CA1241003A - DOPAMINE-.beta.-HYDROXYLASE INHIBITORS - Google Patents

Abstract

Title Dopamine .beta.-hydroxylase Inhibitors Abstract of the Disclosure Potent DBH Inhibitors having the formula:

Description

12410~3 TITLE
Dopamine-B-hydroxylase Inhibitors FIELD OF THE INVENTION
This invention relates to inhibitors of dopamine-~-hydroxylase.
15BAC}~GROUND OF THE IN~tENTION
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 norepine-phrine by dopamine-~-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. Pharm. Ther. 14, S4~ (1973), and Teresawa et al., Japan Circ. J. 35, 339 (1971). Weinshilboum, Mayo Clin. Proc. 55, 39 (1980), reviews compounds which inhibit catecholamine activity by interfering with adrenergic receptors. Alternatively, the catecholamine biosynthetic pathway can be suppressed at any of the three steps, resulting in decreased levels of ~E. In addition to decreasing hypertension, inhibitors of NE synthesis are active as diuretics, natriuretics, cardiotonics and vasodilators. Inhibition of DBH activity can have the added advantage of increasing levels of DA, which as reported by Ehrreich et al., "New Antihypertensive Drugs,"
Spectrum Publishing, 1976, pp. 409-432, has been found to , "

~ Q n 3 2-1 have selective vasodilator activity at certain concentrations.
DBH inhibitors have also been shown to reduce or prevent formation of gastric ulcers in rats by Hidaka 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).
Although there are many known inhibitors of DBH, none of these agents has found clinical application 10 because of non-specific, often toxic, properties they possess. Fusaric acid, for example, has been found to be hepatotoxic. See, for example, Teresawa et al., Japan.
Cir. J. 35, 339 ll971) and references cited therein.
Presumably, the picolinic acid structure interacts with a 15 number of metalloproteins and enzymes in non-specific fashion to produce observed side effects.
In U. K. specification 1,155,580 are disclosed compounds having the formula:

SH

Rl- N N

wherein R2 and R3 can be H and Rl 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 Rl can be phenyl or phen (Cl 3) alkyl, as intermediates to imidazolyl-2-thioalkanoic acid esters.
Iverson, Acta Chem. Scand. 21, 279 (1967) reports a compound having the formula:

lZ4~003 ~CE~2 ~ N ~ N
ll ~ ~
S ~

wherein R can be -CO2H or -CH2NHC6H5, but does not report a pharmaceutical use for the compound.
SUMMARY OF THE INVENTION
The invention provides a compound selected from the group and having the formula:
CHO
~CH2~n /~

~ Xl N N and ~ ~ N
y~

wherein n is 0-4;
M is an organic salt of an alkali metal;
yl is -H, -OCH3, -F, -CF3 or C1_4 alkyl;
xl IS -H, -OCH3, -F, -CF3 or Cl_4 alkyl, or any accessible combination thereof up to four substitutents and a process for their preparation.
The process comprises, desulfurizing a basic thioimidazole, and treating it with an organic salt of an alkali metal so as to obtain a compound of the formula:

12410(~3 -3a-M
I

2~ ~
N
yl_ \~ 1 \=/

and if desired, reacting said ~ H2~n~N ~ N
Y~

with a di-substituted foramide to yield a compound of the formula:
CHO
I

~_~H2~ 3 The invention resides in the discovery that DBH can be inhibited by a compound having an imidazole-2-carboxylic acid or 2-aminomethyl imidazole moiety and a phenethylamine analogue moiety. More particularly, the invention is selected novel compounds having the formula:

~ CH2 ~ N ~ N
Y~ ~/

wherein Y is -H, -OH, -OCH3, -F, -CF3 or C1_4 alkyl;
.~

lZ41003 -3b-X is -H, -OH, -OCH3, -F, -CF3~ C1_4 alkyl~
of any accessible combination thereof up to four substituents;
R is -CO2H or -CH2NHRl;
R1 is -H, phenyl or benzyl; and, n is 0-4, or a pharmaceutically acceptable acid addition salt or hydrate thereof, provided that when R is -CO2H
or -CH2NHC6H5, X is -H and n is 1, Y is not -H.

"

12~10~3 -1 In one preferred embodiment of the compounds of the invention, R is -CO2H and n is 1 or 3. In a second such preferred embodiment, R is -CH2NHR ; Y is -H or -O~; R is -H or benzyl; and n is 1.
The invention is al~o a method of inhibiting DBH
activity in mammals which comprises administering internally to a subject an effective amount of a compound having the formula:

~C H 2~ J~
Y~ ' \~

wherein Y is -H, -OH, -OCH3, -~, -CF3, Cl_4 alkyl;
X is -H, -OH, -OCH3, -F, -CF3, Cl_4 alkyl, or any accessible combination thereof up to four substituents;
R is -CO2H or -CH2NHR ;
Rl i8 -H, phenyl or benzyl; and, n is 0-4, or a pharmaceutically acceptable acid addition salt or hydrate thereof.
In the preferred method of the invention, R is -CO2H and n is 1 or 3, or, R is -CH2NHRl, Y is -H or -o~, R is -H or benzyl, and n is 1.
The invention includes pharmaceutical compositions comprising the compoun,ds which are useful in the method of the invention and a pharmaceutical carrier.
Pharmaceutically acceptable acid addit:ion salts, and hydrates, are included within the above formulae.

1~41C3~

1 The invention is also a compound having the formula:

CHO
~ 2 Y ~Xl ~

wherein yl is -H, -OCH3, -F, -CF3 or Cl_4 y xl is -H, -OCH3, -F, -CF3 or Cl_4 15 alkyl, or any accessible combination thereof up to four substitutents.

n i~ 0-4.

This compound is converted to the 2-aminomethyl imidazole 20Of the invention by reducing the compound.

The invention is also a compound having the formula:

2 5 ~ ~n~ /~?

y~

\

wherein yl is -H, -OCH3, -F, -CF3 or Cl_4 alkyl:

xl is -H, -OCH3, -F, -CF3 or Cl_4 alkyl, or any accessible combination thereof up to four 35 substituents;

~, lZ41003 1 n is 0-4; and, ~ is an organic salt of an alkali metal.
This compound is converted to the imidazole-2-carboxylic acid of the invention by quenching with C02.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention contain a weak metal-chelating functional group. They also contain a phenyl moiety as do phenethylamine analogue inhibitors such as benzy}oxyamine, benzylhydrazine, tryptamine and 10 serotonin.
The compounds of the invention can be prepared from corresponding 2-mercapto-1-(4-methoxyaryl)imidazoles by procedures such as those illustrated in the Examples below. Starting mercaptoimidazoles are known (see, for 15 example, U.S. 3,915,980 and U.K. 1,155,580) or can be prepared from corresponding benzaldehydes, which are known and described in published references or are readily accessible by known techniques, such a~ illustrated in Scheme I, depicted below, wherein Xl and yl are X and 20 Y, respectively, except that w~en Y is _o~, yl is -OCH3 and when X is -OH, Xl is -OCH3. As illustrated, n is one, although n can be 0-4. Scheme I
illustrates reductive amination of the benzaldehydes (I) with an amnoacetaldehyde acetal followed by reduction by, 25 for example, catalytic hydrogenation or treatment with a reducing agent such as NaBH4, LiAlH4 or A1~3, to provide intermediate substituted benzylamines (II). Upon reaction with acidic thiocyanate, the intermediates II
yield starting mercaptoimidazole compounds (III) which can 30 be converted to the compounds of the invention by procedures known in the art, such as described below and as illustrated in the examples which follow.

12~1003 1 Scheme I

J ~ MH2CH2CH(OcH2cH3)2 ~ ~ NCH2CH(OCH2CH3)2 H2/Pd ~ yl ~NH~H2CH(OCH2CH3)2 II
. SH

H+/~CN ~ yl ~ N ~ N
. III .
The l-phenyl sub~tituted 2-mercaptoimidazole starting compounds (n i~ O) are preferably prepared by 20 reaction of an appropriately substituted phenyl isothiocyanate wlth an aminoacetaldehyde acetal followed by ~trong acid c~talyzed cyclization, as illustrated in Example 1, below.
The compoun~s wherein n i~ 2,3 or 4 are 25 preferably prepared as described in Example 4, below.
Coupling of substituted phenyl alkanoic acids as the acid chlorides with aminoacetaldehyde acetals and subsequent reduction provides such intermediate substituted phenyl alkylamines.
yl in Scheme I is the same as Y except that when Y is -OH, yl is -OCH3 deprotection of the 4-alkoxy group with, for example, BBr3 or HBr, or nucleophilic aromatic substitution with dilute hydroxide, provides the phenol (Y is -OH). X may be one or more 35 substituents at the 2-, 3-, 5- or 6-positions provided the combination of substituents i8 accessible, that is, does not result in significant instability due to steric 124~003 1 hindrance. When Xl is -OCH3, it can be deprotected as described above for Y .
Rane ~ nickel desulfurization of the starting mercaptoimidazoles (III) provides parent aralkylimidazoles 5 which can be treated with an organic salt of an alkali metal to provide intermediate aralkyl substituted 2-alkaliimidazoles. The alkali substituent can be replaced such as by quenching with disubstituted formamides to give the 2-aldehydes, as in Example 5, or 10 with C02 to give the 2-carboxylic acid, as in Example 9.
The corresponding substituted aminomethyl compounds (R is -CH2N~Rl wherein Rl is -~, phenyl or benzyl) can be prepared from the 2-aldehydes by reduction of intermediate 2-aldoximes or o-alkyl ethers of 152-aldoximes as illustrated in Example 6, or by reductive amination with primary or secondary amines as illustrated in Example 7.
The pharmaceutically acceptable acid addition salts of the compounds of the inventlon are formed with 20 strong or moderately strong organic 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 such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible 25 solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the described 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,

3~ ethanesulfonate, benzensulfonate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, phosphate and nitrate salts.
The compounds of the invention, because they can be used to inhibit DBH activity, have therapeutic value as 35 diuretic, natriuretic, cardiotonic, antihypertensive and lZ41003 9 1 vasodilator agents, as well as antiulcerogenic and antiparkinson disease agents. Compounds of the invention and the compounds wherein R is -CO2H or -CH2NHC6H5, Y i8 -H, X is -H and n is 1, which compounds are useful in the method of the invention, were screened for in vitro DBH inhibition by a standard procedure for assaying conversion of tyramine to octopamine in the presence of DBH. Octopamine was assayed following sodium periodate oxidation to p-hydroxy-10 benzaldehyde by measuring spectrophotometric absorbance at330 nm. Results are given in Table I, below. Inhibition is given in molar concentration of compound at which DBH
activity was halved (IC50). Melting points ~mp) are given in C. Fusaric acid, by this test was found to 15 have an IC50 of 8x10 7.

~able r Com~ound ~P ICSo R Y X n C82N~2 2~Br OH ~ 1 252-254 3.5 x 10 5 C02~-Hcl a ~ 1 129(dec) 1.1 x 10 5 CO2~ HCl OH H 1 142(dec) 9.0 x 10 5 CO2~ 1/2 ~2 ~ ~ 3 136(dec) 7.0 x 10 5 Co2~-Hcl ~c~3 8 } 132(dec) 7.5 x 10 5 C~2NHC6~5 2BBr OH ~ 1 198-200 ' 10 4 CO2~ HCl OC~3 H 3 130(dec) 9.5 x 10 5 C~ NH 2~Cl H a 1 185-187 2.4 x 10 4 C~2NHC6HS-2HC1 ~ ~ 1 20fi 1.0 x 10 4 The following procedure was used to test, for in vivo activity, compounds which can be used to inhibit DBH
activity in mammals, including certain illustrative compounds of the invention. The compounds wherein R is -CO2H or -CH2NHC6H5, X is -H, Y is -H and n is 1 35 are not compounds of the invention but can be used in the 1~1003 -10-1 method of the invention.
Male~ Okamoto-Aoki strain spontaneously hypertensive rats, 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 compound was administered, p.o., along with a 25 ml/kg load of normal saline. The animals were then placed in metabolism cages, three per cage, and urine was collected for three hours and subsequently analyzed for 10 sodium, potassium, and creatinine Indirect systolic blood pressure and heart rate were measured via a tail-cuff method and the animals received an identical second dose of the test compound. Two hours after the second dose, the systolic blood pressure and heart rate 15 were again determined. Drugs were administered as a solution or suspension in normal saline with 0.02%
ascorbic acid.
Three rat~ weighing 270-320 g were used. Each received two intraperitoneal injection8, in a 24 hour 20 period, of a dose volume of 5 mL and a dose concentration of 50 mg/kg or 25 mg/kg, in 0.9% NaCl, following a 24 hour pretreatment dose. Averaged results were as tabulated in Table II, below. Averaged results with control animals, three per experiment, are reported in parentheses below 25 results of test animals.

3 OD ~O
_ _ _ _ O O O 0-- g 0-- 0 o D ~ ~ ~ O
o /~4 e _ _ _ _ 10 ~ ~
C~
o :1~ D _ _ _ _ CO _l a ~ .
_ _ 20 ~ Is r~
_ ~,~, _ ~ _ 3 ~ o ~ ~ ~ o o o .~ ~o ~ , ~ ~o , 2!j ~ _ O ~ _ _ _ ~
I ~ r~ 0 ~~
z _ _ _ ~ -' co ~o o~ ,, oo 7 ~ , 7 c o ~ 8 1 ' ~ 8 ~
9 11 ~ 11 U ~ O 11 U ~ 3 2 ~ x ~ ~ ~ ~ c ~ ~ x ~: e ~ ~ ~ ~ e ~24~003 1 Analysis of the above-tabulated results indicates that the compounds inhibit DB~ activity as shown by the IC50 data and/or by their in vivo natriuretic, diuretic, and antihypertensive and/or cardiotonic activity. For 5 example, the compound in which R is -C02H, X and Y are -H and n is 3 showed significant in vivo activity as a natriuretic, diuretic, antihypertensive and cardiotonic agent; the compound in which R is -C02H, Y is -OH, X is -R, and n is 3 showed significant diuretic activity; the 10 compound in which R is -CH2NH2, Y is -OH, X is -H, and n is 1 showed significant antihypertensive activity; the compound in which R is -CH2N~C6H5, Y is -OH, X is -H
and n is 1 showed significant cardiotonic activity.
Compounds having diuretic activity are known to be useful 15 as antihypertensives.
The compounds can be incorporated into convenient dosage unit forms such as capsules, tablets or injectable preparations. Pharmaceutical carriers whlch can be employed can be solid or liquid. Solid carriers include, 20 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 time delay material, such as 25 glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier will vary widely but, preferably, will be from about 25 mg to about 1 9 per dosage unit. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin 30 capsule, sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical preparati~ns are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating and compressing, 35 when necessary, for tablet forms, or mixing, filling and ~2~QO313 1 dissolving the ingredients, as appropriate, to give the desired oral or parenteral end products.
Doses of the present compounds in a pharmaceutical dosage unit will be an effective amount, that is, a nontoxic quantity selected from the range of O.1-1,000 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, rectally, by injection or by infu~ion. Parenteral administration, 10 which uses a low dose is preferred. However, oral administration, at a higher dose, can also be used when safe and convenient for the patient.
The following examples are illustrative of preparation of compounds of the invention (Examples 6-14) 15 or intermediates therefore (Examples 1-5). The starting compounds of Examples 1-4 are commercially available or are prepared by known techniques. The examples are not intended to limit the ~cope of the invention as defined hereinabove and as claimed below. All temperatures and 20 melting points (mp) are degrees Celsius (C).

SH
~ / N ~ N

A solution of 10 g (.06 mole) of p-methoxyphenyl-35 isothiocyanate in 100 ml of CHC13 was treated with 6.3 g lZ 4~ 0 3 -14-1 (.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-~ -dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated H2S04 and 20 ml of H20 was refluxed for 3 hr. The mixture wa~ cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 9 (70~), mp 10 215-7.
The compound is deprotected as illustrated, for example, in Example 6, below, to prepare the phenol (Y is -OH).
EXAMPL~ 2 SH
2~N ~ IY' ,L~ ' \;=./ ' ' A mixture of 13.6 g (0.1 mole) of anisaldehyde, 25 13.3 g (0.1 mole) of aminoacetaldehyde diethyl acetal and 1 ml of CH30H was heated at 95 for 10 minutes. A
residue was dissolved in 150 ml of ethanol and hydrogenated over 10% Pd on carbon at 50 psi (0.34 MPa) until ~2 uptake was complete. The catalyst was filtered 30 and the filtrate was treated with 10.4 g ~0.107 mole) of RSCN, 40 ml of 3N HCl and 40 ml of H2O. 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 35 H2O and dried. Recrystallization from ethanol gave 124~L0~)3 1 (1-(4-methoxybenzyl)-2-mercaptomidazole, 15.0 g (68%), mp 140-142.

SH

B ~ \N ~N

A solution of 10.75 g (.05 mole) of 3-bromo-4-methoxybenzaldehyde and 6.65 g ~.05 mole) of amino-acetaldehyde diethyl acetal ln 25 ml of ethanol wa~
refluxed for 30 minutes. The solvent was evaporated and the residue was dissolved in CH2C12. The CH2C12 20 solution of the Schiff base was washed with saturated aqueous NaCl, dried (X2CO3)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 NaBH4. The reaction mixture was 25 allowed to warm to 22 and, after 4 hr, the solvent was evaporated. The residue was taken up in diethyl ether, washed with ~2' dried (MgSO4) and filtered, and the solvent was evaporated. A solution of the residue in CHC13, upon treatment with ethereal HCl gave, on 30 standing, crystals of N-(3-bromo-4-methoxybenzyl) aminoacetaldehyde diethylacetal hydrochloride, 10.75 g (58%), mp. 112-120.
A solution of 10.74 g (.029 mole) of N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethyl 35 acetal hydrochloride and 3.37 g (0.35 mole) of RSCN in 50 ~2~0~)3 1 ml of H20, 50 ml of ethanol and S ml of 3N HC1 was refluxed for 4.5 hr. One hundred ml of H20 was added and the ~ixture was cooled. A solid was filtered, washed with H20 and dried. Recrystallization from ethanol gave 1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72~), mp 188.

}O ~ H2~3~N ~ N

A solution of 12.5 9 (.Q7 mole) of p-methoxyphenylpropionic acid in 100 ml of CH2C12 and one drop of pyridine was treated with 9.8 ~ (.077 mole) of oxalyl chloride. After 2.5 hr, the solvents wer¢
thoroughly evaporated to give the acid chloride as an oii. A solution of the zcid chloride in 100 ml of CH2C12 was slowly added to a cold (0) solution of 14.7 g (0.14 mole) of aminoacetaldehyde dimethyl acetal in 300 ml of CH2Cl2 at a rate such that the temperature stayed below 20. After 1 hr, the reacti~n m$xture was poured into %2~ and the CH2C12 layer was separated and washed with aqueous Na2C03, 0.5N HCl and H20.
Following drying and evaporation of the solvent, N~ dimethoxyethyl)-p-methoxyphenylproponamide was left 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 9 of LiA1~4 in 400 ml of diethyl ether and 350 ml of tetrahydrofuran (THF). After 3.5 hr at 22, excess LiAlH4 was cautiously destroyed, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in 100 ml of 0.15N HCl, washed with diethyl '1 241~3 1 ether, basified with NaHCO3 and extracted with diethyl ether. The extracts were dried (MgSO4)and the solventwas evaporated to give N-[3-(4-methoxyphenyl)-propyl]-amino-acetaldehyde dimethyl acetal, 4.6 g (52%), as an unstable oil.
A solution of 3.62 9 (.014 mole) of N-[3-(4-methoxyphenyl)propyl]dimethyl acetal and 1.4 9 (.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of H20 and 2 ml of concentrated HCl was refluxed for five hr. Fifty ml of 10 ~2 was added, the mixture was cooled and a solid was filtered, washed with H20 and dried. Recrystallization from ethanol gave l-[3-(4-methoxyphenyl) propyl3-2-mercaptoimidazole, 2.4 g (69~), mp 108-109.
Example 5 H C3 ~ CH2\N ~ N

A mixture of 15.0 g (0.068 mole) of 1-(4-methoxy-benzyl)-2-mercaptoimidazole and 80 g of RaneyR nickel in 800 ml of ethanol was refluxed for 4 hr. The nickel was 30 filtered off and the filtrate was evaporated. The residue was dissolved in 100 ml of lN HCl and this solution was washed with diethyl ether. The aqueous layer was basified with ~aHCO3 and extracted with ethyl a~etate. The extracts were dried (K2CO3), filtered and the solvent 35 was evaporated, to give 1-(4-methoxybenzyl)imidazole as ~2410~3 1 an oil, 8.7 9 (68%). A solution of this oil in acetone was treated with hexamic acid and diethyl ether, and the !hexamate salt was crystallized, mp 157-159.
A solution of 4.9 g (.026 mole) of 1-(4-methoxy-benzyl)imidazole in a mixture of lS0 ml of diethyl ether and 30 ml of tetrahydrofuran (THF) under an atmosphere of argon was cooled to -60 and treated with 18 ml of a 1.7M solution of n-butyl lithium in hexane. After 1.5 hr, 2.25 g (.031 mole) of dimethylformamide (~MF) was added, 1 and the reaction mixture was warmed to 22. After 30 min, the reaction mixture was treated with 100 ml of l.SN
HCl, and this aqueous mixture was washed with diethyl ether. The acidic layer was basified with NaHCO3, and extracted with diethyl ether. The extracts were washed 15 well with H2O, dried (K2CO3), and filtered and the solvent was evaporated. The residue was a pale yellow unstable oil, 1-~4-methoxybenzyl) 2-formylimidazole, 4.9 g (87%).
Ex~

r NH2 ~ CH2~ N~N

~0 2HBr A vigorously stirred suspension of 2.5 9 (.012 mole) of l-(4-methoxybenzyl)-2-formyl imidazole in 30 ml 30 of H2O was treated with 6 g of CH3CO2Na 3H2O and l.S g of NH2OH HCl. After 2 hr, the 1-(4-methoxybenzyl)-2-formyl imidazole oxime had solidified. The oxime was filtered, washed with H2O, dried and recrystallized from ethanol to give 1.9 g (68%), mp 201-204.
A solution of the oxime in 100 ml of ethanol was ~z4l0n3 1 hydrogenated over Raney~ nickel at 50 psi tO.34 MPa) for 3 hr. The catalyst was filtered, the filtrate was treated with ethereal HCl and the solvent was evaporated. The residue was recrystallized from ethanol three times togive 1-(4-methoxybenzyl)-2-aminomethyl imidazole dihydro-chloride, 0.53 g (22%). A suspension of this salt in S0 ml of CH2C12 was washed with aqueous NaHCO3. The CH2C12 solution of the free base was dried (K2CO3) and filtered. The filtrate was treated with a solution of 10 1.0 9 (.004 mole) of 8Br3 in 2.5 ml of CH2C12.
After 6 hr, methanol was cautiously added and all the solvents were evaporated. The residue was recrystallized from a mixture of methanol and diethyl ether to give 1-(4-hydroxybenzyl)-2-aminomethyl imidazole dihydro-15 bromide, 0.17 g (27%), mp 252-254.
Example 7 r ~Hc6H!;
~ 2 ~ N 2HCl A solution of 1.88 g (.0087 mole) of 1-(4-methoxy-benzyl)-2-formyl imidazole and 0.81 g (.0087 mole) of aniline in 20 ml of ethanol was refluxed for 1.5 hr. The 30 reaction mixture was cooled to 22 and treated with 3.0 g of NaBH4. After 3 hr, the solvent was evaporated.
The residue was taken up in diethyl ether, washed with H2O, dried and filtered and the solvent was evaporated.
The residue was converted to its dihydrochloride salt in a 35 mixture of CH2C12 and ethyl acetate with ethereal HCl, lz~lon~

1 to give 1-(4-methoxybenzyl)-2-phenylaminomethyl imidazole dihydrochloride, 1.8 g (56%), mp 146-157.
Example 8 rNHCH,jH5 ~ CH2 ~ ~ 2~1Br A suspension of 1.6 g (.0044 mole) of 15 1-~4-methoxybenzyl)-2-phenylaminomethyl imidazole dihydrochloride in 100 ml of CH2C12 was converted to its free ba~e by washing with aqueous NaHCO3. The CH2C12 was dried (K2CO3), ana filtered, and the ~iltrate was treated with a ~olution o~ 3.3 g (.013 mole) 20 of BBr3 in 9 ml of CH2C12. After 3 hr, methanol was cautiously added and.all the solvents were evaporated.
The residue was recrystallized from methanol and diethyl ether to give l-(4-hydroxybenzyl)-2-phenylaminomethyl imidazole dihydrobromide, 0.73 gm (39~), mp 198-200.
Example 9 ~2~3~ N /~N

H3CO ~ ~ HCl 0~3 1 A mixture of S.0 9 ~.02 mole) of 1-13-(4-methoxy-phenyl)propyll-2-mercaptoimidazole~ 40 9 of Rane ~
nickel and 200 ml of ethanol was refluxed for 4 hr. The Ni was filtered off and the filtrate was evaporated. A
residue was dissolved in 25 ml of lN HCl, and washed with diethyl ether. The aqueous phase was basified with aqueous NaHCO3 and extracted with diethyl ether. The extracts were dried over R2CO3 and filtered, and the solvent was evaporated. 1-[3-(4-methoxyphenyl) 10 propyl]imidazole remained as an oil, 2.5 q (58%). This oil was dissolved in 100 ml of diethyl ether and cooled to -60 under an argon atmosphere. A 1.7M solution of n-butyl lithium in hexane, 8.2 ml, was added, and the solution was stirred for 1.5 hr. The argon was replaced 15 with bone dry CO2, and the reaction was stirred vigorously until CO2 uptake ceased. The reaction mixture was warmed to 22, and the white lithium salt was filtered. The f~lter cake was washed with diethyl ether, and dissolved in 10 ml of H2O. HCl, lN, was 20 added to pH4, at which pH a product crystallized. The product wa~ filtered, washed with H2O, and dried. The product was converted to its HCl salt by treatment of an ethanolic solution of the above filtered material with ethereal HCl and diethyl ether. The resultant 1-[3-(4-25 methoxyphenyl)propyl]imidazole-2-carboxylic acid hydrochloride was 1.2 g (35%), mp 130 (dec).
Example 10 3 o ~/ N - N

1.2~2!~)3 1 Substantially by the procedure of Example 9, except that the starting mercaptoimidazole was 1-(4-methoxybenzyl)mercaptoimidazole, the compound 1-(4-methoxybenzyl)imidazole-2-carboxylic acid hydrochloride, m.p. 115 (dec), was prepared.
Example 11 J~ ~=~
H0 . ~ H20 A suspension of 1.1 g (.0037 mole) of 1-~3-~4-methoxyphenyl)propyl]imidazole-2-carboxylic acid hydrochloride in 100 ml of CH2C12 at 5 wa~ treated with a solution o 2.8 g ~.011 mole) of BBr3 in 7 ml of CH2C12. The mixture was allowed to warm to 22, and stirred for 5 hr. Methanol was cautiously added, and when a virgorou~ reaction was over, all solvents were evaporated. A residue was dis~olved in 10 ml of H2O and the pH was adjusted to 3.5 with aqueous NaHCO3. The product crystallized, was filtered, washed with H2O and dried. RecrystallizatiOn from methanol gave 1-[3-(4-hydroxyphenyl)propyl]imidazole-2-carboxylic acid, hemihydrate, 0.65 g (71%), mp 136 (dec).
Example }2 ~ / CH2~ ~
Y . - N N
~ ~ l ~ ~ ~2 3~ .

1 Substantially by the procedure of Example 9, except that the starting mercaptoimidazole was 1-(4-methoxybenzyl) mercaptoimidazole, the compound 1-(4-methoxybenzyl)imidazole-2-carboxylic acid, hydro-chloride, mp 115, was prepared. Substantially following the procedure of Example 11, the carboxylic acid was converted to l-(4-methoxybenzyl)imidazole-2-carboxylic acid hydrochloride hydrate, m.p. 135-142 (dec).
Example 13 CH2~1t2 ¢~4~ /~

Substantial}y by the procedure of 2xample 5, except that the starting mercaptolmldazole was 1-benzyl-2-mercaptoimidazole, a commercially available compound, the compound, 1-benzyl-2-formyl imidazole, was prepared.
Substantially following the procedure of Example 6, the benzyl imidazole was converted to l-benzyl-2-aminomethyl imidazole dihydrochloride, mp 185-187.
Example 14 r~c6~
~4~ /~

W

Substantially by the procedure of Example 5, except that the starting mercaptoimidazole was 1-benzyl-2-i Z 4 1 0 ~ 3 -24-1 mercaptoimidazole, a commercially available compound, the compound, l-benzy}-2-formyl imidazole, was prepared.
Substantially following the procedure of Example 7, the benzyl imidazole was converted to l-benzyl-2-benzyl aminomethyl imidazole dihydrochloride, m.p. 206.
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 precise constructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims (9)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound selected from the group and having the formula:

and wherein n is 0-4;
M is an organic salt of an alkali metal;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substitutents, comprising desulfurizing a basic thioimidazole, and treating it with an organic salt of an alkali metal so as to obtain a compound of the formula:

and if desired, reacting said with a di-substituted foramide to yield a compound of the formula:
.

2. A process for preparing a compound having the formula:

wherein n is 0-4;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents, comprising reacting with a di-substituted foramide a compound having the formula:

wherein M is an organic salt of an alkali metal.

3. A process for preparing a compound having the formula:

wherein Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents;
n is 0-4; and M is an organic salt of an alkali metal comprising desulfurizing a basic thioimidazole and treating it with an organic salt of an alkali metal.

4. A compound selected from the group and having the formula:
and wherein n is 0-4;
M is an organic salt of an alkali metal;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents whenever prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

5. A compound having the formula:

wherein n is 0-4;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents whenever prepared by the process of Claim 2 or an obvious chemical equivalent thereof.

6. A compound having the formula:
wherein Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents;
n is 0-4; and M is an organic salt of an alkali metal whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.

7. A compound selected from the group and having the formula:

and wherein n is 0-4;
M is an organic salt of an alkali metal;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents.

8. A compound having the formula:

wherein n is 0-4;
Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents.

9. A compound having the formula:

wherein Y1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl;
X1 is -H, -OCH3, -F, -CF3 or C1-4 alkyl, or any accessible combination thereof up to four substituents;
n is 0-4; and M is an organic salt of an alkali metal.