Piperazine derivatives as FASN inhibitors

Abstract

Compounds of the formula I ##STR00001##
in which R, X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1, R.sup.2 and q have the meanings indicated in Claim 1,
are inhibitors of fatty acid synthase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

Claims

1. A compound selected from the group consisting of TABLE-US-00005 No. Name “A1” 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-propan-1-one “A2” 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-ethanone “A4” 1-{4-[4-(3-methoxy-isoquinolin-6-yl)-benzoyl]-piperazin-1-yl}- butan-1-one “A5” 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-pentan-1-one “A6” 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-butan-1-one “A7” 1-{4-[4-(2-oxy-isoquinolin-6-yl)-benzoyl]-piperazin-1-yl}- propan-1-one or a pharmaceutically acceptable salt, tautomer and/or stereoisomer thereof, and/or mixtures thereof in all ratios.

2. A pharmaceutical composition comprising at least one compound of claim 1, and/or a pharmaceutically acceptable salt, tautomer and/or stereoisomer thereof in all ratios, and a pharmaceutically acceptable carrier, excipient or vehicle.

Description

EXAMPLE 1

1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-propan-1-one (“A1”)

(1) ##STR00005##

(2) 1.1 Tert-butyl 1-piperazinecarboxylate (0.5 g; 2.69 mmol) was dissolved in 10 ml of dichloromethane (DCM). N-ethyldiisopropylamine for synthesis (1.37 ml; 8.06 mmol) was added and the mixture cooled down to 0° C. Now 4-bromobenzoyl chloride for synthesis (0.66 g; 2.95 mmol) was dissolved in 10 ml of DCM and added dropwise to the reaction, followed by stirring at RT overnight. Regarding to LC-MS the reaction was complete. The reaction mixture was extracted with 50 mL of water. The organic layer was dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 1.0 g (100%) 4-(4-bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester 1 as beige solid.

(3) 1.2 4-(4-Bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester 1 (0.5 g; 1.35 mmol) was dissolved in 15 ml of HCl/isopropanol (5-6N) and then stirred at 55° C. for 2 hrs. The reaction mixture was reduced to dryness under vacuo to yield quantitatively (4-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride 2 as beige solid.

(4) 1.3 (4-Bromo-phenyl)-piperazin-1-yl-methanone hydrochloride 2 (200 mg; 0.66 mmol) was dissolved in 5 ml of DCM, N-ethyldiisopropylamine for synthesis (0.34 ml; 2.0 mmol) was added and then cooled to 0° C. Propionyl chloride for synthesis (0.063 ml; 0.73 mmol) was added dropwise followed by stirring at RT for 14 h. The reaction mixture was separated between DCM and water. The organic layer was separated, dried over MgSO.sub.4, filtered off and then reduced to dryness under vacuo to afford 213 mg (99.3%) 1-[4-(4-bromo-benzoyl)-piperazin-1-yl]-propan-1-one 3 as a brown oil.

(5) 1.4 1-[4-4-(4-Bromo-benzoyl)-piperazin-1-yl]-propan-1-one 3 (213 mg; 0.65 mmol) and isoquinolin-6-ylboronic acid (123 mg; 0.72 mmol) were dissolved in 1,4-dioxane dried (max. 0.005% H.sub.2O) SeccoSolv® (5.0 ml; 0.058 mol) and the mixture was purged with nitrogen for 5 minutes. Cesium carbonate anhydrous (422 mg, 1.30 mmol) and bis(triscyclohexylphosphine)-palladium(II) dichloride, 99% (6.4 mg, 8.7 μM) were added and the reaction was heated to 150° C. for 90 min under microwave. The reaction was complete and extracted with ethyl acetate/water. The organic layer was dried over MgSO.sub.4, filtered off and evaporated in vacuo. The product was purified on prep. HPLC to afford 91 mg (37%) 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1-yl]-propan-1-one (“A1”) as a beige solid;

(6) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ [ppm] 9.36 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.06 (dd, J=8.6, 1.8 Hz, 1H), 7.98-7.92 (m, 2H), 7.90 (d, J=5.8 Hz, 1H), 7.65-7.55 (m, 2H), 3.75-3.35 (m, 8H), 2.44-2.25 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).

(7) The following compounds are prepared analogously

(8) TABLE-US-00003 .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ [ppm] * 500 Mhz no. name and/or structure ** + TFA-d.sub.1 ″A2″ 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1- 9.94 (s, 1H), 8.72-8.65 yl]ethanone (m, 3H), 8.55 (d, J = 6.7 Hz, 1H), 8.41 (dd, J = 8.8, 1.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 3.90-3.30 (m, 8H), 2.09 (s, 3H) ″A3″ (4-cyclopropanecarbonyl-piperazin-1-yl)-(4- * 9.36 (s, 1H), 8.55 (d, J = isoquinolin-6-yl-phenyl)-methanone 5.7 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 5.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 3.94-3.32 (m, 8H), 2.10-1.76 (m, 1H), 0.87- 0.67 (m, 4H) ″A4″ 1-{4-[4-(3-methoxy-isoquinolin-6-yl)-benzoyl]- ** 9.48-9.40 (m, 1H), piperazin-1-yl}-butan-1-one 8.40-8.32 (m, 2H), 8.06- 8.01 (m, 1H), 7.99-7.95 (m, 2H), 7.73 (s, 1H), 7.69- 7.63 (m, 2H), 4.17 (s, 3H), 3.85-3.30 (m, 8H), 1.73-1.45 (m, 2H), 2.39- 2.28 (m, 2H), 1,65-1.51 (m, 2H), 0.94 (t. J = 7.5 Hz, 3H) ″A5″ 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1- * 9.37 (s, 1H), 8.55 (d, J = yl]-pentan-1-one 5.7 Hz, 1H), 8.34 (s, 1H), 8.30-8.19 (m, 1H), 8.07 (dd, J = 8.5, 1.8 Hz, 1H), 8.01-7.90 (m, 3H), 7.70- 7.59 (m, 2H),3.77-3.45 (m, 8H), 2.40-2.28 (m, 2H), 1.50 (p, J = 7.5 Hz, 2H), 1.31 (h, J = 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H) ″A6″ 1-[4-(4-isoquinolin-6-yl-benzoyl)-piperazin-1- * 9.38 (s, 1H), 8.55 (d, J = yl]-butan-1-one 5.7 Hz, 1H), 8.37-8.32 0 (m, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.08 (dd, J = 8.6, 1.7 Hz, 1H), 8.00-7.87 (m, 3H), 7.63-7.56 (m, 2H), 3.89-3.12 (m, 8H), 2.41-2.29 (m, 2H), 1.53 (d, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H) ″A7″ 1-{4-[4-(2-oxy-isoquinolin-6-yl)-benzoyl]- * 8.98 (q, J = 0.8 Hz, 1H), piperazin-1-yl}-propan-1-one 8.36-8.29 (m, 1H), 8.18 (dd, J = 7.0, 1.8 Hz, 1H), 8.05 (dd, J = 8.7, 1.8 Hz, 1H), 7.99 (d, J = 7.7 Hz, 2H), 7.95-7.83 (m, 2H), 7.66-7.49 (m, 2H), 3.81- 3.31 (m, 8H), 2.40-2.23 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).
Pharmacological Data

(9) TABLE-US-00004 TABLE 2 Inhibition of FASN of some representative compounds of the formula I Compound IC.sub.50 FASN No. (enzyme assay) “A1” A “A2” B “A3” A “A4” B “A5” A “A6” A “A7” A IC.sub.50: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

(10) The compounds shown in Table 2 are particularly preferred compounds according to the invention.

(11) The following examples relate to medicaments:

EXAMPLE A: INJECTION VIALS

(12) A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

EXAMPLE B: SUPPOSITORIES

(13) A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

EXAMPLE C: SOLUTION

(14) A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE D: OINTMENT

(15) 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE E: TABLETS

(16) A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F: DRAGEES

(17) Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G: CAPSULES

(18) 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

EXAMPLE H: AMPOULES

(19) A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.