Phthalazine derivatives

Abstract

Compounds of the formula I ##STR00001##
in which R.sup.1, X and n have the meanings indicated in Claim 1, are inhibitors of Tankyrase, 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 of formula I ##STR00035## in which R.sup.1 is H, Hal, CH.sub.3, OCH.sub.3 or CH.sub.2OH, X is Ar or Cyc, Ar is phenyl, biphenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, NO.sub.2, CN, A, [C(R.sup.2).sub.2].sub.pOR.sup.2, S(O).sub.mR.sup.2, [C(R.sup.2).sub.2].sub.pN(R.sup.2).sub.2, [C(R.sup.2).sub.2].sub.pCOOR.sup.2, [C(R.sup.2).sub.2].sub.pCON(R.sup.2).sub.2, [C(R.sup.2).sub.2].sub.pSO.sub.2N(R.sup.2).sub.2, NR.sup.2COR.sup.2, NR.sup.2SO.sub.2R.sup.2, NR.sup.2CON(R.sup.2).sub.2, NHCOOA, O[C(R.sup.2).sub.2].sub.nN(R.sup.2).sub.2, CHO and/or COA, R.sup.2 is H or A, A is unbranched or branched alkyl with 1-10 C-atoms, wherein two adjacent carbon atoms optionally form a double bond and/or one or two non-adjacent CH- and/or CH.sub.2-groups are optionally replaced by N-, O- and/or S-atoms and wherein 1-7 H-atoms are optionally replaced by F, Cl and/or OH, Cyc is cycloalkyl with 3, 4, 5, 6 or 7 C-atoms, Hal is F, Cl, Br or I, m is 0, 1 or 2, n is 1, 2 or 3, and p is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

2. The compound according to claim 1, in which R.sup.1 is H, Hal or CH.sub.3, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

3. The compound according to claim 1, in which Ar is phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, NO.sub.2, CN, A and/or [C(R.sup.2).sub.2].sub.pOR.sup.2, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

4. The compound according to claim 1, in which A is unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms are optionally replaced by F, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

5. The compound according to claim 1, in which R.sup.1 is H, Hal or CH.sub.3, X is Ar or Cyc, Ar is phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, NO.sub.2, CN, A and/or [C(R.sup.2).sub.2].sub.pOR.sup.2, R.sup.2 is H or A, Cyc is cycloalkyl with 3, 4, 5, 6 or 7 C-atoms, A is unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms are optionally replaced by F, Hal is F, Cl, Br or I, p is 0, 1, 2, 3 or 4, and n is 1, 2 or 3, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

6. A compound, which is one of the following compounds TABLE-US-00004 No. Name A1 2-phenyl-N-phthalazin-1-yl-acetamide A2 2-(3-methoxyphenyl)-N-phthalazin-1-yl-acetamide A3 2-(4-methoxyphenyl)-N-phthalazin-1-yl-acetamide A4 2-(4-ethoxyphenyl)-N-phthalazin-1-yl-acetamide A5 N-phthalazin-1-yl-2-(3-trifluoromethoxyphenyl)-acetamide A6 2-(3-cyanophenyl)-N-phthalazin-1-yl-acetamide A7 2-(3-nitrophenyl)-N-phthalazin-1-yl-acetamide A8 N-phthalazin-1-yl-2-(4-trifluoromethoxyphenyl)-acetamide A9 2-(4-tert-butylphenyl)-N-phthalazin-1-yl-acetamide A10 2-(2,6-dichlorophenyl)-N-phthalazin-1-yl-acetamide A11 2-(4-ethoxy-phenyl)-N-(5-fluoro-phthalazin-1-yl)-acetamide A12 N-(5-fluoro-phthalazin-1-yl)-2-(4-methoxy-phenyl)-acetamide A13 3-cyclohexyl-N-phthalazin-1-yl-propionamide A14 3-phenyl-N-phthalazin-1-yl-propionamide A15 3-cyclopentyl-N-phthalazin-1-yl-propionamide A16 3-(2-chloro-phenyl)-N-phthalazin-1-yl-propionamide A17 3-(2,3-dichloro-phenyl)-N-phthalazin-1-yl-propionamide A18 N-(8-methyl-phthalazin-1-yl)-2-phenyl-acetamide A19 N-(5-methyl-phthalazin-1-yl)-2-phenyl-acetamide A20 2-(4-methoxy-phenyl)-N-(8-methyl-phthalazin-1-yl)-acetamide A21 2-(4-methoxy-phenyl)-N-(5-methyl-phthalazin-1-yl)-acetamide A22 3-cyclohexyl-N-(8-methyl-phthalazin-1-yl)-propionamide A23 3-phenyl-N-(8-methyl-phthalazin-1-yl)-propionamide A24 3-cyclopentyl-N-(8-methyl-phthalazin-1-yl)-propionamide A25 3-(2-chlorophenyl)-N-(8-methyl-phthalazin-1-yl)-propionamide or A26 3-(2,3-dichlorophenyl)-N-(8-methyl-phthalazin-1-yl)- propionamide or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

7. A process for preparing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula II ##STR00036## in which R.sup.1 has the meanings indicated for the compound of formula I, with a compound of formula III ##STR00037## in which X and n have the meanings indicated for the compound of formula I, and L is Cl, Br, I or a free or reactively functionally modified OH group, and/or converting a base or acid compound of formula I into one of its salts.

8. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

9. A pharmaceutical composition according to claim 8, and at least one further pharmaceutically active ingredient.

10. A kit comprising separate packs of (a) a compound of formula I according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and (b) a further pharmaceutically active ingredient.

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 2, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 5, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

18. A pharmaceutical composition comprising a compound according to claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

19. A kit comprising separate packs of (a) a compound according to claim 6 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and (b) a further pharmaceutically active ingredient.

20. A kit comprising separate packs of (a) a compound according to claim 6 or a pharmaceutically acceptable salt thereof, and (b) a further pharmaceutically active ingredient.

Description

EXAMPLE 1

Synthesis of 2-phenyl-N-phthalazin-1-yl-acetamide (A1)

(1) ##STR00007##

1.1 4-Chloro-phthalazin-1-ylamine

(2) ##STR00008##

(3) Copper (II)-sulfate pentahydrate (632.4 mg; 2.53 mmol) was dissolved in an aqueous ammonia solution (32%, 25 mL). A suspension von 1,4-dichlorophthalazine (2 g; 10.05 mmol) in THF (25 mL) was added and the 2-phase mixture was heated for 1.5 h at 65-80 C. (max. 13 bar) and 1.5 h at 100 C. in a microwave oven (CEM Discover). In the organic phase a precipitate was formed. The reaction mixture was cooled to room temperature, the precipitate was filtered off by suction, washed with water, little ethyl acetate and diethyl ether and dried in vacuo at 50 C. for 14 h; yield: 1.6 g (89%), pink crystals (purity: 100%, Rt: 2.49 min).

1.2: Phthalazin-1-ylamine

(4) ##STR00009##

(5) 4-Chloro-phthalazin-1-ylamine (750 mg; 4.18 mmol) was hydrogenated in methanol (20 mL) and 2N sodium hydroxide solution (3.7 mL) with Pd/C (5%) at room temperature for 14 h. The reaction solution was filtered and concentrated. The aqueous residue was diluted with water (5 mL) and extracted with ethyl acetate (3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was triturated with diethyl ether, filtered off by suction and dried.

(6) The aqueous phase from the extraction was evaporated to dryness. The residue was dissolved in a mixture of water and acetonitrile and lyophilized. The solid was suspended in dichloromethane/methanol (10%), stirred for 30 min and filtered off by suction. The filtrate was evaporated to dryness. The residue was triturated with dichloromethane, filtered off by suction, washed with diethyl ether and dried. Both solids were combined; yield: 545 mg (90%), light-brown solid (purity: 100%, Rt: 2.25 min).

1.3 2-Phenyl-N-phthalazin-1-yl-acetamide

(7) Phthalazin-1-ylamine (50 mg; 0.34 mmol) was suspended in THF (2 mL) and treated under argon with N-ethyldiisopropylamine (76.2 l; 0.45 mmol). Phenylacetylchloride (54.6 l; 0.41 mmol) was added dropwise at room temperature and the mixture was heated to 70 C. For a short time a clear yellow solution was formed, before a solid precipitated. After stirring at 70 C. for 1 h THF (2 mL), N-ethyldiisopropylamine (76.2 l; 0.45 mmol) and phenylacetylchloride (54.6 l; 0.41 mmol) were added and the reaction mixture was stirred at 70 C. for 14 h. The reaction mixture was cooled to room temperature, treated with methanol (0.5 mL) and evaporated to dryness. The light-brown residue was treated with acetonitrile (1 mL) and methanol (1 mL) and sonicated. The formed precipitate was filtered by suction, washed with methanol and diethyl ether and dried in vacuo at 50 C. Further product was isolated from filtrate via column chromatography; yield: 25 mg (28%), colourless solid (purity: 100%, Rt: 2.89 min);

(8) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.97 (s, 1H), 9.57 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 8.08-7.82 (m, 3H), 7.47-7.20 (m, 5H), 3.89 (s, 2H).

EXAMPLE 2

Synthesis of 2-(3-methoxyphenyl)-N-phthalazin-1-yl-acetamide (A2)

(9) ##STR00010##

(10) Phthalazin-1-ylamine (57 mg; 0.39 mmol) was suspended in 1,2-dichloroethane (4 mL) under argon. N-ethyldiisopropylamine (0.141 mL; 0.83 mmol) was added followed by the dropwise addition of (3-methoxyphenyl)-acetyl chloride (0.123 ml; 0.79 mmol) via a syringe. During the addition the temperature increased from 20 C. to 35 C. After one minute a clear light brown solution was obtained. The reaction was stirred for 18 h at room temperature. The solvent was removed under vacuum. The residue was purified by chromatography (column: 40 g RP18 silica gel; combiflash companion); yield: 6 mg (5%), colourless solid (purity: 100%, Rt: 2.94 min); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.96 (s, 1H), 9.59 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.08-7.79 (m, 3H), 7.29 (t, J=7.9 Hz, 1H), 7.10-6.74 (m, 3H), 3.86 (s, 2H), 3.77 (s, 3H).

EXAMPLE 3

Synthesis of 2-(4-methoxyphenyl)-N-phthalazin-1-yl-acetamide (A3)

(11) ##STR00011##

(12) A3 was prepared from phthalazin-1-ylamine (60 mg; 0.41 mmol), N-ethyldiisopropylamine (0.148 mL; 0.87 mmol) and (4-methoxyphenyl)-acetyl chloride (0.126 mL; 0.83 mmol) in 1,2-dichlorethane (3 mL) according to procedure for example 2; yield: 16 mg (13%), colourless solid (purity: 100%, Rt: 2.91 min); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.92 (s, 1H), 9.58 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.07-7.83 (m, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 3.81 (s, 1H), 3.76 (s, 2H).

EXAMPLE 4

Synthesis of 2-(4-ethoxyphenyl)-N-phthalazin-1-yl-acetamide (A4)

(13) ##STR00012##

(14) (4-Ethoxyphenyl)-acetic acid (74.5 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) were dissolved in DMF (2 mL) at room temperature. After stirring for 15 min phthalazin-1-ylamine (60 mg; 0.41 mmol) was added and the reaction mixture was stirred for 2 h. The solid, which precipitated during the reaction, was filtered off, washed with a small portion of DMF, acetonitrile and diethyl ether and dried at 50 C. in vacuo.

(15) The filtrate was diluted with water (40 mL) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, filtered and evaporated to dryness. The residue (light yellow solid) was triturated with ethanol, filtered off, washed with ethanol and diethyl ether and dried at 50 C. in vacuo. Both solids were combined; yield: 81 mg (63%), amorphous colourless solid (purity: 100%, Rt: 3.03 min);

(16) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.91 (s, 1H), 9.58 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.07-7.84 (m, 3H), 7.33 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.81 (s, 2H), 1.33 (t, J=6.9 Hz, 3H).

EXAMPLE 5

Synthesis of N-phthalazin-1-yl-2-(3-trifluoromethoxyphenyl)-acetamide (A5)

(17) ##STR00013##

(18) A5 was prepared from (3-trifluoromethoxyphenyl)-acetic acid (93.8 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) and phthalazin-1-ylamine (60 mg; 0.41 mmol) in DMF (2 mL) as described for example 4. After 3 h stirring at room temperature the reaction mixture was diluted with water (40 mL) and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate and evaporated to dryness. The residue was triturated in ethanol, filtered off, washed with diethyl ether and dried at 50 C. in vacuo. From the filtrate further product was obtained by chromatography (column: 40 g RP18 silica gel; combiflash companion); yield: 58 mg (39%), light yellow solid (purity: 98%, Rt: 3.29 min); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 11.02 (s, 1H), 9.58 (s, 1H), 8.26-8.15 (m, 1H), 8.09-7.84 (m, 3H), 7.58-7.38 (m, 3H), 7.34-7.22 (m, 1H), 3.98 (s, 2H).

EXAMPLE 6

Synthesis of 2-(3-cyanophenyl)-N-phthalazin-1-yl-acetamide (A6)

(19) ##STR00014##

(20) A6 was prepared from (3-cyanophenyl)-acetic acid (66.6 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) and phthalazin-1-ylamine (60 mg; 0.41 mmol) in DMF (2 mL) as described for example 5; yield: 89 mg (75%), colourless solid (purity: 100%, Rt: 2.91 min);

(21) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 11.03 (s, 1H), 9.60 (s, 1H), 8.26-8.15 (m, 1H), 8.12-7.94 (m, 3H), 7.92-7.52 (m, 4H), 4.03 (s, 2H).

EXAMPLE 7

Synthesis of 2-(3-nitrophenyl)-N-phthalazin-1-yl-acetamide (A7)

(22) ##STR00015##

(23) A7 was prepared from (3-nitrophenyl)-acetic acid (62.4 mg; 0.34 mmol), benzotriazol-1-ol hydrate (54.4 mg; 0.34 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (85.8 mg; 0.45 mmol) and phthalazin-1-ylamine (50 mg; 0.34 mmol) in DMF (2.5 mL) as described for example 4; yield: 84 mg (79%), light yellow solid (purity: 100%, Rt: 3.01 min);

(24) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 11.07 (s, 1H), 9.60 (s, 1H), 8.32 (t, J=2.0 Hz, 1H), 8.25-8.11 (m, 2H), 8.10-7.96 (m, 3H), 7.88 (d, J=7.7 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 4.12 (s, 2H).

EXAMPLE 8

Synthesis of N-phthalazin-1-yl-2-(4-trifluoromethoxyphenyl)-acetamide (A8)

(25) ##STR00016##

(26) A8 was prepared from (4-trifluoromethoxyphenyl)-acetic acid (92.9 mg; 0.41 mmol), benzotriazol-1-ol hydrate (65.3 mg; 0.41 mmol), 1-ethyl-3-(3-dimethyl-amino-propyl)carbodiimide hydrochloride (103 mg; 0.54 mmol) and phthalazin-1-ylamine (60 mg; 0.41) in DMF (2 mL) as described for example 4; yield: 105 mg (72%), colourless solid (purity: 99%, Rt: 3.29 min);

(27) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm]10.99 (s, 1H), 9.57 (s, 1H), 8.23-8.14 (m, 1H), 8.09-7.86 (m, 3H), 7.53 (d, J=8.7 Hz, 2H), 7.41-7.30 (m, 2H), 3.95 (s, 2H).

EXAMPLE 9

Synthesis of 2-(4-tert-butylphenyl)-N-phthalazin-1-yl-acetamide (A9)

(28) ##STR00017##

(29) A9 was prepared from (4-tert-butylphenyl)-acetic acid (66.2 mg; 0.34 mmol), benzotriazol-1-ol hydrate (54.4 mg; 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85.8 mg; 0.45 mmol) and phthalazin-1-ylamine (50 mg; 0.34) in DMF (2 mL) as described for example 5; yield: 67 mg (61%), colourless solid (purity: 100%, Rt: 3.38 min);

(30) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.93 (s, 1H), 9.57 (s, 1H), 8.23-8.14 (m, 1H), 8.08-7.83 (m, 3H), 7.43-7.28 (m, 4H), 3.84 (s, 2H), 1.28 (s, 9H).

EXAMPLE 10

Synthesis of 2-(2,6-dichlorophenyl)-N-phthalazin-1-yl-acetamide (A10)

(31) ##STR00018##

(32) A9 was prepared from (2,6-dichlorophenyl)-acetic acid (70.6 mg; 0.34 mmol), benzotriazol-1-ol hydrate (54.4 mg; 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85.8 mg; 0.45 mmol) and phthalazin-1-ylamine (50 mg; 0.34) in DMF (2 mL) as described for example 5; yield: 74 mg (65%), colourless solid (purity: 100%, Rt: 3.27 min);

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 11.12 (s, 1H), 9.59 (s, 1H), 8.27-8.15 (m, 1H), 7.98-8.07 (m, 3H), 7.51 (d, J=8.1 Hz, 2H), 7.35 (t, J=8.0 Hz, 1H), 4.31 (s, 2H).

(34) The following compounds have been prepared analogously:

2-(4-ethoxy-phenyl)-N-(5-fluoro-phthalazin-1-yl)-acetamide (A11)

(35) ##STR00019##

(36) M+H 326; HPLC 1.73 (X); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.96 (s, 1H), 9.61 (d, J=2.6 Hz, 1H), 8.07-7.99 (m, 2H), 7.80-7.69 (m, 1H), 7.31-7.23 (m, 2H), 6.94-6.84 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.72 (s, 2H), 1.32 (t, J=7.0 Hz, 3H);

N-(5-fluoro-phthalazin-1-yl)-2-(4-methoxy-phenyl)-acetamide (A12)

(37) ##STR00020##

(38) M+H 312; HPLC 1.61 (X);

3-cyclohexyl-N-phthalazin-1-yl-propionamide (A13)

(39) ##STR00021##

(40) M+H 284; HPLC 2.37 (N); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.68 (s, 1H), 9.57 (s, 1H), 8.22-8.14 (m, 1H), 8.06-7.93 (m, 3H), 2.55 (t, J=7.8 Hz, 2H), 1.79-1.54 (m, 7H), 1.36-1.11 (m, 4H), 0.99-0.87 (m, 2H);

3-phenyl-N-phthalazin-1-yl-propionamide (A14)

(41) ##STR00022##

(42) M+H 278; HPLC 1.99 (N); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.74 (s, 1H), 9.56 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.04-7.97 (m, 1H), 7.96-7.88 (m, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.37-7.28 (m, 4H), 7.27-7.19 (m, 1H), 3.00 (t, J=7.3 Hz, 2H), 2.88 (t, J=7.9 Hz, 2H);

3-cyclopentyl-N-phthalazin-1-yl-propionamide (A15)

(43) ##STR00023##

(44) M+H 270; HPLC 2.19 (N); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.68 (s, 1H), 9.57 (s, 1H), 8.21-8.15 (m, 1H), 8.05-7.93 (m, 3H), 2.59-2.53 (m, 2H), 1.90-1.74 (m, 3H), 1.74-1.65 (m, 2H), 1.65-1.46 (m, 4H), 1.22-1.09 (m, 2H);

3-(2-chloro-phenyl)-N-phthalazin-1-yl-propionamide (A16)

(45) ##STR00024##

(46) HPLC 2.21 (N); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.79 (s, 1H), 9.57 (s, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.36-7.24 (m, 2H), 3.10 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.7 Hz, 2H);

3-(2,3-dichloro-phenyl)-N-phthalazin-1-yl-propionamide (A17)

(47) ##STR00025##

(48) HPLC 2.44 (N); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.81 (s, 1H), 9.56 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.05-7.99 (m, 1H), 7.99-7.93 (m, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.55-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.38-7.29 (m, 1H), 3.15 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H);

N-(8-methyl-phthalazin-1-yl)-2-phenyl-acetamide (A18)

(49) ##STR00026##

(50) M+H 278; HPLC 1.61 (X); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.92 (s, 1H), 9.68 (s, 1H), 7.87-7.77 (m, 2H), 7.77-7.68 (m, 1H), 7.45-7.39 (m, 2H), 7.36 (m, 2H), 7.32-7.24 (m, 1H), 3.87 (s, 2H), 2.77 (s, 3H);

N-(5-methyl-phthalazin-1-yl)-2-phenyl-acetamide (A19)

(51) ##STR00027##

(52) M+H 278; HPLC 1.71 (X); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.74 (s, 1H), 9.54 (s, 1H), 8.02 (d, J=6.8 Hz, 1H), 7.87 (t, J=7.6 Hz, 1H), 7.74 (dd, J=7.2, 1.4 Hz, 1H), 7.42-7.30 (m, 4H), 7.30-7.22 (m, 1H), 3.80 (s, 2H), 2.59 (s, 3H);

2-(4-methoxy-phenyl)-N-(8-methyl-phthalazin-1-yl)-acetamide (A20)

(53) ##STR00028##

(54) M+H 308; HPLC 1.61 (X); .sup.1H NMR (400 MHz, DMSO-d.sub.6) [ppm] 10.85 (s, 1H), 9.68 (s, 1H), 7.88-7.76 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.38-7.27 (m, 2H), 6.98-6.88 (m, 2H), 3.79 (s, 2H), 3.75 (s, 3H), 2.77 (s, 3H);

2-(4-methoxy-phenyl)-N-(5-methyl-phthalazin-1-yl)-acetamide (A21)

(55) ##STR00029##

(56) M+H 308; HPLC 1.69 (X); .sup.1H NMR (400 MHz, DMSO-d.sub.6, TFA-d.sub.1) [ppm] 10.11 (s, 1H), 8.44 (d, J=7.6 Hz, 1H), 8.23 (t, J=7.6 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 3.89 (s, 2H), 3.78 (s, 3H), 2.80 (s, 3H);

3-cyclohexyl-N-(8-methyl-phthalazin-1-yl)-propionamide (A22)

(57) ##STR00030##

3-phenyl-N-(8-methyl-phthalazin-1-yl)-propionamide (A23)

(58) ##STR00031##

3-cyclopentyl-N-(8-methyl-phthalazin-1-yl)-propionamide (A24)

(59) ##STR00032##

3-(2-chlorophenyl)-N-(8-methyl-phthalazin-1-yl)-propionamide (A25)

(60) ##STR00033##

3-(2,3-dichlorophenyl)-N-(8-methyl-phthalazin-1-yl)-propionamide (A26)

(61) ##STR00034##

(62) Pharmacological Data

(63) TABLE-US-00002 TABLE 1 Inhibition of tankyrases of some representative compounds of the formula I IC.sub.50 IC.sub.50 Compound TNKS1 TNKS2 IC.sub.50 No. enzyme assay enzyme assay Cell assay A1 A B C A2 B B C A3 A B C A4 A B C A5 B C A6 B C A7 B B A8 A B A9 B B A10 C C A11 C C A12 B C A13 B B A14 A B C A15 A A C A16 A A C A17 A B C A18 B B C A19 C C A20 B B C A21 C C IC.sub.50: <0.3 M = A 0.3-3 M = B 3-50 M = C

(64) The compounds shown in Table 1 are particularly preferred compounds according to the invention.

(65) TABLE-US-00003 TABLE 2 Inhibition of tankyrases of some representative compounds of the formula I IC.sub.50 IC.sub.50 Compound IC.sub.50 TNKS1 TNKS2 No. PARP ELISA ELISA A1 C A B A2 C B B A3 C A A A4 C A A A5 C B B A6 B B B A7 B B B A8 C A A A9 C A A A10 C A13 C A A A14 A A A15 C A A A16 C A A A17 A A A18 B A A A20 B A A IC.sub.50: <0.3 M = A 0.3-3 M = B 3-50 M = C

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

(67) The following examples relate to medicaments:

EXAMPLE A: INJECTION VIALS

(68) 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

(69) 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

(70) 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

(71) 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE E: TABLETS

(72) 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

(73) 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

(74) 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

(75) 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.