CN1099416C - Integrin receptor antagonists - Google Patents
Integrin receptor antagonists Download PDFInfo
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- CN1099416C CN1099416C CN96123837A CN96123837A CN1099416C CN 1099416 C CN1099416 C CN 1099416C CN 96123837 A CN96123837 A CN 96123837A CN 96123837 A CN96123837 A CN 96123837A CN 1099416 C CN1099416 C CN 1099416C
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- alkyl
- compound
- dibenzo
- dihydro
- suberene
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Abstract
The present invention discloses a compound with the formula (I) or medicinally acceptable salt thereof. In the formula, A1, E, X1-X2, X3, R2, R3, R4, R7 and R6 are defined in the specification. The compound is an integrin receptor antagonist which can be used for suppressing the agglutination of platelets and osteoclasts attached to bones.
Description
The present invention relates to be incorporated into integrin (integrins), as the pharmaceutical active compounds of Vitronectic receptor and fibrinogen deceptor.The osteoclast that these compounds can be used for suppressing platelet aggregation and are attached to bone.
Integrin is the common mediated cell bonded heterodimer protein of gang, and typically this proteinoid is Vitronectic receptor (α
vβ
3Heterodimer) and fibrinogen deceptor (α
IIbβ
3).Have been found that these acceptors such as vitronectin and fibrinogenic native ligand share one-Arg-Gly-Asp-aminoacid sequence, this is the bonded key.In fact, a lot of integrin receptors seem can with the part generation crosslinking reaction with this aminoacid sequence.For example make α
IIbβ
3Acceptor and fibronectin and vitronectin, thrombospondin and the Von Willebrand factor, and Fibrinogen reaction.The functional fiber proteinogen is to α
IIbβ
3Two binding sites are arranged, react with the activated receptor of finding on the platelet surface.α
IIbβ
3Acceptor causes the crosslinked principal element that is considered to platelet aggregation by the combination of Fibrinogen on adjacent thrombocyte.Can suppress α
IIbβ
3Acceptor and Fibrinogen bonded compound can demonstrate the vitro inhibition platelet aggregation and suppress thrombotic character in vivo, referring to for example EP-A-0341915.
In various kinds of cell, found Vitronectic receptor, for example in osteoclast and endotheliocyte at blood vessel.Nearest studies show that osteoclast is receptor-mediated by these cell surface inadhesion to adhering to of bone matrix.For example, Davies waits the people, J.Cell Biol., and 1989,109,1817 disclose the functional antigen of osteoclast, and it is relevant with the adjusting of bone resorption, and this antigen is relevant with Vitronectic receptor aspect biochemical.The known broken protein receptor that connects combines with bone matrix protein such as osteopontin, bone birth albumen and thrombospondin, and they contain tripeptides Arg-Gly-Asp (or RGD) primitive.People such as Horton are at Exp.Cell Res., disclose absorption and cellular invasion that the peptide that contains RGD and anti-Vitronectic receptor antibody (23C6) can suppress the dentine that osteoclast causes in 1991,195,368.Bortolini etc. are at J.Bone Min.Res., and 6, Sup.1, S146 points out ring-S, S-N in 252
α-ethanoyl one cysteinyl-N
α-methyl-arginyl-glycyl-aspartyl-Penicillaminamide can suppress osteoclast attached on the bone.In addition, people such as Sato are at J.Cell Biol., and 1990,111,1713 disclose echiststin (echistatin), are a kind of snake venom peptides that contains the RGD sequence, it is the potential inhibitor of bone resorption in the tissue culture, and can suppress osteoclast and be attached to bone.People such as Fisher are at Endocrinology, point out that further echiststin suppresses the intravital bone resorption of rat in 1993,132,1411.EP528587 and 528586 has reported the phenyl derivatives of the replacement of the osteoclast that suppresses the mediation bone resorption.
People such as Bondincll disclose in WO93/00095 (PCT/US92/05463) and WO94/14776 (PCT/US93/12436) and have been used to suppress Fibrinogen (α
IIbβ
3) some of acceptor contain the compound that replaces the 6-7 bicyclic system.Other 6-7 bicyclic system that can suppress fibrinogen deceptor is disclosed in WO93/08174 (PCT/US92/08788) by Blackburn etc.Blackburn etc. also disclose 5-in WO95/04057 CPCT (US94/07989) or 6-unit ring condenses in these 6-7 bicyclic system formation trinucleated systems, and they can be used as the antagonist of fibrinogen deceptor.Other has the 6-7 bicyclic system and can select the compound of inhibition Vitronectic receptor to be disclosed in WO96/00730 (PCT/US95/08306) and WO96/00574 (PCT/US95/08146).Now disclose in preparation is some new three-ring system of useful template during integrain receptor antagaonists, also disclose with this ring system as template, can also suitably replace them, with preparation to one of fibrinogen deceptor or Vitronectic receptor compound selectively.
The purpose of this invention is to provide formula as mentioned below (I) compound, this compound has the pharmaceutical active of inhibition of integrins acceptor.The purpose of this invention is to provide a kind of template, this template is suitably replaced so that its with respect to its each other combination and and other integrin between bound energy and specificity integrin, particularly with Fibrinogen (α
IIbβ
3) or vitronectin (α
vβ
3) the acceptor selection combination.
The invention still further relates to the pharmaceutical composition that contains formula (I) compound and pharmaceutical carrier.
The invention still further relates to the method for treatment disease, the pathology of these diseases may because and integrin, particularly vitronectin or fibrinogen deceptor in conjunction with and change.In particular, compound of the present invention can be used for treating the symptom that osteoporosis, atherosclerosis, restenosis, cancer and needs suppress platelet aggregation, for example thrombus that forms once more after apoplexy, instantaneous local asphyxia, myocardial infarction and the thrombolytic treatment.
The present invention includes following formula (I) compound or its pharmacy acceptable salt:
Wherein
A is C or N;
E is by R
3Or R
4Five of selection replacement-or six-first heteroaryl or six-first aryl rings;
X
1-X
2Be CHR
1-CH, CR
1=CH, NR
1-CH, S (O)
u-CH or O-CH;
X
3Be CR
5R
5 ', NR
5, S (O)
uOr O;
R ' is H, C
1-6Alkyl, C
0-7Cycloalkyl-C
0-4Alkyl, Ar-C
0-4Alkyl;
R " be R ' ,-C (O) R ' or-C (O) OR
5
R is C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
1Be H, C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
2Be-OR '-NR ' R " ,-NR ' SO
2R , NROR ' ,-OCR '
2C (O) OR ' ,-OCR '
2OC (O) R ' ,-OCR '
2C (O) NR '
2, CF
3Or-COCR '
2R
2 '
R
2 'Be-OR '-CN ,-S (O)
rR ', S (O)
2NR '
2,-C (O) R ' C (O) NR
2Or-CO
2R ';
R
5And R
5 'Independently be H separately, C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
6Be W-(CR '
2)
q-Z-(CR ' R
10)
r-U-(CR '
2)
s-V-or W '-(CR '
2)
q-U-(CR '
2)
s
R
3, R
4And R
7Independently be H separately, halogen ,-OR
12,-SR
12,-CN ,-NR ' R
12, NO
2,-CF
3, CF
3S (O)
r-,-CO
2R ' ,-CONR '
2, R
14-C
0-6Alkyl-, R
14-C
1-6Oxoalkyl group-, R
14-C
2-6Alkenyl-, R
4-C
2-6Alkynyl-, R
14-C
0-6Alkoxyl group, R
14-C
0-6Alkylamino or R
14-C
0-6Alkyl-S (O)
r-,
R
8Be R ', C (O) R ', CN, NO
2, SO
2R ', or C (O) OR
5
R
9Be R ' ,-CF
3,-SR ' or-OR ';
R
10Be H, C
1-4Alkyl or-NR ' N ";
R
12Be R ' ,-C (O) R ' ,-C (O) NR '
2,-C (O) OR
5,-S (O)
mR ' or S (O)
2NR '
2
R
14Be H, C
3-6Cycloalkyl, Het or Ar;
R
15Be H, C
1-10Alkyl, C
3-7Cycloalkyl-C
0-8Alkyl or Ar-C
0-8Alkyl;
U and V can not have, or are CO, CR '
2, C (=CR
15 2), S (O)
n, O, NR
15, CR
15 'OR
15, CR ' (OR ") CR '
2, CR '
2CR ' (OR "), C (O) CR '
2, CR
15 2C (O), CONR
15, NR
15CO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR
15, NR
15C (S), SO
2NR
15, NR
15SO
2, N=N, NR
15NR
15, NR
15CR
15 2, NR
15CR
15 2, CR
15 2O, OCR
15 2, C ≡ C, CR
15=CR
15, Het or Ar, condition is that U and V can have simultaneously;
W is R ' R " N-, R ' R " NR ' N-, R ' R " NR ' NCO-, R '
2NR ' NC (=NR ')-, R ' ONR ' C (=NR ')-,
Q is NR ', O or S;
R
aBe H, C
1-6Alkyl, Ar-C
0-6Alkyl, Het-C
0-6Alkyl, or C
3-6Cycloalkyl-C
0-6Alkyl, halogen, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2
R
bAnd R
cBe selected from H independently of one another, C
1-6Alkyl, Ar-C
0-6Alkyl, Het-C
0-6Alkyl, or C
3-6Cycloalkyl-C
0-6Alkyl, halogen, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2, perhaps R
bAnd R
cIn conjunction with formation five or hexa-atomic aromatic ring or non-aromatic ring, and by halogen, C
1-4Alkyl, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2, CN, or R " R ' NC (=NR ')-selection replaces;
X is N=CR ', C (O) or O;
Y can not have, or S or O;
Z is (CH
2)
t, Het, Ar or C
3-7Cycloalkyl;
M is 1 or 2;
N is 0,1,2 or 3;
Q is 0,1,2 or 3;
R is 0,1 or 2;
S is 0,1 or 2;
T is 0,1 or 2;
U is 0,1 or 2;
V is 0 or 1; With
N is 0 or 1.
The present invention also comprises pharmaceutically acceptable addition salt, mixture or the prodrug of The compounds of this invention.Prodrug is can discharge formula of the present invention (I) active parent drug in vivo any with the covalent bonding carrier.Have in The compounds of this invention under the situation of one or more chiral centres, except as otherwise noted, present invention includes every kind of single enantiomeric compounds, they can be synthetic and split with routine techniques.Have at The compounds of this invention under the situation of carbon-to-carbon unsaturated double-bond; Cis (Z) and trans (E) two kinds of isomer are all within protection domain of the present invention.In some compounds, may exist tautomer, as the keto-enol tautomerism body, as
With
, and the tautomer of guanidine type group, as R "
With
, no matter they are suitably to replace and determine that various tautomeric forms all are interpreted as being included within the scope of the invention under the situation of each form under equilibrium state or by R '.A certain in either case substituent meaning is meaning or any other the substituent meaning that is independent of under what its situation in office itself, unless otherwise indicated.
More particularly, The compounds of this invention is general formula (II) or (III) compound:
A wherein
1And R
1-12As general formula (I) definition, A
2-A
5Be selected from CH, CR
3, CR
4And N, B
1-B
3Be selected from CR
3, CR
4, O, N and S, condition is that formed E ring is stable, and makes easily with conventional preparation method.
In one embodiment, the present invention is formula (IV) and isocyclic compound:
Specifically, be formula (V-1) to (V-9) compound:
In another embodiment, The compounds of this invention is to have hetero-aromatic ring to connect thereon carbocyclic ring system, suc as formula (VI) or (VII) compound:
Formula (VIII) or benzo-aza compound (IX) in another embodiment of the present invention, have been comprised
Suitable, A
1Be C.
Preferred X
1-X
2Be CHR
1-CH or NR
1-CH.
Suitable, X
3Be CR
5R
5 ', preferred X
3Be CH
2
Suitable, R
1Be H.Suitable R
2Be OR '.Suitable R
3And R
4Be H.
Suitable U is COR
15, NR
15CO, CH
2CH
2Or CH
2O, wherein R
15Be C
1-10Alkyl is by NO
2, CN, CO
2R ', R
14-C
0-6Alkyl or R
14-C
0-6Alkylamino is selected to replace.
Suitable, it is a phenyl ring when U is Ar, preferably 1, and 3-is dibasic.
Suitable R
15Be R ', R more suitably
15Be C
1-6Alkyl more suitably is H or methyl.
Suitable, when requiring formula (I) compound to the selective affinity of fibrinogen deceptor, R
6Be W-(CR '
2)
q-Z-(CR ' R
10)
r-U-(CR '
2)
s-V-, and R
6Preferably be substituted by:
When requiring the Fibrinogen antagonistic activity, to R
6Suitable substituting group is:
, R " HNC (=NH) NH-(CH
2)
3(CHR
10)-U, and R " HN-(CH
2)
5-O wherein G is N or CH, R
20Be hydrogen, amino ,-or=C
1-4Alkylamino, hydroxyl or C
1-4Alkyl, and U is NR ' CO, CONR ', (CH
2) CO, CH=CH, C ≡ C, CH
2O, OCH
2(CH
2)
2
The best substituting group of energy excitation fiber proteinogen selectivity antagonistic activity is:
Wherein R ' is H or C
1-4Alkyl, preferred R ' is a methyl, and R " is H.
R
6Special preferred group be
Suitable, when requiring formula (I) compound to the selective affinity of Vitronectic receptor, R
6Be W '-(CR '
2)
q-U-, and preferred R
6Be substituted by:
When having required vitronectin in conjunction with activity, preferred W ' substituting group is:
Wherein Q is NH.Preferred R
bAnd R
cIn conjunction with forming cyclohexyl, phenyl or pyridine ring, suitable R
aBe C
1-6Alkyl, C
1-6Cycloalkyl, halogen or R ' NH.
Suitable ,-(CR '
2)
q-U-is (CH
2)
q-NR ' CO, (CH
2)
q-CH
2O or (CH
2)
q-CH
2CH
2
In order to increase the vitronectin activity, particularly preferred R
6Substituting group is:
The position on the phenyl ring of 6-7 member ring systems by suitable selection substituting group W and/or W ' can obtain one of vitronectin and fibrinogen deceptor, or to two kinds of all selective active compounds of acceptor.In general, for the Fibrinogen antagonistic activity, the intramolecularly distance that is connected between the basic nitrogen atom of the Sauerstoffatom of the carbonyl moiety on the seven-membered ring and W and W ' is preferably about 16 dusts; And for the vitronectin antagonistic activity, acidity and the basic center distance between separately is preferably about 14 dusts.
Particular compound of the present invention is:
(±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10, the methyl of 11-dihydro-3-[[[(4-azepine-5-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate; With
(±)-10,11-dihydro-3-[1-(4,4 '-the Lian piperidyl) carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-propyl group]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[[[2-(2-pyridine amino) ethyl] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; With
The methyl of 2-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-6,11-dihydro-5H-dibenzo [a, d] suberene-6-acetate;
Abbreviation and symbol used when this paper describes The compounds of this invention are commonly used in peptide and the chemical field.
C used herein
1-4Alkyl is meant methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.C
1-6Alkyl is meant and in addition also comprises amyl group, n-pentyl, isopentyl, neo-pentyl and hexyl, and their simple aliphatic isomer.Except as otherwise noted, any C
1-4Alkyl and C
1-6Alkyl can be by R
7Replace.C
0-4Alkyl and C
0-6Alkyl is meant the situation (situation that for example, has covalent linkage) that does not have alkyl group to exist that also comprises in addition.
C used herein
2-6Alkenyl is meant that wherein carbon-to-carbon singly-bound is by the displaced C of carbon-to-carbon double bond
2-6Alkyl, C
2-6Alkenyl comprises several isomer of ethene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, iso-butylene and amylene or hexene, and trans and cis-isomeride includes interior.Except as otherwise noted, appoint-C
2-6Alkenyl all can be by R
7Select to replace.
C
2-6Alkynyl is meant that wherein carbon-to-carbon singly-bound is by the displaced C of carbon-to-carbon triple bond
2-6Alkyl, C
2-6Alkynyl comprises the various isomer of acetylene, 1-propine, 2-propine, ethyl acetylene, 2-butyne, 3-butine and penta fast and hexin.C
2-6Arbitrary SP in the alkynyl
3Carbon atom can be by R
7Select to replace.
C
1-4Oxoalkyl group is meant the CH on the alkyl that 4 carbon are arranged at most
2Group is by C (O), or carbonyl group replaces.Formyl radical, ethanoyl, 1-propionic aldehyde, 2-acetone, 3-propionic aldehyde, 2-butanone, 3-butanone, 1-and 4-butyraldehyde group that each replaces naturally.C
1-6Oxoalkyl group also comprises the more high-grade five of carbonyl substituted and the analogue and the isomer of six carbon.C
3-6Oxo alkenyl and C
3-6The oxo alkynyl is meant CH wherein
2The C that group is replaced by C (O) group
3-6Alkenyl or C
3-6Alkynyl.C
3-4The oxo thiazolinyl comprises 1-oxo-2-propenyl, 3-oxo-1-propenyl, 2-oxo-3-butenyl or the like.
At C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl or C
1-6Substituting group on the oxoalkyl group group, for example R
7, can be to form on the either carbon atom of rock steady structure, and be available by conventional synthetic technology.
R
14-C
1-6Alkyl is meant that carbon one hydrogen bond of its arbitrary position is by carbon-R
14Key replaces.With respect to C
2-6Alkenyl and C
2-6Alkynyl R
14-C
2-6Alkenyl and R
14-alkynyl has similar meaning.
Here used Ar, perhaps aryl is meant phenyl or naphthyl, or by 1 to 3 R
7The phenyl or naphthyl that part replaces, specifically, R
7Can be C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, trifluoroalkyl, OH, F, cl, Br or I.
Het, or heterocycle is meant and contains 1 to 3 monocycle that is selected from heteroatomic five or hexa-atomic optional replacement of nitrogen, oxygen and sulphur, or optional nine or ten yuan of dicyclos that replace, they are stable, and can be accessed by the conventional chemical synthetic method.Can illustrate that heterocyclic is cumarone, benzoglyoxaline, chromene, thionaphthene, furans, imidazole, indoles, indoline, morpholine, piperidines, piperazine, pyrroles, tetramethyleneimine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline 99.9 and tetrahydrochysene and perhydro quinoline and isoquinoline 99.9.For the Z part, contain the hexa-member heterocycle of one or two nitrogen, be preferred heterocycle as piperidines, piperazine, tetrahydropyridine and pyridine.At heterocycle three for example R are arranged at most
7Substituent anyly expect, and be chemosynthesis available combination all within the scope of the present invention.
C
3-7Cycloalkyl is meant the carbocyclic ring system of 3 to 7 carbon atoms selecting replacement, can contain 2 unsaturated C-Cs at most.Concrete C
3-7Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and suberyl.And have three for example to be selected from R on the carbocyclic ring at most
7Substituting group, so long as can obtain, and be stable, all within the scope of the invention with conventional chemical is synthetic.
Used herein
Be meant nitrogen heterocyclic, it can be that order has nearly 3 nitrogen-atoms, or contain a nitrogen-atoms and be selected from the heteroatomic saturated of oxygen and sulphur or undersaturatedly stablize five, six or seven yuan of monocycle rings, or seven to ten yuan dicyclo ring system, and be substituted can forming on arbitrary atom of rock steady structure.Nitrogen-atoms on these rings can be substituted, thereby forms level Four nitrogen.Nitrogen heterocyclic can be by R on its arbitrary settling position
20Replace R
20For example be H, C
1-4Alkoxyl group, F, Cl, Br, I, NO
2, NR '
2, OH, CO
2R ', CONHR ', CF
3, R
14-C
0-4Alkyl, R
14-C
1-4Alkyl-S (O)
u(is 0,1 or 2 as U) or the C that replaces by aforementioned arbitrary substituting group
1-4Alkyl.Representational
Be pyrroline, tetramethyleneimine, imidazoles, tetrahydroglyoxaline, imidazolidine, pyrazoles, pyrazoline, pyrazolidine, piperidines, piperazine, morpholine, pyridine, pyridine, tetrahydropyridine, tetrahydrochysene or six hydrogen-azepine, rubane, rubane quinoline, isoquinoline 99.9, and four or perhydro-quinoline or isoquinoline 99.9.Particularly
Can be pyridyl, pyrrolidyl, piperidyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahydro pyridyl.Preferably
Be 4-pyridyl, 4-(2-amino-pyridine base), 4-tetrahydro pyridyl, 4-piperidyl or 4-piperazinyl.
Work as R
bAnd R
cCombine form five or hexa-atomic aromatic ring or non-aromatic ring condense in R
bAnd R
cDuring the ring that connected, formed ring is selected from above five listed-or six-first heterocycle about Hef usually, or phenyl, cyclohexyl or cyclopentyl ring.For W ' part, preferred benzimidazolyl-, 4-azepine benzimidazolyl-, 5-azepine benzimidazolyl-and their substitutive derivative.
Some group provides with abbreviated form herein, and t-Bu is the tertiary butyl, and BOC is meant the tertbutyloxycarbonyl group; Fmoc is meant the fluorenylmethyloxycarbonyl group, and Ph is meant phenyl group, and Cbz is meant the carbobenzoxy-(Cbz) group; BrZ is meant adjacent bromo-benzyloxycarbonyl group; ClZ is meant adjacent benzyloxycarbonylchloride base group, and Bn is meant benzyl group, and 4-MBzl is meant 4-methyl-benzyl group; Me is meant methyl; Et is an ethyl, and Ac is an ethanoyl, and AIR is meant C
1-4Alkyl, Nph are meant 1-or 2-naphthyl, and cHex is meant cyclohexyl, and MeArg is meant N
α-methylarginine, Tet are meant the 5-tetrazyl.
Some reagent provides with abbreviated form herein.DCC is meant dicyclohexyl carbodiimide; DMAP is meant Dimethylamino pyridine; DIEA is meant diisopropylethylamine; EDC is meant N-ethyl-N '-(diethylin propyl group)-carbodiimide; HOBt is meant I-hydroxybenzotriazole; THF is meant tetrahydrofuran (THF), and DMF is meant dimethyl formamide, and NBS is meant N-bromosuccinimide; Pd/c is meant that palladium drapes over one's shoulders C catalyst; DPPA is meant phenylbenzene carbonic acyl radical trinitride, and BOP is meant benzotriazole-1-base oxygen base-three (dimethylamino) hexafluorophosphate, and HF is meant hydrofluoric acid; PPA is meant Tripyrophosphoric acid; TEA is meant triethylamine, and TFA is meant trifluoroacetic acid, and PCC is meant pyridinium chlorochromate.
Useful especially intermediate is formula (X) compound during preparation formula (I) compound:
X wherein
1, X
2, X
3, R
2, R
3, R
4, A
1Define L suc as formula (I) compound with E
1With respect to ring connect be between the position, and be CHO, CO
2R
1, Br, I, OH, CF
3SO
3, CH
2-T or NR ' R
15, T is OH, NHR
15, Cl, Br or I.Preferably, L
1Be OH, CF
3SO
3, CO
2R ' or NR ' R " and R
1Be H, C
1-4Alkyl, C
1-4Oxoalkyl group, R
2Be C
1-6Alkyl or benzyl, R
4Be H or Q-C
1-6Alkyl, and R
5/ R
5 'Be H.Preferred A
1E forms fused benzene rings, X together with ring
1-X
2Be CHR
1-CH or NR
1-CH, and X
3Be CHR
5
Formula (I) compound is usually by formula (X) intermediate and formula (X1) compound coupling preparation:
R
6′-L
2
(XI) R wherein
6 'Be W-(CR '
2)
q-Z-(CR
1R
10)
r-U-(CR '
2)
s-L
2Or W '-(CR '
2)
q-L
2, wherein W, W ', R ', Z, R
10, U, q, r and s be suc as formula the definition of (I) compound, L
2Be OH, NHR
15, C ≡ C, CHO, CO
2R ', Br, I or Cl.Further specify as this paper, in some cases, also require by appropriate reaction W or W ' group further modification introducing functional group, or remove blocking group.Coupling can form U or V group usually, and the method for these coupled reactions is well known in the art.WO93/08174 (PCT/US92/08788; Genentech), WO93/08174 (PCT/US92/08788; Genentech), WO96/00730 (PCT/US95/08306; Smithkiline Beecham), WO96/00574 (PCT/US95/08146; SmithKline Beecham), WO93/00095 (PCT/US92/05463; SmithKline Beecham) and WO94/14776 (PCT/US93/12436; SmithKline Beecham) disclose these reactions prevailingly, this paper quotes and is used as reference.
A wherein
1Be C and A
2-A
4The formula X compound that is CII prepares with flow process 1 described method:
Flow process 1
A) Tf
2O, 2,6 lutidine, CH
2Cl
2B) allyl tributyltin, LiCl, (Ph
3P)
2PdCl
2, DMF; C) RuCl
3, H
5IO
6, CCl
4, CH
3CN, H
2O; D) PPA; E) EtOAc/LiHMDS, THF; F) H
2, 10%Pd/C, dense HCl, AcOH; G) EtSH, AlCl
3, CH
2Cl
2H) Tf
2O, 2,6 lutidine, CH
2Cl
2I) CO, Pd (OAc)
2, KOAc, dppf, DMSO.
As 2, the 6-lutidine exists down, at inert solvent, is generally CH at suitable alkali
2Cl
2In make 2-benzyl-4-methoxyphenol (J.Am.Chem.Soc., 1949,71,64) and trifluoromethanesulfanhydride anhydride (Tf
2O) reaction changes into corresponding triflate, and promptly flow process 1 compound 2 (for example, 1-2).In inert solvent such as DMF, LiCl and palladium catalyst such as two (triphenyl phosphine) Palladous chloride (II) ((Ph are being arranged
3P)
2PdCl
2) exist down, 1-2 and allyl tributyltin are reacted as method (J.Org.Chem., 1990,55,906) as described in the Tilley, obtain 1-3.Make the cracking of flow process 1-3 olefin oxidation directly obtain carboxylic acid, this reaction can be with suitable oxygenant in suitable water-containing solvent such as aqueous acetone or aqueous acetic acid, typically as KMnO
4Reaction is finished.But the oxicracking that is directly obtained carboxylic acid 1-4 by alkene 1-3 preferably carries out (J.Org.Chem., 1981,46,3936, J.Org.Chem., 1985,50,1560, note 4), RuO wherein by the general method of Sharpless
4Be at CCl
4CH
3In the mixed solvent of CN and water, make RuCl
3Or RuO
2With NaIO
4Or H
5IO
6The reaction on-site preparation.In addition, oxidation can divide for two steps carried out, comprise that the first step olefin oxidation is cracked into corresponding aldehyde, this step can be undertaken by the method for knowing in this area, then presses the described (Tetrahedron of pinnick, 1981,37,2091) or press Dalcanale and Mantanari described (J.Org.Chem., 1986,51,567) method NaClO
2Formoxy-is turned to carboxylic acid.1-4 is cyclized into 1-5 can be by Proctor, and Renfrew and Savage described (J.Chem.Soc. (C), 1969,1000) method is finished with Tripyrophosphoric acid.In addition, also can change into 1-5 by the corresponding chloride thing of 1-4, the chloride thing can be with method well known in the art preparation, with this etheride at inert solvent such as CH
2Cl
2Or CS
2Middle with suitable Friedel-Crafts catalyzer such as AlCl
3Or SnCl
4Handle, obtain cyclic ketones 1-5.Make the acetate acetic acidreaction of 1-5 and enolization obtain 1-6 in the reaction of aldehyde alcohol (aldol) type, the latter can be contacted by ethyl acetate and suitable aminate alkali such as di-isopropyl lithamide (LDA) or two (trimethyl silyl) lithamide (LiHMDS) and make.Usually, often select for use THF, though use THF can have several affixtures such as HMPA or TMEDA as the aldehyde alcohol reaction solvent.1-6 is reduced into 1-7 can be in appropriate solvent such as acetate, in the presence of the anhydrous acid example hydrochloric acid, with suitable catalyzer for example metallic palladium (Pd/C) catalytic hydrogenation on the gac finish.In addition, this reduction reaction is also to handle with triethyl-silicane and to finish with Orphanopoulos and the described general method of Smonu (Synth.Commun., 1988,833) in the presence of the boron trifluoride diethyl etherate thing.The methyl ether base of removing 1-7 obtains the reaction of 1-8 can be at inert solvent such as CH
2Cl
2In with BBr
3Reaction, or at inert solvent, preferably at CH
2Cl
2In with sulfur alcohol and AlCl
3Reaction is finished.Described in the process useful such as Greene " Protcctive Groups in Organic Synthesis " (John Wiley and Sons publication) of other removal methyl ether base.Prepare 1-9 by the described method that changes into 1-2 at 1-1 of preamble, (triflate of 1-8), at appropriate solvent, preferably in DMSO, with potassium acetate, 1,1 '-two (diphenyl phosphine) ferrocene (dppf) and palladium catalyst such as acid chloride [Pd (OAc)
2] exist and to press Cacchi and the described general method of Lupi (Tet.Lett., 1992,33,3939) down and itself and carbon monoxide are reacted obtain 1-10.
Be appreciated that what send out is if an anhydro compounds 1-6 replaces carrying out hydrogenation, can obtain the compound of general formula (V-2) in mentioned above.
X wherein
3Be NR
5, O or S (O)
0-2Formula (I) compound with the preparation of the general method of flow process 1, just, for example use 4-methoxyl group-2-(phenylamino)-, 2-(phenoxy group)-, or 2-(thiophenyl) toluylic acid replaces compound 1-4, described compound can prepare with methods known in the art.
X wherein
1-X
2Be NR
1-CH and X
3Be CR
5CR
5 ', NR
1, O or S (O)
0-2Formula (X) compound can be with the described general methods preparation of flow process 2.Flow process 2
Flow process 2-compound 1 (as 2-1) is synthetic with means known in the art, and bromo available iodine generation, the trifluoro-methanesulfonyl oxy group that maybe can change into bromo, iodo or trifluoro-methanesulfonyl oxy substitutes in addition.In appropriate solvent and under proper temperature, compound 2-1 handled with suitable reagent such as formic acid, manthanoate or acetic formic anhydride and change into N-formylation compound 2-2.Mixture process compound 2-2 with suitable reagent such as Tripyrophosphoric acid and phosphoryl chloride under proper temperature makes it change into epimino 2-3.Use Bull.Chem.Soc.Jpn., 1990,63, the described general method of 3122-3131, in appropriate solvent such as methylene dichloride, trimethylsilyl cyanide is being arranged and suitable catalyzer is being arranged as two (1, the 5-cyclooctadiene) two rhodiums ([Rh (COD) Cl] of two-μ-chloro
2) exist down, handle compound 2-3 with the t-butyldimethylsilyl acetal (Ketal acetal) of suitable reagent such as methyl acetate and make it be converted into acetic ester 2-4.In addition, also can use Ball.Soc.Chim.Fr., the general method in 1973,1668 uses Reformatsky reagent; Also can use J.Am.Chem.Soc., the general method in 1950,72,3874 uses the diacetyl oxide in the acetate.
According to the general method described in the flow process 1, make compound 2-4 change into carboxylic acid 2-5.
Wherein U is the also available J.Org.Chem. of formula (I) compound of NR ' CO, and the general method in 1974,39,3327 is directly obtained by handling with CO, uncle or secondary amine and palladium catalyst by compound 1-9 or 2-5.
Simple trisubstituted benzene initiator can be buied, or makes with ordinary method well known in the art.
The couling process that forms amido linkage is normally as known in the art.People such as Bodansky., THEPRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin 1984, Ali etc., J.Med.Chem., 29, the peptide synthetic method of mentioning in 984 (1986) and J.Med.Chem.30,2291 (1987) is that the generality explanation this paper to these technology quotes as a reference.Here used coupling reagent is meant the reagent that can be used for forming amido linkage.Typical couling process uses carbodiimide, activity anhydride and ester and acyl halide.Typical reagent such as EDC, DCC, DPPA, bop reagent, HOBt, N-hydroxy-succinamide and oxalyl chloride.
Specifically, be with or without in the presence of catalyzer such as I-hydroxybenzotriazole (HOBt) and the Dimethylamino pyridine (DMAP), with suitable carbodiimide coupling reagent can make amine or aniline by its free amine coupling on suitable carboxylic acid substrate.Other method for example also can make the free carboxy of the sour substrate of due care form active ester, acid anhydride or carboxylic acid halides, and then the unhindered amina on the amine that is with or without in the presence of the alkali with due care reacts.For example; in anhydrous solvent such as methylene dichloride or tetrahydrofuran (THF); in the presence of alkali such as N-methylmorpholine, DMAP or trialkylamine; the BOC-amino acid or the Cbz-amidino groups phenylformic acid of protection are handled to form " active acid anhydride " with isobutyl chlorocarbonate, itself and the amino acid of second kind of protection or the unhindered amina of aniline are reacted.
For example compound 1-10 can pass through coupled reaction, transforms an accepted way of doing sth (I) compound as the acid amides coupled reaction in the flow process 3.
By flow process 1 described (±) that makes-10,11-dihydro-3-carboxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (1-10) for example EDC and HOBt, or SOCl
2Processing changes into the activated form of carboxylic acid, at appropriate solvent such as DMF, CH
2Cl
2Or CH
3Make above-mentioned activated form compound and suitable amine among the CN, as 1-BOC-4,4 '-reaction of Lian piperidines or 2-(methylamino-) tolimidazole dihydrochloride obtains flow process 3-compound 2 (for example 3-2).No matter in whether needing, can add alkali, [(i-pr) as diisopropylethylamine
2NEt] or pyridine.Known have other method that much carboxylic acid is changed into acid amides, can find for example " Compendium of Organic SyntheticMethods ", Vol.I-VI (Wiley Interscience publication) in the canonical reference bibliography.With moisture alkali lye hydrolysis, the LiOH among described moisture alkali lye such as the moisture THF, or the NaOH in the aqueous methanol with suitable acid for example TFA or HCl acidifying intermediate carboxylate, obtain carboxylic acid 1-3 with ethyl ester 5-2.In addition, if desired, intermediate carboxylate can be separated, perhaps prepare free carboxy acid's carboxylate salt with the procedure known to those skilled in the art.If form when containing blocking group on the amine component (1-10 is to 3-2) in the amido linkage reaction; blocking group can use the suitable selectivity deprotection method of specificity blocking group to slough before or after the ester hydrolysis; these methods have in " protective Groups in Organic Syhthesis " (Wiley-interscience publication) and describe at Green.For example, if having on amine component by the amine groups of tertbutyloxycarbonyl (BOC) radical protection, as compound 3-3, the BOC group can for example be used 4N HCl in dioxan under acidic conditions, or at CH
2Cl
2Middle with trifluoroacetic acid (TFA), obtain ammonium salt 3-4.If desired, above-mentioned ammonium salt can neutralize with the procedure known to those skilled in the art.
Flow process 4 has illustrated the couling process that forms C-C, and this method is by selecting to use suitable reductive agent (as be used for introducing carbon-to-carbon triple bond, two key or singly-bound in step 6).
A) THPOCH
2CH
2CCSn (Bu)
3, (PPh
3)
2PdCl
2, LiCl ， diox, b) H
2, 10% Pd/C, EtOAc; C) p-TsOHH
2O, EtOH; D) 2,2,6,6-tetramethyl-oxo piperidinium chloride, CH
2Cl
2E) NaClO
2, Na
2HPO
3, 2-methyl-2-butene, H
2O; F) isobutyl chlorocarbonate, the 4-methylmorpholine, then 1, the 2-phenylenediamine; G) AcOH; THF; H) 1.0N NaOH, EtOH, acidifying then.
At the Stille of aromatic series trifluoro-acetate and organic stannane type coupled reaction (J.Am.Chem.Soc., 1987,109, make in 5478-5486) flow process 4-compound 1 (4-1) and 4-(2-THP trtrahydropyranyl oxygen base)-1-tributyl stannyl-ethyl acetylene react and obtain 4-2.This reaction is preferably used two (triphenyl phosphine) Palladous chloride (II) [(PPh by palladium salt
3)
2PdCl
2] catalysis, and be at inert solvent, usually in DMF or 1, in the 4-dioxan, in the presence of lithium chloride, react.The unitary reduction reaction of alkynes among the 4-2 is finished under the known standard hydrogenation conditions of those skilled in the art.The compound 4-3 that obtains deprotection under the standard conditions of sloughing THP trtrahydropyranyl (THP) ether obtains 4-4.The various conditions of THP ether deprotection are existing narration in the canonical reference book, Greene for example, " Protective Groupsin Organic Synthesis " (Wiley-Interscience publication).With WovRulick (J.Org.Chem., 1993,58,832-839) two step method described in can change into corresponding carboxylic acid 4-5 with the primary alconol partial oxygen of 4-4.Primary alconol is oxidized to existing description of a lot of other methods of corresponding carboxylic acid, and can in this class book of reference, finds.Carboxylic acid 4-5 can be changed into benzimidizole derivatives 4-6 according to the ordinary method described in the WO.Therefore, can be at inert solvent such as THF or CH
2Cl
2In, suitable alkali is being arranged, generally be that 4-methylmorpholine triethylamine or diisopropylethylamine exist down, earlier 4-5 is changed into the activatory carboxylic acid form with for example isobutyl chlorocarbonate, then make this activated form and excessive suitable 1,2-diamino aromatic derivative is as 1, and the 2-phenylenediamine reacts and obtains corresponding monoamide, make them then under standard conditions, for example refluxing in THF and adding the acetate cyclisation obtains 4-6.With ethyl ester 4-6 with the LiOH among moisture alkali lye such as the moisture THF, or the NaOH hydrolysis in aqueous methanol or ethanol, and with the carboxylate salt intermediate with suitable acid such as TFA or HCl acidifying, obtain carboxylic acid 4-7.In addition, if desired, separablely go out the carboxylate salt intermediate, the perhaps available procedure known to those skilled in the art prepares free carboxy acid's carboxylate salt.
Flow process 5 has illustrated the couling process that forms carbon-oxygen bond, and it can be used for forming ehter bond.Similarly couling process also can be used to form thioether and amine key.
A) amino 2-[(3-hydroxyl-1-propyl group)] pyridine-N-oxide, DEAD, (ph)
3P, DMF; B) tetrahydrobenzene, 10%Pd/C, 2-propyl alcohol; C) 1.0NNaOH, EtOH, acidifying then.
The compound 1 (5-1) of flow process 5 and 2-[(3-hydroxyl-1-propyl group) amino] pyridine-N-oxide carries out Mitsunobu type coupled reaction (Organic Reactions, 1992,42,335-656; Synthesis, 1981,1-28) obtain 5-2.Reaction by diethyl azodiformate and triphenyl phosphine form compound-mediated, and at aprotic solvent such as THF, CH
2Cl
2Or react among the DMF.For example among methyl alcohol, ethanol or the 2-propyl alcohol, using palladium catalyst at inert solvent, the pyridine-N-oxide partial reduction of preferably draping over one's shoulders under the transfer hydrogenation condition of charcoal metallic palladium 5-2 becomes corresponding pyridine 5-3.In this class reaction, use tetrahydrobenzene usually, the 1-4-cyclohexadiene, formic acid and formate such as potassium formiate or ammonium formiate are as hydrogen transfer agent.Make ethyl ester 5-3 saponification obtain 5-4 by flow process 1 is described.
The acid salt of The compounds of this invention can be prepared by standard method by parent compound and excessive sour example hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, toxilic acid, succsinic acid or methylsulfonic acid in appropriate solvent.Some compound can form inner salt or acceptable zwitter-ion.Cationic salts can with excessive, contain suitable cationic alkaline reagents such as oxyhydroxide, carbonate or alkoxide and handle parent compound and prepare; Perhaps handle and prepare with suitable organic amine.Cationic specific examples is Li for example among pharmacy acceptable salt
+, Na
+, K
+, Ca
++, Mg
++And NH
4 +Positively charged ion.
The present invention also provides pharmaceutical composition, wherein, comprises formula (±) compound and pharmaceutically acceptable carrier.Corresponding, formula (I) compound can be used for preparing medicine.Can preparation become solution or be used for the lyophilized powder of parenteral formulation by the pharmaceutical composition of formula (I) compound of the described preparation of preamble.Adding suitable thinner or other pharmaceutically acceptable carrier before use can be with this powder preparation again, and the formulation of liquid can be buffered, and is isoosmotic, aqueous solution.The example of suitable dilution agent is the isotonic saline solution standardized solution, 5% glucose standard water solution or sodium acetate or ammonium acetate buffer solution.These preparations are particularly suitable for the about medicine of parenteral, but also can be used for oral administration, in the sucker or atomizer that can measure administration that the inhalation of perhaps packing into is used.Preferably add vehicle such as polyvinylpyrrolidone, gelatin, hydroxylated cellulose, polyoxyethylene glycol, N.F,USP MANNITOL, sodium-chlor or Trisodium Citrate.
In addition, these compounds can be made into the capsule that is suitable for oral mouthful of medicine, tablet or emulsion or syrup.Can add pharmaceutically acceptable solid or liquid vehicle so that composition increment or stable perhaps more helps preparation.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, carclazyte, Magnesium Stearate or stearic acid, talcum, pectin, gum arabic, agar or gelatin.Liquid vehicle comprises syrup, peanut oil, sweet oil, salt solution and water.Carrier also comprises material such as glyceryl monostearate or the distearin that delays to discharge, and uses separately or uses with paraffin wax.The amount of solid carrier can change, but preferred every dose unit is that about 20mg is to about 1g.Pharmaceutical preparation can comprise grinding with the routine techniques preparation of pharmacy.Mixing, granulation, and when the film-making agent, also need compressing tablet; Perhaps for glutoid scrotiform formula, comprise grinding, mix and filling.When using liquid vehicle, preparation is the suspension agent of syrup, elixir, emulsifying agent or moisture or non-water.These liquid preparations are oral administration directly, the soft gelatin capsule of perhaps packing into.
For rectal administration, The compounds of this invention can be combined and be molded as suppository with vehicle such as theobroma oil, glycerine, gelatin or polyoxyethylene glycol.
Compound of the present invention is a Vitronectic receptor antagonist, is used for the treatment of its pathology and is disease with Vitronectic receptor interaction receptor or cell.For example, these compounds can be used to treat the disease of the pathologic process of bone mass loss.Therefore, The compounds of this invention is used for the treatment of osteoporosis, hyperparathyroidism, Pei Jiteshi (Paget) disease, pernicious hypercalcemia, is shifted the molten bone infringement of generation, lacked the bone loss that causes by ligamentopexis or sexual hormoue by bone.Be sure of that The compounds of this invention also can be used as anti-cancer powder, anti-infection agent, anti-angiogenic former and anti-metastasis agent, can be used for treating cancer, atherosclerosis and restenosis.Specifically, The compounds of this invention is used to be suppressed to narrow that vascular cell causes.
Suppress the method that scleroproein bonded The compounds of this invention provides the platelet aggregation of a kind of inhibition Mammals, particularly people and formed blood coagulation, this method is included in inside and uses formula (I) compound and pharmaceutically acceptable carrier.The indication of this treatment comprises Acute Myocardial Infarction (AMI), venous thrombosis, pulmonary infarction, dissecting anurysm, instantaneous local asphyxia (TIA), apoplexy and other and infraction diseases associated, and unsettled cigarette inflammation.This treatment is for chronic or acute too high agglutinative symptom, seems it also is effective as dispersed intravascular clotting (DIC), septicemia, surgical shock and infectivity shock, postoperative or postpartum wound, cardiopulmonary bypass surgery, inconsistent blood transfusion, placental abruption, thrombotic thrombopenic purpura (TTP), snake venom or immunological disease.In addition, The compounds of this invention also can be used for preventing metastasis symptom, and prevention or treatment fungi and infectation of bacteria reduce immunostimulation, Zhi Liao Sickle shape cell disease, and prevent or treat the disease that the bone absorption factor causes.
The present invention also provides and has suppressed solution fibrin treatment artery and the inaccessible again method of vein, and this method is included in inside and uses formula (I) compound and solution fibrin agent.In fibrinolytic treatment, use formula (I) compound or can prevent obturation more fully, perhaps can postpone the inaccessible again time.The term solution fibrin agent of using in the context of the invention is meant any compound that can dissolve the fibrinogen blood coagulation directly or indirectly, no matter be natural or synthetic.The proplasmin activator is one group of known dissolving scleroproein reagent.Useful proplasmin activator comprises for example anistreplase, urokinase (UK), uPA (pUK), streptokinase, tissue fibrin's dissolving proenzyme activator (tPA) and its mutant, or its mutation.
The compounds of this invention also can for example be used for storing in external use to suppress hematoblastic aggegation in blood and the blood products, perhaps be used for external (ex vivo) operation as when diagnosis or research use.
The compounds of this invention is given patient's medication with oral or parenteral form, medicine use the dense bone resorption that advances should be enough to suppress, or suppress platelet aggregation, or other indication.Use according to patient's situation contain The compounds of this invention pharmaceutical composition to its oral dosage between about 0.1 about 50mg/kg, preferred oral dosage is between about 0.5 to about 20mg/kg.For acute treatment, preferred parenteral admin.Though also use the injection of intramuscular medicine group, 5% G/W of venoclysis The compounds of this invention or conventional salt brine solution, or the similar formulations of adding suitable vehicle is the most effective.Typically, parenteral admin dosage can be about 0.01 to about 100mg/kg; Preferred 0.1 to 20mg/kg.Every day, medication was 1-4 time, was about 0.4 to about 400mg/kg/ day to reach total dosage level.By comparing the concentration of medicament in blood and reaching the required concentration of result of treatment, those of ordinary skills are easy to determine the level and the method for medication.
In one or several biological test, The compounds of this invention is tested needed compound concentration when determining to meet the requirements of the pharmacy effect.The vitronectin bonded suppresses
Solid phase [
3H]-SK﹠amp; F-107260 and α
γβ
3Combination: be dissolved in damping fluid T and (contain 2mM CaCl
2With 1% octyl glucoside) people's placenta or human blood platelets α
γβ
3(0.1-0.3mg/mL) with containing 1mM CaCl
2Damping fluid T, 1mM MnCl
2, 1mM MgCl
2(buffer A) and 0.05%NaN
3The dilution, be added at once then 96-hole enzyme-linked immunosorbent assay (ELIS) plate (Corning, NewYork, NY) in, every hole 0.1ml.Every hole adds 0.1-0.2 μ g α
γβ
3Dull and stereotyped in 4 ℃ of overnight incubation.During experiment, each hole with buffer A washing once and in same buffer, hatching 1 hour under the room temperature with 0.1ml 3.5% foetal calf serum albumen.Inhale the damping fluid that goes in each hole after hatching fully and use 0.2ml buffer A washed twice.
Compound is dissolved in 100% DMSO, obtains the 2mM original solution, this solution binding buffer liquid (15mM Tris-HCl (pH7.4), 100mM NaCl, 1mM CaCl
2, 1mM MnCl
2, 1mM MgCl
2) be diluted to final compound concentration 100 μ M.Then with the compound concentration of this solution dilution to ultimate demand.In each hole, add the unmarked antagonist of different concns (0.001-100 μ M) in triplicate, add 5.0mM[subsequently
3H]-SK﹠amp; F-107260 (65-86Ci/mmol).
With plate in incubated at room temperature 1 hour.Thing also washs the hole mode with the hole with the ice-cooled buffer A of 0.2ml in complete each hole of sucking-off, cultivation back.Acceptor with 0.1ml 1%SDS solubilising and by add 3mL Ready Safe with Beckmam LS liquid scintillation counter carry out liquid scintillation counting(LSC) measure combination [
3H]-SK﹠amp; F107260, efficient 40%.At 2 μ M SK﹠amp; Measure under F-107260 exists [
3H]-SK﹠amp; The non-specific binding of F-107260 and be lower than 1% of total radioligand input all the time.Adopt non-linear least square curve fit method (improved LUNDDON-2 program) to measure IC
50(suppress 50%[
3]-SK﹠amp; F-107260 bonded antagonist concentration).According to following Equation for Calculating Ki (dissociation constant of antagonist):
Ki=IC
50/ (1+L/Kd), L and K in the formula
dExpression respectively [
3H]-SK﹠amp; The concentration of F-107260 and the constant that dissociates.
The compounds of this invention suppresses vitronectin and SK﹠amp in 0.1-25 micro-molar concentration scope; The combination of F-107260.Preferred compound suppresses vitronectin bonded concentration and is lower than 1 micromole.
Adopt this area to estimate and suppress osteoplastic standard test method, alveole described in EP-528587 (pit) forms assay method and measures in the body of The compounds of this invention and external bone resorption, this method also can adopt human osteoclast to replace the rat osteoclast to carry out, and with people such as Wronski at Cells and Materials, 1991, Sup.1, the OO rat model described in the 69-74 carries out.The rat model of parathyroidectomy.
Every experimental group comprises 5-6 Sprague-Dawley rat.Use the parathyroid gland (by seller's excision, Taonic Farms) of preceding 7 days excision rats.Used preceding 24 hours, and measured wherein the Ionized calcium level of circulation in vitro immediately adopting the tail venipuncture whole blood to be retracted to heparinization.Select the rat of ionised calcium level≤1.2mM/L (adopting Ciba-Corning634 type calcium pH analyser to measure) for use.Advance with no calcium food and deionized water to rat then.The heavily about 100g of each rat during the experiment beginning.Measuring basis Ca level and to vein of rat (tail vein) medicine group drug administration by injection control vector (salt solution) or compound (being dissolved in the salt solution), the other parathyrine 1-34 of subcutaneous injection people first peptide (hPTH1-34 immediately, dosage 0.2mg/kg salt solution/0.1% foetal calf serum albumen, Bachem, Ca) or injection PTH carrier.Behind administered compound/PTH 2 hours, measure blood calcium to the replying of PTH (and compound any influence that this is replied).Rat ulna drift model
Every experimental group 8-10 Spargue-Dawley or Wistar rat, every heavily about 30-40g before the experiment beginning.The test medicament was used 7 days with single or mixing per daily dose mode by suitable approach.Before using each agent, give rat with single dose fluorescent marker (tsiklomitsin 25mg/kg, or calcein 10mg/kg), they can reach the position on tense marker bone forming surface.After compound administration finishes, put to death rat and excise two forelimbs, by ankle joint excision foot and peeling from ancon.The freezing sample also is hung vertically on the slicing machine chuck.Cut the transverse section of ulna axis with cryostat.Middle back of the body position at osteoderm utilizes morphometry to measure bone absorption rate.Measurement is undertaken by the following stated: the bone resorption amount on periosteum surface equals periosteum and formed the fluorescent marker progressive distance of mixing on the surface towards the 0th day at bone within bone; This distance is calculated by the width between the 0th day and the 7th day marker and periosteum face is subtracted each other; The result can be calculated the specific absorption (representing with micron) of every day divided by 7.Human osteoclast absorption measurement method (" alveole assay method ") is taken out number equal portions osteoclastoma source cell suspension from the liquid nitrogen storage, be warmed to 37 ℃ rapidly and also use RPMI-1640 substratum centrifuge washing once (1000rpm, 5min, 4 ℃).Suction is removed substratum and is replaced with the mouse-anti-HLA-DR antibody of RPMI-1640 substratum dilution in 1: 3.Cultivated on ice 30 minutes and cell mixing suspension often.Cell goes in the aseptic 15ml centrifuge tube by centrifugal (1000rpm, 5min, 4 ℃) washing secondary and with cell with cold RPMI-1640 substratum.With improved Neubauer counting cell tally sheet karyocyte number.Take out the magnetic bead (5/ monocyte) by the goat anti-mouse IgG coating of capacity in the reservoir bottle, put into 5ml fresh culture (this substratum flush away deleterious trinitride sanitas).Utilize magnet fixedly magnetic bead remove substratum and replace with fresh culture.Cultivate 30 minutes on ice with magnetic bead and cytomixis and with suspension, and mixing suspension often.With magnet fixedly be coated with the cell magnetic bead and with remaining cell (rich osteoclast part) decant(-ation) in the aseptic 50ml centrifuge tube.In being coated with the cell magnetic bead, add fresh culture, to shift out any osteoclast of holding back.This washing process repeats 10 times, discards and is coated with the cell magnetic bead.Utilize disposable pasteurization macropore to mould pipe and in counting cell, inject sample, with counting cell counting osteoclast number.With the cell centrifugation slabbing, regulating osteoclast density in the EMEM substratum is 1.5 * 10
4/ ml adds 10% foetal calf serum and 1.7g/ and rises sodium bicarbonate.Getting 3ml equal portions cell suspending liquid (every treatment group) moves in the 15ml centrifuge tube.With the cell centrifugation slabbing.In every pipe, add 3ml suitable processing thing (in the EMEM substratum, being diluted to 50 μ M).Comprise the suitable carriers contrast equally, positive control (87MEMI is diluted to 100 μ g/ml) and contrast of the same race (IgG2a is diluted to 100 μ g/ml).Cultivated 30 minutes for 37 ℃.0.5ml the equal portions cell inoculation is gone up and was cultivated 2 hours at 37 ℃ to the aseptic dentine section in the 48 hole titer plates.Every kind of handled thing is quadruplicate.Section is added to then and newly joins in handled thing or the contrast with the hot PBS washing (with 6-hole titer plate, every hole 10ml) that changes six times.Cultivated 48 hours in 37 ℃.The Phosphoric acid esterase of anti-tartrate (trap) method (the selective staining agent of osteoclast system) section is also fixed 5 minutes with 2% glutaraldehyde (in 0.2M cacodylic acid sodium) with the salt water washing of phosphate buffered.They are washed with water and in the TRAP damping fluid, cultivated 5 minutes in 37 ℃.After cold water washing, they were cultivated 5 minutes in 4 ℃ in cold acetate buffer/fast red garnet.Excess buffer is gone in suction, the dry air of will cutting into slices after the washing.With the positive osteoclast of bright-field microscope counting TRAP, remove from dentin surface by supersound process then.Adopt Nikon/Lasertec ILM 21W to measure the alveole volume with the focus microscope.The α of RGD-mediation
γβ
3Bonded suppresses purifying α
IIbβ
3
4 ℃, with 10 units outmoded, washed human blood platelets (being obtained by Red Cross) is at 3% octyl glucoside, 20mM Tris-HCl, pH7.4,140mM NaCl 2mM CaCl
2In slow stirring and dissolving 2 hours.With 100, the centrifugal lysate of 000g 1 hour.The supernatant liquor that obtains is added in the 5ml lens culinaris agglutinin Sepharose 4B post (E.Y.Labs), and this post is used 20mM Tris-HCl, pH7.4,100mM NaCl, 2mM CaCl earlier
2, 1% octyl glucoside (buffer A) pre-equilibration.Cultivate after 2 hours, A washes post with 50mL cold buffer liquid.The α of residual lectin
IIbβ
3With the buffer A wash-out that contains 10% glucose.All processes are all carried out at 4 ℃.Sds polyacrylamide gel electrophoresis shows, the α that obtains
IIbβ
3Purity＞95%.In liposome, mix α
IIbβ
3
Under nitrogen gas stream, the mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) is dried on the wall of Glass tubing.The α of purifying
IIbβ
3Use protein: the phosphatide ratio is that (w: phosphatide w) was diluted to the 0.5mg/ml ultimate density and mixed in 1: 3.The resuspending mixture and in the water-bath of ultrasonication machine supersound process 5 minutes.Adopt 12 then, 000-14,000 molecular weight blocks dialysis tubing, with respect to 1000 times of excessive 50mMTris-HCl, pH7.4,100nM NaCl, 2mM CaCl
2(changing 2 times) dialysis mixture overnight.With 12, the centrifugal α that contains liposome of 000g
IIbβ
315 minutes and be resuspended in final protein concentration in the dialysis buffer liquid of about 1mg/ml.When storing liposome to needs for-70 ℃.With α
IIbβ
3The competitiveness combination
Adopt [
3H]-SK﹠amp; F-107260 is as RGD-type part, measures and the combining of fibrinogen deceptor according to the indirect competition combined techniques.(Millipore Corporation, Bedford carry out on MA), use the hydrophilic durapore film of 0.22 μ m in conjunction with being determined at 96-hole microtitration panel assembly.(MO) each hole of precoating is 1 hour for Sigma Chemical Co., St.Louis, with the retardance non-specific binding with 0.2mL 10 μ g/mL polylysines under the room temperature.In each hole, add the unlabelled benzodiazepine of different concns in quadruplicate.In each hole, add [
3H]-SK﹠amp; F-107260, ultimate density is 4.5nM, adds 1 μ g subsequently and contains platelet purification α
II bβ
3Plastid, make to combine α
IIbβ
3[
3H]-SK﹠amp; F-107260 separates with bound fraction not, then with ice damping fluid (2 times, each 0.2ml) washing.(Beckman Instrument, Fullerton measure the binding radioactivity that keeps on the strainer, efficient 40% with Beckman liquid scintillation counter (LS6800 type) counting in CA) at 1.5mLready Solve.At the unmarked SK﹠amp of 2 μ m; F-107260 exists and to measure non-specific binding down and to be lower than 0.14% of the gross activity that joins in the sample all the time.The point of all data is the quadruplicate mean value of measuring.
Adopt non-linearity least square curve fit method to analyze competitive binding data.This method provides the IC of antagonist
50(can suppress 50%[under the equilibrium state
3H]-SK﹠amp; F-107260 specificity bonded antagonist concentration).IC
50Dissociation constant (K with the antagonist that obtains according to following Cheng and Prusoff Equation for Calculating
i) relevant:
K
i=IC
50/ (1+L/K
d), in the formula L represent in the competitive binding assay [
3H]-SK﹠amp; The concentration of F-107260 (4.5mM), and K
dExpression [
3H]-SK﹠amp; The dissociation constant of F-107260, Scatchard analyzes and is measured as 4.5nM.
The inhibition of platelet aggregation can be measured according to the method described in the WO93/00095 (PCT/US/92/05463).Thrombus in vivo forms according to people such as Aiken at Prostaglandins, and method described in 19,620 (1980) confirms by the system and the effect of Hemodynamics on Pathogenesis of the peptide that injects in the record anesthesia dog body.
Compare with fibrinogen deceptor, preferred compound of the present invention, was perhaps compared with Vitronectic receptor greater than 5: 1 the affinity of Vitronectic receptor, to the affinity of fibrinogen deceptor greater than 5: 1.Preferred compound has the specific activity greater than 10: 1.Most preferred has the selectivity greater than 100: 1.With respect to fibrinogen deceptor, The compounds of this invention strengthens the bonded comparative result to Vitronectic receptor and sees the following form shown in the I:
Compound (Ex.#) Ki/ α
IIbβ
3(μ M) Ki/ α
γβ
3(μ M)
1 ＞50 0.23
2 0.009 15 blood vessel smooth muscle cell migration assays
The test The compounds of this invention suppresses smooth muscle tissue in artery or intravenously migration and outgrowth ability, suppresses the ability of restenosis to estimate them, and restenosis generally occurs in after the angioplasty.
Use rat or human aortic smooth muscle cell.Employing has the polycarbonate membrane (Costar) in 8 μ m apertures, detects cell migration in the Transwell Tissue Culture Dish.The lower surface of filter is coated with vitronectin.In the DMEM that adds 0.2% fetal bovine serum albumin, concentration is 2.5-5.0 * 10 with cell suspension
6Cell/ml, and in 20 ℃ with different concns test compounds pre-treatment 20 minutes.Use solvent thing in contrast separately.Get in the last compartment that the 0.2ml cell suspending liquid is placed on the pond.Following compartment contains the DMEM that 0.6ml adds 0.2% fetal bovine serum albumin.Under 37 ℃, at 95% air/5%CO
2Cultivated 24 hours in the atmosphere.After the cultivation, scrape off the non-migrating cell of filter upper surface gently.Then filter is fixed with methyl alcohol, dyeed with 10% Giemsa stain.Measure migration by following any method: a) counting is moved to the cell count on the filter lower surface, perhaps b) with 10% acetic acid extraction staining cell, measure absorbancy at 600nM subsequently.
General introduction
Adopt Bruker AM 250 or Bruker AC 400 spectrographs respectively 250 or 400MHz magnetic field in measure NMR (Nuclear Magnetic Resonance) spectrum.CDCl
3Be meant deuterochloroform, DMSO-d
6Be meant six deuterated dimethyl sulfoxides, and CD
3OD is meant four deuterated methanols.Chemical shift one of 1,000,000 parts of the interior mark tetramethylsilane of distance (δ) downfield report.Abbreviation implication in the NMR data is as follows: s=is unimodal, d=doublet, t=triplet, q=quartet, m=multiplet, dd=double doublet, the apparent peak of app=, br=broad peak.J represents with a hertz NMR coupling constant of measuring.Continuous wave infrared (IR) spectrum Perkin-Elmer683 infrared spectrometer record, Fourier transform infrared (FTIR) spectrum NicoletImpact400D infrared spectrometer record.IR and FTIR spectrum is with the transmission mode record, and band position is with anti-wave number (cm
-1) report.Mass spectrum is to utilize fast atom bombardment(FAB) (FAB) or electrospray ionization technology to adopt VG 70FE, PE Syx API III, or VGZAB HF measures.The ultimate analysis value utilizes Perkin-Elmer 240C elemental analyser to obtain.Fusing point is measured with Thomas-Hoover fusing point instrument and is not calibrated.All temperature are all with a degree centigrade expression.
Thin-layer chromatography uses Analtech silica gel G F and E.Merck silica gel 60F-254 thin layer plate.Quick and gravity chromatogram is all used E.Merck Kieselgel60 (230-400 order) silica gel.Analyzing and preparing HPLC all adopts Rainin or Beckman chromatographic instrument to carry out.ODS is meant the silica gel chromatography carrier that octadecyl is silyl-modified.5 μ Apex-ODS are meant the silyl-modified silica gel chromatography carrier (Colorado makes for Jones Chromatography, Littleton) of octadecyl with 5 μ m nominal particle sizes.YMC ODS-AQ
RBe meant the ODS chromosorb, be YMC Co.Ltd., Kyoto, the trade mark of Japan registration.PRP-1
RBe meant polymeric (vinylbenzene-Vinylstyrene) chromosorb, be hamiliton Co., Reno, the trade mark of Nevada registration.Celite
RBe the flocculating aids that constitutes by pickling diatomite, be Manville Corp., Denver, the trade mark of Colorado registration.
Preparation 1 Preparation (±)-10,11-dihydro-3-carboxyl-5H-dibenzo [a, d] suberene -10-ethyl acetateA) 3-benzyl-4-(trifluoro-methanesulfonyl oxy) phenylmethylether
-78 ℃, under the argon atmospher, (10.0ml 60mmol) is added to 2-benzyl-4-methoxyphenol (10.71g, 5.0mmol with trifluoromethanesulfanhydride anhydride in 3 minutes; By " U.S. state chemistry Hui Chi ", 1949,71,64 described making) and anhydrous 2,6-lutidine (12.0ml, anhydrous CH 100mmol)
2Cl
2(250ml) in the solution.React on-78 ℃ and stirred 0.5 hour, be warmed to RT then.After 1 hour, the reaction with hexane (250ml) dilution, use successively subsequently 1.0N HCl (2 * 100ml), 1.0N NaOH (2 * 50ml), H
2O (100ml) and salt solution (50ml) washing.Dry (Na
2SO
4), concentrating, silica gel column chromatography (10% EtOAc/ hexane) obtains title compound (16.65g, 96%), is light yellow solid.TLC R
f(0.51 10%EtOAc/ hexane);
1H NMR (250MHz, CDCl
3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0,3.1Hz, 1H), 6.66 (d, J=3.1Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl
4) 1492,1423,1405,1249,1216,1161,1144,1039,869cm
-1MS (ES) m/e369 (M+Na)
+, 364.0 (M+NH
4)
+, 347.0 (M+H)
+.b) 4-allyl group-3-benzyl phenylmethylether
Vacuum flame drying places LiCl in the round-bottomed flask, and (3.08g 72.8mmol), and is cooled to room temperature with this system under argon atmospher.Add 3-benzyl-4-(trifluoro-methanesulfonyl oxy) phenylmethylether (21.0g, 60.6mmol), chlorination two (triphenyl phosphines) closes palladium (II) (2.13g, 3.0mmol), dry DMF (150ml) and allyl tributyltin (22.6ml, 72.8mmol), mixture by vacuumize for three times/the argon gas clean cycle cleans with argon gas.Mixture forms the homogeneous phase yellow solution at the oil bath internal heating that is preheated to 95 ℃.1.5 after hour, concentrate dark mixture, residue dimethylbenzene reconcentration with Rotary Evaporators (high vacuum).Resulting residue is dissolved in Et
2Stirred fast 0.5 hour in the O (120ml) and with 10%KF (120ml).Layering, water layer Et
2(2 * 120ml) extract O.By diatomite (celite
) filter the organic phase that merges, to remove insoluble solids, filtrate is used H successively
2O (60ml) and salt solution (60ml) washing.Dry (MgSO
4) and concentrate remaining opaque yellow oil.Chromatography (silica gel, 5% EtOAc/ hexane) provides title compound (14.21g, 98%), is light yellow oil.TLC R
f(5%EtOAc/ hexane) 0.51;
1H NMR (250MHz, CDCl
3) δ 7.03-7.31 (m, 6H), 6.74 (dd, J=8.3,2.7Hz, 1H), 6.66 (d, J=2.7Hz, 1H), 5.79-5.98 (m, 1H), 4.89-5.07 (m, 2H); 3.97 (s, 2H), 3.75 (s, 3H), 3.21-3.33 (m, 2H); FTIR (CCl
4) 1610,1496,1256,1046,914cm
-1MS (ES) m/e369.2 (M+H)
+.c) 2-benzyl-4-methoxyphenylacetic acid
With H
5IO
6(23.83g, water 104.5mmol) (56ml) solution are added to 4-allyl group-3-benzyl phenylmethylether (5.30g, CCl 22.24mmol)
4(28ml) and CH
3In CN (28ml) solution, and well-beaten mixture is cooled to 0 ℃ fully.To wherein adding RuCl
3(231mg 1.11mmol), 0 ℃ of quick stirring reaction 4 hours, so stirs 45min in RT.By diatomite (celite
) filtering mixt, filter cake is used CH earlier
2Cl
2(120ml), use H then
2O (120ml) washing.Layering, water layer CH
2Cl
2(3 * 120ml) extract, dry (Na
2SO
4) and concentrate a remaining brown oil.This oil content fits over Et
2Between O (90ml) and the 0.25N NaOH (90ml), layering, Et
2The O layer with 0.25N NaOH (2 * 10ml) extract, and with the water layer that merges with dense HCl acidifying (pH2), CH
2Cl
2Extract dry (Na
2SO
4), concentrate, obtain title compound, be yellow oil, this oil is solidified into yellow solid (4.19g, 74%).
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); FTIR (CCl
4) 2300-3500 (broad), 1710,1611,1502,1496,1285,1257,1045cm
-1MS (ES) m/e279.0 (M+Na)
+, 274.0 (M+NH
4)
+, 257.0 (M+H)
+.d) 3-methoxyl group-5H-dibenzo [a, d] suberene-10 (11H)-ketone
Under 100-110 ℃, (3.26g 12.72mmol) is added in the well-beaten Tripyrophosphoric acid (165g) with finely powdered 2-benzyl-4-methoxyphenylacetic acid.Behind the 15min, reactant is poured in the ice (330g), added Et
2O (330ml) mixed mixture 15 minutes fast.Separate each layer, water layer Et
2O (330ml) extracts.Organic layer 5% NaHCO that merges
3(2 * 80ml) and salt solution (80ml) wash dry (MgSO successively
4) and concentrate.Residue concentrates once more with toluene, then chromatography (silica gel, 20% EtOAc/ hexane).Obtain title compound.Be yellow solid (1.44g, 48%).TLC R
f(20%EtOAc/ hexane) 0.46;
1H NMR (250MHz, CDCl
3) δ 8.07-8.15 (m, 1H), 7.39-7.49 (m, 1H), 7.25-7.48 (m, 2H), 7.19 (d, J=8.3Hz, 1H), 6.86 (d, J=2.6Hz, 1H), 6.17 (dd, J=8.3,2.6Hz, 1H), 4.21 (s, 2H), 4.11 (s, 2H), 3.77 (s, 3H); FTIR (CCl
4) 1680,1501,1282,1270cm
-1MS (ES) m/e261 (M+Na)
+, 256.0 (M+NH
4)
+, 239.0 (M+H)
+.e) (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
-78 ℃, under the argon atmospher, two (trimethyl silyl) lithamides in placing the dry flask of crossing of flame (1.0M THF solution, 6ml, the anhydrous EtOAc of dropping in anhydrous THF (24ml) solution 6mmol) (0.58ml, 6.6mmol).Yellow solution was added dropwise to 3-methoxyl group-5H-dibenzo [a, d] suberene-10 (11H)-ketone (715mg, anhydrous THF (3ml) solution 3mmol) then in-78 ℃ of stirrings 0.5 hour in 3 minutes.In translator, re-use the anhydrous THF of 0.4ml in addition.At-78 ℃, react after 0.5 hour the saturated NH of reactant
4Cl (15ml) quenching is warmed to RT, and (2 * 30ml) extract with EtOAc.Dry (MgSO
4), concentrate, and chromatography (silica gel earlier with 10% EtOAc/ hexane (400ml), is used 20% EtOAc/ hexane again), be recovered to 3-methoxyl group-5H-dibenzo [a earlier, d] suberene-10 (11H)-ketone (305.4mg, 43%) yellow solid, obtain title compound (531.9mg then, 54%), is light yellow oil.TLC R
f(0.37 20%EtOAc/ hexane);
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), 3.95-4.35m, 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); FTIR (CCl
4) 3580 (spikes), 3509 (broad peaks), 1735,1715,1503,1261,1198,1156,1044cm
-1MS (ES) m/e675.2 (2M+Na)
+, 653.2 (2M+H)
+.f) (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate
10% Pd/C (242mg, 0.23mmol) be added to (±)-10,11-dihydro-10-hydroxyl-3-methoxyl group-5H-dibenzo [a, d] suberene-10-ethyl acetate (741.1mg, 2.27mmol) and dense HCl (0.19ml, 2.27mmol) glacial acetic acid (23ml) solution in, and in RT and nitrogen atmosphere (50psi), mixture is shaken in the Pa Er device.After 6 hours, reactant is by diatomite Celite
Filter, and use the EtOAc washing leaching cake.Concentrated filtrate also utilizes the toluene reconcentration with residue.The resulting light yellow oil residue of chromatography (silica gel, 20% EtOAc/ hexane) gets title compound (643.6mg, 91%) water white oil.TLC R
f(0.57 20%EtOAc/ hexane);
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); FTIR (CCl
4) 1734,1611,1504,1285,1263,1155,1044cm
-1MS (ES) m/e333.0 (M+Na)
+, 328.0 (M+NH
4)
+, 311.0 (M+H)
+, 265.0 (M+H-EtOH)
+.g) (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
0 ℃, under the argon atmospher, with anhydrous AlCl
3(1.38g 10.35mmol) once is added to (±)-10,11-dihydro-3-methoxyl group-5H-dibenzo [a, d]-suberene-10-ethyl acetate (643.6mg, anhydrous CH 2.07mmol)
2Cl
2(21ml) in the solution.Warm yellow solution is to RT and stirred 3 hours, is cooled to 0 ℃ and make to react with the cold HCl of 3N (10ml) and stop then.Separate each layer, with water layer CH
2Cl
2Extract.Dry (MgSO
4) organic layer that merges and concentrating.Silica gel column chromatography (25% EtOAc/ hexane) obtains title compound (611.7mg, 100%), is almost colourless oil.TLC R
f(0.26 20%EtOAc/ hexane);
1H NMR (400MHz, CDCl
3) δ 7.03-7.22 (m, 4H), 6.93 (d, J=8.1Hz, 1H), 6.69 (d, J=2.6Hz, 1H), 6.58 (dd, J=8.1,2.6Hz, 1H), 5.00 (s, 1H), 4.25 (d, J=14.9Hz, 1H), 4.11-4.25 (m, 2H), 3.73-3.88 (m, 1H), 3.79 (d, J=14.9Hz, 1H), 3.28 (dd, J=15.0,4.1Hz, 1H), 2.91 (dd, J=15.0,9.3Hz, 1H), 2.65 (dd, J=15.6,4.9Hz, 1H), 2.53 (dd, J=15.6,9.5Hz, 1H), 1.27 (t, J=7.2Hz, 3H); FTIR (CCl
4) 3611 (spikes), 3447 (broad peaks), 1734,1504,1291,1272,1176,1152cm
-1MS (ES) m/e314.2 (M+NH
4)
+, 297.2 (M+H)
+.h) (±)-10,11-dihydro-3-(trifluoro-methanesulfonyl oxy)-5H-dibenzo [a, d] suberene-10-ethyl acetate
-78 ℃, under the argon atmospher, with trifluoromethanesulfanhydride anhydride (0.45ml, 2.68mmol) be added drop-wise to (±)-10,11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (611.7mg, 2.06mmol) and 2,6-lutidine (0.48ml, anhydrous CH 4.12mmol)
2Cl
2(10.3ml) in the solution.0.5 after hour, warm reactant is to RT and stirred 1 hour.Use Et
2O (50ml) dilutes yellow solution, and uses 1.0N HCl (5ml), 5%NaHCO successively
3(5ml) and salt solution (5ml) washing.Dry (MgSO
4), concentrating, silica gel column chromatography (20% EtOAc/ hexane) obtains title compound water white oil (808.9mg, 92%).TLC R
f(20%EtOAc/ hexane) 0.58;
1H NMR (250MHz, CDCl
3) δ 6.98-7.30 (m, 7H), 4.35 (d, J=15.1Hz, 1H), 6.19 (q, J=7.1Hz, 2H), 3.91 (d, J=15.2Hz, 1H), 3.78-3.95 (m, 1H), 3.37 (dd, J=15.2,4.1Hz, 1H), 3.02 (dd, J=15.2,9.6Hz, 1H), 2.70 (dd, J=15.8,4.8Hz, 1H), 2.53 (dd, J=15.8,9.6Hz, 1H), 1.27 (t, J=7.1Hz, 3H); FTIR (CCl
4) 1735,1493,1427,1250,1215,1144,961,856cm
-1MS (ES) m/e451.1 (M+Na)
+, 446.2 (M+NH
4)
+, 429.2 (M+H)
+.i) (±)-10,11-dihydro-3-carboxyl-5H-dibenzo [a, d]-suberene-10-ethyl acetate
With (±)-10,11-dihydro-3-(trifluoro-methanesulfonyl oxy)-5H-dibenzo [a, d] suberene-10-ethyl acetate (808.9mg, 1.89mmol), KOAc (742mg, 7.56mmol), Pd (OAc)
2(21.2mg, 0.095mmol), 1,1 '-two (diphenyl phosphine) ferrocene (210mg, 0.38mmol) and the mixture of anhydrous DMSO (11ml) clean with CO and (vacuumize/the CO clean cycle for three times, then in mixture, fed the CO bubbling 5 minutes), in 70 ℃ of oil baths, under CO airbag pressure, stir then.After 35 hours, reactant H
2O (11ml) dilution is cooled to 0 ℃, and with 1.0N HCl (about 8ml) acidifying.Use CH
2Cl
2Extract (3 * 30ml), dry (Na
2SO
4), concentrate and utilize the toluene reconcentration, surplus a salmon liquid (2-3ml).Chromatography (silica gel, 3: 2: 0.1 EtOAc/ toluene/AcOH; Mixed fraction is with 1: 1: 0.1 EtOAc/ toluene/AcOH chromatography once more), title compound (581.9g, 95%), be yellow viscous oil, partially crystallizable under 40 ℃ and high vacuum.TLC R
f(3: 2: 0.1 EtOAc/ toluene/AcOH) 0.60;
1H NMR (250MHz, CDCl
3) δ 7.95 (d, J=1.5Hz, 1H), 7.87 (dd, J=7.8,1.5Hz, 1H), 7.00-7.35 (m, 5H), 4.40 (d, J=15.2Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 3.97 (d, J=15.2Hz, 1H), 3.82-4.00 (m, 1H), 3.43 (dd, J=15.3,4.0Hz, 1H), 3.07 (dd, J=15.3,9.5Hz, 1H), 2.69 (dd, J=15.8,4.8Hz, 1H), 2.53 (dd, J=15.8,9.5Hz, 1H), 1.28 (t, J=7.1Hz, 3H); FTIR (CCl
4) 2357-3378 (broad peak), 1735,1692,1280cm
-1MS (ES) m/e342.2 (M+NH
4)
+, 325.2 (M+H)
+, 307.2 (M+H-H
2O)
+.
Preparation 2 Preparation 2-carboxyl-10,11-dihydro-5H-dibenzo [a, d] suberene-10- Ethyl acetateA) 2-benzoyl-5-methoxyphenylacetic acid methyl esters
Press J.Chem.Soc., Perkin Trans I, 1991,171 is described, adopts Benzoyl chloride and aluminum chloride to handle 3-methoxyphenylacetic acid methyl esters, makes title compound.B) 2-benzyl-5-methoxyphenylacetic acid methyl esters
According to Synthesis, the general method described in 1978,763, the compound with sodium borohydride and trifluoroacetic acid Processing of Preparation 2 (a) obtains title compound.C) 2-benzyl-5-methoxyphenylacetic acid
With the compound of aqueous sodium hydroxide solution and methyl alcohol Processing of Preparation 2 (b) and stir, enriched mixture is also handled with dilute hydrochloric acid, obtains title compound.D) 5,11-dihydro-2-methoxyl group-10H-dibenzo [a, d] suberene-10-ketone
According to United States Patent (USP) 3,567, the general method described in 730, the compound that will prepare 2 (c) are added in the mixture of phosphoric acid and Vanadium Pentoxide in FLAKES and heated and stirred to 80 ℃, obtain title compound.E) 5,11-dihydro-2-hydroxyl-10H-dibenzo [a, d] suberene-10-ketone
According to Tetrahedron Letters, the general method in 1978,5211, the compound with sulfur alcohol and aluminum chloride Processing of Preparation 2 (d) obtains title compound.F) 5,11-dihydro-2-(fluoroform sulphonyl) Oxy-1 0H-dibenzo [a, d] suberene-10-ketone
According to J.Chem.Soc., Chem.Commun., the general method described in 1987,904, the compound with trifluoromethanesulfanhydride anhydride Processing of Preparation 2 (e) obtains title compound.G) 5,11-dihydro-2-methoxycarbonyl-10H-dibenzo [a, d]-suberene-10-ketone
According to J.Chem.Soc., Chem.Commun.1987, the general method in 904, with CO, methyl alcohol, acid chloride and 1, the compound of two (diphenyl phosphine) Propare Processing of Preparation 2 (f) of 3-obtains title compound in methyl-sulphoxide.H) 5,11-dihydro-2-carboxyl-10H-dibenzo [a, d] suberene-10-ketone
The compound and the dilute sodium hydroxide aqueous solution that will prepare 2 (g) together stir, and mixture is handled with dilute hydrochloric acid, obtains title compound.I) 5,11-dihydro-2-tertbutyloxycarbonyl-10H-dibenzo [a, d] suberene-10-ketone
According to Synthesis, 1983,2, the general method described in 135 is used N, and the contract compound of two trimethyl carbinol Processing of Preparation 2 (h) of dinethylformamide obtains title compound.J) 2-tertbutyloxycarbonyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
According to Org.Reactions, 1947,1,1 and J.Am.Chem.Soc., 1938,60, the general method described in 2947, the compound with zinc powder and bromoethyl acetate Processing of Preparation 2 (i) obtains title compound.K) 2-carboxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate
With the compound and the stirring of trifluoroacetic acid Processing of Preparation (2j), enriched mixture obtains title compound in methylene dichloride.L) 2-carboxyl-10,11-dihydro-5H-dibenzo [a, d] suberene-10-ethyl acetate
Adopt the general method of embodiment 1 (f), just substitute the compound of preparation 1 (c), obtain title compound with preparation 2 (k) compound.
Preparation 3
Preparation 7-carboxyl-9,10-dihydro-4H-benzo [4,5] ring heptan is [1,2-b] also
Furans-10-ethyl acetate
Adopt the general method of preparation 2, just substitute Benzoyl chloride, obtain title compound with the 3-furoyl chloride.
Preparation 4 Preparation 8-carboxyl-10,11-dihydro-5H-tetrazolo [5,1-c] [1,4] -benzodiazepine -11-methyl acetateA) 4-[N-(tertbutyloxycarbonyl)-N-(methoxycarbonyl) amino methyl]-3-nitrobenzoyl tert-butyl acrylate
To 4-brooethyl-3-nitrobenzoyl tert-butyl acrylate (2.27g, 7.2mmol) (Int.J.Peptide Res., 1990,36,31) add tertiary butyl methyl-imino dicarboxylic acid potassium (J.C.S.Perkin I in dimethyl formamide (25ml) solution, 1977,1088-90) (1.56g, dimethyl formamide 7.3mmol) (20ml) suspension.Stir in this dark brown solution 1 hour and the impouring water (400ml), (3 * 100ml) extract ethyl acetate, the organic layer water that merges (5 * 75ml) washings, dry (sodium sulfate) also concentrates, get light orange oil, flash chromatography on silica gel purifying (20% ethyl acetate/hexane) obtains title compound (2.15g, 73%).
1H NMR (400MHz, CDCl
3) δ 8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H) .b) 4-[N-(tertbutyloxycarbonyl) amino methyls]-3-nitrobenzoyl tert-butyl acrylate
(2.15g 5.24mmol) is dissolved in the mixed solution of methyl alcohol (120ml) and 0.95N sodium hydroxide (15ml) will to prepare the compound of 4 (a).After 15 minutes, add acetate (3.0ml) and enriched mixture.Residue is dissolved in ethyl acetate (300ml) and water (3 * 75ml) extractions.Organic layer salt solution (75ml) washing, drying (sodium sulfate) also concentrate, and get yellow oil, with silica gel chromatography purifying (20% ethyl acetate/hexane) purifying, get title compound (1.0g, 54%).
1H NMR (400MHz, CDCl
3) δ 8.6 (s, 1H), 8.2 (d, 1H), 7.7 (d, 1H), 5.35 (m, 1H), 4.6 (d, 2H), 1.65 (s, 9H), 1.4 (s, 9H) .c) 3-amino-4-[N-(tertbutyloxycarbonyl) amino methyls]-t-butyl perbenzoate
To contain compound (0.80g, ethanol 2.27mmol) (100ml) the solution hydrogenation (40psi) of the preparation 4 (b) of 10% palladium/carbon (0.5g).After 30 minutes, mixture filters and concentrates, and gets title compound (0.72g, 100%).
1H NMR (400MHz, CDCl
3) δ 7.25 (m, 2H), 7.1 (d, 1H), 4.9 (b, 1H), 4.25 (d, 2H), 1.6 (s, 9H), (1.45 s, 9H) .d) (E, Z)-4-[N-(tertbutyloxycarbonyl) amino methyl]-3-[2-(1,4-dimethoxy-1,4-dioxo-crotyl) amino]-t-butyl perbenzoate
To prepare 4 (c) compound (0.7g, 2.2mmol) and dimethyl acetylenedicarbexylate (0.37g, 2.6mmol) mixture heating up in methyl alcohol (40ml) refluxed 30 minutes, cooling also concentrates.Residue gets title compound (0.7g, 70%) with purification by flash chromatography (silica gel, 20% ethyl acetate/hexane).
1H NMR (400MHz, CDCl
3) δ 9.6 (s, 1H), 7.7 (d, 1H), 7.35 (m, 2H), 5.5 (s, 1H), 5.0 (b, 1H), 4.4 (d, 2H), 3.75 (s, 3H), 3.7 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H) .e) 4-[N-(tertbutyloxycarbonyl) amino methyl]-3-[2-(1,4-dimethoxy-1,4-dioxo-2-butyl) amino] t-butyl perbenzoate
(0.68g 1.5mmol) shook under the 40psi hydrogen pressure 1 hour in methyl alcohol (70ml) with 10% palladium/carbon (0.5g) compound of preparation 4 (d), and mixture filters also and concentrates, and got title compound (0.66g, 95%).
1H NMR (400MHz, CDCl
3) δ 7.8 (d, 1H), 7.75 (s, 1H), 7.1 (d, 1H), 5.4 (b, 1H), 4.9 (b, 1H), 4.6 (m, 1H), 4.3 (m, 2H), 3.7 (s, 3H), 3.65 (s, 3H), 2.9 (m, 2H), 1.6 (s, 9H), (1.45 s, 9H) .f) 4-(aminomethyl)-3-[2-(1,4-dimethoxy-1,4-dioxo-2-butyl) amino] phenylformic acid
(0.66g 1.4mmol) kept room temperature 1 hour to the compound of preparation 4 (e) in methylene dichloride (10ml) and trifluoroacetic acid (10ml), concentrate, and got title compound.(g) (R, S)-8-carboxyl-2,3,4,5-tetrahydrochysene-3-oxo-1H-1,4-benzodiazepine -2-methyl acetate
The compound that will prepare 4 (f) is dissolved in methyl alcohol (60ml) and (0.73ml 3.2mmol) handles, and is warmed to 50 ℃ and reacts 1 hour with the methanol solution of 25% sodium methylate.Mixture concentrates with 1N hydrochloric acid (3.5ml) acidifying that is dissolved in the ether, gets title compound (0.44g, 98%).
1H NMR (400MHz, DMSO-d
6) δ 8.15 (t, 1H), 7.2 (s, 1H), 7.1 (d, 1H), 7.05 (d, 1H), 5.0 (dd, 1H), 4.9 (m, 1H), 3.75 (dd, 1H), 3.6 (s, 3H), 2.8 (dd, 1H), 2.6 (dd, 1H). (h) (R, S)-and 8-carboxyl-10,11-dihydro-5H-tetrazolo [5,1-c] [1,4] benzodiazepine -11-methyl acetate
According to J.Org.Chem., 1991,56, the general method described in 2395 with the compound of triphenyl phosphine, diethyl azodiformate and trimethyl silyl trinitride Processing of Preparation 4 (g), gets title compound in tetrahydrofuran (THF).
Preparation 5 Preparation (R, S)-8-carboxyl-10,11-dihydro-5H-imidazo [2,1-c] [1,4] benzodiazepine -11-methyl acetateA) (R, S)-8-carboxylic acid-2,3,4,5-tetrahydrochysene-3-sulfo--1H-1,4-benzodiazepine -2-methyl acetate
According to Tet.Lett., 1980,21,4061 general method with the compound of Lawesson agent treated preparation 4 (g), gets title compound.B) (R, S)-8-carboxyl-2,5-dihydro-3-methylthio group-1H-1,4-benzodiazepine -2-methyl acetate
According to Tetrahedron, 1960,517 general method with the compound of methyl iodide Processing of Preparation 5 (a), gets title compound.C) (R, S)-8-carboxyl-2,5-dihydro-3-[(2,2-dimethoxy-ethyl) amino]-1H-1,4-benzodiazepine -2-methyl acetate
According to J.Heterocyclic Chem., 1989,26,205 general method with the compound of aminoacetaldehyde dimethyl acetal Processing of Preparation 5 (b), gets title compound.D) (R, S)-8-carboxyl-10,11-dihydro-5H-imidazo [2,1-c] [1,4] benzodiazepine -11-methyl acetate
With the compound of trifluoroacetic acid aqueous solution Processing of Preparation 5 (c), get title compound.
Preparation 6 Preparation (R, S)-2-amino-10,11-dihydro-5H-dibenzo [a, d]- Suberene-10-ethyl acetateA) 2-benzyloxycarbonyl amino-5H-dibenzo [a, d] suberene-10-ethyl acetate
Add hot preparation 2 (k) compound, triethylamine and the mixture of hexichol phosphoryl trinitride in toluene.Formed mixture is handled with benzylalcohol, stirs and concentrates.Residue silica gel chromatography purifying gets title compound.B) (R, S)-2-amino-10,11-dihydro-5H-dibenzo [a, d] suberene-10-ethyl acetate
To prepare 6 (a) compound and be dissolved in methyl alcohol also with 10% palladium/carbon and the processing of 1M hydrochloric acid diethyl ether solution, mixture shakes in hydrogen environment.Filtering mixt and concentrate title compound.
Preparation 7 Preparation 2-[1-[4-(carbobenzoxy-(Cbz)) piperazinyl]]-N-methyl-ethamineA) 2-[1-[4-(carbobenzoxy-(Cbz)) piperazinyl] ethamine
Use Tet.Lett., general method protection 2-(1-piperazinyl) ethamine in 1986,27,4391.Under 10 ℃, to 2-(1-piperazinyl) ethamine that stirs (4.0ml, 31mmol) and triethylamine (6.3ml is added dropwise to tert-butyl diphenyl chloromethane silane (7.8ml, acetonitrile 30mmol) (10ml) solution in acetonitrile 35mmol) (20ml) solution.Mixture stirred 2 hours in RT, was chilled to 10 ℃, with triethylamine (6.3ml, 45mmol 0 and chloroformic acid benzyl ester (4.3ml, methylene dichloride 30mmol) (10ml) solution-treated.Mixture stirred 2 hours in RT, filtered and concentrated.Residue stirs in 80% acetate (100ml) and spends the night, and washs in the impouring salt solution and with ethyl acetate.Water alkalizes with saturated sodium carbonate, ethyl acetate extraction, and with organic phase drying (sal epsom), filter and concentrate, get title compound (1.1g, 14%).
1NMR (400MHz, CDCl
3) δ 2.43 (6H, m), 2.80 (2H, m), 3.52 (4H, m), 5.14 (2H, s), 7.38 (5H, s) .b) 2-[1-[4-(carbobenzoxy-(Cbz)) piperazinyls]]-the N-methyl ethyl-amine
Under 10 ℃, utilize syringe to acetic anhydride (1.0mL, drip in 9.8mmol) formic acid (0.5ml, 12.2mmol).Stirred the mixture 10 minutes and be heated to 50 ℃ and reacted 2 hours.Cooling mixture adds anhydrous tetrahydro furan (10ml) to RT, and (1.0g 3.8mmol) is dissolved in the tetrahydrofuran (THF) will to prepare 7 (a) compound subsequently.Mixture stirred 2.5 hours in RT, concentrates and residue is dissolved in tetrahydrofuran (THF) (25ml), and be cooled to 10 ℃.(1ml 10mmol), stirs this mixture, and till no gas evolution, reheat refluxed 2 hours to wherein dripping the 1.0M sulfuration methyl boron (Boron methyl sulfide) that is dissolved in the tetrahydrofuran (THF) (10ml) under 10 ℃.Cooling mixture is carefully used saturated methanol hydrochloride solution (20ml) processing and reflux 1 hour, concentrates this mixture, gets title compound (400mg, 40%).MS(ES)m/e?278.0[M+H]
+；
1NMR(400MHz，CDCl
3)δ2.68-3.92(15H，m)，5.15(2H，s)，7.37(5H，s).
Preparation 8
Preparation 4-[N-(carbobenzoxy-(Cbz))-(amino imino methyl)] Benzoyl chloride
With 4-[N-(carbobenzoxy-(Cbz))-(the amino imino methyl] phenylformic acid (0.23g, 1.0mmol) and the mixture heating up of thionyl chloride (3ml) in methylene dichloride (3ml) refluxed 10 minutes, concentrate, with O for toluene with concentrate for several times, title compound.
Preparation 9
Preparation N-(tertbutyloxycarbonyl)-4,4 '-Lian piperidines
With 4, (2.5g, 10mmol) water-soluble (10ml) also uses the 5N sodium-hydroxide treatment to pH8-9 to 4 '-Lian piperidines dihydrochloride, stirs to 120ml and in RT with alcohol dilution.(mixture stirs in RT for 2.4g, the formed mixture of ethanol 11mmol) (80ml) solution-treated, adds 5NNaOH therebetween to keep pH8-9 once to add tert-Butyl dicarbonate.After 5 hours, enriched mixture also is dissolved in 1: 1 ether with residue: water mixture (100ml), and regulate pH to 12 with 5N sodium hydroxide.Water is used salt solution successively with the ether extraction organic phase, rare citric acid and water washing.Regulate water to pH12-13 and use ether extraction with 5N sodium hydroxide.Organic phase salt water washing, dry (sodium sulfate) is concentrated into limpid oil, and vacuum-drying gets title compound (1.7g, 63%) solid.TLC R
f0.4 (Kieselgel 60 F254,15: 3: 22-butanols: formic acid: water); MS (ES) m/e 268.3[M+H]
+.
Preparation 10 Preparation 2-(methylamino-methyl) benzoglyoxaline dihydrochlorideA) 2-[(tertbutyloxycarbonyl] sarcosyl] amino aniline
Under the argon atmospher, (100g, 0.924mol) (175g, DMF 0.924mol) (1750ml) solution is cooled to-10 ℃, slowly adds DCC (190.8g, CH 0.924mol) in 1 hour continuously with the BOC sarkosine with phenylenediamine
2Cl
2(1750ml) solution.Temperature rises to 0 ℃ between charge period.Stirring reaction spends the night, and makes temperature rise to RT simultaneously.Leach white precipitate, filtrate is used H
2O (3.5L) and saturated brine (1L) dilution.Isolate CH
2Cl
2Layer, (2 * 1L) extract water layer with EtOAc.Organic layer water (1L) that merges and salt solution (0.5L) washing are condensed into yellow residue (341g) then.Residue is developed with EtOAc, gets title compound (179.4g, 70%), mp134-136 ℃.B) amino methyl 2-[(N-tertbutyloxycarbonyl-N-methyl)] benzoglyoxaline
With the 2-[(tertbutyloxycarbonyl) sarcosyl] (178.4g, THF 0.639mol) (900ml) and AcOH (900ml) solution reflux 1 hour under argon atmospher carefully vacuumizes reaction, and boils off most of THF amino aniline then.Residual solution is poured in the frozen water of stirring into enriching NH
4OH solution (1150ml) is regulated PH to 10.The oil that forms stirred to spend the night carry out crystallization, leach solid and, obtain white-yellowish solid (167g, 100%), mp140-150 ℃ in 50 ℃ of normal atmosphere dry 2 days down.Further dry under RT and normal atmosphere, get rough title compound (162g, 97%).B) 2-(methylamino-methyl) benzoglyoxaline dihydrochloride
With 4M HCl/ diox (616mL, 2.46mol) and phenylmethylether (134ml, 1.23mol) solution in argon atmospher, be cooled to 0 ℃, in 30 minutes, slowly continue to add 2-[(N-tertbutyloxycarbonyl-N-methyl again) amino methyl] benzoglyoxaline (161g, CH 0.616mol)
2Cl
2(800ml) solution.Temperature rises to 8 ℃ between charge period, and before material does not add just adularescent precipitation begin to form.Stirring reaction 20 minutes filters then and collects title compound (66.6g, 46%), mp250-255 ℃ (decomposition).Ultimate analysis C
9H
11N
32HCl: calculated value: C, 46.17; H, 5.60; N, 17.95, measured value: C, 46.33; H, 5.68; N, 17.55.Use Et
2O dilutes filtrate, and the mixture placement is spent the night.The filtration title compound (62g, overall yield 128.6g, 89%) of getting back is pink solid, mp248-253 ℃ (decomposition).
Preparation 11 Preparation 2-[(2-amino-ethyl) amino] the pyridine dihydrochlorideA) list-BOC-1, the 2-quadrol
0 ℃, under the argon atmospher, with tert-Butyl dicarbonate (10.91g, CH 50mmol)
2Cl
2(50ml) solution was added drop-wise to 1 (33ml, CH 500mmol) of quick stirring in 30 minutes
2Cl
2(250ml) in the solution.There is precipitation to separate out between charge period.Behind reinforced the end reaction is warmed to RT, stirred 1 hour, utilize Rotary Evaporators to concentrate.Residue is dissolved in H
2O (100ml) removes by filter a small amount of insolubles.Filtrate is used CH
2Cl
2(3 * 100ml) extract, dry (MgSO
4) organism that merges, concentrate, title compound (6.00g, 75%), be turbid liquid.
1H NMR (250MHz, CDCl
3) δ 4.75-5.00 (m, 1H), 3.05-3.25 (m, 2H), 2.65-2.85 (m, 2H), 1.46 (s, 9H), 1.12 (brs, 2H) .b) 2-[[2-(BOC-amino) ethyl] amino] pyridine N-oxides
Reflux list-BOC-1, the 2-quadrol (5.83g, 36.39mmol), 2-chloropyridine-N-oxide salt acidulants (7.25g, 43.67mmol), NaHCO
3(15.25g, 182mmol) and the mixture of tertiary amyl alcohol (36ml).After 47 hours, the cooling dark brown mixture is used CH
2Cl
2(100ml) dilution, and suction filtration is removed insolubles.Concentrated filtrate and use the toluene reconcentration, silica gel column chromatography (10% MeOH/CHCl
3) after obtain impure title compound (8.23g, 89%), be yellow solid, this solid can directly use without being further purified.TLC (10%MeOH/CHCl
3) R
f0.42;
1H NMR (250MHz, CDCl
3) δ 8.16 (dd, J=6.5,1.3Hz, 1H), 7.05-7.30 (m, 2H), 6.68 (br d, J=8.6Hz, 1H), 6.50-6.65 (m, 1H), 5.70-5.95 (m, 1H), 3.25-3.60 (m, 4H), 1.44 (s, 9H); MS (ES) m/e254 (M+H)
+.c) 2-[[2-(BOC-amino) ethyl] amino] pyridine
10%Pd/C (106.4mg 0.10mmol) is added to 2-[[2-(BOC-amino) ethyl] amino] pyridine-N-oxide (and 126.7mg, 0.5mmol) and tetrahydrobenzene (0.25ml is in anhydrous EtOH (5ml) solution 0.25mmol), and the reflux mixture.After 16 hours, reactant is by diatomite (celite
) filter and concentrated filtrate.To prepare the residue merging that (0.5mmol scale) obtains separately, and the material that merges will be passed through silica gel chromatography purifying (5% MeOH/CHCl
3), title compound (148.4g is 63%, by 1mmol 2-[[2-(BOC-amino) ethyl] amino] pyridine-N-oxide is basic calculation), be yellow oil.TLC (5%MeOH/CHCl
3) R
f0.43;
1H NMR (400MHz, CDCl
3) δ 8.05-8.12 (m, 1H), 7.37-7.46 (m, 1H), 6.53-6.61 (m, 1H), 6.41 (d, J=8.3Hz, 1H), 5.12 (br s, 1H), 4.86 (br s, 1H), 3.26-3.51 (m, 4H), 1.44 (s, 9H); MS (ES) m/e238 (M+H)
+.d) amino 2-[(2-amino-ethyl)] the pyridine dihydrochloride
Under 0 ℃, 4N hydrochloric acid De dioxane solution (3.2ml) is added to 2-[[2-(BOC-amino) ethyl continuously] amino] pyridine (148.4mg, anhydrous CH 0.63mmol)
2Cl
2(3.2ml) in the solution, then reaction is warmed to RT.After 2 hours, the suction filtration mixture, the collecting precipitation solid, and use anhydrous Et
2The O washing, the dry title compound (132.8mg, quantitative) that gets is yellow solid.
1H NMR (400MHz, CDCl
3) δ 7.99-8.07 (m, 1H), 7.92-7.98 (m, 1H), 7.19 (d, J=9.1Hz, 1H), 6.98-7.04 (m, 1H), 3.76 (t, J=6.2Hz, 2H), 3.27 (t, J=6.2Hz, 2H, part is hidden by the residual solvent signal); MS (ES) m/e138 (M+H)
+.
Preparation 12 Preparation 2-[(3-hydroxyl-1-propyl group) amino] pyrrole shallow lake-N-oxide compoundA) amino 2-[(3-hydroxyl-1-propyl group)] pyridine-N-oxide
Reflux 2-chloropyridine-N-oxide compound (16.6g, 0.1mol), 3-amino-1-propyl alcohol (15.3ml, 0.2mol); NaHCO
3(42g, 0.5mol) and the mixture of tertiary amyl alcohol (100ml).After 2 hours, the cooling reactant is used CH
2Cl
2(300ml) dilution, and suction filtration is removed insolubles.Concentrated filtrate and use the toluene reconcentration is surplused a yellow oil.Silica gel column chromatography (20%MeOH/CHCl
3) after title compound (15.62g, 93%) yellow solid.TLC(20％MeOH/CHCl
3)R
f?0.48；
1H?NMR(250MHz，CDCl
3)δ8.07(dd，J＝6.6，1.2Hz，1H)，7.34(br?t，1H)，7.10-7.30(m，1H)，6.64(dd，J＝8.5，1.4Hz，1H)，6.40-6.60(m，1H)，4.49(br?s，1H)，3.65-3.90(m，2H)，3.35-3.60(m，2H)，1.75-2.00(m，2H)；?MS(ES)m/e?169(M+H)
+.
Preparation 13 3-carboxyl-10,11-dihydro-5-methyl-dibenzo [b, f] azepine-10- Methyl acetateA) 5-methoxyl group-2-(methoxycarbonyl) pentanoic
Hydrochloric acid between in methyl alcohol, using-methyl alcohol processing 5-methoxyl group-2-(carboxyl) pentanoic (press Chem.Ber., 1956,89, make described in the 2174-2190), get title compound.B) 5,11-dihydro-3-methoxyl group-5-methyl isophthalic acid 0H-dibenzo [b, f] azatropylidene-10-ketone
General method described in the employing NL 7011296 just substitutes 5-chloro-2-(methoxycarbonyl) pentanoic with preparation 13 (a) compound, gets title compound.C) 3-carboxyl-10,11-dihydro-5-methyl-dibenzo [b, f]-azatropylidene-10-methyl acetate
Adopting the method for preparation 1 (e-i), is to substitute preparation 1 (d) compound with preparation 13 (b) compound, gets title compound.
Preparation 14 3-carboxyl-10, [b, f] Evil heptan is because of-10-methyl acetate for 11-dihydro-dibenzoA) [b, f] Evil heptan is because of-10 (11H)-ketone for 3-methoxyl group-dibenzo
Adopt J.Heterocycl.Chem., 1986,23, the general method described in the 265-9 just substitutes the 4-fluorophenol with phenol, gets title compound.B) 3-carboxyl-10, [b, f] Evil heptan is because of-10-methyl acetate for 11-dihydro-dibenzo
Adopting the method for preparation 1 (e-i), is to substitute preparation 1 (d) compound with preparation 14 (a) compound, gets title compound.
Preparation 15
3-carboxyl-10,11-dihydro-dibenzo [b, f] thiophene heptan is because of-10-methyl acetate
Adopt the general method of preparation 1 (e-i), just, get title compound with 3-methoxyl group dibenzo [b, f] thiophene heptan preparing 1 (d) compound because of-10 (11H)-ketone (press Collect.Czech.Chem.Commun.1979,44,2108-23 is described to be made) substitute.
Preparation 16 2-carboxyl-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-6-methyl acetateA) 2-benzyl-4-bromo-N-(formyl radical) aniline
Adopt Coll.Czech.Chem.Commun., 1965,30, general method described in the 1163-1172 (is pressed Khim.Geterotsikl.Soedin., 1983 with 2-benzyl-4-bromaniline, 3,411-414 is described to be made) together heat with ethyl formate, obtain title compound.
B) 2-bromo-11H-dibenzo [b, e] azatropylidene
Adopt Coll.Czech.Chem.Commun., 1965,30, the general method described in the 1163-1172 will prepare 16 (a) compound and heat in Tripyrophosphoric acid and phosphoryl chloride mixture, get title compound.
C) the 2-bromo-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-6-methyl acetate
Adopt Bull.Chem.Soc.Jpn., 1990,63, general method described in the 3122-3131, cooling will prepare 16 (b) compound is used t-butyldimethylsilyl ketene diacetal, trimethylsilyl cyanide and the catalytic amount of methyl acetate in methylene dichloride two-μ-chloro-two (1 down, the 5-cyclooctadiene) closes two rhodiums ([Rh, (COD) Cl]
2Handle, get title compound.
D) 2-carboxyl-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-6-methyl acetate
Adopting the general method of step 1 (i), is to substitute preparation 1 (h) compound with preparation 16 (c) compound, gets title compound.
Preparation 17
7-carboxyl-10,11-dihydro-5-methyl-5H-dibenzo [b, e] [1,
4] diaza -11-methyl acetate
A) 2-amino-5-bromo-N-(methyl) pentanoic
Adopt Ann.Chem., 1898,303, the general method described in 322 just substitutes aniline with methylphenylamine, gets 2-nitro-5-bromo-N-(methyl) pentanoic, and it is reduced with tin protochloride, gets title compound.
B) 7-bromo-5H-dibenzo [b, e] [1,4] diaza
Employing Helv.Chem.Acta, 1964,47, the general method described in the 1163-72 just substitutes 2-amino-N-(methyl) pentanoic with preparation 17 (a) compound, gets title compound.
C) the 7-bromo-10,11-dihydro-5-methyl-5H-dibenzo [b, e] [1,4] diaza -11-methyl acetate
Adopting the general method of preparation 16 (c), is the compound that substitutes preparation 16 (b) with preparation 17 (b) compound, gets title compound.
D) 7-carboxyl-10,11-dihydro-5-methyl-5H-dibenzo [b, e] [1,4] diazepine-11-methyl acetate
Adopt preparation 1 (i)-as method, just substitute the compound of preparation 1 (h) with preparation 17 (c) compound, title compound.
Preparation 18
7-carboxyl-10, [1,4] Evil heptan is because of-11 for 11-dihydro-dibenzo [b, f]
-methyl acetate
A) 4-bromo-N-formyl radical-2-(phenoxy group) aniline
Adopt J.Chem.Soc., Perkin I, 1976, the described general method of 1279-1285 together heats 4-bromo-2-(phenoxy group) aniline (press J.Chem.Soc., 1930, the described preparation of 1202-1208) with formic acid, must title compound.
B) 7-bromo-dibenzo [b, f] [1,4] Evil heptan because of
Adopt J.Chem.Soc., Perkin I, 1976, the general method described in the 1279-1285 will prepare 18 (a) compound and heat in Tripyrophosphoric acid and phosphoryl chloride mixture, get title compound.
C) the 7-bromo-10, and [1,4] Evil heptan is because of-11-methyl acetate for 11-dihydro-dibenzo [b, f]
Adopting the general method of preparation 16 (c), is the compound that substitutes preparation 16 (b) with preparation 18 (b) compound, gets title compound.
D) 7-carboxyl-10, [1,4] Evil heptan is because of-11-methyl acetate for 11-dihydro-dibenzo [b, f]
Adopting the general method of preparation 1 (i), is to substitute preparation 1 (h) compound with the compound for preparing 18 (c), gets title compound.
Preparation 19 7-carboxyl-10,11-dihydro-dibenzo [b, f] [1,4] thiophene heptan is because of-11-acetate Methyl estersA) 2-thiophenyl-4-(bromine) aniline
With tin protochloride reduction 3-bromo-6-; Nitro phenylbenzene disulphide (press J.Chem.Soc., B, 1966, make described in the 963-72), get title compound.B) 7-bromo-dibenzo [b, f] [1,4] thiophene heptan because of
Employing Helv.Chem.Acta, 1964,47, the general method described in the 1163-72 just substitutes 2-(thiophenyl) aniline with preparation 19 (a) compound, gets title compound.C) the 7-bromo-10, and 11-dihydro-dibenzo [b, f] [1,4] thiophene heptan is because of-11-methyl acetate
Adopting the general method of preparation 16 (c), is the compound that substitutes preparation 16 (b) with the compound of preparation 19 (b), gets title compound.D) 7-carboxyl-10,11-dihydro-dibenzo [b, d] [1,4] thiophene heptan is because of-11-methyl acetate
Adopting the general method of preparation 1 (i), is the compound that substitutes preparation 1 (h) with preparation 19 (c) compound, gets title compound.
Preparation 20
2-carboxyl-10,11-dihydro-two dress also [b, f] are disliked heptan because of-10-acetate first EsterA) [b, f] Evil heptan is because of-10 (11H)-ketone for 2-methoxyl group-dibenzo
Adopt J.Heterocycl.Chem., 1986,23, the general method described in the 265-9 just substitutes the 4-fluorophenol with phenol, gets title compound.B) 2-carboxyl-10, [b, f] Evil heptan is because of-10-methyl acetate for 11-dihydro-dibenzo
Adopting the method for preparation 1 (e-i), is the compound that substitutes preparation 1 (d) with the compound of preparation 20 (a), gets title compound.
Following compound has illustrated the method that is prepared bioactive compounds of the present invention by midbody compound described in aforementioned each preparation.
Embodiment 1
Preparation (±)-10,11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl) -methyl] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-acetateA) (±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with EDC (202.4mg, 1.06mmol) disposable (±)-10 that are added to, 11-dihydro-3-carboxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (285.6mg, 0.88mmol), 2-(methylamino-)-tolimidazole dihydrochloride (247.2mg, 1.06mmol), HOBt.H
2O (142.7mg, 1.06mmol) and diisopropylethylamine (0.61ml in dry DMF 3.52mmol) (4.4ml) solution, reacts on RT and stirred 16.5 hours, uses Rotary Evaporators (high vacuum) to concentrate then.Residue utilizes the dimethylbenzene reconcentration, is dissolved in H then
2O (5ml), with EtOAc extract (2 * 5ml), dry (MgSO
4), concentrate, and chromatography (silica gel contains 1: 1 EtOAc/CHCl of 5%MeOH
3), get title compound, be weak yellow foam (389.2mg, 95%).TLC:R
f(10%MeOH was in 1: 1 EtOAc/CHCl
3) 0.60;
1HNMR (400MHz, CDCl
3) δ 7.70-7.80 (and m, 1H) 7.40-7.50 (m, 1H), 7.35 (s, 1H), 7.21-7.32 (m, 3H), 7.04-7.21 (m, 5H), 4.76-4.88 (m, 2H), 4.36 (d J=15.2Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 3.90 (d, J=15.2Hz, 1H), and 3.82-3.95 (m, 1H), 3.38 (dd, J=15.4,4.0Hz, 1H), 3.11 (s, 3H), 3.03 (dd, J=15.4,9.5Hz, 1H), 2.69 (dd, J=15.8,4.8Hz, 1H), 2.52 (dd, J=15.8,9.6Hz, 1H), 1.27 (t, J=7.1Hz, 3H): FTIR (CCl
4) 2700-3470 (broad peak), 1735,1629 (acromions), 1617,1484,1454,1422,1397,1271,1180,1157cm
-1MS (ES) m/e 468.2 (M+H)
+B) (±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-acetic acid sodium salt
1.0N LiOH (1.0ml 1.0mmol) is added to (±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-(389.2mg is 0.83mmol) in THF (4.2ml) and H for 5H-dibenzo [a, d] suberene-10-ethyl acetate
2In the mixture among the O (3.2ml), and the yellow solution that forms stirred 2 hours in RT, stirred 15 hours in 40 ℃, reflux then and stirred 0.5 hour.Then reactant is concentrated into driedly with Rotary Evaporators, residue is dissolved in H
2O (4ml).Solution Et
2O (2 * 4ml) washings, Et
2The O layer is abandoned it.Filter water layer to remove degranulation, then, with 1.0N HCl (1.0ml) neutralization.Suction filtration collecting precipitation solid is also used H
2The O washing is dissolved in it 1: 1 CH of heat then
3CN/H
2O.With the solution heat filtering, remove insoluble brown oil.And be cooled to RT.Because product becomes oil to separate out, and is concentrated into mixture dried with Rotary Evaporators.Residue is dissolved in MeOH (2ml), adds 5%NaHCO
3(2ml).Warm mixture concentrates then and removes MeOH to producing homogeneous solution.ODS chromatography (30%MeOH/H
2, use 1: 1 MeOH/H then
2O is chromatography again), concentrate, lyophilize gets title compound, is colourless powder (187.5mg, 45%).HPLC K ' 1.47 (Hamilton PRP-1
R, 35%CH
3CN/H
2O-0.1%TFA);
1H NMR (400MHz, CD
3OD) rotational isomer mixture; 6.80-7.65 (m, 11H), 4.64-5.05 (m, 2H), 3.68-4.41 (m, 3H), 2.87-3.46 (m, 5H), 2.30-2.58 (m, 2H); MS (ES) m/e 440.2 (M+H)
+Ultimate analysis C
27H
24N
3O
3Na.2.25H
2O: calculated value: C, 64.60; H, 5.72; N, 8.37, measured value: C, 64.52; H, 5.80; N, 8.27.
Embodiment 2
Preparation (±)-10,11-dihydro-3-[1-(4,4 '-the Lian piperidyl) carbonyl Base-5H-dibenzo [a, d] suberene-10-acetateA) (±)-10,11-dihydro-3-[1-(1 '-BOC-4,4 '-the Lian piperidyl) carbonyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with EDC (209.3mg 1.09mmol) once is added to (±)-10,11-dihydro-3-carboxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (296.3mg, 0.91mmol), 1-BOC-4,4 '-the Lian piperidines (293mg, 1.09mmol), HOBtH
2O (147.6mg, 1.09mmol) and diisopropylethylamine (0.32ml is in dry DMF 1.82mmol) (4.6ml) solution.Reactant stirs in RT and spends the night, and concentrates with Rotary Evaporators (high vacuum), and residue dimethylbenzene reconcentration is dissolved in H then
2O (5ml).With EtOAc extract (2 * 5ml), dry (MgSO
4), concentrate silica gel column chromatography (7: the 3EtOAc/ hexane), get title compound (463.4mg, 89%), be weak yellow foam.TLC R
f(7: 3 EtOAc/ hexanes) 0.59;
1H NMR (250MHz, CDCl
3) δ 6.94-7.46 (m, 7H), 4.58-4.88 (m, 1H), 4.37 (d, J=15.2Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 3.89 (d, J=15.2Hz, 1H), and 3.68-4.30 (m, 4H), 3.38 (dd, J=15.3,4.1Hz, 1H), 3.01 (dd, J=15.3,9.4Hz, 1H), 2.40-3.09 (m, 5H), 1.45 (s, 9H), 1.27 (t, J=7.1Hz, 3H), 0.85-1.90 (m, 11H); FTIR (CCl
4(1734,1694,1637,1426,1171cm
-1MS (ES) m/e 1149.8 (2M+H)
+, 597.4 (M+Na)
+, 575.4 (M+H)
+, 519.4 (M+H-C
4H
8)
+B) (±)-10,11-dihydro-3-[1-(4,4 '-the Lian piperidyl) carbonyl]-5H-dibenzo [a, d] suberene-10-acetate
Stir (±)-10 at 40 ℃, 11-dihydro-3-[1-(1 '-BOC-4,4 '-the Lian piperidyl) carbonyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (463.4mg, 0.81mmol), 1.0N LiOH (1.0ml, 1.0mmol), THF (4.1ml) and H
2The heterogeneous mixture of O (3.1ml).After 17 hours, the cooling homogeneous phase solution is also with 1.0N HCl (1.5ml) acidifying, CH in ice
2Cl
2Extract (3 * 10ml), dry (MgSO
4) and concentrate, obtain the canescence foam.It is dissolved in CH
2Cl
2(4.1ml), and cooling solution to 0 ℃.Once add 4.1ml TFA and reactant is warmed to RT.1.5 after hour, with Rotary Evaporators with yellow solution concentrate as for, give fuel-displaced.ODS chromatography (30%CH
3CN/H
2O-0.1%TFA), concentrate and lyophilize, get colourless powder title compound (437.2mg, 86%).HPLC?k′1.91(Hamilton?PRP-1
R，30％CH
3CN/H
2O-0.1％?TFA)；
1H?NMR(400MHz，CD
3OD)δ7.02-7.29(m，7H)，4.53-4.73(m，1H)，4.34(d，J＝15.0Hz，1H)，3.99(d，J＝15.0Hz，1H)，3.65-3.89(m，2H)，3.30-3.50(m，3H)，2.70-3.15(m，5H)，2.68(dd，J＝16.0，5.2Hz，1H)，2.52(dd，J＝16.0，9.1Hz，1H)，1.06-2.09(m，10H)；MS(ES)m/e?447.2(M+H)
+。Ultimate analysis C
28H
34N
2O
31.5CF
3CO
2HO.75H
2O: calculated value: C, 59.00; H, 5.91; N, 4.44.Measured value: C, 58.96; H, 6.00; N, 4.50.
Embodiment 3
Preparation (±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-
Propyl group]-5H-dibenzo [a, d] suberene-10-acetate
A) 4-(2-tetrahydro-pyran oxy)-1-tributyl stannyl-ethyl acetylene
Under 0 ℃, in the argon atmospher, ((47ml is in anhydrous THF (60ml) solution 30mmol) 30mmol) to be added to 2-(3-fourth alkynyloxy group) tetrahydrochysene-2H-pyrans continuously in 2 minutes for 1.6M, 18.8ml with the n-Butyl Lithium hexane solution.0.5 after hour, once add tributyltin chloride (8.1ml, 30mmol) and warm reactant to RT.After 3 hours, reactant is used H subsequently successively with hexane (300ml) dilution
2O (2 * 60ml), 10%KF (2 * 30ml) and saturated brine (60ml) washing, dry (Na
2SO
4), concentrate and silica gel column chromatography (3% EtOAc/ hexane), get title compound (3.58g, 27%), be almost colourless oil.
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) (±)-3-[4-(2-tetrahydro-pyran oxy)-ethyl acetylene-1-yl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-10,11 '-dihydro-3-(trifluoro-methanesulfonyl oxy)-5H-dioxy benzo [a, d] suberene-10-ethyl acetate (1.34g, 3.13mmol), 4-(2-tetrahydro-pyran oxy)-1-tributyl stannyl-ethyl acetylene (1.66g, 3.76mmol), LiCl (398mg, 9.39mmol), dichloride two (triphenyl phosphine) close palladium (110mg, 0.094mmol) and mixture reflux in argon atmospher of no Shui diox (31ml).1.5 after hour, the concentration response thing is dissolved in Et to remove most of dioxan with residue
2O (100ml).Adding 10%KF (50ml) also stirred the mixture 0.5 hour fast.Remove water layer and with Et
2O passes through Celite
RAnd MgSO
4Mixture filter.Concentrated filtrate and silica gel column chromatography residue (10% EtOAc/ hexane) get title compound (1.12g, 83%), are 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) (±)-3-[4-(2-tetrahydro-pyran oxy)-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, with (±)-3-[4-(2-tetrahydrofuran 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 of EtOAc (28ml) vibrating on the Pa Er device under the 50psi hydrogen-pressure, after 3 hours, passes through Celite
RFiltering reaction thing and concentrated filtrate.Silica gel column chromatography (10% EtOAc/ hexane) gets title compound (1.06g, 88%), is water white 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 3.71-3.70 (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) (±)-3-[4-hydroxyl-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Stir (±) 3-[4-(2-tetrahydro-pyran oxy)-1-butyl under the room temperature]-5H-dibenzo [a, d] and suberene-10-ethyl acetate (456.0mg, 1.04mmol) and tosic acid-hydrate (60mg, anhydrous EtOH (10ml) solution 0.31mmol), after 2 hours, reaction 5%NaHCO
3(1ml) all standing concentrates and removes EtOH.Residue H
2O (2ml) dilutes and uses CH
2Cl
2Extract dry (MgSO
4), concentrating, silica gel column chromatography (1: 1 EtOAc/ hexane) gets title compound (34.2mg, 93%), is water white 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), 2.40-2.75 (m, 4H), 1.45-1.80 (m, 4H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e353 (M+H)
+E) (±)-3-[3-carboxyl-1-propyl group]-5H-dibenzo [a, d]-suberene-10-ethyl acetate
Under the argon atmospher, with (±)-3-[4-hydroxyl-1-butyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (342.4mg, anhydrous CH 0.97mmol)
2Cl
2(19ml) solution is cooled to 0 ℃, to wherein once adding 2,2,6,6-tetramethoxy oxo-piperidine father-in-law muriate (J.Org.Chem., 1985,50,1332-1334; 260mg, 1.36mmol).React on 0 ℃ and stirred 1 hour, (1.2ml 11.64mmol), adds cold NaClO subsequently to add the 2-methyl-2-butene then
2(0.88g, 7.76mmol) and NaH
2PO
4(0.90g, water 6.50mmol) (26ml) solution (0 ℃).With EtOAc (100ml) diluting reaction and layering, organic layer is used cold 1.0NHCl1 (10ml) and saturated brine (20ml) washing, dry (MgSO successively after 10 minutes
4), concentrate silica gel column chromatography (gradient: 1: 1 EtOAc/CHCl of elder generation
3, 9: 9: 2 EtOAc/CHCl then
3/ EtOHc), get impure title compound.With silica gel again chromatography (7: 3: 0.1 toluene/EtOAc/AcOH), pure title compound (233.7mg, 66%).TLC(1∶1?EtOAc/CHCl
3)R
f0.46；
1H?NMR(400MHz，CDCl
3)δ7.05-7.22(m，4H)，6.92-7.05(m，3H)，4.34(d，J＝15.0Hz，1H)，4.10-4.25(m，2H)，3.80-3.90(m，2H)，3.33(dd，J＝15.1，4.1Hz，1H)，2.95(dd，J＝15.1，9.4Hz，1H)，2.48-2.60(m，4H)，2.48-2.60(m，4H)，2.37(t，J＝7.4Hz，2H)，1.87-2.00(m，2H)，1.27(t，J＝7.2Hz，3H)；MS(ES)m/e389(M+Na)′，367(M+H)′。
F) amino (±)-3-[3-[[(2-aminophenyl)] carbonyl] third-1-yl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the argon atmospher, with (±)-3-[3-carboxyl-1-propyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate (233.7mg, anhydrous THF (6.4ml) solution 0.64mmol) is cooled to 0 ℃, and adding 4-methylmorpholine (0.14ml, 1.28mmol).With this solution in 0 ℃ of stirred for several minute, drip then isobutyl chlorocarbonate (0.11ml, 0.83mmol).Muddy reactant adds 1 rapidly, 2-phenylenediamine (138mg, anhydrous THF (0.6ml) solution 1.28mmol) then in 0 ℃ of stirring 0.5 hour.Warmly react to RT and stirred 3 hours, use H then
2O (2ml) dilutes and extracts with EtOAc, dry (MgSO
4), concentrate silica gel column chromatography (3: the 2EtOAc/ hexane), get title compound (257.6mg, 88%), be weak yellow foam.TLC (3: 2 EtOAc/ hexanes) R
f=0.40;
1H NMR (250MHz, CDCl
3) δ 6.90-7.23 (m, 10H), 6.72-6.80 (m, 2H), 4.33 (d, J=15.0Hz, 1H), and 4.10-4.25 (m, 2H), 3.71-3.91 (m, 4H), 3.32 (dd, J=15.1,4.0Hz, 1H), 2.95 (dd, J=15.1,9.5Hz, 1H), and 2.59-2.72 (m, 3H), 2.54 (dd, J=15.6,9.5Hz, 1H), 2.34 (t, J=7.4Hz, 2H), 1.98-2.09 (m, 2H), 1.27 (t, J=7.1Hz, 3H); MS (ES) m/e 457 (M+H)
+
G) (±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-propyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate
With (±)-3-[3-[[(2-aminophenyl) amino] carbonyl] third-1-yl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (257.6mg, ice AcOH (2.8ml) 0.56mmol) and anhydrous THF (2.8ml) solution reflux in argon atmospher.After 3 hours, the concentration response thing is residue, and uses the dimethylbenzene reconcentration.Surplus residue is dissolved in Et
2O (30ml) also uses 1.0N NaOH (2ml), H successively
2O (2ml) and saturated brine (2ml) washing, dry (MgSO
4), concentrating, silica gel column chromatography (1: the 1 EtOAc/ hexane that contains 2%EtOH) gets title compound (236.3mg, 96%), is the canescence foam.TLC (2%EtOH was in 1: 1 EtOAc/ hexane) R
f0.34;
1H NMR (400MHz, CDCl
3) δ 7.30-7.80 (m, 2H), 7.03-7.80 (m, 2H), 7.03-7.24 (m, 6H), and 6.80-6.95 (m, 3H), 4.12-4.28 (m, 3H), 3.77-3.89 (m, 1H), 3.74 (d, J=15.1Hz, 1H), 3.28 (dd, J=15.2,4.0Hz, 1H), 2.90 (dd, J=15.2,9.5Hz, 1H), 2.84 (t, J=7.7Hz, 2 H), 2.65 (dd, J=15.7,4.9Hz, 1H), 2.60 (t, J=7.5Hz, 2H), 2.52 (dd, J=15.7,9.6Hz, 1H), 2.03-2.18 (m, 2H), 1.28 (t, J=7.1Hz, 3H); MS (ES) m/e439 (M+H) '.
H) (±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-propyl group]-5H-dibenzo [a, d] suberene-10-acetate, sodium salt
With (±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-propyl group]-5H-dibenzo [a, d] suberene-10-ethyl acetate (236.3mg, 0.54mmol), 1.0N NaOH (0.65ml, 0.65mmol) and the mixture of anhydrous EtOH (4.8ml) warm in being preheated to 50 ℃ oil bath, after 16 hours, the concentration response thing to dry doubling with residue with ODS chromatogram purification (gradient: use 35%MeOH/H earlier
2O, 40%MeOH/H then
2O), concentrate, the lyophilize that continues gets title compound (143mg, 58%), is colourless powder.HPLC (PRP-1
R, contain the 40%CH of 0.1%TFA
3CN/H
2O), K
1=1.5;
1H NMR (400MHz, CD
3OD) δ 7.41-7.49 (m, 2H) 6.86-7.27 (m, 9H), 4.24 (d, J=14.7Hz, 1H), 3.87 (d, J=14.7Hz, 1H), 3.73-3.85 (m, 1H), 3.23-3.25 (part is covered by the residual solvent signal for m, 1H), 2.80-2.93 (m, 3H), 2.62 (t, J=7.5Hz, 2H), 2.46 (dd, J=14.4,5.1Hz, 1H), 2.40 (dd, J=14.4,9.7Hz, 1H), and 2.05-2.17 (m, 2H); MS (ES) m/e 411 (M+H) '.Ultimate analysis C
27H
25N
2O
2Na1.5H
2O: calculated value C, 70.57; H, 6.14; N, 6.10; Real side value: C, 70.65; H, 5.95; N, 5.95.
Embodiment 4
Preparation (±)-10,11-dihydro-3-[[[2-(2-pyridine amino) ethyl
] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate
A) (±)-10,11-dihydro-3-[[[2-(2-pyridine amino) ethyl] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Under the room temperature, (112.7mg 0.59mmol) once is added to 10 with EDC, 11-dihydro-3-carboxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (157.8mg, 0.49mmol), 2-[(2-amino-ethyl) amino] the pyridine dihydrochloride (123.5mg, 0.59mmol), HOBtH
2O (79.5mg, 0.59mmol) and diisopropylethylamine (0.43ml is 2.45mmol) in the mixture in dry DMF (2.5ml).Reactant stirred 18 hours in RT, concentrated then, and residue dimethylbenzene reconcentration is used H then
2O (5ml) dilution is also used EtOAc (2 * 5ml) and CHCl successively
3(2 * 5ml) extract.Merging organic layer also handles to dissolve a small amount of insolubles, dry (MgSO with a small amount of MeOH
4), concentrate silica gel column chromatography (5%MeOH/CHCl
3), get title compound (199.1mg, 92%), be yellow oil.TLC(5％McOH/CHCl
3)R
f0.42；
1H?NMR(400，CDCl
3)δ8.10(d，J＝3.5Hz，1H)，8.02(br?s，1H)，7.60(app.narrowd，1H)，7.53(app.dd，1H)，7.33-7.42(m，1H)，7.08-7.22(m，5H)，6.57-6.64(m，1H)，6.45(d，J＝8.3Hz，1H)，4.79-4.90(m，1H)，4.36(d，J＝15.1Hz，1H)，4.11-4.26(m，2H)，3.92(d，J＝15.1Hz，1H)，3.80-3.95(m，1H)，3.55-3.72(m，4H)，3.38(dd，J＝152.4，4.1Hz，1H)，3.03(dd，J＝15.2，9.5Hz，1H)，2.66(dd，J＝15.8，4.8Hz，1H)，2.50(dd，J＝15.8，9.6Hz，1H)，1.27(t，J＝7.2Hz，3H)；MS(ES)m/e?444(M+H)
+。
B) miss title, add the 90th page of 1-3 capable (±)-10 of translation, 11-dihydro-3-[[[2-(2-pyridine amino) ethyl] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-ethyl acetate (199.1mg, 0.45mmol) and 1.0N NaOH (0.54ml, anhydrous EtOH (4ml) solution 0.54mmol) is warm in 45 ℃ of oil baths.After 23 hours, the concentration response thing and with residue with ODS chromatogram purification (gradient: use earlier 30% MeOH/H
2O, 40%MeOH/H then
2), concentrate and lyophilize, get title compound (95.8mg, 46%), be basic colourless powder.HPLC (PRP-1
R, contain the 30%CH of 0.1%TFA
3CN/H
2) K '=2.0;
1H NMR (400MHz, CD
3OD) δ 7.92 (app.d, J=4.2Hz, 1H), 7.61 (d, J=1.8Hz, 1H), 7.53 (dd, J=7.9,1.8Hz, 1H), 7.38-7.47 (m, 1H), 7.01-7.24 (m, 5H), 6.56 (d, J=7.9Hz, 1H), 6.50-6.60 (m, 1H), 4.34 (d, J=14.9Hz, 1H), 3.97 (d, J=14.9Hz, 1H), and 3.78-3.89 (m, 1H), 3.44-3.61 (m, 4H), 3.39 (dd, J=15.4,4.4Hz, 1H), 3.00 (dd, J=15.4,10.2Hz, 1H) 2.61 (dd, J=14.9,5.1Hz, 1H), 2.43 (dd, J=14.9,9.5Hz, 1H); MS (ES) m/e 416 (M+H) '.Ultimate analysis C
25H
24N
3O
3Na1.33H
2O ': calculated value: C, 65.07; H, 5.82; N, 9.11; Measured value: C, 65.02; H, 5.62; N, 9.17.
Embodiment 5
Preparation (±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-third
The oxygen base]-5H-dibenzo [a, d] suberene-10-acetate
A) (±)-10,11-dihydro-3-[3-[2-(N-oxo pyridine base)-amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Room temperature, under the argon atmospher, with 2-[(3-hydroxyl-1-propyl group) amino] pyridine-N-oxide (2mmol) and diethylazodicarboxylate's (2mmol) dry DMF (10ml) solution slowly is added drop-wise to (±)-10, in dry DMF (10ml) solution of 11-dihydro-3-hydroxyl-5H-dibenzo [a, d] suberene-10-ethyl acetate (1mmol) and triphenyl phosphine (2.1mmol).After reaction finishes, remove with Rotary Evaporators and to desolvate, residue with the dimethylbenzene reconcentration to remove residual DMF.Silica gel column chromatography gets title compound.
B) (±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate
Reflux (±)-10,11-dihydro-3-[3-[2-(N-oxo pyridine base) amino]-the 1-propoxy-]-5H-dibenzo [a, d] suberene-10-ethyl acetate (1mmol), tetrahydrobenzene (10mmol) and the mixture of 10%Pd/C (0.1mmol) in Virahol (10ml).After reacting completely, pass through Celite
Filtering mixt also utilizes the Rotary Evaporators concentrated filtrate, residue toluene reconcentration, and silica gel column chromatography gets title compound then.
C) (±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate, sodium salt
With (±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-propoxy--5H-dibenzo [a, d] suberene-10-ethyl acetate (1mmol) and the mixture of 1.0N NaOH (1.2mmol) in anhydrous EtOH (10ml) are warm in 50 ℃ of oil baths.After reaction is finished, with Rotary Evaporators remove desolvate and with residue by the ODS chromatogram purification, concentrate and lyophilize, title compound.
Embodiment 6
The methyl of 2-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-6,
11-dihydro-5H-dibenzo [b, e] azatropylidene-6-acetate
A) methyl of 2-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-]-carbonyl]-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-6-ethyl acetate
Adopting the method for embodiment 1 (a), is the compound that substitutes preparation 1 (i) with preparation 16 (d) compound, gets title compound.
B) methyl of 2-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-]-carbonyl]-6,11-dihydro-5H-dibenzo [b, e] azatropylidene-6-acetate
Adopt the method for embodiment 1 (b), just, get title compound with compound alternate embodiment 1 (a) compound of embodiment 6 (a).
Above-mentioned explanation fully discloses and how to prepare and use the present invention.But the present invention is not limited to above-mentioned specific embodiment, and should comprise the form of all changes in the claim scope of the present invention.The various periodicals of quoting herein, patent and other public publication reference have constituted prior art, and all documents of listing are all incorporated this paper into for referencial use.
Claims (11)
1. formula (I) compound or its pharmacy acceptable salt:
Wherein
A
1Be C;
E is by R
3Or R
4Five of selection replacement-or six-first heteroaryl or six-first aryl rings;
X
1-X
2Be CHR
1-CH;
X
3Be CR
5R
5 '
R ' is H, C
1-6Alkyl, C
1-7Cycloalkyl-C
0-4Alkyl, or Ar-C
0-4Alkyl;
R " be R ' ,-C (O) R ' or-C (O) OR
5
R is C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
1Be H, C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
2Be-OR '-NR ' R " ,-NR ' SO
2R , NR ' OR ' ,-OCR '
2C (O) OR ' ,-OCR '
2OC (O) R ' ,-OCR '
2C (O) NR '
2, CF
3Or-COCR '
2R
2 '
R
2 'Be-OR '-CN ,-S (O)
rR ', S (O)
2NR '
2,-C (O) R ' C (O) NR '
2Or-CO
2R ';
R
5And R
5 'Independently be H separately, C
1-6Alkyl, C
3-7Cycloalkyl-C
0-4Alkyl or Ar-C
0-4Alkyl;
R
6Be W-(CR '
2)
q-Z-(CR ' R
10)
r-U-(CR '
2)
SV-or W '-(CR '
2)
q-U-(CR '
2)
S-;
R
3, R
4And R
7Independently be H separately, halogen ,-OR
12,-SR
12,-CN ,-NR ' R
12, NO
2,-CF
3, CF
3S (OR '
2)
r-,-CO
2R ' ,-CONR '
2, R
14-C
0-6Alkyl-, R
14-C
0-6Oxoalkyl group-, R
14-C
2-6Alkenyl-, R
4-C
2-6Alkynyl-, R
14-C
0-6Alkoxyl group, R
14-C
0-6Alkylamino or R
14-C
0-6Alkyl-S (O)
r-,
R
8Be R ', C (O) R ', CN, NO
2, SO
2R ', or C (O) OR
5
R
9Be R ' ,-CF
3,-SR ' or-OR ';
R
10Be H, C
1-4Alkyl or-NR ' R ";
R
12Be R ' ,-C (O) R ' ,-C (O) NR '
2,-C (O) OR
5,-S (O)
mR ' or S (O)
2NR '
2
R
14Be H, C
3-6Cycloalkyl, Het or Ar;
R
15Be H, C
1-10Alkyl, C
3-7Cycloalkyl-C
0-8Alkyl or Ar-C
0-8Alkyl;
U and V can not have, or are CO, CR '
2, C (=CR
15 2), S (O)
n, O, NR
15, CR
15, OR
15, CR ' (OR ") CR '
2, CR '
2CR ' (OR "), C (O) CR '
2, CR
15 2C (O), CONR
15, NR
15CO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR
15, NR
15C (S), SO
2NR
15, NR
15SO
2, N=N, NR
15NR
15, NR
15CR
15 2, NR
15CR
15 2, CR
15 2O, OCR
15 2, C ≡ C, CR
15=CR
15, Het or Ar, condition is that U and V can have simultaneously;
W is R ' R " N-, R ' R " NR ' N-, R ' R " NR ' NCO-, R '
2NR ' NC (=NR ')-, R ' ONR ' C (=NR ')-,
W is
Q is NR ', O or S;
R
aBe H, C
1-6Alkyl, Ar-C
0-6Alkyl, Het-C
0-6Alkyl, or C
3-6Cycloalkyl-C
0-6Alkyl, halogen, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2
R
bAnd R
cBe selected from H independently of one another, C
1-6Alkyl, Ar-C
0-6Alkyl, Het-C
0-6Alkyl, or C
3-6Cycloalkyl-C
0-6Alkyl, halogen, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2, perhaps R
bAnd R
cIn conjunction with formation five or hexa-atomic aromatic ring or non-aromatic ring, and by halogen, C
1-4Alkyl, OR
1, SR
1, COR
1, OH, NO
2, N (R
1)
2, CO (NR
1)
2, CH
2N (R
1)
2, CN, or R " R ' NC (=NR ')-selection replaces;
X is N=CR ', C (O) or O;
Y can not have, or S or O;
Z is (CH
2)
t, Het, Ar or C
3-7Cycloalkyl;
M is 1 or 2;
N is 0,1,2 or 3;
Q is 0,1,2 or 3;
R is 0,1 or 2;
S is 0,1 or 2;
T is 0,1 or 2;
U is 0,1 or 2;
V is 0 or 1; With
W is 0 or 1.
2, according to the compound of claim 1, R wherein
6Be selected from:
, R " HNC (=NH) NH-(CH
2)
3(CHR
10)-U, and R " HN-(CH
2)
5-U wherein G is N or CH, R
20Be hydrogen, amino, one or two C
1-4Alkylamino, hydroxyl or C
1-4Alkyl, and U is NR ' CO, CONR ', (CH
2) CO, CH=CH, C ≡ C, CH
2O, OCH
2(CH
2)
2
3, according to the compound of claim 1, R wherein
6Be W '-(CR '
2)
q-U-; And W ' is
Q is NH; R
aBe C
1-6Alkyl, C
1-6Alkoxyl group, halogen or R ' NH; R
bAnd R
cIn conjunction with forming the cyclohexyl of selecting replacement, phenyl or pyridine ring; And U is (CH
2)
q-NR ' CO, (CH
2)
q-CH
2O or (CH
2)
q-CH
2CH
2
4, according to the compound of claim 1, this compound is
Wherein each group definition is with claim 1.
5, according to the compound of claim 4, X wherein
1-X
2Be CH
2-CH and X
3Be CH
2
6, according to the compound of claim 1, this compound is:
(±)-10, the methyl of 11-dihydro-3-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[1-(4,4 '-the Lian piperidyl) carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[3-(2-benzimidazolyl-)-1-propyl group]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[[[2-(2-pyridine amino) ethyl] amino] carbonyl]-5H-dibenzo [a, d] suberene-10-acetate;
(±)-10,11-dihydro-3-[3-(2-pyridine amino)-1-propoxy-]-5H-dibenzo [a, d] suberene-10-acetate; Or
The methyl of 2-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino-] carbonyl]-6,11-dihydro-5H-dibenzo [a, d] suberene-6-acetate.
7, pharmaceutical composition wherein contains the compound and the pharmaceutically acceptable carrier of claim 1.
8, the application of the compound of claim 1 in the medicine of preparation inhibition fibrinogen deceptor.
9, the application of the compound of claim 1 in the medicine of preparation inhibition Vitronectic receptor.
10, the compound of claim 1 is in preparation treatment Mammals sclerotin osteoporosis, the application in the medicine of the restenosis that atherosclerosis, cancer or postangioplasty cause.
11, the compound of claim 1 shows effect in preparation treatment apoplexy, instantaneous local asphyxia, the application in the inaccessible again medicine after myocardial infarction or the treatment of inhibition solution fibrin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96123837A CN1099416C (en) | 1996-12-28 | 1996-12-28 | Integrin receptor antagonists |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96123837A CN1099416C (en) | 1996-12-28 | 1996-12-28 | Integrin receptor antagonists |
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| Publication Number | Publication Date |
|---|---|
| CN1186806A CN1186806A (en) | 1998-07-08 |
| CN1099416C true CN1099416C (en) | 2003-01-22 |
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ID=5127699
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0325755A1 (en) * | 1987-12-14 | 1989-08-02 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
-
1996
- 1996-12-28 CN CN96123837A patent/CN1099416C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0325755A1 (en) * | 1987-12-14 | 1989-08-02 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
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