FI83079B - Process for preparing therapeutically active 5 phenylimidazo[1,5-a]pyridines - Google Patents

Description

83079

Process for the preparation of therapeutically active 5-phenylimidazo-1,5-a] pyridine derivatives (Partitioned Pat. No. 852399)

The invention relates to a process for the preparation of therapeutically active 5-phenylimidazo [1,5-a] pyridines of the formula I (I).

b \ Λ> si; To form cyano, carbamoyl or C 1 -C 4 alkylcarbamoyl, or a pharmaceutically acceptable salt thereof.

PI Patent 75,569 describes certain imidazo [1,5-a] pyridines having thromboxane synthetase inhibitor activity. FI patent 78,089 describes certain 5-phenylimidazo [1,5-a] pyridines with thromboxane synthetase inhibitory activity.

The compounds according to the invention form acid addition salts with acids, in particular pharmaceutically acceptable salts with conventional acids, for example mineral acids, e.g. hydrochloric acid, sulfuric or phosphoric acid, or organic acids, for example aliphatic or aromatic carboxylic or sulfonic acids, e.g. , vinegar, propion, amber, glycol, milk, apple, wine, lemon, ascorbine, maleic, fumaric, hydroxymalein, fire grape, phenylacetic, Bent-soe, 4-Aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, gluconic, nicotinic 2,83079 ni-, methanesulfonyl, ethanesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic , with sulphanilic or cyclohexylsulfamic acid. Salts can also be formed with amino acids such as arginine or lysine.

Preference is given to the above-mentioned pharmaceutically acceptable salts. Salts other than pharmaceutically acceptable salts, e.g. picrates, may also be used in the isolation or purification.

The compounds of the present invention have valuable pharmacological properties, for example, by inhibiting aromatase activity in mammals, including humans. For example, these compounds inhibit the metabolic conversion of androgens to estrogens. Thus, the compounds of formula I are useful, e.g., in the treatment of gynecomastia, i. breast development in the male person, by preventing steroids from aromatizing in male individuals prone to this condition. In addition, the compounds of formula I are useful, e.g., in the treatment of estrogen-dependent diseases, including estrogen-dependent breast cancer, especially in postmenopausal women, because they inhibit estrogen synthesis. These effects can be demonstrated in in vitro assays or in vivo animal experiments, preferably using mammals such as guinea pigs, mice, rats, cats, dogs or monkeys.

In vitro inhibition of aromatase activity can be demonstrated, e.g., using the method described in J. Biol. Chem. 249, 5364 (1974). Furthermore, IC50 values for aromatase inhibition can be obtained, e.g., from in vitro enzyme kinetic studies on the inhibition of the conversion of 4-14C-androstenedione to 4-14C-estrone in human placental microsomes. The 3,83079 compounds of the invention have IC 50 values of from about 10 to about 6 moles per liter. In vivo inhibition of aromatase can be demonstrated, e.g., by a decrease in ovarian estrogen levels in female rats when first injected with serum gonadotropin from a pregnant mare and two days later with human fetal choroidal gonadotropin and treated the following day p.o. with a compound of this invention and an hour later with androstenedione. The effective minimum dose of the compounds of the invention is from about 0.01 to about 10 mg / kg or less. Antitumor activity, especially in estrogen-dependent tumors, can be demonstrated in vivo, e.g., in DMBA-induced mammalian tumors in female Sprague-Dawley rats: the compounds of the invention provide near-complete regression and prevent the appearance of new tumors at about 1 to about 20 mg / kg or less. in daily doses.

Surprisingly, while the compounds of the invention have been found to be potent aromatase inhibitors in vitro and in vivo, they do not have cholesterol side chain cleavage inhibitory activity in vivo because they do not induce adrenal hyperplasia, as found in a thyroid study.

Due to their pharmacological properties as aromatase inhibitors, the compounds according to the invention can be used as medicaments, for example in the form of pharmaceutical compositions for the treatment of hormonal diseases such as estrogen-dependent tumors, in particular breast cancer, anomalies, e.g. gynecomastia in warm-blooded animals. However, the new compounds are also valuable claims for the preparation of other pharmaceutically active compounds.

The compounds of the formula I are prepared by methods known per se so that in the compound of the formula IV 4 83079 A =.

K.K), iv 'i / \ 1 II «♦

S'V

wherein formula 1 is a group which can be converted to R 1 # R 1 is converted to R 1 by any of the following conversion reactions: (1) a compound of formula IV wherein R 1 is carboxy or a functionally modified carboxy is reacted with ammonia or a C 1 -C 4 alkylamine of formula To prepare a compound of formula I wherein R 1 'is carbamoyl or C 1 -C 4 alkylcarbamoyl, or (2) a compound of formula IV wherein R 1' is C 1 -C 4 alkylcarbamoyl is reacted with a dehydrating agent to prepare a compound of formula I, wherein R 1 represents cyano, and / or the salt obtained is converted into the free compound or another salt, and / or the free compound is converted into a salt.

The conversion of a compound of formula IV wherein R 1 'is O-C 1-4 alkylcarbamoyl, for example t-butylcarbamoyl, to a compound of formula I is carried out e.g. with a strong dehydrating agent such as phosphorus pentoxide, phosphoryl chloride, thionyl chloride, phosgene or oxalyl chloride.

The dehydration may preferably be carried out in the presence of a suitable base. A suitable base is, for example, a tertiary amine, for example tri-lower alkylamine, for example trimethylamine, triethylamine or ethyl-diisopropylamine, or Ν, Ν-di-lower alkylaniline, for example Ν, Ν-dimethylaniline, or a cyclic tertiary amine, for example N, 83079 lower alkylated morpholine, for example N-methylmorpholine, or it is, for example, a pyridine-type base, for example pyridine or quinoline.

Unless otherwise stated, the conversion of a compound of formula IV to a compound of formula I is carried out in an inert, preferably anhydrous solvent or solvent mixture, for example a carboxylic acid amide, for example formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride, carbon tetrachloride for example in acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or mixtures thereof, optionally in the presence of an alcohol, for example methanol or ethanol, or water, optionally at reduced or elevated temperature, for example about -40 ° C - in the temperature range of about + 100 ° C, preferably at a temperature between room temperature and the boiling point of the reaction mixture, and optionally in an inert gas atmosphere, for example a nitrogen atmosphere.

The salts of the compounds according to the invention can be prepared in a manner known per se. Thus, they can be formed, e.g., by the methods shown in the examples. The acid addition salts of the compounds of the invention are obtained in a conventional manner, for example by treating the free compound with an acid or a suitable anion exchange reagent. The salts can be converted into the free compounds in a conventional manner, for example by treating the acid addition salt with a suitable basic substance, for example an alcoholate, e.g. potassium tert-butoxide. Due to the relationship between the free compounds and the compounds in the form of their salts, reference to a compound in this context also means the corresponding salt, provided that such is possible or appropriate under the circumstances.

6 83079

Depending on the choice of starting materials and methods, the new compounds may be in the form of a possible isomer or mixtures thereof, for example depending on the presence of chiral carbon atoms as optical isomers such as antipodes or mixtures of optical isomers such as racemates or diastereomers.

The resulting mixtures of diastereomers can be separated on the basis of physicochemical differences between the components, for example by chromatography and / or fractional crystallization.

The racemates obtained can be further decomposed into optical antipodes by known methods, for example by chromatography using an optically active solid phase, recrystallization from an optically active solvent, by microorganisms or by reacting an acidic intermediate or final product with an optically active base which forms salts with a racemic acid. and separating the salts obtained in this way, for example on the basis of their different solubilities, into diastereoisomers from which the antipodes can be released under the action of suitable substances. The basic racemic products can likewise be decomposed into antipodes, for example by separation of its diastereoisomeric salts, e.g. by partitioning the d- or 1-tartrates.

The above reactions are carried out according to standard methods, without diluents or in the presence of diluents, preferably those inert to the solvents and their solvents, in the presence of catalysts, condensing or other substances mentioned above and / or in inert atmospheres, low temperatures or room temperature, room temperature , e.g. in the temperature range -20 ° C to +200 ° C, preferably at the boiling point of the solvents used and at atmospheric or super-atmospheric pressure. Preferred solvents, catalysts and reaction conditions for 7,83079 are set forth in the accompanying illustrative examples.

The compounds, including their salts, may also be obtained in the form of their hydrates or may contain other solvents used for their crystallization.

The invention further includes variations of the present methods / in which the intermediate obtained at some stage is used as starting material and the remaining steps are performed, or in which the process is cleaved at some stage or in which the starting materials are formed under reaction conditions or in which the reaction ingredients are used in their salts or optically pure antipodes. In particular, such starting materials should be used in said reactions which lead to the compounds mentioned above as being very useful. The invention also relates to novel starting materials and methods for their preparation.

The invention further relates to pharmaceutical compositions for enteral or parenteral use comprising a therapeutically effective amount of a compound of the invention, optionally together with a pharmaceutically acceptable carrier or mixture of carriers. Solid or liquid inorganic or organic substances are used as carriers. Suitable dosage unit forms, especially for oral use, e.g. granules, tablets or capsules, preferably contain from about 5 mg to 100 mg, especially from about 10 to 50 mg of a compound of the invention or a pharmaceutically acceptable salt of such a salt-forming compound together with pharmaceutically acceptable carriers.

The daily doses of the compounds of the invention are from about 0.1 to 100 mg / kg, preferably from 0.5 to about 50 mg / kg for mammals depending on the species and also for individuals depending on age, 8 83079 individual condition and route of administration. For parenteral use, e.g. by intramuscular or subcutaneous injection, or by intravenous infusion, the doses in this range are generally lower than in the enteral, i.e. in oral or rectal use. The compounds of the invention are administered orally or rectally, preferably in unit dosage forms such as tablets, granules, capsules or suppositories, and parenterally, especially in the form of injectable solutions, emulsions or suspensions or infusion solutions.

Suitable carriers are, in particular, fillers, such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium bisphosphate, and likewise binders, such as starch pastes, for example. rice or potato starch, gelatin, tragacanth, methylcellulose and / or, if desired, disintegrants such as the above-mentioned starch pastes, further carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are primarily lubricants and flow regulators, e.g. silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol. The granulators are equipped with suitable coatings, possibly resistant to gastric fluid, in which case e.g. concentrated sugar solutions, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or granular coatings, e.g. to identify or label different doses of active ingredient.

9 83079

Other pharmaceutical preparations for oral use include dry filling capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Dry filling capsules may contain the active ingredient in the form of granules, e.g. mixed with excipients such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil, or liquid polyethylene glycols, in which case stabilizers may also be added.

For rectal administration, pharmaceutical preparations include, for example, suppositories consisting of a combination of the active ingredient and a suppository base. Examples of suppository base masses are natural or synthetic triglycerides, paraffin, polyethylene glycols and higher alkanols. Furthermore, rectal capsules of gelatin containing a combination of active ingredient and base mass can also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraffins.

Particularly suitable dosage forms for parenteral use include suspensions of the active ingredient, such as corresponding oily injection solutions or suspensions, using suitable lipophilic solvents or excipients, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglyceride or triglyceride solutions containing viscosity-improving agents, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers.

10 83079

The pharmaceutical preparations according to the present invention are prepared in a manner known per se, e.g. by means of customary mixing, granulating, preparing, dissolving or lyophilizing methods. For example, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating the resulting mixture, and processing the mixture of granules into tablets or granules, if desired or necessary after the addition of suitable excipients.

The following examples illustrate the invention and are not intended to limit it. Temperatures are given in degrees Celsius and all parts shown are by weight. Unless otherwise indicated, all evaporations are performed under reduced pressure, preferably at about 20-130 mbar.

Example 1: 5- (p-cyanophenyl) imidazor, 5-a] pyridyl

A solution of 0.1 g of 5- (p-tert-butylaminocarbonylphenyl) imidazo [1,5-a] pyridine in 3 ml of toluene is treated with 40 [mu] l of phosphorus oxychloride at 90 [deg.] C. for 5 hours. The solvent is evaporated and the residue is redissolved in 30 ml of chloroform at 0 ° C. Ice-cold ammonium hydroxide solution is added and the organic phase is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with ethyl acetate to give the title compound, m.p. 117-118 °.

Example 2: 5- (p-tert-butylaminocarbonylphenyl) imidazo [1,5-a] pyridine

To a suspension of 0.4 g of 5- (p-carboxyphenyl) imidazo [1,5-a] pyridine in 40 ml of methylene chloride under nitrogen at room temperature is added 30 .mu.l of N, N-dimethyl-11,83079 liformamide and then 0.16 ml of oxalyl chloride. The reaction mixture is stirred until gas evolution has ceased and 0.46 ml of tert-butylamine is added dropwise. Stirring is stopped after 90 minutes and 10 ml of saturated sodium bicarbonate solution are added. The organic layer is separated, dried over sodium sulfate and evaporated to give the title compound, m.p. 128-131 °.

The starting material is prepared as follows: 5- (p-ethoxycarbonylphenyl) imidazo [1,5-a] pyridine

A solution of 9.8 g of 2- (p-ethoxycarbonylphenyl) -6-formylaminomethylpyridine and 11.15 g of phosphorus oxychloride in 26 ml of toluene is heated at 90 e for 15 hours. The solvent is evaporated off and the residue is taken up in 50 ml of methylene chloride, cooled to 0 ° and basified with an excess of ice-cold saturated ammonium hydroxide solution. The organic phase is separated, dried and evaporated. The remaining solution is passed through silica gel (100 g) using ethyl acetate as eluent to give, after recrystallization, the title compound, m.p. 118-119 e.

Preparation of starting material: 6-cyano-2- (p-ethoxycarbonylphenyl) pyridine 8.9 ml of 40% peracetic acid are added dropwise to 14.08 g of 2- (p-ethoxycarbonylphenyl) pyridine to maintain the reaction temperature at 80-85 ° . After the addition is complete, the reaction mixture is heated at 90 ° for 3 hours and allowed to cool to room temperature. Excess peracetic acid is decomposed with aqueous sodium sulfite solution. The solvent is evaporated off and the residue is taken up in methylene chloride and filtered again through Celite®. Evaporation gives 2- (p-ethoxycarbonylphenyl) pyridine N-oxide which is treated with 8.66 g of dimethyl sulfate in 62 ml of toluene at 90 ° C for 3 hours. The solvent is evaporated and the residue is redissolved in an ice-cold mixture of 8 ml of water and 9.3 ml of 1N sodium hydroxide. A solution of 13.64 g of potassium cyanide in 10 ml of water is slowly added and the reaction mixture is kept at 0 ° for 24 hours. Extract with methylene chloride, dry over sodium sulfate and evaporate the solvent to give the title compound a); IR (CH 2 Cl 2) 2200 cm -1.

6-Aminomethyl-2- (p-ethoxycarbonylphenyl) pyridine 16.23 g of 6-cyano-2- (p-ethoxycarbonylphenyl) pyridine are hydrogenated at atmospheric pressure in 254 ml of methanol with 12.9 ml of concentrated hydrochloric acid and 2.6 with 3 g. 10% palladium on carbon until 2 molar equivalents of hydrogen have been consumed. Sodium methoxide (6.9 g) is added and the catalyst is filtered off. The solvent is evaporated. The residue is redissolved in 20 ml of methylene chloride and the salts are removed by filtration. Evaporation of the solvent gives a solid which is recrystallized from chloroform to give the title compound b), m.p. 141-143 e.

2- (p-ethoxycarbonylphenyl) -6-pyridine-formyyllaminometyylipyri

A solution of 0.76 g of 6-aminomethyl-2- (p-ethoxycarbonylphenyl) pyridine in 10 ml of formic acid is heated at 90 ° C for 15 hours. The reaction mixture is cooled to 0 ° C, basified with excess saturated ammonium hydroxide solution and extracted with chloroform. The organic extracts are dried and evaporated to give the title compound c) which is recrystallised from toluene, m.p. 119.5-120.5 e.

i3 83079 5- (p-Carboxyphenyl) imidazor-1,5-alpyridine

A solution of 1.18 g of 5- (p-ethoxycarbonylphenyl) imidazo [1,5-a] pyridine in 10 ml of ethanol and 14 ml of 1N sodium hydroxide solution is heated under reflux for 3 hours, cooled and evaporated. The residue is partitioned between water and ethyl acetate. The aqueous phase is separated and adjusted to pH 5. The solid is filtered, washed with water and dried to give the title compound, m.p. 308-310 ° (dec.).

Example 3; 5- (p-carbamoylphenyl) imidazo [1,5-a] -py-piperidine

A solution of 0.18 g of 5- (p-carboxyphenyl) imidazo [1,5-a] pyridine hydrochloride in 5 ml of thionyl chloride is heated under reflux for 30 minutes and evaporated to dryness. The resulting oil is redissolved in 10 ml of methylene chloride and ammonia is bubbled into the solution at 0 ° for one hour. The solution is washed with water and dried over sodium sulfate. Evaporation affords the title compound, m.p. 228-230 0 (dec.).

Claims (2)

A process for the preparation of therapeutically active 5-phenyl-imidazo [1,5-a] pyridines of formula I = 7 x * = · 1 '\ A}' i; Wherein R 1 represents cyano, carbamoyl or -alkylcarbamoyl, or pharmaceutically acceptable salts thereof, characterized in that in a compound of formula IV Kk} IV (IV) R ^ is a group which can be converted into a group Rj, R *s is transferred to the group R ^ with any of the following conversion reactions: (1) a compound of formula IV in which R is reacted with ammonia or a C ^-C ^ alkylamine, to prepare a compound of formula I in which is carbamoyl or C --C ^ alkylcarbamoyl, or (2) a compound of formula IV R C is CLC ^ alkylcarbamoyl, reacted with a dehydrating agent, to prepare a compound of formula I in which R] is cyano and / or , and / or a free compound is transferred into a site. 17 83079 2. A process according to claim 1 for the preparation of 5- (p-cyanophenyl) imidazo [1,5-a] pyridine of the formula e characterized in that, in a compound of formula IVa, the formula R1a represents a group or a residue which can be converted into a compound of formula IVa. cyano group, R 11 is converted into cyano with the following conversion reaction: a compound of formula iva in which 'Sr C 1 -C 4 alkylcarbamoyl is reacted with phosphorus oxychloride; and / or a obtained site is transferred to the free compound or another site, and / or a free compound containing a salt-forming group is transferred to a site.