WO1994021611A1 - Amide derivatives as 5-ht1a ligands - Google Patents
Amide derivatives as 5-ht1a ligands Download PDFInfo
- Publication number
- WO1994021611A1 WO1994021611A1 PCT/GB1994/000455 GB9400455W WO9421611A1 WO 1994021611 A1 WO1994021611 A1 WO 1994021611A1 GB 9400455 W GB9400455 W GB 9400455W WO 9421611 A1 WO9421611 A1 WO 9421611A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- group
- pyridinyl
- cyclohexanecarboxamide
- Prior art date
Links
- 150000001408 amides Chemical class 0.000 title claims abstract description 6
- 239000003446 ligand Substances 0.000 title description 2
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 53
- -1 nitro, cyano, amino Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 101150009274 nhr-1 gene Proteins 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- QOJHQVMYPZZCEA-UHFFFAOYSA-N n-[1-[(2-hydroxy-3-naphthalen-1-yloxypropyl)amino]propan-2-yl]-n-pyridin-2-ylcyclohexanecarboxamide Chemical compound C=1C=CC2=CC=CC=C2C=1OCC(O)CNCC(C)N(C=1N=CC=CC=1)C(=O)C1CCCCC1 QOJHQVMYPZZCEA-UHFFFAOYSA-N 0.000 claims 1
- 239000011230 binding agent Substances 0.000 abstract description 2
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- 238000000034 method Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
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- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- 125000001424 substituent group Chemical group 0.000 description 9
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 8
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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- 239000000843 powder Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
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- 125000006239 protecting group Chemical group 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 3
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 2
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 125000005842 heteroatom Chemical group 0.000 description 2
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000006413 ring segment Chemical group 0.000 description 2
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- AMMCVXWFCSFKMP-UHFFFAOYSA-N n'-methyl-n-pyridin-2-yl-n'-(5,6,7,8-tetrahydroquinolin-7-yl)ethane-1,2-diamine Chemical compound C1CC2=CC=CN=C2CC1N(C)CCNC1=CC=CC=N1 AMMCVXWFCSFKMP-UHFFFAOYSA-N 0.000 description 1
- ZFMCITCRZXLMDJ-UHFFFAOYSA-N n-desisopropylpropranolol Chemical compound C1=CC=C2C(OCC(O)CN)=CC=CC2=C1 ZFMCITCRZXLMDJ-UHFFFAOYSA-N 0.000 description 1
- ZEWIZKPYVPPIPL-UHFFFAOYSA-N n-methyl-5,6,7,8-tetrahydroquinolin-7-amine Chemical compound C1=CN=C2CC(NC)CCC2=C1 ZEWIZKPYVPPIPL-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- This invention relates to novel amide derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them.
- novel compounds act on the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating humans and other mammals.
- novel compounds of the invention are those of general formula (I)
- Rl is a mono or bicyclic heteroaryl radical
- R2 is cycloalkyl
- R3, R3' and R4 each represent hydrogen or lower alkyl
- R5 is a group of formula
- X is -(CH2)n _ > -OCH2- or -SCH2-, m is 0 or 1, n is 1, 2 or 3 and p is 0 or 1 such that (m + p) is 1 and that (m + n) is 1, 2 or 3, R6 is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, (lower)alkoxycarbonyl, carboxamido, nitro, cyano, amino, (lower)alkylamino, di(lower)alkylamino or (lower) alkylcarbonyl,
- Ro' is hydrogen or halogen when X is -(CH2) n - and R6 ' is hydrogen when X is -OCH 2 - or -SCH 2 -,
- R7 is hydrogen or lower alkyl
- Z represents a heteroaromatic ring fused on to the non-aromatic ring containing the Y group
- R6 is as defined above and one or more R6 groups may be attached to the heteroaromatic ring and/or the non-aromatic ring
- R8 is a monocyclic or bicyclic heteroaryl group
- R6 is as defined above and the indicated 7, 8 positions may optionally be fused with a heteroaromatic ring or a further aromatic ring or
- R9 is a mono or bicyclic aryl or bicyclic heteroaryl group
- R.9 is as defined above.
- lower as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of “lower alkyl” radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl.
- cycloalkyl groups are groups containing 3 to 8 carbon atoms e.g. cyclopentyl, cyclohexyl and cycloheptyl.
- aryl means an aromatic radical having 6 to 12 carbon atoms (e.g. phenyl or naphthyl) which optionally may be substituted by one or more substituents.
- substituents are lower alkyl, lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), halogen (e.g. chlorine), halo(lower)alkyl (e.g. trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino and di(lower)alkylamino.
- heteroaryl refers to an aromatic radical containing one or more (e.g. 1, 2 or 3) hetero ring atoms (e.g. oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Examples of suitable substituents are given above in connection with “aryl” radicals.
- the heteroaryl radical may, for example, contain 5 to 10 ring atoms. Unless specified otherwise the heteroaryl radical is preferably mono- or bicyclic. A monocyclic radical may, for example, contain 5 to 7 ring atoms.
- the hetero ring contains a nitrogen atom with or without one or more further hetero atoms.
- heteroaryl groups include, for example, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and indolyl each of which may be optionally substituted as mentioned above.
- heteroaryl group where heteroaryl is defined above. Examples of the preferred meanings of the various substituents in formula (I) are given below:
- Rl is pyridinyl, particularly 2-pyridinyl
- R2 is cyclohexyl
- R3 is hydrogen and R3' is hydrogen or lower alkyl (e.g. methyl),
- R4 is preferably hydrogen, methyl or propyl
- A is preferably a group of formula:
- R6 is as defined above, particularly lower alkoxy
- B is preferably a group of formula:
- C is preferably a group of formula
- R6 is as defined above, particularly lower alkoxy
- D is preferably a group of formula
- E is preferably a group of formula
- F is preferably a group of formula
- the compounds of the invention may be prepared by methods known in the art from known starting materials or starting materials that may be prepared by conventional methods.
- One method of preparing the compounds of the invention comprises the reductive amination of a compound of formula
- a second method of preparing the compounds of the invention comprises acylating an amine of formula
- R2 is as defined above or with an acylating derivative thereof.
- acylating derivatives include the acid halides (e.g. chlorides) azides, anhydrides, imidazolides (e.g. obtained from carbonyldiimidazole), activated esters or O-acyl ureas obtained from a carbodiimide such as a dialkylcarbodiimide particularly cyclohexyl- carbodiimide.
- R4 is preferably lower alkyl. If it is desired to prepare a compound of the invention in which R4 is hydrogen it may be necessary to use a compound of formula (IV) in which R4 is an amine protecting group and to remove the protecting group after the acylation reaction.
- the starting compounds of formula (IV) may be prepared by reductive amination of a compound of formula (II) above with an aldehyde of formula
- Rl, R3, R3' are as defined above and RlO is hydrogen or, preferably, an amino protecting group (e.g. an urethane such as tert-butyloxycarbonyl), in presence of a reducing agent (e.g. a hydride reducing agent such as sodium triacetoxyborohydride) followed by deprotection of the amino group.
- a reducing agent e.g. a hydride reducing agent such as sodium triacetoxyborohydride
- RlO is, for example, tert- butyloxycarbonyl
- the protecting group may be removed by treatment with trifluoracetic acid or dilute hydrochloric acid.
- a third method of preparing the compounds of the invention comprises alkylating an amide of formula
- the alkylating agent may be, for example a compound of formula
- R3, R3', R4 and R5 are as defined above and Q is a leaving group such as a halogen (e.g. bromine) or an ester (e.g. a tosylate or trifluoromethylsulphonate).
- R4 is preferably lower alkyl.
- a fourth method of preparing the compounds of the invention comprises heteroarylating a compound of formula
- reaction can be carried out with a fluoro compound of formula R IF in the presence of a strong non-nucleophilic base (e.g. lithium diisopropylamide).
- a strong non-nucleophilic base e.g. lithium diisopropylamide.
- the reaction is preferably carried out with a 2-fluoro- or 4- fluoropyridine-N-oxide followed by deoxygenation of the product pyridine-N-oxide with a reducing agent such as phosphorus trichloride.
- a substituent on the group R is other than the one required the substituent may be converted to the desired substituent by known methods.
- a substituent on R5 may also need protecting against the conditions under which the reaction is carried out. In such a case the protecting group may be removed after the reaction has been completed.
- the processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
- acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.
- the compounds of the invention contain one or more asymmetric carbon atoms, so that the compounds can exist in different steroisomeric forms.
- the compounds can be for example, racemates or optically active forms.
- the optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
- the compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors.
- the compounds of the invention can be used for the treatment of CNS disorders, such as anxiety in mammals, particularly humans. They may also be used as antidepressants, antipsychotics, hypotensives and as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function and for treating cognition disorders.
- the compounds of the invention are tested for 5-HT ⁇ - receptor binding activity in rat hippocampal membrane homogenate by the method of B S Alexander and M D Wood, J Pharm Pharmacol, 1988, 40, 888-891.
- the compounds are tested for 5-HT i A receptor antagonism activity in a test involving the antagonism of 5-carboxamidotryptamine in the guinea-pig ileum in vitro (based upon the procedure of Fozard et al, Br J Pharmac, 1985, 86, 601P).
- the invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid or liquid.
- Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries.
- a solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99%, e.g.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
- Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions.
- the active ingredient for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweetners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution, alcohols, e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compostions in package form.
- the quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.
- a stirred suspension of potassium hydride, 35 wt. % suspension in mineral oil (0.01 mol) in dimethylformamide (DMF) (100 ml) is treated dropwise under argon with N-(3-(N'- (l,2,3,4-tetrahydro-8-methoxynaphth-2-yl)methylamino)-2-propyl)-N-(2- pyridinyl)amine (0.01 mol) in DMF (100 ml), after 1 h treated dropwise with cyclohexanecarbonyl chloride (0.01 mol), after 1 h treated dropwise with water (500 ml), acidified with 2N-HC1, washed with hexane (3 x 300 ml), basified with 2N-NaOH, and extracted with ethyl acetate (3 x 300 ml).
- DMF dimethylformamide
- This compound is prepared using the procedure of Example 1 with N-(3-(N'-(5,6,7,8- tetrahydroquinolin-7-yl)methylamino)-2-propyl)-N-(2-pyridinyl)amine in place of the amine reagent.
- Example 4 This compound is prepared using the procedure of Example 1 with N-(3-(N'-(2-(3-(5- methoxyindolyl)ethyl))methylamino)-2-propyl)-N-(2-pyridinyl)amine in place of the amine reagent.
- Example 4 N-(3-(N'-(2-(3-(5- methoxyindolyl)ethyl))methylamino)-2-propyl)-N-(2-pyridinyl)amine in place of the amine reagent.
- This compound is prepared using the procedure of Example 4 with 2-hydroxy-3-(l- naphthyloxy)-l-propylamine in place of the amine component.
- step (b) The basic solution was washed with ethyl acetate (3 x 30 ml) and the combined organic phases washed with brine (30 ml), water (30 ml), dried (MgSO4) and concentrated to give the title compound of step (b) as an oil (1.26g).
- step (b) A solution of the product of step (b) (1.26g, 4.46 mmol), cyclohexanecarbonyl chloride (0.65g, 4.46 mmol), diisopropylethylamine (0.58g, 4.46 mmol) and a catalytic amount of 4-N,N-dimethylaminopyridine in dichloromethane (15 ml) was stirred overnight at room temperature. The separated organic phase was washed with water (15 ml), dried
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT94908456T ATE225335T1 (en) | 1993-03-19 | 1994-03-09 | AMIDE DERIVATIVES AS 5-HT1A LIGANDS |
US08/446,651 US5629323A (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-HT1A ligands |
AU61490/94A AU6149094A (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-ht1a ligands |
DE69431471T DE69431471T2 (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-HT1A ligands |
JP6520749A JPH08507779A (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-HT1A ligands |
EP94908456A EP0689534B1 (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-ht 1a? ligands |
DK94908456T DK0689534T3 (en) | 1993-03-19 | 1994-03-09 | Amide derivatives such as 5-HT1A ligands |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939305672A GB9305672D0 (en) | 1993-03-19 | 1993-03-19 | Amide derivatives |
GB9305672.9 | 1993-03-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994021611A1 true WO1994021611A1 (en) | 1994-09-29 |
Family
ID=10732342
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1994/000455 WO1994021611A1 (en) | 1993-03-19 | 1994-03-09 | Amide derivatives as 5-ht1a ligands |
Country Status (13)
Country | Link |
---|---|
US (1) | US5629323A (en) |
EP (1) | EP0689534B1 (en) |
JP (1) | JPH08507779A (en) |
AT (1) | ATE225335T1 (en) |
AU (1) | AU6149094A (en) |
DE (1) | DE69431471T2 (en) |
DK (1) | DK0689534T3 (en) |
ES (1) | ES2181711T3 (en) |
GB (1) | GB9305672D0 (en) |
PH (1) | PH31589A (en) |
PT (1) | PT689534E (en) |
WO (1) | WO1994021611A1 (en) |
ZA (1) | ZA941739B (en) |
Cited By (9)
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US5541179A (en) * | 1995-05-02 | 1996-07-30 | American Home Products Corporation | Tropon-2-one piperazine carboxamides as serotonergic agents |
US5990114A (en) * | 1996-02-28 | 1999-11-23 | Recordati, S.A., Chemical And Pharmaceutical Company | Use of 5-HT1A receptor antagonists for the treatment of urinary incontinence |
WO2001060818A1 (en) * | 2000-02-14 | 2001-08-23 | Tularik Inc. | Lxr modulators |
US6479483B2 (en) | 1999-02-24 | 2002-11-12 | Hoffmann-La Roche Inc. | 4-phenyl-pyridine derivatives |
US6673543B2 (en) | 2000-04-05 | 2004-01-06 | Tularik, Inc. | Solid phase synthesis of LXR ligands |
US6906069B1 (en) | 1999-01-08 | 2005-06-14 | Amgen Inc. | LXR modulators |
US7112606B2 (en) | 2002-01-30 | 2006-09-26 | Amgen Inc. | Heterocyclic arylsulfonamidobenzylic compounds |
US7288658B2 (en) | 2003-07-15 | 2007-10-30 | Hoffmann-La Roche Inc. | Process for preparation of pyridine derivatives |
US8852634B2 (en) | 2005-09-23 | 2014-10-07 | Hoffmann-La Roche Inc. | Dosage formulation |
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US10316025B2 (en) | 2015-06-03 | 2019-06-11 | Sunshine Lake Pharma Co., Ltd. | Substituted piperazine compounds and methods of use and use thereof |
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---|---|---|---|---|
EP0170213A1 (en) * | 1984-07-30 | 1986-02-05 | Merrell Dow Pharmaceuticals Inc. | Glutarimide antianxiety and antihypertensive agents |
EP0367888A1 (en) * | 1988-11-08 | 1990-05-16 | ISTITUTO LUSO FARMACO D'ITALIA S.p.A. | 2,2-Disubstituted 2,3-dihydro-1,4-benzodioxin derivatives having hypotensive activity |
WO1992006082A1 (en) * | 1990-10-03 | 1992-04-16 | John Wyeth & Brother Limited | Piperazine derivatives |
EP0512755A2 (en) * | 1991-05-02 | 1992-11-11 | JOHN WYETH & BROTHER LIMITED | Piperazine derivatives |
-
1993
- 1993-03-19 GB GB939305672A patent/GB9305672D0/en active Pending
-
1994
- 1994-03-09 PT PT94908456T patent/PT689534E/en unknown
- 1994-03-09 DE DE69431471T patent/DE69431471T2/en not_active Expired - Fee Related
- 1994-03-09 EP EP94908456A patent/EP0689534B1/en not_active Expired - Lifetime
- 1994-03-09 AU AU61490/94A patent/AU6149094A/en not_active Abandoned
- 1994-03-09 DK DK94908456T patent/DK0689534T3/en active
- 1994-03-09 US US08/446,651 patent/US5629323A/en not_active Expired - Lifetime
- 1994-03-09 AT AT94908456T patent/ATE225335T1/en not_active IP Right Cessation
- 1994-03-09 WO PCT/GB1994/000455 patent/WO1994021611A1/en active IP Right Grant
- 1994-03-09 ES ES94908456T patent/ES2181711T3/en not_active Expired - Lifetime
- 1994-03-09 JP JP6520749A patent/JPH08507779A/en not_active Withdrawn
- 1994-03-11 ZA ZA941739A patent/ZA941739B/en unknown
- 1994-03-17 PH PH47940A patent/PH31589A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0170213A1 (en) * | 1984-07-30 | 1986-02-05 | Merrell Dow Pharmaceuticals Inc. | Glutarimide antianxiety and antihypertensive agents |
EP0367888A1 (en) * | 1988-11-08 | 1990-05-16 | ISTITUTO LUSO FARMACO D'ITALIA S.p.A. | 2,2-Disubstituted 2,3-dihydro-1,4-benzodioxin derivatives having hypotensive activity |
WO1992006082A1 (en) * | 1990-10-03 | 1992-04-16 | John Wyeth & Brother Limited | Piperazine derivatives |
EP0512755A2 (en) * | 1991-05-02 | 1992-11-11 | JOHN WYETH & BROTHER LIMITED | Piperazine derivatives |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5541179A (en) * | 1995-05-02 | 1996-07-30 | American Home Products Corporation | Tropon-2-one piperazine carboxamides as serotonergic agents |
US5990114A (en) * | 1996-02-28 | 1999-11-23 | Recordati, S.A., Chemical And Pharmaceutical Company | Use of 5-HT1A receptor antagonists for the treatment of urinary incontinence |
US6906069B1 (en) | 1999-01-08 | 2005-06-14 | Amgen Inc. | LXR modulators |
US6479483B2 (en) | 1999-02-24 | 2002-11-12 | Hoffmann-La Roche Inc. | 4-phenyl-pyridine derivatives |
WO2001060818A1 (en) * | 2000-02-14 | 2001-08-23 | Tularik Inc. | Lxr modulators |
US6673543B2 (en) | 2000-04-05 | 2004-01-06 | Tularik, Inc. | Solid phase synthesis of LXR ligands |
US7112606B2 (en) | 2002-01-30 | 2006-09-26 | Amgen Inc. | Heterocyclic arylsulfonamidobenzylic compounds |
US7473703B2 (en) | 2002-01-30 | 2009-01-06 | Amgen Inc. | Heterocyclic arylsulfonamidobenzylic compounds |
US7288658B2 (en) | 2003-07-15 | 2007-10-30 | Hoffmann-La Roche Inc. | Process for preparation of pyridine derivatives |
US8852634B2 (en) | 2005-09-23 | 2014-10-07 | Hoffmann-La Roche Inc. | Dosage formulation |
Also Published As
Publication number | Publication date |
---|---|
PT689534E (en) | 2003-01-31 |
DE69431471D1 (en) | 2002-11-07 |
ZA941739B (en) | 1995-09-11 |
PH31589A (en) | 1998-11-03 |
AU6149094A (en) | 1994-10-11 |
ATE225335T1 (en) | 2002-10-15 |
EP0689534A1 (en) | 1996-01-03 |
ES2181711T3 (en) | 2003-03-01 |
US5629323A (en) | 1997-05-13 |
DE69431471T2 (en) | 2003-07-10 |
GB9305672D0 (en) | 1993-05-05 |
EP0689534B1 (en) | 2002-10-02 |
DK0689534T3 (en) | 2003-02-03 |
JPH08507779A (en) | 1996-08-20 |
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