DOPAMINE-ss-HYDROXYLASE INHIBITORS

Abstract: Potent DBH inhibitors having formula (I) can be used to inhibit DBH activity in mammals.

Description: TITLE Dopamine-β-Hydroxylase Inhibitors FIELD OF THE INVENTION This invention relates to inhibitors of dopamine-β-hydroxylase. BACKGROUND OF THE INVENTION In the catecholamine biosynthetic pathway, • tyrosine is converted in three steps to norepinephrine (NE) . Intermediates are dihydroxyphenylalanine (DOPA) and dopamine (DA). The latter is hydroxylated. to norepinephrine by dopamine-β-hydroxylase (DBH) in the presence of oxygen and ascorbic acid. Inhibition of catecholamine activity has been found to decrease hypertension. See, for example, Matta et al. , Clin. Phar . Ther. 14, 541 (1973), and Teresawa et jil., Japan Circ. J. 35, 339 (1971). Weinshilboum, Mayo Clin. Proc. 55, 39 (1980) , reviews compounds which inhibit catecholamine activity by interfering with adrenergiσ receptors. Alternatively, the catecholamine biosynthetic pathway can be suppressed at any of the three steps, resulting in decreased levels of NE. In addition to decreasing hypertension, inhibitors of NE synthesis are active as diuretics, natriuretics, cardiotonics and vasodilator-?. Inhibition of DBH activity can have the added advantage of increasing levels of DA, which as reported by Ehrreich e_t ^1., "New Antihypertensive Drugs," Spectrum Publishing, 1976, pp. 409-432, has been found to have selective vasodilator activity at certain concentrations. DBH inhibitors have also been shown to reduce or prevent formation of gastric ulcers in rats by Hida a et al. , "Catecholamine and Stress," edit, by Usdin et al. , Permagon Press, Oxford, 1976, pp. 159-165 and by Osumi et al., Japan. J. Pharmacol. 23, 904 (1973). A number of DBH inhibitors are known. These are 0 generally divided into two classes, namely, metal chelating agents, which bind to copper in the enzyme, and phenethyla ine analogues. Rosenberg et a3.. , "Essays in Neurochemistry and Neuropharmacology, Vol. 4," edit, by Youdim et al.., John Wiley & Sons, 1980, pp. 179-192, and 5 Goldstein, Pharmacol. Rev. .18(1), 77 (1966), review DBH inhibitors. The former report that many of the potent DBH inhibitors have a hydrophobiσ side chain of size comparable to the aromatic ring of DA, leading the authors * to suggest that incorporation of a terminal hydcoxyl group 2 ^ on a 4- to 6- carbon side chain on a phenethylamine analogue might yield a potent inhibitor. Known inhibitors include: 5-alkylpicoliniσ acids [See, Suda et al., Chem. Pharπ Bull. 17, 2377 (1969) ; Umezawa e_t al., Biochem. 25 Pharmacol. 19, 35 (1969); Hidaka et al., Mol. Pharmacol. .9, 172 (1973) ; Miyano et al.., Chem. Phar . Bull. 26, 2328 (1978) ; Miyano et al., Heterocycles 14, 755 (1980) ; Claxton ej: al., Eur. J. Pharmacol. 37, 179 (1976)]; BRL 8242 [See, Claxton et al., Eur. J. Pharmacol. 30 31_, 179 (1976)] ; l-alkyl-2-mercaptoimidazole [See, Hanlon et al.. Life Sci. 12, 417 (1973); Fuller et al.. Adv. Enzym. Requl. 15, 267 (1976)]; • 35 substituted thioureas [See, Johnson e_t .al., J. Pharmacol. Exp. Ther. 168, 229 (1969)]; and benzyloxyamine and benzylhydrazine [See, Creveling e_t al_. , Biochim. Biophys. Acta 64, 125 (1962) ; Creveling et al., Biochim. Biophys. Res. Commun. .8, 215 (1962) ; van der Schoot et al., J. Pharmacol. Exp. Ther. 141, 74 (1963). Bloom, Ann. N. Y. Acad. Sci. 107, 878 (1963) ] . All of the above compounds except benzyloxyamine 1.0 and benzylhydrazine apparently owe their inhibitory effect to metal σhelating properties. Alkyl derivatives of 2-mercaρtoimidazole are more potent, presumably due to non-specific interaction of the alkyl substituent with the enzyme. Benzyloxyamine and benzylhydrazine are l- > phenethylamine derivatives which apparently act as competitive inhibitors. In addition to the above compounds, Runti e_t al. , • II Farmaco Ed. Sc. 36, 260 (1980) , report that other * fusaric cid derivatives and analogues inhibit DBH. ' These 2 ^ include phenypiσoliniσ acid, which is reported ' to have twice the inhibitory activity of fusaric acid, and 5-(4- chlorobutyl)piσolinic acid, and others such as substituted amides of fusaric acid and acids and amides of 5-butyroylpicolinic acid, 5-aminopiσolinic acid and ^ 5-hydrazinopiσolinic acid, and derivatives thereof. Hidaka et al.. Molecular Pharmacology, 9_ , 172-177 (1973) report that 5-(3,4-dibromo)butyl piσoliniσ acid and 5-(dimethyldithiocarbamoyl)methyl piσolinic acid are DBH inhibitors. 0 Bupicomide, 5-(n-butyl)picolinamide, is reported by Ehrreich e_t .al., "New Antihypertensive Drugs," Spectrum Publications, 1976, pg. 409-432, to be a DBH inhibitor and to have antihypertensive activity. 5 Friedman t al. Psychosomatic Med. 40, 107 (1978) , report that patients treated with alpha-methyl-DOPA, guanethidine and reserpine, but not propanolol and diuretics, have lowered DBH levels, although the significance of the observation is uncertain. Although there are many known inhibitors of DBH, most of these agents have not found clinical application because of non-specific, often toxic, properties they possess. Fusaric acid, for example, is hepatotoxiσ. See, for example, Teresawa et al., Japan. Cir. J. 35, 339 (1971) and references cited therein. Presumably, the picolinic acid structure interacts with a number of metalloproteins and enzymes in non-specific fashion to produce observed side effects. In U.K. specification 1,555,580 are disclosed compounds having the formula: 2 3 1 wherein R and R can be H and R can be substituted phenyl. The compounds are said to have analgesic, anti- inflammatory and antipyretic properties. Gebert et al., U.S. Patent 3,915,980, disclose such compounds wherein R can be phenyl or ρhen(C ]L _ 3 ) alkyl, as intermediates to imidazolyl-2-thioalkanoic acid esters. Iverson, Acta Chem. Scand. 21, 279 (1967) reports a compound having the formula: 10. herein R can be -C0 2 H or -CH-NCHgH-, but does not report a pharmaceutical use for the compound. In European Patent Application No. 125,033 (published November 14, 1984) a series of 1-phenyl and 1-phenylalkylimidazole compounds having a mercapto or 15 alkylthio group in the 2-position are disclosed. These compounds are described as having DBH inhibiting activity, United States Patent No. 4,532,331 describes various l-benzyl-2-aminom.ethylimidazole derivatives that inhibit DBH activity and includes pharmaceutical 20 compositions containing these derivatives and methods of using these derivatives to inhibit DBH activity. SUMMARY OF THE INVENTION The invention resides in the discovery that DBH is inhibited by a compound having a mercaptoimidazole 25 moiety and a phenethylamine analogue moiety. More particularly, the invention is selected novel compounds having the formula: SR 5 where in: X is -H, -OH, halogen, C, 4 alkyl, -CN,- 0 2 ,-S0 2 H 2 , -C0 2 H, - CONH-,, -CHO, -CH 2 OH, -CF 3 , C 1-4 alkoxy, " s0 c ι-4 al ^Y^ r -S0 2 C, . fluoroalkyl, ~ C0 2 τ-4 al <k l or an Y accessible combination thereof up to four substituents; Y is -H, -OH, C,_. alkoxy, halogen, C χ _ 4 alkyl, -CN,-N0 2 ,-S0 2 H 2 , -C0 2 H, -CO H 2 , -CHO, -CH 2 OH, -CF-, -S0 2 C 1 _ 4 alkyl, - s 0 2 C l-4 fluoroalkyl, or ~ C0 2 ι-4 al^Y 1 ? R is -H or C, 4 alkyl; and n is 0-4, or a hydrate or, when R is C, . alkyl, a pharmaceutically acceptable acid addition salt thereof, provided that when n is 0, Y is -OH and when n is 1-3, at least one of Y and X is not -H. As used herein, "accessible combination thereof" means any other stable combination of . substituents available by chemical synthesis. In preferred compounds of the invention, Y is -OH 0 or -OCH-; R is -H; n is 1 or 3; and X is -H, -OH or halogen (in particular, 3,5-dichloro, 3,5-difluoro, 3-chloro, or 3-fluoro) or Y is -H; R is -H; n is 1 or 3 and X is halogen (in particular, 3,5-dichloro, 3,5-difluoro, 3-σhloro, or 3-fluoro) . In the most ^ preferred compound of the invention, Y is -H, X is 3,5-difluoro, R is -H and n is 1. The invention is also a method of inhibiting DBH activity in mammals which comprises administering internally to a subject an effective amount of a compound 0 having the formula: SR 5 * wherein: X is -H, -OH, halogen, C 1-4 alkyl, -CN, -N0 2 ,-S0 2 NH 2 , "C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF_, C 1 _ 4 alkoxy, -S0 2 C 1 _ 4 alkyl, - s0 2 c ι-4 fluoroalkyl, ~ c0 2 C ι-4 ailζ yl or an Y accessible combination thereof up to four substituents; Y is -H, -OH, C,_ 4 alkoxy, halogen, C, alkyl, -CN,-N0 2 , -S0 2 NH 2 , -C0 2 H, -CONH 2 , -CHO, -CH 2 OH, -CF-, -S0 2 C 1 _ 4 alkyl, "SO- j C-^ fluoroalkyl, or " c0 2 C ι-4 al^yl; R is -H or C, 4 alkyl; and n is 0-4, or a hydrate or, when R is C, . alkyl, a pharmaceutically acceptable acid addition salt thereof. Compounds found to be especially potent, and therefore preferred in the method of invention, are those in which Y is -OH or OCH_; R is -H; n is 1 or 3; and X is -H, -OH or halogen (in particular, 3,5-dichlpro 3,5-difluoro, 3-chloro or 3-fluoro) 'or Y is -H; ' R is -H; n is 1 or 3 and X is halogen (in particular, 3,5-dichloro, 3,5-difluoro, 3-chloro, or 3-fluoro) . In the most preferred method of the invention, Y is -H; X is 3,5-difluoro, R is -H and n is 1. It is intended that the above formulae include the tautomer of the compounds wherein R is -H, that is, the compounds having the above formulae wherein the imidazole moiety has the formula: The above formulae also include hydrates of the compounds and pharmaceutically acceptable acid addition salts of the compounds wherein R is C, 4 alkyl. The invention also includes pharmaceutical compositions comprising the compounds having the above formulae, provided that when n is 0, Y is -OH, and pharmaceutical carriers. The invention is also intermediates to the compound of the invention, said intermediates having the formula: 15 II wherein Y and X are the same as Y and X. but are not -OH and n is 0-4 and 20 .NHC(S)NHCH 2 CH(OC 1 _4-_Lyl) 2 .1 25. II A wherein X is the same as X but is not -OH, Y is c τ__ alkoxy, preferably -OCH- and n is 0. 30 The invention is also a process for preparing the compound of the invention which comprises contacting and reacting compound II, above, with acidic thiocyanate and such process which comprises contacting and reacting compound II A, above, with an acid to cyσlize the 35 compound. In both processes, when Y and/or X are C,_ 4 alkoxy, Y and/or X are optionally deproteσted to prepare the compound wherein Y and/or X are -OH. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention contain weak metal-chelating functional groups derived from N-methyl-2-π.erσaptoimidazole which is known to be a weak DBH inhibitor. The compounds of the invention also contain phenyl moieties as do phenethylamine analogue inhibitors such as benzyloxyamine, benzylhydrazine, tryptamine and serotonin. The compounds of the invention and the compounds used in the method of the invention can be prepared from corresponding starting benzyl or phenyl compounds such as benzaldehydes, which are known and described in published references or are readily accessible, by known techniques such as illustrated in Scheme I, below, wherein X and Y are X and Y, respectively, except that when Y is -OH, i Y is C- ' alkoxy, preferably -OCH 3 , and when X is -OH, X is C._ 4 alkoxy, preferably -OCH 3 . As illustrated, n is one, although n can be 0-4. Scheme I illustrates reductive amination of benzaldehydes (I) with an aminoacetaldehyde acetal followed by reduction by, for example, catalytic hydrogenation or treatment with a reducing agent such as NaBH., LiAlH. or A1H.,, to provide intermediate substituted benzylamines (II) . Upon reaction with acidic thioσyanante, the intermediates (II) yield mercaptoimidazole products (III) . The mercaptoimidazole products can be prepared from other than benzaldehydes, as illustrated in Examples 1 and 4, below. Scheme I III 25. 30 35 - II - , The 1-phenyl substituted 2-mercaρtoimidazoles (n is 0) are preferably prepared by reaction of an appropriately substituted phenyl isothiocyanate with an aminoaσetaldehyde acetal followed by strong acid catalyzed c σyσlization, as illustrated in Example 1, below. The σompounds wherein n is 2, 3 or 4 are preferably prepared as illustrated in Example 4 and in Examples 23 and 24, below. Coupling of substituted phenyalkanoiσ acids as the acid halides, preferably τ_0 chlorides, with aminoacetaldehyde aσetals and subsequent reduσtion provides suσh intermediate substituted phenyl- alkylamines. Y in Sσheme I is the same as Y except that when Y is -OH, Y is C,_ 4 alkoxy, preferably -OCH-,, τ_5 optional deprotection of the 4-alkoxy group with, for example, BBr, or HBr, or nuσleophiliσ aromatic substitution with dilute hydroxide, provides the phenol (Y is -OH). X may be one or more substituents at -the 2-, 3-, 5- or 6- positions, provided the combination of 2o substituents is acσessible*, ' that is,,does not result insignificant instability due to steriσ hindranσe. When X is C, 4 alkoxy, preferably -OCH-, it σan be deproteσted as desσribed above for Y . The σompounds in which R is C, 4 alkyl are 5 preferably prepared by allowing the deprotection with, for example, BBr.-, in an alkanol to proceed to formation of an alkyl bromide which alkylates the mercapto group as illustrated in Example 6, below. Alternatively, a solution or suspension of an appropriately substituted 0 mercaptoimidazole in an inert solvent, for example, methanol, tetrahydrofuran or aqueous dimethylformamide, σan be reaσted with an alkylating agent, for example, alkyl iodide, broiride or tosylate. Methyl iodide is preferred in this alternative procedure. 5 67 , - . The pharmaceutiσally aσceptable acid addition salts of the compounds wherein R is C, 4 alkyl are formed with strong or moderately strong organiσ or inorganic acids by methods known to the art. For example, the base is reacted with an inorganic or organic acid in an aqueous miscible solvent suσh as ethanol with isolation of the salt by removing the solvent or in an aqueous immisσible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent. Exemplary of the salts which are included in this invention are maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydroσhloride, hydrobromide, sulfate, phosphate and nitrate salts. The compounds of the invention, because they σan be used to inhibit DBH aσtivity, have therapeutiσ value as diuretic, natriuretic, " σardiotonic, antihypertensive and vasodilator agents, as well as antiulcerogenic and anti- parkinson disease agents. Compounds of the invention and other σompounds useful in the method of the invention were sσreened for in vitro DBH inhibition by a standard proσedure for assaying conversion of tyramine to oσtopamine in the presenσe of DBH. Octopamine was assayed following sodium periodate oxidation to p-hydroxybenzaldehyde by measuring spectrophotometriσ absorbance at 330 nm. Results are given in Table I, below. Inhibition is given in molar concentration of compound at which DBH activity was halved (IC- Q ). Melting points (mp) are given in °C. By this procedure fusaric acid was found to have an IC_ n of about 8x10 -7 TABLE I π X Y R m ICso 1.0 1 3-Br OH H 181 1.2xlO _s 1 3-F OH H 172 1.4xl0 's 1 3-F 0CH 3 H 156-157 10- 4 (677. inhibi tion) 1 3-OH H H 167 1.5xl0 -4 5 1 2-OH H H 158 5.8xϊ0 '4 1 3-CH 3 OH H 214-216 4.8x10 " s - 1 • 2-OCH3 H H 159 10 "4 (687. inhibi tion) 0 1 3-OCH3 H H 118-121 10 -4 (72% inhibi tion) 4 H OH H 132-134 10 "4 (127. inhibi tion) 3 H OH 5 CH 3 140-1 2 7.9xlO "s 1 3,5-Cl 2 OH H 220-222 (dec ) 7.4xl0 "7 1 3-N0 2 OH H 224-227 2.0xl0 's 1 2,6-C OH H >235 (dec ) 7.5xlO _s 0 1 3,5-F 2 OH H 213-215 7.4xl0 "8 1 3,5-F 2 OCH3 H 160-161 3.6xlO "s 1 3-CF3 OH H 220 ( dec ) 1.2xl0 "4 1 2,3,5,6-F, OH H 203-5 6.2xl0 's 1 H H H 144-5 1.IxlO "5 2 H OH H 181-184 1.8xl0 "s TABLE " I (Con t i n ued ) ICso H H H 180-182 l.OxlO '4 H OH H 188-190 2.3xl0 "ε H OH H 183-185 2.0xl0 "s 3-OH OH H 209-212 4.0xl0 "s H OH H 260-264 3.2xl0 "4 3-CT OH H 186-1 0 2xl0 "s 2,6-C.z H H 242-243 10- 4 (77. inhibition) 2-C1 206-207 10 "4 (147. Inhibition)" 2,5-Cl 2 H H 265 (dec) 9.7x10 "ε 4-C1 H H 187-189 9.6xl0 "s 2,3-Cl_ H H 195-197 5.2xl0 "5 H F H 167-169 4.7xl0 "s 3,4-Cl. H H 178-181 2.8xl0 "s 2,4-C H H 185-187 1.7xl0 's 3-C1 H H 129-131 1.2xl0 "s 3,5-Cl 2 H H 209-211 2.4xl0 "ε 2,4,6-Cl 3 H H 240-244 l.OxlO "4 3-F H H 113-114 5.6xl0 "6 3,5-F 2 H H 140-141 1.2xl0 "s 3,5-Cl 2 H H 98-99 2.0xl0 _s 3,5-F 2 H H 131-132 4.7xl0 _β The above results illustrate that σompounds of the invention and other σompounds useful in the method of the invention inhibit DBH aσtivity. The following proσedure was used to sσreen σompounds of the invention for aσtivity _in ivo. Male • Okamoto-Aoki strain spontaneously hypertensive rats (SHR) , 270-340 g, aged 16-20 weeks, were used for testing. The afternoon before testing, the animals were fasted and the following morning the first dose of the test σompound was administered, p.o., along with a 25 ml/kg, load of normal saline. The animals were then plaσed in metabolism cages, three per cage, and urine was colleσted for three h4 and subsequently analyzed for sodium, potassium, and creatinine. Indirect systolic blood pressure and heart rate were measured via a tail-cuff method and, within 24 hr of the first dose, the animals received an identical second dose of the test compound. Two hr after the second dose, the systolic blood pressure and heart rate were again determined. Drugs were administered intraperitoneally as a solution or suspension -in 0.9% NaCl with 0.02% ascorbiσ acid. The dose volume was 5 ml. Averaged results of the j-n. vivo screens are given in Table II. In all compounds tested, R is -H and Y is -OH. Except where otherwise indicated, the conσentration was 50 g/kg. Averaged results with σontrol animals are listed in parentheses below results of treated animals. TABLE II Compound NO. Of Electrolytes Urine NaVK* Systolic Blood Heart Rate Animals Execrated Vol. Ratio Pressure ( beats/mi n) (mEq/rat) (ml /rat) (nrnHg) X. n a* K- First Second First Second Dose Dose Dose Dose 3-CT 1 3 280.33 182.22 8 1.538 173 180 400 440 (3) (381.56) (133.79) (8) (2.852) (174) (170) (440) (460) 3-F 1 3 162.07 134.81 3 1.202 177 191 460 420 (3) (214.16) (198.80) (6) (1.077) (188) (189) (460) (440) H 3 <n 3 185.31 160.59 5 1.157 181 185 440 440 H 3 <2> 3 339.19 231.19 8 1.467 187 180 380 440 (3) (390.84) (231.19) (8) (1.691) (193) (192) (480) (460) 'r- H 3 3 334.84 104.72 8 3.197 181 163 460 460 (3) (183.41) (91.11) (4) (2.013) (183) (180) (460) (460) 3,5 -Hz 3 541. OS- 293.07 13.0 1.846 167 160 440 500 (3) OSS.42) (153.17) (6.5) (2.177) (167) (176) (400) (460) 3-OH 1 - 3 149.10 174.26 4 0.856 ' 185 173 460 480 (3) (161.19) (154.61) (4) (1.043) ' (180) (185) (480) (400) 3-OH \ c∑y 3 383.61 205.29 10 1.869 173 178 440 440 (3) (395.72) (164.23) (8) (2.409) (171) (199) (420) (480) H 3 369.40 251.79 11 1.467 181 183 jCl ) 400 440 3 495.00 229.27 11 2.159 193 182 480 480 (3) (344.55) (137.84) (9) (2.500) (171) (183) (380) (440) 3,S-C1 2 ' 3 3 103.46 53.34 1 1.940 147 153 320 400 (3) (146.06) (20.11) (2) (7.264) (179) (186) (420) (460) 3.,.5-α 2 * 3 3 86.67 54.32 3.5 1.596 159 141 360 360 (3) 128.60 77.25 3 1.665 172 182 400 480 (1) dose concentration = 12.5 mg/kg. r Y is -H. (2) dose concentration = 25.0 mg/kg. 30 35 It is apparent from Table II that the σompounds tested have signifiσant diuretiσ and/or cardiotonic aσtivity. The σompounds in whiσh X is 3,5-diσhloro showed signifiσant natriuretiσ aσtivity as well as diuretiσ, 5 antihypertensive and σardiotoniσ aσtivity. Compounds having diuretic activity are known to be useful as antihyper ensives. In additional experiments carried out substantially by the above procedure, the compound in 10. whiσh X is 3,5-F 2 , Y is -H, R is -H and n is 1 (.50 mg/kg) was found to have an espeσially pronounσed effeσt on. urine exσretion, inσreasing urine volume about four fold over σontrols. Heart rate was generally deσreased by administration of the σompound. 15 Various σompounds of the invention, as well as various known DBH inhibitors, were tested for their effeσts on peripheral dopamine and norepinephrine levels substantially by the proσedure of DaPrada and Zurσher, Life Sσi. 19, 1161 (1976) . Spontaneously hypertensive * 20 rats were dosed twiσe, the seσond dose being about 18 hr after the first, and were saσrifiσed about 2 hr after the seσond dose. Averaged results, expressed in miσrograms of DA per gram of tissue, are given in Table III and in Table III A, whiσh follow. In Table III, R= -H, Y= -OH 25 and n=l; in Table III A, R= -H, Y= -H and n=l; in Table III B, R= -a, Y= -OCH 3 , and n=l. 30 35 TABLE III Compound No. of DA DA/NE Animals __q/g ) Ratio Control (H 2 0) 11 .260 .019 .040 .002 Fusaric Acid 11 .520 .053(D .100 .007(D Control 3 .219 .044 .035 .002 Hydralazine.- (25-mg/kg) 3 .417 .026( ) .078 .015( 2) (50-mg/kg) 1 .835 .127 .098 .018 Control 1 .299 .038 .039 .004 X=3-F (50 mi/kg) 1 .476 .023(3) .064 .004(2 ) Control 1 .261 .046 .041 .007 X-3-F • (50 mg/kg) 1 .430 .027(3 ) .082 .'005(3 ) (100 mg/kg) 1 .619 .071(3 ) .099 .003M ) Control 273 .019 .040 .002 X=3,5-C1 2 (50 mg/kg) 241 .031(3 ) 045 .006(3) Control (cold -stressed) 242 .014 .030 .002 X=.3.,5-C1 2 (50 mg/kg) (cold-stressed) 313 .019(2' 038 .003(2) (1) P < 0.001 (2) P < 0.05 (3) P <0.01 TABLE III (Continued) Compound No. of DA DA/NE Animals -______2! Ratio Control .270 .025 .0307 .0019 Fusaric Acid (50 mg/kg) 675 .OSOd ) .0871 .0047( 1 X=3,5-F 2 (50 mg/kg) 708 Oδθd ) .0824 .0128 ( 2 (1) P < 0.001 (2) P <0.05 (3) P < 0.01 1. TABLE IIIA C mpound No. of DA DA/NE Animals ( yq/q ) 1 Ratio Control 4 .319 + . .104 .042 + .012 Fu sar c Ac id 5 .642 + I .114 .1240 + .014θ(D X=3-F 5 1.096 + . .080 .1946 + .0112(1 ) n = 1. (50 mg/kg . ) 10 X=3 , 55~F ' 2 5 2.109 + . .123 .4485 + .0532(D (.50 mg/kg-) Control 5 .250 + . .014 .037 + .003 X=3,S Cl 2 5 .670 + 1 ,065 .110 + .008(D 15 (50 mg/kg) Control 5 .308 + . ,023 .045 + .004 X=3,5-C1 2 » 5 .688 + . ,020 .103 + .002(D (50 mg/kg) 20 (1) P < 0.001 253 30 35 TABLE IIIB Compound No. of DA DA/NE Animals (uq/q) Ratio Control 6 .318 + .008 .0393 X=3-F 6 1.397 + .111 .239 ( D X=3,5-F 2 6 1.178 + .087 .204 ( D 10. (1) 0.001 The above results illustrate that the compounds of the invention inhibit DBH aσtivity in mammals when 15 administered internally in effective amounts. The compound of the invention in whiσh X is -H, Y is -OH, R is -H and n is 3 was also tested in one rat. The results did not indiσate signifiσant inhibition ' of DBΗ aσtivity. Nevertheless, beσause only a single experiment was- run, 20 beσause other σompounds of the invention show suσh aσtivity, and beσause the σompound has a low in. vitro IC,- 0 (See Table I) , the σompound is believed to be useful in inhibiting DBH aσtivity in mammals. 25 The compounds in which Y is -H and X is halogen, especially difluoro and dichloro, show high ij2 vivo aσtivity, as shown in Table IIIA. The σompound in whiσh X is ' 3,5 difluoro, Y is -H, R is -H and n is 1 (IC 5Q = 1.2 x 10~ ) showed an espeσially pronounσed effeσt on the 0 DA/NE ratio _in vivo. Additionally, although relatively weak iii vitro DBH inhibitors, as indiσated by the data in Table IIIB, σompounds in whiσh Y is -OCH_, n is 1, and X is 3-F or 3,5-F 2 proved very potent DBH inhibitors in vivo. 5 — •____• In a study on the effeσt on blood pressure in spontaneously hypertensive rats of daily doses of σompounds of the invention (50 mg/kg, i.p.), the σompound in whiσh X is 3,-5-diσhloro, Y is -H, R is -H and n is 1 exhibited a cumulative effect, that is, blood pressure continued to decrease on each day of the four day study period. Another study was conducted to compare the effects on blood pressure of compounds wherein Y is -OH, X is 3-F or 3,5-F 2 and n is 1 to their Y is "OCH 3 analogues. The maximum blood pressure reduσtion observed after administration of the hydroxy σompound in whiσh X is 3-F was 18%, whereas one-half the dose of its methoxy analogue produσed a 35% blood pressure reduσtion. Also, equivalent doses of the σompound in which Y is -OH, X is 3,5-F 2 , and n is 1 and its Y is -OCH 3 analogue produced, respectively, 20% and 35% blood pressure reductions. The compounds can be incorporated into convenient dosage unit forms suσh as σapsules, tablets or injeσtable preparations. Pharmaσeutiσal σarriers whiσh σan be employed σan be solid or liquid. Solid σarriers inσlude, among.others, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include, among others, syrup, peanut oil, olive oil and water. Similarly, the carrier or diluent may include any delayed release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. -The amount of solid σarrier will vary widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. If a liquid σarrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin σapsule, sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension. The pharmaσeutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral end products. Doses of the present compounds in a pharmaceutiσal dosage unit will be an effeσtive amount, that is, a nontoxiσ quantity selected from the range of lu. 0.1-1,00.0. mg/kg of active compound, preferably 10-100 mg/kg. The selected dose is administered to a patient in need of treatment from 1-5 times daily, orally, reσtally, by injeσtion or by infusion. Parenteral administration, whiσh uses a low dose, is preferred. 15 However, oral administration, at a higher dose, σan also be used when safe and σonvenient for the patient. Use of lowest effeσtive doses is reσommended beσause toxiσity has been assoσiated with sulfur-σontaining σompounds. The following examples'are illustrative of 20 preparation of σompounds of the invention or intermediates therefor. The starting σompounds are commerσially available or are prepared by known teσhniques. The Examples are not intended to limit the sσope of the invention as defined herein above and as σlaimed below. 25 The σompounds listed in Tables I, II and III, above, were prepared substantially by the illustrated proσedures. All temperatures and melting points (mp) are in degrees Celsius (°C) . 0 EXAMPLE 1 l-(4-Methoxyphenyl) -2-merσaptoimidazole A solution of 10 g (.06 mole) of p-methoxyphenyl isothioσyanate in 100 ml of CHC1 3 was treated with 6.3 g (.06 mole) of aminoaσetaldehyde dimethyl aσetal. The 5 __ . - 24 - solvent was evaporated and the residue was reσrystallized from ethanol to yield N-(p-methoxyphenyl) -N' -(β,β- dimethoxyethyl) thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of σoncentrated H 2 S0. and 20 ml of E D was refluxed for 3 hours. The mixture was cooled and a solid was filtered, washed with H 2 0 and dried. Recrystallization from ethanol gave l-(4-methoxyphenyl) -2-merσaptomidazole, 4.9 g (70%), p 215-7°. The σompound σan be deproteσted, for example, as illustrated in Example 5 and 6, below, to prepare the phenol, Y is -OH. EXAMPLE 2 l-(4-Methoxybenzyl) -2-merσaptoimidazole mixture of 13.6-g (0.1 mole) of anisaldehyde, 13.3 g (0.1 mole) of aminoaσetaldehyde diethyl aσetal and 1 ml of CH-OH was heated at 95° for 10 minutes. A residue was dissolved in 150 ml of ethanol and hydrogenated over 10% Pd on σarbon at*'50 psi (0.34 MPa) until H 2 uptake was σoπtplete. The σatalyst was filtered and the filtrate was treated with 10.4 g (0.107 mole) of KSCN, 40 ml of 3N HC1 and 40 ml of H-,0. The mixture was refluxed, letting the solvent evaporate until the volume of the reaction mixture was 100 ml. After 45 minutes, the mixture was cooled, and a solid was filtered, washed with H 2 0 and dried. Recrystallization from ethanol gave (l-(4-methoxybenzyl) -2-mercaptoimidazole, 15.0 g (68%), mp 140-142°. EXAMPLE 3 l-(3-Bromo-4-methoxybenzyl) -2-merσaptoimidazole A solution of 10.75 g (.05 mole) of 3_-bromo-4- methoxybenzaldehyde and 6.65 g (.05 mole) of amino- acetaldehyde diethyl acetal in 25 ml of ethanol was refluxed for 30 minutes. The solvent was evaporated and the residue was dissolved in CH 2 C1 2 . The CH 2 C1 2 solution of the Schiff base was washed with saturated aqueous NaCl, dried (K 2 C0 3 ) and filtered, and the solvent was evaporated. Residual Schiff base was dissolved in 100 ml of methanol, cooled to 5°, and treated with 5.0 g of NaBH 4 . The reaction mixture was allowed to warm to 22° and, after 4 hr, the solvent was evaporated. The residue was taken up in diethyl ether, washed with H-,0, dried (MgS0 4 ) and filtered, and the solvent was evaporated. A solution of the residue in CHC1-, upon treatment with ethereal HC1, gave, on standing, crystals of N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethylaσetal hydroσhloride, 10.75 g (58%), mp 112-120°. A solution of 10.74 g (.029 mole) of N-(3-bromo- 4-methoxybenzyl) aminoaσetaldehyde diethyl aσetal hydro- σhlorid.e and 3.37 g (0.35 mole) of KSCN in 50 ml of H 2 0, .50 ml of ethanol and 5 ml of 3N HC1 was refluxed for 4.5 ' hours. One hundred ml of H 2 0 wa≤ added and the mixture was σooled. A solid was filtered, washed with H 2 0 and dried. Reσrystallization from ethanol gave l-(3-bromo-4- methoxybenzyl) -2-merσaptoimidazole, 6.3 g (72%), mp 188°. EXAMPLE 4 1- [3-(4-Methoxyphenyl) -propyl]-2-merσaptoimidazole A solution of 12.5 g (.07 mole) of p-methoxy- phenylpropioniσ aσid in 100 ml of CH 2 C1 2 and one drop of pyridine was treated with 9.8 g (.077 mole) of oxalyl σhloride. After 2.5 hours, the solvents were thoroughly evaporated to give the aσid σhloride as an oil. A solution of the aσid σhloride in 100 ml of CH-,C1-, was slowly added to a σold (0°) solution of 14.7 g (0.14 mole) of aminoaσetaldehyde dimethyl aσetal in 300 ml of CH 2 1 2 at a rate such that the temperature stayed 1 below 20°. After 1 hr, the reaction mixture was poured into H-,0,- and the CH 2 C1 2 layer was separated and washed with aqueous a 2 C0 3 , 0.5N HC1 and H 2 0. Following drying and evaporation of the solvent, N-(β, 5 β-dimethoxyethyl) -p-methoxyphenylpropionamide was obtained as a solid, 10.3 g (55%). A solution of this amide in 300 ml of diethyl ether was slowly added to a slurry of 4.0 g of LiAlH 4 in 400 ml of diethyl ether and 350 ml of tetrahydrofuran (THF) . After 3.5 hours at 22°, excess 1°- LiAlH- 4 was cautiously destroyed, the reaction mixture was; filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of 0.15N HC1, washed with diethyl ether, basified with NaHC0 3 and extracted with diethyl ether. The extracts were dried (MgSO and the solvent I 5 was evaporated to give N- [3-(4-methoxyphenyl)proρyl] aminoacetaldehyde dimethyl acetal, 4.6 g (52%), as an unstable oil. A solution of 3.62 g (.014 mole) of N-[3-(4- methoxyphenyDpropyl]aminoaσetaldehyde dimethyl acetal and 20 1.4 g (.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of - H 2 0 and 2 ml of concentrated HC1 was refluxed for five hours. Fifty ml of H-,0 was added, the mixture was cooled and a solid was filtered, washed with H D and dried. Recrystallization from ethanol gave 25 1- [3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole, 2.4 g (69%) , mp 108-109°. Example 5 1-(3-Fluoro-4-methoxybenzyl) -2-merσaptoimidazole 30 3-Fluoro-4-methoxybenzaldehyde (5.0 g, 0.0324 mole) was added to aminoaσetaldehyde dimethyl acetal (3.53 ml, 0.0324 mole) and the mixture was heated at 100°C for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alσohol (50 ml) and sodium borohydride 35 1 (1.23 g, 0.0324 mole) was added and the mixture was stirred overnight at 25°C. The solvent was removed under reduσed pressure and the residue was dissolved in ethyl aσetate and the solution was washed with water and brine 5 and then dried with sodium sulfate. The mixture was filtered and the solvent removed under reduσed pressure to give N-(3-fluoro-4-methoxybenzyl) -aminoaσetaldehyde dimethyl aσetal as an oil (6.68 g, 85%). To a solution of l-(3-fluoro-4-methoxybenzyl) - 10 aminoaσetaldehyde dimethyl aσetal (6.68 g, 0.0275 mole) in ethyl alσohol (40 ml) was added potassium thioσyanate (2.94 g, 0.0302 mole) in water (65 ml) followed by 12 N hydroσhloriσ aσid (6 ml) and the reaσtion mixture was heated under reflux for 3 hours. The solvent was 15 partially removed under reduσed pressure and the mixture was σooled in iσe and the produσt filtered. The produσt was reσrystallized from ethyl alσohol to give l-(3-fluoro- 4-methoxybenzyl) -2-merσaptoimidazole as a solid melting at 156-157° (3.98 g, 61%) . " 20 Example 6 1-(3,5-Difluoro-4-methoxybenzyl) -2-merσaptoimidazole A mixture of 3,5-difluoro-4-methoxybenzonitrile (3.50 g, 0.0207 mole) and Raney σatalyst powder (3.5 g) in 25 90% formiσ aσid (35 ml) was stirred and heated under reflux for 2.5 hours and the σatalyst was filtered and washed with hot water and hexane. The hexane layer was separated and the aqueous solution was extraσted an additional three times with hexane. The σombined hexane 0 extraσts were washed with water and brine, dried and the solvent was removed to give 3,5-difluoro-4-methoxy- benzaldehyde as an oil (3.38 g, 95%). 3,5-Difluoro-4-methoxybenzaldehyde (3.38 g, 0.0196 mole) was added to aminoaσetaldehyde dimethyl 5 . „ . - 28 - acetal (2.14 ml, 0.0196 mole) and the mixture was heated at.100°C for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (35 ml), and sodium borohydride (0.743 g., 0.0196 mole) was added and the mixture was stirred overnight at 25°C. The solvent was removed under reduσed pressure, the residue was dissolved in ethyl aσetate, and the solution was washed with water and brine and then dried with sodium sulfate. The mixture was filtered, and the solvent removed under reduσed 0- ' pressure to give N-(3,5-difluoro-4-methoxybenzyl)amino¬ aσetaldehyde dimethyl aσetal as an oil (4.94 g, 96%). To a solution of N-(3,5-difluoro-4-methoxybenzyl) ■ aminoaσetaldehyde dimethyl aσetal (4.94 g, 0.0189 mole) in ethyl alσohol (30 ml) was added potassium thioσyanate 5 (2.10 g, 0.0216 mole) in water (48 ml) followed by 12 N hydrochloric acid (4 ml) , and the reaction mixture was heated under reflux for 3.5 hours. The solvent was partially removed under reduced pressure, the mixture was cooled in ice, and the product was filtered. The produσt ° was recrystallized from ethyl alcohol - hexane to give l-(3,5-difluoro-4-methoxybenzyl) -2-merσaptoimidazole as a solid melting at 160-161° (2.22 g, 46%). EXAMPLE 7 5- 1-[3-(4-Hydroxyphenyl)propyl]-2-merσaptoimidazole A solution of 1.75 g (.007 mole) of l-[3-(4- methoxyphenyl)propyl]-2-merσaptoimidazole in 60 ml of CH 2 C1 2 was deproteσted by treatment with a solution of 7.0 g (.028 mole) of BBr 3 in 10 ml of CH 2 C1 2 . After 0 1.5 hr, the reaction mixture was cooled to 0°, and methanol was σautiously added. After a vigorous reaσtion subsided, ';he solvents were evaporated. The residue was reσrystallized from ethanol to give 1- [3-(4-hydroxyρhenyl) - propyl]-2-merσaptoimidazole, 1.02 g (67%), mp 185°. 5 EXAMPLE 8 1- [3-(4-Hydroxyphenyl)propyl] -2-thiomethylimidazole A solution of 1.2 g (.0046 mole) of l-[3-(4- methoxyphenyl)propyl] -2-merσaptoimidazole in 40 ml of CH 2 C1 2 was treated with a solution of 3.5 g (.014 mole) of BBr 3 in 10 ml of CH 2 C1 2 . After 4 hours, methanol was σautiously added, the mixture was stirred for an additional 18 hours, and the solvents were evaporated. The residue was dissolved in H 2 0, washed with ethyl aσetate, neutralized with NaHCO-. and extraσted with ethyl acetate. The extracts were dried (MgSO and filtered and the solvent was evaporated. The residue was dissolved in 5 ml of ethanol, and treated with ethereal HC1. A crystalline produσt was filtered and reσrystallize from ethanol, to give 1- [3-(4-hydroxyphenyl)propyl] -2- thiomethylimidazole hydroσhloride, 0.61 g (45%), mp 140-142°. . 'EXAMPLE 9 1-(3-Nitro-4-hydroxybenzyl) -2-merσaptoimidazole A solution of 1- [3 1 -nitro-4 1 -methoxybenzyl] -2- merσaptoimidazole (1.59 g, 6.0 moles) in 10% aqueous NaOH (200 ml) was refluxed for two hours, σooled, aσi ified with σonσentrated HC1, σooled and filtered. The σrystalline produσt was washed with water. Reσrystallization from ethanol provided 1.25 g (80%) of produσt as yellow prisms: mp 225-227° (deσ) . EXAMPLE 10 l-(2,6-Diσhloro-4-hydroxybenzyl) -2-merσaρtoimidazole A mixture of 1- [2* ,6* -diσhloro-4' -methoxybenzyl] - 2-merσaptoimidazole (1 g' in σonσentrated aqueous hydrobromiσ aσid (50 ml) was heated at reflux under argon for 1.25 hr, and then σooled. The produσt was σolleσted by filtration. Washing with σonσentrated aqueous hydrobromiσ aσid and water and drying yielded 0.64 g (60%) of produσt as light yellow σrystals: mp 235° (deσ) . EXAMPLE 11 l-(3-Trifluoromethyl-4-hydroxybenzyl) -2-merσaρtoimidazole A mixture of l-(3' -t ifluoromethy1-4* -methoxy¬ benzyl) -2-merσaptoimidazole (2.0 g) and pyridine hydroσhloride (15 g) was melted at 210° for 30 minutes, σooled, diluted with water and extraσted with ethyl aσetate. The ethyl aσetate extraσts were treated with σharσoal, dried over sodium sulfate and σonσentrated to give a thiσk oil. Addition of THF (3 ml) , ether (6 ml) , and hexane (15 ml) produced yellow crystals. Recrystallization from ethyl acetate/hexane yielded 0.7 g (37%) of cream colored crystals: mp 220° (dec) . „ . EXAMPLE' 12 l-(3* ,5' -Diσhlorobeήzyl) -2-merσaptoimidazole A mixture of 3,5-diσhlorobenzaldehyde (17.5 g, 0.1 mole) and aminoacetaldehyde diethylaσetal (13.3 g, 0.1 mole) was heated on a steam bath. The resulting solution was stirred at room temperature during slow addition of sodium borohydride (3 g, 0.08 mole) and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed sequentially with water and brine, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was heated at reflux with water (100 ml) , conσentrated hydroσhloriσ aσid (22 ml), ethanol (41 ml), and potassium thiocyanante (10.7 g, 0.11 mole) fot 2 hours. The mixture was σooled and diluted with water (250 ml), and the σrude produσt was σolleσted by filtration and dried. Reσrystallization twiσe from aσetiσ aσid provided 7.3 g (30%) of the title σompound as light yellow σrystals: mp 209-211°. EXAMPLE 13 1-(2' ,6* -Diσhlorobenzyl) -2-merσaptoimidazole Reaσtion of 2,6-dichlorobenzaldehyde (17.5 g, 0.1 mole) and aminoaσetaldehyde diethyl acetal (13.3 g, 0.1 mole) substantially as above yielded 5.4 g (21%) of the title compound as white needles: mp 242-3° (ethanol/ether) . EXAMPLE 14 l-(2* -Chlorobenzyl) -2-mercaptoimidazole Reaσtion of 2-σhlorobenzaldehyde (14 g, 0.1 mole) and aminoacetaldehyde diethylacetal (13.3 g, 0.1 mole) substantially as above yielded 11.2 g (50%) of the -title σompound as white σrystals: mp 206-7° (aσetone/ethanol) .- EXAMPLE 15 l-( 2 1 , 5' -Diσhlorobenzyl) -2-merσaptoimidazole Reaσtion of 2, 5-diσhlorobenzaldehyde (10.25 g, 0.059 mole) and aminoaσetaldehyde diethyl acetal (7.79 g, 0.059 mole) substantially as above yielded 5.2 g (34%) of the title compound as white crystals: mp 265° (dec) (propioniσ acid) . EXAMPLE 16 l-(4* -Chlorobenzyl) -2-mercaptoimidazole Reaσtion of 4-σhlorobenzaldehyde (14 g, 0.1 mole) and aminoacetaldehyde diethyl acetal (13.3 g, 0.1 mole) substantially as above yielded 8.3 g (36%) of the title σompound as white σrystals: mp 187-9° (acetonitrile) . EXAMPLE 17 1-(2* ,3* -Diσhlorobenzyl) -2-merσaptoimidazole Reaσtion of 2,3-diσhlorobenzaldehyde (8.7 g, 0.05 mole) and aminoaσetaldehyde diethyl aσetal (6.65 g, 0.05 mole) substantially as above yielded 3.0 g (23%) of the title σompound as white σrystals: mp 195-7° (ethanol) . EXAMPLE 18 l-(4* -Fluorobenzyl) -2-mercaptoimidazole Reaσtion of 4-fluorobenzaldehγde (12.4 g, 0.1 mole) and aminoacetaldehyde diethyl aσetal (13.3 g, 0.1 mole) substantially as above yielded 13.0 g (62.5%) of the title compound as white σrystals: mp 167-9° (ethanol) , EXAMPLE 19 l-(3* ,4'-Dichlorobenzyl) -2-merσaptoimidazole Reaction of 3,4-diσhlorobenzaldehyde (17.5 g, 0.1 mole) .and aminoacetaldehyde diethyl aσetal (13.3 g, 0.1 mole) substantially as above yielded 10 g (39%) of the title σompound as white σrystals: mp 178-81° (ethan'ol) . . EXAMPLE 20 l-(2' ,4* -Dichlorobenzyl) -2-mercaptoimidazole Reaσtion of 2,4-diσhlorobenzaldehyde (17.5 g, 0.1 mole) and aminoacetaldehyde diethyl aσetal (13.3 g, 0.1 mole) substantially as above yielded 8.5 g (33%) of the title σompound as of white σrystals: mp 185-7° (2-propanol) . EXAMPLE 21 l-(3* -Chlorobenzyl) -2-merσaptoimidazole Reaσtion of 3-chlorobenzaldehyde (14 g, 0.1 mole) and aminoacetaldehyde diethyl aσetal (13.3 g, 0.1 mole) substantially as above yielded 14 g (62.5%) of the title compound as white σrystals: mp 129-131° (acetonitrile) . EXAMPLE 22 l-(2' ,4' ,6'-Triσhlorobenzyl) -2-merσaptoimidazole Reaσtion of 2,4,6-triσhlorobenzaldehyde (20.9 g, 0.1 mole) and aminoaσetaldehyde diethylaσetal (13.3 g, 0.1 mole) substantially as above yielded 12 g (46%) of the title σompound as white σrystals: mp 240-4° (ethanol) . EXAMPLE 23 l-(3-Fluorobenzyl) -2-mercaptoimidazole °- Reaction of 3-fluorobenzaldehyde (24.8 g, 03.>2 mole) and aminoacetaldehyde diethyl acetal (26.6 g, 0.2 mole) subs antially as above yielded 28 g (67%) of the title σompound as white σrystals: mp 112.5-114° (2-propanol/water) . 5 EXAMPLE 24 1-(3' ,5' -Difluorobenzyl) -2-merσaptoimidazole Reaction of 3,5-difluorobenzaldehyde (14.7 g, 0.104 mole) and aminoacetaldehyde dimethyl acetal (10.8 g, 0.104 mole) substantially as above yielded 10.0 g (43%) of the title compound as white crystals: mp 140-141° (ethyl aσetate/hexane) . EXAMPLE 25 1- [3-(3 1 ,5' -Difluorophenyl)propyl] -2-mercaptoimidazole 3,5-Difluorobenzaldehyde (5.5 g, 0.039 mole), maloniσ aσid (6.06 g, 0.058 mole), pyridine (2.1 ml) and piperidi-ne (0.105 ml) were heated on a steam bath for 2 hours and then at 155° for 1 hour. The reaσtion mixture was poured into σold 3N aqueous hydroσhloriσ aσid, and then filtered. Reσrystallization from ethanol provided 4.7 g (66%) of 3,5-difluorocinnamic aσid as buff needles: mp 199-231°. τ_ 3-5-Difluoroσinnamiσ aσid (4.6 g, 0.025 mole) was dissolved in tetrahydrofuran (50 ml) and added to a slurry of 0.75 g palladium/σarbon in ethyl aσetate. The mixture was shaken under 50 psi (.34 MPa) hydrogen for 5 hours and 5 then was filtered and σonσentrated to provide 4.5 g (97%) of 3-(3 1 ,5' -difluorophenyDpropanoiσ acid as colorless σrystals: mp 56° (methanol) . A solution of 3-(3* 5' -difluorophenyl) propanoiσ aσid (4.4 g, 0.024 mole) N,N-dimethylformamide (one drop) UX and thionyl σhloride (15 ml) was heated at 60° for 3 rxours. Exσess thionyl σhloride was removed by distillation at reduσed pressure. Distillation (Kugelrohr) at reduσed pressure (about 0.25 mm [33 Pa]) yielded 4.1 g (85%) of 3-(3' ,5' -difluorophenyl)propionyl 15 σhloride as an oil. A solution of 3-(3* ,5' -difluorophenyl) ropionyl σhloride (4 g," 0.0196 mole) in me ' thylene σhloride (40 ml) .was slowly added to a 0° solution of amino acetaldehyde dimethyl acetal (4.3 g, 0.0412 mole) in methylene chloride " 20 (100 ml) at a rate such that the temperature did not exceed 20°. The reaσtion mixture was stirred for 1 hour. Then it was poured into water and the layers were separated. The organiσ layer was washed with 5% aqueous sodium σarbonate, 0.05% aqueous hydrogen chloride, and 5 water and then was dried over sodium sulfate and concentrated to yield 5.5 g (103%) of 3-(3',5'- difluorophenyl) )propanamide N-acetaldehyde dimethyl aσetal as an oil. A solution of 3-(3* ,5' -difluorophenyl)propana ide 0 N-aσetaldehyde dimethyl aσetal (5.3 g, 0.0194 mole) in diethyl ether (100 ml) was slowly added to a slurry of lithium aluminum hydride (4.4 g, 0.116 mole) in diethyl ether (200 ml) . The reaσtion mixture was stirred at ambient temperature (20-25°) for 18 hours. Then water 5 1 (4.5 ml) was σare fully added, followed by 10% aqueous sodium hydroxide (7 ml) and water (11 ml) . The mixture was filtered and the filtrate was dried over sodium sulfate and σonσentrated to yield 4.4 g (88%) of 5 3' -( 3' , 5' -dif luorophenyl) propanamine N-aσetaldehyde dimethyl aσetal as σolorless oil. A solution of 3-( 3 1 , 5' -dif luorophenyl) propanamine N-aσetaldeh.yde dimethyl aσetal (4.3 g, 0.0166 mole) and potassium thioσyanate (1.6 g, 0.0166 mol) in ethanol 10 (12 ml), water (20 ml), and concentrated hydrochloriσ aσid (4 ml) was refluxed for 1 hour and then σooled and a large volume of water was added. The produσt was filtered and recrystallized to yield 2.2 g (55%) of 1- [3-( 3' , 5' - difluorophenyl) propyl] -2-mercaptoimidazole as white 15 needles: mp 131-132° (ethanol). EXAMPLE 26 3- ( 3 1 , 5' -Diσhlorophenyl) ropyl- 2-merσaptoimidazole Reaσtion of 3, 5-diσhlorobenzaldehyde (26.9 g, -20 0.154 mole) , aloniσ aσid (24.1 g, 0.232 mole) , pyridine ■ (8 ml) and piperidine (0.4 ml) substantially as above yielded 22.9 g U59%) of 3 , 5-diσhloroσinnamiσ aσid as white needles: mp 169-170° (ethanol) . Reaσtion of 3, 5-diσhloroσinnamiσ aσid (22.9 g, 25 0.106 mol) and 3 g palladium/σarbon substantially as above yielded 23 g (99%) of 3-( 3' ,5' -diσhlorophenyl) propanoiσ aσid as an oil. A one molar solution of borane in tetrahydrofuran (233 ml) was added dropwise to a σooled (0°) solution of 30 3- ( 3' , 5' -dichlorophenyDpropanoic acid (23 g, 0.106 mole) in distilled tetrahydrofuran (200 ml). The reaσtion was stirred at room temperature for 2 hours. Then methanol was ad led and the solution was σonσentrated to yield 21.2 g (98%) of 1- [3- ( 3' , 5 1 -diσhlorophenyl) ] propanol as a 35 σlear oil. 1 Dimethyl sulfoxide (6.75 g, 0.083 mole) in dry ethylene σhloride (15 ml) was added dropwise to a solution of oxalylσhloride (6.2 g, 0.049 mole) in dry methylene σhloride '(15 ml) at -78°. The reaσtion mixture 5 was stirred for 2 minutes. Then l-.S-^SS 1 - diσhlorophenyl) ]-propanol (5 g, 0.0245 mole) in dry methylene σhloride (20 ml) was slowly added, keeping the temperature below -60°. After stirring for 15 minutes at -70°, triethylamine (16 g, 0.160 mol) was added dropwise. 1° The reaction mixture was stirred for an additional 5 minutes at -60° and then was warmed to room temperature and diluted with water. The organic layer was separated, washed with 3N hydrogen chloride and th ' en with brine, and was dried over sodium sulfate. The solution was I 5 σoncentrated to give 5.0 g (100%) of 3-(3',5 ! - *" dichlorophenyl) propionaldehyde as a yellow oil. Amino aσetaldehyde dimethyl acetal (2.1 g, 0.0197 mole) was added with stirring to a solution of - 3-(3' ,5' -diσhlorophenyl)propionaldehyde (5 g, 0.025 mole) 2 0 in hexane (10 ml) . After stirring for 1 hour at room temperature, sodium borohydride (7.3 g, 0.193 mole) in ethanol (25 ml) was added. The reaction mixture was stirred for 18 hours and then was diluted with water and concentrated. The residue was taken up in ethyl acetate, " washed with water, dried over sodium sulfate and σonσentrated to yield 6.8 g (93%) of 3-(3',5'- dichlorophenyDpropanamide N-acetaldehyde dimethyl aσetal as a yellow oil. A solution of 3-(3* ,5' -dichlorophenyDpropanamide 30 N-acetaldehyde dimethyl acetal and potassium thioσynate (2.2 g, 0.0223 mole) in ethanol (20 ml), water (30 ml), and σoncentrated hydrochloriσ acid was refluxec for 1 hour. The reaction mixture was σooled and diluted with water. After standing for 3 hours, the σrude produσt 35 - 37 - solidified and was filtered. Chromatography on siliσa, eluting with 0.5 to 1% methanol in methylene σhloride, provided 2.0 g (31%) of 3-(3' ,5' -diσhlorophenyl)proρyl-2- merσaptoimidazole as white, σrystals: mp 98-99° (ethanol), EXAMPLES 27-58 The σompounds listed in Table IV, below, are prepared substantially by the proσedures illustrated in the preceding Examples exσept that equivalent molar ° amounts of appropriate starting σompounds and of other reaσtants and reagents are used. The σompounds in whiσh X and/or Y is -OH are prepared from 'σorresponding methoxy-substituted σompounds whiσh are deproteσted as illustrated above. In partiσular, the σompounds of Examples 29, 32, 36 and 38 are prepared from merσaptoimidazoles as follows: Example Merσaptoimidazoles . 30 1- [ 3- ( 3-σarboxamido -4-methoxyphenyl ) - propyl ] - 2.-merσaρtoimidazo le • 33 l-[2-(2,3-di(trifluoromethyl) -4- methoxyphenylethyl]-2-merσapto- imidazole 36 1- [2-(3-σyano-4-methoxyphenyl) - ethyl]-2-merσaptoimidazole 38 1- [3-(2-methoxy-4-σarbomethoxyphenyl) propyl]-2-merσaptoimidazole The compound of Example 33, in whiσh R is -(CH_), CH- is prepared by allowing the deproteσtion with BB , in butanol to proσeed to formation of butyl bromide. The butyl bromide alkylates the merσapto moiety as in Example 6, above. TABLE IV EXAMPLE n 27 ' 0 3-CH 3 ,5-CH 3 CH 3 H 28 3 2-CN CH 2 OH H 29 1 3-S0 2 NH 2 H H 0 30. Z 3-C0 H 2 OH H 31 4 * 2 -CHO H H 32 4 2-CH 2 OH, 3-CH 3 " CF 3 H 2 2-CF 3 ,3-CF 3 OH (CH 2 ) 3 CH 3 5 V 34 1 3-S0 2 CF 3 H H 35 1 3-C0 2 (CH 2 ) 3 CH 3 H ' H 36 2 3-CN OH . H .37 4 H " " S0 2 NH 2 •- H 0 38 3 2 -OH C0 2 H H 39 0 H CONH 2 H 40 1 3-OCH 3 Sθ2CH2CH 3 H 53 41 1 H S0 2 (CF 2 ) 3 CF '3 H 42 1 3-(CF 2 ) 3 CF 3 C0 2 CH 3 H 43 1 2,3,5,6-F4 F 44 3 2,3,5,6-F 4 F H O 45 1 2,3-F 2 H H 46 1 2-F F H 5 TABLE IV (Continued) EXAMPLE n X Y R 47 1 2,5-F 2 H H 48 1 2,6-F 2 H H 49 1 3-F F H 50 1 3,5-F 2 F H 51 4 3,5-F 2 H H 52 3 3-Cl,5-F H H 53 1 3-Cl,5-F H H 54 2 3,5-F 2 H H 5 555^ "; 0 0 3 3,,55--FF 22 H H H 56 1 3-Cl,5-F F H 57 1 3-Br,5-F H H 58 1 * 3-I,5-F H H ' '' . ' . EXAMPLES 59-68 The σompounds shown in Table V, below, are prepared by alkylating corresponding mercaptoimidazoles of the invention with methyl iodide in methanol by known techniques. Other alkyl halides, for example, methyl bromide, methyl σhloride and butyl iodide, are substituted for methyl iodide in an appropriate solvent. The salts are neutralized to the free base with, for example, sodium hydroxide or sodium carbonate, and can be converted to another pharmacologically acσeptable aσid addition salt. TABLE V EXAMPLE Compound ri X Y R 59 1 3-(CH 2 ) 3 CH 3 F CH 3 60 1 3-S0 CH 3 (CH 2 ) 3CH3 CH 3 61 4 2-CHO CHO CH 3 _ . 62 1 3,5-F 2 H CH 3 63 1 2,4-F 2 H CH 3 64 3 3,5-F 2 H CH 3 65 4 3,5-F 2 H CH 3 66 3 3,5-F 2 H CH 2 CH 67 1 3,5-F 2 H (CH 2 ) 3 CH 68 1 3,5-F 2 H CH2CH 3 EXAMPLE 69 The ingredients in Table VI, below, are sσreened, mixed and .tilled into a hard gelatin σapsule. TABLE VI Ingredients Amounts 1- [3-(4-hydroxyphenyl) -propyl] -2- 50 mg raerσaptoimidazole magnesium stearate 5 mg laσtose 75 mg EXAMPLE 70 The suσrose, σalσium sulfate dihydrate and imidazole shown in Table VII, below, are mixed and granulated with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and steariσ aσid, screened and compressed into a tablet. TABLE VII Ingre ients - Amounts ' l-[2' ,6 , -dichloro-4'-J Iroxybenzyl]- 100 mg 2-mercaρtoimidazble calcium sulfate dihydrat :ee 150 mg sucrose 20 mg starσh 10 mg talσ 5 mg steariσ aσid 3 mg EXAMPLE 71 1- [3-(4-Hydroxyphenyl) propyl] -2-thiomethylimidazol hydroσhloride, 75 mg, is dissolved in 25 ml of normal saline to prepare an injeσtable preparation. While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the preσise σonstruσtions herein disσlosed and that the right to all modifiσations σoming within the sσope of the following σlaims is reserved.

Claims: - What is claimed is 1. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a compound having the formula: in which: Y ls C l-4 alkoxy; 5 X is -H, -OH, halogen, C._. alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -C0NH 2 , -CHO, -CH 2 OH, -CF 3 , C χ _ 4 alkoxy, -SO 2 C 1 _ 4 alkyl, ~SO 2 C 1 _ 4 fluoroalkyl, or ~CO 2 C- . alkyl or any accessible combination thereof up to four substituents; 0 R- is -H or C- . alkyl; and, n is 1-4 or a hydrate or, when R is C._ 4 alkyl, a pharmaceutically acceptable acid addition salt thereof. 2. A composition of Claim 1 wherein the 5 compound is l-(3-fluoro-4-methoxybenzyl)-2- mercaptoimidazole or l-(3,5-difluoro-4-methoxybenzyl)-2- mercaptoimidazole. 3. A compound of the formula: O 88/01267 - 44 - , in which : Y 1S C l-4 alkoxy; X is -H, -OH, halogen, C χ _ 4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -C0 2 H, -C0NH 2 , -CHO, - H 2 OH, -CF 3 , C 1 _ 4 alkoxy, -SO 2 C 1-4 alkyl , ~SO 2 C ]L _ 4 fluoroalkyl, or _ C° 2 C l - 4 alkyl or any accessible combination thereof up to four substituents; R is -H or C,_ 4 alkyl; and, n is 1-4 10. or a hydrate or, when R is C, 4 alkyl, a pharmaceutically acceptable acid addition salt thereof for use a_r a therapeutic agent. 4. A compound of the formula: in which: Y is C '.1-4 alkoxy; 25. X is -H, -OH, halogen, C. . alkyl, -CN, -NO 2 „ -SO 2 H 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 OH, - F 3 , C 1 _ 4 alkoxy, -SO 2 C, 4 alkyl, ~ s0 2 ι- 4 fluoroalkyl, or ~C° 2 c ι_ alkyl or any accessible combination thereof up to four substituents; 30 R is -H or C,_ 4 alkyl; and, n is 1-4 or a hydrate or, when R is C, 4 alkyl, e. pharmaceutically acceptable acid addition salt thereof for use as a dopamine-β-hydroxylase inhibitor. 35 5. A compound that is l-(3-fluoro-4- methoxybenzyl)-2-mercaptoimidazole or l-(3,5-difluoro-4- methoxybenzyl)-2-mercaptoimidazole. 6. A process for preparing a pharmaceutical composition that comprises adding a pharmaceutically suitable carrier to a compound of the formula: in which: Y ls C l-4 alkoxy; X is -H, -OH, halogen, C, 4 alkyl, -CN, -NO 2 , -SO 2 NH 2 , -CO 2 H, -CONH 2 , -CHO, -CH 2 0H, -CF 3 , C 1 _ 4 alkoxy, -SO 2 C 1 _ 4 alkyl, -SO 2 C 1 _ 4 fluoroalkyl, or "" O 2 C 1 _ 4 alkyl or any accessible combination thereof up to four substituents; R is -H or C,_ 4 alkyl; and, *n is 1-4 , or a hydrate or ' , when R is C 1-4 alkyl,.a pharmaceutically acceptable acid addition salt thereof. 7. A process of Claim 6 wherein the compound is l-(3-fluoro-4-methoxybenzyl)-2-mercaptoimidazole or l-(3,5-difluoro-4-methoxybenzyl)-2-mercaptoimidazole. 8. A process for preparing l-(3-fluoro-4- methoxybenzyl)-2-mercaptoimidazole that comprises reacting l-(3-fluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal with acidic thiocyanate. 9. A process for preparing l-(3,5-difluoro-4- methoxybenzyl)-2-mercaptoimidazole that comprises reacting l-(3,5-difluoro-4-methoxybenzyl)aminoacetaldehyde dimethyl acetal with acidiσ thiocyanate.

Inventors: FINKELSTEIN JOSEPH ALAN, FRAZEE JAMES SIMPSON, KAISER CARL, KRUSE LAWRENCE IVAN, LEONARD THOMAS BRENT, FINKELSTEIN, JOSEPH, ALAN, FRAZEE, JAMES, SIMPSON, KAISER, CARL, KRUSE, LAWRENCE, IVAN, LEONARD, THOMAS, BRENT
Applicants: SMITHKLINE BECKMAN CORP, SMITHKLINE BECKMAN CORPORATION
Application year: 1987
Main classification: C07D233
IPC codes: C07D233