WO1996011929A1 - Biheteroaryl-carbonyl and carboxamide derivatives with 5ht 2c/2b antagonists activity - Google Patents
Biheteroaryl-carbonyl and carboxamide derivatives with 5ht 2c/2b antagonists activity Download PDFInfo
- Publication number
- WO1996011929A1 WO1996011929A1 PCT/EP1995/003887 EP9503887W WO9611929A1 WO 1996011929 A1 WO1996011929 A1 WO 1996011929A1 EP 9503887 W EP9503887 W EP 9503887W WO 9611929 A1 WO9611929 A1 WO 9611929A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrrolo
- pyridylcarbonyl
- methyl
- formula
- indole
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title abstract description 3
- 230000000694 effects Effects 0.000 title description 6
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 title description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 75
- -1 SCF3 Chemical group 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- DPVNFGHYGGOJEF-UHFFFAOYSA-N (5-nitro-2,3-dihydroindol-1-yl)-(1h-pyrrolo[2,3-b]pyridin-3-yl)methanone Chemical compound C1=CC=C2C(C(=O)N3C4=CC=C(C=C4CC3)[N+](=O)[O-])=CNC2=N1 DPVNFGHYGGOJEF-UHFFFAOYSA-N 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- QVTAXEPYJMXCEA-UHFFFAOYSA-N (5-amino-2,3-dihydroindol-1-yl)-(1h-pyrrolo[2,3-b]pyridin-3-yl)methanone Chemical compound C1=CC=C2C(C(=O)N3C4=CC=C(C=C4CC3)N)=CNC2=N1 QVTAXEPYJMXCEA-UHFFFAOYSA-N 0.000 claims description 4
- RNTRRQCGFJKUDI-UHFFFAOYSA-N (6-chloro-5-methyl-2,3-dihydroindol-1-yl)-(1h-pyrrolo[2,3-b]pyridin-3-yl)methanone Chemical compound C1=CC=C2C(C(=O)N3CCC=4C=C(C(=CC=43)Cl)C)=CNC2=N1 RNTRRQCGFJKUDI-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- SIRSJHLHJNPRQY-UHFFFAOYSA-N [5-(diethylamino)-2,3-dihydroindol-1-yl]-(1h-pyrrolo[2,3-b]pyridin-3-yl)methanone Chemical compound C1=CC=C2C(C(=O)N3C4=CC=C(C=C4CC3)N(CC)CC)=CNC2=N1 SIRSJHLHJNPRQY-UHFFFAOYSA-N 0.000 claims description 4
- NFXLFOLIMGIODT-UHFFFAOYSA-N [5-(dimethylamino)-2,3-dihydroindol-1-yl]-(1h-pyrrolo[2,3-b]pyridin-3-yl)methanone Chemical compound C1=CC=C2C(C(=O)N3C4=CC=C(C=C4CC3)N(C)C)=CNC2=N1 NFXLFOLIMGIODT-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- GGZZXYSFFVEBLO-UHFFFAOYSA-N n-(1-methylindol-5-yl)-1h-pyrrolo[2,3-b]pyridine-3-carboxamide Chemical compound C1=CC=C2C(C(=O)NC=3C=C4C=CN(C4=CC=3)C)=CNC2=N1 GGZZXYSFFVEBLO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- UVOMXDZIIPHCIM-UHFFFAOYSA-N pyrrolo[2,3-f]indole Chemical compound C=1C2=NC=CC2=CC2=NC=CC2=1 UVOMXDZIIPHCIM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- BXOVWVNVTVJFAY-UHFFFAOYSA-N 1-methyl-n-(1-methylindol-5-yl)pyrrolo[2,3-b]pyridine-3-carboxamide Chemical compound C1=CC=C2C(C(=O)NC=3C=C4C=CN(C4=CC=3)C)=CN(C)C2=N1 BXOVWVNVTVJFAY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 229910052751 metal Chemical group 0.000 claims description 3
- 239000002184 metal Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- MJYFVDNMTKLGTH-UHFFFAOYSA-N 4-bromo-6-(3,4-dichlorophenyl)sulfanyl-1-[[4-(dimethylcarbamoyl)phenyl]methyl]indole-2-carboxylic acid Chemical group BrC1=C2C=C(N(C2=CC(=C1)SC1=CC(=C(C=C1)Cl)Cl)CC1=CC=C(C=C1)C(N(C)C)=O)C(=O)O MJYFVDNMTKLGTH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 229910006095 SO2F Inorganic materials 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 34
- 238000011282 treatment Methods 0.000 abstract description 10
- 208000015114 central nervous system disease Diseases 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 113
- 239000000243 solution Substances 0.000 description 56
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000000725 suspension Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 229910001868 water Inorganic materials 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
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- 239000007787 solid Substances 0.000 description 16
- KYBIRFFGAIFLPM-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=N1 KYBIRFFGAIFLPM-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 229960004756 ethanol Drugs 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
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- IZPRBMBNUDLUMD-UHFFFAOYSA-N 1-methylpyrrolo[2,3-b]pyridine-3-carbaldehyde Chemical compound C1=CN=C2N(C)C=C(C=O)C2=C1 IZPRBMBNUDLUMD-UHFFFAOYSA-N 0.000 description 1
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- UYFAPJGHSQYTDE-UHFFFAOYSA-N 3-methyl-7,8-dihydro-6h-pyrrolo[3,2-e]indole;hydrochloride Chemical compound Cl.C1=C2N(C)C=CC2=C2CCNC2=C1 UYFAPJGHSQYTDE-UHFFFAOYSA-N 0.000 description 1
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- ZAMJLADJGLXVOJ-UHFFFAOYSA-N 6-chloro-5-methyl-2,3-dihydro-1h-indole Chemical compound C1=C(Cl)C(C)=CC2=C1NCC2 ZAMJLADJGLXVOJ-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
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- 239000011149 active material Substances 0.000 description 1
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- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
- WO 95/01976 (SmithKline Beecham plc) describes indoline derivatives which are described as possessing 5HT 2C receptor antagonist activity.
- a structurally distinct class of compounds has now been discovered, which have been found to have 5HT 2C receptor antagonist activity.
- Certain compounds of the invention also exhibit 5HT 2B antagonist activity.
- 5HT 2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
- the present invention provides a compound of formula (I) or a salt, solvate or hydrate thereof:
- A, B, C and D are all carbon atoms or one of A, B, C or D is nitrogen and the others are all carbon;
- E is oxygen, sulphur, CH 2 or NR 1 where R 1 is hydrogen or C 1 -6 alkyl;
- R 2 is hydrogen, halogen, C 1 -6 alkyl, C 1-6 alkylthio, nitro, CF 3 , cyano, NR 4 R 5 ,
- R 3 is a group of formula (i) in which:
- X and Y are both nitrogen, one is nitrogen and the other is carbon or a CH group or one is a CH group and the other is carbon or a CH group;
- R 8 and R 9 groups are independently C 1-6 alkyl optionally substituted by one or more halogen atoms, C 2-6 alkenyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylC 1-6 alkoxy,
- R 10 and R 1 1 are independently hydrogen or C 1-6 alkyl
- R 3 is a group of formula (ii):
- R 8 and R 9 are as defined in formula (i), X and Y are both nitrogen, one is nitrogen and the other is a CH group or X and Y are both CH groups;
- R 12 is hydrogen or C 1-6 alkyl
- R 3 is a group of formula (iii):
- R 8 , R 9 , X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH 2 or NR 13 where R 13 is hydrogen or C 1-6 alkyl.
- C 1-6 alkyl moieties whether alone or as pan of another group can be straight chain or branched.
- A, B, C and D are all carbon atoms giving an indole ring, or one of A, B, C or D is nitrogen and the others are all carbon giving an azaindole ring, that is to say, a 4-, 5-, 6- or 7-azaindole ring.
- A, B and C are all carbon atoms and D is a nitrogen atom, giving a 7-azaindole ring, also known as a pyrrolo[2,3-b]pyridine ring
- E is NR 1 where R 1 is hydrogen.
- R 2 is hydrogen
- R 3 is a group of formula (i).
- X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups.
- R 3 is an indoline ring, that is to say a group of formula (A):
- R 8 and R 9 form part of an aromatic ring
- suitable rings include thiophene, furan and pyrrole rings.
- Preferred R 8 and R 9 groups which can be the same or different, include C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen, CF3, and CO 2 R 6 where R 6 is hydrogen or C 1-6 alkyl.
- R 8 is trifluoromethyl and R 9 is C 1-6 alkylthio, for example methylthio.
- Particularly preferred compounds of formula (I) include:
- N-(1-Methyl-5-indolyl)-1-methylpyrrolof2,3-b]pyridine-3-carboxamide 2,3-Dihydro-5-methyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-ethyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-pyrrolo[3,2-b]pyridylcarbonyl)pyrrolor2,3-f]indole,
- the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, ic and methanesulphonic.
- acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, ic and methanesulphonic.
- the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II):
- A, B, C, and D are as defined in formula (I)
- E is as defined in formula (I) or is a group NR 1
- L is a leaving group and X is hydrogen or a metal atom
- the variables, R 1 ' , R 2' and R 3 are R 1 , R 2 and R 3 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, convening any R 1' , R 2' and R 3' when other than R 1 , R 2 and R 3 respectively to R 1 , R 2 and R 3 , interconverting R 1 , R 2 and R 3 and forming a pharmaceutically acceptable salt thereof.
- L is a leaving group such as halogen, in particular chloro.
- X is hydrogen or a metal atom such as lithium or magnesium.
- R 1 is hydrogen
- C 1 -6 alkyl group by conventional alkylation using 1 molar equivalent of a C 1 -6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
- R 2 ' , A, B, C, D and E are as defined in formula (II) using standard procedures.
- compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
- Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT 2B/2C receptor antagonist activity and are believed to be of potential use fo the treatment or prophylasis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
- the invention further provides a method of treatment or prophylaxis of the above disorders, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis the above disorders.
- the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
- Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
- aqueous or oily suspension solutions, emulsions, syrups or elixirs
- a dry product for reconstitution with water or other suitable vehicle before use.
- preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
- suspending agents such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
- fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
- suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg; and such therapy may extend for a number of weeks or months.
- N-acetyl-5-nitroindoline (D1) (4 g), excess acetaldehyde (20 ml) and 5% Pd/C (0.5 g) in ethanol (150 ml) was hydrogenated at a pressure of 45 psi for 18 h.
- the mixture was then filtered through Kieselguhr, and evaporated to dryness to afford crude N-acetyl-5-diethylaminoindoline as a white solid (4.3 g). This was dissolved in cone. HCl (5 ml) and heated over a steambath for 0.5 h.
- the solution was then basified by dropwise addition of aqueous K 2 CO 3 and extracted with chloroform(3 ⁇ 20 ml).
- the indole (D10) (67.63g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) using standard methodology to afford the title indoline (67.73g, 99%) as an off-white solid.
- N-(1-Methyl-5-indolyl)pyrrolo[2,3-b]pyridine-3-carboxamide (E6) A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid 1 (162 mg, 1 mmol) in thionyl chloride (2 ml) was heated under reflux for 2 h then kept at room temperature overnight. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (10 ml) was added in portions to a solution of 1-methyl-5-aminoindole (146 mg, 1 mmol) and triethylamine (0.28 ml, 2 mmol) in dichloromethane (10 ml).
- N-(1-Methyl-5-indolyl)pyrrolo[2,3-c]pyridine-3-carboxamide (E14) A suspension of pyrrolo[2,3-c]pyridine-3-carboxylic acid 1 (118 mg, 0.73 mmol) in thionyl chloride (5 ml) was heated under reflux overnight at room temperature. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (5 ml) was added in portions to a solution of 1-methyl-5-aminoindole (106 mg, 0.73 mmol) and triethylamine (221 mg, 2.2 mmol) in dichloromethane (10 ml).
- 6-Chloro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline E19
- a suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (109 mg, 0.67 mmol) in thionyl chloride (5 ml) was stined for 18 h at room temperature. Excess thionyl chloride was evaporated in vacuo and the residue dissolved in dichloromethane was added to a solution of 6-chloro-5-methylindoline (see WO 95/01976) (90 mg, 0.53 mmol) and triethylamine (16 mg, 1.6 mmol) in dichloromethane (5 ml).
- the compounds of examples 1 to 20 have pKi values of 5.2 to 8.3.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to indole and indoline compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of CNS disorders (5HT 2C/2B) antagonists.
Description
BI HETEROARYL-CARBONYL AND CARBOXAMIDE DERIVATIVES WITH
5HT 2C/2B ANTAGONISTS ACTIVITY
This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
WO 95/01976 (SmithKline Beecham plc) describes indoline derivatives which are described as possessing 5HT2C receptor antagonist activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT2C receptor antagonist activity. Certain compounds of the invention also exhibit 5HT2B antagonist activity. 5HT2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
Accordingly, in a first aspect, the present invention provides a compound of formula (I) or a salt, solvate or hydrate thereof:
wherein:
A, B, C and D are all carbon atoms or one of A, B, C or D is nitrogen and the others are all carbon;
E is oxygen, sulphur, CH2 or NR1 where R1 is hydrogen or C1 -6 alkyl;
R2 is hydrogen, halogen, C1 -6 alkyl, C1-6 alkylthio, nitro, CF3, cyano, NR4R5,
CONR4R5, CO2R6 or OR7 where R4, R5, R6 and R7 are as hydrogen or C1 -6 alkyl; and
X and Y are both nitrogen, one is nitrogen and the other is carbon or a CH group or one is a CH group and the other is carbon or a CH group;
R8 and R9 groups are independently C1-6 alkyl optionally substituted by one or more halogen atoms, C2-6 alkenyl, C3-6cycloalkyloxy, C3-6cycloalkylC1-6alkoxy,
C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-6 alkylthio,
C3-6 cycloalkylthio, C3-6 cycloalkyl-C1-6 alkylthio, C1-6alkoxy, hydroxy, halogen, nitro, CF3, C2F5, OCF3, SCF3, SO2CF3, SO2F, formyl, C2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR4R5, CONR4R5 or CO2R6 where R4, R5 and R6 are as defined for R1 ; or R8 and R9 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring; and
R10 and R1 1 are independently hydrogen or C1-6 alkyl;
or R3 is a group of formula (ii):
in which R8 and R9 are as defined in formula (i), X and Y are both nitrogen, one is nitrogen and the other is a CH group or X and Y are both CH groups; and
R12 is hydrogen or C1-6 alkyl,
or R3 is a group of formula (iii):
in which R8, R9, X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH2 or NR13 where R13 is hydrogen or C1-6 alkyl.
C1-6 alkyl moieties whether alone or as pan of another group can be straight chain or branched.
Suitably A, B, C and D are all carbon atoms giving an indole ring, or one of A, B, C or D is nitrogen and the others are all carbon giving an azaindole ring, that is to say, a 4-, 5-, 6- or 7-azaindole ring. Preferably A, B and C are all carbon atoms and D is a nitrogen atom, giving a 7-azaindole ring, also known as a pyrrolo[2,3-b]pyridine ring
Preferably E is NR1 where R1 is hydrogen.
Preferably R2 is hydrogen.
Preferably R3 is a group of formula (i). Preferably X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups. Most preferably R3 is an indoline ring, that is to say a group of formula (A):
in which R8 and R9 are as defined in formula (i).
When R8 and R9 form part of an aromatic ring suitable rings include thiophene, furan and pyrrole rings. Preferred R8 and R9 groups, which can be the same or different, include C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, halogen, CF3, and CO2R6 where R6 is hydrogen or C1-6 alkyl. Preferably R8 is trifluoromethyl and R9 is C1-6alkylthio, for example methylthio.
Particularly preferred compounds of formula (I) include:
1-(3-Pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5-Nitro-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5- Amino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5-Dimethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5-Diethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
N-(1-Methyl-5-indolyl)pyrrolo[2,3-b]pyridine-3-carboxamide,
2,3-Dihydro-6-methyl-3-(3-pyrrolo[2,3-b]pyridylcarbonyl)-1H-pyrrolo[3,2-e]indole, 2,3-Dihydro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole,
N-(1-Methyl-5-indolyl)-1-methylpyrrolof2,3-b]pyridine-3-carboxamide,
2,3-Dihydro-5-methyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-ethyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-pyrrolo[3,2-b]pyridylcarbonyl)pyrrolor2,3-f]indole,
2,3-Dihydro-5-ethyl-1-(3-py rrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f|indole
N-(1-Methyl-5-indolyl)pyrrolo[2,3-c]pyridine-3-carboxamide,
2,3-Dihydro-5-ethyl-1-(3-pyrrolo[2,3-c]pyridylcarbonyl)pyrrolo[2,3-f]indole
2,3-Dihydro-5-methyl-1-(3-indolylcarbonyl)pyrrolo[2,3-f]indole,
2,3-Dihydro-5-methyl-1-(1-methyl-3-indolylcarbonyl)pyrrolo[2,3-f]indole
5-Methoxy-6-trifluoromethyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl) indoline
6-Chloro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
6,7-Dihydro-5-(3-pyrrolo[2,3-b]pyridylcarbonyl)-5H-thieno[2,3-f] indole,
or pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tanaric and methanesulphonic.
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II):
with a compound of formula (III):
wherein A, B, C, and D are as defined in formula (I), E is as defined in formula (I) or is a group NR1 , L is a leaving group and X is hydrogen or a metal atom, and the variables, R1 ', R2' and R3 are R1 , R2 and R3 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, convening any R1' , R2' and R3' when other than R1, R2 and R3 respectively to R1, R2 and R3, interconverting R1, R2 and R3 and forming a pharmaceutically acceptable salt thereof.
Suitably L is a leaving group such as halogen, in particular chloro.
Suitably X is hydrogen or a metal atom such as lithium or magnesium.
Interconversion of a compound of formula (I) into another compound of formula (I) is carried out by conventional procedures well known in the art.
For example, in the case wherein R1 is hydrogen, it is possible to introduce a
C1 -6alkyl group by conventional alkylation using 1 molar equivalent of a C1 -6alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
It should be appreciated that it may be necessary to protect certain reactive groups during coupling reaction (a) above. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981).
Compounds of formula (II) are known compounds or can be prepared from compounds of formula (IV):
Compounds of formula (III) can be prepared according to the procedures outlined in WO 95/01976. Compounds of formula (IV) are commercially available or can be prepared using standard procedures.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT2B/2C receptor antagonist activity and are believed to be of potential use fo the treatment or prophylasis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
Thus the invention also provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis the above disorders.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene
oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg; and such therapy may extend for a number of weeks or months.
The following Examples illustrate the preparation of compounds of the invention.
Description 1
N-Acetyl-5-nitroindoline (D1)
A solution of 5-nitroindoline (12 g) in acetic anhydride (150 ml) was treated with pyridine (2 ml). The solution was then heated under reflux for 1 h, cooled and the excess acetic anhydride removed by evaporation in vacuo. On addition of water (150 ml), the title compound precipitated as a tan solid (13 g, 86%): 1H NMR δ
(CD3OD/CDCI3) 2.29 (3H, s), 3.29 (2H, t, J = 8 Hz), 4.20 (2H, t, J = 8 Hz), 8.04 (1H, s), 8.13 (1H, dd, J = 2, 9 Hz) and 8.3 (1H, d, J = 9 Hz).
Description 2
5-Dimethylaminoindoline (D2)
A suspension of N-acetyl-5-nitroindoline (Dl) (10 g), 37% aqueous
formaldehyde (10 ml), and 5% Pd/C (1.5 g) in ethanol (200 ml) was hydrogenated at a pressure of 45 psi for 18 h. The mixture was then filtered through Kieselguhr, and evaporated to dryness to afford crude N-acetyl-5-dimethylaminoindoline as a white solid. This was dissolved in cone. HCl (6 ml) and heated over a steambath for 45 minutes. The solution was then basified by dropwise addition of aqueous K2CO3 and extracted with chloroform (3×20 ml). The organic fraction was dried (MgSO4) and evaporated in vacuo to give an oil. Purification by flash chromatography, eluting with 5%
methanol/chloroform gave the title compound as an oil (3.4 g, 86%): 1H NMR δ (CD3OD/CDCI3) 2.8 (6H, s), 3.0 (3H, t, J = 8 Hz), 3.51 (2H, t, J = 8 Hz), 6.61 (2H, m) and 6.75 (1H, br s).
Description 3
5-Diethylaminoindoline (D3)
A suspension of N-acetyl-5-nitroindoline (D1) (4 g), excess acetaldehyde (20 ml) and 5% Pd/C (0.5 g) in ethanol (150 ml) was hydrogenated at a pressure of 45 psi for 18 h. The mixture was then filtered through Kieselguhr, and evaporated to dryness to afford crude N-acetyl-5-diethylaminoindoline as a white solid (4.3 g). This was dissolved in cone. HCl (5 ml) and heated over a steambath for 0.5 h. The solution was then basified by dropwise addition of aqueous K2CO3 and extracted with chloroform(3 × 20 ml). The organic fraction was dried (MgSO4) and evaporated in vacuo to give an oil. Purification by flash chromatography, eluting with 5% methanol/chloroform gave the tide compound as an oil (3 g, 86%): 1H NMR δ (CD3OD/CDCI3) 1.08 (6H, t, J = 8
Hz), 3.0 (2H, t, J = 8 Hz), 3.19 (4H, q, J = 7, 14 Hz), 3.52 (2H, t, J = 8 Hz), 6.53 (1H, dd, J = 2, 8 Hz), 6.6 (1H, d, 8 Hz) and 6.71 (1H, br s).
Description 4
1-Methyl-pyrrolo[2,3-b]pyridine-3-carboxylic acid (D4)
A solution of 1-methyl-pyrrolo[2,3-b]pyridine (2.82 g, 21 mmol) and hexamethylenetetramine (4.41 g, 32 mmol) in acetic acid (8.4 ml) and water (17.7 ml) was heated under reflux for 6 h. Water (150 ml) was added and the mixture was extracted with ether. The extracts were washed with water and brine, then dried (Na2SO4) and evaporated in vacuo. Flash chromatography eluting with ether gave 1-methylpyrrolo[2,3-b]pyridine-3-carboxaldehyde (900 mg, 27%).
A solution of this aldehyde (560 mg, 3.5 mmol) in acetone (20 ml) and sodium carbonate (371 mg, 3.5 mmol) in water (2 ml) was treated over 20 min with a solution of potassium permanganate (1.1 g, 7 mmol) in water (40 ml). Further quantities (2 × 300 mg) of potassium permanganate were added after 30 and 60 min. The mixture was filtered and the solution was evaporated to dryness. The residue was triturated with 50% methanol/ethyl acetate, the resulting solution was evaporated to dryness and the residual solid was triturated with 5% methanol/ethyl acetate to give the title compound as a white solid (390 mg, 63%). Flash chromatography of a sample eluting with 10%
ethanol/chloroform gave the title compound: mp 249-251 °C; 1H NMR δ (d6DMSO) 3.87 (1H, s), 7.26 (1H, dd, J = 5, 8 Hz), 8.24 (1H, s), 8.30 (2H, m) and 12.25 (1H, br s); Found C, 59.81; H, 4.80; N, 15.62; C9H8N2O2.0.75 H2O requires C, 59.82; H, 4.74; N,15.51%.
Description 5
2-Nitro-2-pyridylacetic acid, ethyl ester (D5) Ethyl acetoacetate (6.37 ml, 50 mmol) was added dropwise to a stirred suspension of 80% sodium hydride (1.5 g, 50 mmol) in dry DMF (20 ml), keeping the temperature below 50 °C. After 30 min 2-chloro-3-nitropyridine (3.96 g, 25 mmol) was added in portions. The mixture was stirred at room temperature for 90 min and at 70 °C for 1 h, then concentrated in vacuo. The residue was diluted with water (150 ml), acidified (HOAc) and extracted with ether. The extracts were washed with water and brine, then dried (Na2SO4) and evaporated to leave an orange oil (6.7 ml).
This crude product was dissolved in dry ether (80 ml), made acidic with 1N ethereal HCl and stirred at room temperature overnight. The precipitated solid was filtered off and washed with dry ether to give the HCl salt of the title compound as a pale yellow solid (4.3 g, 70%). The free base was obtained by treating an aqueous solution of the product with 10% sodium carbonate, then extracting with ethyl acetate. After drying (Na2SO4) and evaporating the extracts, the title compound was obtained as a yellow oil (3.38 g): 1H NMR δ (CDCI3) 1.26 (3H, t, J = 7 Hz), 4.20 (2H, q, J = 7 Hz), 4.34 (2H, s), 7.49 (1H, dd, J = 5, 8 Hz), 8.43 (1H, d, J = 8 Hz) and 8.80 (1H, d, J = 5 Hz). Description 6
Ethyl α-(3-nitro-2-pyridyI)-β-dimethylaminoacrylate (D6)
A solution of dimethylformamide diethyl acetal ( 1.3 ml, 7.5 mmol) in dry DMF (5 ml) was added to a stined solution of 2-nitro-2-pyridylacetic acid, ethyl ester (D5) (1 g, 4.8 mmol) in DMF (20 ml) to give a red solution which was heated at 70 °C overnight. The solution was evaporated in vacuo and the residue was extracted repeatedly with boiling hexane. On cooling the title compound separated as red crystals (545 mg, 43%): mp 135-138 °C ; 1H NMR δ (CDCI3) 1.14 (3H, t, J = 1 Hz), 2.86 (6H, br s), 4.07 (2H, br s), 7.28 (1H, dd, J = 5, 8 Hz), 7.78 (1H, s), 8.19 (1H, d, J = 8 Hz) and 8.76 (1H, d, J - 5 Hz); Found C, 54.40; H, 5.68; N, 15.76; C12H15N3O4 requires C, 54.33; H, 5.70; N, 15.84%.
Description 7
Ethyl pyrrolo[3,2-b]pyridyl-3-carboxylate (D7)
A suspension of ethyl α-(3-nitro-2-pyridyl)-β-dimethylaminoacrylate (D6) (0.5 g, 1.9 mmol) in ethanol (150 ml) was hydrogenated over 10% Pd/C at atmospheric pressure for 24 h. The catalyst was filtered off and the solvent was evaporated. The residual solid was chromatographed, eluting with 5% ethanol/ethyl acetate, to give the title compound (250 mg, 70%): mp 213-216 °C (EtOAc); 1H NMR δ (d6DMSO) 1.31 (3H, t, J = 7 Hz), 4.27 (2H, d, J = 7 Hz), 7.20 (1H, dd, J = 5, 8 Hz), 7.85 (1H, d, J = 8 Hz), 8.30 (1H, s), 8.48 (1H, d, J = 5 Hz) and 12.1 (1H, br s); Found C, 63.05; H, 5.34; N, 14.73; C10H10N2O2 requires C, 63.15; H, 5.30; N, 14.73%.
Description 8
1-Methoxy-4-nitro-2-trifluoromethylbenzene (D8)
Sodium (11.78g, 0.512 mol) was dissolved in dry methanol (1 1) and to the resulting solution was added a solution of 1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22g, 0.427 mol) in methanol (100 ml). The reaction mixture was refluxed for 3 h then cooled and evaporated in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3 × 400 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (93.76g, 99%) as a white solid.
NMR (CDCI3) δ: 4.05 (3H, s), 7.12 (1H, d), 8.45 (1H, dd), 8.52 (1H, d).
Description 9
(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D9)
A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D8) (93g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85g, 0.927 mol) in dry DMF (400 ml) at - 10° C. After complete addition the resulting purple solution was maintained at -10° C for 1 h then poured into a mixture of ice/water ( 1.5 l) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3 × 1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13g, 78%) as a white solid. Mp 103-104 °C.
NMR (CDCI3) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).
Description 10
5-Methoxy-6-trifluoromethylindole (D10)
(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D9) (85g, 0.327 mol) in ethanol/water (9:1, 1.6 1) and glacial acetic acid (16 ml) was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 h at room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between aqueous K2CO3 (1 1) and dichloromethane (2 × 1 l) and the combined organic extract was dried (Na2SO4) and evaporated to afford the title indole (67.63g, 96%) as a grey solid.
NMR (CDCI3) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H, m), 7.64 (1H, s), 8.25 (1H, br s). Description 11
5-Methoxy-6-trifluoromethylindoline (D11)
The indole (D10) (67.63g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) using standard methodology to afford the title indoline (67.73g, 99%) as an off-white solid.
NMR (CDCI3) δ: 3.07 (2H, t), 3.58 (2H, t), 3.67 (1H, br s), 3.83 (3H, s), 6.83 (1H, s), 6.88 (1H, s). Example 1
1-(3-Pyrrolo[2,3-b]pyridylcarbonyl)indoline (E1)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (103 mg, 0.635 mmol) in thionyl chloride (5 ml) was heated under reflux for 2 h, then cooled and the excess thionyl chloride evaporated in vacuo. The residue in dichloromethane (10 ml) was added in portions to a solution of indoline (76 mg, 0.635 mmol) and triethylamine (193 mg, 1.9 mmol) in dichloromethane (20 ml). The mixture was heated under reflux for 4 h, cooled and diluted with chloroform (20 ml). The solution was washed with water, then dried (MgSO4) and evaporated in vacuo. Flash chromatography, eluting with 10% methanol in chloroform gave the title compound (30 mg,18%): mp 257-260 °C; 1H NMR δ
(CD3OD) 3.23 (2H, t, J = 10 Hz), 4.42 (2H, t, J = 10 Hz), 7.05 (1H, t, J = 10 Hz), 7.1-7.35 (3H, m), 7.92 (1H, d, J = 8 Hz), 7.99 (1H, s), 8.32 (1H, dd, J = 6, 2 Hz) and 8.4 (1H, dd, J = 2, 8 Hz); Found C, 72.75; H, 5.10; N, 15.89, C16H13N3O requires C, 72.99; H, 4.98; N, 15.96%.
Example 2
5-Nitro-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E2)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (1.51 g, 9.3 mmol) in thionyl chloride (20 ml) was heated under reflux for 4 h, then cooled and the excess thionyl chloride evaporated in vacuo. The residue in dichloromethane (150 ml) was added in portions to a solution of 5-nitroindoline (1.37 g, 8.4 mmol) and triethylamine
(0.94 g, 27.9 mmol) in dichloromethane (20 ml). The mixture was heated under reflux overnight, cooled and diluted with chloroform (100 ml). The solution was washed with water, then dried (MgSO4) and evaporated in vacuo. Flash chromatography, eluting with 10% methanol in chloroform gave the title compound (0.83 g, 32%): mp 320-322 °C; 1H NMR δ (CD3OD) 3.3 (2H, overlapping with solvent peak), 4.42 (2H, t, J = 8 Hz), 7.25 (1H, dd, J = 3, 8 Hz), 8.1-8.35 (6H, m), and 8.45 (1H, dd, J = 1.5, 8 Hz); Found C, 59.44; H, 4.01; N, 16.80; C16H12N4O3.H2O requires C, 58.89; H, 4.32; N, 17.16%.
Example 3
5-Amino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E3)
A suspension of 5-nitro-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E2) (100 mg) in ethanol (20 ml) was treated with 5% Pd/C (20 mg). The suspension was hydrogenated at 50 psi overnight, then filtered through celite and the solvent evaporated in vacuo. The residue was purified by flash chromatography eluting with 5% and then 10% ethanol in chloroform to give the title compound as a solid (34mg, 38%): 1H NMR δ (CD3OD/CDCI3) 3.13 (2H, t, J = 8 Hz), 4.32 (2H, t, J = 8 Hz), 6.58 (1H, br d), 6.67 (1H, s), 7.22 (1H, dd, J = 5, 8 Hz), 7.75 (2H, s), 8.3 (1H, dd, J = 1, 5 Hz) and 8.9 (1H, br d); Found C, 65.64; H, 5.09; N, 18.99; C16H14N4O. 0.75H2O requires C, 65.85; H, 5.35; N, 19.19%.
Example 4
5-Dimethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E4)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (306 mg, 1.88 mmol) in thionyl chloride (10 ml) was stined for 18 h at room temperature. Excess thionyl chloride was evaporated in vacuo and the residue dissolved in chloroform was added in portions to a solution of 5-dimethylamino-indoline (305 mg, 1.88 mmol) and
triethylamine (570 mg, 5.6 mmol) in chloroform (20 ml). The mixture was heated at 50 °C for 18 h cooled and diluted with chloroform (20 ml). The solution was washed with water, then dried (MgSO4) and evaporated in vacuo. Flash chromatography, eluting with 10% ethanol /dichloromethane gave the title compound (21 mg, 21%): 1H NMR δ (CD3OD) 2.93 (6H, s), 3.15 (2H, t, J = 8 Hz), 4.3 (2H, t, J = 8 Hz), 6.58 (1H, br d, J = 9 Hz) 6.69 (1H, s), 7.16 (1H, m), 7.72 (1H, s) 7.88 (1H, br s), 8.36(1H, d, J = 4 Hz) and 8.42(1H, br d, 9 Hz); Found C, 69.73; H, 6.01; N, 17.87; C18H18N4O. 0.25H2O requires C, 69.55; H, 5.99; N, 18.02%.
Example 5
5-Diethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E5)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (200 mg, 1.23 mmol) in thionyl chloride (10 ml) was stirred for 18 h at room temperature. Excess thionyl chloride was evaporated in vacuo and the residue dissolved in dichloromethane was added in portions to a solution of 5-diethylamino-indoline (235 mg, 123 mmol) and triethylamine (374 mg, 3.74 mmol) in dichloromethane. The mixture was heated at 50 °C for 18 h cooled and the solvent evaporated in vacuo. Flash chromatography, eluting with 5% and then 10% ethanol /dichloromethane gave the title compound as a white solid (108 mg, 26%): mp 221-223 °C. 1H NMR δ (CD3OD/CD3CI) 1.08 (6H, t, J 0= 7), 3.0 (2H, t, J = 8 Hz), 3.19 (4H, q, J = 7, 14 Hz), 4.35 (2H, t, J = 8 Hz), 6.50 (1H, dd, J = 2, 8 Hz), 6.63 (1H, s ), 7.18(1H, dd, J = 4, 8 Hz), 7.9 (1H, br d), 8.08 (1H, d, J = 2 Hz), 8.3 (1H, m) and 8.39(1H, d, 7 = 8 Hz); Found C, 70.87; H, 6.41; N, 16.50; C20H22N4O. 0.25H2O requires C, 70.88; H, 6.56; N, 16.53%.
Example 6
N-(1-Methyl-5-indolyl)pyrrolo[2,3-b]pyridine-3-carboxamide (E6) A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid1 (162 mg, 1 mmol) in thionyl chloride (2 ml) was heated under reflux for 2 h then kept at room temperature overnight. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (10 ml) was added in portions to a solution of 1-methyl-5-aminoindole (146 mg, 1 mmol) and triethylamine (0.28 ml, 2 mmol) in dichloromethane (10 ml). After 2 h the mixture was washed with 10% sodium carbonate solution and brine, then was dried (Νa2SO4) and evaporated in vacuo. Flash chromatography, eluting with ethyl acetate gave the title compound (138 mg, 48%): mp 250-253 °C; 1H NMR δ (d6DMSO) 3.78 (3H, s), 6.41 (1H, d, J = 4 Hz), 7.23 (1H, dd, J = 8, 4 Hz),7.32 (1H, d, J = 4 Hz), 7.44 (2H, m), 8.0 (1H, s), 8.32 (1H, d, J = 4 Hz), 8.53 (1H, d, J = 8 Hz) 9.7 (1H, s) and 12.2 (1H, s); Found C, 69.95; H, 5.10; N, 18.89; C17H14N4O requires C, 70.33; H, 4.86; N, 19.30%. iRobison, M. M. and Robison, B. L. J. Am Chem. Soc, 1956, 78, 1247
Example 7
23-Dihydro-6-methyl-3-(3-pyrrolo[2,3-b]pyridylcarbonyl)-lH-pyrrolo[3,2-e]indole
(E7) A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (162 mg, 1 mmol) in thionyl chloride (4 ml) was heated under reflux for 30 min. The mixture was evaporated in vacuo and the residue was added in portions as a suspension in dichloromethane (10 ml) to a solution of 2,3-dihydro-6-methyl-1H-pyrrolo[3,2-e]indole hydrochloride (208 mg, 1 mmol) and triethylamine (0.42 ml, 3 mmol) in dichloromethane (10 ml). After 2 h the dark green solution was washed with water and brine, then dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue, eluting with ethyl acetate gave the title compound (87 mg, 28%): mp 238-245 °C; 1Η NMR δ (d6DMSO) 3.3 (2H, m), 3.8 (3H, s), 4.48 (2H, t, 7 = 8 Hz), 6.36 (1H, d, 7 = 4 Hz), 7.2 (1H, dd, 7 = 8, 4 Hz), 7.28 (1H, d, 7 = 9 Hz), 7.36 (1H, d, 7 = 4 Hz), 8.05 (1H, br d, 7 = 9 Hz), 8.13 (1H, s), 8.32 (1H, d, 7 = 4 Hz), 8.42 (1H, d, 7 = 8 Hz) and 12.3 (1H, br s); Found C, 71.16; H, 5.23; N, 17.42; C19H 1 6N4O. 0.25 H2O requires C, 71.12; H, 5.18; N, 17.46%.
Example 8
2,3-Dihydro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)pyrroIo[2,3-f]indole (E8)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (D1) (154 mg, 0.95 mmol) in thionyl chloride (3 ml) was heated under reflux for 2 h. The mixture was evaporated in vacuo and the residue was added in portions as a suspension in
dichloromethane (10 ml) to a solution of 2,3-dihydro-5-methylpyrrolo[2,3-f]indole (120 mg, 0.7 mmol) and triethylamine (0.29 ml, 2.1 mmol) in dichloromethane (20 ml). After 2 h the dark green solution was washed with water and brine, then dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the residue, eluting with ethyl acetate gave the title compound (40 mg, 14%): mp 266-272 °C; 1H NMR δ (d 6DMSO) 3.24 (2H, t, 7 = 8 Hz), 3.76 (3H, s), 4.44 (2H, t, 7 = 8 Hz), 6.37 (1H, d, 7 = 3 Hz), 7.22 (2H, m), 7.30 (1H, s), 8.11 (1H, d, 7 = 2 Hz), 8.31 (1H, d, 7 = 3 Hz), 8.42 (1H, d, 7 = 8 Hz) and 12.30 (1H, s); Found C, 72.42; H, 5.31; N, 17.70; C19H16N4O requires C, 72.14; H, 5.10; N, 17.71%.
Example 9
N-(1-Methyl-5-indolyl)-1-methylpyrrolo[2,3-b]pyridine-3-carboxamide (E9)
A solution of 1-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid (50 mg, 0.28 mmol) in thionyl chloride (1.5 ml) was stined at room temperature overnight. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (5 ml) was added in portions to a solution of 1-methyl-5-aminoindole (45 mg, 0.31 mmol) and triethylamine (0.12 ml, 0.86 mmol) in dichloromethane (10 ml). After 1 h the mixture was evaporated in vacuo. Flash chromatography, eluting with ethyl acetate gave the title compound (73 mg, 86%): mp 183-185 °C (EtOAc); 1H ΝMR δ (d6DMSO) 3.78 (3H, s), 3.92 (3H, s), 6.39 (1H, d, 7 = 3 Hz), 7.25 (2H, m), 7.42 (2H, m), 8.00 (1H, d, 7 = 1 Hz), 8.36 (1H, dd, 7 = 5, 1.5 Hz), 8.44 (1H, s), 8.52 (1H, dd, 7 = 8, 1.5 Hz) and 9.75 (1H, s); Found C, 69.70; H, 5.36; Ν, 18.05; C1 8H16Ν4O. 0.25H2O requires C, 70.00; H, 5.39; N, 18.14%.
Example 10
2,3-Dihydro-5-methyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3- fjindole (E10) A mixture of crude 1-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid (176 mg,
1 mmol) in thionyl chloride (3 ml) was stirred at room temperature overnight.. The reagent was evaporated in vacuo and the residue was added in portions as a suspension in dichloromethane (10 ml) to a solution of 2,3-dihydro-5-methylpyrrolo[2,3-f]indole (172 mg, 1 mmol) and triethylamine (0.42 ml, 3 mmol) in dichloromethane (10 ml). After 1 h the solution was evaporated in vacuo. Flash chromatography of the residue, eluting with ethyl acetate gave the title compound (137 mg, 41%): mp 214-225 °C; 1H NMR δ (d6DMSO) 3.26 (2H, t, 7 = 7 Hz), 3.76 (3H, s), 3.91 (3H, s), 4.45 (2H, d, 7 = 7 Hz), 6.38 (1H, d, 7 = 3 Hz), 7.25 (2H, m), 7.33 (1H, s), 8.27 (1H, s), 8.32 (1H, s), 8.48 (1H, d, 7 = 3 Hz) and 7.97 (1H, d, 7 = 6 Hz); M+ (Found) 330.147186; C20H18N4O requires 330.148061.
Example 11
2,3-Dihydro-5-ethyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-g]indole (E11)
A mixture of crude 1-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid (260 mg, 1.5 mmol) in thionyl chloride (4 ml) was stirred at room temperature overnight. The
reagent was evaporated in vacuo and the residue was added in portions as a suspension in dichloromethane (10 ml) to a solution of 2,3-dihydro-5-ethylpyrrolo[2,3-f]indole (280 mg, 1.5 mmol) and triethylamine (0.63 ml, 4.5 mmol) in dichloromethane (25 ml). After 2 h the solution was evaporated in vacuo. Flash chromatography of the residue, eluting with ethyl acetate, followed by trituration with ether gave the title compound (165 mg, 32%): mp 210-213 °C; 1H NMR δ (CDCI3) 1.48 (3H, t, 7 = 7 Hz), 3.30 (2H, t, 7 = 7 Hz), 3.95 (3H, s), 4.15 (2H, q, 7 = 7 Hz), 4.40 (2H, t, 7 = 7 Hz), 6.46 (1H, d, 7 = 3 Hz), 7.08 (1H, d, 7 = 3 Hz), 7.18 (2H, m), 7.53 (1H, s), 8.20 (1H, br s) and 8.40 (2H, m); Found C, 73.13; H, 5.89; N, 16.11, C21H20N4O requires C, 73.23; H, 5.85; N, 16.27%.
Example 12
2,3-Dihydro-5-methyl-1-(3-pyrrolo[3,2-b]pyridylcarbonyl)pyrrolo[2,3-f]indole (E12)
A solution of ethyl pyrrolo[3,2-b]pyridyI-3-carboxylate (D4) (260 mg, 1.37 mmol) and 2,3-dihydro-5-methylpyrrolo[2,3-f]indole (353 mg, 2.05 mmol) in xylene (20 ml) were heated under reflux for 48 h. The mixture was cooled, filtered, and washed with hexane. The resulting white solid was boiled in methanol (15 ml), cooled and filtered to give the title compound (310 mg, 72%): mp 338-342 °C; 1H NMR δ (CDCI3) 3.27 (2H, d, 7 = 7 Hz), 3.79 (3H, s), 4.4 (2H, m), 6.4 (1H, br s), 7.03 (1H, d, 7 = 3 Hz), 7.21 (1H, s), 7.25 (1H, m), 7.90 (1H, d, 7 = 8 Hz), 7.93 (1H, s) and 8.42 (1H, d, 7 = 3 Hz).
Example 13
2,3-Dihydro-5-ethyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole (E13) A solution of pyrrolo[2,3-b]pyridine-3-carboxylic acid (D1) (200 mg, 1.20 mmol) in thionyl chloride (20 ml) was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was added in portions to a solution of 2,3-dihydro-5-ethylpyrrolo[2,3-f]indole (230 mg, 1.20 mmol) and triethylamine (0.61 ml, 4.2 mmol) in dichloromethane (20 ml). After 2 h the dark purple solution was washed with water and brine, then dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in methanol and stirred overnight with activated charcoal, filtered and solvent removed in vacuo. Flash chromatography of the residue, eluting with ethyl acetate, gave the title compound (130 mg, 33 %): mp 255-258 °C; 1H NMR δ (CDCI3) 1.46 (3H, t, 7 = 7 Hz), 3.29 (2H, t, 7 = 8 Hz), 4.12 (2H, q, 7 = 7 Hz), 4.41 (2H, t, 7 = 7 Hz), 6.42 (1H, d, 7 = 2 Hz), 7.05 (1H, d, 7 = 3 Hz), 7.20 (3H, m), 7.80 (1H, s), 8.40 (1H, d, 7 = 5 Hz), 8.50 (1H, d, 7 = 7 Hz) and 11.22 (1H, s); Found C, 72.30; H, 5.62; N, 16.67; C20H18N4O requires C, 72.71; H, 5.49; N, 16.96%.
Example 14
N-(1-Methyl-5-indolyl)pyrrolo[2,3-c]pyridine-3-carboxamide (E14) A suspension of pyrrolo[2,3-c]pyridine-3-carboxylic acid1 (118 mg, 0.73 mmol) in thionyl chloride (5 ml) was heated under reflux overnight at room temperature. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (5 ml) was added in portions to a solution of 1-methyl-5-aminoindole (106 mg, 0.73 mmol) and triethylamine (221 mg, 2.2 mmol) in dichloromethane (10 ml). The suspension was heated under reflux for 4 h, then washed with water (2 × 10 ml), dried (MgSO4) and evaporated in vacuo to afford an oil. Flash chromatography, eluting with 5% methanol in chloroform gave the title compound (25 mg, 12%): mp 295-297 °C; 1H NMR δ (CDCI3/CD3OD) 3.8 (3H, s), 6.42 (1H, d, 7 = 4 Hz), 7.15 (1H, d, 7 = 4 Hz), 7.32 (2H, m, 7 = 4 Hz), 7.84 (1H, s), 8.2 (2H, s), 8.33 (1H, br s), 8.7 (1H, br s); Found C, 69.38; H, 4.85; N, 18.72; C17H14N4O.0.25 H2O requires C, 69.26; H, 4.87; N, 19.00%. 1Prokopov, A. A. and Yakhontov, L. N. Khim. Geterotsikl. Soedin., 1978, 496
Example 15
2,3-Dihydro-5-ethyl-1-(3-pyrrolo[2,3-c]pyridylcarbonyl)pyrrolo[2,3-f]indole (E15)
A mixture of crude pyrrolo[2,3-c]pyridine-3-carboxylic acid (209 mg, 1.47 mmol) in thionyl chloride (10 ml) was stined at room temperature overnight. The reagent was evaporated in vacuo and the residue was added in portions as a suspension in dichloromethane (5 ml) to a solution of 2,3-dihydro-5-ethylpyrrolo[2,3-f]indole (291 mg, 2.94 mmol) and triethylamine (296 mg, 2.94 mmol) in dichloromethane (5 ml). After 2 h the solution was evaporated in vacuo. Flash chromatography of the residue, eluting with 10% ethanol in chloroform, followed by trituration with ether gave the title compound (90 mg, 19%): mp 287-290 °C; 1H NMR δ (CDCI3/CD3OD), 1.48 (3H, t, 7 = 7 Hz), 3.30 (2H, t, 7 = 7 Hz), 4.15 (2H, q, 7 =15, 7 Hz), 4.38 (2H, t, 7 = 7 Hz), , 6.4 (1H, br s), 7.08 (1H, d, 7 = 3 Hz), 7.22 (1H, s), 7.9 (2H, br s), 8.22 (1H, d, 7 = 7 Hz) and 8.75 (1H, s).
Example 16
2,3-Dihydro-5-methyl-1-(3-indolylcarbonyl)pyrrolo[2,3-f]indole (E16)
A solution of indole-3-carboxylic acid (150 mg, 0.93 mmol) and oxalyl chloride (0.1 ml) in dicloromethane (20 ml) was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was added in portions to a solution of 2,3-dihydro-5-methylpyrrolo[2,3-f]indole (160 mg, 0.93 mmol) and triethylamine (0.47 ml, 3.2 mmol) in dichloromethane (20 ml). After 2 h the solvent was evaporated in vacuo and the residue was purified by flash chromatography, eluting with ethyl acetate, to give the title compound (220 mg, 75 %): mp 279-282 °C; 1H NMR δ (d6DMSO) 3.25 (2H, t, 7 = 7 Hz), 3.77 (3H, s), 4.41 (2H, t, 7 = 7 Hz), 6.37 (1H, d, 7 = 2 Hz), 7.08 - 7.24 (3H, m), 7.33 (1H, s), 7.49 (1H, d, 7 = 7 Hz), 7.98 (1H, d, 7 = 2 Hz), 8.05 (1H, d, 7 = 7 Hz), 8.30 (1H, s); Found C, 74.09; H, 5.60; N, 12.60; C20H17N3O.0.5H2O requires C, 74.05; H, 5.59; N, 12.95%.
Example 17
2,3-Dihydro-5-methyl-1-(1-methyl-3-indolylcarbonyl)pyrrolo[2,3-f]indole (E17)
A solution of 1-methylindole-3-carboxylic acid (160 mg, 0.93 mmol) and oxalyl chloride (0.1 ml) in dicloromethane (20 ml) was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was added in portions to a solution of 2,3-dihydro-5-methylpyrrolo[2,3-f]indole (160 mg, 0.93 mmol) and triethylamine (0.47 ml, 3.2 mmol) in dichloromethane (20 ml). After 2 h the solvent was evaporated in vacuo and the residue was purified by flash chromatography, eluting with ethyl acetate, to give the title compound (200 mg, 65 %): mp 242-244 °C; 1H NMR δ (d6DMSO) 3.25 (2H, t, 7 = 7 Hz), 3.75 (3H, s), 3.88 (3H, s), 4.40 (2H, t, 7 = 7 Hz), 6.35 (1H, d, 7 = 2 Hz), 7.12 - 7.32 (4H, m), 7.52 (1H, d, 7 = 7 Hz), 8.03 (1H, s), 8.07 (1H, d, 7 = 7 Hz) and 8.30 (1H, s). Example 18
5-Methoxy-6-trifluoromethyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl) indoline (E18)
To a suspension of pyrrolo [2,3-b] pyridine-3-carboxylic acid (0.16g, 1 mmol) in dry tetrahydrofuran (10 ml) was added oxalyl chloride (85 mL, 1 mmol) and N,N- dimethylformamide (1 drop). After stirring at room temperature for 1 h, a solution of 5-methoxy-6-trifluoromethyl indoline (D11) (0.22g, 1 mmol) and triethylamine (0.19 mL, 2 mmol) in dry tetrahydrofuran (5 mL) was added. The mixture was stirred for 4 h, then
poured into water. The precipitate was filtered off, washed with water and dried. The crude product was recrystallised from dichloromethane/methanol to give the title compound (0.10g, 28%), mp. >250°C. NMR (d6DMSO) δ: 3.28 (2H, t, J = 7), 3.89 (3H, s), 4.49 (2H, t, J = 7), 7.21 (1H, dd, J = 7,5), 7.27 (1H, s), 8.17 (1H, s), 8.32 (1H, d, J = 5), 8.41 (1H, s), 8.45 (1H, d, J = 7).
Found M+ 361
C18H14N3O-F3 requires 361
Example 19
6-Chloro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline (E19) A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (109 mg, 0.67 mmol) in thionyl chloride (5 ml) was stined for 18 h at room temperature. Excess thionyl chloride was evaporated in vacuo and the residue dissolved in dichloromethane was added to a solution of 6-chloro-5-methylindoline (see WO 95/01976) (90 mg, 0.53 mmol) and triethylamine (16 mg, 1.6 mmol) in dichloromethane (5 ml). The mixture was heated at 50°C for 18 h cooled and diluted with dichloromethane (20 ml). The solution was washed with water, then dried (MgSO4) and evaporated in vacuo. The residue was triturated repeatedly with diethyl ether to give the title compound as a brown solid (22 mg, 14.%). 1H NMR δ (DMSO): 2.30 (3H, s), 3.15 (2H, t, J = 8Hz), 4.48 (2H, t, J = 8 Hz), 7.20 (1H, m), 7.25 (1H, br s), 8.25 (2H, br s), 8.32 (1H, m), 8.42 (1H, m), HR EI-MS calcd for C17H14N3O CI (M+) 311.0825 found 31 1.0808.
Example 20
6,7-Dihydro-5-(3-pyrrolo[2,3-b]pyridyIcarbonyl)-5H-thieno[2,3-f] indole (E20)
A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (0.5g, 3 mmol) in thionyl chloride (10 ml) was stined at room temperature for 24 hrs and evaporated to dryness. To a solution of 6,7-dihydro-5H-thieno[2,3-f]indole (see WO 94/22871) (0.49g, 2.8 mmol) in dichloromethane (10 ml) stining under argon at room temperature was added a solution of the acid chloride in dichloromethane (5 ml). The solution was stined for 24
hrs and the precipitate collected by suction filtration and recrystallised from ethanol/dichloromethane to afford the title compound (0.18g, 20%) as a green powder, m.pt. 273° - 275°C.
1H NMR (250 MHz DMSO) δ: 12.35 (br 1H), 8.55 (s, 1H), 8.40 (dd, 1H), 8.26 (m, 1H), 8.12 (m, 1H), 7.80 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 7.17 (m, 1H), 4.46 (t, 2H), 3.23 (t, 2H).
Pharmacological data
[3H]-mesulergine binding to rat or human 5-HT2C clones expressed in 293 cells in vitro
Compounds can be tested following the procedure outlined in WO 94/04533.
The compounds of examples 1 to 20 have pKi values of 5.2 to 8.3.
Claims
1. A compound of formula (I) or a salt, solvate or hydrate thereof:
wherein:
A, B, C and D are all carbon atoms or one of A, B, C or D is nitrogen and the others are all carbon;
E is oxygen, sulphur, CH2 or NR1 where R 1 is hydrogen or C1 -6 alkyl;
R2 is hydrogen, halogen, C1-6 alkyl, C1-6 alkylthio, nitro, CF3, cyano, NR4R5, CONR4R5, CO2R6 or OR7 where R4, R5, R6 and R7 are as hydrogen or C1-6 alkyl; and R3 is a group of formula (i)
in which:
X and Y are both nitrogen, one is nitrogen and the other is carbon or a CH group or one is a CH group and the other is carbon or a CH group;
R8 and R9 groups are independently C1-6 alkyl optionally substituted by one or more halogen atoms, C2-6 alkenyl, C3-6cycloalkyloxy, C3-6cycloalkyl C1-6alkoxy,
C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-6 alkyl, C1-6 alkylthio,
C3-6 cycloalkylthio, C3-6 cycloalkyl-C1-6 alkylthio, C1-6alkoxy, hydroxy, halogen, nitro, CF3, C2F5, OCF3, SCF3, SO2CF3, SO2F, formyl, C2-6 alkanoyl, cyano, optionally substituted phenyl or thienyl, NR4R5, CONR4R5 or CO2R6 where R4, R5 and R6 are as defined for R 1 ; or R8 and R9 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring; and R10 and R11 are independently hydrogen or C1-6 alkyl;
or R3 is a group of formula (ii):
in which R8 and R9 are as defined in formula (i), X and Y are both nitrogen, one is nitrogen and the other is a CH group or X and Y are both CH groups; and
R12 is hydrogen or C1- 6 alkyl,
or R3 is a group of formula (iii):
in which R8, R9, X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH2 or NR13 where R13 is hydrogen or C1-6 alkyl.
2. A compound according to claim 1 in which R1 and R2 are hydrogen
3. A compound according to claim 1 or 2 in which R3 is a group of formula (i).
4. A compound according to any one of claims 1 to 3 in which A, B and C are all carbon and D is nitrogen.
5. A compound according to any one of claims 1 to 4 in which E is NH.
6. A compound according to claim 1 which is selected from:
1-(3-Pynolo[2,3-b]pyridylcarbonyl)indoline, 5-Nitro-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5- Amino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5-Dimethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
5-Diethylamino-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
N-(1-Methyl-5-indolyl)pyrrolo[2,3-b]pyridine-3-carboxamide,
2,3-Dihydro-6-methyl-3-(3-pyrrolo[2,3-b]pyridylcarbonyl)-1H-pyrrolo[3,2-e]indole, 2,3-Dihyodro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole,
N-(1-Methyl-5-indolyl)-1-methylpyrrolo[2,3-b]pyridine-3-carboxamide,
2,3-Dihydro-5-methyl-1-(1-methyl-3-pyrτolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-ethyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-pyrrolo[3,2-b]pyridylcarbonyl)pyrrolo[2,3-f]indole,
2,3-Dihydro-5-ethyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole
N-(1-Methyl-5-indolyl)pyrrolo[2,3-c]pyridine-3-carboxamide,
2,3-Dihydro-5-ethyl-1-(3-pyrrolo[2,3-c]pyridylcarbonyl)pyrrolo[2,3-f]indole
2,3-Dihydro-5-methyl-1-(3-indolylcarbonyl)pyrrolo[2,3-f]indole,
2,3-Dihydro-5-methyl-1-(1-methyl-3-indolylcarbonyl)pyrrolo[2,3-f]indole
5-Methoxy-6-trifluoromethyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl) indoline
6-Chloro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline,
6,7-Dihydro-5-(3-pyrrolo[2,3-b]pyridylcarbonyl)-5Η-thieno[2,3-f] indole
or pharmaceutically acceptable salts thereof.
7. A process for the preparation of a compound according to claim 1 which comprises:
the coupling of a compound of formula (II):
wherein A, B, C, and D are as defined in formula (I), E is as defined in formula (I) or is a group NR1 ', L is a leaving group and X is hydrogen or a metal atom, and the variables, R1 ', R2' and R3 are R1, R2 and R3 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R1 ', R2 and R3 when other than R1, R2 and R3 respectively to R1, R2 and R3, interconverting R1, R2 and R3 and forming a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 6 for use in therapy.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 in association with a pharmaceutically acceptable carrier or excipient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9420521A GB9420521D0 (en) | 1994-10-12 | 1994-10-12 | Novel compounds |
GB9420521.8 | 1994-10-12 |
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PCT/EP1995/003887 WO1996011929A1 (en) | 1994-10-12 | 1995-10-02 | Biheteroaryl-carbonyl and carboxamide derivatives with 5ht 2c/2b antagonists activity |
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