AU2006226544A1 - 2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl-piperidines used as CGRP antagonists - Google Patents

2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl-piperidines used as CGRP antagonists Download PDF

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AU2006226544A1
AU2006226544A1 AU2006226544A AU2006226544A AU2006226544A1 AU 2006226544 A1 AU2006226544 A1 AU 2006226544A1 AU 2006226544 A AU2006226544 A AU 2006226544A AU 2006226544 A AU2006226544 A AU 2006226544A AU 2006226544 A1 AU2006226544 A1 AU 2006226544A1
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mmol
oxo
salts
general formula
hydrates
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Kirsten Arndt
Henri Doods
Alexander Dreyer
Philipp Lustenberger
Stephan Georg Mueller
Fabio Paleari
Klaus Rudolf
Marco Santagostino
Gerhard Schaenzle
Dirk Stenkamp
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Boehringer Ingelheim International GmbH
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Priority claimed from PCT/EP2005/003094 external-priority patent/WO2005092880A1/en
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Description

au-f il COMMONWEALTH OF AUSTRALIA PATENTS ACT 1990 IN THE MATTER of a Patent Application by Boehringer Ingelheim International GmbH VERIFICATION OF TRANSLATION Patent Application No.: PCT/EP2006/002557 I, JANE ROBERTA MANN, B.A., of Frank B. Dehn & Co., 59 St Aldates, Oxford OXI IST, am the translator of the documents attached and I state that the following is a true translation to the best of my knowledge and belief of the specification as published of International Patent Application No. PCT/EP2006/002557 of Boehringer Ingelheim International GmbH. Signature of translator Dated: 3rd October 2007 90721 pct 2-Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl-piperidines used as CGRP antagonists 5 The present invention relates to new CGRP antagonists of general formula I 0 B R N O R2 -6H wherein B, R 1 and R 2 are defined as in claim 1, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts 10 thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof. 15 BACKGROUND TO THE INVENTION In International Patent Applications PCT/EP03/11762 and PCT/EP2005/003094 and in US 2005/0215576, CGRP antagonists have already been described for the treatment of migraine. 20 DETAILED DESCRIPTION OF THE INVENTION In the above general formula I in a first embodiment 25 B denotes a group selected from -2 CI Br CI Br OH OH OH OH * C1 *,& Br *
CH
3
CH
3
CF
3 OH NH2 * CH 3 CH * CF 3 * a CF 3 and * CH 3 5 R' and R 2 together with the enclosed nitrogen atom denote a group of general formula il R 4 N Y" R wherein 10 Y1 denotes the carbon atom or, if R 4 denotes a free pair of electrons, it also denotes the nitrogen atom,
R
3 denotes a cyclopentyl, cyclohexyl or cycloheptyl group or 15 R 3 denotes a heterocycle selected from a morpholin-4-yl, 1,1-dioxo thiomorholin-4-y, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl or pyrrolidin-1-yl group, wherein the above-mentioned monocyclic heterocycles in the ring may be 20 mono- or disubstituted by hydroxy, methyl, ethyl, trifluoromethyl, hydroxymethyl or hydroxyethyl groups, or may optionally additionally be monosubstituted by a hydroxycyclopropyl, trifluoromethylcarbonylmethyl, amino, carboxy-carbonyl, methoxycarbonyl, ethoxycarbonyl-carbonyl, -3 carboxymethyl, carboxyethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, carboxy-ethylcarbonyl, ethoxycarbonyl-ethylcarbonyl, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, methylsulphonyl, ethylsulphonyl, isopropylsulphonyl, cyclopropylsulphonyl, (hydroxyamino) 5 carbonylmethyl, hydroxy-(methyl)-aminocarbonyl-methyl or methoxyaminocarbonyl-methyl group, wherein the substituents may be identical or different and may be bound to a ring carbon or ring nitrogen atom, or 10 the above-mentioned monocyclic heterocycles in the ring may be monosubstituted by a carboxy group, if this carboxy group is not bound via a nitrogen atom, and
R
4 denotes the hydrogen atom, if Y' denotes the carbon atom, or 15
R
4 denotes a free pair of electrons, if Y' denotes the nitrogen atom, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the 20 physiologically acceptable salts thereof with inorganic or organic acids or bases. The following compounds are mentioned for example as most particularly preferred compounds of the above general formula I: No. Structure OH N N HOON N H O No. Structure HOH HO0 OH (4) OA,&-, Br NCNYrN '0 HO0 HOH (7) Hol N CNJAN-C~N NJ<O HO0 ( 9
)H
-5 No. Structure OH (10) Br (10) N N NNOH H O (11) N N O N N N O H O OH (12)0N N ( N N OH HO OH (1 3 )N N O N H O H 0H (14) N (OH HH (15) c N-CNON N H O OH (16)N N O N N 'H H O -6 No. Structure p& OH (17) NN H O OH N CN O NOH H 0 OH (20) QN QNXOAN NY H O H O hOH N-N O. H O (2)
OH
-7 No. Structure OH H O H O OH (26) N ON H O OH (27) N N O N N H O N N O N N NH H O (29) N H O OH (30) N N. O N0 N N'O N SN H O -8 No. Structure 4OH (32)e g§ N-GJN O >N .N ZN.S HOH (33) Q 705 O, N N O H O OH (34) Q N N 0 N N (3 5 ) N N y N Ns H O (37) N N N N O H O OH - Br (39) N O N N H O -9 No. Structure (40)4 (40) NO H0O H O ,&OH (45) a H O H O H OH (46)N H O ( 4 7 ) N N I O N N N H O -10 No. Structure tb OH 0 (48) N N H H O OH (49) N H O Br OH (50) \N N OyN N 0 H O Br H 0 (51) H O Br OH (52) N O' H O OH (53) N0 N H Ol H OH H OH (55) NBrON
N
-11 No. Structure OH (56) N N. ~ 00 H O Br Y.H (57) N NO N N H 0 0 H O OHH (58) N N O H4 0 H 0 HO (60) N N H O (61) N NI O N N H 0 OH (62) N H H O OHH (63) N O N N S N ' H O -12 No. Structure OH (64) N N2N H O ( 6 5 ) N N N H H O (66) N N HO0 COH (6 7 ) NN N ~~>O H 00 H O (68)NO N H O r (70) N N H 0 0 -13 No. Structure (71) > N \ N O N N" H 0 0,H 0 OH (72) N O HO 0 Br OH (74N)N O N O H O Br OH (75) O Br H 0 Br OH (76) NN O 2 N Or H O ~ H0 0 0 Br OH (77) NONBr HOO H - 14 No. Structure Br OH 0 ,&Br (78) N N N H O Br OH (79) NBr (0) N CN LO N\A NY H O OH (80) , -IN 82N-C NO :N\ ND /e N O N N H 0 OH (81) 0Br<NQ k'N N- N . O N V H H 00 HO0 Br ~OH (82) N.4 0 HO0 SOH (83) Q' yNz~ HO0 (84)Y OH HO0 No. Structure (85) O '1 j 'Xo OH HO0 H OO (86) -\INyN-A OQH CNI 0 NN O HO0 "& OH (87) 7 N ~ O N HO 0 HOH h O HO HO0 No. Structure (93) A OH HO0 (9) & O fNCNOAr~N~NH HO0 (97) 0~~O HO' NCNXOYNo (98 OH HO0 (99) OkO j~ NM HO0 - 17 No. Structure OH (100) N NO N N O N H O OOH H O Br (103) N N N H O OH ( 1 0 4 ) N N H O (105)N N O N NH H O (103) "& OH 0' (16)NNO N\-NN IN H O OH (10 7) N 0 N H, H O No. Structure (108) &O HO0 Br (109) &O HON HO 0 HOO (110) HO=N , O" hOH N4NN0 HO0 - 19 No. Structure rOH ( 1 1 6 ) N O OH 0HO 0\" (117) NN H O HOH (119) N N O N N\ ,_ (120) N-- j N 0 N.4 0 H O H O - OH 2N-CNIOrN O N4 0 H O h",OH H O -20 No. Structure OH (124) 090 H O OH HO (126)N NO NN O H O (127) N N OHN O H O OH (128) N N N N O H O (130) N N N 0 OH H
N
-21 No. Structure OH (132) 0 : Nr N-CN O N N O H O OH H- 1 (133)1 &0 (1 ~JOH N N H O OH (135) N NN H O (136)N NO N N N O H O OH (139) N HO O N N H H O OHH (139) N0 H O -22 No. Structure "& fOH HOH (141) 9 H O H O (3 &OH 43NCNI Oy N,- N, H H O Br (144) 0.b9 N CN O NN NN H N4 H O "&OH H. ( 1 4 5 ) N1O NH H O ( 1 4 6 ) N O NNI N H H O (147) H O -23 No. Structure OH 48) N HO 0 (149) N NOJNN N4 0 H O OH (1 5 0 ) N N N O H N4 0 0 H O rNN >NN O 0 OH (152) N HO (153) N NO N 0 H O OOH H O 0 -24 No. Structure Br (155) N N b OH H 0 Br (156) N N O N (17)N-CN O: NN 0 H O Br OH (157) HO 0 Br OH (158) N 0 \ H 0 H Br 0 O OH (159) 0- N H O No. Structure Br OH (161) 0 N N H 0 Br OH (162) N- O y N o HO 00 (163) N H O OH (164) N N H 0 OH (165) H O OH ( 1 6 6 ) N N ON N H O (167) N NONNO H O -26 No. Structure - OH (168) N H O H (169) N l N *H 0 OH (170) N N yN\ N OH H O OH (171) HNNO N NOH H ~ CF, HOO OH (173) H O HOH H OH (175) HO0 -27 No. Structure (176) N OH (177) 0
N
5 NO N N OH H O OH (178) N H O O A OH (179) N N OC N NOH H O OH (18) N 0 N H O - OH (181) 0 NN HO0 -28 No. Structure - OH H O OH (184) N H O OH 7N s (185) N N4 0 H O OH (186) N N N N OH 0 H O OH N4. (188) Nr -~ XO rNzA. N cN NP H O (189) N H O (190) N 0 -29 No. Structure -OH (19 1 ) N O1 N N HOH (193)N N 0 N H OH HOH (196) N : N N (19 ) N O0 N ' (194) N N O HN HO0 (196) CI- C ,o H 0 (197) - O"' H4 0 H 0H (196) 0 crNIN I. NN ' HO0 -30 No. Structure OH (19 9 ) N N (2 0)N N N N Fc OH (200) N HO O H. O (201) N N NN H O H 0 (202) N i N4 H O - OH (203) NN O' H O (20OH N4 N HO0 (205) HO0 O&H (206) HO0 No. Structure OH (207) H O (208) H 00 H O OH (209) N H O (210) N N H H O j N N O N tN - 0 H O H 0 (214)00 H O H OH N-CN O0
O
No. Structure OH (215) N 02 0 H O (216)N NO N N N O' H O OH (217) N H O OH (218) H O OH (219) NNN/--NN'H N 0 H O OH (220) N N O N N . H 0 - OH H .H (222) NO N yN NH H 0 -33 No. Structure &7 0H (223) 1 N N ON N ,-N , 14 0 0 H O >OH (224)9 0 N0 r'N-Dl N O N N H H O (225)H N Na HO OH (2 2 6 ) NN O N N 0 H O OH (227)N N O N N N H N4 0 0 H O OH (228) N N4 0 H O O&H (229) NN H O OH (230) NCN O NHN O H O -34 No. Structure - OH (231) &7~~Or~IAO N- N OI N - N O' H H O OH (232) N N O N N0 H4 0 O (233) N O YN N H 0 OH 0 H N0 (234) N O N N O H :OH N N H O OH (235) N N OHON N 0 H H0 0 0H (236) N- N 0 00 HO0 OH (237) 0 H HO0 No. Structure OH (238) 0 H 0 O OH (239) H O H OH (240) N NO N N? HOH jN- N O N O.H, H O OH (241) N N O N -CN0 H O OH (242) HO 0 OH (243) J0: (244 ~2CN-CN H 0 -36 No. Structure OH (2 4 5 ) N ? N H O (246) N N H O H O (248) N N , 0 H O OH (249) N N NN, N 0 H O J(OH (250) C N H O (21 N0 O0 N" H O OH (252) N N N HO0 No. Structure OH (253) N N1O. (254)N N O N H 0 H (255) N NN cN-CNIO Y N--OH H O (256) N NON O H O OH (2 5 7 ) N N O N Q7-rN-QN OYN\N < H O HOOH H 0 OH (260)N H O -38 No. Structure OH (26 1) NN N N H O OH (262) N N O N N N (263) N N O H N QN CNO"; X~N H O OH (264)N NO N N N H O HOH (265) NON (266) \N NON N H H O OH (268) N H O -39 No. Structure OH (269) (270) 0 N- N~ O N N O H O '--OH H O (272)~H HO 0 HO 0 (274)N N O NN H OH (274) N N N N OH H O OH (275) N N O H O (2 7 ) ., , O H H O (27 ) N N O HN .H O - 4U No. Structure (2 7 7 ) N N O N O H N -yNH H O OH (278) N H 0 OH OH (280) N H O ( OH H O SNH, (282) N N O H O CI NCNI >N ,ZN-Sl N4N 0 H O NH ( 2 8 4 ) N O N H HO 0 -41 No. Structure . NH 2 (285) N N H O N4N 0 (287) N NO N N O H O H O (289) N 0N O NN H O (289) H N OH N N, NH H O Nz (292) N N O\N N OH N0 H O NNH (292)N O N N N H O -42 No. Structure (293) N NO N. H O (294) N NO N N O 0 H 0 F'6C (295) 0 N H O (296) NO H O Z&CF (297) N N O N H O* (298) N- N' OA N N OH H 0 H 0 (298) 0 O N N H O H 0 (300) 0 CF Q CNI HNN~ H O -43 No. Structure YF (301) N N N NH H 0 (302) N N N OH (303)N O NON H 0 OH (303) N> J-47N O rNc.N N H O (3 0 4 ) N N O N\ N H O F (306) N O N H4 N (306) cC cN N O CN H O : CF 3 (308) "N N H O -44 No. Structure O A ICF (309) AN N O N N NH H O (1)N-C N O :N\ ' ,:N,H H 0 H 0 O C (311) - N N4 0 H O (312) N N NN OH H O 0ZaCF (313) -N NAO N N H O aCF, (314) N N O N NH H O O aCF HO (316) C 0NH No. Structure (317) N H O N N 0 H O (319) H O H 0 321-CNN O N N' N, H O (321) N N O N N H O (322) NN O N H H O (324) N N HO0 (324) HO0 -46 No. Structure (325) N__ON, N O (326) N N NH (327) N N\ O H 0 OH the enantiomers, the diastereomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), 10 (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76), (77), (78), (79), (80) and (81), 15 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. Examples of other preferred compounds of the above general formula I are the 5 following compounds, which are selected from the group consisting of: (82), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (103), (104), (105), (106), (107), (108), (109), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), 10 (122), (123), (124), (125), (126), (127), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (144), (145), (146), (147), (148), (149), (150), (151), (152), (153), (154), (155), (156), (157), (158), (159), (160), (161), and (162), 1s the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 20 Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: (163), (164), (165), (166), (167), (168), (169), (170), (171), (172), (173), (174), (175), (176), (177), (178), (179), (180), (181), (182), (183), (184), (185), (186), 25 (187), (188), (189), (190), (191), (192), (193), (194), (195), (196), (197), (198), (199), (200), (201), (202), (203), (204), (205), (206), (207), (208), (209), (210), (211), (212), (213), (214), (215), (216), (217), (218), (219), (220), (221), (222), (223), (224), (225), (226), (227), (228), (229), (230), (231), (232), (233), (234), (235), (236), (237), (238), (239), (240), (241), (242) and (243), 30 -48 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: (244), (245), (246), (247), (248), (249, (250), (251), (252), (253), (254), (255), 10 (256), (257), (258), (259), (260), (261) and (262), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic 15 acids or bases. Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: 20 (263), (264), (265), (266), (267), (268), (269), (270), (271), (272), (273), (274), (275), (276), (277), (278), (279), (280) and (281), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, 25 particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: 30 (282), (283), (284), (285), (286), (287), (288), (289), (290), (291), (292) and (293), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic 5 acids or bases. Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: 10 (294), (295), (296'), (297), (298), (299), (300), (301), (302), (303), (304) and (305), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic 15 acids or bases. Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: 20 (306), (307), (308), (309), (310), (311), (312), (313), (314), (315) and (316), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic 25 acids or bases. Examples of other preferred compounds of the above general formula I are the following compounds, which are selected from the group consisting of: 30 (317), (318), (319), (320), (321), (322), (323), (324), (325), (326) and (327), - 50 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 TERMS AND DEFINITIONS USED Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. An asterisk (*) in the 10 structural formula of the substituent is to be understood as being the linking point to the rest of the molecule. Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, 15 for example one, two, three, four or five hydrogen atoms, are replaced by deuterium. Compounds of general formula I may have acid groups, mainly carboxyl groups, and/or basic groups such as e.g. amino functions. Compounds of general formula I 20 may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as for example hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid or organic acids such as for example malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic 25 acid, lactic acid, tartaric acid, citric acid or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, 30 dicyclohexylamine, inter alia.
-51 As mentioned hereinbefore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof. These salts may on the one hand be in the form of the physiologically and pharmacologically acceptable acid addition S salts of the compounds of formula I with inorganic or organic acids. On the other hand, if B contains a phenolic OH group, the compound of formula I may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter ion. The acid addition salts may be prepared for example using 10 hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above mentioned acids. The alkali and alkaline earth metal salts of the compound of formula I are preferably the alkali and alkaline earth metal hydroxides and hydrides 15 thereof, of which the hydroxides and hydrides of the alkaline earth metals, particularly of sodium and potassium, are preferred and sodium and potassium hydroxide are particularly preferred. The compounds according to the invention may occur as racemates if they have 20 only one chiral element, but they may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Preferred compounds are those which occur as racemates or as the (R) form. However, the application also includes the individual diastereomeric pairs of 25 antipodes or the mixtures thereof which are present when there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up. 30 The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in - 52 the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as for example acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid or organic acids - such as for example oxalic, fumaric, 5 diglycolic or methanesulphonic acid. PREPARATION METHODS The compounds of general formula I are prepared by methods known in principle. 10 The following methods have proved particularly suitable for preparing the compounds of general formula I according to the invention: (a) In order to prepare compounds of general formula I wherein all the groups are as hereinbefore defined: 15 reacting a piperidine of formula Ill j N/ N11 N NH H 20 with a carbonic acid derivative of general formula IV 0 wherein Y 2 and Y 3 represent nucleofugic groups which may be identical or 25 different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, and with a compound of general formula V -53 B H,0 _ ,Z 0 wherein B is as hereinbefore defined and Z' denotes a protective group for a 5 carboxy group, for example a C1.
6 -alkyl or benzyl group, wherein the alkyl groups may be straight-chain or branched and the benzyl group may be substituted by one or two methoxy groups. Preferably Z' denotes the methyl, ethyl, tert-butyl or benzyl group. 10 In a first step the compounds of general formula Ill are reacted in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof, at a temperature from -20 to 500C in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, with the carbonic acid derivatives of general formula IV. The resulting intermediate may be purified or further reacted without purification. 15 The reaction of these intermediates with compounds of general formula V is also carried out in one of the above-mentioned solvents, and at the temperatures specified hereinbefore, in the presence of a base, such as triethylamine or pyridine, with or without the addition of an activating reagent, such as e.g. 4 dimethylaminopyridine. To activate them the compounds of general formula V may 20 also be deprotonated by means of a metal hydride such as e.g. NaH or KH, in which case there is no need for the presence of the base or the activating reagent. The starting compounds of formula Ill and IV are either commercially available, known from the literature or may be prepared using methods known from the 25 literature. Processes for preparing compounds of general formula III are described for example in EP 1 619 187 Al.
- 54 (b) In order to prepare compounds of general formula I wherein all the groups are as hereinbefore defined: coupling a carboxylic acid of general formula VI 5 B 0 N OC O0 H ILI- 0 N C H wherein B is as hereinbefore defined, with an amine of general formula VII 10 H-NR'R 2 , wherein R 1 and R 2 are as hereinbefore defined. Before the reaction is carried out any carboxylic acid functions, primary or secondary amino functions or hydroxy functions present in the groups R1 and R 2 of the amine of general formula Vil may 15 be protected by conventional protecting groups and any protecting groups used may be cleaved again after the reaction using methods familiar to the skilled man. The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), 20 for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, 0-(1H-benzotriazol-1-yl)- NN-N',N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1 -yl-oxy tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 25 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling - 55 reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30'C and +30*C, preferably -20*C and +250C. If necessary, N-ethyl-diisopropylamine (Honig base) 5 is preferably used as an additional auxiliary base. The so-called "anhydride process" is used as a further coupling method for synthesising compounds of general formula I (cf. also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, p. 58-59; M. Bodanszky, "Principles of Peptide 10 Synthesis", Springer-Verlag 1984, p. 21-27). The Vaughan variant of the "mixed anhydride process" is preferred (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the carboxylic acid of general formula VI which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methylmorpholine or 15 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines of general formula VII are carried out in a one-pot process, using the above-mentioned solvents and at temperatures between -20 and +25*C, preferably between 00C and +25'C. 20 (c) In order to prepare compounds of general formula I wherein all the groups are as hereinbefore defined: coupling a compound of general formula Vill B 0 NNO Nu 25 H wherein B is as hereinbefore defined and Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or 5 trisubstituted by chlorine or bromine atoms or by methyl or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, optionally substituted by one or two methyl groups in the carbon skeleton, a 1H-pyrazol-1-yl, a 1 H-1,2,4-triazol-1 -yl, 1 H-1,2,3-triazol-1 -yl, 1 H-1,2,3,4-tetrazol-1 -yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, 10 pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1 yl-oxy, 2,5-dioxopyrrolidin-1 -yloxy, phthalimidyloxy, 1 H-benzo-triazol-1 -yloxy or azide group, with an amine of general formula VII
H-NR'R
2 15 wherein R' and R 2 are as hereinbefore defined. Before the reaction any carboxylic acid functions, primary or secondary amino functions or hydroxy functions present in the groups R' and R 2 of the amine of 20 general formula VII may be protected by conventional protecting groups and after the reaction any protecting groups used may be cleaved again using methods familiar to those skilled in the art. The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the 25 components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between -50*C and +120*C, preferably -10*C and +300C, and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, 30 potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,O]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or 5 mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent. 10 The new compounds of general formula I according to the invention contain one or more chiral centres. If for example there are two chiral centres the compounds may occur in the form of two pairs of diastereomeric antipodes. The invention covers the individual isomers as well as the mixtures thereof. 1s The diastereomers may be separated on the basis of their different physico chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases. 20 Racemates covered by general formula I may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric 25 acid, (+) or (-)-monomethyl tartrate or (+) or (-)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(-)-1 phenylethylamine or (S)-brucine. According to a conventional method of separating isomers, the racemate of a 30 compound of general formula I is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting - 58 crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume 5 of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (-) form. 10 The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula I may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration. 15 The hydroxycarboxylic acids of general formula V needed for the synthesis B o rz 0 20 wherein B is as hereinbefore defined and Z' denotes a protective group for a carboxy group, for example a C 1
.
6 -alkyl or benzyl group, wherein the alkyl groups may be straight-chain or branched and the benzyl group may be substituted by one or two methoxy groups, wherein Z' preferably denotes the methyl, ethyl, tert butyl or benzyl group, may be obtained from compounds of general formula IX 25 B H O'H H O - 59 wherein B is as hereinbefore defined. By diazotising compounds of general formula IX with a suitable diazotising 5 reagent, preferably sodium nitrite in an acid medium, it is possible to obtain the compounds of general formula V. When enantiomerically pure compounds are used the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, the reaction taking place with retention of configuration. 10 An alternative method of obtaining compounds of general formula V comprises reacting aldehydes of general formula X H YB 15 wherein B is as hereinbefore defined, with N-acetylglycine in acetic anhydride as solvent in the presence of alkali metal acetate, preferably sodium or potassium acetate, at a suitable temperature, preferably at 80 to 1300C. The azlactones obtained as primary product are hydrolysed without being isolated 20 to form the compounds of general formula XI B 0 N sH H 0 wherein B is as hereinbefore defined. 25 By further reaction in the presence of aqueous inorganic acids, such as for example sulphuric, phosphoric or hydrochloric acid, but preferably hydrochloric acid, compounds of general formula XII - bU B 0 H 0 are obtained wherein B is as hereinbefore defined. These are then converted with 5 suitable reducing agents into the compounds of general formula V. Suitable reducing agents are alkali metal borohydrides, such as sodium or potassium borohydride. Other suitable reducing agents are chlorodialkylboranes, such as chlorodicyclohexylborane. If chiral chlorodialkylboranes, such as e.g. B 10 chlorodiisopinocampheylborane, are used, the compounds of general formula V may be isolated in enantiomerically pure form. The further reaction of compounds of general formula V, wherein Z' denotes the hydrogen atom, to compounds of general formula V, wherein Z' is as hereinbefore 15 defined, takes place in an alcoholic medium, preferably in methanol or ethanol, in the presence of a suitable acid, such as hydrochloric acid. The reaction may alternatively be carried out by reaction in alcoholic solvents, preferably methanol, with thionyl chloride. 20 Another method of obtaining compounds of general formula V comprises alkylating a compound of formula XIII 0 0 0o)N 0 O -61 with an aryl- or heteroaryl-methylhalide of general formula XIV B Hal 5 wherein Hal denotes a chlorine, bromine or iodine atom, and B is as hereinbefore defined, analogously to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [2000]). The diastereomeric products obtained may then be separated using physicochemical methods, preferably by chromatographic methods or 10 recrystallisation. The hydrolytic cleaving of the chiral auxiliary and cleaving the benzyl protecting group also provides a method of obtaining enantiomerically pure hydroxycarboxylic acid compounds of general formula V. All the compounds of general formula I which contain primary or secondary amino, hydroxy or hydroxycarbonyl functions are preferably obtained from precursors 15 provided with protective groups. Examples of protective groups for amino functions include for example a benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitro benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chioro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-a,c-dimethyl-benzyloxycarbonyl or 3,5 20 dimethoxy-a,ca-dimethyl-benzyloxycarbonyl group, an alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl moiety, for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or tert-butyloxycarbonyl group, the allyloxycarbonyl, 2,2,2-trichloro-(1,1 -dimethylethoxy)carbonyl or 25 9-fluorenylmethoxycarbonyl group or a formyl, acetyl or trifluoroacetyl group. Examples of protective groups for hydroxy functions include a trimethylsilyl, triethylsilyl, triisopropyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl group, a tert butyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl group. A protective group for hydroxycarbonyl functions might be, for example, an alkyl 30 group with a total of 1 to 5 carbon atoms, for example the methyl, ethyl, n-propyl, - 62 isopropyl, n-butyl, tert-butyl, allyl, 2,2,2-trichloroethyl, benzyl or 4-methoxybenzyl group. The new compounds of general formula I and the physiologically acceptable salts 5 thereof have valuable pharmacological properties, based on their selective CGRP antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, their use and the preparation thereof. The new compounds mentioned above and the physiologically acceptable salts 10 thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter. 15 The following experiments were carried out to demonstrate the affinity of the above-mentioned compounds for human CGRP-receptors and their antagonistic properties: A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor) 20 SK-N-MC cells are cultivated in "Dulbecco's modified Eagle medium". The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of "Balanced Salts 25 Solution" [BSS (in mM): NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 x g and resuspended in BSS. After the number of cells has been determined, the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000 x g. The supernatant is discarded and the pellet is 30 recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1% bacitracin, and resuspended (1 ml / 1000000 cells). The homogenised product is frozen at -80 0 C. The membrane preparations are stable for more than 6 weeks under these conditions. 5 After thawing, the homogenised product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 pl of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM 1 2 s-iodotyrosyl-Calcitonin-Gene Related Peptide (Amersham) and increasing concentrations of the test substances 10 in a total volume of 250 pl. The incubation is ended by rapid filtration through GF/B glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 pM human CGRP-alpha during incubation. 15 The concentration binding curves are analysed using computer-aided non-linear curve matching. The compounds mentioned hereinbefore show IC 5 0 values 10000 nM in the test 20 described. B. CGRP Antagonism in SK-N-MC cells SK-N-MC cells (1 million cells) are washed twice with 250 pl incubation buffer 25 (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre incubated at 37 0 C for 15 minutes. After the addition of CGRP (10 pl) as agonist in increasing concentrations (10-11 to 10-6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
- 64 Intracellular cAMP is then extracted by the addition of 20 pl of 1 M HCI and centrifugation (2000 x g, 4'C, for 15 minutes). The supematants are frozen in liquid nitrogen and stored at -20'C. 5 The cAMP contents of the samples are determined by radioimmunoassay (Messrs. Amersham) and the pA 2 values of antagonistically acting substances are determined graphically. The compounds according to the invention exhibit CGRP-antagonistic properties 10 in the in vitro test'model described, in a dosage range between 10-2 and 10-5 M. TYPES OF INDICATIONS In view of their pharmacological properties the compounds according to the 15 invention and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine, cluster headaches and tension headaches. Moreover, the compounds according to the invention also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), cardiovascular diseases, 20 morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, lichen, prurigo, pruriginous toxidermies and severe itching, inflammatory diseases, e.g. inflammatory diseases of the joints (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalised soft tissue rheumatism (fibromyalgia), neurogenic 25 inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, COPD, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g. shock and sepsis, chronic pain, such as e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, post-herpetic neuropathies, neuropathies induced by tissue trauma, 30 trigeminal neuralgias, temporomandibular dysfunctions, CRPS (complex regional pain syndrome), back pain and visceral diseases such as for example irritable - 65 bowel syndrome (IBS), inflammatory bowel syndrome. In addition, the compounds according to the invention have a general pain-relieving effect. The symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma 5 and castrated men are favourably affected by the CGRP antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects. 10 Preferably, the compounds according to the invention are suitable for the acute and preventive treatment of migraine and cluster headaches, for treating irritable bowel syndrome (IBS) and for the preventive and acute therapeutic treatment of hot flushes in oestrogen-deficient women. 15 The dosage required to achieve a corresponding effect is conveniently 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneously, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight when administered orally, nasally or by inhalation, 1 to 3 times a day in each case. 20 If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional hormone replacement, it is advisable to reduce the doses specified above, in which case the dosage may be from 1/5 of the lower limits mentioned above up to 1/1 of the upper limits specified. 25 The invention further relates to the use of the compounds according to the invention as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by tritiation of suitable precursors, for example 30 by catalytic hydrogenation with tritium or replacing halogen atoms with tritium, and as a diagnostic or analytical adjuvant in neurotransmitter research.
- 66 COMBINATIONS Categories of active substance which may be used in the combination include e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, 5 anticonvulsants, histamine-H1 -receptor antagonists, p-blockers, a-agonists and a-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT1B/1D-agonists or other anti-migraine agents which may be formulated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline 10 cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, 15 solutions, metered dose aerosols or suppositories. Thus, other active substances which may be used for the combinations mentioned above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, acetaminophen (paracetamol), azathioprine, 20 diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and other selective COX2-inhibitors, such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as 25 substances which inhibit earlier or later stages in prostaglandin synthesis or prostaglandin receptor antagonists such as e.g. EP2-receptor antagonists and IP receptor antagonists. It is also possible to use ergotamine, dihydroergotamine, metoclopramide, 30 domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, pregabaline, - 67 duloxetine, topiramate, riboflavin, montelukast, lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem 5 and other 5-HT1B/lD-agonists such as, for example, almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. In addition, CGRP-antagonists may be combined with vanilloid receptor antagonists, such as e.g. VR-1 antagonists, glutamate receptor antagonists, such 10 as e.g. mGlu5-receptor antagonists, mGlul-receptor antagonists, iGlu5-receptor antagonists, AMPA-receptor antagonists, purine receptor blockers, such as e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. iNOS inhibitors, calcium channel blockers, such as e.g. PQ-type blockers, N-type blockers, potassium channel openers, such as e.g. KCNQ channel openers, sodium channel blockers, 15 such as e.g. PN3 channel blockers, NMDA-receptor antagonists, acid-sensing ion channel antagonists, such as e.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1-receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2 agonists, CB1 agonists, somatostatin receptor agonists, such as e g. sst2 receptor agonists. 20 The dosage for these active substances is conveniently 1/5 of the normally recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg sumatriptan. 25 FORMULATIONS The compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intra-articular, 30 intrarectal or intranasal route, by inhalation, topically, transdermally or orally, while aerosol formulations are particularly suitable for inhalation. The combinations may - 68 be administered either simultaneously or sequentially. Suitable forms for administration include for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The proportion of 5 pharmaceutically active compound or compounds should be in the range from 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the total composition, i.e. in amounts which are sufficient to achieve the dosage range mentioned hereinbefore. 10 The preparations may be given orally in the form of tablets, powders, powders in capsules (e.g. hard gelatine capsules), or as solutions or suspensions. When taken by inhalation the active substance combination may be administered as a powder, an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation. 15 Preferably, therefore, pharmaceutical formulations are characterised in that they contain one or more compounds of formula I according to the preferred embodiments described hereinbefore. 20 It is particularly preferable if the compounds of formula I are administered orally, and it is most preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders 25 such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced 30 analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to - 69 achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups containing the active substances or combinations thereof according to the 5 invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such 10 as p-hydroxybenzoates. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided 15 for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable 20 oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants 25 (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). For oral use the tablets may obviously contain, in addition to the carriers specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additional substances such as starch, preferably potato 30 starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulphate and talc may also be used to produce the tablets. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the abovementioned excipients.
- 70 It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant 5 containing metered-dose aerosols or propellant-free inhalable solutions which are optionally in admixture with conventional physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. 10 The formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification. EXPERIMENTAL SECTION 15 As a rule, 1 H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, Rf values are obtained using ready-made silica gel TLC plates 60 F254 (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. 20 The ratios given for the eluants relate to units by volume of the solvents in question. The units by volume specified for NH 3 refer to a concentrated solution of
NH
3 in water. Unless otherwise stated, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems of the specified concentrations. 25 For chromatographic purification, silica gel made by Millipore (MATREX m, 35-70 pim) is used. The HPLC data given are measured using the parameters shown below: 30 Method A: time (min) percent by volume of water percent by volume of (with 0.1% formic acid) acetonitrile (with 0.1% formic acid) 0 95 5 4.5 10 90 5 10 90 5.5 90 10 Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 pm; 4.6 x 75 mm; column temperature: 30CC; flow: 1.6 mL / min; injection 5 volume: 5 pL; detection at 254 nm Method B: time (min) percent by volume of water percent by volume of (with 0.1% formic acid) acetonitrile (with 0.1% formic acid) 0 95 5 9 10 90 10 10 90 11 95 5 Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 10 3.5 pm; 4.6 x 75 mm; column temperature: 300C; flow: 0.8 mL / min; injection volume: 5 pL; detection at 254 nm Method C: time (min) percent by volume of water percent by volume of (with 0.1% formic acid) acetonitrile (with 0.1% formic acid) 0 95 5 4 50 50 4.5 10 90 5 10 90 5.5 90 10 Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 pm; 4.6 x 75 mm; column temperature: 300C; flow: 1.6 mL / min; injection volume: 5 pL; detection at 254 nm 5 Method D: time (min) percent by volume of water percent by volume of (with 0.04% TFA) acetonitrile (with 0.04% TFA) 0 80 20 30 20 80 Analytical column: Waters Symmetry C8, 5 pam, 4.6 X 150 mm; column temperature: 250C, flow: 1.3 ml/min, injection volume: 5 pl, detection at 254 nm. 10 Method E: time (min) percent by volume of water percent by volume of (with 0.04% TFA) acetonitrile (with 0.04% TFA) 0 80 20 15 20 80 17 20 80 Analytical column: Symmetry C8 Waters - 4.6 X 150 mm; 5 micron, flow: 1.3 ml/min, column temperature: 25*C, detection at 254 nm.
In preparative HPLC purifications as a rule the same gradients are used as were used to collect the analytical HPLC data. The products are collected under mass control and the fractions containing the product are combined and freeze-dried. 5 If no detailed information is given as to the configuration, it is not clear whether it is a pure enantiomer or whether partial or even complete racemisation has occurred. The following abbreviations are used in the description of the experiments: 10 Cyc cyclohexane DCM dichloromethane DIPE diisopropylether DMF N,N-dimethylformamide EtOAc ethyl acetate 15 EtOH ethanol HATU O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium-hexafluoro phosphate AcOH acetic acid i.vac. in vacuo (under vacuum) 20 MeOH methanol MTBE tert-butylmethylether NaOAc sodium acetate NMP N-methylpyrroldinone PE petroleum ether 25 RT ambient temperature TBTU O-(benzotriazol-1 -yl)-N, N, N', N'-tetramethyluronium-tetrafluoroborate TFA trifluoroacetic acid THF tetrahydrofuran 30 Preparation of the starting compounds: - 74 Amine Al Ethyl [4,4'lbipiperidinyl-l-vl-oxo-acetate H--N N 09/ 0 5 Ala) tert-butyl 1'-ethoxvoxalvl-[4,4'1bipiperidinyl-1-carboxylate 1.68 mL (15.0 mmol) ethyl chloro-oxo-acetate were slowly added dropwise to a solution of 4.0 g (14.9 mmol) tert-butyl [4,4']bipiperidinyl-1-carboxylate and 2.15 mL (15.4 mmol) triethylamine in 80 mL DCM while cooling with ice and the 10 reaction mixture was stirred for 1 h at RT. A little water was added to the reaction solution, the organic phase was separated off and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was taken up in EtOAc and filtered through silica gel, wherein the product was eluted with EtOAc. After evaporation i.vac. the product was obtained, which was further reacted without 15 purification. Yield: 3.1 g (57% of theory) ESI-MS: (M+NH 4 )* = 386 Al b) Ethyl [4,4'lbipiperidinyl-1 -vl-oxo-acetate 20 5 mL TFA were added dropwise to a solution of 3.08 g (8..36 mmol) tert-butyl 1' ethoxyoxalyl-[4,4']bipiperidinyl-1-carboxylate in 40 mL DCM and the reaction mixture was stirred for 4 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 50 mL DCM and this solution was slowly stirred into an ice-cooled solution of 4 g Na 2
CO
3 in 20 mL water. After the addition had ended the 25 mixture was stirred for a further 15 min, the organic phase was separated off, the aqueous phase was extracted twice more with DCM and the combined organic phases were dried over Na 2
SO
4 .After the desiccant and solvent had been eliminated the product was obtained as the hydrogen carbonate salt. Yield: 2.33 g (84% of theory) 30 ESI-MS: (M+H)* = 269 - 75 Amine A2 ethyl 4-[4,4'lbipiperidinyl-1-yI-4-oxo-butanoate 0 0, 5 A2a) tert-butyl 1'-(3-carboxy-propionyl)-[4,4'lbipiperidinyl-1-carboxylate A solution of 4.07 g (41.0 mmol) succinic anhydride in 50 mL THF was slowly added dropwise to a solution of 10.0 g (37.0 mmol) tert-butyl [4,4']bipiperidinyl-1 carboxylate in 100 mL THF and the reaction mixture was stirred overnight at RT. 10 To complete the reaction a further 2.0 g (20.0 mmol) succinic anhydride were added, the reaction mixture was stirred for 4 h at 50 0 C and overnight at RT. The mixture was carefully combined with 200 mL 7.5% K 2
CO
3 solution and 200 mL EtOAc, the organic phase was separated off, extracted again with 100 mL 7.5%
K
2
CO
3 solution and the combined aqueous phases were acidified with 10% citric 15 acid solution. The aqueous phase was extracted with 300 mL EtOAc, the organic phase was separated off and the solvent was eliminated i.vac.. Yield: 11.7 g (85% of theory) ESI-MS: (M-H)- = 367 20 A2b) ethyl 4-[4,4']bipiperidinyl-1-yl-4-oxo-butanoate A solution of 11.7 g (31.7 mmol) tert-butyl 1'-(3-carboxy-propionyl) [4,4']bipiperidinyl-1-carboxylate in 250 mL ethanolic HCI (1.25 M) was stirred overnight at RT. The mixture was evaporated to dryness i.vac., the residue was taken up in 100 mL EtOAc and 100 mL 15% K 2
CO
3 solution, the organic phase 25 was separated off and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the product was further reacted without purification. Yield: 4.3 g (46% of theory) ESI-MS: (M+H)* = 297 30 Preparation of the final compounds: - /O - Example 1 (R)-2-[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -ylI-2-oxo- 1 -(3-trifluoromethyl-benzyl) ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate CF, I a IN- N O~y N\ , N -- N.-CH3 N4 0 H O 1 a) (Z,E)-2-acetylamino-3-(3-trifluoromethyl-phenvl)-acrylic acid A solution of 15.8 g (115 mmol) 3-trifluoromethyl-benzaldehyde and 21.3 g (182 10 mmol) N-acetylglycine in 60 mL acetic anhydride was heated for 4 h to 1200C (bath temperature). After cooling 40 mL water were slowly added and the mixture was stirred for 1 h at 800C. After cooling it was combined with 400 mL water and 150 mL toluene, stirred for 1 h, the precipitate formed was filtered off, washed with toluene and dried at 500C. 15 Yield: 16.7 g (53% of theory) ESI-MS: (M+H)* = 274 R= 0.4 (silica gel, DCM/MeOH/AcOH 90:10:1) 1 b) 2-oxo-3-(3-trifluoromethyl-phenvl)-propionic acid 20 200 mL 4 M HCL were added dropwise to a suspension of 16.6 g (60.8 mmol) (Z,E)-2-acetylamino-3-(3-trifluoromethyl-phenyl)-acrylic acid in 200 mL 1,4-dioxane heated to 800C (bath temperature), the reaction mixture was refluxed for 1.5 h and then stirred overnight at RT. To complete the reaction the mixture was refluxed for a further 4 h. The organic solvent was eliminated i.vac., the aqueous residue was 25 combined with NaOH until an alkaline reaction occurred, washed with MTBE and acidified with HCI. The mixture was extracted exhaustively with EtOAc and the combined organic phases were dried over MgSO 4 . After the desiccant and solvent - 77 had been eliminated the desired product was obtained, which was further reacted without purification. Yield: 5.7 g (40% of theory) ESI-MS: (M-H)- = 231 5 Rf = 0.19 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) 1 c) (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionic acid Under a nitrogen atmosphere a solution of 11.8 g (36.8 mmol) (1 R)-B chlorodiisopinocampheylborane in 40 mL THF was added dropwise to a solution, 10 cooled to -350C, of 5.70 g (24.6 mmol) 2-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid and 4.4 mL (31.4 mmol) triethylamine in 60 mL THF, within 15 min, and the reaction solution was stirred overnight at RT. Then the reaction solution was carefully made alkaline with 20 mL 1 M NaOH while cooling with ice and stirred for 30 min. 40 mL EtOAc was added, the aqueous phase was separated off, the 15 organic phase was washed three times with 15 mL 1 M NaOH solution and once with 15 mL water. The combined aqueous phases were acidified with semiconcentrated HCI, extracted twice with 40 mL EtOAc and the combined organic phases were dried over MgSO 4 . After the desiccant and solvent had been eliminated the product was obtained, which was further reacted without 20 purification. Yield: 4.25 g (74% of theory) ESI-MS: (M-H)~ = 233 Rf = 0.35 (silica gel, DCM/MeOH/'Cyc/NH 3 70:15:15:2) 25 1 d) methyl (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl)-propionate A solution of 4.20 g (17.9 mmol) (R)-2-hydroxy-3-(3-trifluoromethyl-phenyl) propionic acid in 80 mL methanolic HCI was stirred for 70 h at RT. The reaction solution was evaporated down i.vac., the residue was taken up in water and exhaustively extracted with EtOAc. The combined organic phases were washed 30 three times with 15% K 2
CO
3 solution and once with water and dried over MgSO 4
.
- 18 After the desiccant and solvent had been eliminated the residue was further reacted without purification. Yield: 2.47 g (55% of theory) ESI-MS: (M+H)* = 249 5 Rf = 0.73 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) 1e) (R)-1-methoxycarbonyl-2-(3-trifluoromethyl-phenyl)-ethyl 4-(2-oxo-1.2,4,5 tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate Under a nitrogen atmosphere 2.10 g (10.4 mmol) 4-nitrophenyl chloroformate were 10 added to a solution of 1.64 g (13.4 mmol) 4-dimethylaminopyridine in 40 mL pyridine and stirred for 3 h at RT. Then 2.47 g (9.95 mmol) methyl (R)-2-hydroxy 3-(3-trifluoromethyl-phenyl)-propionate in 20 mL pyridine were added and the reaction mixture was stirred for 2.5 h at RT. The reaction solution was combined with 4.1 g (10.9 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one 15 (purity 65%) and stirred for 20 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 60 mL EtOAc, the organic phase was washed twice with 15% K 2
CO
3 solution, four times with saturated NaHCO 3 solution and dried over Na 2
SO
4 .After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, Cyc/EtOAc 1:2). 20 Yield: 3.16 g (61% of theory) ESI-MS: (M+H)+ = 520 Rf = 0.93 (silica gel, EtOAc/MeOH/NH 3 80:20:2) 1f) (R)-1-carboxy-2-(3-trifluoromethyl-phenyl)-ethyl 4-(2-oxo-1.2,4,5-tetrahvdro 25 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate A solution of 0.22 g (9.00 mmol) LiOH in 40 mL water was added to a solution of 3.10 g (5.97 mmol) (R)- 1 -methoxyca rbonyl-2-(3-trifluoro-methyl-phenyl)-ethyl 4-(2 oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate in 80 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was 30 eliminated i.vac., the aqueous residue was combined with 80 mL water and - (9 acidified with 1 M HCI. The precipitate formed was suction filtered and dried overnight at 35CC. Yield: 2.80 g (93% of theory) ESI-MS: (M+H)* = 506 5 Rf = 0.58 (silica gel, EtOAc/MeOH/NH 3 70:30:3) 1g) (R)-2-[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yll-2-oxo-1 -(3-trifluoromethyl benzyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate 10 30 mg (0.16 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added at RT to a solution of 80.0 mg (0.16 mmol) (R)-1-carboxy-2-(3-trifluoromethyl-phenyl)-ethyl 4 (2-oxo-1,2,4,5-tetra hydro- 1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate, 61 mg (0.19 mmol) TBTU and 27 pL (0.20 mmol) triethylamine in 1 mL DMF and the reaction solution was stirred for 70 h at RT. This was purified by HPLC without any 15 further working up; the fractions containing the product were combined and lyophilised. Yield: 67 mg (63% of theory) ESI-MS: (M+H)* = 671 Rf= 0.4 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) 20 The following compounds were prepared analogously from in each case 80 mg (Examples 1.1 to 1.4) or 140 mg (Examples 1.5 and 1.6) (R)-1-carboxy-2-(3 trifluoro-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate and the corresponding amount of amine: CF, eN O R / 0 25 H Example R Yield (%) Mass Rf ) spectrum (method) 1.1 93 656 0.68 [M+H]* 1.2 64 671 0.35 [M+H]* 1.3 74 670 0.53 [M+H]* 1.4 148 685 5.1 min NH2 [M+H] (B) 1.5 62 757 0.51 N~Ok [M+H]~ 1.6 71 757 0.50 N Z N 0( [M+H]' )(silica gel, DCM/MeOH/ Cyc/NH 3 70:15:15:2) or retention time HPLC Example 1.7 5 (R)-1 -(3-methyl-benzyl)-2-oxo-2-(4-piperazin-1 -yl-piperidin-1-yl)-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate aCF, N N N N H -C IH Q A solution of 131 mg (0.17 mmol) tert-butyl 4-{1-[(R)-2-[4-(2-oxo-1,2,4,5 tetra hydro-1, 3-benzod iazepin-3-yl)-piperidine- 1 -carbonyloxy]-3-(3-trifluoromethyl 10 phenyl)-propionyl]-piperidin-4-yl}-piperazine-1-carboxylate (Example 1.5) in 1.5 mL 4 M HCI was stirred overnight at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised. Yield: 75 mg (67% of theory) ESI-MS: (M+H)* = 657 5 Rf = 0.38 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) Example 1.8 (R)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-1-(3-trifluoromethyl-benzyl)-ethyl 4-(2 10 oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate CF, H Analogously to Example 1.7 the product was obtained from 149 mg (0.20 mmol) (R)-1-(3-trifluoromethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl) piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 15 piperidine-1-carboxylate (Example 1.6). Yield: 66 mg (51% of theory) ESI-MS: (M+H)* = 657 Rf = 0.18 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) 20 Example 2 (R)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(3-methyl-benzyl)-ethyl 4 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate N4 0 H 0 25 - ?oZ 2a) (ZE)-2-acetylamino-3-m-tolyl-acrylic acid Analogously to Example 1a the product could be obtained from 25.0 g (212 mmol) 3-methyl-benzaldehyde and 24.9 g (212 mmol) N-acetylglycine. Yield: 26.0 g (56% of theory) 5 ESI-MS: (M+H)* = 220 retention time (HPLC): 5.4 min (method B) 2b) 2-oxo-3-m-tolyl-propionic acid 400 mL 4 M HCI were added to a solution of 13.0 g (59.3 mmol) (Z,E)-2 10 acetylamino-3-m-tolyl-acrylic acid in 200 mL 1,4-dioxane and the reaction mixture was refluxed for 2.5 h. The organic solvent was evaporated down i.vac., the precipitate formed was suction filtered and dried. This was taken up in 300 mL EtOAc, the organic phase was washed twice with 200 mL water and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was 15 reacted further without purification. Yield: 9.2 g (88% of theory) ESI-MS: (M-H)~ = 177 retention time (HPLC): 7.3 min (method B) 20 2c) (R)-2-hydroxy-3-m-tolyl-propionic acid Analogously to Example 1c the product could be obtained from 9.24 g (51.9 mmol) 2-oxo-3-m-tolyl-propionic acid and 24.0 g (74.8 mmol) (1R)-B chlorodiisopinocampheylborane. Yield: 8.4 g (90% of theory) 25 ESI-MS: (M-H)~ = 179 retention time (HPLC): 7.2 min (method B) 2d) methyl (R)-2-hydroxy-3-m-tolyl-propionate 3.74 mL (51.28 mmol) SOC12 were slowly added dropwise to a solution, cooled to 30 O'C, of 8.40 g (46.6 mmol) (R)-2-hydroxy-3-m-tolyl-propionic acid in 200 mL MeOH and after the addition had ended the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac. and the residue was purified by chromatography (silica gel, Cyc/EtOAc 3:1). Yield: 6.28 g (69% of theory) ESI-MS: (M+H)* = 195 5 retention time (HPLC): 6.9 min (method B) 2e) (R)-1-methoxvcarbonyl-2-m-tolyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1.3 benzodiazepin-3-yl)-piperidine-1 -carboxylate Analogously to Example 1e the product could be obtained from 1.12 g (5.76 mmol) 10 methyl (R)-2-hydroxy-3-m-tolyl-propionate and 1.41 g (5.76 mmol) 3-piperidin-4-yl 1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. Yield: 2.07 g (77% of theory) ESI-MS: (M+H)* = 466 retention time (HPLC): 9.0 min (method B) 15 2f) (R)-1-carboxy-2-m-tolyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-vl)-piperidine-1 -carboxylate Analogously to Example 1f the product could be obtained from 2.07 g (4.45 mmol) (R)-1 -methoxycarbonyl-2-m-tolyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 20 benzodiazepin-3-yl)-piperidine-1-carboxylate and 0.16 g (6.72 mmol) LiOH. Yield: 1.86 g (93% of theory) ESI-MS: (M+H)* = 452 retention time (HPLC): 8.0 min (method B) 25 2g) (R)-2-r4-(4-methyl-piperazin-1-vl)-piperid in-1-yll-2-oxo-1 -(3-methvl-benzyl) ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate A solution of 80.0 mg (0.18 mmol) (R)-1-carboxy-2-m-tolyl-ethyl 4-(2-oxo-1,2,4,5 tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 57 mg (0.18 mmol) 30 TBTU and 31 pL (0.22 mmol) triethylamine in 1 mL DMF were stirred for 1 h at RT. Then 33 mg (0.18 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added to the reaction solution, which was then stirred overnight at RT. It was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised. Yield: 46.7 mg (43% of theory) 5 ESI-MS: (M+H)* = 617 retention time (HPLC): 5.5 min (method B) The following compounds were prepared analogously from in each case 80 mg (R)-1-carboxy-2-m-tolyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 10 piperidine-1-carboxylate and the corresponding amount of amine: R N O N O 0 Example R Yield (%) Mass retention spectrum time HPLC (method) 2.1 80 617 5.0 min [M+H]* (B) 2.2 75 616 6.2 min [M+H]* (B) Example 3 15 (R)-1 -(3,5-bis-trifluoromethyl-benzyl)-2-(1'-ethoxyca rbonylmethyl-4,4'-bipiperidinyl 1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y)-piperidine-1 carboxylate O LCF _ N O N N O I N 0(,N~ 0 3a) methyl 2-acetylamino-3-(3,5-bis-trifluoromethyl-phenvl)acrylate Under a nitrogen atmosphere 50.0 g (171 mmol) 3,5-bis-(trifluoromethyl) 5 bromobenzene and 25.0 g (171 mmol) methyl 2-acetylamino-acrylate in 475 mL triethylamine and 250 mL acetonitrile were combined with 3.9 g (12.4 mmol) tri-o tolyl-phosphane and 2.8 g (12.5 mmol) Pd(OAc) 2 and stirred for 18 h at 80 0 C. After the reaction had ended the reaction mixture was evaporated down i.vac. to approx. 200 mL, combined with 400 mL EtOAc and 400 mL water, the precipitate 10 was suction filtered and the phases were separated. The organic phase was dried over Na 2
SO
4 , combined with activated charcoal, filtered and evaporated to dryness. The residue was stirred with DIPE, suction filtered and dried i.vac.. Yield: 19.5 g (32 % of theory) ESI-MS: (M+H) = 356 15 Rf = 0.76 (silica gel, PE/EtOAc 1:1) 3b) 3-(3,5-bis-trifluoromethyl-phenvl)-2-oxo-propionic acid 19.5 g (54.9 mmol) methyl 2-acetylamino-3-(3,5-bis-trifluoromethyl-phenyl) acrylate in 100 mL 1,4-dioxane were heated to 100*C bath temperature, combined 20 with 100 mL 4 M HCI and stirred for 8 h at 100 C bath temperature. The reaction mixture was evaporated down i.vac., the crystals were suction filtered, washed with water and dried in the drying cupboard at 50*C. Yield: 16.1 g (98 % of theory) ESI-MS: (M-H)~ = 299 25 Rf = 0.18 (silica gel, EtOAc) - 00 3c) (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionic acid 16.1 g (53.6 mmol) 3-(3,5-bis-trifluoromethyi-phenyl)-2-oxo-propionic acid in 9.5 (70.0 mmol) triethylamine and 100 mL THF were combined at -35 0 C with a solution of 26.0 (81.1 mmol) (1 R)-B-chlorodiisopinocampheylborane in 40 mL THF 5 within 30 min, stirred for 1 h at this temperature and stirred overnight at RT. After the reaction had ended the reaction mixture was made alkaline at 0*C with 160 mL 1 M NaOH, stirred for 15 min, combined with 100 mL MTBE and the phases were separated. The organic phase was washed with 50 mL water and 50 mL 1 M NaOH. The combined aqueous phases were acidified with 4 M HCI, exhaustively 10 extracted with MTBE, the combined organic phases were dried over Na 2
SO
4 , suction filtered through activated charcoal and evaporated down i.vac.. The product was reacted further without purification. Yield: 12.5 g (77% of theory) ESI-MS: (M-H)- = 301 15 Rf = 0.45 (silica gel, EtOAc) 3d) methyl (R)-3-(3,5-bis-trifluoromethvl-phenyl)-2-hydroxv-propionate 12.5 g (41.4 mmol) of (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionic acid in 150 mL methanolic HCI (1.25 M) were stirred for 4 h at RT and then 20 evaporated down i.vac.. The residue was taken up in EtOAc and washed with saturated NaHCO 3 solution, the organic phase was dried over Na 2
SO
4 , suction filtered through activated charcoal and evaporated down i.vac.. The residue was stirred with PE, suction filtered and evaporated down i.vac.. The product was reacted further without purification. 25 Yield: 11.4 g (87% of theory) ESI-MS: (M+H)* = 316 Ri = 0.80 (silica gel, PE/EtOAc 1:1) 3e) (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo 30 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y)-piperidine-1 -carboxylate Analogously to Example 1e the product was obtained from 6.0 g (8.2 mmol) - O/ methyl (R)-3-(3,5-bis-trifluoromethyl-phenyl)-2-hydroxy-propionate and 5.13 g (20.9 mmol) 3-piperidin-4-yi-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. Purification was carried out by chromatography (silica gel, gradient PE/EtOAc 1:1 to 1:9). 5 Yield: 5.1 g (46 % of theory) ESI-MS: (M+H)* = 588 R= 0.63 (silica gel, DCM/MeOH/cyc/NH 3 70:15:15:2) 3f) (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1 -carboxy-ethyl 4-(2-oxo-1,2,4,5 10 tetrahydro-1, 3-benzod iazepin-3-yl)-piperidine-1 -carboxylate A solution of 307 mg (12.8 mmol) LiOH in 5 mL water was added to a solution of 5.0 g (8.5 mmol) of (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-methoxy-carbonyl-ethy 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred overnight at RT. The mixture was 15 evaporated down i.vac., the residue was taken up in water, acidified with 1 M HCI, the precipitate was filtered off and dried in the vacuum drying cupboard at 400C. Yield: 4.5 g (92% of theory) ESI-MS: (M+H)* = 574 Rf= 0.32 (silica gel,DCM/MeOH/cyc/NH 3 70:15:15:2) 20 3g) (R)-1 -(3,5-bis-trifluoromethyl-benzyl)-2-(1'-ethoxvcarbonvlmethyl-4,4' bi piperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4.5-tetrahydro-1,3 benzodiazepin-3-vl)-piperidine-1 -carboxylate 50 mg (0.20 mmol) ethyl [4,4']bipiperidinyl-1-yl-acetate were added at RT to a 25 solution of 100 mg (0.17 mmol) (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-carboxy ethyl 4-(2-oxo-1,2,4,5-tetrahydro-benzodiazepin-3-yl)-piperidine-l-carboxylate, 61 mg (0.20 mmol) TBTU and 33 pL (0.16 mmol) ethyldiisopropylamine in 1 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was filtered through a syringe filter and purified directly by HPLC without any further 30 working up. The fractions containing the product were combined and lyophilised. Yield: 55 mg (39% of theory) - 88 ESI-MS: (M+H)* = 810 retention time (HPLC-MS): 7.3 min (method B) Example 3.1 5 (R)-1 -(3,5-bis-trfluoromethyl-benzyl)-2-(1'-carboxymethyl-4,4'-bipiperid inyl-1 -yl)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate F , N CCF N O-/N\N0OH 1 0 10 H A solution of 1.5 mg (0.06 mmol) LiOH in 1 mL water was added to a solution of 35 mg (0.04 mmol) (R)-1 -(3,5-bis-trifluoromethyl-benzyl)-2-(1'-ethoxycarbonylmethyl 4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 15 3-yl)-piperidine-1-carboxylate (Example 3g) in 5 mL THF and the reaction solution was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in water, acidified with 1 N HCI, the precipitate was filtered off and dried in the vacuum drying cupboard. Yield: 15 mg (44% of theory) 20 ESI-MS: (M+H)* = 782 Rf = 0.41 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) Example 3.2 25 (R)-2-(4-amino-4-methyl-1,4'-bipiperidinyl-1'-yl)-1 -(3,5-bis-trifluoromethyl-benzyl) 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate F 3 0 CFC N N O N\ NkNH2 0CH 3 H 52 mg (0.14 mmol) tert-butyl (4-methyl-[1,4']bipiperidinyl-4-yl)-carbamate (used as the bis-hydrochloride salt) were added at RT to a solution of 80.0 mg (0.14 mmol) (R)-2-(3,5-bis-trifluoromethyl-phenyl)- 1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro 5 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 58 mg (0.18 mmol) TBTU and 140 pL (1.00 mmol) triethylamine in 1.8 mL DMF and the reaction solution was shaken overnight at RT. It was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised. The coupling product was dissolved in 4 mL DCM, the solution was combined with 0.5 mL TFA, 10 stirred for 5 h at RT and then left overnight at RT during which time the solvent evaporated. The residue was taken up in 2 mL 15% K 2
CO
3 solution, extracted twice with 2 mL DCM and the combined organic phases were shaken overnight during which time the solvent evaporated. The residue was purified by HPLC; the fractions containing the product were combined and lyophilised, and the product 15 was obtained as the formate salt. Yield: 47 mg (42% of theory) ESI-MS: (M+H)* = 753 retention time (HPLC): 5.4 min (method B) 20 Example 4 (R)-1 -(4-amino-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1 -yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate H NH, N NN O O{ - -0 1 0
H
- U 4a) methyl (ZE)-2-acetylamino-3-(4-amino-3,5-dimethyl-phenyl)-acrylate Under a nitrogen atmosphere first of all a solution of 90.0 g (441 mmol) 4-bronio 2,6-dimethyl-phenylamine in 200 mL acetonitrile was added to a mixture of 7.2 g (32.1 mmol) Pd(OAc) 2 and 10.1 g (32.1 mmol) tri-o-tolyl-phosphane in 1.2 L 5 triethylamine and 600 mL acetonitrile and then a solution of 65.0 g (445 mmol) methyl 2-acetylamino-acrylate in 200 mL acetonitrile was added dropwise. After the addition had ended the mixture was stirred for 18 h at 80 0 C. To complete the reaction the reaction mixture was again combined with 4.0 g (17.8 mmol) Pd(OAc) 2 and 5.0 g (16.4 mmol) tri-o-tolyl-phosphane and kept for another 5 h at 10 80 0 C. The mixture was evaporated down i.vac to approx. 200 mL, the residue was combined with 400 mL EtOAc, the residue (A) was filtered and the organic phase was dried over Na 2
SO
4 . After elimination of the desiccant by filtration over activated charcoal the filtrate was evaporated down to about 100 mL, the precipitated substance was suction filtered, washed with 30 mL EtOAc and dried. 1s The above residue A was combined with 1 L DCM, Na 2
SO
4 and activated charcoal and filtered through Celite. The filtrate was evaporated down, the residue was combined with 350 mL diethyl ether, the precipitate formed was suction filtered, then washed with 100 mL diethyl ether and dried. The two product fractions were combined. 20 Yield: 74.8 g (65% of theory) ESI-MS: (M+H)* = 263 R= 0.51 (silica gel, EtOAc) 4b) 3-(4-amino-3,5-dimethyl-phenyl)-2-oxo-propionic acid 25 A suspension of 74.0 g (282 mmol) methyl (Z,E)-2-acetylamino-3-(4-amino-3,5 dimethyl-phenyl)-acrylate in 500 mL 1,4-dioxane was heated to 100 0 C and combined with 460 mL 4 M HCI, whereupon a solution was formed. The mixture was heated for another 8 h at 1 00*C and the cooled solution was evaporated down i.vac. to approx. 200 mL, during which time the product crystallised out. It 30 was filtered, the residue was washed with 50 mL water and the product was dried at 50 0
C.
Yield: 43.6 g (63% of theory) ESI-MS: (M+H)+ = 208 Rf = 0.68 (silica gel, PE/EtOAc 1:1) 5 4c) methyl (R)-3-(4-amino-3,5-d imethyl-phenyl)-2-hyd roxy-propionate Under a nitrogen atmosphere a mixture of 20.0 g (82.1 mmol) 3-(4-amino-3,5 dimethyl-phenyl)-2-oxo-propionic acid and 25.7 mL (189 mmol) triethylamine in 400 mL THF was cooled to -35*C. Then a solution of 40.0 g (125 mmol) (1R)-B chlorodiisopinocampheylborane in 100 mL THF was added dropwise so that the 10 reaction temperature remained between -35*C and -25*C. The reaction mixture was kept for 1 h at this temperature, the cooling bath was removed and the reaction mixture was stirred overnight at RT. THF was evaporated off i.vac., the residue was combined with methanolic HCI (1.25 M) and stirred for 2 h at RT. It was evaporated down i.vac., the residue was taken up in 2 M HCI and extracted 15 exhaustively with EtOAc. The aqueous phase was made alkaline with semiconcentrated NaOH and exhaustively extracted with EtOAc. The combined organic phases were dried over Na 2
SO
4 , suction filtered through activated charcoal and evaporated down. The product was obtained as a brown oil. Yield: 8.3 g (45% of theory) 20 ESI-MS: (M+H)* = 224 Rf = 0.46 (silica gel, PE/EtOAc 1:1) 4d) (R)-2-(4-amino-3,5-dimethyl-phenvl)-1-methoxycarbonyl-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y)-piperidine-1 -carboxylate 25 Analogously to Example le the desired product was obtained from 4.0 g (17.9 mmol) methyl (R)-3-(4-amino-3,5-d imethyl-phenyl)-2-hydroxy-propionate and 4.8 g (19.6 mmol) 3-piperidin-4-y-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. Yield: 3.2 g (36% of theory) ESI-MS: (M+H)* = 495 30 Rf = 0.35 (silica gel, DCM/MeOH/NH 3 90:10:1) 4e) (R)-2-(4-amino-3,5-dimethyl-phenvl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro- 1,3-benzod iazepin-3-yl)-piperid ine-1 -carboxylate A solution of 500 mg (20.9 mmol) LiOH in 10 mL water was added to a solution of 6.7 g (13.6 mmol) of (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 5 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 300 mg (12.5 mmol) LiOH were added and the reaction solution was stirred for 3 h at 40 0 C. It was evaporated down i.vac., the residue was taken up in 15% K 2
CO
3 solution and extracted exhaustively with DCM. The aqueous 10 phase was acidified with 4 M HCI, exhaustively extracted with DCM and the combined organic phases were dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 4.2 g (65% of theory) ESI-MS: (M+H)* = 481 15 R,= 0.21 (silica gel, DCM/MeOH/cyc/NH 3 70:15:15:2) 4f) (R)-1 -(4-amino-3,5-dimethyl-benzvl)-2-(4-morpholin-4-yl-piperidin-1 -y)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahvdro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate 20 Analogously to Example 3g the product was obtained from 80 mg (0.17 mmol) (R) 2-(4-amino-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate and 32 mg (0.19 mmol) 4-piperidin-4 yl-morpholine. Yield: 52 mg (49% of theory) 25 ESI-MS: (M+H)* = 633 retention time (HPLC): 4.9 min (method B) Example 4.1 (R)-1 -(4-amino-3,5-dimethyl-benzyl)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperid inyl 1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 5 carboxylate O
NH
2 0 N 0N N \ O \-/ 1 0 Analogously to Example 3g the product was obtained from 100 mg (0.21 mmol) (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 59 mg (0.23 mmol) ethyl 10 [4,4']bipiperidinyl-1-yl-acetate. Yield: 58 mg (39% of theory) ESI-MS: (M+H)+ = 717 retention time (HPLC): 4.7 min (method B) 1s Example 4.2 (R)-1 -(4-amino-3,5-dimethyl-benzyl)-2-(1'-carboxymethyl-4,4'-bipiperidiny-1 -yl)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate O NH 2 0 N\ O N CN -O - N O 1 0 20 H A solution of 3.1 mg (0.13 mmol) LiOH in 1 mL water was added to a solution of 55 mg (0.08 mmol) (R)-1-(4-amino-3,5-d imethyl-benzyl)-2-(1'-ethoxycarbonylmethyl 4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 3-yl)-piperidine-1-carboxylate (Example 4.1) in 5 mL THF and the reaction mixture was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 1 mL DMF and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised. Yield: 22 mg (42% of theory) 5 ESI-MS: (M+H)+ = 689 retention time (HPLC): 4.8 min (method B) Example 5 10 (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yI-piperidin-1 -yl)-2-oxo ethyl 4-(2-oxo-1,2,4.5-tetrahyd ro- 1, 3-benzodiazepin-3-yl)-piperidine-1-carboxylate OH 00 H 5a) 2-benzvloxy-5-bromo-1, 3-d imethylbenzene 15 39.9 g (286 mmol) K 2
CO
3 were added to a solution of 50.0 g (249 mmol) 2,6 dimethyl-4-bromophenol in 500 mL DMF and stirred for 20 min. Then 34.0 mL (286 mmol) benzylchloride were slowly added dropwise and the reaction mixture was stirred for 3 h at 1 00*C bath temperature. After the reaction had ended the mixture was poured onto 500 mL water and exhaustively extracted with EtOAc. 20 The organic phases were combined, dried over Na 2
SO
4 and evaporated down i.vac.. Yield: quantitative GC-MS: (M*) = 290/292 (Br) Rf= 0.87 (silica gel, cyc/EtOAc 3:1) 25 5b) methyl 2-acetylamino-3-(4-benzvloxy-3,5-dimethyl-phenyl)-acrylate Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol) 2-benzyloxy-5bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl 2-acetylamino-acrylate in 420 niL triethylamine and 200 mL acetonitrile was combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g (11.1 mmol) Pd(OAc) 2 and the mixture was stirred for 18 h at 800C. The precipitate was suction filtered, the filtrate was 5 evaporated down i.vac. and combined with 800 mL DCM and 800 mL water. The organic phase was separated off, suction filtered over Na 2
SO
4 , the solvent was removed i.vac., the residue was stirred with EtOAc, suction filtered and dried i.vac.. Yield: 31.1 g (64% of theory) 10 ESI-MS: (M+H)* = 354 retention time (HPLC-MS): 8.6 min (method B) 5c) 3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-oxo-propionic acid 31.1 g (88.1 mmol) methyl 2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl) 15 acrylate in 150 mL 1,4-dioxane were combined with 125 mL 4 M HCI, stirred for 7 h at reflux temperature and stirred overnight at RT. The precipitate was suction filtered, washed with water and dried at 450C in the vacuum drying cupboard. Yield: 14.3 g (54 % of theory) E!MS: (M = 298 20 retention time (HPLC-MS): 9.0 min (method B) 5d) (R)-3-(4-benzoyl-3,5-dimethyl-phenyl)-2-hyd roxy-propionic acid Under a nitrogen atmosphere a solution of 14.3 g (47.8 mmol) 3-(4-benzyloxy-3,5 dimethyl-phenyl)-2-oxo-propionic acid and 8.3 mL (59.8 mmol) triethylamine in 170 25 mL THF at -35 0 C was combined with a solution of 22.1 (69.0 mmol) (1R)-B chlorodiisopinocampheylborane in 70 mL THF within 30 min. After the addition had ended the cooling bath was removed and the reaction solution was stirred overnight at RT. The reaction mixture was made alkaline at 0*C with 70 mL 1 M NaOH, combined with 100 mL MTBE, stirred for 15 min and the phases were 30 separated. The organic phase was washed with 50 mL water and three times with 50 mL 1 M NaOH. The combined aqueous phases were acidified with semiconc.
HCI, exhaustively extracted with EtOAc and the combined organic phases were dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 14.0 g (98% of theory) 5 ESI-MS: (M-H)- = 299 retention time (HPLC-MS): 7.9 min (method B) 5e) methyl (R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate To a solution cooled to 0"C of 14.0 g (23.3 mmol) of (R)-3-(4-benzoyl-3,5-dimethyl 10 phenyl)-2-hydroxy-propionic acid in 150 mL MeOH, 2.0 mL (27.4 mmol) SOC1 2 were added dopwise and the reaction mixture was stirred for 1 h at RT. The reaction solution was evaporated down i.vac. and the residue was purified by chromatography (silica gel, cyc/EtOAc 3:1). Yield: 5.7 g (78% of theory) 1s ESI-MS: (M+NH 4 )* = 332 retention time (HPLC-MS): 9.1 min (method B) 5f) (R)-2-(4-benzyloxy-3.5-dimethyl-phenyl)-1-methoxycarbonyl-ethy 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate 20 Under a nitrogen atmosphere 1.93 g (9.58 mmol) 4-nitrophenyl chloroformate was added to a solution of 1.17 g (9.58 mmol) 4-dimethylaminopyridine in 50 mL pyridine, stirred for 1.5 h at RT, combined with 3.0 g (9.58 mmol) methyl (R)-3-(4 benzyloxy-3,5-d imethyl-phenyl)-2-hydroxy-propionate and stirred for 20 min at RT. Then 2.35 g (9.58 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2 25 one were added and the mixture was stirred for 20 h at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in EtOAc, the organic phase was washed with 10% KHSO 4 and saturated NaHCO 3 solution and dried over Na 2
SO
4 .After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient cyc/EtOAc 1:1 to 1:2). 30 Yield: 3.21 g (57% of theory) ESI-MS: (M+H)* = 586 retention time (HPLC-MS): 10.4 min (method A) 5g) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro-1, 3-benzodiazepin-3-yl)-piperidine-1 -carboxylate 5 A solution of 3.21 g (5.48 mmol) of (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1 methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate in 80 mL THF was combined with a solution of 200 mg (8.35 mmol) LiOH in 40 mL water and stirred for 1 h at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in 100 mL water, acidified 10 with 2 M HCI, the precipitate was suction filtered and dried in the vacuum drying cupboard at 400C. Yield: quantitative ESI-MS: (M+H)* = 572 retention time (HPLC-MS): 9.2 min (method B) 15 5h) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4.5 tetrahyd ro-1, 3-benzod iazepin-3-yl)-piperidine-1 -carboxylate 3.72 g (6.51 mmol) of (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1 -carboxy-ethyl 4 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 20 mL DCM were combined with 300 mg 10% Pd/C and shaken at RT and 3000 hPa hydrogen pressure until the reaction came to a stop. The catalyst was suction filtered and the solvent was evaporated down i.vac.. The residue was triturated with DIPE and suction filtered. Yield: 2.41 g (77% of theory) 25 ESI-MS: (M+H)* = 482 retention time (HPLC-MS): 7.0 min (method B) 5i) (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2(4-morpholin-4-l-piperidin-1 -yl)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 30 carboxylate A solution of 70 mg (0.15 mmol) of (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1 carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate, 51 mg (0.16 mmol) TBTU and 26 pL (0.18 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 25 mg (0.15 mmol) 4-piperidin-4-yl 5 morpholine was added to the reaction solution, which was then stirred for 16 h at RT. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised. Yield: 35 mg (38% of theory) ESI-MS: (M+H)* = 634 10 retention time (HPLC-MS): 5.6 min (method B) Example 5.1 (R)-2-(4-hydroxy-1,4'-bipiperidinyl-1'-yl)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo 15 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate OH N-- N O. N N'' OH N4 N I 0 H Analogously to Example 5i the product was obtained from 70 mg (0.15 mmol) (R) 20 2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate and 27 mg (0.15 mmol) [1,4']bipiperidinyl-4-ol. Yield: 35 mg (37% of theory) ESI-MS: (M+H)* = 648 25 retention time (HPLC): 5.5 min (method B) Example 5.2 (R)-1 -(4-hydroxy-3,5-d imethyl-benzyl)-2-(4-hyd roxy-4-methyl-[1,4']bipiperidinyl-1' yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-benzod iazepin-3-yl)-piperid ine- 1 5 carboxylate OH HOH N 0 H 5.2a) (R)-1-(4-hyd roxy-3,5-dimethyl-benzvl)-2-oxo-2-(4-o xo-piperidin-1 -yl)-ethyl 4 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-vl)-piperidine-1 -carboxylate 10 130 mg (0.83 mmol) piperidin-4-one (used as the hydrate of the hydrochloride salt) were added at RT to a solution of 400 mg (0.83 mmol) (R)-2-(4-hydroxy-3,5 dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3 yl)-piperidine-1-carboxylate, 320 mg (1.00 mmol) TBTU and 260 pL (1.87 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 16 h at RT. 15 The mixture was evaporated down i.vac., the residue was taken up in EtOAc, the organic phase was washed with semisaturated NaHCO 3 solution and dried over Na 2
SO
4 .After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc). The fractions containing the product were evaporated down, the residue stirred with DIPE, suction filtered and 20 dried. Yield: 333 mg (71% of theory) ESI-MS: (M+H)* = 563 retention time (HPLC-MS): 6.9 min (method B) 25 5.2b) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl [1,4'lbipiperidinvl-1'-vl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahvdro-1,3 benzodiazepin-3-yl)-piperid ine-1 -carboxylate - IU A solution of 50 mg (0.09 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4 oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate in 1.5 mL DCM was combined with 21 mg (0.18 mmol) 4 methyl-piperidin-4-ol and 10.3 pL (0.19 mmol) AcOH, cooled to OC cooled and 5 stirred for 2 h. Then 28 mg (0.19 mmol) sodium-triacetoxyborohydride were added and the mixture was stirred overnight at 0"C. After the solvent had been eliminated the residue was combined with 2 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised. Yield: 25 mg (42% of theory) 10 ESI-MS: (M+H)* = 662 retention time (HPLC-MS): 2.90 min (method A) Example 5.3 15 (R)-2-(4,4-dimethyl-[1,4']bipiperidinyl-1'-yl)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro- 1, 3-benzod iazepin-3-yl)-piperid ine- 1 carboxylate OH N N ON N ' 0 H Analogously to Example 5.2b the product could be obtained from 50.0 mg (0.09 20 mmol) (R)-1 -(4-hyd roxy-3,5-d imethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate (Example 5.2a) and 31.0 mg (0.18 mmol) 4,4-dimethylpiperidin. Yield: 18.3 mg (31% of theory) ESI-MS: (M+H)* = 660 25 retention time (HPLC-MS): 3.2 min (method A) - IUl Example 5.4 (R)-2-(4-amino-4-methyl-[1,4']bipiperidinyl-1'-yl)-1 -(4-hydroxy-3,5-dimethyl-benzyl) 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 5 carboxylate OH 'NO N O N N , N H 2 N4 0 I 0 H A solution of 150 mg (0.27 mmol) (R)-1 -(4-hyd roxy-3,5-d imethyl-benzyl)-2-oxo-2 (4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate (Example 5.2a) in 4 mL DCM was combined with 120 mg 10 (0.53 mmol) tert-butyl (4-methyl-piperidin-4-yl)-carbamate and 31 pL (0.56 mmol) AcOH, cooled to 0*C and stirred for 2 h. Then 85 mg (0.56 mmol) sodium triacetoxyborohydride were added and the mixture was stirred overnight at 0 0 C. Then the reaction solution was combined with 0.5 mL TFA and again stirred overnight at RT. After elimination of the solvents the residue was dissolved in 2 mL 15 DMF and purified by HPLC. The fractions containing the product were combined and lyophilised, wherein the product was obtained as the TFA salt. Yield: 94 mg (46% of theory) ESI-MS: (M+H)* = 661 retention time (HPLC-MS): 2.5 min (method A) 20 Example 5.5 (R)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl- 1-yl)-1 -(4-hydroxy-3,5-dimethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1 ,2,4,5-tetrahyd ro- 1,3-benzodiazepin-3-yl)-piperidine 25 1-carboxylate O OH N4 - 0 H 117 mg (0.46 mmol) ethyl [4,4']bipiperidinyl-1 -yl-acetate were added at RT to a solution of 200 mg (0.42 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate 5 (Example 5h), 148 mg (0.46 mmol) TBTU and 64 pL (0.46 mmol) triethylamine in 10 mL THF and 1 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was evaporated down i.vac., the residue was taken up in MeOH and purified by HPLC. The fractions containing the product were combined, evaporated down i.vac., the residue was triturated with DIPE, suction filtered and 10 dried. Yield: 222 mg (74% of theory) ESI-MS: (M+H)* = 718 retention time (HPLC): 3.1 min (method A) 15 Example 5.6 (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1 -yl)-1 -(4-hydroxy-3,5-dimethyl-benzyl) 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate OH N - N1 - NYQN O >ZN YNI H N 0 O 1 0 20 H A solution of 3.8 mg (0.16 mmol) LiOH in 1 mL water was added to a solution of 100 mg (0.14 mmol) (R)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1 -yl)-1 -(4 hyd roxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction - iuj solution was stirred overnight at RT. The organic solvent was removed in the nitrogen stream, the residue was combined with 1 mL water and acetonitrile and acidified with formic acid. The product was purified by HPLC; the fractions containing the product were combined and lyophilised. 5 Yield: 56 mg (58% of theory) ESI-MS: (M-H)- = 688 retention time (HPLC): 3.0 min (method A) Example 5.7 10 (R)-2-(4-cyclohexyl-piperazin-1 -yl)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzod iazepin-3-yl)-piperidine-1 -carboxylate OH N 0 N N 0 I 0 H Analogously to Example 3g the product could be obtained from 69 mg (0.14 mmol) 15 (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 5h) and 24 mg (0.14 mmol) 1-cyclohexyl-piperazine. Yield: 51 mg (91% of theory) ESI-MS: (M+H)* = 632 20 retention time (HPLC): 3.1 min (method A) Example 5.8 (R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1 -yl)-piperidin-1 -yl]-1 -(4-hyd roxy-3,5 25 dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate 00 00 H Analogously to Example 5i the product could be obtained from 150 mg (0.31 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro-1,3-benzod iazepin-3-yl)-piperid ine- 1-carboxylate (Example 5h) and 87 5 mg (0.34 mmol) ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate. Yield: 64 mg (28% of theory) ESI-MS: (M+H)* = 719 retention time (HPLC): 3.6 min (method A) 10 Example 5.9 (R)-2-[4-(4-carboxymethyl-piperazin-1 -yl)-piperidin-1 -yl]-1 -(4-hydroxy-3,5-dimethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yt)-piperidine 1-carboxylate OH N-CN H N N N O, N40 c 15 H A solution of 2.3 mg (0.09 mmol) LiOH in 5 mL water was added to a solution of 40.0 mg (0.06 mmol) (R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin 1 -yl]-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethy 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 5 mL THF and the reaction 20 mixture was stirred for 2 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 1 mL DMF and purified by HPLC; the fractions containing the product were combined and lyophilised. Yield: 20 mg (38% of theory) ESI-MS: (M+H)* = 691 - I UO retention time (HPLC): 2.6 min (method A) Example 5.10 5 (R)-2-[4-(1 -ethoxycarbonylmethyl-piperidin-4-y)-piperazin-1 -yl]-1 -(4-hydroxy-3,5 dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate O H 0 O N - 0{ H 5.1 Oa) (R)-1 -(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1 -ethoxycarbonylmethyl 10 piperidin-4-yl)-piperazin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1.3 benzodiazepin-3-yl)-piperidine-1 -carboxylate A solution of 8.00 g (14.0 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1 carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-benzod iazepin-3-yl)-piperid ine- 1 carboxylate (Example 5g), 5.17 g (16.1 mmol) TBTU and 8.84 mL (63.0 mmol) 15 triethylamine in 100 mL DMF was stirred for 1 h at RT. Then 5.28 g (16.1 mmol) ethyl (4-piperazin-1-yl-piperidin-1-yI)-acetate (used as the bis-hydrochloride salt) was added to the reaction mixture, which was then stirred for 1 h at RT. 150 mL of 15% K 2
CO
3 solution were added, the mixture was extracted with 200 mL EtOAc, the organic phase was separated off and extracted with 150 mL 10% citric acid 20 solution. The aqueous phase was made alkaline with K 2
CO
3 , extracted with 200 mL EtOAc and the organic phase was dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOH). The fractions containing the product were combined, evaporated down i.vac., the residue was stirred with DIPE, suction filtered and dried. 25 Yield: 8.58 g (76% of theory) ESI-MS: (M+H) 4 = 809 retention time (HPLC): 3.7 min (method A) - IUD 5.1 Ob) (R)-2-[4-(1 -ethoxvcarbonvlmethyl-iperidin-4-yl)-piperazin-1 -l-1 -(4 hydroxy-3.5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4.5-tetrahydro-1.3 benzodiazepin-3-vl)-piperidine-1 -carboxylate A suspension of 4.00 g (4.94 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4 5 (1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 400 mg 10% Pd/C in 50 mL EtOH was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical hydrogen uptake had occurred. The catalyst was filtered off, the filtrate was evaporated down i.vac., the residue was stirred with 10 DIPE, suction filtered and dried. Yield: 3.40 g (96% of theory) ESI-MS: (M+H)* = 719 retention time (HPLC): 2.5 min (method A) 15 Example 5.11 (R)-2-[4-(1 -carboxymethyl-piperid in-4-yl)-piperazin- 1 -yl]-1 -(4-hydroxy-3,5-dimethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine 1-carboxylate OH N NIT. 0, 20 H A solution of 126 mg (5.25 mmol) LiOH in 10 mL water was added at RT to a solution of 2.50 g (3.48 mmol) (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl) piperazin-1 -yl]-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5 tetra hydro-1, 3-benzodiazepin-3-yl)-piperid ine-1-carboxylate in 30 mL THF and the 25 reaction mixture was stirred overnight at RT. The mixture was evaporated to dryness i.vac. and the residue was purified by chromatography (silica gel, gradient DCM to DCM/MeOH/NH 3 70:30:3). The fractions containing the product were - It combined, evaporated down i.vac., the residue was triturated with DIPE, suction filtered and dried. Yield: 1.80 g (75% of theory) ESI-MS: (M+H)* = 691 5 Rf = 0.10 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) Example 5.12 (R)-2-{4-[1-(2-ethoxycarbony-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy 10 3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3 yl)-piperidine-1 -carboxylate OH 352 mg (0.93 mmol) ethyl 3-(4-piperazin-1-yl-piperidin-1-yl)-propionate (used as the bis-Hydrochloride salt) were added to a solution of 400 mg (0.83 mmol) (R)-2 15 (4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate, 299 mg (0.93 mmol) TBTU and 477 plL (3.40 mmol) triethylamine in 5 mL DMF and the reaction mixture was stirred for 2 h at RT. The reaction solution was combined with 15%'K2CO3 solution, exhaustively extracted with DCM and the combined organic phases were dried 20 over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by HPLC; the fractions containing the product were combined and lyophilised. Yield: 305 mg (50% of theory) ESI-MS: (M+H)* = 733 25 retention time (HPLC): 2.6 min (method A) - lud Example 5.13 (R)-2-{4-[1 -(2-carboxy-ethyl)-piperid in-4-yl]-piperazin-1 -yl}-1 -(4-hyd roxy-3,5 dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 5 piperidine-1-carboxylate 0 H Analogously to Example 5.11 the product could be obtained from 2.60 g (3.55 mmol) (R)-2-{4-[1 -(2-ethoxycarbonyl-ethyl)-pi peridin-4-yl]-piperazin- 1-yl}-1-(4 hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 10 benzodiazepin-3-yl)-piperidine-1-carboxylate and 128 mg (5.33 mmol) LiOH. Yield: 1.60 g (64% of theory) ESI-MS: (M+H)* = 705 Rf = 0.07 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) 1s Example 5.14 (R)-2-[1'-(2-ethoxycarbonyl-ethyl)-4,4'-bipiperidinyl-1-yl]-1 -(4-hydroxy-3,5-dimethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzbd iazepin-3-yl)-piperid ine 1-carboxylate SOH I N N O 0 00 20 H A solution of 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1 -carboxy ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro- 1, 3-benzodiazepin-3-yl)-piperidine-1 -carboxylate (Example 5h), 59 mg (0.18 mmol) TBTU and 76 pL (0.54 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 49 mg (0.18 mmol) ethyl 3- - I Utp [4,4']bipiperidinyl-1-yl-propionate were added to the reaction mixture, which was then stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised. Yield: 11 mg (9% of theory) 5 ESI-MS: (M+H)* = 732 retention time (HPLC): 3.4 min (method C) Example 5.15 10 (R)-2-[1 '-(2-carboxy-ethyl)-4,4'-bipiperidinyl-1 -yl]-1 -(4-hydroxy-3,5-d imethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine 1-carboxylate OH IN N N 0'-H N 0 00 H Analogously to Example 5.11 the product could be obtained from 2.50 g (3.42 15 mmol) (R)-2-[1 '-(2-ethoxycarbonyl-ethyl)-4,4'-bipiperidinyl-1 -yl]-1 -(4-hydroxy-3,5 dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate and 128 mg (5.33 mmol) LiOH. Yield: 1.70 g (71% of theory) ESI-MS: (M+H)+ = 704 20 Rf = 0.20 (silica gel, DCM/MeOH/Cyc/NH 3 70:15:15:2) Example 5.16 (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-{1'-[(hydroxy-methyl-carbamoyl)-methyl] 25 4,4'-bipiperidinyl-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 3-yl)-piperidine-1 -carboxylate - I V OH NN ON 00 0 H H A solution of 80.0 mg (0.12 mmol) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1-yl) 1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 5.6), 44.6 mg (0.14 mmol) 5 TBTU and 64.6 pL (0.46 mmol) triethylamine in 1.2 mL DMF was stirred for 1 h at RT. Then 29.1 mg (0.35 mmol) N-methylhydroxylamine (used as the hydrochloride salt) was added to the reaction mixture, which was then stirred for 20 h at RT. To the reaction mixture were added 5 drops of AcOH, the mixture was filtered through a syringe filter and purified by HPLC. The fractions containing the product were 10 combined, 30 mL EtOAc and 5% NaHCO 3 solution were added, the organic phase was separated off and dried over Na 2
SO
4 .After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, DCM/MeOH/NH 3 90:10:1). The fractions containing the product were combined, evaporated down i.vac., the residue was triturated with DIPE, suction filtered and 15 dried in the air until a constant weight was obtained. Yield: 12.4 mg (15% of theory) ESI-MS: (M+H)* = 719 Rf = 0.16 (silica gel, DCM/MeOH/NH 3 90:10:1) retention time (HPLC): 3.0 min (method A) 20 Example 5.17 (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-[1'-(methoxycarbamoyl-methyl)-4,4' bipiperidinyl-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 25 piperidine-1 -carboxylate - II| OH N 0NNO NfN N ~ 0 0 H Analogously to Example 5.16 the product could be obtained from 80.0 mg (0.12 mmol) (R)-2-(1'-carboxymethyl-4,4'-bipiperidinyl-1 -yl)-1 -(4-hydroxy-3,5-di methyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro- 1, 3-benzodiazepin-3-yl)-piperidine 5 1-carboxylate (Example 5.6) and 29.1 mg (0.35 mmol) 0-methylhydroxyamine (used as the hydrochloride salt). Yield: 13.0 mg (16% of theory) ESI-MS: (M+H)* = 719 Rf = 0.27 (silica gel, DCM/MeOH/NH 3 90:10:1) 10 retention time (HPLC): 3.0 min (method A) Example 5.18 (R)-2-(4-cyclopentyl-piperazin-1 -yl)-1 -(4-hyd roxy-3,5-d imethyl-benzyl)-2-oxo-ethyl 15 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y)-piperidine-1-carboxylate OH N-CN O0 N N- 0 00 5.18a) (R)-1 -(4-benzvloxy-3.5-dimethyl-benzvl)-2-(4-benzvl-piperazin-1 -yl)-2-oxo ethyl 4-(2-oxo-1.2.4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate 20 A solution of 1.54 g (2.69 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1 carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate (Example 5g), 0.95 g (2.96 mmol) TBTU and 0.47 mL (3.37 mmol) triethylamine in 20 mL THF and 2 ml DMF was stirred for 1 h at RT. Then 0.52 mL (2.96 mmol) N-benzylpiperazine were added to the reaction mixture, which was - I I then stirred for 14 h at RT. 30 mL EtOAc were added to the reaction mixture, it was washed with semisaturated NaHCO 3 solution and the organic phase was dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, EtOAc/Cyc 95:5). The fractions 5 containing the product were evaporated down, the residue was triturated with DIPE, suction filtered and dried. Yield: 1.62 g (82% of theory) ESI-MS: (M+H)* = 730 retention time (HPLC): 4.3 min (method A) 10 5.18b) (R)-1-(4-hydroxy-3,5-dimethyl-benzvl)-2-oxo-2-piperazin-1-vl-ethyl 4-(2-oxo 1, 2.4,5-tetrahyd ro-1, 3-benzod iazePin-3-yl)-piperidine-1 -carboxylate A suspension of 1.62 g (2.22 mmol) (R)-1 -(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4 benzyl-piperazin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 15 3-yl)-piperidine-1-carboxylate and 150 mg 10% Pd/C in 40 mL MeOH was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical hydrogen uptake had occurred. The catalyst was suction filtered, the solvent was evaporated down i.vac. and the residue was purified by chromatography (silica gel, EtOAc + 15% MeOH/NH 3 9:1). 20 Yield: 1.03 g (85% of theory) ESI-MS: (M+H)* = 550 retention time (HPLC): 2.7 min (method A) 5.18c) (R)-2-(4-cvclopentvl-Diperazin-1 -v)-1 -(4-hydroxv-3.5-dimethyl-benzvl)-2 25 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahvdro-1,3-benzodiazepin-3-vl)-piperidine-1 carboxylate A solution of 100 mg (0.18 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2 piperazin-1-yl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzod iazepin-3-yl)-piperidine 1-carboxylate, 48 pL (0.55 mmol) cyclopentanone and 20 pL (0.37 mmol) AcOH in 30 2 mL THF/MeOH (2:1) was stirred ovemight at RT. Then 24 mg (0.36 mmol) sodium cyanoborohydride was added to the reaction solution which had been cooled to 00C, and this was then stirred for 4 h at 0*C and overnight at RT. The solvents were eliminated at 400C, the residue was dissolved in 1 mL DMF and purified by HPLC; the fractions containing the product were combined and lyophilised. 5 Yield: 48 mg (43% of theory) ESI-MS: (M+H)* = 618 retention time (HPLC): 3.2 min (method A) Example 5.19 10 (R)-2-(4-cycloheptyl-piperazin-1-yl)-l-(4-hydroxy-3,5-dimethvl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-y)-piperidine-1 -carboxylate OH N0 N N / 0 H Analogously to Example 5.18c the product could be obtained from 100 mg (0.18 15 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-piperazin-1-yI-ethyl -(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 40.8 mg (0.36 mmol) cycloheptanone and 12 mg (0.18 mmol) sodium cyanoborohydride. Yield: 21 mg (18% of theory) ESI-MS: (M+H)* = 646 20 retention time (HPLC): 3.5 min (method A) Example 5.20 (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-(1'-methanesulphonyl-4,4'-bipiperidinyl-1 25 yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate J H -CN 0 ' 0 H A solution of 100 mg (0.21 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzod iazepin-3-yl)-piperid ine- 1 carboxylate, 73 mg (0.23 mmol) TBTU and 36 pL (0.26 mmol) triethylamine in 1 5 mL DMF was stirred for 1 h at RT. Then 56 mg (0.23 mmol) 1-methanesulphonyl [4,4']bipiperidinyl was added to the reaction mixture, which was then stirred for 5 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised. Yield: 63 mg (43% of theory) 10 ESI-MS: (M-H)- = 708 retention time (HPLC): 4.0 min (method A) Example 5.21 15 (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methanesulphonyl-piperazin-1 -yl) piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate OH O 0 N NS C ] 0 H Analogously to Example 5.20 the product could be obtained from 100 mg (0.21 20 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethy and 57 mg (0.23 mmol) 1-methanesulphonyl-4-piperidin-4-yI-piperazine 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate. Yield: 43 mg (29% of theory) ESI-MS: (M+H)* = 711 retention time (HPLC): 3.1 min (method A) Example 5.22 5 (R)-1 -(4-hydroxy-3,5-dimethyl-benzyl)-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1 -yl] piperidin-1-yl}-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate OH N O' NH O0 H Analogously to Example 5.20 the product could be obtained from 80 mg (0.17 10 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro-1,3-benzodiazepin-3-y)-piperidine-1 -carboxylate and 52 mg (0.18 mmol) 2-(4-piperidin-4-yl-piperazin-1-yl)-ethanol. Yield: 63 mg (56% of theory) ESI-MS: (M+H)* = 677 15 retention time (HPLC): 2.4 min (method A) Example 5.23 (R)-2-{1 '-(3-ethoxycarbonyl-propionyl)-4,4'-bipiperidinyl-1 -yl]-l -(4-hydroxy-3,5 20 dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate OH N O N ZN 0 0 H 207 mg (0.70 mmol) ethyl 4-[4,4']bipiperidinyl-1 -yl-4-oxo-butyrate (amine A2) were added at RT to a solution of 300 mg (0.62 mmol) (R)-1 -carboxy-2-(4-hydroxy-3,5- - llt dimethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate, 225 mg (0.70 mmol) TBTU and 97 pL (0.70 mmol) triethylamine in 5 mL DMF and the reaction mixture was shaken overnight at RT. It was directly purified by HPLC without any further working up; the fractions 5 containing the product were combined and lyophilised. Yield: 170 mg (36% of theory) ESI-MS: (M+H)* = 760 retention time (HPLC): 4.1 min (method A) 10 Example 5.24 (R)-2-[1'-(3-carboxy-propionyl)-4,4'-bipiperid inyl-1 -yl]-1 -(4-hyd roxy-3,5-d imethyl benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine 1-carboxylate OH 3 0 N O OH - 0 15H A solution 0.96 mg (0.04 mmol) LiOH in 1 mL water was added to a solution of 20.0 mg (0.03 mmol) (R)-2-[1 '-(3-ethoxycarbonyl-propionyl)-4,4'-bipiperidinyl-1-yl] 1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture 20 was stirred for 2 h at RT. The solvents were eliminated in a nitrogen stream, the residue was taken up in water/acetonitrile and lyophilised. The product was obtained as the Li salt. Yield: 17 mg (88% of theory) ESI-MS: (M+H)* = 732 25 Rf = 0.13 (silica gel, DCM/MeOH/NH 3 90:10:1) - I Example 5.25 (R)-2-(1'-ethoxyoxalyl-4,4'-bipiperidinyl-1 -yl)- 1 -(4-hyd roxy-3,5-d imethyl-benzyl)-2 oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 5 carboxylate OH NN N O -0 0 H O 231 mg (0.70 mmol) ethyl [4,4']bipiperidinyl-1-yl-oxo-acetate (amine Al, used as the hydrogen carbonate salt) were added at RT to a solution of 300 mg (0.62 mmol) (R)-l-carboxy-2-(4-hydro xy-3,5-d imethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5 10 tetrahyd ro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 225 mg (0.70 mmol) TBTU and 197 pL (1.40 mmol) triethylamine in 5 mL DMF and the reaction mixture was stirred for 3 h at RT. The mixture was evaporated down i.vac., the residue was taken up in DCM, the organic phase was washed with 15% K 2
CO
3 solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the 15 residue was purified by HPLC; the fractions containing the product were combined, evaporated down i.vac., the residue was triturated with DIPE, suction filtered and dried. Yield: 360 mg (79% of theory) ESI-MS: (M+H)* = 732 20 retention time (HPLC): 4.0 min (method A) Example 5.26 (R)-1 -(4-hyd roxy-3,5-dimethyl-benzyl)-2-(1'-oxalyl-4,4'-bipiperidinyl- 1 -yl)-2-oxo 25 ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate OH N NN N H 0 0 H A solution 0.96 mg (0.04 mmol) LiOH in 1 mL water was added to a solution of 20.0 mg (0.03 mmol) (R)-2-(1'-ethoxyoxalyl-4,4'-bipiperidinyl-1-yl)-1-(4-hydroxy 3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3 5 yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture was stirred for 2 h at RT. The solvents were eliminated in a nitrogen stream, the residue was taken up in waterlacetonitrile and lyophilised. The product was obtained as the Li salt. Yield: 19 mg (99% of theory) ESI-MS: (M+H)* = 704 10 Rf = 0.10 (silica gel, DCM/MeOH/NH 3 90:10:1) Example 6 (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-ethyl 15 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate OH -/ -N O0 N 1 0 H 6a) (Z,E)-3-(4-acetoxy-3,5-dibromo-phenyl)-2-acetylamino-acrlic acid Under a nitrogen atmosphere a mixture of 30.0 g (107 mmol) 3,5-dibromo-4-hy 20 droxy-benzaldehyde, 18.8 g (268 mmol) N-acetylglycine and 13.2 g (161 mmol) NaOAc in 120 mL acetic anhydride was heated to 130"C for 1.5 h. The mixture was cooled to 90*C and 15 mL water was slowly added dropwise thereto in such a way that the temperature did not exceed 100"C. After the addition had ended the mixture was kept for a further 2 h at 900C, cooled to 70 0 C, combined with 300 mL water and stirred for 30 min. The precipitate was filtered off, washed with water and dried at 500C. The crude product was further reacted without purification. Yield: 35.7 g (79% of theory) ESI-MS: (M+H)* = 420/422/424 (2 Br) 5 Rf = 0.20 (silica gel, DCM/MeOH/AcOH 90:10:1) 6b) 3-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-propionic acid While cooling with ice 325 mL of 4 M HCI was added to a solution of 35.7 g (84.8 mmol) (Z,E)-3-(4-acetoxy-3,5-dibromo-phenyl)-2-acetylamino-acrylic acid in 290 10 mL NMP and the reaction mixture was heated to 1200C (bath temperature) for 1.5 h. The mixture was cooled to 0*C, combined with 1.4 L water and stirred for a further 30 min. The precipitate formed was filtered off and dried. Yield: 20.5 g (72% of theory) ESI-MS: (M-H)~= 335/337/339 (2 Br) 15 Rf = 0.35 (silica gel, DCM/MeOH/AcOH 80:20:2) 6c) (R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid Under an argon atmosphere 6 mL (43.1 mmol) triethylamine was added to a solution of 14.5 g (42.9 mmol) 3-(3,5-dibromo-4-hydroxy-phenyl)-2-oxo-propionic 20 acid in 250 mL THF and the mixture was cooled to -320C. Then a solution of 22.6 g (70.5 mmol) (1R)-B-chlorodiisopinocanpheylborane in 90 mL THF was added dropwise such that the temperature did not exceed -20'C. The reaction mixture was stirred for 30 min at -300C and allowed to heat up to 00C within 2.5 h. To complete the reaction the mixture was again cooled to -32*C, a solution of 5.8 g 25 (18.1 mmol) (1R)-B-chlorodiisopinocampheylborane in 40 mL THF was added dropwise such that the temperature did not exceed -200C and then the reaction mixture was stirred overnight in the ice bath. After cooling again to -32*C a further 2.5 g (7.8 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL THF were added dropwise, the reaction mixture was stirred for 30 min at this temperature, 30 heated to 00C within 2.5 h and then stirred for 66 h at RT. 100 mL 10% NaOH were added to the reaction solution such that the temperature did not exceed 250C, stirred for a further 30 min, combined with MTBE, the organic phase was separated off and again extracted with 20 mL 10% NaOH solution. The combined aqueous phases were washed several times with MTBE, acidified with 20% HCI and exhaustively extracted with diethyl ether/EtOAc (1:1). The combined organic 5 phases were combined with activated charcoal and filtered. The product was further reacted without purification. Yield: 12.7 g (87% of theory) ESI-MS: (M-H)- = 337/339/341 (2 Br) R= 0.4 (silica gel, DCM/MeOH/AcOH 80:20:2) 10 retention time (HPLC-MS): 6.4 min (method D) 6d) methyl (R)-3-(3.5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionate A solution of 14.0 g (34.8 mmol) (R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy propionic acid in 100 mL methanolic HCI (6 M) was stirred for 3 h at RT. The 15 mixture was evaporated down i.vac. and the residue was purified by chromatography (silica gel, n-hexane/EtOAc 7:3). Yield: 7.0 g (57% of theory) ESI-MS: (M-H)~= 351/353/355 (2 Br) retention time (HPLC-MS): 9.8 min (method D) 20 6e) methyl (R)-3-{3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyll-2 hydroxy-propionate Under a nitrogen atmosphere 11.1 g (76.6 mmol) 40% KF/A1 2 0 3 were added to a solution of 6.78 g (19.2 mmol) methyl (R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2 25 hydroxy-propionate in 100 mL acetonitrile and the resulting suspension was stirred for a few min at RT. Then a solution of 4.07 mL (23.0 mmol) (2-chloromethoxy ethyl)-trimethylsilane in 20 mL acetonitrile was added and the reaction mixture was stirred for 20 h at RT. The mixture was filtered through Celite, the solvent was evaporated down i.vac. and the residue was purified by chromatography (silica 30 gel, n-hexane/EtOAc 7:3). Yield: 5.49 g (59% of theory) - It I Rf = 0.45 (silica gel, n-hexane/EtOAc 1:1) 6f) (R)-2-[3,5-dibromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyll-1 -methoxy carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 5 piperidine-1 -carboxylate Under a nitrogen atmosphere 1.23 g (10.0 mmol) 4-dimethylaminopyridine was added to a solution of 1.99 g (9.56 mmol) 4-nitrophenyl chloroformate in 80 mL acetonitrile cooled to 15 0 C. The resulting suspension was cooled to -7 0 C and slowly combined with a solution of 4.63 g (9.56 mmol) methyl (R)-3-[3,5-dibromo 10 4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-2-hydroxy-propionate in 20 mL acetonitrile. The mixture was stirred for a further 15 min at this temperature, 2.35 g (9.56 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one was added and the reaction mixture was stirred for 2.5 h at RT. The mixture was evaporated down i.vac., the residue was taken up in EtOAc, the organic phase 15 was washed with 10% citric acid and 10% Na 2
CO
3 solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient n-hexane/EtOAc 1:1 to 2:8). Yield: 4.35 g (69% of theory) ESI-MS: (M+H)* = 754/756/758 (2 Br) 20 retention time (HPLC): 29.2 min (method D) 6g) (R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-vl)-piperidine-1 -carboxylate Under a nitrogen atmosphere 5.46 mL methanolic H 2
SO
4 (0.5 M) were added to a 25 solution of 4.30 g (5.69 mmol) (R)-2-[3,5-dibromo-4-(2-trimethylsilanyl ethoxymethoxy)-phenyl]-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL THF and 40 mL MeOH and the reaction solution was stirred for 6 h at RT. The reaction mixture was evaporated down i.vac. and the residue was further reacted without purification. 30 Yield: quantitative ESI-MS: (M+H)* = 624/626/628 (2 Br) retention time (HPLC): 17.3 min (method D) 6h) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro- 1, 3-benzod iazepin-3-vl)-piperid ine- 1-carboxylate s A solution of 0.51 g (21.3 mmol) LiOH was added to a solution of (R)-2-(3:5 dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate (crude product from Example 6g) in 80 mL THF and the reaction mixture was stirred for 3 h at RT. The THF was eliminated i.vac., the aqueous phase was washed with EtOAc, acidified with 10% 10 HCI and the aqueous phase was exhaustively extracted with EtOAc. The combined organic phases were evaporated down i.vac., suspended in diethyl ether, filtered, the residue was dried and then purified by chromatography (silica gel, DCM/MeOH/AcOH 90:10:1). Yield: 3.5 g (100% of theory) 15 ESI-MS: (M+H)* = 610/612/614 (2 Br) retention time (HPLC): 14.1 min (method D) 6i) (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 20 carboxylate 30 mg (0.18 mmol) 1-cyclohexyl-piperazine were added at RT to a solution of 100 mg (0.16 mmol) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethy 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 58 mg (0.18 mmol) TBTU and 25 pL (0.18 mmol) triethylamine in 1 mL DMF and the reaction 25 mixture was stirred overnight at RT. The reaction solution was filtered through a syringe filter and directly purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised. Yield: 64 mg (51% of theory) ESI-MS: (M+H) = 760/762/764 (2 Br) 30 retention time (HPLC-MS): 3.3 min (method A) - ILI) Example 6.1 (R)-1 -(3,5-dibromo-4-hyd roxy-benzyl)-2-(4-morpholin-4-yl-piperidin-1 -yl)-2-oxo ethyl 4-(2-oxo-1,2,4,5-tetrahyd ro-1,3-benzodiazepin-3-y)-piperid ine-1-carboxylate 5 OH N-CN 0 - Br N N 1 0 H Analogously to Example 6i the product could be obtained from 100 mg (0.16 mmol) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5 10 tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate and 31 mg (0.18 mmol) 4-piperidin-4-yl-morpholine. Yield: 72 mg (58% of theory) ESI-MS: (M+H)* = 762/764/766 (2 Br) retention time (HPLC-MS): 3.1 min (method A) 15 Example 6.2 (R)-1 -(3,5-dibromo-4-hydroxy-benzyl)-2-[4-(4-ethoxvcarbonylmethyl-piperazin-1 yl)-piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 20 piperidine-1 -carboxylate H N (N O0 Analogously to Example 6i the product could be obtained from 100 mg (0.16 mmol) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate and 46 mg (0.18 mmoi) ethyl (4-piperid in-4-yl-piperazin-1-yl)-acetate. Yield: 5 mg (4% of theory) ESI-MS: (M+H)* = 847/849/851 (2 Br) 5 retention time (HPLC-MS): 2.9 min (method A) Example 7 (R)-1 -(3-bromo-4-hydroxy-benzyl)-2-(4-cyclohexyl-piperazin-1 -yl)-2-oxo-ethyl 4-(2 10 oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate OH Br NCN O NN -0 H 7a) (ZE)-3-(4-acetoxy-3-bromo-phenyl)-2-acetylamino-acrylic acid Prepared analogously to Example 6a from 75.0 g (366 mmol) 3-bromo-4-hydroxy 15 benzaldehyde and 64.2 g (548 mmol) N-acetylglycine. After cooling of the reaction mixture the product precipitated out and was filtered, washed with water and dried. Yield: 69.8 g (56% of theory) retention time (HPLC): 7.6 min (method D) 20 7b) 3-(3-bromo-4-hydroxy-phenyl)-2-oxo-propionic acid While cooling with ice, 750 mL 4 M HCI was added to a solution of 69.7 g (204 mmol) (Z,E)-3-(4-acetoxy-3-bromo-phenyl)-2-acetylamino-acrylic acid in 300 mL NMP and the reaction mixture was heated to 950C heated (bath temperature) for 2.5 h. It was cooled overnight to RT, combined with 2 L water, extracted three 25 times with 300 mL EtOAc, the combined organic phases were washed twice with 1 L water and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 45.8 g (87% of theory) - 12b retention time (HPLC): 7.8 min (method D) 7c) (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid Under an argon atmosphere 29 mL (356 mmol) triethylamine was added to a 5 solution of 45.0 g (174 mmol) 3-(3-bromo-4-hydroxy-phenyl)-2-oxo-propionic acid in 350 mL THF and the mixture was cooled to -27*C. Then a solution and 114 g (356 mmol) (1R)-B-chlorodiisopinocampheylborane in 200 mL THF was added dropwise such that the temperature did not exceed -20*C. The reaction mixture was stirred for 15 min at -30"C and allowed to warm up to RT within 1 h. 200 mL 10 10% NaOH were added to the reaction solution such that the temperature did not exceed 25*C, stirred for a further 15 min, diluted with 400 mL water, combined with 400 mL MTBE and the aqueous phase was separated off. It was washed with 400 mL MTBE, acidified with 150 mL 4 M HCI, extracted twice with 400 mL EtOAc, the combined organic phases were washed with saturated NaCl solution and dried 15 over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 53.7 g (89% of theory) retention time (HPLC): 4.0 min (method D) 20 7d) methyl (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-prOpionate 2.5 mL concentrated sulphuric acid were added to a solution of 53.6 g (154 mmol) (R)-3-(3-bromo-4-hyd roxy-phenyl)-2-hyd roxy-propionic acid in 250 mL MeOH and the reaction mixture was stirred for 4 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 250 mL EtOAc, the organic phase was washed 25 twice with 100 mL saturated NaHCO 3 and saturated NaC1 solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: quantitative retention time (HPLC): 6.8 min (method D) 30 7e) methyl (R)-3-[3-bromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyll-2 hydroxy-propionate 6.7 mL (39.1 mmol) ethyldiisopropylamine were added to a solution of 10.2 g (34.6 mmol) methyl (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL 5 DCM and the reaction mixture was cooled in the ice bath. Then a solution of 7.9 mL (44.6 mmol) (2-chloromethoxy-ethyl)-trimethylsilane in 20 mL DCM was added. The reaction mixture was stirred for 3 h at RT and then to complete the reaction combined with another 0.67 mL ethyldiisopropyla mine and 0.8 mL (4.5 mmol) (2 chloromethoxy-ethyl)-trimethylsilane and stirred for 1.5 h at RT. The reaction 10 mixture was washed with 5% Na 2
CO
3 and saturated NaCl solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, Cyc/EtOAc 75:25). Yield: 9.6 g (68% of theory) retention time (HPLC): 15.1 min (method E) 15 7f) (R)-2-[3-bromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyll-1 methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1-carboxylate Prepared analogously to Example 6f from 4.55 g (11.2 mmol) methyl (R)-3-{3 20 bromo-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-2-hyd roxy-propionate and 2.75 g (11.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. Yield: 5.46 g (72% of theory) retention time (HPLC): 16.5 min (method E) 25 7g) (R)-2-(3-bromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-vl)-piperidine-1-carboxylate Prepared analogously to Example 6g from 5.40 g (7.98 mmol) (R)-2-[3-bromo-4 (2-trimethylsilanyl-ethoxy-methoxy)-phenyl]-1-methoxycarbonyl-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 7.7 mL 30 (4.2 mmol) methanolic sulphuric acid (0.5 M). The crude product (5.44 g) was further reacted without purification.
-'12/ retention time (HPLC): 9.9 min (method E) 7h) (R)-2-(3-bromo-4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5 tetrahyd ro- 1, 3-benzodiazepin-3-yl)-piperidine-1 -carboxylate 5 A solution of 0.84 g (34.1 mmol) LiOH in 20 mL water was added to a solution of 5.44 g of the crude product from Example 7g in 80 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was eliminated i.vac., the aqueous phase was washed with EtOAc, acidified with 10% HCI and exhaustively extracted with EtOAc. The combined organic phases were washed with saturated 10 NaCl solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was triturated with 90 mL diethyl ether, filtered, the solid was washed with diethyl ether and dried at 45*C. Yield: 4.10 g (89% of theory over 2 steps) retention time (HPLC): 8.2 min (method E) 15 7i) (R)-1 -(3-bromo-4-hydroxy-benzyl)-2-oxo-2-[4-(tetrahydro-pyran-4-vl) piperazin-1-yll-ethyl 4-(2-oxo-1.2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) piperidine-1 -carboxylate Prepared analogously to Example 5.20 from 100 mg (0.19 mmol) (R)-2-(3-bromo 20 4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 3-yl)-piperidine-1-carboxylate and 35 mg (0.21 mmol) 1-cyclohexyl-piperazine. Yield: 62 mg (49% of theory) ESI-MS: (M+H)* = 682/684 (Br) retention time (HPLC-MS): 3.2 min (method A) 25 Example 7.1 (R)-1 -(3-bromo-4-hyd roxy-benzyl)-2-(4-morpholin-4-yl-piperid in-1 -yl)-2-oxo-ethyl 4 (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate -128 OH Br O{O N4 0 H Prepared analogously to Example 5.20 from 100 mg (0.19 mmol) (R)-2-(3-bromo 4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 5 3-yl)-piperidine-1-carboxylate and 36 mg (0.21 mmol) 4-piperidin-4-yl-morpholine. Yield: 66 mg (51% of theory) ESI-MS: (M+H)* = 684/686 (Br) retention time (HPLC-MS): 2.9 min (method A) 10 Example 7.2 (R)-1 -(3-bromo-4-hydroxy-benzyl)-2-(1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1 yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate 15 OH 0 Br N \ IH Prepared analogously to Example 5.20 from 150 mg (0.28 mmol) (R)-2-(3-bromo 4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzodiazepin 3-yl)-piperidine-1-carboxylate and 79 mg (0.31 mmol) ethyl [4,4']bipiperidinyl-1-yl 20 acetate. Yield: 63 mg (29% of theory) ESI-MS: (M+H)* = 768/770 (Br) retention time (HPLC-MS): 3.2 min (method A) 25 -129 Example 7.3 (R)-1 -(3-bromo-4-hydroxy-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1 -yl) piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) 5 piperidine-1 -carboxylate OH 0 Br N NJO N N N O - 0 0 H Prepared analogously to Example 5.20 from 150 mg (0.28 mmol) (R)-2-(3-bromo 4-hydroxy-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin 10 3-yl)-piperidine-1-carboxylate and 79 mg (0.31 mmol) ethyl (4-piperidin-4-yl piperazin-1 -yl)-acetate. Yield: 82 mg (38% of theory) ESI-MS: (M+H)* = 769/771 (Br) retention time (HPLC-MS): 3.1 min (method A) 15 Example 7.4 (R)-1 -(3-bromo-4-hydroxy-benzyl)-2-[4-(4-carboxymethyl-piperazin-1 -yl)-piperidin 1-yl]-2-oxo-ethyl 4-(2-oxo-1 ,2,4,5-tetrahyd ro-1,3-benzod iazepin-3-yl)-piperidine-1 20 carboxylate OH I N-- N O N -- N' OH A solution of 3.0 mg (0.12 mmol) LiOH in 5 mL water was added at RT to a solution of 50 mg (0.07 mol) (R)-1-(3-bromo-4-hydroxy-benzyl)-2-[4-(4-ethoxy 25 carbonylmethyl-piperazin-1 -yl)-piperidin-1 -yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5- -130 tetrahydro-1 ,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 5 mL THF and the reaction mixture was stirred for 1 h. The organic solvent was eliminated i.vac., the aqueous residue was acidified with 1 M HCI and again evaporated down i.vac.. The residue was purified by HPLC; the fractions containing the product were 5 combined and lyophilised. Yield: 28 mg (59% of theory) ESI-MS: (M+H)*= 741/743 (Br) retention time (HPLC-MS): 2.5 min (method A) 10 Example 8 (R)-1 -(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1 -yl)-piperidin-1 -yl] 2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 carboxylate 15 OH N0 ' 0 H 8a) 2,6-dichloro-4-iodo-phenol Solutions of 40.7 g (245 mmol) sodium iodide in 160 mL water and 9.6 mL (143 mmol) ethane-1,2-diamine in 16 mL water were added to a solution of 40.0 g (245 20 mmol) 2,6-dichloro-phenol in 180 mL EtOH and the mixture was stirred for 15 min at RT. Then 62.3 g (245 mmol) iodine was added in small batches to the reaction mixture. To complete the reaction, after 3 h at RT, a further 31.1 g (122 mmol) iodine and 4.8 mL (72 mmol) ethane-1,2-diamine were added and the reaction mixture was stirred overnight at RT. Saturated NaHSO 3 solution was added until 25 an acidic reaction occurred, the mixture was extracted three times with 400 mL EtOAc, the combined organic phases were washed with saturated NaCl solution -131 and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 69.0 g (97% of theory) R= 0.5 (silica gel, n-hexane/EtOAc 4:1) 5 8b) [2-(2,6-dichloro-4-iodo-phenoxymethoxy)-ethyll-trimethylsilane Under a nitrogen atmosphere 33.5 g (242 mmol) K 2
CO
3 and 20.7 mL (117 mmol) (2-chloromethoxy-ethyl)-trimethylsilan were added to a solution of 28.0 g (96.9 mmol) 2,6-dichloro-4-iodo-phenol in 800 mL acetonitrile and the reaction mixture 10 was refluxed for 1 h. The reaction mixture was evaporated down i.vac., the residue was taken up in 300 mL water, extracted three times with 300 mL EtOAc and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was reacted further without purification. Yield: 38.4 g (95% of theory) 15 Rf = 0.83 (silica gel, n-hexane!EtOAc 4:1) 8c) 3,5-dichloro-4-hydroxy-benzaldehyde Under an argon atmosphere 39.4 mL (78.8 mmol) isopropylmagnesium chloride (2 M in THF), diluted with 50 mL THF, was slowly added dropwise to a solution of 20 30.0 g (71.6 mmol) [2-(2,6-dichloro-4-iodo-phenoxymethoxy)-ethyl]-trimethylsilane in 200 mL THF, cooled to -20C. After the addition had ended 11.0 mL (143 mmol) DMF were added at -10*C and the reaction mixture was allowed to come up slowly to RT. After the reaction had ended (monitored by TLC) 100 mL of 2 M HCL were added and the reaction solution was stirred overnight at RT. It was extracted twice 25 with 300 mL EtOAc, the combined organic phases were washed with saturated NaCl solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was purified by recrystallising twice from Cyc/EtOAc (1:1). Yield: 12.0 g (88% of theory) 30 - 132 8d) (ZE)-3-(4-acetoxy-3.5-dichloro-phenyl)-2-acetylamino-acrylic acid A mixture of 12.2 g (64 mmol) 3,5-dichloro-4-hydroxy-benzaldehyde, 11.2 g (96 mmol) N-acetylglycine and 7.86 g (96 mmol) sodium acetate in 50 mL acetic anhydride was heated to 1300C (bath temperature) for 3 h. The reaction mixture 5 was cooled to 900C and 5 mL water were added such that the internal temperature did not exceed 100*C. The mixture was stirred for 2 h at 90*C and 200 mL water were added, whereupon a precipitate formed. This was filtered off, thoroughly washed with water and dried. Yield: 12.0 g (57% of theory) 10 Rf = 0.84 (silica gel, Cyc/EtOAc 1:1) 8e) 3-(3,5-dichloro-4-hydroxy-p henyl)-2-oxo-propionic acid 131 mL 4 M HCI were added at RT to a solution of 12.0 g (36.1 mmol) (Z,E)-3-(4 acetoxy-3,5-dichloro-phenyl)-2-acetylamino-acrylic acid in 70 mL NMP and the 15 reaction mixture was heated to 1300C (bath temperature) for 4 h. After cooling to 00C 200 mL water were added and the mixture was stirred overnight, whereupon a precipitate formed. This was filtered off and dried (2.9 g; purity 95%). The filtrate was extracted three times with 300 mL Cyc/EtOAc (1:3), the combined organic phases were dried and evaporated down i vac.. After the desiccant and solvent 20 had been eliminated 4 g of the product (purity: 80%) were obtained. Yield: 6.0 g (66% of theory) ESI-MS: (M+H)* = 250/252/254 (2C) Rf = 0.30 (silica gel, DCM/MeOH/AcOH 90:10:1) 25 8f) (R)-3-(3,5-dichloro-4-hydroxy-phenyl)-2-hydroxy-propionic acid Prepared analogously to Example 7c from 3.00 g (10.0 mmol) 3-(3,5-dichloro-4 hydroxy-phenyl)-2-oxo-propionic acid (purity: 80%) and 6.34 g (20.0 mmol) (1 R)-B chlorodiisopinocampheylborane. The crude product (1.9 g) was further reacted without purification. 30 - I J-j 8g) methyl (R)-3-(3,5-dichloro-4-hydroxy-phenyl)-2-hydroxy-propionate 2 mL concentrated sulphuric acid were added to a solution, cooled to OC, of the crude product from Example 8f in 30 mL MeOH and the reaction mixture was stirred for 2 h at this temperature. The mixture was neutralised with solid KHCO 3 , 5 diluted with water and extracted exhaustively with EtOAc. The combined organic phases were washed with saturated NaCl solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the product was further reacted without purification. Yield: 1.8 g (75% of theory over 2 steps) 10 8h) methyl (R)-3-[3.5-dichloro-4-(2-trimethylsilanyl-ethoxymethoxy)-p hen'll-2 hydroxy-propionate Under a nitrogen atmosphere 5.79 g (76.6 mmol) 40% KF/A1 2 0 3 were added to a solution of 2.64 g (9.96 mmol) methyl (R)-3-(3,5-dichloro-4-hydroxy-phenyl)-2 15 hydroxy-propionate in 20 mL acetonitrile and the resulting suspension was stirred for a few min at RT. Then a solution of 2.12 mL (12.0 mmol) (2-chloromethoxy ethyl)-trimethylsilane in 20 mL acetonitrile was added and the reaction mixture was stirred for 20 h at RT. The mixture was filtered through Celite and the solvent was evaporated down i.vac.. The residue was further reacted without purification. 20 Yield: 3.80 g (97% of theory) 8i) (R)-2-[3.5-dichloro-4-(2-trimethylsilanyl-ethoxymethoxv)-phenyll-1 methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) Diperidine-1 -carboxylate 25 Prepared analogously to Example 6f from 3.80 g (8.65 mmol) methyl (R)-3-[3,5 dichloro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-2-hydroxy-propionate and 2.12 g (8.65 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. The product was purified by chromatography (silica gel, DCM/MeOH 98:2). Yield: 3.10 g (54% of theory) 30 - I s-t 8k) (R)-2-(3,5-dichloro-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo 1,2,4,5-tetra hydro-1 ,3-benzodiazepin-3-yi)-piperidine-I -carboxylate Prepared analogously to Example 6g from 3.10 g (4.65 mmol) (R)-2-[3,5-dichloro 4-(2-trimethyl-silanyl-ethoxy-methoxy)-phenyl]-1-methoxycarbonyl-ethyl 4-(2-oxo s 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 4.48 mL methanolic sulphuric acid (0.5 M). Yield: 2.49 g (100% of theory) 81) (R)-1-carboxy-2-(3,5-dichloro-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5 10 tetrahydro- 1, 3-benzodiazepin-3-yl)-piperidine-1-carboxylate A solution of 0.42 g (17.3 mmol) LiOH in 20 mL water was added to a solution of 2.49 g (4.64 mmol) (R)-2-(3,5-dichloro-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent 15 was eliminated i.vac., the aqueous phase was washed with EtOAc, acidified with 10% HCl, exhaustively extracted with EtOAc, the combined organic phases were washed with saturated NaCl solution and dried over Na 2
SO
4 . After the desiccant and solvent had been eliminated the residue was triturated with diethyl ether, suction filtered and dried. 20 Yield: 1.60 g (66% of theory) Rf = 0.05 (silica gel, DCM/MeOH 9:1) 8m) (R)-1-(3,5-dichloro-4-hydroxy-benzyl)-2-[4-(4-methyl-piperazin-1-vl) piperidin-1-yll-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3 25 yl)-piperidine-1 -carboxylate Under a nitrogen atmosphere a mixture of 150 mg (0.29 mmol) (R)-1-carboxy-2 (3,5-dichloro-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperid ine- 1 -carboxylate, 63.8 mg (0.34 mmol) 1-methyl-4 piperidin-4-yl-piperazine and 0.17 mL (0.98 mmol) ethyldiisopropylamine in 10 mL 30 DMF was stirred for 5 min at RT. Then 124 mg (0.32 mmol) HATU was added to the reaction mixture, which was then stirred for 4 h. This was evaporated down i.vac. and the residue was purified by chromatography (silica gel, gradient DCM to DCM/MeOH 85:15). The fractions containing the product were combined, evaporated down i.vac. and filtered through aluminium oxide, wherein the product was eluted with DCM/MeOH 9:1. The mixture was evaporated down i.vac., the 5 residue was triturated with diethyl ether, and the product was filtered and dried. Yield: 43 mg (22% of theory) ESI-MS: (M+H)* = 687/689 (2CI) retention time (HPLC-MS): 2.8 min (method A) 10 The following compounds were prepared analogously from in each case 150 mg (R)-1-carboxy-2-(3,5-dichloro-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro 1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and the corresponding amount of amine: OH 0 : ' CI I R 1 0 H 15 Example R Yield (%) Mass retention spectrum time HPLC (method) 8.1 21 687/689 2.6 [M+H]* (A) 8.2 39 672/74 3.1 [M+H]* (A) 8.3 38 686/688 3.1 [M+H]*
(A)
Example 8.4 (R)-1 -(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-2-(4-piperidin-4-y-piperazin-1 -yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate 5 OH - H H Under a nitrogen atmosphere a mixture of 150 mg (0.29 mmol) (R)-1-carboxy-2 (3,5-dichloro-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3 benzodiazepin-3-yl)-piperidine-1-carboxylate, 105 mg (0.34 mmol) tert-butyl 4 10 piperazin-1-yl-piperidine-1-carboxylate (used as the hydrochloride salt) and 0.17 mL (0.98 mmol) ethyldiisopropylamine in 10 mL DMF was stirred at RT for 5 min. Then 124 mg (0.32 mmol) HATU was added to the reaction mixture, which was then stirred for 4 h. This was evaporated down i.vac. and the residue was purified by chromatography (silica gel, gradient DCM to DCM/MeOH 85:15). The fractions 15 containing the product were combined and evaporated down i.vac.. The residue was taken up in 10 mL formic acid and stirred for 3 h at RT. The mixture was evaporated down i.vac., the residue was taken up in saturated NH 3 solution, extracted exhaustively with EtOAc, the combined organic phases were washed with saturated NaCl solution and dried over Na 2
SO
4 .After the desiccant and 20 solvent had been eliminated the residue was triturated with diethyl ether, suction filtered and dried. Yield: 47 mg (24% of theory) ESI-MS: (M+H)* = 673/675 (2C) retention time (HPLC-MS): 2.6 min (method A) 25 Example 8.5 (R)-2-4,4'-bipiperidinyl- 1 -yl-1 -(3,5-dichloro-4-hydroxy-benzyl)-2-oxo-ethyl 4-(2-oxo 1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1 -carboxylate 5 H N4 m ' 0 H Prepared analogously to Example 8.4 from 150 mg (0.29 mmol) (R)-1 -carboxy-2 (3, 5-dichloro-4-hyd roxy-phenyl )-ethyl 4-(2-oxo-1 ,2,4, 5-tetrahyd ro-1 ,3 benzod iazepin-3-yl)-piperidine-1 -carboxylate and 92 mg (0.34 mmol) tert-butyl 10 [4,4']bipiperidinyl-1 -carboxylate. Yield: 84 mg (44% of theory) ESI-MS: (M+H) 4 = 672/674 (2Cl) retention time (HPLC-MS): 3.1 min (method A)

Claims (4)

1. CGRP antagonists of general formula I O B R N O N R 2 0 N 5 - H wherein B denotes a group selected from 10 Br CI Br OH OH OH OH * CI * Br * C H CH 3 CF 3 OH NH 2 * CH 3 * CH , * CF 3 CF 3 and CH 3 15 R 1 and R 2 together with the enclosed nitrogen atom denote a group of general formula 11 R 4 N ' -139 wherein Y1 denotes the carbon atom or, if R 4 denotes a free pair of electrons, it 5 may also denote the nitrogen atom, R 3 denotes a cyclopentyl, cyclohexyl or cycloheptyl group or R 3 denotes a heterocycle selected from a morpholin-4-yl, 1, 1 -dioxo 10 thiomorholin-4-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl or pyrrolidin-1-yl group, wherein the above-mentioned monocyclic heterocycles in the ring may be mono- or disubstituted by hydroxy, methyl, ethyl, trifluoromethyl, 15 hydroxymethyl or hydroxyethyl groups, or may optionally additionally be monosubstituted by a hydroxycyclopropyl, trifluoromethylcarbonylmethyl, amino, carboxy-carbonyl, methoxycarbonyl, ethoxycarbonyl-carbonyl, carboxymethyl, carboxyethyl, ethoxycarbonyl methyl, ethoxycarbonylethyl, carboxy-ethylcarbonyl, ethoxycarbonyl-ethylcarbonyl, aminosulphonyl, 20 methylaminosulphonyl, dimethylaminosulphonyl, methylsulphonyl, ethylsulphonyl, isopropylsulphonyl, cyclopropylsulphonyl, (hydroxyamino) carbonylmethyl, hydroxy-(methyl)-aminocarbonyl-methyl or methoxyaminocarbonyl-methyl group, wherein the substituents may be identical or different and may be bound to a ring carbon or ring nitrogen 25 atom, or the above-mentioned monocyclic heterocycles in the ring may be monosubstituted by a carboxy group, if this carboxy group is not bound via a nitrogen atom, and 30 R 4 denotes the hydrogen atom, if Y' denotes the carbon atom, or R 4 denotes a free pair of electrons, if Y' denotes the nitrogen atom, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the 5 physiologically acceptable salts thereof with inorganic or organic acids or bases.
2. The following CGRP antagonists of general formula I according to claim 1: No. Structure OH (1) Ky'~~\~\ .,&Br H O OH 0 cNN O N H O OH H O SOH (4) c2N-c~ j,&Br H O OH (5) N O - 114 1 No. Structure (6) NN N O H O CH (7) N N NN(D N N yOH H O ( ) OH OeN GNLO>NZ N OH (9 N N O N0 OH HH - N N OCNN ,O H O OH cN N O Ny N -,OH H O OH H O OH c NC NIO; N\ N NH H O (13)H HO0 - 142 No. Structure h O H ->N e0NO OH (14) N N N O H 0 OH Br OH (1) OH H O Br OH (17) 0 O H 0 Br OH N'' N O N H H OB (17) N IN NO CQ 0 H O OH (18) N N N I HOy HO0 HO0 No. Structure OH N N O0 , QN 0 H O OH r:N-N O ,N N "S H4 0 NOH H O (2) NcA- N -\ & OH OHN H O (26) NNON4N NH2 H O OH (27) ( J N43 N5 O BN N N NH NH O Br (2 7 ) N N0 N N N~ Is, H O OH -> o N ON NN NH, H 0 - 144 No. Structure h OH (29) N ,-/ N ' N H O OH (30) N N SN r ' N-CN\.>j' 'r, H O &OH c N N ON N N .4 0 H O OH N C N N N H 0 OH N N O N N O (34) f, &B \ H OY (3N) N O H O OH (35) N N N HN N O N N H O (34) H 01 - 145 No. Structure OH (37) N N O N N HO k 0OH (38) N OH (39) N (40) N\N ON NN HO 0 OH (41) r O N0O N N N (42) cc' H O N ( 43) H O &OH cN 0 No. Structure OH (45)N NO NN HO SOH (46) N H O OH (47) N N0O N N H O I" OH H O N~OH (49) - N-CNIO Ni N1-N H 0 OH (52) Br N .'' NN-t- ")O H H 0 OH OH (52) Nl _ NJO N O' H -147 No. Structure OH (53) N NNc hOH (54) NN N BrN N HOO OH (56) H ( 5 8 )N N O NN HO 0 OH (59)N NON H H H (60)N N O0 No. Structure OH (61) N N O H O I NCNI Oy NH COHH (63) N9" N N ' OHH (66 )N N O N N N OH (67) N H O , OH (66) Nr N9 OH (68) N H O - 149 No. Structure OH ( 6 9 ) NN HOO OH Br (71) INO( N O , N N O NH 0 0 (7O H OH (73) NH N O NN ' Br OH ( 7 4 ) N ON B H O Br OH (75) NO& N Br H 0 H No. Structure Br OH (76) N N4 N H O Br OH (77) NBrO N H O H Br OH (78) N C N O N B N - N { 0 N '~ H 00 Br OH (79) N O NBO.H H 0 00 (80) . 0 ~OH H 0 OH (81) N O .H H 0 LhOH (82) rN O N DN O H O -151 No.1 Structure (83) O N4 0 H 0 (84) 0 JOH QN-NO>CZO HO0 OH (85)
12-G 0'V,&~ HO0 Br HOH (87) 1$o HO0 ( 8 ) N & H OONJN ?'rN\,N,,-(,OH HO0 Br (89) & O HO0 (90) N> O aKi-\N-CNIO:r ~O H 0 CF, - 152 No. Structure OH (91)N NIO N OH H O OH (92) N N N N NN H4 0 ( 9 3 ) N N O NN O H O Br (9 ) H- 0r O H (95) N N O ; N NH2N H 0 (96) c2N-cN O N N0 H O (97) QN-CN O rN N, OH (98 ) N N O N H O -153 No. Structure OCN-C & O6OH 0>(-' --- \,,, N OH cc 0 HO0 (100)hlI HO0 Br (101) &OH (1 2 0 OH cI2NGNBr HO (104) UI~ 00 ' N4Y cN 0S HO 0 (105) hO HV 0 (106) OH HO0 No. Structure (107) N O N N NH H O (108) N NOH N N H O CH (109) HOH (110) N N O N N H O H O OH H O (113) 01, H O OH killN) O N N HO0 -155 No. Structure (115) c NcN~ O N N OOH (116) N .O N N (117) N- N O N Ns ~0 H O OH (118) N -O H O Br HOO Br (1 2 0 )N N O NN O Br (122)%NO Nj- NON NN No. Structure H& 0OH (123) H OH "&OH (124) N N N N N (1 6) N NC 1 O N N - O' N 0 Br O0H (1 2 5 ) NN H 0 OH (126) 0 N H O (12N H O (128) h O OH (129) N ON N H O (130) -\- N 0 J HO0 -157 No. Structure (131) 0 N 5 N O OH ~ J OH H O OH (134) N N O N N"OH HOO OH (136) H 0 OH (137) N N IO N N H H H ON ( 1 3 8 ) 'N C N 0 0 0 HO0 -101 No. Structure OH HH (139) Br HOOH HO 0 (142)N N O NN H H O (4 , OH HO 0 N.H HO O H 0 HO0 (145) N 9 H OH (14 ) NO N O OHN N No. Structure (14 7 ) N ON HO 0 (1 OH (48) N ' H 0 49) N H O (150) NOH NXrNOH N4 0 H O hOO (1 5 ) O H4 0 H '0 0 O&O (152) N2 O N N O, OH 0 OH (153) N N H~O0 - 160 No. Structure ( 1 5 4 ) NOHO NN ' Br O OH (155)N N O N 0 - OH (156 N N O N fl N H O H Br OH (157) No N O N\ N OO (15)N H 0 H H OH (159)N N O N N Br 0 brO&H (159) )O :N H 0 0 OH (160) N N rN O ' 0 H 0 0 H - 161 No. Structure Br (16 1) N H 0 Br OH ( 1 6 2 ) N N O NO . (163)O N N N o H O OH (163) N N4 0 H O OH (166) N 0 N4 0 HO0 OH (165) HO0 OH N4 0 HO0 (167)N HO0 No. Structure OH (168) N OH N4 0 H O ,,&H (169) H O (170) N N0 O HN N OH H 0 OH (171) H4 H (172) N NO NN O H O HOH H O -OH (175) N H O H OH (175) N. N,_NN H - 163 No. Structure -OH NN (176) ONNO N O N O H H O OH (177) N N ON ' H O N OH (17)NO H O OH (18) N N O N N H Hj 0 N4N (179) H O OH C8' o N-N0 O NN H O H OH (182) HO0 No. Structure
98-CNNIO N N\ H4 O H O - OH (185) N 0 N4 0 HOO ( 1 8 6 ) N N O N N H H- OH (185) r ~N N O NN NH0 H O OH ( 1 8 6 )N O N N N N H O (18 9 ) N\ N ON 0 H (1 88)N N N N H 0 NH, HO0 (189) 00 &NNo NH H OH 0NN N4N HO0 -165 No. Structure HOH HOO (194) N()I N I N, N,, Nl, N -' I OH (196) N O N0 HOH S(197) N NO N (196) N H O - 166 No. Structure OH (199) H OO OH (200)N - N O N N N F N4 N H 0 0 Z&H (200) NNFON N jNN HO0 OH (202) NO N O NN (20)O N0 - H N4 0 (20) H 0 C H (204) NN HO (D O 0 j NOH N4 0 (25)H 00 H 0OH N4 0 (206)H0 -167 No. Structure OH (207) NI N ON 0 H O OH ( 2 0 8 )N N O NN O , H O OH (2 0 9 ) N N O N N N O H O OH (210) NO. HQ 0 HOO H O (212) HO iNNJH OH jN N OtNN"N O.H 1.4 0 H O OH N4 N (214) ,I N 4,, O N H OH 1N-N O NoNO' No. Structure OH (215) N 0 HOH ( 2 1 6 ) N N O N N H O OH (2 17 ) N O , N4 0 H O OH (218) N N O NN ZNN"O N4 0 0 HH (219) O \N NH N4 0 0 HH H HNH 0 OH HOH -169 No. Structure SOH H 223) O H 0 - OH (224) N HO H OH (225) 9 H me>N-NIO NNO HO 0 HO H (227) 9: H H O N ZH (227) 9 HO 0 (229) N4O0 (230) ,, N O HO 0 No. Structure OH (231) N 0 0 HO0 (232) C N- NlO N - OH N4 N (232) NO N O H 0 0 - OH (233) KYN l .CN O N N H 0 H 0 OHO (234) N NO N H OH IYNI HO0 OH (236) Ol H 0 0 N O HO0 - l I No. Structure OH (238) 0K & NCN O N Q H O OH (239) NO N N HO H OH (240) N0 O HOH OH OO (2O 1) NNN H O (242) N N- N H OH (243)N-(N N-, HO 00 (24)0e&,O HO0 No. Structure (245) 02(AI h OH (248) -aNC HO0 (247) OHC HO0 HOH (251) , HO0 (252) 40 OCAN-CNI ' ' HOH - 173 No. Structure OH (2 5 3 ) NN NCNI0 (254) ) N N 0 , H O (254) OHH H 0 H O (256) N N O NC N OH H O &OH (257) NH N O NHN H O (258) NiNO yN~ N NH2 H O OH (259) H N OH OH (260) Ny N\ N H 0 No. Structure OH (261) N N O N N H O (262) KYN5\N ON H O OH (263) N H 0 (2 64 ) bN OON H N N H O >OH (265) NQN O0N N H O OH (2 6 6 ) N N O H O OH (267) N $ , H O OH (268) N NjO N N, H O -175 No. Structure OH (269) N NO N N H O (270)N NO N N ONJNOYZ N4 0 HO O (27 ) N N , O ON H HO 0 (274) N O H O b OH (275) N5N O N N OH H OO (276) NOH H O H 0OH hOH (276) NO N , O NV N -176 No. Structure OH N4 N (277) QN. N O o~N N NH2 HO0 OH (278) N N \H H 0 OH (279) NO N H O (280) N N N HOH (281) N N O N H O NH2 <281) hN N H O 0 N4N H O NH, (283 ) N N : N H O NH, N4 N 0 H0 No. Structure . NH 2 (285) N , N ' HO N (286) O NN N O N N OH H O NH. (2 87 ) N N N O H O SNH 2 H O NH. (289) N \ N, NH H O NH, (290) yN N N N.NH2 (21/ NAO fN N H O (29) )6C-GN HOH (292)N - NI O yN N N HNO HO0 No. Structure . NHz (293) N N N H O F1 3 ( 2 9 4 ) N N C N 0 H O ( 2 9 5 ) N N N O -CWKZ O-YNV, ,,: H O (296) NOF 3 N4 0 HO0 Z&F ( 2 9 7 ) N O H O (299) 0 H O (300) A&\. HO -179 No. Structure N(30) N N NH, H O (302) N HNC O OH H 0 OH F (303) : N, N H O (304) YN NiO N N cl,- -\N-C 0 N, S'O H O H O (307) N N Nl N H O HO0 (3 0 8 ) N: N O CF H O - 180 No. Structure (309) 0 H H O OCF (310) NC N O NH H O CF3 <311> fe N- N O' N N'H H O (312)O 10CF (3>N N -O'y\ N, NOH N4 00 H O (313) N H 0OOH <3- c N N N 0 H 0 OaCF, (315) N0 N\ N NH H O ZCF (316) N0 N OH H O0O No. Structure 0 (317) H O (318) NO N H O (3 1 9 ) N N O N N H O 0O N (320) N N H O (321) N N O N N N- 0 H O <322> N N O yN\ N, H H 0 (322) O N N H N4 0 H O HOO (324) N H O -182 No. Structure HO (326) N40 HO0 (327) N j N 0 N O HO OH the enantiomers, the diastereomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 3. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (1 ), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), 10 (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76), (77), (78), (79), (80) and (81), 15 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, - 103 particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 4. The following CGRP antagonists of general formula I according to claim 2, 5 which are selected from the group consisting of: (82), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (103), (104), (105), (106), (107), (108), (109), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), 10 (122), (123), (124), (125), (126), (127), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (144), (145), (146), (147), (148), (149), (150), (151), (152), (153), (154), (155), (156), (157), (158), (159), (160), (161), and (162), 15 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 20 5. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (163), (164), (165), (166), (167), (168), (169), (170), (171), (172), (173), (174), (175), (176), (177), (178), (179), (180), (181), (182), (183), (184), (185), (186), 25 (187), (188), (189), (190), (191), (192), (193), (194), (195), (196), (197), (198), (199), (200), (201), (202), (203), (204), (205), (206), (207), (208), (209), (210), (211), (212), (213), (214), (215), (216), (217), (218), (219), (220), (221), (222), (223), (224), (225), (226), (227), (228), (229), (230), (231), (232), (233), (234), (235), (236), (237), (238), (239), (240), (241), (242) and (243), 30 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 6. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (244), (245), (246), (247), (248), (249, (250), (251), (252), (253), (254), (255), 10 (256), (257), (258), (259), (260), (261) and (262), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic 15 acids or bases. 7. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: 20 (263), (264), (265), (266), (267), (268), (269), (270), (271), (272), (273), (274), (275), (276), (277), (278), (279), (280) and (281), the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, 25 particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 8. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: 30 (282), (283), (284), (285), (286), (287), (288), (289), (290), (291), (292) and (293), - 185 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 9. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (294), (295), (296), (297), (298), (299), (300), (301), (302), (303), (304) and (305), 10 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 15 10. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (306), (307), (308), (309), (310), (311), (312), (313), (314), (315) and (316), 20 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 25 11. The following CGRP antagonists of general formula I according to claim 2, which are selected from the group consisting of: (317), (318), (319), (320), (321), (322), (323), (324), (325), (326) and (327), 30 - '100 the enantiomers thereof, the diastereomers thereof, the hydrates thereof, the mixtures thereof and the salts thereof, as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases. 5 12. Physiologically acceptable salts of the compounds according to one of claims 1 to 11 with inorganic or organic acids or bases. 13. Pharmaceutical compositions, containing a compound according to one of 10 claims 1 to 11 or a physiologically acceptable salt according to claim 12 optionally together with one or more inert carriers and/or diluents. 14. Use of a compound according to one of claims 1 to 12 for preparing a pharmaceutical composition composition for the acute and prophylactic treatment 15 of headaches, particularly migraine or cluster headaches, for the treatment of non-insulin-dependent diabetes mellitus ("NIDDM"), complex regional pain syndrome (CRPS1), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory 20 diseases of the joints (arthritis), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resultant reduced circulation of the blood, e.g. shock and sepsis, for alleviating pain or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased 25 blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma. 15. Process for preparing a pharmaceutical composition according to claim 13, characterised in that a compound according to one of claims 1 to 12 is 30 incorporated in one or more inert carriers and/or diluents by a non-chemical method. -187 16. Process for preparing the compounds of general formula I according to one of claims 1 to 12, characterised in that (a) a piperidine of general formula III NH H is reacted with a carbonic acid derivative of general formula IV 100 10 y2-< y3 wherein Y 2 and Y 3 represent nucleofugic groups, which may be identical or different, and with a compound of general formula V x H,'O Z 15 0 wherein B is defined as in claim 1 and Z' denotes a protective group for a carboxy group, or 20 (b) a carboxylic acid of general formula VI B 0 NJ 0 / \ O 0 - H wherein B is defined as in claim 1, is coupled with an amine of general formula VII 5 H-NR' R 2 , wherein R' and R 2 are defined as in claim 1, wherein before the reaction is carried out any carboxylic acid function, primary or secondary amino function or hydroxy function present in the groups R' and R 2 of the amine of general formula Vil is 10 protected by conventional protecting groups and any protecting groups used are cleaved again after the reaction, or (c) a compound of general formula Vill B 0 N kO Nu N 0 15 H wherein B is defined as in claim 1 and Nu denotes a leaving group, is coupled with an amine of general formula Vil 20 H-NR'R 2 , - IOU wherein R' and R 2 are defined as in claim 1, wherein before the reaction is carried out any carboxylic acid function, primary or secondary amino function or hydroxy function present in the groups R 1 and R 2 of the amine of general formula Vil is protected by conventional protecting groups and any protecting groups used are 5 cleaved again after the reaction, and if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or 10 a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
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