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CN1278260A - Aminomethyl-benzo [a] quinolizidine derivatives, prepns. and therapeutic applications for neurodegenrative diseases - Google Patents

Aminomethyl-benzo [a] quinolizidine derivatives, prepns. and therapeutic applications for neurodegenrative diseases Download PDF

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CN1278260A
CN1278260A CN98810769A CN98810769A CN1278260A CN 1278260 A CN1278260 A CN 1278260A CN 98810769 A CN98810769 A CN 98810769A CN 98810769 A CN98810769 A CN 98810769A CN 1278260 A CN1278260 A CN 1278260A
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methyl
hydrogen
benzo
quinolizinyl
methoxyl group
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P·梅耶
J－L·维达鲁克
T·伊姆伯特
M·马瑞恩
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Pierre Fabre Medicament SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

The invention concerns 2-aminomethyl-benzo[a]quinolizidine derivatives, corresponding to general formula (I) in which: R1 represents either a hydrogen atom or a branched, linear or cyclic C1-C4 alkyl group, a branched, linear or cyclic C1-C4 hydroxy or alkoxy group, or a halogen atom such as F or Cl; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a hydrogen atom or can constitute a unit (C=X)-NR4R5 and in that case constitutes a urea or thiourea with X = oxygen or sulphur; R4 and R5 can independently be a hydrogen atom or a linear, branched, cyclic C1-C8 alkyl group, an aryl, aralkyl, aroyl group, said aryl groups capable of being substituted as well; R4 and R5 can be bound by a carbon chain optionally incorporating a heteroatom.

Description

Amino methyl-benzo [a] quinolizine alkane derivatives, its preparation and the application in the treatment neurodegenerative disease thereof
The present invention relates to new benzo [a] quinolizine alkane (quinolizidine) derivative, and relate to its preparation method.Also relate to these compounds and be used as α as medicine and preparation 2Thereby-adrenergic receptor antagonist is used for the treatment of the application of the medicine of neurodegenerative disease.Described disease comprises: disease behind Parkinson's disease, presenile dementia, huntington's chorea, cognition and dysmnesia, the elderly's attention and alertness deficiency and cerebral ischemia and the ischemic.
Show that locus coeruleus is recovering by giving the main effect of performance (Mavridis, neuroscience (Neuroscience) (1991), 41,507) in the monkey dopaminergic function that MPTP is damaged.Its destroyed restore funcitons that then causes reduces.
In addition, has α 2The compound of antagonist action can alleviate monkey (Colpaert, brain research journal (Brain Res.Bull.), (1991), 26,627) or rat (Colpaert, neuropharmacology (Neuropharmacology) (1987), 26,143) symptoms of Parkinson's Disease, this effect may be (Marien, the parkinsonian norepinephrine energy mechanism (Noradrenergic Mechanisims inParkinson ' s Disease) that produces by the release that increases Dopamine HCL, 139 pages, (1994), CRC press, Boca Raton; Marien and Colpaert, (+)-efaroxan is to the metabolic effect of striatum Dopamine HCL in the mouse body.Dopamine?94-Satellite?Meeting?of?the?XIIth?Int.Congr.Pharmacology，Quebec?City，Canada，July?20-24，1994)。
And, a kind of known α 2Agonist compounds Idazoxan has demonstrated to cerebral ischemia (Gustafson, experiment brain research (Exp.Brain.Res.), (1991), 86,555 and J.Cereb. blood flow and metabolism (Blood Flow Metab.), (1990), 10,885), paralysis and neurodegenerative disease (Ghika, neuroscience (Neurology), (1991) on the carrying out property nuclear, 41,986) the harmful work that causes has antagonistic action.Also demonstrate and have α 2The compound of antagonistic activity causes the increase (Tellez, neurochemistry magazine (J.Neurochem.) (1997), 68,778) that prefrontal cortex vagusstoff discharges.
Therefore, the material that activates noradrenergic system may have and suppresses the character that neurodegeneration further develops, and this relates to and activates different brain district systems again, and no matter they are dopaminergic or cholinergic system or the release that relates to somatomedin.Therefore, these compounds can be used for treating Parkinson type or presenile dementia type neurodegenerative disease and further develop caused disease.
Much has α 2The derivative of-noradrenergic receptor antagonistic activity is known, especially those are at patent US4855308, EP486385, WO91/18886, US4497818, EP524004 and at " pharmaceutical chemistry magazine " (J.Med.Chem.), 1991, compound described in 34,705.
Can distinguish The compounds of this invention by following characteristics, promptly they are replace to constitute benzo [a] the quinolizine alkane derivatives that the amino methyl of urea or acid amides replaces on by nitrogen in the 2-position.These product innovations have particularly advantageous, relevant with other α 2The pharmacological property that-agonist compounds is different.Especially, in central nervous system, they have selectively acting in noradrenergic receptor (α 2) rather than dopaminergic acceptor (D 2) effect.
Parkinsonian conventional treatment compensated low-level endogenous Dopamine HCL thus based on the effect of dopaminergic agonist.Therefore, the l-DOPA used nearly 30 years.Yet this treatment is not to be free from side effects, and comprises dopaminergic effect itself (exhaustion of effect) and dyskinesia and disadvantageous periphery cardiovascular disorder.Compound with dopaminergic agonist component may have presynaptic effect and therefore produce needed increase Dopamine HCL is discharged disadvantageous effect autoreceptor.
Show that dopaminergic agonist or partial agonist may have the disadvantageous effect of neuronic survival.In fact, survival of dopaminergic neurons may increase relevant (Michel P.Agid Y.J. neurochemistry (Neurochem.), (1996), 67,1633) with the formation of second messenger's horizontal loops AMP.Yet, the D2 agonist will cause that ring AMP forms minimizing, as (the catecholamine in the basic neurochemistry: molecule, cell and medical science aspect (Catechlolamines in Basic Neurochemistry:Molecular, Cellular and Medical aspects) as described in Weiner and the Molinoff (1994); People such as 5th Ed.G.J.Siegal, Raven press, NY.pp.261-281).The compounds of this invention lacks the dopaminergic effect and has following feature, promptly has fabulous maincenter trafficability characteristic and has very long acting duration.Has selectivity α 2No matter the active compound of-adrenergic receptor antagonist is the dopaminergic neuron or the built-in function of cholinergic neuron if may activating other again by the release norepinephrine.Therefore, they can suppress pathological sex change and slow down or even suppress the progress of disease.
These compounds have selectively acting to central nervous system, and do not have the side effect of periphery cardiovascular systems.
The invention particularly relates to compound of Formula I:
Figure A9881076900141
Wherein:
R 1Represent hydrogen atom or straight chain, side chain or ring-type C 1-6Alkyl, hydroxyl or side chain, straight chain or ring-type C 1-6Alkoxyl group, halogen atom such as F or Cl.
R 2Represent hydrogen atom or C 1-6Alkyl.
R 3Represent hydrogen atom or constitute unit (C=X)-NR 4R 5Thereby, when X=oxygen or sulphur, constitute urea or thiocarbamide.
R 4And R 5Can be hydrogen atom or straight chain, side chain or ring-type C independently 1-8Alkyl, aryl, aralkyl or aroyl.These aryl also can be substituted.
R 4And R 5Can connect by comprising or do not contain heteroatomic carbochain.
R 4And R 5Also can represent the alkyl sulphonyl or the aryl sulfonyl that do not replace or replace.
R 3Can constitute amino-sulfonyl.
R 3Represent acyl group or sulfo-acyl group as (C=X)-R 6, wherein X represents oxygen or sulphur atom.
R 6Can represent hydrogen or comprise or do not contain heteroatoms such as oxygen or sulphur, comprise straight chain, side chain or ring-type C with carbonyl C=X conjugation or non-conjugated double bond 1-10Alkyl or alkenyl.
R 6Also can represent straight chain, side chain or ring-type C 1-8Alkoxyl group, the not aralkoxy that replaces or replace.
R 6Also can represent not and to replace or by C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl, halogen Cl, F, NO 2, CF 3, CN replaces aryl or heteroaryl or thiophene, furans, pyrroles, pyridine and the benzo derivative thereof of one or many.
R 6Represent aralkyl or aryloxy alkyl, wherein aryl moiety can be replace and wherein alkyl chain can be straight chain, straight chain or cyclic.
R 6Can comprise a plurality of fragrance or non-aromatic ring system, as 2-(2, the 3-indanyl) or fluorenyl, tonka bean camphor base, benzopyranyl.
R 6Also can represent arylalkenyl or sweet-smelling alkynyl.With two key conjugated aryl can be phenyl, naphthyl, many aromatic bases such as xenyl or fluorenyl, heteroaryl and benzo-fused derivative thereof.Described aryl can be unsubstituted or by C 1-8Alkyl, hydroxyl, C 1-8Alkoxyl group, halogen such as Cl or F, NO 2, CF 3, CN, OCF 3, OCH 2O replaces one or many or forms the second cycle line system with the saturated or unsaturated ring that comprises or do not contain heteroatoms such as O, N or S, forms indoles, cumarone or thionaphthene thus.Described thiazolinyl can be unsubstituted or be replaced by halogen, CN, alkyl, phenyl.Therefore, unit (C=X)-R 6Form cinnamoyl.
Especially, if R 3Base forms (C=X)-R 6Group and R 6Represent arylalkenyl, so (C=X)-R 6Be selected from aromatic ring and partly use one or more C 1-4Alkoxyl group, methylene radical dioxy base, C 1-6Cinnamoyl or sulfo-cinnamoyl that alkyl, OH, halogen such as F, Cl replace.
On behalf of phenyl or naphthyl nuclear, term aralkyl, term aryl be meant to be connected to and is contained a carbon atom at least and can be aryl on straight chain, side chain or the cyclic alkyl chain.
Heteroaryl can be to have one or more N of being selected from, O or the heteroatomic 5-of S or 6-unit's aromatic ring and benzo-fused derivative thereof.Therefore, they form pyridine, furans, thiophene, indoles, cumarone, thionaphthene, benzoxazine, quinoxaline, quinazoline, benzoglyoxaline, benzopyrazoles.
The present invention also relates to prepare the method for these compounds, it is characterized in that preparing wherein R 1As mentioned above and R 2=R 3The formula I compound of=H is so that form formula II intermediate.Insert original text 6 page II and formula IIIs
Figure A9881076900161
Benzo [a] quinolizine alkane-2-ketone for preparing formula III according to the method for Brossi (Helv.Chim.Acta 1958,41,119).This method can change according to the substituting group of 9-position among the formula I.
Therefore, begin to prepare intermediate II (R from the 3-F phenylethylamine 1=F).By the Pictet-Spengler reaction, obtain the 6-F tetrahydroisoquinoline by acid hydrolysis then.By handling, be translated into 3 with NaOH then, the 4-dihydro-isoquinoline with NBS.For intermediate II (R 1=Me), reported 3,4-two-H-6-Me-isoquinoline 99.9 (people such as D.Pitea, Gazz-Chim.Ital., (1984), 114).According to the method (J.O.C. (1997), 42,3114) that Oldenziel describes, in the presence of potassium tert.-butoxide, use of the 2-position cyaniding of tolylsulfonyl ylmethyl isonitrile with ketone.In this step, separate with calm nitrile axial.At NiCl 2Or the aluminum hydride existence down, and any nitrile is carried out reduction reaction with sodium borohydride, obtains amino methyl derivative (II).According to ordinary method, in the presence of alkali, carry out the reaction of acyl chlorides RCOCl and this amine.
By will be by formula I (R 2=CHO or COCH 3) the corresponding amide reduction (LAH) that obtains obtains wherein R 2=alkyl, R 3The formula I intermediate of=H.
At P 2S 5/ toluene exists down or uses Lawesson ' s reagent that resulting acid amides is vulcanized.The reaction of these amine and alkyl chloroformate obtains corresponding carbamate.
By isocyanic ester or different thiocyanide or urea chloride or thiocarbamyl chlorine or aliphatics, aromatic series acyl chlorides or cinnamyl chloride and amine II (R with alkyl, aralkyl or aroyl 2=H or alkyl, R 3=H) reaction obtains R 3Representative (C=X)-NR 4R 5Urea or thiourea compound.
Also can only separate (separating of diastereomer and enantiomer) with the synthetic final Compound I of the mixture of diastereomer in final step.
The present invention also relates to by will be in building-up process, the non-enantiomer mixture that obtains when chiral centre appears in the 2-position carries out the method that chromatographic separation or crystallization prepare the diastereisomericallypure pure compound.
Therefore, the enantiomer pure compound that claim 10 can be obtained carries out the separation of HPLC chiral column.
Then, resulting basic cpd can be handled with stoichiometric acid reagent.
Preferably, substituent R 1Be hydrogen or methoxyl group, oxyethyl group, methyl or fluorine, R 2=H, methyl, ethyl, R 3Be COCH 3, CO-phenyl, CS-phenyl, do not replace or with cinnamoyl and the furans acryl or the thiophene acryl of one or more methoxyl groups, F, Cl replacement.
Preferably, R 3Connect nitrogen with it and represent urea or thiourea group, this group be unsubstituted or by alkyl or aryl two-, three-or quaternary.
The present invention also relates to the salt that they and inorganic or organic acid form.The present invention relates to the various diastereomers between two asymmetric centers of 2-and 11b-position.
The present invention relates to their enantiomeric pure left-handed and dextrorotatory form and additive salt thereof, comprise hydrochloride, vitriol, mesylate, maleate, fumarate, oxalate, tartrate, succinate, Citrate trianion.
They comprise following compounds:
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] propionic acid amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the cyclohexyl methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] isobutyramide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenyl (α, α-cyclopropyl) ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenylacetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-9 ' H-fluorenyl-9 '-methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-the 3-hydrocinnamamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-(2, the 3-indane) methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-chlorophenoxy ethanamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 ', 4 ', 5 ', 6 '-penta fluoro benzene oxygen yl acetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenoxy-acetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the methoxyl group ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] thioacetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-1 '-methoxyl group-2 '-naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-pyridine carboxamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-thenoyl amine
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-furoylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-1 '-naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-trifluoromethyl benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-trifluoromethyl benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] thiobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the sulfo-cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-cyclohexyl acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(2 '-furyl) acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-benzofuran carboxamides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(1 '-naphthyl) acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(2 '-naphthyl) acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-9 ' H-fluorenyl-9 '-methylene radical methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-phenyl cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-tonka bean camphor methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-(2 '-thienyl)-3-acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-(3 '-thienyl)-3-acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-fluoro-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 ', 4 ', 5 ', 6 '-five fluorine cinnamides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2,3-phenylbenzene propylene acid amides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-cyano group-3-Phenyl Acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-methyl-3-Phenyl Acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-fluoro-3-Phenyl Acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-nitrobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-trifluoromethyl cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-cinnamoyl chloride amine
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 ', 5 '--the trifluoromethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-fluorine cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-chloro-6 '-fluorine cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 4 ', 5 '-trimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 '-dimethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-mecinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 '-dimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 5 '-dimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 4 '-dimethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-methoxyl group cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-fluorine cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 '-methylene radical dioxy base cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(2-methoxy ethyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-uncle's octyl group thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-tertiary butyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-cyclohexyl methyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-butyl thiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-2-styroyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl thiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-methylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-isobutyl-thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-cyclohexyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzoylthioureas
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(2 '-naphthyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(1 '-naphthyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylurea (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-methyl urea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl urea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl]-N '-methylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-methyl benzamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-the ethyl cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-mecinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-methyl-N '-phenylurea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-methyl, N '-methylthiourea
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzoylureas
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the benzylamino manthanoate
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl methyl uride
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-sulfonyloxy methyl amine
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-phenyl-sulfamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl aminocarbonyl methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-H-chromene-3 '-methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3, the 3-DMAA
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-phenyl propine acid amides
(SS), (RR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-4 '-nitro cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] mecinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-methyl-N ', N '-dimethyl thiourea.
By with α 2-adrenergic receptor is in conjunction with testing the α that measures these compounds 2-adrenergic antagonistic activity, wherein with tritium for 2-methoxyl group-Idazoxan, [ 3H] RX821002 is as the radioligand of these acceptors people such as (, Britain's pharmacology magazine (Br.J.Pharmacol.) (1991), 102,221) N.J.Mallard.
By way of example, these specificity bonded numerical value are shown in the following table:
The embodiment sequence number of compound With α 2[ 3H] RX821002 bonded IC 50(nM)
????90 ????88 ????78 ????39 ????1 ????68 ????18 ????69 ????1 ????7 ????3 ????12 ????9 ????1.3 ????6 ????8.5
Therefore show that compound of Formula I of the present invention has strong α 2-adrenergic receptor affinity.
According to S.C.Dilsaver, in Pharmacol.Biochem.Behav. (1993), the method described in 45,247 is studied in vivo to guanabenz (α 2Agonist) reverse of institute's induced low temperature.This test can detect The compounds of this invention to α 2The antagonistic action of-adrenergic receptor and in the activity of central nervous system.Inhibition ability ED 50Expression, its expression produces obvious inhibiting dosage to guanabenz inductive low temperature.These numerical value are that the method (J.Pharmacol.Exp.Ther. (1949), 96,99) of utilizing J.T.Litchfield and F.Wilcoxon obtains, and have only and just calculate this value when 60% above experimental animal is produced restraining effect.
What following table showed is the numerical value that product of the present invention obtains by the intraperitoneal approach:
The embodiment sequence number of compound The cryogenic ED of guanabenz inductive 50????MG/KG(I.P.)
????39 ????88 ????78 ????1 ????70 ????55 ????18 ????31 ????0.47 ????0.34 ????0.91 ????0.56 ????0.63 ????0.53 ????0.98 ????0.71
Therefore, to go out be α to formula I compound exhibits of the present invention 2Therefore-adrenergic receptor antagonist also causes the release norepinephrine.They can be used in people's the treatment and to treatment neurodegenerative disease and progress thereof as benumb on Parkinson's disease, presenile dementia, huntington's chorea, the carrying out property nuclear, cognitive illnesses, attention and the memory disorder relevant with the age, brain injury that cerebral ischemia causes be meaningful.
The present invention also relates to pharmaceutical composition, it comprises a kind of formula I compound and a kind of suitable vehicle at least.The compounds of this invention can adopt suitable method, by oral, injection or parenteral route, with soft capsule, hard capsule, tablet or injection form and every day 0.1-200mg dosage give.
The following example is used to the present invention is described and does not limit its scope.Embodiment 1:(RS), (SR)-9-methoxyl group-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-methylamine
Synthesize this compound by following 6 steps: step 1N-formyl radical-2-[3 '-p-methoxy-phenyl] ethamine
Under 80 ℃, with 31.2g 3-anisole ethamine (0.206mol), 35.2g ethyl formate (38.3ml; 0.475mol; 2.3 equivalent) heating of the solution in 125ml toluene is 7 hours.After solvent evaporation fallen, separate obtaining the 37g orange, this oily matter is used for subsequently synthetic (quantitative yield).Rf (methylene chloride 9/1)=0.63 1H NMR (400MHz, CDCl 3): 8.06ppm (wide s; 1H; NH); 8.00ppm (s; 1H; CHO); 7.20ppm (m; 1H; H5 '); 6.77ppm (m; 3H; H2 ', H4 ', H6 '); 3.74ppm (s; 3H; OCH 3); 3.35ppm (m; 2H; CH 2N); 2.70ppm (m; 2H; Ar-CH 2). step 26-methoxyl group-3,4-dihydro-isoquinoline hydrochloride
Keeping on the ice bath under 0 ℃, with 2 hours time, with 37g N-formyl radical-2-[3 '-p-methoxy-phenyl] drips of solution of ethamine (0.206mol) in the 20ml methylene dichloride be added to 48.12gPCl 5(0.23mol; 1.12 equivalent) in the solution in the 160ml methylene dichloride.This reactant was kept under 0 ℃ 2 hours again, then solvent evaporation is fallen.The crude product residue is dissolved in the sherwood oil, handles with icy water carefully then.
Behind extraction and the decantation, water is alkalized with sodium hydroxide, use dichloromethane extraction then.With the organic phase dried over mgso, be evaporated to dried then.
(32.9g) is dissolved in the ether with crude product oily matter.The solution that adds 72.4ml 3.3N (0.22mol) HCl/iPrOH.Resulting crystallization is filtered and wash with ether.In 55 ℃ of moisture eliminators, after the drying, obtain 35.3g yellow crystal (productive rate=87%).Rf (methylene chloride 95/5): 0.16 1H NMR (400MHz, CDCl 3): 13.76ppm (wide s; 1H; NH); 9.08ppm (s; 1H; H1); 7.91ppm (d, J=8.5Hz; 1H; H8); 7.10ppm (m, 2H; H5, H7); 3.92ppm (s; 3H; OCH 3); 3.86ppm (m; 2H; H3); 3.12ppm (m; 2H; H4). step 39-methoxyl group-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-ketone
Under 60 ℃, with 35.3g 6-methoxyl group-3,4-dihydro-isoquinoline hydrochloride (0.178mol) and 44.6ml methyl vinyl ketone (37.5g; 0.535mol; 3 equivalents) mixture heating up 3 hours 30 minutes.The reaction medium that forms dough is dissolved in the acetone, filters then.
With resulting hertz-pink colour crystallization dry (m=37.18g in 55 ℃ of moisture eliminators; Productive rate=78%).
Obtain free alkali by dichloromethane solution with the described salt of 1N sodium-hydroxide treatment.Rf (methylene chloride 95/5): 0.40 1H NMR (400MHz; CDCl 3) (alkali): 6.98ppm (d; J=8.6Hz; 1H; H11); 6.74ppm (dd; J=8.6Hz and 2.4Hz; 1H; H10); 6.66ppm (d; J=2.4Hz; 1H; H8); 3.78ppm (s; 3H; OCH 3); 3.49ppm (m; 1H; H11b); 3.25ppm (m; 1H; H4eq); 3.20-3.08ppm (m; 2H; H6eq, H7ax); 2.91ppm (m; 1H; H1eq); 2.56-2.82ppm (m; 4H; H3ax, H4ax, 6ax, H7eq); 2.48-2.39ppm (m; 2H; H1ax, H3eq). step 4 (RS), (SR)-9-methoxyl group-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-formonitrile HCN
With 30.18g ketone alkali (0.13mol); 25.5g tolylsulfonyl ylmethyl isonitrile (0.13mol; 1 equivalent); 7.6ml ethanol (6.01g; 0.13mol; 1 equivalent) solution in 600ml DEM is cooled to 0 ℃ on ice bath.
Add 29.3g tBuOK (0.26mol; 2 equivalents), reaction mixture was kept 1 hour 30 minutes down at 0 ℃, at room temperature kept 1 hour.Then this solution was heated 2 hours down at 90 ℃, at room temperature place then and spend the night.
Solid residue is removed and solution evaporation is extremely done by filtering.By chromatography on silicagel column (eluent: sherwood oil/AcOEt 5/5) resulting brown oil is separated.
Separate and obtain 13g diastereomer A (calm CN): productive rate=41%, 2.8g the mixing portion of two kinds of diastereomers: productive rate=9%, 6.16g diastereomer B (axially CNl): productive rate=19.5%, promptly the overall yield of cyaniding derivative is 69.5%.Diastereomer A ((RS), (SR)) Rf (ethyl acetate/methanol 95/5): 0.71 1H NMR (200MHz; CDCl 3): 7ppm (d; J=8.5Hz; 1H; H11); 6.70ppm (dd; J=8.5 and 2.4Hz; 1H; H10); 6.60ppm (d; J=2.4Hz; 1H; H8); 3.75ppm (s; 3H; OCH 3); 3.18-2.86ppm (m; 4H; 4a, 6a, 7a, 11b); 2.73-2.22ppm (m; 4H; H1a, H2, H7b, H6b); 2.11-1.88ppm (m; 2H; H3a, H3b); 2.65ppm (m; 1H; H1b). 13C NMR (50.32MHz; CDCl 3): 125.7ppm (C11); 113.5ppm (C8); 112.2ppm (C10); 61.5ppm (C11b); 55.2ppm (OCH 3And C4); 54.8ppm (C6); 34.4ppm (C1); 29.6ppm (C7); 28.7ppm (C3); 27.4ppm (C2). diastereomer B ((RR), (SS)) Rf (ethyl acetate/methanol 95/5): 0.49 1H NMR (200MHz; CDCl 3): 7.07ppm (d; J=8.5Hz; 1H; H11); 6.74ppm (dd; J=8.5Hz and 2.4Hz; 1H; H10); 6.64ppm (d; J=2.4Hz; 1H; H8); 3.77ppm (s; 3H; OCH 3); 3.54ppm (d; J=11.5Hz; 1H; H11b); 3.28-2.91ppm (m; 4H; H2, H4a, H6a, H7a); 2.80-2.45ppm (m; 4; H1a, H4b, H6b, H7b); 2.00ppm (m; 2H; H3a, H3b); 1.70ppm (m; 1H; H1b). 13C NMR (50.32MHz; CDCl 3): 125.7ppm (C11); 113.5ppm (C8); 112.2ppm (C10); 58.8ppm (C11b); 55.2ppm (OCH3); (52.2ppm C4 and C6); 33.4ppm (C1); 29.7ppm (C7); 27.6ppm (C3); 26.3ppm (C2) step 5 (RS), (SR)-9-methoxyl group-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-methylamine
The solution of nitrile diastereomer A (37mmol) in 300ml methyl alcohol that the 9g previous step is obtained is cooled to 0 ℃.Add 44.14g NiCl 26H 2O (186mmol; 5 equivalents), this mixture is continued down to stir 15 minutes at 0 ℃, slowly add 11.24g NaBH then 4(300mmol; 8 equivalents).Add NaBH 4Speed should make the temperature of reaction mixture keep below 5 ℃.
Stirred 2 hours 30 minutes to the temperature of room temperature at 0 ℃.Then this mixture is evaporated to driedly, and the residue of black is dissolved in 1N methylene dichloride/sodium hydroxide.Two-phase is filtered on diatomite.After a large amount of flushings of methylene dichloride, by decantation organic phase is separated, use dried over mgso then.
Obtain 9g yellow oil (productive rate=87%) after the evaporation. 1H NMR (400MHz; CDCl 3): 7.20ppm (d; J=8.4Hz; 1H; H11); 6.71ppm (d, J=8.4Hz; 1H; H10); 6.62ppm (s; 1H; H8); 3.77ppm (s; 3H; OCH 3); 3.20-2.92ppm (m; 4H; H4a, H6a, H7a, H11b); 2.72-2.62ppm (m; 3H; H7b; CH 2NH 2); 2.51ppm (m; 1H; H1a); 2.42-2.30ppm (m; 2H; H4b, H6b); 1.80ppm (m; 1H; H3a); 1.59ppm (m; 1H; H2); 1.33ppm (m; 1H; H3b); 1.08ppm (m; 1H; H1b). step 6 (RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizine) methyl] benzamide
With 113 μ l Benzoyl chloride (137mg; 0.97mmol; 1.2 equivalent) be added to amine diastereomer A (0.81mmol) and the 166 μ l pyridine (162mg that the 200mg previous step obtains; 2.05mmol; 2.5 equivalent) in the solution in 5ml THF.After at room temperature reacting 24 hours, solvent evaporation is fallen.Residue is dissolved in the methylene dichloride, then with the washing of 1N sodium hydroxide.With the organic phase dried over mgso, filter, be evaporated to dried then.By (eluent: methylene chloride/ammonium hydroxide 95/5/1) behind the purifying, separation obtaining the 150mg pure compound at chromatography on the silicagel column.Productive rate=53%.Rf (methylene chloride/ammonium hydroxide 90/10/2): 0.53m.p. (oxalate): 112 ℃ 1H NMR (200MHz; DMSO d6) (oxalate): 8.61ppm (t; 1H; NH): 7.87ppm (m; 2H; H2 '; H6 '); 7.42-7.58ppm (m; 3H; H3 ', H4 ', H5 '); 7.25ppm (d; J=8.6Hz; 1H; H11); 6.75-6.89ppm (m; 2H; H8, H10); 4.13ppm (d; J=10Hz; 1H; H11b); 3.75ppm (s; 3H; OCH 3); 3.58-2.87ppm (m; 8H; H1a; H3a, H4a, H4b, H6a, H6b, H7a, H7b); 2.55ppm (m; 1H; H2); 1.88ppm (m; 1H; H3b); 1.45ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (65.44), H (6.41), N (6.36);
Experimental value: C (64.89), H (6.21), N (6.18).
In the method that is similar to embodiment 1, use reagent corresponding to obtain formula 1 compound and be listed in the table below in 1 by the embodiment order:
Table 1
Figure A9881076900321
Figure A9881076900361
Figure A9881076900371
Embodiment 46:(SS), (RR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide
Synthesize this compound by following 2 steps: step 1:(SS), (RR)-9-methoxyl group-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl-2-methylamine
With 220 μ l sulfuric acid (405mg; 4.13mmol; 1 equivalent) is added drop-wise to 8.25ml 1MLiAlH 4/ Et 2O solution (8.25mmol; 2 equivalents) and in the mixture of 10ml THF.Form white precipitate and emit gas.This reaction mixture was at room temperature stirred 1/2 hour, on ice bath, be cooled to 0 ℃ then.Drip the solution of axial cyano group diastereomer B (4.13mmol) in 2ml THF that obtains in 1g embodiment 1 step 4 then.After adding, continue at room temperature to react 1 hour.With reaction mixture sodium sulfate/water hydrolysis.By filtering precipitation is removed, then filtrate is evaporated to dried.Separate and obtain 925mg yellow oil (productive rate=91%).Step 2 (SS), (RR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide
With 689mg cinnamyl chloride (4.14mmol; 1.1 equivalent) be added to amine (3.76mmol) and the 577 μ l methylamine (419mg that the 925mg previous step obtains; 4.14mmol; 1.1 equivalent) in the solution in the 10ml methylene dichloride.This reaction is thermopositive reaction.After 1/4 hour, with this reaction mixture 1N sodium-hydroxide treatment.With the organic phase dried over sodium sulfate, filter, be evaporated to dried then.At (the eluent: methylene chloride/ammonium hydroxide 98/1.7/0.3), separate obtaining the 865mg pure compound of chromatography on the silicagel column.Rf (methylene chloride/ammonium hydroxide 95/5/0.5): 0.31m.p. (hydrochloride): 161 ℃ 1H NMR (400MHz; CDCl 3) (alkali): 7.65ppm (d; J=15.6Hz; 1H; CH=CH-Ar); 7.52ppm; (m; 2H; H2 ' and H6 '); 7.38ppm (m; 3H; H3 ', H4 ' and H5 '); 7.06ppm (d, J=8.6Hz; 1H; H11); 6.71ppm (dd; J=8.6 and 2.6Hz; 1H; H10); 6.61ppm (d; J=2.6Hz; 1H; H8); 6.42ppm (d; D=15.6Hz; 1H; CH=CH-Ar); 5.30ppm (m; 1H; NH); 3.77ppm (s; 3H; OCH 3); 3.62-3.50ppm (m; 3H; H11b and CH 2N); 3.14ppm (m; 1H; 7Ha); 3.00ppm (m; 1H; H6a); 2.92-2.57ppm (m; 4H; H4a, H4b, H6b, H7a); 2.12ppm (m; 1H; H1a); 2.05ppm (m; 1H; H2); 1.93ppm (m; 1H; H3a); 1.83ppm (m; 1H; H3b); 1.61ppm (H1b). ultimate analysis:
Theoretical value: C (69.80), H (7.08), N (6.78);
Experimental value: C (69.75), H (7.04), N (6.76).Embodiment 47:(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] ethanamide
With 139 μ l diacetyl oxide (151mg; 1.48mmol; 1.2 equivalent) be added to amine (1.21mmol) and the 0.25ml pyridine (3mmol that 300mg embodiment 1 step 5 obtains; 2.5 equivalent) in the solution in 8mlTHF.After at room temperature stirring 3 hours, solvent evaporation is fallen and residue is dissolved in methylene dichloride/1N sodium hydroxide.Behind the decantation,, filter, be evaporated to dried then the organic phase dried over mgso.Crude product is passed through chromatography (eluent: purifying methylene chloride/ammonium hydroxide 90/9/1) on silica gel.Separate and obtain 230mg yellow oil (productive rate=65%).Rf (methylene chloride/ammonium hydroxide 90/10/2): 0.50m.p. (oxalate): 98 ℃ 1H NMR (200MHz; DMSO d6) (alkali): 7.96ppm (wide t; 1H; NH): 7.23ppm (d; J=8.7Hz; 1H; H11); 6.82ppm (dd; J=8.7Hz and 2.5Hz; 1H; H10); 6.77ppm (d; J=2.5Hz; 1H; H8); 4.10ppm (d; J=12Hz; 1H; H11b); 3.74ppm (s; 3H; OCH 3); 3.52-3.33ppm (m; 2H) and 3.18-2.88ppm (m; 6H) (H1a, H3a, H4a, H4b, H6a, H6b, H7a, H7b); 2.40ppm (m; 1H; H2); 1.78ppm (m; 1H; H3b); 1.32ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (60.31), H (6.92), N (7.40);
Experimental value: C (60.19), H (6.62), N (7.09).
In embodiment 1 similar method, use reagent corresponding to obtain formula 1 compound and be listed in the table below in 2 by the embodiment order:
Table 2
Figure A9881076900411
Figure A9881076900421
Embodiment 64:(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenyl-sulfamide
With 0.19ml benzene sulfonyl chloride (263mg; 1.49mmol; 1.2 equivalent) be added to amine (1.21mmol) and the 0.25ml pyridine (3mmol that 300mg embodiment 1 step 5 obtains; 2.5 equivalent) in the solution in 10ml THF.
Reaction mixture was at room temperature kept 10 days.After adding the 0.19ml benzene sulfonyl chloride again and reacting 10 days again, solution evaporation is extremely done.Residue is passed through chromatography (eluent: methylene chloride 95/5) purifying on silicagel column.Separate obtaining 166mg oily matter, when placing, this oily matter crystallization (productive rate=35%).Rf (methylene chloride 95/5): 0.26m.p. (oxalate): the 130-135 ℃ of data of inserting 32 pages of embodiment 64 of original text 1H NMR (200MHz; CDCl 3) (alkali): 7.87ppm (dd; J=6.2Hz and 1.7Hz; 2H; H2 ' and H6 '); 7.60-7.46ppm (m; 3H; H3 ', H4 ', H5 '); 7.01ppm (d; J=8.6Hz; 1H; H11); 6.68ppm (dd; J=8.6Hz and 2.5Hz; 1H; H10); 6.60ppm (d; J=2.5Hz; 1H; H8); 4.81ppm (wide t; 1H; NH); 3.77ppm (s; 3H; OCH 3); 3.22-2.86ppm (m; 6H; CH 2N; H4a, H6a, H7a, H11b); 2.65ppm (m; 1H; H7b); 2.48ppm (m; 1H; H6b); 2.36-2.18ppm (m; 2H; H4b and H1a); 1.88ppm (m; 1H; H2); 1.70ppm (m; 1H; H3a); 1.30ppm (m; 1H; H3b); 1.00ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (57.97), H (5.92), N (5.88);
Experimental value: C (57.47), H (5.92), N (5.81).Embodiment 65 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] sulfonyloxy methyl amine
Press and embodiment 64 similar methods, use methylsulfonyl chloride to obtain title compound:
M.p. (oxalate): 156 ℃ of ultimate analyses:
Theoretical value: C (52.16), H (6.32), N (6.76);
Experimental value: C (52.73), H (6.25), N (6.85).Embodiment 66 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl methyl uride
Press and embodiment 64 similar methods, use N, N-dimethyl methyl acyl chlorides obtains title compound:
M.p. (oxalate): 110 ℃ of ultimate analyses:
Theoretical value: C (51.45), H (6.59), N (9.47);
Experimental value: C (51.27), H (6.61), N (9.24).Embodiment 67 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] benzyl carbamate
0.18ml is diluted in chloroformic acid benzyl ester (215mg among the 1ml DME; 1.26mmol; 1.05 equivalent) be added drop-wise to amine (1.22mmol) that 300mg embodiment 1 step 5 obtains in 5ml contains solution in the water of a small amount of DME.100 ℃ of down reactions after 4 days, reaction mixture is evaporated to dried, be dissolved in the methylene dichloride, then with the washing of 1N sodium hydroxide.By behind chromatogram chromatography purification on the silicagel column, separate obtaining 118mg title compound carbamate (productive rate=36%).Rf (methylene chloride/ammonium hydroxide 90/9/1): 0.54m.p. (oxalate): 104 ℃ 1H NMR (CDCl 3400MHz) (alkali): 7.28ppm (m; 5H; Ph): 7.03ppm (d; J=8.6Hz; 1H; H11); 6.66ppm (dd; J=8.6Hz and 2.4Hz; 1H; H10); 6.53ppm (d; J=2.4Hz; 1H; H8); 5.03ppm (s; 2H; Ph CH 2O); 3.71ppm (s; 3H; OCH 3); 3.14-2.88ppm (m; 6H; CH 2N, H11b, H7a, H6a, H4a); 2.62ppm (m; 1H; H1a); 2.45ppm (m; 1H; H7b); 2.26ppm (m; 2H; H4b and H6b); 1.71ppm (m; 2H; H2 and H3a); 1.35ppm (m; 1H; H3b); 1.08ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (63.82), H (6.43), N (5.95);
Experimental value: C (63.82), H (6.83), N (5.92).Embodiment 68 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] thiobenzamide
With 322mg (0.80mmol) [2,4-two-(4-methoxyl group-phenyl)-1,3-dithia-2,4-two phospha fourth rings-2,4-dithio] (Lawesson ' s reagent) be added to the N-[2-(1,3 that obtains among 305mg (0.79mmol) embodiment 1,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] in the solution of benzamide in 100ml toluene.With this medium reflux and continuously stirring 2 days.With filtration residue on solvent evaporation and the alumina, use the methylene dichloride wash-out.The filtrate evaporation is obtained 250mg (85%) yellow oil, it is obtained the faint yellow oxalate crystal deposition of 239mg (77%) with oxalic acid treatment.Rf (methylene chloride 90/9/1): 0.58m.p. (oxalate): 165 ℃ 1H NMR (200MHz; CDCl 3) (alkali): 7.81ppm (wide s; 1H; NH); 7.76ppm (dd; J=7.6Hz and 1.3Hz; 2H; H2 ' and H6 '); 7.42ppm (m; 3H; H3 ', H4 ', H5 '); 7.10ppm (d; J=8.6Hz; 1H; H11); 6.72ppm (dd; J=8.6Hz and 2.7Hz; 1H; H10); 6.61ppm (d; J=2.7Hz; 1H; H8); 3.82ppm (m; 2H; CH 2N); 3.77 (s; 3H; OCH 3); 3.28-2.97ppm (m; 4H; H4a, H6a, H7a, H11b); 2.77-2.38ppm (m; 4H; H1a, H4b, H6b, H7b); 2.25 ppm (m; 1H; H3a); 1.88ppm (m; 1H; H2); 1.68ppm (m; 1H; H3b); 1.33ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (63.14), H (6.18), N (6.13);
Experimental value: C (63.38), H (6.16), N (6.07).Embodiment 69 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the thioacetyl acid amides
Press and embodiment 68 similar methods, use reagent corresponding to obtain title compound:
M.p. (oxalate): 113 ℃ of ultimate analyses:
Theoretical value: C (57.85), H (6.64), N (7.10);
Experimental value: C (58.01), H (6.36), N (6.75).Embodiment 70 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the sulfo-cinnamide
Press and embodiment 68 similar methods, use reagent corresponding to obtain title compound:
M.p. (oxalate): 128 ℃ of ultimate analyses:
Theoretical value: C (64.71), H (6.27), N (5.80);
Experimental value: C (64.94), H (6.29), N (5.62).Embodiment 71 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylurea
With 90 μ l phenylcarbimide (98mg; 0.82mmol; 1 equivalent) drips of solution in the 5ml methylene dichloride is added in the solution of amine (0.82mmol) in the 5ml methylene dichloride that 200mg embodiment 1 step 5 obtains.After at room temperature reacting 16 hours, solvent evaporation is fallen, the oiliness residue is passed through chromatography (eluent: methylene chloride 95/5) purifying on silicagel column.Separate obtaining the 160mg yellow oil, when placing, this oily matter crystallization (productive rate=54%).Rf (methylene chloride 90/10): 0.35m.p. (hydrochloride): 185 ℃ 1H NMR (200MHz; DMSO d6) (hydrochloride): 7.45-7.10ppm (m; 5H; H2 ', H3 ', H5 ', H6 ', H11); 6.81-6.95ppm (m; 3H; H4 ', H8, H10); 4.42ppm (d; J=11.3Hz; 1H; H11b); 3.74ppm (s; 3H; OCH 3); 3.62-2.92ppm (m; 6H; CH 2N, H4a, H6a, H6b, H7a, H7b); 2.92ppm (m; 1H; H2): 1.95ppm (m; 2H) and 1.70-1.30ppm (m; 2H) (H1a, H1b, H3a, H3b). ultimate analysis:
Theoretical value: C (65.74), H (7.02), N (10.45);
Experimental value: C (65.32), H (6.97), N (10.19).Embodiment 72 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-methyl urea
Press and embodiment 71 similar methods, use reagent corresponding to obtain title compound:
M.p. (hydrochloride): 160 ℃ of ultimate analyses:
Theoretical value: C (60.08), H (7.71), N (12.36);
Experimental value: C (60.24), H (8.00), N (11.86).Embodiment 73 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzoylureas
Press and embodiment 71 similar methods, use reagent corresponding to obtain title compound:
M.p. (oxalate): 210 ℃ of ultimate analyses:
Theoretical value: C (62.10), H (6.04), N (8.69);
Experimental value: C (62.00), H (5.87), N (8.37).Embodiment 74 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl urea
With 0.24ml dimethylcarbamyl chloride (280mg; 2.6mmol; 1.2 equivalent) drips of solution in 2mlTHF is added to amine (2.15mmol) and the 0.44ml pyridine (425mg that 530mg embodiment 1 step 5 obtains; 5.4mmol; 2.5 equivalent) in the solution in 30ml THF.After adding a spear amount DMAP, at room temperature reacted 2 days, heated 5 days down at 80 ℃ then.
Reaction mixture is dissolved in 1N sodium hydroxide/methylene dichloride.With the organic phase dried over mgso, filter, be evaporated to dried then.Crude product oily matter is passed through chromatogram chromatography purification on silicagel column.Separate and obtain the 390mg product.Rf (methylene chloride 95/5)=0.17m.p. (oxalate): 122 ℃ 1H NMR (400MHz; CDCl 3) (alkali): 7.11ppm (d; J=8.7Hz; 1H; H11); 6.72ppm (dd; J=8.7 and 2.6Hz; 1H; H10); 6.61ppm (d; J=2.6Hz; 1H; H8); 4.55ppm (t; J=5.2Hz; 1H; NH); 3.77ppm (s; 3H; OCH 3); 3.28-3.08ppm (m; 4H; H11b, H7a and CH 2N); 3.03ppm (m; 1H; H4a); 2.96ppm (m; 1H; H6a); 2.91ppm (s; 6H; N (CH 3) 2); 2.68ppm (m; 1H; H1a); 2.50ppm (m; 1H; H7b); 2.38-2.29ppm (m; 2H; H6b and H4b); 1.83ppm (m; 1H; H2); 1.78ppm (m; 1H; H3a); 1.41ppm (m; 1H; H3b); 1.12ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (58.95), H (7.17), N (10.31);
Experimental value: C (59.26), H (6.96), N (9.83).Embodiment 75 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylthiourea
With 230 μ l (260mg; 1.92mmol; 1.2 equivalent) thiocarbanil is added drop-wise in the solution of 400mg amine (1.6mmol) in the 20ml methylene dichloride.At room temperature reacted 4 hours.With the reaction mixture sodium-hydroxide treatment.Organic phase is washed with saturated sodium-chloride, use dried over mgso, filter, be evaporated to dried then.The oiliness residue is passed through chromatography (eluent: methylene chloride/ammonium hydroxide 98/1.7/0.3) purifying on silicagel column.Productive rate=53%.Rf (methylene chloride/ammonium hydroxide 90/9/1): 0.38m.p. (oxalate): 146 ℃ 1H NMR (400MHz; CDCl 3) (alkali): 7.63ppm (wide s; 1H; NH); 7.49ppm (m; 2H; H3 ' and H5 '); 7.35ppm (t; J=7.4Hz; 1H; H4 '); 7.23ppm (d; J=7.8Hz; 2H; H2 ', H6 '); 7.05ppm (d; J=8.6Hz; 1H; H11); 6.72ppm (dd; J=8.6 and 2.6Hz; 1H; H10); 6.61ppm (d; J=2.6Hz; 1H; H8): 6.18ppm (wide s; 1H; NH); 3.77ppm (s; 3H; OCH 3); 3.64ppm (m; 1H; HA (CH 2N)); 3.53ppm (m; 1H; H B(CH 2N)); 3.22-3.10ppm (m; 2H; H11b, H7a); 3.07-2.95ppm (m; 2H; H7a and H4a); 2.68ppm (m; 1H; H7b); 2.54ppm (m; 1H; H6b); 2.36ppm (m; 1H) and 2.27ppm (m; 1H) (H1a and H4b); 2.05ppm (m; 1H; H2); 1.7ppm (m; 1H; H3a); 1.42ppm (m; 1H; H3b); 1.12ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (61.13), H (6.20), N (8.91);
Experimental value: C (61.31), H (6.14), N (8.68).
Press and embodiment 75 similar methods, use reagent corresponding, obtain formula 1 compound of embodiment in the following table 3:
Table 3
Figure A9881076900501
Figure A9881076900511
Embodiment 88:(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl thiourea
238mg is dissolved in dimethyl sulphide among the 5ml THF for urea chloride (2.11mmol; 1.2 equivalent) be added to the amine (392mg that embodiment 1 step 5 obtains; 1.6mmol), in 0.32ml pyridine (2.5 equivalent) and the solution of 233mg 4-dimethylaminopyridine (1.2 equivalent) in 50ml THF.After the reflux 48 hours, reaction mixture is evaporated to dried, is dissolved in the methylene dichloride, use the 1N dissolution of sodium hydroxide then.With the organic phase dried over mgso, filter, be evaporated to dried then.Resulting brown oil is passed through chromatogram chromatography purification on silicagel column.Separate and obtain 81mg product title thiocarbamide (productive rate=23%).Rf (methylene chloride/ammonium hydroxide 90/9/1): 0.48m.p. (oxalate): 105 ℃ 1H NMR (200MHz; CDCl 3): 7.08ppm (d; J=8.6Hz; 1H; H11); 6.69ppm (dd; J=8.6 and 2.4Hz; 1H; H10); 6.58ppm (d; J=2.4Hz; 1H; H8); 5.55ppm (wide m; 1H; NH); 3.75ppm (s; 3H; OCH 3); 3.6ppm (m; 2H; CH 2H); 3.27ppm (5,6H; NMe 2); 3.14-2.89ppm (m; 4H; H4a; H6a; H7a; H11b); 2.66ppm (m; 1H; H7b); 2.48ppm (m; 1H; H6b); 2.33ppm (m; 2H; H1a; H4b); 2.04ppm (m; 1H; H2); 1.78ppm (m; 1H; H3a); 1.46ppm (m; 1H; H3b); 1.12ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (56.72), H (6.90), N (9.92);
Experimental value: C (56.93), H (6.39), N (9.52).Embodiment 89 steps 1 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methane amide
On ice bath, with 193mg (2.27mmol; 1 equivalent) 0-formyl radical hydroxyacetonitrile (according to J.Prakt Chem, 1996,338, the method preparation described in the 488-90) is added in the solution of amine (2.27mmol) in the 10ml methylene dichloride that 560mg embodiment 1 step 5 obtains.
This reaction mixture was at room temperature kept 20 hours.Then reaction mixture is washed with 1N sodium hydroxide, use dried over mgso, filter and be evaporated to dried.Resulting crude product solid is passed through chromatography (eluent: methylene chloride 92/8) purifying on silicagel column.Separate and obtain 422mg methane amide (productive rate=68%).Rf (methylene chloride 9/1): 0.38 1H NMR (400MHz; CDCl 3): 8.22ppm (s; 1H; CHO); 7.10ppm (d; J=8.6Hz; 1H; H11); 6.71ppm (dd; J=8.6Hz and 2.5Hz; 1H; H10); 6.62ppm (d; J=2.5Hz; 1H; H8); 5.69ppm (wide s; 1H; NH); 3.78ppm (s; 3H; OCH 3); B.27ppm (m; 2H; CH 2N); 3.15ppm (m; 1H; H7a); 3.10ppm (m; 1H; H11b); 3.05ppm (m; 1H; H4a); 2.98ppm (m; 1H; H6a); 2.70ppm (m; 1H; H7a); 2.52ppm (m; 1H; H6b); 2.48-2.30ppm (m; 2H; H1a, H4b); 1.85ppm (m; 1H; H2); 1.77ppm (m; 1H; H3a); 1.44ppm (m; 1H; H3b); 1.17ppm (m; 1H; H1b). step 2 (RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methylamine
Under 0 ℃, the lithium aluminium hydride (16mmol that 640mg was ground; 2 equivalents) gradation is added in the solution of methane amide (8.02mmol) in 50ml THF that the 2.2g previous step obtains.After heating 48 hours under 45-50 ℃, with reaction mixture sodium sulfate/water hydrolysis.Filter out formed solid by crossing.Filtrate is evaporated to dried, then by on silica gel chromatography (eluent: purifying methylene chloride/ammonium hydroxide 90/9/1).Rf (methylene chloride/ammonium hydroxide 80/18/2): 0.56 1H NMR (400MHz; CDCl 3) alkali: 7.14ppm (d; J=8.7Hz; 1H; H11); 6.70ppm (dd; J=8.7 and 2.6Hz; 1H; H10); 6.61ppm (d; J=2.6Hz; 1H; H8); 3.77ppm (s; 3H; OCH 3); 3.15ppm (m; 1H; H7a); 3.08ppm (d; J=11.2Hz; 1H; H11b); 3.02ppm (m; 1H; H4a); 2.96ppm (m; 1H; H6a); 2.68ppm (m; 1H; H7a); 2.56-2.48ppm (m; 3H; CH 2N and H6b); 2.46ppm (s; 3H; NMe); 2.42-2.30ppm (m; 2H; H1a and H4b); 1.81-1.70ppm (m; 2H; H2 and H3a); 1.39ppm (m; 1H; H3b); 1.11ppm (m; 1H; H1b). 13C NMR (100.63MHz; CDCl 3): 157.7ppm (C9); 135.8ppm and 130.6ppm (C7a and C11a); 125.8ppm (C11); 113.3ppm and 111.8ppm (C8 and C10); 62.4ppm (OCH 3); 58.5ppm (CH 2N); 56.3ppm (C4); 55.1ppm (C11b); 52.4ppm (C6); 36.83ppm and 36.80ppm (NCH 3And C2); 36.2ppm (C1); 30.2ppm and 29.9ppm (C3 and C7). embodiment 90 (RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-N '-methylthiourea
With 345mg (4.7mmol; 1.2 equivalent) Trapex is added in the solution of amine (3.8mmol) in the 20ml methylene dichloride that 1g embodiment 89 obtains.After at room temperature reacting 17 hours, reaction mixture with the washing of 1N sodium hydroxide, is used dried over mgso, be evaporated to dried then.Resulting crude product oily matter is passed through chromatography (eluent: methylene chloride/ammonium hydroxide 95/4.5/0.5) purifying on silicagel column.Separate obtaining the product thiocarbamide, productive rate is 37%.Rf (methylene chloride 90/10): 0.40m.p. (oxalate): 105 ℃ 1H NMR (400MHz; CDCl 3) (alkali): 7.10ppm (d; J=8.7Hz; 1H; H11); 6.72ppm (dd; J=8.7 and 2.6Hz; 1H; H10); 6.62ppm (d; J=2.6Hz; 1H; H8); 5.50ppm (m; 1H; NH); 3.78ppm (s; 3H; OCH 3); 3.68ppm (m; 2H; CH 2N); 3.22ppm (s; 3H; NMe); 3.17ppm (d; J=4.4Hz; 3H; NHMe); 3.27-3.14ppm (m; 2H; H7a, H11b); 3.11-2.98ppm (m; 2H; H6a and H4a); 2.72ppm (m; 1H; H7a); 2.56ppm (m; 1H; H1a); 2.40ppm (m; 1H; H6b); 2.32-2.18ppm (m; 2H; H4b and H2); 1.76ppm (m; 1H; H3a); 1.56ppm (m; 1H; H3b); 1.24ppm (m; 1H; H1b). ultimate analysis:
Theoretical value: C (56.72), H (6.90), N (9.92);
Experimental value: C (56.64), H (6.71), N (9.68).Embodiment 91 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-N '-phenylurea
Press and embodiment 90 similar methods, use reagent corresponding to obtain title compound: m.p. (oxalate): 117 ℃ of ultimate analyses:
Theoretical value: C (63.95), H (6.65), N (8.95);
Experimental value: C (64.29), H (6.54), N (8.49).Embodiment 92 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] mecinnamide
Press on embodiment 1 similar method, use reagent corresponding to obtain title compound.M.p. (oxalate): 124 ℃ of ultimate analyses:
Theoretical value: C (67.48), H (6.71), N (5.83);
Experimental value: C (67.44), H (6.44), N (5.82).Embodiment 93 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the ethyl cinnamide
Press on embodiment 1 similar method, use reagent corresponding to obtain title compound.Wherein press and embodiment 89 similar methods, use embodiment 47 compounds to obtain (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] ethamine.M.p. (oxalate): 120 ℃ of ultimate analyses:
Theoretical value: C (6 8.00), H (6.93), N (5.66);
Experimental value: C (67.72), H (6.76), N (5.60).Embodiment 94 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl benzamide
By method similar to Example 1, use reagent corresponding to obtain title compound: m.p. (oxalate): 150 ℃ of ultimate analyses:
Theoretical value: C (66.06), H (6.65), N (6.16);
Experimental value: C (65.47), H (6.24), N (5.82).Embodiment 95 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-cyclohexyl acrylamide step 13-cyclohexyl ethyl propenoate
With 17.1g carboxyl methylene tri phenyl phosphorane (49.1mmol; 1.1 equivalent) be added in the solution of 5g hexahydrobenzaldehyde (44.6mmol) in the 100ml methylene dichloride.After at room temperature reacting 72 hours, solvent evaporation is fallen and residue is dissolved in the sherwood oil.Insolubles is come out by filtering separation and filtrate is evaporated to dried.Separate and obtain the faint yellow oily thing of 5.25g (productive rate=65%). 1H NMR (400MHz; CDCl 3): 6.82ppm (dd; J=15.8 and 6.8Hz; 1H; H3); 5.77ppm (dd; J=15.8 and 1.3Hz; 1H; H2); 4.11ppm (q; J=7.1Hz; 2H; CH 3CH 2O); 2.15ppm (m; 1H; H1 '); 1.73-1.59ppm (m; 5H; Calm H); 1.33-1.06ppm (m; 8H; Axial H and CH 3CH 2O). step 23-cyclohexyl vinylformic acid
The solution of 5.25g (28.8mmol) 3-cyclohexyl ethyl propenoate, 50ml 1N sodium hydroxide and 50ml THF was at room temperature stirred 50 hours.Behind the decantation, water is washed with ether, with using dichloromethane extraction after the concentrated hydrochloric acid acidifying.With the organic phase dried over mgso, filter, be evaporated to dried then.Separate and obtain 4.4g Off-white solid (productive rate=99%). 1H NMR (400MHz; CDCl 3): 6.75ppm (dd; J=15.7 and 6.7Hz; 1H; H3); 5.68ppm (dd; J=15.7 and 0.7Hz; 1H; H2); 2.12ppm (m; 1H; H1 '); 1.75-1.58ppm (m; 5H; Calm H); 1.32-1.04ppm (m; 5H; Axial H). step 33-cyclohexyl acrylate chloride
To contain 1g 3-cyclohexyl vinylformic acid (6.5mmol) and 2.38g SOCl 2(4.63g; 39mmol; 6 equivalents) solution stirred 4 hours down at 75 ℃.Residue is dissolved in the toluene, is evaporated to dried then.Separate and obtain 1.1g brown oil (productive rate=98%). 1H NMR (400MHz; CDCl 3): 6.76ppm (dd; J=15.7 and 6.8Hz; 1H; H3); 5.70ppm (dd; J=15.7 and 1.3Hz; 1H; H2); 2.15ppm (m; 1H; H1 '); 1.80-1.58ppm (m; 5H; Calm H); 1.32-1.03ppm (m; 5H; Axial H). step 4 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-cyclohexyl acrylamide
With 320mg acyl chlorides (1.8mmol; 1.2 equivalent) be added drop-wise in the solution of amine (1.5mmol) in 15ml THF that 380mg embodiment 1 step 5 obtains.At room temperature keep reaction 48 hours.Then reaction mixture is evaporated to dry doubling residue is dissolved in the methylene dichloride, then with the washing of 1N sodium hydroxide.With the organic phase dried over mgso, filter, be evaporated to dried then.Resulting crude product oily matter is passed through silica gel column chromatography chromatography (eluent: methylene chloride/ammonium hydroxide 98/1.7/0.3) purifying.Separate and obtain 184mg brown solid (productive rate=31%).Rf (methylene chloride/ammonium hydroxide 90/9/1): 0.47m.p. (oxalate): 140 ℃ 1H NMR (400MHz; CDCl 3) (alkali): 7.11ppm (d; J=8.6Hz; 1H; H11); 6.81ppm (dd; J=15.4 and 6.7Hz; 1H; Cyclohexyl-CH=C); 6.72ppm (dd; J=8.6 and 2.6Hz; 1H; H10); 6.61ppm (d; J=2.6Hz; 1H; H8); 5.71ppm (dd; J=15.4 and 1.0Hz; 1H;-CH=CH-CO); 5.65ppm (m; 1H; NH); 3.77ppm (s; 3H; OCH 3); 3.29ppm (m; 2H; CH 2N); 3.23-3.10ppm (m; 2H; H7a, H11b); 3.07ppm (m; 1H; H4a); 3.01ppm (m; 1H; H6a); 2.70ppm (m; 1H; H1a); 2.54ppm (m; 1H; H7b); 2.41-2.30ppm (m; 2H; H4b and H6b); 2.10ppm (m; 1H; Cyclohexyl CH); 1.94-1.70ppm (m; 6H; Calm H2 and cyclohexyl); 1.65ppm (m; 1H, H3a); 1.48ppm (m; 1H; H3b); 1.35-1.08ppm (m; 6H; H1a, axial rings hexyl H). ultimate analysis:
Theoretical value: C (66.08), H (7.68), N (5.93);
Experimental value: C (65.70), H (7.26), N (5.67).Embodiment 96 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl] cinnamide step 13, the 4-dihydro-isoquinoline hydrochloride
20ml (150mmol) is dissolved in 1,2,3 in the 350ml methylene dichloride, and 4-tetrahydroisoquinoline, 29.5g (1.1 equivalent) NBS are added in 1 liter of round-bottomed flask.Reaction mixture was at room temperature stirred 4 hours and placed after adding the 100ml concentrated sodium hydroxide and spend the night.Reclaim organic phase behind the decantation, wash with water, use the 1N hydrochloric acid extraction then.Water is alkalized with dense ammonium hydroxide, use dichloromethane extraction then.New organic phase with the saturated nacl aqueous solution washing, is used dried over mgso, filter, be evaporated to dried then.Obtain brown oil: m=16.5g.Obtain the salt that exists with the yellow solid form by the hydrochloric acid/iPrOH solution that adds 44.6ml 3.1M.Overall yield is 73.4%. 1H NMR (400MHz, DMSO d6): 13.99ppm (s, 1H, NH); 9.23ppm (s, 1H, H1); 7.92ppm (m, 1H, H8); 7.79ppm (m, 1H, H5); 7.52ppm (m, 2H, H6, H7); 3.94ppm (t; J=8Hz, 2H, H3); 3.15ppm (t, J=8Hz, 2H, H4). step 21,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-ketone
Hydrochloride that will 10g (60mmol) step 1 in round-bottomed flask obtains and 15ml (3 equivalent) ethylene methacrylic ketone are 60 ℃ of heating 4 hours down.After adding ketone, obtain brown solid by filtration.This solid is dissolved in the methylene dichloride, uses the 1N hydrochloric acid extraction then.After the alkalization, with the water dichloromethane extraction.Organic phase is filtered, use dried over mgso, be evaporated to dried then.Obtain the 9.52g brown solid.Productive rate is 67%. 1H NMR (400MHz, CDCl 3): 7.17ppm (m, 3H, fragrant H); (7.08ppm m, 1H, fragrant H); 3.58ppm (dd, J=12Hz and 2.4Hz, 1H, H11b); 3.28ppm (m, 1H, H4eq); (3.16ppm m, 2H, H7ax and H6eq); 2.95ppm (dm, J=14.4Hz, 1H; H1eq); 2.83ppm (m, 1H, H7eq); (2.74-2.62ppm m, 3H, H3eq, H4ax and H6ax); (2.52-2.42ppm m, 2H, H1ax and H3ax). step 3 (RS), (SR)-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizine-2-formonitrile HCN
Under 0 ℃, ketone, 150ml DME, 8.26g (1 equivalent) TosMIC and 2.5ml (1 equivalent) ethanol that 8.52g (42.3mmol) step 2 is obtained are added in the round-bottomed flask.Reaction mixture was stirred 30 minutes; Add 9.5g (2 equivalent) tBuOK and 0 ℃ of following restir 30 minutes.After returning to room temperature, reaction mixture was stirred 4 hours down at 90 ℃, filter, be evaporated to dried then.By flash chromatography chromatography (petrol ether/ethyl acetate: 8/2) separate two kinds of isomer.Obtain three cuts: first cut is diastereomer A, 3.2g yellow solid (Y=36%); Second cut is diastereomer A and B mixture (Y=8.1%); The 3rd cut is diastereomer B, 1.17g yellow solid (Y=13%). 1H NMR (400MHz, CDCl 3): diastereomer A:(RR), (SS)-7.20-7.09ppm (m, 4H, fragrant H); 3.18ppm (d, J=10.4Hz, 1H, H11b); 3.06ppm (m, 1H, H7ax); 3.03ppm (dm, J=12Hz, 1H, H4eq); 2.94ppm (m, 1H, H6eq); 2.74-2.63ppm (m, 3H, H1ax, H2, H7eq); 2.55ppm (dt, J=11.6Hz, J=3.6Hz, 1H, H6ax); 2.34ppm (dt, J=12Hz, J=2Hz, 1H, H4ax); (2.08-1.92ppm m, 2H, H3ax and H3eq); 1.74ppm (q, J=12.4Hz, 1H, H1eq).
Diastereomer B:(RR), (SS)-7.19-7.09ppm (m, 4H, fragrant H); 3.58ppm (d, J=11.2Hz, 1H, H11b); (3.18-3.07ppm m, 2H, H7ax and H2); (2.98-2.94ppm m, 2H, H6eq and H6ax); (2.76-2.60ppm m, 3H, H1eq, H4eq and H7ax); 2.53ppm (d, J=13.6Hz, 1H, H4ax); (2.19ppm m, 2H, H3ax and H3eq); 1.17ppm (dt, 1H, H1ax). step 42-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl)-methylamine
The diastereomer A of 1g (4.7mmol) nitrile is dissolved in the 80ml methyl alcohol.Mixture is cooled to 0 ℃, adds 5.2g (5 equivalent) nickelous chloride then.Add sodium borohydride (8 equivalent) lentamente.This reaction mixture was stirred 1 hour down at 0 ℃, at room temperature stirred then 30 minutes.Solvent evaporation is fallen.Nickel salt suspended with 1N sodium hydroxide and with the amine dichloromethane extraction.Filter out nickel composite by on diatomite, crossing.With the methylene dichloride continuous washing several times after, filtrate is evaporated to dried.Obtain the 0.9g brown oil, productive rate is 86%. 1H?NMR(400MHz，DMSO?d6)：7.26ppm(m，1H，
Fragrance H); 7.14-7.05ppm (unresolved complex spike, 3H,
Fragrance H); 3.30ppm (wide s, 1H, NH 2); 3.03ppm (d, J=10.8Hz, 1H, H11b); (2.95-2.88ppm unresolved complex spike, 2H, H7ax and H4eq); 2.66-2.34ppm (unresolved complex spike, 6H, CH 2NH 2, H7eq, H6eq, H4ax and H1eq); 2.22ppm (m, 1H, H6ax); 1.68ppm (d, J=12.8Hz, 1H, H3eq); 1.46ppm (m, 1H, H2); 1.17ppm (m, 1H, H3ax); 0.88ppm (q, J=12Hz, 1H, H1ax). step 5 (RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl] cinnamide
Methylamine, 15ml THF and 0.4ml (2.5 equivalent) pyridine that 450mg (2mmol) step 4 is obtained is added in the 100ml round-bottomed flask.Drip 416mg (1.2 equivalent) and be dissolved in the cinnamyl chloride among the 10mlTHF.Reaction mixture at room temperature stirred spend the night.Solvent evaporation fallen and reclaim brown solid.With methylene dichloride/1N sodium hydroxide extraction and by flash chromatography chromatography (eluent: methylene chloride/ammonium hydroxide: 98/1.7/0.3), obtain 279mg orange solids (Y=39%).The oxalic acid that is dissolved in the small amount of acetone is added in this alkali that is dissolved in the small amount of methanol.Therefore form the oxalate of title compound, it is a kind of yellow solid, and fusing point is 188 ℃. 1H NMR (400MHz, CDCl 3) (alkali): 7.64ppm (d, J=15.6Hz, 1H, Ph-CH=CH), 7.50ppm (d, J=6Hz, 2H, styracin ortho position H), 7.34ppm (m, 3H, position H and styracin contraposition H between styracin); 7.21-7.08ppm (unresolved complex spike, 4H, H8, H9, H10, H11); 6.40ppm (d, J=15.6Hz, 1H, CH=CHCO); 5.79ppm (wide s, 1H, NH); 3.37ppm (m, 2H, CH 2NH); 3.18ppm (d, J=12Hz, 1H, H11b); 3.16ppm (m, 1H, H7ax); 3.01ppm (d, J=11.6Hz, 1H, H4eq); 2.97pm (m, 1H, H6eq); 2.71ppm (d, J=16Hz, 1H, H7eq); 2.53ppm (dt, J=11.6 and 3.6Hz, 1H, H6ax); (2.41-2.33ppm m, 2H, H4ax and H1eq); 1.92ppm (m, 1H, H2); 1.80ppm (d, J=12.4Hz, 1H, H3eq); 1.47ppm (dq, J=12.4 and 4Hz, 1H, H3ax); 1.22ppm (q, J=12Hz, 1H, H1ax) .Rf (methylene chloride/ammonium hydroxide 90/9/1)=0.49 ultimate analysis:
Theoretical value: C (68.79), H (6.47), N (6.42);
Experimental value: C (69.24), H (6.42), N (6.39).Embodiment 97 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl]-N '-methylthiourea
183mg (1.2 equivalent) is dissolved in Trapex in the 20ml methylene dichloride to be added drop-wise to 450mg (2mmol) and to be dissolved in the amine aqueous solution that embodiment 96 steps 4 in the 25ml methylene dichloride obtain.At room temperature stir and spend the night.After solvent evaporation fallen, obtain brown oil.With its purifying (eluent: methylene chloride/ammonium hydroxide 97/2.5/0.5) on silicagel column.Rf (methylene chloride/ammonium hydroxide 90/9/1)=0.37m.p. (oxalate): 194 ℃ 1H NMR (400MHz, CDCl 3): 7.26-7.09ppm (unresolved complex spike, 4H, fragrant H); 4.74ppm (wide s, 2H, NH); 3.42ppm (m, 2H, CH 2NH); 3.17ppm (d, J=12Hz, 1H, H11b); 3.15ppm (m, 1H, H7ax); 3.03ppm (s, 3H, CH 3N); 3.12-2.96ppm (m, 2H, H6eq, H4eq); 2.71ppm (d, J=16Hz, 1H, H7eq); 2.53ppm (dt, J=11.6and3.6Hz, m, 1H, H6ax); (2.40-2.33ppm unresolved complex spike, 2H, H4ax and H1ax); 1.98ppm (m, 1H, H2); 1.80ppm (d, J=12.8Hz, 1H, H3eq); 1.45ppm (dq, J=12.4 and 4Hz, 1H, H3ax); 1.18ppm (q, J=12Hz 1H, H1ax). ultimate analysis:
Theoretical value: C (56.97), H (6.64), N (11.07);
Experimental value: C (56.90), H (6.84), N (10.40).Embodiment 98 (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-fluoro-2H-benzo [a] quinolizinyl) methyl] cinnamide step 16-fluoro-1,2,3, the 4-tetrahydroisoquinoline
9ml (69mmol) 3-fluorophenethylamine, 90ml concentrated hydrochloric acid and 41ml formaldehyde are mixed.This reaction mixture was heated 6 hours down at 100 ℃, then in the impouring water.Water is washed with ether, with concentrated sodium hydroxide alkalization and use dichloromethane extraction.Organic phase is washed with saturated nacl aqueous solution, use dried over mgso, filter, be evaporated to dried then.Obtain N, the yellow mashed prod of N '-methylene radical two (6-fluoro-1,2,3,4-tetrahydroisoquinoline).
With this aminal hydrolysis: under 75 ℃, hydrolysis is 4 hours in 1N hydrochloric acid.Water is neutralized with sodium hydroxide, use dichloromethane extraction then.By at methylene chloride/ammonium hydroxide: behind the flash chromatography chromatography, obtain the yellow oil of 1.835g title compound in 95/4/1 mixture, productive rate is 17.5%. 1H NMR (400MHz, DMSO d6): 7.02ppm (m, 1H, H8); 6.90ppm (m, 2H, H5, H7); 3.78ppm (s, 2H, H1); 2.90ppm (t, J=5.8Hz, 2H, H4); 2.67ppm (d, J=5.8Hz, 2H, H3). 13C NMR (100.6MHz, CDCl 3): 161.09ppm (d, 1J C-F=243Hz, C6); 136.76ppm (t, 3J C-F=7Hz, C4); 131.28ppm (C8a); 127.61ppm (d, 3J C-F=7.9Hz, C8); 115.44ppm (d, 2J C-F=20.4Hz, C5orC7); 112.85ppm (d, 2J C-F=21.4Hz, C5orC7); 47.70ppm (C1); 43.42ppm (C3); 29.22ppm (C4). step 26-fluoro-3,4-dihydro-isoquinoline
Saturated compound, 5ml methylene dichloride and 451mg (1.1 equivalent) NBS that 350mg (2.3mmol) previous step is obtained is added in the 100ml round-bottomed flask.The method that Application Example 96 steps 1 are identical obtains 230mg yellow oil (Y=66.8%). 1H NMR (400MHz, DMSO d6): 8.32ppm (s, 1H, H1); 7.46ppm (dd, 1H, H8); 7.12ppm (m, 2H, H7, H5); 3.62ppm (t, 2H, H3); 2.70ppm (t, 2H, H4). step 39-fluoro-1,3,4,6,7,11b-six hydrogen (2H) benzos [a] quinolizine-2-ketone
The hydrochloride of the compound that 2.03g (10.9mmol) previous step is obtained and 2.7ml (3 equivalent) ethylene methacrylic ketone mix.This reaction mixture was heated 3 hours down at 60 ℃.Obtain the salt of 1.39g title compound.Acid-alkali obtains the 1.15g brown oil after extracting, and productive rate is 48%. 1H NMR (400MHz, CDCl 3): 7.03ppm (dd, J=8.6Hz, J=5.6Hz, 1H, H11); 6.87ppm (m, 2H, H8, H10); 3.54ppm (d, J=11.6Hz, 1H, H11b); 3.28ppm (m, 1H, H4eq); (3.14ppm m, 2H, H7ax and H6eq); 2.92ppm (dm, J=14.4Hz, 1H, H1eq); 2.83ppm (m, 1H, H7eq); (2.73-2.61ppm m, 3H, H3eq, H4ax and H6ax); (2.50-2.42ppm unresolved complex spike, 2H, H1ax and H3ax). step 4 (RS), (SR)-and 9-fluoro-1,3,4,6,7,11b-six hydrogen (2H)-benzo [a] quinolizine-2-formonitrile HCN
Method is identical with the method for compound 96 steps 3.Employed amount is ketone, 20ml dimethoxy ether, 1.03g (1 equivalent) tolylsulfonyl ylmethyl isonitrile, 0.3ml (1 equivalent) ethanol and the 1.18g tBuOK that 1.15g (5mmol) previous step obtains.The reaction overall yield that obtains behind the flash chromatography chromatography in petrol ether/ethyl acetate 5/5 mixture is 68.4%.Separate and obtain 40.8% diastereomer A and 23.3% diastereomer B. 1H NMR (400MHz, CDCl 3): diastereomer A:(RS), (SR)-7.10ppm (dd, J MF=5.6Hzand J OH=8.6Hz, 1H, H11); 6.87ppm (ddd, J OF=8.5Hz, J MH=2.5Hz, 1H, H8); 6.80ppm (dd, J OF=9.3Hz, J MH=2.5Hz, 1H, H10); 3.13ppm (d, J=10.8Hz, 1HH11b); 3.10ppm (m, 1H, H7ax); 3.02ppm (dm, J=12Hz, 1H, H4eq); 2.94ppm (m, 1H, H6eq); 2.74-2.65ppm (m, 2H, H2, H6ax); 2.61ppm (dm, J=12.8Hz, 1H, H7eq); 2.51ppm (m, 1H, H1eq); 2.34ppm (td, J=12Hz, J=2.8Hz, 1H, H4ax); 2.07ppm (m, 1H, H3eq); 1.99ppm (m, 1H, H3ax); 1.72ppm (q, J=11.6Hz, 1H, H1ax).
Diastereomer B:(RR), (SS)-7.10ppm (dd, J MF=5.6Hz, J OH=8.6Hz, 1H, H11); 6.88ppm (ddd, J OF=8.4Hz, J OH=8.6Hz, J MH=2.5Hz, 1H, H8); 6.80ppm (dd, J OF=9.3, J MH=2.5Hz, 1H, H10); 3.53ppm (d, J=11.2Hz, 1H, H11b); (3.18-3.07ppm m, 2H, H7ax and H2); (2.98-2.94ppm m, 2H, H6eq and H6ax); (2.76-2.60ppm m, 3H, H1eq, H4eq and H7ax); 2.49ppm (d, J=13.2Hz, 1H, H4ax); (1.98ppm m, 2H, H3ax and H3eq); 1.70ppm (ddd, 1H, H1ax). step 5 (RS), (SR)-2-(9-fluoro-1,3,4,6,7,11b-six hydrogen (2H)-benzo [a] quinolizinyl) methylamine
Method is identical with embodiment 96 steps 4.Employed amount is nitrile A, 3.16g (5 equivalent) nickelous chloride, 649mg (8 equivalent) NaBH of 494mg (2.7mmol) previous step 4, 40ml methyl alcohol.Obtain brown oil, productive rate is 97.8%.This amine can be directly used in next step.Step 6 (RS), (SR)-N-[2-(9-fluoro-1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl] cinnamide
Method is identical with embodiment 96 steps 5.Employed amount is amine, 15ml THF, 0.4ml (2.5 equivalent) pyridine, 425mg (1.2 equivalent) cinnamyl chloride that 498mg (5mmol, 1 equivalent) previous step obtains.Chromatography obtains the 304mg title compound on silicagel column.Rf (methylene chloride/ammonium hydroxide 97/5/0.5)=0.43m.p. (oxalate): 164 ℃ 1H NMR (400MHz, CDCl 3): 7.65ppm (d, J=15.6Hz, 1H, ph-CH=CH); (7.50ppm dd, J=7.7 and 2.7Hz, 2H, styracin ortho position H); (7.36ppm m, 3H, Hmeta and styracin contraposition H); 7.15ppm (dd, J MF=5.7Hz, J OH=8.6Hz, 1H, H11); 6.83ppm (dt, J OF=8.5Hz, J MH=2.6Hz, 1H, H10); 6.76ppm dd, J OF=9.4Hz, J MH=2.3Hz, 1H, H8); 6.41ppm (d, J=15.6Hz, 1H, CH=CHCO); 5.83ppm (wide s, 1H, NH); 3.36ppm (m, 2H, CH 2NH); 3.11ppm (d, J=11.6Hz, 1H, H11b); 3.10ppm (m, 1H, H7ax); 3.03ppm (dm, J=11.6Hz, 1H, H4eq); 2.96pm (m, 1H, H6eq); 2.69ppm (d, J=16.8Hz, 1H, H7eq); 2.50pm (dt, J=11.6 and 4Hz, 1H, H6ax); 2.37-2.31ppm (m, 2H, H4ax, H1eq); 1.91ppm (m, 1H, H2); 1.80ppm (d, J=12.8Hz, 1H, H3eq); 1.45ppm (ddd, J=12.4 and 4Hz, 1H, H3ax); 1.18ppm (q, J=14.2Hz, 1H, H1ax). ultimate analysis:
Theoretical value: C (66.07), H (5.99), N (6.16);
Experimental value: C (65.72), H (6.02), N (6.13).

Claims (15)

1, formula I compound:
Figure A9881076900021
Wherein:
R 1Represent hydrogen atom or straight chain, side chain or ring-type C 1-4Alkyl, hydroxyl or side chain, straight chain or ring-type C 1-4Alkoxyl group, halogen atom such as F or Cl,
R 2Represent hydrogen atom or C 1-6Alkyl,
R 3Represent hydrogen atom or can constitute unit (C=X)-NR 4R 5Thereby, when X=oxygen or sulphur, constitute urea or thiocarbamide,
R 4And R 5Can be hydrogen atom or straight chain, side chain or ring-type C independently 1-8Alkyl, aryl, aralkyl or aroyl, these aryl also can be substituted,
R 4And R 5Can connect by comprising or do not contain heteroatomic carbochain,
R 3Also can represent the alkyl sulphonyl or the aryl sulfonyl that do not replace or replace,
R 3Can represent hydrogen or acyl group or sulfo-acyl group as (C=X)-R 6, wherein X represents oxygen or sulphur atom,
R 6Can represent hydrogen or comprise or do not contain heteroatoms such as oxygen or sulphur, comprise and carbonyl C=X conjugation or not straight chain, side chain or the ring-type C of the two keys of conjugated 1-10Alkyl,
R 6Also can represent straight chain, side chain or ring-type C 1-8Alkoxyl group, the aralkoxy that does not replace or replace,
R 6Also can represent aryl or heteroaryl, as not replacing or by C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl, halogen, NO 2, CF 3, CN, COCH 3The phenyl or naphthyl or thiophene, furans, pyrroles, pyridine and the benzo-fused derivative thereof that replace one or many,
R 4Represent aralkyl or aryloxy alkyl, wherein aryl moiety can be replace and wherein alkyl chain can be straight chain, straight chain or cyclic,
R 6Can comprise several aromatic ring systems, as 2-(2, the 3-indane) base, fluorenyl, tonka bean camphor base or benzopyranyl,
R 6Also can represent arylalkenyl; With two key conjugated aryl can be phenyl, naphthyl, many aromatic bases such as xenyl or fluorenyl, heteroaryl and benzo-fused derivative thereof,
This aryl can be unsubstituted or by C 1-8Alkyl, hydroxyl, C 1-8Alkoxyl group, halogen, NO 2, CF 3, CN, OCF 3, OCH 2O replaces one or many, or forms two rings with the saturated or unsaturated ring that comprises or do not contain heteroatoms such as O, N or S, forms indoles, cumarone or thionaphthene thus; Described thiazolinyl can be unsubstituted or be replaced by halogen, CN, alkyl, phenyl; Therefore, unit (C=X)-R 6Form cinnamoyl;
Term aryl is represented phenyl or naphthyl, and term aralkyl is meant to be connected to and contains a carbon atom at least and can be aryl on straight chain, side chain or the cyclic alkyl chain;
Heteroaryl can be to have one or more N of being selected from, O or the heteroatomic 5-of S or 6-unit's aromatic ring and benzo-fused derivative thereof, therefore, they form pyridine, furans, thiophene, indoles, cumarone, thionaphthene, benzoxazine, quinoxaline, quinazoline, benzoglyoxaline, benzopyrazoles.
2, claim 1 compound is characterized in that R 1Represent hydrogen, methoxyl group, methyl or fluorine.
3, claim 1 and 2 compounds is characterized in that R 2Represent hydrogen, methyl or ethyl.
4, claim 1,2 and 3 compounds is characterized in that R 3Represent group (C=X)-NR 4R 5Therefore and form urea or thiocarbamide, X=O or S.
5, claim 1,2 and 3 compounds is characterized in that R 3Form group (C=X) R 6And R 6Represent alkyl or aryl.
6, claim 1,2 and 3 compounds is characterized in that R 3Form group (C=X) R 6And R 6Represent arylalkenyl; (C=X) R 6Be selected from aromatic ring one or more C are partly arranged 1-4Alkoxyl group, methylene radical dioxy base, C 1-6Cinnamoyl or sulfo-cinnamoyl that alkyl, OH, halogen such as F, Cl replace.
7, claim 1-6 compound is characterized in that they are selected from following compounds:
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] propionic acid amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the cyclohexyl methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] isobutyramide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenyl (α, α-cyclopropyl) ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenylacetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-9 ' H-fluorenyl-9 '-methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-the 3-hydrocinnamamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-(2, the 3-indane) methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-chlorophenoxy ethanamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 ', 4 ', 5 ', 6 '-penta fluoro benzene oxygen yl acetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenoxy-acetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the methoxyl group ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] ethanamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] thioacetamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-1 '-methoxyl group-2 '-naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-pyridine carboxamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-thenoyl amine
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-furoylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-1 ' naphthoamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-trifluoromethyl benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-chlorobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-trifluoromethyl benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] thiobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the sulfo-cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-cyclohexyl acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the cyclohexenyl methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(2 '-furyl) acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-benzofuran carboxamides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(1 '-naphthyl) acrylamide acid amides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3-(2 '-naphthyl) acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-9 ' H-fluorenyl-9 '-methylene radical methane amide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-phenyl cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-tonka bean camphor methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-(2 '-thienyl)-3-acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-(3 '-thienyl)-3-acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-fluoro-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 ', 4 ', 5 ', 6 '-five fluorine cinnamides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2,3-phenylbenzene propylene acid amides
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-cyano group-3-Phenyl Acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-methyl-3-Phenyl Acrylamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2-fluoro-3-Phenyl Acrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-methoxy benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-nitrobenzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-trifluoromethyl cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-cinnamoyl chloride amine
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 ', 5 '--the trifluoromethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-fluorine cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-chloro-6 '-fluorine cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 4 ', 5 '-trimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 '-dimethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-mecinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 3 '-dimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 5 '-dimethoxy cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 ', 4 '-dimethoxy cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-methoxyl group cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-4 '-fluorine cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 ', 4 '-methylene radical dioxy base cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(2-methoxy ethyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-uncle's octyl group thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-tertiary butyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-cyclohexyl methyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-butyl thiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-2-styroyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl thiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-methylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-isobutyl-thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-cyclohexyl thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzoylthioureas
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(2 '-naphthyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-(1 '-naphthyl) thiocarbamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylthiourea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-phenylurea (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-methyl urea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl urea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-2H-benzo [a] quinolizinyl) methyl]-N '-methylthiourea
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl benzamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the ethyl cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] mecinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-N '-phenylurea
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl, N '-methylthiourea
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N '-benzoylureas
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] the carboxylamine benzyl ester
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-N ', N '-dimethyl methyl uride
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] sulfonyloxy methyl amine
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] phenyl-sulfamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl oxaminic acid acid amides
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-2 '-H-chromene-3 '-methane amide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3, the 3-Methacrylamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl]-3 '-Phenylpropionamide
(SS), (RR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide (RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-4 '-nitro cinnamide
(RS), (SR)-and N-[2-(1,3,4,6,7,11b-six hydrogen-9-oxyethyl group-2H-benzo [a] quinolizinyl) methyl] cinnamide
(RS), (SR)-N-[2-(1,3,4,6,7,11b-six hydrogen-9-methoxyl group-2H-benzo [a] quinolizinyl) methyl] methyl-N ', N '-dimethyl thiourea.
8, the compound of claim 1-7, it is characterized in that compound exists with diastereisomericallypure pure and enantiomeric pure form, form salt, example hydrochloric acid salt, vitriol, mesylate, maleate, fumarate, Citrate trianion, succinate, tartrate with inorganic or organic acid.
9, the method for preparing claim 1-8 compound; it is characterized in that in alkaline medium; with formula II compound and tolylsulfonyl ylmethyl isonitrile reaction; separate diastereomer; described nitrile is reduced to primary amine, with this amine and alkyl or aryl isocyanic ester or lsothiocyanates, urea chloride or the reaction of thiocarbamyl chlorine or with the acyl chloride reaction of acid, aliphatic acid, aromatic acid or styracin.
10, the method for preparing the diastereisomericallypure pure compound, the non-enantiomer mixture that obtains in the time of will chiral centre appears in the 2-position in claim 9 building-up process are carried out chromatography and are separated or crystallization.
11, the method for preparing the enantiomer pure compound is separated in chirality HPLC, and Accessory Right requires 10 compound that obtain.
12, preparation is by the method for the salt of claim 11 gained compound, it is characterized in that basic cpd with stoichiometric sour agent treated.
13, claim 1-8 compound is as the application of medicine.
14, pharmaceutical composition is characterized in that it comprises formula I compound and a kind of suitable vehicle of at least a claim 1-8.
15, claim 1-8 Chinese style I compound is used for the treatment of application in the medicine of neurodegenerative disease in preparation, described disease especially comprise Parkinson's disease, presenile dementia, huntington's chorea, cognition and dysmnesia, the elderly's attention and and alertness deficiency, cerebral ischemia and ischemic after the development of disease and neurodegenerative disease.
CN98810769A 1997-10-28 1998-10-26 Aminomethyl-benzo [a] quinolizidine derivatives, prepns. and therapeutic applications for neurodegenrative diseases Pending CN1278260A (en)

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FR9713499A FR2770215B1 (en) 1997-10-28 1997-10-28 AMINOMETHYL-BENZO [A] QUINOLIZIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION FOR NEURODEGENERATIVE DISEASES

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