GB2310136A - Dihydropyridine derivatives as aromatase inhibitors - Google Patents

Description

DIHYDROPYRIDINE DERIVATIVES USEFUL AS AROMATASE INHIBITORS The present invention relates to the use of known Nimidazolyl derivatives of 4-phenyl-1,4-dihydropyridines in the manufacture of a medicament for use as aromatase inhibitors.

WO 90/06923 and US 5,362,729 disclose certain imidazolyl derivatives of 4-phenyl substituted 1,4-dihydropyridine. The compounds according to the prior-art international application are thromboxane A2 synthase inhibitors and calcium antagonists, whereas those according to the US patent are useful for re-sensitizing multi-drug resistant cells to chemotherapeutic agents.

We have now found that compounds falling within the above cited publications are also useful as aromatase inhibitors, i.e. inhibitors of the biotrasformation of androgens into estrogens, for controlling the amount of circulating estrogens, estrogen-dependent processes in reproduction and estrogen-dependent tumors.

Accordingly, one object of the present invention is the use of a N-imidazolyl derivative of 4-phenyl-1,4-dihydropyridine of formula (I)

wherein R is hydrogen, halogen, C1-C3 alkyl or C1-Cz alkoxy; n is zero or 1; each of R3 and R4, which may be the same or different, is C1-C3 alkyl unsubstituted or omega substituted by C1-C3 alkoxy; R5 is hydrogen or C1-C4 alkyl; one of R1 and R2 is a group OR', wherein R' is Cl-C6 alkyl and the other is independently, C1-C3 alkyl or a group OR' as defined above; or a pharmaceutical salt thereof, in the manufacture of a medicament having steroidal aromatase inhibitory activity.

The invention includes also all the possible isomers and stereoisomers of the compounds of formula (I) and their mixtures. Also the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I) i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I) are included within the scope of the invention.

Pharmaceutically acceptable salts of the compounds of formula (I) are, especially, acid addition salts with inorganic, e.g.

nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, fumaric, methanesulfonic and salicylic acids.

The substitution position on the phenyl ring of the (CH2)n Het group is preferably meta or para.

The alkyl groups may be branched or straight chain groups.

A C1-C3 alkyl group is preferably methyl, ethyl or n-propyl.

A Cl-C6 alkyl group is preferably a C1-C4 alkyl group, in particular methyl, ethyl, q-propyl, isopropyl or isobutyl.

A Cl-C3 alkoxy group is, preferably, methoxy or ethoxy, particularly methoxy.

A halogen is, preferably, chlorine, bromine or fluorine, in particular chlorine or fluorine.

A preferred class of compounds according to the invention are the compounds of formula (I) in which n is zero and R is hydrogen; and the pharmaceutically acceptable salts thereof.

Specific examples of compounds of formula (I) are: 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, dimethyl ester, m.p. 212-2160C; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, ethyl methyl ester, m.p. 1972000C; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester, m.p. 202-2040C; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, isopropyl methyl ester; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-1,4- dihydro-l,2,6-trimethyl-4-[3-(lH-imidazol-l-yl)phenylJ-3,5- pyridinedicarboxylic acid, diethyl ester; 1H-NMR (CDC13) 6 p.p.m.: 1.27 (6H, t, 2 COOCH,C,) 2.49 (6H, s, 2 =C-CH3) 3.21 (3H, s, N-CH3) 4.19 (4H, q, 2 COOCH2CH3) 5.12 (1H, s, C at 4 position of dihydropyridine) 7.0-7.3 (6H, m, phenyl ring + CH at 4 and 5 positions of imidazole 7.78 (1H, bs, -N=CH-N-).

1,4-dihydro-2-(methoxy)methyl-6-methyl-4-[3-(lH-imidazol-1- yl)phenyl]-3,5-pyridinedicarboxylic acid, 3-ethyl 5-methyl ester, m.p. 153-40C; 1,4-dihydro-5-acetyl-2,6-dimethyl-4-[3-(lH-imidazol-1-yl) phenyl]-3-pyridine-dicarboxylic acid, methyl ester, m.p.

2260C; 1,4-dihydro-2,6-diethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester, m.p. 171-1720C; and the pharmaceutically acceptable salts thereof.

As stated above, the compounds of the invention and the salts thereof fall within the disclosure of WO 90/06923 and US 5,362,729, therefore they can be obtained according to the teaching of such prior art. In particular the compounds of the invention and the salts thereof can be obtained by a process comprising: a) reacting a compound of formula (II)

wherein R, n, R2 and R3 are as defined above, with a compound of formula (III)

wherein R1, R4 and Rs are as defined above; or b) reacting a compound of formula (II) with a compound of formula (IV)

wherein R1 and R4 are as defined above, in the presence of an ammonium salt or hydroxide, thus obtaining a compound of the invention wherein R, n, R1, R2, R3 and R4 are as defined above and R5 is hydrogen; or c) reacting a compound of formula (V)

wherein R and n are as defined above, with a compound of formula (III) and a compound of formula (IV) together; or d) reacting a compound of formula (V) with a compound of formula (IV) wherein R1 is a group -OR' as defined above in the presence of an ammonium salt or hydroxide, thus obtaining a compound of the invention wherein R, n, R3, R4 and R5 are as defined above and each of R1 and R2 is a group -OR' wherein R is as defined above and R1 is equal to R2 and R3 is equal to R4; e) alkylating a compound of the invention wherein R5 is hydrogen to obtain a corresponding compound of the invention in which R5 is C1-C9 alkyl and, if desired, converting a compound of the invention into another compound of the invention, and/or, if desired, converting a compound of the invention into a pharmaceutically acceptable salt thereof, and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of compounds of the invention, into the single isomers.

Details about the process variants described above for the preparation of the compounds of the invention are to be found in the two above cited references.

A further object of the present invention is a method of treating of a human patient in need of aromatase inhibition said method comprising administering to said patient therapeutically effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof.

PHARRACOLOGY The compounds of the present invention are inhibitors of the biotransformation of androgens into estrogens, i.e. they are steroidal aromatase inhibitors.

Basic and clinical data indicate that aromatized metabolites of androgens, i.e. the estrogens, are the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers, such as breast, endometrial and ovarian carcinomas.

Estrogens are also involved in the pathogenesis of benign prostatic hyperplasia. Endogenous estrogens are ultimately formed from either androstenedione or testosterone as immediate precursors. The reaction of central importance is the aromatization of the steroidic ring A, which is performed by the enzyme aromatase. As aromatization is a unique reaction and the last in the series of steps in the biosynthesis of estrogens, it has been envisaged that an effective inhibition of the aromatase, resulting from compounds able to interact with the aromatizing steps, may have useful application for controlling the amount of circulating estrogens, estrogen dependent processes in reproduction, and estrogen-dependent tumors.

The aromatase inhibitory activity of the compounds of the invention was demonstrated e.g. by employing the in vitro test described by Thompson and Siiteri (E.A. Thompson and P.K. Siiteri, J. Biol. Chem. 249, 5364, 1974) which utilizes the human placental microsomal fraction as enzyme source. In this test the aromatization rate of androstenedione into estrone was evaluated by incubating (lp-3H) androstenedione (50 nM) in the presence of NADPH with the enzyme preparation and by measuring the amount of 3H2O formed during 15 min incubation at 370C.

The compounds, incubated at various concentrations, showed a relevant aromatase inhibitory activity.

For example the representative compounds of the invention 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester (internal code FCE 24265) inhibited human placental aromatase with IC50 = 3.6 nM in comparison with a IC50 value of the reference compound aminoglutethimide of 2280 nM.

Thus the exemplified compound is about between two and three order of magnitude more potent than reference compound aminoglutethimide, a drug used in the treatment of estrogendependent breast cancer (see e.g. C.R.C. Crit. Rev. Oncol.

Hematol. 5, 361, (1986).

By virtue of their ability to inhibit aromatase and, consequently, to reduce estrogen levels, the compounds of the invention are therefore useful in mammals, including humans, in the treatment or prevention of various estrogen-dependent diseases, i.e. breast, endometrial, ovarian and pancreatic cancers, gynecomastia, benign breast disease, endometriosis, polycystic ovarian disease and precocious puberty. Another application of the compounds of the invention is in the therapeutic and/or prophylactic treatment of prostatic hyperplasia, a disease of the estrogen-dependent stromal tissue. The compounds of the invention can find also use for the treatment of male infertility associated with oligospermia and for female fertility control, by virtue of their ability to inhibit ovulation and egg nidation.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramusculary, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example, the dosage adopted for oral administration to adult humans for compound FCE 24265 may range from about 10 to about 150-200 mg pro dose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions having aromatase inhibiting activity comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g.

cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the present invention.

Example 1 Tablets, each weighing 150 mg and containing 50 mg of the active substance are manufactured as follows: Composition (for 10.000 tablets): 1,4-dihydro-2,6-dimethyl-4- [3- (lH-imidazol- 1-yl)phenyl] -3, 5-pyridinedicarboxylic acid, diethyl ester 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-y1)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester lactose and a half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings.

Corn starch (18 g) is suspended in warm water (180 ml).

The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium is added, carefully mixed, and processed into tablets using punches of 8 mm diameter.

Example 2 Capsules, each dosed at 0.5 g and containing 50 mg of the active substance can be prepared.

Composition for 200 capsules: 1,4-dihydro-2,6-dimethyl-4- [3-(1H-imidazol- l-yl)phenyl]-3,5-pyridinedicarboxylic acid, diethyl ester 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5g This formulation is encapsulated in two-piece hard gelatin capsules and dosed at 0.5g. for each capsule.

Example 3 By the usual pharmaceutical technique, suppositories having the following composition can be prepared: 1,4-dihydro-2,6-dimethyl-4- [3- (lH-imidazol- 1-yl)phenyl]-3,5-pyridinedicarboxylic acid, diethyl ester 0.05 g Lecithin 0.07 g Cacao butter 0.88 g Example 4 Intravenous injection 50 mg/ml.

An injectable pharmaceutical preparation can be manufactured by dissolving 50 g of 1,4-dihydro-2,6-dimethyl-4-[3-(lH imidazol-1-y1)phenyl] -3, 5-pyridinedicarboxylic acid, diethyl ester hydrochloride in water for injection (1000 ml) and sealing in ampoules of 1-10 ml.

Claims (8)

1. Use of a compound which is an N-imidazolyl derivative of 4-phenyl-1,4-dihydropyridine of formula (I)

wherein R is hydrogen, halogen, C1 -C3 alkyl or Cl-C3 alkoxy; n is zero or 1; each of R3 and R4, which may be the same or different, is C1- C3 alkyl unsubstituted or omega substituted by Cl-C3 alkoxy; Rs is hydrogen or Cl-C4 alkyl; one of Rl and R2 is a group OR', wherein R is Cl-C6 alkyl and the other is independently, C1-C3 alkyl or a group OR' as defined above; or a pharmaceutical salt thereof, in the manufacture of a medicament having steroidal aromatase inhibitory activity.

2. Use as claimed in claim 1 wherein n in formula (I) is zero and R is hydrogen.

3. Use as claimed in claim 1 wherein the compound is chosen from: 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, dimethyl ester; 1,4-dihydro-2,6-dimethyl-4-[3(1H-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, ethyl methyl ester; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, isopropyl methyl ester; 1,4-dihydro-2,6-dimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-1,4- dihydro-1,2,6-trimethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester; 1,4-dihydro-2-(methoxy)methyl-6-methyl-4-[3-(lH-imidazol-1- yl)phenyl]-3,5-pyridinedicarboxylic acid, 3-ethyl-5-methyl ester; 1,4-dihydro-5-acetyl-2,6-dimethyl-4-[3-(lH-imidazol-1-yl) phenyl] -3-pyridine-dicarboxylic acid, methyl ester; 1,4-dihydro-2,6-diethyl-4-[3-(lH-imidazol-1-yl)phenyl]-3,5- pyridinedicarboxylic acid, diethyl ester; and the pharmaceutically acceptable salts thereof.

4. Use as claimed in 1 wherein the medicament is for use in the treatment or prevention of an estrogen-dependent disease.

5. Use as claimed in claim 4, wherein the estrogendependent disease is breast, endometrial or pancreatic cancer, gynecomastia, benign breast disease, endometriosis, polycistic ovarian disease, precocious puberty, prostatic hyperplasia or male infertility.

6. Use as claimed in claim 1 wherein the medicament is for use in female fertility control.

7. A method of treating of a human patient in need of aromatase inhibition, which method comprises administering to said patient a therapeutically effective amount of a compound as defined in claim 1.

8. A pharmaceutical composition having aromatase inhibitory activity containing a pharmaceutically acceptable carrier and/or diluent and a compound as claimed in claim 1 as an active principle.