PT100275A - HETEROCYCLIC COMPOUNDS CONTAINING THE 3-PYRIDYLETHYL GROUP OR ITS DERIVATIVES, ITS PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

Background of the Invention 1. Technical Pampo of the Invention

This invention relates to compounds which comprise. the 3-pyridylacetyl functional group, in particular 3-pyridylacetic acid esters and amides, very closely to ketones together with certain of their derivatives, to the process of their preparation and use in the treatment of prostate cancer. 2. Description of Prior Art E * McOague, M * G. Eowlands, S * E * Sarrie and J. Hou-ghton, J. Med. Chem. 33, 3050-3055 (1990), found that certain esters of 4-pyridylacetic acid,

Ra-O-CO-O-

(I) in which: Ra represents a specific alicyclic group (for example cyclohexyl or a terpene residue) or (2) wherein: R 1 represents a hydrogen atom or a methyl group, inhibit the enzyme lyase 17 OD-hydroxylase / C2q which is essential for the androgen biosynthesis. Inhibition of androgen synthesis by inhibition of hydroxylase / lyase indicates that the compounds of MoOague et al., Supra, may be useful in the treatment of prostate cancer, since numerous tumors are dependent on androgen for their growth.

The features of McCague et al. are also aromatase inhibitors. Flavor is an enzyme required in the biosynthesis of estrogens. The ability to inhibit aroma-tase I is considered a desired property in the compounds to be used in the treatment of breast cancer. It is undesirable, however, for the treatment of prostatic cancer, since a cooiposto for such an effect must be a strong inhibitor of both aromatase and the enzymatic complex hydroxylase / lyase, since the inhibition of aromatase will avoid the removal, by subsequent conversion into estrogens, of any products of the enslavic complex, hydroxylase / lyase, which escape the blocking of hydroxylasease. As a result, a patient may lose some of the benefits of the inhibition of hydroxylase / lyase.

Accordingly, for the present application of prostate cancer treatment it is desirable to maintain the IC 50 versus 10aseus aromatase ratio as low as possible. (A low numerator indicates that the compound is a powerful lyase inhibitor. A high denominator indicates that compound I is a weak aromatase inhibitor). The best compound in this view is cyclobexyl 2-methyl-2- (4-pyridyl) propanoate of formula (2), wherein R 1 is methyl and of formula (26) in this description, although it should be present in our minds that these data are based on human aromatase and rat lyase. The same compound has also been slowed down more slowly by porcine liver esterases than the monomethylated compound (formula (2), or the unmethylated compound [formula (I) , Ra = cyclohexyl. This description defends the similar dimethyl substitution of the compound of formula (I) in which -

'Cu'

Ra is an olicyclic group of the terpene residue type, not establishing that in such compounds the rate of the lyase / aromatase in the non-methylated compounds is higher than that of the cyclohexyl compounds (i).

An immediately subsequent study of 0. A. Laughton and S. Neidle, J. Med. Chem. 33, 3055-3060 (1990) attempts to explain the data of McCague et al. in the terms of the imitation of the natural steroid substrates for aromatase and hydroxylase by the 4-pyridylacetates and propanoates with reference to the compounds: [formula (I): Ra = cyclobexyl *] and its oc-methyl, (4-pyridyl) propanoate, (formula V η ** (2), R = Bj, as the α-methyl substitution decreases the IC 50 lyase / aromatase rate from 67 to 1.0. With regard to inhibition of aromatase, the article suggests that the carbon atom attached to the carbonyl ester function occupies a spatial position with the carbon atom 0 (2) of the natural steroid substrate (testosterone), and that the configuration of the molecule as a whole is favorable, but that the Î ± -methyl substituent will then emit a substituent on the steroid 0 (2). Since either evidence suggests that the ester grouping in the 0 (2) region is not favorable for aromatase inhibition, weak inhibition of aromatase Thus, the substituent may be rationalized in this way. However, with respect to the inhibition of Mroxilase / lyase, there is not much literature, and the authors make many statements suggesting that the oc-methyl 2- (4-pyridyl) propanoate group falls into the spatial position of the carbon atoms 0 ( 16) or 0 (20) of the natural steroid substrate pregnololone, and include that the inhibitory activity arises from the hydrophilic interactions of the methyl group with the active zone of the enzyme. This view, however, does not explain why the hydroxylase / lyase activity of compounds without the

methyl group, for example 4-ethylhexyloxy-4-pyridyl acetate, is as good as that of the α-methyl compound for molting and therefore suggests that the structural requirements for hydroxylase / lyase activity are unpredictable.

Summary of the Invention i

It has now been discovered, surprisingly, that the com. 3-pyridylacetyl compounds of formula (3) possess atypical hydroxylase / lyase activity at a low 10% lyase / aro-matase rate, and therefore have potential value for the treatment of androgen-induced canoes, such as prostate. These compounds have the general formula:

Wherein each R 1 and R 2 are each independently hydrogen or a lower alkyl, or together represent the hard residue of the cycloalkyl group of 3 to 6 carbon atoms; A represents an O atom; R1 is defined as R1 and R2, or R5, wherein R6 and R7 are as defined for R3 or R4, as separate substituents; and R 3 represents an alicyclic group with bridges; as free bases or their pharmaceutically acceptable salts, especially acid addition salts. The term " lower molecular weight " means here that the group has from 1 to 4 carbon atoms. The invention includes each of the optical isomers and mixtures thereof, especially racemic mixtures. or

DESCRIPTION OF THE PREFERRED EMBODIMENTS To the preferred compounds of the invention may be defined in various ways, all of which reflect the fact that R1 is one. hydrocarbyl, cyclic and non-aromatic and has at least one bridge through the ring. Because it is defined as having a bridge, it comprises at least two alicyclic rings, either having more than one bridge or by pivoting one or more other fused rings (not bridges). In this invention, a bridge is understood as a bond between 2 non-adjacent carbon atoms of the ring by means of at least one intermediate carbon atom. A molten ring is used when two non-adjacent carbon atoms are directly joined by a bond.

In the preferred compounds it is possible to understand the R group as a substituted cyclobexyl group, wherein the substituents comprise bridging members. The ex < Preferred R "groups within the scope of this definition are as follows, with their adjacent oxygen atom (isopinocamphenyl-isopropylidene 2-oethyl) (cyclohexyl substituted by a 3'-bridge and additionally having a substituent

borneyl (exylobexyl substituted by the 2,5-isopropylidene bridge and additionally having the 2-methyl substituent)

isoborneyl

endo-norborneyl (cyclobexyl substituted by a 2,5-methylene bridge)

exo-norborneyl

adamantyl (oxylohexyl substituted by a first 1,3- (1,3-propylene) bridge, and subsequently by a second bridge between the atom of 05 and the carbon atom of the middle of the second

(cyclobexyl) substituted by a first 2,4- (1-3-propylene) bridge, and further substituted by a bridge segment between its carbon atom 6 and the carbon atom of the middle of the first bridge, and additionally having a sub-

1-methyl substituent on the cyclohexane ring)

(Cyclohexyl substituted by a 2,4-isobutyl bridge having a methyl substituted cyclopentane ring fused to the carbon atom 4 of the cyclohexane ring and the carbon atom 1 of the bridge and additionally having a 1-methyl substituent in the cyclohexane ring). 1

Alternatively, preferred R1 groups may be defined by reference to the longer carboxyl ring having a bridge, which in the cedryl is a cycloheptane ring and in the adamantyl I is a cyclooethane ring. Accordingly, this definition represents an alicyclic group having a bridge having 6 to 8 carbon atoms (excluding all atoms of the same) and optionally having one or more alicyclic groups, for example a substituted cyclopentane or cyclohexane ring. By way of illustration, the bridges usually have 1 to 2 carbon atoms in the linear direction (counting only the carbon atoms in the yue which form the bridge between the ring atoms, not counting as belonging to the bridge the ring atoms, where the bridge starting or ending, and not counting as from the bridge any carbon atom which is attached to an atom of the atom, for example in the two methyl groups of a bridged isopropylene group).

The bridging R 1 groups which are bridged are cycloalkane rings which may be unsaturated, but are aromatic, and may be substituted by one or more hydrocarbyl substituents, such as especially methyl 1 to 4 carbon alkyls. Bridges do not need to be complete

and may therefore have a Câ, â, <â, "pendant alkyl, especially methyl groups, for example. Likewise, the said cyclohexane or bridged rings or both may, have a halogen, especially Cielopenane or cyclohexane or their fused rings. The fused rings may themselves be simply substituted, as mentioned above for bridged rings, especially for an alkyl having 1 to 4 carbon atoms. The invention comprises optically active forms of the compounds of formula (3), particularly with boraneyl, isoborneyl, oedryl and isopinocampheyl. The group A in formula (3) preferably represents -0-, but when -CH3 is not present, hydrolysable esters and amide linkages are potentially present, which is also advantageous. all lower alkyl groups &quot; mentioned herein are preferably methyl or ethyl. R 2 and R 2 are both preferably methyl, except when R 2 denotes an extremely attached group such as oedry, wherein the pendent substituents on one side extend in the vicinity of the oxygen atom of the ester

In such a case, preferably not more than one of the groups R 1 and R 2 denotes a lower alkyl group and more preferably both are hydrogen. Alternatively, R1 and R2 together with the carbon atom to which they are attached may complete a ring of 3, 4, 5 or 6 carbon atoms, 0 cyclopentane being preferred.

The divalent amino group R3a is preferably hydrogen but may have any of the other 12 meanings for the R5 and R5 substituents individually, of which lower molecular weight alkyl is preferred, eg

especially methyl. 5 6

Oetone dias, R and R are preferably hydrogen; one is methyl and the other is hydrogen, or aminos are methyl. Ir and R 4 together do not represent an oxyloalkyl or aloylene group.

The compounds of the invention may be prepared in various forms conveniently starting from 3-pyridylacetic acid or from an ester thereof. Preferably, the starting ester is the methyl ester or the ethyl ester. The initiation compounds (A = -O-) have the general formula (4)

in which Σ is -OH or a reactive substituent and R3 are as defined above for formula (3). Simple esterification or transesterification with an alcohol

The formula of formula (3) gives the esters of formula (3) wherein the reactive substituent X is any group reactive for the purpose of forming an ester or amide of formula (3). For amidation of amides (A = -HH-), compounds of formula (4) may be reacted with primary amines in the usual manner.

To prepare the ketones of formula (3) in which A = -CH 2, a suitable technique involves the reaction between an alkali metal salt of 3-picoline, for example 3-picolylphthiol (0.0001, Screttas, T., P. Estbam, C.M. Kamienski, Chimia, 24, 109-11, 1970) and an appropriate methyl ester R4 ACCOO, wherein A p is another CR5 R group, in accordance with the procedure used by J,

L 'Bond, D. 1. Krottinger, R. 1. Schumacher, E. H. Sund and 3J. J. Yifeaver, Journal of Chemical and Engineering Bata, 18, 349-350, (1973) for the preparation of 4-pyridylketones alkyl from 4-picolylsodium and RCQgMe.

When the compounds of formula (3) to be prepared are those in which R or R represents a radical other than hydrogen, it may be convenient to use as starting material the compound of formula (4), a pyridyl lactic acid compound (3) and subsequently introducing the desired R or R substituent by the action of an alkali metal hydrogen, followed by a lower alkyl or an alkyl or iodide bromide. The methylene (CHâ,,) or ethylene derivatives (CHâ,, = CHâ,,) can be prepared from the corresponding oethyl and ethyl derivatives by thermal decomposition of the phenyl sulfoxide, see 33. M. Crost et al., J. Amer . Chem. Soc., 98, 4487-4902 (1976).

The compounds may be prepared in the form of salts, for example hydrochloride and converted into their free base form and thereafter in other conventional pharmaceutically acceptable salts, such as acetates, citrates and lactates, as appropriate. The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in association with a therapeutically acceptable carrier or diluent. The composition of the invention may, for example, be in a form suitable for parenteral (e.g. intravenous, intramuscular or intracavital) administration, oral, topical or rectal. Particular forms

for example, solutions, suspensions, emulsions, buds, tablets, capsules, lipsomas or micro-reservoirs, especially oral or sterile injectable compositions. The preferred form of the composition contemplated is the solid, dry form, which comprises granulated capsules, tablets, pills, lozenges and powders. The solid carriers may comprise one or more exo-peptides, for example laotoses, fillers, disintegrating aids, binders, for example cellulose, carboxylmethylcellulose or starch, or anti-stiffening agents, for example magnesium stearate , so as to prevent tablets from adhering to the tabletting apparatus. The tablets, pills and lozenges may be shaped so as to disintegrate rapidly or in a slow and controlled manner in terms of release of the active ingredient.

When national laws regulate pateh. Accordingly, the present invention further comprises a method for the treatment of androgen dependent tumors in the mammalian body which comprises administering a compound of the invention to a mammalian patient in a therapeutically effective dosage, for example in the range comprised between 0.001 to 0.04 mmol / kg body weight, preferably in the range of 0.001 to 0.01 mmol / kg body weight, administered once or twice a day during the course of the treatment. This dosage is therapeutically effective for the human at a dosage in the range of 20 to 800 mg / patient per day. Alternatively, the invention comprises the compounds of the invention for use in said treatment and their use in the production of medicaments for such purposes.

The Examples which follow will illustrate the invention. At

temperatures are presented in 1

(1S, 2S, 3S, 5S) -Isopinoeanphenyl 3-pyridylacetate

A stirred solution of (+) - isopynoanophenol (3 g, 086 g, 20 mmol) in dry tetrahydrofuran (20 ml) under cooling with an ice cold salt bath. A solution of n-butyllithium ( A solution of 3-pyridylacetate (2.776 g, 16.7 mmol) in tetrahydrofuran (5 ml) was added a solution of 3-pyridylacetate (2.746 g, 16.7 mmol) clear yellow solution, which was allowed to reach room temperature. After 4 hours the mixture was partitioned between diethyl ether and water, and the ether layers were concentrated. Chromatography of the residue afforded, by eluting with. petroleum ether (M.P. 60-80-80 ° C) -diethyl ether-triethylamine 50: 50: 1, the title compound (3 g, 79 g, 76%) as an oil. Passing hydrogen chloride gas through a solution of the product in diethyl ether gave the hydrochloride. This was recrystallized from 1: 1 dioxane-ether, m.p. 158-160 ° C. Anal. Calc .: 0-65.90, H-7.81, N-4.52. Found: 0-65.36, H-7.62, N, 4.65%. EXAMPLE 2 (1S, 2S, 3S, 5R) -Isopropoxyphenyl) -2- (3-pyridyl)

A solution of the product of Example 1 as a free base (912 mg, 3 g, 34 mmol) in tetrahydrofuran (3 ml) was added to a stirred suspension of potassium hydride (35% by weight of the dispersion in oil, 383 mg, 3.34 mmol) in tetrahydrofuran (10 mL) under nitrogen at 0 ° C. After 10 minutes, methyl iodide (0.17 mL, 380 mg, 2.68 mmol)

and 1 hour later at 20 ° C was worked up as described above and chromatographed on the column with diethyl ether-petroleum, 5 sec. to give the title compound (345 mg, 36%) as an oil . (d, 3H, J = 6.8 Hz, COCHOS), 3.33 (d, 3H, J = 6.8 Hz, , 7.30 (dd, 1H, J = 4.8, 7.95 Hz, H-5), 7.80 (m, 1H, 1H, 3-4), 8.60 (m, 2H, H-2 and H-6). Anal. Calcd: C, 75.23; H, 8.77; N, 4.87. EXAMPLE 3 (1S, 2S, 38, 5R) -isopropanenyl 2-methyl-2- (3-pyridyl) propanoate.

A solution of (1S, 23S, 5R) -isophenyl-5-phenylphenyl (7.06 mg, 2.58 mmol) in dry tetrahydrofuran (8 ml) was added dropwise a stirred suspension of potassium hydroxide (35% w / w dispersion in oil, 650 mg, 5.68 mmol) in tetrahydrofuran (6 ml) under argon at 0 ° C. 10 minutes later, methyl iodide (733 mg, 5.16 mmol) was added in two equal portions, each in tetrahydrofuran (2 ml). Under the addition of 1 equivalent, the mixture became turbid and hydrogen was evolved. When adding the equivalent of the equivalent, the yellow solution became colorless. 20 minutes later the reaction was quenched by the addition of iso-propanol (0.5 ml). The title compound (539 mg, 69%) was obtained as a colorless oil, which afforded a crystalline eluate, mp 144 DEG-144 DEG. ° C-146 ° C. Anal. Calc. 0-67.57, H-8.35, H-4.15, 01-10.49. Yield 0.75%, H-8.30, 1-4.11, 01-10.61%. EXAMPLE 4 (1S, 2R) -borneyl 3-pyridilao-ethyl.

Following essentially the procedure of Example 1, (-) - borneol (2.232 g, 14.47 mmol) in dry tetrahydrofuran (15 ml), n-butyllithium (5.79 mg, 47 mmol) and ethyl B-pyrrole-2-acetate (1.91 g, 11.57 mmol) in tetrahydrofuran (5 ml) gave the title compound isolated after elution with diethyl ether petroleum, as a colorless oil (2.87 mg, 73%). 1 H NMR (DMSO-d 6): δ 0.7 (s, 3H), 0.84 (s, 6H, O (OH) 2), 3.64 (s, 2H, (M, 1H, CHOCO), 7.26 (m, 1H, H-5), 7.64 (m, 1H, H-4), 8.50 (m, 2H, H-2 and H -6). The hydrochloride had a mp 151-153 ° Anal. Calc'd: C, 65.90; H, 7.81; N, 7.81; N, 4.52; 01, 11.44. Verified; 0, 65.61; H, 7.69; H, 4.46; 01, 11.4%. EXECUTIVE 5 (1R, 2S) -borneyl 3-pyridylacetate.

Following the procedure of Example 4 using (+) - borane the title compound was obtained as a colorless oil (2.95 g, 75%). The obtained Î »-6 data were the same as obtained in Example 4. Anal Cal (free base): C-74.69, H-74.69, H-8.48, H-5.13 Found: C 74.49, H 8.62, N, 4.87%

EXAMPLE 6 (L) -Adamantyl 3-pyridylacetate.

Following essentially the technique described in Example 1, using (1) -adamantanol (3.35 g, 22 mmol) in dry tetrahydrofuran (20 ml), n-butyllithium (1.6 M, 12 mmol) , 5 mL, 20 mmol) in bexane, and methyl 3-pyridylacetate (3.02 g, ε-IV r 20 tmaols) in THF (8 mL). After allowing the reaction mixture to reach room temperature, it was heated under reflux for 18 hours. The product obtained was subjected to chromatography, as described in example 1, comprising unreacted 1-dodanthanol. It was further purified by conversion to the hydrochloride which was washed with dry ether and the free base freed to give the title compound (1.35 g, 24%) which crystallized from hexane (mp 71-72 ° C) . 1 H NMR (CDCl3): 1.70 and 2.08 (2S, 12H, adamantyl CH3), 2.14 (s, 3H, adamantyl OH), 3.54 (s, 2H, OCH3), 7.27 (m, 1H , H-5), 7.66 (m, 1H, H-4), 8.50 (bt, 2H, and H-2 and H-6). Anal. , 80.1, 5.16. C, 75.12; H, 7.89; 1.03, EXAMPLE 7 1-Adamantyl 2- (3-pyridyl) propanoate: The procedure essentially followed was that of Example 2, using 1-adamantyl 3-pyridylacetate (542 mg, 2.0 mmol) in dry THF (2 mL), potassium hydride (35% w / w dispersions in < , 229 mg, 2.0 mmol) in CH 3 Cl 2 (6 mL) and methyl iodide (0.10 mL, 1.6 mmol). 50: 50: 1 yielded the title compound (143 mg, 25%) as an oil. 1 H NMR (d6 -DMSO): δ 1.47 (d, 3H, J = 7.2 Hz, GEKe), 1.64 and 2.04 (2s, 12H, adamantyl OH), 2.14 (s, 3H, adamantyl OH), 3.33 (q, 1H, J = 7.2 1H), 7.66 (bt, 1H, H-4), 8.52 (m, 2H, H-2 and H-6). Calc'd: C, 75.76; H, 8.12; N, 4.81 Found: C, 75.76; H, 8.28; N, 4.54%.

The process 1, essentially followed, is as described in Example 3> (1-adamantyl) -8-methyl-2- (3-pyridyl) propanoate. using 1-adamantyl pyridyl acetate (542 Dpt, 2.0 mmol), dry DMF (2 mL), potassium hydride (35 μg / well dispersed in oil , 504 mg, 4.4 mmol) in THF (6 mL), and methyl iodide (0.25 mL, 4.0 mmol). Chromatography under elution with petroleum (bp: 60-80 ° C): diethyl ether-triethylamine gave the title compound (262 mg, 39%) as a colorless oil. 1.63 and 2.03 (2s, 12H, adamantyl OH), 2.13 (s, 3H), 2.63 (s, 6H, (M, 1H, B-2 or 6), 8.47 (m, 1H, H-5), 7.65 (m, 1H, H-4), 8.47 , 62 (m, 1H, H-2 or 6). Anal. Found: C, 67.955; H, 7.80; N, 4.17. Verified? 0, 68.00; E, 7.86; N, 4.17%.

iia

The procedure essentially followed is as in Example 1, using (+) - oedrol (2.45 g, 11 mmol) as a white solid (0.25 g, 11 mmol) (2.5 mL, 4.4 mmol, 11 mmol) in hexane, and 3-pyridylacetate (1.51 g, 10 mmol) in 1 N, ml). After allowing the reaction mixture to reach room temperature, stirring was continued for a further period of 24 hours. Following the completion and chromatography, eluting with petroleum (b.p. 60-80Â ° C) -diethyl ether-triethylamine 250: 50, the product obtained comprised some unreacted hydrochloride. This solution was further purified by the formation of its hydrochloride, which was washed with dry diethyl ether, and the free base was recovered to give the title compound (1.30 g, 3%) as an oil. (D, 3H, J = 7.2 Hz, oedryl), 0.96 and 1.08 (2s, 6H, oxy) (S, 2H, OOC Hg), 7.26 (m, 1H, H-5), 7.63 (m, 1H, H- 4), 8.51 (ai, &quot; 2H, S-2 and H-6), Anal. Calc'd: C, 77.37; H, 9.15; F, 4.10. Found: C, 77.56; H, 9.19; I, 3.9%. The procedure essentially followed was Example 1, but using 2-methyl-2-ada-aanthol (3.66 g, 22 mmol) in dry H2 O (30 ml) ), n-butyl lithium (2.5M, 8.8 mL, 22 mmol) in hexane, and 3-pyridyl acetate (3.02 g, 20 mmol) in SHF (10 mL). At &lt; 5s if the reaction mixture was allowed to reach room temperature, stirring was continued for an additional 96 hours. After the completion and chromatography eluting with 250: 50: 1 petroleum-diethyl tert-triethylamine. The product obtained comprised some unreacted 2-methyl-2-adamantanol. This solution was then purified to form the hydrochloride, which was washed with diethyl ether and the recovered free base gave the title compound (1.77 g, 31%) as an oil, &quot; 4-Ϊ - (s, 3H, adenosine OOFe), 3.60 (s H-5), 7.65 (bt, 1H, H-4), 8.52 (m, C, 75.75 59 59 mm (CHCl3) inter alia SI, 2H, CH2 Hg), 7.26 (m, 1H, 2H, H-2 and H-6). PA3-ES m / z H, 8.12; F, 4.91. Found: C, 75.19; H, 8.16; 4.83%. To a solution of 3-pyridylacetic acid hydrochloride (2.60 g, 15 mmol) in dry DMF (30 ml) and dry DMF (15 ml) at 0øC.

Or

) was added 1,1â € ²-carbonitrile diisobazole (2.43 g, 15 mmole). After stirring for 30 minutes, 1-acyl mantanarin (2.50 g, 16.5 mmol) was added and stirring was continued for 12 hours. The mixture was poured into water (50 ml), basified with aqueous sodium hydroxide (1: 1) and extracted with ethyl acetate. diethyl ether (3 x 50 ml). The ether extracts were combined, dried (lipoCOΛ) and concentrated. Chromatography by elution with 15: 5: 1 ethyl acetate-dichloromethane-triethylamine afforded the title compound (2.63 g, 65%) as white crystals, mp 176-177 ° C. · ΝΒκ 1649 cm -1; (CDCl3): 1.66 and 1.96 (2H, 12H, adamantyl CIL2), 2.05 (s, 3H, adamantyl OH), 3.46 (s, 2H, (M, 1H, H-5), 7.68 (m, 1H, H-4), 8.51 (m, 2H, H-2 and H-6) ). 1A3-KS m / e 271 (M + 1). (1S, 2E, 5S, -cyryl) -1- (3-pyridyl) cyclopeanane carboxylate

J 7E, SR)

A solution of (1S, 2R, 5S, 7R, 8R) -tyryl-3-pyridylacetate (341 mL, 1.0 mmol) in dry (3 mL) was added to a stirred suspension of potassium hydride ( 35% w / w dispersion in oil, 252 mg, 2.2 mmole) was dissolved in argon. After 20 minutes, 1,4-di-dodobutane (132 μl, 1.0 mmol) was added and 30 minutes later the mixture was partitioned between diethyl ether and water, the extracts dried (Na 2 O 3) and concentrated. Chromatography by eluting with petroleum diethyl ether (3: 1) provided the title compound (96 mg, 24%) which crystallized from petroleum at -20 ° C, mp 81-82 ° C. (Ds, 3H, J = 7.1 Hz, cedrilo OHHe), 1.34 (d, 3H, J = 7.1 Hz, s, 3H, cedryl OOKe), 7.22

(m, 1H, 5-H), 7.66 (m, 1H, 4-H), 8.45 (b, 1H, 6-H), 8.62 (bt, 1H, 2-H). Mal. Oalca: 0.78, &quot; 945 H, 9.43; N, 3.54. Found: C, 79.01; H, 9.61; N, 3.48%. keslQjSabqs of the tests

The assay was performed as described by E. E. Barry et al., J. Steroid Biochem. 6, 1191-5, (1989) except that radioactivity at the peaks of interest has been monitored in-line by mixing the effluent from HP10 (low resolution thin layer chromatography) with Βοοβο int A (National Diagnostica) fluid of scintillation, 1 * 1, and passing the mixture through hard &quot; radiochemical monitor Ber-told 1B5060. ara

Human trials were performed on previously untreated patients undergoing orchidectomy of prostate cancer. The assays were decapsulated and stored in liquid nitrogen until used. A myosorphic prep was prepared essentially as described, by S.E.

Barrie et al., Supra. The material was then thawed, finely chopped and homogenized in a 0.25 L sucrose solution (5 w / w wet weight) using a PoTiCer homogenizer. The magnetized product was centrifuged at 12,000 g for 30 minutes, and the miorossomas were then pelleted by spinning the supernatant at 100,000 g for 1 hour. The pellet was washed sin the resuspend in 0.25 M sucrose and repopulated. The microsome pellet was then resuspended in 50 mM sodium phosphate / glycerol (3/1 v / v) and stored in liquid nitrogen. £ 2

Enzymatic activity was measured separately.

For 17Î ± -hydroxylase: the basic assay mixture was the same as that used for the rat enzyme, except that the EDITA concentration was 0.2 mM, and for the β-progesterone substrate, the concentration was of 3%. The human enzyme was more sensitive to ethanol than the mouse, and consequently the compound under test was dissolved in 50% BMSO, and the final concentrations of ethanol and ethanol were 1% each. For the compound of Example 2 and its 4-pyridyl analogs, the reaction was carried out in 15 minutes. For all other compounds, the reaction time was extended for 1 hour. The reaction was terminated with the addition of 2 volumes of methanol / acetonitrile (2æl / v), comprising approximately 100æl un-labeled pro-gestate, 17Î ± -hydroxyprogesterone, an-drostenedione, testosterone, and 16Î ± -hydroxyprogesterone. The latter ester was added as it appeared that the human enzyme would be capable of 16Î ± -hydroxylation and 17Î ± -hydroxylamine.

For the compound of example 2 and its 4-pyridyl analog, separation of the steroids by HP10 was performed according to the procedure described for the rat assay in E. Barrie et al., Supra. For all other compounds the separation was performed on a 10 cm column &quot; Núcleosil &quot; 5 / · 018, with a pre-oolumn &quot; Cores !! &quot;. Elution was performed with 60% methanol at 1 ml / 1 ml. The effluent was mixed in a 1: 1 line with Ecoscint A comprising 25% acetonitrile and then passed through a Berthold LB5060 radio-chemical detector. In all cases, hydroxylase activity was measured, such as the production of 17α-hydroxyprogesterone, androstenedione and testosterone. ♦ 2

For C 17 H 15 Cl 2 O 3 S The mixture was as described above for 17Î ± -hydroxylase, except that the substrate used was 11-17 β-hydroxyprogesterone. The reaction was carried out for 1 hour and the addition of 2 volumes of methanol / acetonitrile (2/1 v / v) comprising approximately 17Î ± -hydroxyprogesterone, androstenedione, and testosterone 100 was terminated. The KPLO separation used for A 10x10 Apex 018 column was filled with a 5 cm PELL 0D8 018 column. The eluent was methanol-acetonitrile-water 38 * .150 flowing at 1 ml / t. The effluent was mixed with Ecoscint A11 comprising methanol at 10%, and the radioactivity was measured directly by a radioimmunoassay Berthold 1135060. The activity of the lyase was measured, such as the production of androgens, nodal and testosterone. The enzymatic activity was measured in the presence of at least 4 concentrations of each compound, and the data were fixed by the linear regression of the Dixon equation (Dixon, K., ΐ / ebb, E. 0, Enzymes, 2nd ed., Academic Press, New York, 1964). 0 1050 and their confidence limits were calculated from the sampling and their confidence limits. When the complete determination of 10 ^ was not performed, the values given are approximate and no confidence limits values are given.

The results are presented in

You know, I followed you

Activities of 17α-hydroxylase / C-α-O-lyase. (K) with limits of confidence (95%) in parentheses, with enzymes from rats, (R) or human enzymes (H) SERIES 3-PLEIDII0

(5)

SERIES 4 ~ ΡΙΡΠ) Ι10

Hydroxylase (6)

Compound HilroxylaseEx. 1, 1 2 ΈΓ = ΊΓ-lí ϊ. . Ir = isopi-noofexy H 0.50

Liase 0.10 0.041 0.0066 (0.44-0.58) (P, 09-0.12) (0.038-0.045) (0.006-0.007) R 0.46 0.52 0.26 (0.42 -0.50) (0.48-0.57) (0.24-0.27)

Ex. 2, OH-3 0.1-0.3 0.04 P, 02 0.28 (0.24-0, 0.00534) H1 H2

R 2 isopropanol. 3S 1 H 0.043 0.016 0.05-0.1 P 0.01 CH 3, R 2 = CH 3, R 5 = isopyno-nofexy R 0.047 0.052 (0.042-0.0552) (0.045-0.061) not tested 25

SiShies 3-piribho

SlfeJSS 4-PYRIDYL

Hydroxylase Liase 1.5 2.2 (1.4-1.6) (2.0-2.5) not tested

Hydroxidase Liase

Ex, 4, H not tested 3 2 d-1-R 3 = R 2 SO 2.3 (-) t) euracil (1.9-2.1) (2.0-2.6)

Ex. 5 H 1.5 0.4

(+) borneyl

Ex. 6 3 1.0 0.6 1 2 Rx = R = H 5 Ir = adamantyl Ex. 7 R 0.3 0.1 R = 04 S1 = OH. 3 E2 = CH3 R = Unassayed unassayed unassayed unassayed adamantane

Ex. 9 H 0.16 0.12 1 2

R = R = E R 3 = (+) cedryl)) -

Assay on aromatase activity The activity of aromatase was determined by the procedure of A. B. Poster et al., J. Med. Obem. 26, 50-54 (1983) using placental microsomes. For the microsomes used, the Miobaelis constant for 1B-H androstenedione was 0.039 Μ. The E values were obtained from the reciprocal velocity Dixon graphs of the reaction versus concentration of the inhibitor at two concentrations of the androstenedione substrate. The values E ^ are given in parentheses after the values 10 ^ q. The comparative results are presented in Table 2 below.

Table 2: Aromatase activity, IC 50 M with 11 values in Mmana parenthesis in M, enzyme 1 SERIES 3-PYRIDYL SERIES 4-PYRIBULUS Compound Ex. 1 6 (1.01 + 0.07) 0.12 (0.015 + 0.005) Ex 8.9 (0.81 + 0.09) 1.32 (0.12 + 0.03) Ex * 30 (5.2 + 1.0) 3.85 (0.35 + 0, 06) Ex. 4 3.0 (0.207 + 0.03) 0.097 (0.009 + 0.0003) Ex. 5 2.9 not tested Ex. 6 8.9 not tested Ex. 7.9.1 not tested Ex. 8 35 Unassisted Ex. 9 1.7 not tested The more fragile inhibition of aromatase revealed by the 3-pyridyl series compounds will benefit the IC50 ratio and / aromatase.

Claims (1)

27 27 The. Heterocyclic compounds containing the 3-pyridylacetyl group or derivatives thereof of the general formula (3) in which R1 and R2 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; or together represent the radical of a cycloalkyl group having 3 to 6 carbon atoms; A represents an oxygen atom? a NR 4 group wherein R 412 has the same meanings as R or R; or a group '5 6 5 6 1! CR R, where R and R have the same meanings as R 2 or R, as the separate substituents; and R 2 represents a bridged alicyclic group; in the form of free bases or their pharmaceutically acceptable salts. 2a. Compounds according to claim 1, characterized in that A represents oxygen, NH or CH 2. 3a. Compounds according to claims 1 or 2, characterized in that R represents a bridged alicyclic group having from 6 to 8 carbon atoms ring (excluding bridged atoms), which is unsubstituted or is substituted by alkyl of 1 to 4 carbon atoms or by a fused alicyclic group. 4a. Compounds according to claim 3, characterized in that the fused alicyclic group is a cyclopentane or cyclohexane ring, which itself is unsubstituted or substituted by alkyl of 1 to 4 carbon atoms. 5a. Compounds according to claims 1, 2, 3 or 4, wherein R has one or two bridged substituents, each having 1 or 2 straight chain, unsubstituted or alkyl substituted carbon atoms having 1 to 2 4 carbon atoms. 6a. Compounds according to claims 1, 2, 3, 4 or 5, characterized in that any alkyl group having 1 to 4 carbon atoms is a methyl group. 7a. Compounds according to claims 1, 2, 3, 4, 35 or 6, wherein R represents a boraneyl, isoborneyl, cedryl or isopinocamphoyl group, in each of their optically active forms, or an adamantyl group. Ôa. Compounds according to claims 1, 2, 3, 4, 35 or 6, characterized in that R represents a methyladamantyl group. 9a. A process for the preparation of heterocyclic compounds containing the 3-pyridylacetic group or derivatives thereof of the general formula (3) according to claim 1, characterized in that a) to prepare a compound of general formula (3) wherein A means -0-, a compound of the general formula (4) is esterified or transesterified, : N (4) in which. X represents -OH or a reactive substituent thereof and R R and R possuem have the meanings mentioned in claim 1, with an alcohol of the formula wherein R tem has the meanings indicated in claim 1, giving an ester of formula (3); or (b) to prepare an amide of general formula (3) wherein [Delta] denotes -NH-, a compound of general formula (4) is reacted with an appropriate primary amine; !; c) in order to prepare a ketone of the general formula (3) wherein A = CEU, - an alkali metal salt of 3-picoline, for example 3-picolyl-lithium, is reacted with a methyl ester of formula General R 3a CO 2 Me 5 6! in which A is a group CR R ' or (d) in case of preparing a compound of formula (II) wherein R or R is other than hydrogen, A compound of formula (4) wherein R 1 and R 2 are hydrogen are reacted in order to prepare the corresponding compound of formula (3) and subsequently the substituent R or R is introduced by reaction with a metal hydride alkali metal bromide followed by a lower alkyl or cycloalkyl bromide or iodide; or (e) for the preparation of the methylene () or ethylene (CH 2 CH 2) derivatives, thermal decomposition of the corresponding methyl or ethyl derivatives of the phenyl sulfoxide is carried out. 10a. A process for the preparation of the pharmaceutically acceptable salts of the compounds of general formula (3) according to one or more of claims 1 to 9, characterized in that said compound of formula (3) is reacted with a pharmaceutically inorganic or organic acid acceptable. 11a. Pharmaceutical compositions comprising at least one compound of general formula (3) according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, in admixture with a therapeutically acceptable carrier or diluent . 12a. Use of the compounds according to claims 1,2,3,4,5,6,7,8,9 for the treatment of prostate cancer. Lisbon, March 20, 1992. The official agent of Industrial Property Américo d a Silva Carvalho Agent of Industrial Property; Rua Marquês de Fronteira, No. 127 - 2 ° 1000 LISBOA Tals.3877373-3877453