synthesis, 4, 336 (1986). A mixture of 10 g (0.75 nol) biimidazole, 17 ml 5 N sodium hydroxide, and 150 ml ethanol was refluxed for ona hour, After the mixture was cooled to room temperature, 8.6 g (0.055 mol) L- methoxybenzyl chloride was added and the reaction was refluxed for 24 hours, The mixture was cooled to room . temperature and was filtered to remove any unreacted 2,2'- biimidazole solid. The filtrate waa concentrated under reduced pressure to yield 14.7 g crude (1) and (2).

Purification by flash chromatography (35% acetone/CH,CR, then 50% acetone) yielded 3.0 g (31%)(1) and 2.0 g (20%) 2). © (1)1 mp 204-205%C (8, 2), 6.77-7.26 (m, 7)§ M8 EI at 70eV (8, 3)y 5.85 (8, 2), 6.70e7.43 (m, 8) MS (EI at 70e V)2s4(45) (M*), 147(100), 121(81). Anal. Calcd. for

Cyl N 0s Co 66.133 H, 5.55§ N, 22.03. Found: c, 66.03

H, 5.65; N, 21.73. _8-

(2)s mp 138-140 ( toluene/hexane) ; 1 NMR (DMSO-d) 3.7% (s, 3), 5.85% (=, 2), 6.71=7.43 (m, 8) MS (EX at 70e Vv) ’ n/3 254(6) (M*), 147(3), 121(100),

EXAMPLE 2 3 he(Phenylmethyl)=2,2'~bi=1H-inidazole (3) and 1- (Phenylmethyl)-2,2'-~bi-1H-imidasole (4) . The procedure described in Example 1 was followed, substituting benzyl bromide for the 4L-methoxybensyl chloride used in Example 1, to produce 16% (3), 23% (4) and 17% 1,1'dialkylated biimidagole. . (3)s mp 208-210%C (isopropanol); 1y (DMBO-d,) 3.9% (so, 2), 6.81-7.34 (=, 8)y M3 (EI at 70 eV) n/s 224 (30) (¥") 147(100), 91(33), ?77(44)., Anal, Caled for Cy 3H ay? C, 69.623 H, 5.39. Found: Cc, 69.673 H, 5.54, (5) mp 138-140°C (toluene/hexane); 'H NMR (DMSO-d¢) 5.81 (8, 2), 6.99=7.28 (m, 9); M8 (EI- at 70eV) n/s . 224(13) (M*), 147(40), 91(100), 77(9). Anal. Caled for

Cy ti aly Cc, 69.62; H, 5.39. Found C, 70.003 H, 5.49. The dibensylated material had md 132-134°¢4 M8 (EI at 70 eV) u/s 314(81) (M*), 237(23), 223(60), 91(100).

EXAMPLE 3 1-(2-Furylmethyl)=2,2'=bi-1H-inidagole (5) and 4-(2- furylmethyl)-2,2'=bi-1H~imidasole (6) :

If the procedure of Example 1 is repeated using 2- bromomethylfuran rather than 4-methoxybenayl chloride of

Exemple 1, the products obtained are title compounds (3) and (6).

EXAMPLE 4 1-(2-THiagolylmethyl)-2,2'~bi~1li-imidazole (7) and be (2

Thiagolylmethyl)-2,2'-1i~-imidazole (8) : If the procedure of Example 1 is repeated using 2- : : bromomethylthiazole rather than -methoxybenzyl chloride of Example 1, the products obtained are title compounds (7) and 18).

Similarly, if an appropriate halo- or methyle : substituted (bromomethyl) thiazole is used in the above procedure, the corresponding halo- or methyl-subastituted thiazole product is obtained. : An alternate route for making a compound of this invention is presented in Example 5.

EXAMPLE 5 1-(2-Thienylmethyl)~2,2'~bi~1H-imidasole (9)

Under nitrogen, a adlution of 6.1 g (0.05 nol) be dimethylaminopyridine in 100 ml dimethyl formamide was cooled to 10°C ant 5.3 g (0.05 mol) oyanogen bromide was : added. The reaction was warmed to 20°C and a precipitate of cyanogen bromide~dimethydaminopyridine complex formed,

Upon cooling to 10°C, 3.3g (0.02 mol) 1-(2-thienyl-

methyl)«lH-i{midasole (which may be produced in a manner set forth in German patent application 3,228,266, 29 July 1982) was added. The reaction was stirred at room tempergture for 6 hours and then quenched 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 l-(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 vas stirred at room temperature under nitrogen for 1% 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 recrystallized (isopropanol) to yield 4',5'-dihydro-l-(2-thienylmethyl)- 2,2'~bi-1H-imidazole b (mp 101-103°C; Anal. Caled 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 manganese oxide, and 200 ml dry dichloromethane was stirred at room temperatures for 13 days. The reaction was filtered hot and the solids washed again with hot dichloromethane. Concentration under 25% reduced pressure yielded 4.0 g crude (9). Purification by flash chromatography (ethyl acetate) resulted in 1.26 g (42%) of the title product (9). mp 153-155°C; Anal Caled for Cy H oN 88 Co 57.373 Hy 4.383 Ny 24.3%; Found: C, 37.25; H, 4.4%) N, 24.30.

EXAMPLE 6 2-Phenyl-b=(3-thienylmethyl)-1ii-inidasole (10), 2-Phenyl= lt 5=bis=(3-thienylaethyl)~1H-iaidasole (11) and 2-phenyl- 1-(3-thienylmethyl)=1i=inidasole (12).

A mixture of 7.2 g (0.0% mol) 2-phenylimidazole, 12 ml 5M NaOH, and 100 ml ethanol was refluxed for 1 hour.

After cooling to room temperature, 7.1 g (0.0h mol) 3- thienylmethyl bromide was added and the resotion was again heated to reflux, After 24 hours, the reaction was cooled and concentrated to give 23 g brown residue. The products were separated 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-phenylimidaszole. (10): mp 166-168°C3 IR (XBr) 3100 oat brs y NMR (DMSO oo dg) 3.90 (8, 2), 6.85-7.96 (my, 9), 12.37 (br 8s, 1)3 MS (EX at 70 oF) m/z 240(100) (M'), 157(9), 136(62), 97(8). Anal.

Caled for Cp,H,,N,85 Co 69.973 H, 5.033 N, 11.66. Found c, 69.83; H, 5.13; N, 11.58. (11): mp 163-165°C; IR (KBr) 3100 on! bry YH NMR (DMSO- dg) 3.88 (8s, 4), 6.93-7.98 (m, 0), 12.20 (br 8, 1)§ M3 (EI at 70 aV) m/s 336 (870.7), 239(50), 97(100). Anal.

Calod for Gyg) N,8, 6, 67.82; H, b.79; X, 8.32, TYounds C, 67.60; H, 4.83; N, 8.35. (12): 1H NMR (DMSO-d) 5.42 (s, 2), 6.95-7.0 (m, 10); MS (EI at 70 eV) w/z 280(53) (M.%), 157(1), 136(2), 97(100).

The compounds of this invention inhibit the ensyme dopamine p-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 . norepinephrine (NE), the presence of an inhibitor should decrease the amount of NE produced, and thereby have an antihypertensive effect, 18 ~ 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 ensymatic activity was - ascertained in aqueous solution in the presence of molecular oxygen, an electron donor such as ascorbate, a a substrate such as tyramine, an inhibitor, and the necessary cofactors for the enzyme at a pil of 4.5 to 5.5, : preferably pH 5.0, and at a temperature of 20°C to 4°c, preferably 37°%c. The inhibitor was assayed over a range 29 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., Jo Biole

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

TABLE I

DBH INHIBITORY ACTIVITY

Compound ICsod : 1-(3-thienylmethyl)- 29.0 pM +/~6.0pM 2,2'=-bi-1H-imidazole

Yu(3-thienylmethyl)= 8.8 pM +/=1.8pM 2,2'=bi-~1H-imidazole 1-(2-thienylmethyl) 65.5 pM +/=ho3pM 2,2'«bi-1H-imidazole *Concentration at which the reaction is inhibited by 50%. : Thus, based on this and ddther 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 dosage of the compounds of this invention can readily be oo determined. In general, effective antihypertensive

: 2060p, : results can be achieved at a dose of about $ to about 100 mg per kilogram body weight per day. Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the hypertension as determined by the attending diagnostician,

In their funotion as therapeutically useful compounds, it is advantageous to administer the compounds to the host animal in admixture with an acceptable and suitable : 10 pharmaceutical carrier. Such preparations may be in such forms as, for example, tablets, caplets and suppositories, or in liquid forms, as for example, elixirs, emulsions, sprays and injectables. In the formulation of phagmaceutical preparations, such subatances can be employed which do not react with active substances as, for ’ .- example, water, gelatin, lactose, starches, magnesium sterate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and the like,

Claims (1)

CLAIMS: 26 0 9 pot :

1. A process for preparing compounds of the formula P (X-CH —IF Ny 2 n ~y - ) wherein X is 2- or 3-thienyl, 2- or 3-furyl, 2- or he thiszolyl 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 selected from the group consisting of chlero, fluoro, ‘ promo 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 alkyl of from 1 to 6 carbon atoms, " alkoxy of from 1 to 6 carbon atoms, trifluoromethyl, amino, sulfhydryl; and S(O) R wherein m is 0, Y or 2 and R is lower alkyl of from 1 to 6 carbon atoms and n is 1 or 2; and wherein Y ie alkyl, aryl, or trialkylailyl, the _ alkyl groups being atraight- or branched-chain and : containing one to ten carbon atoms, and the aryl groups being phenyl or naphthyl, optionally substituted with from 1 to 3 substituents selected from the group containing alkyl of from 1 to 6 carbon atoms, chloro, bromo, fluoro

\

: . \ 26027 and alkoxy of from 1 to 6 carbon atoms, which comprises readting a 2-substituted imidasole of the formula N C NY N } H with an appropriate debrominated or d-chlorinated : 5 methylated, substituted or non-substituted, monocaromatio ring of the formula X=-CH,=Br, or X=~CHg~C1 wherein X is defined above, in ethanol in the presence of sodium hydroxide under reflux conditions. \ i! DONALD P. MATTHEWS ~ JEFFREY P. WHITTEN JAMES R. Mo@ARTHY : Inventors