PYRIDINE DERIVATIVES

Abstract

The invention relates to compound of formula (I)

##STR00001##

wherein R.sup.1 to R.sup.3 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Claims

1. A compound of formula (I) ##STR00047## wherein R.sup.1 is halophenyl, cycloalkylalkoxy, alkyloxetanylalkoxy, alkoxycarbonylpyrrolidinylalkoxy, alkoxycarbonylpyrrolidinyloxy, alkyl sulfonylphenylalkoxy, haloalkoxy, (alkyl)(halo)cycloalkylalkoxy, benzotriazolyloxy, halopyridinylalkoxy or halopyridinyl; R.sup.2 is halogen, cycloalkyl, haloalkyl, cycloalkylalkoxy, 2-oxa-6-azaspiro[3.3]heptyl or phenylalkoxy; R.sup.3 is —C(O)—NH—C(R.sup.4R.sup.5).sub.m(CH.sub.2).sub.n—R.sup.6 or alkyloxadiazolyl; R.sup.4 and R.sup.5 are independently selected from hydrogen, alkyl, hydroxyalkyl, haloalkyl, azetidinyl, cycloalkylalkyl and cycloalkyl; R.sup.6 is hydroxyl, hydroxycycloalkyl, alkoxycarbonyl, alkoxycycloalkyl, aminocarbonyl, phenyl, alkyl-1,2,4-oxadiazolyl, alkylaminocarbonyl, haloalkyl or alkyl-1,3,4-oxadiazolyl; m is 0 or 1; and n is 0 or 1; or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1, wherein R.sup.1 is alkoxycarbonylpyrrolidinylalkoxy, alkoxycarbonylpyrrolidinyloxy, alkylsulfonylphenylalkoxy, (alkyl)(halo)cycloalkylalkoxy, benzotriazolyloxy, halopyridinylalkoxy or halopyridinyl.

3. A compound according to claim 1, wherein R.sup.1 is tert.-butyloxycarbonylpyrrolidinylmethoxy, butyloxycarbonylpyrrolidinyloxy, methyl sulfonylphenylmethoxy, (methyl)(difluoro)cyclopropylmethoxy, benzotriazolyloxy, fluoropyridinylmethoxy or fluoropyridinyl.

4. A compound according to claim 1, wherein R.sup.2 is haloalkyl, cycloalkylalkoxy, 2-oxa-6-azaspiro[3.3]heptyl or phenylalkoxy.

5. A compound according to claim 1, wherein R.sup.2 is hydrogen, trifluoromethyl, cyclopropylmethoxy, 2-oxa-6-azaspiro[3.3]heptyl or phenylmethoxy.

6. A compound according to claim 1, wherein R.sup.3 is —C(O)—NH—C(O)—NH—C(R.sup.4R.sup.5).sub.m(CH.sub.2).sub.n—R.sup.6 or tert.-butyloxadiazolyl.

7. A compound according to claim 1, wherein R.sup.6 is hydroxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl.

8. A compound according to claim 1, wherein R.sup.6 is hydroxyl, methoxycarbonyl, aminocarbonyl or methylaminocarbonyl.

9.-13. (canceled)

14. A pharmaceutical composition comprising a compound in accordance with claim 1, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

15.-17. (canceled)

18. A method for the treatment of pain, neuropathic pain, asthma, osteoporosis, inflammation, psychiatric diseases, psychosis, oncology, encephalitis, malaria, allergy, immunological disorders, arthritis, gastrointestinal disorders, psychiatric disorders rheumatoid arthritis, psychosis or allergy, which method comprises administering an effective amount of a compound of claim 1 to a patient in need thereof.

19. (canceled)

20. A process for the preparation of a compound according to claim 1, comprising the reaction of a compound of formula (A) ##STR00048## in the presence of NH.sub.2R, an amide bond forming coupling agent and a base.

21. A compound manufactured according to the process of claim 20.

22. A process for the preparation of a compound according to claim 1, comprising heating a compound of formula (B) ##STR00049## wherein R is —C(R.sup.4R.sup.5).sub.m(CH.sub.2).sub.n—R.sup.6 and wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, m and n are as defined claim 1.

23. A compound manufactured according to the process of claim 22.

Description

EXAMPLES

Abbreviations

[0121] BINAP=2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl; CAN=chemcial abstract service number; DMF=dimethylformamide; DMSO=dimethyl-sulfoxide; EtOAc=ethyl acetate; HATU=2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V); HPLC=LC=high performance liquid chromatography; MS=mass spectrometry; TBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate; THF=tetrahydrofuran; TLC=thin layer chromatography.

Example 1

5-(Cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]pyridine-2-carboxamide

[0122] ##STR00008##

a) [6-Chloro-5-(cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-2-pyridyl]methanol

[0123] ##STR00009##

[0124] To a suspension of [6-chloro-5-(cyclopropylmethoxy)-4-iodo-2-pyridyl]methanol (1.5 g, 4.4 mmol; CAN 1364677-02-0) in toluene (15 mL) were added [1,1′-dis(diphenylphosphino)ferrocene]dichloropalladium (II)×CH.sub.2Cl.sub.2 (1:1) (180 mg, 220 μmol), 2,4-dichlorophenylboronic acid (927 mg, 4.9 mmol; CAN 68716-47-2) and a 2 M aqueous solution of Na.sub.2CO.sub.3 (4.4 mL, 8.8 mmol) under a nitrogen atmosphere. The mixture was stirred at 90° C. for 20 h, cooled to ambient temperature and poured over a chem elut column (Varian, 20 g). The column was washed with EtOAc (50 mL). The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 70 g, EtOAc/heptane) to obtain the title compound (1.5 g, 95%) as yellow oil, LC-MS: 357.9 [MH.sup.+].

b) [5-(Cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-2-pyridyl]methanol

[0125] ##STR00010##

[0126] To a solution of [6-chloro-5-(cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-2-pyridyl]methanol (1.5 g, 4.2 mmol) in 95% acetic acid (4.2 mL) was added tetramethylammonium bromide (6 mg, 42 μmop under an argon atmosphere. The solution was warmed to 40° C. Within 2 h activated zinc powder (820 mg, 12.5 mmol) was added in five portions. The mixture was stirred for 17 h at 50° C., cooled to ambient temperature, poured onto water (50 mL), and brought to pH 14 by adding 2 N aqueous NaOH solution (30 mL). The mixture was filtered over celite and extracted with EtOAc (200 mL). The layers were separated and the aqueous layer was extracted two more times with EtOAc (2×100 mL). The combined extracts were dried over sodium sulfate, filtered and the filtrate was brought to dryness under reduced pressure. The crude product was purified by column chromatography (silica gel, 90 g, 50% to 100% EtOAc in heptane) to obtain the title compound (800 mg, 59%) as yellow crystals, LC-MS: 324.1 [MH.sup.+].

c) 5-(Cyclopropylmethoxy)-4-(2,4-dichlorophenyl)pyridine-2-carboxylic acid

[0127] ##STR00011##

[0128] To a solution of [5-(cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-2-pyridyl]methanol (780 mg, 2.41 mmol) in pyridine (10 mL) was added a solution of tetrabutylammonium permanganate (2.6 g, 7.22 mmol) in pyridine (10 mL) under an argon atmosphere. The mixture was stirred at 80° C. for 1 h, cooled to ambient temperature and poured onto ice water (250 mL). Saturated aqueous NaHSO.sub.3 solution (25 mL) and 2 N aqueous HCl solution (200 mL) were added. The mixture was extracted with diethyl ether (2×250 mL). The combined extracts were dried over sodium sulfate, filtered and the filtrate was evaporated to dryness to obtain the title compound (780 mg, 96%) as light brown solid, LC-MS: 336.1 [M-H.sup.−].

d) 5-(Cyclopropylmethoxy)-4-(2,4-dichlorophenyl)-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]pyridine-2-carboxamide

[0129] To a solution of 5-(cyclopropylmethoxy)-4-(2,4-dichlorophenyl)pyridine-2-carboxylic acid (100 mg, 296 μmop in DMF (4 mL) were added TBTU (104 mg, 325 μmop, N,N-diisopropyl ethyl amine (191 mg, 253 μL, 1.48 mmol) and L-Leucinol (39 mg, 43 μL, 325 μmol; CAN 7533-40-6). The mixture was shaked for 16 h at ambient temperature at 380 rpm. The solvent was removed in vacuo and the crude purified by column chromatography (silica gel, 20 g, heptane/EtOAc) to obtain the title compound (102 mg, 79%) as colorless foam, LC-MS: 437.1 [MH.sup.+].

Example 2

4-(4-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl] pyridine-2-carboxamide

[0130] ##STR00012##

[0131] In analogy to the procedure described in example 1 d, 4-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carboxylic acid (200 mg, 658 μmol; CAN 1018782-76-7) was reacted with (1S,2R)-2-amino-cyclohexanol hydrochloride (110 mg, 724 μmol; CAN 200352-28-9) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (236 mg, 89%) as white foam, LC-MS: 401.1628 [MH.sup.+].

Example 3

4-(4-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[(1S,2R)-2-hydroxycyclohexyl] pyridine-2-carboxamide

[0132] ##STR00013##

[0133] In analogy to the procedure described in example 1 d, 4-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carboxylic acid (200 mg, 658 μmol; CAN 1018782-76-7) was reacted with (1R,2S)-2-amino-cyclohexanol hydrochloride (110 mg, 724 μmol; CAN 190792-72-4) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (236 mg, 89%) as white solid, LC-MS: 401.1636 [MH.sup.+].

Example 4

Methyl 2-[[4-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carbonyl]amino]-2-ethylbutanoate

[0134] ##STR00014##

[0135] In analogy to the procedure described in example 1 d, 4-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carboxylic acid (200 mg, 658 μmol; CAN 1018782-76-7) was reacted with methyl 2-amino-2-ethyl-butanoate hydrochloride (132 mg, 724 μmol; CAN 92398-54-4) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (264 mg, 93%) as white solid, LC-MS: 431.1742 [MH.sup.+].

Example 5

Methyl 2-[[5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)pyridine-2-carbonyl]amino]-2-ethylbutanoate

[0136] ##STR00015##

a) [6-Chloro-5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)-2-pyridyl]methanol

[0137] ##STR00016##

[0138] In analogy to the procedure described in example 1 a, [6-chloro-5-(cyclopropylmethoxy)-4-iodo-2-pyridyl]methanol (23 g, 68 mmol; CAN 1364677-02-0) was reacted with 3,4-dichlorophenylboronic acid (12.9 g, 68 mmol; CAN 151169-75-4) in the presence of [1,1′-dis(diphenylphosphino)ferrocene]dichloropalladium (II)×CH.sub.2Cl.sub.2 (1:1) and Na.sub.2CO.sub.3 to give the title compound (23.6 g, 97%) as off-white solid, LC-MS: 358.0161 [MH.sup.+].

b) [5-(Cyclopropylmethoxy)-4-(3,4-dichlorophenyl)-2-pyridyl]methanol

[0139] ##STR00017##

[0140] In analogy to the procedure described in example 1 b, [6-chloro-5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)-2-pyridyl]methanol (23.6 g, 66 mmol) was reacted with tetramethylammonium bromide and activated zinc powder to obtain the title compound (18.6 g, 87%) as light brown solid, LC-MS: 324.0551 [MH.sup.+].

c) 5-(Cyclopropylmethoxy)-4-(3,4-dichlorophenyl)pyridine-2-carboxylic acid

[0141] ##STR00018##

[0142] In analogy to the procedure described in example 1 c, [5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)-2-pyridyl]methanol (18.6 g, 57 mmol) was oxidized with tetrabutylammonium permanganate in pyridine to give the title compound (19.1 g, 98%) as off-white solid, LC-MS: 336.1 [M-H.sup.−].

d) Methyl 2-[[5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)pyridine-2-carbonyl]amino]-2-ethylbutanoate

[0143] In analogy to the procedure described in example 1 d, 5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)pyridine-2-carboxylic acid (200 mg, 591 μmop was reacted with methyl 2-amino-2-ethyl-butanoate hydrochloride (118 mg, 651 μmol; CAN 92398-54-4) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (238 mg, 86%) as white solid, LC-MS: 465.1333 [MH.sup.+].

Example 6

Methyl 2-[[5-(cyclopropylmethoxy)-4-(3,4-dichlorophenyl)pyridine-2-carbonyl]amino]-2-ethylbutanoate

[0144] ##STR00019##

[0145] To an ice cold solution of 4-(4-chlorophenyl)-5-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (70 mg, 175 μmol; example 2) in THF (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (8.4 mg, 210 μmol). The mixture was stirred for 1 h at ambient temperature. Methyl iodide (24.8 mg, 10.9 μL, 175 μmop was added and stirring was continued for 23 h. The suspension was poured onto ice water and extracted with EtOAc (2×60 mL). The combined extracts were dried over sodium sulfate, filtered and the filtrate was brought to dryness. The crude product was purified by column chromatography (silica gel, 10 g, EtOAc/heptane) to obtain the title compound (28 mg, 39%) as colorless oil, LC-MS: 415.1784 [MH.sup.+].

Example 7

5-Chloro-4-(cyclopropylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]pyridine-2-carboxamide

[0146] ##STR00020##

[0147] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (68 mg, 300 μmol; CAN 1613238-32-6) was reacted with (2R)-2-amino-2-phenyl-ethanol (49 mg, 360 μmol; CAN 56613-80-0) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (54 mg, 52%) as colorless oil, LC-MS: 347.1161 [MH.sup.+].

Example 8

5-Chloro-4-(cyclopropylmethoxy)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]pyridine-2-carboxamide

[0148] ##STR00021##

[0149] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (68 mg, 300 μmol; CAN 1613238-32-6) was reacted with (2S)-2-amino-N,3,3-trimethyl-butanamide (51 mg, 360 μmol; CAN 89226-12-0) in the presence of HATU (137 mg, 360 μmol) and N,N-diisopropyl ethyl amine to obtain the title compound (91 mg, 86%) as colorless oil, LC-MS: 354.1581 [MH.sup.+].

Example 9

(−) 5-Chloro-4-(cyclopropylmethoxy)-N-[2,2,2-trifluoro-t-pyridin-2-ylethyl]pyridine-2-carboxamide

[0150] ##STR00022##

[0151] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (68 mg, 300 μmol; CAN 1613238-32-6) was reacted with 2,2,2-trifluoro-1-(2-pyridyl)ethanamine (62 mg, 350 μmol; CAN 503173-14-6) in the presence of HATU (137 mg, 360 μmol) and N,N-diisopropyl ethyl amine to obtain (rac) 5-chloro-4-(cyclopropylmethoxy)-N-[2,2,2-trifluoro-1-pyridin-2-ylethyl]pyridine-2-carboxamide which was purified by chiral preparative HPLC to provide the title compound (37 mg, 32%) as colorless oil, LC-MS:386.0878 [MH.sup.+].

Example 10

5-Chloro-4-(cyclopropylmethoxy)-N-[(1R)-2,2,2-trifluoro-1-pyridin-3-ylethyl]pyridine-2-carboxamide

[0152] ##STR00023##

[0153] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (23 mg, 100 μmol; CAN 1613238-32-6) was reacted with (1R)-2,2,2-trifluoro-1-(3-pyridyl)ethanamine; CAN 1212813-98-3) in the presence of HATU (137 mg, 360 μmol) and N,N-diisopropyl ethyl amine to obtain the title compound (30 mg, 78%) as colorless oil, LC-MS: 386.0878 [MH.sup.+].

Example 11

5-Chloro-4-(cyclopropylmethoxy)-N-[(2S)-4-methyl-1-(methylamino)-1-oxopentan-2-yl]pyridine-2-carboxamide

[0154] ##STR00024##

[0155] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (20 mg, 88 μmol; CAN 1613238-32-6) was reacted with (S)-2-amino-N,4-dimethylpentanamide*HCl (21 mg, 114 μmol; CAN 99145-71-8) in the presence of HATU (137 mg, 360 μmol) and N,N-diisopropyl ethyl amine to obtain the title compound (31 mg, quant.) as light yellow oil, LC-MS: 354.1578 [MH.sup.+].

Example 12

5-Chloro-4-(cyclopropylmethoxy)-N-[(2R)-4-methyl-1-(methylamino)-1-oxopentan-2-yl]pyridine-2-carboxamide

[0156] ##STR00025##

[0157] In analogy to the procedure described in example 1 d, 5-chloro-4-(cyclopropylmethoxy)pyridine-2-carboxylic acid (20 mg, 88 μmol; CAN 1613238-32-6) was reacted with (R)-2-amino-N,4-dimethylpentanamide*HCl (21 mg, 114 μmol; CAN 99145-71-8) in the presence of HATU (137 mg, 360 μmol) and N,N-diisopropyl ethyl amine to obtain the title compound (31 mg, quant.) as light yellow oil, LC-MS: 354.1573 [MH.sup.+].

Example 13

5-Cyclopropyl-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-4-[(3-methyloxetan-3-yl)methoxy]pyridine-2-carboxamide

[0158] ##STR00026##

[0159] To a solution of 5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridine-2-carboxylic acid (39 mg, 150 μmol; CAN 1613239-78-3) in dry DMF (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (46 mg, 165 μmol) and N,N-diisopropyl ethyl amine (68 mg, 92 μL, 525 μmol). The reaction mixture was stirred at ambient temperature for 45 min followed by the addition of (2S)-2-amino-N,3,3-trimethyl-butanamide (24 mg, 165 μmol; CAN 89226-12-0). Stirring was continued for 14 h and the crude mixture was purified by preparative HPLC to obtain the title compound, LC-MS: 390.4 [MH.sup.+].

Example 14

6-[6-(5-tert-Butyl-1,2,4-oxadiazol-3-yl)-4-(cyclopropylmethoxy)pyridin-3-yl]-2-oxa-6-azaspiro[3.3]heptane

[0160] ##STR00027##

[0161] To a solution of 3-(5-bromo-4-(cyclopropylmethoxy)pyridin-2-yl)-5-tert-butyl-1,2,4-oxadiazole (60 mg, 170 μmol; CAN 1629991-68-9) in dry toluene (1 mL) under an argon atmosphere were added 2-oxa-6-azaspiro[3.3]heptane hemioxalate (29.5 mg, 102 μmol; CAN 1045709-32-7), Pd(OAc).sub.2 (3.8 mg, 17 μmol), BINAP (10.6 mg, 17 μmop and Cs.sub.2CO.sub.3 (111 mg, 341 μmop. The reaction mixture was stirred at 115° C. for 14 h, filtered over a pad of Celite and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel, 10 g, EtOAc/heptane) to obtain the title compound (15 mg, 24%), LC-MS: 371.0 [MH.sup.+].

Example 15

tert-Butyl (2S)-2-[[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxymethyl]pyrrolidine-1-carboxylate

[0162] ##STR00028##

[0163] To a solution of 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (50 mg, 180 μmol; CAN 1629991-73-6) in dry DMF (1 mL) were added NaH (10.8 mg, 270 μmop and Boc-L-prolinol (54.3 mg, 270 μmol; CAN 69610-40-8). The reaction mixture was stirred at ambient temperature for 15 min and subsequently under microwave irradiation for 30 min at 100° C. Quenching with ice water and purification via preparative HPLC provided the title compound (6 mg, 7%), LC-MS: 443.7 [MH.sup.+].

Example 16

tert-Butyl (3R)-3-[2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-5-cyclopropylpyridin-4-yl]oxypyrrolidine-1-carboxylate

[0164] ##STR00029##

[0165] In analogy to the procedure described in example 15, 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (50 mg, 180 μmol; CAN 1629991-73-6) was reacted with Boc-(R)-3-hydroxypyrrolidine (50.6 mg, 270 μmol; CAN 109431-87-0) in the presence of NaH to obtain the title compound (43 mg, 56%), LC-MS: 429.7 [MH.sup.+].

Example 17

5-tert-Butyl-3-[5-cyclopropyl-4-[(3-methylsulfonylphenyl)methoxy]pyridin-2-yl]-1,2,4-oxadiazole

[0166] ##STR00030##

[0167] In analogy to the procedure described in example 15, 5-tert-butyl-3-(4-chloro-5-cyclopropylpyridin-2-yl)-1,2,4-oxadiazole (50 mg, 180 μmol; CAN 1629991-73-6) was reacted with (3-(methylsulfonyl)phenyl)methanol (30 mg, 161 μmol; CAN 220798-39-0) in the presence of NaH to obtain the title compound (8 mg, 10%), LC-MS: 428.6 [MH.sup.+].

Example 18

N-[1-(azetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide

[0168] ##STR00031##

a) 1-(1-Benzhydrylazetidin-3-yl)ethanone

[0169] ##STR00032##

[0170] To a solution of 1-benzhydryl-N-methoxy-N-methylazetidine-3-carboxamide (1.62 g, 5.22 mmol, CAN 359402-66-7) in dry THF (30 mL) cooled to −78° C. under an argon atmosphere was slowly added a 1.6 M solution of methyl lithium in diethyl ether (3.75 mL, 6 mmol). The reaction mixture was stirred at −78° C. for 30 min and for 14 h at ambient temperature. After cooling to −15° C. a 1.6 M solution of methyl lithium in diethyl ether (1.63 mL, 2.61 mmol) was added. The reaction mixture was stirred at −15° C. for 1 h, water was carefully added and stirring was continued at 0° C. for 10 min. The reaction medium was diluted with ethyl acetate and washed with 1 M aq. NaHCO.sub.3 solution. The layers were separated, the aqueous layer was extracted with ethy acetate and the combined organic phases were dried over Na.sub.2SO.sub.4. After filtration the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 50 g, ethyl acetate/heptane) to obtain the title compound (1.1 g, 80%), LC-MS: 266.5 [MH.sup.+].

b) (E)-N-(1-(1-Benzhydrylazetidin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0171] ##STR00033##

[0172] To a solution of 1-(1-benzhydrylazetidin-3-yl)ethanone (1.1 g, 4.15 mmol) in dry THF (30 mL) under an argon atmosphere were added 2-methylpropane-2-sulfinamide (528 mg, 4.35 mmol; CAN 146374-27-8) and titanium(IV) ethoxide (993 mg, 913 μL, 4.35 mmol). The reaction mixture was stirred at 70° C. for 16 h and carefully quenched by addition of saturated aqueous NaCl solution (5 mL). Stirring was continued at ambient temperature for 20 min. The formed precipitate was removed by filtration over a pad of Celite. The filter cake was washed twice with THF. The filtrate was brought to dryness, redissolved in ethyl acetate and washed with brine. After drying over Na.sub.2SO.sub.4 and filtration the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, 70 g, ethyl acetate/heptane) to obtain the title compound (975 mg, 64%), LC-MS: 369.6 [MH.sup.+].

c) N-(1-(1-Benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide

[0173] ##STR00034##

[0174] To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (243 mg, 1.49 mmol; CAN 864750-58-3) in dry THF (5 mL) cooled to −15° C. under an argon atmosphere was added a 1.3 M isopropyl magnesium chloride lithium chloride complex solution in THF (1.15 mL, 1.49 mmol). The reaction mixture was stirred at −15° C. for 30 min followed by addition of a mixture of a 2 M trimethylaluminum solution in heptane (746 μL, 1.49 mmol) and (E)-N-(1-(1-benzhydrylazetidin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (0.5 g, 1.36 mmol) in dry toluene (8 mL). The mixture was stirred at ambient temperature for 14 h and carefully quenched by dropwise addition of water. Ethyl acetate and 1 M aq. NaHCO.sub.3 solution were added. The layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the filtrate was brought to dryness. The residue was purified by column chromatography (silica gel, 70 g, dichloromethane/methanol) to obtain the title compound (443 mg, 72%), LC-MS: 453.6 [MH.sup.+].

d) 1-(1-Benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethanamine

[0175] ##STR00035##

[0176] To a solution of N-(1-(1-benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (433 mg, 957 μmol) in MeOH (5 mL) was added a 4 M solution of HCl in dioxane (598 μL, 2.39 mmol). The reaction mixture was stirred for 2 h at ambient temperature and concentrated in vacuo. The residue was redissolved in ethyl acetate and washed with 2 M aq. Na.sub.2CO.sub.3 solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the filtrate was brought to dryness. The residue was purified by column chromatography (silica gel, 20 g, dichloromethane/methanol) to obtain the title compound (123 mg, 37%), LC-MS: 349.6 [MH.sup.+].

e) N-(1-(1-Benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide

[0177] ##STR00036##

[0178] In analogy to the procedure described in example 1 d, 5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinic acid (85 mg, 325 μmol; CAN 1613238-51-9) was reacted with 1-(1-benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethanamine (119 mg, 342 μmol) in the presence of TBTU and N,N-diisopropyl ethyl amine to obtain the title compound (100 mg, 52%), LC-MS: 592.6 [MH.sup.+].

f) N-[1-(Azetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide

[0179] To a solution of N-(1-(1-benzhydrylazetidin-3-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)picolinamide (100 mg, 169 μmol) in EtOH (1 mL) under an argon atmosphere were added a 4 M aqueous HCl solution (30.8 mg, 25.7 μL, 845 μmol) and Pd/C 10% (10% w/w, 10 mg, 94 μmol). The reaction was put under an H.sub.2 atmosphere of 2.5 bar and stirred at room temperature for 14 h. Trifluoro acetic acid (193 mg, 130 μL, 1.69 mmol) and Pd/C 10% (10% w/w, 10 mg, 94 μmol) were added to the mixture. Stirring was continued at 50° C. under an H.sub.2 atmosphere of 2 bar for 3 h. The mixture was filtered through a pad of Celite and the filter cake was washed twice with ethanol. The filtrate was concentrated and the crude was immediately purified by preparative HPLC to obtain the title compound (25 mg, 35%) as white solid, LC-MS: 426.3 [MH.sup.+].

Example 19

Ethyl 2-[[5-cyclopropyl-4-[(3-methyloxetan-3-yl)methoxy]pyridine-2-carbonyl] amino]-2-ethylbutanoate

[0180] ##STR00037##

[0181] In analogy to the procedure described in example 13, 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinic acid (19.5 mg, 74.1 μmol; CAN 1613239-78-3) was reacted with ethyl 2-amino-2-ethylbutanoate hydrochloride (14.5 mg, 74 μmol; CAN 1135219-29-2) in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride and N,N-diisopropyl ethyl amine to give the title compound (26 mg, 86%), LC-MS: 405.7 [MH.sup.+].

Example 20

5-Chloro-N-[1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-4-[(2,2-difluoro-1-methylcyclopropyl)methoxy]pyridine-2-carboxamide

[0182] ##STR00038##

a) 4,5-Dichloro-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)picolinamide

[0183] ##STR00039##

[0184] A mixture of 4,5-dichloropicolinic acid (100 mg, 521 μmol; CAN 73455-13-7), 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (136 mg, 625 μmol; CAN 1415900-39-8), 2-bromo-1-ethylpyridinium tetrafluoroborate (284 mg, 885 μmol) and N,N-diisopropyl ethyl amine (212 mg, 281 μL) in dioxane (0.8 mL) was stirred for 14 h at 80° C., poured onto ice/brine (1×25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice water/brine (25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness and the residue was purified by column chromatography (silica gel, 10 g, heptane/ethyl acetate) to obtain the title compound (120 mg, 65%) as colorless liquid, LC-MS: 355.2 [MH.sup.+].

b) 5-Chloro-N-[1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-4-[(2,2-difluoro-1-methylcyclopropyl)methoxy]pyridine-2-carboxamide

[0185] Potassium tert-butoxyde (28 mg, 246 μmol) and potassium benzoate (39.4 mg, 246 μmol) were added to a solution of (2,2-difluoro-1-methylcyclopropyl)methanol (15 mg, 123 μmol; CAN 128230-72-8) and 4,5-dichloro-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)picolinamide (65.5 mg, 184 μmol) in DMF (375 μL). The mixture was heated for 5 h at 130° C. in a microwave oven, poured onto ice/0.1 N HCl (1×25 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice/brine (1×25 mL), dried over Na.sub.2SO.sub.4 and brought to dryness after filtering. The crude was purified by preparative TLC (silica gel, 1.0 mm, hexanes/EtOAc 1:1) to give the title compound, LC-MS: 441.2 [MH.sup.+].

Example 21

4-(Benzotriazol-1-yloxy)-N-[1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-5-(trifluoromethyl)pyridine-2-carboxamide

[0186] ##STR00040##

[0187] A mixture of 4-chloro-5-(trifluoromethyl)picolinic acid (20 mg, 88.7 μmol; CAN 1211591-26-2) 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (23.2 mg, 106 μmol; CAN 1415900-39-8), TBTU (48.4 mg, 151 μmol) and N,N-diisopropyl ethyl amine (36.1 mg, 47.8 μL, 279 μmol) in DMF (200 μL) was stirred at ambient temperature for 3 h, poured onto ice/brine/1N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with saturated aqueous NaHCO.sub.3-solution (25 mL) and ice water/brine (25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness and the residue was purified by preparative TLC (silica gel, 2.0 mm, hexanes/EtOAc 1:1) to obtain the title compound (27 mg, 63%) as colorless liquid, LC-MS: 488.2 [MH.sup.+].

Example 22

N-(4-Amino-2-cyclopropyl-4-oxobutan-2-yl)-5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy]pyridine-2-carboxamide

[0188] ##STR00041##

a) N-(4-amino-2-cyclopropyl-4-oxobutan-2-yl)-4-chloro-5-cyclopropylpicolinamide

[0189] ##STR00042##

[0190] In analogy to the procedure described in example 20 a, 4-chloro-5-cyclopropylpicolinic acid (80 mg, 405 μmol; CAN 1256790-74-5) was reacted with 3-amino-3-cyclopropylbutanamide hydrochloride (145 mg, 486 μmol; CAN of free base: 1534510-01-4) in the presence of 2-bromo-1-ethylpyridinium tetrafluoroborate and N,N-diisopropyl ethyl amine to obtain the title compound (55 mg, 42%) as colorless liquid, LC-MS: 322.2 [MH.sup.+].

b) N-(4-Amino-2-cyclopropyl-4-oxobutan-2-yl)-5-cyclopropyl-4-[(5-fluoropyridin-2-yl)methoxy] pyridine-2-carboxamide

[0191] Potassium tert-butoxyde (13.9 mg, 124 μmol) and potassium benzoate (19.9 mg, 124 μmol) were added to a solution of N-(4-amino-2-cyclopropyl-4-oxobutan-2-yl)-4-chloro-5-cyclopropylpicolinamide (20 mg, 62.2 μmol) and (5-fluoropyridin-2-yl)methanol (9.48 mg, 74.6 μmol; CAN 802325-29-7) in DMF (500 μL). The reaction mixture was heated for 5 h to 130° C. in a microwave oven, poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness and the residue was purified by preparative TLC (silica gel, 2.0 mm, EtOAc) to obtain the title compound (2 mg, 8%) as colorless liquid, LC-MS: 413.2 [MH.sup.+].

Example 23

N-[(2S)-1-Cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-4-(6-fluoropyridin-3-yl)-5-phenylmethoxypyridine-2-carboxamide

[0192] ##STR00043##

a) Methyl 5-(benzyloxy)-4-bromopicolinate

[0193] ##STR00044##

[0194] A mixture of methyl 4-bromo-5-hydroxypicolinate (200 mg, 862 nmol; CAN 1256836-99-3), potassium carbonate (477 mg, 3.45 mmol) and (chloromethyl)benzene (164 mg, 149 μL, 1.29 mmol; CAN 100-44-7) in DMF (8 mL) was stirred for 20 h at ambient temperature. Stirring was continued at 50° C. for 8 h, then the reaction mixture was poured onto ice water/brine (25 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with ice water/brine (2×25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness and the residue was purified by preparative column chromatography (silica gel, 10 g, heptanes/EtOAc) to obtain the title compound (155 mg, 56%) as off-white solid, LC-MS: 324.1 [MH.sup.+].

b) 5-(Benzyloxy)-4-bromopicolinic acid

[0195] ##STR00045##

[0196] A mixture of methyl 5-(benzyloxy)-4-bromopicolinate (153 mg, 475 nmol) and lithium hydroxide hydrate (29.9 mg, 712 nmol) in THF (1.5 mL) and water (0.75 mL) was stirred at ambient temperature for 20 h, poured onto ice water/0.1 N aqueous HCl solution (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed ice water/brine (25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness to obtain the title compound (128 mg, 88%) as off-white solid, LC-MS: 308.1 [MH.sup.+].

c) (S)-5-(Benzyloxy)-4-bromo-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)picolinamide

[0197] ##STR00046##

[0198] In analogy to the procedure described in example 20 a, 5-(benzyloxy)-4-bromopicolinic acid (30 mg, 97.4 μmol) was reacted with (S)-1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (25.4 mg, 117 μmol; (S)-enantiomer of CAN 1415900-39-8) in the presence of 2-bromo-1-ethylpyridinium tetrafluoroborate and N,N-diisopropyl ethyl amine to obtain the title compound (38 mg, 42%) as colorless liquid, LC-MS: 473.3 [MH.sup.+].

d) N-[(2S)-1-Cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]-4-(6-fluoropyridin-3-yl)-5-phenylmethoxypyridine-2-carboxamide

[0199] 1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride (4.24 mg, 5.2 μmol) was added to a mixture of (S)-5-(benzyloxy)-4-bromo-N-(1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)picolinamide (35 mg, 74.3 μmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (21.5 mg, 96.5 μmol; CAN 444120-95-0) and 2 M aqueous Cs.sub.2CO.sub.3 solution (92.8 μL, 186 μmol) in dioxane (7004) under an argon atmosphere. The mixture was heated for 8 h to 120° C. in a microwave oven, poured onto ice/1 N HCl and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/sat. aqueous NaHCO.sub.3 solution (25 mL) and ice water/brine (25 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was brought to dryness and the residue was purified by preparative TLC (silica gel, 2.0 mm, hexanes/EtOAc 1:1) to obtain the title compound (20 mg, 55%) as colorless liquid, LC-MS: 488.4 [MH.sup.+].

Example 24

Pharmacological Tests

[0200] The following tests were carried out in order to determine the activity of the compounds of formula I:

Radioligand Binding Assay

[0201] The affinity of the compounds of the invention for cannabinoid receptors was determined using recommended amounts of membrane preparations (PerkinElmer) of human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or 2.6 nM [3H]-CP-55,940 (Perkin Elmer) as radioligand, respectively. Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl.sub.2, 2.5 mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4 for CB1 receptor and 50 mM Tris, 5 mM MgCl.sub.2, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1 h at 30° C. shaking. The reaction was terminated by rapid filtration through microfiltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited), with the Kd values for [3H]CP55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 receptor.

[0202] The compounds according to formula (I) have an activity in the above assay (Ki) between 10 nM and 10 μM. Particular compounds of formula (I) have an activity in the above assay (Ki) between 10 nM and 3 μM. Other particular compounds of formula (I) have an activity in the above assay (Ki) between 10 nM and 100 nM.

cAMP Assay

[0203] CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hours prior to the experiment 50.000 cells per well in a black 96 well plate with flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No. 31331), 1×HT supplement, with 10% fetal calf serum and incubated at 5% CO.sub.2 and 37° C. in a humidified incubator. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at 30° C. for 30 min. Compounds were added to a final assay volume of 100 μl and incubated for 30 min at 30° C. Using the cAMP-Nano-TRF detection kit the assay (Roche Diagnostics) was stopped by the addition of 50 μl lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN.sub.3) and 50 μl detection solutions (20 μM mAb Alexa700-cAMP 1:1, and 48 μM Ruthenium-2-AHA-cAMP) and shaken for 2 h at room temperature. The time-resolved energy transfer is measured by a TRF reader (Evotec Technologies GmbH), equipped with a ND:YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the emission with a delay of 100 ns and a gate of 100 ns, total exposure time 10 s at 730 (bandwidth 30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is calculated as follows: FRET=T730-Alexa730-P(T645-B645) with P=Ru730-B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm, respectively. cAMP content is determined from the function of a standard curve spanning from 10 μM to 0.13 nM cAMP.

[0204] EC.sub.50 values were determined using Activity Base analysis (ID Business Solution, Limited). The EC.sub.50 values for a wide range of cannabinoid agonists generated from this assay for reference compounds were in agreement with the values published in the scientific literature.

[0205] In the foregoing assay, the compounds according to the invention have a human CB2 EC.sub.50 which is between 5 nM and 10 μM. Particular compounds according to the invention have a human CB2 EC.sub.50 between 5 nM and 1 μM. Further particular compounds according to the invention have a human CB2 EC.sub.50 between 5 nM and 100 nM. They exhibit at least 10 fold selectivity against the human CB1 receptor in, either both of the radioligand and cAMP assay, or in one of these two assays.

[0206] Results obtained for representative compounds of the invention are given in the following table.

[0207] In the second column is given the relative efficacy (in %) compared to the reference agonist CP55940 for which this value is set to +100%, measured in analogy to the assay described in Ullmer, C. et al. Functional monoclonal antibody acts as a biased agonist by inducing internalization of metabotropic glutamate receptor 7. Br. J. Pharmacol. 167, 1448-66 (2012). The negative values demonstrate that the compounds of formula (I) are inverse agonists.

TABLE-US-00001 Percent relative cAMP assay efficacy compared to human the reference agonist CB2 EC.sub.50 CP55940 for which this Example [μM] value is set to +100% 1 0.0152 −40.1 2 0.2566 −90.6 3 0.0466 −85.1 4 0.0144 −70.5 5 0.0069 −128.6 6 0.1244 −102.9 7 0.4971 −41.7 8 0.0044 −141.9 9 0.2964 −114.7 10 1.5551 −36.8 11 0.1810 −28.5 12 3.2338 −40.1 13 0.0261 −158.8 14 0.0367 −65.9 15 1.5090 −75.2 16 0.3147 −103.1 17 2.0088 −49.9 18 7.2062 −48.7 19 0.1479 13 20 0.4197 −150.8 21 0.0870 −147.5 22 0.0471 −78.4 23 1.0334 −87.7

Example A

[0208] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0 mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0 mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate 12.5 mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg

[0209] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.

Example B

[0210] Capsules containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00003 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

[0211] The components are sieved and mixed and filled into capsules of size 2.

Example C

[0212] Injection solutions can have the following composition:

TABLE-US-00004 Compound of formula (I)  3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

[0213] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.