CN1335850A - Quinoline derivatives - Google Patents
Quinoline derivatives Download PDFInfo
- Publication number
- CN1335850A CN1335850A CN99816080A CN99816080A CN1335850A CN 1335850 A CN1335850 A CN 1335850A CN 99816080 A CN99816080 A CN 99816080A CN 99816080 A CN99816080 A CN 99816080A CN 1335850 A CN1335850 A CN 1335850A
- Authority
- CN
- China
- Prior art keywords
- pyrrolo
- quinoline
- pyrazine
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title abstract 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 142
- -1 bicyclic aryl Chemical group 0.000 claims description 101
- VGIZCOWDBPHQIO-UHFFFAOYSA-N 1h-pyrrolo[2,3-g]quinoline Chemical compound C1=CC=C2C=C(NC=C3)C3=CC2=N1 VGIZCOWDBPHQIO-UHFFFAOYSA-N 0.000 claims description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- OFRAGXRGYZEEON-SFHVURJKSA-N CN1N=C(C=C1C1=CC=C(S1)C(=O)N1CCC=2C1=CC=1C(=CC=NC=1C=2)N1C[C@H]2N(CC1)CCC2)C(F)(F)F Chemical compound CN1N=C(C=C1C1=CC=C(S1)C(=O)N1CCC=2C1=CC=1C(=CC=NC=1C=2)N1C[C@H]2N(CC1)CCC2)C(F)(F)F OFRAGXRGYZEEON-SFHVURJKSA-N 0.000 claims description 4
- WTDCWXLEQKXOFX-INIZCTEOSA-N [8-[(8as)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-2-yl]-2,3-dihydropyrrolo[2,3-g]quinolin-1-yl]-(5-chlorothiophen-2-yl)methanone Chemical compound S1C(Cl)=CC=C1C(=O)N1C2=CC3=C(N4C[C@@H]5CCCN5CC4)C=CN=C3C=C2CC1 WTDCWXLEQKXOFX-INIZCTEOSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 208000024732 dysthymic disease Diseases 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
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- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- NGIIFXMMSDWKAY-INIZCTEOSA-N N(C1=CC2=C(N3CCN4[C@H](C3)CCC4)C=CN=C2C=C1)C(=O)C1=C(C(Cl)=CC=C1)Cl Chemical compound N(C1=CC2=C(N3CCN4[C@H](C3)CCC4)C=CN=C2C=C1)C(=O)C1=C(C(Cl)=CC=C1)Cl NGIIFXMMSDWKAY-INIZCTEOSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 47
- 230000000144 pharmacologic effect Effects 0.000 abstract description 5
- 208000015114 central nervous system disease Diseases 0.000 abstract description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
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- 239000002585 base Substances 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- CQKHKDNXMJRBFB-AWEZNQCLSA-N 8-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2,3-dihydro-1H-pyrrolo[2,3-g]quinoline Chemical compound C1C[C@H]2CN(CCN2C1)c1ccnc2cc3CCNc3cc12 CQKHKDNXMJRBFB-AWEZNQCLSA-N 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
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- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 7
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- 238000013016 damping Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- NBMJISAJLZTPOX-UHFFFAOYSA-N 5-borononaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1C(O)=O NBMJISAJLZTPOX-UHFFFAOYSA-N 0.000 description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 4
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- QWRPAHBTNODUAP-ZDUSSCGKSA-N 4-[(8as)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-2-yl]-6-nitroquinoline Chemical compound C1CN2CCC[C@H]2CN1C1=CC=NC2=CC=C([N+](=O)[O-])C=C21 QWRPAHBTNODUAP-ZDUSSCGKSA-N 0.000 description 3
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- 239000012071 phase Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003555 thioacetals Chemical class 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D471/22—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 systems contains four or more hetero rings
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Abstract
The invention relates to novel quinoline derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
Description
The pharmaceutical composition that the present invention relates to the preparation method of new quinoline, these compounds and comprise these compounds.
United States Patent (USP) 5,703,072 discloses bicyclic nonane and the decane compound with Dopamine Receptors affinity, requires these compounds of patent protection to can be used for treating schizophrenia.WO98/50358, WO98/50346, WO98/47868, WO98/47885 and WO98/50343 disclose a series of new compounds, claim in the patent that these compounds have 5-HT concurrently
1A, 5-HT
1BAnd 5-HT
1DReceptor antagonist activity and be useful in the various central nervous system diseases in treatment.WO97/36867 and WO98/14433 disclose a series of lactam derivatives and have claimed that these derivatives are 5-HT
1AAnd 5-HT
1DOne of acceptor or both selective agonists or antagonist.
Now found the different compound of a class formation, these compounds have 5-HT concurrently
1A, 5-HT
1BAnd 5-HT
1DReceptor affinity.Expect that these compounds will be useful to treatment and prevention various diseases.Therefore first aspect the invention provides the compound or its salt of formula (I):
R wherein
aBe selected from formula (i) or group (ii); Formula (i) group
P wherein
1Be phenyl, bicyclic aryl, C
3-6Cycloalkyl, contain 1 to 3 and be selected from heteroatomic 5 to 7 element heterocycles of oxygen, nitrogen and sulphur or contain 1 to 3 heteroatomic bicyclic heterocycle that is selected from oxygen, nitrogen and sulphur; R
1Be halogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkyloyl, NO
2, CF
3, CN, SR
9, SOR
9, SO
2R
9, SO
2NR
10R
11, CO
2R
10, CONR
10R
11, CONR
10(CH
2)
cCO
2R
11, (CH
2)
cNR
10R
11, (CH
2)
cCONR
10R
11, (CH
2)
cNR
10COR
11, (CH
2)
cCO
2C
1-6Alkyl, CO
2(CH
2)
cOR
10, NR
10R
11, NR
10CO
2R
11, NR
10CONR
10R
11, CR
10=NOR
11, CNR
10=NOR
11, R wherein
9, R
10, R
11Independent separately is hydrogen or C
1-6Alkyl and c are 1 to 4; And a is 0,1,2 or 3; Formula is group (ii)
P wherein
2And P
3Independent separately for phenyl, bicyclic aryl, contain 1 to 3 and be selected from heteroatomic 5 to 7 element heterocycles of oxygen, nitrogen and sulphur or contain 1 to 3 heteroatomic bicyclic heterocycle that is selected from oxygen, nitrogen or sulphur; A is a key, O, S (O)
n, wherein n be 0 to 2, carbonyl, CH
2Or NR
4, R wherein
4Be hydrogen or C
1-6Alkyl; R
1And R
2Independent of separately R in the above-mentioned formula (i)
1Definition; And a and b independently are 0,1,2 or 3 separately; L be following formula group-Y-C (=O)-DG-or-C (=O)-DG-or-DG-C (=O)-group wherein Y be NH, NR
5, R wherein
5Be C
1-6Alkyl or Y are CH
2, O, CH=CH or OCH
2D is nitrogen, carbon or CH base, and G is hydrogen or C
1-6Alkyl, condition are that D is nitrogen or CH base, or G and R
B1Form group W together, W is (CR herein
16R
17)
tWherein t is 2,3 or 4 and R
16And R
17Independent separately is hydrogen or C
1-6Alkyl, perhaps W is (CR
16R
17)
uJ, wherein u be 0,1,2 or 3 and J be oxygen, sulphur, CR
16=CR
17, CR
16=N ,=CR
16O ,=CR
16S or=CR
16-NR
17, condition is that u is not 0 when J is oxygen or sulphur; R
B1For hydrogen or form group W with G as mentioned above; X is nitrogen, carbon or CH, when X is nitrogen or CH=be singly-bound, and when X is carbon=be two keys; M is 1,2 or 3.
C
1-6Alkyl or separately or as the part of another group can be straight or branched.Terminology used here ' halogen ' except as otherwise noted, is a group that is selected from fluorine, chlorine, bromine or iodine.P
1, P
2Or P
3The bicyclic aryl of representative can be a fractional saturation, is preferably naphthyl.Term naphthyl used herein except as otherwise noted, refers to naphthalene-1-base and naphthalene-2-base.At R
aIn the definition of formula (i)
Work as P
1Be C
3-6During cycloalkyl, preferred example is cyclopentyl and cyclohexyl.Work as P
1When being 5 to 7 element heterocycles, suitable example comprises 5 to 6 Yuans heteroaryl, as thienyl, furyl, pyrryl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazole base, isothiazolyl, isoxazolyl, thiadiazolyl group, pyrimidyl, pyrazinyl and pyridyl.Non-fragrant 5 to 7 element heterocycles comprise pyrrolidyl, piperidyl or piperazinyl.Work as P
1During for bicyclic heterocycle, suitable example comprises the thick and ring of benzo, as quinolyl, isoquinolyl, indyl, benzofuryl, benzothiazolyl and benzo [1,3] dioxolyl.Heterocyclic radical of listing above and bicyclic heterocyclic radical can maybe when existing, be connected on the rest part of molecule through a suitable nitrogen-atoms through a carbon atom.P
1Be preferably phenyl, naphthyl, quinolyl, pyridyl or thienyl.
When a greater than 1 the time, radicals R
1Can be identical or different.Preferred a is 0,1 or 2.Preferred R
1Group comprises halogen (particularly chlorine), C
1-6Alkyl (particularly methyl), CN, CF
3, or C
1-6Alkoxyl group (particularly methoxy or ethoxy).At R
aIn the formula definition (ii)
Work as P
2And/or P
3When being 5 to 7 element heterocycles or bicyclic heterocyclic radical, suitable example comprise top those to P
1The group of listing.Preferred P
2Be phenyl, naphthyl, pyridyl, thienyl or furyl.It is 1,4 or more preferably 1,5 that preferred replacement is arranged naphthyl, and naphthalene-1-base group A wherein is connected on 4 or 5 in other words.
Preferred P
3Be phenyl, pyridyl, thienyl, pyrazolyl Huo oxazolyl.
When a and/or b are 2, radicals R
1And/or R
2Can be respectively identical or different.Preferred group R
1And/or R
2Comprise halogen (particularly chlorine), C
1-6Alkyl (particularly methyl), CN, CF
3, or C
1-6Alkoxyl group (particularly methoxy or ethoxy).
A is preferably a key or oxygen, most preferably is a key.
L is preferably group :-Y-C (=O)-DG-or-C (=O)-DG-wherein Y be preferably NH or CH
2, D is preferably nitrogen and G is preferably hydrogen atom or and R
B1Form the another one group W together, be preferably (CH
2)
2, (CH
2)
3, CH=CH, most preferably (CH
2)
2
R
B1Be preferably hydrogen or form above-mentioned group W with G.
X is preferably nitrogen-atoms, and m is preferably 1 or 2, most preferably is 1.
The particularly preferred compound of the present invention is:
(S)-(-)-and N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3, the 4-dichloro-benzamide,
(S)-(-)-and N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3, the 4-dichloro-benzamide,
(S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-6-[5-(5-picoline-2-yl) naphthalene-1-formyl radical amino]-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline,
(S)-(-)-6-(2,3-dichloro-benzoyl base amino)-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline,
(S)-(-)-and 1-(2,3-dichloro-benzoyl base)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[4-(5-Jia Ji oxazole-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(5-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline trifluoroacetate,
(S)-(-)-2,3-dihydro-1-[5-(2,5-lutidine-4-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl)-1-(quinolyl-4 carbonyl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2-Jia Ji oxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(3-methyl-isoxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-1-(4-chlorobenzene formacyl)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[2-(4-chloro-phenyl-)-3-trifluoromethyl pyrazol-4-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2-methyl-5-trifluoromethyl pyrazol-3-yl)-thiophene-2-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-chlorothiophene-2-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[1-methyl-7-(2-picoline-6-yl) indoles-3-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(5-Jia Ji oxazole-2-yl) naphthalene-1-base ethanoyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base aminocarboxyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline or its pharmacologically acceptable salt.
Other preferred compound of the present invention comprises example E6-E9, E25-E72 and E75-E80 (shown in following tabulation) or its pharmacologically acceptable salt.The especially preferred compound of the present invention is E23.
The preferred salt of formula (I) compound is pharmacologically acceptable salt.These salt comprise acid salt such as hydrogen chlorate, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate and right-tosylate.
Some compound of formula (I) can exist with stereoisomer form.Can be regarded as the formula of the present invention includes (I) compound all how much and optical isomer and composition thereof comprise racemoid.
The compounds of this invention can make with methods known in the art.The invention provides the preparation method of formula (I) compound on the other hand, this method comprises:
(a) when L be-C (=O)-DG-or-DG-(C=O)-time, make formula (II) compound:
R
a-L
1
(II) with the coupling of formula (III) compound:
R wherein
a, R
B1, X and m define and L suc as formula (I)
1And L
2Contain and to react the suitable functional group that forms the L part jointly; Or
(b) when L be-Y-C (=O)-DG, wherein D is nitrogen and Y when being NH, the derivative that formula (IV) compound or its have been protected:
R
a-NC(＝O)
(IV) R wherein
aDefine the derivative coupling of having protected with formula V compound or its suc as formula (I):
R wherein
B1, X, m and G define suc as formula (I); Or
(c) when L be-Y-C (=O)-DG-, wherein D is that nitrogen and Y are NH or NR
5The time, make formula (VI) compound
R
a-NH
2Or R
a-NR
5H
(VI) R wherein
aAnd R
5Define suc as formula (I), form reagent react with common and a kind of suitable urea of formula V compound; Or
(d) when L be-Y-C (=O)-DG-, wherein D is that nitrogen and Y are CH
2Or during O, make formula (VII) compound
R
a-Y-(C＝O)-L
3
(VII) R wherein
aDefine suc as formula (I), and L
3Be a suitable leavings group, react with the formula V compound; Or
(e) when L be-Y-C (=O)-DG-, wherein D is CH and Y when being NH, makes formula (VI) compound
R
a-NH
2
(VI) R wherein
aDefine suc as formula (I), react with formula (VIII) compound;
D wherein, G, R
B1, X and m define and L suc as formula (I)
3It is a suitable leavings group;
And after this can be arbitrarily selectively:
Remove any protecting group;
Form a kind of pharmacologically acceptable salt.
In the reaction of formula (II) and (III) compound, group L
1And L
2Suitable example comprise:
L
1Be COL
aAnd L
2Be NH
2
L
1Be NH
2And L
2Be COL
a
L wherein
aIt is a suitable leavings group.
That suitable is L
1And L
2One of be activatory carboxylic acid derivative such as chloride of acid or acid anhydrides, another then is amino.Formula (II) also can be by corresponding carboxylic acid and a kind of coupler such as dicyclohexyl carbodiimide with active compound (III), and carbonyl diurethane imidazole or diphenyl phosphoryl azide reaction make.Preferred L
1Or L
2Be group COL
aL wherein
aBe especially chlorine of halogen.
Formula (II) is typically at inert solvent with (III) the common reaction of compound, as dimethyl formamide, in tetrahydrofuran (THF) or the methylene dichloride, under room temperature or comparatively high temps, at alkali, as alkali metal hydroxide, carries out under the existence of triethylamine or pyridine.
In step (b), react and be convenient to, as carrying out in the methylene dichloride at organic solvent.
Urea formation reagent can be the carbonyl diurethane imidazole in step (c), triphosgene or phosgene, and this reaction is at inert organic solvents, as dimethyl formamide, in tetrahydrofuran (THF) or the methylene dichloride, under room temperature or comparatively high temps, at alkali, as what carry out under the existence of triethylamine or pyridine.
Leavings group L in step (d)
3Be that for example cl radical and this reaction can be at inert organic solvents, in tetrahydrofuran (THF) or methylene dichloride, under room temperature or comparatively high temps, at alkali, as what carry out under the existence of triethylamine or pyridine for halogen.
Leavings group L in step (e)
3Be that for example cl radical and this reaction can be at inert organic solvents, in tetrahydrofuran (THF) or methylene dichloride, under room temperature or comparatively high temps, at alkali, as what carry out under the existence of triethylamine or pyridine for halogen.
Formula (II) obtains to the midbody compound of (VIII) is commercially available, also can make by literature method or similar approach described herein.
Those skilled in the art understand be necessary to protect some active substituting group in some above-mentioned steps.But the protection of application standard and remove resist technology.For example, primary amine can protectedly be a phthalimide, benzyl, benzyl oxygen base carbonyl or trityl derivative.These groups can be removed with conventional steps well known in the art.
The carboxylic acid group can protectedly be an ester.The aldehydes or ketones base can protectedly be an acetal, ketal, thioacetal, thio ketal ization.Can go protection with the condition of standard.
At R.A.Glennon: " serotonin receptor: clinical meaning ", neuroscience and behavior summary (" Serotonin Receptors:Clinical Implications ", Neuroscience and BehaviouralReviews), 1990,14,35 and L.O.Wilkinson and C.T.Dourish: " serotonin receptor hypotype: basis and clinicing aspect " (" Serotonin receptor Subtypes:Basic and ClinicalAspects ") S.Peroutka Ed., John Wiley andSons, New York1991, p.147, middlely summarized getting in touch of serotonin receptor and a lot of pharmacological actions.
Thrombotonin (serotonine; 5-HT) acceptor is relevant with a lot of pharmacological actions, comprising: comprise the losing one's balance of dysthymia disorders, seasonal emotion disorder and depression, anxiety disorder, comprise extensive anxiety disorder, panic disease, agoraphobe, social phobia, obsessive obsession, post-traumatic anxiety; Dysmnesia comprise dementia, amnesia and the memory impairment relevant with the age; The dietary behavior obstacle, comprise anorexia nervosa and bulimia nervosa, dyssomnias (comprising the diel rhythm imbalance), dyskinesia, the parkinsonism and the tardive dyskinesia that cause as the dementia in Parkinson disease, the Parkinson disease, tranquilizer, and other mental disorder.The application that the serotonin receptor part has demonstrated the treatment vomiting and felt sick, and also be used for endocrine disturbance, as high lactose mass formed by blood stasis, vasospasm (particularly in the brain vascular system), cerebellar ataxia and hypertension, and the gastrointestinal disturbance that relates to motoricity and secretion variation.The serotonin receptor part also can be used for therapeutic dysfunction and hypothermy.
To 5-HT
1Acceptor has the part of high-affinity to be considered to have to can be used in the above-mentioned treatment of diseases of treatment to use.For example: WO 95/31988 mentions 5-HT
1DReceptor antagonist and 5-HT
1AReceptor antagonist is united and is used for the treatment of CNS (central nervous system) disease, endocrine disturbance and GI (stomach and intestine) disease; K.Rasmussen (medicochemistry annual report (AnnualReportsin Medical Chemistry), (1995) 30,1) has described application 5-HT
1AReceptor stimulant and partial agonist are treated various CNS disease; P.Trouillas (brain progress (Progress in Brain Research), C.I.deZeeuw, P.StaraandJ.Voogd, editor, 1994,144589) and G.Maura (neurochemistry magazine (J.Neurochemistry), 1996,66,202) suggestion is taken 5-HT
1AAcceptor or 5-HT
1AAnd 5-HT
1DAcceptor selectively agonist ligand should be able to effectively be treated human cerebellar ataxia.
The present invention also is provided for treating general formula (I) compound or pharmaceutically acceptable salt thereof or its solvate of above-mentioned disease.
On the other hand, the invention provides the method for the above-mentioned disease of treatment, wherein comprise general formula (I) compound or pharmaceutically acceptable salt thereof or its solvate of using significant quantity to the patient of this treatment of needs.
The present invention is provided for treating or preventing general formula (I) compound or pharmaceutically acceptable salt thereof or its solvate of dysthymia disorders especially.
Compound of the present invention is to 5-HT
1A, 5-HT
1BAnd 5-HT
1DThe affinity of acceptor can be measured by following radioligand binding assay.To express 5-HT
1AThe HEK293 cell (4 * 10 of acceptor
7Individual cell/ml) evenly spread in the Tris damping fluid also is divided into the 1ml equal portions and stores.To express 5-HT
1BThe Chinese hamster ovary celI (4 * 10 of acceptor
7Individual cell/ml) evenly spread in the Tris damping fluid also is divided into the 1.5ml equal portions and stores.To express 5-HT
1DThe Chinese hamster ovary celI (0.563 * 10 of acceptor
8/ ml) evenly spread in the Tris damping fluid and be divided into the 1ml equal portions and store.For 5-HT
1B/1DAcceptor with the 0.4ml cell suspending liquid with [
3H]-5HT (4nM), for 5-HT
1AAcceptor with the 0.4ml cell suspending liquid with [
3H]-8-OH DPAT (1 nM) at Tris Mg HCl damping fluid (pH7.7) and testing drug in 37 ℃ of incubations 45 minutes.Each testing drug is surveyed 10 concentration, and (ultimate density is that 0.01mM～0.3nM), non-specific binding is measured with the 5-HT of 0.01mM.Total test volume 0.5ml.Incubation by filter fast with Packard Filtermate (filter membrane with 0.3% polymine pre-soaking) stop and radioactivity with Topcount scintillometer mensuration.Use the IC that obtains by iterative least square side's curve fitting procedure
50Calculate the pKi value.
The intrinsic activity of The compounds of this invention can be determined through the following steps.With the human 5-HT of stably express
1AThe human 5-HT of the HEK293 cytolemma of acceptor and stably express
1BThe Chinese hamster ovary celI film of acceptor is dispersed in the HEPES/EDTA damping fluid and is divided into the 1ml equal portions and stores, [
35S] the GTP γ S method of substantially press (life science (Life Sci.), 1993,52,449) descriptions such as Lazareno in conjunction with research carries out and carries out some little improvement.Will be by 10
6The cytolemma that individual cell obtains is in 20mM HEPES damping fluid (pH7.4), at MgCl
2(3mM), NaCl (100mM), GDP (10 μ M) and ascorbate salt (0.2mM) exist down, have or do not have compound, 30 ℃ of following preincubation 30 minutes.By adding 10 μ l[
35S] GTP γ S (100pM, measure concentration) starts reaction, then at 30 ℃ of incubations 30 minutes again.Be used in the GTP γ S (20 μ M) that adds the non-radioactive mark that adds before the film and measure non-specific binding.Filter termination reaction fast through Whatman GF/B graded filter, use ice-cold HEPES (20mM)/MgCl then
2(3mM) damping fluid 5 * 1ml washing.Radioactivity is measured with the liquid-scintillation spectrometry method.This method after this be called as [
35S] GTP γ S functional examination method.
Formula (I) compound is to 5-HT
1A, 5-HT
1BAnd 5-HT
1DAcceptor shows high-affinity.With [
35S] GTP γ S functional examination method, have been found that some formula (I) compound shows the specific efficacy of different levels, this effect is determined (1 is defined as the peak response that is obtained by agonist 5-HT, and 0 is defined as antagonistic action) by one 1.0 to 0 grade.The difficulty of intrinsic activity that description acts on the medicine of g protein coupled receptor is (Hoyer and the Boddeke that generally acknowledges in the art, the trend of pharmacology science (Trendsin Pharmacological Science), in July, 1993, [the 14th volume], the 270th～275 page).Yet we think that these parts are classified by this functional examination method, and The compounds of this invention will be the useful interior thymoleptic of body.The preferred compound of the present invention is considered to 5-HT in the performance body
1A, 5-HT
1BAnd 5-HT
1DAntagonistic activity and think that these compounds will play a role very soon.Play a role fast to the antidepressant compounds particularly advantageous: we are meant ' playing a role fast ' at the beginning administered compound and can see that treatment responds this and the tricyclics of SSRI and about 21 days of the typical treatment phase or the more microscler paired ratio of buspirone in 7 days.
[
35S] have in the GTP γ S functional examination method intrinsic activity be 0.5 or littler formula (I) compound be particularly preferred because these compounds are complete antagonist probably in vivo.As disclosed among the WO 95/31988,5-HT
1A/1B/1DThe presynaptic while antagonistic action of acceptor will cause the interior 5-HT of body to discharge increase and this will improve the neurotransmission of 5-HT.
Persons skilled in the art will recognize that The compounds of this invention and one or more other medicines, coupling may be favourable as selective serotonin cell reabsorption inhibitor (SSRI) thymoleptic.
The present invention also provides pharmaceutical composition, comprises formula (I) compound or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention that is suitable for making by blending under room temperature and barometric point often is suitable for oral, non-enteron aisle or rectal administration and itself can tablet, capsule, oral liquid formulations, pulvis, granule, lozenge, duplicate pulvis, injectable or pourable solution or suspension or suppository.Composition for oral administration generally is preferred.
Being used for oral tablet and capsule can unit dosage form, and can contain vehicle commonly used, as tackiness agent, filler, compressing tablet lubricant, disintegrating agent and acceptable wetting agent.Tablet can carry out dressing according to the method for knowing in the normal medicinal practice.
Oral liquid formulations can following form exist: for example, water-based or oily suspensions, solution, emulsion, syrup or elixir, perhaps the form with dry products exists, and water or other suitable vehicle duplicate before using.These liquid preparations can comprise conventional additives, reach as suspension agent, emulsifying agent, non-water vehicle (comprising edible oil), sanitas, if need, and conventional seasonings or staining agent.
To parenterai administration, the fluid units formulation can prepare with the sterilization vehicle with The compounds of this invention or its pharmacologically acceptable salt.According to used vehicle and concentration, compound can suspend or be dissolved in the vehicle.In preparation solution, the compound solubilized is used to inject and filtration sterilization and sealing before pack into suitable bottle or ampoule.Advantageously, be dissolved in the vehicle as local anesthetic, sanitas and buffer reagent with adjutant.For increasing stability, can be after bottling with composition freezing and vacuum-drying anhydrate.Except being is suspended in compound in the vehicle to replace the dissolving, non-enteron aisle suspension press substantially with quadrat method and is prepared, and can not pass through filtration sterilization.Before can be in being suspended in aseptic vehicle compound be exposed in the oxyethane and sterilizes.Comprising a kind of tensio-active agent or wetting agent in composition is favourable to the uniform distribution that promotes compound.
According to administering mode, composition can comprise 0.1%～99% (weight), the active substance of preferred 10%～60% (weight).
The dosage that is used for the treatment of the compound of aforementioned diseases can be routinely according to the severity of the state of an illness, patient's body weight and other similar factors vary.Yet as total guidance, suitable unitary dose can be 0.05～1000mg, more is suitable for 1.0～200mg, and this unitary dose can be administered once every day above, for example one day twice or three times.This treatment can extend to several weeks or some months.
Following description example and embodiment are used to illustrate the preparation of The compounds of this invention.Example 1 (S)-(-)-6-nitro-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (D1) is described
Stir down with (S)-(-)-octahydro pyrrolo-[1,2-a] pyrazine (J.Med.Chem.1993,36,2311) (500mg 3.97mmol) handles 4-chloro-6-nitroquinoline (J.Org.Chem.1944,9,302) (cooling and vacuum concentration are to doing then for 750mg, toluene solution 3.69mmol) and reflux 48h, (DCM/MeOH19: 1) purifying gets yellow oily title compound (620mg, 56%) through silica gel column chromatography.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.98 (d, 1H), 8.84 (d, 1H), 841 (dd, 1H), 8.14 (d, 1H), 6.98 (d, 1H), 3.74-3.56 (m, 2H), 3.26-3.17 (m, 3H), 2.88 (t, 1H), 2.70 (td, 1H), 2.55-2.45 (m, 1H), and 2.43-2.32 (m, 1H), 2.03-1.80 (m, 3H), (m, 1H) .MS:m/z (MH)=299. describes example 2 (S)-(-)-6-amino-4-(octahydro pyrrolo-[1,2-α] pyrazine-2-yl) quinoline (D2) to 1.65-1.51
Stir down with iron powder (0.72g, 12.9mmol) and NH
4Cl (86 mg, 1.6mmol) processing (S)-(-)-6-nitro-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (D1,600mg, 2.01mol) ethanol (36ml) and the solution and the reflux 4h of water (18ml), after the cooling, mixture is done with diatomite filtration and with the filtrate vacuum concentration.Resistates is handled and is washed with water with DCM (50ml), organic phase drying (MgSO
4), filter and the dried yellow crystal shape solid title compound (300mg, 56%) that obtains of vacuum concentration.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.50 (d, 1H), 7.90 (d, 1H), 7.14-7.10 (m, 2H), 6.82 (d, 1H), 3.99 (br.s, 2H), 3.65-3.50 (m, 2H), 3.22-3.17 (m, 2H), 3.05 (td, 1H), 2.72 (t, 1H), 2.62 (td, 1H), 2.50-2.40 (m, 1H), 2.40-2.29 (m, 1H), 2.01-1.80 (m, 3H), (m, 1H) .MS:m/z (MH)=269. describes routine 31-benzyl-5-nitro indoline (D3) to 1.62-1.47
Under agitation, (50g adds anhydrous K in acetone 0.30mol) (500ml) solution to 5-nitro indoline
2CO
3(55.3g, 0.40mol), then with surpass 45 minutes and drip bromotoluene (42ml, 0.35mol).At room temperature stir gained mixture 24h.Add again bromotoluene (10.0ml, 0.08mol) and K
2CO
3(12.0g 0.09mol) and under refluxing refluxed 3 days.Cooling, filtering mixt, vaporising under vacuum filtrate obtains garnet oily matter, obtains orange crystalline solid title compound (79.0g, 100%) with the hexane development.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.05 (d, 1H), 7.91 (s, 1H), (m, 5H), 6.35 (d, 1H), 4.35 (s, 2H), 3.63 (t, 2H), 3.09 (t, 2H) .MS:m/z (MH)=255. describes routine 45-amino-1-benzyl indoline (D4) to 7.40-7.25
With 1-benzyl-5-nitro indoline (D3,20.0g, 0.08mol), tin chloride (II) (60.0g, 0.32mol) and MeOH (400ml) the mixture reflux 16h of dense HCl (40ml).After the cooling, mixture vacuum-evaporation is obtained red oil, red oil is distributed between DCM and water, the NaOH solution alkalization with 40% also removes by filter insoluble tin resistates.Filtrate extracts with DCM (2x), dry (Na
2SO
4) and vacuum-evaporation obtain sap green oily title compound (10.5g, 60%).
1H NMR (250MHz, CDCl
3) δ (ppm): 7.41-7.23 (m, 5H), 6.58 (s, 1H), 6.45 (dd, 1H), 6.37 (d, 1H), 4.13 (s, 2H), 3.31 (br, s, 2H), 3.18 (t, 2), 2.87 (t, 2H) .MS:m/z (MH)=225. describes example 5 (1-benzyl indoline-5-base is amino) methylene radical propanedioic acid diethyl ester (D5)
(9.45ml, (1.5h refluxes mixture in toluene 0.05mol) (500ml) solution and under argon atmospher for D4,10.5g 0.05mol) to be added to 5-amino-1-benzyl indoline with oxyethyl group methylene radical propanedioic acid diethyl ester.After the cooling, under vacuum, remove desolvate brown oil (19.6g).Through the silica gel chromatography purifying, use hexane: EtOAc (70: 30) wash-out obtains yellow crystalline solid title compound (14.3g, 77%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.42 (d, 1H), 7.38-7.28 (m, 5H), 6.93 (s, 1H), 6.83 (dd, 1H), 6.44 (d, 2H), 4.33-4.17 (m, 6H), 3.36 (t, 2H), 2.99 (t, 2H), 1.40-1.25 (m, 6H) .MS:m/z (MH)=395. describes routine 61-benzyl-8-chloro-2, and the 3-pyrrolin is [2,3-g] quinoline-7-yl carboxylic acid ethyl ester (D6) also
Under argon atmospher in phosphorus oxychloride (40ml) reflux (1-benzyl indoline-5-base amino) methylene radical propanedioic acid diethyl ester (D5,10.0g, 25.3mmol) 2.5h, after the cooling, enriched mixture under vacuum, the remaining oily matter of gained is with 10% Na
2CO
3The aqueous solution transfers to alkalescence, with DCM extract red jelly, this jelly silica gel chromatography purifying, use hexane: EtOAc (70: 30) wash-out obtains yellow crystalline solid title compound (6.3g, 68%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.81 (s, 1H), 7.69 (s, 1H), 7.40-7.27 (m, 5H), 7.02 (s, 1H), 4.51 (s, 2H), 4.46 (q, 2H), 3.59 (t, 2H), 3.24 (t, 2H), 1.44 (t, 3H), MS:m/z (MH)=367. describes example 7 (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline-7-yl carboxylic acid ethyl ester (D7)
To 1-benzyl-8-chloro-2,3-pyrrolin also [2,3-g] and quinoline-7-yl carboxylic acid ethyl ester (D6,4.0g, 10.9mmol) and (S)-(-)-octahydro pyrrolo-[1,2-a] pyrazine (J.Med.Chem., 1993,36,2311) (6.0g, 47.6mmol) DMF (60ml) mixture in add triethylamine (20ml), and under argon atmospher, 90 ℃ of heated mixt 40 hours.After the cooling, under vacuum, remove DMF, resistates silica gel chromatography purifying, use EtOAc: MeOH (19: 1) wash-out obtains dark orange crystalline solid title compound (4.5g, 90%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.56 (s, 1H), 7.67 (s, 1H), 7.41-7.26 (m, 5H), 6.79 (s, 1H), 4.49-4.37 (m, 4H), 3.60 (t, 2H), 3.35-3.06 (m, 6H), and 2.99-2.89 (m, 2H), 2.26-2.09 (m, 2H), and 1.86-1.64 (m, 4H), 1.43-1.37 (m, 4H) .MS:m/z (MH)=457. describes example 8 (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline-7-yl carboxylic acid (D8)
With (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline-7-yl carboxylic acid (ethyl) ester (D7,1.8g, 4.1mmol) in EtOH (36ml), use NaOH (0.35g, (7ml) solution-treated of water 8.8mmol) and reflux mixture 16 hours, remove EtOH under vacuum, the dilute with water resistates also uses the HCl solution regulator solution of 2M to pH7.Under vacuum, remove to anhydrate and obtain yellow solid title compound (1.7g, 100%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.69 (s, 1H), 7.85 (s, 1H), and 7.41-7.27 (m, 5H), 6.50 (s, 1H), 4.47 (s, 2H), and 4.10-3.78 (br.s, 2H), 3.70 (t, 2H), 3.66-3.28 (br.m, 3H), and 3.27-3.03 (br.m, 3H), 2.85-2.38 (br.s, 3H), 2.13 (br.s, 1H), 1.97 (br.s, 1H), 1.86 (br.s, 2H). do not observe sour proton MS:m/z (M-H)=427. and describe example 9 (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D9)
With (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline-7-yl carboxylic acid (D8,1.7g 4.0mmol) reflux 30 minutes in dowtherm A (200ml) is after the cooling, pour into this mixture in the hexane (600ml) and be extracted in the 2MHCl solution (3x), merge acid extract liquid and also use K
2CO
3Alkalization is then with EtOAc extraction (3x).Merge organic extract liquid, drying (MgSO
4), filter and vacuum concentration obtains orange oily title compound (1.4g, 90%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.41 (d, 1H), 7.69 (s, 1H), 7.42-7.26 (m, 5H), 6.75 (d, 1H), 6.63 (s, 1H), 4.40 (s, 2H), 3.59-3.47 (m, 3H), 3.36 (dd, 1H), 3.22-2.88 (m, 5H), 2.58 (t, 1H), 2.37 (dt, 1H), 2.24-2.17 (m, 2H), 1.95-1.73 (m, 3H), and 1.47-1.34 (m, 1H) .MS:m/z (MH)=385. describes example 10 (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10)
With (S)-(-)-1-benzyl-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D9,1.4g, 3.6mmol) hydrogenation 32 hours in the presence of the palladium/charcoal of the pressure of room temperature, 50psi and 10% in EtOH (100ml) and 2MHCl solution (4ml).Use diatomite filtration mixture and vacuum concentration then, resistates is at the Na of DCM and 10%
2CO
3Distribute in the aqueous solution, tell organic phase, drying (MgSO
4) and vacuum concentration as for, obtain orange solids title compound (0.66g, 62%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.45 (d, 1H), 7.72 (s, 1H), 6.98 (s, 1H), 6.79 (d, 1H), 4.13 (br.s, 1H), 3.68 (t, 2H), 3.58 (dd, 1H), 3.47 (dd, 1H), 3.25-3.15 (m, 3H), 2.99 (dt, 1H), 2.67-2.56 (m, 2H), 2.39-2.24 (m, 2H), (m, 5H) .MS:m/z (MH)=295. describes routine 115-carboxyl naphthalene-1-ylboronic acid (D11) to 1.97-1.45
Under-60 ℃, argon atmospher, stirring, surpassing 15 minutes clockwise 5-bromo-1-naphthoic acids (Bull.Soc.Chim.Fr., 1968,7,2957) (22.3g, (125ml 0.20mol) handles the hexane solution of dropping 1.6M n-Butyl Lithium in dry THF 0.089mol) (1000ml) solution.After first equivalent adds, the cream-coloured precipitation that from initial brown solution, settles out, this is deposited in when adding the second equivalent n-Butyl Lithium and dissolves again.Gained solution stirred 40 minutes down at-60 ℃, and (51ml 0.22mol) and before being warming to-10 ℃ gradually continued to stir the mixture 1 hour under-60 ℃ to add tri-isopropylborate then.Add saturated NH
4The Cl aqueous solution (300ml) adds entry (400ml) and 5MHCl solution (200ml) then successively.Under vacuum, concentrate the gained mixture to the about 1000ml of volume, add 40% the NaOH aqueous solution then and alkalize and wash with EtOAc.Water is added in the excessive 5MHCl solution and solid that filtering-depositing goes out, washes with water and dry white solid (9.67g), wherein contain have an appointment 50% title compound and 1-naphthoic acid.Example 122 is described, 6-dimethyl-4-iodine pyridine (D12)
Under agitation, (17.6g is 120mmol) with 4-toluenesulphonic acids (3.4g with sodium iodide, 18mmol) handle 4-chloro-2,6-lutidine (Chem.Abs.1952,46,4541) (2.6g, (250ml) solution of 2-butanone 18mmol) and reflux mixture 72 hours under argon atmospher.With the reaction mixture cooling, under vacuum, concentrate then, resistates water (200ml) is handled and is extracted with EtOAc, and extraction liquid washs with sodium thiosulfate solution, dry (Na
2SO
4) and vacuum concentration obtain the white solid title compound, in acetone, convert it into its hydrochloride, be white solid (3.44g, 69%).
1H NMR (free alkali) (250MHz, CDCl
3) δ (ppm): 7.37 (s, 2H), 2.46 (s, 6H) MS:m/z (MH)=234. describes routine 135-(2,6-lutidine-4-yl)-1-naphthoic acid (D13)
Under agitation, to 2,6-dimethyl-4-iodine pyridine (D12,1.66g, 7.1mmol) and 5-carboxyl naphthalene-1-ylboronic acid (D11,1.54g, 7.1mmol) 1,2-glycol dimethyl ether (60ml) and contain Na
2CO
3(2.27g fed argon gas 20 minutes in the suspension in water 21.4mmol) (15ml).(0.41g, 0.36mmol), the reflux mixture is 18 hours under argon atmospher to add tetrakis triphenylphosphine palladium (O).Under vacuum, remove 1, the 2-glycol dimethyl ether, resistates washs with 2M NaOH solution dilution and with EtOAc.Water is acidified to pH1 and with the EtOAc washing, uses K then with dense HCl
2CO
3Transfer to pH5 and use DCM (3x) extraction.Merge the DCM extraction liquid, dry (Na
2SO
4) and vacuum concentration obtain white solid title compound (1.38g, 70%).
1H NMR (250MHz, d
6DMSO) δ (ppm): 8.75 (d, 1H), 7.99 (dd, 1H) 7.80 (d, 1H), 7.60-7.52 (m, 1H), 7.50-7.32 (m, 2H), 7.00 (s, 2H), 2.36 (s, 6H). now do not examine sour proton.MS:m/z (M-H)=276. describes routine 145-(2,6-lutidine-4-yl)-1-naphthoyl chloride (D14)
With oxalyl chloride (0.13ml, 1.49mmol) processing 5-(2,6-lutidine-4-yl)-1-naphthoic acid (D13,200mg, 0.72mmol) DCM (10ml) suspension and at room temperature stirred 16 hours, vacuum concentration obtains cream-colored solid title compound to doing then, and it is directly used in next step.Example 15 isocyanic acids (5-(2,6-lutidine-4-yl) naphthalene-1-yl) ester (D15) is described
(0.16ml, (DCM 0.91mmol) (10ml) suspension also at room temperature stirred 18 hours for D13,250mg, and vacuum concentration is to doing then 1.81mmol) to handle 5-(2,6-lutidine-4-yl)-1-naphthoic acid with oxalyl chloride.Resistates is dissolved in DCM (20ml) and rapid and ice-cold saturated NaHCO again
3The aqueous solution (10ml) mixes jolting.Separate organic phase immediately and under agitation under 5 ℃, be added to sodiumazide that (111mg is 1.71mmol) and in water (10ml) solution of tetrabutylammonium iodide (22mg).In 0～5 ℃ of following vigorous stirring mixture 1.5 hours, water (10ml) diluted and isolates DCM layer, dry (Na then
2SO
4) and at room temperature carefully be concentrated in vacuo to the about 10ml of volume.Use toluene (10ml) to handle this solution and reflux 1.5 hours under argon atmospher then.Reaction mixture, isocyanate solution is directly used in next step.Routine 165-(5-picoline-2-yl)-1-naphthoic acid (D16) is described
With being similar to the step of describing example 13, prepare beige solid title compound (64%) by 2-iodo-5-picoline and 5-carboxyl naphthalene-1-ylboronic acid (D11).
1H NMR (250Mz, d
6DMSO) δ (ppm): 13.3 (br s, 1H), 8.94 (d, 1H), 8.55 (s, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.89 7.70 (m, 2H), 7.70-7.50 (m, 2H), 7.45 (d, 1H), 2.60 (s, 3H). routine 175-(6-picoline-2-yl)-1-naphthoic acid (D17) is described
With being similar to the step of describing example 13, prepare beige solid title compound (46%) by 2-bromo-6-picoline and 5-carboxyl naphthalene-1-ylboronic acid (D11).
1H NMR (250MHz, d
6DMSO) δ (ppm): 8.90 (d, 1H), 8.13 (d, 1H), 8.06 (dd, 1H), 7.84 (t, 1H), 7.67 (t, 1H), 7.62-7.46 (m, 2H), 7.41 (d, 1H), 7.32 (d, 1H), 2.55 (s, 3H). do not observe sour proton.Routine 184-bromo-N-propargyl-1-naphthoamide (D18) is described
Under agitation, (3.4ml 39mmol) handles 4-bromo-1-naphthoic acid (J.Chem.Soc.1958,1426) (3.30g, DCM 13mmol) (180ml) suspension with oxalyl chloride.After 5 hours, vacuum concentrated mixture is to doing, resistates is dissolved among the DCM (120ml) and with propargylamine (0.83g, 15mmol) and triethylamine (2ml, DCM 15mmol) (50ml) solution-treated is more than 30 minutes.At room temperature stir the mixture and spend the night, and use 2M HCl solution (50ml), 20%K successively
2CO
3The aqueous solution (2 * 50ml) and salt solution (50ml) washing, dry (Na
2SO
4) and vacuum concentration to doing.Resistates Et
2The positive hexanaphthene development of O/ obtains cream-colored powder title compound (2.62g, 70%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.30 (dd, 2H), 7.78 (d, 1H), 7.64 (m, 2H), 7.43 (d, 1H), 6.21 (s, 1H), 4.32 (q, 2H), 2.31 (t, 1H). routine 191-bromo-4-(5-first base oxazole-2-yl) naphthalene (D19) is described
With 4-bromo-N-propargyl-1-naphthoamide (D18,2.60g, 9.0mmol) and mercuric acetate (0.02g, 0.06mmol) the mixture stirring heating in Glacial acetic acid (40ml) refluxed 3 hours.Refrigerative mixture vacuum concentration is extremely done, and resistates is dissolved in also uses 20%K among the EtOAc (100ml) successively
2CO
3The aqueous solution (2 * 25ml), the washing of water (50ml) and salt solution (25ml), dry (Na
2SO
4) and vacuum concentration to doing.Resistates obtains cream-colored powder title compound (2.03g, 78%) with silica gel flash chromatography method purifying with the DCM wash-out.
1H NMR (250MHz, CDCl
3) δ (ppm): 9.32 (m, 1H), 8.34 (m, 1H), 7.97 (d, 1H), 7.83 (d, 1H), 7.65 (m, 2H), 6.99 (s, 1H), 2.46 (s, 3H). routine 201-cyano group-4-(5-first base oxazole-2-yl) naphthalene (D20) is described
With 1-bromo-4-(5-Jia Ji oxazole-2-yl) naphthalene (D19,2.00g, 6.9mmol), cupric cyanide (I) (1.11g, 12.4mmol) and N-Methyl pyrrolidone (20ml) under argon atmospher, stirred 3 hours in 160 ℃.The refrigerative mixture is poured into (2.00g 30mmol) is added in the suspension of gained among water (200ml) and the EtOAc (150ml) and with KCN.Stir under the room temperature after 1.5 hours, layering is also used EtOAc (2 * 50ml) aqueous layer extracted.The organic extract liquid that merges washes with water, dry (Na
2SO
4) and vacuum concentration to doing.Resistates Et
2The positive hexanaphthene development of O/ obtains oldlace solid title compound (1.24g, 76%).
1H NMR (250MHz, CDCl
3) δ (ppm): 9.46 (q, 1H), 831 (q, 1H), 8.18 (d, 1), 7.96 (d, 1H), 7.77 (q, 2H), 7.03 (s, 1H), 2.49 (s, 3H). routine 214-(5-first base oxazole-2-yl)-1-naphthoic acid (D21) is described
(4.0mmol), (2.24g, 40.0mmol), PrOH (70ml) and water (10ml) reflux and stirred 48 hours KOH for D20,1.00g with 1-cyano group-4-(5-Jia Ji oxazole-2-yl) naphthalene.To doing, resistates distributes between EtOAc (50ml) and water (70ml) with refrigerative mixture vacuum concentration.Stir after 15 minutes, filtering mixt also divides water-yielding stratum, is acidified to the pH1. collecting precipitation with EtOAc (25ml) washing and with 5M HCl solution, and washing with water also, vacuum-drying obtains colorless solid title compound (0.64g, 59%).
1H NMR (250MHz, d
6-DMSO) δ (ppm): 13.46 (s, 1H), 9.39 (m, 1H), 8.91 (m, 1H), 8.20 (s, 2H), 7.75 (m, 2H), 7.22 (s, 1H), 2.47 (s, 3H). routine 225-(2,5-lutidine-4-yl)-1-naphthoic acid (D22) is described
With being similar to the method for describing example 13, by 4-bromo-2,5-lutidine and 5-carboxyl naphthalene-1-ylboronic acid (D11) makes white solid title compound (47%).
1H NMR (250MHz, d
6DMSO) δ (ppm): 13.3 (br s, 1H), 8.90 (d, 1H), 8.45 (s, 1H), 8.17-8.10 (m, 1H), 7.75-7.66 (m, 1H), 7.57-7.47 (m, 2H), 7.41 (d, 1H), 7.12 (s, 1H), 2.50 (s, 3H), 1.86 (s, 3H). routine 235-(3-picoline-2-yl)-1-naphthoic acid (D23) is described
With being similar to the method for describing example 13, make beige solid title compound (46%) by 2-bromo-3-picoline and 5-carboxyl naphthalene-1-ylboronic acid (D11).
1H NMR (20MHz, d
6DMSO) δ (ppm): 8.92 (d, 1H), 8.56 (dd, 1H), 8.15 (dd, 1H), 7.83 (d, 1H), 7.74 (dd, 1H), 7.55-7.40 (m, 4H), 2.00 (s, 3H). do not observe sour proton.Routine 245-bromo-N-propargyl-1-naphthoamide (D24) is described
With being similar to the method for describing example 18, make light yellow solid title compound (5.48g, 70%) by 5-bromo-1-naphthoic acid (Bull.Soc.Chim.Fr., 1968,7,2957).
1H NMR (250MHz, CDCl
3) δ (ppm) 8.35 (d, 1H), 8.28 (d, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.58 (t, 1H), 7.38 (t, 1H), 6.2.4 (s, 1H), 4.33 (q, 2H), 2.31 (t, 1H). routine 251-bromo-5-(5-first base oxazole-2-yl) naphthalene (D25) is described
With being similar to the method for describing example 19, make light yellow solid title compound (2.80g, 50%) by 5-bromo-N-propargyl-1-naphthoamide (D24,5.45g, 18.9mmol)).
1H NMR (250MHz; CDCl
3) δ (ppm): 930 (d, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 7.84 (d, 1H), 7.64 (t, 1H), 7.45 (t, 1H), 6.99 (s, 1H), 2.46 (s, 3H). routine 265-(2-first base oxazole-2-yl)-1-naphthyl propanedioic acid diethyl ester (D26) is described
Under agitation, (3.42g adds sodium hydride (0.86g, 60% oil dispersion) in batches and handles in dry diox (100ml) solution 21.4mmol) to diethyl malonate.Add successively after 15 minutes cuprous bromide (I) (3.07g, 21.4mmol) and 1-bromo-5-(5-Jia Ji oxazole-2-yl) naphthalene (D25,3.09g, 10.7mmol), reflux mixture 8 hours under argon atmospher then.Cooled mixture through Celite (diatomite) filter and vacuum concentration to doing, resistates is dissolved in EtOAc (100ml) and use successively 2M HCl solution (2 * 30ml), water (30ml), salt solution (30ml) washing, dry (Na
2SO
4) and vacuum concentration to doing, resistates obtains yellow oily title compound (1.70g, 43%) with fast silica gel chromatogram method purifying with DCM-MeOH (0-2%MeOH gradient elution) wash-out.
1H NMR (250MHz, d
6DMSO) δ (ppm): 9.28 (d, 1H), 8.18 (m, 2H), 7.70 (m, 2H), 7.55 (dd, 1H) 7.16 (s, 1H), 4.26-4.07 (m, 5H), 2.45 (s, 3H), 1.17 (t, 6H). routine 275-(5-first base oxazole-2-yl)-1-naphthylacetic acid (D27) is described
(4.6mmol), Glacial acetic acid (10ml) and dense HCl (10ml) reflux and stirred 7 hours for D26,1.70g with 5-(5-Jia Ji oxazole-2-yl)-1-naphthyl propanedioic acid diethyl ester.To doing, resistates water (25ml) development leaches solid and vacuum-drying obtains light grey powder title compound (0.90g, 73%) with refrigerative mixture vacuum concentration.
1H NMR (250MHz, d
6DMSO) δ (ppm): 9.06 (d, 1H), 8.02 (d, 2H), 7.58-7.40 (m, 3H), 7.02 (s, 1H), 4.03 (s, 2H), 2.33 (s, 3H). do not observe sour proton.Routine 285-bromo-1-naphthoic acid ethyl ester (D28) is described
Stir down, use dense H
2SO
4(7ml) handle 5-bromo-1-naphthoic acid (Bull.Soc.Chim.Fr., 1968,7,2957) (10.0g, EtOH 0.040mol) (150ml) suspension, and reflux 24 hours.After the cooling, under vacuum EtOH is removed, resistates is at EtOAc and 10%Na
2CO
3Distribute between the aqueous solution.Isolate organic phase,, merge organic phase, dry (Na with more EtOAc aqueous phase extracted
2SO
4) and vacuum concentration to the dried white solid title compound (10.14g, 91%) that obtains.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.88 (d, 1H), 8.49 (d, 1H), 8.20 (dd, 1H), 7.84 (dd, 1H), 7.61 (dd, 1H), 7.43 (dd, 1H), 4.48 (q, 2H), 1.46 (t, 3H). routine 295-ethanoyl-1-naphthoic acid ethyl ester (D29) is described
Stir down, to 5-bromo-1-naphthoic acid ethyl ester (D28,8.98g, 32.2mmol) and tributyl (1-vinyl ethyl ether base) tin (13.9g, drying 1 38.5mmol) blast argon gas and outgased in 20 minutes in the 4-dioxane solution.Add two (triphenylphosphine) palladium chlorides (II), under argon atmospher, mixture heating up was refluxed 18 hours.After the cooling, add 2MHCl solution (20ml) and water (50ml), and with this mixture vigorous stirring 4 hours at room temperature.Then with the mixture vacuum concentration, resistates between water and EtOAc, distribute and through diatomite filtration to remove relict catalyst.Isolate organic phase, dry (MgSO
4) and vacuum concentration obtain light yellow crystalline solid to dried, crystal ground and remove the detin resistates with 60-80 gasoline thorough washing, leaching also then, vacuum-drying obtains light yellow solid title compound (5.31g, 68%).
1H NMR (250MHz, CDCl
3) δ (ppm): 9.10 (d, 1H), 8.89 (d, 1H), 8.20 (dd, 1H); 7.97 (dd, 1H), 7.66-7.57 (m, 2H), 4.48 (q; 2H), 2.76 (s, 3H), 1.47 (t, 3H) .MS:m/z (MH)=243. describes routine 305-acetyl bromide-1-naphthoic acid ethyl ester (D30)
Stir down, (7.38g 18.9mmol) handles 5-ethanoyl-1-naphthoic acid ethyl ester (D29,4.80g, the 17.2mmol) solution in the mixture of DCM (80ml) and MeOH (40ml), and at room temperature stirring 18 hours with the tribromide benzyltrimethylammon.um.Solvent removed in vacuo and resistates is distributed between DCM and water then.Isolate organic phase, dry (Na
2SO
4) and vacuum concentration to the dried orange-brown solid title compound (5.52g, 100%) that obtains.
1H NMR (250MHz, CDCl
3) δ (ppm): 9.16 (d, 1H), 8.75 (d, 1H), 8.23 (dd, 1H); 7.95 (dd, 1H), 7.68-7.61 (m, 2H), 4.58 (s; 2H), 4.49 (q, 2H), 1.47 (s, 3H). routine 315-glycyl-1-naphthoic acid ethyl ester hydrochloride (D31) is described
(D30,3.50g 10.9mmol) are dissolved among the DCM (40ml), and are cooled in ice bath～5 ℃ with 5-acetyl bromide-1-naphthoic acid ethyl ester.With tetrabutylammonium iodide (0.20g, 0.54mmol) and sodiumazide (simultaneously temperature is to room temperature for 1.06g, water 16.3mmol) (8ml) this solution of solution-treated and vigorous stirring 3 hours.Add entry (30ml) and isolate organic phase, dry (Na
2SO
4) and careful vacuum concentration to the about 20ml of volume.Add EtOH (40ml) and with the mixture vacuum concentration to the about 40ml of volume (to remove remaining DCM).Dilute this solution with EtOH (200ml), with dense HCl (5ml) handle and under room temperature and pressure with palladium/hydrogenated carbon of 10% 48 hours.Then mixture is extremely done through diatomite filtration and vacuum concentration, obtained white solid title compound (2.26g, 71%).
1H NMR (250MHz, d
6DMSO) δ (ppm): 8.98 (d, 1H), 8.84 (d; 1H), 8.45 (br s, 3H); 8.32 (dd, 1H), 8.19 (dd; 1H), and 7.86-7.77 (m, 2H); 4.70 (s, 2H), 4.44 (q; 2H), 1.40 (t, 3H) .MS:m/z (MH)=258. describes routine 325-kharophen ethanoyl-1-naphthoic acid ethyl ester (D32)
With 5-glycyl-1-naphthoic acid ethyl ester hydrochloride (D31,2.26g, 7.70mmol) stirring suspension in DCM (60ml) and with triethylamine (1.2ml, 8.50mmol) and diacetyl oxide (0.86g, 8.5mmol) processing.After 18 hours, the mixture vacuum concentration to dry doubling with the Na of resistates at EtOAc and 10%
2CO
3Distribute between the aqueous solution.Isolate organic phase, dry (Na
2SO
4), vacuum concentration to dry doubling through the silica gel chromatography purifying, obtain white solid title compound (1173g, 60%) with the EtOAc wash-out.
1H NMR (250MHz, CDCl
3) δ (ppm): 9.17 (d, 1H), 8.90 (d, 1H), 8.23 (dd, 1H), 8.02 (dd, 1H), 7.69-7.62 (m, 2H), 6.57 (br s, 1H), 4.82 (d, 2H), 4.49 (q, 2H), 2.15 (s, 3H), 1.47 (t, 3H) .MS:m/z (MH)=300. describes example 33 (2-Jia Ji oxazole-5-yl)-1-naphthoic acid ethyl ester (D33)
(D33,1.71g 5.72mmol) cover with polyphosphoric acid (about 48g), with gained viscous mixt stirring heating under argon atmospher with 5-kharophen ethanoyl-1-naphthoic acid ethyl ester.When arriving 140 ℃, mixture partly cooled off and stir under be poured in the beaker trash ice (about 50ml).Add entry (50ml) and extract this solution with EtOAc.Isolate organic phase, dry (Na
2SO
4) and vacuum concentration to the dried light yellow solid that obtains,
1H NMR shows that it is the mixture of title compound and 5-(2-Jia Ji oxazole-5-yl)-1-naphthoic acid.Routine 345-(2-Jia Ji oxazole-5-yl)-1-naphthoic acid (D34) is described
Under agitation, with 5-(2-Jia Ji oxazole-5-yl)-1-naphthoic acid ethyl ester (D33,5.72mmol) be suspended in the mixture of EtOH (30ml) and 2M NaOH solution (30ml) and reflux 1 hour, mixture is partly cooled off and under vacuum, remove EtOH, resistates Et
2O washing, water layer is acidified to pH1 with dense HCl, then with the EtOAc extraction (3 * 200ml), merge organic extract liquid, drying (Na
2SO
4) and vacuum concentration to doing, obtain light yellow solid title compound (1.19g, two step yields 82%).
1H NMR (250MHz, d
6DMSO) δ (ppm): 8.89 (d, 1H), 8.49 (d, 1H), 8.18 (dd, 1H), 7.82 (dd, 1H), 7.76-7.66 (m, 2H), 7.55 (s, 1H), 2.56 (s, 3H). do not observe sour proton.MS:m/z (M-H)=252. describes routine 355-(3-methyl-isoxazole-5-yl)-1-naphthoic acid ethyl ester (D35)
Under agitation, (9.3mmol) (drying 1 of tributyl stannyl) isoxazole (Tetrahedron, 1991,47,5111), the drum argon gas outgased in 20 minutes in the 4-dioxane solution with 3-methyl-5-for D28,2.59g to 5-bromo-1-naphthoic acid ethyl ester.Add two (triphenylphosphine) palladium chlorides (II) and reflux mixture 24 hours under argon atmospher.The cooling back removes 1 under vacuum, the 4-diox, and resistates distributes in water and DCM, tells organic phase, dry (MgSO
4) and vacuum concentration to doing, obtain orange/brown oil, through the silica gel chromatography purifying, use 60-80 gasoline: Et
2O (2: 1) wash-out obtains cream-colored solid title compound (857mg, 33%).
1H NMR (250MHz, CDCl
3) δ (ppm): 9.03 (d, 1H), 8.46 (d, 1H), 8.21 (dd, 1H), 7.80 (dd, 1H), 7.66 (dd, 1H), 7.58 (dd, 1H), 6.43 (s, 1H), 4.50 (q, 2H), 2.44 (s, 3H), 1.47 (t, 3H) .MS:m/z (MH)=282. describes routine 365-(3-methyl-isoxazole-5-yl)-1-naphthoic acid (D36)
(D35,815mg 2.90mmol) prepare white solid title compound (638mg, 87%) with 5-(3-methyl-isoxazole-5-yl)-1-naphthoic acid ethyl ester to be similar to the method for describing example 34.
1H NMR (250MHz, d
6DMSO) δ (ppm): 13.38 (brs, 1H), 9.00 (d, 1H), 8.40 (d, 1H), 8.21 (dd, 1H), 7.90 (dd, 1H), and 7.80-7.69 (m, 2H), 6.90 (s, 1H), 2.38 (s, 3H) .MS:m/z (M-H)=252. describes example 37 (S)-(-)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D37)
Use PdCl
2(354mg, 2mmol) and Et
3(280ml 2mmol) handles (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,588mg, (15ml) solution of MeOH 2mmol) and reflux 15 hours to N.Suspension is used the MeOH thorough washing through diatomite filtration, and the methyl alcohol of merging is used K mutually
2CO
3Be transferred to pH10 and distribute in water and EtOAc, MgSO is used in organic phase salt water washing
4Drying, filtration and vacuum concentration are to the dried brown solid (150mg, 26%) that obtains.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.68 (d, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.48 (dd, 1H), 6.81 (d, 1H), 6.73 (s, 1H), 3.73-3.58 (m, 2H), 3.21-3.03 (m, 3H), 2.78-2.56 (m, 2H), 2.43-2.24 (m, 3H), 1.96-1.79 (m, 3H), (m, 1H) .MS:m/z (MH)=293. describes routine 385-(6-picoline-2-yl)-1-naphthoyl chloride (D38) to 1.55-1.46
With oxalyl chloride (0.15ml, 1.8mmol) processing 5-(6-picoline-2-yl)-1-naphthoic acid (D17,180mg, 0.68mmol) DCM (20ml) solution and at room temperature stirred 2 hours, vacuum concentration obtains cream-colored solid title compound to dried then, and this compound is directly used in next step.Routine 397-bromo-3-trifluoroacetyl group indoles (D39) is described
Stir down, (2.0g, (1.74ml 12.2mmol) handles to drip trifluoroacetic anhydride in DMF 10.2mmol) (8ml) solution to ice-cooled 7-bromo indole.Surpassing 2 hours with this solution temperature, be poured into saturated NaHCO then to room temperature
3In the aqueous solution.The white solid that is settled out is washed also and descend the dry title compounds (2.88g, 96%) that get in 50 ℃ in vacuum drying oven after filtration.MS：m/z(M-H)＝290，292。Routine 407-bromo indole-3-formic acid (D40) is described
With 7-bromo-3-trifluoroacetyl group indoles (D39; 2.88g; 9.8mmol) be dissolved in 20% the NaOH aqueous solution (30ml) and reflux 1 hour, cooling then, water (30ml) dilution; wash with EtOAc (40ml); tell water, the HCl acidified aqueous solution of using 5M is settled out the white solid title compound after filtration to pH1; wash and under vacuum dry (2.10g, 89%).MS：m/z(M-H)＝238，240。Routine 417-bromo-1-skatole-3-formic acid methyl ester (D41) is described
Use K
2CO
3(2.4g, 17.5mmol) and MeI (1.1ml 17.5mmol) handles 7-bromo indole-3-formic acid (D40,2.0g, (100ml) solution of acetone 8.3mmol) and argon atmospher, 50 ℃ of heating 40 hours.Cooling mixture leaches solid then, uses washing with acetone.Filtrate is concentrated into dried under vacuum, and resistates is handled with DCM, refilters and filtrate is concentrated into the dried light yellow solid title compound (1.95g, 87%) that obtains under vacuum.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.16 (dd, 1H), 7.72 (s, 1H), 7.41 (dd, 1H), 7.07 (dd, 1H), 4.20 (s, 3H), 3.90 (s, 3H) .MS:m/z (MH)=268,270. describes routine 421-methyl-7-(6-picoline-2 base) indole-3-carboxylic acid methyl ester (D42)
Under agitation, (730mg 2.24mmol) handles 7-bromo-1-skatole-3-formic acid methyl ester (D41,500mg, (10ml) solution of dry toluene 1.87mmol) and bubbling argon-degassed 20 minutes with hexa methyl ditin.Add Pd (PPh
3) and under argon atmospher, 110 ℃ of heated mixt 18 hours.Cooling mixture, through diatomite filtration, with the EtOAc washing, filtrate obtains light yellow oily indyl stannane intermediate through vacuum concentration.Under agitation this oily matter is dissolved in the dry DMF (5ml), (35mg is 0.19mmol) with 2-bromo-6-picoline (449mg, dry DMF 2.61mmol) (5ml) solution-treated, and bubbling argon-degassed with CuI.Add Pd (PPh
3)
2Cl
2And under argon atmospher, 110 ℃ of heated mixt 18 hours.Mixture is through the part cooling and remove DMF under vacuum, and resistates is used Et through the silica gel chromatography purifying
2The O wash-out obtains yellow oily title compound (159mg, 30%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：8.25(d，1H)，7.72-7.66(m，2H)，7.37-7.18(m，4H)，3.92(s，3H)，3.41(s，3H)，2.64(s，3H).MS：m/z(MH)＝281.
Embodiment 1 (S)-(-)-N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3,4-dichloro-benzamide (E1)
With dichlorobenzoyl chloride (113mg, 0.54mmol) and DMAP (1mg 8mmol) handles (S)-(-)-6-amino-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (D2,70mg, DCM solution 0.26mmol).After 15 hours, dilute this solution with DCM, and with saturated NaHCO
3Solution washing.Dry (MgSO
4) organic phase, filtration and vacuum concentration are to doing.Obtain white glass shape title compound through silica gel chromatography (DCM/MeOH 93: 7) purifying, with this compound of acetone treatment, the ethereal solution of the HCl that usefulness is done is handled and is concentrated into dried, obtains white powder hydrochloride (60mg, 52%).
1H?NMR(free?base)(400MHz，CDCl
3)δ(ppm)：9.45(s，1H)，8.68(s，1H)，8.58(d，1H)，8.00(s，1H)，7.91(d，1H)，7.72-7.66(m，2H)，7.41(d，1H)，6.83(d，1H)，3.68?(br.d，1H)，3.61(br.d，1H)，3.12-3.00(m，3H)，2.72(t，1H)，2.56(td，1H，2.38-2.30(m，1H)，2.20-2.14(m，1H)，1.90-1.80(m，2H)，1.75-1.65(m，1H)，1.51-1.40(m，1H).MS：m/z(MH)＝441.
Embodiment 2 (S)-(-)-1-[(3, the 4-dichlorophenyl) carbonyl]-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E2)
With pyridine (0.5ml), 3, the 4-dichlorobenzoyl chloride (161mg, 0.77mmol) and DMAP (1.5mg 12mmol) handles (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,100mg, 0.34mmol) DCM (4ml) solution, and under argon atmospher reflux.After 17 hours, wash with solution cooling and with 5% citric acid solution.Dry (MgSO
4) organic phase, filtration and vacuum concentration are to doing.Obtain title compound (44mg, 28%) through silica gel chromatography (DCM/MeOH 19: 1) purifying.
1H?NMR(400MHz，CDCl
3)δ(ppm)：8.85-8.75(br.s，1H)，8.63(d，1H)，7.87(s，1H)，7.76(s，1H)，7.56(d，1H)，7.45(dd，1H)，6.83(d，1H)，4.17(br.s，2H)，3.64(br.s，2H)，3.40-3.27(m，2H)，3.18-3.02(m，4H)，2.71(br.s，2H)，2.32(br.d，1H)，1.93-1.79(m，3H)，1.49(br.s，1H).MS：m/z(MH)＝467.
Embodiment 3 (S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E3)
With the method that is similar to embodiment 2, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,100mg, 0.34mmol) and 5-(2,6-lutidine-4-yl) naphthoyl chloride (D14,150mg, 0.51mmol) make cream-colored solid title compound (31mg, 16%).
1H?NMR(400MHz，CDCl
3)δ(ppm)：9.09(s，1H)，8.64(d，1H)，8.00(d，1H)，7.94(d，1H)，7.86(s，1H)，7.64-7.54(m，3H)，7.45(d，1H)，7.11(s，2H)，6.88(d，1H)，3.97-3.69(br.m，3H)，3.46-3.22(br.m，3H)，3.19-3.10(br.m，2H)，2.81-2.76(br.m，2H)，2.64(s，6H)，2.62-2.46(br.m，2H)，2.33-2.28(m，1H)，2.00-1.87(br.m，2H)，1.84-176(br.m，1H)，1.58-1.50(br.m，1H).MS：m/z(MH)＝554.
Embodiment 4 (S)-(-)-6-[5-(5-picoline-2-yl) naphthalene-1-formyl radical amino]-4-(the octahydro pyrrolo-[, 2-a] and pyrazine-2-yl) quinoline (E4)
With 1,3-di-isopropyl carbodiimide (255 μ mol) is handled (S)-(-)-6-amino-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (D2,85 μ mol), 5-(5-picoline-2-yl) naphthoic acid (D16, and jolting at room temperature 48 hours 255 μ mol) and DCM (3ml) solution of I-hydroxybenzotriazole (255 μ mol).Solution by solid phase cationic exchange (SCX) post, is washed with MeOH.Use 2M NH
3The MeOH eluant solution, vacuum-evaporation obtains the glassy title compound of light brown (46%) then.
1H?NMR(250MHz，CDCl
3)δ(ppm)：8.81(s，1H)，8.66(d，1H)，8.57(s，1H)，8.47(d，1H)，8.42(d，1H)，8.03(d，1H)，7.90(d，1H)，7.78(d，1H)，7.70-7.58(m，3H)，7.45(d，2H)，7.31(d，H)，6.89(d，1H)，3.78(br.d，1H)，3.69(br.d，1H)，3.22-3.05(br.m，3H)，2.81-2.65(m，1H)，2.67(s，1H)，2.51-2.43(br.m，1H)，2.26(q，1H)，1.99-1.70(br.m，3H)，1.50(m，1H).MS：m/z(MH)＝514.
Embodiment 5 (S)-(-)-6-[2,3-dichloro-benzoyl base amino]-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (E5)
With the method that is similar to embodiment 4, make yellow glass shape title compound (67%) by (S)-(-)-6-amino-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline (D2,85 μ mol) and 2 3,dichloro benzoic acid 99 (255 μ mol).
1H NMR (250MHz, CDCl
3) δ (pm): 8.74 (d, 1H), 8.72 (d, 1H), 8.58 (d, 1H), 7.97 (d, 1H), 7.61 (dd, 1H), 7.53-7.48 (m, 2H), 7.23 (t, 1H), 6.84 (d, 1H), 3.74 (br.d, 1H), 3.66 (br.d, 1H), 3.19-3.02 (m, 3H), 2.72 (t, 1H), 2.62 (td, 1H), 2.44-2.33 (br.m, 1H), 2.22 (q, 1H), 1.95-1.74 (br.m, 3H), 1.48 (m, 1H) .MS:m/z (MH)=441, method makes 442,443,444. embodiment E 6-E9 described in the embodiment 4 with being similar to.
Embodiment 10 (S)-(-)-1-(2,3-dichloro-benzoyl base)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E10)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 2 3,dichloro benzoic acid 99 (255 μ mol) make light yellow glassy title compound (51%).
1H?NMR(400MHz，CDCl
3)δ(ppm)：8.93(s，1H)，8.62(d，1H)，7.86(s，1H)，7.57(dd，1H)，7.37(m，2H)，6.85(d，1H)，4.05-3.65(br.m，3H)，3.34(t，2H)，3.24-3.11(br.m，2H)，2.74(br.t，2H)，2.52(br.s，1H)，2.30(q，1H)，1.98-1.74(m，5H)，1.60-1.48(br.m，1H).MS：m/z(MH)＝467，468，469，470.
Embodiment 11 (S)-(-)-2,3-dihydro-1-[4-(5-Jia Ji oxazole-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E11)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 4-(5-Jia Ji oxazole-2-yl)-1-naphthoic acid (D21,255 μ mol) make brown glass shape title compound (47%).
1H?NMR(400MHz，CDCl
3)δ(ppm)：9.39(d，1H)，9.09(s，1H)，8.64(d，1H)，8.24(d，1H)，7.99(d，1H)，7.84(s，1H)，7.71-7.56(M，3H)，7.05(S，1h)，6.88(d，1H)，3.90-3.67(br.m，3H)，3.26(t，2H)，3.19-3.09(br.m，2H)，2.80(br.t，2H)，2.49(s，3H)，2.31(br.m，1H)，2.00-1.87(br.m，3H)，1.60-1.48(br.m，1H).MS：m/z(MH)＝530.
Embodiment 12 (S)-(-)-2,3-dihydro-1-[5-(5-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline trifluoroacetates (E12)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(5-picoline-2-yl)-1-naphthoic acid (D16,255 μ mol) make title compound.Further obtain the glassy trifluoroacetate of light brown (20%) with this compound of reversed-phase HPLC purifying and separation.
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.01(s，1H)，8.83(s，1H)，8.71(s，1H)，8.25(s，1H)，8.23(dd，1H)，8.02(d，1H)，7.88(br.d，1H)，7.64-7.54(m，4H)，7.58(d，1H)，7.25(d，H)，4.23(br.d，1H)，4.10-3.65(br.m，10H)，3.43(t，2H)，2.90(s，3H)，2.51-2.43(br.?m，1H)，2.35-2.18(br.m，3H).MS：m/z(MH)＝540.
Embodiment 13 (S)-(-)-2,3-dihydro-1-[5-(2,5-lutidine-4-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E13)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(2,5-lutidine-4-yl)-1-naphthoic acid (D22,255 μ mol) make the glassy title compound of light brown (35%) .MS:m/z (MH)=554.
Embodiment 14 (S)-(-)-2,3-dihydro-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E14)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(6-picoline-2-yl)-1-naphthoic acid (D17,255 μ mol) make yellow glass shape title compound (46%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.07(s，1H)，8.63(d1H)，8.16(d，1H)，7.98(d，1H)，7.90(s，1H)，7.75(t，1H)，7.66-7.49(m，4H)，7.37(d，1H)，7.25(d，1H)，6.90(d，1H)，3.87-3.76(br.m，3H)，3.37-3.19(br.m，4H)，3.00-2.87(br.m，2H)，2.69(s，3H)，2.42(q，1H)，2.08-1.83(br.m，3H)，1.71-1.60(br.m，1H).MS：m/z(MH)＝540.
Embodiment 15 (S)-(-)-2,3-dihydro-1-[5-(3-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E15)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(3-picoline-2-yl)-1-naphthoic acid (D23,255 μ mol) make light yellow glassy title compound (64%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.09(s，1H)，8.65-8.60(m，2H)，8.03(d，1H)，7.86(s，1H)，7.74-7.59(m，4H)，7.51(s，1H)，7.49(d，1H)，7.32(dd，1H)，6.88(d，1H)，3.90-3.71(br.m，3H，3.32-3.13(br.m，5H)，2.87-2.73(br.m，2H)，2.64-2.52(m，1H).2.38-2.26(m，2H)，2.08-1.83(br.m，3H)，2.07(s，3H)，1.71-1.60(br.m，1H).MS：m/z(MH)＝540.
Embodiment 16 (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl)-1-(quinolyl-4 carbonyl) pyrrolo-[2,3-g] quinoline (E16)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 4-quinolinecarboxylic acid (255 μ mol) make yellow glass shape title compound (72%) .MS:m/z (MH)=450.
Embodiment 17 (S)-(-)-2,3-dihydro-1-[5-(2-Jia Ji oxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E17)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(2-first base oxazole-5-yl)-1-naphthoic acid (D34,255 μ mol) make yellow glass shape title compound (36%).
1H NMR (250MHz, CDCl
3) δ (ppm): 9.08 (s, 1H), 8.62 (d, 1H), 8.39 (m, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.78 (d, 1H), 7.66-7.55 (m, 3H), 7.31 (s, 1H), 6.88 (d, 1H), 3.85-3.67 (br.m, 3H), 3.25 (t, 2H), 3.21-3.11 (br.m, 2H), 2.79 (br.t, 2H), 2.62 (s, 3H), 2.30 (m, 1H), and 1.98-1.75 (br.m, 3H), 1.60-1.45 (br.m, 1H) .MS:m/z (MH)=530.
Embodiment 18 (S)-(-)-2,3-dihydro-1-[5-(3-methyl-isoxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E18)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(3-methyl-isoxazole-5-yl)-1-naphthoic acid (D36,255 μ mol) make yellow glass shape title compound (26%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.06(s，1H)，8.63(d，1H)，8.41(m，1H)，8.07(d，1H)，7.90(s，1H)，7.84(d，1H)，7.67-7.58(m，3H)，6.89(d，1H)，6.49(s，1H)，3.90-3.69(br.m，3H)，335-3.15(br.m，4H)，2.79(br.m，2H)，2.46(s，3)，2.40-2.30(m，1H)，2.02-1.80(br.m，3H)，1.71-1.55(br.m，1H).MS：m/z(MH)＝530.
Embodiment 19 (S)-(-)-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E19)
Under 4 ℃, argon atmospher, stirring, (18mg 0.77mmol) handles (S)-(-)-8-(octahydro pyrrolo-[1 with NaH, 2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D37,150mg, 510 μ mol) in exsiccant DMF (15ml) solution and 30 minutes the temperature to room temperature.(DMF 0.77mmol) (5ml) solution also continues to stir 20 hours for D38,190mg to add 5-(6-picoline-2-yl)-1-naphthoyl chloride.With this solution at EtOAc and saturated NaHCO
3Distribute between the aqueous solution.With saturated NaHCO
3The aqueous solution, water and salt water washing organic phase are used MgSO
4Drying is filtered and vacuum concentration is extremely done.Through the silica gel chromatography purifying, use 9: 1 wash-outs of DCM/MeOH to obtain yellow gluey product (15mg, 5%) again with DCM earlier.
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.37(s，1H，8.82(d，1H)，8.50(d，1H)，8.31(d，1H)，7.94(d，1H)，7.78-7.57(m，4H)，7.40(d，1H)，7.27(d，1H)，7.17(d，1H)，6.97(d，1H)，6.73(d，1H)，3.95-3.80(m，2H)，3.49-3.24(m，5H)，3.07(d，2H)，2.71(s，3H)，2.14-1.94(m，4H).MS：m/z(MH)＝430.
Embodiment 20 (S)-(-)-1-(4-chlorobenzene formacyl)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E20)
Stir down, handle the solution of (S)-(-)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D37,150mg, 510 μ mol) in exsiccant DMF (15ml) with DMAP and 4-chloro-benzoyl chloride (0.38mmol).After 18 hours, with this solution at DCM and saturated NaHCO
3Distribute between the aqueous solution.With salt water washing organic phase, use MgSO
4Drying is filtered and vacuum concentration is extremely done.Through the silica gel chromatography purifying, use 19: 1 wash-outs of DCM/MeOH to obtain yellow gluey product (19mg, 21%) again with DCM earlier.
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.10(s，1H)，8.76(d，1H)，8.28(d，1H)，7.74(d，2H)，7.56(d，2H)，7.49(dd，1H)，6.90(d，1H)，6.82(d，1H)，3.73(m，2H)，3.16(m，2H)，2.78(m，2H)，2.36(m，2H)，1.90(m，4H)，1..54(m，1H).MS：m/z(MH)＝430.
Embodiment 21 (S)-(-)-2,3-dihydro-1-[2-(4-chloro-phenyl-)-3-trifluoromethyl pyrazol-4-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E21)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,170 μ mol) and 2-(4-chloro-phenyl-)-3-trifluoromethyl pyrazol-4-formic acid (250 μ mol) makes yellow glass shape title compound (52%).
1H NMR (250MHz, CDCl
3) δ (ppm): 8.90 (s, 1H), 8.63 (d, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.51 (d, 2H), 7.44 (d, 2H), 6.85 (d, 1H), 4.18-4.06 (br.t, 2H), 3.78-3.63 (br.m, 2H), 3.37 (t, 2H), 3.20-3.05 (br.m, 3H), 2.70-2.78 (br.t, 2H, 2.50-2.60 (br.m, 1H), and 1.79-1.97 (br.m, 4H), 1.45-1.57 (br.m, 1H) .MS:m/z (MH)=568.
Embodiment 22 (S)-(-)-2,3-dihydro-1-[5-(2-methyl-5-trifluoromethyl pyrazol-3-yl)-thiophene-2-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E22)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,170 μ mol) and 5-(2-methyl-5-trifluoromethyl pyrazol-3-yl)-thiophene-2-carboxylic acid (250 μ mol) make yellow glass shape title compound (80%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：8.64(s，1H)，8.60(d，1H)，7.83(s，1H)，7.58(d，1H)，7.31(d，1H)，6.85(s，1H)，6.82(d，1H)，4.48(t，2H)，4.02(s，3H)，3.69-3.57(br.m，2H)，3.39(t，2H)，3.20-3.02(m，3H)，2.75-2.63(m，2H)，2.502.40(br.m，1H)，2.25-2.21(br.m，1H)，1.92-1.76(brm，3H)，1.44-1.55(m，1H).MS：m/z(MH)＝553.
Embodiment 23 (S)-(-)-2,3-dihydro-1-(5-chlorothiophene-2-carbonyl)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E23)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,170 μ mol) and 5-chlorothiophene-2-formic acid (250 μ mol) makes yellow glass shape title compound (66%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：8.62(s，1H)，8.60(d，1H)，7.83(s，1H)，7.40(d，1H)，6.95(d，1H)，6.81(d，1H)，4.42(t，2H)，3.68-3.56(br.m，2H)，3.39(t，2H)，3.20-3.00(m，3H)，2.76-2.64(m，2H)，2.47-2.39(br.m，1H)，1.98-1.79(br.m，4H)，1.46-1.59(m，1H).MS：m/z(MH)＝438.
Embodiment 24 (S)-(-)-2,3-dihydro-1-[1-methyl-7-(2-picoline-6-yl) indoles-3-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E24)
Under argon atmospher, stirring, with 1-methyl-7-(6-picoline-2 base) indole-3-carboxylic acid methyl ester (D42,54mg, 0.19mmol) solution-treated (S)-(-)-2 in dry toluene (5ml), 3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,45mg, dry toluene 0.15mmol) (5ml) solution.Add AlMe with syringe
3(0.15ml, reflux is 18 hours 0.29mmol) and under argon atmospher.The reaction solution cooling is also directly poured on the silica sep pak (5g) the MeOH/DCM wash-out with 5%.Merge the fraction that contains product, vacuum concentration is to doing, and with preparation thin-layer chromatography purifying, the MeOH/DCM wash-out with 15% obtains yellow solid title compound (20mg, 24%) to resistates again.
1H NMR (250MHz, CDCl
3) δ (ppm): 8.58 (d, 1H), 8.39 (br.s, 1H), 7.98-7.93 (m, 2H), 7.70 (dd, 1H), 7.51 (s, 1H), 7.37 (d, 1H), 726-7.19 (m, 3H), 6.83 (d, 1H), 4.37 (br.t, 2H), 3.71 (br.d, 1H), 3.46 (s, 3H), 3.35 (br.t, 2H), 3.38-3.23 (br.m, 4H), 2.97 (br.s, 2H), 2.70-2.40 (br.s, 2H), 2.65 (s, 3H), (br.m, 4H) .MS:m/z (MH)=543. embodiment E 25-E72 makes with being similar to embodiment 4 described method being parallel 2.07-1.70.
Embodiment 73 (S)-(-)-2,3-dihydro-1-[5-(5-Jia Ji oxazole-2-yl) naphthalene-1-base ethanoyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E73)
With the method that is similar to embodiment 4, by (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,85 μ mol) and 5-(5-Jia Ji oxazole-2-yl) naphthalene-1-guanidine-acetic acid (D27,255 μ mol) make the glassy title compound of light brown (70%).
1H?NMR(250MHz，CDCl
3)δ(ppm)：9.24(d，1H)，8.87(s，1H)，8.60(d，1H)，8.18(d，1H)，8.14(d，1H)，7.80(s，1H)，7.64-7.48(m，3H)，6.99(s，1H)，6.82(d1H)，4.37(s，2H)，4.17(t，3H)，3.68(br.t，2H)，3.34(t，2H)，3.20-2.99(m，3H)，2.71(t，2H)，2.47(s，3H)，2.31(q，1H)，1.95-1.70(br.m，3H)，1.55-1.42(br.m，1H).MS：m/z(MH)＝544.
Embodiment 74 (S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base aminocarboxyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (E74)
With (S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline (D10,100mg, 340 μ mol) DCM (10ml) solution joins isocyanic acid (5-(2,6-lutidine-4-yl) naphthalene-1-yl), and (D15 is in DCM 0.38mmol) (10ml) solution for ester.With mixture reflux 16 hours under argon atmospher, vacuum concentration obtains crude product then.Crude product is used DCM through the silica gel chromatography purifying: MeOH (93: 7) wash-out obtains cream-colored solid title compound (80mg, 41%).
1H NMR (400MHz, CDCl
3) δ (ppm): 8.56 (d, 1H), 8.47 (s, 1H), 8.03 (d, 1H), 7.85 (d, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.55 (dd, 1H), 7.47 (dd, 1H), 7.40 (d, 1H), 7.09 (s, 1H), 7.08 (s, 2H), 6.82 (d, 1H), 4.30 (t, 2H), 3.64 (d, 1H), 3.56 (d, 1H), 3.44 (t, 2H), 3.07-2.98 (m, 3H), 2.69 (t, 1H), 2.62 (s, 6H), 2.55 (dt, 1H), 2.32 (br.m, 1H), 2.14 (q, 1H), 1.87-1.61 (br.m, 3H), (m, 1H) .MS:m/z (M-H)=567. embodiment E 75-E80 makes with being similar to embodiment E 74 described method being parallel 1.42-1.38.
Embodiment 23,29, (R)-enantiomorph of 33 and 35 is used according to the described method of D7-D10 by (R)-(+)-octahydro pyrrolo-[1,2-a] pyrazine (J.Med.Chem. with the method that is similar to embodiment 4,1993,36,2311) Zhi Bei (R)-(+)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline and carboxylic acid coupling preparation.Pharmacological datum
The affinity of The compounds of this invention is measured with the radiolabeled binding analysis method of foregoing description.
5-HT
1A, 5-HT
1BAnd 5-HT
1DReceptors bind
Among all embodiment, 5-HT
1A, 5-HT
1BAnd 5-HT
1DPKi value＞7.5 of acceptor.
Claims (10)
1, formula (I) compound or its salt:
R wherein
aBe selected from formula (i) or group (ii); The group of formula (i)
P wherein
1Be phenyl, bicyclic aryl, C
3-6Cycloalkyl, contain 1 to 3 and be selected from heteroatomic 5 to 7 element heterocycles of oxygen, nitrogen and sulphur or contain 1 to 3 heteroatomic bicyclic heterocycle that is selected from oxygen, nitrogen and sulphur; R
1Be halogen, C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkyloyl, NO
2, CF
3, CN, SR
9, SOR
9, SO
2R
9, SO
2NR
10R
11, CO
2R
10, CONR
10R
11, CONR
10(CH
2)
cCO
2R
11, (CH
2)
cNR
10R
11, (CH
2)
cCONR
10R
11, (CH
2)
cNR
10COR
11, (CH
2)
cCO
2C
1-6Alkyl, CO
2(CH
2)
cOR
10, NR
10R
11, NR
10CO
2R
11, NR
10CONR
10R
11, CR
10=NOR
11, CNR
10=NOR
11, R wherein
9, R
10, R
11Be hydrogen or C independently of one another
1-6Alkyl and c are 1 to 4; And a is 0,1,2 or 3; Formula is group (ii)
P wherein
2And P
3Independent separately for phenyl, bicyclic aryl, contain 1 to 3 and be selected from heteroatomic 5 to 7 element heterocycles of oxygen, nitrogen and sulphur or contain 1 to 3 heteroatomic bicyclic heterocyclic group that is selected from oxygen, nitrogen and sulphur; A is a key, O, S (O)
n, wherein n be 0 to 2, carbonyl, CH
2Or NR
4, R wherein
4Be hydrogen or C
1-6Alkyl; R
1And R
2Independently of one another as R in the above-mentioned formula (i)
1Definition; And a and b are 0,1,2 or 3 independently of one another; L be following formula group :-Y-C (=O)-DG-or-C (=O)-DG-or-DG-C (=O)-wherein Y is NH, NR
5, R wherein
5Be C
1-6Alkyl or Y are CH
2, O, CH=CH or OCH
2D is nitrogen, carbon or CH base, and G is hydrogen or C
1-6Alkyl, condition are that D is nitrogen or CH base, or G and R
B1Form group W together, W is (CR herein
16R
17)
tWherein t is 2,3 or 4 and R
16And R
17Be hydrogen or C independently of one another
1-6Alkyl, perhaps W is (CR
16R
17)
uJ, wherein u be 0,1,2 or 3 and J be oxygen, sulphur, CR
16=CR
17, CR
16=N ,=CR
16O ,-CR
16S or=CR
16-NR
17, condition is that u is not 0 when J is oxygen or sulphur; R
B1For hydrogen or form group W with G as mentioned above; X is nitrogen, carbon or CH, when X is nitrogen or CH=be singly-bound, and when X is carbon=being two keys, m is 1,2 or 3.
2, according to the compound of claim 1, wherein X is that nitrogen-atoms and m are 1.
3, according to the compound of aforementioned arbitrary claim, wherein group D is that nitrogen and group G are hydrogen or and R in the definition of L
B1Form another group (CH
2)
2
4, according to the compound of aforementioned arbitrary claim, R wherein
aGroup and P for formula (i)
1Be phenyl, naphthyl, quinolyl, pyridyl or thienyl.
5, according to each compound among the claim 1-3, wherein R
aBe formula group and P (ii)
2Be phenyl, naphthyl, pyridyl, thienyl or furyl.
6, according to the compound of claim 1, these compounds are:
(S)-(-)-and N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3, the 4-dichloro-benzamide,
(S)-(-)-and N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3, the 4-dichloro-benzamide,
(S)-(-)-and N-[4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline-6-yl]-3, the 4-dichloro-benzamide,
(S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-6-[5-(5-picoline-2-yl) naphthalene-1-formyl radical amino]-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline,
(S)-(-)-6-(2,3-dichloro-benzoyl amino)-4-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) quinoline,
(S)-(-)-and 1-(2,3-dichloro-benzoyl base)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[4-(5-Jia Ji oxazole-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(5-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline trifluoroacetate,
(S)-(-)-2,3-dihydro-1-[5-(2,5-lutidine-4-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl)-1-(quinolyl-4 carbonyl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2-Jia Ji oxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(3-methyl-isoxazole-5-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-1-[5-(6-picoline-2-yl) naphthalene-1-formyl radical]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-1-(4-chlorobenzene formacyl)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[2-(4-chloro-phenyl-)-3-trifluoromethyl pyrazol-4-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2-methyl-5-trifluoromethyl pyrazol-3-yl)-thiophene-2-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-(5-chlorothiophene-2-carbonyl)-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[1-methyl-7-(2-picoline-6-yl) indoles-3-carbonyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(5-Jia Ji oxazole-2-yl) naphthalene-1-base ethanoyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline,
(S)-(-)-2,3-dihydro-1-[5-(2,6-lutidine-4-yl) naphthalene-1-base aminocarboxyl]-8-(octahydro pyrrolo-[1,2-a] pyrazine-2-yl) pyrrolo-[2,3-g] quinoline or its pharmacologically acceptable salt.
7, the method for a kind of preparation formula (I) compound, this method comprises:
(a) when L be-C (=O)-DG-or DG-(C=O)-time, make formula (II) compound:
R
a-L
1
(II) with the coupling of formula (III) compound:
R wherein
a, R
B1, X and m define and L suc as formula (I)
1And L
2Contain and to react the suitable functional group that forms the L part jointly; Or
(b) when L be-Y-C (=O)-DG, wherein D is nitrogen and Y when being NH, makes formula (IV) compound:
R
a-NC(＝O)
(IV) R wherein
aSuc as formula the derivative that (I) defines or it has been protected, the derivative coupling of having protected with formula V compound or its:
R wherein
B1, X, m and G define suc as formula (I); Or
(c) when L be-Y-C (=O)-DG-, wherein D is that nitrogen and Y are NH or NR
5The time, make formula (VI) compound
R
a-NH
2Or R
a-NR
5H
(VI) R wherein
aAnd R
5Define suc as formula (I), form reagent react with common and a kind of suitable urea of formula V compound; Or
(d) when L be-Y-C (=O)-DG-, wherein D is that nitrogen and Y are CH
2Or during O, make formula (VII) compound
R
a-Y-(C＝O)-L
3
(VII) R wherein
aDefine suc as formula (I), and L
3Be a suitable leavings group, react with the formula V compound; Or
(e) when L be-Y-C (=O)-DG-, wherein D is CH and Y when being NH, makes formula (VI) compound
R
a-NH
2
(VI) R wherein
aDefine suc as formula (I), react with formula (VIII) compound;
D wherein, G, R
B1, X and m define and L suc as formula (I)
3It is a suitable leavings group; And after this can be arbitrarily selectively:
Remove any protecting group;
Form a kind of pharmacologically acceptable salt.
8, be used for the treatment of according to each compound among the claim 1-6.
9, be used for the treatment of dysthymia disorders according to each compound among the claim 1-6.
10, a kind of pharmaceutical composition, it comprises according to each compound and pharmaceutically acceptable carrier among arbitrary claim 1-6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9827882.3A GB9827882D0 (en) | 1998-12-17 | 1998-12-17 | Novel compounds |
| GB9827882.3 | 1998-12-17 |
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|---|---|
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|---|---|---|---|
| CN99816080A Pending CN1335850A (en) | 1998-12-17 | 1999-12-03 | Quinoline derivatives |
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| JP (1) | JP2002532501A (en) |
| KR (1) | KR20010108028A (en) |
| CN (1) | CN1335850A (en) |
| AU (1) | AU3036000A (en) |
| BR (1) | BR9916307A (en) |
| CA (1) | CA2355234A1 (en) |
| CO (1) | CO5150146A1 (en) |
| CZ (1) | CZ20012151A3 (en) |
| GB (1) | GB9827882D0 (en) |
| HK (1) | HK1041480A1 (en) |
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| CN108570450A (en) * | 2017-03-11 | 2018-09-25 | 华中科技大学鄂州工业技术研究院 | A kind of application of cell model and its construction and screening Serotonin receptor target active substance |
| CN106883192B (en) * | 2017-03-30 | 2019-05-14 | 苏州汉德创宏生化科技有限公司 | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification |
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|---|---|---|---|---|
| WO1995006644A1 (en) * | 1993-09-03 | 1995-03-09 | Smithkline Beecham Plc | Amide derivatives as 5ht1d receptor antagonists |
| WO1998047868A1 (en) * | 1997-04-18 | 1998-10-29 | Smithkline Beecham Plc | Heterocycle-containing urea derivatives as 5ht1a, 5ht1b and 5ht1d receptor antagonists |
| BR9809092A (en) * | 1997-04-18 | 2002-01-22 | Smithkline Beecham Plc | Indole derivatives having combined 5ht1a, 5ht1b and 5ht1d receptor antagonist activity |
| JP2002508366A (en) * | 1997-12-12 | 2002-03-19 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Quinoline piperazine and quinoline piperidine derivatives, methods for their preparation, and their use as complex 5-HT1A, 5-HT1B and 5-HT1D receptor antagonists |
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1998
- 1998-12-17 GB GBGB9827882.3A patent/GB9827882D0/en not_active Ceased
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1999
- 1999-12-03 IL IL14378299A patent/IL143782A0/en unknown
- 1999-12-03 PL PL99353156A patent/PL353156A1/en not_active Application Discontinuation
- 1999-12-03 BR BR9916307-1A patent/BR9916307A/en not_active Application Discontinuation
- 1999-12-03 TR TR2001/01764T patent/TR200101764T2/en unknown
- 1999-12-03 EP EP99964526A patent/EP1140946A2/en not_active Withdrawn
- 1999-12-03 AU AU30360/00A patent/AU3036000A/en not_active Abandoned
- 1999-12-03 CZ CZ20012151A patent/CZ20012151A3/en unknown
- 1999-12-03 KR KR1020017007626A patent/KR20010108028A/en not_active Application Discontinuation
- 1999-12-03 JP JP2000588178A patent/JP2002532501A/en active Pending
- 1999-12-03 CN CN99816080A patent/CN1335850A/en active Pending
- 1999-12-03 CA CA002355234A patent/CA2355234A1/en not_active Abandoned
- 1999-12-03 WO PCT/EP1999/009564 patent/WO2000035919A2/en not_active Application Discontinuation
- 1999-12-03 HU HU0104662A patent/HUP0104662A2/en unknown
- 1999-12-17 CO CO99078949A patent/CO5150146A1/en unknown
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2001
- 2001-06-15 NO NO20013003A patent/NO20013003L/en not_active Application Discontinuation
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2002
- 2002-02-19 HK HK02101212.8A patent/HK1041480A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO20013003L (en) | 2001-07-25 |
| WO2000035919A2 (en) | 2000-06-22 |
| EP1140946A2 (en) | 2001-10-10 |
| TR200101764T2 (en) | 2001-10-22 |
| GB9827882D0 (en) | 1999-02-10 |
| KR20010108028A (en) | 2001-12-07 |
| HK1041480A1 (en) | 2002-07-12 |
| JP2002532501A (en) | 2002-10-02 |
| AU3036000A (en) | 2000-07-03 |
| WO2000035919A3 (en) | 2000-10-26 |
| CO5150146A1 (en) | 2002-04-29 |
| IL143782A0 (en) | 2002-04-21 |
| NO20013003D0 (en) | 2001-06-15 |
| CA2355234A1 (en) | 2000-06-22 |
| BR9916307A (en) | 2002-01-15 |
| HUP0104662A2 (en) | 2002-04-29 |
| PL353156A1 (en) | 2003-10-20 |
| CZ20012151A3 (en) | 2001-12-12 |
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