OA18375A - Indole derivatives. - Google Patents
Indole derivatives. Download PDFInfo
- Publication number
- OA18375A OA18375A OA1201700391 OA18375A OA 18375 A OA18375 A OA 18375A OA 1201700391 OA1201700391 OA 1201700391 OA 18375 A OA18375 A OA 18375A
- Authority
- OA
- OAPI
- Prior art keywords
- diazepino
- indol
- dihydropyridin
- methoxy
- mmol
- Prior art date
Links
- 229940054051 antipsychotic Indole derivatives Drugs 0.000 title 1
- 150000002475 indoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 101700067919 MCHR1 Proteins 0.000 claims abstract description 30
- 102100009276 MCHR1 Human genes 0.000 claims abstract description 30
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 98
- -1 5-chloro-pyridin-2-yl Chemical group 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 27
- 208000008589 Obesity Diseases 0.000 claims description 21
- 235000020824 obesity Nutrition 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Chemical group 0.000 claims description 11
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 10
- 206010057666 Anxiety disease Diseases 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 9
- 206010009191 Circadian rhythm sleep disease Diseases 0.000 claims description 8
- 208000008466 Metabolic Disease Diseases 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 201000009032 substance abuse Diseases 0.000 claims description 8
- 231100000736 substance abuse Toxicity 0.000 claims description 8
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000004584 weight gain Effects 0.000 claims description 7
- 235000019786 weight gain Nutrition 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- KMAKOBLIOCQGJP-UHFFFAOYSA-M indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)[O-])=CNC2=C1 KMAKOBLIOCQGJP-UHFFFAOYSA-M 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 238000006011 modification reaction Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- GYCYNQGNDPHXCO-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=CC(N(C=C1)C1=CC=2C(=C3N(C=2C=C1)CCN(CC3)C(C)C)Cl)=O Chemical compound C(C1=CC=CC=C1)OC1=CC(N(C=C1)C1=CC=2C(=C3N(C=2C=C1)CCN(CC3)C(C)C)Cl)=O GYCYNQGNDPHXCO-UHFFFAOYSA-N 0.000 claims 1
- BSYFXFLGOGQHFU-UHFFFAOYSA-N pyrrolo[2,3-g][1,2]benzodiazepine Chemical class N1=NC=CC=C2C3=NC=CC3=CC=C21 BSYFXFLGOGQHFU-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 254
- 239000000203 mixture Substances 0.000 description 137
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 136
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 118
- 239000000243 solution Substances 0.000 description 92
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 78
- 239000012458 free base Substances 0.000 description 76
- 239000011541 reaction mixture Substances 0.000 description 71
- 230000015572 biosynthetic process Effects 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 66
- 230000002194 synthesizing Effects 0.000 description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 52
- 239000011976 maleic acid Substances 0.000 description 52
- 239000012265 solid product Substances 0.000 description 49
- 239000012071 phase Substances 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 35
- 239000003480 eluent Substances 0.000 description 34
- 239000003463 adsorbent Substances 0.000 description 31
- 239000012043 crude product Substances 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- ORRDHOMWDPJSNL-UHFFFAOYSA-N Melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 22
- 108060004714 Melanin-concentrating hormone Proteins 0.000 description 22
- 239000012267 brine Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 102400001132 melanin-concentrating hormone Human genes 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 21
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 13
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cells Anatomy 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- 230000003042 antagnostic Effects 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000037406 food intake Effects 0.000 description 6
- 235000012631 food intake Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 102000030939 Melanin-concentrating hormone receptors Human genes 0.000 description 5
- 108010047068 Melanin-concentrating hormone receptors Proteins 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
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- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
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- 235000019270 ammonium chloride Nutrition 0.000 description 4
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 4
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- 230000037396 body weight Effects 0.000 description 3
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- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to compounds of the general form (I). The present invention relates to new substituted diazepino-indole derivatives of the general formula, and to pharmaceutically acceptable salts thereof, as well as to pharmaceutical compositions comprising such compounds, to new intermediate thereof, as well as to the use of such compounds in treatment or prevention of disorders associated with melaninconcentrating hormone receptor 1 activity.
Description
FIELD OF THE INVENTION
The présent invention relates to new substituted diazepino-indole dérivatives of the general formula (I), and to pharmaceutically acceptable salts thereof, as well as to pharmaceutical compositions comprising such compounds, to new intermediate thereof, as well as to the use of such compounds in treatment or prévention of disorders associated with melanin-concentrating hormone receptor 1 activity.
BACKGROUND OF THE INVENTION
Melanin-concentrating hormone (MCH), a cyclic neuropeptide, consist of 19 amino acids, which was originally described in salmon pituitary and isolated from its extract (Kawauchi et al., Nature 305: 321-323 (1983)). Later MCH was identified in mammals also as a cyclic nonadeca peptide.
The first MCH receptor (which was called later MCHR1), a G-protein coupled receptor (GPCR), was identified with “reverse pharmacological” approach, namely it was shown, that in mammals MCH is the natural ligand of orphan GPCR (SLC1). Thereafter a second MCH receptor (MCHR2) was also identified. In human both receptor sub-type can be found, while in rodents only MCHR1.
The melanin-concentrating hormone receptor 1 (MCHR1) plays an important rôle in the régulation of the energy homeostasis, food intake, reward as well as the nutrition behaviour. The rôle of MCH in the energy homeostasis and food intake of mammals has long been studied (Qu et al., Nature 380: 243-247 (1996); Rossi et al., Endocrinology 138: 351-355 (1997); Shimada et al., Nature 396: 670-674 (1998)).
The neurons, producing the melanin-concentrating hormone (MCH), can be found in the tuberal région of hypotalamus, which is the integrating center of the neurohumoral régulation of the energy homeostasis and stress reactions. MCHR1 can be found in many régions of the brain and is distributed mainly in areas implicated in the régulation of nutrition, energy balance, émotion and stress. (Hervieu et al., Eur J Neurosci 12: 1194-16 (2000), Saito et al., J Comp Neurol 435: 36-40 (2001), Borowsky et al., Nat Med 8: 825-30 (2002)). The MCH is expressed mainly in the latéral hypothalamic area as well as in the subthalamic zona incerta.
In rodents the MCH simultaneously stimulâtes food intake as well as energy balance. (Pissios and Maratos-Flier, Trends Endocrinol Metabol 14: 243-48 (2003); Pissios 5 et al., Peptides 30: 2040-44 (2009)). MCH expression is increased in fasted animais and in leptin-deficient ob/ob mice. Upon acute icv administration of MCH food intake substantially increased and catabolic activity decreased. (Qu et al., Nature 380: 243-47 (1996)). Cronic icv adminsitration of MCH results in an encreased calorie uptake and a significant increase in bodyweight. Furthermore the treated animais showed - similarly to 10 the human metabolic symptoms - an increased glucose, insulin and leptin level (Gomori et al., Am J Physiol Endocrinol Metab 284: E583-88 (2003)).
In line with this élimination of the MCH gen (KO) makes the mice résistant to dietinduced obesity (DIO = diet-induced obesity). Transgenic mice overexpressing the MCH gen consumed 10% more calories and gained 12% more weight than controls on high fat 15 diet. High blood glucose and insulin-resistance also appeared, consistent with a prediabetic state (Ludwig et al., J. Clin. Invest. 107, 379-386 (2001)). The MCHR1 KO mice, exhibited slightly increased food intake, but are résistant to diet-induced obesity and their metabolism is increased (Shimada et al.: Nature 396: 670-674 (1998)).
Rodents treated with MCHR1 antagonist showed a decreased food intake and better 20 metabolic condition, especially when they were placed on a high-fat diet (Pissios et al., Peptides 30:2040-44 (2009); Ito et al., Eur J Pharmacol 624: 77-83 (2009)).
MCHR1 antagoniste may play a rôle not only in the régulation of body weight, but also in the treatment of anxiety and dépréssion (Smith et al., Neuropsychopharmacol 31: 1135-45 (2006); David et al., J Pharmacol Exp Ther 321: 237-48 (2007); Gehlert et al., J 25 Pharmacol Exp Ther 329:429-38 (2009)).
The MCHR1 is also involved in the patogenesis of the experimentalcolitis which is considered to be the relevant modell of the human inflammatory bowel disease (e.g. Crohn disease). The systemic application of MCHR1 antibody or MCHR1 antagonist to rodents dicreased the severity of the experimentally induced acut inflammation of the colon and 30 increased the rate of recovery (Kokkotou et al., Proc Natl Acad Sci USA 105: 10613-18 • i »
(2008); Fitzpatrik et al., AGA Abstracts, Gastroenterology 136 (5 supl l)A-403 (2009); Ziogas et al., Am J Physiol Gastrointest Liver Physiol 304: G876-84 (2013)).
The MCHR1 plays also a rôle in the development of acut intestinal inflammatiom which was proved in mice treated with C. difficile A toxin (Kokkotou et al., Gut 58: 34-40 (2009)).
Antagonization of MCHR1 with low molecular weight substances is consîdered to be a promising strategy for the treatment of obesity, dépréssion, anxiety and inflammatory bowel diseases. The following patent applications deal with MCH receptor antagonists: Tempest et al. W02005/019240; Washbum et al. W02008/134480; Suh et al. W02008/140239; Stein et al. W02009/009501; Johansson et al. WO2010/125390; Christensen et al. W02010/141539; Lin et al. WO2011/127643; Oost et al. WO2013/131935; Qinétal. WO2013/149362; Ahmadétal. W02014/039411.
Since the discovery of the MCH receptors a large number of compounds with antagonistic activity were described. Despite several clinical investigations none of the compounds reached the therapeutic application, even Phase 1 clinical studies were carried out only with 6 compounds. The first investigations were carried out in 2004 by the Glaxo Group and Amgen with the compounds called GW856464 and AMG-076/071, respectively, with obesity indication. According to the Phase lb “proof of confidence” investigation of Bristol-Meyers Squibb (2011) the compound BMS-830216 proved to be inactive. The last Phase 1 investigation was launched by Astra-Zeneca in March 2014 and was terminated in October. In most cases the poor pharmatokinetic profile and the CYP induction were responsible for the failor of these compounds.
There is a need for developing such melanin-koncentrating hormon antagonists, which would be suitable for the treatment and/or prévention of obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfunctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
SUMMARY OF THE INVENTION
Our aim was to synthesize new, sélective and drug-like MCHR1 antagonists.
Surprisingly it was found, that the synthesized new diazepino-indole dérivatives, which were not known in the literature, show MCHR1 antagonist activity profile.
The présent invention relates to compounds of the general formula (I), as well as to salts, stereoisomers, géométrie isomers, diastereomers, hydrates, solvatés, and polymorph modifications thereof
wherein the meaning of A is CH or nitrogen atom;
the meaning of R is hydrogen or halogen atom or Ci-Cô straight or branched chain alkyl group;
the meaning of R1 is hydrogen or halogen atom or
Ci-Ce straight or branched chain alkyl group, or
Ci-Cô straight or branched chain alkoxy group, or mono- or polyhalogenated Ci-Cô straight or branched chain haloalkyl group;
the meaning of R2 is hydrogen or halogen atom or
Ci-Cô straight or branched chain alkyl group, or
Ci-Cô straight or branched chain alkoxy group or mono- or polyhalogenated C1-C4 straight or branched chain haloalkyl group;
the meaning of R3 is hydrogen or
Ci-Cô straight or branched chain alkyl group, optionally substituted with C3-C6 cycloalkyl group, or mono- or polyhalogenated Ci-Cô straight or branched chain haloalkyl group; or
C3-C6 cycloalkyl group, or
Ci-Cr, straight or branched chain alkanoyl group.
t
The invention further relates to pharmaceutical compositions containing a compound of the general formula (I).
According to a further embodiment the compounds of the general formula (I) of the présent invention or the pharmaceutical compositions containing them can be used for the treatment and/or prévention of obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfonctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
The présent invention forther relates to the use of compounds of the general formula (I) for manufacturing pharmaceutical compositions, which can be used for the treatment and/or prévention of obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfonctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
DETAILED DESCRIPTION OF THE INVENTION
The présent invention relates to compounds of the general formula (I), as well as to salts, stereoisomers, géométrie isomers, diastereomers, hydrates, solvatés, and polymorph modifications thereof
wherein the meaning of A is CH or nitrogen atom;
the meaning of R is hydrogen or halogen atom or Ci-Ce straight or branched chain alkyl group;
the meaning of R1 is hydrogen or halogen atom or
Ci-Cô straight or branched chain alkyl group, or
Ci-Cô straight or branched chain alkoxy group, or mono- or polyhalogenated Ci-Cô straight or branched chain haloalkyl group;
the meaning of R2 is hydrogen or halogen atom or
Ci-Cô straight or branched chain alkyl group, or
Ci-Cf, straight or branched chain alkoxy group or mono- or polyhalogenated C1-C4 straight or branched chain haloalkyl group;
the meaning of R3 is hydrogen or
Ci-Cô straight or branched chain alkyl group, optionally substituted with C3-C6 cycloalkyl group, or mono- or polyhalogenated Ci-Cô straight or branched chain haloalkyl group; or
C3-C6 cycloalkyl group, or
Ci-Cô straight or branched chain alkanoyl group.
We note that the term alkyl group as used herein refers to Ci-Cô straight or branched chain alkyl groups.
The term “alkoxy” as used herein refers to -O-alkyl groups, wherein the meaning of alkyl groups is as defined above.
The term “halogen atom” as used herein refers to for example fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.
The term “cycloalkyl” or “C3-C6 cycloalkyl” as used herein refers to monovalent carbocyclic groups of 3 to 6 carbons, preferably 3 to 5 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, cyclobutyl and cyclopropyl groups are particularly preferred.
The term “haloalkyl” or “Ci-Cô haloalkyl group” as used herein refers to such alkyl groups, which are substituted with one or more halogen atom(s), preferably with fluorine atom(s). Halogen-(short-chained alkyl) groups are for example -CF3, -CHF2, -CH2CI, CH2CH2F, -CH2CF3, -CH(CF3)2, -CF2-CF3 groups as well as the groups specifically described in the examples.
t
The term “alkanoyl” as used herein refers to alkyl-C(O)- groups, wherein the meaning of term “alkyl” is as defined above and the “alkyl” group is single bonded to the carbon atom of the -·C(O)- carbonyl group.
A preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R3 is:
- hydrogen atom or acetyl group,
- C1-C4 straight or branched chain alkyl group, optionally substituted with C3-C6 cycloalkyl group,
- C3-C6 cycloalkyl group, or
- C1-C4 straight or branched chain haloalkyl group.
A further preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R3 is:
- hydrogen atom,
- C1-C4 straight or branched chain alkyl group, optionally substituted with C3-C4 cycloalkyl group or fluorine atom, or
- C3-C4 cycloalkyl group.
A more preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R3 is methyl, ethyl, isopropyl, cyclopropylmethyl, cyclobutyl or fluoroethyl group, most preferably isopropyl or cyclopropylmethyl groups.
A preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R2 is hydrogen or halogen atom or trifluoromethyl or C1-C3 alkyl group, more preferably hydrogen, fluorine or chlorine atom or methyl group, most preferably hydrogen atom.
A further preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R* is:
- hydrogen or halogen atom,
- C1-C4 straight or branched chain alkyl group, optionally substituted with one or more halogen atom(s) or
- C1-C3 alkoxy group.
A further preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of R1 is hydrogen, fluorine or chlorine atom or methoxy or trifluoromethyl group, more preferably hydrogen, fluorine or chlorine atom.
Another preferred group of compounds comprises those compounds of the general formula 5 (I) wherein the meaning of R is preferably hydrogen atom.
A preferred group of compounds comprises those compounds of the general formula (I) wherein the meaning of Ris hydrogen atom and R1 is chlorine atom.
A further preferred group of compounds comprises those compounds of the general formula (I) wherein the above mentioned preferred embodiments of substituents R3, R2, R1, 10 R are optionally combined. In preferred embodiments of the invention the meaning of A substituent can either be CH group or nitrogen atom. The optional combination of the above mentioned more preferred or most preferred embodiments of substituents R3, R2, R1, R also comprises more preferred and most preferred groups of compounds of the general formula (I).
A preferred group of compounds comprises for example the following compounds of the general formula (I) and pharmaceutically acceptable salts thereof:
4-[(5-chloro-pyridin-2-yl)methoxy]-l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9yl} -1,2-dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-{3-methyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,720 a] indol-9-y 1} -1,2-dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-{3-ethyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl} -1,2-dihydropyridin-2-one
4-[(5-fluoro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H- [1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one
4-(benzyloxy)-l-[3-(propan-2-yl)-l H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl]-l ,2dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H[ 1,4]diazepino[ 1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one
4-[(4-fluoro-phenyl)methoxy]-1 -[3-(propan-2-yl)-1 H,2H,3H,4H,5H-[1,4]diazepino[l ,7a] indol-9-yl]-1,2-dihydropyridin-2-one
4-[(4-chloro-phenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl] -1,2-dihydropyridin-2-one
4-[(2-fluoro-phenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl]-1,2-dihydropyridin-2-one l-[ll-chloro-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-4-[(5chloro-pyridin-2-yl)methoxy]-1,2-dihydropyridin-2-one
4-(benzyloxy)-l -[11 -chloro-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l ,4]diazepino[l ,7-a]indol-
9-yl]-1,2-dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-[3-(cyclopropylmethyl)-lH,2H,3H,4H,5H- [1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one
4- [(5-chloro-pyridin-2-yl)methoxy] -1 - {3 -cyclopropyl-1 H,2H,3H,4H,5H- [1,4]diazepino[l ,7-a]indol-9-yl}-l ,2-dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-{3-cyclobutyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl} -1,2-dihydropyridin-2-one
4-[(5-chloro-pyridin-2-yl)methoxy]-l-[ll-methyl-3-(propan-2-yl)-lH,2H,3H,4H,5H- [1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one
The term “pharmaceutically acceptable sait” as used herein refers to acid- or base addition salts of compounds of the general formula (I) that maintain the biological activity and characteristics of the parent compound, and which can be formed with suitable nontoxic organic or inorganic acids or organic or inorganic bases. Acid addition salts can be formed from inorganic acids such as for example hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and perchloric acid, as well as from organic acids such as for example acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleinic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluensulfonic acid,
ΙΟ methanesulfonic acid, oxalic acid, tartane acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Base addition salts can be formed for example from ammonium-, potassium-, sodium- and quatemery ammonium hydroxides, such as for example tétraméthylammonium hydroxide.
The compounds of formula (I) of the présent invention can be synthesized according to reaction sequence depicted in scheme 1.
Unless otherwise stated the meaning of substituents is as described for the general formula (I).
The intermediate of formula (2) was obtained from compound of formula (1) [Bioorganic & Médicinal Chemistry Letters 13 (2003) 2369-2372; compound of formula (13)] by reacting it with an oxidizing agent, preferably with 5,6-dicyano-2,3-dichloro-l,415 benzoquinone in an inert solvent, preferably in tetrahydrofuran, at room température or under cooled reaction conditions, preferably at 0°C.
Compounds of the general formula (I), wherein R2=H, R3=tert-butoxycarbonyl, were synthesized by reacting the compound of formula (2) with a compound of the general formula (3) in the presence of a catalyst, preferably copper(I) iodide, a base, preferably 20 potassium carbonate or césium carbonate, a ligand, preferably trans-N,N’dimethylcyclohexane-l,2-diamine, under heated reaction conditions, preferably at 110°C, in an inert solvent, preferably in toluene. When R2=H, and R3=tert-butoxycarbonyl those compounds of the general formula (I) wherein R3=H were obtained after removal of the protective group. When R2=H and R3=H those compounds of the general formula (I) wherein R3=alkyl or haloalkyl were obtained by reductive alkylation, alkylation or haloalkylation. When R2=H, and R3=H those compounds of the general formula (I) wherein R3=acyl were obtained by acylation. When R2=T1, and R3=alkyl or haloalkyl those compounds of the general formula (I) wherein R2=halogen were obtained by halogénation. When R2=iodine, and R3=alkyl those compounds of the general formula (I) wherein R2=alkyl were obtained by a palladium catalyzed cross-coupling reaction.
Compounds of the general formula (3), needed for the synthesis of compounds of the general formula (I) of the présent invention, were synthesized according to the reaction sequence depicted in scheme 2.
o
Scheme 2
Compound of formula (4) was reacted with compounds of formula (5) under phase transfer conditions, in the presence of a phase transfer catalyst, preferably benzyltriéthylammonium chloride and a base, preferably sodium hydroxide, in a mixture of water and an inert solvent, preferably dichloromethane, at a température about from room température to reflux température, preferably at room température, to yield intermediate compounds of the general formula (6). Intermediate compounds of the general formula (3) were synthesized by reacting compounds of the general formula (6) with acetic anhydride at reflux température, then with methanol and ethyl acetate at a température about from room température to reflux température, preferably at reflux température.
Reagents required for the above reactions and the details of synthetic steps are described in the examples.
One embodiment of the présent invention is the new intermediate of formula (2), the tert-butyl 9-bromo-1 H,2H,3 H,4H,5 H- [ 1,4] diazepino[ 1,7-a] indol-3 -carboxylate, synthesized in the process for the synthesis of compounds of the general formula (I).
The présent invention also relates to the pharmaceutical compositions having melanin-concentrating hormone receptor 1 antagonistic activity, containing a compound of the general formula (I) or salts thereof as active ingrédient in therapeutically effective amount together with one or more pharmaceutically applicable excipients and/or solvent.
The pharmaceutical compositions can be in single dosage forms containing predetermined amount of active ingrédient. This dosage can contain the therapeutically 5 effective amount of compound of the general formula (I) or sait thereof or a given percentage of the therapeutically effective amount in such a way that these single dosage forms for repeated administration can be administered over a given period of time in order to reach the desired therapeutically effective dose. Preferred single dosage forms are those which contain the daily dose or sub-dose or - as it was mentioned above - a given 10 percentage of the active ingrédient. Furthermore these pharmaceutical compositions can be manufactured in any pharmacy by known methods.
The term “therapeutically effective amount” as used herein refers to the amount of the active ingrédient - compared to the subject, who did not receive such an amount which results in the improved treatment, curing, prévention or improvement of an illness or 15 pathological condition or side-effect, or suppresses the degree of progression of an illness or pathological condition. The term includes the effective amounts required for improving normal physiological fùnctions as well. In the therapeutic applications compounds of the general formula (I) or salts thereof can be administered in therapeutically effective amount as unformulated drug substances or the active ingrédient can be formulated as médicament.
The exact therapeutically effective amount of compounds of the présent invention or salts thereof dépends on several factors, including - but not exclusively - the âge and the bodyweight of the treated subject (patient), the type and the seriousness of the disease to be treated, the type of the pharmaceutical composition/medicament and the way of administration.
Furthermore the présent invention relates to the process for the treatment and/or prévention of disorders or conditions associated with melanin-concentrating hormone receptor 1 activity, such treatment comprises the step of administering a therapeutically effective amount of the compound of the general formula (I) or therapeutically acceptable sait thereof as such or in combination with a therapeutically acceptable carrier and/or solvent as pharmaceutical composition to a subject in need, preferably to a mammal, more preferably to a human. The aforementioned processes are preferably used for the treatment and/or prévention of diseases or conditions associated with the melanin concentrating hormone receptor 1 function, such as obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfimctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
The term “treatment” as used herein refers to preventing and alleviating the specified pathological condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. The profilaxis (or prévention, or the delaying of the disease) can be acchieved by 10 administering the drug the same way or similarly as in the case of patients who suffer from manifested disease or condition.
The présent invention relates to the treatment of subjects, preferably mammals, more preferably humans who suffer from obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight 15 gain, inflammatory bowel diseases, affective dysfimctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders or a combination of these diseases. Such treatment comprises the step of administering a therapeutically effective amount of the compound of the general formula (I) or a sait thereof to a subject in need, preferably to a mammal, more preferably to a human. Such treatment can also comprise the 20 step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of the general formula (I), or a sait thereof to a subject in need, prefereably to a mammal, more preferably to a human.
The term “effective amount” as used herein refers to an amount of a drug or active ingrédient which is sufficient, in the subject to which it is administered, to elicit the 25 biological or medical response of a tissue, System, animal (including human) that is being sought, for instance, by a researcher or clinician.
The compounds of the présent invention can be administered by any appropriate route, for example, by the oral, rectal, transdermal, subeutaneous, local, intravenous, intramuscular, or intranasal route.
β
The pharmaceutical compositions of the présent invention can be formulated in many ways, for instance as tablet, capsule, powder, suspension, émulsion, solution, syrup, aérosol (with a solid or a liquid carrier) soft or hard gelatin capsule, suppositorie, injection in a steril form.
Pharmaceutically suitable excipiens can be for example the following: starch, cellulose, talcum, glucose, lactose, gelatin, malt, rice-flour, chalk, silikagel, magnésium stéarate, sodium stéarate, glycerin monostearate, sodium cloride, dried skimmed milk, glycerin, propyleneglycol, water, éthanol and like. The usual pharmaceutical ingrédients, for example conservation agents, stabilizing agents, moisturizing or emulsifying agents, salts for adjusting the osmotic pressure, buffers, and the like can be added to the pharmaceutical composition.
The suitable auxiliaries and carrier agents as well as the production methods of the pharmaceutical compositions are known for a person skilled in the art or can be found in the literature.
EXAMPLES
The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
From the above description and examples a person skilled in the art would recognize the basic principles of the présent invention and can carry on certain alterations and modifications without varying the essential features and contents of the invention in order to adapt the invention for different applications and conditions. Consequently the présent invention is not limited to the following examples, but the scope of the invention is defined by the claims which follow.
Generally compounds of the general formula (I) can be synthesized according to the knowledge of a person skilled in the art and/or according to methods described in the examples and/or by similar processes to either. Solvents, températures, pressures and other reaction conditions can easily be determined by a person skilled in the art. Starting materials are commercially available and/or can be prepared according to procedures in the literature. During the synthesis of compounds combinatorical methods can also be used, for *
example in that case when the functional groups of the obtained intermediates are suitable for the application of this methods.
Mass spectra and 1I INMR data of examples are given in ail cases.
Reference example 1 fert-butyl 9-bromo-lH,2H3H,4H,5H-[l,41diazepino[l,7-alindol-3-carboxvlate (a) Synthesis of /er/-butyl lH,2H,3H,4H,5H.llH,llaH-n.41diazepinori.7-alindol-3carboxylate
To a solution of 3.4 g (18 mmol) of lH,2H,3H,4H,5H,llH,llaH- [1.4] diazepino[l,7-a]indol [WO0172752 Example 1, step 6] in 170 ml of dichloromethane
3.8 ml (27.09 mmol) of triethylamine was added, then a solution of 4.73 g (21.67 mmol) of di-/er/-butyl-dicarbonate in 25 ml of dichloromethane was added dropwise at 0°C. The reaction mixture was stirred at room température for 3.5 h, then 150 ml of saturated Nal ICCh solution was added, the phases were separated and the water phase was extracted with 2x50 ml of dichloromethane. The combined organic phases were washed with 50 ml of brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 4:1 mixture of hexane and ethyl acetate as eluent to yield 4.88 g (94%) of Zeri-butyl lH,2H,3H,4H,5H,llH,llaH-[l,4]diazepino[l,7-a]indol-3carboxylate. MS (El) 289.2 [M+H]+.
(b) Synthesis of /erf-butyl 9-bromo-lH,2H,3H,4H.5H,llH,llaH-n,41diazepinori,7alindol-3-carboxylate
To a solution of 4.87 g (16.9 mmol) of fért-butyl lH,2H,3H,4H,5H,llH,llaH- [1.4] diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (a)] in 160 ml of acetonitrile a solution of 3 g (16.9 mmol) of V-bromo-succinimide in 45 ml of acetonitrile was added dropwise at 0°C. The reaction mixture was stirred at room température for 2.5 h, then 1 ml of acetone was added, stirrung was continued for 5 min, then the reaction mixture was concentrated in vacuum. The residue was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5 mixture of cyclohexane and acetone as eluent to yield 4.96 g (80%) of ZerZ-butyl 9-bromolH,2H,3H,4H,5H,llH,llaH-[l,4]diazepino[l,7-a]indol-3-carboxylate. MS (El) 367.1 [M+H]+.
(c) Synthesis of /ert-butyl 9-bromo-lH.2H.3H,4H.5H-ri.41diazepinon.7-a1indol-3carboxylate
To a solution of 4.95 g (13.5 mmol) of /erAbutyl 9-bromo1H,2H,3H,4H,5H,11H,1 laH-[l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (b)] in 120 ml of tetrahydrofuran 3.37 g (14.8 mmol) of 5,6-dicyano-2,3-dichloro1,4-benzoquinone was added in small portions at 0°C, then the reaction mixture was stirred at 0°C for 45 min. 320 ml of 2 M aqueous sodium hydroxide was added to the reaction mixture, the phases were separated and the water phase was extracted with 3x120 ml of ethyl acetate. The combined organic phases were washed with 2x60 ml of water, 1x120 ml of brine, then dried over anhydrous Na2SÜ4, filtered and concentrated in vacuum. The crude product was dissolved in 25 ml of éthanol at reflux température, then the solid product separated at room température was filtered, washed with éthanol and hexane and dried to yield 4.05 g (82%) of the title compound. MS (El) 387.0 [M+Na]+.
Reference example 2
4-[(2-fluorobenzyl)oxvl pyridin-2(l H)-one (a) Synthesis of 4-r(2-fluorobenzvl)oxv1pyridine 1-oxide
To a solution of 7.74 g (61.4 mmol) of 2-fluoro-benzyl alcohol and 8.6 g (61.4 mmol) of 4-nitro-pyridin-A-oxide in 140 ml of dichloromethane 0.392 g (1.72 mmol) of benzyltriéthylammonium chloride and 81 ml of 9 N aqueous NaOH solution were added at 0 °C. The reaction mixture was stirred at room température ovemight. After addition of dichloromethane and water the phases were separated, the water phase was extracted twice with dichloromethane, the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was dissolved in 350 ml of ethyl acetate at reflux température, then the solid product separated at room température was filtered, washed with cold ethyl acetate and dried to yield 7.85 g (58%) of 4-[(2fluorobenzyl)oxy]pyridine 1-oxide. MS (El) 220.1 [M+H]+.
(b) Synthesis of 4-r(2-fluorobenzvl)oxv]pyridin-2(lH)-one
A mixture of 7.85 g (35.8 mmol) of 4-[(2-fluorobenzyl)oxy]pyridine 1-oxide [Reference example 2, step (a)] and 125 ml (1.33 mol) of acetic anhydride was refluxed for 4 h, then concentrated in vacuum. 142 ml of ethyl acetate and 28 ml of methanol were added to the residue and the so obtained mixture stirred at reflux température for 1 h, then concentrated in vacuum. 63 ml of ethyl acetate was added to the residue and the so obtained suspension was stirred at room température ovemight. The solid material was filtered, washed with cold ethyl acetate and dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 10:1 mixture of dichloromethane and methanol as eluent to yield 2.95g (37%) of the title compound. MS (El) 220.1 [M+H]+.
Reference example 3
4-[(4-methoxvbenzvl)oxv1pyridin-2(lH)-one (a) Synthesis of4-[(4-methoxvbenzvl)oxv1pyridine 1-oxide
To a solution of 7.87 g (56.96 mmol) of 4-methoxy-benzyl alcohol and 7.98 g (56.96 mmol) of 4-nitro-pyridin-7V-oxide in 130 ml of dichloromethane 0.363 g (1.59 mmol) of benzyltriéthylammonium chloride and 75 ml of 9 N aqueous NaOH solution were added at 0°C. The reaction mixture was stirred at room température ovemight. After addition of dichloromethane and water the phases were separated, the water phase was extracted twice with dichloromethane, the combined organic phases were dried over anhydrous Na2SÜ4, filtered and concentrated in vacuum. The crude product was refluxed with 350 ml of ethyl acetate, then the solid product separated at room température was filtered, washed with cold ethyl acetate and dried to yield 10.06 g (58%) of the title compound. MS (El) 232.1 [M+H]+.
(b) Synthesis of 4-r(4-methoxvbenzyl)oxv1pyridin-2(lH)-one
A mixture of 10.06 g (43.5 mmol) of 4-[(4-methoxybenzyl)oxy]pyridine 1-oxide [Reference example 3, step (a)] and 152 ml (1.61 mol) of acetic anhydride was stirred at reflux température for 4 h, and the next day for further 5 h, then concentrated in vacuum. 173 ml of ethyl acetate and 35 ml of methanol were added to the residue and the so obtained mixture stirred at reflux température for 1 h, then concentrated in vacuum. 77 ml of ethyl acetate was added to the residue and the so obtained suspension was stirred at room température ovemight. The solid material was filtered, washed with cold ethyl acetate and dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 10:1 mixture of dichloromethane and methanol as eluent to yield 2.089 g (20%) of the title compound. MS (El) 232.1 [M+H]+.
Reference example 4 /ert-butyl 9-(4-[(5-fluoronvridin-2-vl)mcthoxvl-2-oxo-l,2-dihvdronvridin-l-yl}1 H3H3H,4II3H-[1 ,41 diazepino ί 1,7-al indol-3-carboxylate
A mixture of 0.51 g (1.4 mmol) of ter/-butyl 9-bromo-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)], 0.31 g (1.4 mmol) of 4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2(lH)-one [EP1916239], 0.27 g (1.4 mmol) of copper(I) iodide, 0.64 g (1.96 mmol) of CS2CO3, 0.22 ml (1.4 mmol) of transN,N'-dimethylcyclohexan-l,2-diamine and 30 ml of toluene was stirred at room température for 1 h while nitrogen gas was bubbled through the mixture. Then the reaction flask was sealed with a septum, immersed into an oil bath of 110 °C and the mixture was stirred ovemight at this température. The reaction mixture was concentrated in vacuum, 14 ml of saturated aqueous ammonium chloride solution was added to the residue and the suspension was stirred at room température for 2 h. The solid product was filtered, washed with saturated aqueous ammonium chloride solution and water, then dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and first dichloromethane, then a 98:2 mixture of dichloromethane and methanol as eluent to yield 0.48 g (68%) of the title compound. MS (El) 505.2 [M+H]+.
Reference example 5 tert-butyl 9-i4-[(4-methoxvphenvl)methoxvl-2-oxo-l,2-dihvdropvridin-l-yl)lH,2H3H,4H,5H-[l,41diazepino[l,7-anndol-3-carboxvlate
The title compound was obtained from ter/-butyl 9-bromo-lH,2H,3H,4H,5H- [1.4] diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)] and 4-[(4methoxy-benzyl)oxy]pyridin-2(lH)-one [Reference example 3, step (b)] according to the method described in Reference example 4. MS (El) 516.3 [M+H]+.
Reference example 6
Zert-butyl 9-[4-(benzvloxv)-2-oxo-l,2-dihvdropyridin-l-il]-lH,2H,3H,4H,5H[1.4] diazepino[l,7-alindol-3-carboxylate
The title compound was obtained from terf-butyl 9-bromo-lH,2H,3H,4H,5H- [1.4] diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)] and 4(benzyloxy)pyridin-2(lH)-one according to the method described in Reference example 4. MS (El) 486.24 [M+H]+.
Reference example 7 /ert-butyl 9-i4-[(5-chloronvridin-2-vl)methoxy]-2-oxo-l,2-dihvdropvridin-l-vl}lH,2H3H,4H,5H-[l,4|diazepino[l,7-alindol-3-carboxylate
A mixture of 0.92 g (2.52 mmol) of /erf-butyl 9-bromo-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)], 0.64 g (2.7 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(lH)-one [EP1916239], 0.51 g (2.7 mmol) of copper(I) iodide, 1.14 g (3.5 mmol) of CS2CO3, 0.43 ml (2.7 mmol) of transN,N'-dimethylcyclohexan-l,2-diamine and 50 ml of toluene was stirred at room 10 température for 1 h while nitrogen gas was bubbled through the mixture. Then the reaction flask was sealed with a septum, immersed into an oil bath of 110 °C and the mixture was stirred ovemight at this température. The reaction mixture was poured into a mixture of 165 ml of dichloromethane:methanol:ccNH4OH (9:1:0.1), and the phases were separated. The organic phase was washed with brine portions (each 30 ml) until the separated water 15 phase remained colorless, then dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and first dichloromethane, then a 98:2 mixture of dichloromethane and methanol as eluent to yield 0.86 g (66%) of the title compound. MS (El) 521.2 [M+H]+.
Reference example 8 fert-butyl 9-i4-K4-fluoro-phcnvl)methoxvl-2-oxo-l,2-dihvdropvridin-l-yl?lH,2H3H,4H,5H-H,41diazepino[l,7-a1indol-3-carboxylate
The title compound was obtained from terf-butyl 9-bromo-lH,2H,3H,4H,5H25 [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)] and 4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one [EP1916239] according to the method described in Reference example 4. MS (El) 504.3 [M+H]+.
Reference example 9 te/7-butyl 9-(4-[(4-chloro-phenvl)methoxv1-2-oxo-l,2-dihydropvridin-l-vl}1 H,2H3H,4H,5H-[1,41 d iazepino [ 1,7-al indol-3-carboxylate
The title compound was obtained from ferf-butyl 9-bromo-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)] and 4-[(4-chloro18375 benzyl)oxy]pyridin-2(lH)-one [EP1916239] according to the method described in Reference example 4. MS (El) 520.2 [M+H]+.
Reference example 10 ferï-butyl 9-{4-[(2-fluoro-phenyl)methoxvî-2-oxo-l,2-dihvdropvridin-l-yl)1 H,2H,3H,4H,5H-f 1,41 diazcninoll ,7-al indol-3-carboxylate
The title compound was obtained from /err-butyl 9-bromo-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)] and 4-[(2-fluorobenzyl)oxy]pyridin-2(lH)-one [Reference example 2, step (b)] according to the method 10 described in Reference example 4. MS (El) 504.2 [M+H]+.
Reference example 11
Ze/7-butyl 9-(2-oxo-4-{[4-(trifluoromcthvl)phenvllmethoxv}-l,2-dihvdropyridin-l-vl)1 H,2H3H,4H,5H-[1,41 diazepino [ 1,7-al indol-3-carboxy late
A mixture of 0.34 g (0.93 mmol) of Zerf-butyl 9-bromo-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 1, step (c)], 0.25 g (0.93 mmol) of 4-{[4-(trifïuoromethyl)benzyl]oxy}pyridin-2(lH)-one [WO200989482], 0.18 g (0.95 mmol) of copper(I) iodide, 0.42 g (1.3 mmol) of CS2CO3, 0.15 ml (0.95 mmol) of /ran5-N,N'-dimethylcyclohexane-l,2-diamine and 18 ml of toluene was stirred at room 20 température for 1 h while nitrogen gas was bubbled through the mixture. Then the reaction flask was sealed with a septum, immersed into an oil bath of 110 °C and the mixture was stirred ovemight at this température. The reaction mixture was concentrated in vacuum, 14 ml of saturated ammonium chloride solution was added to residue, and the suspension was stirred at room température for 1 h. The solid product was filtered, washed with saturated 25 ammonium chloride solution and water, then dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and first dichloromethane, then a 98:2:0.1 mixture of dichloromethane, methanol and CCNH4OH as eluent. The obtained product was further purified by column chromatography using a 98:2 mixture of dichloromethane and methanol as eluent to yield 0.27 g (52%) of 30 the title compound. MS (El) 554.3 [M+H]+.
λ
Example 1 l-ilH,2H3H,4H,5H-U,4]diazepinoU,7-a]indol-9-vl)-4-[(5-fluoror>vridin-2vl)methoxv]-l^-dihvdropyridin-2-one hydrochloride sait (a) Synthesis of the free base
A mixture of 0.48 g (0.95 mmol) of /eri-butyl 9-{4-[(5-fluoropyridin-2yl)methoxy] -2-oxo-1,2-dihydropyridin-1 -yl} -1 H,2H,3H,4H,5H- [ 1,4] diazepino [ 1,7-a] indol3-carboxylate [Reference example 4], 17 ml of ethyl acetate and 8.2 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température ovemight. The solid product was filtered, washed with ethyl acetate and diethyl ether, and dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and first dichloromethane, then a 95:5:1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.29 g (71%) of 1-{1H,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-4-[(5-fluoropyridin-2-yl)methoxy]-l,2-dihydropyridin-2one as free base. MS (El) 405.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
0.12 g (0.28 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4-[(5fluoropyridin-2-yl)methoxy]-l,2-dihydropiridin-2-one [Example 1, step (a)] was dissolved in a mixture of 5 ml of methanol and 2 ml of 20% hydrogen chloride in ethyl acetate, then the reaction mixture was concentrated. The solid residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried to yield 0.089 g (65%) of the title compound. MS (El) 405.2 [M+H]+. *H NMR (400 MHz, DMSO-de) δ: 9.70-9.85 (br m, 2H), 8.63 (d, J=2.9 Hz, 1H), 7.83 (td, J=8.7, 2.9 Hz, 1H), 7.66 (dd, J=8.7, 4.4 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.42 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.6,2.2 Hz, 1H), 6.42 (s, 1H), 6.13 (dd, J=7.6, 2.8 Hz, 1H), 5.98 (d, J=2.8 Hz, 1H), 5.22 (s, 2H), 4.62-4.70 (br m, 2H), 3.31-3.39 (brm, 4H), 3.22-3.31 (br m, 2H).
Example 2
1- ilH<2H3H,4H,5H-[l<41diazepino[l,7-a]indol-9-vn-4-[(4-methoxyphenvl)-methoxvll,2-dihydropyridin-2-one hydrochloride sait (a) Synthesis of the hydrochloride sait
A mixture of 0.44 g (0.85 mmol) of terr-butyl 9-{4-[(4-methoxyphenyl)-methoxy]-
2- oxo-l,2-dihydropyridin-l-yl}-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]-indol-3carboxylate [Reference example 5], 13 ml of ethyl acetate, 1.95 ml of 20% hydrogen chloride in ethyl acetate and 20 ml of methanol was stirred at room température for 3 h, then 20 ml of methanol was added and stirring was continued for 3 days. The solid product was filtered, washed with diethyl ether and dried to yield 0.078 g (20%) of the title compound. MS (El) 416.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 9.39-9.53 (br m,
2H), 7.50-7.56 (m, 2H), 7.38-7.43 (m, 3H), 7.04 (dd, J=8.7, 2.1 Hz, 1H), 6.95-7.00 (m,
2H), 6.42 (s, 1H), 6.04 (dd, J=7.6, 2.7 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 5.05 (s, 2H), 4.584.66 (m, 2H), 3.77 (s, 3H), 3.33-3.41 (br m, 2H), 3.24-3.33 (br m, 4H). Concentration of the filtrate resulted in further 0.26 g (67%) of the title compound.
(b) Svnthesis of the free base
A mixture of 0.32 g (0.71 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(4-methoxyphenyl)methoxy]-l,2-dihydropyridin-2-one hydrochoride [Example 2, step (a)], 40 ml of a 9:1 mixture of dichloromethane and 2-propanol and 5% aqueous NaHCCh solution (pH=8-9) was stirred at room température for 10 min, then the phases were separated. The water phase was extracted with 30 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 30 ml of brine, then dried over anhydrous Na2SÜ4, filtered and concentrated in vacuum. The crude product was crystallized with éthanol, the solid product was filtered and washed with éthanol to yield 0.097 g (33%) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4[(4-methoxyphenyl)methoxy]-l,2-dihydropyridin-2-one as free base. MS (El) 416.2 [M+H]+.
Concentration of the mother liquid resulted in further 0.08 g (27%) of the free base.
Example 3 4-(benzyloxv)-l-ilH,2H3H,4H,5H-il,41diazepinori,7-alindol-9-vn-l^25 dihydropyridin-2-one maleîc acid sait (a) Svnthesis of the hydrochloride sait
A mixture of 0.65 g (1.34 mmol) of /er/-butyl 9-[4-(benzyloxy)-2-oxo-l,2dihydropyridin-1 -yl] -1 H,2H,3 H,4H,5H- [ 1,4] diazepino [ 1,7-a] indol-3 -carboxylate [Reference example 6], 20 ml of ethyl acetate and 6 ml of 20% hydrogen chloride in ethyl 30 acetate was stirred at room température for 2 h, then 6 ml of 20% hydrogen chloride in ethyl acetate was added and the mixture was stirred at room température ovemight. The solid product was filtered, washed with ethyl acetate and diethyl ether and dried to yield
0.62 g (100%) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}- l,2-dihydropyridin-2-one hydrochloride sait. MS (El) 386.2 [M+H]+.
(b) Synthesîs of the free base
A mixture of 0.58 g (1.37 mmol) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H5 [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one hydrochloride [Example 3, step (a)], 14 ml of 5% aqueous NaHCCh solution and 40 ml of a 9:1 mixture of dichloromethane and 2-propanol was stirred at room température for 10 min, then the phases were separated. The water phase was extracted with 2x12 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 15 ml of brine, then dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum to yield 0.44 g (83%) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2dihydropyridin-2-one as free base. MS (El) 386.2 [M+H]+.
(c) Synthesis of the maleic acid sait
To a solution of 0.21 g (0.54 mmol) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H15 [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 3, step (b)] in a 10:1 mixture of dichloromethane and methanol 0.078 g (0.67 mmol) of maleic acid was added and the reaction mixture was concentrated. The solid residue was triturated with éthanol, filtered, washed with éthanol and diethyl ether and dried to yield 0.218 g (80%) of the title compound. MS (El) 386.2 [M+H]+. *H NMR (400 MHz, DMSO-de) δ: 8.80-9.15 (br m, 20 1.6H), 7.51-7.56 (m, 2H), 7.34-7.49 (m, 6H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.43 (s, 1H),
6.08 (dd, J=7.6,2.7 Hz, 1H), 6.04 (s, 2.2H), 5.95 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.50-4.62 (br m, 2H), 3.20-3.45 (m, 6H).
Example 4
4-K5-chloropvridin-2-vl)methoxv]-l-flH,2H3H,4H,5H-[l,41diazepino[l,7-a1indol-9vl}-l,2-dihvdronvridin-2-onc dihydrochloride sait (a) Synthesis of the dihydrochloride sait
A mixture of 1.32 g (2.54 mmol) of ier/-butyl 9-{4-[(5-chloropyridin-2yl)methoxy] -2-oxo-1,2-dihydropyridin-1 -yl} -1 H,2H,3 H,4H,5H- [ 1,4] diazepino [ 1,7-a] indol30 3-carboxylate [Reference example 7], 15 ml of methanol, 1.25 M hydrogen chloride in methanol and 30 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température ovemight. The solid product was filtered, washed with diethyl ether and dried to yield 1.26 g (100%) of the title compound. MS (El) 421.1 [M+H]+. *H NMR (400 MHz,
DMSO-de) δ: 9.72-9.82 (br m, 2H), 8.68 (d, J=2.5 Hz, 1H), 8.03 (dd, J=8.2, 2.5 Hz, 1H), 7.51-7.64 (m, 3H), 7.42 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.8,2.2 Hz, 1H), 6.42 (s, 1H), 6.006.40 (br m, the signal of HCl overlapped by the signal of H2O; 1H), 6.13 (dd, J=7.5, 2.6 Hz, 1H), 5.96 (d, >2.7 Hz, 1H), 5.23 (s, 2H), 4.62-4.70 (m, 2H), 3.22-3.40 (m, 6H).
(b) Synthesis of the free base
A mixture of 4.44 g (8.52 mmol) of Zer/-butyl 9-{4-[(5-chloropyridin-2yl)methoxy] -2-oxo-1,2-dihydropyridin-1 -yl} -1 H,2H,3 H,4H,5H- [ 1,4] diazepino[ 1,7-a] indol-
3- carboxylate [Reference example 7], 130 ml of ethyl acetate and 20 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température for 2 h. The solid product was 10 filtered, washed with éthanol and diethyl ether and dried. 85 ml of 5% aqueous NaHCCh solution and 250 ml of a 9:1 mixture of dichloromethane and 2-propanol were added to the crude product, the phases were separated, the water phase was extracted with 2x80 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 80 ml of brine, then dried over anhydrous NaiSCh, filtered and concentrated 15 in vacuum. 50 ml of diethyl ether was added to the residue and the mixture was stirred at room température ovemight. The solid product was filtered, washed with diethyl ether and dried to yield 3.39 g (95%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one as free base. MS (El) 421.2 [M+H]+.
Example 5 l-ilHJH3H,4H,5H-H,41diazepino[l,7-alindol-9-vn-4-r(4-fluorophenyl)methoxvll,2-dihydropyridin-2-one hydrochloride sait (a) Synthesis of the free base
A mixture of 0.28 g (0.55 mmol) of teri-butyl 9-{4-[(4-fluorophenyl)methoxy]-2oxo-1,2-dihydropyridin-1 -yl} -1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a] indol-3-carboxylate [Reference example 8], 10 ml of ethyl acetate and 1.25 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température ovemight, then 1.25 ml of 20% hydrogen chloride in ethyl acetate was added and the mixture was stirred at room température for 2h.
After this 50 ml of methanol was added to the reaction mixture and stirring was continued at room température ovemight, then the mixture was concentrated. 40 ml of a 9:1 mixture of dichloromethane and 2-propanol and 5% aqueous NaHCCh solution were added to the residue (pH of the water phase is 8-9), the mixture was stirred at room température for 10 • » min, then the phases were separated. The water phase was extracted with 30 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 30 ml of brine, then dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The crude product was triturated with éthanol, the solid product was filtered and washed with éthanol to yield 0.104 g (46%) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(4-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one as free base. MS (El) 404.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
0.035 g (0.08 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4[(4-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one [Example 5, step (a)] was dissolved in a mixture of 2 ml of éthanol and 25.5% hydrogen chloride in éthanol (pH=2), then the reaction mixture was concentrated. The solid residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried to yield 0.021 g (60%) of the title compound. MS (El) 404.2 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 9.22-9.33 (br m, 2H), 7.49-7.56 (m, 4H), 7.42 (d, J=2.1 Hz, 1H), 7.22-7.30 (m, 2H), 7.05 (dd, J=8.6, 2.1 Hz, 1H), 6.42 (s, 1H), 6.06 (dd, J=7.6, 2.7 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 5.12 (s, 2H), 4.57-4.63 (m, 2H), 3.34-3.42 (brm, 2H), 3.26-3.33 (m, 4H).
Example 6 4-Ff4-chlorophenvl)methoxvl-l-ilH<2H3Ht4H,5H-H,4]diazepinon,7-alindol-9-vl)l,2-dihvdropyridin-2-one hydrochloride sait (a) Synthesis of the hydrochloride sait
A mixture of 0.6 g (1.15 mmol) of /erf-butyl 9-{4-[(4-chlorophenyl)methoxy]-2oxo-1,2-dihydropyridin-1 -yl}-1 H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-3-carboxylate [Reference example 9], 20 ml of ethyl acetate and 5 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température for 2 h, then 5 ml of 20% hydrogen chloride in ethyl acetate was added and the mixture was stirred at room température for 95 min. 5 ml of dichloromethane was added to the reaction mixture and stirring was continued at room température ovemight. The solid product was filtered, washed with ethyl acetate and diethyl ether, then dried to yield 0.6 g (100%) of the title compound. MS (El) 420.1 [M+H]+. Ή NMR (400 MHz, DMSO-de) δ: 9.43-9.62 (br m, 2H), 7.51-7.57 (m, 2H), 7.50 (s, 4H), 7.42 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.7, 2.1 Hz, 1H), 6.42 (s, 1H), 6.08 (dd, J=7.6,
2.7 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.59-4.67 (m, 2H), 3.24-3.41 (m, 6H).
(b) Synthesis of the base
0.56 g (1.2 mmol) of 4-[(4-chlorophenyl)methoxy]-l-{lH,2H,3H,4H,5H- [1.4] diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one hydrochloride [Example 6, step (a) ] was dissolved in a mixture of 15 ml of 5% aqueous NaHCCh solution and 40 ml of a
9:1 mixture of dichloromethane and 2-propanol. The phases were separated, the water phase was extracted with 1x40 ml, 2x20 ml and 3x40 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 50 ml of brine, then dried over anhydrous Na2SÜ4, filtered and concentrated in vacuum to yield 0.44 g (87%) of 4-[(4-chlorophenyl)methoxy]-l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol10 9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 420.1 [M+H]+.
Examplc 7 l-ilH^H3H,4H,5H-H,41diazepino[l,7-alindol-9-vn-4-[(2-fluorophenvl)methoxvll,2-dihvdropyridin-2-onc hydrochloride sait (a) Synthesis of the hydrochloride sait
A mixture of 0.44 g (0.87 mmol) of Zeri-butyl 9-{4-[(2-fluorophenyl)methoxy]-2oxo-1,2-dihydropyridin-1 -yl} -1 H,2H,3 H,4H,5H- [ 1,4] diazepino[ 1,7-a] indol-3 -carboxylate [Reference example 10], 15 ml of ethyl acetate and 8 ml of 20% hydrogen chloride in ethyl acetate was stirred at room température ovemight. The solid product was filtered, washed 20 with ethyl acetate and diethyl ether, then dried to yield 0.37 g (96%) of the title compound.
MS (El) 404.1 [M+H]+. ‘H NMR (400 MHz, DMSO-d6) δ: 9.50-9.65 (br m, 2H), 7.40-7.63 (m, 5H), 7.24-7.34 (m, 2H), 7.05 (dd, J=8.8,2.2 Hz, 1H), 6.42 (s, 1H), 6.06 (dd, J=7.6,2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H), 5.17 (s, 2H), 4.60-4.68 (m, 2H), 3.23-3.42 (m, 6H).
(b) Synthesis of the free base
0.33 g (0.75 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4-[(2fluorophenyl)methoxy]-l,2-dihydropyridin-2-one hydrochloride [Example 7, step (a)] was dissolved in 15 ml of 5% aqueous NaHCCh solution and 20 ml of a 9:1 mixture of dichloromethane and 2-propanol. The phases were separated, the water phase was extracted with 2x20 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 25 ml of brine, then dried over anhydrous NaîSCh, filtered and concentrated in vacuum to yield 0.237 g (78%) of 1-{1H,2H,3H,4H,5H- [1.4] diazepino[l,7-a]indol-9-yl}-4-[(2-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one as free base. MS (El) 404.2 [M+H]+.
t
Example 8 l-(lHJH3H,4Ht5H-fl<4ldiazepinofl,7-alindol-9-in-4-ii4(trifluoromethvl)phenvl1methoxv)-l,2-dihvdropyridin-2-one hvdrochloride sait (a) Synthesis of the hydrochloride sait
A mixture of 0.27 g (0.46 mmol) of tert-butyl 9-(2-oxo-4-{[4(trifluoromethyl)phenyl]methoxy}-l,2-dihydropyridin-l-yl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-3-carboxylate [Reference example 11], 15 ml of ethyl acetate,
1.1 ml of 20% hydrogen chloride in ethyl acetate and 30 ml of methanol was stirred at room température for 4 h, then 25 ml of methanol was added and the mixture was stirred at room température ovemight. Further 1.1 ml of 20% hydrogen chloride in ethyl acetate was added to the reaction mixture and stirring was continued at room température for 4 h, then the mixture was concentrated. The residue was triturated with ethyl acetate, the solid product was filtered, washed with ethyl acetate and dried to yield 0.138 g (61%) of the title compound. MS (El) 454.1 [M+H]+. ‘H NMR (400 MHz, DMSO-de) δ: 9.30-9.41 (br m, 2H), 7.78-7.84 (m, 2H), 7.66-7.73 (m, 2H), 7.51-7.58 (m, 2H), 7.42 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.7,2.1 Hz, 1H), 6.42 (s, 1H), 6.11 (dd, J=7.6, 2.7 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 5.28 (s, 2H), 4.57-4.66 (br m, 2H), 3.33-3.41 (br m, 2H), 3.26-3.33 (m, 4H).
(b) Synthesis of the free base
0.21 g (0.43 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4-{[4(trifluoromethyl)phenyl]methoxy}-l,2-dihydropyridin-2-one hydrochloride [Example 8, step (a)] was dissolved in a mixture of 6 ml of 5% aqueous NaHCCh solution and 15 ml of a 9:1 mixture of dichloromethane and 2-propanol. The phases were separated, the water phase was extracted with 2x15 ml of a 9:1 mixture of dichloromethane and 2-propanol. The combined organic phases were washed with 20 ml of brine, then dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield 0.148 g (76%) of 1(lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4-{[4(trifluoromethyl)phenyl]methoxy}-l,2-dihydropyridin-2-one as free base. MS (El) 454.1 [M+H]+.
Example 9 4-[(5-fluoropvridin-2-yl)methoxvl-l-(3-methvl-lH,2H3H<4H,5H-fl<4]diazepino[l,7a]indol-9-vl}-l,2-dihvdropyridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.05 g (0.124 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(5-fluoropyridin-2-yl)methoxy]-l ,2-dihydropyridin-2-one [Example 1, step (a)], 2.5 ml of methanol, 0.093 ml (1.24 mmol) of 37% aqueous formaldehide solution and 0.105 g (1.67 mmol) of sodium cyanoborohydride was shaken in a closed reaction vessel at 70°C for 1 h. 7 ml of saturated aqueous NaHCCh solution and 15 ml of dichloromethane were added to the reaction mixture, the phases were separated, and the water phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and first a 98:2:1, then a 95:5:1 mixture of dichloromethane, methanol and ccNthOH as eluent to yield 0.039 g (76%) of 4-[(5-fluoropyridin-2yl)methoxy]-l-{3-methyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2dihydropyridin-2-one as free base. MS (El) 419.2 [M+H]+.
(b) Synthesis of the maleic acid sait
0.039 g (0.093 mmol) of 4-[(5-fluoropyridin-2-yl)methoxy]-l-{3-methyl1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a]indol-9-yl} -1,2-dihydropyridin-2-one free base [Example 9, step (a)] was dissolved in 10 ml of a 9:1 mixture of dichloromethane and éthanol, 0.011 g (0.095 mmol) of maleic acid was added, then the dichloromethane was 20 evaporated in vacuum. Diethyl ether was added to the residue, the solid product was filtered, washed with diethyl ether and dried to yield 0.030 g (60%) of the title compound. MS (El) 419.2 [M+H]+. *H NMR (400 MHz, DMSO-d6) δ: 9.50-10.50 (br m, 0.6H), 8.62 (d, J=2.9 Hz, 1H), 7.83 (td, J=8.7,2.9 Hz, 1H), 7.65 (dd, J=8.7,4.4 Hz, 1H), 7.52-7.60 (m, 2H), 7.43 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.7,2.1 Hz, 1H), 6.42 (s, 1H), 6.11 (dd, J=7.5,2.7 25 Hz, 1H), 6.04 (s, 2H), 5.96 (d, J=2.7 Hz, 1H), 5.21 (s, 2H), 4.20-5.00 (br m, 2H), 3.00-3.70 (br m, 6H), 2.88 (br s, 3H).
Example 10 4-(benzvloxv)-l-(3-methyI-lH,2H3H,4H,5H-[l,41diazepino[l,7-a1indol-9-vl)-lJ30 dihydropyridin-2-one hydrochloridc sait (a) Synthesis of the free base
A mixture of 0.07 g (0.18 mmol) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one free base [Example 3, step (b)], ml of methanol, 0.132 ml (1.82 mmol) of 37% aqueous formaldehide solution and 0.153 g (2.43 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 70°C for 90 min, then at room température ovemight. The reaction mixture was concentrated, 8 ml of saturated aqueous NaHCCh solution and 15 ml of dichloromethane were added to the residue, the phases were separated, and the water phase was extracted with 2x15 ml of dichloromethane. The combined organic phases were washed with 25 ml of brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:2:1 mixture of dichloromethane, methanol and ccNILOH as eluent, then the so obtained product was further purified by column chromatography using a 98:2:1 mixture of dichloromethane, methanol and ccNfUOH as eluent to yield 0.046 g (63%) of 4-(benzyloxy)-l-{3-methyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}- l,2-dihydropyridin-2-one as free base. MS (El) 400.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
0.046 g (0.115 mmol) of 4-(benzyloxy)-l-{3-methyl-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one free base [Example 10, step (a)] was dissolved in 10 ml of dichloromethane, 2 ml of 20% hydrogen chloride in ethyl acetate was added and the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.039 g (77%) ofthe title compound. MS (El) 400.2 [M+H]+. *H NMR (400 MHz, DMSOd6) δ: 11.08-11.24 (br m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.34-7.50 (m, 6H), 7.05 (dd, J=8.8, 2.2 Hz, 1H), 6.42 (s, 1H), 6.07 (dd, J=7.4, 2.7 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.83-4.94 (br m, 1H), 4.43-4.54 (br m, 1H), 3.65-3.81 (br m, 2H), 3.04-3.46 (br m, 4H), 2.89 (br d, J=4.2 Hz, 3H).
Example 11 4-f(5-chloropvridin-2-vl)methoxv1-l-i3-methyl-lH,2H3H,4H,5H-[l,4]diazepinoH,7a1indol-9-vl)-l^-dihvdropvridin-2-one (a) Synthesis of the free base
To a solution of 0.3 g (0.71 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one free base [Example 4, step (b)] in 50 ml of acetonitrile and 25 ml of dichloromethane 0.7 ml (9.4 mmol) of 37% aqueous formaldehide solution and 0.34 g (1.6 mmol) of sodium triacetoxyborohydride were added at 0°C. The reaction mixture was stirred at room température ovemight, 0.17 g (0.8 mmol) of sodium triacetoxyborohydride was added and the mixture was further stirred for 2.5 h. 50 ml of dichloromethane and 40 ml of 5% aqueous NaHCCh solution were added to the reaction mixture, the phases were separated, 5 and the organic phase was washed with 2x40 ml of water and 40 ml of brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. Ethanol was added to the residue and the mixture was concentrated. Ethanol addition was repeated and the solid product was filtered, washed with éthanol and dried to yield 0.067 g (21%) of the title compound. MS (El) 435.1 [M+H]+. Further 0.065 g (21%) of the title compound was obtained from the 10 mother liquid.
(b) Synthesis of the maleic acid sait
To a solution of 0.087 g (0.2 mmol) 4-[(5-chloropyridin-2-yl)methoxy]-l-{3methyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 11, step (a)], in 5 ml of dichloromethane and 2 ml of acetone 0.024 g (0.206 15 mmol) of maleic acid was added. The reaction mixture was concentrated in vacuum, acetone was added to the residue and the mixture was concentrated to a final volume of 0.5 ml. The solid product separated from acetone, it was filtered, washed with acetone and dried to yield 0.083 g (75%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3-methyllH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one maleic acid 20 sait. MS (El) 435.1 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 9.50-10.50 (br m, 0.6H), 8.67 (dd, J=2.5, 0.6 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.53-7.63 (m, 3H), 7.43 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.42 (s, 1H), 6.12 (dd, J=7.5, 2.7 Hz, 1H), 6.04 (s, 2H), 5.94 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 4.20-5.00 (br m, 2H), 3.10-3.65 (br m, 6H), 2.89 (br s, 3H).
Example 12
4-K4-chlorophenvl)methoxvl-l-(3-methyl-lH,2H3H,4H,5H-H,41diazepino[l,7a1indol-9-vl)-1.2-dihvdropyridin-2-onc maleic acid sait (a) Synthesis of the free base
A mixture of 0.05 g (0.119 mmol) of 4-[(4-chlorophenyl)methoxy]-l{1H,2H,3H,4H,5H-[1,4]diazepino[l,7-a]indol-9-yl}-l ,2-dihydropyridin-2-one [Example 6, step (b)], 2.5 ml of methanol, 0.089 ml (1.19 mmol) of 37% aqueous formaldehide solution, 0.014 ml (0.24 mmol) of acetic acid and 0.10 g (1.59 mmol) of sodium cyanoborohydride was shaked in a closed reaction vessel at 70°C for 1 h. 7 ml of saturated aqueous NaHCCh solution and 15 ml of dichloromethane were added to the reaction mixture, the phases were separated, and the water phase was extracted with 15 ml of dichloromethane. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) adsorbent (Merck) and a 98:2:1 mixture of dichloromethane, methanol and ccNFhOH as eluent to yield 0.042 g (82%) of
4-[(4-chlorophenyl)methoxy] -1 - {3 -methyl-1 H,2H,3 H,4H,5H-[ 1,4] diazepino-[ 1,7-a] indol-
9-yl}-l,2-dihydropyridin-2-one as free base. MS (El) 434.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.042 g (0.097 mmol) of 4-[(4-chlorophenyl)methoxy]-l-{3methyl-1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a] indol-9-yl} -1,2-dihydropyridin-2-one free base [Example 12, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and éthanol 0.011 g (0.095 mmol) of maleic acid was added, then the dichloromethane was evaporated 15 in vacuum. Diethyl ether was added to the residue, the solid product was filtered, washed with diethyl ether and dried to yield 0.039 g (74%) of the title compound. MS (El) 434.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) δ: 7.57 (d, J=8.8 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.50 (s, 4H), 7.43 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.41 (s, 1H), 6.08 (dd, J=7.5,2.7 Hz, 1H), 6.04 (s, 2H), 5.94 (d, J=2.7 Hz, 1 H), 5.15 (s, 2H), 4.25-4.90 (br m, 2H), 20 3.00-3.75 (br m, 6H), 2.88 (br s, 3H).
Example 13
4-[(2-fluorophenvl)methoxv1-l-(3-methyl-lH,2H3H,4H,5H-[l ,41 diazepino [ 1,7alindol-9-vl)-l,2-dihvdropyridin-2-one hydrochloride sait (a) Synthesis of the free base
The free base form of 4-[(2-fluorophenyl)methoxy]-l-{3-methyl-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one was obtained from 1{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-4-[(2-fluorophenyl)methoxy]-l,2dihydropyridin-2-one [Example 7, step (b)] according to the method described in step (a) 30 of Example 12. MS (El) 418.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
To a solution of 0.042 g (0.10 mmol) of 4-[(2-fluorophenyl)methoxy]-l-{3-methyl1H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl}-l ,2-dihydropyridin-2-one free base k
[Example 13, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and éthanol 1 ml of 20% hydrogen chloride in ethyl acetate was added, and the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.030 g (66%) of the title compound. MS (El)
418.2 [M+H]+. *H NMR (400 MHz, DMSO-d6) δ: 10.98-11.16 (br m, 1H), 7.51-7.63 (m,
3H), 7.42-7.51 (m, 2H), 7.25-7.33 (m, 2H), 7.06 (dd, J=8.7,2.1 Hz, 1H), 6.42 (s, 1H), 6.06 (dd, J=7.5, 2.7 Hz, 1H), 6.02 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.80-4.99 (br m, 1H), 4.384.60 (br m, 1H), 3.60-3.83 (br m, 2H), 3.00-3.46 (br m, 4H), 2.89 (br s, 3H).
Example 14 l-i3-ethvl-lH3H3H,4H,5H-il,41diazepinoil,7-a1indol-9-vl)-4-K4methoxvphenvl)methoxvÎ-l,2-dihydropvridin-2-one
To a solution of 0.177 g (0.22 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(4-methoxyphenyl)methoxy]-l,2-dihydropyridin-2-one [Example 2, step 15 (b)] in 20 ml of dichloromethane 0.03 ml (0.53 mmol) of acetaldehyde was added, then
0.11 g (0.52 mmol) of sodium triacetoxyborohydride was added at 0°C and the reaction mixture was stirred at room température ovemight. 30 ml of dichloromethane and 25 ml of saturated aqueous NaHCCh solution were added to the reaction mixture, the phases were separated, the organic phase was washed with 2x40 ml of water, dried over anhydrous 20 Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5 mixture of dichloromethane and methanol as eluent. The obtained product was triturated with diethyl ether, filtered, washed with diethyl ether and dried to yield 0.024 g (25%) of the title compound. MS (El) 444.3 [M+H]+.
Example 15
4-K5-chloropvridin-2-vl)methoxv1-l-(3-etil-lH,2H3H,4H,5H-[l,41diazepino[l,7alindol-9-yl)-l,2-dilivdropvridin-2-one (a) Synthesis of the free base
To a solution of 0.3 g (0.71 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 4, step (b)] in 50 ml of dichloromethane 0.08 ml (1.4 mmol) of acetaldehyde was added at 0°C and the reaction mixture was stirred at this température for 10 min. Then 0.33 g (1.56 mmol) of sodium triacetoxyborohydride was added at 0°C, and the reaction mixture was stirred at room température ovemight. 40 ml of 5% aqueous NaHCCh solution was added to the reaction mixture, the phases were separated, the organic phase was washed with 2x40 ml of water, dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 9:1 mixture of dichloromethane and methanol as eluent. The obtained solid product was triturated with éthanol and diethyl ether, filtered, washed with diethyl ether and dried to yield 0.144 g (45%) of the title compund. MS (El) 449.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.10 g (0.23 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3ethyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 15, step (a)] in 5 ml of dichloromethane and 2 ml of acetone 0.027 g (0.233 mmol) of maleic acid was added. The reaction mixture was concentrated in vacuum acetone was added to the residue and the mixture was concentrated to a final volume of 0.5 ml. The solid product separated from acetone, it was filtered, washed with acetone and dried to yield 0.116 g (89%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3-ethyI1 H,2H,3 H,4H,5H-[ 1,4]diazepino [ 1,7-a] indol-9-yl} -1,2-dihydropyridin-2-one maleic acid sait. MS (El) 449.15 [M+H]+. ’H NMR (400 MHz, DMSO-de) δ: 9.30-10.00 (br m, 0.7H), 8.67 (dd, J=2.5, 0.7 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.53-7.63 (m, 3H), 7.43 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.43 (s, 1 H), 6.12 (dd, J=7.5, 2.7 Hz, 1H), 6.04 (s, 2H), 5.94 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 5.10-4.20 (br m, 2H), 2.90-4.00 (br m, 8H), 1.26 (t, J=7.1 Hz, 3H).
Example 16 143-ethvl-lH,2H3H,4H.5H-[l,41diazeDino[l,7-alindol-9-vl}-4-[(4fluorophenyl)methoxvl-l^-dihydropyridin-2-one
To a solution of 0.097 g (0.24 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(4-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one [Example 5, step (a)] in 20 ml of dichloromethane 0.03 ml (0.53 mmol) of acetaldehyde was added at 0°C and the reaction mixture was stirred at this température for 10 min. Then 0.11 g (0.52 mmol) of sodium triacetoxyborohydride was added at 0°C and the reaction mixture was stirred at room température ovemight. 20 ml of dichloromethane and 40 ml of 10% aqueous
NaHCÛ3 solution were added to the reaction mixture, the phases were separated, the organic phase was washed with 2x30 ml of water, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5 mixture of 5 dichloromethane and methanol as eluent. The obtained product was triturated with diethyl ether, filtered, washed with diethyl ether and dried to yield 0.022 g (21%) of the title compound. MS (El) 432.29 [M+H]+.
Example 17 l-(3-acetvl-lHJH3H,4H,5H-ri,41diazepinori,7-a]indol-9-vn-4-K5-chloropyridin-2vl)methoxvl-l,2-dihvdropyridin-2-one
To a solution of 0.3 g (0.71 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one [Example 4, step (b)] in 50 ml of dichloromethane 0.2 ml (1.4 mmol) of triethylamine and 0.08 ml (1.12 15 mmol) of acetic anhydride were added below 10°C. The reaction mixture was stirred at room température ovemight, 25 ml of dichloromethane was added and the organic phase was washed with 3x40ml of water. The organic phase was dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was triturated with éthanol, filtered, washed with éthanol and diethyl ether, and dried to yield 0.21 g (63%) of the title 20 compound. MS (El) 463.2 [M+H]+.
Example 18 4-K5-fluoropvridin-2-vl)methoxvl-l-i3-(propan-2-yl)-lH,2H3H,4H,5HH,4ÎdiazepinoH,7-alindoI-9-vl]-l,2-dihvdropyridin-2-one malcic acid sait (a) Synthesis of the free base
A mixture of 0.11 g (0.27 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(5-fluoropyridin-2-yl)methoxy]-l ,2-dihydropyridin-2-one [Example 1, step (a)], 10 ml of methanol, 0.73 ml (9.94 mmol) of acetone, 0.028 ml (0.45 mmol) of acetic acid and 0.21 g (3.34 mmol) of sodium cyanoborohydride was stirred in a closed 30 reaction vessel at 70°C for 6.25 h, then 20 ml of saturated aqueous NalICCh solution was added and the reaction mixture was stirred at room température ovemight. The reaction mixture was extracted with 3x20 ml of dichloromethane, the combined organic phases were dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2:1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.068 g (56%) of 4-[(5-fluoropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one 5 as free base. MS (El) 447.2 [M+H]+.
(b) Svnthesis of the maleic acid sait
To a solution of 0.037 g (0.084 mmol) of 4-[(5-fluoropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-l H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one free base [Example 18, step (a)] in a 9:1 mixture of dichloromethane and éthanol 0.01 g 10 (0.084 mmol) of maleic acid was added, then the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.043 g (90%) of the title compound. MS (El) 447.2 [M+H]+. ’H NMR (400 MHz, DMSO-de) δ: 9.20-10.10 (br m, 0.7H), 8.62 (br d, J=2.9 Hz, 1H), 7.83 (td, J=8.7, 3.0 Hz, 1H), 7.65 (dd, J=8.7,4.4 Hz, 1H), 7.51-7.58 (m, 2H), 7.44 (d, 15 J=2.0 Hz, 1H), 7.06 (dd, J=8.8, 2.2 Hz, 1H), 6.44 (s, 1H), 6.11 (dd, J=7.6, 2.7 Hz, 1H),
6.05 (s, 2H), 5.95 (d, J=2.9 Hz, 1H), 5.21 (s, 2H), 4.20-5.10 (br m, 2H), 2.90-3.90 (br m, 7H), 1.26 (br d, J=6.6 Hz, 6H).
Example 19
4-(benzvloxv)-l-[3-(propan-2-vl)-lH,2H,3H,4H,5H-H,41diazcpinoH,7-alindol-9-vlll,2-dihvdropyridîn-2-one hydrochloride sait (a) Svnthesis of the free base
A mixture of 0.07 g (0.18 mmol) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 3, step (b)], 5 ml of 25 methanol, 0.53 ml (7.2 mmol) of acetone, 0.011 ml (0.19 mmol) of acetic acid and 0.153 g (2.43 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 75°C for 4.25 h, then at room température ovemight. 0.039 g (0.62 mmol) of sodium cyanoborohydride was added and the reaction mixture was stirred at 75°C for 24 h. 10 ml of saturated aqueous NaHCCh solution was added and the reaction mixture was extracted 30 with 3x15 ml of dichloromethane, the combined organic phases were washed with water, and brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum to yield 0.073 g (95%) of 4-(benzyloxy)-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 428.2 [M+H]+.
I i
(b) Synthesis of the maleic acid sait
To a solution of 0.0326 g (0.076 mmol) of 4-(benzyloxy)-l-[3-(propan-2-yl)1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base [Example 19, step (a)] in 2 ml of a 9:1 mixture of dichloromethane and éthanol 0.0089 g (0.076 mmol) of maleic acid was added, then the dichlorormethane was evaporated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.039 g (94%) of 4-(benzyloxy)-l-[3-(propan-2-yl)1 H,2H,3 H,4H,5H- [ 1,4]diazepino [ 1,7-a] indol-9-yl]-1,2-dihydropyridin-2-one maleic acid sait. MS (El) 428.2 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 9.20-9.90 (br m, 0.6H), 7.50-7.58 (m, 2H), 7.34-7.50 (m, 6H), 7.05 (dd, J=8.8, 2.2 Hz, 1H), 6.43 (s, 1H), 6.08 (dd, J= 7.5, 2.6 Hz, 1H), 6.04 (s, 2H), 5.95 (d, J=2.6 Hz, 1H), 5.14 (s, 2H), 4.20-5.00 (br m, 2H), 2.90-3.90 (br m, 7H), 1.25 (br d, J=5.9 Hz, 6H).
(c) Synthesis of the hydrochloride sait
0,073g (0,17mmol) of 4-(benzyloxy)-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one free base [Example 19, step (a)] was taken up in 10 ml of dichloromethane and 10 ml of methanol. 5 ml of 20% hydrogen chloride in ethyl acetate was added, the reaction mixture was filtered and the solution was evaporated. The residue was triturated with 4 ml of a 3:1 mixture of éthanol and diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0,061g (77%) of 4-(benzyloxy)-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol9-yl]-l,2-dihydropyridin-2-one hydrochloride sait. MS (El) 428,2 [M+H]+.
Example 20 4-[(5-chloropvridin-2-yl)methoxy]-l-[3-(propan-2-vl)-lH3H3H,4H,5H[l,41diazepino[l,7-alindol-9-vl1-l,2-dihvdropyridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.57 g (1.36 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{1 H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl}-1,2-dihydropyridin-2-one [Example 4, step (b)], 60 ml acetonitrile, 0.38 g (2.72 mmol) of K2CO3 and 1.36 ml (13.6 mmol) of 2iodopropane was stirred at reflux température for 45 h. The reaction mixture was concentrated, the residue was triturated with 20 ml of water, the solid product was filtered and washed with water. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5:0.1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.4 g (64%) of 4-[(5chloropyridin-2-yl)methoxy]-l -[3-(propan-2-yl)-l H,2H,3H,4H,5H-[1,4]diazepino[l ,7a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 463.2 [M+H]+.
(b) Svnthesis of the maleic acid sait
To a solution of 0.47 g (1.015 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-1 H,2H,3 H,4H,5H-[ 1,4] diazepino[ 1,7-a] indol-9-yl] -1,2-dihydropyridin-2-one free base [Example 20, step (a)] in a 10:1 mixture of dichloromethane and methanol 0.13 g (1.117 mmol) of maleic acid was added and the mixture was concentrated. The residue was triturated with éthanol, and after 1 h stirring the solid product was filtered, washed with éthanol and dried to yield 0.57 g (96%) of the title compound. MS (El) 463.2 [M+H]+. 1 IT NMR (500 MHz, DMSO-d6) δ: 9.00-10.00 (br m, 0.5H), 8.67 (br d, J=2.4 Hz, 1H), 8.03 (dd, J=8.4,2.5 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.53-7.58 (m, 2H), 7.44 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.7, 2.0 Hz, 1H), 6.43 (s, 1H), 6.12 (dd, J=7.6, 2.8 Hz, 1H), 6.05 (s, 2H), 5.93 (d, J=2.8 Hz, 1H), 5.23 (s, 2H), 4.10-5.10 (br m, 2H), 2.70-4.00 (br m, 7H), 1.26 (br d,
J=6.7 Hz, 6H).
Example 21 4-[(4-fluorophenvl)methoxyl-l-[3-(propan-2-vl)-lH,2H3H,4H,5H-[l,41diazepino[l,7alindol-9-vll-l,2-dihvdropyridin-2-one
To a solution of 0.060 g (0.15 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(4-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one [Example 5, step (a)], 20 ml of dichloromethane, 0.2 ml (1.43 mmol) of triethylamine and 0.04 ml (0.545 mmol) of acetone 0.1 g (0.47 mmol) of sodium triacetoxyborohydride was added at 0°C and the reaction mixture was stirred at room température ovemight. 0.02 ml (0.27 mmol) of acetone and 0.050 g (2.35 mmol) of sodium cyanoborohydride were added and the reaction mixture was stirred at room température for 24 h. After this further 0.02 ml (0.27 mmol) of acetone and 0.050 g (2.36 mmol) of sodium triacetoxyborohydride were added and the reaction mixture was stirred for further 24 h. 40 ml of dichloromethane and 10 ml of saturated aqueous NaHCCh solution were added and the reaction mixture was stirred for
10 min. The phases were separated, the organic phase was washed with 2x30 ml of water, dried over anhydrous NaîSCU, filtered and concentrated in vacuum. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 9:1 mixture of dichloromethane and methanol as eluent. The obtained product was crystallized with éthanol, the precipitated solid product was filtered, washed with diethyl ether and dried. The so obtained product and the concentrated mother liquid were purified together (0.046 g) by column chromatography using Kieselgel 60 (0.0400.063 mm) as adsorbent (Merck) and a 95:5 mixture of dichloromethane and methanol as 5 eluent to yield 0.021 g (31%) of the title compound. MS (El) 446.25 [M+H]+.
Example 22
4-[(4-chlorophenyl)methoxvl-l-[3-(propan-2-yl)-l H,2H,3H,4H,5H-[ 1,41diazepino [ 1,7alindol-9-vl]-1.2-dihvdropyridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.070 g (0.167 mmol) of 4-[(4-chlorophenyl)methoxy]-l{1H,2H,3H,4H,5H-[1,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one free base [Example 6, step (b)], 6 ml of methanol, 0.49 ml (6.67 mmol) of acetone and 0.142 g (2.26 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 70°C 15 ovemight. 6 ml of methanol and 15 ml of saturated aqueous NaHCCh solution were added and the reaction mixture was stined at room température for 3 h. The reaction misture was extracted with 3x20 ml of dichloromethane, the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent 20 (Merck) and a 95:5:1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.065 g (84%) of 4-[(4-chlorophenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 462.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.065 g (0.14 mmol) of 4-[(4-chlorophenyl)methoxy]-l-[3(propan-2-yl)-lH,2H,3H,4H,5H-[l ,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one free base [Example 22, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and éthanol 0.0164 g (0.14 mmol) of maleic acid was added, then the dichlorormethane was evaporated. The residue was triturated with diethyl ether, the solid product was filtered, 30 washed with diethyl ether and dried to yield 0.066 g (81%) of the title compound. MS (El)
462.2 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 9.00-10.00 (br m, 0.7H), 7.48-7.58 (m, 6H), 7.43 (d, J=1.9 Hz, 1H), 7.05 (dd, J=8.7, 2.0 Hz, 1H), 6.44 (s, 1H), 6.03-6.11 (m, >
3.3H), 5.94 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.20-5.05 (br m, 2H), 2.90-3.90 (br m, 7H), 1.18-1.34 (br d, J=6.4 Hz, 6H).
Example 23 4-[(2-fluorophenvl)methoxvl-l-i3-(propan-2-yl)-lH^H3H,4H,5H-[l,41diazepinoH.7a]indol-9-vl]-l,2-dihydronvridin-2-one hydrochloride sait (a) Synthesis of the free base
A mixture of 0.070 g (0.174 mmol) of l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7a]indol-9-yl}-4-[(2-fluorophenyl)methoxy]-l,2-dihydropyridin-2-one [Example 7, step (b) ], 5 ml of methanol, 0.51 ml (6.95 mmol) of acetone, 0.02 ml (0.35 mmol) of acetic acid and 0.21 g (3.34 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 70°C for 6.25 h. 15 ml of saturated aqueous NaHCÛ3 solution was added and the reaction mixture was stirred at room température ovemight. The reaction misture was extracted with 3x15 ml of dichloromethane, the combined organic phases were dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2:1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.030 g (38%) of 4-[(2-fluorophenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 446.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
To a solution of 0.030 g (0.067 mmol) of 4-[(2-fluorophenyl)methoxy]-l-[3(propan-2-yl)-1 H,2H,3H,4H,5H-[1,4]diazepino[ 1,7-a] indol-9-yl]-1,2-dihydropyridin-2-one [Example 23, step (a)] in 8 ml of dichloromethane 1 ml of 20% hydrogen chloride in ethyl acetate was added and the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.025 g (77%) of the title compound. MS (El) 446.2 [M+H]+. 1I I NMR (400 MHz, DMSO-dô) δ: 10.69-10.84 (br m, 1H), 7.42-7.62 (m, 5H), 7.24-7.33 (m, 2H), 7.06 (dd, J=8.7,2.1 Hz, 1H), 6.44 (s, 1H), 6.06 (dd, J=7.5,2.7 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.85-4.95 (br m, 1H), 4.56-4.67 (br m, 1H), 3.67-3.80 (br m, 3H), 3.50-3.61 (br m, 1H), 3.20-3.49 (br m, 2H), 2.99-3.10 (br m, 1H), 1.26-1.34 (m, 6H).
Example 24 i
l-[ll-chloro-3-(propan-2-vl)-lH3H3H,4H,5H-H,4]diazepino[l,7-alindol-9-yll-4-K5chloropvridin-2-yl)methoxvl-l,2-dihvdropyridin-2-one maleic acid sait (a) Synthesis of the free base
To a solution of 0.20 g (0.43 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-l H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one [Example 20, step (a)] in 2 ml of dichloromethane 0.064 g (0.48 mmol) of Nchlorosuccinimide was added and the reaction mixture was stirred at room température for 45 min. The reaction mixture was concentrated and the residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and different mixtures of dichloromethane and methanol as eluent: first a 98:2, then a 97:3, and finally a 95:5 mixture to yield 0.146 g (67%) of l-[ll-chloro-3-(propan-2-yl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-4-[(5-chloropyridin-2-yl)methoxy]-l,2dihydropyridin-2-one as free base. MS (El) 497.1 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.1 g (0.2 mmol) of l-[ll-chloro-3-(propan-2-yl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-4-[(5-chloro-pyridin-2-yl)methoxy]- l,2-dihydropyridin-2-one free base [Example 24, step (a)] in 3 ml of a 9:1 mixture of dichloromethane and éthanol 0.0233 g (0.2 mmol) of maleic acid was added, then the dichlorormethane was evaporated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.104 g (84%) ofthe title compound. MS (El) 497.2 [M+H]+. Ή NMR (400 MHz, DMSO-de) δ: 9.00-
10.20 (br m, 0.7H) 8.68 (dd, J=2.5, 0.6 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.56-7.64 (m, 2H), 7.39 (d, J=2.0 Hz, 1H), 7.18 (dd, J=8.7, 2.1 Hz, 1H), 6.14 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (s, 1.86H), 5.95 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 5.10-
4.20 (br m, 2H), 2.85-4.00 (br m, 7H), 1.12-1.32 (br d, 6H).
Example 25 l-[ll-bromo-3-(propan-2-vl)-lH,2H3H,4H,5H-ll,41diazepinoH,7-alindol-9-yl1-4-f(5chloropvridin-2-vl)methoxv]-l,2-dihydropvridin-2-one maleic acid sait (a) Synthesis of the free base
To a solution of 0.20 g (0.43 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-lH,2H,3H,4H,5H-[l ,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one [Example 20, step (a)] in 4 ml of dichloromethane 0.089 g (0.5 mmol) of N* bromosuccinimide was added and the reaction mixture was stirred at room température for 75 min. 40 ml dichloromethane and 10 ml of IN aqueous NaOH solution were added. The mixture was stirred at room température for 1 h, then the phases were separated. The organic phase was washed with 2x10 ml of IN aqueous NaOH solution, water and brine, then dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2 mixture of dichloromethane and methanol as eluent. The so obtained solid product was triturated with diethyl ether, filtered, washed with diethyl ether and dried to yield 0.056 g (24%) of the title compound l-[ll-bromo-3-(propan-2-yl)lH,2H,3H,4H,5H-[l,4]diazepmo[l,7-a]indol-9-yl]-4-[(5-chloropyridin-2-yl)methoxy]-l,2dihydropyridin-2-one as free base. MS (El) 543.1 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.037 g (0.068 mmol) of l-[ll-bromo-3-(propan-2-yl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-4-[(5-chloropyridin-2-yl)methoxy]-l,2dihydropyridin-2-one [Example 25, step (a)] in 2 ml of a 9:1 mixture of dichloromethane and éthanol 0.0079 g (0.068 mmol) of maleic acid was added, then the dichlorormethane was evaporated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.038 g (83%) of the title compound. MS (El) 543.1 [M+H]+. Ή NMR (400 MHz, DMSO-de) δ: 9.10-10.00 (br m, 0.6H), 8.68 (dd, J=2.5, 0.6 Hz, 1H), 8.03 (dd, J=8.3, 2.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.56-7.64 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.7, 2.1 Hz, 1H), 6.14 (dd, J=7.6,
2.7 Hz, 1H), 6.04 (s, 1.8H), 5.95 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.15-5.10 (br m, 2H), 2.80-4.00 (br m, 7H), 1.15-1.30 (br d, 6H).
Example 26 4-[(5-chloropvridin-2-vl)methoxvl-l-fll-iodo-3-(Dropan-2-yl)-lH,2H3H,4H,5H[l,41diazepino[l,7-alindol-9-vl]-l,2-dihvdropvridin-2-one maleic acid sait (a) Synthesis of the free base
To a solution of 0.20 g (0.43 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(propan-2-yl)-l H,2H,3H,4H,5H-[1,4]diazepino[ 1,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one [Example 20, step (a)] in 4 ml of dichloromethane 0.113 g (0.5 mmol) of Niodosuccinimide was added and the reaction mixture was stirred at room température for 1
h. 40 ml dichloromethane and 10 ml of IN aqueous NaOH solution were added. The mixture was stirred at room température for 1 h, then the phases were separated. The organic phase was washed with 2x10 ml of IN aqueous NaOH solution, water and brine, then dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as 5 adsorbent (Merck) and a 95:5 mixture of dichloromethane and methanol as eluent to yield
0.171 g (67%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[ll-iodo-3-(propan-2-yl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 589.1 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.040 g (0.068 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[l 1iodo-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l ,4]diazepino[l ,7-a]indol-9-yI]-l ,2dihydropyridin-2-one [Example 26, step (a)] in 1.2 ml of a 9:1 mixture of dichloromethane and éthanol 0.0079 g (0.068 mmol) of maleic acid was added, then the reaction mixture 15 was concentrated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.026 g (63%) of the title compound. MS (El) 589.1 [M+H]+. Ή NMR (400 MHz, DMSO-de) δ: 9.20-10.00 (br m, 0.5H), 8.68 (dd, J= 2.5,0.6 Hz, 1H), 8.03 (dd, J=8.2,2.5 Hz, 1H), 7.56-7.64 (m, 3H), 7.107.19 (m, 2H), 6.14 (dd, J=7.6, 2.7 Hz, 1H), 6.03 (s, 1.34H), 5.95 (d, J=2.7 Hz, 1H), 5.24 (s, 20 2H), 4.25-5.15 (br m, 2H), 2.70-4.00 (m, 7H), 0.90-1.40 (br d, 6H).
Example 27 4-(benzvIoxv)-l-[ll-chIoro-3-(propan-2-yl)-lH,2HJH,4H,5H-[l,41diazepino[l,7alindol-9-vl]-l,2-dihvdropyridin-2-one hydrochloride sait (a) Synthesis of the free base
To a solution of 0.073 g (0.17 mmol) of 4-(benzyloxy)-l-[3-(propan-2-yl)1 H,2H,3 H,4H,5H-[ 1,4] diazepino[ 1,7-a] indol-9-yl] -1,2-dihydropyridin-2-one [Example 19, step (a)] in 2 ml of dichloromethane 0.024 g (0.18 mmol) of N-chlorosuccinimide was added and the reaction mixture was stirred at room température for 70 min. 20 ml 30 dichloromethane and 5 ml of IN aqueous NaOH solution were added. The mixture was stirred at room température for 1 h, then the phases were separated. The organic phase was washed with 2x5 ml of IN aqueous NaOH solution, water and brine, then dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2 mixture of dichloromethane and methanol as eluent to yield 0.038 g (48%) of 4(benzyloxy)-l-[ll-chloro-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9yl]-l,2-dihydropyridin-2-one as free base. MS (El) 462.2 [M+H]+.
(b) Synthesis of the hydrochloride sait
To a solution of 0.025 g (0.054 mmol) of 4-(benzyloxy)-l-[ll-chloro-3-(propan-2yl)-l H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl]-l,2-dihydropyridin-2-one free base [Example 27, step (a)] in 5 ml of dichloromethane 1 ml of 20% hydrogen chloride in ethyl acetate was added, then the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.025 g (77%) ofthe title compound. MS (El) 462.2 [M+H]+. Ή NMR (400 MHz, DMSO-dô) δ: 10.74-10.88 (br m, 1H), 7.68 (br d, J=8.7 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.34-7.50 (m, 6H), 7.18 (br d, J=8.8 Hz, 1H), 6.10 (dd, J=7.6, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.90-5.02 (br m, 1H), 4.58-4.71 (br m, 1H), 3.68-3.82 (br m, 3H), 3.25-3.60 (brm, 3H), 3.06-3.21 (brm, 1H), 1.21-1.36 (brm, 6H).
Example 28 4-[(5-chloropvridin-2-vl)methoxvl-l-[3-(cvclopropylmethvl)-lH,2H3H,4H,5HH,4]diazepino[l,7-alindol-9-vl]-l,2-dihvdropyridin-2-ond maleic acid sait (a) Synthesis of the free base
A mixture of 0.060 g (0.14 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]mdol-9-yl}-l,2-dihydropyridin-2-one [Example 4, step (b)], 4 ml of methanol, 0.017 ml (0.3 mmol) of acetic acid, 0.112 ml (1.49 mmol) of cyclopropanecarboxaldehyde and 0.127 g (2.02 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 70°C for 70 min. 6 ml of saturated aqueous NalICCh solution was added and the reaction mixture was extracted with 2x15 ml of dichloromethane, the combined organic phases were dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2:1 mixture of dichloromethane, methanol and CCNH4OH as eluent to yield 0.061 g (91%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3-(cyclopropyImethyl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 475.2 [M+H]+.
ib) Synthesis of the maleic acid sait
To a solution of 0.061 g (0.128 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(cyclopropylmethyl)-l H,2H,3H,4H,5H-[l,4]diazepino[l ,7-a]indol-9-yl]-l ,2dihydropyridin-2-one [Example 28, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and éthanol 0.015 g (0.128 mmol) of maleic acid was added, then the dichloromethane was evaporated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.059 g (77%) of the title compound. MS (El) 475.2 [M+H]+. ‘H NMR (400 MHz, DMSO-de) δ: 9.50-10.40 (br m, 0.6H), 8.67 (br d, J=2.4 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.52-7.64 (m, 3H), 7.44 (d, J=2.2 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.43 (s, 1 H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.04 (s, 1.9H), 5.94 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 4.20-5.10 (br m, 2H), 2.95-4.10 (br m, 8H), 1.05-1.18 (br m, 1H), 0.63-0.72 (br m, 2H), 0.34-0.42 (br m, 2H).
Example 29 4-(benzvloxv)-l-{3-cvclopropyl-lH,2H3H,4H^H-il,41diazepinoil,7-alindol-9-vl}-l,2dihvdropyridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.1 g (0.26 mmol) of 4-(benzyloxy)-l-{lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 3, step (b)], 7 ml of methanol, 0.030 ml (0.52 mmol) of acetic acid, 0.52 ml (2.6 mmol) of (1ethoxycyclopropoxy)trimethylsilane and 0.22 g (3.5 mmol) of sodium cyanoborohydride was stirred in a closed reaction vessel at 70°C ovemight. 7 ml of methanol was added to the concentrated reaction mixture and it was stirred at 70°C for 10 min. After cooling to room température 15 ml of saturated aqueous NaHCCh solution was added and the reaction mixture was extracted with 3x20 ml of dichloromethane, the combined organic phases were washed with 10 ml of water and 15 ml of brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was triturated with 5 ml of a 3:1 mixture of éthanol and diethyl ether, the solid product was filtered, washed with diethyl ether and dried. The crude product was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2:1 mixture of dichloromethane, methanol and ccNHîOH as eluent to yield 0.062 g (55%) of 4-(benzyloxy)-l-{3cyclopropyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one as free base. MS (El) 426.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.062 g (0.145 mmol) of 4-(benzyloxy)-l-{3-cyclopropyl1 H,2H,3H,4H,5H-[1,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 29, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and éthanol 0.017 g (0.146 mmol) of maleic acid was added, then the dichloromethane was evaporated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.057 g (72%) ofthe title compound. MS (El) 426.2 [M+H]+. Ή NMR (400 MHz, DMSO-de) δ: 7.34-7.56 (m, 8H), 7.02 (dd, J=8.7, 2.0 Hz, 1H), 6.36 (s, 1H), 6.15 (s, 2H), 6.07 (dd, J=7.6, 2.7 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 4.35-4.55 (br m, 2H), 2.90-3.80 (br m, 6 H), 2.36-2.58 (br m, 1H), 0.62-0.82 (br m, 4H).
Example 30 4-[(5-chloropvridin-2-vl)methoxvÎ-l-(3-cvclopropyl-lH,2H3H,4H,5H[l,4]diazenino|l,7-a|indol-9-vl)-l,2-dihvdropvridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.3 g (0.71 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{1 H,2H,3H,4H,5H-[1,4]diazepino[l ,7-a]indol-9-yl}-1,2-dihydropyridin-2-one [Example 4, step (b)], 30 ml of methanol, 0.41 ml (7.16 mmol) of acetic acid, 1 g of powdered 4Â molecular sieves, 0.43 ml (0.21 mmol) of (l-ethoxycyclopropoxy)trimethylsilane and 0.12 g (1.92 mmol) of sodium cyanoborohydride was stirred at reflux température for 4 h. The reaction mixture was filtered, the solid material was washed with methanol and the filtrate was concentrated in vacuum. The residue was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 9:1 mixture of dichloromethane and methanol as eluent. The so obtained residue was triturated with éthanol, filtered, washed with éthanol and dried. The obtained solid product was further purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5 mixture of dichloromethane and methanol as eluent, then again purified by column chromatography using a 98:2 mixture of dichloromethane and methanol as eluent. The residue was triturated with diethyl ether, then the diethyl ether was evaporated to yield 0.041 g (12.5%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3-cyclopropyllH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one as free base. MS (El) 461.2 [M+H]+.
(b) Synthesis of the maleic acid sait f
»
To a solution of 0.018 g (0.039 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3cyclopropyl-1 H,2H,3 H,4H,5H- [ 1,4] diazepinof 1,7-a] indol-9-yl} -1,2-dihydropyridin-2-one free base [Example 30, step (a)] in 3 ml of dichloromethane and 1 ml of acetone 0.0046 g (0.040 mmol) of maleic acid was added, then the reaction mixture was concentrated in vacuum. Acetone was added to the residue and the mixture was concentrated to a final volume of 1.0 ml. The solid product separated from acetone, it was filtered, washed with acetone and dried to yield 0.008 g (35%) of the title compound. Concentration of the mother liquid resulted in further 0.005 g (21%) of the title compound. The two fractions were combined. MS (El) 461.2 [M+H]+. *H NMR (400 MHz, DMSO-d6) δ: 8.67 (dd, J=2.5, 0.7 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.50-7.63 (m, 3H), 7.40 (d, J=1.9 Hz, 1H), 7.02 (br d, J=9.0 Hz, 1H), 6.37 (br s, 1H), 6.17 (s, 2.8H), 6.11 (dd, J=7.5,2.7 Hz, 1H), 5.94 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 4.28-4.62 (br m, 2H), 2.40-3.80 (br m, 7 H), 1.20-1.33 (br m, 1H), 0.62-0.83 (br m, 3H).
Example 31 4-[(5-chloropvridin-2-vl)methoxvl-l-(3-cvclobutvl-lH<2H,3H,4H<5H[l,41diazepino[l,7-aHndol-9-vl}-l^-dihvdropvridin-2-one maleic acid sait (a) Synthesis of the free base
To a mixture of 0.3 g (0.71 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{1H,2H,3H,4H,5H-[1,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one [Example 4, step (b)], 50 ml of dichloromethane, 0.2 ml (1.43 mmol) of triethylamine and 0.07 ml (0.93 mmol) of cyclobutanone 0.23 g (1.09 mmol) of sodium triacetoxyborohydride was added below 10°C and the reaction mixture was stirred at room température ovemight. 0.2 ml (1.43 mmol) of triethylamine and 0.12 g (0.57 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred for 24 h. The reaction mixture was washed with 40 ml of 5% aqueous NaHCCh solution and 2x40 ml of water, the organic phase was dried over anhydrous NazSCh, filtered and concentrated in vacuum. The residue was triturated with éthanol, the solid product was filtered, washed with éthanol and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 9:1 mixture of dichloromethane and methanol as eluent. The so obtained residue was triturated with éthanol, filtered, washed with éthanol and diethyl ether and dried to yield 0.10 g (30%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3-cyclobutyl18375 lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one as free base. MS (El) 475.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.060 g (0.126 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-{3cyclobutyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one free base [Example 31, step (a)] in 8 ml of dichloromethane and 2 ml of acetone 0.015 g (0.13 mmol) of maleic acid was added, then the reaction mixture was concentrated in vacuum. Acetone was added to the residue and the mixture was concentrated to a final volume of 0.5 ml. The solid product separated from acetone, it was filtered, washed with acetone and dried to yield 0.055 g (74%) of the title compound. MS (El) 475.2 [M+H]+. 'H NMR (400 MHz, DMSO-de) δ: 9.40-10.40 (br m, 0.7H), 8.67 (d, J=2.5 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.50-7.63 (m, 3H), 7.43 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.43 (s, 1H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 6.06 (s, 2H), 5.94 (d, J=2.7 Hz, 1H), 5.22 (s, 2H), 4.15-5.00 (br m, 2H), 2.70-3.90 (br m, 7H), 2.12-2.31 (br m, 4H), 1.61-1.83 (br m, 2H).
Example 32 4-K5-chloropyridin-2-vl)methoxv1-l-[3-(2-fluoroethvl)-lH^H3H,4H,5H[l,41diazepinoH,7-a]indol-9-vIl-l,2-dihydronvridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 0.060 g (0.143 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l{1 H,2H,3H,4H,5H-[ 1,4]diazepino[l ,7-a]indol-9-yl} -1,2-dihydropyridin-2-one [Example 4, step (b)], 6 ml of acetonitrile, 0.041 g (0.3 mmol) of potassium carbonate, 0.25 g (1.5 mmol) of potassium iodide and 0.112 ml (1.5 mmol) of l-bromo-2-fluoro-ethane was stirred in a closed reaction vessel at 65°C ovemight, at 50°C for 72 h, then at 70°C for 48 h. 10 ml of saturated aqueous NaHCCh solution was added to the reaction mixture and it was extracted with 3x15 ml of dichloromethane, the combined organic phases were washed with water and brine, dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum to yield 0.059 g (85%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3-(2-fluoro-ethyl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one as free base. MS (El) 467.1 [M+H]+.
(b) Synthesis of the maleic acid sait
I
To a solution of 0.056 g (0.12 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3-(2fluoroethyl)-1 H,2H,3 H,4H,5H-[ 1,4] diazepino[ 1,7-a] indol-9-yl] -1,2-dihydropyridin-2-one free base [Example 32, step (a)] in 2.5 ml of a 9:1 mixture of dichloromethane and éthanol 0.014 g (0.12 mmol) of maleic acid and 0.7 ml of éthanol were added, then the 5 dichloromethane was evaporated in vacuum. The precipitated solid product was filtered, washed with éthanol and diethyl ether and dried to yield 0.052 g (74%) of the title compound. MS (El) 467.2 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 8.67 (d, J=2.4, 0.5 Hz, 1H), 8.03 (dd, J=8.3, 2.4 Hz, 1H), 7.51-7.643 (m, 3H), 7.40 (d, J=2.2 Hz, 1H), 7.02 (dd, J=8.7,2.1 Hz, 1H), 6.37 (br s, 1H), 6.13 (s, 2H), 6.11 (dd, J=7.7,2.8 Hz, 1H), 5.94 (d, 10 J=2.7 Hz, 1H), 5.22 (s, 2H), 4.77 (br d, J=47.6 Hz, 2H), 4.30-4.62 (br m, 2H), 2.80-3.90 (br m, 8H).
Example 33 l-[ll-chloro-3-(2-fluoroethyl)-lH3H3H,4H,5H-[l,41diazepino[l,7-alindol-9-vl1-4-[(515 chloropvridin-2-vl)methoxvl-l,2-dihvdropvridin-2-one dihydrochloride sait (a) Synthesis of the free base
To a solution of 0.060g (0.128 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[3(2-fluoroethyl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2one [Example 32, step (a)] in 2 ml of dichloromethane 0.018 g (0.138 mmol) of N20 chlorosuccinimide was added and the reaction mixture was stirred at room température for min. 20 ml of dichloromethane and 5 ml of IN aqueous NaOH solution were added to the reaction mixture. The mixture was stirred at room température for 1 h, then the phases were separated. The organic phase was washed with 2x5 ml of IN aqueous NaOH solution, water and brine, then dried over anhydrous Na2SO4, filtered and concentrated in vacuum.
The residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 98:2 mixture of dichloromethane and methanol as eluent to yield 0.022 g (34%) of l-[ll-chloro-3-(2-fluoroethyl)-lH,2H,3H,4H,5H- [l,4]diazepino[l,7-a]indol-9-yl]-4-[(5-chloropyridin-2-yl)methoxy]-l,2-dihydropyridin-2one as free base. MS (El) 501.1 [M+H]+.
(b) Synthesis of the dihydrochloride sait
To a solution of 0.022 g (0.044 mmol) of l-[ll-chloro-3-(2-fluoroethyl)lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-4-[(5-chloropyridin-2-yl)methoxy]-l,2dihydropyridin-2-one [Example 33, step (a)] in 5 ml of dichloromethane 1 ml of 20%
hydrogen chloride in ethyl acetate was added, then the reaction mixture was concentrated. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.022 g (88%) of the title compound. MS (El) 501.1 [M+H]+. *H NMR (400 MHz, DMSO-de) δ: 11.48-11.64 (br m, 1H), 8.68 (dd, J=2.5, 0.6 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.58-7.64 (m, 2H), 7.40 (d, J=2.2 Hz, 1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 6.14 (dd, J=7.5, 2.8 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.86-5.05 (br m, 3H), 4.55-4.69 (br m, 1H), 3.75-4.05 (br m, 3H, the signal of HCl overlapped by the signal of H2O), 3.58-3.74 (br m, 2H), 3.22-3.52 (br m, 4H).
Example 34 4-i(5-chloropyridin-2-vl)methoxy]-l-[ll-methvl-3-(propan-2-vl)-lH,2H3H,4H,5H[l,41diazepino[l/7-a]indol-9-vll-l,2-dihvdroDvridin-2-one maleic acid sait (a) Synthesis of the free base
A mixture of 1.26 g (2.13 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[l 1-iodo3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2one [Example 26, step (a)], 44 ml of tetrahydrofuran, 0.162 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) and 8 ml (16 mmol) of 2M trimethylaluminum solution in toluene was refluxed for 170 min. The reaction mixture was cooled to room température, 150 ml of ethyl acetate, 50 ml of saturated aqueous ammonium chloride solution and 25 ml of brine were added. The phases were separated and the water phase was extracted with 2x50ml of ethyl acetate. The combined organic phases were washed with 2x50ml of brine, then dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.87 g of crude product. To a solution of 0.568 g of crude product in 25 ml of dichloromethane 0.054 g (0.24 mmol) of 7V-iodosuccinimide was added at 0°C and the mixture was stirred at 0°C for 30 min, then at room température for 30 min. 0.027 g (0.12 mmol) of /V-iodosuccinimide was added, then after stirring at room température for 50 min further 0.027 g (0.12 mmol) of 7V-iodosuccinimide was added and the reaction mixture was stirred at room température for 2 h, then it was kept at 8°C for 3 days. 100 ml of dichloromethane was added and the reaction mixture was washed with 2x45 ml of IN aqueous NaOH solution, 1x45 ml of brine, then dried over anhydrous Na2SÛ4, filtered and concentrated in vacuum. The residue was purified by flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and a 95:5 mixture of dichloromethane and methanol as eluent. The concentrated fractions (0.159 g) were dissolved in 1.5 ml of éthanol, then the solid product precipitated at room température was filtered, washed with éthanol, and a 2:1 mixture of diethyl ether and hexane and dried 5 to yield 0.126 g (18%) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[l l-methyl-3-(propan-2y I)-1 H,2H,3 H,4H,5 H-[ 1,4] diazepino [ 1,7-a] indol-9-yl] -1,2-dihydropyridin-2-one as free base. MS (El) 477.2 [M+H]+.
(b) Synthesis of the maleic acid sait
To a solution of 0.108 g (0.23 mmol) of 4-[(5-chloropyridin-2-yl)methoxy]-l-[llmethyl-3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2dihydropyridin-2-one free base [Example 34, step (a)] in 10 ml of a 9:1 mixture of dichloromethane and acetone 0.0271 g (0.23 mmol) of maleic acid was added, then the 15 reaction mixture was concentrated in vacuum. Ethanol was added to the residue and the mixture was concentrated to a final volume of 0.5 ml. Diethyl ether was added and the mixture was concentrated in vacuum. The residue was triturated with diethyl ether, the solid product was filtered, washed with diethyl ether and dried to yield 0.119 g (87%) of the title compound. MS (El) 477.2 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ: 9.10-9.90 20 (m, 0.6H), 8.68 (dd, J=2.5, 0.6 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.48-7.64 (m, 3H),
7.40 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.7,2.1 Hz, 1H), 6.12 (dd, J=7.6,2.7 Hz, 1H), 6.03 (s,
1.9H), 5.93 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.15-5.05 (br m, 2H), 2.80-3.95 (br m, 7H), 2.21 (s, 3H), 1.24 (br d, J=5.7 Hz, 6H).
EVALUATION OF MCHR1 ANTAGONISM IN FUNCTIONAL ASSAY
In vitro activity data of selected compounds of the présent invention - shown in
Table 1 - were determined by the following method.
Materials used:
Cells: human MCH1 (SLC1) AequoScreen® Cell Line (Perkin Elmer ES-370-A, lot Ne: 30 M4W-A2) • > ’ r
5l
F12 medium (Gibco 21765)
FBS (Gibco 10500)
Antibiotic Antimycotic Solution (Sigma A5955)
G418 (Gibco 11811-023)
Zeocin (Life Technologies R250-01)
96-well plate (Costar 3595)
FLIPR Calcium 5 (no-wash) kit (Molecular Devices R8186)
Probenecid (Sigma P8761)
MCH (Bachem H-1482)
MCH was dissolved in MilliQ water (1 mM), aliquots were taken from the stock solution, and were kept at -20 °C. One aliquot was used only once.
HEPES - buffered sait solution (HBSS): 140 mM NaCl, 5 mM KC1, 10 mM HEPES, 2 mM CaCh, 2 mM MgCh, 20 mM glucose, pH=7.4,305-315 mOsm
Assay buffer: HBSS + 2 mM probenecid, pH=7.4
Measuring of cytoplasmic calcium concentration (rCa2+Ii ):
Cells (human MCH1 (SLC1) AequoScreen® Cell Line, Perkin Elmer ES-370-A, lot Jf»; M4W-A2) expressing human MCH1 receptor, Aequorint and Gai6 were cultured in F12 medium (Gibco 21765) containing 10% FBS (Gibco 10500), lx Antibiotic Antimycotic 20 Solution (Sigma A5955), 400 pg/ml G418 (Gibco 11811-023) and 250 pg/ml zeocin (Life
Technologies R250-01).
One day before the [Ca2+]i measurement cells were plated in a 96-well plate (96-well plate, Costar 3595) at a density of 30000 cells/well in the above described culturing medium, but without G418 and zeocin. On the day of measurement the culture medium was removed 25 from the cells and a fluorescent Ca2+-sensitive dye (FLIPR Calcium 5 kit, Molecular
Devices R8186) was added to the cells at a 4x dilution compared to the recommended dilution by the manufacturer, in a volume of 100 μΐ/well, and cells were incubated at 37°C for 10 min. DMSO stock solutions were made from the test compounds, which were diluted with assay buffer (HEPES buffered sait solution (HBSS): 140 mM NaCl, 5 mM 5 KC1,10 mM HEPES, 2 mM CaCh, 2 mM MgCh, 20 mM glucose, pH=7.4,305-315m0sm + 2mM probenecid (Sigma P8761)) (final DMSO concentration was 1%). The vehicle (DMSO, control treatment), or the buffer containing test compounds were added to the cells in a volume of 50 μΐ/well, and cells were incubated at 37 °C for further 60 min.
[Ca2+]i measurement was carried out by FlexStation II (Molecular Devices) plate reader 10 fluorimeter (excitation 485 nm, émission 525 nm). MCH was used as agonist (Bachem H1482). 1 mM stock solution was made from the agonist in distilled water, this solution was distributed into aliquots, which were kept at -20 °C until use. One aliquot was used only once. Fluorescence was detected before addition of MCH for 20 s, and after addition of
MCH for 40 s. MCH was applied at an ECso concentration, the ECso-values were 15 determined individually for every plate/experiment. For this whole MCH dose-response curves were determined on one part of the plate, 4 parameter sigmoidal curves were fitted to the experimental data by nonlinear régression, MCH ECso values were derived from the fitted curve. The raw fluorescence data were converted into AF/F values (the maximum fluorescence value obtained after addition of MCH was normalized to the baseline fluorescence: AF/F= (Fmax.-Fbaseiine)/Fbaseiine). Inhibitory potency of test compounds was expressed as percent inhibition calculated according to the following formula:
inhibition % = 100x(l-( AF/Fcompound- AF/FdMSO buffer)/(AF/FMCH control - AF/FdMSO buffer))·
IC50 values of the tested compounds were determined by fitting 4 parameter sigmoidal curves to inhibition % data. Data processing, including fitting curves by nonlinear 25 régression, was done by SoftMaxPro software.
IC50 values
IC50 values of Examples are given in Table 1 below. IC50 values of ail Examples of the présent invention are lower than 50 nM. One third of the compounds hâve IC50 values, determined by the above described method, lower than 10 nM, and IC50 values of about 30 one third of the compounds were between 10 nM and 20 nM.
ICso values generated by the above described MCHR1 rCa2+1i measurement are given in Table 1 below.
Table 1
Example | MCHR1 ICso (nM) | Example | MCHR1 IC5o (nM) |
1 | 17.6 | 19 | 8.2 |
2 | 32.9 | 20 | 6.2 |
3 | 17.7 | 21 | 8 |
4 | 9.8 | 22 | 7.2 |
5 | 12 | 23 | 15.7 |
6 | 11.9 | 24 | 18.5 |
7 | 27.7 | 25 | 30.7 |
8 | 123.3 | 26 | 38.8 |
9 | 14.9 | 27 | 29.9 |
10 | 9.2 | 28 | 6.2 |
11 | 9.6 | 29 | 12.9 |
12 | 9 | 30 | 17.2 |
14 | 7.9 | 31 | 12.3 |
15 | 6.5 | 32 | 10 |
16 | 7.2 | 33 | 15.5 |
17 | 18.9 | 34 | 14.3 |
18 | 15.2 |
It is to be understood that the above examples are merely illustrative and do not limit the scope of our invention. The above examples could be modified in numerous respects, and the use of any such modifications or any équivalents is to be consîdered 5 within the scope of our invention.
Claims (25)
- Claims1. Compounds of the general formula (I) wherein the meaning of A is CH or nitrogen atom;the meaning of R is hydrogen or halogen atom or Ci-Cô straight or branched chain alkyl group;the meaning of R1 is hydrogen or halogen atom orCi-Cô straight or branched chain alkyl group, orCi-Cô straight or branched chain alkoxy group, or mono- or polyhalogenated Ci-Cô straight or branched chain haloalkyl group;the meaning of R2 is hydrogen or halogen atom orCi-Cô straight or branched chain alkyl group, orCi-Cô straight or branched chain alkoxy group or mono- or polyhalogenated C1-C4 straight or branched chain haloalkyl group;the meaning of R3 is hydrogen orCi-Cô straight or branched chain alkyl group, optionally substituted with C3-C6 cycloalkyl group, or mono- or polyhalogenated Ci-Cf, straight or branched chain haloalkyl group; orC3-C6 cycloalkyl group, orCi-Cô straight or branched chain alkanoyl group and/or salts, and/or géométrie isomers, and/or stereoisomers, and/or diastereomers, and/or hydrates, and/or solvatés, and/or polymorph modifications thereof.
- 2. Compounds of the general formula (I) according to claim 1 characterized by that the meaning of R3 is:hydrogen atom, orC1-C4 straight or branched chain alkyl group, optionally substituted with C3-C6 cycloalkyl group, orC3-C6 cycloalkyl group, orC1-C4 straight or branched chain alkanoyl group, or acetyl group.
- 3. Compounds of the general formula (I) according to claim 1 or 2 characterized by that the meaning of R3 is:hydrogen atom,C1-C4 straight or branched chain alkyl group, optionally substituted with C3-C4 cycloalkyl group or fluorine atom, orC3-C4 cycloalkyl group.
- 4. Compounds of the general formula (I) according to any of claims 1-3 characterized by that the meaning of R3 is methyl, ethyl, isopropyl, cyclopropylmethyl, cyclobutyl or fluoroethyl group.
- 5. Compounds of the general formula (I) according to any of claims 1-4 characterized by that the meaning of R3 is isopropyl or cyclopropylmethyl.
- 6. Compounds of the general formula (I) according to any of claims 1-5 characterized by that the meaning of R2 is hydrogen or halogen atom, trifluoromethyl or C1-C3 alkyl group.
- 7. Compounds of the general formula (I) according to any of claims 1-6 characterized by that the meaning of R2 is hydrogen, fluorine or chlorine atom, or methyl group.
- 8. Compounds of the general formula (I) according to any of claims 1-7 characterized by that the meaning of R2 is hydrogen atom.
- 9. Compounds of the general formula (I) according to any of claims 1-8 characterized by that the meaning of R1 is hydrogen or halogen atom, orC1-C4 straight or branched chain alkyl group, optionally mono- or polyhalogenated; orC1-C3 alkoxy group.
- 10. Compounds of the general formula (I) according to any of claims 1-9 characterized by that the meaning of R1 is hydrogen, fluorine or chlorine atom, or methoxy or trifluoromethyl group.
- 11. Compounds of the general formula (I) according to any of claims 1-10 characterized by that the meaning of R1 is hydrogen, fluorine or chlorine atom.
- 12. Compounds of the general formula (I) according to any of claims 1-11 characterized by that the meaning of Ris hydrogen atom.
- 13. Compounds ofthe general formula (I) according to any of claims 1-12 characterized by that the meaning of R is hydrogen atom and the meaning of R1 is chlorine atom ‘ al >!
- 14. Compounds of the general formula (I) according to any of claims 1-13 characterized by that the meaning of A is nitrogen atom
- 15. Compounds of the general formula (I) according to any of claims 1-14 characterized by 5 that the meaning of A is CH.
- 16. The following compounds according to claim 1 and pharmaceutically acceptable salts thereof:4-[(5-chloro-pyridin-2-yl)methoxy]-1 - {1 H,2H,3H,4H,5H-[ 1,4]diazepino[ 1,7-a] indol-910 yl}-l,2-dihydropyridin-2-one4-[(5-chloro-pyridm-2-yl)methoxy]-l-{3-methyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl} -1,2-dihydropyridin-2-one4-[(5-chloro-pyridin-2-yl)methoxy]-l-{3-ethyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl} -1,2-dihydropyridin-2-one15 4-[(5-fluoro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H[ 1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one4-(benzyloxy)-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl]-l,2dihydropyridin-2-one4-[(5-chloro-pyridin-2-yl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H20 [1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one4-[(4-fluoro-phenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl] -1,2-dihydropyridin-2-one4-[(4-chloro-phenyl)methoxy]-l-[3-(propan-2-yl)-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-9-yl] -1,2-dihydropyridin-2-one25 4-[(2-fluoro-phenyl)methoxy]-1 -[3-(propan-2-yl)-1 H,2H,3H,4H,5H-[ 1,4]diazepino [ 1,7a] indol-9-yl] -1,2-dihydropyridin-2-oneI -[11 -chloro-3-(propan-2-yl)-l Η,2Η,3Η,4Η,5Η-[1,4]diazepino[l ,7-a] indol-9-yl]~4-[(5chloro-pyridin-2-yl)methoxy]-1,2-dihydropyridin-2-one4-(benzyloxy)-1 -[ 11 -chloro-3 -(propan-2-yl)-1 H,2H,3 H,4H,5H- [ 1,4] diazepino [ 1,7-a] indol9-yl] -1,2-dihydropyridin-2-one5 4-[(5-chloro-pyridin-2-yl)methoxy]-l-[3-(cyclopropylmethyl)-lH,2H,3H,4H,5H- [1,4]diazepino[l ,7-a]indol-9-yl]-l ,2-dihydropyridin-2-one4- [(5-chloro-pyridin-2-yl)methoxy] -1 - {3 -cyclopropyl-1 H,2H,3 H,4H,5H- [1.4] diazepino[l ,7-a]indol-9-yl}-l ,2-dihydropyridin-2-one4-[(5-chloro-pyridin-2-yl)methoxy]-l-{3-cyclobutyl-lH,2H,3H,4H,5H-[l,4]diazepino[l,710 a] indol-9-yl} -1,2-dihydropyridin-2-one4-[(5-chloro-pyridin-2-yl)methoxy]-l-[ll-methyl-3-(propan-2-yl)-lH,2H,3H,4H,5H- [1.4] diazepino[l,7-a]indol-9-yl]-l,2-dihydropyridin-2-one
- 17. Use of a compound according to any of claims 1-16 for treatment and/or prévention of 15 a disorder or condition associated with melanin concentrating hormone receptor 1 activity.
- 18. Use of a compound according to any of claims 1-16 for treatment and/or prévention of obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases,20 affective dysfunctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
- 19. Use of a compound according to any of claims 1-16 for manufacturing a pharmaceutical composition.
- 20. A pharmaceutical composition comprising a compound according to any of claims 1-16 together with excipients and carrier materials generally used for manufacturing pharmaceutical compositions.
- 21. Use of a pharmaceutical composition according to claim 20 for treatment and/or prévention of a disorder or condition associated with melanin concentrating hormone receptor 1 activity.
- 22. Use of a pharmaceutical composition according to claim 21 for treatment and/or prévention of obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatoiy bowel diseases, affective dysfunctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders.
- 23. Method of treating and/or preventing a disease or condition associated with melanin concentrating hormone receptor 1 activity characterized by administering to a subject in need a therapeutically effective amount of a compound according to any of daims 1-16.
- 24. Method of treating and/or preventing obesity, obesity related comorbid conditions and complications, diabètes, metabolic disorders, psychiatrie diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfunctions, anxiety disorders, sleep-wake cycle disorders, substance abuse and addictive disorders characterized by administering to a subject in need a therapeutically effective amount of a compound according to any of claims 1-16.
- 25. Compound of formula (2), tert-butyl 9-bromo-lH,2H,3H,4H,5H-[l,4]diazepino[l,7a] indol-3 -carboxylate
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