DE3228266A1 - Imidazolylalkylthiophenes, process for their preparation and pharmaceutical preparations containing them - Google Patents

Abstract

The invention relates to novel imidazolylalkylthiophenes of the general formula I <IMAGE> and their acid addition salts, to a process for their preparation and to pharmaceutical preparations containing them.

Description

The present invention relates to new imidazolylalkylthiophenes and their physiologically acceptable acid addition salts, processes for their preparation and their use as active ingredients in medicaments.

The imidazolylalkylthiophenes according to the invention correspond to the general formula I. I.

where, m is an integer from 1-8, R [high] 1 is hydrogen, alkyl or phenyl and X is C = O, C = NZ, C (O-alkyl) [low] 2, dioxolan-2-yl or 1,3-dioxan-2-yl, where Z can be OH, NH [deep] 2, NH-alkyl, NH-aryl or NH-acyl and R [high] 2 is hydrogen or a straight-chain or branched hydrocarbon with 1 -17 carbon atoms means.

Preferred are compounds in which m is 1 or 2, R [high] 1 is hydrogen or methyl, X is C =O or C =N-OH and R [high] 2 is a straight-chain or branched carbon means hydrogen radical with 1-7 carbon atoms.

Examples of compounds according to the invention are:

1 - {[5- (1-Oxo-ethyl) -thien-2-yl] -methyl} -imidazole,

1 - {[5- (1-Oxo-propyl) -thien-2-yl] -methyl} -imidazole,

1 - {[5- (1-Oxo-butyl) -thien-2-yl] -methyl} -imidazole,

1 - {[5- (3-Methyl-1-oxo-butyl) -thien-2-yl] -methyl} -imidazole,

1 - {[5- (1-Oxo-octyl) -thien-2-yl] -methyl} -imidazole,

2-methyl-1 - {[5- (1-oxo-ethyl) -thien-2-yl] -methyl} -imidazole,

1- {2- [5- (1-Oxo-ethyl) -thien-2-yl] -ethyl} -imidazole,

1 - {[5- (1-Oxo-ethyl) -thien-3-yl] -methyl} -imidazole,

1 - {[2- (1-Oxo-ethyl) -thien-3-yl] -methyl} -imidazole,

1 - {[5- (1-Hydroximino-ethyl) -thien-2-yl] -methyl} -imidazole.

This also includes acid addition salts and derivatives of the carbonyl group such as oximes, hydrazones and acetals.

Acid addition salts are in particular pharmaceutically usable, non-toxic acid addition salts with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or with organic acids, such as corresponding carboxylic acids, e.g. acetic acid, propionic acid, oxalic acid, malonic acid, glycolic acid, succinic acid, maleic acid, fumaric acid Citric acid, benzoic acid, cinnamic acid. Derivatives of the carbonyl group are, in particular, oximes, hydrazones, methylhydrazones, phenylhydrazones, acetylhydrazones, dimethylacetals, diethylacetals, ethylene acetals and propylene acetals.

The compounds of the formula I according to the invention have valuable therapeutic properties, in particular a strong lipid-lowering effect.

The compounds of the formula I according to the invention are prepared by methods known per se. Thus, the 1- (small omega-thienylalkyl) imidazoles of the formula II required as starting compounds II

where m and R [high] 1 have the same meaning as in formula I, by alkylating imidazole or imidazole sodium salt with the corresponding small omega-haloalkylthiophenes, optionally with the addition of an organic solvent, such as dimethylformamide, with the possible use of an auxiliary base, such as sodium hydride, produced (DE-OS 29 33 649). The 1- (small omega-thienalkyl) -imidazoles of the formula II are with carboxylic acid halides of the formula III according to the processes familiar to the person skilled in the art (Houben-Weyl, Methods of Organic Chemistry, Vol. 7 / 2a, p. 89 ff) III

where R [high] 2 has the same meaning as in formula I and R [high] 3 stands for chlorine, optionally with the addition of an organic solvent such as 1,2 dichloroethane, chlorobenzene, nitrobenzene, carbon disulfide, using a Friedel-Crafts -Catalyst, such as aluminum chloride, tin tetrachloride, reacted at temperatures between -20 ° C and + 100 ° C to the imidazole alkylthienyl alkyl ketones of the formula I (X is C = O), the hydrolysis of the product catalyst complex preferably in the presence of a complexing agent such as Ethylenediaminetetraacetic acid is carried out.

The imidazolylalkylthienylalkyl ketones of the formula I can also be prepared by reacting the 1- (small omega-thienylalkyl) imidazoles of the formula II with carboxylic anhydrides of the formula III, III

wherein R [high] 2 has the same meaning as in formula I and R [high] 3 for stands, with the preferred use of phosphoric acid or polyphosphoric anhydride as a catalyst.

The imidazolylalkylthiophenaldehydes of the formula I (R [high] 2-H) can be prepared, for example, by reacting the compounds of the formula II with formyl fluoride, preferably in carbon disulfide with boron trifluoride catalysis. (Weygand-Hilgetag, organic-chemical experimental art, Bart-Verlag, Leipzig, 1970, p. 977).

The 1- (small omega-thienalkyl) -imidazoles of the formula II can be used, for example:

1- (Thien-2-yl-methyl) -imidazole,

1- [2- (Thien-2-yl) -ethyl] -imidazole,

1- [3- (Thien-2-yl) propyl] imidazole,

1- [4- (Thien-3-yl) -butyl] -imidazole,

1- [5- (Thien-2-yl) pentyl] imidazole,

1- [6- (Thien-2-yl) -hexyl] -imidazole,

1- [7- (Thien-2-yl) -heptyl] -imidazole,

1- [8- (Thien-2-yl) octyl] imidazole,

2-methyl-1- (thien-2-yl-methyl) -imidazole,

2-methyl-1- [2- (thien-2-yl) -ethyl] -imidazole,

2-methyl-1- [3- (thien-2-yl) propyl] imidazole,

2-methyl-1- [4- (thien-2-yl) -butyl] -imidazole,

2-methyl-1- [5- (thien-2-yl) pentyl] imidazole,

2-methyl-1- [6- (thien-2-yl) -hexyl] -imidazole,

2-methyl-1- [7- (thien-2-yl) -heptyl] -imidazole,

2-methyl-1- [8- (thien-2-yl) octyl] imidazole,

2-ethyl-1- (thien-2-yl-methyl) -imidazole,

2-ethyl-1- [2- (thien-2-yl) -ethyl] -imidazole,

2-ethyl-1- [3- (thien-2-yl) propyl] imidazole,

2-ethyl-1- [4- (thien-2-yl) -butyl] -imidazole,

2-ethyl-1- [5- (thien-2-yl) pentyl] imidazole,

2-ethyl-1- [6- (thien-2-yl) -hexyl] -imidazole,

2-ethyl-1- [7- (thien-2-yl) -heptyl] -imidazole,

2-ethyl-1- [8- (thien-2-yl) octyl] imidazole,

2-phenyl-1- (thien-2-yl) methyl] imidazole,

2-phenyl-1- [2- (thien-2-yl) -ethyl] -imidazole,

2-phenyl-1- [3- (thien-2-yl) propyl] imidazole,

2-phenyl-1- [4- (thien-2-yl) -butyl] -imidazole,

2-phenyl-1- [5- (thien-2-yl) pentyl] imidazole,

2-phenyl-1- [6- (thien-2-yl) -hexyl] -imidazole,

2-phenyl-1- [7- (thien-2-yl) -heptyl] -imidazole,

2-phenyl-1- [8- (thien-2-yl) octyl] imidazole,

1- (Thien-3-yl-methyl) -imidazole,

1- [2- (Thien-3-yl) -ethyl) -imidazole,

1- [3- (Thien-3-yl) propyl) imidazole,

2-methyl-1- (thien-3-yl-methyl) -imidazole,

2-methyl-1- [2- (thien-3-yl) -ethyl] -imidazole,

2-methyl-1- [3- (thien-3-yl) propyl] imidazole,

2-ethyl-1- (thien-3-yl-methyl) -imidazole,

2-ethyl-1- [2- (thien-3-yl) -ethyl] -imidazole,

2-ethyl-1- [3- (thien-3-yl) propyl] imidazole,

2-phenyl-1- (thien-3-yl-methyl] -imidazole,

2-phenyl-1- [2- (thien-3-yl) -ethyl] -imidazole,

2-phenyl-1- [3- (thien-3-yl) propyl] imidazole.

The carboxylic acid halides of the formula III are, for example, formyl fluoride, acetyl chloride, propionic acid chloride, butyric acid chloride, pentanoic acid chloride, hexanoic acid chloride, heptanoic acid chloride, octanoic acid chloride, nonanoic acid chloride, decanoic acid chloride, undecanoic acid chloride, dodecanoic acid chloride, tetradecanoic acid chloride, 2-pionic acid chloride, methyl-octanoic acid chloride, 2-methyl-octanoic acid chloride, hexanoic acid chloride -Methylpentanoic acid chloride, 3-methylpentanoic acid chloride, 2,2-dimethylpropionic acid chloride, 3,3-dimethylbutyric acid chloride, 2-ethylhexanoic acid chloride.

The acid addition salts of the formula I (X corresponds to C =O) with inorganic or organic acids can be prepared by mixing the underlying imidazole compound with the corresponding acids in aqueous, aqueous-organic, for example alcohol-water or organic media such as, for example, alcohols, alcohol-ethers - Prepare mixtures or ether-petroleum ether mixtures at temperatures between 0 ° and 100 ° C.

The preparation of derivatives of the carbonyl compounds of the formula I (X corresponds to C =O) takes place according to methods known per se. The corresponding oximes of the formula I (X corresponds to C = N-OH) are prepared by reacting the carbonyl compounds of the formula I with hydroxylamine or its salts (Houben-Weyl, Methods of Organic Chemistry, Vol. 10/4, p. 55 ff). Hydrazones, methylhydrazones, phenylhydrazones or acetylhydrazones of the formula I (X corresponds to C = N-NH [deep] 2, C = N-NH-CH [deep] 3, C = N-NH-C [deep] 6H [deep] 5 , C = N-NH-CO-CH [deep] 3) are obtained from the corresponding carbonyl compounds of the formula I by reaction with hydrazine, methyl hydrazine, phenyl hydrazine or acetyl hydrazine, their hydrates or salts (Houben-Weyl, methods of organic chemistry, Vol. 7/1, p. 461 ff). Dimethylacetals, diethylacetals, ethylene acetals, propylene acetals of the formula I (X corresponds to C (OCH [deep] 3) [deep] 2, C (OC [deep] 2H [deep] 5) [deep] 2, dioxolan-2-yl, 1 , 3-Dioxan-2-yl) are formed from the corresponding carbonyl compounds of the formula I by reaction with methanol, ethanol, glycol or 1,3-propanediol, by reaction with orthoformic acid esters or by transacetalization of acetals of the formula I (Houben-Weyl, Methods of Organic Chemistry Vol. 6/3, p. 204 ff).

The present invention also relates to pharmaceutical preparations which contain compounds of the formula I or their pharmaceutically usable acid addition salts of this compound. The pharmaceutical preparations according to the invention are those for enteral, oral, rectal, and parental administration which contain the pharmacological active ingredients alone or together with a customary, pharmaceutically applicable carrier material. The pharmaceutical preparation of the active ingredient is advantageously in the form of individual doses which are tailored to the desired administration, such as tablets, coated tablets, capsules, suppositories, granules, solutions, emulsions or suspensions.

The dosage of the compounds is usually between 1-500 mg per dose, preferably between 5-150 mg per dose, and can be administered one or more times, preferably two to three times, daily.

The preparation of the compounds according to the invention is illustrated in more detail by the following examples. The melting points given were measured with a Büchi 510 melting point apparatus and are given as ° C. and are not corrected. The IR spectra were recorded with the Perkin-Elmer 257 or Nicolet NIC-3600 and the mass spectra with the Varian MAT-311-A (70eV).

example 1

1 - {[5- (1-Oxo-ethyl) -thien-2-yl] -methyl} -imidazole.

15.7 g of acetyl chloride are added dropwise to a mixture of 58.5 g of aluminum chloride and 100 ml of 1,2-dichloroethane in the course of 20 minutes, the internal temperature being kept below 20 ° C. by cooling. A solution of 32.8 g of 1- (thien-2-yl-methyl) -imidazole in 100 ml of 1,2-dichloroethane is then added dropwise at the same temperature. The reaction mixture is then stirred at 50 ° C. for 3 hours. After cooling, it is poured onto a mixture of 500 g of ice and 163 g of ethylenediaminetetraacetic acid and the pH is adjusted to about 8 by adding sodium hydroxide solution. The phases are separated and the aqueous phase is carefully extracted with chloroform. The combined organic phases are dried over sodium sulfate and concentrated. The residue is distilled in vacuo and the product is recrystallized from a little chloroform.

Yield: 23 g, b.p. 0.15 160-165 ° C, m.p. 84 ° C.

IR (in KBr): 1651 cm [high] -1

MS [m / e]: 206 (M [high] +, 51%), 139 (100%), 124 (3%), 111 (10%), 97 (30%)

Example 2

1 - {[5- (1-Oxo-propyl) -thien-2-yl] -methyl} -imidazole.

The reaction is carried out as in Example 1 with 43.9 g of aluminum chloride, 200 ml of 1,2-dichloroethane, 13.9 g of propionic acid chloride and 25 g of 1- (thien-2-yl-methyl) -imidazole.

Yield: 20.5g, bp [low] 0.08 176-180 ° C, m.p. 58-59 ° C

IR (inKBR): 1656 cm [high] -1

MS [m / e]: 220 (M [high] +, 36%), 191 (6%), 153 (100%), 125 (32%), 97 (20%)

Example 3

1 - {[5- (1-Oxo-butyl) -thien-2-yl] -methyl} -imidazole.

As in Example 1, the reaction is carried out with 29.3 g of aluminum chloride, 200 ml of 1,2-dichloroethane, 16.4 g of butyric acid chloride and 10.7 g of 1- (thien-2-yl-methyl) -imidazole.

Yield: 10.2g, b.p. 0.1 182-183 ° C, m.p. 63-64 ° C

IR (film): 1659 cm [high] -1

MS [m / e]: 234 (M [high] +, 41%), 206 (3%), 191 (10%), 167 (100%), 139 (15%), 124 (7%), 97 (37%)

Example 4

1 - {[5- (3-Methyl-1-oxo-butyl) -thien-2-yl] -methyl} -imidazole.

The reaction is carried out as in Example 1 with 35.1 g of aluminum chloride, 200 ml of 1,2-dichloroethane, 14.5 g of 3-methyl-butyric acid chloride and 20 g of 1- (thien-2-yl-methyl) -imidazole.

Yield: 20 g, b.p. 0.1, 193-196 ° C, m.p. 70-71 ° C

IR (inKBr): 1658 cm [high] -1

MS [m / e]: 248 (M [high] +, 17%), 206 (26%), 191 (23%), 181 (80%), 139 (29%), 124 (1%), 97 (100%)

Example 5

1 - {[5- (1-Oxo-octyl) -thien-2-yl] -methyl} -imidazole.

As in Example 1, the reaction is carried out with 46.8 g of aluminum chloride, 200 ml of 1,2-dichloroethane, 31.2 g of octanoic acid chloride and 17.3 g of 1- (thien-2-yl-methyl) -imidazole.

Yield: 17.7 g, b.p. 0.05, 208-210 ° C, m.p. 61-62 ° C

IR (inKBr): 1656 cm [high] -1

MS [m / e]: 290 (M [high] +, 3%), 223 (69%), 206 (46%), 191 (16%), 139 (100%), 124 (11%), 111 (7%), 97 (45%)

Example 6

2-methyl-1 - {[5 - (- oxo-ethyl) -thien-2-yl] -metehyl} -imidazole.

The reaction is carried out analogously to Example 1 with 70.5 g of aluminum chloride, 400 ml of 1,2-dichloroethane, 18.8 g of acetyl chloride and 40 g of 2-methyl-1- (thien-2-yl-methyl) -imidazole

After the distillation, the product is recrystallized from toluene.

Yield: 23.4 g, bp [low] 0.17, 170-174 ° C, melting point 60-62 ° C,

IR (inKBr): 1658 cm [high] -1

MS [m / e]: 220 (M [high] +, 28%), 139 (100%), 124 (3%), 111 (22%), 97 (36%)

Example 7

1- {2 [5- (1-Oxo-ethyl) -thien-2-yl] -ethyl} -imidazole.

The reaction is carried out analogously to Example 1 with 11.7 g of aluminum chloride, 80 ml of 1,2-dichloroethane, 3.1 g of acetyl chloride and 6.3 g of 1- [2- (thien-2-yl) ethyl] imidazole.

Yield: 2.5 g, oil, bp [low] 0.02, 154-156 ° C

IF (film): 1654 cm [high] -1

MS [m / e]: 220 (M [high] +, 100%), 205 (2%), 177 (4%), 152 (15%), 139 (99%), 124 (2%), 110 (20%), 97 (26%), 81 (89%).

Example 8

1 - {[5- (1-Oxo-ethyl) -thien-3-yl] -methyl} -imidazole.

The reaction is carried out analogously to Example 1 with 67.3 g of aluminum chloride, 400 ml of 1,2-dichloroethane, 18 g of acetyl chloride and 37 g of 1- (thien-3-yl-methyl) -imidazole. After the distillation, the product is recrystallized from a little chloroform.

Yield: 20 g, bp [low] 0.02, 145-161 ° C, mp 55 ° C, R [low] f value: 0.33 (chloroform / methanol = 9/1)

IR (inKBR): 1656 cm [high] -1

MS [m / e]: 206 (M [high] +, 45%), 139 (100%), 97 (23%)

Column chromatography of the concentrated mother liquor (silica gel / chloroform) gives 3.5 g of the isomeric 1 - {[2- (1-oxo-ethyl) -thien-3-yl-methyl} -imidazole.

IR (film): 1654 cm [high] -1, R [low] f value: 0.45 (chloroform / methanol = 9/1)

Example 9 is mentioned as an example of a carbonyl derivative.

Example 9

1 - {[5- (1-Hydroximino-ethyl) -thien-2-yl] -methyl} -imidazole.

A mixture of 2.1 g of 1 - {[5- (1-oxo-ethyl) -thien-2-yl] -methyl} -imidazole, 0.8 g of hydroxylamine hydrochloride, 5 ml of ethanol and 5 ml of pyridine is added for 2 hours. stirred at a bath temperature of 120 ° C. It is then concentrated, 30 ml of water are added and the resulting solid is filtered off with suction, washed several times with water and dried.

Yield: 1.7 g, melting point 184 ° C,

IR (inKBr): 3505, 1657, 1513 cm [high] -1

MS [m / e]: 221 (M [high] +, 25%), 154 (100%), 138 (4%), 123 (4%), 113 (20%), 96 (19%)

Example 10 is mentioned as an example of an acid addition salt.

Example 10

1 - {[5- (1-Oxo-ethyl) -thien-2-yl] -methyl} -imidazole-fumaric acid salt

A mixture of 12.4 g of 1 - {[5- (1-oxo-ethyl) -thien-2-yl] -methyl} -imidazole and 7 g of fumaric acid is heated in 50 ml of ethanol until dissolved. It is then concentrated and the residue is dried.

Yield: 18.6 g, m.p. 146 ° C

IR (inKBr): 2728, 1604, 1512 cm [high] -1

Analogously to example 10, e.g. oxalates, succinates, malonates etc. as well as inorganic salts such as hydrochlorides, hydrogen sulfates etc. can be prepared.

Claims (14)

1. Imidazolylalkylthiophenes of the general formula I. I. wherein: R [high] 1 is hydrogen, an alkyl or phenyl radical, m means an integer from 1-8, X for C = O, C = N-Z, C (O-alkyl) [deep] 2, dioxolan-2-yl, 1,3-Dioxan-2-yl, Z for OH, NH [deep] 2, NH-alkyl, NH-aryl, NH-acyl, and R [high] 2 is hydrogen or a straight-chain or branched hydrocarbon having 1-17 carbon atoms, and their acid addition salts with inorganic or organic acids. 2. imidazolylalkylthiophenes according to claim 1, formula I, where R [high] 1 is hydrogen and CH [low] 3, m is 1 or 2, X denotes C = O or C = N-OH and R [high] 2 is a straight-chain or branched hydrocarbon radical with 1-7 carbon atoms. 3. 1 - {[5- (1-Oxo-ethyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 4. 1 - {[5- (1-Oxo-propyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 5. 1 - {[5- (1-Oxo-butyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 6. 1 - {[5- (3-Methyl-1-oxo-butyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 7. 1 - {[5- (1-Oxo-octyl) -thien-2-yl] -thien-2-yl -] - methyl} -imidazole and its pharmaceutically acceptable salts. 8. 2-Methyl-1 - {[5- (1-oxo-ethyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 9. 1- {2- [5- (1-Oxo-ethyl) -thien-2-yl] -ethyl} -imidazole and its pharmaceutically acceptable salts. 10. 1 - {[5- (1-Oxo-ethyl) -thien-3-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 11. 1 - {[2- (1-Oxo-ethyl) -thien-3-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 12. 1 - {[5- (1-Hydroximino-ethyl) -thien-2-yl] -methyl} -imidazole and its pharmaceutically acceptable salts. 13. Process for the preparation of compounds according to claims 1-12, characterized in that a 1- (small omega-thienylalkyl) imidazole of the formula II II where R [high] 1 and m have the meaning given for formula I, with a carboxylic acid halide or anhydride of the formula III III where R [high] 2 has the meaning given in formula I and R [high] 3 stands for chlorine, fluorine or is, optionally with the addition of an organic solvent using a Friedel-Crafts catalyst or a Lewis acid and, if desired, converts a carbonyl compound of the formula I thus obtained in a manner known per se into an acid addition salt, an oxime, hydrazone or acetal convicted. 14. Medicinal preparations, characterized in that they contain a compound according to claims 1-12 together with a pharmaceutically suitable diluent or carrier material.