Imidazopyrazine Derivatives and the Use Thereof as Medicament

Abstract

The present invention relates to novel imidazopyrazines of general formula A, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment or prevention of conditions having an association with NR2B negative allosteric modulating properties.

##STR00001##

Claims

1. A compound of formula A ##STR00018## in which R.sup.1 represents phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoro, chloro, methyl, ethyl, cyclopropyl, F.sub.2HC—, FH.sub.2C—, and F.sub.3C—.

2. The compound according to claim 1, wherein R.sup.1 represents phenyl which is optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro and methyl.

3. The compound according to claim 1, wherein R.sup.1 represents ##STR00019##

4. The (S)-enantiomer according to claim 1, selected from the group consisting of: TABLE-US-00023 Exp 1 5 3 10 4 12

5. A pharmaceutically acceptable salt of a compound according to claim 1.

6. (canceled)

7. A method for treating and/or preventing a psychiatric disease and/or disorder, comprising administering to a patient in need thereof the, compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the disease and/or disorder is: bipolar disorder I depressed, hypomanic, manic or mixed form; bipolar disorder II; single depressive episode, recurrent major depressive disorder, minor depressive disorder, depressive disorder with postpartum onset, depressive disorders with psychotic symptoms; or major depressive disorder with or without concomitant anxious distress, mixed features, melancholic features, atypical features, mood-congruent psychotic features, mood-incongruent psychotic features, or catatonia.

8. The method according to claim 7, characterized in that the compound is administered in combination with another antidepressant drug.

9. The method according to claim 7, wherein the patient is further undergoing behavioural therapy.

10. A pharmaceutical composition comprising the compound according to claim 1 in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

Description

EXPERIMENTAL SECTION

Abbreviations

[0102] ACN acetonitrile [0103] APCI Atmospheric pressure chemical ionization [0104] Boc tert-butyloxycarbonyl [0105] CDI 1,1′-carbonyldiimidazole [0106] C02 Carbon Dioxide [0107] d day [0108] DA Diode Array [0109] DAD Diode Array Detector [0110] DCM dichloromethane [0111] DIPE diisopropylether [0112] DIPEA diisopropylethylamine [0113] DMF dimethylformamide [0114] ee, e.e. enantiomeric excess [0115] ELSD Evaporative Light Scattering Detector [0116] ESI electrospray ionization (in MS) [0117] EtOAc ethylacetate [0118] EtOH ethanol [0119] Exp. example [0120] h hour(s) [0121] HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate [0122] HPLC high performance liquid chromatography [0123] HPLC-MS coupled high performance liquid chromatography-mass spectrometry [0124] IPA Isopropanol [0125] M molar (mol/L) [0126] MeOH methanol [0127] min minute(s) [0128] MS mass spectrometry [0129] MW molecular weight [0130] NH.sub.3 ammonia [0131] PSI Pound per square inch [0132] rt room temperature [0133] R.sub.t retention time [0134] scCO2 supercritical CO2 [0135] Sol Solvent [0136] solv solvent [0137] TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [0138] TEA triethylamine [0139] TFA trifluoroacetic acid [0140] THE tetrahydrofuran [0141] TLC thin-layer chromatography [0142] SFC Supercritical fluid chromatography

[0143] General Analytics

[0144] All reactions were carried out using commercial grade reagents and solvents. NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using Top-Spin 3.2 p16 software. Chemical shifts are given in parts per million (ppm) downfield from internal reference trimethylsilane in 6 units. Selected data are reported in the following manner: chemical shift, multiplicity, coupling constants (J), integration. Analytical thin-layer chromatography (TLC) was carried out using Merck silica gel 60 F.sub.254 plates. All compounds were visualized as single spots using short wave UV light. Low resolution mass spectra were obtained using a liquid chromatography mass spectrometer (LCMS) that consisted of an Agilent 1100 series LC coupled to a Agilent 6130 quadru-pole mass spectrometer (electrospray positive ionization).

[0145] Methods:

[0146] For solvent mixtures used for HPLC-MS methods and Chiral SFC analytical methods, % solvent are given as volume percent of the corresponding solvent.

[0147] HPLC-MS methods:

TABLE-US-00005 Method 1 Method Name: Z011_S03 Device description: Agilent 1200 with DA- and MS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer: Waters Description:

TABLE-US-00006 Method Name: Z011_S03 Gradient/ % Sol Back Solvent [Water % Sol Flow Temp pressure Time [min] 0.1% NH.sub.3] [Acetonitrile] [ml/min] [° C.] [PSI] 0.0 97.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0 100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

[0148] Chiral SFC analytical methods:

TABLE-US-00007 Method 2: I_C2_20_MeOH_NH.sub.3 —001 Method Name: I_C2_20_MEOH_NH.sub.3 —001 Device description: Agilent 1260 SFC with DAD and ELSD Column: Lux ® Cellulose-2_4.6 × 250 mm_5 μm Column producer: Phenomenex

TABLE-US-00008 Gradient/ % Sol Back Solvent % Sol [MeOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0

TABLE-US-00009 Method 3: I_C2_40_IPA_NH.sub.3 —001 Method Name: I_C2_40_IPA_NH.sub.3 —001 Device description: Agilent 1260 SFC with DAD and ELSD Column: Lux ® Cellulose-2_4.6 × 250 mm_5 μm Column producer: Phenomenex

TABLE-US-00010 Gradient/ % Sol Back Solvent % Sol [IPA Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 60.0 40.0 4.0 40.0 2175.0 10.0 60.0 40.0 4.0 40.0 2175.0

TABLE-US-00011 Method 4: I_SA_20_MEOH_NH.sub.3 —001 Method Name: I_SA_20_MEOH_NH.sub.3 —001 Device description: Agilent 1260 SFC with DAD and MS Column: CHIRAL ART ® Amylose SA_4.6 × 250 mm_5 μm Column producer: YMC

TABLE-US-00012 Gradient/ % Sol Back Solvent % Sol [MeOH Flow Temp pressure Time [min] [scCO2] 20 mM NH.sub.3] [ml/min] [° C.] [PSI] 0.0 80.0 20.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0

[0149] Preparation of Intermediates:

Example 1a

[0150]

TABLE-US-00013 [00008] S-Morpholin-2,4-dicarboxylic acid 4-tertbutylester (1.26 g, 5.45 mmol) was dissolved in DMF (20 ml). Then HATU (2.28 g, 5.99 mmol) was added, followed by Pyrazine-2,3-diamine (600 mg, 5.45 mmol, CAS No. 13134-31-1) and TEA (1.52 ml, 10.9 mmol). The reaction mixture was stirred 20 h at room termperature before the work-up: The reaction mixture was filtered with a glass filter and the filtrate was concentrated in vacuo. The residue was treated with 40 mL H.sub.2O and stirred for 2 h. The obtained precipitate was filtered off and dried in the air. Obtained 1.60 g of the desired product. HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.76 MS: 324 (M + H).sup.+

Example 2a—Method A (According to Scheme 1)

[0151]

TABLE-US-00014 [00009] A mixture of example 1a (1.60 g, 4.95 mmol), potassium carbonate (2.74 g, 19.8 mmol) and isopropanol (50 ml) was stirred for 6 h at 80° C. The precipitate was filtered off, washed with isopropanol and the filtrate was concentrated in vacuo. The residue was dried overnight. Obtained 1.50 g of the desired product. HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.58 MS: 306 (M + H).sup.+

Example 2a—Method B (Direct Cyclisation, According to Scheme 2)

[0152]

TABLE-US-00015 [00010] S-Morphline-2,4-dicarboxylic acid 4-tertbutylester (3.15 g, 13.62 mmol) was dissolved in DMF (30 ml). Then HATU (5.7 g, 15 mmol) was added, followed by Pyrazine-2,3-diamine (1.5 g, 13.62 mmol, CAS No. 13134-31-1) and TEA (3.8 ml, 27.2 mmol). The reaction mixture was stirred 7 h at room temperature before the work-up: The reaction mixture was filtered with a glass filter and the filtrate was concentrated in vacuo. The residue was treated with 100 mL H.sub.2O and stirred for 12 h. The obtained precipitate was filtered off and dried in the air. Obtained 2.0 g of the desired cyclised product. HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.76 MS: 306 (M + H).sup.+ Chiral SFC; Method: I_C2_20_MEOH_NH3_001; ee: 100% R.sub.t [min]: 3.36 min

Example 3a

[0153]

TABLE-US-00016 [00011] Example 2a (2 g, 6.55 mmol) was dissolved in DCM (120 ml), HCl in dioxane (4 M, 9.83 ml, 39.3 mmol) was added and the reaction mixture was stirred 3.5 h at rt. The solvents were evaporated in vacuo and the obtained residue was used as such in the next step. Obtained 1.8 g of the desired product as a salt. Chiral SFC; Method: I_C2_20_MEOH_NH3_001; MS: 206 (M + H).sup.+ R.sub.t [min]: 6.48 min ee: 100%

EXEMPLARY EMBODIMENTS

Example 1

[0154] (2-Fluoro-4-methylphenyl)methanol (151 mg; 1.08 mmol, CAS No. 252004-38-9) and CDI (175 mg; 1.08 mmol) were mixed together in DMF (3 ml); the reaction mixture was heated at 50° C. during 30 minutes. Example 3a (150 mg; 0.54 mmol) and DIPEA (0.28 ml; 1.62 mmol) were then added in sequence and the reaction mixture was stirred 2 hours at rt. The reaction mixture was diluted with 3 ml of a mixture MeOH/Water (1/1; volume/volume) before being filtered and separated via semipreparative HPLC.

[0155] The residue was triturated with 3 mL DIPE, filtered and dried in the air. Obtained 157 mg of the desired compound.

TABLE-US-00017 Example 1 [00012] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.68 MS: 372 (M + H).sup.+ Chiral SFC; Method: I_SA_20_MEOH_NH.sub.3—001 Rt [min]: 4.13 ee: 92.4%

Example 3

[0156] (2-Fluoro-3-methylphenyl)methanol (151 mg; 1.08 mmol, CAS No. 307975-03-7) and CDI (175 mg; 1.08 mmol) were mixed together in DMF (3 ml); the reaction mixture was heated at 50° C. during 30 minutes. Example 3a (150 mg; 0.54 mmol) and DIPEA (0.28 ml; 1.62 mmol) were then added in sequence and the reaction mixture was stirred 16 hours at rt. The reaction mixture was diluted with 3 ml of a mixture MeOH/Water (1/1; volume/volume) before being filtered and separated via semipreparative HPLC. Obtained 80 mg of the desired compound.

TABLE-US-00018 Example 3 [00013] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.69 MS: 372 (M + H).sup.+ Chiral SFC; Method: I_SA_20_MEOH_NH.sub.3—001 Rt [min]: 3.3 ee: 94.4%

Example 4

[0157] (2-Fluorophenyl)methanol (116 μl; 1.08 mmol, CAS No. 446-51-5) and CDI (175 mg; 1.08 mmol) were mixed together in DMF (3 ml); the reaction mixture was heated at 50° C. during 30 minutes. Example 3a (150 mg; 0.54 mmol) and DIPEA (0.28 ml; 1.62 mmol) were then added in sequence and the reaction mixture was stirred 3 hours at rt.

[0158] The reaction mixture was diluted with 3 ml of a mixture MeOH/Water (1/1; vol-ume/volume) before being filtered and separated via semipreparative HPLC. Obtained 98 mg of the desired compound.

TABLE-US-00019 Example 4 [00014] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.63 MS: 358 (M + H).sup.+ Chiral SFC; Method: I_SA_20_MEOH_NH.sub.3—001 Rt [min]: 3.37 ee: 100%

Example 5

[0159] Example 5 was synthesised in analogy to Example 4. Starting materials: Example 3a (150 mg, 0.54 mmol) and (2,4-Difluorophenyl)methanol (121 μl, 1.08 mmol, CAS No. 56456-47-4). The crude was purified via semipreparative HPLC. Obtained 112 mg of the desired compound.

TABLE-US-00020 Example 5 [00015] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.64 MS: 376 (M + H).sup.+ Chiral SFC; Method: I_SA_20_MEOH_NH.sub.3—001 Rt [min]: 3.18 ee: 100%

Example 10

[0160] (4-Fluorophenyl)methanol (157 μl, 1.44 mmol, CAS No. 459-56-3) was dissolved in DMF (6 ml); TEA (0.3 ml; 2.16 mmol) was added followed by Bis-[1,2,4]triazol-1-yl-methanone (236 mg, 1.44 mmol) and Example 3a (200 mg, 0.72 mmol). The reaction mixture was stirred 2 h at 50° C. before being diluted with H.sub.2O/MeOH (4 ml; 1/1; volume/volume mixture), filtered and purified with semipreparative HPLC.

[0161] Obtained 150 mg of the desired compound.

TABLE-US-00021 Example 10 [00016] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.61 MS: 358 (M + H).sup.+ Chiral SFC; Method : I_SA_20_MEOH_NH.sub.3—001 Rt [min]; 4.25 ee: 100%

Example 12

[0162] Example 12 was synthesised in analogy to Example 10. Starting materials: Example 3a (200 mg, 0.72 mmol) and (4-Methylphenyl)methanol (176 mg, 1.44 mmol, CAS No. 589-18-4). The reaction mixture was purified via semipreparative HPLC. Obtained 117 mg of the desired compound.

TABLE-US-00022 Example 12 [00017] HPLC-MS; Method: Z011_S03; R.sub.t [min]: 0.67 MS: 354 (M + H).sup.+ Chiral SFC; Method: I_C2_40_IPA_NH.sub.3—001 Rt [min]; 3.65 ee: 66.7%