DE2161209A1 - Substituted imidazoles, their pharmacologically acceptable salts, processes for their preparation, and medicinal preparations containing these compounds - Google Patents

Description

Brentford, Middlesex, UK

¹¹ Substituted imidazoles, their pharmacologically acceptable salts, processes for their production, and medicinal products containing these compounds "

Priority: December 9, 1970, Great Britain, No. 58 385/70

The invention relates to new substituted imidazoles, a method for their production and their use in medicinal products as active ingredients with pharmacodynamic activity.

Compounds with anti-tumor effects, such as 5- (3,3 ~ dimethyltriazeno) imidazole-4-carboxamide (formula Ia) and some analogues (see: Shealy and coworkers in "Biochem.Pharmacol,"
Vol. 11, 674, (1962) and "J. Org. Chem.", Vol. 27, 2150 (1962)) are treated in the specialist literature as analogs of 5-amino-imidazole-4-carboxamide (formula Ib), which plays a role in the biosynthesis of purine ribonuoleotides and nucleic acids;

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_ 2 -

(Ia) Rx = NNN (CH ₃ ) ₂
(Ib) RX =

Since the first publication mentioned above in 1962, modifications to the two compounds have been sought according to formula Ia and Ib largely adhered to this structure, and it was considered essential for the anti-tumor effect of a Compound that it contains the group (II).

(II)

Triazenoimidazole of the general formula (III) (see CA-PS No. 871 699), in which R _{2 is} an amino or an optionally substituted.

1 1-tuated hydroxyl group and IL · and R, - optionally substituted Are hydrocarbon groups, have weak antileukemia and antibiotic effects, yet it was suggested that they only be used for disinfection of bed linen should be used.

(in)

A particularly successful modification of the structure according to formula (Ib) is the compound 5- / 3,3-bis (2-chloroethyl) -l-triazene-7iniidazole-4-carboxamide with the formula (IV) (see Shealy and

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Contributed in "Journal of Pharmaceutical Sciences", 5_7, 83 bis 86 (1968)):

H ^ n

.A

This compound is unstable, isomerizes rapidly, and shows weak activity against L1210 indoor lymphoid leukemia (See: Shealy and co-workers in "Nature", 210, 208, (1966)). The isoraeration product, on the other hand, which is formed when the Compound (IV) is not kept under exclusion of license and temperatures below 0 C is not active against leukemia. Besides that the compound (IV) is difficult to prepare, since one starts from the unstable 5-diazo-imidazole-4-carboxaniid of the formula (V) got to.

CO-NH ₂

The preparation of the compound with the formula (III) and (IV) is consistent with the fact that no changes in the "2" position have been reported or suggested since it was previously of the opinion that all modifications were natural occurring purine precursor 5-amino-imidazole-4-carboxamide should be as similar as possible.

The object of the invention was therefore to make changes to the group of the formula (II) to produce compounds that are not only more stable and biologically active, but in some cases also

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- 4 are less toxic than the previously known compounds.

The invention accordingly relates to imidazoles of the general type Formula (Vl)

, CO-R ₂

as well as their automers or structural isomers, also in the form of their "Acid addition salts, the corresponding solvates and solvated Acid addition salts, in which R-, a carbocyclic- or heterocyclic aromatic group, optionally with one or more halogen atoms, with optionally substituted Hydroxyl, amino, thiol, sulfonyl or carboxyl groups, is substituted by cyano, nitro, acyl, alkyl, aryl or haloalkyl groups, R? an amino or hydroxyl group or is an alkoxy, aryloxy or arylalkyloxy group, the optional

one wise with one or more halogen atoms or with / optionally

are substituted by a hydroxyl or / or tertiary amino group which is in turn substituted, R means a methyl group or a negative charge when Rz is N2, or a hydrogen st of fat cm or a methyl group when R * -K = MRcRg, where R _{1 is} a methyl or ß-halogen-substituted ethyl group and Rg is a hydrogen of fatom or a Kohl env / water st off group, which is optionally with a halogen atom or with an optionally one of its-

with a

substituted hydroxyl or / tertiary amino group substituted is.

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Phenyl or naphthyl groups or 5- or are suitable for Rn 6-membered heterocyclic groups, such as pyridyl, furyl, Thiazolyl, thienyl, oxazolyl and like groups, optionally with one or more fluorine, chlorine, bromine or iodine atoms, Hydroxyl, methoxy, benzyloxy, nitro, methyl or similar groups are substituted.

Preferred groups for R ₁ are phenyl, naphthyl, tolyl, fluorophenyl, chlorophenyl,. Dichlorophenyl, nitrophenyl, furyl, shienyl and thiazolyl groups. ,.

Suitable for R2 are amino and hydroxyl groups and a hydroxyl group which is substituted by a C-, ΐ2-Κ ° & 1 ^βη ^ ^{& Ξ8βΓ3} ^ ^ο ££ δ ^Γυ · ΡΡ ^θ , which can be aliphatic, alicyclic, aromatic or arylaliphatic and which in turn can be substituted with one or more fluorine, chlorine, bromine or iodine atoms or with amino, hydroxyl, or alkylated or acylated amino or plydroxyl groups ..

The amino, hydroxyl, methoxy, Ethoxy, propyloxy, butoxy and 2-chloroethoxy groups. R, is preferably a hydrogen atom.

Suitable for R ^ are methyl, ethyl, propyl, butyl, benzyl, Hexyl, cyclohexyl and ß-substituted ethyl groups.

For R ^ the methyl, butyl, benzyl, cyclohexyl and 2-hydroxyethyl groups are preferred.

The methyl group is preferred for R ^.

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Although the compounds of the invention only by the one general Formula (VI) are characterized, include all tautomers and the two isomers that occur when R. is a methyl group (see formulas VIIa below to VIIe):

R ₂ -CO

^R l
(Vila)

R ₂ -CO.

N = N-NR ₅ H ₆

(VIIe)

The invention further relates to a process for the preparation of compounds of the general formula (VI), which is characterized in that one or both stages of the following reaction scheme carried out v / ground and that after formation of the triazenoimidazole the R - ^ - and / or Itj groups by known per se Methods replaced or to other R, and / or Rp groups be modified.

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0-R,

Diazotize

Implement with

(VIII) "

(Via)

(VIb)

(In the compound according to formula VIa, if R. is a methyl group is, a countercation such as Cl-, Br-, BIV- is present)

The optional replacement of groups R- and / or Rp by other corresponding groups or the optional modification takes place according to methods known per se, such as an esterification. In order to obtain compounds in which R _{2 is,} for example, an ethoxy group, compounds in which R _{2 is} an OPI group are esterified; if R _{2 is to be} an OH group, the ester group is split off; if R- ^ should be a hydroxyl-substituted phenyl group, the protective group, for example a benzyl group, can be removed by methods known per se.

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The conversion of the amine of the formula (VIII) into the diazonium salt of the formula (VIa) takes place by treating the amine (VIII) or an acid addition salt with nitrous acid, a nitrite or a nitrous acid ester in the presence of an acid, which releases the nitrous acid from the salt or ester.

The reaction is generally carried out in water. Suitable Nitrites are sodium or potassium nitrite, the sodium salt is preferred. Suitable acids are mineral acids such as sulfuric, nitric, hydrogen halide, fluoroboron and ^ Phosphoric acid, or organic acids such as acetic or formic acid. Hydrochloric acid is generally preferred.

The inventive method is generally in one aqueous medium with an excess of sodium nitrite. The mineral acid is added slowly. The aminimidazole of the formula (VIII) is preferably used in the form of an acid addition salt, generally the hydrochloric acid salt. ■

P Thanks to the stabilizing effect of the aromatic group R-, The compounds of the formula (VIb) are easier to prepare than the corresponding ones on the diazonium compound of the formula (VIa) 2-H connections. Therefore, the reaction temperatures do not have to be lowered (as for the preferred preparation 2-H compounds), but elevated temperatures should be avoided. A reaction temperature of 0 to 35 G, in particular Room temperature, is for the Hex's division of the connection Formula (VIa) is particularly suitable.

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The diazonium compounds of formula (Via) are generally Insoluble in water and therefore precipitate when they are formed. she can be isolated by simple filtration. In those cases in which the diazonium compound of the formula (VIa) in V / water is soluble, it can be extracted by a suitable solvent such as chloroform and worked up in the usual way will. Any cleaning is carried out by recrystallization from a suitable solvent such as cyclohexane or methanol, achieved.

In order to avoid side reactions in the process according to the invention to switch off, you can optionally add an acidic solution of the aminoimidazole to an equivalent amount of an aqueous nitrite solution to add. This reaction is then generally carried out at reduced or room temperature.

In those cases in which the diazonium compound is unstable, it is advantageous not to isolate the compound before the next reaction stage, but rather to isolate the reaction in the solution, which contains the crude diazonium compound to perform.

When R ^ is a methyl group, so is the diazonium compound unstable that the reaction has to be carried out at low temperatures, e.g. O G.

To the 'compounds of the general formula (VIa), which by the Diazotization described above are produced, include in particular also those of the general formula (IX):

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• (ix)

where R _{2 is} an OH or NHg group or an OR group, where R is a methyl, ethyl, straight or branched propyl or butyl, hexyl, decyl, phenyl, benzyl, halogen-substituted benzyl or ethyl, 2-diethylaminoethyl or cyclohexyl group.

To the compounds of the general formula (VIa), which by the Diazotization described above are prepared, in particular also include those of the general formula (X):

D ₂ C ₂ H ₅

(X)

where Rn is a phenyl, honohalophenyl, hydroxyphenyl, dichlorophenyl, Dibromophenyl-, Witrophenyl-, TοIyI-, Trifluormethylphenyl-, C - ^ _ g-alkoxyphenyl, dimethoxyphenyl, benzyloxyphenyl, Diphenyl, carboethoxyphenyl, pyridyl, thienyl, furyl, thiazolyl, naphthyl or chloronaphthyl group.

The diazu compound of the formula (VIa) is by reacting with an organic amine HNRcRg into the triazine compound of the formula (VIb) converted.

In general, an excess of the amine is used and the reaction is carried out in a liquid medium using either an aqueous alcohol such as methanol or ethanol, or

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an ether such as diethyl ether or tetrahydrofuran, or one chlorinated hydrocarbon such as chloroform.

The reaction is carried out at low, room or higher temperatures, but low or room temperatures are preferred. The most suitable temperature range is between O and 180 ° C, in particular between 0 to 40 ⁰ C. The products obtained are generally solid, and can be prepared from suitable solvents, such as methanol or ethyl acetate, are recrystallized.

Regarding the compounds of the general formula (YIb), which according to the Processes according to the invention are produced in particular include also those of the general formula (Xl)

(XI)

where R _{2 is} a methoxy or ethoxy group and Rg is a methyl, ethyl, straight or branched propyl and butyl, hexyl, cyclohexyl, phenyl, benzyl, 2-dialkylaminoethyl or 2-haloethyl group.

To the compounds of the general formula (VIb), which according to the Processes according to the invention are produced in particular include also those of the general formula (XII):

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^H X (X-Ii)

where Rj has the meaning given in the preceding for formula (X) Has.

The compounds of the formula (VIb) according to the invention are pharmacological active, e.g. they are bactericidal (Example 57) and "fungicidal (see Example -58), they also show in mammals a weak anti-tumor effect (see Examples 53 and 54), e.g. against Ik lymphoma and ADJ / PCö plaßma cell tumor.

The invention therefore also relates to medicinal preparations which can be used for at least one of the above purposes and are characterized by a content axi of a compound of the formula (YIb) as active ingredient, optionally in combination with a pharmaceutically suitable carrier ^. Suitable carrier substances are conventional binders or lubricants or other auxiliaries for tablets, granules or capsules or sterile water for parenteral administration.

The preparation is preferably used in single doses between 5 mg and 5 g formulated and administered in amounts of 0.5 to 250 mg / kg body weight.

Although the compounds of the general formula (VIa) are not sufficient have biological activity in order to use them for medicinal purposes, so they are docli as intermediate products

- '13 -

the preparation of the active compounds of the general formula (VIb) is valuable.

The Aminoirnidazole used as starting materials of the general Formula (VIII) are according to the methods of Shaw and coworkers ("Journal of the Chemical Society!", (1962) p. 2941) and Cook et al (Journal of the Chemical Society, (1950), p. 1884).

This synthesis consists in the implementation of a <tf-aminonitrile of formula

_. "2

R ₂ CO CH. (R ₂ / 0H)

with a benzylthioformamino hydrochloride of the formula

JIH. HCl C ₆ H ₅ CH ₂ - S - C

¹
in a suitable solvent, preferably at an elevated temperature. This reaction is described in more detail in Example 59.

Further details of the preparation of the compounds of the general Formula (VIII) can be found in DT-OS 21 42 831 and 21 42 832.

The following examples illustrate the invention. The structure of all compounds was checked by IR and NMR spectra. All diazo compounds had a characteristic absorption band at about 2160 cm ", all triazines at 1080 cm".

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_. 14 -

The methyl groups of all 3,3-dimetriyltriazines had a resonance band corresponding to 6 protons at about (S = 3.3.

Example 1 4-Carbathoxy-5-diazo-2-phen.ylimid.azole

37.0 g of ^ Amino-S-carbäthoxy ^ -phenylimidazole hydrochloride in an aqueous sodium nitrite solution from 15 g of sodium nitrite suspended in 750 ml of water, and the mixture is at Room temperature stirred.

100 ml of 2N hydrochloric acid are added in portions over a period of 5 minutes trains sets, and the mixture is stirred for one hour. That yellow reaction product is collected, washed with water and dried in vacuo. Yield: 31.4 g of the crude diazo compound.

Recrystallization from ethanol / water gives 26.3 g of pure 4-carbethoxy-5-diazo-2-phenylimidazole with a melting point of 111 G (with decomposition). The product is in organic Solvents such as diethyl ether or chloroform, soluble, and P shows the characteristic diazo band in the infrared spectrum about 2160 cm "".

The following compounds of the formula (VIa) are prepared by the method of Example 1 (1L · is a negative charge).

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Table I.

example
Mr. ■■. ^R i R ₂ OC ₂ H ₅ j? p.- (under
Decomposition)
⁰ C 2 If 122 3 C ₆ H ₄ IOg (P). It > 200 4th 3-thienyl Il 117 5 2-thienyl 11 131 6th 5-nitro-2-furyl OCHgC ₆ H ₄ CKp) 183 7th ° 6 ^H 5 OCH ₂ C ₆ H ₅
OC ₂ H ₅ : 119 8th
9 ^C 6 ^H 5
C ₆ H ₄ F (O) OCH ₂ CHgCH ₅
00H (CHj) ₂ 126
.108 10
11 C ₆ H ₅
^C 6 ^H 5 NHg 88
96 12th ^C 6 ^H 5 290

Example 13 4-carbethoxy-5- _(3? 3 ~ dimethyl-triazeno) -2-phenylimidazole

8.0 g of 4-carbätlioxy-5-diazo-2-phenyl-imid.azole are in 75 ml Dissolved methanol and with 25 parts of a 30 percent Blmethylaniinlösung added in methanol. The reaction mixture is mixed with water diluted. The product is obtained as pale yellow crystals, which are collected, washed with water and dried in vacuo. Yield 8.22g. A sample is made from methanol / water recrystallized, the pure compound is obtained with a melting point of 171 C.

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ORIGINAL INSPECTED

Example 14

4-carbathoxy ~ 5 ~ (3,3 ~ dimethyltriazeno) -2- (p-fluorophenyl) -imidaz oil

2.0 g of 4-carbethoxy-5-amino-2- (p-fluorophenyl) imidazole hydrochloride are suspended in 20 ml of Vi / asoer containing 1.0 g of sodium nitrate. The mixture is stirred at liaumtemperatur / l and 25 ml of ⁿ hydrochloric acid are slowly added. The mixture is stirred for a further 10 minutes and then extracted with 25 ml of chloroform. The organic phase is separated off, the aqueous phase is extracted with a further 25 ml of chloroform, and the combined chloroform solutions are washed with 25 ml of saturated sodium chloride solution. 7 ml of a 25 percent dimethylamine solution in ethanol are added. The solvents are evaporated. The oil product is recrystallized from ethanol / water / water. Yield 1.55g; Melting point 177 ° C (with decomposition).

Examples 15 to 41 Compounds of the formula

are manufactured according to the procedure of Ben games 13 and 14. The results obtained are summarized in Table 11.

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- 17 Table II

example
No. C ₆ II ₄ CKp) R ₂ OC ₂ II ₅ Fp .., ⁰ C (un
ter Zerset C ₆ H ₄ CF ₃ (P) ti tongue) 15th C ₆ H ₄ CH ₃ (P) Il 144 16 O ₆ H ₄ NO ₂ (P) OC ₂ II ₅ 175 17th C ₆ H ₄ OCH ₃ (P) ti 177 18th C ₆ H ₄ OCH ₂ C ₆ H ₅ (P) ti 176 19th ^c 6V ^C 6 ⁿ 5 ^(p) Il 168 20th C ₆ H ₄ CH ₃ (Di) π 168 21st C ₆ H ₄ F (Ri) ti 175 22nd O ₆ H ₄ F (O) It 176 23 C ₆ H ₅ (OCII ₃ ) ₂ (3.4) II 177
ι C ₆ H ₃ Cl ₂ (3.4) Il 130 25th C ₆ H ₃ Cl ₂ (3.5) Il 180 26th 2-thienyl 11 27 3-thienyl Il 183 28 2-puryl Il 175 29 4-'l'Jiiazolyl Il 178 30th β-naphthyl Il 148 31 ^G 6 ^H 5 OOII ₃ 171 32 Il OCH ₂ CH ₂ CH ₃ 194 33 Il
Il
It • OCH (CH ₃ ) ₂
OCII ₂ C ₆ H ₅
OCH ₂ C ₆ H ₄ CKp) 181 34 Il OCH ₂ CH ₂ Cl 167 35
36
37 Il NH ₂ 165
_H (mono
^öö uydrate)
155 38 C ₆ H ₄ CKp) NH ₂ 166 39 2-thienyl NH ₂ 178 40 170 (wide) 41 193 (wide)

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• Example 42

4-carbethoxy-5- (3-methyl-3 ~ ß-hydroxyethyl) triazeno-2-phenylimidazole

4.04 g of 4-carbethoxy-5-diazo-2-phenylimida2; ol in 100 ml of methanol reacted with a slight excess of H-methylethanolamine. The mixture is diluted to cloudiness rad i gasoline (60 to 80 G). The product is allowed to crystallize out, and it is recrystallized from ethyl acetate. Yield: 4.70 g with a melting point of 158 ° C. (with decomposition).

Examples 43 to 47

Compounds of the formula

CO-R,

NNN (CH ₃ ) R ₆

are following the procedure described in Example 42, manufactured. The results are summarized in Table III,

Table III

example
No. R ₁ ^C 6 ^H 5 H ₂ ^R 6 Fp., ⁰ C (under
Decomposition) 43 ^G 6 ^H 5 OC ₂ H ₅ ^C 6 ^H 5 167 44 C ₆ H ₅ OC ₂ H ₅ CH ₂ C ₆ H ₅ 140 45 ^C 6 ^H 5 OC ₂ H ₅ CH ₂ CH ₂ CH ₂ CH ₇ 118 46 C ₆ H ₄ Cl (P) OC ₂ H ₅ CyClO-C ₆ II ₁₁ 132 47 OC ₂ H ₅ CH ₂ C ₆ H ₅

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Example 48
A -Carbathoxy-5- ( 'j> , 3-dimethylt-riazeno) -2- (3-pyridyl) -imidazole

1 "90 g of 4-Carbätho>: y-5-amino-2- (3-pyridyl) imidazol ~ hydrochloride are dissolved in 10 ml $ N hydrochloric acid and the solution stirred at room temperature" A solution of 0.5 g of sodium nitrite in.
5 ml water is then added in small portions and the
resulting solution stirred for 5 minutes. The mixture is then
Poured into a vigorously stirred solution of 1 ml of 30 percent aqueous dimethylamine and 20 ml of 10 percent aqueous sodium carbonate, a pale brown precipitate is obtained. The crude product is recrystallized from methanol / ether. Yield: 0.65 g of off-white crystals which melt at 125 ° C. with decomposition.

Example A 9

4-carbethoxy-5- (3,3-d imethyItriazeno) -2-p-hydroxyphenyH imiuazole.

0.50 g of 4-carbethoxy-5- (3, 3-dimethyltriazeno) -2-p-benz.yloxyphenylimidazole are dissolved in 50 ml of methanol, the solution is saturated with carbon dioxide and 100 g of 10 percent palladium is added
Charcoal added. The mixture is at room temperature and
Hydrogenated atmospheric pressure. 40 ml of hydrogen are adsorbed within 4 minutes. The mixture is filtered and the Piltrat evaporated. A green residue is obtained which is dissolved in hot methanol, treated with charcoal and then precipitated again as a pale brown powder by adding petrol (60 to 80 ° C.). Yield: 170 mg, melting point 192 ° C. with decomposition. The IiPiR spectrum confirms the presence of a dimen-

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thyltriazeno group and the complete elimination of the protecting benzyl group.

"Example 50. 5- (3,3-Dimethyltriazeno) -2-phenylimidazole-4-carboxylic acid

1 »0 g of 4-carbobenzoxy-5- (3,3-dimethyltriazeno) -2-phenyliniidazole is dissolved in 50 ml of methanol and the solution is saturated with carbon dioxide * 100 ml of 10 percent palladium-on-charcoal are grounded added and the mixture was hydrogenated at room temperature and atmospheric pressure. 60 ml of hydrogen become within 1 hour and absorbed for 20 minutes.

The mixture is filtered and the piltrate is evaporated. You get a dark red oil that grows in vacuo over phosphorus pentoxide is dried. Yield: 600 mg of a red pest. The NMR spectrum shows the complete elimination of the Benzy! Group. The melting point is indistinct, a slight decomposition is observed at around 140 C.

Example 51

4-carbethoxy-5- (3,3-dimethyltriazeno) -2-phenylimidazole hydrochloride

47.4 g of 4-carbethoxy-5- (3,3-dimethyltriazeno) -2-phenylimidazole are stirred into 500 ml of methanol at room temperature and then 20 ml of concentrated hydrochloric acid are added. The clear one The solution is stirred well and diluted with 4 liters v / as of free ether, the product slowly crystallizing out. It is collected, washed well with ether and dried in vacuo. Yield: 52.0 g of off-white crystals with a melting point

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of about 125 G with decomposition. JJaB Product contains one molecule Crystal water.

'Example 52

4-carbethoxy-5- (3, 3-dimethyltriazeno) -2-phenylimidaaol ~ mono ~ hydrate

10.0 g of 4-carbethoxy-5- (3,3-climethyltriazeno) -2-phenylimidazole are in a phosphate solution buffered to pH 7.0 at room temperature stirred in. The originally lemon-yellow solution becomes lighter and after 3 hours the mixture is almost colorless. The product is collected, washed with water and in vacuo dried over phosphorus pentoxide. Yield: 10.4 g. When drying The product only loses its water through phosphorus pentoxide very slowly.

The infrared spectra of this product and an anhydrous one are compared. The following characteristic band maxima (in cm ~) v / earth observed.

(Hujol technique) (G = O) (triazine)

'Anhydrous - 1710 - 1080

Monohydrate 3250, .1650, 1130, 1080

The melting points and the HMR spectra are grounded by the monohydrate unaffected.

Example 53

Some compounds of the invention show antitumor activity against the Kj mouse lymphorn. This R-j lymphoma is usually against Antimetabolite sensitive. Typically, mice die with them a graft of 1.5 x 10 tumor cells on the 9th to 11th day after the graft on the metastatic tumor.

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The compounds listed in Table IV below are dated in a solution of 10 percent acetone in arachis oil Day 3 to 7 after tumor transplantation daily intraperitoneally injected. The prolongation of the survival time compared to controls is eagerly appreciated.

Table IV

connection of
Example lir. Dose, mg / kg Average ver
extension of survival
benszeit in ^c / o control _ 0 39 50 80 33 16 400 13th 32 300 41 128 50 47 100 40 19th . 33 50 • 22 128 150 24 ' ■ 10 100 25th 33 • 200. 32 128 170 29 33 200 48 32 170 "Methotrexate"
(4-amino-10-methyl-
oleic acid) 2 100

Example 54

The breadth of the anti-tumor spectrum of the compounds of the invention in mice is indicated by activity against the ADJ / PC6 plasma cell tumor explained. This solid tumor is sensitive to most alkylating gowns. Good activity against this tumor and against the R-j lymphoma is rarely observed. The percentage inhibition of the tumor weight is compared with controls

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compared. The therapeutic index indicates the dose at which 90 percent inhibition is achieved (IDqq) compared with the dose at which 50 percent of the animals die
The results are summarized in Table V.

Table V

link
from Bei
game no. Dose i.p. (5 times the dose) 16.0
3.5
20th
inactive Therapcuti-
scner index 39
13;
14th
Hethotrexate
(see table
le IV) ^LD 50,. ^ID 90
mg / kg 15th
88 -
10 240
310
200

Example 55

Compounds of the invention also show activity against Friend's leukemia. The Friend leukemia virus produced in mice a prolonged infection that leads to splenomegallia. The compound of Example 13 is used in a dose of 250 mg / kg / Injected subcutaneously one day before and one, two and three days after infection. The splenomegaly does not occur.

Example 56

Some compounds of the invention are less toxic than previously known compounds. E.g. the connection of the example 13 and dimethyltriazeno-imidazole carboxamide administered to male and female dogs both orally and intravenously. The dose is 20 mg / kg on the first day, 45 mg on the fourth day and finally 90 mg / kg on the ninth day. The both compound of the example administered orally and intravenously

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. - 24 -

13 did not cause negative clinical symptoms and the animals remained in good shape. Both orally and intravenously administered dirnethyltriazeno-imidazolecarboxamide

• a massive decrease in total white blood cells and platelets. Oral administration of the dimethyltriazeno-imidazole carboxamide had to be stopped in one test animal after the second dose. The connection of the example 13 does not cause any of these adverse effects.

Example. 57

Some compounds of the invention show bacterial activity. The compound of Example 13 is tested, for example, in DST agar with 5 percent lysed horse blood against the following bacteria; the minimum inhibitor concentration (M.I.G.) is given:

Staphylococcus aureus, M.I.C. 10 ug / ml Streptococcus haemolyticus, M.I.C. 1 µg / ml.

Example 58

Some compounds of the invention also show fungicidal activity. The compound of Example 13 is tested against the following fungi, for example, and the minimum inhibitor concentration (M.1.C.) is given:

Candida albicans 10 jag / ml

C. neoformans 10-50 ig / ml

Trychopyton mentagrophytes - 10 ng / ml

This activity against Candida and related organisms is particular for use in potential antileukemia agents important, since secondary mi-

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kosen more and raeiir are responsible for death in leukemia (see J. G. Gr-Jm, "Cancer", Vol. 16, p. 61, (1963).

Example 59 5-Amino-4-carbethoxy-2-phenylimida2ol

29.0 g of phenylformamino-benzyl-thioether hydrochloride are mixed with 170 g of amirio-cyanoacetic acid ethyl ester in 200 ml of chloroform and refluxed for 1 hour. The mixture is left to stand for 8 hours. After addition of 250 ml of dry diethyl ether, the hydrochloride precipitates out .. It is crystallized from ethanol to- ". Yield: 25 g, mp 228 ⁰ C. (Uach treating the salt with aqueous sodium carbonate gives the free base.)

Example 60. 5-Carbethoxy-4- (3,3-dimethyltriazeno) -1-methyl-2-phenylimidazole

2.84 g of 4-amino-5-carbethoxy-1-methyl-2-phenylimidazole, according to Cook and coworkers ("Journal of the Chemical Society," (1950) p. 2775 produced, are dissolved in 24.0 ml of 5N hydrochloric acid and cooled to 0 C, then a cold solution of 0.96 g of sodium nitrate in 5 ml of water is slowly added with stirring. The temperature of the mixture is kept at 0.degree. The resulting solution becomes a cold (0 C) solution drop by drop of 120 ml of 30 percent sodium carbonate and 2.5 ml of 25 percent aqueous dimethylamine were added.

The resulting rubber-like product is separated off and with

brown crystals. Yield: 1.7 g, melting point 79 ° C

mixed with a solution of gasoline and diethyl ether. You get swan-brown crystals,
(with decomposition).

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Claims (19)

Claims ' 1. Substituted imidazoles of the general formula ■ -! ■ * W i ^ VU * »S i * JW **" VI * ^ »A * V- /« J ^ K ^ V ^ ~ i-Hi -JL * V ^ ^^ <J ^ CO-R ₂ I. ^ R ₅ ^R i- and their tautomers or structural isomers, also in the form of their acid addition salts, the corresponding solvates and solvated acid addition salts, characterized in that R _{1 is} a carbocyclic or heterocyclic aromatic group which optionally has one or more halogen atoms, with optionally substituted hydroxyl, Amino, thiol, sulfonyl or carboxyl groups, is substituted with cyano, nitro, acyl, alkyl, aryl or haloalkyl groups, Rp is an amino or hydroxyl group or an alkoxy, aryloxy or arylalkyloxy group, which is optionally with a one or more halogen atoms or with / optionally submit one
substituted hydroxyl or / tertiary amino group, R / denotes a methyl group or a negative charge when R * is N ₂ , or R, a V / as s only of f atom or a methyl group when R ₇ -HR- NRcRg, where R, - is a methyl or ß-halogen-substituted ethyl group, and Rg is a hydrogen atom or a hydrocarbon group, which is optionally substituted with a halogen atom or with an optionally in turn mlt one
ierten hydroxyl or / tertiary amino group is substituted. 209826/1 UO ~ 27 - 2. imidazoles according to claim 1, characterized in that the remainder R- * an Up group, the remainder R / a negative charge, the radical R2 is an amino, hydroxyl, methoxy or ethoxy group and the radical R- is a phenyl group, optionally with one or two halogen atoms, one hydroxyl, methoxy, benzyloxy, Methyl or Hitrοgruppe is substituted. 3. The methyl or ethyl ester of 4-carboxy-5-diazo- * 2-phenylimidazole. 4. imidazoles according to claim 1, characterized in that the radical R, an N = Ii-NRt-Rg ~ group, the radical R, a hydrogen atom and the radical R2 is an amino, hydroxyl or a C-, ~ -alkoxy-, Is aryloxy or arylalkoxy group. 5. imidazoles according to claim 4, characterized in that the radical R2 is an ethoxy or methoxy group. 6. imidazoles according to claim 4 and 5, characterized in that the radical R-i is a phenyl group, optionally with one or two halogen atoms or is substituted with hydroxyl, methoxy, benzyloxy, methyl or nitro groups. 7. imidazoles according to claim 4 to 6, characterized in that the radical R ₁ - and the radical R / - is each a methyl group. 8. imidazoles according to claim 4 to 6, characterized in that the radical Rc is the methyl group and the radical Rg is an ethyl, Butyl, cyclohexyl, 2-chloroethyl or 2-hydroxyethyl group is. 2MJBUUUA1AQ 9. The methyl or ethyl ester of 4-carboxy-2-phenyl-5- (3,3-triazeno) imidazole. 10. Imidazoles according to claim 1, characterized in that the radical R _{7 is} an IJ-N-II (CEz)? Group, the radical 11 »is the methyl group, the radical -Ro is an amino, methoxy or ethoxy group and the remainder R- is a phenyl group which is optionally substituted by one or two halogen atoms, methyl or methoxy groups. P 11. imidazoles according to claim 10, characterized in that " the radical R, a methoxy or ethoxy group and the radical R, is a phenyl group. 12. Process for the preparation of a compound of the formula / U- si,
R ₁ , in which the radicals R ^ and Rp are defined according to claim 1, characterized in that a compound of the formula with nitrous acid, which is developed in the reaction mixture by known methods, is diazotized. 13. The method according to claim 12 for the preparation of a compound according to claim 1, in which the radical Rg is an amino, methoxy 2QJAZ3JJJA0 or ethoxy group and the radical R-. is a phenyl group, the is optionally substituted with one or two halogen atoms, methyl or methoxy groups. 14. Process for the preparation of a compound of the formula CO-R ₂
R ₁ . in which the radicals R ₁ , R ₂ , Rk and Rg are defined according to claim 1, characterized in that a compound of the formula is reacted with an organic amine HMRcRg and that the Residues R-. and / or Rp optionally changed according to known methods or be replaced by other R -, - and / or Rp groups. 15. The method according to claim 14 for the preparation of a compound according to claim 1, in which the radical Rp is an amino or a 0- ^ n- alkoxy, aryloxy or arylalkoxy group and the radical R _{1 is} a phenyl group, optionally with a or two halogen atoms, hydroxyl, methoxy, benzyloxy, methyl or nitro groups is substituted. 209826/1 UO - 30 - 16. The method according to claim 14 and 15 for the preparation of a compound according to claim 1, in which the radical Hp is an amino, Methoxy or ethoxy group, the radical R and the radical Rr each one Is methyl group. 17. The method according to claim 14 for the preparation of a compound of formula in which the radical R- is a phenyl group which is optionally substituted by one or two halogen atoms, a methyl or methoxy group, and the radical Rp is an amino, methoxy or ethoxy group. 18. Medicinal preparation, characterized by a content of a compound according to claim 1, in particular according to claim k or claim IQ, as an active ingredient, optionally in combination with pharmacologically acceptable carriers or active ingredients. 19. Medicinal preparation according to claim 18, characterized by a Content from 5 mg to 5 g of the active compound. 209826/1 UO