Bicyclic, Nitrogen-Containing Heterocycles and Aromatase Inhibitors

Abstract

The application relates to novel heterocyclic compounds of the general formula (I) (I*) in which R, R1, R2, X, Y, Z and n have the meanings defined in the description, to a process for their preparation and to the use of these compounds as medicaments, in particular as aromatase inhibitors.

Description

EXAMPLE 1

4-(6,7-Dihydro-5H-[2]pyridin-2-yl)benzonitrile hydrochloride

A solution of 1.240 mmol of N-tert-butyl-4-(6,7-dihydro-5H-[2]pyridin-7-yl)benzamide and 1.0 ml of thionyl chloride in 30 ml of chloroform is stirred under reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in dichloromethane and mixed with saturated aqueous sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×). The combined organic phases are dried with sodium sulphate and evaporated. The residue is dissolved in diethyl ether, and the title compound is converted into the hydrochloride salt by adding ethereal HCl solution (2 N). The solid is stirred in diethyl ether/acetone (1:1), filtered and dried. The title compound is obtained as a dark grey solid. Rf (free base)=0.36 (EtOAc); Rt=4.98.

The starting materials are prepared as follows:

a) N-tert-Butyl-4-(6,7-dihydro-5H-[2]pyridin-7-yl)benzamide

A solution of 1.250 mmol of N-tert-butyl-4-(5H-[2]pyridin-7-yl)benzamide in 10 ml of ethanol is mixed with 360 mg of 10% Pd/C, and the reaction mixture is then hydrogenated at 20-25° C. under atmospheric pressure for 6 hours. The reaction mixture is clarified by filtration and the filtrate is evaporated. The crude title compound is obtained as a brown oil from the residue.

b) N-tert-Butyl-4-(5H-[2]pyridin-7-yl)benzamide

A solution of 1.260 mmol of N-tert-butyl-4-(7-hydroxy-6,7-dihydro-5H-[2]pyridin-7-yl)benzamide in 20 ml of 4 M HCl is stirred at 50° C. for 20 hours. The reaction mixture is cooled to room temperature and cautiously adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane (3×)—the combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is obtained as a yellow oil from the residue. Rt=5.47.

c) N-tert-Butyl-4-(7-hydroxy-6,7-dihydro-5H-[2]pyridin-7-yl)benzamide

5.3 ml of n-butyllithium (1.6 M in hexane) are added dropwise to a solution of 4.250 mmol of 4-bromo-N-tert-butylbenzamide in 70 ml of tetrahydrofuran at −78° C. After 30 minutes, a solution of 3.270 mmol of 5,6-dihydro-[2]pyridin-7-one [51907-18-7] in 10 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at −78° C. for 1 hour and at room temperature for 2 hours and then quenched with saturated aqueous ammonium chloride solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a white foam from the residue by flash chromatography (SiO₂ 60 F). Rf=0.29 (toluene:methanol=85:15), Rt=5.00.

Example 2

4-(5,6,7,8-Tetrahydroquinazolin-5-yl)benzonitrile

A solution of 0.480 mmol of 4-(7,8-dihydroquinazolin-5-yl)benzonitrile in 12 ml of ethanol is mixed with 33 mg of 10% Pd/C, and the reaction mixture is then hydrogenated at 20-25° C. under atmospheric pressure for 50 hours. The reaction mixture is clarified by filtration, and the filtrate is evaporated. The title compound is obtained as a yellow oil from the residue by flash chromatography (SiO₂ 60 F). Rf=0.26 (dichloromethane:methanol=95.5); Rt=5.92.

The starting materials are prepared as follows:

a) 4-(7,8-Dihydroquinazolin-5-yl)benzonitrile

A solution of 0.500 mmol of 4-(5-hydroxy-5,6,7,8-tetrahydroquinazolin-5-yl)benzonitrile in 1.25 ml of 2 M HCl is stirred at 50° C. for 8 hours. The reaction mixture is cooled to room temperature and cautiously adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate (3×) and the combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is obtained as a yellow oil from the residue. Rf=0.20 (toluene:methanol=85:15), Rt=6.21.

b) 4-(5-Hydroxy-5,6,7,8-tetrahydroquinazolin-5-yl)benzonitrile

1.0 ml of isopropylmagnesium chloride (2.0 M in tetrahydrofuran) is added dropwise to a solution of 2.000 mmol of 4-iodobenzonitrile in 5 ml of tetrahydrofuran at −20° C. After 30 minutes, a solution of 1.000 mmol of 7,8-dihydro-6H-quinazolin-5-one [21599-28-0] in 2 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at −20° C. for 30 minutes and at room temperature for 1 hour and then quenched with 0.1 M HCl. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a brown oil from the residue by flash chromatography (SiO₂ 60 F). Rf=0.16 (toluene:methanol=85:15), Rt=5.15.

Example 3

(S or R)-4-(5,6,7,8-Tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzonitrile

The preparative separation of the enantiomers of (rac)4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzonitrile is performed with a Chiralpak AD-H column (5 μm, 250×20 mm) using 70:30:0.1 heptane/ethanol/diethylamine as the mobile phase at a flow rate of 50 ml/min. For analytical determinations of the optical purity, a Chiralpak AD-H column (5 μm, 250×4.6 mm) using 70:30:0.1 heptane/ethanol/diethylamine as the mobile phase at a flow rate of 1 ml/min is employed. The first eluting enantiomer is concentrated in vacuo to provide the title compound as a white solid. Rt=10.6.

The starting materials are prepared as follows:

a) (rac)-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzonitrile

Analogously to Example 1, 1.74 mmol of N-tert-Butyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride are reacted. The title compound is obtained as a cream-colored solid. Rf=0.37 (toluene:methanol=85:15); Rt=4.88

b) N-tert-Butyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride

Analogously to Example 1a, 1.79 mmol of N-tert-Butyl-4-(5,6-dihydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride are reacted. The crude title compound is obtained as a brown solid. Rf=0.35 (toluene:methanol=85:15), Rt=5.54

c) N-tert-Butyl-4-(5,6-dihydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride

Analogously to Example 1b, 1.85 mmol of N-tert-Butyl-4-(8-hydroxy-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide are reacted. The crude title compound is obtained as a grey solid. Rt=5.54

d) N-tert-Butyl-4-(8-hydroxy-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide

Analogously to Example 1c, 6.00 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [51907-18-7] are reacted. The title compound is obtained as a yellow solid. Rf=0.16 (dichlormethane:methanol=95:5), Rt=4.96

The following compound is prepared in a manner analogous to the processes described in Examples 1-3.

Example

4 4-(5,6,7,8-Tetrahydroisoguinolin-8-yl)benzonitrile starting from 6,7-dihydro-5H-isoquinolin-8-one [21917-88-4]

Claims

1. Compound of the general formula

2. Compound according to claim 1, characterized in that it corresponds to the general formula

3. Compound according to claim 1, where R is hydrogen or C1-C8-alkyl, particularly preferably hydrogen or methyl.

4. Compound according to claim 1, where R1 is aryl or unsaturated heterocyclyl, very particularly preferably optionally mono- or disubstituted benzofuranyl, benzothiophenyl, indazolyl, indolyl, phenyl, pyrrolyl, thiazolyl, thiophenyl or oxazolyl.

5. Compound according to claim 1, where R2 is hydrogen, halogen, C1-C8-alkyl or aryl-C1-C4-alkyl.

6. Compound according to claim 1, where n is a number 0 or 1.

7. Compound according to claim 2, where R is hydrogen or C1-C8-alkyl;R1 is aryl or unsaturated heterocyclyl, in each case optionally substituted by halogen, cyano, trifluoromethyl, heterocyclyl or C1-C8-alkylcarbonyl; andR2 is hydrogen, halogen, C1-C8-alkyl or aryl-C1-C4-alkyl.

8-9. (canceled)

10. Method for the prevention, for delaying the progression or for the treatment of a disease or condition which responds to aromatase inhibition where a therapeutically effective amount of a compound of the general formula (I) or (I*) according to claim 1 is used.

11. Pharmaceutical product comprising a compound of the general formula (I) or (I*) according to claim 1, and conventional excipients.

12. Compound according to claim 2, where R is hydrogen or C1-C8-alkyl, particularly preferably hydrogen or methyl.

13. Compound according to claim 2, where R1 is aryl or unsaturated heterocyclyl, very particularly preferably optionally mono- or disubstituted benzofuranyl, benzothiophenyl, indazolyl, indolyl, phenyl, pyrrolyl, thiazolyl, thiophenyl or oxazolyl.

14. Compound according to claim 2, where R2 is hydrogen, halogen, C1-C8-alkyl or aryl-C1-C4-alkyl.

15. Method for the prevention, for delaying the progression or for the treatment of a disease or condition which responds to aromatase inhibition, where a therapeutically effective amount of a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2 is used.

16. Method for the prevention, for delaying the progression or for the treatment of a disease or condition which is a proliferative disease, where a therapeutically effective amount of a compound of the general formula (I) or (I*) according to claim 1 is used.

17. Method for the prevention, for delaying the progression or for the treatment of a disease or condition which is a proliferative disease, where a therapeutically effective amount of a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2 is used.

18. Pharmaceutical product comprising a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2, and conventional excipients.