GB2231568A - New aromatase inhibiting 4(5)-imidazoles - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
Imidazole derivatives of the formula <IMAGE> [wherein R1, R2, R'1, and R'2, which can be the same or different, are H, CH3 or C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN or halogen; R' is H or <IMAGE> where R3 is H, CH3 or halogen; R4 is H or OH and R5 is H or R4 and R5 together form a bond; and n is 0 to 4] and their pharmaceutically acceptable acid addition salts exhibit aromatase and desmolase inhibiting properties. Very selective aromatase inhibiting compounds are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer. <IMAGE>
Description
NEW AROMATASE INHIBITING 4(5)-IMIDAZOLES
The present invention relates to substituted imidazole derivatives and their non-toxic, pharmaceutically acceptable acid addition salts, and their preparation, to pharmaceutical compositions containing the same and their use.
The imidazole derivatives of the present invention have the general formula:
wherein R1, R2, R'1 and R'21 which can be the same or different, are H, CH, CvHF, CrH7, OCHr, OH, CHOH, NO2, NH2, CN or halogen; R' is H or
where R3 is H, CH3 or halogen; R4 is H or OH and R5 is
H or R4 and R5 together form a bond and n is 0 to 4.
The non-toxic pharmaceutically acceptable acid addition salts of these compounds are also within the scope of the invention.
The compounds of the formula (I) form acid addition salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, as, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
The invention includes within its scope pharmaceutical compositions comprising a compound of formula (I) or a non-toxic, pharmaceutically accepttable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.
The compounds of the present invention have been found, depending on the substituents R', R1, R2, R'1 and R'2, to possess varying degrees aromatase and desmolase inhibiting properties. Very selective enzyme aromatase inhibiting compounds are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer.
The compounds of formula (I) can be prepared by a successive sequence of reactions comprising firstly a Grignard reaction of 4(5)-imidazole aldehyde (II)
with an appropriate arylalkylmagnesiumhalide (III)
which leads to the following compounds (IV)
In the formulae (II) to (IV) R' is H or
where R3 is H, CH3 or halogen, R1 and R2, which can be the same or different, are H, CH3 C2H5, C3H7, OCH3,
NO2, CN or halogen, Hal is halogen and n is 0 to 4.
In the reaction the arylalkylmagnesium halide derivative can be, for example, an arylalkylmagnesiumbromide derivative, which is prepared by reacting the corresponding arylalkylbromide derivative with magnesium.
Suitable solvents for the reaction include a variety of ethers, preferably tetrahydrofuran.
The arylalkylmagnesiumhalide derivative is prepared in the usual way by adding the arylalkylhalide derivative in a suitable solvent, e.g. tetrahydrofuran, dropwise onto magnesium turnings covered by tetrahydrofuran, at the boiling point of the reaction mixture. When the magnesium turnings have reacted, the mixture is cooled slightly and the 4(5)-imidazole aldehyde (II) is added in solid form in small portions or dropwise in tetrahydrofuran. After the addition, the reaction mixture is ref fluxed until all of the 4(5)-imidazole aldehyde (II) has reacted. The reaction time varies between one and five hours.
The compounds (IV) are further oxidized with manganese dioxide to achieve compounds of formula (V) which are allowed to react with another Grignard reagent (VI) to give the compounds of formula (I) where R4 is OH (VII).
The reaction scheme for these steps can be illustrated as follows:
In the formulae (V) to (VII) R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7,
OCH3, NO2, CN or halogen, R' and n are as defined before and Hal is halogen. The arylmagnesium halide (VI) is prepared by reacting the corresponding halogenated aromatic compound with magnesium turnings in the usual way.
According to the feature of the invention, the compounds of formula (I), wherein R4 and R5 both are hydrogen or together form a bond, are prepared by dehydration of the compounds of formula (I), where R4 is OH, and by catalytic addition of hydrogen in the second step.
Water is eliminated by usual methods, i.e. by heating with concentrated hydrochloric acid or by heating with dry potassium hydrogen sulfate. The unsaturated derivatives (VIII) (the compounds of formula (I) wherein
R4 and R5 together form a bond) are isolated and after that hydrogenated. Alternatively they can be hydrogenated directly in an acid medium without previous isolation.
The hydrogenation is conveniently carried out at room temperature with good stirring in alcohol, e.g. ethanol in the presence of a catalyst in a hydrogen atmosphere.
Suitable catalysts are for example platinium oxide, palladium-on-carbon or Raney-nickel.
The reaction scheme for these steps can be illustrated as follows:
wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, NO2, CN or halogen and R' and n are as defined before.
If R' is a substituted or unsubstituted benzyl, this group may be removed by hydrogenation as well. In this case the hydrogenation is performed in an acidic medium such as hydrochloric acid-ethanol mixture at elevated temperature.
The reaction scheme of this hydrogenation which leads to compounds of formula (I) wherein R', R4 and R5 each are hydrogen can be illustrated as follows:
Another method to remove the benzylic R' group is a hydrogen transfer reaction in which the starting compound (IX) is ref fluxed with ammonium formate and 10 % Pd/C in aqueous ethanol. The compounds (X) can also be prepared directly from the compounds (VIII) by hydrogen transfer reaction with ammonium formate or by hydrogenating both the double bond and the protecting benzyl group at the same time.
The benzylic R' can be removed already before the oxidizing reaction by the methods described before. The reaction scheme for this hydrogenation can be illustrated as follows:
The Grignard reagents (III) and (VI) cannot be prepared when the substituents are OH, CH2OH or NH2. The compounds of formula (I), wherein one or several of the substituents R1, R2, R'1 and R'2 are OH, CH2OH or NH2, can be prepared by the following methods.
The compounds of formula (I) wherein one or several of the substituents R1, R2, R'1 and R'2 are OH can be prepared by reacting the 4(5)-imidazole derivative (II) first with a Grignard reagent (III) and then with reagent (VI) where the substituent/substituents are OCH2Ph or
OTHP (THP = tetrahydropyranyl) and then hydrogenating catalyticly by the methods described to hydrogenate the benzylic R' group. If R' is protecting benzyl group it will be removed conveniently at the same time. Another method is to dealkylate the compounds of formula (I) where the substituent/substituents are OCH3 by allowing them to react with BBr3, for example.
The compounds of formula (I) wherein one or several of the substituents R1, R2, R'1 and R'2 are CH2OH may be prepared from the corresponding compounds where the substituent/substituents are CN by conventional methods, i.e. by hydrolyzing the nitrile group and then reducing the acid group.
The compounds of formula (I) wherein one or several of the substituents R1, R2, R'1 and R'2 are NH2 can be prepared by hydrogenating the corresponding compounds where the substituent/substituents are NO2. The protecting benzyl group will be hydrogenated as well.
Another method for the preparation of compounds of formula (I) where R' is a benzyl is the benzylation of the corresponding compound where R' is hydrogen. The starting compound is first treated with a strong base such as sodium hydroxide in water or sodium hydride in an appropriate solvent, e.g. dimethyl formamide, to give the alkali metal salt of the imidazole and then in the second step adding to this benzyl halide. The reaction scheme can be illustrated as follows:
wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2Hs, C3H7, OCH3, CH2OH, NO2, NH2, CN or halogen and R3, R4, R5 and n are as defined before.
Compounds of formula (I), their nontoxic, pharmaceutically acceptable acid salts or mixtures thereof may be administered parenterally, intravenously or orally. Typically, an effective amount of the derivative is combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount" encompasses those amounts which yield the desired activity without causing adverse side-effects. The precise amount employed in a particular situation is dependent upon numerous factors such as method of administration, type or mammal, condition for which the derivative is administered, etc., and of course the structure of the derivative.
The pharmaceutical carriers which are typically employed with the derivatives of the present invention may be solid or liquid and are generally selected with the planned manner of administration in mind.
Thus, for example, solid carriers include lactose, sucrose, gelatin and agar, while liquid carriers include water, syrup, peanut oil and olive oil. Other suitable carriers are well-known to those skilled in the art of pharmaceutical formulations. The combination of the derivative and the carrier may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions and powders.
The compounds of the invention are especially valuable as aromatase inhibiting agents and are therefore useful in the treatment of estrogen dependent diseases, e.g.
breast cancer.
Estrogens are essential steroids in the physiology and function of normal development of breast and sex organs in women. On the other hand estrogens are known to stimulate the growth of estrogen dependent cancers, especially breast and endometrial cancers, and they may increase the risk of development of breast cancer if given at pharmacological doses for a long time. Excessive production of estradiol may also cause other, benign disorders in hormone dependent organs. The importance of estrogens as cancer growth stimulators and/or regulators is clearly stressed by the fact that antiestrogens have reached a central position in the treatment of estrogen receptor rich breast cancers.
Antiestrogens act by binding to estrogen receptors and thereby inhibiting the biological effects of estrogens.
Another approach for blocking estrogen effect is to inhibit the synthesis of estrogens. This has been achieved clinically by the unspecific steroid synthesis inhibitor aminoglutethimide. The estrogen synthesis could be blocked specifically by inhibiting the enzyme aromatase, which is the key enzyme in biochemical estrogen synthesis pathway. Aromatase inhibition is important because several breast tumors synthesize estradiol and estrone in situ and exhibit therefore continuous growth stimulation (Alan Lipton et al.,
Cancer 59:779-782, 1987).
The ability of the compounds of the invention to inhibit the enzyme aromatase has been tested by in vitro assay according to M. Pasanen (Biological Research in
Pregnancy, vol. 6, No. 2, 1985, pp. 94-99). Human aromatase enzyme was used. The enzyme was prepared from human placenta, which is rich of the enzyme. Microsomal fraction (100000 x g precipitate) was prepared by centrifugation. The enzyme preparation was used without further purification. Test compounds were added together with 100000 dpm of l,2E3HJ-androstene-3,17-dione and
NADPH generating system. The concentrations of the test compounds were 0,001; 0,01; 0,1 and 1,0 mM. The incubation was carried out at 370C for 40 min.
Aromatization of 1,2t3H]-androstene-3,17-dione results in the production of 3H20. The tritiated water and the tritiated substrate are easily separated by a Sep-PakR minicolumn, which absorbs the steroid but allows free water elution. Radioactivity was counted by a liquid scintillation counter. Aromatase inhibition was evaluated by comparing the 3H20-radioactivity of inhibitor treated samples to controls containing no inhibitor. IC-5 values were calculated as concentrations which inhibited the enzyme activity 50 %. These concentrations are presented in Table 2.
Cholesterol side chain cleavage (CSCC) activity (desmolase) was measured according to the method of
Pasanen and Pelkonen (Steroids 43:517-527, 1984).
Incubations were carried out in 1,5 ml Eppendorf plastic tubes, and an Eppendorf shaker, centrifuge and incubator were used as a unit. In a 300 g1 incubation volume, the substrate (5 CLAM) was prepared according to Hanukoglu and Jefcoate (J. Chromatogr. 190:256-262, 1980), and 100000 dpm of radioactive 3H-4-cholesterol (the purity of the compound was checked by TLC) in 0,5 % Tween 20, 10 mM Mac12, 5 SM cyanoketone and 2 mM NADPH was added.
Controls contained all the above substances but the enzyme preparation was inactivated prior to the incubation by the addition of 900 g1 of methanol. The mitochondrial fraction (1 mg protein) from human placenta or bovine adrenals was used as a source of enzyme.
After 30 min incubation at 370C, the reaction was terminated by the addition of 900 p1 of methanol; 1500 dpm of marker 14C-4-pregnenolone was added to each incubate and the tubes were vigorously shaken.
After 10 min equilibration, the methanol-precipitated proteins were separated by centrifugation (8000 x g for 2 min) and the supernatant was sucked into 1 ml plastic injection syringe and loaded onto the preequilibrated (75 % methanol) minicolumn. The column was washed with one ml of 75 % methanol and then with 3 ml of 80 % methanol. The 80 * methanol eluate was run into the counting vial and 10 ml of scintillation liquid was added. Radioactivity was counted using a double-label program on a liquid scintillation counter (LKB RackBeta).
Typical activities for placental and bovine adrenal enzyme preparation were 0,5-3 and 50-100 pmol pregnenolone formed/mg protein/min, respectively.
In inhibition experiments, the substance (final concentration range from 1 to 1000 WM) was added into incubation mixture in a volume of 10-20 g1, usually as methanol or ethanol solution. The same volume of the solute was added into control incubation vial. The IC-50 values (concentration causing a 50 % inhibition) were determined graphically and are presented in Table 2.
Table 1: compounds tested
No. Name 1. 4-tl-(4-fluorophenyl)-5-phenylpentyl]-lH-imidazole 2. 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-1H- imida zole 3. 4-[1-(4-fluorophenyl)-5-(3-methylphenyl)pentyl]-1H-
imidazole 4. 4-tl-(4-fluorophenyl)-5-(4-methylphenyl)pentyl]-lH- imidazole 5. 4-[5-(3,5-dimethylphenyl)-1-(4-fluorophenyl)pentyl]- 101-imidazole 6. 4-(1,5-diphenylpentyl)-1H-imidazole 7. 4-(1,3-diphenylpropyl)-1H-imidazole 8. 1-benzyl-5-(1,3-diphenylpropyl)-1H-imidazole
Table 2: Inhibition of human aromatase and desmolase
(CSCC) by test compounds. IC-50 represents the
concentration which inhibits the enzyme 50 %.
Compound IC-50 IC-50 CSCC
No. gmol/l gmol/l 1 2,8 19
2 3,5 16
3 3,8 57
4 8,5 170
5 7,5
6 25
7 4,5 7,5
8 30
The daily dose for a patient varies from 20 to about 200 mg, administered orally.
The following examples illustrate the invention.
1H NMR spectra were determined with a Bruker WP 80 DS apparatus (80 MHz). The reference substance was tetramethylsilane. MS spectra were determined with a Kratos
MS80RF Autoconsole apparatus.
Example 1 4-tl-(4-fluorophenyl)-5-phenylpentyl]-lH-imidazole a) l-benzyl-5-(1-hydroxy-5-phenylpentyl)-lH-imidazole 2,1 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. A solution of 4-phenylbutylbromide (18,8 g) in 20 ml of dry tetrahydrofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is ref fluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of l-benzyl-5imidazolecarbaldehyde (6,5 g) in 80 ml of tetrahydrofuran at 600C. After the addition is complete, the reaction mixture is ref fluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc.
hydrochloric acid is added to the solution. The product which is separated as an oil, is extracted with methylene chloride and evaporated to dryness.
b) 4- ( 1-hydroxy-5-phenylpentyl ) -lH-imidazole l-benzyl-5-(1-hydroxy-5-phenylpentyl)-lH-imidazole hydrochloride (8,5 g), prepared in the Step a, is hydrogenated in the mixture of 100 ml of 2 N hydrochloric acid and 10 ml of ethanol at 600C Pd/C (10 %) as catalyst. When the uptake of the hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to methylene chloride which is washed with water, dried with sodium sulphate and evaporated to dryness. The residue is the product as base, and it is used as such in Step c.
1H NMR (as base, MeOH-d4 + a drop of CDC13): 1.2-2.0 (m, 6H), 2.61 (distorted t, 2H), 4.65 (t, 1H), 6.91 (dd, 1H), 7.0-7.3 (m, 5H), 7.56 (d, 1H) c) 4-(1-oxy-5-phenylpentyl) -1H-imidazole 5,5 g of 4-(1-hydroxy-5-phenylpentyl)-1H-imidazole and 7,0 g of manganese dioxide are ref fluxed stirring in tetrachioroethylene for four hours. The reaction mixture is filtered and the filtrate is evaporated to dryness.
Water is added and the product is extracted into methylene chloride. The combined extracts are washed with water and evaporated to dryness.
d) 4-[1-(4-fluorophenyl)-1-hydroxy-5-phenylpentyl]-lH- imidazole 0,52 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of l-bromo-4fluorobenzene (3,8 g) in 60 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is ref fluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 4-(1-oxy-5-phenylpentyl)-lH-imidazole (3,8 g) in 40 ml of tetrahydrofuran at 600C. After the addition is complete, the reaction mixture is ref fluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc. hydrochloric acid is added to the solution. The product is extracted as hydrochloric salt into methylene chloride.Combined methylene chloride extracts are then evaporated to dryness.
e) 4-l-(4-fluorophenyl)-5-phenyl-l-pentenyl)-lH- imidazole 4-[1-(4-fluorophenyl)-1-hydroxy-5-phenylpentyl]-lH- imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150 0C for 4 hours. The mixture is cooled and 90 ml of ethanol is added to dissolve the product. The mixture is then filtered and the filtrate is evaporated to minor volume.
Water is added and the mixture is made alkaline with sodium hydroxide. The product is extracted into methylene chloride, washed with water and evaporated to dryness.
The product is then made to hydrochloride salt with dry hydrogen chloride in dry ethylacetate.
1H NMR (as base, CDCl3): 1.5-2.7 (m, 6K), 4.8 (broad s, 1H), 6.34 (t, 1H), 6.48 (broad s, 1H), 6.9-7.4 (m, 9H), 7.52 (broad s, 1H) Using the same method for example the following compounds included in the invention were prepared:: 4-tl-(4-fluorophenyl)-5-(3-methylphenyl)-1-pentenyl]- 1H-imidazole 4-[1-(4-fluorophenyl)-5-(4-methylphenyl)-1-pentenyl]- lH-imidazole 4-tl-(4-fluorophenyl)-5-(2-methylphenyl)-1-pentenyl]- 1H-imidazole 4-t5-(3,5-dimethylphenyl)-1-(4-fluorophenyl)-1-pentenyl]- lH-imida zole 4-[1-(4-fluorophenyl)-5-(3-methoxyphenyl)-1-pentenyl]- 101-imidazole 4-[5-(3,5-dimethoxyphenyl)-1-(4-fluorophenyl)-1- pentenyl) -101-imidazole f) 4-[1-(4-fluorophenyl)-5-phenylpentyl]-lH-imidazole 4-[1-(4-fluorophenyl)-5-phenyl-l-pentenyl]-lH-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount 10 % Pd/C is added.The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloridemethanol mixture.
1H NMR (as base, CDCl3): 1.1-2.7 (m, 8H), 3.84 (t, lH), 6.71 (broad s, 1H), 6.80-7.38 (m, 9H), 7.47 (broad s, 1H), 9.22 (broad s, 1H)
Using the same method for example the following compounds included in the invention were prepared: 4-[1-(4-fluorophenyl)-5-(3-methylphenyl)pentyl]-1H- imidazole
MS: 322 (20, M+), 189 (28), 176 (38), 175 (72), 149 (100), 125 (20), 121 (14), 109 (42), 105 (16), 97 (21) 1H NNR (as HC1-salt, NeOH-d4): 1.1-2.7 (m, 8H), 2.27 (s, 3H), 4.06 (t, 1H), 6.7-7.5 (m, 8H), 7.37 (d, 1H), 8.77 (d, 1H) 4-[1-(4-fluorophenyl)-5-(4-methylphenyl)pentyla-lH- imida zole H NMR (as HCl-salt, MeOH-d4): 1.1-2.7 (m, 8H), 2.26 (s, 3H), 4.05 (t, 1H), 6.8-7.6 (m, 9H), 8.78 (d, 1H) 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-1H- imidazole MS: 322 (53, M+'), 189 (30), 176 (55), 175 (100), 148 (18), 121 (12), 105 (42), 101 (11), 79 (12), 77 (13) 1H NMR (as HC1-salt, MeOH-d4): 1.1-2.7 (m, 8H), 2.24 (s, 3H), 4.11 (t, 1H), 6.9-7.5 (m, 9H), 8.79 (d, 1H) 4-t5-(3,5-dimethylphenyl)-1-(4-fluorophenyl)pentyl]-lH- imidazole
MS: 336 (47, M+'), 189 (90), 176 (67), 175 (100), 166 (13), 148 (16), 121 (12), 119 (16), 91 (14) 1H NMR (as HCl-salt, MeOH-d4): 1.1-2.6 (m, 8H), 2.22 (s, 6H), 4.09 (t, 1H), 6.6-7.4 (m, 7H), 7.40 (broad s, 1H), 8.80 (broad s, 1H) 4-tl-(4-fluorophenyl)-5-(3-methoxyphenyl)pentyl]-lH- imidazole 4-[5-(3,5-dimethoxyphenyl)-1-(4-fluorophenyl)pentyl]-1H- imidazole
Example 2 4-(1,3-diphenylpropyl)-1H-imidazole a) 1-benzyl-5-(1-oxo-3-phenylpropyl)-1H-imidazole 1-benzyl-5-(1-hydroxy-3-phenylpropyl)-1H-imidazole is oxidized with manganese dioxide in tetrachloroethylene, as it is described in Example 1 c).
1H NMR (as base, cDCl3): 3.03 (m, 4H), 5.53 (s, 2H), 7.07-7.4 (m, 10H), 7.60 (s, 1H), 7.77 (s, 1H)
Using the same method for example the following compounds included in the invention were prepared: l-benzyl-5-15-(2,6-dimethylphenyl)-1-oxopentyl]-lH- imidazole. M.p. of hydrochloride 175-1800C.
l-benzyl-5-(1-oxo-5-phenylpentyl)-lH-imidazole. M.p. of hydrochloride 185-1890C.
b) l-benzyl-5-(1-hydroxy-1,3-diphenylpropyl)-lH-imidazole Grignard reagent is prepared from 5,0 g of bromobenzene and 0,76 g of Mg turnings in tetrahydrofuran. This solution is then added to 3,1 g of l-benzyl-5-(1-oxo-3- phenylpropyl)-lH-imidazole in tetrahydrofuran and the reaction mixture is ref fluxed for 3 hours. The mixture is then poured into cold water, tetrahydrofuran is evaporated and the solution is made acidic with hydrochloric acid. The hydrochloride of the product is filtered, washed with toluene and dried. M.p. 196-1980C.
Using the same method for example the following compounds included in the invention were prepared: 1-benzyl-5-(1-hydroxy-1,5-diphenylpentyl)-lH-imidazole.
M.p. of hydrochloride 193-1960C.
1-benzyl-5-[5-(2,6-dimethylphenyl)-1-hydroxy-1- phenylpentyl]-lH-imidazole. M.p. of hydrochloride 1901920C.
c) l-benzyl-5-(1,3-diphenylpropyl)-lH-imidazole l-benzyl-5-(1-hydroxy-1,3-diphenylpropyl)-lH-imidazole is treated with anhydrous potassium hydrogen sulphate at 1500C as described in Example 1 e). The double bond of the obtained intermediate, l-benzyl-5-(1,3-diphenyl l-propenyl)-1H-imidazole, is hydrogenated as described in Example 1 d). M.p. of the hydrochloride salt is 1541740C (from diethylether).
101 NMR (as HCl-salt, MeOH-d4): 2.2-2.7 (m, 4H), 3.90 (t, 1H), 5.12 (AB q, the middle of the quartet, 2H), 6.90-7.37 (m, 15H), 7.70 (broad s, 1H), 8.88 (d, 1H)
Using the same method for example the following compounds were prepared: l-benzyl-5-(1,5-diphenylpentyl)-lH-imidazole 1H NMR (as base, CDC13): 1.18-2.61 (m, 8H), 3.56 (t, 1H), 4.59 and 4.81 (AB q, 2H), 6.76-7.40 (m, 17H) l-benzyl-5-t5-(2,6-dimethylphenyl)-1-phenylpentyl]-lH- imidazole d) 4-(1,3-diphenylpropyl)-1H-imidazole l-benzyl-5-(1,3-diphenylpropyl)-lH-imidazole is hydrogenated in the mixture of 2N hydrochloric acid and ethanol at 600C 10 % Pd/C as catalyst. The product is isolated as in Example 1 b) and is purified by flash chromatography methylene chloride-methanol (9,5:0,5) as eluent.
101 NMR (as base, CDCl3): 2.1-2.7 (m, 4H), 3.88 (t, 1H), 6.71 (broad s, 1H), 7.01-7.26 (m, 10H), 7.30 (d, 1H), 10.5 (broad s, 1H)
Using the same method for example the following compound was prepared: 4-(1,5-diphenylpentyl)-1H-imidazole NMR (as HCl-salt, NeOH-d4): 1.2-2.3 (m, 6H), 2.57 (distorted t, 2H), 4.05 (t, lH), 7.05-7.40 (m, 11H), 8.73 (d, 1H)
Example 3 l-benzyl-4-(1,3-diphenylpropyl)-lH-imidazole 2,0 g of benzylbromide in 5 ml of toluene is added dropwise to the mixture of 4-(1,3-diphenylpropyl)-1Himidazole (2,6 g), 48 8 NaOH (10 ml), toluene (20 ml) and tetrabutylammoniumbromide (0,2 g) at room temperature. After addition the reaction mixture is stirred at room temperature for 3 hours. Water is added and the toluene layer is separated. The toluene phase is then washed with water and evaporated to dryness.
The residue contains the isomers l-benzyl-4-(l,3- diphenylpropyl)-lH-imidazole and l-benzyl-5- (1,3- diphenylpropyl)-1H-imidazole and the former is separated and purified by flash chromatography (methylene chloridemethanol 9,5:0,5).
Claims (11)
1. A substituted imidazole of the formula
wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, OH, C0120H, NO2, NH2, CN or halogen; R' is H or
where R3 is H, CH3 or halogen; R4 is H or OH and R5 is H or R4 and R5 together
form a bond and n is 0 to 4, or a pharmaceutically
acceptable acid addition salt thereof.
2. A compound according to claim 1, which is 4-11-(4- fluorophenyl)-5-phenylpentyl]-1H-imidazole or a
non-toxic pharmaceutically acceptable acid addition
salt thereof.
3. A compound according to claim 1, which is 4-[1-(4 fluorophenyl)-5-(2-methylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid
addition salt thereof.
4. A compound according to claim 1, which is 4-[1-(4 fluorophenyl)-5-(3-methylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid
addition salt thereof.
5. A compound according to claim 1, which is 4-11-(4- fluorophenyl)-5-(4-methylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid
addition salt thereof.
6. A compound according to claim 1, which is 4-[5-(3,5 dimethylphenyl)-l-(4-fluorophenylJpentyll-lH- imidazole or a non-toxic pharmaceutically acceptable
acid addition salt thereof.
7. A compound according to claim 1, which is 4-(1,5
diphenylpentyl)-lH-imidazole or a non-toxic
pharmaceutically acceptable acid addition salt
thereof.
8. A compound according to claim 1, which is 4-(1,3
diphenylpropyl)-1H-imidazole or a non-toxic
pharmaceutically acceptable acid addition salt
thereof.
9. A compound according to claim 1, which is l-benzyl
5-(1,3-diphenylpropyl)-1H-imidazole or a non-toxic
pharmaceutically acceptable acid addition salt
thereof.
10. A compound according to claim 1, which is l-benzyl 5-(1,5-diphenylpentyl)-1H-imidazole or a non-toxic
pharmaceutically acceptable acid addition salt
thereof.
11. A compound according to claim 1 or pharmaceutically
acceptable acid addition salt thereof as hereinbefore
specifically described.
Priority Applications (31)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8907309A GB2231568B (en) | 1989-03-31 | 1989-03-31 | New aromatase inhibiting 4(5)-imidazoles |
| CS92593A CZ281546B6 (en) | 1989-03-31 | 1990-02-07 | Novel aromatase inhibiting 4/5/-diarylalkylimidazoles |
| FI901317A FI901317A0 (en) | 1989-03-31 | 1990-03-16 | FREQUENCY REFRIGERATION FOR NY 4 (5) -IMIDAZOLER. |
| AU52325/90A AU627559B2 (en) | 1989-03-30 | 1990-03-28 | Novel aromatase inhibiting 4(5)-imidazoles |
| JP2080548A JPH032168A (en) | 1989-03-30 | 1990-03-28 | Novel 4 (5)-imidazole having aromatase inhibitive activity |
| HU914010A HU206685B (en) | 1989-03-30 | 1990-03-29 | Process for producing new 4/5/-imidazol derivatives |
| IL9394090A IL93940A (en) | 1989-03-30 | 1990-03-29 | Aromatase inhibiting diphenylalkyl 4(5)-imidazoles and pharmaceutical compositions containing them |
| NZ233127A NZ233127A (en) | 1989-03-30 | 1990-03-29 | Imidazole derivatives and pharmaceutical compositions |
| NO901451A NO172797C (en) | 1989-03-30 | 1990-03-29 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SUBSTITUTED IMIDAZOLE COMPOUNDS |
| AT90303362T ATE111084T1 (en) | 1989-03-30 | 1990-03-29 | AROMATASE INHIBITING 4(5)-IMIDAZOLE. |
| UA4895673A UA13471A (en) | 1989-03-30 | 1990-03-29 | METHOD OF OBTAINING SUBSTITUTED IMIDAZOLE OR ITS NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID-ADDITIVE SALT |
| ES90303362T ES2063260T3 (en) | 1989-03-30 | 1990-03-29 | NEW 4 (5) -IMIDAZOLES INHIBITORS OF AROMATASE. |
| IE115290A IE64655B1 (en) | 1989-03-30 | 1990-03-29 | Novel aromatase inhibiting 4(5)-imidazoles |
| CS901555A CZ281611B6 (en) | 1989-03-30 | 1990-03-29 | 4(5)-diarylalkylimidazole derivatives, process of their preparation, pharmaceutical preparatin in which said derivatives are comprised and their use |
| DE69012184T DE69012184T2 (en) | 1989-03-30 | 1990-03-29 | Aromatase inhibiting 4 (5) imidazoles. |
| IL10726090A IL107260A (en) | 1989-03-30 | 1990-03-29 | Aromatase inhibiting diphenylalkyl 4(5)-imidazoles and pharmaceutical compositions containing them |
| PT93606A PT93606B (en) | 1989-03-30 | 1990-03-29 | METHOD FOR PREPARING NEW 4 (5) -IMIDAZOES THAT INHIBIT THE AROMATASE |
| HU901894A HU205345B (en) | 1989-03-30 | 1990-03-29 | Process for producing new 4(5)-imidazole derivatives |
| EP90303362A EP0390558B1 (en) | 1989-03-30 | 1990-03-29 | Aromatase inhibiting 4(5)-imidazoles |
| DK90303362.9T DK0390558T3 (en) | 1989-03-30 | 1990-03-29 | Aromatase inhibitor 4 (5) -imidazoles |
| PL28896390A PL162555B1 (en) | 1989-03-31 | 1990-03-30 | Method of obtaining novel derivatives of imidazole |
| PL28896490A PL162556B1 (en) | 1989-03-31 | 1990-03-30 | Method of obtaining novel derivatives of imidazole |
| PL28455290A PL162513B1 (en) | 1989-03-30 | 1990-03-30 | Method for manufacturing new derivatives of imidazol |
| CN90102676A CN1046527A (en) | 1989-03-30 | 1990-03-30 | Novel aromatization enzyme inhibitor 4 (5)-imidazoles |
| NO911040A NO172119C (en) | 1989-03-30 | 1991-03-15 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SUBSTITUTED IMIDAZOLE COMPOUNDS |
| SU914895631A RU2067578C1 (en) | 1989-03-31 | 1991-06-19 | Method of synthesis of substituted imidazoles or their pharmaceutical acceptable acid additive salts |
| SU914895673A RU1836354C (en) | 1989-03-30 | 1991-06-25 | Method for obtaining substituted imidazole or its nontoxic pharmaceutically acceptable acid-additive salt |
| US08/063,471 US5439928A (en) | 1989-03-30 | 1993-05-19 | Aromatase inhibiting 4(5)-imidazoles |
| CN93108897A CN1086812A (en) | 1989-03-30 | 1993-07-14 | The preparation method of novel aromatization enzyme inhibitor 4 (5)-imidazoles |
| IL107260A IL107260A0 (en) | 1989-03-30 | 1993-10-12 | Aromatase inhibiting diphenylalkyl 4(5)-imidazoles and pharmaceutical compositions containing them |
| LVP-95-273A LV11027B (en) | 1989-03-30 | 1995-09-07 | Aromatase inhibiting 4(5)-imidazoles aromatase inhibiting 4(5)-imidazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8907309A GB2231568B (en) | 1989-03-31 | 1989-03-31 | New aromatase inhibiting 4(5)-imidazoles |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8907309D0 GB8907309D0 (en) | 1989-05-17 |
| GB2231568A true GB2231568A (en) | 1990-11-21 |
| GB2231568B GB2231568B (en) | 1992-07-08 |
Family
ID=10654267
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8907309A Revoked GB2231568B (en) | 1989-03-30 | 1989-03-31 | New aromatase inhibiting 4(5)-imidazoles |
Country Status (5)
| Country | Link |
|---|---|
| CZ (1) | CZ281546B6 (en) |
| FI (1) | FI901317A0 (en) |
| GB (1) | GB2231568B (en) |
| PL (2) | PL162555B1 (en) |
| RU (1) | RU2067578C1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2248058A (en) * | 1990-09-21 | 1992-03-25 | Orion Yhtymae Oy | Aromatase inhibiting 4(5)-imidazoles |
-
1989
- 1989-03-31 GB GB8907309A patent/GB2231568B/en not_active Revoked
-
1990
- 1990-02-07 CZ CS92593A patent/CZ281546B6/en unknown
- 1990-03-16 FI FI901317A patent/FI901317A0/en not_active IP Right Cessation
- 1990-03-30 PL PL28896390A patent/PL162555B1/en unknown
- 1990-03-30 PL PL28896490A patent/PL162556B1/en unknown
-
1991
- 1991-06-19 RU SU914895631A patent/RU2067578C1/en active
Non-Patent Citations (1)
| Title |
|---|
| Chemical Abs * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2248058A (en) * | 1990-09-21 | 1992-03-25 | Orion Yhtymae Oy | Aromatase inhibiting 4(5)-imidazoles |
| GB2248058B (en) * | 1990-09-21 | 1994-09-14 | Orion Yhtymae Oy | Aromatase inhibiting 4(5)-imidazoles |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8907309D0 (en) | 1989-05-17 |
| FI901317A0 (en) | 1990-03-16 |
| PL162556B1 (en) | 1993-12-31 |
| PL162555B1 (en) | 1993-12-31 |
| CZ281546B6 (en) | 1996-11-13 |
| CZ59392A3 (en) | 1996-07-17 |
| PL288964A1 (en) | 1991-10-21 |
| GB2231568B (en) | 1992-07-08 |
| RU2067578C1 (en) | 1996-10-10 |
| PL288963A1 (en) | 1991-10-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 773K | Patent revoked under sect. 73(2)/1977 |