CN1278250A - Vitronectin receptor antagonists - Google Patents

Vitronectin receptor antagonists Download PDF

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CN1278250A
CN1278250A CN98810811A CN98810811A CN1278250A CN 1278250 A CN1278250 A CN 1278250A CN 98810811 A CN98810811 A CN 98810811A CN 98810811 A CN98810811 A CN 98810811A CN 1278250 A CN1278250 A CN 1278250A
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dibenzo
dihydro
suberene
compound
amino
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W·E·邦迪内尔
W·H·米勒
D·希尔丁
J·M·萨马南
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SmithKline Beecham Corp
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Abstract

Compounds of formula (I) are disclosed which are vitronectin receptor antagonists and are useful in the treatment of osteoporosis wherein: A is CH2 or O; R<1> is H, halo or C1-6alkyl; R<2> is H, C1-6alkyl or CH2NR''R''; X is O or CH2; Y is (a), (b), (c), (d), (e), (f) or (g); G is NR'', S or O; R' is H, C1-6alkyl, OC1-6alkyl, SC1-6alkyl, NR''R'' or halo; each R'' independently is H or C1-6alkyl; and s is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

Description

Vitronectic receptor antagonist
Invention field
The present invention relates to pharmaceutically active compound, it can suppress Vitronectic receptor and can be used for treating inflammation, cancer and cardiovascular disorder, and as atherosclerosis and restenosis, and wherein bone resorption is the disease of the cause of disease, as osteoporosis.
Background of invention
Integrin is the superfamily of cell adhesion acceptor, and the cell adhesion acceptor is the transmembrane glycoprotein that is expressed on the various cells.These cell surface adhesion receptors comprise gpIIb/IIIa (fibrin original receptor) and α Vβ 3(Vitronectic receptor).Fibrin original receptor gpIIb/IIIa is expressed in platelet surface, and the mediation platelet aggregation reaches at the wound formation hemostasis grumeleuse of bleeding.Philips etc., Blood., 1988,71,831.Vitronectic receptor α Vβ 3Be expressed on many cells, comprise endotheliocyte, smooth muscle cell, osteoclast and tumour cell, so it has multiple function.Be expressed in this α on the osteoclast film Vβ 3Receptor-mediated osteoclast is to the adhesion of ground substance of bone, and it is the committed step in the bone resorption process.Ross etc., J.Biol.Chem., 1987,262,7703.The disease that is absorbed as feature with excessive bone is an osteoporosis.Be expressed in this α on the human aortic smooth muscle cell Vβ 3Receptor-mediated migration to neointima, this process causes the restenosis behind the skin coronary angioplasty.Brown etc., CardiovascularRes., 1994,28,1815.In addition, Brooks etc.Cell, 1994,79,1157 have shown α Vβ 3Antagonist can promote tumour regression, comprises the apoptosis that forms blood vessel.Therefore, the medicine of blocking-up Vitronectic receptor can be used for treating disease, as osteoporosis, restenosis and cancer.
It is now know that, and this Vitronectic receptor is meant three kinds of different integrins, uses α Vβ 1, α Vβ 3And α Vβ 5Expression.Horton etc., Int.J.Exp.Pathol., 1990,71,741.α Vβ 1In conjunction with fibronectin and vitronectin.α Vβ 3In conjunction with multiple part, comprise fibrin, fibrinogen, ln, thrombospondin, vitronectin, the vonWillebrandShi factor, osteopontin and bone sialoprotein I.α Vβ 5In conjunction with vitronectin.Shown this Vitronectic receptor α Vβ 5Relate to the cytoadherence of various cell types, comprise capillary endothelium, (Davis etc., J.Cell.Biol., 1993,51,206), it is proved to the effect that blood vessel takes place.Brooks etc., Science, 1994,264,569.Integrin expression is on the blood vessel of injury of human particle formative tissue, but not on normal skin.
Known vitronectin combines with the bone matrix protein matter that contains tripeptides Arg-Gly-Asp (or RGD) motif.Therefore, Horton etc., Exp.Cell Res.1991 openly contains the peptide of RGD and anti-Vitronectic receptor antibody (23C6) in 195,368 and suppresses dentine and absorb the cellular invasion that causes with osteoclast again.In addition, Sato etc., at J.Cell Biol.1990, open echistatin in 111,1713, a kind of snake venom peptide that contains the RGD sequence is effective bone resorption inhibitor in a kind of tissue culture, and suppresses osteoclast adhering to bone.
Have now found that some compound is α Vβ 3And α Vβ 5Effective inhibitor of acceptor.More particularly, found that these compounds are to suppress Vitronectic receptor than suppressing the more effective inhibitor of fibrin original receptor.
Summary of the invention
The present invention includes formula as described below (I) compound, it has the pharmacologically active that suppresses Vitronectic receptor, and can be used for treating inflammation, cancer and cardiovascular disorder, as atherosclerosis and restenosis, and wherein bone resorption is the disease of the cause of disease, as osteoporosis.
The present invention also comprises medicinal compositions, and it comprises according to the compound of formula (I) and pharmaceutically acceptable carrier.
The present invention also comprises the method for treatment by the disease of Vitronectic receptor mediation.More particularly, The compounds of this invention be used for the treatment of atherosclerosis, restenosis, inflammation, cancer and wherein bone resorption be the disease of the cause of disease, as osteoporosis.
Describe in detail
The present invention includes new compound, it is to suppress Vitronectic receptor than suppressing the more effective inhibitor of fibrin original receptor.This new compound comprises a dibenzocycloheptene parent nucleus, and the substituting group that wherein contains nitrogen-atoms is on one of aromatics six-ring of this dibenzocycloheptene, and the aliphatic substituting group that contains acidic moiety is on the seven-membered ring of this dibenzocycloheptene.Think that this dibenzocycloheptene ring system is oriented in the substituting group side chain on this hexa-atomic and seven-membered ring, so they can successfully interact with Vitronectic receptor.Preferably about 12-14 covalent linkage that inserts by path between short molecule is present between the substituent nitrogen-atoms that contains nitrogen-atoms on one of acidic-group on the aliphatic substituting group of seven-membered ring of this dibenzocycloheptene and aromatics six-ring of this dibenzocycloheptene.
The present invention includes formula (I) compound or its pharmacy acceptable salt: Wherein:
A is CH 2Or O;
R 1Be H, halogen or C 1-6Alkyl;
R 2Be H, C 1-6Alkyl or CH 2NR " R ";
X is O or CH 2
Y is
Figure A9881081100141
Figure A9881081100142
Or
Figure A9881081100143
G is NR ", S or O;
R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen;
" independent separately is H or C to R 1-6Alkyl; And
S is 0,1 or 2.
The present invention also comprises the additive salt and the mixture of pharmaceutically acceptable The compounds of this invention.The compounds of this invention can have under the situation of one or more chiral centres therein, unless describe in detail, what the present invention includes each uniqueness can be synthetic by common technology or the non-racemic compound that splits.Compound has under the unsaturated carbon-to-carbon double bond situation therein, and cis (Z) and trans (E) formula isomer all are included within the scope of the invention.Compound exists under the tautomeric form situation therein, as the keto-enol tautomerism body, as:
Figure A9881081100144
With
Figure A9881081100145
, no matter exist or by existing with suitable a kind of form of substituent R ' locking, every kind of tautomer all is included within the present invention with equilibrium state.
Formula (I) compound suppresses vitronectin and other contains the peptide of RGD and combining of Vitronectic receptor.The restraining effect of the Vitronectic receptor on osteoclast is suppressed the bone resorption of broken bone, can be used for treating wherein on the pathology and the bone resorption diseases associated, as osteoporosis and osteoarthritis.
On the other hand, the invention provides the stimulation of bone formation method, it comprises the compound that gives to cause osteocalcin release increase.The bone that increases produces to wherein lacking the mineralising sclerotin or needing the disease of bony remodeling obviously useful, as the prevention of union of fracture and fracture.Cause the disease and the metabolism disorder of bone structure loss also can from these treatments, benefit.For example, hyperparathyroidism, PagetShi disease, pernicious hypercalcemia, bone shift the molten bone infringement that causes, bone loss, BehcetShi disease, osteomalacia, hyperostosis and the osteopetrosis that is caused by ligamentopexis or sex hormone deficiency all can have benefited from giving The compounds of this invention.
In addition, because The compounds of this invention suppresses the Vitronectic receptor on the number of different types cell, so this compound can be used for treating inflammation, as rheumatoid arthritis and psoriasis, and cardiovascular disorder, as atherosclerosis and restenosis.Formula of the present invention (I) compound can be used for treatment or prevents other disease, include, but are not limited to thromboembolic disorders, asthma, anaphylaxis, adult respiratory distress syndrome, graft versus host disease, organ-graft refection, septic shock, eczema, contact dermatitis, enteritis and other autoimmune disease.The compounds of this invention also can be used for the healing of wound.
The compounds of this invention also can be used for treatment, comprises prevention vasculogenesis disease.Term vasculogenesis disease used herein comprises the illness that relates to unusual neovascularization.The reason of neovascularity growth or be attributed to the pathological factor relevant with disease suppresses the harmful effect that vasculogenesis can reduce this disease.The example of this disease target is a diabetic retinopathy.Owing to need neovascularity growth to support the growth of harmful tissue, suppress vascularization and can reduce blood is provided to this tissue, so can reduce based on blood supply need liver mass.Example comprises tumor growth, wherein for making tumor growth and making the solid tumor transfer of formation need continue neovascularization.Therefore, The compounds of this invention can suppress the tumor tissues vasculogenesis, so suppressed the transfer and the growth of tumor of tumour.
Therefore, the method according to this invention suppresses the symptom that vasculogenesis can be alleviated this disease with compound of the present invention, can cure this disease in some cases.
Another therapeutic goal of The compounds of this invention is to be the eye disease of feature with the neovascularization.These eye diseases comprise the cornea neovascular disorders, as corneal transplantation, herpetic keratitis, syphilitic keratitis, pteryium with use the relevant neovascularity pannus of contact eyeglass.Other eye disease also comprises ocular histoplasmosis, retinopathy of prematurity and the neovascular glaucoma of the macular degeneration relevant with the age, supposition.
The present invention also provides the method that suppresses tumor growth, and it comprises and progressively giving or with form giving construction (I) compound and the antineoplastic agent of physical composition, as the holder pool for may and cis-platinum.
For formula (I) compound:
Suitable Y is:
Figure A9881081100161
Wherein R ' is H, C 1-4Alkyl, OC 1-4Alkyl, SC 1-4Alkyl, NR " R " or Cl, " independent separately is H or C to R 1-4Alkyl.
Perhaps, Y is:
Figure A9881081100162
Wherein " each is H or C naturally for R 1-4Alkyl.
Perhaps, Y is:
Figure A9881081100163
Wherein R " independently is H or C separately 1-4Alkyl, s are 1.
Perhaps, Y is:
Figure A9881081100171
Wherein G is S, R " independently is H or C 1-4Alkyl.
Perhaps, Y is:
Figure A9881081100172
Wherein R " is H or C 1-4Alkyl.
Below be representative or its pharmacy acceptable salt of new compound of the present invention.(±)-10,11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimidine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-aminopyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-dibenzo [b, f] oxa-English in heptan (oxepine)-10-acetate; (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] oxa-English in heptan-10-acetate; (S)-10,11-dihydro-3-[3-(2-aminopyridine-4-yl)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate.
The compounds of this invention can have under the situation of one or more chiral centres therein, and unless stated otherwise, what the present invention includes each uniqueness can be synthetic by common technology and the non-racemic compound that splits.According to the present invention, (S) configuration of preferred formula (I) compound.
Compound has under the situation of unsaturated carbon-to-carbon double bond therein, and cis (Z) and trans (E) isomer all are included within the scope of the invention.Any substituent meaning under any circumstance all is a meaning independently, under what its situation perhaps in office, and any other substituent meaning.
The present invention also comprises the prodrug of The compounds of this invention.Prodrug is considered to discharge in vivo any carrier with covalent bonds of formula (I) active parent drug.Therefore, the present invention is new formula (II) prodrug or its pharmacy acceptable salt on the other hand, and it also is the intermediate of preparation formula (I) compound:
Figure A9881081100191
Wherein: A is CH 2Or O; R 1Be H, halogen or C 1-6Alkyl; R 2Be H, C 1-6Alkyl or CH 2NR " R "; X is O or CH 2Y is
Figure A9881081100201
Or
Figure A9881081100203
G is NR ", S or O; R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen; " independent separately is H or C to R 1-6Alkyl; And s is 0,1 or 2.The present invention is new formula (III) intermediate or its pharmacy acceptable salt on the other hand: Wherein:
A is CH 2Or O;
R 1Be H, halogen or C 1-6Alkyl;
R 2Be H, C 1-6Alkyl or CH 2NR " R ";
X is O or CH 2
R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen; And
" independent separately is H or C to R 1-6Alkyl.
Adopt general abbreviation used in peptide and the chemical field and nomenclature compound of the present invention herein.Generally speaking, amino acid abbreviations is followed Eur.J.Biochem., the biochemical nomenclature mo of the IUPAC-IUB joint committee described in 158,9 (1984).
C used herein 1-4Alkyl is meant the alkyl of optional 1-4 the carbon atom that replaces, and comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.C 1-6Alkyl also comprise amyl group, n-pentyl, isopentyl, neo-pentyl and hexyl with and simple aliphatic isomer.C 0-4Alkyl and C 0-6Alkyl also represents to have alkyl to have (as: having covalent linkage).
Any C 1-4Alkyl or C 1-6Alkyl can be chosen wantonly by R XReplace R XCan be on any carbon atom that can produce rock steady structure and can obtain by synthetic technology commonly used.Suitable R XGroup comprises C 1-4Alkyl, OR ", SR ", C 1-4Alkyl sulphonyl, C 1-4Alkyl sulfoxyl ,-CN, N (R ") 2, CH 2N (R ") 2,-NO 2,-CF 3,-CO 2R " ,-CON (R ") 2,-COR ", NR " C (O) R ", F, Cl, Br, I or CF 3S (O) r-, wherein r is 0,1 or 2.
Halogen or halo refer to F, Cl, Br and I.
Ar used herein or aryl refer to phenyl or naphthyl or by 1-3 alkyl, particularly C as defined above 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkylthio, CF 3, NH 2, OH, F, Cl, Br or I the phenyl or naphthyl that replaces of substituting group.
Herein with some group abbreviation.T-Bu refers to the tertiary butyl, and Boc refers to tert-butoxycarbonyl, and Fmoc refers to the fluorenyl methoxy carbonyl, and Ph refers to phenyl, and Cbz refers to the benzyloxy carbonyl, and Bn refers to phenmethyl, Me nail base, and Et refers to ethyl, and Ac refers to ethanoyl, and Alk refers to C 1-4Alkyl, Nph refer to 1-or 2-naphthyl and cHex finger ring hexyl.Tet refers to the 5-tetrazyl.
Some reagent uses abbreviation herein.DCC refers to dicyclohexyl carbodiimide, and DMAP refers to Dimethylamino pyridine, and DIEA refers to diisopropylethylamine, and EDC refers to 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride.HOBt refers to I-hydroxybenzotriazole, and THF refers to tetrahydrofuran (THF), and DIEA refers to diisopropylethylamine, and DEAD refers to diethyl azodiformate, PPh 3Refer to triphenyl phosphine, DIAD refers to diisopropyl azodiformate, and DME refers to glycol dimethyl ether; DMF refers to dimethyl formamide; NBS refers to N-bromosuccinimide, and Pd/C refers to palladium-carbon catalyst, and PPA refers to Tripyrophosphoric acid; DPPA refers to diphenyl phosphoryl azide; BOP refers to benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate, and HF refers to hydrofluoric acid, and TEA refers to triethylamine; TFA refers to trifluoroacetic acid, and PCC refers to pyridinium chlorochromate.
Formula (I) compound is generally by making the reaction of formula (IV) compound and formula V compound:
Figure A9881081100221
Y-(CH 2) 2-3-L 1(V)
R wherein 1, R 2, Y and A be by definition in the formula (I), can have any protected active function groups, L 1Be OH or halogen; Remove any protecting group then and prepare, and the optional pharmacy acceptable salt that forms.
Suitably, some formula (I) compound can react by making formula (IV) compound and formula (VI) compound:
Figure A9881081100222
R wherein 1, R 2, " and A can have any protected active function groups by definition in the formula (I) for R ', R; Remove any protecting group then and prepare, and the optional pharmacy acceptable salt that forms.
Reaction between formula (IV) compound and formula (VI) compound is suitable for carrying out in the presence of diethyl azodiformate and triphenyl phosphine in non-protonization solvent.
In addition, some formula (I) compound can react by making formula (IV) compound and formula (VII) compound:
R wherein 1, R 2, " and A can have any protected active function groups by definition in the formula (I) to R; Remove any protecting group then and prepare, and the optional pharmacy acceptable salt that forms.
Reaction between formula (IV) compound and formula (VII) compound is suitable in aprotic solvent, carries out in the presence of diethyl azodiformate and triphenyl phosphine.
Formula (I) compound can be by the described method preparation of Bondinell etc. (PCT publication No. WO 97/01540 (international application no PCT/US96/11108), 1997, in January, 16 open), and all disclosures are attached among the present invention as a reference.
In addition, formula (I) compound can by with the similar approach preparation described in the scheme of following detailed description.
Scheme I A) 10%Pd/C, HOAc; B) SOCl 2, toluene; C) AlCl 3, CH 2Cl 2
Scheme I elaborates the method for making of the intermediate that is used for preparation formula (I) compound.
Scheme II
Figure A9881081100241
A) LiN (TMS) 2, bromoethyl acetate; B) Jones reagent, OsO 4C) H 2, 10%Pd/C, HOAC; D) C 2O 2Cl 2, DMF; E) AlCl 3, CH 2Cl 2, RT; F) H 2, 10%Pd/C, HOAC
Scheme II also elaborates the method for making of the intermediate that is used for preparation formula (I) compound.
Scheme III A) EtOAc/LiHMDS, THF; B) H 2, 10%Pd/C, dense HCl, AcOH; C) EtSH, AlCl 3, CH 2Cl 2D) amino 2-[(3-hydroxyl-1-propyl group)]-4-nitropyridine-N-oxide compound, DEAD, (Ph) 3P; E) NaOEt, EtOH; F) suberene, 10%Pd/C, EtOH; G) 1.0N NaOH, EtOH; H) HCl.
Scheme III elaborates the method for preparation formula (I) compound.III-1 (being scheme I-3 compound) in aldol condensation-type reaction obtains III-2 with the enolate reaction of ethyl acetate, and this enolate can be by being exposed to ethyl acetate in suitable amide alkali (as producing in di-isopropyl lithamide (LDA) or two (trimethyl silyl) lithamide (LiHMDS).Though often use the THF in the presence of various additives (as HMPA or TMEDA), THF is the common agents of aldolisation.By ore deposit acid as HCl in the presence of, in appropriate solvent such as acetate, hydrogenolysis is finished the reduction reaction of III-2 to III-3 (being scheme II-6 compound) under suitable catalyzer such as palladium carbon (Pd/C) act on.Perhaps, the logical method of available Orfanopoulos and Smonou (Synth.Commun.1988,833), in the presence of boron-trifluoride etherate, by with III-2 with triethyl silicane this reduction reaction of finishing dealing with.By at inert solvent such as CH 2Cl 2In with BBr 3Reaction is perhaps passed through at the preferred CH of inert solvent 2Cl 2In with sulfur alcohol and AlCl 3The piptonychia ether reaction of III-3 to III-4 finished in reaction.Other process useful of removing methyl ether is seen Greene, described in " Protective Groups in Organic Synthesis " (John Wileyand Sons publication).At Mitsunobu-type coupled reaction (Organic Reactions1992,42,335-656; Synthesis 1981,1-28) in, the compound 4 (III-4) that makes scheme 3 and 2-[(3-hydroxyl-1-propyl group) amino]-4-nitropyridine-N-oxide compound reaction obtains III-5.This reaction is compound-mediated by what form between diethyl azodiformate and triphenyl phosphine, and at aprotic solvent such as THF, CH 2Cl 2Or carry out among the DMF.Make the compound III-5 and an alkali metal salt reaction of suitable alcohol obtain III-6.Suitable basic metal comprises lithium, sodium, potassium and caesium, and the alcohol that is used for replacement(metathesis)reaction is general as this solvent.To those skilled in the art, the method that forms an alkali metal salt of alcohol is familiar with.Become corresponding pyridine III-7 to use palladium catalyst under the transfer hydrogenolysis condition pyridine-N-oxide partial reduction of III-6, preferred active carbon-supported palladium carries out in inert solvent such as methyl alcohol, ethanol or 2-propyl alcohol.In the type reaction, as hydrogen transfer agent be generally tetrahydrobenzene, 1, formic acid and formate, as potassium formiate or ammonium formiate.The aqueous solution of available bases as the THF aqueous solution of LiOH or methyl alcohol or the aqueous ethanolic solution of NaOH, with the ethyl ester hydrolysis of III-7, and generates carboxylic acid III-8 with suitable acid such as TFA or this intermediate carboxylate of HCl acidifying.Perhaps, this intermediate carboxylic acid can be separated, perhaps this free carboxy acid's carboxylate salt can be prepared by the method that those skilled in the art are familiar with as needs.
Scheme IV (a) NaH, 2-[N-(3-mesyloxy-1-propyl group)-N-(tertbutyloxycarbonyl) amino] pyridine-N-oxide, DMSO; (b) TFA, CH 2Cl 2(c) square case III.
Scheme IV illustrates the method for another kind of preparation formula (I) compound.In polarity, aprotic solvent, be generally in THF, DMF, DMSO or its mixture, make compound IV-1 and alkali, preferred as alkali hydride such as sodium hydride or potassium hydride KH, reaction obtains corresponding alkali phenolate.In addition, available alkali metal ammonia compound such as LDA, or the lithium of hexamethyldisilazane, sodium or sylvite carry out hydrogenation reaction.The intermediate of this phenates is generally without separation, but in position with suitable electrophilic reagent, as 2-[N-(3-mesyloxy-1-propyl group)-N-(tertbutyloxycarbonyl) amino] pyridine-N-oxide, reaction generates coupling product IV-2.Under acidic conditions, as 1 of 4M HCl, the CH of 4-dioxane liquid or TFA 2Cl 2Liquid, the tert-butoxycarbonyl protecting group of removing among the IV-2 obtains IV-3.To those skilled in the art, remove the condition of this tert-butoxycarbonyl protecting group and be familiar with, some useful method is at canonical reference book such as Greene, explanation in " Protective Groups in Organic Synthesis ".Then, IV-3 is changed into IV-4 by the method for scheme III explanation.
Plan V (a) PhOH, Cu, K 2CO 3(b) sulphur, morpholine; (c) KOH, H 2O, i-PrOH; (d) SOCl 2, benzene; (e) AlCl 3, CH 2Cl 2(f) EtOAc, LiN (TMS) 2, TMEDA, THF; (g) Et 3SiH, BF 3OEt 2, CH 2Cl 2(h) H 2, Pd/C, EtOH; (i) BBr 3, CH 2Cl 2
At copper metal and suitable alkali such as K 2CO 3Exist down, the 2-fluoro-4-methoxyacetophenone that commerce is provided obtains diaryl ether V-2 with alcohol as phenol reactant.According to the logical method of Harris (J.Med.Chem.1982,25,855), handle with sulphur and suitable uncle or secondary amine (preferred morpholine), in typical Willgerodt-Kindler reaction, V-2 is converted into V-3.By in the aqueous solution of alcohol,,, the above thioamides hydrolysis that obtains is obtained corresponding carboxylic acid V-4 with alkali-metal oxyhydroxide (KOH is suitable) reaction as the aqueous solution of MeOH, EtOH or i-PrOH.The condition of being familiar with according to those skilled in the art, by with SOCl 2Or the oxalyl chloride reaction, carboxylic acid V-4 is changed into corresponding acyl chlorides.In inert solvent, as CH 2Cl 2Or CS 2In, with this acyl chlorides with suitable Friedel-Crafts catalyzer, as AlCl 3Or SnCl 4, handle obtaining cyclic ketones V-5.In addition, can be under acidic conditions, as have under the Tripyrophosphoric acid condition, sour V-4 is converted into ketone V-5.The reaction of the V-5 in aldol condensation-type reaction and the enolate of ethyl acetate obtains V-6, and this enolate can be by being exposed to ethyl acetate in suitable amide alkali (as producing in di-isopropyl lithamide (LDA) or two (trimethyl silyl) lithamide (LiHMDS).Though often use the THF in the presence of various additives (as HMPA or TMEDA), THF is the common agents of aldolisation.The logical method of available Orphanopoulos and Smonu (Synth.Commun.1988,833) in the presence of boron-trifluoride etherate, is finished the reaction that V-6 is reduced into V-7 by handling V-6 with triethyl silicane.Can with suitable catalyzer such as palladium carbon (Pd/C) effect hydrogenation down, this alcohol be eliminated any alkene by product reduction that generates in the reaction by in appropriate solvent such as MeOH or EtOH.In addition, can ore deposit acid as HCl in the presence of, finish the reaction that V-6 is reduced into V-7 by hydrogenolysis.In general, Pd/C catalysis is used in this reaction, and is suitable for most carrying out in acetate.By at inert solvent such as CH 2Cl 2In with BBr 3Reaction is perhaps passed through at the preferred CH of inert solvent 2Cl 2In with sulfur alcohol and AlCl 3The piptonychia ether reaction of V-7 to V-8 finished in reaction.Other process useful of removing methyl ether is seen Greene, " described in the Protective Groups in OrganicSynthesis ＂ (John Wiley and Sons publication).By the method for being carried among the scheme III, again V-8 is converted into formula (I) compound.
The available standards method in appropriate solvent, with this parent compound and excessive acid, example hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, toxilic acid, succsinic acid or methylsulfonic acid, prepares the acid salt of this compound.Acceptable inner salt of some compound formation or zwitter-ion.Cationic salts can by with this parent compound with the excessive suitable cationic alkali reagent that contains, as oxyhydroxide, carbonate or alkoxide, perhaps use suitable organic amine Processing of Preparation.Positively charged ion such as Li +, Na +, K +, Ca ++, Mg ++And NH 4 +It is the cationic specific examples that is present in the pharmacy acceptable salt.
The present invention also provides medicinal compositions, and it comprises according to the compound of formula (I) and pharmaceutically acceptable carrier.Therefore, formula (I) compound can be used for preparing medicine.Medicinal compositions by formula (I) compound of the above preparation can be mixed with solution or cryodesiccated powder for parenterai administration.Before using,, powder is copied into solution by adding suitable dilution agent or other pharmaceutically acceptable carrier.Liquid preparation can be the buffering, etc. ooze, the aqueous solution.Suitably the example of thinner is the buffered soln of physiology normal isotonic saline solution, standard 5% D/W or amine acetate or sodium acetate.These preparations are specially adapted to parenterai administration, but also can be used for oral administration be loaded on metered dose inhaler or atomizer in for being blown into administration.It can add vehicle, as polyvinylpyrrolidone, gelatin, hydroxylated cellulose, gum arabic, polyoxyethylene glycol, mannitol, sodium-chlor or Trisodium Citrate.
In addition, can or make emulsion or syrup is for oral administration with these compound encapsulate capsules, compressing tablet.Can add pharmaceutically acceptable solid or liquid vehicle with enhancing or stable said composition, or so that preparation composition.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, terra alba, Magnesium Stearate or stearic acid, talcum powder, pectin, Sudan Gum-arabic, agar or gelatin.Liquid vehicle comprises syrup, peanut oil, sweet oil, salt solution and water.Carrier can comprise sustained-release materials such as glyceryl monostearate or distearin, can share separately or with the wax class.The amount of solid carrier can change, preferably at the about 1g of the about 20mg-of every dose unit.Pharmaceutical preparation can be by drug technique preparation commonly used, the compressing tablet when comprising grinding, mixing, granulate and making tablet form in case of necessity; Or grinding, mixing and the filling of making hard gelatin capsule.When using liquid vehicle, preparation is syrup, elixir, emulsion or water or non-aqueous suspension form.Can be with this liquid preparation directly oral or be filled in administration in the soft gelatin capsule.
During for rectal administration, The compounds of this invention can be combined with vehicle,, and be molded as suppository as theobroma oil, glycerine, gelatin or polyoxyethylene glycol.
Compound of the present invention is the antagonist of Vitronectic receptor, and can be used for treating the disease that wherein basic pathology and the interactional part of Vitronectic receptor or cell cause.For example, this compound can be used for treating the disease that wherein ground substance of bone loss causes.Therefore, these compounds can be used for treating the bone loss that osteoporosis, hyperparathyroidism, PagetShi disease, pernicious hypercalcemia, bone shift the molten bone infringement that causes, caused by ligamentopexis or sex hormone deficiency.Think that also The compounds of this invention has antitumor, angiogenesis inhibitor, anti-inflammatory and anti-metastasis agent effect, and can be used for treating atherosclerosis and restenosis.
Can be enough to suppress bone resorption or other symptoms form with drug level, give the patient the oral or non-enteron aisle of this compound.Can be according to patient's situation, the medicinal compositions that will contain The compounds of this invention gives the patient with the about 50mg/kg oral dosage of about 0.1-.Preferred oral dosage is the about 20mg/kg of about 0.5-.For acute treatment, preferred parenterai administration.Though also available intramuscular large bolus injection, the most effectively intravenous infusion of 5% D/W of this peptide or normal saline solution or have the similar formulations of appropriate excipients.Generally speaking, parenterai administration dosage is about the about 100mg/kg of 0.01-; Preferably between 0.1-20mg/kg.This compound can be given 1-4 time every day, to reach the total dose every day level of about 0.4-about 400mg/kg/ day.By the blood levels and the concentration that need have result of treatment of this medicine relatively, the technician of this area routine is easy to determine to give the accurate level of this compound and give method.
The present invention also provides the treatment osteoporosis or suppresses the method for bone loss, it comprises and progressively giving or with physical composition form giving construction (I) compound and other bone resorption inhibitor, for example diphosphonates (as Alendronate (allendronate)), Hormone Replacement Therapy, estrogen antagonist or thyrocalcitonin.In addition, the invention provides,, be used to suppress the bone loss and/or increase sclerotin as bone shaping fibroin, different third flavones (iproflavone) with The compounds of this invention and anabolic agent.
In addition, the method that the present invention also provides treatment to suppress tumor growth, it comprises and progressively giving or with form giving construction (I) compound and the antineoplastic agent of physical composition.The camptothecin analogues compounds, as holder pool for may, irinotecan and 9-aminocamptothecin, and platinum coordination complex as cis-platinum, ormaplatin and four platinum, all is the antineoplastic agent of knowing.In United States Patent(USP) Nos. 5,004,758,4,604,463,4,473,692,4,545,880,4,342,776,4,513,138,4,399,276, European patent application published number 0418099 and 0088642, Wani etc., J.Med.Chem., 1986,29,2358, Wani etc., J.Med.Chem., 1980,23,554, Wani etc., J.Med.Chem., 1987,30,1774 and Nitta etc., Proc.14th International Congr.Chemotherapy., 1985, Anticancer Section I, the compound of explanation camptothecin analogues class in 28 is attached among the present invention as a reference in these all disclosures with every piece.Platinum coordination complex, cis-platinum is provided with trade(brand)name Platinol  by Bristol Myers-SquibbCorporation.The useful preparation of cis-platinum is at U.S. Patent number 5,562, and explanation in 925 and 4,310,515 is attached among the present invention as a reference in these all disclosures with every piece.
Comprise therein progressively giving or suppressing in the method for tumor growth, give iridium-platinum complex with venoclysis at a slow speed, as cis-platinum with form giving construction (I) compound of physical composition and antineoplastic agent.Preferred carrier is glucose/the contain salt solution of N.F,USP MANNITOL.The administration arrangement of iridium-platinum complex can be according to the about 500mg (mg/m of the about 1-of each course of treatment of every square metre of body surface area 2) be foundation.The infusion iridium-platinum complex can give 1-2 time weekly, and this cycle treatment can repeat several times.Use non-enteron aisle to give the camptothecin analogues compounds, this therapeutic process is generally the about 0.1-300.0mg (mg/m of every body surface area about five day every day continuously 2).Most preferably using the holder pool is continuously the about five day about 2.0mg (mg/m of the about 1.0-of every body surface area every day for the therapeutic process of bearing 2).Preferably about 7 days to about 28 day intervals, this therapeutic process repeats once at least.
Medicinal compositions can be prepared an accepted way of doing sth (I) compound and the formulation of antineoplastic agent in same package, but preferably in Different Package.When two kinds of medicines all are liquid form, it can be contained in the infusion/injection system for the while administration or by the priority administration.
Be convenient simultaneously or not giving construction (I) compound and antineoplastic agent simultaneously, the preparation test kit, comprise single packing, as box, carton or other container, single bottle, bag, phial or other container, its each have significant quantity for aforesaid formula (I) compound of parenterai administration and the aforesaid antineoplastic agent for parenterai administration of significant quantity.These test kits can comprise, and are as the independent packaging or the same packaged form of these medicines, optional as cryodesiccated plug shaped article and contain the vessel form that is used for again reconstituted solution.This class solution and cryodesiccated plug shaped article that blended before use in two Room that are included in single container Gong duplicates that change form.This class arrangement can the independent packaging in two containers with antineoplastic agent and compound of the present invention, or lyophilize powdered and providing in same container together.
When two kinds of reagent are the solution form, they can be made into the transfusion/injecting systems that is used for synchronous administration or be made into form of medication in succession.For example, formula (I) compound can be an intravenous injection form or by the infusion bag form of intubate with antineoplastic agent in another infusion bag polyphone.Use this system, the patient can accept the initial large bolus injection or the infusion of formula (I) compound, infusion antineoplastic agent then earlier.
A kind of this compound of test of available several bioassay methods is to determine the having needed compound concentration of certain pharmacologically active.That the vitronectin bonded suppresses is solid-state [ 3H]-SK﹠amp; F-107260 is to α Vβ 3Combination: damping fluid T (is contained 2mM CaCl 2With 1% octyl group glycoside) in Placenta Hominis or human body platelet α Vβ 3(0.1-0.3mg/mL) with containing 1mM CaCl 2, 1mM MnCl 2, 1mM MgCl 2(buffer A) and 0.05%NaN 3Damping fluid T dilution, then with every hole 0.1mL join immediately 96-hole ELISA flat board (Corning, New York, NY) in.Every hole adds the α of 0.1-0.2 μ g Vβ 3Under 4 ℃, this flat board is incubated overnight.During experiment, with every hole once with buffer A washing, then under the room temperature, in same buffer with 0.1ml 3.5% bovine serum albumin(BSA) incubation.Behind the incubation, every hole is extracted out fully, with 0.2ml buffer A washed twice.
Compound is dissolved in preparation 2mM storing solution among the 100%DMSO, it is used binding buffer liquid (15mM Tris-HCl (pH7.4), 100mM NaCl, 1mM CaCl 2, 1mMMnCl 2, 1mM MgCl 2) to obtain final compound concentrations be 100 μ M in dilution.Then with this solution dilution to required final compound concentrations.The unmarked antagonist (0.001-100 μ M) of various concentration is joined in each hole in triplicate, add then 5.0nM [ 3H]-SK﹠amp; F-107260 (65-86Ci/mmol).
Should the flat board incubation under the room temperature 1 hour.Behind the incubation, every hole is extracted out fully,, wash once with the buffer A that 0.2mL is ice-cold in the mode of Kong Zhikong.This receptor with the 1%SDS solubilising of 0.1ml, on Beckman LS liquid scintillation counter, is added 3mL ReadySafe, by liquid scintillation counting(LSC) measure 40% bonded of rendeing a service [ 3H]-SK﹠amp; F-107260.At 2 μ M SK﹠amp; Measure under F-107260 exists not the specificity bonded [ 3H]-SK﹠amp; F-107260, non-specific combination generally is less than 1% of gross activity part input.By being applicable to conventional nonlinear least square curve determination IC from the LUNDON-2 program is improved 50Value (promptly suppresses 50%[ 3H]-SK﹠amp; The concentration of this antagonist of F-107260 bonded).According to equation: K i=IC 50/ (1+L/K d) calculating K i(dissociation constant of antagonist), wherein L and K dBe respectively [ 3H]-SK﹠amp; The concentration of F-107260 and the constant that dissociates.
The compounds of this invention suppresses vitronectin and SK﹠amp; F 107260 bonded concentration ranges are about 2.5-0.001 μ mol.
Also can estimate the standard determination method that bone forming is suppressed by this area, form laboratory method as disclosed recess (pit) in EP 528587, wherein available human body osteoclast replaces the osteoclast of rat, and by Wronski etc., Cells and Materials 1991, Sup.1, the described ovariectomized rat model of 69-74 comes The compounds of this invention is carried out bone resorption test in the external and body.Vascular smooth muscle cells migration is measured
Use the aortic smooth muscle cell of rat or human body.By using the polycarbonate membrane (Costar) in 8um hole, in the Transwell cell culture incubator, detect the migration of this cell.With the lower surface of this filter membrane vitronectin coating.Cell is suspended to concentration in the DMEM that is supplemented with 0.2% bovine serum albumin(BSA) be 2.5-5.0 * 10 6Cell/mL is then under 20 ℃, with the test-compound pre-treatment of different concns 20 minutes.With solvent in contrast.Put into this cell suspending liquid of 0.2mL on the top of this incubator.The lower section comprises the DMEM that 0.6mL is supplemented with 0.2% bovine serum albumin(BSA).Under 37 ℃, at 95% air/5%CO 2Middle incubation 24 hours.Behind the incubation, the cell that this filter membrane upper surface is not moved scrapes off gently.Then that this filter membrane is fixing in methyl alcohol, dye with 10% Giemsa stain.Pass through a) to measure the cell quantity of this filter membrane lower surface of having moved or pass through b) with the painted cell of 10% acetic acid extraction, measure optical density then at the 600nM place and measure migration.The rat model of Tiroidina parathyroidectomy
Each experimental group comprises 5-6 bull Sprague-Dawley rat (body weight 250-400g).The Tiroidina parathyroid gland (finishing) of 7 days before use excision rats by seller TaconicFarms.All rats accepted to replace the thyroxine of dosage in per 3 days.Receive rat, get blood to heparinization Guan Zhonghou, measure the level of the circulation ionised calcium in the whole blood immediately by the tail venipuncture.If this Ionized Ca level (with Ciba-Coming type 634 calcium pH analysis-e/or determinings)＜1.2mM/L, this rat can be used.Vein is buried in the assembling of every rat and ductus arteriosus transmits experiment material and blood sample to be respectively applied for.Feed the omnivorous and deionized water of no calcium to rat then.Establishment of base line Ca level, pass through continuously to the ductus venosus venoclysis with outer syringe pump then, give every rat contrast solvent or human pthrp hormone 1-34 peptide (hPTH1-34, dosage is salt solution/0.1% bovine serum albumin(BSA) liquid of 1.25 μ g/kg/h, Bachem, Ca) or the mixture of hPTH1-34 and experiment material.During 6-8 hour of infusion, the blood calcium of every mouse of measuring space response every two hours.The human body osteoclast absorbs and adheres to be measured
Carry out and absorption of stdn recess and adhesion mensuration with the normal human's osteoclast that comes from the osteoclast tumor tissue.Measure 1 by using laser focusing measurement microscope osteoclast recess volume to carry out.Measure 2 and undertaken by high flux screening, wherein the former fragment of amine (discharging in the absorption) is measured by competitive ELISA.Measure 1 (using the laser focusing microscope)
The suspension that equal portions is come from human body osteoclast oncocyte is stored up taking-up from liquid nitrogen, is warmed to 37 ℃ rapidly, and by centrifugal (under 4 ℃, 1000rpm 5 minutes), washing is 1 time in the RPMI-1640 substratum.
This substratum sucking-off is also replaced with anti--HLA-DR antibody of mouse, in the RPMI-1640 substratum, diluted then with 1: 3.With this suspension incubation 30 minutes and constantly mixing in ice.With this cell with cold RPMI-1640 substratum washing 2 times, centrifugal then (under 4 ℃, 1000rpm 5 minutes), again with this cell transfer to aseptic 15ml centrifuge tube.The monocytic number of metering in improved Neubauer nucleonics.(capacity magnetic bead NY) (5/ monocyte) takes out from its storage bottle for Dynal, GreatNeck, places the fresh substratum of 5ml (this step is used to wash off toxic trinitride sanitas) again will to be coated with goat anti-mouse IgG.By on magnet fixedly magnetic bead remove substratum, replace with fresh substratum again.With this magnetic bead and cytomixis, again on ice with this suspension incubation 30 minutes.Constantly mix this suspension.The cell that is coated with magnetic bead is fixing on magnet, more remaining cell (being rich in the osteoclast part) is poured in the aseptic 50ml centrifuge tube.Fresh substratum is joined in the cell that is coated with magnetic bead to remove any osteoclast of being held back.This washing process is repeated 10 times.Discard the cell that is coated with magnetic bead.With the cell that the fluorescein diacetate mark is lived, the osteoclast of survival is counted in nucleonics.With the disposable plastics pasteur pipet of macropore sample is joined in this nucleonics.By centrifugal with osteoclast precipitation, in the EMEM substratum that is supplemented with 10% foetal calf serum and 1.7g/L sodium bicarbonate, with Auto-regulating System of Density of Heavy Medium to appropriate value (number of this osteoclast changes with tumour).This cell suspending liquid of 3ml equal portions (each compound treatment) is poured in the 15ml centrifuge tube.With this cell by centrifugation.In each pipe, add the suitable compound treatment of 3ml (in the EMEM substratum, being diluted to 50 μ M).Comprise that also the contrast of suitable solvent, positive control (will resist-monoclonal antibody [87MEM1] of Vitronectic receptor mouse be diluted to 100 μ g/ml) and homotype contrast (IgG 2aBe diluted to 100 μ g/ml).Under 37 ℃, with this sample incubation 30 minutes.In the aseptic dentine section of this cell inoculation of 0.5ml equal portions in the flat board of 48-hole, 37 ℃ of following incubations 2 hours.Handle screening sample four times with every part.This section is alternately washed (in the six hole flat boards, the 10ml/ hole) 6 times with warm PBS, place the new substratum that contains this compound treatment or control sample then.Under 37 ℃, with this sample incubation 48 hours.Tolerate tartaric acid phosphatase (TRAP) method (to the dyeing of the cell selective of osteoclast pedigree) and will contain the bone slice that adheres to osteoclast and in phosphate buffered saline (PBS), wash, fix 5 minutes in 2% glutaraldehyde (in the 0.2M natrium cacodylicum) then.In water, wash then, again under 37 ℃, the incubation that in the TRAP damping fluid, (is dissolved in N, the 0.5mg/ml naphthols AS-BI phosphoric acid salt of dinethylformamide, and mix) 4 minutes with the 0.25M citrate buffer solution (pH4.5) that contains the 10mM sodium tartrate.In cold water after the washing, (0.1M flooded in pH6.2), 4 ℃ of following incubations 4 minutes at the cold acetate buffer that contains 1mg/ml fast red garnet with this section.Excessive damping fluid is removed in suction, after the washing, should cut into slices at air drying.Measure the positive osteoclast of this TRAP (brick red/red-purple precipitation) number by bright field microscope, remove from this dentine surface by ultrasonic then.Measure the recess volume with Nikon/Lasertec ILM21W focusing microscope.Measure 2 (reading) with ELISA
By measuring enrichment described in 19 steps that begin and preparation human body osteoclast for SCREENED COMPOUND.For clarity sake, these steps are repeated below.The suspension that equal portions is come from human body osteoclast oncocyte takes out from the liquid nitrogen deposit, is warmed to 37 ℃ rapidly, and by centrifugal (under 4 ℃, 1000rpm 5 minutes), washing is 1 time in the RPMI-1640 substratum.This substratum sucking-off is also replaced with anti--HLA-DR antibody of mouse, in the RPMI-1640 substratum, diluted then with 1: 3.With this suspension incubation on ice 30 minutes and constantly mix.With this cell with cold RPMI-1640 substratum washing 2 times, centrifugal then (under 4 ℃, 1000rpm 5 minutes), again with this cell transfer to aseptic 15ml centrifuge tube.The monocytic number of metering in improved Neubauer nucleonics.(capacity magnetic bead NY) (5/ monocyte) takes out from its storage bottle for Dynal, Great Neck, places the fresh substratum of 5ml (this step is used to wash off toxic trinitride sanitas) again will to be coated with goat anti-mouse IgG.By on magnet fixedly magnetic bead remove substratum, replace with fresh substratum again.With this magnetic bead and cytomixis, again on ice with this suspension incubation 30 minutes.Constantly mix this suspension.The cell that is coated with magnetic bead is fixing on magnet, more remaining cell (being rich in the osteoclast part) is poured in the aseptic 50ml centrifuge tube.Fresh substratum is joined in the cell that is coated with magnetic bead to remove any osteoclast of being held back.This washing process is repeated 10 times.Discard the cell that is coated with magnetic bead.With the cell that the fluorescein diacetate mark is lived, the osteoclast of survival is counted in nucleonics.With the disposable plastics pasteur pipet of macropore sample is joined in this nucleonics.By centrifugal with osteoclast precipitation, in the EMEM substratum that is supplemented with 10% foetal calf serum and 1.7g/L sodium bicarbonate, with Auto-regulating System of Density of Heavy Medium to appropriate value (number of this osteoclast changes with tumour).
Opposite with the method described in the above mensuration 1, by following described, obtain IC with 4 dose screening compounds 50Value.Under 37 ℃, with osteoclast prepared product and test-compound (4 dosage) or contrast preincubation 30 minutes.Then in the section with the ox cortex bone of this cell inoculation in the tissue culture plate of 48-hole, incubation 2 hours again under 37 ℃.The section of this bone is alternately washed 6 times removing NA cell with warm phosphate buffered saline (PBS) (PBS), and then join in the hole of the 48 hole flat boards that contain new compound or contrast.Then under 37 ℃, with this tissue culture plate incubation 48 hours.The supernatant liquor in each hole is drawn in each pipe, and screens in competitive ELISA, ELISA can detect the proteic c-end of the type i collagen that discharges peptide in absorption process.ELISA can provide (Osteometer by commerce, Denmark), it contains the rabbit antibody that can specificity reacts with 8-aminoacid sequence (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg), and this aminoacid sequence is present on the end peptide of carboxyl-terminal of the proteic a1-chain of type i collagen.Its result uses the % with respect to the absorption inhibition of solvent contrast to represent.The human body osteoclast adheres to be measured
Supply the human body osteoclast of SCREENED COMPOUND by enrichment described in initial 9 steps of above mensuration and preparation.For clarity sake, these steps are repeated below.The suspension that equal portions is come from human body osteoclast oncocyte takes out from the liquid nitrogen deposit, is warmed to 37 ℃ rapidly, and by centrifugal (under 4 ℃, 1000rpm 5 minutes), washing is 1 time in the RPMI-1640 substratum.This substratum sucking-off is also replaced with anti--HLA-DR antibody of mouse, in the RPMI-1640 substratum, diluted then with 1: 3.With this suspension incubation on ice 30 minutes and constantly mix.With this cell with cold RPMI-1640 substratum washing 2 times, centrifugal then (under 4 ℃, 1000rpm 5 minutes), again with this cell transfer to aseptic 15ml centrifuge tube.The monocytic number of metering in improved Neubauer nucleonics.(capacity magnetic bead NY) (5/ monocyte) takes out from its storage bottle for Dynal, GreatNeck, places the fresh substratum of 5ml (this step is used to wash off toxic trinitride sanitas) again will to be coated with goat anti-mouse IgG.By on magnet fixedly magnetic bead remove substratum, replace with fresh substratum again.With this magnetic bead and cytomixis, again on ice with this suspension incubation 30 minutes.Constantly mix this suspension.The cell that is coated with magnetic bead is fixing on magnet, more remaining cell (being rich in the osteoclast part) is poured in the aseptic 50ml centrifuge tube.Fresh substratum is joined in the cell that is coated with magnetic bead to remove any osteoclast of being held back.This washing process is repeated 10 times.Discard the cell that is coated with magnetic bead.With the cell that the fluorescein diacetate mark is lived, the osteoclast of survival is counted in nucleonics.With the disposable plastics pasteur pipet of macropore sample is joined in this nucleonics.By centrifugal with osteoclast precipitation, in the EMEM substratum that is supplemented with 10% foetal calf serum and 1.7g/L sodium bicarbonate, with Auto-regulating System of Density of Heavy Medium to appropriate value (number of this osteoclast changes with tumour).Under 37 ℃, will come from the osteoclast and the compound (4 dosage) of osteoclastoma or contrast preincubation 30 minutes.Then with this cell inoculation (osteopontin of people or mouse, 2.5 μ g/ml) on the slide glass that is coated with osteopontin, 37 ℃ of following incubations 2 hours.In phosphate buffered saline (PBS), to remove not adherent cell, that the cell of leaving on the slide glass is fixing in acetone by this slide glass of violent flushing.Osteoclast is tolerated tartaric acid phosphatase (TRAP) dyeing, and promptly the selected marker of this phenotype cell (seeing step 15-17) is counted by opticmicroscope.The result uses the % with respect to the adherence inhibition of solvent contrast to represent.Cell adhesion is measured cell and cell culture medium
Human body embryonic kidney cells (HEK293 cell) from ATCC (catalog number (Cat.No.) CRL 1573) acquisition.Culturing cell in containing the EarlShi MEM (EMEM) of EarlShi salt, 10% foetal calf serum, 1% glutamine and 1% penicillin-Streptomycin sulphate.Construction and transfection
With α VThe 3.2kb EcoRI-KpnI fragment and the β of subunit 3The 2.4kb XbaI-XhoI fragment of subunit is inserted into the EcoRI-EcoRV clone position (Aiyar etc., 1994) of pCDN carrier, and this carrier contains CMV promotor and the G418 selected marker thing that is connected by flush end.Be stably express, use gene pulse producer (Gene Pulser) (Hensley etc., 1994) 80 * 10 6HEK 293 cells and α V+ β 3Construction (every subunit 20 μ g DNA) electricity transforms, and is inoculated in the 100mm flat board (5 * 10 then 5Cell/flat board).After 48 hours, (Bethesda MD) replenishes for G418 vitriol, GIBCO-BRL with 450 μ g/mL Geneticins with this growth medium.This cell is kept in the selective medium to grow up until colony can be used for test.The immunocytochemical assay of transfectional cell
For determining whether HEK 293 transfectants express Vitronectic receptor, by centrifugal with this cell fixation on glass microscope slide, in acetone, fix 2 minutes under the room temperature, dry air.The available standards indirect immunofluorescence is measured the single-minded activity with 23C6, to this α Vβ 3Mixture monoclonal antibody specificity.Cellular adhesion studies
Under 4 ℃, Coming 96-hole ELISA flat board is wrapped quilt in advance with 0.1mL human body vitronectin (0.2 μ g/mL in the RPMI substratum).During experiment, should wash once with the RPMI substratum by flat board, then at room temperature in the RPMI substratum, with 3.5%BSA sealing 1 hour.293 cells of transfection are suspended in the RPMI substratum again, in density 0.5 * 10 6Under cell/mL, this culture medium supplemented 20mM Hepes, pH7.4 and 0.1%BSA.At various α Vβ 3Antagonist existed or does not exist down, adds the 0.1mL cell suspension in each hole, 37 ℃ of following incubations 1 hour.Behind the incubation, add 0.025mL 10% formaldehyde solution, pH7.4, under the room temperature with this cell fixation 10 minutes.Flat board with 0.2mL RPMI substratum washing three times, is used 0.1mL 0.5% Toluidine blue staining 20 minutes with this adherent cell under the room temperature.With the deionized water thorough washing to remove excessive dyestuff.Be incorporated into the toluidine blue of cell by adding 50% ethanol elution that 0.1mL contains 50mM HCl.With the microtitration card reader (Titertek Multiskan MC, Sterling, VA), quantitative cell adhesion under optical density(OD) 600nm.Solid-state α Vβ 5In conjunction with measuring
Purifying Vitronectic receptor α from Placenta Hominis Vβ 5With acceptor prepared product 50mMTris-HCl, pH7.5,100mM NaCl, 1mM CaCl 2, 1mM MnCl 2, 1mMMgCl 2(buffer A) dilution joins in the ELISA flat board of 96-hole immediately with every hole 0.1mL then.Every hole adds the α of 0.1-0.2 μ g Vβ 3Under 4 ℃, this flat board is incubated overnight.In when experiment, with each hole once with the buffer A washing, under the room temperature, in same buffer with 0.1ml 3.5% bovine serum albumin(BSA) incubation.Behind the incubation, each hole is extracted out fully, with 0.2ml buffer A washed twice.
[ 3H]-SK﹠amp; In the F-107260 competitive assay, (0.001-100 μ m) joins in each hole with the unlabelled antagonist of various concentration, add then 5.0nM [ 3H]-SK﹠amp; F-107260.Should the flat board incubation under the room temperature 1 hour.Behind the incubation, each hole is extracted out fully, in the mode of Kong Zhikong, once with 0.2m1 ice-cold buffer A washing.This receptor with the 1%SDS solubilising of 0.1ml, on Beckman LS6800 liquid scintillation counter, is added 3mLReady Safe, by liquid scintillation counting(LSC) measure 40% bonded of rendeing a service [ 3H]-SK﹠amp; F-107260.At 2 μ M SK﹠amp; F-107260 exists down, measure not the specificity bonded [ 3H]-SK﹠amp; F-107260, non-specific combination generally is less than 0.1% of gross activity part input.By being applicable to conventional nonlinear least square curve determination IC from the LUNDON-2 program is improved 50Value (promptly suppresses 50%[ 3H]-SK﹠amp; The concentration of this antagonist of F-107260 bonded).According to Cheng and Prusoff equation: K i=IC 50/ (1+L/K d) calculating K i(dissociation constant of antagonist), wherein L and K dBe respectively [ 3H]-SK﹠amp; The concentration of F-107260 and the constant that dissociates.
RGD-mediation GPIIb-IIIa bonded suppresses the purifying of GPIIb-IIIa
With ten unit out of date, the human body platelet (obtaining) washed from Red Cross at 4 ℃ 3% octyl group glycoside, 20mM Tris-HCl, pH7.4,140mM NaCl, 2mMCaCl 2In stir dissolving in 2 hours gently.With this lysate 100, under the 000g centrifugal 1 hour.20mM Tris-HCl, pH7.4,100mMNaCl, 2mM CaCl are used in the supernatant liquor adding that obtains in advance 2, on 1% octyl group glycoside (buffer A) the equilibrated 5mL lens lectin sepharose 4B post (E.Y.Labs).Behind 2 hours incubations, this post is washed with 50mL cold buffer liquid A.With the lectin GPIIb-IIIa buffer A wash-out that contains 10% glucose that keeps.All processes are carried out under 4 ℃.Show GPIIb-IIIa purity＞95% that obtains by sds polyacrylamide gel electrophoresis.The infiltration of GPIIb-IIIa in the liposome
Under the logical nitrogen gas stream, that the mixture (Avanti Po1ar Lipids) of phosphatidylserine (70%) and phosphatidylcholine (30%) is dry on the wall of Glass tubing.The GPIIb-IIIa of purifying is diluted to ultimate density 0.5mg/mL, again with phosphatide with protein: 1: 3 (w: w) mix of phosphatide ratio.With this mixture suspendible again, with ultrasonic 5 minutes of water-bath ultrasonic machine.Use 12 then, 000-14,000 molecular weight block dialysis tubing to 1000 times of excessive 50mM Tris-HCl, pH7.4,100mM NaCl, 2mM CaCl 2In (replacing 2 times) with this mixture dialysed overnight.The liposome that will contain GPIIb-IIIa is 12, and under the 000g centrifugal 15 minutes, suspendible again in dialysis buffer liquid, the about 1mg/mL of final protein concentration.This liposome is deposited under-70 ℃, standby.Combine with GPIIb-IIIa is competitive
By use [ 3H]-SK﹠amp; F-107260 carries out measuring in conjunction with fibrin original receptor (GPIIb-IIIa) as the indirect competition combining method of RGD-type part.96-hole filter plate device (Millipore Corporation, Bedford, MA) in, use 0.22 μ m wetting ability durapore film to carry out this in conjunction with experiment.At room temperature, with 0.2mL 10 μ g/mL polylysines (SigmaChemical Co., St.Louis, MO.) with this hole precoating 1 hour with the blocking-up non-specific binding.With the non-marked benzo-aza of various concentration to join in quadruplicate in these holes.Will [ 3H]-SK﹠amp; F-107260 joins in each hole with ultimate density 4.5nM, adds the liposome that 1 μ g contains the thrombocyte GPIIb-IIIa of purifying then.Under the room temperature, with this mixture incubation 1 hour.Filter arm with Millipore, by filter in the middle of unconjugated with the GPIIb-IIIa bonded [ 3H]-SK﹠amp; F-107260 isolates, then with ice-cooled damping fluid washing (2 times, each 0.2mL).1.5mL Ready Solve (BeckmanInstruments, Fullerton, CA) in, on Beckman liquid scintillation counter (LS6800 type), calculate 40% render a service be retained in bonded radioactivity on the filter.At the unlabelled SK﹠amp of 2 μ M; F-107260 exists and to measure non-specific combination down, and non-specific combination generally is less than 0.14% of total radioactivity of adding sample.All data points are the mean value of four parts of mensuration.
By the competitive binding data of the nonlinear least square tracing analysis that is applicable to method.This method provides the IC50 value of this antagonist (promptly to suppress 50%[in the balance 3H]-SK﹠amp; The concentration of this antagonist of F-107260 specificity bonded).This IC50 is relevant with the equilibrium dissociation constant (Ki) based on this antagonist of Cheng and Prusoff equation: Ki=IC50/ (1+L/Kd), and wherein L is that this competition is in conjunction with used [3H]-SK﹠amp in measuring; The concentration of F-107260 (4.5nM), Kd be the 4.5nM that analyze to determine by Scatchard [ 3H]-SK﹠amp; The dissociation constant of F-107260.
The preferred compound of the present invention to the avidity of Vitronectic receptor with respect to the fibrin original receptor greater than 10: 1.Most preferred compounds have the activity ratio greater than 100: 1.
The effectiveness that available several portable mouse tumor model is measured formula (I) compound itself or united with antineoplastic agent.The detailed content of these models is seen U.S. Patent number 5,004,758 and 5,633,016.
Following examples limit scope of the present invention never in any form, how to realize and use compound of the present invention but be used for explanation.To those skilled in the art, many other embodiments are conspicuous.
Embodiment
General provisions
Proton magnetic resonance (PMR) ( 1H NMR) spectrum 250 or 400MHz under measure.Rise to low thing with the chemical shift (δ) of per 1,000,000/umber record with interior mark tetramethylsilane.The abbreviation of NMR data is as follows: s=is unimodal, the d=doublet, and the t=triplet, the q=quartet, the m=multiplet, two doublets of dd=, two triplets of dt=, app=is apparent, and br=is wide.J represents the NMR coupling constant with hertz mensuration.CDCl 3Be deuterochloroform, DMSO-d 6Be six deuterated dimethyl sulfoxides, CD 3OD is four deuterated methanols.Infrared (IR) spectrum is with the transmission mode record, and band position is with the inverse (cm of wave number -1) record.Measure mass spectrum with electronic spraying (ES) or FAB ionization techniques.Ultimate analysis can by inside or by Quantitative Technologies Inc., Whitehouse, NJ measures.Fusing point is measured with Thomas-Hoover fusing point instrument, and fusing point is not calibrated.All temperature are centigradetemperature.Carry out thin-layer chromatography with Analtech silica gel G F and E.Merck silica gel 60F-254 thin layer plate.Quick and gravitational stratification all uses E.Merck Kieselgel60 (230-400 order) silica gel to carry out.Analyze and prepare HPLC and carry out with Rainin or Beckman chromatographic instrument, ODS refers to the silica gel chromatography stationary phase of octadecyl silicomethane derivatize.5 μ Apex-ODS refer to have the silica gel chromatography stationary phase of the octadecyl silicomethane derivatize of 5 μ nominal granularities, by Jones Chromatography, and Littleton, Colorado makes.YMCODS-AQ  is an ODS chromatographic stationary phase, and it is the trade mark of Japanese Kyoto YMC Co.Ltd. registration.PRP-1  is polymerization (vinylbenzene-divinylbenzene) chromatographic stationary phase, and it is HamiltonCo., Reno, the trade mark of Nevada registration.The flocculating aids that Celite  is made up of the diatomite of pickling, it is Manville Corb., Denver, the trade mark of Colorado registration.
(±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate, (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate and (±)-10,11-dihydro-3-(trifluoro-methanesulfonyl oxy)-5H-dibenzo [a, d] suberene-10-ethyl acetate prepares according to WO 9701540-A1.2-[2-(4-methoxybenzyl amino) pyridine-6-yl] ethanol is according to WO 95/32710 preparation.6-methoxyl group-1-(2, the 3-indone) is according to the method preparation of House and Hudson (J.Org.Chem.1970,35,647).
Preparation 1 preparation 2-[(3-hydroxyl-1-propyl group) amino] a) 2-[(3-hydroxyl-1-propyl group of pyridine-N-oxide) amino] pyridine-N-oxide
With 2-chloropyridine-N-oxide hydrochloride (16.6g, 0.1mol), 3-amino-1-propyl alcohol (15.3mL, 0.2mol), NaHCO 3(42g, 0.5mol) and the mixture heating up of tertiary amyl alcohol (100mL) reflux.After 21 hours,, use CH with this reactant cooling 2Cl 2(300mL) dilution, suction filtration is removed insoluble substance.Concentrated filtrate obtains yellow oil with the toluene reconcentration.Silica gel column chromatography (20%MeOH/CHCl 3) obtain title compound (15.62g, 93%), be yellow solid: TLC (20%MeOH/CHCl 3) R f0.48; 1H NMR (250, CDCl 3) δ 8.07 (dd, J=6.6,1.2Hz, 1H), 7.34 (brt, 1H), 7.10-7.30 (m, 1H), 6.64 (dd, J=8.5,1.4Hz, 1H), 6.40-6.60 (m, 1H), 4.49 (brs, 1H), and 3.65-3.90 (m, 2H), 3.35-3.60 (m, 2H), 1.75-2.00 (m, 2 H); MS (ES) m/e 169 (M+H) +.
Preparation 2 preparation 2-[(3-hydroxyl-1-propyl group) amino]-a) 2-chloro-4-nitropyridine-N-oxide compound of 4-nitropyridine-N-oxide compound
Under 0 ℃, with dense H 2SO 4(30mL) and the HNO of being fuming 3Drips of solution (54mL) is added to 2-chloropyridine-N-oxide hydrochloride (15.2g, dense H 91.56mmol) 2SO 4(30mL) in the solution.Under 90 ℃, with this reaction mixture heating 1 hour, be cooled to room temperature then, pour in the ice (500g).This reaction mixture is kept spending the night under RT, with the ice bath cooling, slowly add 50%NaOH and obtain precipitation then.Collecting precipitation, drying obtain title compound (5.88g, 37%), are light yellow solid: 1H NMR (400MHz, CDCl 3) δ 8.42-8.37 (m, 2H), 8.06-8.04 (m, 1H).B) amino 2-[(3-hydroxyl-1-propyl group)]-4-nitropyridine-N-oxide compound
According to the method for preparation 1, replace 2-chloropyridine-N-oxide hydrochloride, silica gel column chromatography (1: 9 MeOH/CH with 2-chloro-4-nitropyridine-N-oxide compound 2Cl 2) after obtain title compound, be yellow powder.From MeOH/CH 2Cl 2/ Et 2Recrystallization obtains this title compound: MS (ES) 214.1 (M+H) among the O +
Preparation 3 preparation 2-[(3-hydroxyl-1-propyl group) amino]-a) 2-chloro-4-picoline of 4-methylpyridine N oxide
Under 0 ℃, (13.88g, (15.0g is in dense HCl (200mL) solution 139mmol) 200mmol) slowly to join 2-amino-4-picoline with Sodium Nitrite.This reaction mixture is warmed to room temperature, stirred 16 hours, pour into then in the ice (500g).Use dense NH 4OH transfers to 8.0 with pH, and (3 * 300mL) extract with ether with this mixed solution.The ether layer that merges is used H in turn 2O (2 * 200mL) and salt solution (200mL) washing.Dry (MgSO 4), concentrate and obtain title compound (10.3g, 58%), be dark yellow oily thing: MS (ES) m/e 127.8 (M+H) +B) 2-chloro-4-methylpyridine N oxide hydrochloride
With 2-chloro-4-picoline (10.0g, 78.3mmol) and 34% peracetic acid (76.05g, ice AcOH (10mL) mixed solution 91.0mmol) be heated to 70 ℃ 3 hours.With this reaction mixture cooling, add dense HCl (35mL), this mixed solution is concentrated on rotatory evaporator.Use the propyl carbinol recrystallization, grind with ether then and obtain title compound (7.16g, 51%), be white solid: MS (ES) m/e 143.9 (M+H) +C) amino 2-[(3-hydroxyl-1-propyl group)]-the 4-methylpyridine N oxide
With 2-chloro-4-methylpyridine N oxide hydrochloride (7.16g, 39mmol), the 3-aminopropanol (6.01g, 80mmol) and NaHCO 3(16.8g, tertiary amyl alcohol 200mmol) (50mL) mixed solution reflux 19 hours.With this reaction mixture CH 2Cl 2(200mL) dilution is filtered, and this filtrate is concentrated on rotatory evaporator.From CH 2Cl 2/ Et 2Recrystallization obtains title compound (5.41g, 75%) among the O, is yellow solid: TLC (15%MeOH/CH 2Cl 2) R f0.44; 1HNMR (400, CDCl 3) δ 7.92 (d, J=6.7,1H), 7.28 (brt, 1H), 6.43 (s, 1H), 6.33 (dd, J=6.6,2.1Hz, 1H), 3.73 (t, J=5.7Hz, 2H), 3.47 (q, H=6.3Hz, 2H), 2.29 (s, 3H), 1.82-1.88 (m, 2H), MS (ES) m/e 183 (M+H) +
Preparation 4 preparation 6-(methylamino-)-2-pyridine ethanol are 2-(tert-butoxycarbonyl amino)-6-picoline a)
Under 50 ℃, with 2-amino-6-picoline (21.63g, 200mmol) and tert-Butyl dicarbonate (52.38g, CH 240mmol) 2Cl 2(200mL) solution concentrates on rotatory evaporator, and the residue that obtains is rotated in 50 ℃ of following vacuum with rotatory evaporator.21.5 after hour, this reaction solution with hexane (400mL) dilution, is filtered by silica gel (hexane, 20%EtOAc/ hexane then).Concentrate and obtain title compound (41.84g, quantitative), be glassy yellow oily matter, place gradually and solidify: 1H NMR (250MHz, CDCl 3) δ 7.71 (d, J=8.3Hz, 1H), 7.40-7.65 (m, 2H), 6.80 (d, J=7.5Hz, 1H), 2.43 (s, 3H), 1.50 (s, 9H); MS (ES) m/e 153 (M+H-C 4H 8) +B) methylamino-2-[(tert-butoxycarbonyl)]-the 6-picoline
(60% in Dormant oils with NaH with several minutes, 3.60g, 90mmol) gradation join (cooling bath) under 15 ℃ 2-(tert-butoxycarbonyl amino)-6-picoline (15.62g, 75mmol) and methyl iodide (9.3mL is in anhydrous DMSO (75mL) solution 150mmol).Interior temperature rise to 35 ℃.After stopping to emit gas, remove cooling bath, under RT, stir this reactant.0.5 after hour, this dark yellow mixed solution is poured in ice/water (300mL), is used Et 2(3 * 300mL) extract O.The organic layer that merges is used H in turn 2O (2 * 75mL) and salt solution (75mL) washing.Dry (MgSO 4), concentrate and obtain yellow oil, through silica gel column chromatography (7%EtOAc/ hexane).Obtain title compound (13.01g, 78%), be faint yellow oily thing: 1H NMR (250MHz, CDCl 3) δ 7.51 (appt, 1H), 7.37 (d, J=8.2Hz, 1H), 6.86 (d, J=7.2Hz, 1H), 3.38 (s, 3H), 2.49 (s, 3H), 1.51 (s, 9H); MS (ES) m/e 223 (M+H) +C) methylamino-6-[(tert-butoxycarbonyl)]-2-pyridyl ethyl acetate
Under 0 ℃, logical argon gas, with diisopropylamine (19.5mL, 139.14mmol) and hexane liquid (46.4mL, dry THF 115.95mmol) (350mL) the formulations prepared from solutions LDA of 2.5M n-Butyl Lithium.This solution is cooled to-78 ℃, with 10 minutes dropping 2-[(tert-butoxycarbonyls) methylamino-]-6-picoline (10.31g, dry THF 46.38mmol) (46mL) solution.Use dry THF (2mL) to shift again.Under-78 ℃, this orange solution was stirred 15 minutes, add fast then diethyl carbonate (6.2mL, 51.02mmol).Under-78 ℃, this red solution was stirred 15 minutes, use half saturated NH then 4Cl (175mL) quencher.This mixed solution temperature to+5 ℃, is extracted with EtOAc (175mL), used CH then 2Cl 2(2 * 100mL) extract.The organic liquor that merges is washed dry (MgSO with salt solution (100mL) 4), concentrate.Should muddiness, yellow oil obtains title compound (10.72g, 79%) through silica gel column chromatography (15%EtOAc/ hexane), is glassy yellow oily matter: 1H NMR (250MHz, CDCl 3) δ 7.51-7.63 (m, 2H), 6.91-7.03 (m, 1H), 4.19 (q, J=7.1Hz, 2H), 3.77 (s, 2H), 3.38 (s, 3H), 1.27 (t, J=7.1Hz, 3H), 1.51 (s, 9H), MS (ES) m/e295 (M+H) +D) 6-(methylamino-)-2-pyridyl ethyl acetate
With the 6-[(tert-butoxycarbonyl) methylamino-]-2-pyridyl ethyl acetate (10.72g, dry dioxane (91mL) solution 36.42mmol) is cooled to solvent partial crystallization point, adding 4MHCl/ dioxane (91mL, 364.2mmol).This solution is warmed to RT, stirred 17 hours, concentrate then.With the glassy yellow solid CH that obtains 2Cl 2/ toluene is made slurry and is concentrated and obtains title compound (8.48g, quantitative), is the glassy yellow powder: 1H NMR (250MHz, CD 3OD) δ 7.84 (dd, J=9.0,7.2Hz, 1H), 6.96 (d, J=9.0Hz, 1H), 6.78 (d, J=7.2 Hz, 1H), 4.22 (q, J=7.1Hz, 2H), 3.93 (s, 2H), 3.05 (s, 3H), 1.27 (t, J=7.1Hz, 3H), MS (ES) m/e 195 (M+H) +E) 6-(methylamino-)-2-pyridyl ethanol
Under 0 ℃, logical argon gas, with 1.0M LiAlH 4THF solution (95mL, (7.34g is in dry THF 31.82mmol) (64mL) suspension 95mmol) to be added drop-wise to 2-(methylamino-)-6-pyridyl ethyl acetate under the mechanical stirring.Slowly add until stopping to emit gas, the solution with remainder adds fast then.Need 5-7 minute again.This reaction solution is warmed to RT, stirred 45 minutes, then reflux.After 10 minutes, this reaction solution is cooled to 0 ℃, by dripping H in turn 2O (3.6mL), 15%NaOH (3.6mL) and H 2O (10.8mL) handles.This mixed solution was stirred 15 minutes down at 0 ℃, under RT, stirred 15 minutes again, filter by B then.With the THF washing of filter cake with capacity, concentrated filtrate.With residue toluene reconcentration, then through silica gel column chromatography (1: 1 EtOAc/CHCl of 5%MeOH 3Liquid) obtain title compound (3.23g, 67%), be yellow oil, it is cured as waxy solid: 1HNMR (250MHz, CDCl 3) δ 7.36 (dd, J=8.3,7.3Hz, 1H), 6.42 (d, J=7.3Hz, 1H), 6.26 (d, J=8.3Hz, 1H), 4.93-5.28 (m, 1H), 4.38-4.60 (m, 1H), 3.96 (t, J=5.4Hz, 2H), 2.90 (d, J=5.2Hz, 3H), 2.84 (t, J=5.4Hz, 2H); MS (ES) m/e 153 (M+H) +
Preparation 5 preparation 2-(ethylamino)-4-thiazoleethanols are 2-acetylaminohydroxyphenylarsonic acid 4-thiazole ethyl acetate a)
(3.72g 20mmol) joined in acetate (4mL) and the diacetyl oxide (4mL), with the aaerosol solution reflux that obtains 3 hours with 2-amino-4-thiazole ethyl acetate.Concentrate, through flash chromatography on silica gel (5%MeOH/CH 2Cl 2) obtain title compound (4.1g, 91%), be white solid: MS (ES) m/e 229 (M+H) +B) 2-(ethylamino)-4-thiazoleethanol
To the 1.0M LiAlH that stirs 4THF solution (179mL drips 2-acetylaminohydroxyphenylarsonic acid 4-thiazole ethyl acetate (4.4g, THF 17.9mmol) (50mL) solution in 179mmol).After adding, with reaction mixture reflux 3 hours, then by adding H in turn 2O (0.7mL), 10%NaOH (0.7mL) and H 2O (2.1mL) handles.The mixed solution that obtains is filtered concentrated filtrate by celite .Through flash chromatography on silica gel (5%MeOH/CH 2Cl 2) purifying obtains title compound (1.6g, 53%), is amber oily thing: MS (ES) m/e 173 (M+H) +
Preparation 6 preparation 6-amino-2-pyridyl ethanol are 6-amino-2-pyridyl ethanol a)
2-[2-(the 4-methoxybenzyl amino) pyridine-6-yl that will prepare according to the method for WO 95/32710] (0.95g, 6N HCl solution 3.7mmol) is heated to 60 ℃ to ethanol.After 16 hours,, make residue be alkalescence with dry KOH with this reactant vacuum concentration.The mixed solution that obtains is extracted with MeOH, with this MeOH extracting solution drying (MgSO 4), concentrate.Through flash chromatography on silica gel (5%MeOH/CH 2Cl 2) obtain title compound (0.2g, 40%), be light yellow oil: MS (ES) m/e 139 (M+H) +
Preparation 7 preparation 3-(4-nitro benzyloxycarbonyl) amino-1-propyl alcohol are 3-(4-nitro benzyloxycarbonyl) amino-1-propyl alcohol a)
Under room temperature, the chloroformic acid 4-nitrobenzyl ester of logical argon gas (5g, 23mmol) and triethylamine (6.4mL, adding 3-amino-1-propyl alcohol in THF 46mmol) (25mL) suspension (1.9mL, 26mmol).The mixed solution that obtains was stirred 72 hours, concentrate then.Residue is through silica gel column chromatography (0.5-2%MeOH/CH 2Cl 2) obtain title compound (2g, 34%), be light yellow oil: MS (ES) m/e 255.3 (M+H) +
Preparation 8 preparation 1-[(3-hydroxyl-1-propyl group) amino] a) 1-chlorine isoquinoline-N-oxide of isoquinoline-N-oxide
According to document (Brown, E.V., J.Amer.Chem.Soc.1957,79, logical method 3565-3566), (Deady, L.W.Synthetic Communications 1977 509-514) are converted into 1-chlorine isoquinoline-N-oxide with 1-aminoisoquinoline-N-oxide hydrochloride to use potassium nitrite and dense HCl.Prepared title compound is bright brown solid: MS (ES) m/e179.9 (M+H) +B) amino 1-[(3-hydroxyl-1-propyl group)] isoquinoline-N-oxide
According to the method among preparation 1 (a), replace 2-chloropyridine-N-oxide hydrochloride with 1-chlorine isoquinoline-N-oxide, prepared title compound is amber solid: MS (ES) m/e219.1 (M+H) +
Preparation 9 preparation 2-[N-(3-mesyloxy-1-propyl group)-N-(tert-butoxycarbonyl) amino] a) 2-[N-(3-hydroxyl-1-propyl group)-N-(tert-butoxycarbonyl) amino of pyridine-N-oxide] pyridine-N-oxide
With 2-[(3-hydroxyl-1-propyl group) amino] (8.0g, (11.4g 55.3mmol) handles trimethyl carbinol 47.6mmol) (80mL) solution pyridine-N-oxide with two dimethyl dicarbonate butyl esters.After 18 hours,, residue is ground with hexane this solution concentration.The solid vacuum-drying that obtains is obtained title compound (12.5g, 98%), be pale solid: MS (ES) m/e 269.3 (M+H) +B) 2-[N-(3-mesyloxy-1-propyl group)-N-(tert-butoxycarbonyl) amino] pyridine-N-oxide
Under 0 ℃, with methylsulfonyl chloride (0.17mL 2.20mmol) is added drop-wise to 2-[N-(3-hydroxyl-1-propyl group)-N-(tert-butoxycarbonyl) amino] pyridine-N-oxide (0.50g, 1.86mmol) and pyridine (0.23mL, CHCl 2.84mmol) 3(5mL uses K 2CO 3Drying) in the solution.After finishing by the TLC detection reaction, with this reaction solution CHCl 3Dilution, with the frozen water washing, dry (Na 2SO 4), concentrate.Silica gel column chromatography (10%MeOH/CHCl 3) obtain title compound (0.41g, 64%), be colorless oil: 1H NMR (250MHz, CDCl 3) δ 8.25 (dd, J=6.0,1.9Hz, 1H), 7.25 (m, 4H), 4.35 (t, J=6.2Hz, 2H), 3.75 (t, J=6.6Hz, 2H), 3.00 (s, 3H), 2.00 (m, 2H), 1.40 (s, 9H).Also recyclable unchanged 2-[N-(3-hydroxyl-1-propyl group)-N-(tert-butoxycarbonyl) amino from chromatogram is purified] pyridine-N-oxide (0.18g, 36%).
Preparation 10 preparation (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is 6-methoxyl group-1-phenylindan a)
Under room temperature, the logical argon gas, with the Et of 3.0M phenyl-magnesium-bromide 2(680mL 2.04mol) uses Et under the stirring to O solution 2O (700mL) dilution was with 1 hour dropping 6-methoxyl group-1-(2, the 3-indone) (277g, THF 1.71mol) (1400mL) solution.Under the room temperature, this reaction mixture was stirred 2 hours, stir then and pour saturated NH down into 4Among the Cl (2.8L).Add H 2O (1.4L) separates organic layer.With water layer Et 2(2 * 1L) extract O, and organic extracting solution that will merge again concentrates and obtains crude product 6-methoxyl group-1-phenyl-1-indanol (445g), is brown oil.This oily matter is dissolved in the toluene (2.5L), and adding tosic acid monohydrate (12.3g, 0.065mol).With the Dean-Stark water trap that has condenser with this solution stirring and reflux 16 hours.The H that collects after 2 hours 2O is minimum, altogether 28mL.With this solution cooling, use 5%Na in turn 2CO 3(1L) and H 2(2 * 1L) extract O.With the concentrated burgundy oily matter (400g) that obtains of organic layer.This oily matter vacuum distilling is obtained title compound (298.2g, 79%), be yellow oil: bp 152-190 ℃/2.0 Torr; TLC (10%EtOAc/ hexane) R f0.75.B) 2-benzoyl-4-methoxyphenylacetic acid
Acetone (4.2L) is cooled to 10 ℃, and (271g, (1.8L is from CrO for (1.8L) solution of acetone 1.22mol) and Jones reagent to add 6-methoxyl group-1-phenylindan together with 1.5 hours 3(470g, 4.70mol), H 2O (1L) and dense H 2SO 4(405mL) preparation).In the mixed solution that obtains, add 4%OsO at twice 4The aqueous solution (153mL), once when reinforced beginning, in the time of for the second time in the middle of reinforced, during keep temperature of reaction to be lower than 15 ℃.After adding, this reaction mixture is warmed to 22 ℃, and stirred 1.5 hours, during gentle heat release elevated temperature to 28 ℃.Then this reaction mixture is cooled to below 20 ℃, adds Virahol (1L), initial dropping, and in the adding fast of initial heat release disappearance back.Stir the difficulty that becomes during this time.Add in the Virahol, temperature reaches 32 ℃.Add H 2O (2L) is transferred to this mixed solution in the separating funnel.Add H again 2O is with the chromous acid of dissolution precipitation, with this mixed solution CH 2Cl 2(2L) extract.Separate organic layer (upper strata), with water CH 2Cl 2(2 * 1L) extract.With the CH that merges 2Cl 2Extracting solution is used H in turn 2O (2L) and saturated brine (2L) washing concentrate then and obtain moistening gray solid (416g).Its mixture with acetone and EtOAc is ground, filter, drying obtains title compound (225.4g, 71%), is pale solid: mp 158-159 ℃.C) 2-benzyl-4-methoxyphenylacetic acid
(215.5g 0.80mol) is divided into two equal portions, in every part of ice AcOH (1.5L) that is dissolved in the 2.5L pressure bottle with 2-benzoyl-4-methoxyphenylacetic acid.In every part, add 5%Pd/C (10g, 0.0048mol), under room temperature, the logical hydrogen, on the Parr device with every part of mixture jolting.2.5 after hour, this mixture is removed by filter catalyzer, uses the EtOAc washing leaching cake.Filtrate the concentrating that merges obtained title compound (215g, quantitative), is deep yellow oily thing, place crystallization: 1H NMR (250MHz, CDCl 3) δ 7.05-7.35 (m, 6H), 6.77 (dd, J=8.3,2.7Hz, 1H), 6.71 (d, J=2.7Hz, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 3.54 (s, 2H).D) 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone
Under room temperature, the logical argon gas, with 2-benzyl-4-methoxyphenylacetic acid CH of (215g is for containing the crude product of the pure product of 204.6g (0.80mol)) 2Cl 2Solution stirring (1L) adds DMF (1mL) again, add then oxalyl chloride (400mL, 4.59mol).With 1 hour adding oxalyl chloride, the initial dropping acutely emitted gas to control.With this solution stirring 16 hours, concentrate then and obtain thick acyl chlorides (207.7g, 0.756mol, 95%) under the room temperature, be yellow liquid.This liquid is dissolved in CH 2Cl 2In make cumulative volume to 500mL, under room temperature, the logical argon gas, stir down with 1 hour this solution and AlCl 3(100.8g 0.756mol) joins CH simultaneously 2Cl 2(3.7L).After adding, temperature is 28 ℃.Under the room temperature this reaction mixture was stirred 16 hours, during solid precipitation.With 30 minutes, the initial dropping added H 2O (1L).Separate this mixed solution then, organic phase is used H in turn 2O (1L) and 5%NaHCO 3The aqueous solution (1L) washing.Then with CH 2Cl 2Solution concentration obtains yellow solid (175.3g).Obtain title compound (128g, 71%) with EtOAc/ hexane recrystallization: mp107-109 ℃.E) (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under-70 ℃, logical argon gas, with the hexane of two (trimethyl silyl) lithamides of 1.0M (1282mL 1.282mol) joins among the THF (4.0L), then with 20 minutes dropping EtOAc (146mL, 1.49mol).This reaction mixture was stirred 15 minutes, then with 20 minutes adding N,N,Ns (378mL, 2.5mol).This reaction mixture was stirred 10 minutes, dripped 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone (119.2g, anhydrous THF (1.26L) solution 0.50mo1) with 40 minutes then.Add during these materials, temperature keeps below-65 ℃.In-65 to-70 ℃ are stirred this reaction mixture 20 minutes, pour NH under the vigorous stirring then 4In Cl (6.2L) saturated aqueous solution.Separate organic layer, (2 * 1L) extract with EtOAc with water layer.With the organic extracting solution H that merges 2(2 * 1L) washings concentrate and obtain light brown oily thing (175g) O then.Thin-layer chromatography (20%EtOAc/ hexane) shows principal constituent (product that requires) R f0.5, inferior composition (ketone of recovery) R f0.7.This crude product obtains title compound (101g, 61%) through silica gel column chromatography (2kg, 10%EtOAc/ hexane), is yellow oil: 1H NMR (250MHz, CDCl 3) δ 7.63 (d, J=7.7Hz, 1H), 7.00-7.30 (m, 4H), 6.80 (d, J=2.6Hz, 1H), 6.69 (dd, J=8.2,2.6Hz, 1H), 3.95-4.35 (m, 2H), 4.07 (s, 2H), 3.76 (s, 3H), 3.68 (s, 1H), 3.64 (d, J=14.2Hz, 1H), 3.35 (d, J=14.2Hz, 1H), 2.79 (d, J=16.0Hz, 1H), 2.66 (d, J=16.0Hz, 1H), 1.22 (t, J=7.2Hz, 3H).F) (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate (101g 0.31mol) is dissolved in the Glacial acetic acid (1.8L), and adding 12N HCl (28.5mL, 0.34mol).With this mixed solution place contain 5%Pd/C (20g, in 2.5L pressure bottle 0.0094mol), under 35 ℃, logical hydrogen, on the Parr device of equipment cover layered heating with the mixed solution jolting that obtains.After 18 hours, this reaction solution is cooled to room temperature, removes by filter catalyzer.Filtrate concentrating obtains light yellow oil (85.1g).Obtain title compound (69.1g, 72%) through silica gel column chromatography (2kg is with 5%-10%EtOAc/ hexane gradient elution progressively), be oily matter: 1H NMR (250MHz, CDCl 3) δ 7.05-7.22 (m, 4H), 7.01 (d, J=8.2Hz, 1H), 6.76 (d, J=2.7Hz, 1H), 6.67 (dd, J=8.2,2.7Hz, 1H), 4.30 (d, J=15.0Hz, 1H), 4.11-4.25 (m, 2H), 3.85 (d, J=15.0Hz, 1H), and 3.70-3.90 (m, 1H), 3.77 (s, 3H), 3.31 (dd, J=15.0,4.1Hz, 1H), 2.93 (dd, J=15.0,9.2Hz, 1H), 2.64 (dd, J=15.6,5.0Hz, 1H), 2.52 (dd, J=15.6,9.3Hz, 1H), 1.27 (t, J=7.1Hz, 3H).G) (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under logical argon gas, the stirring, with (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate (8.5g, CH 0.027mol) 2Cl 2(150mL) solution is cooled to-10 ℃.Add sulfur alcohol (10.7mL, 0.144mol), then with adding AlCl in 15 minutes at twice 3(20.6g, 0.154mol).After adding, heat release makes temperature rise to 0 ℃, makes temperature rise to 25 ℃ with water-bath then.Under 25 ℃-30 ℃, this reaction mixture was stirred 2.25 hours, pour in ice-water then.Separate organic layer, add methyl alcohol (100mL), this mixed solution CH 2Cl 2(2 * 50mL) extract.With the CH that merges 2Cl 2Extracting solution H 2O (250mL) washing concentrates then and obtains viscosity oily matter (8.6g).It is dissolved in Et 2Among the O (150mL), the evaporation ether adds hexane and replaces.Isolate desired the be phenol of oily matter, crystallization under the stirring at room earlier.Collect the solid that obtains for twice, obtain title compound (7.1g, 89%): mp110-112 ℃.
Preparation 11HPLC separates (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] a) (R)-(+)-10 of enantiomorph of suberene-10-ethyl acetate, 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate and (S)-(-)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
With following condition with (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is split as enantiomorph: Daicel Chiralcel OJ  post (21.2 * 250mm), moving phase is 20% alcoholic acid hexane liquid, flow velocity is 15mL/min, detect at the uv of 254nm place, injection volume is 140mg; (S)-(-)-10, the t of 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate R=10.4min; (R)-(+)-10, the t of 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate R=13.1min.
Preparation 12 preparation (±)-10,11-dihydro-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is 1-(3-fluorophenyl)-6-methoxyl group-1-indanol a)
According to the method for preparation 10 (a), but replace phenyl-magnesium-bromide, obtain title compound, be amber oily thing: MS (ES) m/e 276.0 (M+H) with 3-fluorophenyl magnesium bromide +B) 1-(3-fluorophenyl)-6-methoxyl group indenes
Method according to preparation 10 (a), but replace 6-methoxyl group-1-phenyl-1-indanol with 1-(3-fluorophenyl)-6-methoxyl group-1-indanol, behind the silica gel column chromatography (4%EtOAc/ hexane), obtain title compound, be colorless oil: MS (ES) m/e 241.1 (M+H) +C) 2-(3-fluoro benzoyl)-4-methoxyphenylacetic acid
According to the method for preparation 10 (b), but replace 6-methoxyl group-1-phenylindan, obtain title compound, be white solid: MS (ES) m/e 289.2 (M+H) with 2-(3-fluorophenyl)-6-methoxyl group indenes +D) 2-(3-fluorobenzene methyl)-4-methoxyphenylacetic acid
According to the method for preparation 10 (c), but replace 2-benzoyl-4-methoxyphenylacetic acid, obtain title compound, be colorless oil: MS (ES-) m/e 273.2 (M-H) with 2-(3-fluoro benzoyl)-4-methoxyphenylacetic acid -E) 10,11-dihydro-7-fluoro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone
According to the method for preparation 10 (d), but replace 2-phenmethyl-4-methoxyphenylacetic acid, obtain title compound, be white solid: Mp129-130 ℃ with 2-(3-fluorobenzene methyl)-4-methoxyphenylacetic acid; MS (ES) m/e 279.2 (M+Na) +F) (±)-10,11-dihydro-7-fluoro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
Method according to preparation 10 (e), but with 10,11-dihydro-7-fluoro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone replacement 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone, behind the silica gel column chromatography (8%EtOAc/ hexane), obtain title compound: MS (ES) m/e362.2 (M+NH 4) +G) (±)-10,11-dihydro-7-fluoro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
Method according to preparation 10 (f), but with (±)-10,11-dihydro-7-fluoro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate is behind the silica gel column chromatography (10%EtOAc/ hexane), obtain title compound, be colorless oil: MS (ES) m/e 329.2 (M+H) +H) (±)-10,11-dihydro-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method for preparation 10 (g), but with (±)-10,11-dihydro-7-fluoro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate, silica gel column chromatography (1%MeOH/CH 2Cl 2) after, obtain title compound, be white solid: MS (ES) m/e315.0 (M+H) +, 332.0 (M+NH 4) +
Preparation 13 preparation (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] a) (±)-10 of suberene-10-ethyl acetate, 11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, the logical argon gas, to (±)-10, (0.4g adds 37% formalin (0.5mL) to 11-dihydro-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate in 95% ethanolic soln of the MeOH that contains the 2M dimethylamine (1.0mL) liquid 1.33mmol).After 20 hours,, on rotatory evaporator, concentrate then this reaction solution reflux 5 hours.With residue at H 2O and Et 2Distribute layering between the O.With water layer Et 2O extracts, with the organic layer salt water washing that merges, and dry (MgSO 4), rotary evaporation concentrates and obtains title compound (330mg, 67%), is colorless oil: 1H NMR (400MHz, CDCl 3) δ 7.20 (m, 1H), 6.88 (m, 2H), 6.67 (s, 2H), 4.25 (d, J=15.1Hz, 1H), 4.18 (q, 2H), 3.78 (m, 1H), 3.74 (d, J=15.1Hz, 1H), 3.55 (s, 2H), 3.20 (dd, 1H), 2.80 (dd, 1H), 2.60 (dd, 1H), 2.53 (dd, 1H), 2.29 (s, 6H), 1.27 (t, 3H); MS (ES) m/e 372.3 (M+H) +
Preparation 14 preparation (±)-10,11-dihydro-3-hydroxy-2-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is (±)-10 a), 11-dihydro-2-formyl radical-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, the logical argon gas, with POCl 3(17mL) be added drop-wise to (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate (1.0g, in dry DMF (40mL) solution 3mmol), should dead color solution be heated to 90 ℃ 48 hours.This reaction solution is concentrated on rotatory evaporator, again with residue at H 2Distribute between O and the EtOAc.Separate organic layer, dry (MgSO 4), rotary evaporation concentrates.Residue with dimethylbenzene reconcentration (removing any residual DMF), is obtained title compound (230mg, 21%) through silica gel column chromatography (the hexane liquid of 7%EtOAc) then, be colorless oil: MS (ES) m/e 339.3 (M+H) +B) (±)-10,11-dihydro-3-methoxyl group-2-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, the logical hydrogen (60psi); with (±)-10; 11-dihydro-2-formyl radical-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate (220mg, 0.65mmol), the mixed solution jolting of 10%Pd/C (90mg), Glacial acetic acid (15mL) and dense HCl (2mL).After 20 hours, this mixed solution is filtered by celite , concentrate this filtrate and obtain title compound (200mg, 95%), be colorless oil: MS (ES) m/e 325.2 (M+H) +C) (±)-10,11-dihydro-3-hydroxy-2-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
To the dry CH of ice bath refrigerative 2Cl 2(0.38mL 3.3mmol), adds AlCl again to add diethyl sulfide (30mL) 3(438mg, 3.3mmol).In this solution, drip (±)-10,11-dihydro-3-methoxyl group-2-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (200mg, dry CH 0.6mmol) 2Cl 2(6mL) liquid stirs the mixed solution that obtains 2 hours under the RT.Layering should be reacted with 1.0N HCl (10mL) quencher.With organic layer drying (MgSO 4), rotary evaporation concentrates and obtains title compound (100mg, 56%), is colorless oil: MS (ES) m/e 311.2 (M+H) +
Preparation 15 preparation (±)-10,11-dihydro-3-hydroxyl-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is 6-methoxyl group-1-(2-aminomethyl phenyl)-1-indanol a)
According to the method for preparation 10 (a), but replace phenyl-magnesium-bromide, obtain title compound, be oily matter: MS (ES) m/e 277.0 (M+Na) with 2-aminomethyl phenyl magnesium bromide +B) 6-methoxyl group-1-(2-aminomethyl phenyl) indenes
Method according to preparation 10 (a), but replace 6-methoxyl group-1-phenyl-1-indanol with 6-methoxyl group-1-(2-aminomethyl phenyl)-1-indanol, behind the silica gel column chromatography (3%EtOAc/ hexane), obtain title compound, be colorless oil: MS (ES) m/e 237.2 (M+H) +C) 4-methoxyl group-2-(2-methyl benzoyl) toluylic acid
According to the method for preparation 10 (b), but replace 6-methoxyl group-1-phenylindan, obtain title compound, be viscosity oily matter: MS (ES) m/e 285.3 (M+NH with 6-methoxyl group-1-(2-aminomethyl phenyl) indenes 4) +D) 4-methoxyl group-2-(2-methylbenzene methyl) toluylic acid
According to the method for preparation 10 (c), but replace 2-benzoyl-4-methoxyphenylacetic acid, obtain title compound, be viscosity oily matter: MS (ES) m/e 288.2 (M+NH with 4-methoxyl group-2-(2-methyl benzoyl) toluylic acid 4) +E) 10,11-dihydro-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ketone
Method according to preparation 10 (d), but replace 2-phenmethyl-4-methoxyphenylacetic acid with 4-methoxyl group-2-(2-methylbenzene methyl) toluylic acid, behind the silica gel column chromatography (6%EtOAc/ hexane), obtain title compound, be white solid: MS (ES) m/e 253.0 (M+H) +F) (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Method according to preparation 10 (e), but with 10,11-dihydro-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ketone replacement 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone, behind the silica gel column chromatography (8%EtOAc/ hexane), obtain title compound: MS (ES) m/e358.2 (M+NH 4) +G) (±)-10,11-dihydro-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Method according to preparation 10 (f), but with (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate is behind the silica gel column chromatography (5%EtOAc/ hexane), obtain title compound, be colorless oil: MS (ES) m/e 325.3 (M+H) +H) (±)-10,11-dihydro-3-hydroxyl-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
Method according to preparation 10 (g), but with (±)-10,11-dihydro-3-methoxyl group-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate is after grinding with MeOH, obtain title compound, be white solid: MS (ES) m/e 311.2 (M+H) +
Preparation 16 preparation (±)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-ethyl acetate, 11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, the logical argon gas, with 2-[(3-hydroxyl-1-propyl group) amino]-4-nitropyridine-N-oxide compound (0.85g, 4mmol) and diethyl azodiformate (0.63mL, dry DMF (10mL) drips of solution 4mmol) is added to (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.59g, 2mmol) and triphenyl phosphine (1.10g is in dry DMF (10mL) solution 4.2mmol).After 23 hours, reaction solution is concentrated residue dimethylbenzene (2x) reconcentration.Silica gel column chromatography (gradient: 1: 1 EtOH/ hexane, EtOAc then, then 1 of 5%MeOH: 1EtOAc/CHCl 3Liquid) obtain the crude product title compound.Recyclable unchanged (±)-10 from 1: 1 EtOH/ hexane part, 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-acetic ester.With crude product title compound chromatography (1: 1 EtOAc/CHCl of 3%MeOH again 3Liquid) obtain pure title compound (0.72g, 73%), be yellow foam: TLC (1: 1 EtOAc/CHCl of 10%MeOH 3Liquid) R f0.59; 1H NMR (250MHz, CDCl 3) δ 8.19 (d, J=7.1Hz, 1H), 7.46 (d, J=2.9Hz, 1H), 7.35 (dd, J=7.1,2.9Hz, 1H), 7.00-7.30 (m, 5H), 7.00 (d, J=8.2Hz, 1H), 6.81 (d, J=2.6Hz, 1H), 6.70 (dd, J=8.2,2.6Hz, 1H), 4.29 (d, J=15.1Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 4.08 (t, J=5.5Hz, 2H), 3.86 (d, J=15.1Hz, 1H), 3.72-3.90 (m, 1H), 3.59 (q, J=6.3Hz, 2H), 3.30 (dd, J=15.0,4.2Hz, 1H), 2.93 (dd, J=15.0,9.3Hz, 1H), 2.64 (dd, J=15.6,5.1Hz, 1H), 2.51 (dd, J=15.6,9.3Hz, 1H), 2.10-2.30 (m, 2H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e 492 (M+H) +
Preparation 17 preparation (S)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-ethyl acetate, 11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to preparation 16 method, but with (S)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate, preparation title compound: MS (ES) m/e 492 (M+H) +
Preparation 18 preparations 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone is 2-benzyl-4-methoxyphenylacetic acid a)
Under the logical argon gas, (hydrogenation is 17 hours under 50psi for 13.0g, 0.048mol) Glacial acetic acid (600mL) the solution 4.3g 10%Pd/C processing of (according to J.Med.Chem.1981,24,998 method preparation) with 2-benzoyl-4-methoxyphenylacetic acid.This mixed solution is filtered by celite , and concentrated filtrate obtains the 14.2g title compound with toluene and methylene dichloride reconcentration: 1H NMR (400MHz, CDCl 3) δ 3.52 (s, 2H), 3.75 (s, 3H), 4.0 (s, 3H), 6.7 (m, 2H), 7.15 (m, 6H).B) 10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ketone
(14.2g, benzene 0.055m) (120mL) and protochloride alum (28mL) solution refluxed 1 hour, concentrated with 2-benzyl-4-methoxyphenylacetic acid.This acyl chlorides is dissolved in the exsiccant methylene dichloride (40mL), under the logical argon gas, this drips of solution is added to AlCl 3(14.7g is in methylene dichloride 0.11mol) (600mL) solution.Under room temperature, the logical argon gas, this reactant was stirred 2.5 hours, then with ice-water (200mL) quencher.Layering is washed organic phase in turn with 10%NaOH, water and rare HCl.The solution that obtains is diluted with ether (200mL), use MgSO 4Drying concentrates.This solid residue is ground with ether/hexane (1: 1), filter collection and obtain 9.35g title compound: Mp105-106 ℃; 1H NMR (400MHz, CDCl 3) δ 3.72 (s, 3H), 4.1 (s, 2H), 4.2 (s, 2H), 6.7 (d, 1H), 6.82 (s, 1H), 7.30 (m, 4H), 8.1 (d, 1H).
Preparation 19 preparation (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate is (±)-3-(3-p-methoxy-phenyl) indeneacetic acid ethyl ester a)
(4g is 18mmol) in the solution that the THF (15mL) of (according to J.Med.Chem.1981,24,998 method preparation) is cold, with 5 minutes dropping LiN (TMS) for 3-under 0 ℃ (3-p-methoxy-phenyl) indenes 2(20mL, the THF liquid of 1M).Under-78 ℃, (3.34g is in THF 20mmol) (15mL) solution with 30 minutes the drips of solution that obtains to be added to bromoethyl acetate.2.5 after hour, with the saturated ammonium chloride solution quencher of this mixed solution, layering.With the organic layer MgSO that obtains 4Drying concentrates and obtains crude product, through column chromatography (SiO 2/ 2-4%EtOAc/ hexane) purifying obtains title compound (1.1g): 1H NMR (400MHz, CDCl 3) δ 1.30 (t, 3H), 2.50 (m, 1H), 2.85 (m, 1H), 3.85 (s, 3H), 4.0 (m, 1H), 4.20 (q, 2H), 6.6 (s, 1H), 6.9 (m, 1H), 7.2 (s, 1H), 7.35 (m, 6H).B) phenyl ethyl succinate (±)-3-[(3-anisoyl)]
With (±)-3-(3-p-methoxy-phenyl) indeneacetic acid ethyl ester (1.1g, 3.6mmol) acetone (30mL) solution handle with the 4% perosmic anhydride aqueous solution (0.5mL), drip then according to literature method (J.Org.Chem.1993,58,4745) Zhi Bei 1.2M Jones reagent (5mL, 6mmol).Stir under the room temperature spend the night after, should the dark color reaction mixture with Virahol (2.5mL) quencher, add sodium bisulfite (0.9g) and water (30mL) again.Should dark color product ethyl acetate extraction, use the salt water washing, through MgSO 4Drying concentrates and obtains solid residue.Obtain the 0.76g title compound with ether/hexane grinding in 1: 1: 1H NMR (400MHz, CDCl 3) δ 1.18 (t, 3H), 2.90 (m, 1H), 3.3 (m, 1H), 3.92 (s, 3H), 4.1 (q, 2H), 4.4 (m, 1H), 4.4 (d, 1H), 7.25 (m, 2H), 7.5 (m, 6H).C) phenyl ethyl succinate (±)-3-[(3-mehtoxybenzyl)]
With (±)-3-[(3-anisoyl)] and the phenyl ethyl succinate (0.76g, 2.1mmol) and the hydrogenation 17 hours under 50psi of Glacial acetic acid (35mL) mixing solutions of 10%Pd/C (0.6g).This mixed solution is filtered with celite , filter cake is washed with acetate.Concentrated filtrate obtains the 0.65g title compound with toluene and methylene dichloride reconcentration: 1H NMR (400MHz, CDCl 3) δ 1.20 (t, 3H), 2.20 (m, 1H), 3.0 (m, 1H), 3.74 (s, 3H), 4.1 (q, 2H), 4.18 (q, 2H), 4.4 (d, 1H), 6.2 (m, 2H), 7.22 (m, 6H).D) (±)-10,11-dihydro-3-methoxyl group-11-oxo-5H-dibenzo [a, d] suberene-10-ethyl acetate
(±) under magnetic agitation-3-[(3-mehtoxybenzyl)] the phenyl ethyl succinate (0.65g, add in dry methylene chloride 1.9mmol) (10mL) solution DMF (0.2mL) and oxalyl chloride (0.2mL, 2.28mmol).1.5 after hour, this drips of solution is added to AlCl 3(0.6g is in dry methylene chloride 4.5mmol) (15mL) suspension.After 2 hours, with this mixed solution of frozen water quencher, layering is with the water layer dichloromethane extraction.With the organic layer MgSO that merges 4Drying concentrates.Residue is through column chromatography (SiO 2/ 2-4%EtOAc/ hexane) purifying obtains title compound (0.3g): 1H NMR (400MHz, CDCl 3) δ 1.28 (t, 3H), 2.88 (m, 1H), 3.55 (m, 1H), 3.84 (s, 3H), 3.88 (d, 1H), 4.18 (q, 2H), 4.85 (d, 1H), 4.95 (m, 1H), 5.8 (m, 2H), 7.22 (m, 4H), 8.1 (s, 1H).E) (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10, and 11-dihydro-3-methoxyl group-11-oxo-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.3g, 0.93mmol) and the hydrogenation 18 hours under 50psi of Glacial acetic acid (25mL) mixed solution of 10%Pd/C (0.3g).This mixed solution is filtered with celite , wash with acetate.Concentrated filtrate obtains the 0.25g title compound with toluene and methylene dichloride reconcentration: 1H NMR (400MHz, CDCl 3) δ 1.28 (t, 3H), 2.60 (m, 2H), 2.90 (m, 1H), 3.30 (m, 1H), 3.80 (s, 3H), 3.85 (d, 1H), 4.18 (q, 2H), 4.30 (d, 1H), 6.70 (m, 2H), 7.0 (d, 1H), 7.22 (m, 4H).
Preparation 20 preparation (±)-10,11-dihydro-3-hydroxyl-dibenzo [b, f] oxa-English in heptan-10-ethyl acetate is 4-methoxyl group-2-metaphenoxy acetophenone a)
According to Harris, the method for T.W. etc. (J.Med.Chem.1982,25 (7), 855-858), make 2-fluoro-4-methoxyacetophenone (1.00g, 5.95mmol) with phenol reactant obtain title compound (1.27g), be oily matter: 1H NMR (300MHz, CDCl 3) δ 7.90 (d, J=8.8Hz, 1H), 7.35 (m, 2H), 7.20 (m, 1H), 7.05 (m, 2H), 6.70 (dd, J=2.4,8.8Hz, 1H), 6.35 (d, J=2.4Hz, 1H), 3.75 (s, 3H), 2.61 (s, 3H).B) 2-(4-methoxyl group-2-Phenoxyphenyl)-1-morpholine-4-base second-1-thioketones
According to Harris, T.W. method (the J.Med.Chem.1982 that waits, 25 (7), 855-858), make 4-methoxyl group-2-metaphenoxy acetophenone (1.69g, 6.98mmol), sulphur (0.36g, 11.2mmol) and morpholine (0.98mL, 11.2mmol) reaction obtain title compound (1.24g), be white solid: MS (ES) m/e 344.0 (M+H) +C) 2-(4-methoxyl group-2-Phenoxyphenyl) acetate
To 2-(4-methoxyl group-2-Phenoxyphenyl)-1-morpholine-4-base second-1-thioketones (0.35g, i-PrOH 1.02mmol) (15mL) and H 2Add in O (15mL) solution KOH (0.57g, 10.2mmol).With this reactant reflux 18 hours, be cooled to room temperature then, use H 2Et is used in the O dilution 2The O washing.With dense HCl this water layer is acidified to pH ≈ 4, uses CHCl 3Extract.With the extracting solution that merges through MgSO 4Drying concentrates and obtains title compound (0.22g), is white solid.Can be without being further purified use: MS (ES) m/e 259.0 (M+H) +D) 3-methoxyl group dibenzo [b, f] oxa-English in heptan-10-ketone
With 2-(4-methoxyl group-2-Phenoxyphenyl) acetate (594mg, thionyl chloride 2.3mmol) (10mL) vlil 30 minutes, be concentrated into then dried, with residue toluene reconcentration.The residue that obtains is dissolved in exsiccant CH 2Cl 2(3mL), under RT, the logical argon gas, this drips of solution is added to AlCl is housed 3(673mg, dry CH 5.06mmol) 2Cl 2(4mL) in the flame-dried flask of suspension.Stir after 2.5 hours, this mixed solution CH 2Cl 2(10mL) 1.0N NaOH and salt water washing are used in dilution in turn.Dry (MgSO 4), concentrate, obtain title compound (264mg, 48%) through flash chromatography on silica gel (5%EtOAc/ hexane), be faint yellow oily thing: 1H NMR (300MHz, CDCl 3) δ 3.80 (s, 3H), 4.02 (s, 2H), 6.74-8.08 (m, 7H).E) (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Under-78 ℃, logical argon gas, (0.94mL 9.6mmol) is added drop-wise to and two (trimethyl silyl) lithamides is housed (the THF liquid of 1.0M, 7mL is in the flame-dried flask of dry THF 7mmol) (7mL) solution with anhydrous EtOAc.0.5 after hour, and adding TMEDA (2.4mL, 16mmol).After 5 minutes, with 3 minutes dropping 3-methoxyl group dibenzo [b, f] oxa-English in heptan-10-ketone (760mg, THF 3.2mmol) (2ml) solution.Use dry THF (0.4mL) to shift again.Under-78 ℃ to-40 ℃, this reaction solution was stirred 1 hour, use saturated NH then 4Cl (10mL) quencher.This mixed solution temperature to room temperature, is extracted with EtOAc.Dry (MgSO 4), concentrate, obtain title compound through flash chromatography on silica gel (10%EtOAc/ hexane), be clarification oily matter: 1H NMR (300MHz, CDCl 3) δ 1.14-1.20 (t, 3H), 1.21-1.30 (m, 1H), 2.62-2.68 (dd, 1H), 2.94-3.02 (dd, 1H), 3.24-3.30 (dd, 1H), 3.40-3.46 (dd, 1H), 3.40-3.46 (dd, 1H), 3.78 (s, 3H), 4.08-4.18 (m, 2H), 6.60-7.26 (m, 6H), and 7.64-7.68 (dd, 1H).F) (±)-10,11-dihydro-3-methoxyl group dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Under 0 ℃, logical argon gas, (0.48mL 3.9mmol) joins (±)-10 with boron-trifluoride etherate, 11-dihydro-10-hydroxyl-3-methoxyl group dibenzo [b, f] and oxa-English in heptan-10-ethyl acetate (690mg, 1.95mmol) and triethyl silicane (0.62mL, dry CH 3.9mmol) 2Cl 2In the solution.After 20 minutes, with this reaction solution 5%NaHCO 3Quencher is with this mixed solution CH 2Cl 2Extract.Dry (MgSO 4), concentrate yellow oil.It is dissolved in the dehydrated alcohol (20mL), and adding 10%Pd/C (413mg, 0.39mmol).In the Parr hydrogenation apparatus, with the hydrogenation 3 hours under 50psi of this mixed solution.Remove by filter catalyzer by celite , filtrate concentrating obtained title compound (523mg, 86%), be clarification oily matter: 1HNMR (300MHz, CDCl 3) δ 7.18-6.58 (m, 7H), 4.18-4.08 (m, 2H), 3.80 (s, 3H), 3.80-3.74 (m, 1H), 3.40-3.30 (dd, 1H), 2.98-2.84 (dd, 1H), 2.74-2.62 (dd, 1H), 2.60-2.52 (m, 1H), 1.32-1.20 (t, 3H).G) (±)-10,11-dihydro-3-hydroxyl dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Under 0 ℃, logical argon gas, with (±)-10,11-dihydro-3-methoxyl group dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (523mg, CH 1.68mmol) 2Cl 2(6.8mL) drips of solution is added to BBr 3CH 2Cl 2Cold soln (1.0M, 6.7mL, 6.7mmol) in.This reaction solution stirring was carefully added CH in 20 minutes then 3OH (7mL).This mixed solution is concentrated, and residue obtains title compound (407mg, 89%) through flash chromatography on silica gel (15-20%EtOAc/ hexane), is light yellow oil: MS (ES) m/e 299 (M+H) +
Preparation 21 preparation 2-[(3-bromo-1-propyl group) amino]-a) 2-[(3-bromo-1-propyl group of 4-methylpyridine N oxide hydrobromate) amino]-4-methylpyridine N oxide hydrobromate
Under 0 ℃, use 15-20 minute with SOBr 2(5.0mL, CH 64.5mmol) 2Cl 2(20mL) drips of solution is added to 2-[(3-hydroxyl-1-propyl group) amino]-4-methylpyridine N oxide (10.0g, CH 54.87mmol) 2Cl 2(100mL) in the solution.This reaction solution is warmed to room temperature, stirred 2 hours, slowly add Et then 2O (200mL).From gelatinous precipitate, incline and desolvate, should precipitate and use CH again 2Cl 2/ Et 2O washs (for several times).The yellowish brown residue that obtains is placed the curing of spending the night in refrigerator.Collect this solid, use Et 2The O washing obtains title compound (15.07g), is yellow solid.By the organic layer that concentrate the to merge title compound (2.05g) of getting back, be the white needles thing.The total recovery of title compound is 17.89g (96%): MS (ES) m/e 245 and 247 (M+H) +
Following compound explanation prepares the method for bioactive compounds of the present invention from the midbody compound described in above preparation.
Embodiment 1 preparation (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-a) 4-(2-THP trtrahydropyranyl oxygen base)-1-tributyl stannyl-ethyl acetylene of 5H-dibenzo [a, d] suberene-10-acetate
((4.7mL was in dry THF 30mmol) (60mL) solution 30mmol) to join 2-(3-fourth alkynyloxy group) tetrahydrochysene-2H-pyrans under 0 ℃ of the logical argon gas continuously for 1.6M, 18.8mL with 2 minutes hexane solutions with n-Butyl Lithium.0.5 after hour, once all add tributyltin chloride (8.1mL, 30mmol); With this reactant temperature to room temperature.After 3 hours, this reactant with hexane (300mL) dilution, is used H in turn 2O (2 * 60mL), 10%KF (2 * 30mL) and saturated brine (60mL) washing.Dry (Na 2SO 4), concentrate, obtain title compound (3.58g, 27%) with silica gel column chromatography (3%EtOAc/ hexane), be almost colourless oily matter: TLC (5%EtOAc/ hexane) R f0.37; 1H NMR (400MHz, CDCl 3) δ 4.66 (narrow t, 1H), 3.75-3.96 (m, 2H), 3.49-3.62 (m, 2H), 2.56 (app t, 2H), 1.76-1.91 (m, 1H), 1.65-1.78 (m, 1H), 1.42-1.65 (m, 10H), 1.22-1.41 (m, 6H), 0.82-1.08 (m, 15H).B) (±)-10,11-dihydro-3-[4-(2-THP trtrahydropyranyl oxygen base)-ethyl acetylene-1-yl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (±)-10,11-dihydro-3-(trifluoro-methanesulfonyl oxy)-5H-dibenzo [a, d] suberene-10-ethyl acetate (1.34g, 3.13mmol), 4-(2-THP trtrahydropyranyl oxygen base)-1-tributyl stannyl-ethyl acetylene (1.66g, 3.76mmol), LiCl (398mg, 9.39mmol), two (triphenyl phosphine) palladium chloride (110mg, 0.094mmol) and the mixture heating up of anhydrous dioxane (31mL) reflux.1.5 after hour, reactant concentrated removes most of dioxane, residue is dissolved in Et 2Among the O (100mL).Add 10%KF (50mL), this mixed solution was fully stirred 0.5 hour.Remove water layer, with Et 2The O layer is by celite  and MgSO 4Mixture filters.Filtrate is concentrated, and residue obtains title compound (1.12g, 83%) through silica gel column chromatography (10%EtOAc/ hexane), is light yellow oil: TLC (20%EtOAc/ hexane) R f0.40; 1H NMR (400MHz, CDCl 3) δ 7.21-7.30 (m, 1H), 7.06-7.20 (m, 5H), 7.00 (d, J=7.8Hz, 1H), 4.69 (t, J=3.6Hz, 1H), 4.31 (d, J=15.2Hz, 1H), 4.11-4.23 (m, 2H), 3.76-3.97 (m, 4H), 3.59-3.68 (m, 1H), 3.48-3.57 (m, 1H), 3.34 (dd, J=15.2,4.1Hz, 1H), 2.97 (dd, J=15.2,9.5Hz, 1H), 2.70 (t, J=7.3Hz, 2H), 2.65 (dd, J=15.7,4.8Hz, 1H), 2.51 (dd, J=15.7,9.5Hz, 1H), 1.78-1.92 (m, 1H), 1.68-1.78 (m, 1H), 1.44-1.68 (m, 4H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e 455 (M+Na) +C) (±)-10,11-dihydro-3-[4-(2-THP trtrahydropyranyl oxygen base)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under room temperature, the logical hydrogen (50psi), in the Parr device, with (±)-10,11-dihydro-3-[4-(2-THP trtrahydropyranyl oxygen base)-ethyl acetylene-1-yl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (1.2g, 2.77mmol), 10%Pd/C (0.3g, 0.28mmol) and the mixture jolting of EtOAc (28mL).After 3 hours, this reaction solution is filtered concentrated filtrate by celite .Silica gel column chromatography (10%EtOAc/ hexane) obtains title compound (1.06g, 88%), is colorless oil: TLC (20%EtOAc/ hexane) R f0.51; 1H NMR (400MHz, CDCl 3) δ 7.05-7.20 (m, 4H), 6.92-7.03 (m, 3H), 4.53-4.60 (m, 1H), 4.34 (d, J=15.1Hz, 1H), and 4.12-4.26 (m, 2H), 3.80-3.90 (m, 3H), and 3.71-3.80 (m, 1H), 3.44-3.53 (m, 1H), and 3.35-3.44 (m, 1H), 3.33 (dd, J=15.1,4.1Hz, 1H), 2.95 (dd, J=15.1,9.4Hz, 1H), 2.65 (dd, J=15.5,4.9Hz, 1H), 2.49-2.61 (m, 3H), and 1.77-1.90 (m, 1H), 1.45-1.77 (m, 9H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e 459 (M+Na) +D) (±)-10,11-dihydro-3-(4-hydroxyl-1-butyl)-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with (±)-10,11-dihydro-3-[4-(2-THP trtrahydropyranyl oxygen base)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (456.0mg, 1.04mmol) and tosic acid monohydrate (60mg, anhydrous EtOH (10mL) solution stirring 0.31mmol).After 2 hours, with this reaction solution 5%NaHCO 3(1mL) quencher concentrates and removes EtOH.With residue H 2CH is used in O (2mL) dilution 2Cl 2Extract.Dry (MgSO 4), concentrating, silica gel column chromatography (1: 1 EtOAc/ hexane) obtains title compound (342.4mg, 93%), is colorless oil: TLC (1: 1 EtOAc/ hexane) R f0.49; 1H NMR (250MHz, CDCl 3) δ 6.85-7.25 (m, 7H), 4.34 (d, J=15.1Hz, 1H), 4.08-4.30 (m, 2H), 3.75-3.95 (m, 2H), 3.53-3.72 (m, 2H), 3.33 (dd, J=15.1,4.1Hz, 1H), 2.95 (dd, J=15.1,9.4Hz, 1H), and 2.40-2.75 (m, 4H), 1.45-1.80 (m, 4H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e 353 (M+H) +E) (±)-10,11-dihydro-3-[4-(adjacent two acyliminos of N-benzene)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under room temperature, the logical argon gas, with diethyl azodiformate (0.2mL, 1.26mmol) be added dropwise to (±)-10,11-dihydro-3-(4-hydroxyl-1-butyl)-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.37g, 1.05mmol), triphenyl phosphine (0.33g, 1.26mmol) and phthalimide (0.19g is in anhydrous THF (10mL) solution 1.26mmol).After 23 hours, this reaction solution is concentrated on rotatory evaporator.Silica gel column chromatography (30%EtOAc/ hexane) obtains title compound (0.35g, 70%), is colorless oil: MS (ES) m/e 504.3 (M+Na) +F) (±)-10,11-dihydro-3-(4-amino-1-butyl)-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with the hydrazine monohydrate (0.11g 2.18mmol) joins (±)-10,11-dihydro-3-[4-(N-benzene adjacent two acyliminos)-1-butyl]-5H-dibenzo [a, d] (0.35g is in anhydrous EtOH (10mL) 0.73mmol) and toluene (2mL) solution for suberene-10-ethyl acetate.Under RT, this reaction solution was stirred 17 hours, filter then, with the filter cake toluene wash.On rotatory evaporator, concentrate and obtain title compound (0.23g, 90%), be colorless solid: MS (ES) m/e 352.3 (M+H) +G) (±)-10,11-dihydro-3-[4-(1-oxo pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With 2-chloropyridine-N-oxide hydrochloride (0.31g, 1.88mmol), (±)-10,11-dihydro-3-(4-amino-1-butyl)-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.22g, 0.63mmol) and NaHCO 3(0.26g, tertiary amyl alcohol 3.13mmol) (6mL) vlil 21 hours.With this reaction mixture CH 2Cl 2(100mL) dilution is filtered, and filtrate is concentrated with rotatory evaporator.Silica gel column chromatography (1: 9: 5 MeOH/CH 2Cl 2/ EtOAc) obtain title compound (82mg, 30%), be yellow oil: MS (ES) m/e 445.2 (M+H) +H) (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (±)-10,11-dihydro-3-[4-(1-oxo pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.07g, 0.16mmol), 10%Pd/C (0.08g, 0.075mmol), (0.16mL 1.6mmol) and Virahol (4mL) mixed solution reflux 14 hours, removes by filter catalyzer by celite  to tetrahydrobenzene then.With Virahol and MeOH washing, with the concentrated title compound (0.046g, 69%) that obtains of rotatory evaporator, is clarification oily matter: MS (ES) m/e 429.3 (M+H) with filtrate with filter cake +I) (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, with (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-(46mg is 0.11mmol) with 1.0N LiOH (0.66mL, THF 0.66mmol) (3mL) and H for 5H-dibenzo [a, d] suberene-10-ethyl acetate 2O (3mL) mixing solutions stirs.After 24 hours, this reaction mixture is concentrated residue H with rotatory evaporator 2O (5mL) dilution.With this solution ice bath cooling, slowly add 1.0N AcOH and obtain white precipitate.(the 45%CH that contains 0.1TFA of chromatography on C-18YMC 3CN/H 2O) obtain title compound (13mg, 21%), be white solid: MS (ES) m/e 401.3 (M+H) +C 26H 28N 2O 20.75H 2O1.5CF 3CO 2H analytical calculation value: C, 59.54; H, 5.31; N, 4.72.Measured value: C, 59.69; H, 5.31; N, 4.72.
Embodiment 2 preparation (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-oxyethyl group-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.67g, 1.36mmol), the ethanol liquid (6.8mL of 1.0M NaOEt, 6.8mmol) and dehydrated alcohol (6.8mL) mix, be that this mixture is heated in 70 ℃ oil bath with setting in advance.Heat and obtained dark-coloured solution in 10 minutes, remove oil bath then, under no indirect heating, this solution restir 5-7 minute.The solution that obtains is cooled off in ice, and (0.47mL, 8.2mmol) quencher should reaction to use Glacial acetic acid then.This mixed solution is concentrated, again with residue at CH 2Cl 2(10mL) with semi-saturation NH 4Distribute between the Cl (10mL).Layering is with water layer CH 2Cl 2(2 * 10mL) extract.With the organic layer drying (MgSO that merges 4), concentrating, residue obtains red-orange with the toluene reconcentration.Silica gel column chromatography (5%MeOH/CHCl 3) obtain title compound (601.1mg, 90%), be yellow oil: TLC (5%MeOH/CHCl 3) R f0.36; 1H NMR (250MHz, CDCl 3) δ 7.95 (d, J=7.1Hz, 1H), 6.88-7.30 (m, 6H), 6.77 (d, J=2.6Hz, 1H), 6.67 (dd, J=8.2,2.6Hz, 1H), and 5.95-6.20 (m, 2H), 4.28 (d, J=15.0Hz, 1H), 4.18 (q, J=7.2Hz, 2H), 4.04 (t, J=5.6Hz, 2H), 3.65-4.00 (m, 4H), (3.46 q, J=6.5Hz, 2 H), 3.30 (dd, J=15.0,4.2Hz, 1H), 2.93 (dd, J=15.0,9.2Hz, 1H), 2.65 (dd, J=15.6,5.0Hz, 1H), 2.52 (dd, J=15.6,9.4Hz, 1H), 1.95-2.25 (m, 2H), 1.10-1.45 (m, 6H); MS (ES) m/e 491 (M+H) +B) (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (±)-10,11-dihydro-3-[3-(4-oxyethyl group-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (601.1mg, 1.23mmol), tetrahydrobenzene (1.2mL, 12.3mmol), 10%Pd/C (130mg, 0.012mmol) and the mixture heating up of dehydrated alcohol (12.3mL) reflux.23.5 after hour, this reaction solution is passed through celite  heat filtering, with the filter cake washing with alcohol.Concentrated filtrate is with residue toluene reconcentration.Silica gel column chromatography (1: 1 EtOAc/CHCl of 5%MeOH 3Liquid) obtain title compound (528.1mg, 90%), be glassy yellow oily matter: the TLC (EtOAc/CHCl of 10%MeOH 3Liquid) R f0.67; 1H NMR (400MHz, CDCl 3) δ 7.89 (d, J=5.8Hz, 1H), 7.05-7.18 (m, 4H), 6.99 (d, J=8.2Hz, 1H), 6.77 (d, J=2.6Hz, 1H), 6.66 (dd, J=8.2,2.6Hz, 1H), 6.17 (dd, J=5.8,2.1Hz, 1H), 5.86 (d, J=2.1Hz, 1H), 4.73 (brt, 1H), 4.28 (d, J=14.9Hz, 1H), 4.11-4.25 (m, 2H), 4.04 (t, J=5.9Hz, 2H), 3.98 (q, J=7.0Hz, 2H), 3.83 (d, J=14.9Hz, 1H), 3.76-3.85 (m, 1H), 3.43 (q, J=6.4Hz, 2H), 3.30 (dd, J=15.0,4.1Hz, 1H), 2.93 (dd, J=15.0,9.2Hz, 1H), 2.64 (dd, J=15.6,4.8Hz, 1H), 2.52 (dd, J=15.6,9.5Hz, 1H), and 2.01-2.11 (m, 2H), 1.37 (t, J=7.0Hz, 3H), 1.27 (t, J=7.0Hz, 3H); MS (ES) m/e 475 (M+H) +C) (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
Under the room temperature, with 1.0N NaOH (1.7mL, 1.7mmol) be added dropwise to (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (528.1mg, 1.11mmol) dehydrated alcohol (11mL) solution in, be 45 ℃ oil bath heating with this solution with setting in advance.After 20 hours, this reactant is concentrated, again with residue H 2O concentrates.The residue that obtains is dissolved in H 2Among the O (10mL), filter.With 1.0N HCl this pH is transferred to 7, this mixed solution is fully stirred make the gelatinous precipitate of initial formation change into solid.Grind this conversion process of promotion with glass stick and curet.The pH of the mixing solutions that obtains is transferred to 7 again, collect this solid, with the H of capacity 2The O washing.This filtrate is concentrated, residue is dissolved in the H that a small amount of 1.0N NaOH is arranged 2Among the O.PH is transferred to 7 obtain a small amount of secondary product.Product is merged, and vacuum-drying (40-50 ℃) obtains title compound (453.7mg, 82%), is that (Hamilton PRP-1  contains the 45%CH of 0.1%TFA to pale solid: HPLC 3CN/H 2O liquid) k '=1.32; 1H NMR (400MHz, DMSO-d 6) δ 7.78 (d, J=6.6Hz, 1H), 7.35-7.65 (m, 1H), 7.02-7.22 (m, 4H), 6.97 (d, J=8.3Hz, 1H), 6.82 (d, J=2.4Hz, 1H), 6.68 (dd, J=8.3,2.4Hz, 1H), 6.29 (dd, 1H), 6.15 (narrow d, 1H), 4.20 (d, J=14.6Hz, 1H), 3.93-4.12 (m, 4H), 3.89 (d, J=14.6Hz, 1H), 3.60-3.71 (m, 1H), and 3.30-3.50 (m, 2H), 3.20 (dd, J=15.1,4.1Hz, 1H), 2.83 (dd, J=15.1,10.1Hz, 1H), 2.60 (dd, J=16.0,5.3Hz, 1H), 2.48 (dd, J=16.0,8.9Hz, 1H, part is covered by residual solvents signals), 1.90-2.05 (m, 2H), 1.30 (t, J=6.9Hz, 3H); MS (ES) m/e 447 (M+H) +C 27H 30N 2O 41.5HCl analytical calculation value: C, 64.70; H, 6.33; N, 5.59.Measured value: C, 64.53; H, 6.14; N, 5.31.
Embodiment 3 preparation (±)-10,11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] a) (±)-10 of suberene-101 acetate, 11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with 5 minutes with 2-(ethylamino)-4-thiazoleethanol (0.33g, 1.9mmol) and diethyl azodiformate (0.30mL, 1.9mmol) dry DMF (5mL) drips of solution add (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (296.4mg, 1mmol) and triphenyl phosphine (525mg is in dry DMF 2mmol) (5mL) solution.In the dropping process, this reactant is cooled off with the RT water-bath.After 16 hours, this reaction solution is concentrated, with residue dimethylbenzene (2x) reconcentration.Silica gel column chromatography (20%EtOAc/ hexane) obtains title compound (145.0mg, 32%), is yellow oil: TLC (1: 1 EtOAc/ hexane) R f0.60; 1H NMR (250MHz, CDCl 3) δ 7.00-7.30 (m, 4H), 6.98 (d, J=8.2Hz, 1H), 6.77 (d, J=2.6Hz, 1H), 6.68 (dd, J=8.2,2.6Hz, 1H), 6.21 (s, 1H), 5.00-5.25 (m, 1H), and 4.04-4.38 (m, 5H), 3.81 (d, J=15.1Hz, 1H), 3.70-3.90 (m, 1H), 3.13-3.40 (m, 3H), 2.99 (t, J=6.7Hz, 2H), 2.92 (dd, J=14.9,9.3Hz, 1H), 2.64 (dd, J=15.6,5.0Hz, 1H), 2.51 (dd, J=15.6,9.3Hz, 1H), 1.27 (t, J=7.2Hz, 3H); MS (ES) m/e 451 (M+H) +B) (±)-10,11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate
With 1.0N LiOH (0.32mL, 0.32mmol) be added dropwise to (±)-10 under 0 ℃, 11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate (145.0mg, THF 0.32mmol) (2.4mL) and H 2In O (0.48mL) solution.Under 0 ℃, the orange two-phase mixed solution of the powder that obtains was stirred 10 minutes, during color gradient be orange-yellow, be warmed to room temperature then.1.5 after hour, add less water (5) again, then this reactant was stirred 42 hours, be cooled to 0 ℃ again, with TFA (0.025mL) neutralization.Rotary evaporation is removed THF, with the oily residue 0.1%TFA/CH that obtains 3The CN dilution obtains homogeneous phase solution.ODS chromatography (gradient: the 40%CH that contains 0.1%TFA 3CN/H 2O liquid contains the 45%CH of 0.1%TFA then 3CN/H 2O liquid) obtain containing the part of title compound.Merge this part, rotary evaporation is removed CH 3CN.Under 0 ℃, the water mixed liquid alkalization that contains that obtains is obtained homogeneous phase solution.Carefully be acidified to pH4-5 with 1.0N HCl and obtain solid precipitation, collecting precipitation is used capacity H 2O washing, drying obtains title compound (80.9mg, 51%), is that (Hamilton PRP-1  contains the 45%CH of 0.1%TFA to pale solid: HPLC 3CN/H 2O liquid) k '=0.89; 1H NMR (400MHz, CD 3OD) δ 7.02-7.18 (m, 4H), 7.00 (d, J=8.3Hz, 1H), 6.79 (d, J=2.6Hz, 1H), 6.68 (dd, J=8.3,2.6Hz, 1H), 6.45 (s, 1H), 4.26 (d, J=14.9Hz, 1H), 4.20 (t, J=6.4Hz, 2H), 3.87 (d, J=14.9Hz, 1H), 3.68-3.80 (m, 1H), 3.34 (q, J=7.3Hz, 2H, part is covered by residual solvents signals), 3.30 (dd, 1H is covered by residual solvents signals), 2.99 (t, J=6.4Hz, 2H), 2.92 (dd, J=15.0,9.4Hz, 1H), 2.62 (dd, J=15.9,5.0Hz, 1H), 2.47 (dd, J=15.9,9.3Hz, 1H), 1.27 (t, J=7.3Hz, 3H); MS (ES) m/e 423 (M+H) +C 24H 26N 2O 3S0.67CF 3CO 2H analytical calculation value: C, 61.03; H, 5.39; N, 5.62.Measured value: C, 61.21; H, 5.36; N, 5.60.
Embodiment 4 preparation (S)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, to (S)-10 of stirring, 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (35g, add 2-[(3-hydroxyl-1-propyl group in dry THF 118mmol) (1.1L) and dry DMF (600mL) solution) amino] pyridine-N-oxide (29.4g, 175mmol) and triphenyl phosphine (45.9g, 175mmol).Treat all solids dissolve fully the back (about 1 hour), this reactant is cooled to 0 ℃ with ice bath, with syringe add diisopropyl azodiformate (36.4mL, 95%, 175mmol).This reactant slowly is warmed to room temperature, stirred 18 hours.Concentrate, through flash chromatography on silica gel (95: 5 CHCl 3/ MeOH), and then through flash chromatography on silica gel (80: 20: 5 CHCl 3/ EtOAc/EtOH) purifying obtains title compound (37.66g, 71%) for the second time, is the light yellow solid foam: 1H NMR (400MHz, DMSO-d 6) δ 8.08 (dd, J=6.3,1.1Hz, 1H), 7.29 (t, 1H), 7.19-7.06 (m, 5H), 6.97 (d, J=8.3Hz, 1H), 6.84 (d, J=2.5,1H), 6.79 (dd, J=8.5,1.6Hz, 1H), 6.69 (dd, J=8.3,2.6Hz, 1H), 6.57 (m, 1H), 4.17 (d, J=14.7Hz, 1H), 4.13-4.07 (m, 2H), 4.00 (t, 2H), 3.91 (d, J=14.7Hz, 1H), 3.66 (m, 1H), 3.39 (t, 2H), 3.19 (dd, J=15.1,4.5Hz, 1H), 2.85 (dd, J=15.1,10.0Hz, 1H), 2.65 (dd, J=15.8,5.4Hz, 1H), 1.99 (m, 2H), 1.18 (t, 3H); MS (ES) m/e 447.3 (M+H) +B) (S)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
To (S)-10 of stirring, 11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (37.66g, add 10% activated carbon supported palladium (18g in Virahol 84mmol) (700mL) solution, 16.9mmol, carefully wetting in Virahol in advance under the logical argon gas) and tetrahydrobenzene (85mL, 839mmol).Then under logical argon gas, be set in 90 ℃ the oil bath this reactant of heating again to refluxing.After 6 hours, add again 10% activated carbon supported palladium (18g, 84mmol, carefully wetting in Virahol in advance under the logical argon gas) and tetrahydrobenzene (85mL, 839mmol).After 18 hours, with this reaction solution by celite  heat filtering, with filter cake with 1: 1 MeOH/CHCl 3(600mL) washing.Vacuum concentrated filtrate, residue is through flash chromatography on silica gel (95: 5 CHCl 3/ MeOH) purifying obtains title compound (29.2g, 81%), is light yellow oil: 1HNMR (400MHz, DMSO-d 6) δ 7.94 (dd, J=5.4,1.9Hz, 1H), 7.35-7.31 (m, 1H), 7.18 (d, J=7.2,1H), 7.14-7.06 (m, 3H), 6.97 (d, J=8.3Hz, 1H), 6.83 (d, J=2.6,1H), 6.68 (dd, J=8.3,2.6Hz, 1H), 6.54 (t, 1H), 6.44 (m, 2H), 4.17 (d, J=14.6Hz, 1H), 4.13-4.02 (m, 2H), 4.00 (t, 2H), 3.91 (d, J=14.7Hz, 1H), 3.66 (m, 1H), 3.35 (m, 2H), 3.19 (dd, J=15.1,4.4Hz, 1H), 2.86 (dd, J=15.1,10.1Hz, 1H), 2.65 (dd, J=15.8,5.4Hz, 1H), 2.55 (dd, J=15.8,8.7Hz, 1H), 1.93 (m, 2H), 1.18 (t, 3H); MS (ES) m/e 431.4 (M+H) +C) (S)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
To (S)-10 of stirring, 11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (29.20g, and the adding 1.0N NaOH aqueous solution in dioxane 68mmol) (350mL) solution (110mL, 110mmol).Reaction solution that should muddiness in the oil bath under 50 ℃ stirred 24 hours, then with the homogeneous phase solution that obtains with the 1.0NHCl aqueous solution (110mL, 110mmol) neutralization.Rotary evaporation is settled out product with near the doing of this solution concentration.Inclining supernatant liquor, the colloidal solid of drying under reduced pressure remainder, and then be dissolved in 1: 1 methyl alcohol/CHCl 3In.This settled solution of rotary evaporation reconcentration then, the vacuum finish-drying.The solid of remainder is ground with less water, filter, vacuum-drying obtains title compound (26.85g, 94%), is that (Hamilton PRP-1  contains the 35%CH of 0.1%TFA to pale powder: HPLC 3CN/H 2O liquid) k '=2.88; 1H NMR (400MHz, DMSO-d 6) δ 7.94 (dd, J=4.7,1.6Hz, 1H), 7.38 (m, 1H), 7.18 (d, J=7.3,1H), 7.14 (d, J=3.9Hz, 2H), 7.08 (m, 1H), 6.97 (d, J=8.4Hz, 1H), 6.83 (d, J=8.6Hz, 1H), 6.78 (brs, 1H), 6.68 (dd, J=8.3,2.6Hz, 1H), 6.50 (d, J=8.3Hz, 1H), 6.47 (dd, 1H), 4.20 (d, J=14.6Hz, 1H), 4.00 (t, 2H), 3.88 (d, J=14.6Hz, 1H), 3.67 (m, 1H), 3.37 (m, 1H), 3.20 (dd, J=15.2,4.4Hz, 1H), 2.83 (dd, J=15.2,10.1Hz, 1H), 2.60 (dd, J=15.9,5.3Hz, 1H), 2.50 (dd, 1H), 1.95 (m, 2H); MS (ES) m/e 403.3 (M+H) +C 25H 26N 2O 3H 2O analytical calculation value: C, 71.41; H, 6.71; N, 6.66.Measured value: C, 71.21; H, 6.53; N, 6.54.
Embodiment 5 preparation (±)-10,11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with 6-amino-2-pyridyl ethanol (0.23g, 1.68mmol) and diethyl azodiformate (0.26mL, 1.68mmol) dry DMF (5mL) drips of solution add (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] (0.48g is in dry DMF 1.82mmol) (5mL) solution for suberene-10-ethyl acetate and triphenyl phosphine.After 1 hour, this reaction solution is concentrated, residue obtains title compound (0.030g): MS (ES) m/e 417 (M+H) through flash chromatography on silica gel (1: 1 EtOAc/ hexane) purifying +B) (±)-10,11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate
Under the room temperature, with (±)-10,11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.030g, 0.072mmol) and 1.0N NaOH (0.14mL, MeOH 0.14mmol) (2mL) solution stirring is spent the night, and concentrates then.Residue is soluble in water, with 1.0N HCl regulator solution pH to 7.Concentrate, through C-18 bonding wash-out column chromatography (10: 9: 1 CH 3CN/H 2O/TFA) obtain title compound (0.013g): MS (ES) m/e 389 (M+H) +
Embodiment 6 preparation (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (R)-10 of suberene-10-acetate, 11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under room temperature, the logical argon gas, with 10 minutes with 2-[(3-hydroxyl-1-propyl group) amino] pyridine-N-oxide (0.70g, 4mmol) and diethyl azodiformate (0.65mL, dry DMF 4mmol) (20mL) drips of solution is added to (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.45g, 2mmol) and triphenyl phosphine (1.2g is in dry DMF 4mmol) (8mL) solution.23.5 after hour, rotary evaporation concentrates this reaction solution, residue is removed residual DMF with the dimethylbenzene reconcentration.Silica gel column chromatography (1-4%CH 3OH/CH 2Cl 2) obtain title compound (0.50g, 74%), be yellow oil: MS (ES) m/e 447 (M+H) +B) (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.5g, 1mmol), 10%Pd/C (0.25g, 0.2mmol), tetrahydrobenzene (2mL, 20mmol) and Virahol (10mL) mixed solution reflux 18 hours, remove by filter catalyzer by celite  then.Silica gel column chromatography (0.5-2%CH 3OH/CH 2Cl 2) obtain title compound (0.4g, 83%), be glassy yellow oily matter: MS (ES) m/e 431 (M+H) +C) (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
With (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] (0.4g, 93mmol) (1.1mL, anhydrous EtOH (10mL) mixed solution 1.1mmol) is warm in the oil bath that is set under 50 ℃ with 1.0N NaOH for suberene-10-ethyl acetate.After 18 hours, this reaction solution rotary evaporation is concentrated, residue is dissolved in H 2Among the O.This aqueous solution is adjusted to pH4 with 3N HCl, collects solid precipitation, use H 2The O washing.Obtain title compound (0.36g, 96%) at 40 ℃ of these materials of following high vacuum dry, be nearly colorless solid: [α] D+ 50.8 ° of (c=0.12, CH 3OH); MS (ES) m/e 403 (M+H) +C 25H 26N 2O 30.5H 2O analytical calculation value: C, 72.97; H, 6.61; N, 6.80.Measured value: C, 73.09; H, 6.38; N, 6.58.
Embodiment 7 preparation (S)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but replace 2-[(3-hydroxyl-1-propyl group with 6-(methylamino-)-2-pyridyl ethanol) amino] pyridine-N-oxide and usefulness (S)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate, through silica gel column chromatography (0.2-2%MeOH/CH 2Cl 2) obtain title compound, be colorless oil: MS (ES) m/e 431.2 (M+H) +B) (S)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate
With (S)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-(80mg 0.18mmol) is dissolved among the THF (4mL) 5H-dibenzo [a, d] suberene-10-ethyl acetate, adds LiOHH 2O (35mg, H 0.84mmol) 2O (4mL) solution.Under the RT,, use ether (10mL) dilution then with this solution stirring 72 hours.The supernatant liquor that inclines, this solid is miscible in H 2Among the O.Carefully be acidified to pH4 with 3N HCl and obtain title compound, be white solid: MS (ES) 403 (M+H) +C 25H 26N 2O 30.75H 2O analytical calculation value: C, 72.18; H, 6.66; N, 6.73.Measured value: C, 72.44; H, 6.52; N, 6.71.
Embodiment 8 preparation (±)-10,11-dihydro-3-[3-(3,4,5,6-hydrogen pyrimidine-2--amino)-the 1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-nitro benzyloxycarbonyl) amino-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but replace 2-[(3-hydroxyl-1-propyl group with 3-(4-nitro benzyloxy carbonylamino)-1-propyl alcohol) amino] pyridine-N-oxide and usefulness (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be amber oily thing: MS (ES) 533.3 (M+H) +B) (±)-10,11-dihydro-3-(3-amino-1-propoxy-)-5H-dibenzo [a, d] suberene-10-ethyl acetate
At H 2(48psi), with (±)-10,11-dihydro-3-[3-(4-nitro benzyloxy carbonylamino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (1.6g, 3mmol), 10%Pd/C (0.8g, 1mmol) and ethanol (50mL) mixed solution jolting 3 hours, remove by filter catalyzer by celite  then.Filtrate concentrating obtained title compound (1.2g, 100%), be yellow oil: MS (ES) 348.2 (M+H) +C) (±)-10,11-dihydro-3-[3-(pyrimidine-2--amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (±)-10,11-dihydro-3-(3-amino-1-propoxy-)-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.4g, 1mmol), sodium bicarbonate (0.5g, 6mmol), the 2-brominated pyrimidine (0.34g, 2mmol) and ethanol (10mL) mixed solution reflux 18 hours.With this solution decant, concentrate then.Residue is through silica gel column chromatography (0.2-2%MeOH/CH 2Cl 2) purifying obtains title compound (0.17g, 34%), is light yellow oil: MS (ES) 432.3 (M+H) +D) (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimidine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
At H 2(48psi), with (±)-10,11-dihydro-3-[3-(pyrimidine-2--amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.17g, 0.38mmol), 10%Pd/C (0.085g, 0.08mmol), (0.1mL 0.4mmol) and ethanol (5mL) mixed solution jolting 6 hours, removes by filter catalyzer by celite  then for the dioxane of 4M HCl.Filtrate concentrating obtained title compound (0.19g), be yellow oil: MS (ES) 436.3 (M+H) +E) (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimidine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
Under the room temperature,, 11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimidine-2-base is amino)-1-propoxy-with (±)-10]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.17g, 0.36mmol), LiOHH 2O (0.042g, 1mmol), THF (3mL) and H 2The solution stirring of O (10mL) 20 hours concentrates then.Residue is soluble in water, with 3N HCl this solution is acidified to pH4.The solution that obtains placed in refrigerator spend the night, supernatant liquor inclines from solid.This solid of vacuum-drying obtains title compound (0.145g, 91%), is brown solid: MS (ES) 408.3 (M+H) +C 24H 29N 3O 31.3HCl analytical calculation value: C, 63.37; H, 6.71; N, 9.23.Measured value: C, 63.67; H, 6.84; N, 9.46.
Embodiment 9 preparation (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-3-[3-(1-oxo isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but with 1-[(3-hydroxyl-1-propyl group) amino]-isoquinoline-N-oxide replacement 2-[(3-hydroxyl-1-propyl group) amino] pyridine-N-oxide and usefulness (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound is light yellow oil: MS (ES) m/e 497.2 (M+H) +B) (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (b), but with (±)-10,11-dihydro-3-[3-(1-oxo isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound is clarification oily matter: MS (ES) m/e481.3 (M+H) +C) (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound is amber solid: MS (ES) m/e 453.2 (M+H) +C 29H 28N 2O 31.3TFA0.25H 2O analytical calculation value: C, 62.71; H, 4.96; N, 4.63.Measured value: C, 62.45; H, 4.92; N, 4.41.
Embodiment 10 preparation (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-3-[3-[4-(ethylmercapto group)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (300mg, 0.61mmol) and the sulfo-sodium ethylate (145mg, DMF 1.22mmol) (5mL) solution be heated to 70 ℃ 3 hours.Rotary evaporation removes and desolvates, and residue is through silica gel column chromatography (2-6%CH 3OH/CH 2Cl 2) purifying obtains title compound (90mg), is orange-yellow oily thing: MS (ES) m/e 507.3 (M+H) +B) (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (60mg, 0.119mmol), Fe powder (70mg) and Glacial acetic acid (2mL) mixed solution be heated to 100 ℃ 1.5 hours.Mixed solution is cooled to RT, uses H 2Solid Na is used in O and EtOAc dilution 2CO 3With pH regulator to 7-8.Layering is extracted water layer with EtOAc.With the organic layer H that merges 2The O washing, dry (MgSO 4), concentrate and obtain title compound (60mg), be yellow oil: MS (ES) m/e 491.3 (M+H) +C) (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound is yellow: 1H NMR (400MHz, DMSO-d 6) δ 7.77-7.76 (d, 1H), 7.17-7.15 (d, 1H), 7.13-7.12 (d, 2H), and 7.08-7.07 (m, 1H), 6.96-6.94 (d, 1H), 6.81-6.80 (s, 1H), 6.68-6.67 (d, 1H), 6.52 (s, 1H), 6.35-6.33 (d, 2H), 6.30 (s, 1H), 4.20-4.16 (d, 1H), 3.99-3.96 (t, 2H), 3.89-3.85 (d, 1H), 3.65-3.63 (m, 1H), 3.36-3.32 (m, 2H), 3.22-3.15 (m, 1H), 2.96-2.90 (m, 2H), 2.85-2.78 (m, 1H), 2.62-2.56 (m, 2H), 1.94-1.90 (m, 2H), 1.26-1.22 (t, 3H); MS (ES) m/e 463.4 (M+H) +
Embodiment 11 preparation (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-2-methyl-3-[3-[N-(tert-butoxycarbonyl)-N-(1-oxo pyridine-2-yl) amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, (60% is dispersed in the Dormant oils with NaH, 0.14g, 0.37mmol) join (±)-10, (100mg is in DMSO 0.32mmol) (2mL) solution for 11-dihydro-3-hydroxy-2-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate, under RT, this reactant was stirred 0.5 hour.Drip 2-[N-(3-mesyloxy-1-propyl group)-N-(tertbutyloxycarbonyl) amino then] pyridine-N-oxide (160mg, DMSO 0.4mmol) (1mL) solution.Under RT, logical argon gas, this reactant was stirred 18 hours, water (20mL) quencher should be reacted then, extracted with EtOAc.Dry (MgSO 4), concentrate, through silica gel column chromatography (1%MeOH/CH 2Cl 2) obtain title compound (85mg, 42%), be colorless oil: MS (ES) m/e 561.3 (M+H) +B) (±)-10,11-dihydro-2-methyl-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With TFA (0.16g, 1.4mmol) be added drop-wise to (±)-10,11-dihydro-2-methyl-3-[3-[N-(tert-butoxycarbonyl)-N-(1-oxo pyridine-2-yl) amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (80mg, dry CH 0.14mmol) 2Cl 2(3mL) in the solution.This reactant was stirred 5 hours, and rotary evaporation concentrates and obtains title compound (60mg, 43%) then, is colorless oil: MS (ES) m/e 461.1 (M+H) +C) (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (b), but with (±)-10,11-dihydro-2-methyl-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound is pale solid: MS (ES) m/e417.3 (M+H) +D) (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be pale solid: 1HNMR (400MHz, CDCl 3) δ 7.75 (d, 1H), 7.65 (t, 1H), 7.15 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 6.7 (d, 1H), 6.65 (m, 1H), 6.60 (s, 1H), 4.25 (d, J=15.1Hz, 1H), 4.05 (t, 2H), 3.80 (m, 1H), 3.75 (d, J=15.1Hz, 1H), 3.50 (t, 2H), 3.25 (dd, 1H), 2.85 (dd, 1H), 2.68 (dd, 1H), 2.60 (dd, 1H), 2.15 (t, 2H), 2.10 (s, 3H); MS (ES) m/e 417.3 (M+H) +
Embodiment 12 preparation (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but with (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is through silica gel column chromatography (gradient: 1: 1EtOH: hexane, EtOH, 20%MeOH/CH then then 2Cl 2, 30%MeOH/CH then 2Cl 2) obtain title compound: MS (ES) m/e 522.3 (M+H) +B) (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (b), but with (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, silica gel column chromatography (10%MeOH/CH 2Cl 2) after obtain title compound: MS (ES) m/e 506.2 (M+H) +C) (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
Carry out saponification reaction according to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate.With the Glacial acetic acid acidifying of this reactant, crude product is obtained title compound through the desalination of XAD-2 resin chromatography, be white solid: MS (ES) m/e 478.3 (M+H) +C 30H 36FN 3O 51.25H 2O analytical calculation value: C, 64.32; H, 6.92; N, 7.50.Measured value: C, 63.87; H, 6.47; N, 7.96.
Embodiment 13 preparation (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under RT, logical argon gas, with 10 minutes with 2-[(3-hydroxyl-1-propyl group) amino]-4-methylpyridine N oxide (1.72g, 9.45mmol) and diethyl azodiformate (1.49mL, 9.45mmol) dry DMF (50mL) drips of solution be added to (S)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (1.4g, 4.72mmol) and triphenyl phosphine (2.60g is in dry DMF 9.92mmol) (50mL) solution.After 19 hours, this reaction solution rotary evaporation is concentrated, residue is removed residual DMF with the dimethylbenzene reconcentration.Silica gel column chromatography (gradient: 30%EtOAc/ hexane (0.5L), EtOAc (1L), 5%MeOH/CHCl then then 3) obtain title compound (1.31g, 60%), be yellow oil: MS (ES) m/e 461.3 (M+H) +B) (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (S)-10,11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.86g, 1.87mmol), 10%Pd/C (0.86g, 0.81mmol), (1.89mL 18.7mmol) and Virahol (20mL) mixed solution reflux 19 hours, removes by filter catalyzer by celite  to tetrahydrobenzene then.Silica gel column chromatography (1: 9: 10 MeOH/CH 2Cl 2/ EtOAc) obtain title compound (0.65g, 78%), be clarification oily matter: MS (ES) m/e 445.2 (M+H) +C) (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
With (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] (2.08g, 4.69mmol) (7.0mL, anhydrous EtOH (45mL) mixed solution 7.0mmol) heats with the oil bath that is set to 45 ℃ suberene-10-ethyl acetate with 1.0N NaOH.After 18 hours, this reaction solution rotary evaporation is concentrated, use 1.0N HCl pH regulator to 7.Collect solid precipitation, use H 2The O washing.Dried overnight obtains title compound (1.61g, 82%), is nearly colorless solid: MS (ES) m/e 417.4 (M+H) +C 26H 28N 2O 31.0H 2O analytical calculation value: C, 71.87; H, 6.96; N, 6.45.Measured value: C, 71.63; H, 6.96; N, 6.30.
Embodiment 14 preparation (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-[4-(2-propoxy-)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-isopropyl acetate
With (S)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (0.2g, 0.4mmol) and sodium isopropylate (0.067g, 0.8mmol) Virahol (5mL) mixed solution 80 ℃ of down heating 3.5 hours, and then add sodium isopropylate (0.05g, 0.6mmol), under RT, this reactant stirring is spent the night.Concentrate silica gel column chromatography (gradient: 5%-15%MeOH/CH 2Cl 2) obtain title compound (0.106g, 52%), be bright brown oil: MS (ES) 519.3 (M+H) +B) (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-isopropyl acetate
According to the method among the embodiment 13 (b), but with (S)-10,11-dihydro-3-[3-[4-(2-propoxy-)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-isopropyl acetate replacement (S)-10,11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, silica gel column chromatography (5%MeOH/CH 2Cl 2) after obtain title compound, be little yellow oil: MS (ES) 503.4 (M+H) +C) (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 13 (c), but with (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-isopropyl acetate replacement (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be white powder: MS (ES) 461.3 (M+H) +C 28H 32N 2O 40.96HCl analytical calculation value: C, 67.86; H, 6.70; N, 5.65.Measured value: C, 68.26; H, 6.86; N, 5.25.
Embodiment 15 preparation (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-chloro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (S)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-(0.47g, (7mL, 98mmol) vlil is 1 hour for Acetyl Chloride 98Min. 0.96mmol) for 5H-dibenzo [a, d] suberene-10-ethyl acetate.This reaction mixture is poured in the ice (50g), used saturated NaHCO 3(note: violent bubbling! ) pH is transferred to 8.0.With this mixed solution CH 2Cl 2(2 * 100mL) extract, and the organic layer that merges is used H in turn 2O (50mL) and salt solution (50mL) washing.Dry (MgSO 4), concentrate and obtain title compound: MS (ES) 481.2 (M+H) +B) (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (S)-10,11-dihydro-3-[3-(4-chloro-1-oxo pyridine-2-base is amino)-1-propoxy-]-(0.13g is 0.27mmol) with 2.0M PCl for 5H-dibenzo [a, d] suberene-10-ethyl acetate 3CH 2Cl 2(8mL, mixed solution reflux 16mmol) 22 hours.With this reaction mixture cooling, pour in the ice (200g), with 40%NaOH pH is transferred to 12.Use CH 2Cl 2(2 * 100mL) extract, dry (MgSO 4), concentrate silica gel column chromatography (4%MeOH/CH 2Cl 2) obtain title compound (93mg, 74%), be glassy yellow oily matter: MS (ES) 465.3 (M+H) +C) (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 13 (c), but with (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be pale powder: MS (ES) 437.2 (M+H) +C 25H 25N 2O 31.0HCl analytical calculation value: C, 63.43; H, 5.54; N, 5.92.Measured value: C, 63.11; H, 5.82; N, 5.62.
Embodiment 16 preparation (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-chloro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-(0.47g, (7mL, 98mmol) vlil is 1 hour for Acetyl Chloride 98Min. 0.96mmol) for 5H-dibenzo [a, d] suberene-10-ethyl acetate.This reaction mixture is poured in the ice (50g), used saturated NaHCO 3PH is transferred to 8.0 (to be noted: violent bubbling! ).With this mixed solution CH 2Cl 2(2 * 100mL) extract, and the organic layer that merges is used H in turn 2O (50mL) and salt solution (50mL) washing.Dry (MgSO 4), concentrate and obtain the crude product title compound, directly carry out next step reaction: MS (ES) 481.3 (M+H) without being further purified +B) (S)-10,11-dihydro-3-[3-[4-(dimethylamino)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (S)-10,11-dihydro-3-[3-(4-chloro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] MeOH solution (3mL, mixed solution reflux 6mmol) 16 hours of suberene-10-ethyl acetate (0.96mmol) and 2.0M dimethylamine.Concentrate silica gel column chromatography (7%MeOH/CH 2Cl 2) obtain title compound (0.049g, 10%), be bright brown ceramic powder: MS (ES) 490.3 (M+H) +Also from chromatography purification, reclaim unchanged (S)-10,11-dihydro-3-[3-(4-chloro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate.C) (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 13 (b), but with (S)-10,11-dihydro-3-[3-[4-(dimethylamino)-1-oxo pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (S)-10,11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, silica gel column chromatography (8%MeOH/CH 2Cl 2) after obtain title compound, be white powder: MS (ES) 474.3 (M+H) +D) (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 13 (c), but with (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be white powder: MS (ES) 446.2 (M+H) +C 27H 31N 3O 30.5H 2O10HCl analytical calculation value: C, 66.04; H, 6.77; N, 8.56.Measured value: C, 65.96; H, 6.60; N, 8.26.
Embodiment 17 preparation (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-oxyethyl group-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 2 (a), but with (S)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (496.9mg, 1.01mmol) replacement (±)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, and in replacement(metathesis)reaction, use 0.53M NaOEt (4.0mL, 2.12mmol) and dehydrated alcohol (10mL), preparation title compound (456.2mg, 92%): MS (ES) m/e 491 (M+H) +B) (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 2 (b), but with (S)-10,11-dihydro-3-[3-(4-oxyethyl group-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (456.2mg, 0.93mmol) replacement (±)-10,11-dihydro-3-[3-(4-oxyethyl group-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, the preparation title compound (475.2mg, quantitatively): MS (ES) m/e 475 (M+H) +C) (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
With 1.0N NaOH (2.0mL, 2.0mmol) join (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (475.2mg, 1.0mmol) dehydrated alcohol (10mL) solution in, with oil bath this solution is heated to 50 ℃.After 20 hours, this reaction solution is concentrated, ice bath is cooled to 0 ℃ with this residue aqueous solution.Stir slowly add down the 1.0N HCl aqueous solution (2.0mL, 2.0mmol).Opaque solid residue precipitation is collected with sintered glass funnel.Spend the night at the vacuum drier inner drying and to obtain title compound (452.6mg, 83%): MS (ES) m/e 447 (M+H) +C 27H 30N 2O 40.20H 2O1.75HCl analytical calculation value: C, 63.10; H, 6.30; N, 5.45.Measured value: C, 63.10; H, 5.98; N, 5.38.
Embodiment 18 preparation (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-7-fluoro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but with (±)-10,11-dihydro-7-fluoro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is through silica gel column chromatography (gradient: 1: 1 EtOAc/ hexane, EtOAc, 4%MeOH/CH then then 2Cl 2) after obtain title compound, be colorless oil: MS (ES) m/e465.3 (M+H) +B) (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (b), but with (±)-10,11-dihydro-7-fluoro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound: MS (ES) m/e 449.2 (M+H) +C) (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound: MS (ES) m/e 421.1 (M+H) +C 25H 25FN 2O 30.5H 2O analytical calculation value: C, 69.99; H, 6.10; N, 6.52.Measured value: C, 69.86; H, 5.90; N, 6.35.
Embodiment 19 preparation (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (±)-10 of suberene-10-acetate, 11-dihydro-6-methyl-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (a), but with (±)-10,11-dihydro-3-hydroxyl-6-methyl-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate is through silica gel column chromatography (gradient: 1: 1 EtOAc/ hexane, EtOAc, 4%MeOH/CH then then 2Cl 2) obtain title compound, be colorless oil: MS (ES) m/e461.3 (M+H) +B) (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to the method among the embodiment 6 (b), but with (±)-10,11-dihydro-6-methyl-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, through silica gel column chromatography (1%MeOH/CH 2Cl 2) obtain title compound: MS (ES) m/e 445.3 (M+H) +C) (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
According to the method among the embodiment 6 (c), but with (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate replacement (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate, obtain title compound, be white solid: MS (ES) m/e 417.3 (M+H) +C 26H 28N 2O 31.25H 2O analytical calculation value: C, 71.13; H, 7.02; N, 6.38.Measured value: C, 71.33; H, 6.67; N, 6.01.
Embodiment 20 preparation (S)-10,11-dihydro-3-[3-(4-aminopyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] a) (S)-10 of suberene-10-acetate, 11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under 0 ℃, logical argon gas, with diisopropyl azodiformate (1.7mL, THF 8mmol) (10mL) drips of solution is added to (S)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (426.5mg, 1.5mmol), 2-[(3-hydroxyl-1-propyl group) amino]-4-nitropyridine-N-oxide compound (1.7g, 8mmol) and triphenyl phosphine (2.5g is in dry DMF 8mmol) (20mL) solution.Under 0 ℃, this yellow solution was kept 10 minutes, be warmed to room temperature then.After 23 hours, this reaction solution is concentrated.Silica gel column chromatography (gradient: the 30-100%EtOAc/ hexane) obtain title compound (2.7g, 81%), be orange foam: MS (ES) m/e 491.8 (M+H) +B) (S)-10,11-dihydro-3-[3-(4-aminopyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the logical argon gas, with (S)-10,11-dihydro-3-[3-(4-nitro-1-oxo pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (2.7g, 6mmol), tetrahydrobenzene (6mL, 60mmol), 10%Pd/C (1.2g, 1.10mmol) and Virahol (30mL) mixed solution reflux 20.5 hours, then by celite  heat filtering.Filter cake is washed with hot EtOAc, the filtrate that merges is concentrated.Residue is through silica gel column chromatography (5%MeOH/CHCl 3) obtain title compound (2.4g, 98%), be colourless foam shape thing: MS (ES) m/e 445.9 (M+H) +C) (S)-10,11-dihydro-3-[3-(4-aminopyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
Under RT,, 11-dihydro-3-[3-(4-aminopyridine-2-base amino)-1-propoxy-with (S)-10]-5H-dibenzo [a, d] suberene-10-ethyl acetate (2.4g, 5mmol), LiOH H 2O (0.3g, 7mmol), THF (30mL) and H 2O (10mL) mixed solution stirred 48 hours, concentrated then.With residue H 2Et is used in the O dilution 2O extracts.Discard Et 2The O layer.Stir water layer under vacuum heats slightly and remove residual organic solvent, filter then.Under RT, the aqueous solution that obtains is stirred, during slowly reach carefully pH regulator to 5.5-6.0 with 1.0N HCl.This mixed solution was stirred 0.5 hour, and suction filtration is collected solid then, with the H of capacity 2The O washing.Obtain title compound (1.0g, 42%) 60 ℃ of following vacuum-dryings, be vitreous solid: MS (ES) m/e 417.7 (M+H) +C 25H 27N 3O 31.4HCl analytical calculation value (468.554): C, 64.08; H, 6.11; N, 8.97.Measured value: C, 64.16; H, 6.20; N, 8.71.
Embodiment 21 preparation (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-] dibenzo [b, f] a) (±)-10 of oxa-English in heptan-10-acetate, 11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-] dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Under RT, the logical argon gas, with (±)-10,11-dihydro-3-hydroxyl dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (257mg, 0.86mmol), 2-[(3-bromo-1-propyl group) amino]-4-methylpyridine N oxide hydrobromate (308mg, 0.94mmol), the NaOH sheet (110mg, 2.75mmol) and CH 3CN (4mL) mixed solution stirs and spends the night.Filter this mixed solution, solid CH 3The CN washing.This filtrate is concentrated, and residue is through flash chromatography on silica gel (1-2.5%CH 3OH/CH 2Cl 2) to obtain title compound (190mg, 48%) be white foam: MS (ES) m/e 462.6 (M+H) +B) (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
With (±)-10,11-dihydro-3-[3-(4-methyl isophthalic acid-oxo pyridine-2-base is amino)-1-propoxy-] dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (183mg, 0.4mmol), 10%Pd/C (85mg, 0.08mmol), tetrahydrobenzene (810mg, 8mmol) and Virahol (4mL) mixed solution reflux spend the night.Remove by filter catalyzer by celite , filter cake is washed with ether, concentrated filtrate obtains title compound (122mg, 68%), is the clear oily matter of orange: MS (ES) m/e446.9 (M+H) +C) (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-dibenzo [b, f] oxa-English in heptan-10-acetate
With (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (119mg, 0.27mmol) and 0.991 NNaOH (0.545mL, anhydrous EtOH (2mL) mixed solution 0.54mmol) heats in being set to 45 ℃ oil bath.After 20 hours, this reaction solution rotary evaporation is concentrated, residue is dissolved in H 2Among the O (1.5mL).This solution is removed by filter insoluble substance, and (0.54mL 0.54mmol) carefully neutralizes by dripping 1.0N HCl with filtrate.Collecting precipitation, drying obtains title compound (68mg, 58%) under the high vacuum, is white solid: MS (ES) m/e 418.9 (M+H) +C 25H 26N 2O 40.45HCl analytical calculation value: C, 69.05; H, 6.13; N, 6.44.Measured value: C, 69.25; H, 6.27; N, 6.16.
Embodiment 22 preparation (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] a) (±)-10 of oxa-English in heptan-10-acetate, 11-dihydro-3-[2-[6-(N-tert-butoxycarbonyl)-N-methylamino-] pyridine-2-yl]-the 1-oxyethyl group] dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Under RT, logical argon gas, with 10 minutes with 6-[N-(tert-butoxycarbonyl)-N-methylamino-]-2-pyridyl ethanol (397mg, 1.58mmol) and diisopropyl azodiformate (0.31mL, anhydrous CH 1.58mmol) 2Cl 2(8mL) drips of solution is added to (±)-10, and 11-dihydro-3-hydroxyl dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (186mg, 0.63mmol) and triphenyl phosphine (413mg, anhydrous CH 1.58mmol) 2Cl 2(3.2mL) in the solution.After 22 hours, this reaction solution rotary evaporation is concentrated, residue obtains title compound (146mg, 44%) through flash chromatography on silica gel (2-13%EtOAc/ hexane), is clarification oily matter: MS (ES) m/e 533.0 (M+H) +B) (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] oxa-English in heptan-10-ethyl acetate
Dioxane liquid (1.3mL with 4N HCl, 5.2mmol) be added drop-wise to (±)-10,11-dihydro-3-[2-[6-(N-tert-butoxycarbonyl)-N-methylamino-] pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] oxa-English in heptan-10-ethyl acetate (140mg, CH 0.26mmol) 2Cl 2(1.3mL) in the solution.After 12 hours, this mixed solution is concentrated, residue grinds with ether and obtains title compound, is white solid: MS (ES) m/e 432.9 (M+H) +C) (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] oxa-English in heptan-10-acetate
With (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] (0.525mL, anhydrous EtOH (2mL) mixed solution 0.52mmol) heats in being set to 50 ℃ oil bath for oxa-English in heptan-10-ethyl acetate (0.26mmol) and 0.991N NaOH.After 20 hours, this reaction solution rotary evaporation is concentrated, residue is dissolved in H 2Among the O (1.5mL).This solution is removed by filter insoluble substance, filtrate is carefully neutralized by dripping 1.0N HCl.Collecting precipitation, high vacuum dry obtain title compound (72mg, two steps 30%), are pale solid: MS (ES) m/e 405.0 (M+H) +C 24H 24N 2O 41.25HCl0.25H 2O analytical calculation value: C, 63.42; H, 5.71; N, 6.16.Measured value: C, 63.35; H, 5.9; N, 6.16.
Embodiment 23 preparation (S)-10,11-dihydro-3-[3-(2-aminopyridine-4-yl)-1-propoxy-]-a) 3-(2-aminopyridine-4-yl) third-1-alcohol of 5H-dibenzo [a, d] suberene-10-acetate
Will (0.73g, THF 3.60mmol) (10mL) suspension join in the lithium aluminum hydride (12mL, 12mmol, the THF liquid of 1M) under 0 ℃ according to 3-(2-aminopyridine-4-yl) the propionic salt hydrochlorate of WO94/14776 preparation with 45 minutes.Remove ice bath, under the RT this reactant was stirred 4.5 hours.This reactant is cooled to 0 ℃,, adds H in turn with toluene (22mL) dilution 2O (0.86mL) and NaF (1.54g) quencher.Under 0 ℃, the suspension that obtains was stirred 45 minutes.This reaction mixture is filtered, precipitate CHCl with other 10%MeOH 3The liquid washing.The filtrate decompression that merges is concentrated.Flash chromatography (10%MeOH/CHCl 3, silica gel) and obtain the desired material of 0.25g, be clarification oily matter: MS (ES+) m/z 152.7[M+H] +B) (S)-10,11-dihydro-3-[3-(2-aminopyridine-4-yl)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under 0 ℃, with embodiment 1 (a) (0.23g, 1.51mmol) and diisopropyl azodiformate (0.29mL, CH 1.50mmol) 2Cl 2(7.5mL) drips of solution is added to triphenyl phosphine (0.39g, 1.50mmol) and 2-[(10S)-3-hydroxyl-10,11-dihydro-5H-dibenzo [a, d] suberene-10-yl] ethyl acetate (0.30g, CH 1.00mmol) 2Cl 2(5mL) in the solution.Remove ice bath, this reaction solution is risen to room temperature.After 18 hours, removal of solvent under reduced pressure.Flash chromatography (50%EtOAc/ hexane to 100%EtOAc, silica gel) obtains 0.32g and contains the material that requires product to some extent.The secondarily purified desired material of 0.23g: MS (ES+) the m/z 430.9[M+H that obtains of flash chromatography (75-90%EtOAc/ hexane, silica gel)] +C) (S)-10,11-dihydro-3-[3-(2-aminopyridine-4-yl)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate
With embodiment 1 (b) compound (0.22g, 0.50mmol) be dissolved in 1N NaOH (0.77mL, 0.77mmol), among EtOH (3mL) and the THF (3mL).50 ℃ with the heating of this reactant after 18 hours, removal of solvent under reduced pressure.Residue is dissolved in H 2Among the O (4mL), filter.With the H of this filtrate with 30%TFA 2The precipitation that obtains is collected in the acidifying of O solution.Preparation HPLC (Hamilton PRP-1 , 3%CH 3CN/H 2O-0.1%TFA) obtain the desired material of 10mg, be water absorbability solid: MS (ES+) m/z 402.6[M+H] +
Embodiment 24 non-enteron aisle unit dosage compositions
By the preparation that is prepared as follows the aseptic dried powder of conduct that contains 20mg embodiment 1 compound: this compound of 20mg is dissolved in the 15mL distilled water.Under aseptic condition, this solution is filled in the 25mL multiple doses ampoule lyophilize.This powder is copied into intravenously or intramuscularly agent by the D/W (D5W) that adds 20mL 5%.Therefore determine this dosage by volume injected.Thereafter diluent can be by adding metered volume this dose unit to another volume for making among the injection D5W, maybe the dosage of metering can be joined in another device that disperses this medicine, as instil for IV the bottle of other injection-infusion system or bag in.
Embodiment 25 oral dosage form unit composition
Oral capsule can be by mixing 50mg embodiment 1 compound and grinding preparation with 75mg lactose and 5mg Magnesium Stearate.The powder that screening obtains is filled in the hard gelatin capsule then.
Embodiment 26 oral dosage form unit composition
Oral tablet can prepare by 20mg sucrose, 150mg calcium sulfate dihydrate and 50mg embodiment 1 compound are mixed and granulate with 10% gelatin solution.This wet granular is sieved, and drying is mixed with 10mg starch, 5mg talcum powder and 3mg stearic acid; Compacting in flakes then.
How the above full disclosure prepares and uses the present invention.But, the invention is not restricted to above-described specific embodiment, but comprise its all change in following claims scope.Cited hereinly variously comprise the condition of this technology, as presenting fully, be attached in this patent as a reference with reference to magazine, patent and other publication.

Claims (38)

1. formula (I) compound or its pharmacy acceptable salt:
Figure A9881081100021
Wherein:
A is CH 2Or O;
R 1Be H, halogen or C 1-6Alkyl;
R 2Be H, C 1-6Alkyl or CH 2NR " R ";
X is O or CH 2
Y is
Figure A9881081100022
Figure A9881081100023
Or
Figure A9881081100024
G is NR ", S or O; R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen; " independent separately is H or C to R 1-6Alkyl; And s is 0,1 or 2.
2. according to the compound of claim 1, wherein Y is: Wherein R ' is H, C 1-4Alkyl, OC 1-4Alkyl, SC 1-4Alkyl, NR " R " or Cl, " independent separately is H or C to R 1-4Alkyl.
3. according to the compound of claim 1, wherein Y is: Wherein " each is H or C naturally for R 1-4Alkyl.
4. according to the compound of claim 1, wherein Y is: Wherein R " independently is H or C separately 1-4Alkyl, s are 1.
5. according to the compound of claim 1, wherein Y is:
Figure A9881081100034
Wherein G is S, R, and " each is H or C naturally 1-4Alkyl.
6. according to the compound of claim 1, wherein Y is: Wherein R " is H or C 1-4Alkyl.
7. according to compound or its pharmacy acceptable salt of claim 1: (±)-10,11-dihydro-3-[2-(6-aminopyridine-2-yl)-1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[4-(pyridine-2-base is amino)-1-butyl]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (R)-10,11-dihydro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(3,4,5,6-tetrahydropyrimidine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[2-[2-(ethylamino) thiazole-4-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(isoquinolyl-1 amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-ethoxy pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-6-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-2-(dimethylamino) methyl-7-fluoro-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-[4-(2-propoxy-) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-[4-(dimethylamino) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-[4-(ethylmercapto group) pyridine-2-base is amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-chloropyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-2-methyl-3-[3-(pyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (S)-10,11-dihydro-3-[3-(4-aminopyridine-2-base is amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; (±)-10,11-dihydro-3-[3-(4-picoline-2-base is amino)-1-propoxy-]-dibenzo [b, f] oxa-English in heptan-10-acetate; (±)-10,11-dihydro-3-[2-[6-(methylamino-) pyridine-2-yl]-the 1-oxyethyl group]-dibenzo [b, f] oxa-English in heptan-10-acetate; Or (S)-10,11-dihydro-3-[3-(2-aminopyridine-4-yl)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate.
8. medicinal compositions, it comprises according to the compound of claim 1 and pharmaceutically acceptable carrier.
9. medicinal compositions, it comprises compound, antineoplastic agent and pharmaceutically acceptable carrier according to claim 1.
10. according to the medicinal compositions of claim 9, wherein this antineoplastic agent is that the holder pool is for bearing.
11. according to the medicinal compositions of claim 9, wherein this antineoplastic agent is a cis-platinum.
12. treatment wherein shows α Vβ 3The method of the morbid state of receptor antagonism comprises the curee that needs it compound according to claim 1.
13. treatment wherein shows α Vβ 5The method of the morbid state of receptor antagonism comprises the curee that needs it compound according to claim 1.
14. the method for treatment osteoporosis comprises the curee that needs it compound according to claim 1.
15. suppress the method that blood vessel takes place, comprise the curee that needs it compound according to claim 1.
16. suppress the method for tumor growth or metastases, comprise the curee that needs it compound according to claim 1.
17. the method for treatment atherosclerosis or restenosis comprises the curee that needs it compound according to claim 1.
18. the method for treatment inflammation comprises the curee that needs it compound according to claim 1.
19. suppress the method for tumor growth, comprise progressively giving or giving compound and antineoplastic agent according to claim 1 in the mode of physical composition.
20. according to the method for claim 19, wherein this antineoplastic agent is that the holder pool is for bearing.
21. according to the method for claim 19, wherein this antineoplastic agent is a cis-platinum.
22. formula (II) compound or its pharmacy acceptable salt: Wherein:
A is CH 2Or O;
R 1Be H, halogen or C 1-6Alkyl;
R 2Be H, C 1-6Alkyl or CH 2NR " R ";
X is O or CH 2
Y is
Figure A9881081100072
Figure A9881081100073
Or
Figure A9881081100074
G is NR ", S or O; R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen; " independent separately is H or C to R 1-6Alkyl; And s is 0,1 or 2.
23. formula (III) compound or its pharmacy acceptable salt:
Figure A9881081100081
Wherein:
A is CH 2Or O;
R 1Be H, halogen or C 1-6Alkyl;
R 2Be H, C 1-6Alkyl or CH 2NR " R ";
X is O or CH 2
R ' is H, C 1-6Alkyl, OC 1-6Alkyl, SC 1-6Alkyl, NR " R " or halogen; And
" independent separately is H or C to R 1-6Alkyl.
24. prepare the method for defined formula (I) compound in the claim 1, this method comprises makes formula (IV) compound and the reaction of formula V compound: Y-(CH 2) 2-3-L 1(V)
R wherein 1, R 2, Y and A definition cotype (I), can have any protected active function groups, L 1Be OH or halogen;
Remove any protecting group then, and can choose the formation pharmacy acceptable salt wantonly.
25. prepare the method for defined formula (I) compound in the claim 1, this method comprises makes formula (IV) compound and the reaction of formula (VI) compound:
Figure A9881081100091
R wherein 1, R 2, " and A definition cotype (I) can have any protected active function groups for R ', R;
Remove any protecting group then, and can choose the formation pharmacy acceptable salt wantonly.
26. prepare the method for defined formula (I) compound in the claim 1, this method comprises makes formula (IV) compound and the reaction of formula (VII) compound:
R wherein 1, R 2, " and A definition cotype (I) can have any protected active function groups to R;
Remove any protecting group then, and can choose the formation pharmacy acceptable salt wantonly.
27. as medicine according to each compound among the claim 1-7.
28. defined formula (I) compound is used for the treatment of and wherein shows α in the application rights requirement 1 Vβ 3The medicine of the disease of receptor antagonism.
29. defined formula (I) compound is used for the treatment of and wherein shows α in the application rights requirement 1 Vβ 5The medicine of the disease of receptor antagonism.
30. defined formula (I) compound is used for the treatment of the medicine of osteoporosis in the application rights requirement 1.
Defined formula (I) compound is used to suppress the medicine that blood vessel takes place in 1 31. application rights requires.
32. defined formula (I) compound is used to suppress the medicine of tumor growth or metastases in the application rights requirement 1.
33. defined formula (I) compound is used for the treatment of the medicine of atherosclerosis or restenosis in the application rights requirement 1.
34. defined formula (I) compound is used for the treatment of the medicine of inflammation in the application rights requirement 1.
35. application rights require defined formula (I) compound and antineoplastic agent preparation in 1 be used for the physical composition mode or progressively administering mode suppress the medicine of tumor growth.
36. according to the application of claim 35, wherein this antineoplastic agent is that the holder pool is for bearing.
37. according to the application of claim 35, wherein this antineoplastic agent is a cis-platinum.
38. application rights require defined formula (I) compound and bone resorption inhibitor preparation in 1 be used for the physical composition mode or progressively administering mode treat the medicine of osteoporosis.
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CO5011087A1 (en) 2001-02-28
PL339381A1 (en) 2000-12-18
AU9397298A (en) 1999-04-12
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NZ503389A (en) 2002-03-28
JP2001517658A (en) 2001-10-09
DZ2609A1 (en) 2003-03-01
CA2303487A1 (en) 1999-04-01
EA200000336A1 (en) 2000-10-30
BR9812340A (en) 2001-12-18
AU738433B2 (en) 2001-09-20
NO20001407D0 (en) 2000-03-17
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EP1025090A4 (en) 2000-11-08
TR200000721T2 (en) 2000-11-21

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