CN1209744A - Vitronectin receptor antagonists - Google Patents

Vitronectin receptor antagonists Download PDF

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Publication number
CN1209744A
CN1209744A CN96180113A CN96180113A CN1209744A CN 1209744 A CN1209744 A CN 1209744A CN 96180113 A CN96180113 A CN 96180113A CN 96180113 A CN96180113 A CN 96180113A CN 1209744 A CN1209744 A CN 1209744A
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methyl
carbonyl
benzimidazolyl
oxo
alkyl
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W·H·米勒
W·E·邦迪内尔
T·W·F·库
R·M·克南
J·M·萨马仁
C·克安
F·E·F·阿利
M·A·拉戈
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SmithKline Beecham Corp
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Abstract

Compounds of formulae (I-V) are disclosed which are vitronectin receptor antagonists and are useful in the treatment of osteoporosis.

Description

Vitronectic receptor antagonist
The field of the invention
The present invention relates to pharmaceutically active compound, they can suppress Vitronectic receptor and be used for the treatment of inflammation, cancer and cardiovascular disease, and for example absorbing again of atherosclerosis and restenosis and bone is the disease of a factor, for example osteoporosis.
Background of the present invention
Integrin is the superfamily of cell adhesion receptor, and they are the transmembrane glycoproteins of expressing on various cells.These cell surface adhesion receptors comprise gp II b/ III a, i.e. fibrinogen deceptor, and α vβ 3, Vitronectic receptor.Fibrinogen deceptor gp II b/ III a expresses at platelet surface, and it mediates hematoblastic gathering and forms hemostasis piece (Philips etc., Blood., 1988,71,831) in the wound location of bleeding.Vitronectic receptor α vβ 3Can express on various kinds of cell, described cell comprises endotheliocyte, smooth muscle cell, osteoclast and tumor cell, and therefore, it has multiple function.The α that on the cell membrane of osteoclast, expresses vβ 3The absorption process again of receptor-mediated bone also helps osteoporotic development (Ross etc., J.Biol.Chem., 1987,262,7703).The α that on the human aortic smooth muscle cell, expresses vβ 3The receptor for stimulating smooth muscle cell migration enters different inner membrance (neointima), and this will cause the formation (Brown etc., Cardiovascular Res, 1994,28,1815) of postangioplasty atherosclerosis and restenosis.In addition, the nearest α that studies show that vβ 3Antagonist can promote the degeneration (Brooks etc., Cell, 1994,79,1157) of tumor by the apoptosis (apoptosis) of the former blood vessel of induction of vascular.The reagent that therefore can hinder Vitronectic receptor can be used for the treatment of the disease of this receptor mediation, for example osteoporosis, atherosclerosis, restenosis and cancer.
Known Vitronectic receptor can be in conjunction with bone matrix protein, for example osteopontin, bone saliva liquid eggs white (sialoprotein) and glycoprotein G, and they contain tripeptides Arg-Gly-Asp (or RGD) feature structure.Therefore Horton etc. (Exp.Cell Res.1991,195,368) openly contains the RGD feature structure.Therefore Horton etc. (Exp.Cell Res.1991,195,368) openly contains absorption again and the cellular invasion that the polypeptide of RGD and the antibody of anti-Vitronectic receptor (23C6) can suppress tooth by osteoclast.Open echistatin of Sato etc. (J.CelL Biol.1990,111,1713) in addition, a kind of snake venom peptide (containing the RGD sequence) in tissue culture medium for bone absorb strong inhibitor again, and suppress osteoclast and adhere on the bone.Fisher etc. (Endocrinology1993,132,1411) prove that further echistatin suppresses the intravital bone resorption of rat.Bertolini etc. (J.Bone Min.Res, 6, Sup.l S146252) shows ring-S, S-N α-acetyl group cysteinyl--N α-methyl-arginyl--glycyl-asparagyl-penicillamine suppresses osteoclast and adheres on the bone.The phenyl derivatives that EP 528587 and 528586 reports replace, they can suppress the absorption again of the bone of osteoclast mediation.
Open part of compounds such as (EP0478328), Sugihara etc. (EP529858), Porter such as (WO93/00095), Blackburn etc. (WO95/04057), Egbertson such as (EP0540334), Blackburn etc. (WO93/08174), Bondinell such as Alig etc. (EP0381033), Hartman etc. (EP0542363) and Fisher (EP0635492), they are used to suppress fibrinogen deceptor.Have now found that the chemical compound that part suitably replaces is the strong inhibitor of Vitronectic receptor.Particularly, have been found that this compounds contains the fibrinogen deceptor antagonists template to stronger inhibitory action and this compounds of Vitronectic receptor comparison fibrinogen deceptor.
General introduction of the present invention
The present invention includes after this described formula I-(V) chemical compound and (X XI)-(X XII) chemical compound, they have the pharmacologically active that suppresses Vitronectic receptor and can be used for the treatment of inflammation, cancer and cardiovascular disease, for example atherosclerosis and restenosis, and the wherein disease that is absorbed as a factor again of bone, for example osteoporosis.
The present invention also provides the Pharmaceutical composition that contains formula I-(V) (X XI)-(X XII) and carrier pharmaceutically.
The present invention also provides the method for the disease of treatment Vitronectic receptor mediation.Particularly, chemical compound of the present invention is used for the treatment of atherosclerosis, restenosis, inflammation, cancer and its
The present invention describes in detail
The present invention includes new chemical compound, with respect to for fibrinogen deceptor, they are stronger inhibitor of Vitronectic receptor.Chemical compound of the present invention comprises the fibrinogen deceptor antagonists template, and this template is connected on nitrogenous 5 yuan of rings, and this ring is optional to condense with 6 yuan of rings of fragrance.The aliphatic substituent group that the fibrinogen deceptor antagonists template can be contained acid moieties replaces.The preferred covalent bond that 14 insertions are arranged approximately is present between the nitrogen of the acidic-group of fibrinogen deceptor antagonists template and optional condensed 5 yuan of rings by the shortest intramolecularly approach.
As used herein, term " fibrinogen deceptor antagonists template " means the core texture of fibrinogen deceptor antagonists, and described core is replaced by an acidic-group and is connected on the organic group that is partly replaced by basic nitrogen.Fibrinogen deceptor antagonists is an inhibitor, and it can suppress being connected of Fibrinogen and template bonded fibrinogen deceptor GP II b-III a.Purpose of the present invention is for being converted into Vitronectic receptor antagonist by the organic group that partly replaces with the nitrogen that can choose alkalescence on condensed nitrogenous 5 yuan of heterocycles (preferred imidazole ring, most preferably benzimidazole ring) replacement fibrinogen deceptor antagonists wantonly with fibrinogen deceptor antagonists.
The present invention includes formula I-(V) chemical compound or its pharmaceutically acceptable salt: Or
Figure A9618011300272
Or
Figure A9618011300273
Or Wherein:
W is-(CHR g) b-V '-or Ar;
A is the fibrinogen deceptor antagonists template;
V ' is CONR 21Or NR 21CO;
G is NR e, S or O;
R gBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl or Ar-C 0-6Alkyl;
R 21Be Het-C 0-6Alkyl-U '-C 1-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl-U '-C 1-6Alkyl or Ar-C 0-6Alkyl-U '-C 1-6Alkyl-;
U ' is CONR fOr NR fCO;
R fBe H, C 1-6Alkyl or Ar-C 0-6Alkyl;
R eBe H, C 1-6Alkyl, Ar-C 1-6Alkyl, Het-C 1-6Alkyl, C 3-7Cycloalkyl-C 1-6Alkyl, (CH 2) qOH or (CH 2) kCO 2R g
K is 0,1 or 2;
Q is 1 or 2;
B is 0,1 or 2;
R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 1-6Alkyl, halogen, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2(NR f) 2Or R bAnd R cIn conjunction with forming 5 yuan or 6 yuan of fragrance or non-aromatic carbocyclic or heterocycle, optionally be selected from halogen, CF by 3 of as many as 3, C 1-4Alkyl, OR f, S (O) kR f, COR f, CO 2R fOH, NO 2, N (R f) 2, CO (NR f) 2And CH (NR f) 2Or the substituent group of methylene-dioxy replaces.
The present invention also comprises formula (X XI)-(X XII) chemical compound or its pharmaceutically acceptable salt:
Figure A9618011300281
Or Wherein:
B is formula-(CHR g) a-U-(CHR g) bThe coupling part of-V-;
A is the fibrinogen deceptor antagonists template;
G is NR e, S or O;
R gBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl or Ar-C 0-6Alkyl;
R kBe R g,-C (O) R gOr-C (O) OR f
R iBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl-U '-C 1-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl-U '-C 1-6Alkyl or Ar-C 0-6Alkyl-U '-C 1-6Alkyl-or C 1-6Alkyl;
R fBe H, C 1-6Alkyl or Ar-C 1-6Alkyl;
R cBe H, C 1-6Alkyl, Ar-C 1-6Alkyl, Het-C 1-6Alkyl, C 3-7Cycloalkyl-C 1-6Alkyl, (CH 2) qOH or (CH 2) kCO 2R g
U, U ' and V independently do not exist or are CO, CR g 2, C (=CR g 2), S (O) k, O, NR g, CR gOR g, CR g(OR k) CR g 2, CR g 2CR g(OR k), C (O) C Rg 2, CR g 2C (O), CONR iNR iCOOC (O), C (O) O, C (S) O, OC (S), C (S) NR g, NR gC (S), S (O) 2NR g, NR gS (O) 2, N=N, NR gNR g, NR gCR g 2, NR 8CR g 2, CR g 2O, OCR g 2, C ≡ C, CR g=CR g, Ar or Het;
K is 0,1 or 2;
Q is 1 or 2;
A is 0,1 or 2;
B is 0,1 or 2;
R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2(NR f) 2Or R bAnd R cIn conjunction with forming 5 yuan or 6 yuan of fragrance or non-aromatic carbocyclic or heterocycle, can choose wantonly by 3 of as many as and be selected from halogen, CF 3, C 1-4Alkyl, OR f, S (O) kR f, COR f, CO 2R fOH, NO 2, N (R f) 2, CO (NR f) 2And CH 2(NR f) 2Or the substituent group of methylene-dioxy replaces.
Preferably, U ' is CONR fOr NR fCO.
The pharmaceutically acceptable addition salt of The compounds of this invention, complex or prodrug are also included among the present invention.Think that prodrug is any covalently bound carrier, can discharge the active parent drug of formula I in vivo.Except that specializing, when chemical compound of the present invention has one or more chiral centre, the present invention includes each non-racemoid, described chemical compound can synthesize or split with routine techniques.When chemical compound contained unsaturated carbon-carbon double bond, cis (Z) and trans (E) isomer were all within the scope of the present invention.When can there be tautomeric forms in chemical compound, ketoenol tautomerization body for example, as With
Figure A9618011300302
Think that each tautomer all is included in the scope of the present invention, and no matter whether exist balance still by R 1Suitable replacement sealing be a kind of form.
Formula I-(V) and (X XI)-(X XII) chemical compound suppresses vitronectin and other polypeptide that contains RGD and vitronectin (α vβ 3) connection of receptor.The inhibitory action of Vitronectic receptor suppresses the absorption again of the bone of osteoclast on the osteoclast, and is used for the treatment of the disease that absorbs relevant pathology again of bone, for example osteoporosis.In addition, because chemical compound of the present invention suppresses the Vitronectic receptor on the cell of number of different types, therefore described chemical compound can be owing to treatment inflammation and cardiovascular disease, for example atherosclerosis and restenosis, and as metastasis and antitumor agent.
In special embodiment, chemical compound of the present invention is formula II chemical compound, wherein R bAnd R cIn conjunction with forming the aromatic rings that contains 2 nitrogen-atoms of as many as.In preferred embodiments, R bAnd R cIn conjunction with form formula (phenyl ring of II chosen wantonly replacement a):
Figure A9618011300303
Wherein G is N-R c, S, CH or O.
The W that is fit to is-(CHR g) aNR iCO-or
Figure A9618011300311
Or when G is CH, W is-CH 2CH 2NR iDuring CO-, R wherein iFor being connected in the methylene of G.
Preferred W is-CHR gNR iCO-.
The R that is fit to iBe H, C 1-6Alkyl, C 3-7Cycloalkyl, Ar or be selected from halogen, CN, NR by one to three g 2, OR g, SR g, CO 2R g, CON (R g) 2, Ar, Het or C 3-7The C of cycloalkyl substituted 1-6Alkyl.Particularly, R 1Be H, methyl, butyl, cyano methyl, carboxyl methyl, phenylethyl or benzimidazole ylmethyl.
The R that is fit to x, R yAnd R zIndependently be selected from C 1-6Alkyl, methoxyl group, nitro, trifluoromethyl, fluoro, chloro, amino or R xAnd R yAdjacent and combination forms methylenedioxy group.
Preferred G is NR e
The R that is fit to eBe H, C 1-4Alkyl, Ar, Het or the C that is replaced by Ar or Het 1-4Alkyl.Be more suitable for R cBe H, methyl or benzimidazole ylmethyl.
In another special embodiment, R wherein bAnd R c6 yuan of aromatic rings that contain the formula (II b-d) of 1 to 2 nitrogen-atoms in conjunction with formation:
Figure A9618011300312
Wherein G, R x, R yAs (II definition a) of above-mentioned formula.
Particularly, chemical compound of the present invention contains nitrogenous condensed 5 yuan of rings, linking group W and the fibrinogen deceptor antagonists template A of choosing wantonly.Particularly, fibrinogen deceptor antagonists template A such as Bondinell etc. (WO93/00095, on January 7th, 1993 is open) defined inferior formula VI or its pharmaceutically acceptable salt:
A 1To A 5Form 7 yuan of rings of come-at-able replacement, described ring can be saturated or unsaturation, can choose wantonly and contain 2 hetero atoms that are selected from O, S and N of as many as, and wherein S and N can choose wantonly oxidized.
D 1To D 4Form 6 yuan of rings of come-at-able replacement, can choose wantonly and contain 2 nitrogen-atoms of as many as.
R is at least one and is selected from R 7, Q-C 1-4Alkyl, Q-C 2-4Alkenyl, Q-C 2-4The substituent group of alkynyl can be chosen wantonly by one or more=O, R 11Or R 7Replace;
R *Be H, Q-C 1-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 3-4Oxo alkenyl, Q-C 3-4Oxo alkynyl, Q-C 2-4Alkynyl, C 3-6Cycloalkyl, Ar or Het can choose wantonly by one or more R 11Replace;
Q is H, C 3-6Cycloalkyl, Het or Ar;
R 7For-COR 8,-COCR ' 2R 9,-C (S) R 8,-S (O) mOR ' ,-S (O) mNR ' R " ,-PO (OR ') ,-PO (OR ') 2,-B (OR ') 2,-NO 2And Tet;
R 8For-OR ' ,-NR ' R " ,-NR ' SO 2R ' ,-NR ' OR ' ,-OCR ' 2C (O) OR ' ,-OCR ' 2OC (O)-R ' ,-OCR ' 2C (O) NR ' 2, CF 3Or AA 1
R 9For-OR ' ,-CN ,-S (O) rR ', S (O) mNR ' 2,-C (O) R ' C (O) NR ' 2Or-CO 2R ';
R 11For H, halogen ,-OR 12,-CN ,-NR ' R 12,-NO 2,-CF 3, CF 3S (O) r,-CO 2R ' ,-CONR ' 2, Q-C 0-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 2-6Alkynyl, Q-C 0-6Alkoxyl, Q-C 0-6Alkyl amino-or Q-C 0-6Alkyl-S (O) r-;
R 12For R ' ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR 15,-S (O) mR ' or S (O) mNR ' 2
R 13For R ' ,-CF 3,-SR ' or-OR ';
R 14For R ' ,-C (O) R ', CN, NO 2, SO 2R ' or C (O) OR 15
R 15Be H, C 1-6Alkyl or Ar-C 0-4Alkyl;
R ' is H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R " be R ' ,-C (O) R ' or-C (O) OR 15
R " ' be R " or AA2;
AA1 is the aminoacid by its amino connection, and it is protected that its carboxylic group can be chosen wantonly, the aminoacid of AA2 for connecting by its carboxyl, and its amino group can be chosen wantonly protected;
M is 1 or 2;
N is 0 to 3;
P is 0 or 1; With
T is 0 to 2.
With reference to formula VI, be fit to,
A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S (O) x
A 2Be CR 2R 2 ', CR 2, NR 2
A 3Be CR 3R 3 ', CR 3, NR 3, N, O or S (O) x
A 4Be CR 4R 4 ', CR 4, NR 4Or N;
A 5Be CR 5R 5 ', CR 5, NR 5, N, O or S (O) x
D 1-D 4Be CR 11, CR 6Or N;
R 1And R 1 'Be R *Or R, perhaps be together=O;
R 2And R 2 'Be R *, R or=O;
R 3And R 3 'Be R *, R or=O;
R 4And R 4 'Be R *, R or=O;
R 5And R 5 'Be R *, R or=O; With
X is 0 to 2.
Be more suitable for A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S; A 2Be CR 2R 2 ', NR 2Or CR 2A 3Be CR 3R 3 'A 4Be CR 4R 4 ', CR 4, NR 4Or N; A 5Be CR 5R 5 ', CR 5, NR 5, N, O; D 1-D 4Be CH; R 2Or R 4Be R; R 3, R 3 'And R 5, R 5 'For=O or R *, H.
Preferably, A 1Be CHR 1, CR 1, NR ", N or S; A 2Be CR 2Or CR 2R 2 'A 3Be CR 3R 3 'A 4Be CR 4R 4 'Or NR 4A 5Be CR 5R 5 'And D 1-D 4Be CH.
In one embodiment, A 1Be CR 1, A 2Be CR 2, A 3Be C=O, A 4Be NR 4And A 5Be CHR 5
In another embodiment, A 1Be NR 1, A 2Be CHCR 2, A 3Be CR 3R 3 ', A 4Be NR 4And A 5Be C=O.
In another embodiment, A 1And A 4Be C=O, A 2Be NR 2, A 3Be CHR 3 'And A 5Be NR 5
In a preferred embodiment, A 1Be NR 1, A 2Be CHR 2, A 3Be C=O, A 4Be NR ' and A 5Be CHR 5
With following formula (a)-(VI i) each provides the representative of (VI) inferior formula to VI:
Figure A9618011300341
In an embodiment special embodiment of the present invention is named, wherein said fibrinogen deceptor antagonists template A belongs to inferior formula VI.
The preferred chemical compound of the present invention is following compounds or its pharmaceutically acceptable salt:
The methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1H-benzimidazolyl-2 radicals-glycine;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl) methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-(2-cyano methyl) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(4-phthalyl imino group butyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
4-[[[3-(propyl group of benzimidazolyl-2 radicals-yl)] amino] carbonyl] piperidines-1-acetic acid;
4-[[[3-(propyl group of benzimidazolyl-2 radicals-yl)] amino] carbonyl] phenylacetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-acetamide;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(5, the methyl of 6-difluoro benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-diaza _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-4-methyl-7-[[[(4-nitrobenzimidazole-2-yl] methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
The methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-the 3-phenylbutyric acid;
(±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-the 4-valeric acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[[1-(2-ethoxy) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1,4-benzo dihydro is assorted _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the amino benzimidazole of 5-tetrahydrochysene-7-[[[(4--2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid [(2,2-dimethyl-2-methoxyl group acetyl group) oxygen base] methyl ester;
2,3,4,5-tetrahydrochysene-7-[[[((1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
(±)-N-[2-(amino methyl)-4-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl] phenyl] aspartic acid;
(±)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(phenanthro-imidazoles-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
The methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-3-(dimethylamino carbonyl) butanoic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-the 2-acetas;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(2-carboxylbenzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate;
2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[[(±) the biotin acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(2RS)-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-5-[[2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) ammonia
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-(N-hydroxyl) acetamide;
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-ethyl valerate;
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-valeric acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1 R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid; With
(±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid.
Most preferred fibrinogen deceptor antagonists template is inferior formula (VI a), CR wherein 2R 2Be CHCH 2CO 2H, CR 3R 3 'Be C=O and CR 5R 5 'Be CH 2When the A-W-substituent group is connected in 3-oxo-2,3,4,5-tetrahydrochysene-1H-1, during the 7-position of 4-benzodiazepine _ loop systems, the fibrinogen deceptor antagonism is remarkable especially.
Except that specializing, in following formula for identical in substituent definition and formula I-(V) and (XX)-(the X XI).
Another embodiment of preferred fibrinogen deceptor template A is by 1 of inferior formula (VII), 4-benzodiazepine _ 2, and the 5-diketone is representative: Wherein:
Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2, methylene-dioxy, CN, CO 2R f, OC (O) R f, or NHC (O) R fWith
R hBe (CH 2) qCO 2R f
(WO93/08174, on April 29th, 1993 is open) such as Bondinell etc. (WO93/00095, on January 7th, 1993 is open) and Blackburn is described in detail the preparation and the application of this substructure when the fibrinogen deceptor antagonists of this Asia formula of preparation.
The table I has been summed up other preferred fibrinogen deceptor templates that the scope of the invention comprises below.These templates are:
Table 1
VIII)
Figure A9618011300401
Or Wherein: R 21And R 22Independent be H ,-Z-CO 2R fOr Z-CON (R f) 2, prerequisite is A 1Or A 2One of be-Z-CO 2R fOr Z-CON (R f) 2Z is-CH 2-,-O (CH 2) q-,-NR f(CH 2) q-,-S (CH 2) q,-CH 2CH 2-,-CH (CH 3) CH 2-,-(CH 2) 3-,-CH=CH-,-C (CH 3)=CH-, CH 2-CH=CH-or CH=CHCH 2Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2, methylene-dioxy or Z-COR f, at the EP0381033 of Alig etc. (August 8 nineteen ninety is open).(IX)
Figure A9618011300411
Wherein:
R 6Be aryl, C 1-10Alkyl, C 3-6Cycloalkyl, C 4-10Aralkyl, C 1-10Alkoxyalkyl, C 1-10Alkaryl, C 1-10Alkyl-thio-alkyl, C 1-10Alkoxyl alkylthio, C 1-10Alkyl amino, C 4-10Aryl alkyl amino, C 1-10Alkanoyl amino, C 4-10Aralkanoyl amino, C 1-10Alkanoyl, C 4-10Aralkanoyl or C 1-10Carboxyalkyl; With
Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2, methylene-dioxy, CN, CO 2R f, OC (O) R fOr NHC (O) R f, at Egbertson etc., EP is open on April 1st, 0478328,1992.(X) Wherein:
M 1Be CH or N;
M 2Be CH or N, prerequisite is for working as M 1During for CH, M 2Be N; And G ' is N or N _R ", at Eldred etc., EP0542363, on May 19th, 1993 is open.(XI)
Figure A9618011300422
Wherein:
M 1Be CH or N; With
M 2Be CH or N, prerequisite is for working as M 1During for CH, M 2Be N, at Porter etc., EP0537980, on April 21st, 1993 is open.(XII)
Figure A9618011300423
Wherein:
M 1Be CH or N;
Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2, methylene-dioxy, CN, CO 2R f, OC (O) R fOr NHC (O) R f
D 3Be CH 2Or C=O; With
R hBe (CH 2) qCO 2R f, at Klinnick etc., EP 0635492, and January 25 nineteen ninety-five is open.(X III)
Figure A9618011300431
Wherein:
Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2, methylene-dioxy, CN, CO 2R f, OC (O) R fOr NHC (O) R f
R hBe (CH 2) nCO 2R fAnd
Figure A9618011300432
Or
Figure A9618011300433
At Blackburn etc., WO95/04057, February 9 nineteen ninety-five is open.(X IV) Wherein:
L *Be-C (O) NR g-(CH 2)-,-C (O)-(CH 2) q-, NR g-(CH 2) q-,-O-(CH 2) q-, or S (O) k-(CH 2) q-,
At Hartman etc., EP is open on May 5th, 0540331,1993.(X V)
Figure A9618011300441
At Sugihara etc., EP is open on March 3rd, 0529858,1993.(X VI)
Figure A9618011300442
Wherein:
Y is H, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkoxy carbonyl, F, Cl, Br, I, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (RN f) 2, CH 2N (R f) 2, methylene-dioxy, CN, CO 2R f, OC (O) R fOr NHC (O) R f, at Himmeisbach etc., EP is open on May 6th, 0483667,1992.(X VII)
Figure A9618011300443
At Linz etc., EP is open on November 3rd, 0567968,1993.(X VIII)
Figure A9618011300444
Wherein:
R dBe Het-C 0-6Alkyl; With
Z ", Z " ' independent be hydrogen, C 1-4Alkyl, halogen, OR f, CN, S (O) kR f, COR fOr OH, at Bovy etc., EP is open on April 28th, 0539343,1993.
In an embodiment to containing the chemical compound name of the present invention of special fibrin original template.These embodiment are used to illustrate the present invention, and do not limit the scope of the invention.
Above-mentioned the description that is used for fibrinogen deceptor template of the present invention is derived from common unsettled publication application.Should be with reference to these patent applications open completely, comprise the described template of preparation and prepare the method for special chemical compound that it is for referencial use to be incorporated herein disclosing completely of these patent applications with described template.
The table II is described other fibrinogen deceptor antagonists below, and its core texture is used to implement the present invention.Should deliver thing with reference to other of the patent application of full disclosure and they, comprise the method that prepare described template and prepare the method for chemical compound specifically bind with described template, to deliver thing for referencial use with other to be incorporated herein the patent application of being annotated.Because think that being connected in any fibrinogen deceptor antagonists that can choose wantonly on condensed nitrogenous 5 yuan of rings has new utilizability described herein, therefore tabulation does not limit the scope of the invention down.
Table II Adir et CompagnieFR 928004, June 30,1992, Fauchere, J.L., et.al.EP 0578535.June 29,1993, Fauchere, J-L describes the X-RGDW-OH analog,
Wherein X contains cationic amine.CA 2128560, Jan.24,1995, Godfroid, J-J, the piperazine of replacement.Asahi Breweries, Ltd.JP 05239030, Sep.17,1993, amino methyl tetrahydroisoquinoline.Asahi GlassWO 90/02751, Ohba, M.et al.:Sept.8,1989: describe the cyclic polypeptide that contains RGD.WO 90/115950, Mar.22,1990, Ohba, M., et al.EP 0406428,1/9/91: describe the cyclic polypeptide that contains RGD.WO 92/09627, Isoai, A.et al.:Nov.29,1991: describe the cyclic polypeptide that contains RGD.Cassella?AGDE?4207254,(Der?93-289298/37)Mar.7,1992,Zoller,G.,et?al.：
Guanidine radicals propyl group-4-oxo-2-thiocarbamoyl imidazole alkane-3-base-Asp-X analog EP 93904010 is described, Feb.24,1993, Zoller, G., 4-oxo-2-thiocarbamoyl imidazole alkane derivatives.EP?0565896,Mar.18,1993,Klinger,O,et?al.：
GE phenoxy group acetyl group-Asp-X analog EP 0566919 is described, (Der 93-338002/43) Apr.3,1993, Zoller, G., et al.:
Guanidine radicals propyl group-4-oxo-2-thiocarbamoyl imidazole alkane-3-base-Asp-X-analog is described.EP 580008, (Der 94-027663/04) July 6,1993, Zoller, G., et al.: describe the 5-m-guanidino phenyl
-2,4-dioxo alkyl imidazole-3-yl) acetyl group-Asp-Phg.DE 224414, and July 6,1993, Zoller, G., et al.: describe 5-m-guanidino phenyl-2, the 4-dioxo alkyl imidazole
-3-yl) acetyl group-Asp-Phg.EP 584694, (Der 94-067259/09) Apr.2,1994, Zoller, G., et al.: describe the 5-m-guanidino phenyl
-2,4-dioxo alkyl imidazole-3-yl) acetyl group-Asp-Phg.DE 4301747, (Der 94-235891/29) Jul.28,1994, Zoller, G., et al.: describe the 5-m-guanidino phenyl
-2,4-dioxo alkyl imidazole-3-yl) acetyl group-Asp-Phg analog.DE 4308034, (Der 94-286666/36) Sept.15,1994, Klinger, O.et al.: describe the 5-m-guanidino phenyl
-2,4-dioxo alkyl imidazole-3-yl) acetyl group-Asp-Phg analog.DE 4309867, Sept.29,1994, Klingler, O, et al.: describe 5-m-guanidino phenyl-2,4-dioxo miaow
Azoles alkane-3-yl) acetyl group-Asp-Phg.ChironWO 93/07169, (Der 93-134382/16), Mar.15,1993, Deviin, J.J., et al.: describe RGD
Polypeptide.Ciba GeigyEP 0452210, (Der 91-305246/42) Apr, 5,1990, amino-alkane acyl group-GDF analog is described.EP 0452257, Mar.26,1991, Allen, M.C., et al.: describe amino-alkane acyl group Asp-Phe analog.COR TherapeuticsWO 90/15620, June 15,1990: describe the cyclic polypeptide that contains RGD.EP 0477295, Apr.1, and 1992:Scarborough, R.M.et al.WO 92/08472, May 29,1992, Scarborough, R.M.et al.WO 93/223356, April 27,1993, Swift, R.L., et al.: describe the cyclic polypeptide that contains RGD.EP?0557442,Sept.1,1993,Scarborough,R.M.,et?al.Scarborough,R.M.；Rose,J.W.；Hsu,M.A.；Phillips,D.R.；Fried,V.A.；
Campbell, A.M.; Nunnizzi, L.; Charo, I.F., Barbourin derives from Sistrurus
The endogenous antagonist of GP II b-III a specificity of M.Barbouri snake venom.
Biol.Chem., 266,9359,1991.Daiichi Pharm Co Ltd.JP 05078344-A, (Der 93-140339/17) Mar.30,1993: two amidino groups heterocycles are described,
Benzofuran for example.Dupont MerekWO 93/07170, Apr.15,1993: describe the cyclic polypeptide that contains RGD.WO 94/11398, and May 26,1994:Wells, and G.J.et al. describes the cyclic polypeptide that contains RGD.IL 109237, Jul.31, and 1994.WO 94/22909, (Der 94-333113/41) Oct.13,1994:DeGrado W.F., et al.WO 94/22910, (Der 94-333114/41 Oct.13,1994:DeGrado W.F., et al. prodrug WO 94/22494, (Der 94-332838/41) Oct.13,1994:DeGrado W.F., et al. cyclic peptide EP 625164, Nov.23,1994:Degrado, W.F., et al. cyclic peptide Mousa, S.A.; Bozarth, J.M.; Forsythe, M.S.; Jackson, S.M.; Leamy, A.; Diemer,
M.M.；Kapil,R.P.；Knabb,R.M.；Mayo,M.C.；Pierce,S.K.；al.,e.,
DMP728, a kind of antiplatelet of new platelet GP II b/ III a receptor antagonist and anti-
The blood coagulation effect.,Circulation,89,3,1994.Jackson,S.；DeGrado,W.；Dwivedi,A.；Parthasarathy,A.；Higley,A.；Krywko,J.；
Rockwell,A.；Markwalder,J.；Wells,G.；WexJer,R.；Mousa,S.；Harlow,R.,
-restricted template cyclic peptide: the design of the efficient binding partner of GP II b/ III a.
.J.Amer.Chem.Soc., 116,3220,1994.Ellem Ind Farma SpaGB 2207922, Aug, 3,1988, linear RGD analog is described.Farmitalia Erba SRL CarloEP 611765 (Der 94-265375/33), Aug 24, and 1994:Cozzi, P., et al. describe 5-(2-pyrazinyl methyl
-2-imidazoles-1-yl)-and 1-cyclohexyl ethylidene) amino oxygen base valeric acid.Fuji Photo FilmJP 04208296-A (Der.92-303598/38), Nov.30,1990, the RGD peptide is described.JP 04213311-A (Der.92-305482/38), Nov.27,1990, multicenter (multimeric) RGD is described
Peptide.JP 04217693-A, (Der 92-312284/38), Oct.23,1990, multicenter RGD peptide is described.JP 04221394-A (Der.92-313678/38), Oct.26,1990, multicenter RGD peptide is described.JP 04221395-A (Der.92-313679/38), Oct.26,1990, multicenter RGD peptide is described.JP 04221396-A (Der.92-313680/38), Oct.26,1990, multicenter RGD peptide is described.JP 04221397-A (Der.92-313681/38), Dec.20,1990, multicenter RGD peptide is described.EP 0482649 A2, April 29,1992, Kojima, M.et al.: describe the RGD peptide.EP 0488258A2, June 3,1992, Komazawa, H., et al: describe the RGD peptide.EP 503301-A2, Feb.14,1991, Kitaguchi, H.et al.: describe the RGD peptide.JP 05222092, and May 21,1993, Nishikawa, N., et al.: describe linear X-RGDS.JP 06239885, and (Der 94-313705/39), Aug 30,1993, Nishikawa, N.et al.: in how describing
Heart RGD peptide.WO 9324448, (Der 93-405663/50), Dec.9,1993, Nishikawa, N., et al.: in how describing
The heart is anti--contrary RGD peptide.JP 06228189, and (Der 94-299801/37), Aug.16,1994. describe the RGD peptide.EP 619118, (Der 94-311647/39), Oct.12,1994, Nishikawa, N.et al.: describe linear
The RGD peptide.FujisawaEP 0513675, and May 8,1992, N.Umekita, et al.: describe amidino groups
Phenoxy group alkanoyl-Asp-Val-OH analog .WO 9409030-A1, Apr.28,1994, Takasugi, H., et al.: describe amidino groups
Phenoxy group bytyry-Asp-Val-OH analog.EP 0513675, (Der 92-383589/47): describe amidino groups phenoxy group bytyry-Asp-Val analog.WO 9500502, Jan, and 5,1995, Oku, T., et al.: describe " aminopiperazine derivatives ".FR 144633:Thromb Haem.69,706,1993.Cox, D.; Aoki, T.; Seki, J.; Motoyama, Y.; Yoshida, K., Pentamidine: the non-peptide of specificity
GP II b/ III a antagonist, Thromb.Haem., 69,707,1993.GenentechWO 90/15072 (Der 91007159): describe and contain the RGD peptide.WO 91/01331 (Der 91058116), July 5,1990, P.L.Barker, et al.: describe and contain RGD
Cyclic peptide.WO 91/04247, Sept.24,1990, T.R.Webb: describe (guanidine alkylation) Pro-GD analog.WO 91/11458 (Der 91252610), Jan.28,1991, P.L.Barker, et al.: describe and contain RGD
Cyclic peptide.WO 92/07870, Oct.24,1991 J.P.Bumier, et al.: describe the cyclic peptide that contains RGD.WO 92/17492, Oct.15,1992, Burnier, J.P.et al.: describe the cyclic peptide that contains RGD.CA 2106314, Oct.6,1992, Burnier, J.P.et al.WO 93/08174, Oct.15,1991, B.K.Blackbum, et al.: describe 2,5-dioxo-1,4-benzo two
Azepine _.CA 2106314, Oct.6,1992, Burnier, J.P., et al.EP 0555328, Aug.18,1993, J.P.Burnier, et al.WO 95/04057, Feb.9,1995, Blackburn, B.K., et al.: be described in 1,2 contain heterocyclic 1,4-benzene
And diaza _.Scarborough,R.M.,Naughton,M.A.,Teng,W.,Rose,J.W.,Phillips,D.R.,
Nannizzi,L,Arfsten,A.,Campbell,A.M.,and?Charo,I.F.,J.Biol.Chem.
268,1066,1993.Dennis,M.S.；Henzei,W.J.；Pitti,R.M.；T.,L.M.；Napier,M.A.；Deisher,T.A.；
Bunting, S.; Lazarus, R. derives from the platelet glycoprotein II b-III a protein antagonist of snake venom:
The evidence of anticoagulant family,
,Proc.Natl.Acad.Sci.USA,87,2471,1989.Barker,P.L.；Bullens,S.；Bunting,S.；Burdick,D.J.；Chan,K.S.；Deisher,T.；
Eigenbrot,C.；Gadek,T.R.；Gantzos,R.；Lipari,M.T.；Muir,C.D.；Napier,
M.A.；Pitti,R.M.；Padua,A.；Quan,C.；Stanley,M.；Struble,M.；Tom,J.Y.
K.; Burnier, J., P. is as the ring RGD peptide analogues of antiplatelet anticoagulation thing.
, J.Med.Chem., 35,2040,1992.McDowell, R.S.; Gadek, T.R., the structural research of the RGD peptide of operative constraint.
, Amer.Chem.Soc., 114,9245,1992.GlaxoEP 537980, Oct.13,1992, B.Porter, et al.: describe 6 cis 4-[4-(4-amidino groups phenyl)
-1-piperazinyl]-1-hydroxyl Cyclohexaneacetic acid analog.EO 0542363, Nov.10,1992, Porter, B., et al.: describe 4-[4-amidino groups phenyl-Piperazine base]-piperidines
-1-acetic acid analogs.WO 93/22303, Jan.11,1993, Middleniss, D., et al.: describe amidino groups phenyl aryl piperazines second
Acid-like substance.WO 93/22303, Jan.11,1993, Middlemiss, D., et al.: describe amidino groups phenyl aryl piperazines second
Acid-like substance.WO 93/14077, Jan.15,1993, B.Porter, et al.: describe amidino groups phenylpiperazine phenylpiperidines-acetic acid class
Like thing EP 609282 Al, Aug.10,1994, Porter, B.et al.: describe Cyclohexaneacetic acid derivatives.EP 612313, Aug.31, and 1994, Porter, B., et al. describe α Alkylpiperidine acetogenin.EP 93911769, Apr.20,1994, Midlemiss, D., et al.EP 637304 Al, Feb.8,1995, Middlemiss, D., et al. piperazine acetogenin.Hann,M.M.；Carter,B.；Kitchin,J.；Ward,P.；Pipe,A.；Broomhead,J.；Hornby,E.；
Forster, M.; Perry, C. contains cyclic peptide and the snake venom peptide that suppresses human platelet aggregation
The investigation of the biological activity conformation of ARG-GLY-ASP,
In?Molecular?Recognition；
Chemical?and?Biochemical?Problems?Ⅱ＂,S.M.Roberts,Ed.,The?Royal
Society of Chemistry, Cambridge, 1992.Ross, the non-peptide fibrinoid of B.C. original receptor antagonist ", (SAR leadingto the
discovery?of?GR?144053),In?Seventh?RSC-SCI?Medicinal?Chemistry
Symposium,The?Royal?Society?of?Chemistry?Fine?Chemicals?and
Medicinals?Group?and?SCI?Fine?Chernicals?Group,Churchill?College,
Cambridge, 1993, L20.Pike, N.B.; Foster, M.R.; Hornby, E. J.; Lumley, P., fibrinogen deceptor antagonists
GR144053 vein and per os give behind Marmoset and the Cynomologous monkey at live body
Outer effect to platelet aggregation.
, Thromb.Haem., 69,1071,1993.HoechstDE 4009506, Mar.24,1990, Konig, W., et al.: the description hydantoin-(Arg-Gly)-Asp-X
Analog.Hoffmann-La RocheAU 9344935, (Der 94-118783/15), Mar.10,1994, ring RGD analog is described.EP 0592791, Apr.20,1994, Bannwarth.W.et al.: describe ring RGD analog.Kogyo GijutsuinJP 06179696, June 28,1994, Maruyarma, S., et al.: describe Gly-Pro-Arg-Pro-Pro and class
Like thing.Kyowa Hakko Kogyo KKJP 05078244-A, Mar.30,1993: describe dibenzo (b, e) oxepine derivant.Laboratoire ChauvinWO 9401456, Jan.20,1994, Regnouf, D.V.J.et al.: describe Ac-Arg-Gly-Asp-NHBn
Analog.La Jolla Cancer Res.FndnWO 9500544, Jan.5,1994, Pierschbacher, M.D.et al.US 079441, Jan 5,1994, Pierschbacher, M.D.et al.: describe the RGD peptide.Lilly/COREP?0635492,Jan.25,1995,Fisher,M.J.,Happ,A.M.,Jakubowski,J.A.,Kinnick,
M.D., Kline, A.D., Morin, Jr, J.M., Sall, M.A., Vasileff, R.T.: description has
6, the chemical compound of 6-template.Medical University of South CarolinaEP 587770, Mar.23,1994 Halushka, P.V., Spicer, K.M.MerckEP 0368486 (Der 90-149427/20), Nov.10,1988: describe the X-R-Tyr-D-Y analog.EP 0382451 (Der90248531): describe the RGD that contains the snake venom inhibitor.EP 0382538 (Der 90248420): describe the RGD that contains the snake venom inhibitor.EP 0410537, and July 23,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0410539, and July 25,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0410540, and July 25,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0410541, and July 25,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0410767, and July 26,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0411833, and July 26,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0422937, Oct.11,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0422938, Oct.11,1990, R.F.Nutt, et al.: describe the cyclic peptide that contains RGD.EP 0487238, and Octover 13,1991, T.M.Connolly, et al.: describe the linear peptides that contains RGD.EP 0437367 (Der 91209968), M.Sato et al.: the cyclic peptide that contains RGD is described, thin for breaking bone
The resorbent inhibitor of the bone of born of the same parents' mediation.EP 576898, Jan.5,1994, Jonczyk, A., et al.: describe linear RGD peptide analogues and be used for the cell suction
Attached inhibition.WO 9409029, Apr.28, and 1994, Nutt, R.F.and Veber, D.F. describes piperidyl
N-ethyl pyrrole N-alkyl acetyl group-Asp-Trp (tetrazolium).EP 618225, (Der94-304404/38) Oct.5, and 1994, be described as anti-RGD peptide class of moving chemical compound
Like thing.DE 4310643, and (Der 94-311172/39), Oct.6,1994, Jonczyk, A..et al.: be described as resisting
The ring RGD analog of migration agent.NO 9404093, Oct.27, and 1994, Jonczyk, A..et al.EP 0632053, Jan.4,1995, Jonczyk, A..et al.: the ring RGD analog that is described as anti-migration agent.EP 0479481, Sept.25,1991, M.E.Duggan et al.: describe the linear not exclusively peptide of X-GlyAsp-Y.EP 0478328, Sept.26,1991, M.S.Egbertson, et al.: describe tyrosine derivative.EP 0478362, Sept.27,1991 M.E.Duggan et al.: describe X-Gly-(3-phenethyl)
β Ala analog.EP 0478363, Sept.27,1991, W.L.Laswell, et al.: describe the tyrosine sulfonamide.EP 0512829, May, and 7,1992, Duggan, M.E., et al.: chirality 3-hydroxyl-6-(4-piperidyl) is described ,-
Heptanoyl group-β-X-β-Ala-OH analog changes on X and center chain alkyl chain.EP 0512831, May, 7,1992, Duggan, M.E., et al.: describe chirality 2-oxo-3-(piperidyl ethyl)
Piperidyl acetyl group-β-X-β-Ala-OH analog changes on X and center piperidine ring.EP 0528586, and August 5,1992, M.S.Egbertson, et al.: be described as osteoclast mediation
The tyrosine sulfonamide of the reuptake inhibithors of bone.EP 0528587, and August 5,1992, M.S.Egbertson, et al.: describe as osteoclast
The tyrosine sulfonamide of the reuptake inhibithors of the bone of mediation.EP 0540334, and October 29,1992, G.D.Hartman, et al.: describe benzimidazole US 5227490, Feb.21,1992, G.D.Hartman, et al.: describe tyrosine sulfonamide CA 2088518, Feb.10,1993, Egbertson, M.S., the aminoalkyl-phenyl derivatives of etla. bone resorption inhibitor.US 5206373-A, (Der93-151790/18) Apr.27,1993, Chug, J.Y.L., et al.: describe MK-
383-type chemical compound.WO 9316994, (Der 93-288324/36), Sep.2,1993, Chung, J.Y.L., et al.: describe pyridine radicals
Butyl-L-Tyr butyl sulfonamide.US 5264420-A, Nov.23,1993, piperidyl alkyl-Gly-β Ala analog is described.US 5272158, Dec.21, and 1993, Hartman, G.D.et al.: piperidyl is described
The different inole analog of ethyl.US 5281585, Jan.25, and 1994, Ihle, N., et al.: 3-(piperidyl ethyl)-piperidones analog is described.GB 945317 A, Mar.17,1994 (Priority US 34042A, Mar.22,1993) .GB 2271567 A, Apr20,1994, Hartman, G.D.et al.: describe with β succinic acid phenyl ester generation
Chemical compound for Tyr.US 5294616, (Der 94-091561/11) Mar.15,1994, Egbertson, M.S., et al.US 5292756, (Der 94-082364) Apr.8,1994, Hartman, G.D.et al.WO 9408577, Apr.28,1994, Hartman, G.D., et al.WO 9408962, Apr.28,1994, Hartman, G.D., et al.WO 9409029, (Der 94-151241/18) Apr.28,1994, Hartman, G.D., et al. describes piperidyl
Pyrrolinyl acetyl group-Asp-Trp-tetrazolium.US 5312923, and May 17,1994, Chung, and J.Y.L. et al.HU 9400249, May 30,1994, Gante, J.et al.: the piperazine analog is described.WO 9412181, and (Der 94-199942/24), Jun.9,1994, Egbertson, M.S.et al.: piperidyl is described
The ethoxyl phenenyl acetic acid analogs.US 5321034, and June 14,1994, Duggan, M.E., et al.: describe piperidyl alkyl beta amino acids.US 5334596, Aug.2,1994, Hartman, G.D.et al.EP 0608759 A, Aug.3,1994, GAnte, J.P.et al.: describe amidino groups piperazinyl chemical compound.WO 9418981, (Der 94-293975/36) Sep.1,1994, Claremon, D.A..et al.: describe various
Amine succedaneum together.GB?2276384,(Der?94-287743/36)Sep.28,1994,Claremon,D.A..,Liverton,N..,：
Piperidyl ethyl quinazoline analogs is described.WO 9422825, Oct.13, and 1994, Claremon, D.A..Liverton, N.J.: piperidyl is described
Ethyl-anti--benzodiazepine _ analog.EP?0623615A,Nov.9,1994,Raddatz,P.et?al：Describes
Mi base Ben Ji oxazolidinyl methyl-piperidines-4-carboxylic acid and analog thereof.WO?9504531,Feb.16,1995,Hartman,G?D.,et?al.：Describes
The piperidyl alkyl heterocycle.Nutt,R.F.；Brady,S.F.；Colton,C.D.；Sisko,J.T.；Ciccarone,T.M.；Levy,M.R.；
Duggan,M.E.；Imagire,I.S.；Gould,R.J.；Anderson,P.S.；Veber,D.F.,
Exploitation as the fibrinogen deceptor antagonists new, high selectivity of effective anticoagulant.
In?Peptides,Chemistry?and
Biology,Proc.12th?Amer.Peptide?Symp.,J.A.Smith?and?J.E.Rivier,Ed.,
ESCOM,Leiden,1992；914.Hartman,G.D.；Egbertson,M.S.；Halszenko,W.；Laswell,W.L.；Duggan,M.E.；
Smith,R.L.；Naylor,A.M.；Manno,P.D.；Lynch,R.J.；Zhang,G.；Chang,
C.T.C.; Gould, R.J., non-peptide fibrinoid original receptor antagonist.1.Exosite suppress
The discovery of agent and design.,J.Med.Chem.,35,4640,1992.Gould,R.J.；Barrett,S.；Ellis,J.D.；Holahan,M.A.；Stranieri,M.T.；Theoharides,
A.D.；Lynch,J.J.；Friedman,P.A.；Duggan,M.E.；Ihle,N.C.；Anderson,
P.S.; Hartman, G.D., L-703014, a kind of new fibrinogen deceptor antagonists, n
Evaluation after per os gives Canis familiaris L..,Thromb.
Haem., 69,539,1993.Merrell DowWO 93/24520, May 14,1993, Harbeson, S.L., et al.: describe ring RGD peptide.WO 9324520, Dec.9, and 1993, Harbeson, Bitonti, J., A.: the ring RGD peptide that is described as anti-migration agent.WO 9429349, Dec.22, and 1994, Harbeson, Bitonti, J., A.: the ring as the metastasis agent is described
RGD analog Nippon Steel CorpWO 9405696, Mar.17,1993, Sato, Y., et al .EP 628571, Dec.14,1994, Sato, Y.et al.WO 9501371, Jan.12,1995, Sato, Y.et al.: describe the RWSRGDW analog.ONO PharmaceuticalsJP 05286922 (Der 93-383035/48) describes guanidine radicals phenol benzoic acid alkyl ester.RocheEP 038,362, Feb.19,1990, M.Muller, et al.: describe X-NHCHYCO-Gly-Asp-NHC
HZCO 2The H analog.EP 0372486, June, and 13,1990, Allig, L., et al.EP 0381033, July, 8,1990, Allig, L., et al.EP 0384362, August 29,1990, Allig, L.et al.: the Gly-Asp-X that describes the connection of amidino groups phenyl is intact
Full peptide.EP0445796, Sept.11,1991, Allig, L.et al.: the Gly-Asp-X that describes the connection of amidino groups phenyl is intact
Full peptide.EP 0505868, Sept.30, and 1992, Allig, L.et al.: N-acetyl group-alpha amino acid derivant is described,
It is the analog that EP0381003 changes at the phenoxyacetic acid group.US 5273982-A, (Der 94-006713/01) Dec.28,1993: describe the Gly-Asp-X that the amidino groups phenyl connects
Incomplete peptide.Alig,L.；Edenhofer,A.；Hadvary,P.；Hurzeler,M.；Knopp,D.；Muller,M.；Steiner,
B.; Trzeciak, A.; Weller, T., low-molecular-weight, non-peptide fibrinoid original receptor antagonist
.Med.Chem., 35,4393,1992.Rhone-Poulenc RorerUS 4952562, Sept.29,1989, S.I.Klein et al.: describe the X-Gly-Asp-Val-OH analog.US 5064814, (Der 91-353169/48) Apr5,1990: describe piperidyl-azetidinyl-Asp-X-
Analog.WO 9104746, Sept.25,1990, S.I.Klein et al.: describe the X-Asp-Val-OH analog.WO 91/05562, Oct.10,1989, S.I.Klein et al.: describe the X-Gly-Asp-Val-OH analog.WO 91/07976, (Der 91-192965) Nov.28,1990, S.I.Klein et al.: describe X-ring AA-Asp-Val-OH analog.WO 91/04746, S.I.Klein et al.: describe the arginine RGD analog that deaminizes.WO 92/18117, Apr.11,1991, S.I.Klein et al.: describe the X-Asp-Val-OH analog.US 5086069, (Der 92-064426/08) Apr2, and 1992: the X-Gly-Asp-Val-OH analog is described.WO 92/17196, Mar.30,1992, S.I.Klein et al.: describe the X-Gly-Asp-Val-OH analog.
Analog.US 5328900, (Der 94-221950/27) Jul.12, and 1992: the X-azetidinyl is described
-Asp-Val-OH analog.US 5332726, (Der 94-241043/29) Jul.26, and 1994: guanidine radicals alkanoyl-(N-alkyl) Gly-Asp-Val-OH analog is described.WO 93/11759, Dec.7,1992, S.I.Klein et al.: describe biguanide phenylalkanoic acid analog.EP 0577775, and Jan 12,1994, Klein, S.I.et al.CA 2107088, Sept.29,1992, Klein, S.I.et al.SandozEP 0560730, Mar.8,1993 G.Kottirisch and R.Metternich: describe amidino groups benzene
Base alkanamid-S-α-acetic acid analogs.G.Kottirisch, et al.Biorg.Med.Chem.Lett 3,1675-1680,1993, amidino groups benzene is described
Base acetyl group-(Gly-Asp-γ propionic acid amide .-imitation) analog.Schering AGE 530937, Mar.10,1993, Noeski-Jungblut, C., et al. " coagulate by the inductive platelet of collagen protein
Collection inhibitor ".Searle/MonsantoEP 0319506, (Der 89-3195506) Dec.2,1988, S.P.Adams, et al.: describe the RGD-X analog.EP 0462,960, June, 19.1991, Tjoeng, F.S., et al.: describe guanidine radicals caprylyl-Asp-Phe analog.US 4857508, S.P.Adams, et al.: describe the RGD analog.EP 0502536, (Der 92-301855) Mar.3,1991, R.B.Garland, et al.: describe guanidine radicals benzene
Base alkanoyl-Asp-Phe analog.EP 0319506, Dec.2,1988, S.P.Adams et al.: describe the RGDX analog.US 4992463, Aug.18,1989: describe guanidine radicals alkanoyl-Asp-X analog.US 5037808, Apr.23,1990: describe guanidine radicals alkanoyl-Asp-X analog.EP 0454651 A2, Oct.30,1991, Tjoeng, F.S., et al.: describe amidino groups alkanoyl-Asp-X
Analog.US 4879313, July, 20,1988: describe guanidine radicals alkanoyl-Asp-X analog.WO 93/12074, Nov.19,1991, N.Abood, et al.: describe amidino groups phenyl alkanoyl-β-X-AlaOH
Analog.WO 93/12103, Dec.11,1991, P.R. Bovy, et al.: describe amidino groups phenyl alkanoyl-β-X-lactone
Analog.US 5091396, Feb.25,1992, Tjoeng, F.S., et al.: describe amidino groups alkanoyl-Asp-X analog.WO 92/15607, Mar.5,1992, Garland, R.B., et al.: describe amidino groups benzene
Base alkanoyl-Asp-X analog.WO 93/07867, Apr.29,1993, P.R.Bovy, et al.: describe amidino groups phenyl acylamino-propiono-β-X-AlaOH analog.US 888686, and May 22,1992, Bovy, P.R.et al.CA 2099994, Sept.7,1992, Garland, R.B., et al.US 5254573, Oct.6,1992, Bovy, P.R., et al.: describe amidino groups benzene
Base acylamino-propiono-β-X-β-Ala-OH analog.(PF54C06), EP 0539343, Oct.14,1992, P.R.Bovy et al.: describe amidino groups benzene
Base acylamino-propiono-β-X-β-Ala-OH.WO 93/12074, Nov.27,1992, N.A.Abood, et al.: describe amidino groups benzene
Base alkyl amino-(R)-Asp-(promptly trans-Asp) alkyl and aryl amide and sulfonamide.WO 93/12103, Dec.11,1992, P.R.Bovy et al.: describe amidino groups phenyl alkanoyl-Asp-X-lactone.EP 0 539343, Apr.28, and 1993, Bovy, P.R., et al.EP 0542708, May, 19,1993, Bovy.P.R., et al.WO 94/00424, June 23,1993, Abood, N.A., et al.: describe with previous
The amidino groups phenyl alkane acids lactone WO 93/16038 that chemical compound is relevant, Aug.16,1993, Miyano.M.et al.: describe amidino groups benzene
Base valeryl-beta-aromatic sulfoamido methyl-β-Ala-OH analog.WO 93US7975, Aug.17,1993, Zablocki, J.A., Tjoeng, F.S.WO 93/18058, Sept.16,1993, Bovy, P.R.et al.: describe amidino groups benzene
Base amide groups propiono-Asp-OH analog.US 5254573, Oct.19, and 1993, Bovy, P.R., et al. describes amidino groups phenyl propiono amino acid derivativges.US, 5272162, Dec.21,1993, Tjoeng, F.S., et al.: describe amidino groups phenyl-X-NHCO-β-Y-β-Ala-OH analog.EP 0574545, Dec.22,1993, Garland, R.B., et al.: describe amidino groups phenyl X-Asp analog.WO 9401396, Jan.20, and 1994, Tjoeng, F.S., et al. describes the amidino groups phenyl
The alkylamidoalkyl amino acid derivativges.WO 9405694, (Der 94-101119/12) Mar.17,1994, Zablocki, et al.: describe the amidino groups phenyl
The alkylamidoalkyl amino acid derivativges.US 5314902, and May 24,1994, Adams, S.P.et al.: describe the amidino groups phenyl
Amide groups alkanoyl derivant.WO 9418162, Aug, 18,1994, Adams, S.P., et al.: describe the amidino groups phenyl
The alkanoyl amino acid derivativges.WO 9419341, Sept.1,1994, Tjoeng, F.S., et al.: describe amidino groups phenyl nipecotic acid derivant.US?5344837,(Der?94-285503/35),Sept.6,1994,Zablocki,J.A.,et?al.EP?614360,Sept.14,1994,Bovy,P.R.,et?al.WO?9420457,(Der?94-302907/37)Sep.15,1994,Tjoeng,F.S.et?al.
Has the center ring amidinylphenyl compounds.WO?9421602,(Der?94-316876/39),Sept.29,1994,Tjoeng,F.S.,et?al.
Guanidine alkylation amino carbonyl amino acid derivative is described.WO 9422820, Oct.13,1994, Abood, N.A., et al.: describe the amidino groups phenyl
Pyrollidinonyl-β-Ala derivant.EP 630366, Dec.28,1994, Bovy, P.R., et al.US 5378727, Jan.3,1995, Bovy, P.R.et al.K.F.Fok, et al., Int.J.Peptide Prot.Res., 38,124-130,1991, the SAR of RGDY
Analog.J.A.Zablocki, et al.J.Med.Chem.35,4914-4917,1992, guanidine radicals alkanoyl
The SAR of-Asp-Phe analog sums up.Tjoeng,F.S.；Fok,K.F.；Zupec,M.E.；Garland,R.B.；Miyano,M.；Panzer-Knodle,
S.；King,L.W.；Taite,B.B.；Nicholson,N.S.；Feigen,L.P.；Adams,S.P.,
The peptide dummy of RGD order.In?Peptides,Chem.and?Biol.Proc.
12th?Amer.Peptide?Symp.,J.A.Smith?and?J.E.Rivier,Ed.,ESCOM,
Leiden,1992；752.Nicholson,N.；Taite,B.；Panzer-Knodle,S.；Salyers,A.；Haas,N.；Szalony,J.；
Zablocki,J.；Feigen,L.；Glenn,K.；Keller,B.；Broschat,K.；Herin,M.；
Jacqmin, P.; Lesne, M., Orally active glycoprotein antagonist SC-54684
Thromb.Haem.,69,975,1993.SmithKline?Beecham?CorporationWO?93/00095,WO?94/14776,and?WO?95/18619,Bondinell,et?al.,
(6,7) bicyclic fibrinogen template is described.WO 94/12478, Keenan, and et al.,, (6,5) bicyclic fibrinogen template is described.WO 94/22440, Callahan, and et al. describes (8,6) bicyclic fibrinogen template.WO 94/22444, Callahan, and et al. describes (8,6,7) bicyclic fibrinogen template.WO 94/29273, Samanen, and J. describes (6,6) bicyclic fibrinogen template.Sumitomo Pharm.Co.Ltd.WO 9501336, June 6,1994, Ikeda, Y., et at. describes piperidyl oxygen base acetyl group-Tyl-
Piperidyl ethoxyacetic acid derivant.Sumitomo Seiyaku KK.JP 06025290, (Der 94-077374/10) Feb.1,1994. describe multicenter RGDT Taisho Pharm. (Teijin, Ltd) JP 05230009, (Der 93-317431/40, Feb.24,1992: describe aminoacrylic acid phenyl ester between amidino groups-Cbz-.JP 9235479, Feb.24,1992: describe the amidino groups phenyl carbamate.(PFD4C06),WO?94/17804,Aug.18,1994,Mizushima,Y.
The Pharmaceutical composition of treatment cerebellum blood coagulation.(EP 634171), Jan.18,1995, Nizushima, the Pharmaceutical composition of M. treatment cerebellum blood coagulation.
ProstaglandinsTakedaEP 0529858, Apr.3,1993, H.Sugihara, et al.: describe amidino groups benzoyl-Gly-piperazine keto analog.EP 606881, Jul.20, and 1994, have the cyclic peptide that β and γ change.EP 614664, Sept.14,1994, Miyake, A., et al: as the quinolonecarboxylic acid of cell adhension inhibitors.TanabeWO 89/07609, T.J.Lobl, et al.: describe the RGD analog.WO 92/00995, and July 9,1991, T.J.Lobl, et al.: describe ring RGD analog.WO 93/08823, Nov.6,1991, T.C.McKenzie: describe guanidine radicals alkanoyl-Gly-Asp-X-
Analog.CA 2087021, and Jan 10,1991, Lobl, T.J., et al: describe ring RGD analog.WO 92/O8464, Nov.15,1991, T.C.McKenzie, et al.: describe.Telios/La?Jolla?Cancer?ResearchUS.4578079,Nov.22,1983,E.Ruoslahti,and?M.Merschbacher：
The X-RGD-Y analog is described.US.4614517,June?17,1985,E?Ruoslahti,and?M.Pierschbacher：
The X-RGD-Y analog is described.US.4792,525,June?17,1985,E?Ruoslahti,and?M.Pierschbacher：
The X-RGD-Y analog is described.US 4879237, (Der 90-154405/20) May, and 24,1985, the X-RGD-Y analog is described.WO 91/15515, (Der 91-325173/44) Apr.6, and 1990, ring RGD analog is described.US.5041380,1991, E.Ruoslahti, and M.Pierschbacher: describe the RGD-X analog.WO?95/00544?Jan.5,1995,Craig,W.S.,et.al.Cheng,S.；Cfaig,W.S.；Mullen,D.；Tschopp,J.F.；Dixon,D.；Pierschbacher,M.
F., as efficient and selectivity beta 2 integrin alpha II bβ 3Antagonist new contains the RGD cyclic peptide
Design and synthetic.J.Medicin.Chem.,
37,1,1994.Collen,D.；Lu,H.R.；Stassen,J.-M.；Vreys,I.；Yasuda,T.；Bunting,S.；Gold,H.K.,
In the animal model of platelet-mediated Blood clotting, has synthetic platelet GP II b/ III a
The prolongation in inhibitor blood coagulation resisting function and bleeding time,
Thrombosis and Haemostasis, 71,95,1994.Temple U.WO 9409036, (Der 94-151248/18), and Apr.28,1994, non-integrin peptide Terumo KKJP 6279389 is described, Oct.4,1994, Obama, H., et al.:.
3-(4-amidino groups phenoxymethyl) phenyl amide base propanoic acid analog alogs (ala Roche I-is described
35) .Karl Thomae/Boehringer IngelheimEP 0483667, May 6,1992, Himmelsbach, F., et al.: description amidino groups xenyl oxygen ylmethyl-
-2-Pyrrolidone acetic acid.EP 0496378, Jan.22, and 1992, Himmelsbach, F., et al.: description amidino groups xenyl amino carbonyl-
Cyclohexyl carboxyl analog.EP 0503548, Sep.16, and 1992, Himmelsbach, F., et al.: description amidino groups Phenylpyrrolidine ketone-
The phenylpropionic acid analog.AU A-86926/91, May7,1992, Himmelsbach, F.et al.: describe amidinylphenyl compounds.EP 0528369, Feb.24,1993, Austel, V., et al.: describe amidino groups xenyl oxygen ylmethyl-2-
Ketopyrrolidine acetic acid.EP 0537696, Apr.21,1993 Linz, G., et al.: describe amidino groups phenyl pyridazine analog.DE 4124942, Jan.28,1993, Himmelsbach, F.et al.: describe amidino groups triaryl propanoic acid analog.DE 4129603, Mar.11,1993, Pieper, H, et al.: describe amidino groups xenyl benzimidazole.EP 0547517 A1, (Der 93-198544) June 23,1993, Soyka, R., et al.: describe pyridinyl compounds.EP 0567966, Nov.3,1993, Himmelsbach, F., et al.: describe amidino groups xenyl oxygen ylmethyl
-2-Pyrrolidone acetic acid.EP 0567967, and Nov.3 1993, Weisenberger, and J., et al.: description amidino groups xenyl oxygen ylmethyl-
-2-Pyrrolidone acetic acid.EP 0567968, Nov.3,1993, Linz, G., et al.: describe amidino groups xenyl-lactams-acetic acid and
Amidino groups phenyl lactams phenylpropionic acid analog.EP 0574808, and June 11,1993, Pieper, H., et al.: describe amidino groups-X-biphenyl acetic acid ester analogs.Der 93-406657/51, Austel, V.., et al.; Amidino groups xenyl analog EP 587134 is described, (Der 94-085077/11) Mar.16,1994, Himmerlsbach, F.D.D., et al.,
Amidino groups Phenyltriazole keto analog is described.EP?589874,Apr.6,1994,Grell,W.,et?al.(P534005),DE?4234295,Apr.14,1994,Pieper,H.,et?al.,
Heteroaryl piperidyl carboxylic acid analog is described.EP 0592949, Apr.20, and 1994, Pieper, H.D., et al. describes amidino groups phenyl-4-piperidines amide
Base-4-cyclohexane carboxylic acid analog.EP?596326,May,11,1994,Maier,R.et?al.DE?4241632,June?15,1994,Himmelsbach,F.,et?al.,
Piperidino phenyl amide groups phenyl propiono analog is described.EP?0604800?A,Jul.6,1994,Himmelsbach,F.et?al.,
Piperidino phenyl amide groups Phenylalamine derivatives is described.DE 4302051, (Der 94-235999/29) July, and 28,1994, the chemical compound that contains 2H-pyrazoles-5-ketone is described.EP 0608858 A, Aug, 3,1994, Linz, G.D., et al. describes the amidino groups biphenyl compounds.DE 4304650, and (Der 94-256165/32), Aug, 18,1994, Austel, V., et al., description has
The chemical compound of 5,6 templates.EP 611660, Aug, and 24,1994, Austel, V., et al. describes three ring templates.DE?4305388,(Der?94-264904/33),Aug.25,1994,Himmelsbach,F.,et?al.,
6,6 and 7,6 templates are described.(P5D4005),EP?612741,(Der?94-265886/33),Aug.31,1994,Himmelsbach,F.,et
Al., 6,6 and 7,6 templates are described.EP 0639575 A, Feb.22,1995, Linz, G., et al.: describe also [5,4, c] pyridine sun of tetrahydro-thiazoles
The ion substitution thing.DE?4324580,Jan.26,1995,Linz,G.et?al.EP?0638553,Feb.15,1995,Himmelsbach,F.,et?al.F.Hiummelsbach,V.Austel,G.Kruger,H.Pieper,H.Weisenberger,T.H.Muller,
and?W.G.Eisert,in?ⅩⅡth?Int.Symp.on?Med.Chem.Basel,Book?of
Abstracts,47,1992.V.Austel,W.Eisert,F.Himmelsbach,G.Kruger,G.Linz,T.Muller,H.Pieper,and
J.Weisenberger,Natl.Mtg.Amer.Chem.Soc.Book?of?Abstracts,Denver,
Div.Med.Chem.,1993.Muller,T.H.；Schurer,H.；Waldmann,L.；Bauer,E.；Himmelsbach,F.；Binder,K.,
Orally Activity of BIBU 104, the non-peptide fibrinoid original receptor in mice and monkey
Antagonist BIBU52 prodrug, Thromb.Haem., 69,
975,1993.Univ.CaliforniaWO 94/14848, July, and 7,1994, Zanetti, M derives from the RGD peptide of CDR.Univ.New YorkWO 94/00144, June 29,1993, Qjima, I.et al.: describe the many bodies of RGD peptide.Yeda Res.and Dev.Co.WO 93/09795, (Der 93-182236/22), Lido, O.et al.: describe guanidine radicals valeric acid analog.ZenecaWO 9422834, Oct.13, and 1994, Wayne, M.G., et al. describe pyrido piperazine and phenyl carbonylamino acid.WO 9422835, Oct.13, and 1994, Wayne, M.G.,, et al. describes pyrido piperidines amide groups phenylacetic acid.EP?632016,Jan.4,1995,Brewster,A.G..,et?al.
Pyrido propiono diazanyl benzoyl analog is described.EO?632019,Jan.4,1995,Brown,G.,Shute,R.E.EO?632020,Jan.4,1995,Brown,G.,Shute,R.E.
Except that specializing, when chemical compound of the present invention has one or more chiral centre, the present invention includes each non-racemic chemical compound, these chemical compounds can the synthetic and fractionation with routine techniques.When chemical compound had unsaturated carbon-carbon double bond, cis (Z) and trans (E) isomer all belonged to scope of the present invention.Any in either case substituent meaning does not rely on the meaning of itself, or any in another case substituent meaning.
Be used in peptide and normally used abbreviation of chemical field and denotational description chemical compound of the present invention at this.Generally speaking, amino acid abbreviations is followed Eur.J.Biochem, 158,9 (1984) described IUPAC-IUB Joint Commission on Biochemical Nomenclature.
C used herein 1-4Alkyl refers to the alkyl group of the optional replacement of 1-4 carbon atom, comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group and the tert-butyl group.C 1-6Alkyl comprise in addition amyl group, n-pentyl, isopentyl, neopentyl and hexyl with and simple aliphatic isomeric compound.C 0-4Alkyl and C 0-6Alkyl shows that in addition there be (for example having covalent bond) in no alkyl.
Any C 1-4Alkyl or C 1-6Alkyl, C 2-6Alkenyl, C 2-6Alkynyl or C 1-6Oxoalkyl group can be chosen wantonly by R xReplace, described substituent group can and can be obtained by the synthetic technology of routine on any carbon atom that produces rock-steady structure.R xThe group that is fit to comprises C 1-4Alkyl, OR ', SR ', C 1-4Alkyl, C 1-4Alkyl sulphonyl, C 1-4Alkyl sulphoxylic acid base ,-CN, N (R ') 2, CH 2(R ') 2,-NO 2,-CF 3,-CO 2R ' ,-CON (R ') 2,-COR '-NR ' C (O) R ', OH, F, Cl, Br, I, N 3Or CF 3S (O) r-, wherein r is 0-2.
Ar used herein or aryl refer to phenyl, or naphthyl or be selected from the phenyl or naphthyl that following substituent group replaces by to three: the as above defined C of alkyl for example 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkylthio group, three fluoro-alkyls, N 3, OH, CO 2H, F, Cl, Br or I.
Het or heterocycle refer to choose wantonly 5 or 6 yuan of monocyclic rings of replacement, contain one to three heteroatomic 9 or 10 yuan of dicyclo that are selected from nitrogen, oxygen and sulfur, and described ring is stable and can be obtained by the chemosynthesis of routine.Heterocyclic example comprises benzofuran, benzimidazole .alpha.-5:6-benzopyran, benzothiophene, biotin, furan, imidazoles, indoline, morpholine, piperidines, piperazine, pyrroles, pyrrolidine, pyridine, tetrahydropyridine, pyridine, thiazole.Thiophene.Quinoline.Isoquinolin and tetrahydrochysene and perhydrogenate quinoline and isoquinolin.Any three substituent combinations of feasible as many as on the Het ring, for example defined that can be obtained by chemosynthesis and the stable substituent group of abovementioned alkyl all belongs to scope of the present invention.
C 3-7Cycloalkyl refers to choose wantonly the carbon-loop system of 3-7 carbon atom of replacement, and it can contain two unsaturated carbon carbon bonds of as many as.C 3-7The typical example of cycloalkyl is cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group and suberyl.Can obtain by the chemosynthesis of routine and three substituent combinations of stable any as many as on cycloalkyl ring, for example abovementioned alkyl is defined all belongs to scope of the present invention.
Work as R bAnd R cIn conjunction with forming 5 or 6 yuan of fragrance or non-aromatic carbocyclic or and R bAnd R cDuring the ring condensed heterocycle that connects, the ring of formation is generally and is selected from 5 or 6 yuan of listed heterocycles of above-mentioned Het or is phenyl, cyclohexyl or cyclopenta ring.Preferred R bAnd R cFor-D1=D2-D3=D4, wherein D1-D4 independently is CH, N or C-R x, prerequisite is to be no more than two among the D1-D4 to be N.Most preferably, work as R bAnd R cIn conjunction with the time, their formation-CH=CH-CH=CH-.
The abbreviation of part group is as follows.T-Bu refers to tertiary butyl groups, and Boc refers to the tert-butoxycarbonyl group, and Fmoc refers to the fluorenyl methoxy carbonyl group; Ph refers to phenyl group; Cbz refers to the benzyloxycarbonyl group, and BrZ refers to adjacent bromo benzyloxycarbonyl group, and CIZ refers to adjacent chloro benzyloxy carbonyl group; Bzl refers to benzyl group; 4-MBzl refers to 4-methyl-benzyl group, Me fingernail base, and Et refers to ethyl; Ac refers to acetyl group, and Alk refers to C 1-4Alkyl, Nph refer to 1-or 2-naphthyl and chex finger ring hexyl.Tet refers to the 5-tetrazole radical.
The abbreviation of part reagent is as follows.DCC refers to dicyclohexylcarbodiimide, and DMAP refers to dimethyl aminopyridine, and DIEA refers to diisopropylethylamine, and EDC refers to 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.HOBt refers to I-hydroxybenzotriazole, and THF refers to oxolane, and DIEA refers to diisopropylethylamine; DME refers to dimethoxy-ethane, and DMF refers to dimethyl formamide, and NBS refers to N-bromosuccinimide; Pd/C refers to palladium carbon catalyst; PPA refers to 1-propane phosphonic acid cyclic acid anhydride, and DPPA refers to diphenyl phosphoryl azide, and BOP refers to benzotriazole-1-base oxygen base-three (dimethyl-amino) hexafluorophosphoric acid phosphorus; HF refers to Fluohydric acid.; TEA refers to triethylamine, and TFA refers to trifluoroacetic acid, and PCC refers to chloro chromic acid pyridine.
Preparation formula I-(V) chemical compound, for example by formula (X IX) chemical compound and formula (XX) chemical compound being reacted with the method known to general in this area, L wherein 1And L 2Be to be reflected at the group that W partly forms covalent bond.
Figure A9618011300681
Typical method comprises that coupling forms amido link, nucleophilic displacement reaction and palladium catalyzed coupling.For example, when W contains ether or amine connection, can form key by displacement reaction, L 1And L 2One of contain amino or hydroxyl and another contains the displacement group, for example chlorine, bromine or iodine group.When W contains amido link, general L 1And L 2One of contain amino group, another contains hydroxy-acid group.On the other hand, L 1Can be aryl or heteroaryl bromide, iodide or trifluoromethyl sulfonyl oxygen radical derivative, L 2Can contain amino group, can for example form amido link by palladium catalytic amino carbonylation and carbon monoxide in dimethyl formamide or the toluene in appropriate solvent.
L clearly 1And L 2Identity depends on the position that key forms accurately.Preparation key-(CHR ") described r-U-(CHR ") sThe conventional method of-V-for example in EP-A0372486 and EP-A0381033 and EP-A0478363, is incorporated herein for referencial use.
For example, if V is CONH, L 1Can be-NH 2, L 2Can be OH (as in acid) or Cl (as in acyl chlorides), and R 6 "Can for W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) s-C (O), any functional group can be chosen wantonly protected.For example, R 6 "Can be (benzyloxycarbonyl-amidino groups) benzoyl-or (N α-Boc, N Guan-Tos) arginyl--.Work as L 2During for OH, use coupling reagent.
Equally, if V is NHCO, L 1Can be-CO 2H or CO-Cl, L 2Can be-NH 2, R 6 "Can for W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) s-.R for example 6 "Can for (benzyloxycarbonyl-amidino groups) phenyl, (benzyloxycarbonyl amino) methyl-benzyl-or 6-(benzyloxycarbonyl amino) hexyl-.
When V is NHSO 2The time, L 1Can be SO 2Cl, L 2Can be-NH 2And R 6" can be as above-mentioned.When V is SO 2During NH, L 1Can be-NH 2, L 2Can be SO 2Cl.The method that openly prepares this sulfonyl chlorine is for example at J.Org.Chem., in 23,1257 (1958).
If V is CH=CH, L 1Can be-CHO, L 2Can be CH=P-Ph 3And R 6 "Can for W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) s-.Perhaps L 1Can be CH=P-Ph 3, L 2Can be CHO, as R 6 "Can for W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) S-1-CHO.
Can be CH by chemical compound (wherein V is CH=CH) the acquisition V of reduction due care 2CH 2Chemical compound.
When V is CH 2O, CH 2When N or C ≡ C, L 1Can be respectively-OH ,-NH or-C ≡ CH; L 2Can be-Br; R 6 "Can for W-(CR ' 2) q-Z-(CR ' R 10) r-U-(CR ' 2) s-.R for example 6 "Can be (benzyloxycarbonyl amino)-methyl-benzyl-or 2-(N-benzyl-4-piperidyl)-ethyl.Equally, when U or V be OCH 2, NR ' CH 2Or during C ≡ C, L 1Can be-CH 2Br, L 2Can be respectively-OH ,-NH or-C ≡ CH.Perhaps, when U or V are C ≡ C, L 1Can be Br, I, CF 3SO 3, L 2Can and can use palladium and base catalysis coupling for C ≡ CH.
Can pass through J.Org.Chem, 54,1354 (1989) disclosed methods are wherein V=CH of CH=CH compound by the wherein V of due care 2The CHOH chemical compound.
Can pass through Tet.Lett, 31,231 (1990) disclosed methods prepare wherein V=CHOHCH by the chemical compound (wherein V is CH=CH) of due care 2Chemical compound.
By method well known in the art, (J.Het.Chem, 1988,25,1173): Muller etc. (Helv.Chin.Acta, 1982,65,2118) such as Hynes for example; The condensed loop systems of 6-7 of the core of Mori etc. (Heterocycles, 1981,16,1491) preparation formula VI chemical compound.Equally, known and open, for example in (International Patent Application WO 93/00095) such as Bondinell, phenylpropyl alcohol azepine _ 1, the 4-benzothiazepine _, 1,4-benzo oxygen azepine _ and 1, the 4-benzodiazepine _ preparation method.
Following flow process describes the preparation of The compounds of this invention in detail.
The flow process I A) EtOAc/LiN (TMS) 2, THF; B) Et 3SiH, BF 3OEt 2, CH 2Cl 2C) H 2, 10%Pd/C, EtOH; D) EtSH, AlCl 3, CH 2Cl 2E) Tf 2O, 2,6-lutidines, CH 2Cl 2F) CO, KOAc, Pd (OAc) 2, dppf, DMSO; G) 2-(methylamino methyl) benzimidazole dihydrochloride, EDC, HOBtH 2O, (i-Pr) 2NEt, CH 3CN; H) 1.0N NaOH, EtOH.
Make the deoxybenzoin of suitable replacement, 2-(4-methoxyphenyl)-1-phenyl ethyl ketone (Chem.Ber for example, 1958,91,755-759) enolate with ethyl acetate (can make ethyl acetate be exposed to suitable amide alkali, for example diisopropyl lithamide (LDA) or two (trimethyl silane) lithamide (LiN (TMS) 2) carry out aldehyde alcohol type condensation reaction and obtain I-2.Often select the solvent of THF, although for example also use THF in the presence of HMPA or the TMEDA at various other materials as aldol reaction.I-2 and triethyl silicane (Et 3SiH) at boron fluoride etherate (BF 3.OEt 2) reduction reaction that exists down conventional method according to Orphanopoulos and Smonu (Synth.Commun.1988,833) to carry out uncle's benzylalcohol obtains I-3 and by the product of the β-deutero-alkene of elimination of alcohol.Can use palladium catalyst, for example for example in methanol, ethanol or the ethyl acetate, hydrogenation is converted into I-3 with the product of alkene to the palladium metal on the active carbon (Pd/C) easily at suitable atent solvent.Can be at the Lewis acid catalyst, preferred aluminum trichloride (anhydrous) (AlCl 3) exist down, for example obtain I-4 by the methyl ether of removing I-3 with the reaction of mercaptan (EtSH) in the dichloromethane at atent solvent.Other methods of removing methyl ether are disclosed in Greene " Protective Groupsin Organic Synthesis " (Wiley-Interscience publication).At suitable non-nucleophilic amine alkali for example 2, the 6-lutidines exists down, atent solvent be generally in the dichloromethane by with trifluoromethanesulfonic acid anhydride (Tf 2O) reaction is converted into pure I-4 its triflate I-5.At potassium acetate, 1,1 '-two (diphenylphosphine) ferrocene (dppf) and palladium catalyst, for example acid chloride (Pd (OAc) 2) exist down, in appropriate solvent, among the preferred DMSO, make I-5 and carbon monoxide (CO) reaction carry out the carboxylated of trifluoromethanesulfonic acid aromatic ester according to the method among Cacchi and the Lupi (Tet.Lett.1992,33,3939).With for example EDC and HOBT or SOCl 2, the benzoic derivatives I-6 that produces is converted into the activatory form of carboxylic acid, make its activated form and suitable amine subsequently, 2-(methylamino methyl) tolimidazole dihydrochloride for example is at appropriate solvent for example DMF, CH 2Cl 2Or CH 3Reaction obtains I-7 among the CN.Depend on whether need neutralizing acid, can add for example diisopropylethylamine ((i-Pr) of alkali 2NEt) or pyridine.The known multiple other method that carboxylic acid can be converted into amide, can for example find among " Compendium of Organic Synthetic Methods " the I-VI volume (publishing) or the Bodansky " The Practice of Peptide Synthesis " (publishing) at the handbook of standard by Springer-Verlag by Wiley-Intersciene.Use aqueous alkali, for example Lithium hydrate makes the ethyl ester hydrolysis of I-7 at THF aqueous solution or sodium hydroxide in methanol or ethanol water, and for example TFA or hcl acidifying intermediate carboxylate obtain carboxylic acid I-8 with suitable acid.Perhaps, if desired can the separation of intermediates carboxylate or prepare free carboxy acid's carboxylate by method well known to those skilled in the art.
The flow process II A) isobutene., TfOH, CH 2Cl 2B) acrylic acid methyl ester., Pd (OAc) 2, P (tol) 3, (i-Pr) 2NEt, propionitrile e; C) H 2, 10%Pd/C, MeOH, EtOAc; D) 1.0N LiOH, THF, H 2O; E) dimethyl amine hydrochlorate, EDC, HOBtH 2O, (i-Pr) 2NEt, CH 3CN; F) LiN (TMS) 2, THF, BrCH then 2CO 2Et; G) TFA, CHCl 2H) 2-(methylamino methyl) benzimidazole dihydrochloride
EDC,HOBt·H 2O,(i-Pr) 2NEt,CH 3CN；i)1.0N?LiOH,THF,H 2O.
By with the acid of isobutene. at catalytic amount, for example trifluoromethanesulfonic acid (TfOH) or sulphuric acid exist down, at atent solvent, be generally in dichloromethane or the ether the available 4-bromobenzene of commerce formic acid (II-1) is converted into the tert-butyl ester (II-2).The method of the formation tert-butyl ester is in addition described in Greene " Protective Groups in Organic Synthesis " (Wiley-Interscience publication).Can use other ester, as long as can be compatible and when needs, can optionally remove with chemical treatment thereafter.Carry out the reaction of Heck-type between II-2 and acrylic acid methyl ester. and obtain II-3.The generic condition of Heck reaction is summarized by Heck (Org.Reaction 1982,27,345).For example II-2 and acrylic acid methyl ester. are at acid chloride (II) (Pd (OAc) 2) and tri-o-tolyl phosphine (P (tol) 3) exist down, at atent solvent for example in acetonitrile, propionitrile or the toluene, at suitable acid scavenger diisopropylethylamine ((iPr) for example 2NEt) existing down, reaction obtains II-3.The α of II-3, the reduction of beta-unsaturated esters obtains saturated compound ii-4, this is reflected under the hydrogenation conditions of standard and takes place, for example in the presence of the palladium metal (Pd/C) on the preferred active carbon of suitable catalyst, at atent solvent, be generally in methanol, ethanol, ethyl acetate or its mixture and hydrogen reaction.Use aqueous alkali, for example Lithium hydrate makes the methyl ester hydrolysis of II-4 at THF aqueous solution or sodium hydroxide in methanol or ethanol water, and for example TFA or hcl acidifying intermediate carboxylate obtain carboxylic acid II-5 with suitable acid.With for example EDC and HOBt or SOCl 2Be translated into the activatory form of carboxylic acid, make its activated form and suitable amine subsequently, dimethylamine hydrochloride for example is at appropriate solvent for example DMF, CH 2Cl 2Or CH 3Reaction obtains II-6 among the CN.Depend on whether need neutralizing acid, can add for example diisopropylethylamine ((i-Pr) of alkali 2NEt) or pyridine.The known multiple other method that carboxylic acid can be converted into amide, can for example find among " Compendium of Organic Synthetic Methods " the I-VI volume (publishing) or the Bondansky " The Practice of Peptide Synthesis " (Syringer-Verlag publication) at the handbook of standard by Wiley-Interscinence.II-6 and for example two (trimethyl silyl) lithamide (LiN (TMS) of amide alkali 2), two (trimethyl silyl) ammonification sodium (NaN (TMS) 2), two (trimethyl silyl) ammonification potassium (KN (TMS) 2) or diisopropyl lithamide (LDA) at atent solvent, be generally THF or glycol dimethyl ether (DMF) reaction and obtain the midbody acid amide enolate.Generally not with its separation, but make its on the throne and electrophilic reagent, for example the bromoethyl acetate reaction obtains alkylating product II-7.Those skilled in the art knows various other auxiliary substances, for example HMPA.Tetramethylethylened (TMEDA) or 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-hybar X (DMPU) can be used to improve the usefulness of alkylated reaction).In atent solvent, be generally dichloromethane, 1,4-dioxane or its mixture, under acid condition, tert-butyl ester group common and TFA or HCl reaction removal II-7 obtains sour II-8.Other methods that are used to remove the tert-butyl ester are disclosed in Greene " ProtectiveGroups in Organic Synthesis " (Wiley-Interscience publication).The flow process I described I-6 is converted into I-7 and I-7 is converted under the common condition of I-8 respectively II-8 is converted into II-9 and II-9 is converted into II-10.
The flow process III
Figure A9618011300771
A) 3-carbomethoxy propionyl chloride, (i-Pr) 2NEt, CH 2Cl 2B) 1.0N NaOH, MeOH; C) 3-amino-4-pentinoic acid ethyl ester, EDC, HOBtH 2O, (i-Pr) 2NEt, CH 3CN, DMF; D) 1.0N LiOH, THF, H 2O, CH 3CN.
Suitable acid scavenger for example triethylamine, diisopropylethylamine or pyridine in the presence of, be generally at neutral flux and make 2-(2-amino-ethyl) benzimidazole that is easy to get and the reaction of 3-carbomethoxy propionyl chloride obtain III-2 in the dichloromethane.Can obtain III-3 in the described conversion I-7 of flow process I for the methyl ester of hydrolysis III-2 under the common condition of I-8.Perhaps suitable alkali for example triethylamine, diisopropylethylamine or pyridine in the presence of, be generally at neutral flux and make the reaction of III-1 and succinic anhydrides directly obtain III-3 in the dichloromethane.Under the described common condition that I-6 is converted into I-7 of flow process I by III-3 being converted into III-4 with known 3-amino-4-pentinoic acid ethyl ester (WO93/07867) reaction.Obtain III-5 according to the hydrolysis of finishing III-4 ethyl ester under the described common condition that I-7 is converted into I-8 of flow process I.
The flow process IV A) 4-(chloroformyl) methyl butyrate, Et 3N, THF; B) AcOH; C) 1.0N NaOH, MeOH; D) Boc-Gly, EDC, HOBtH 2O, (i-Pr) 2NEt, CH 3CN; E) TFA, CH 2Cl 2F) 3, EDC, HOBtH 2O, (i-Pr) 2NEt, CH 3CN; G) 1.0 N LiOH, THF, H 2O.
Finish the synthetic reaction of IV-8 by two reactions that prepare intermediate IV-3 and IV-6 independently.Available 2 by commerce, 3-diamino-pyridine (IV-1) begins to prepare intermediate IV-3.According to this flow process, at suitable acid scavenger, for example triethylamine, diisopropylethylamine or pyridine exist down, are generally among dichloromethane or the THF at neutral flux to make IV-1 acidylate obtain the derivant of intermediate one acidylate with 4-(chloroformyl) tetrolic acid methyl ester.Make this derivant cyclisation then, for example obtain IV-2 with the acetic acid that refluxes.The hydrolysis of carrying out IV-2 methyl ester under the described general condition that makes I-7 be converted into I-8 of flow process I obtains IV-3.Make known 3-amino-4-pentinoic acid ethyl ester (WO93/07867) and commercial available tert-butoxycarbonyl glycine (Boc-Gly) coupling prepare intermediate IV-6 at the Bodansky of above-mentioned reference publication with under the peptide bond formation condition of the described conversion I-6 of flow process I for the standard of I-7.With the product of above-mentioned reaction, IV-5 goes protection to obtain IV-6 under the acid condition of known removal Boc blocking group.Describe in the Bodansky of the condition of this type of reaction reference formerly and the Greene publication.Formerly make two intermediate IV-3 and IV-6 coupling obtain IV-7 under the peptide coupling condition of described standard, for the usual way of I-8 its hydrolysis is obtained IV-8 according to the described conversion I-7 of flow process I.
The flow process V
Figure A9618011300811
A) (Boc) 2O, DMAP, CH 3CN; B) carbonochloridic acid isobutyl ester, Et 3N, TH-F, then 1,2-phenylenediamine, AcOH then; C) (n-Bu 3Sn) 2, (PPh 3) 2PdCl 2, DMF; D) CuI, (PPh 3) 2PdCl 2, DMF; E) 4 M HCl/ dioxane; F) 1.0 N NaOH, MeOH.
React the synthetic reaction of finishing V-7 by the intermediate V-2 and the V-5 that make two independent preparations.Can be at acylation catalyst, preferred 4-dimethylaminopyridine (DMAP) or 4-pyrrolidine and pyridine exist down, at neutral flux CH for example 3CN, THF or CH 2Cl 2In make the V-1 that is easy to get and bicarbonate di tert butyl carbonate (di-tert-butyl dicarbonate) ((Boc) 2O) reaction prepares V-2 easily.The available 3-iodobenzoic acid of commerce (V-3) is converted into benzimidizole derivatives V-4 preparation intermediate V-5.According to this flow process, can be at suitable amine alkali, for example triethylamine, diisopropylethylamine or 4-methyl morpholine exist down, at neutral flux, are generally and make V-3 and the reaction of carbonochloridic acid isobutyl ester obtain intermediate mixed acid anhydride derivant among dichloromethane or the THF.Without separation, make the reaction of this derivant and suitable phenylenediamine obtain the phenylenediamine intermediate of one-N-acidylate.Make this intermediate cyclisation obtain V-4 with acetic acid then.In the palladium catalytic reaction, for example two (triphenylphosphine) Palladous chloride. (II) ((PPh 3) 2PdCl 2) exist down, be generally V among the DMF-4 at atent solvent and produce V-5 with two (tributyl tin) reaction.V-2 obtains V-the 6th with the coupling reaction of the Stille-type of V-5, at for example two (triphenylphosphine) Palladous chloride. (II) ((PPh of palladium catalyst 3) 2PdCl 2) participate in down, Copper diiodide (I) (CuI) in the presence of, be generally at suitable neutral flux and carry out among the DMF.For obtaining V-7, remove the blocking group of V-6 with method known to those skilled in the art and the described method of Greene publication.Therefore, under acid condition, for example the dichloromethane solution of 4M HCl dioxane solution or TFA is removed the Boc blocking group, according to the flow process I is described I-7 is converted into the described methyl ester of I-8 hydrolysis.
The flow process VI
Figure A9618011300831
A) 3-butine-1-alcohol, (PPh 3) 2PdCl 2, PPh 3, CuI, Et 3N; B) H 2, 10%Pd/C, EtOH; C) 2,2,6,6-tetramethyl oxo piperidinium chloride, CH 2Cl 2, NaClO then 2, Na 2HPO 3, 2-methyl 1-2-butylene ne, H 2O; D) carbonochloridic acid isobutyl ester, Et 3N, then 1,2-phenylene two is pressed AcOH; E) 1.0N LiOH, THF, H 2O; F) TFA, CH 2Cl 2.
In a kind of amine solvent (as triethylamine (Et 3N)), [use two (triphenylphosphine) Palladous chloride. II ((PPh usually at the palladium salt of catalytic amount 3) 2PdCl 2)] and the Copper diiodide (I) of catalyst when (CuI) existing, make chemical compound VI-1 (its preparation as flow process V as described in) obtain VI-2 with 3-butine-1-alcohol reaction.Can add a kind of phosphine part, as triphenylphosphine (PPh 3), to improve the efficient of reaction.Under standard hydrogenation conditions well-known to those skilled in the art, finish the reduction of the alkynyl unit of VI-2.According to Wovkulich (J.Org.Chem.1993,58,832-839) described two-stage process is oxidized to corresponding carboxylic acid VI-4 with gained chemical compound VI-3.The many selectable method that primary alconol is oxidized to corresponding carboxylic acid is open, can reference volume as " Compendium of Organic Synthetic Methods " (Wiley-Interscience publications) in discovery.According to the described method of above-mentioned technological process, carboxylic acid VI-4 can be converted into benzimidizole derivatives VI-5.According to the described method of above-mentioned flow process, the methyl ester of VI-5 is removed, and (in 4MHCl Yu diox, or TFA is in CH under acid condition 2Among the Cl) remove its Boc blocking group and can obtain VI-6.
The flow process VII A) 1,2-phenylenediamine, DCC, DMF, CH 2Cl 2B) AcOH, THF; C) TsCl, NaH, THF; D) O 3, CH 2Cl 2, MeOH, DMS then; E) NH 2OHHCl, NaOAc, MeOH; F) NCS, DMF; G) the 3-butenoic acid tert-butyl ester, Et 3N; H) 4M HCl dioxane, CH 2Cl 2I) 3-aminobutyric acid ethyl ester, EDC, HOBtH 2O, (i-Pr) 3NEt, CH 3CN; J) 1.0N LiOH, THF, H 2O.
Adopt aforementioned general technology flow process, can derive from commercial 4-penetenoic acid (VII-1) and be converted into benzimidizole derivatives VII-2.In atent solvent (preferred THF); when existing, a kind of suitable alkali (is generally sodium hydride or alkali metal hydroxide aqueous solution); by reacting with a kind of sulfonic acid chloride (as p-toluenesulfonyl chloride), can finish the protection of one of benzimidazole nitrogen-atoms partly in the VII-2, obtain VII-3.Can use the known selectable blocking group of those skilled in the art,, and can remove when needed and get final product as long as they are compatible with later chemical treatment.Such blocking group is as described in " Protective Groups and Organic Synthesis " (Wiley-Interscience publication) of Greene.(be generally CH by atent solvent 2Cl 2Or be CH 2Cl 2Mixture with MeOH) ozonolysis reactions in uses a kind of suitable Reducing agent (being generally methyl thioether (DMS) or triphenylphosphine) with ozonide reduction on the throne then, and the oxicracking that can finish VII-3 alkene at an easy rate is to obtain aldehyde VII-4.Can use the selectable method of oxicracking, as Lemieux-Johnson reaction (J.Org.Chem.1956,21,478).According to normal process well known to those skilled in the art, above-mentioned aldehyde can be converted into aldoxime VII-5, according to WO 95/14682 and WO 95/14683 described method, this aldoxime can be oxidized to oxime chloride derivative VII-6.According to WO 95/14682 and WO 95/14683 described method, in a kind of atent solvent such as benzene or toluene, when a kind of suitable alkali such as triethylamine or diisopropylethylamine exist, make VII-6 and a kind of alkene such as the 3-butenoic acid tert-butyl ester (Tet.Lett.1985,26,381-384) reaction can obtain encircling adduct I-7.Under the standard acidic condition, be generally TFA in CH 2Cl 2In or in the HCl Yu diox, VII-7 uncles-butyl ester removed can get carboxylic acid VII-8.With as EDC and HOBt or SO 2Cl 2Make the activation of this carboxylic acid, make subsequently this activated form at neutral flux (as DMF, CH 2Cl 2Or CH 3CN) the suitable derivatives reaction with suitable amine such as Beta-alanine in produces VII-9.According to whether needs acid neutralizes, can use a kind of alkali such as diisopropylethylamine ((i-Pr) of adding 2NEt) or pyridine.Many other methods that carboxylic acid are converted into amide are known, and can find in the canonical reference book, as " Compendium of Organic SyntheticMethods ", and the I-VI volume.(Wiley-Interscience publication) or Bondansky, " The Practice of Peptide Synthesis " (Spring-Verlag publication).According to the whole bag of tricks well known to those skilled in the art, can easily obtain the racemate or the optically pure form of the derivant of Beta-alanine.A kind of representational method is disclosed in WO 93/07867.With aqueous alkali such as LiOH in the THF aqueous solution or NaOH in methanol or ethanol water, can remove the ethyl ester or the sulfonyl blocking group of VII-9.With a kind of suitable acid such as TFA or HCl the acidify of intermediate product carboxylate is obtained carboxylic acid VII-10.Selectable, in the time of if desired, intermediate carboxylate can be separated by method well-known to those skilled in the art, perhaps prepare free carboxy acid's carboxylate.
The flow process VIII
Figure A9618011300881
A) COCl 2In toluene, Na 2CO 3, H 2O; B) Beta-alanine benzyl ester toluene fulfonate, DMAP, pyridine; C) CH 3I, 2,6-lutidines, DMF; D) BrCH 2COBr, Et 3N, CH 2Cl 2E) NaH, DMF; F) CO, (Ph 3P) 2PdCl 2, DIEA, 2-(methylamino methyl) benzimidazole dihydrochloride, NMP; G) H 2, Pd/C, EtOH.
According to the flow process of US 5403836 and WO 9504057, with from 2-amino-4-iodobenzoic acid (VIII-1) beginning but not begin preparation chemical compound VIII-5 from 2-amino-5-iodobenzoic acid.In a kind of atent solvent (optional 1-Methyl-2-Pyrrolidone NMP), (preferred (Ph under the condition that palladium catalyst exists 3P) 2PdCl 2, in the carbon monoxide environment, make VIII-5 and a kind of suitable amine such as 2-(methylamino methyl) benzimidazole react amide VIII-6.According to whether needs neutralize, can use a kind of alkali such as diisopropylethylamine (DIEA) or pyridine of interpolation.Under standard hydrogenation conditions well-known to those skilled in the art, the benzyl ester of removing VIII-6 can obtain VIII-7.Selectable, use a kind of aqueous alkali such as LiOH in the THF aqueous solution or NaOH in methanol or ethanol water, can be with the saponification of benzyl ester.With a kind of suitable acid such as TFA or HCl the acidify of intermediate product carboxylate can be obtained carboxylic acid.If desired, adopt method well known to those skilled in the art the intermediate carboxylate of VIII-7 can be separated, perhaps prepare the suitable salt of carboxylic acid.
The flow process IX
Figure A9618011300901
A) Beta-alanine carbethoxy hydrochloride, DMAP, pyridine; B) BrCH 2COBr, Et 3N, CH 2Cl 2C) NaH, DMF; D) Lawesson ' s reagent., THF, 50 ℃; E) CH 3I, (n-Bu) 4NHSO 4, NaOH, CH 2Cl 2, H 2O; F) propargylamine, pyridine HCl, toluene; G) CO, (Ph 3P) 2PdCl 2, DIEA, 2-(methylamino methyl) benzimidazole dihydrochloride, NMP; H) LiOH, THF, H 2O.
According to the flow process of US 5403836 and WO 9504057, from 4-iodo isatoic anhydride (IX-1 is seen the flow process I) but not begin from 5-iodo isatoic anhydride, preparation chemical compound IX-6.Step according in the flow process X III X III-5 being converted into X III-7 is converted into IX-7 with IX-6.
The flow process X A) 1-Boc-piperazine, NaBH 3CN, HCl, MeOH; B) 4 M HCl/ dioxane, CH 2Cl 2C) SOCl 2, CH 2Cl 2D) 3, DIEA, DMF; E) 1.0 N NaOH, MeOH.
The 1-that is easy to get (ethoxy carbonyl methyl)-4-piperidones (X-1, EP A0542363 A2) can obtain amine X-2 with the 1-Boc-piperazine that can derive from commerce and a kind of suitable Reducing agent (preferred sodium cyanoborohydride) through reductive amination process.This reaction is carried out in (HCl commonly used) and the oh soln (as methanol and ethanol) under acidic catalyst usually.At appropriate solvent such as CH 2Cl 2In, (preferred HCl/ dioxane or TFA) removes the Boc blocking group and can obtain amine X-3 under acid condition.In polar solvent (preferred DMF), in the presence of a kind of suitable acid scavenger (as diisopropylethylamine DIEA), make itself and 2-(2-chloro ethyl) benzimidazole (X-5) reaction obtain coupling product X-6.At atent solvent such as CH 2Cl 2In, when triphenylphosphine exists, can prepare 2-(2-chloro ethyl) benzimidazole by 2-(2-hydroxyethyl) benzimidazole and a kind of suitable halogenating agent (as thionyl chloride or carbon tetrachloride) reaction.Use the aqueous solution of alkali such as LiOH in the THF aqueous solution or NaOH in alcohol or ethanol water, remove the ethyl ester of X-6.With a kind of suitable acid such as TFA or HCl with the intermediate carboxylate acidify with preparation carboxylic acid X-7.Selectable, if desired, intermediate carboxylate can be separated according to method well-known to those skilled in the art, perhaps prepare free carboxy acid's carboxylate.
The flow process XI A) 2-(3-bromo propyl group) benzimidazole, DIEA, DMF; B) 4M HCl/ dioxane CH 2Cl 2.
In polar solvent (preferred DMF), at a kind of suitable acid dissociation agent such as diisopropylethylamine (DIEA) when existing, make bridged piperazine derivatives XI-1 (EPA 0537980Al) that is easy to get and 2-(the 3-bromo propyl group) benzimidazole (J.Org.Chem that is easy to get, 1962,27,2165) reaction obtains coupling product XI-2.At appropriate solvent such as CH 2Cl 2In, (preferred HCl/ dioxane or TFA) removes the tert-butyl ester protecting group and obtains carboxylic acid XI-3 under the acid condition of standard.The suitable salt that can prepare if desired, this carboxylic acid according to method well known to those skilled in the art.
The flow process XII
Figure A9618011300951
A) 2-(benzimidazolyl) propanoic acid, BOP-Cl, NMM, CH 2Cl 2B) LiOH, THF, H 2O; C) Beta-alanine benzyl ester, EDC, HOBtH 2O, NMM, CH 2Cl 2D) H 2, 10%Pd/C, AcOH, THF, H 2O.
According to the flow preparation XII-4 of (WO 95/25091, and embodiment 1) such as Beavers, but replace N with (2-benzimidazolyl) propanoic acid α-Boc-D-lys (Cbz)-OH.
Flow process X III
A) 2-(amino methyl) benzimidazole, Et 3N, benzene; B) 1.0N LiOH, MeOH, H 2O; C) Beta-alanine ethyl ester, BOP, Et 3N, CH 3CN.
At 1H-iso-indoles-5-Methanamide, 2,3-dihydro-N-(2-carboxyl-ethyl)-2-[2-(piperidyl) ethyl]-3-oxo (preparation 1-12, EPA 0540334 A1) preparation-as under the condition, make a kind of suitable functionalized amine such as 2-(amino methyl) benzimidazole and 4-bromomethyl benzene-1,3-dimethyl dicarboxylate (X III-1; As synthesizing among the EP 0540334Al) reaction obtains X III-2.Use the aqueous solution of alkali such as LiOH in the THF aqueous solution or NaOH in methanol or ethanol water, with the methyl ester hydrolysis of X III-2, with suitable acid such as TFA or HCl the intermediate carboxylate acidify is obtained carboxylic acid X III-3 then.With for example EDC and HOBt, SOCl or bop reagent the carboxylic acid of X III-3 is converted into a kind of activated form of this carboxylic acid, this activated form is at appropriate solvent such as DMF, CH subsequently 2Cl 2Or CH 3Obtain X III-4 with a kind of suitable amine such as the reaction of Beta-alanine ethyl ester among the CN.According to whether needs acid neutralizes, use a kind of alkali such as diisopropylethylamine ((i-Pr) of interpolation 2NEt) or pyridine.Many other methods that carboxylic acid are converted into amide are known, and roll up as " Compendium of Organic Synthetic Methods " the I-VI at the canonical reference book, (Wiley-Interscience publication), or Bondansky, can find in " The Practice of Peptide Synthesis " (Springer-Verlag publication).Aforesaid ester hydrolysis is converted into X III-3 with X III-2, obtains X III-5 then.Selectable, as needs, the intermediate carboxylate of X III-5 can be separated or prepared free carboxy acid's carboxylate according to method well known to those skilled in the art.
Flow process XI V
Figure A9618011300981
A) (Boc) 2O, NaOH, 1,4-dioxane H 2O; B) BrCH 2CO 2Bn, K 2CO 3, acetone; C) 4MHCl/ dioxane; D) 2-(benzimidazolyl) acetic acid d, EDC, DIEA, DMF; E) H 2, 5%Pd/C, MeOH.
In the dioxane aqueous solution, obtain X IV-2 with bicarbonate di tert butyl carbonate and naoh treatment X IV-1, in acetone, the o-alkylation on the X IV-2 is obtained X IV-3 with monobromo-acetic acid benzyl ester and potassium carbonate.With the Boc group of removing in the hydrogen chloride Zai diox on the X IV-3, gained XI V-4 in DMF with 2-(benzimidazolyl) acetic acid, EDC and DIEA acidylate on nitrogen obtain XI V-5.In methanol, the benzyl ester cracking in the X IV-5 is obtained XI V-6 with hydrogen and Pd/C processing.
Flow process X V
Figure A9618011300991
A) 2-(benzimidazolyl) acetic acid, EDC, DIEA, DMF; B) NaOH, H 2O, CH 3OH.
In appropriate solvent (in DMF or acetonitrile), when EDC and DIEA exist, make XI-1 (equaling to prepare described in the EPA0372486) and the carboxylic acid such as the condensation of 2-(benzimidazolyl) acetic acid that suitably replace as Alig.Many other methods that carboxylic acid are converted into amide are known, and roll up in (Springer-Verlag publication) and can find as " Compendium of Organic Synthesis " the I-VI at the canonical reference book.By in appropriate solvent such as methanol aqueous solution, carry out the hydrolysis that saponification can be finished ester with suitable reagent such as sodium hydroxide.Selectable, in appropriate solvent such as methanol, ethanol or acetic acid,, the benzyl ester can be converted into acid with suitable catalyst such as Pd/C and hydrogen processing.
Flow process X VI
Figure A9618011301001
A) 2-(benzimidazolyl) acetic acid, EDC, DIEA, DMF; B) TFA
In appropriate solvent such as DMF or acetonitrile, when EDC and DIEA exist, make X VI-1 (as Aeig etc., EPA 0505868 described preparation) obtain X VI-2 as (2-benzimidazolyl) acetic acid condensation with a kind of suitable carboxylic acid.Many other methods that carboxylic acid are converted into amide are known, and in the canonical reference book, as finding in " Compendium of Organic Synthesis " the I-VI volume (Springer-Verlag publication).Finish the hydrolysis of ester in the X VI-2 to obtain X VI-3 with three fluoro acetic acid or hydrogen chloride.Selectable, in appropriate solvent such as methanol, with suitable reagent such as the 1NNaOH ester in can saponification X VI-2.
Flow process X VII
Figure A9618011301011
A) 2-(benzimidazolyl) acetic acid, EDC, DIEA, DMF; B) TFA, CH 2Cl 2
Make X VII-1 (as preparation as described in Sugihara etc., EP0529858) carboxylic acid with suitable replacement obtains X VII-2 as (2-benzimidazolyl) acetic acid condensation, according to the general flow of (embodiment 59) such as Sugihara, with TFA with uncle-butyl ester cracking to obtain X VII-3.Many other methods that carboxylic acid are converted into amide are known, and at the canonical reference book, as finding in " Compendium ofOrganic Synthesis " the I-VI volume (Springer-Verlag publication).
Flow process X VIII
Figure A9618011301021
A) 4-[2-(benzimidazolyl) methyl] phenol, Cs 2CO 3, DMF; B) TFA
Conventional method (embodiment 3 (51)) according to Himmelsbach etc., with suitable fortified phenol such as 4-[2-(benzimidazolyl) methyl] (general flow according to Wahlgren and Addison prepares phenol, J.Heterocycl.Chem, 1 989,26,541-3) handle chemical compound X VIII-1 (as preparation as described in the Himmelsbaeh etc., Australian Patent Application AU-A-86926/91, embodiment VI (28)) and obtain X VIII-2.According to the general flow (embodiment 7 (3)) of Himmelsbach etc., with 1N NaOH in CH 3Among the OH tert-butyl ester hydrolysis in the X VIII-2 is obtained X VIII-3.Selectable, with TFA or HCl with tert-butyl ester cracking.
Flow process X IX
Figure A9618011301031
A) HO-CCH 2Ph-4-CE 2CH 2CO 2CH 3, Ph 2POCl, Et 3N, DMAP, THF; B) NaH, DMF, BrCH 2CO 2CH 3C) KOt-Bu, TH-F, DMF; D) KOt-Bu, CH 3I, DMF; E) LiOH, THF, H 2O.
The flow preparation X IX-5 of (EP 0567968) such as employing Linz, but replace the 4-cyano-aniline with (2-benzimidazolyl) methylamine.
The flow process XX
Figure A9618011301051
A) ClCH 2CO 2Et, Et 3N, DMF; B) BBr 3C) (CF 3SO) 2O; D) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H 2O; E) H 2N-R, EDC/HOBt, DIEA, DMF; F) H 2N-R, CO, Pd (OAc) 2, PPh, DIEA, NMP, NH 4HCO 3, H 2O; G) 1N NaOH, HOEt
As (EP 0635492, Jan, 25,1995) as described in M.J.Fisher etc., the flow process XX provides a kind of preparation as 1,2,3 of fibrinogen deceptor antagonists exemplary, the method for 4-tetrahydro isoquinoline compound.As previously mentioned, according to D.J.Shall and G.L.Grunewald (J.Med.Chem.1987,30,2208-16) described method prepares 6-methylamino-3,4-dihydro-isoquinoline such as chemical compound XX-1.When tertiary amine exists, handle isoquinolin with the halogenated acetic acids ester and obtain the 2-acetas as XX-2 representative.Adopt method BBr known in the art 36-methoxylation compound is transformed into corresponding 6-hydroxy compounds, is translated into fluoroform sulphonate with three fluorosulfonic anhydride then.Obtain 6-carboxyl compound such as chemical compound XX-5 by the catalytic carbonylation of palladium, the amine key of using a kind of standard forms reagent, and XX-5 and amine are obtained needed amine such as chemical compound XX-6 as (2-benzimidazolyl) acetic acid condensation.Saponification obtains XX-7, and is selectable, and the catalytic carbonylation with triflate such as XX-4 of palladium can be intercepted and captured by described amino methyl chemical compound, after saponification, obtains corresponding 6-(2-benzimidazolyl) methylamino carbonyl compound XX-7.
Flow process X XI
Figure A9618011301061
A) 1.LiN (TMS) 2, 2.ClCH 2CO 2Et, DMF; B) BBr 3C) (CF 3SO 2) 2O; D) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H 2O; E) H 2N-R, EDC/HOBt, DIEA, DMF; F) H 2N-RCO, Pd (OAc) 2, PPh 2, DIEA, NMP, NH 4HCO 3, H 2O; G) 1N NaOH, HOEt
Flow process X XI provides a kind of preparation 3, and the method for 4-dihydro-isoquinoline-1-ketone (as can illustrative fibrinogen deceptor antagonists) (as described in M.J.Fisher etc., EP 0635492, Jan.25,1995) is corresponding, with alkali such as LiN (TMS) 2With the halogenated acetic acids ester handle 1-oxo-compounds X XI-1 (the described method of D.J.Sall and G.L.Grunewald of press prepares, J.Med.Chem.1987,30,2208-2216) obtain 2-acetas such as chemical compound X XI-2.Then the 1-oxo-compounds is applied to a series of similar reaction that the flow process XX is adopted, replaces corresponding 1-oxo analog, shown in flow process X XI, obtain X XI-7.As with the flow process XX in identical, selectable, the carbonylation of palladium is catalytic and triflate such as chemical compound X XI-4 usefulness amine are intercepted and captured, and after saponification, obtain X XI-7.
Flow process X XII
Figure A9618011301071
A) RCO-X; B) TFA/CH 2Cl 2
Flow process X XII provides as the preparation method of the 6-acylamino-tetralin compounds of illustrative fibrinogen deceptor antagonists (as described in M.J.Fisher etc., EP0635492, Jan.25,1995).As previously mentioned, with 6-amino-2-tert-butyl oxygen base carbonyl-tetrahydronaphthalene-1-ketone as chemical compound X XII-1 (according to method preparation as described in the M.J.Fisher etc., EP0635492, Jan.25,1995) with the reactive derivative condensation of a kind of activatory derivant of carboxylic acid as (2-benzimidazolyl) acetic acid, behind deesterify, obtain amide such as X XII-2.
Flow process XX III
Figure A9618011301081
A) CF 3SO 2O; B) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H 2O; C) H 2N-R, EDC/HOBt, DIEA, DMF; D) H 2N-R, CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H 2O; E) 1NNaOH, HOEt
Flow process XX III provides the preparation method (as described in M.J.Fisher etc., EP0635492, Jan.25,1995) of the 6-aminoacyl tetralin compounds of the fibrinogen deceptor antagonists that a kind of conduct can copy.As previously mentioned; with trifluoromethanesulfanhydride anhydride handle ethoxy carbonyl methyl-6-hydrogen-tetrahydronaphthalene-1-ketone as chemical compound XX III-1 (according to method preparation as described in the M.J.Fisher etc.; EP0635492; Jan.25; 1995) obtain triflate such as chemical compound XX III-2; be applied to the catalytic carbonylation of palladium and obtain carboxylic acid such as chemical compound XX III-3, then with itself and amide condensed, behind deesterify, promptly get 6-aminoacyl chemical compound XX III-5.Selectable, palladium is catalytic can be intercepted and captured by described amines with the carbonylation as chemical compound XX III-2 triflate, can obtain corresponding 6-aminoacyl chemical compound XX III-5 after saponification.
Flow process XX IV A) BrCH 2CO 2Et, K 2CO 3, NaI; B) 1.DBU, EtOH, 2.HCl, EtOH; C) DiBAL ,-78 ℃; D) NaH, THF; E) H 2, 10%Pd-C; F) R 2CO-X; G) 1N NaOH, MeOH
The preparation method of 5-acylamino-benzofuran that the fibrinogen deceptor that flow process XX IV provides a kind of conduct to copy is short of money dose and 5-acylamino-Dihydrobenzofuranes chemical compound (as described in M.L.Denney etc., EP0655439,31/5/95).Therefore, obtain phenoxy acetic acid ester such as chemical compound XX IV-2 with halogenated acetic acids ester processing 4-nitrosalicylaldehyde such as chemical compound XX IV-1.Handle aldehyde with alkali such as DBU and can obtain for example chemical compound XX IV-3 of 2-alkoxy carbonyl furan.With for example DiBAL the 2-alkoxy carbonyl is reduced into aldehyde.2-acrylate such as chemical compound XX IV-4 be can obtain by the Wittig reaction, benzofuran-2-propionic ester such as chemical compound XX IV-5 and Dihydrobenzofuranes-2-propionic ester such as chemical compound X XI V-6 then it are reduced to.Amine XX IV-5 becomes amide 5 XX IV-8 with the activatory derivant condensation of carboxylic acid behind deesterify.Selectable, amine XX IV-6 becomes amide XX IV-7 with the activatory form condensation of carboxylic acid behind deesterify.
Flow process XX V a A) 1.TBDMS-Cl, imidazoles; B) DiBAl-H ,-78 ℃, d) NaH, THF; E) H 2, 5%Pd-C; F) Et 4N+F-
Flow process XX V b
Figure A9618011301121
A) (CF 3SO 2) 2O; B) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H 2O; C) H 2N-R, EDC/HOBt, DIEA, DMF; D) H 2N-R, CO, Pd (OAc) 2, PPh 2, DIEA, NMP, NH 4HCO 3, H 2Oe) 1NNaOH, EtOH
Flow process XX V c
Figure A9618011301131
A) (CF 3SO 2) 2O; B) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4HCO 3, H2O; C) H 2N-R, EDC/HOBt, DIEA, DMF; D) H 2N-R, CO, Pd (OAc) 2, PPh 2, DIEA, NMP, NH 4HCO 3, H 2Oe) 1NNaOH, EtOH
Flow process XX V provides a kind of method as the 5-aminoacyl benzofuran and the 5-aminoacyl Dihydrobenzofuranes chemical compound of the fibrinogen deceptor antagonists that can copy (as described in M.L.Denney etc., EP 0655439,31/5/95) for preparing.Therefore, handle the TBDMS derivant XX V a-2 that 5-hydroxyl benzofuran-2-carboxylate such as XX V a-1 (with the method preparation of M.L.Denney etc., EP 0655439,31/5/95) can obtain ester with TBDMS-Cl.Ester is reduced into as aldehyde compound XX V a-3.Obtain acrylate XX V a-4 by the Wittig reaction.Obtain benzofuran-2-acetas and Dihydrobenzofuranes-2-acetas by catalytic reduction.By method known in the art, the silicyl ether group cracking of each ester can be obtained benzofuran-2-acetas XX V a-5 or Dihydrobenzofuranes-2-acetas XX V a-6.
Seen in flow process XX V b and XX V c, by the catalytic carbonylation of palladium, can respectively each alcohol be converted into carboxylic acid such as chemical compound XX V b-2 or XX V c-2, then they respectively with the amine condensation behind deesterify, obtain amide XX V b-4 or XX V c-4.Selectable, palladium catalytic with triflate as the carbonylation of XX V b-1 or XX V c-1 can with as described in the intercepting and capturing of amino methyl chemical compound, behind deesterify, obtain corresponding 6-aminoacyl chemical compound XX V b-4 or XX V c-4.
Here used amide coupling reagent is the reagent that expression can be used to form peptide bond.Typical coupling method uses carbodiimide, activatory anhydride and ester and carboxylic acid halides.Typical reagent such as EDC, DCC, DPPA, PPA, bop reagent, HOBt, N-hydroxy-succinamide and oxalyl chloride.
The coupling method that forms peptide bond is well known in the art.Bodansky equals THE PRACTICE OF PEPTIDE SYNTHESIS (Springer-Verlag, Berlin, 1984), Ali equals J.Med.Chem., 29,984 (1986) and J.Med.Chem., the synthetic method of peptide that is proposed in 30,2291 (1987) has generally been illustrated Technology, here is incorporated herein by reference.
Typically, optional at catalyst such as I-hydroxybenzotriazole (HOBt) and dimethyl aminopyridine (DMAP) when existing, use a kind of suitable carbodiimide coupling agent such as N ', N ' dicyclohexyl carbonyl diimine (DCC) is coupled to a kind of suitable carboxylic acid substrate with amine or aniline by its free amine group group.Other method also is suitable, for example, forms activatory ester, anhydride or the carboxylic acid halides of the free carboxy of suitable protected described substrate, then randomly when alkali exists and the reaction of the free acyl of suitable protected amine.For example; in anhydrous solvent as dichloromethane or oxolane (THF); when alkali such as N-methylmorpholine, DMAP or trialkylamine exist; Boc-aminoacid or the Cbz-amidino groups benzoic acid of handling protection with the carbonochloridic acid isobutyl ester form " activatory anhydride ", and its unhindered amina with second kind of protected aminoacid or aniline is reacted.
Formula (X IX) and (XX) chemical compound are that commerce is easy to get, perhaps adopt methods known in the art to prepare method in the Open Standard handbook as described here, as COMPENDIUM OF ORGANIC SYNTHETIC METHODUS the I-VI volume (Wiley-Interscience).The common method of preparation benzimidazole is disclosed in Nestor etc., J.Med.Chem.1984,27,320.Representational method this area of preparation formula (XX) chemical compound also is known, and can find in EP-A 0381033.
The acid-addition salts of described chemical compound can be prepared by its parent compound and a kind of excessive acid such as hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or the methanesulfonic acid mode with standard in appropriate solvent.Part of compounds forms acceptable inner salt or zwitterionic compound.By preparing its cationic salts with excessive alkaline reagent (as containing suitable cationic hydroxide, carbonate or alkoxide) or with suitable organic amine processing parent compound.The cationic specific example such as the Li that exist in the pharmaceutically acceptable salt +, Na +, K +, Ca ++, Mg ++And NH 4 +
The present invention also provides a kind of pharmaceutical compositions, and it comprises chemical compound and a kind of pharmaceutically acceptable carrier based on formula I-(V) and formula (X XI)-(XX XII).Therefore, the chemical compound of formula I-(V) and formula (X XI)-(XX XII) can be used for medicine production.The pharmaceutical compositions for preparing formula I-(V) and formula (X XI)-(X XII) chemical compound as previously mentioned can be made into solution or the freeze-dried powder form is used for parenteral.Powder can add the suitable dilution agent before use or other pharmaceutically acceptable carrier duplicates.Liquid dosage form can be a kind of buffered, isoosmotic, water-soluble fluidity solution.The example of suitable diluent has 5% D/W or the buffered sodium acetate or the ester acid ammonium solution of isoosmotic normal saline solution, standard.Such prescription is specially adapted to parenteral, but also can be used for oral administration or be contained in the metered-dose inhaler or inhalation administration in the nebulizer.It is auxilliary as polyvinylpyrrolidone, gelatin, hydroxylated cellulose, arabic gum, Polyethylene Glycol, mannitol, sodium chloride or sodium citrate to add other if desired.
Selectable, these chemical compounds can incapsulate, are pressed into tablet or make Emulsion or syrup is used for oral administration.Can add pharmaceutically acceptable solid or liquid-carrier to increase or stabilizing solution compositions or compositions is prepared easily.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, kaolin, magnesium stearate or stearic acid, Pulvis Talci, pectin, arabic gum, agar or gelatin.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, saline or water.Carrier also comprises slow release composition such as glyceryl monostearate or glycerol distearate, uses separately or adds and wax.The amount of solid carrier changes, but preferably arrives between about 1g at the about 20mg of each dosage unit.Prepare according to traditional handicraft on the pharmaceutics,, in the time of if desired, comprise grinding, mixing, granulation and tabletting for tablet; Perhaps for hard capsule comprise grinding, mix or fill, when using liquid-carrier, the form of preparation is the suspension of syrup, elixir, Emulsion or water-soluble fluidity or non-aqueous solution.A kind of like this liquid form is oral administration or load Perle directly.
For rectally, chemical compound of the present invention also can combine with adjuvant such as cupu oil, glycerol, gelatin or Polyethylene Glycol, moulds and makes suppository.
Chemical compound described herein is a glass body protein receptor antagonist, can be used for treating its pathology owing to part or the interactional disease of cell Vitronectic receptor.For example, these chemical compounds are used for the treatment of bone matrix wherein and lose the disease that produces pathology.So these chemical compounds can be used for treating osteoporosis, hyperparathyroidism, Paget ' s disease, malignant hypercalcemia, bone shifts and the molten bone infringement that produces.The bone loss that causes owing to fixation or sex hormone deficiency.Chemical compound of the present invention is believed also following purposes: antitumor agent, anti-angiogenic agent, antiinflammatory and metastasis agent, so can be used for the treatment of atherosclerosis and restenosis.
This peptide can be oral or injection give patient's medication, in this case, drug concentrations should be sufficient to suppress heavily absorbing of bone or other this type of indication.The oral dose that contains the pharmaceutical compositions administration of this peptide is between about 0.1 to about 50mg/kg, should be in the mode consistent with the patient disease.Preferred oral dosage is about 0.5 to about 20mg/kg.For acute treatment, preferred intestinal external administration.The venous transfusion of the described peptide in the similar prescription of 5% G/W or normal saline or suitable vehicle is the most effective, although the injection of intramuscular agglomerate (bolus) medicine also is useful.Typically, parenteral dosage is about 0.01 to about 100mg/kg; Preferably between 0.1 to 20mg/kg.Chemical compound administration every day one to four time is arrived about 400mg/kg/ days level to reach TDD about 0.4.By the blood levels and the required concentration of generation therapeutic effect that compare reagent, those skilled in the art can more easily determine the accurate level and the method for compound administration.
Chemical compound can be by an experiment in several biological tests to determine to require to reach the compound concentration of predetermined pharmacological action.
Vitronectin is in conjunction with inhibition test
Solid phase [ 3H]-SK﹠amp; F-107260 and α vβ 3Combination: with containing 1mMCaCl 2, 1mMMnCl 2, 1mM MgCl 2(buffer A) and 0.05%NaN 3Buffer T be diluted in buffer T and (contain 2mM CaCl 2With 1% Octyl glucoside) in people's Placenta Hominis or human blood platelets α vβ 3(0.1-0.3mg/ml), then with every hole 0.1ml be added to immediately 96 hole ELISA flat boards (Coming, New York, NY) in, every hole adds the α of 0.1-0.2 μ g vβ 3This flat board is in 4 ℃ of night incubation.During experiment, with buffer A washing eyelet once, the 3.5% bovine serum albumin 0.1ml that is used in the same buffer was at room temperature hatched 1 hour.Hole content after hatching is extracted out fully, with 0.2ml buffer A washed twice.
Chemical compound is dissolved in the storing solution that 100%DMSO obtains 2mM, and it is used binding buffer liquid (15mM Tris-HCl (pH 7.4), 100mM NaCl, 1mM CaCl 2, 1mM MnCl 2, 1mM MgCl 2) to make the concentration of final compound be 100 μ M in dilution.This solution is diluted to needed chemical compound ultimate density then.The various concentration of unlabelled antagonist (0.001-100 μ M) add in the eyelets with three parts respectively, add then 5.0mM [ 3H]-SK﹠amp; F-107260 (65-86Ci/mmol).
Flat blood was at room temperature hatched 1 hour.Hatch the metapore content and extracted out fully, wash once with the ice-cold buffer A of 0.2ml to the mode in hole with the hole.With the 1%SDS of 0.1ml dissolving receptor, add 3ml Ready Safe in Beckman LS Liquid Scintillation Counter, the efficient with 40% by the liquid scintillation counting calculations incorporated [ 3H]-SK﹠amp; F-107260.At 2 μ M SK﹠amp; Measure when F-107260 exists [ 3H]-SK﹠amp; The non-special combination of F-107260 should conformingly be less than 1% of gross activity part input.By by improved non-linear, the least square diagram method program determination IC of LUNDON-2 program 50(suppress [ 3H]-SK﹠amp; The concentration of F-107260 50% bonded antagonist).According to following Equation for Calculating K i(dissociation constant of antagonist): K i=IC 50/ (1+L/K d), wherein L and K dBe respectively [ 3H]-SK﹠amp; The concentration of F-107260 and the constant that dissociates.
When concentration range was approximately 0.001 to 50 micromole, chemical compound of the present invention can suppress vitronectin and SK﹠amp; The combination of F-107260.
Also can carry out in the body and the re-absorbed experiment of external bone with the touchstone in this area to chemical compound of the present invention, be used to estimate osteoplastic inhibition, the indenture that for example is disclosed in EP 528587 forms check, the osteoclast that also can choose replaces the osteoclast of rat and finishes experiment with ovariectomized rat model that (Wronski etc. are published in Cell and Materials1991, sup.1,69-74).Vascular smooth muscle cells migration detects
Use rat and people's aortic smooth muscle cell.In Transwell cell camera incubata, a kind ofly there is the polycarbonate membrane in 8 μ m holes (Costar) to monitor cell migration by using.The lower surface of filter is with vitronectin bag quilt.Cell is with 2.5-5.0 * 10 6The concentration of individual cell/ml is suspended among the DMEM that is supplemented with 0.2% bovine serum albumin, and in the time of 20 ℃ earlier with the experimental compound pretreatment of various concentration 20 minutes.Independent solvent is used as contrast.0.2ml cell suspending liquid is placed in the camera incubata upper strata.The 0.6ml DMEM that replenishes with 0.2% bovine serum albumin is contained in lower floor.Hatch in 37 ℃ at 95% air/5%CO 2Carried out in the gas 24 hours.After hatching, scrape off the not migrating cell on the filter upper surface gently.Then with the filter fixation in methanol, with the dyeing of 10%Giemsa coloring agent.Can pass through a) to count to fit to move on to the cell number of filter lower surface or pass through b) with 10% acetic acid extraction staining cell, measure two kinds of methods of trap in 600nm then and measure migration.The parathyroidectomy rat model
Each experimental group comprises 5-6 male Sprague-Dawley rat.Use and these rats were carried out parathyroidectomy (being carried out Taconic Farms by the seller) in preceding 7 days.Use preceding 24 hours (be tail vein get blood be placed in the anticoagulant heparin test tube back) to measure the concentration of circulation ionized calcium in whole blood immediately.Selection comprises that those ionized calcium levels (Cika-Comingmodel 634 calcium pH analysis-e/or determinings) are the rats of 1.2mM/E.The diet of rat is not calcareous food and deionized water then.During the experiment beginning, the body weight of rat is about 100g.Measure basic calcium level, rat is given control vector (saline) or chemical compound (being dissolved in the saline) in the mode of single vein (tail vein) medicine agglomerate injection then, single subcutaneous injection is gone into parathyroid hormone 1-34 peptide (hPTH1-34 immediately then, dosage be 0.2mg/kg in saline/0.1% bovine serum albumin, Bachem, Ca) or the PTH carrier.Measured the response (with chemical compound any effect to this response) of blood calcium after chemical compound/PTH administration in 2 hours to PTH.Rat ulna drift model
During the experiment beginning, each experimental group comprises that the only male body weight of 8-10 is approximately Sprague-Dawley or the Wistar rat of 30-40g.Underproof reagent is with suitable administration 7 days, the administration of daily dose single or multiple.Before the dosed administration, give the fluorescent marker (tetracycline 25mg/kg, or calcein 10mg/kg) of rat single dose, for the first time in order to be marked at the position on time point bone formation surface at that time.After compound administration is finished, kill rat and cut away two forelimbs, cut away foot, divest skin in ankle at the elbow place.Freezing sample and it vertically is placed on the microtome chuck.On the constant temperature microtome, the cross section of ulna middle part is cut into slices.In cortical bone-back measures the re-absorbed ratio of bone with morphometry.Assay method is as follows: periosteum surface bone is equaled the distance that move to mark on the periosteum surface by re-absorbed amount, and mark and the 0th day inner membrance bone formation surfaces mate are also.Calculate this distance by the width that deducts bone between perimyelis surface and the mark from the 0th day width; The result is the heavily absorption ratio of every day in micron divided by 7.The human body osteoclast heavily absorbs the deutero-cell suspending liquid of osteoclastoma is taken out in check (" PIT check ") from the liquid nitrogen bin aliquot, rapidly in 37 ℃ of intensifications, and centrifuge washing once (1000rpm, 5min, 4 ℃) in the PRMI-1640 medium.Extract medium out, with anti--HLA-DR antibody replacement of Mus, this antibody uses RPMI-1640 with dilution in 1: 3.Hatched 30 minutes on ice, and stir cell suspension frequently.By centrifugal (1000rpm, 5min, 4 ℃) washed twice, cell is transferred in the disinfectant 15ml centrifuge tube cell with cold RPMI-1640.Number goes out monocytic quantity in the Neubauer counting chamber of improvement.From storage bottle, take out enough magnetic beads (5/ mononuclear cell), insert in the 5ml fresh medium and (remove the deleterious azide that may exist) with anti--Mus IgG bag quilt of sheep.Magnetic bead is fixed on the Magnet to remove medium, the replacement of reuse fresh medium.Magnetic bead and mixing with cells, suspension constantly stirs suspension in hatching 30 minutes on ice.Bag is fixed on the Magnet by the cell of magnetic bead, and remaining cell (osteoclast is enriched part) is introduced in the disinfectant 50ml centrifuge tube.With fresh medium add bag by in the cell of magnetic bead so that the osteoclast that is adsorbed break away from.This washing process repeats 10 times.Bag is discarded by the cell of pearl.Use the disposable plastics Pasteur of a macropore to place the chamber that sample is housed, number goes out osteoclast in counting chamber.Becoming piller by the centrifugal cell that makes, is 1.5 * 14 at the EMEM medium with the osteoclast concentration adjustment 4Ml, additional with the sodium bicarbonate of 10% hyclone and 1.7g/l.Every deal 3ml of cell suspension (the each processing) is introduced in the 15ml centrifuge tube.By centrifugal cell is become piller.3ml through suitably handling is added in each pipe and (is diluted to 50 μ M in the EMEM medium).Also comprise appropriate carriers contrast, positive control (being diluted to 100 μ g/ml in the 87 MEM1 media) and a kind of homotype contrast (IgG2a is diluted to 100 μ g/ml).Hatched 30 minutes for 37 ℃.The per minute amount 0.5ml of cell is inoculated on the dentine thin slice of aseptic 48-hole flat board, hatches 2 hours at 37 ℃.The each processing all monitored to quadruplicate.Through the warm PBS (10ml/ hole in six hole flat boards) of six replacings washing thin slice, place new processing or contrast then.Hatched 48 hours for 37 ℃.The acid p'tase of anti-tartrate (TRAP) method (the cell selective coloring agent of osteoclast pedigree).In phosphate buffered saline (PBS), wash thin slice, fix 5 minutes among the gluteraldehyde 2% (glutaraldehyde) (in the sodium dimethyl arsine of 0.2M).Wash them in the water, in the time of 37 ℃, hatched 5 minutes in the TRAP buffer.After the washing, it was hatched 5 minutes in cold acetate buffer/fast red garnet in 4 ℃ in the cold water.Excessive buffer is drained, and thin slice is air drying after water washing.With the positive osteoclast of clear zone microscopic counting TRAP, remove osteoclast with supersound process from dentin surface then.With Nikon/LasertecILM21W with focus measurement microscope indenture volume.Human osteoclast absorbs with adhesion again to be checked
Normal person's osteoclast that use derives from the osteoclast tumor tissue carries out that indenture absorbs and adhesion is checked and grown up and form standardization.(Dynal Inc, NY) the non-osteoclast oncocyte that is selected from mixes liquid to osteoclast group with magnetic bead.These magnetic beads monoclonal antibody bag quilt of Mus, this antibody can be discerned human body II type major histocompatibility antigen, and above-mentioned antigen is present in the cell suspension.Use Magnet in cell mixture, to remove can to express this antigen and subsequently with the bonded cell of magnetic bead.The suspension that will be rich in osteoclast then is ready in the check under being specified in.Absorb check (using the ELISA reading method)
Arise from 37 ℃ of preincubates 30 minutes with being rich in the prepared product of osteoclast and experimental compound (4 dosage) or tester one.Then it is inoculated on the calf cortical bone thin slice, this thin slice and was further hatched 2 hours at 37 ℃ in the hole of 48-hole tissue incubation flat board.This bone thin slice washs to remove not AC with the warm phosphate buffered saline (PBS) (PBS) of six replacings, then it is placed again the hole of the 48 hole flat boards that contain new system chemical compound or tester.Then tissue incubation's flat board was hatched 48 hours in 37 ℃.The extraction of supernatant in each hole is placed different test tubes, monitor among the emulative ELISA of the collagen polypeptide that in can being determined at heavy absorption process, discharges.This be a kind of can be available from the ELISA (Osteometer of commerce, Denmark), it contain a kind of can be specifically and the rabbit antibody of a kind of 8-amino acid series (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg) reaction, above-mentioned amino acid series is present in the carboxyl-terminal tail peptide of the α 1-chain of I Collagen Type VI.The result is expressed as with the absorption relatively of vehicle Control thing and suppresses.
The adhesion check
Derive from the osteoclast of osteoclastoma and chemical compound (4 dosage) or tester one and arise from 37 ℃ of preincubates 30 minutes.(osteopontin of people or Mus 2.5ug/ml) and in 37 ℃ was hatched 2 hours on the fragmentation that is surrounded by osteopontin with cell inoculation then.Violent washing slide is removed not AC in PBS, and the cell that is retained on the slide is fixing in acetone.Acid phosphatase (TRAP) to the tartrate-resistant acid phosphatase of osteoclast dyes, and this enzyme is a kind of selected marker of dominance cell, counts by optical microscope then.The result is expressed as with the adhesion relatively of vehicle Control thing and suppresses %.The purification of the bonded inhibition of the GP II b-III a GP III b-III a of RGD-mediation
Octyl glucoside 3%, 20mM Tris-HCl, pH 7.4 140mM NaCl, 2mM CaCl 2In, in the time of 4 ℃, stirred gently 2 hours, with the out of date human blood platelets that has washed (the deriving from Red Cross) dissolving of 10 units.Lysate centrifugal 1 hour with 100000g.The gained supernatant be added to 5ml through 20mM Tris-HCl, pH 7.4 140mM NaCl, 2mM CaCl 2The Radix Crotalariae szemoensis lectins agar gel 4B post (E.Y.Labs) of the pre-equilibration of 1% Octyl glucoside (buffer A).After hatching in 2 hours,, keep lectins GP II b-III a with the buffer A eluting that contains 10% glucose with 50ml cold buffer liquid A washing pillar.All processes are all carried out at 4 ℃.Shown in sds polyacrylamide gel electrophoresis, resulting GP II b-III a purity＞95%.The combination of GP III b-III a in the liposome
Under nitrogen current, with the mixture drying of phosphatidyl serine (70%) and lecithin (30%) (Avanti PolarLipids) on the glass tubing tube wall.It is 0.5mg/ml that the GP II b-III a of purification is diluted to ultimate density, and with albumen: the ratio of phospholipid is 1: 3 (w: w) mix with phospholipid.Mixture is suspendible again, and ultrasonic molten in supersound process 5 minutes.Use the Dialysis tubing that blocks of 12000-14000 molecular weight, to 1000 times of excessive 50mMTris-HCl, pH 7.4 with mixture, 100mM NaCl, 2mM CaCl 2(changing 2 times) dialyzed overnight.The liposome that contains GP II b-III a centrifugal 15 minutes with 12000g, and be suspended in again in the dialysis buffer liquid, final proteinic concentration is about 1mg/ml.Liposome is stored in-70 ℃ when needs.
Combine with the competition of GP II b-III a
Use [ 3H]-SK﹠amp; F-10726 is as the part of RGD-type, detects and fibrinogen deceptor (GP II b-III combining a) with the bonded method of indirect competition.Use the hydrophilic porous film of 0.22 μ m, filter board device (Millipore Corporation, Bedford finish in conjunction with detecting in MA) in 96 holes.Eyelet is at room temperature used the 10 μ g/ml polylysines of 0.2ml, and (SigmaChemical Co., St.Louis MO) wrap by 1 hour to block nonspecific combination in advance.Unlabelled benzodiazepine _ various concentration be added in the eyelet in quadruplicate.[ 3H]-SK﹠amp; F-10726 is added in each eyelet with ultimate density 4.5nm, adds the platelet liposome that contains purification of the GP II b-III a of 1 μ g then.Mixture was at room temperature hatched 1 hour.Filter by using Mullipore to filter manifold, with GP II b-III a-in conjunction with [ 3H]-SK﹠amp; F-10726 separates with unconjugated, then with the washing of ice-cold buffer (2 times, each 0,2ml).(Beckman nstrucments, Fullerton, the CA efficient with 40% in Beckman liquid scintillation counter (Model LS 6800) is counted the bonded radioactivity that still remaines on the filter at 1.5mlReady Solve.At the unlabelled SK﹠amp of 20 μ m; Measure non-specific binding among the F-10726, should be consistent less than being added to 0.14% of gross activity in the sample.All data points all are the meansigma methodss of four parts of measured values.
By the competitive bonded data of non-linear least square diagram method program analysis.This method can provide the IG of antagonist 50(when balance, suppress [ 3H]-SK﹠amp; The concentration of the fixed antagonist in conjunction with 50% o'clock of F-107260).IG 50Equilibrium dissociation constant (K with antagonist i) relevant, according to Chemg and Prusoff equation: K i=IC 50/ (1+L/K d), wherein L be used to compete in conjunction with check [ 3H]-SK﹠amp; The concentration of F-107260 (4.5nM), K dBe [ 3H]-SK﹠amp; The dissociation constant of F-107260, Scatchard assay determination are 4.5nM.
Chemical compound of the present invention suppresses vitronectin and SK﹠amp; The combination of F007260 is to the K of this chemical compound of Vitronectic receptor iFor about 10 times to value to fibrinogen deceptor.The K that preferred compound has iValue to 30 times of Vitronectic receptors to fibrinogen deceptor.The K that most preferred compound has iValue to 100 times of Vitronectic receptors to fibrinogen deceptor.
The embodiment of back never is intended to limit the scope of the invention, and how to prepare and uses chemical compound of the present invention but be used for describing.For those skilled in the art, many other embodiments also are conspicuous.
Ordinary circumstance
Can be respectively with Brkuer AM 250 or Bruker 400 spectrogrphs in 250 or 400MHz record nuclear magnetic resoance spectrum.CDCl 3Be deteriochloroform, DMSO-d 6Be six deuterium dimethyl sulfoxide, CD 3OD is four deuterium methanol.With several (δ) record chemical shift that divides to low field offset percentage from interior mark tetramethylsilane.The abbreviation of NMR data is as follows: S=is unimodal, d=is bimodal, t=three peaks, q=four peaks, m=multimodal, dd=double doublet, dt=are three bimodal, app=significantly, the br=broad peak.J represents the NMR even summation constant of measuring in Hertz.Record continuous wave band infrared (IR) spectrum on Perkin-Elmer 683 infrared spectrometers.Record Fourier shifts infrared (FTIR) spectrum on Nicolet Impact400D infrared spectrometer.With radiation pattern record IR and FTIR spectrum, with the inverse (cm of wavelength -1) record infrared grade the position.With fast atom bombardment (FAB) or electronic spraying (ES) ionization techniques,, write down mass spectrum on PE Syx API III or the VG ZAB HF instrument in VG70FE.Use Perkin-Elmer 240C elemental analyser can obtain elementary analysis.Measure fusing point and be corrected in Thomas-Hoover fusing point instrument.Degree centigrade to write down all temperature.
Analtech Silica Gel GF and E.Merck.Silica Gel 60 F-254 lamellaes are used to thin layer chromatography.Quick and gravity chromatograph is carried out on E.Merck Kieselgel 60 (230-400 order) silica gel.Analyze and prepare HPLC and on Rainin or Beckman chromatograph, carry out.ODS refers to the deutero-silica gel column chromatography immobile phase of a kind of octadecane silicyl.It is the deutero-silica gel column chromatography immobile phase of octadecyl silicyl of 5 μ m that 5 μ Apex-ODS refer to have demarcation particle size, and it is by Jones Chromatography Littleton, and Colorado produces.YMCODS-AQ _Be a kind of by YMC Co.Ltd., Kyoto, the trade mark of Japan registration also is a kind of ODS chromatographic stationary phase.PRP-1 _Be Hamilton Co., Reno, the registered trade mark of Nevada is a kind of polymer (styrene-divinylbenzene) chromatographic stationary phase.Celite _By the filter aid that the kieselguhr of pickling is formed, be Manville Corp., Denver, the registered trade mark of Colorado.
Equal method preparation (±)-7-carboxyl-4-methyl-3-oxo-2 of WO 93/00095 according to Bondinell, 3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (2S)-and 7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (2R)-and 7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-7-carboxyl-4-isopropyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-7-carboxyl-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-8-carboxyl-2-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-2-benzo-aza _-the 4-methyl acetate, (±)-7-amino-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate and the 4-fluoro-3-ar-Toluic acid tert-butyl ester.According to P50256-1 preparation (±)-7-carboxyl-4-(2-methoxy ethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-7-carboxyl-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-7-carboxyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate, (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid, 2-(methylamino methyl) benzimidazole dihydrochloride and 4-azepine-5-methyl-2-(methylamino) tolimidazole.
Preparation 1
The preparation of 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride
A) 2,3-diaminourea-6-picoline
With 10%Pd/C (3.2g, 3mmol) add to 2-amino-6-methyl-3-nitro pyridine (2.30g, 15mmol) in the solution in dehydrated alcohol (150ml), the described mixture of jolting under room temperature hydrogen (50psi) environment.1.5 after hour, pass through celite _Filter described mixture, vacuum concentrated filtrate obtains the target compound into yellow oil.With it without being further purified application:
1H?NMR(250MHz,CD 3OD)δ6.82(d,1H),6.36(d,1H),2.25(s,3H).
B) 2-amino-3-[(benzyloxycarbonyl) glycyl] amino-6-picoline
(3.09g 15mmol) adds to 2, and (3.14g is 15mmol) in the solution in DMF (19ml) and dichloromethane (19ml) for 3-diaminourea-6-picoline (15mmol) and Cbz-glycine with DCC under 0 ℃ of ar gas environment.After DCC dissolving, the solution of slight muddiness is warmed to room temperature.18.5 after hour, pass through celite _Filter described mixture, and on Rotary Evaporators (rotavap), be concentrated into filtrate dried.Residue reconcentration (removing DMF) in dimethylbenzene is obtained yellow solid.Through silica gel column chromatography (10%MeOH/CHCl 3Eluting) obtains being yellow solid target compound (2.24g, 48%): TLCR f(10%MeOH/CHCl 3) 0.57; 1H NMR (250MHz, DMSO-d 6) δ 9.11 (brs, 1H), 7.48-7.60 (brt, 1H), 7.20-7.48 (m, 6H), 6.40 (d, 1H), 5.69 (brs, 2H), 5.06 (s, 2H), 3.82 (d, 2 H), 2.23 (s, 3H).
C) 4-azepine-2-(benzyloxycarbonyl) amino methyl-5-tolimidazole
Reflux 2-amino-3-[(benzyloxycarbonyl under ar gas environment) glycyl] amino-6-picoline (2.24g, 7.13mmol) solution in glacial acetic acid (70ml).After 17 hours, concentrate described solution (Rotary Evaporators, high vacuum), with residue reconcentration (removal acetic acid) in toluene.Handle the yellow oil of generation and described mixture is chilled to room temperature with the ethyl acetate (20ml) of heat.Wash the target compound (1.72g, 81%) that obtains to pale solid by suction filtration collection solid and with ethyl acetate:
TLC?R f(15％MeOH/CHCl 3)0.63；MS(ES)m/e?297.4(M+H) +.
D) 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride
(153mg, (213.4mg, 0.72mmol) (1.44ml is 1.44mmol) in the solution in dehydrated alcohol (7.2ml) with 1.0N HCl 0.14mmol) to add to 4-azepine-2-(benzyloxycarbonyl) amino methyl-5-tolimidazole with 10%Pd/C.In described mixture, feed hydrogen, under hydrogen environment (balloon) room temperature, stir fast then.After 2 hours, by the described reactant of diatomite filtration, concentrated filtrate obtains the target compound into pale solid: MS (ES) m/e 163.2 (M+H) on Rotary Evaporators +
Preparation 2
(±)-2,3,4,5-tetrahydrochysene-7-carboxyl-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-methyl acetate
A) 3-[(3, the 3-dimethylbutyl) amino] methyl-4-nitrobenzoyl tert-butyl acrylate
Reflux 3-methyl-(WO 93/00095 for 4-nitrobenzoyl tert-butyl acrylate; 17.7g, 74.7mmol), NBS (19.9g, 112.0mmol), benzoyl peroxide (1.81g, 7.47mmol) and the mixture of carbon tetrachloride (370ml).17.5 after hour, described reactant is thoroughly cooled off in ice and filtration removal butanimide precipitation.Concentrated filtrate obtains pale brown color grease.
With this grease (4.2g 13.29mmol) is dissolved among the anhydrous THF (50ml) and disposable immediately adding 3, the 3-dimethyl butylamine (3.0g, 29.64mmol).Under room temperature,, concentrate then and remove THF orange colour solution stirring 80 minutes.Wash with 1.0N sodium hydroxide (25ml) and water (25ml) with ether (150ml) dilution residue and order.Return the extraction combining water layer with ether (50ml), with organic layer and dry (magnesium sulfate) of saline (25ml) washing merging.Concentrate and to obtain the thick target compound of light brown oily thing that is: MS (ES) m/e 337.2 (M+H) +
B) 3-[[N-(3, the 3-dimethylbutyl)-N-(tert-butoxycarbonyl)] amino] methyl-4-nitrobenzoyl tert-butyl acrylate
Under room temperature with bicarbonate di tert butyl carbonate (4.0g, 18.39mmol) the disposable 3-[(3 that adds to, 3-dimethylbutyl) amino] in the solution of methyl-4-nitrobenzoyl tert-butyl acrylate (4.12g, 1 2.26mmol) in chloroform (80ml).After 18 hours, concentrate described reactant and reconcentration (removal chloroform) in hexane.Obtain target compound (5.0g, 93%) through silica gel column chromatography (10-25% ethyl acetate/hexane eluting): MS (ES) m/e 437.2 (M+H) into yellow oil +, 459.2 (M+Na) +
C) 4-amino-3-[[N-(3, the 3-dimethylbutyl)-N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester
With 10%Pd/C (1.0g, 0.94mmol) add to 3-[[N-(3, the 3-dimethylbutyl)-and N-(tert-butoxycarbonyl)] amino] methyl-4-nitrobenzoyl tert-butyl acrylate (4.95g, 11.35mmol) in the solution in ethyl acetate (50ml), and under hydrogen environment (55psi) room temperature with the described mixture of Parr device jolting.After 4 hours, pass through celite _Filter described reactant, concentrated filtrate obtains being the target compound of rufous grease (4.3g, 93%): MS (ES) m/e 407.4 (M+H) +
D) (±)-4-[2-(1,4-dimethoxy-1,4-dioxo butyl) amino]-3-[[N-(3, the 3-dimethylbutyl)-N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester
With 4-amino-3-[[N-(3, the 3-dimethylbutyl)-and N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester (5.6g, 13.79mmol) and dicarboxylic acids 2-butyne ester (1.86ml, 15.17mmol) vlil in methanol (28ml) is 1 hour, is chilled to room temperature then.With the solution that produces and methanol (80ml) and 10%Pd/C (2.9g, 2.76mmol) merging, and under hydrogen environment (50psi) room temperature on the Parr device the described mixture of jolting.After 22 hours, pass through celite _Filter described reactant, filtrate is concentrated on Rotary Evaporators.With residue reconcentration (removal methanol) in chloroform, then through silica gel column chromatography (with 25% ethyl acetate/hexane eluting).Obtain the target compound (2.64g, 42%) of faint yellow oily: MS (ES) m/e 551.2 (M+H) +
E) (±)-2,3,4,5-tetrahydrochysene-7-carboxyl-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
In 0 ℃ with disposable (±)-4-[2-(1 that adds to of TFA (25ml), 4-dimethoxy-1,4-dioxo butyl) amino]-3-[[N-(3, the 3-dimethylbutyl)-and N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester (12.64g, 4.8mmol) in the solution of anhydrous methylene chloride (25ml), faint xanchromatic solution is warmed to room temperature.After 1 hour, on Rotary Evaporators, concentrate described solution, reconcentration residue from toluene (removing residual TFA).With residual grease and toluene (50ml) and Et 3(3.34ml 24mmol) merges the described mixture of reflux to N.Produce the solution of faint yellow homogeneous.After 16 hours, on Rotary Evaporators, concentrate described reactant liquor and obtain solid residue.It is dissolved in a spot of methanol (about 10ml), and water (10ml) dilution is acidified to pH4.5 with glacial acetic acid.Filter described mixture, order is washed described precipitation with methanol and ether, then the dry almost colourless powder target compound (1.88g, 93%) that obtains under high vacuum: MS (ES) m/e 363.2 (M+H) +
Preparation 3
The preparation of two [(benzimidazolyl-2 radicals-yl) methyl] amine three (trifluoroacetate)
A) two [[1-N-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl] methyl]-N-(tert-butoxycarbonyl) amine
With 1-(tert-butoxycarbonyl)-2-(bromomethyl) benzimidazole (P50256-1,2.00g, 9.48mmol) solution in THF (30ml) adds to 2-amino methyl benzimidazole dihydrochloride hydras (6.26g, 28.4mmol) and triethylamine (4.0ml is 28.4mmol) in the solution of the stirring in anhydrous THF (50ml).After 8 hours, slowly add bicarbonate di tert butyl carbonate (10.0g, 45.84mmol) solution in chloroform (50ml).Under room temperature, spend the night the mixture stirring that produces concentrated then.Residue is absorbed in the dichloromethane (150ml) order water (60ml), 5% sodium bicarbonate (60ml) and saline (60ml) washing.Dry (magnesium sulfate) concentrates, and obtains target compound (0.46g, 8%) into faint yellow oil through silica gel column chromatography (6% ethanol/methylene eluting): MS (ES) m/e 578.4 (M+H) +
B) two [(benzimidazolyl-2 radicals-yl) methyl] amine three (trifluoroacetate)
Under room temperature with the solution of TFA (3ml) and dichloromethane (9ml) disposable add to two [[1-N-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl] methyl]-N-(tert-butoxycarbonyl) amine (0.23g, 0.4mmol) in.After 35 minutes, on Rotary Evaporators, concentrate described solution, residue reconcentration (removing residual TFA) in toluene is obtained target compound (0.17g, 68%) into pale powder: MS (ES) m/e 278.0 (M+H) +
Preparation 4
The methyl of 2-[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazole] methyl] preparation of amine two (triacetate)
A) [[1-N-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl] methyl]-N-(tert-butoxycarbonyl) amine
In 0 ℃ with bicarbonate di tert butyl carbonate (6.54g, 30.0mmol) solution in dichloromethane (50ml) adds to 2-amino methyl benzimidazole dihydrochloride hydras (3.0g, 13.63mmol) and triethylamine (8.44ml is 61.3mmol) in the solution of the stirring in anhydrous methylene chloride (50ml).Under room temperature, described reactant was stirred 1 hour, add then more triethylamine (1.9ml, 13.8mmol) and the bicarbonate di tert butyl carbonate (2.97g, 13.63mmol).The mixture that stirring generates under room temperature 24 hours, reconcentration.Be absorbed in residue in the dichloromethane (50ml) and order 0.5NHCl (2 * 40ml), 5% sodium bicarbonate (50ml) and saline (50ml) washing.Make thick product recrystallization from dichloromethane/ether obtain target compound (2.8g, 59%): MS (ES) m/e 348.2 (M+H) into white powder +
B) 2-[[1-[[(1-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl] methyl] benzimidazole] methyl]-N, N-two-(tert-butoxycarbonyl) amine
With 1-(tert-butoxycarbonyl)-2-(bromomethyl) benzimidazole (0.6g, 1.93mmol) add to [[1-N-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl] methyl]-N-(two tert-butoxycarbonyls) amine (0.6g, 1.73mmol) and sodium hydride (0.1g is 4.17mmol) in the solution of the stirring in anhydrous THF (12ml) and DMF (4ml).Under room temperature, the mixture that produces was stirred 1 hour, concentrate then.Residue is absorbed in the dichloromethane (100ml), then order water (50ml), 5% sodium bicarbonate (30ml) and saline (30ml) washing.Dry (magnesium sulfate) concentrates, and obtains target compound (0.27g, 27%) into faint yellow oil through silica gel column chromatography (2: 3 ethyl acetate/hexane eluting): MS (ES) m/e 578.2 (M+H) +
C) methyl of 2-[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazole] methyl] amine two (trifluoroacetate)
Under room temperature with all TFA/CH 2Cl 2Disposable 2-[[1-[[(1-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl that adds to of (30ml, 25%) solution] methyl] benzimidazole] methyl]-N, N-two-(tert-butoxycarbonyl) amine (0.25g, 0.43mmol) in.After 25 minutes, on Rotary Evaporators, concentrate described solution, make thick product recrystallization in dichloromethane/ether obtain target compound (0.17g, 63%): MS (ES) m/e 278.0 (M+H) into pale powder +
Embodiment 1
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with EDC (138mg, 0.72mmol) add to (±)-7-carboxyl-4-(2-methoxy ethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (202mg, 0.60mmol), 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride (0.72mmol), HOBt.H 2O (97mg, 0.72mmol) and diisopropylethylamine (0.84ml is 4.8mmol) at anhydrous CH 3In the solution among the CN (3ml).After 16 hours, concentrate described reactant, reconcentration residue in dimethylbenzene/chloroform.Obtain target compound (impure) through silica gel column chromatography (15% methanol/chloroform): TLC R f(15% methanol/chloroform) 0.55; MS (ES) m/e 481.5 (M+H) +Without being further purified use.
B) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with biphase (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.60mmol), 1.0N LiOH (1.8ml, 1.8mmol) and the mixture of THF (4.2ml) stirred 45 minutes, concentrate then and remove THF.(2 * 2ml) wash water layers, and discard ether layer with ether.Also use TFA (0.23ml) acidify with acetonitrile (2ml) dilution water layer.The solution that concentrate to produce on rovatap is to doing, with residue through ODS chromatography purification (O.1%TFA 12% acetonitrile/water contains (250ml), and 15% acetonitrile/water contains 0.1%TFA then).Concentrated and lyophilization obtains the target compound (199.5mg, 50% liang of step productive rate) into pale yellow powder:
HPLC (PRP-1_, 15%CH 3CN/H 2O contains 0.1%TFA) K 1=1.4; MS (ES) m/e 467 (M+H) +. value of calculation C 23H 26N 6O 51.5CF 3CO 2H1.33 H 2O:C, 47.21; H, 4.60; N, 12.70. measured value: C, 47.20; H, 4.73; N, 12.79.
Embodiment 2
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with EDC (230mg, 1.2mmol) add to (±)-7-carboxyl-4-(2-methoxy ethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (336.4mg, 1.0mmol), 2-(amino methyl) benzimidazole dihydrochloride hydras (264mg, 1.2mmol), HOBt.H 2O (162mg, 1.2mmol) and diisopropylethylamine (0.70ml is 4.0mmol) in the solution in dry DMF (5ml).After 17 hours, concentrate described reactant, in dimethylbenzene (2x) with the concentrated residues thing to remove DMF.Water (3ml) dilution residue is with chloroform (3 * 5ml) extractions.The extract that handle to merge with methanol (2ml) is with dissolution precipitation, then dry (magnesium sulfate) and concentrate.Reconcentration in dimethylbenzene (removing residual DMF) residue faint yellow solid.It is dissolved in methanol/chloroform, and concentrated described solution obtains grease.Obtain pale solid through silica gel column chromatography (10% methanol/chloroform), it is ground the target compound (397.1mg, 85%) that obtains to colorless solid with ethyl acetate (3ml): TLC R f(10% methanol/chloroform) 0.46; MS (ES) m/e 466.2 (M+H) +
B) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (1.0ml, 1.0mmol) add to (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-(397mg is 0.85mmol) in the suspension in THF (4.3ml) and water (3.3ml) for the 2-methyl acetate.In 40-50 ℃ flaxen mixture was stirred 1 hour, then under room temperature with the solution stirring of the homogeneous that produces 17.5 hours.Concentrate described reactant, in the grease water-soluble (4ml) that produces.Filter described solution removal microgranule, use 1.0N hydrochloric acid (1.0ml) neutralization filtrate then.Collect xanchromatic solid and under fully stirring, grind with 1: 1 acetonitrile/water of heat.The solid that collect to produce washs with a large amount of 1: 1 acetonitrile/water, and (40 ℃) drying obtains target compound (327.9mg, 85%) into colourless powder under high vacuum:
HPLC (PRP-1_, 15%CH 3CN/H 2O contains 0.1%TFA) K '=4.6; MS (ES) m/e 452.2 (M+H) +. value of calculation C 23H 25N 5O 5: C, 61.19; H, 5.58; N, 15.51. measured value: C, 61.18; H, 5.58; N, 15.39.
Embodiment 3
The methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-preparation of 3-phenylbutyric acid
A) 3-hydroxyl-4-(4-methoxyphenyl)-3-phenylbutyrate
In-78 ℃ of ar gas environments down with 5-6 minute with anhydrous ethyl acetate (4.3ml, 44mmol) drop to two (trimethyl silyl) lithamides (1.0M in THF, 40ml, 40mmol) in anhydrous THF (60ml) in flame-dried flask in the solution.In-78 ℃ yellow solution was stirred 0.5 hour, then with 12 minutes dropping 2-(4-methoxyphenyl)-1-phenyl ethyl ketone (Chem.Ber.1958,91,755-759; 4.53g, the 20mmol) solution in anhydrous THF (20ml).Use other THF (2ml) as transfer agent.0.5 after hour, with the described reactant of saturated ammonium chloride (120ml) quenching and be warmed to room temperature.Use ethyl acetate extraction, dry (magnesium sulfate) concentrates, and obtains target compound (6.13g, 96%) into faint yellow oily thing through silica gel column chromatography (20% ethyl acetate/hexane):
TLCR f(20%EtOAc/ hexane) 0.34; MS (ES) m/e 315.2 (M+H) +.
B) 4-(4-methoxyphenyl)-3-phenylbutyrate
Descend with 3 minutes trifluoroboranes etherate (4.8ml in 0 ℃ of ar gas environment, 39mmol) drop to 3-hydroxyl-4-(4-methoxyphenyl)-3-phenylbutyrate (6.13g, 19.5mmol) and triethyl silicane (6.2ml is 39mmol) in the solution in anhydrous methylene chloride (49ml).Under room temperature, described reactant stirring is spent the night, use 5% sodium bicarbonate (100ml) quenching then.Described mixture was stirred 10 minutes fast, separate then.With dichloromethane (100ml) aqueous layer extracted, the organic layer that dry (sodium sulfate) merges also concentrates.With residue from the residual yellow oil of hexane (removal dichloromethane) reconcentration.It is dissolved in dehydrated alcohol (100ml), and adding 10%Pd/C (775mg, 1.95mmol).Under room temperature hydrogen (50psi) environment on the Parr device the described mixture of jolting 2 hours, pass through celite then _Filter.Concentrated filtrate, with residue through silica gel column chromatography (15% ethyl acetate/hexane).Obtain to be the target compound of colorless oil (5.27g, 91%): TLCR f(15%EtOAc/ hexane) 0.40; MS (ES) m/e 299.2 (M+H) +.
C) 4-(4-hydroxy phenyl)-3-phenylbutyrate
Under 0 ℃ of ar gas environment with all aluminum trichloride (anhydrous) (4.49g, 33.7mmol) disposable 4-(4-the methoxyphenyl)-3-phenylbutyrate (2.01g that adds to, 6.74mmol) and ethyl mercaptan (2.5ml is 33.7mmol) in the solution in anhydrous methylene chloride (67ml).Xanchromatic solution is warmed to room temperature and stirs 3 hours, and then be chilled to 0 ℃ also with the cold hydrochloric acid of 3N (67ml) quenching.Described mixture was stirred 5 minutes, separate then.(2 * 100ml) aqueous layer extracted, the organic layer that dry (sodium sulfate) merges also concentrates with dichloromethane.Obtain target compound (1.84g, 96%) through silica gel column chromatography (25% ethyl acetate/hexane) into colorless oil:
TLC R f(30%EtOAc/ hexane) 0.47; MS (ES) m/e 285.2 (M
D) 3-phenyl-4-[4-(trifluoro-methanesulfonyl oxy) phenyl] ethyl n-butyrate.
Under-78 ℃ of ar gas environments with trifluoromethanesulfanhydride anhydride (1.4ml, 8.4mmol) drop to 4-(4-hydroxy phenyl)-3-phenylbutyrate (1.84g rapidly, 6.47mmol) and 2, (1.5ml is 12.9mmol) in the solution in anhydrous methylene chloride (32ml) for the 6-lutidines.0.5 after hour, described yellow solution be warmed to room temperature and stirred 1 hour.Wash with 1.0N hydrochloric acid (15ml), 5% sodium bicarbonate (15ml) and saturated brine (15ml) with ether (150ml) described reactant of dilution and order.Dry (magnesium sulfate) concentrates, and obtains the target compound (2.62g, 97%) of almost colourless grease: TLCR through silica gel column chromatography (15% ethyl acetate/hexane) f(20%
The EtOAc/ hexane) 0.55; MS (ES) m/e 417.0 (M+H) +.
E) 4-(4-carboxyl phenyl)-3-phenylbutyrate
To 3-phenyl-4-[4-(trifluoro-methanesulfonyl oxy) phenyl] ethyl n-butyrate. (2.62g, 6.29mmol), anhydrous acetic acid potassium (2.47g, 25.16mmol), Pd (OAc) 2(70.6mg, 0.31mmol), dppf (697.4mg, 1.26mmol) and the mixture of anhydrous DMSO (31ml) in feed carbon monoxide (three emptyings/charge into the circulation of carbon monoxide, and then in mixture, fed carbon monoxide 5 minutes), then in the heating down of 70 ℃ of carbon monoxides.3.5 after hour, water (31ml) dilution, in cooled on ice, with 1.0N hydrochloric acid (25ml) acidify, (2 * 100ml) extractions, dry (magnesium sulfate) concentrates the liquid of the residual tangerine color of reconcentration in toluene with dichloromethane.Obtain being the solid target compound of cream color (1.78g, 91%) through silica gel column chromatography (7: 3 toluene/ethyl acetate of 1%AcOH):
TLC R f(7: 3 toluene of 1%AcOH in/EtOAc) 0.47; MS (ES) m/e 313.2 (M+H) +.
F) methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-the 3-phenylbutyrate
Under room temperature with EDC (230mg, 1.2mmol) add to 4-(4-carboxyl phenyl)-3-phenylbutyrate (312.4mg, 1.0mmol), 2-(methylamino methyl) benzimidazole dihydrochloride (28lmg, 1.2mmol), HOBt.H 2O (162mg, 1.2mmol) and diisopropylethylamine (0.70ml is 4.0mmol) in the solution in anhydrous acetonitrile (5ml).After 18 hours, concentrate described reactant, with brown residue through silica gel column chromatography (5%MeOH 1: 1 ethyl acetate/chloroform in).Obtain to be the target compound of light Fructus Citri tangerinae color foam (439.2mg, 96%): TLC R f(5%MeOH was in 1: 1 EtOAc/CHCl 3) 0.50; MS (ES) m/e 456.2 (M+H) +.
G) methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-the 3-phenylbutyric acid
Stir the methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl) in 50 ℃] methylamino] carbonyl] phenyl]-the 3-phenylbutyrate (439.2mg, 0.96mmol) and 1.0N sodium hydroxide (1.2ml, 1.2mmol) solution in ethanol (8.4ml).After 24 hours, described reactant is concentrated into dried, with residue through ODS chromatography (35% methanol) purification.Concentrated and lyophilization obtains the target compound (412.2mg, 86%) into colourless powder: HPLC (PRP-1_, 35%CH 3CN/H 2O contains 0.1%TFA) K1=1.4; MS (ES) 428 (M+H) +, 450 (M+Na) -. value of calculation C 26H 24N 3O 3Na2.75H 2O:C, 62.58; H, 5.96; N, 8.42. measured value: C, 62.34; H, 5.84; N, 8.44.
Embodiment 4
The methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-the butyro-preparation of 3-(dimethylamino carbonyl)
A) 4-bromobenzene t-butyl formate
With trifluoromethanesulfonic acid (0.18ml, 2mmol) drop to 4-bromobenzene formic acid (20.10g, 100mmol), anhydrous methylene chloride (100ml) and concentrated isobutene. (78 ℃ in mixture 100ml), make the mixture of generation reflux under the dry ice/acetone condenser.After 40 minutes, add more isobutene. (30ml), continue then to reflux 20 minutes.Incline described reactant to the ether (500ml) and order with the 1.0N potassium hydroxide (2 * 50ml), water (50ml) and saturated brine (50ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (15.28g, 59%) into faint yellow oily thing through silica gel column chromatography (5% ethyl acetate/hexane): TLC R f(5%EtOAc/ hexane) 0.59; MS (ES) m/e259/257 (M+H) +.
B) 3-[4-(tert-butoxycarbonyl) phenyl] acrylic acid methyl ester.
With 4-bromobenzene t-butyl formate (5.14g, 20mmol), acrylic acid methyl ester. (9.1ml, 100mmol), acid chloride (224.5mg, 1mmol), three p-methylphenyl phosphine (608.8mg, 2mmol) and diisopropylethylamine (7.0ml, 40mmol) in propionitrile (100ml), refluxed 3 hours, on Rotary Evaporators, concentrate then.With ether (200ml) dilution residue, and order 1.0N hydrochloric acid (2 * 50ml), 5% sodium bicarbonate (50ml) and saturated saline (50ml) washing.Dry (magnesium sulfate) concentrates and obtains target compound (3.34g, 64%) into faint yellow solid through silica gel column chromatography (15% ethyl acetate/hexane): TLC R f(20%
The EtOAc/ hexane) 0.51; MS (ES) m/e 263.0 (M+H) +.
C) 3-[4-(tert-butoxycarbonyl) phenyl] methyl propionate
With 10%Pd/C (2.71g, 2.55mmol) add to 3-[4-(tert-butoxycarbonyl) phenyl] acrylic acid methyl ester. (3.34g, 12.73mmol) in the solution in methanol (65ml) and ethyl acetate (65ml), under the room temperature with described mixture in (50psi) jolting on the Parr device under the hydrogen environment.After 3 hours, pass through celite _Filter described reactant, on Rotary Evaporators, filtrate is concentrated into dried.In hexane reconcentration residual be the target compound (3.27g, 97%) of muddy Lycoperdon polymorphum Vitt grease: TLCR f(20%EtOAc/ hexane) 0.63; MS (ES) m/e 265.0 (M+H) +.
D) 3-[4-(tert-butoxycarbonyl) phenyl] propanoic acid
Under room temperature with 3-[4-(tert-butoxycarbonyl) phenyl] methyl propionate (3.27g, 12.37mmol), 1.0N LiOH (14.8ml, 14.8mmol), the mixture of THF (31ml) and water (16ml) stirred 1.5 hours, on Rotary Evaporators, concentrate to remove THF then.(2 * 30ml) wash water solution also discard ether layer with ether.With 1.0N hydrochloric acid (about 17ml) acidify water layer, (3 * 50ml) extract described mixture with chloroform.Dry (sodium sulfate) also concentrates the target compound (3.04g, 98%) that obtains to colourless powder: mp 88.5-89.5 ℃; MS (DCI/NH 3) m/e268.0 (M+NH 4) +
E) N, N-dimethyl 3-[4-(tert-butoxycarbonyl) phenyl] propionic acid amide.
Under room temperature with EDC (2.09g 10.88mmol) adds to 3-[4-(tert-butoxycarbonyl) phenyl] propanoic acid (2.27g, 9.07mmol), dimethylamine hydrochloride (0.88g, 10.88mmol), HOBt.H 2O (1.47g, 10.88mmol) and diisopropylethylamine (3.2ml is 18.14mmol) in the solution in anhydrous acetonitrile (45ml).19.5 after hour, concentrate described reactant, with residue through silica gel column chromatography (ethyl acetate).Obtain to be the target compound of colorless oil (2.46g, 98%):
TLC?R f(EtOAc)0.52；MS(ES)m/e?278.4(M+H) +.
F) 4-[4-(tert-butoxycarbonyl) phenyl]-3-(dimethylamino carbonyl) ethyl n-butyrate.
To two (trimethyl silyl) lithamides at THF (1.0M in-78 ℃ of ar gas environments are following with 2.5 minutes, 5.8ml, 5.8mmol) in drips of solution add to N, N-dimethyl 3-[4-(tert-butoxycarbonyl) phenyl] (1.34g is 4.83mmol) in the solution in anhydrous THF (48ml) for propionic acid amide..In-78 ℃ with xanchromatic solution stirring 0.5 hour, use 15 seconds then along flask walls (pre-cooling) adding bromoethyl acetate (2.7ml, 24.15mmol).0.5 after hour, described reactant is inclined to saturated ammonium chloride (50ml), (2 * 100ml) extract described mixture with ethyl acetate.Dry (magnesium sulfate) concentrates and the residual faint yellow oily thing of reconcentration from dimethylbenzene.Obtain target compound (453.5mg, 26%) through silica gel column chromatography (1: 1 ethyl acetate/hexane) into faint yellow oily thing:
TLC R f(1: 1 EtOAc/ hexane) 0.44; MS (ES) m/e 364.2 (M+H) +.
G) 4-(4-carboxyl phenyl)-3-(dimethylamino carbonyl) ethyl n-butyrate.
In 0 ℃ with disposable 4-[4-(tert-butoxycarbonyl) phenyl that adds to of all TFA (2.3ml)]-(168.6mg is 0.46mmol) in the solution in anhydrous methylene chloride (2.3ml) for 3-(dimethylamino carbonyl) ethyl n-butyrate..Under room temperature,, on Rotary Evaporators, be concentrated into dried then with described solution stirring 0.5 hour.Residue reconcentration in toluene is obtained target compound into faint yellow oily thing: MS (ES) m/e 308.0 (M+H) +.
H) methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-3-(dimethylamino carbonyl) ethyl n-butyrate.
Under room temperature with EDC (105.8mg, 0.55mmol) add to 4-(4-carboxyl phenyl)-3-(dimethylamino carbonyl) ethyl n-butyrate. (0.46mmol), 2-(methylamino methyl) benzimidazole dihydrochloride (129.2mg, 0.55mmol), HOBt.H 2O (74.6mg, 0.55mmol) and diisopropylethylamine (0.32ml is 1.84mmol) in the solution in anhydrous acetonitrile (2.3ml).After 22 hours, concentrate described reactant, with xanchromatic residue through silica gel column chromatography (1: 1 ethyl acetate/chloroform of 10% methanol).Obtain to be the target compound of faint yellow oily thing (191.5mg, 92%):
TLC?R f(10％MeOH?in?1∶1?EtOAc/CHCl 3)0.44；MS(ES)m/e451(M+H) +.
I) methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-3-(dimethylamino carbonyl) butanoic acid
Under room temperature with the methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-3-(dimethylamino carbonyl) ethyl n-butyrate. (191.5mg, 0.43mmol) and 1.0N Lithium hydrate (0.52ml, 0.52mmol) solution stirring in THF (2.2ml) and water (1.6ml) 17 hours, use TFA (0.10ml, 1.29mmol) acidify then.Concentrate the aqueous solution that obtains residue, through ODS chromatography purification (17% acetonitrile/water contains 0.1%TFA, uses 15% acetonitrile/water, contains 0.1%TFA chromatography once more).Concentrated and lyophilization obtains the target compound (133.4mg, 47%) into colourless powder: HPLC (PRP-1_, 20%CH 3CN/H 2O contains 0.1%TFA) K '=1.3; MS (ES) m/e423.2 (M+H) +. value of calculation C 23H 26N 4O 4.2CF 3CO 2H0.5H 2O:C, 49.17; H, 4.43; N, 8.49. measured value: C, 49.13; H, 4.62; N, 8.52.
Embodiment 5
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid, the preparation of [(2,2-dimethyl-2-methoxyl group acetyl group) oxygen base] methyl ester
A) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-(tert-butoxycarbonyl) benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
To (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid (444mg, 1.0mmol), (0.1464ml 1.05mmol) drips bicarbonate di tert butyl carbonate (230mg, 1.05mmol) solution in DMF (2ml) to triethylamine in the mixture in DMF (8ml).Under room temperature, described reactant mixture was stirred 18 hours.Getting portion measures and shows only have 50% to transform.Add the triethylamine and the bicarbonate di tert butyl carbonate of another deal again and continue stirring 18 hours.Therefore mensuration shows still the part unreacted matters, adds the reaction reagent of the 3rd deal and restir 18 hours.Described reactant mixture is concentrated into dried, residual grease is ground with water, filter and obtain target compound (0.442g, 85%) into white solid in 40-50 ℃ of vacuum drying.MS(ES)m/e?522.4[M+H] +。
B) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-(tert-butoxy) benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid, [(2,2-dimethyl-2-methoxyl group acetyl group) oxygen base] methyl ester
To embodiment 5a chemical compound (0.209g, 0.4mmol) add in the solution in anhydrous propanone (10ml) Anhydrous potassium carbonate (0.25g, 1.8mmol).Under the room temperature ar gas environment, described reactant mixture was stirred 1 hour.Add then 2-methoxyl group-2 Methylpropionic acid chloro methyl ester (US4602012, July, 22 days, 1986) (0.334g, 2.0mmol), then add tetrabutylammonium iodide (0.03g, 0.08mmol).Under the room temperature ar gas environment, described reactant was stirred 48 hours.Filter then and with the target compound of filtrate simmer down to yellow oil (0.67g, quantitatively).TLC R f(0.48 silica gel, 6% methanol is in dichloromethane).MS(ES)m/e?652.2[M+H] +。
C) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid, [(2,2-dimethyl-2-methoxyl group acetyl group) oxygen base] methyl ester
(0.67g 1mmol) adds TFA (1mL) in the solution of dichloromethane (5mL) to embodiment 5b chemical compound.Under argon, reactant is stirred 4h in RT.It is concentrated into dried, with dichloromethane with residue evaporation three times to remove trace TFA, obtain target compound (0.4g, 73%).With its purification (gradient, 2-3% methanol is in dichloromethane) on quick silicagel column.Collection contains the part of pure compound, concentrates the target compound (65mg) that obtains pale solid.MS (ES) m/e 552.2[M+H] +. 1H NMR (400MHz, (CDCl 3) δ 7.6 (br s, 1H), 7.22 (m, 6H), 6.5 (d, 1H), 5.85 (d, 1H), 5.8 (d, 1H), 5.4 (d, 1H), 5.05 (m, 1H), 4.79 (q, 2H), 4.3 (d, 1H), 3.7 (d, 1H), 3.25 (s, 3H), 3.15 (s, 3H), 3.05 (s, 3H), 3.02 (dd, 1H), 2.7 (dd, 1H), 1.4 (s, 6H) value of calculation C 28H 33N 5O 71.25H 2O:C, 58.58; H, 6.23; N, 12.20. measured value: C, 58.60, H, 5.94, N, 12.00.
Embodiment 6 (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-a) (±)-2 of the preparation of 2-(N-hydroxyl) acetamide, 3,4, the methylamino of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-(N-hydroxyl) acetamide is NaOMe (Aldrich, the MeOH solution of 25%wt., 2.2mL, 9.7mmol) (0.69g 9.7mmol) in the solution of MeOH (40mL), stirs 5min with mixture to add to oxammonium hydrochloride. in 45 ℃.With (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.82g 1.9mmol) is suspended among MeOH (2mL) and the THF (15mL) the 2-methyl acetate, and it is added drop-wise in the above-mentioned solution.To react on 45 ℃ then stirred 24 hours.Mixture is concentrated in vacuum, then with the 10%CH that contains 0.1%TFA 3CN/H 2O (5mL) handles.All substance dissolves, a kind of then solid precipitation comes out.By adding excessive TFA half of this material dissolved in mobile phase, and (flow velocity=80mL/min contains the 10%CH of 0.1%TFA for YMC ODS-AQ, 50x250mm with preparation HPLC 3CN/H 2O; t R=57min) purification obtains the target compound (91mg, 22%) as white solid.MS(ES)m/e?423.1[M+H] +. 1H?NMR(400MHz,DMSO-d 6)δ9.06(bt,J=4Hz,1H),7.77(m,2H),7.58(m,2H),7.50(m,2H),6.60(d,J=10Hz,1H),6.40(bs,1H),5.52(d,J=19Hz,1H),5.18(bt,J=9Hz,1H),4.85(d,J=6Hz,1H),3.83(d,J=19Hz,1H),2.95(s,3H),2.60(dd,J=17,9Hz,1H),2.28(dd,J=15,7Hz,1H).
Value of calculation C 21H 22N 6O 41.5C 2HF 3O 21.0H 2O): C, 47.14; H, 4.20; N, 13.74. measured value: C, 46.95; H, 4.24; N, 13.37.
Embodiment 7 (±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-a) 2-(3-iodine substituted phenyl) benzimidazole of the preparation of 2-acetic acid
With the carbonochloridic acid isobutyl ester (2.9mL, 21mmol) add to the 3-iodobenzoic acid (5.0g, 20mmol) and Et 3(3.7mL is 26mmol) in the cold solution in THF (50mL) for N.Solution is stirred 1h in 10 ℃.All solution is slowly added 1, and (2.2g is 20mmol) in the solution of THF (50mL) for the 2-diaminobenzene.Behind the 18hr, reactant is concentrated, residue is at EtOAc and 5%Na 2CO 3Between distribute.Layering washes the EtOAc layer with water.Concentrated organic layer obtains residue, handles this residue and continues 15min with EtOAc.Filtration obtains a kind of solid, handles and be heated to 110 ℃ with AcOH (50mL).Behind the 18hr, with solution concentration.Handle residue with EtOAc, solution is filtered obtain target compound (3.14g, 50%): MS (ES) m/e321.2 (M+H) +B) phenyl 2-[(3-tributyl stannyl)] benzimidazole
Under argon, with 2-(3-iodine substituted phenyl) benzimidazole (1.0g, 3.1mmol), two tributyl tin (3.9mL, 6.2mmol) and PdCl 2(PPh 3) 2(100mg, 0.14mmol) solution in DMF (10mL) is heated to 90 ℃.Behind the 2hr, with solution concentration.Handle residue and filtration with normal hexane.Add EtOAc and solution is filtered.Filtrate concentrating obtained target compound (812mg, 54%): MS (ES) m/e 485.4 (M+H) +C) (±)-2,3,4,5-tetrahydrochysene-1-(uncle-butoxy carbonyl)-7-iodo-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With bicarbonate di-t-butyl ester (2.0g 8.6mmol) adds to 7-iodo-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (1.6g, 4.3mmol) and DMAP (10mg is 0.08mmol) in CH 3In the solution of CN (10mL), solution is stirred in RT.(total amount is 8g to the other two dimethyl dicarbonate butyl esters of the adding of discontinuity, 34.4mmol) finishes up to reaction.Concentrate with silica gel column chromatography and obtain target compound (1.8g, 90%): MS (ES) m/e497.2 (M+H) +D) (±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-1-(uncle-butoxy carbonyl)-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With 2-[(3-tributyl stannyl) phenyl] benzimidazole (0.24g, 0.5mmol), (±)-1-(uncle-butoxy carbonyl)-7-iodo-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.223g, 0.7mmol), CuI (10mg, 0.05mmol) and PdCl 2(PPh 3) 2(40mg, 0.05mmol) mixed liquor in DMF (10mL) is heated to 100 ℃ under argon.Behind the 18hr, with solution concentration.Behind silica gel column chromatography, obtain target compound (0.06g, 22%): MS (ES) m/e 541.5 (M+H) +E) (±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-1-(uncle-butoxy carbonyl)-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.06g, 0.11mmol) solution in 4MHCl/ dioxane (3mL) stirs 1hr to the 2-methyl acetate under room temperature.Solution concentration is obtained target compound (0.05g, 100%): MS (ES) m/e 441.4 (M+H) +F) (±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
(0.22mL 0.22mmol) is added drop-wise to (±)-2,3 with 1.0N NaOH under room temperature, 4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.05g is 0.11mmol) in 1: 1MeOH/H for the 2-methyl acetate 2In the solution of O (2mL),, concentrate then gained solution stirring 18hr.Residue is dissolved in water, solution is acidified to pH4 (Litmus reagent paper) with AcOH.Filter and promptly get target compound (0.005g, 10%):
1H NMR (250MHz, DMSO-d 6) δ 2.4-2.9 (m, 2H), 3.0-3.1 (s, 3H), 3.8-4.0 (d, 1H), 5.0-5.1 (m, 1H), 5.5-5.6 (d, 1H), 6.7-6.8 (d, 1H), 7.5-8.5 (m, 11H); MS (ES) m/e 427.5 (M+H) +. value of calculation C 25H 22N 4O 31.5HCl1.0AcOH0.5H 2O:C, 58.94; H, 5.22; N, 10.18. measured value: C, 59.00; H, 5.15; N, 9.92.
Embodiment 8 (±)-2,3,4, the luxuriant and rich with fragrance imidazoles of 5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-a) 2-[[(N-benzyloxycarbonyl of the preparation of 2-acetic acid) amino] methyl] luxuriant and rich with fragrance imidazoles
According to the general flow of embodiment 7 (a), replace the 3-iodobenzoic acid with the N-Cbz-alanine, with 9, the 10-diaminourea is luxuriant and rich with fragrance to replace 1,2-diaminobenzene, preparation target compound (0.41g, 45%): MS (ES) m/e 382.4 (M+H) +B) the luxuriant and rich with fragrance imidazoles of 2-(amino methyl)
With the 2-[[(N-benzyloxycarbonyl) amino] methyl] (0.2g, 0.52mmol) solution in the acetic acid (0.8mL) of 30%HBr stirs 1hr to luxuriant and rich with fragrance imidazoles under room temperature.With solution concentration, residue Et 2O handles.Filter the target compound (0.138g, 80%) that promptly gets as the oily residue: MS (ES) m/e 248.3 (M+H) +C) (±)-2,3,4, the luxuriant and rich with fragrance imidazoles of 5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with EDC (0.08g, 0.42mmol) add to the luxuriant and rich with fragrance imidazoles of 2-(amino methyl) (0.138g, 0.42mmol), (±)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.123g, 0.42mmol), HOBtH 2O (0.063g, 0.42mmol) and Et 3(0.14mL is 1mmol) in dry DMF (5mL) solution for N.Behind the 18hr, reactant is concentrated, residue is at EtOAc and 5%NaHCO 3Between distribute.Layering washes organic layer with water.Dry (Na 2SO 4) and the concentrated target compound (0.2g, 90%) that promptly gets: MS (ES) m/e 522.4 (M+H) +D) (±)-2,3,4, the luxuriant and rich with fragrance imidazoles of 5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid
According to the flow process of embodiment 7 (f), with (±)-2,3,4, the luxuriant and rich with fragrance imidazoles of 5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.2g, 0.38mmol) promptly get target compound (0.014g, 10%) through saponification and purification:
MS (ES) m/e 508.5 (M+H) +. value of calculation C 29H 25N 5O 41.0 TFA 3.0H 2O:C, 55.11; H, 4.77; N, 10.37. measured value: C, 55.38; H, 5.13; N, 10.74
Embodiment 9
(±)-7-carboxyl-4-(2,2, the 2-trifluoroethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-preparation of 2-methyl acetate
A) 3-[(2,2, the 2-trifluoroethyl) amino] methyl-4-nitrobenzoyl tert-butyl acrylate
With 3-bromomethyl-4-nitrobenzoyl tert-butyl acrylate (2.4g 8mmol) is dissolved among the anhydrous THF (50ml), and disposable immediately adding 2,2,2-trifluoro ethamine (3ml, 38mmol).Under room temperature,, concentrate then and remove THF orange colour solution stirring 40 minutes.Residue is dissolved in the ether (100ml) also with 10% aqueous sodium carbonate (50ml) and saline (5ml) washed twice.Dry (magnesium sulfate) organic layer.Concentrate and obtain target compound (1.6g, 63%) into yellow oil through silica gel column chromatography (2.5%-10% ethyl acetate/hexane):
1HNMR(250MHz,CDCl 3)δ8.21(d,J=1.3Hz,1H),8.03(dd,J=8.4,1.3?Hz,1H),7.96(d,J=8.4Hz,1H),4.20(s,2H),3.24(q,J=9.3Hz,2H),1.62(s,9H).
B) 3-[[N-(2,2, the 2-trifluoroethyl)-N-(tert-butoxycarbonyl)-amino] methyl-4-nitrobenzoyl tert-butyl acrylate
Under room temperature with bicarbonate di tert butyl carbonate (2.15g, 10mmol) the disposable 3-[(2 that adds to, 2,2-trifluoroethyl) amino] (1.6g is 5mmol) in the solution in dichloromethane (25ml) for methyl-4-nitrobenzoyl tert-butyl acrylate.Concentrate described reactant and under vacuum, be heated to 50 ℃ 18 hours.Obtain target compound (2g, 96%) through silica gel column chromatography (2%-5% ethyl acetate/hexane) into yellow oil: 1H NMR (400MHz, CDCl 3) δ
7.85-8.15(m,3H),4.75-5.05(m,2H),3.80-4.10(m,2H),1.60(s,9H),
1.15-1.80(m,9H).
C) 4-amino-3-[[N-(2,2, the 2-trifluoroethyl)-N-(tert-butoxycarbonyl) amino] the ar-Toluic acid tert-butyl ester
10%Pd/C (.4g .4mmol) adds to 3-[[N-(2,2, the 2-trifluoroethyl)-N-(tert-butoxycarbonyl) amino] (2.0g is 5mmol) in the solution in ethyl acetate (20ml) for methyl-4-nitrobenzoyl tert-butyl acrylate.In (55psi) under the room temperature hydrogen environment described mixture of jolting on the Parr device.After 4 hours, pass through celite _Filter described reactant, concentrated filtrate obtains the target compound (1.9g, 99%) into colorless oil: 1H NMR (400MHz, CDCl 3) δ 7.76 (dd, J=8.5Hz, 1.8Hz, 1H), 7.68 (d, J=1.8Hz, 1H), 6.62 (d, J=8.4Hz, 1H), 4.53 (s, 2H), 3.69 (m, 2H), 1.58 (s, 9H), 1.51 (m, 9H).
D) (±)-4-[2-(1,4-dimethoxy-1,4-dioxo butyl) amino]-3-[[N-(2,2, the 2-trifluoroethyl)-N-(tert-butoxycarbonyl) amino] the ar-Toluic acid tert-butyl ester
With 4-amino-3-[[N-(2,2,2-trifluoroethyl)-and N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester (1.9g, 5mmol) and dimethyl acetylenedicarbexylate (0.58ml, 5.5mmol) reflux 60 minutes in methanol (10ml), be chilled to room temperature then.(0.5g, 5mmol) merging is in (50psi) under the room temperature hydrogen environment described mixture of jolting on the Parr device with the solution that produces and methanol (20ml) and 10Pd/C.After 3 hours, pass through celite _Filter described reactant, concentrated filtrate on Rotary Evaporators.Obtain target compound (1.6g, 62%) for faint yellow oil:
1H?NMR(400MHz,CDCl 3)δ7.85(dd,J=8.4,2.0Hz,1H),7.68(d,J=2.0Hz,1H),6.65(d,J=8.4Hz,1H),6.15(br?s,1H),4.55-4.70(m,2H),4.40(1/2?AB,J=15.3Hz,1H),3.71(s,3H),3.70(s,3H),3.35-3.50(m,2H),2.95(dd,J=16.9,6.8Hz,1H),2.84(dd,J=16.9,6.9Hz,1H),1.56(s,18H).
E) (±)-7-carboxyl-4-(2,2, the 2-trifluoroethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
In 0 ℃ with disposable (±)-4-[2-(1 that adds to of TFA (7ml), 4-dimethoxy-1,4-dioxo butyl) amino]-3-[[N-(2,2, the 2-trifluoroethyl)-and N-(tert-butoxycarbonyl)] amino] the ar-Toluic acid tert-butyl ester (1.6g, 3mmol) in anhydrous methylene chloride (20ml), faint xanchromatic solution is warmed to room temperature.After 2 hours, on Rotary Evaporators, concentrate described solution, reconcentration residue in toluene (removing residual TFA).With grease and toluene (10ml) and the Et that produces 3(2ml 15mmol) merges the described mixture of reflux under ar gas environment to N.Cooled off described solution and vacuum concentration in 18 hours to doing.Residue is dissolved in the methanol (about 15ml) of a small amount of backflow, water (10ml) dilution is with glacial acetic acid (4) acidify.Place refrigerator overnight to filter then in described mixture.The high vacuum drying solid obtains the target compound (0.80g, 76%) into brown powder:
1HNMR(400MHz,DMSO-d 6)δ7.61(2,1H),7.57(dd,J=8.5,2Hz,1H),6.63(d,J=2Hz,1H),6.59(d,J=8.5Hz,1H),5.59(d,J=16.7Hz,1H),5.25(m,1H),4.28(m,2H),4.15(d,J=16.7Hz,1H),3.61(s,3H),2.86(dd,J=16.8,8.7Hz,1H),2.74(dd,J=16.8,5.4Hz,1H).
F) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under the room temperature ar gas environment with EDC (0.16g 0.86mmol) adds to (±)-7-carboxyl-4-(2,2, the 2-trifluoroethyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.2g, 0.71mmol), HOBt.H 2O (0.12g, 0.86mmol), 2-amino methyl benzimidazole dihydrochloride (0.19g, 0.86mmol), (0.5ml is 2.8mmol) and in the solution of acetonitrile (5ml) for DIEA.Under room temperature, the solution stirring that produces is spent the night, concentrate then.Make residue be allocated between ethyl acetate and the water stratum disjunctum.With salt water washing organic layer, dry (magnesium sulfate) also concentrates.Obtain target compound (0.12g, 44%) through silica gel column chromatography (1%-10% methanol is in dichloromethane) into brown solid:
NMR(400MHz,DMSO-d 6)δ8.59(t,J=5Hz,1H),7.61(m,2H),7.50(m,2H),7.16(m,2H),6.57(d,J=11.1Hz,1H),6.17(d,J=5Hz,1H),5.53(d,J=16.7Hz,1H),5.13(m,1H),4.75(m,2H),4.10(m,2H),3.62(s,3H),2.94(dd,J=16.8,8.5Hz,1H),2.69(dd,J=16.8,5.4Hz,1H).
G) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.12g, 0.25mmol) and the Lithium hydrate monohydrate (0.017g, 0.4mmol) solution stirring in THF (10ml), methanol (2ml) and water (2ml) is spent the night.Concentrated and residue is soluble in water then.With 3N hydrochloric acid the pH of described solution is transferred to 4, freezing then 1 hour.Filter and collect solid and the dry target compound (0.11g, 90%) that obtains to white solid that produces: Ms (ES) m/e476[M+H] +C 22H 20N 5F 3O 4.1.25H 2O value of calculation: C, 53.07; H, 4.55; N, 14.06.Measured value: C, 52.85; H, 4.36; N, 13.98.
Embodiment 10
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the method for embodiment 9 (f), but replace 2-amino methyl benzimidazole dihydrochloride with 2-(methylamino methyl) benzimidazole dihydrochloride, the preparation target compound:
1HNMR(400MHz,CDCl 3)δ7.67(m,2H),7.37(m,2H),7.25(m,2H),6.54(d,J=8?Hz,1H),5.46(d,J=16.7Hz,1H),5.20(m,1H),5.04(s,2H),4.71(m,1H),4.17(m,1H),3.94(m,1H),3.92(d,J=16.7,1H),3.74(s,3H),3.23(s,3H),2.98(m,1H),2.74(m,1H).
B) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Method according to embodiment 9 (g), with (±)-2,3,4,5-tetrahydrochysene-7-carboxyl-[[[(benzimidazolyl-2 radicals-yl) methyl] methylamino] carbonyl]-3-oxo-4-(2,2,2-trifluoroethyl)-and 1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate obtains target compound: MS (ES) m/e 490.2[M+H] +C 23H 22N 5F 3O 4.2.25H 2O value of calculation: C, 52.12; H, 5.04; N, 13.21.Measured value: C, 52.00; H, 5.12; N, 13.09.
Embodiment 11
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the method for embodiment 9 (f), but replace 2-amino methyl benzimidazole dihydrochloride, preparation target compound: MS (ES) m/e 505.2 (M+H) with 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride +
B) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Method according to embodiment 9 (g), with (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-4-(2,2,2-trifluoroethyl)-and 1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate obtains target compound: MS (ES) m/e 491.2[M+H] +C 22H 21N 6F 3O 4.27/8H 2O value of calculation: C, 48.73; H, 4.97; N, 15.50.Measured value: C, 48.50; H, 4.59; N, 15.33.
Embodiment 12
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1,4-benzo two chlora _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under the room temperature ar gas environment with EDC (0.10g, 0.55mmol) add to 7-carboxyl-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.14g, 0.3mmol), 2-(methylamino methyl) benzimidazole dihydrochloride (0.12g, 0.51mmol), HOBt.H 2O (0.072g, 0.55mmol), (0.32ml is 1.84mmol) in the solution in DMF (5ml) for DIEA.Under room temperature, the solution stirring that produces is spent the night, concentrate then.Make residue be allocated between ethyl acetate and the water stratum disjunctum.Use the ethyl acetate extraction water layer, with the organic layer that the salt water washing merges, dry (magnesium sulfate) also concentrates.Obtain the target compound (0.11g, 59%) of colourless foam shape through silica gel column chromatography:
1H?NMR(CDCl 3)δ7.62(m,2H),7.31(m,2H),7.20(d,J=8.1Hz,1H),7.07(s,1H),6.65(d,J=7.9Hz,1H),6.60(s,1H),6.55(d,J=7.9Hz,1H),6.46(d,J=8.1Hz,1H),5.90(d,J=5.4Hz,2H),5.26(d,J=16.5Hz,1H),5.02(m,1H),4.93,(d,J=14.6,1H),4.83(d,J=14.6Hz,1H),4.51(d,J=5Hz,1H),3.74(s,3H),3.71(m,1H),3.60(m,1H),3.58(d,J=16.5Hz,1H),3.18(s,3H),2.99(dd,J=16,6.8?Hz,1H),2.70(m,1H).
B) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature to (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-(0.11g 0.19mmol) adds Lithium hydrate monohydrate (0.01g, 0.23mmol) solution in water (1ml) to the 2-methyl acetate in THF (1ml).Under room temperature, the solution stirring that produces is spent the night, be concentrated into dried then.Residue is soluble in water, wash described solution with ethyl acetate, with 3N hydrochloric acid pH is transferred to 4 then.Filter and collect the precipitation that produces, and the dry target compound (0.055g, 51%) that obtains to white solid: MS (ES) m/e 556.2[M+H] +C 30H 29N 5O 6.H 2O value of calculation: C, 62.82; H, 5.45; N, 12.21.Measured value: C, 62.69; H, 5.26; N, 12.15.
Embodiment 13
(±)-2,3,4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
(0.27g 1.4mmol) adds to (±)-2,3 with EDC under room temperature, 4,5-tetrahydrochysene-7-amino-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetas (0.40g, 1.1mmol), (Archiv.Der Pharmazie 1960,293,758 for benzimidazolyl-2 radicals-acetic acid; 0.25g, 1.4mmol), HOBt.H 2O (0.20g, 1.5mmol) and DIEA (0.35ml is 2mmol) in the solution of acetonitrile (5ml).With gained solution stirring 2 days, be concentrated into dried then.Make residue between ethyl acetate and water, distribute layering.With salt water washing organic facies, dry (magnesium sulfate) also concentrates.Through silica gel column chromatography (1%-10%CH 3OH is in CH 2Cl 2In) obtain amber foamed target compound (0.21g, 36%): MS (ES) m/e 512.2[M+H] +
B) (±)-2; 3; 4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid under room temperature with (±)-2; 3; 4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.21g; 0.41mmol) and lithium hydroxide monohydrate (0.022g is 0.52mmol) in THF (10mL) and H 2The solution stirring of O (2mL) is spent the night, and concentrates then.Residue is water-soluble, uses the ethyl acetate wash solution, transfers to pH4 with 3N HCl then.Filter collecting precipitation, be drying to obtain target compound (0.12g, 59%): MS (ES) m/e 498.2[M+H] into pale solid +C 28H 27N 5O 4.1.5H 2The value of calculation of O: C, 64.11; H, 5.76; N, 13.35.Measured value: C, 64.36; H, 5.57; N, 13.21.
Embodiment 14
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetamide
A) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-acetamide
Will be in (±)-2 among the anhydrous MeOH (10mL), 3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (330mg, 0.76mmol) in ice bath, cool off, in solution, be blown into ammonia 0.5hr simultaneously.Then reactant is placed 18hr under room temperature is airtight.After concentrating, residue is through quick silica gel column chromatography (90: 10 CH 2Cl 2/ MeOH) purification obtains the target compound (52%) into white solid: MS (ES) m/e 421.2[M+H] +C 22H 24N 6O 31.5H 2The value of calculation of O: C, 59.05; H, 6.08; N, 18.78.Measured value: C, 58.90; H, 6.04; N, 18.45.
Embodiment 15
(±)-5-[[2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl] 3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] a) (±)-2,3 of preparation of tetrazolium, 4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (±)-2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(1.0g 2.6mmol) is suspended in the toluene (10mL) the 2-methyl acetate, drip N, and dinethylformamide-two-tert-butyl acetal (5mL, 20.8mmol).Reactant mixture is cooled to room temperature then in 80 ℃ of heating 1.5hr, pours 5%Na into 2CO 3In the solution.Layering, aqueous solution extracts (2x) with toluene.With the organic layer that the salt water washing merges, through dried over mgso, filtration and evaporation promptly get target compound (0.91g, 82%): MS (ES) m/e 439.2[M+H] +
B) (±)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Use H 2O (20mL) and 0.91N NaOH (5mL) handle (±)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-methyl acetate (1.5g, 3.4mmol) solution in ethylene glycol dimethyl ether (160mL).In ar gas environment, under room temperature, reactant was stirred 24 hours, be acidified to pH3 with ice AcOH then, be concentrated into small size (10mL), pour in the frozen water.The solid of collecting precipitation is drying to obtain quantitative target compound.MS(ES)m/e?425.2[M+H] +。
C) (±)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-[N-(2-cyano ethyl) acetamide]
Under ar gas environment with diisopropyl ethyl amine (0.65g, 5mmol), EDC (0.764g, 4mmol) and HOBtH 2O (0.54g 4mmol) handles (±)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, and the 4-benzodiazepine _-2-acetic acid (1.2g, 2.6mmol) solution in dry DMF (12mL).With gained solution stirring 10 minutes, then with containing diisopropylethylamine (0.85g, dry DMF (2mL) solution-treated of 3-aminopropionitrile fumarate 6.6mmol).Reactant was stirred 18 hours under ar gas environment, be concentrated into dried then.Residue distributes between water and ethyl acetate, layering.With salt water washing organic layer, dry on the magnesium sulfate, filter and concentrate.The oily residue is through flash chromatography on silica gel post (98: 2 CH 2Cl 2/ MeOH) purification promptly gets target compound (750mg, 50%): MS (ES) m/e 477.2[M+H] +D) (±)-1-(2-cyano ethyl)-5-[[2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium
Under ar gas environment and room temperature, with triphenylphosphine (1.14g, 4.6mmol), trimethyl silyl azide (0.52g, 4.6mmol) and diethylazodicarboxylate (0.8mL, 4.6mmol) processing (±)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-[N-(2-cyano ethyl) acetamide] (750mg, 1.3mmol) solution in anhydrous THF (15mL).After 50 hours, reactant is concentrated into dried, residue is through flash chromatography on silica gel post (98.5: 1.5 CH 2Cl 2/ MeOH) purification promptly gets target compound (0.56g, 86%): MS (ES) m/e 502.2[M+H] +
E) (±)-1-(2-cyano ethyl)-5-[[2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium
Use solution-treated (±)-1-(2-the cyano ethyl)-5-[[2 of 4M hydrochloric acid in dioxane (10ml) down in the room temperature ar gas environment, 3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium (0.5g, 1mmol) solution in dichloromethane (20ml).After 20 hours, described reactant is concentrated into dried, with 5% sodium carbonate dilution residue.With the described solution of ethyl acetate extraction, discard ethyl acetate layer.Extract with dilute hydrochloric acid acidify water layer and with ethyl acetate (3x).Acetic acid ethyl ester extract with the salt water washing merges obtains target compound (0.36g, 81%) through dried over mgso and evaporation: MS (ES) m/e445.4[M+H] +
F) (±)-1-(2-cyano ethyl)-5-[[2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium
In ar gas environment down with DIEA (129mg, 1mmol), EDC (172mg, 0.9mmol) and HOBt.H 2(122mg 0.9mmol) handles (±)-1-(2-cyano ethyl)-5-[[2,3 to O, 4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium (360mg, 0.8mmol) solution in dry DMF (5ml).Under room temperature, described reactant was stirred 10 minutes, add then and contain DIEA (413mg, 3.2mmol) 2-amino methyl benzimidazole dihydrochloride hydras (352mg, 1.6mmol) solution in DMF (2ml).After 20 hours, described reactant is concentrated into dry doubling residue is allocated between water and the ethyl acetate.Stratum disjunctum is used the ethyl acetate extraction water layer.Merge organic layer,, filter and concentrate through dried over mgso.Residue is obtained target compound (120mg, 21%) through flash chromatography on silica gel purification (95: 5 methylene chloride).MS(ES)m/e?575.2[M+H] +。G) (±)-5-[[2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium
Handle (±)-1-(2-cyano ethyl)-5-[[2 with thiophenol (0.02ml), 3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium (100mg, 0.2mmol) solution in methanol (1ml), then handle with 1N sodium hydroxide solution (2.2ml).After 3 hours, described reactant is concentrated into dried, with residue through preparation property TLC purification (85: 15 methylene chloride).Isolating product is soluble in water, filter the insoluble impurity of described solution removal.Handle described filtrate with 2 glacial acetic acids.Collecting precipitation solid and drying obtain target compound (45mg, 41%): MS (ES) m/e 522.2[M+H] +C 30H 31N 9O 4.2.25H 2O value of calculation: C, 56.15; H, 5.52; N, 19.65.Measured value: C, 56.51; H, 5.05; N, 19.72.
Embodiment 16
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[4-[(2-carboxylbenzoyl) amino] fourth-1-yl]-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) N-[[2-(N-4-hydroxyl fourth-1-yl) amino methyl-4-tert-butoxycarbonyl] phenyl-L-aspartic acid β-methyl ester
Under the room temperature ar gas environment with N-[[2-formoxyl-4-tert-butoxycarbonyl] phenyl]-(WO 95/18619 for L-aspartic acid β-methyl ester; 2.55g, 7.2mmol), 4A molecular sieve and 4-hydroxyl butylamine (0.64g, 7.26mmol) mixture in methanol (35ml) stirred 30 minutes, add then sodium cyanoborohydride (0.49g, 0.79mmol) and acetic acid (0.3ml).Described reactant mixture is placed ambient temperature overnight, and vacuum is removed solvent then.With residue soluble in water and with this solution of dilute hydrochloric acid acidify to pH4.Ethyl acetate extraction, dry (magnesium sulfate), filter and concentrate the target compound (1.75g, 57%) that obtains to faint yellow solid:
TLC R f(4: 20: 20: 56 MeOH/EtOAc/ hexane/Cl 2CH 2) 0.22; 1H NMR (CDCl 3) δ 1.55 (s, 9H), 1.56 (m, 2H), 1.80 (m, 2H), 3.01 (m, 4H), 3.55 (m, 2H), 3.70 (s, 3H), 4.05 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 6.81 (d, J=8.4Hz, 1H), 7.70 (s, 1H), 7.89 (d, J=8.4Hz, 1H).
B) (S)-and 7-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-3-oxo-4-(4-hydroxyl fourth-1-yl)-1H-1,4-benzodiazepine _-2 methyl acetates
Under the room temperature ar gas environment with benzotriazole-1-base oxygen base-three (dimethylamino) hexafluorophosphoric acid phosphine (2.08g, 14.7mmol) add to N-[[2-(N-4-hydroxyl fourth-1-yl) amino methyl-4-tert-butoxycarbonyl] phenyl-L-aspartic acid β-methyl ester (1.75g, 4.1mmol) and triethylamine (1.15ml is 8.2mmol) in the solution in dichloromethane (150ml).Under room temperature described reactant mixture stirring is spent the night, order is washed with ice-cold dilute hydrochloric acid, water, 5% sodium bicarbonate, saturated brine then, then dry (magnesium sulfate).Filter also and concentrate, with residue through the flash chromatography on silica gel purification (5% methanol: ethyl acetate) obtain target compound (0.631g, 38%):
TLC?R f(4％MeOH/EtOAc)0.26； 1H?NMR(CDCl 3)δ1.46-1.61(m,4H),1.57(s,9H),2.64(d,J=6.9Hz,1H),2.66(dd,J=15.9,6.3Hz,1H),2.99(dd,J=15.6,6.9Hz,1H),3.56-3.54(m,4H),3.74(s,3H),3.84(d,J=16.2Hz,1H),4.54(m,1H),5.10(m,1H),5.41(d,J=16.2Hz,1H),6.49(d,J=8.3Hz,1H),7.59(d,J=1.8Hz,1H),7.67(dd,J=8.3,1.8Hz,1H)；MS(ES)m/e?407.2[M+H] +；[α] D=-185.4°(c=1,CH 3OH).
C) (S)-and 7-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-3-oxo-4-(4-phthalimido fourth-1-yl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under the room temperature ar gas environment to (S)-7-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-3-oxo-4-(4-hydroxyl fourth-1-yl)-1H-1,4-benzodiazepine _-2 methyl acetates (437mg, 1.07mmol) and triphenylphosphine (308mg 1.17mmol) adds phthalimide (173mg in the solution in THF (20ml), 1.17mmol) and the diethylazodicarboxylate (205mg, 1.17mmol).Under room temperature, described reactant mixture stirred and spends the night, remove solvent, with residue through the flash chromatography on silica gel purification (4: 20: 20: 56 methanol/ethyl acetate/hexanes/ch) obtain target compound (0.430g, 75%):
TLC?R f(4∶20∶20∶56MeOH/EtOAc/hexane/Cl 2CH 2)0.32； 1H?NMR(CDCl 3)δ1.55(s,9H),1.55-1.61(m,4H),2.68(dd,J=14.0,5.7Hz,2H),2.98(dd,J=14.0,6.6Hz,1H),3.46-3.64(m,4H),3.71(s,3H),3.85(d,J=16.5Hz,1H),4.63(d,J=4.4Hz,1H),5.08(dd,J=5.7,6.6Hz,1H),5.37(d,J=16.5Hz,1H),6.48(d,J=8.3Hz,1H),7.67(s,1H),7.69(d,J=8.3,1.8Hz,1H),7.72-7.76(m,2H),7.81-7.86(m,2H).
D) (S)-2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(4-phthalimido butyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under the room temperature ar gas environment with 4N hydrochloric acid/dioxane (5ml, 20mmol) add to (S)-7-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-3-oxo-4-(4-phthalimido butyl)-1H-1, the 4-benzodiazepine _-(660mg is 0.89mmol) in the solution in dichloromethane (20ml) for the 2-methyl acetate.Described mixture was stirred 18 hours.Concentrated described suspension obtains the target compound (425mg, 98%) into pale solid: 1HNMR (CDCl 3) δ 1.55-1.61 (m, 4H), 2.71 (dd, J=14.1,6.0Hz, 2H), 3.01 (dd, J=14.1,6.3Hz, 1H), 3.50-3.65 (m, 4H), 3.75 (s, 3H), 3.89 (d, J=16.5Hz, 1H), 4.68 (d, J=4.5Hz, 1H), 5.12 (dd, J=6.0,6.3Hz, 1H), 5.40 (d, J=16.6Hz, 1H), 6.41 (bs, 1H), 6.53 (d, J=8.4Hz, 1H), 7.69-7.75 (m, 4H), 7.82-7.85 (m, 2H); MS (ES) m/e 480.2[M+H] +.
E) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(4-phthalimido fourth-1-yl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with EDC (240mg, 1.25mmol) add to (S)-2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(4-phthalimido fourth-1-yl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.85g, 0.88mmol), 2-(amino methyl) benzimidazole dihydrochloride (230mg, 1.04mmol), HOBt.H 2O (169mg, 1.25mmol) and diisopropylethylamine (0.78ml is 4.5mmol) in the solution of the stirring in anhydrous acetonitrile (10ml).After 19 hours, go up concentrated described reactant, residue is allocated between water (5ml) and the ethyl acetate (20ml) at Rotary Evaporators (high vacuum).Stratum disjunctum and water (5ml) washing organic layer.Dry (magnesium sulfate) concentrates and obtains target compound (230mg, 43%) into pale solid through silica gel column chromatography (5% ethanol/methylene):
TLC?R f(5％MeOH/Cl 2CH 2)0.30； 1H?NMR(CD 3OD)δ1.42-1.56(m,5H),2.63(dd,J=6.4,16.2Hz,1H),2.95(dd,J=6.7,16.2Hz,1H),3.33-3.40(m,2H),3.48-3.55(m,2H),3.57(d,J=16.5?Hz,1H),3.67(s,3H),4.72-4.80(m,3H),5.03(dd,J=6.4,6.7Hz,1H),5.20(d,J=16.5Hz,1H),6.44(d,J=8.4Hz,1H),7.18-7.21(m,2H),7.52-7.63(m,6H)；7.74-7.76(m,2H),9.08(br?s,1H).
F) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[4-[(2-carboxylbenzoyl) amino] fourth-1-yl]-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with Lithium hydrate (30mg, 0.71mmol) add to (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(4-phthalimido fourth-1-yl)-1H-1, the 4-benzodiazepine _-(223mg is 0.33mmol) in the solution in methanol (2ml) and water (3ml) for the 2-methyl acetate.Under room temperature, described reactant mixture was stirred 19 hours.Be acidified to pH 4 and concentrate the generation solid with dilute hydrochloric acid.Filtration obtains the target compound (145mg, 66%) into white solid: [α] D=-100.4 ° of (c=1, CH 3OH); 1H NMR (CD 3OD) δ 1.32-1.65 (m, 5H), 2.58 (dd, J=16.4,6.7Hz, 1H), 2.90 (dd, J=16.4,7.9Hz, 1H), 3.06 (m, 1H), 3.69 (m, 1H), 4.00 (d, J=16.7Hz, 1H), 4.69 (br s, 2H), 5.11 (dd, J=7.9,6.7Hz, 1H), 5.36 (d, J=16.7 Hz, 1H), 6.50 (d, J=8.4Hz, 1H), 7.29 (m, 2H), 7.37 (m, 4H); 7.51 (m, 2H), 7.664 (s, 1H), 7.74 (d, J=6.8Hz, 1H); MS (ES) m/e 613.2[M+H] +. value of calculation C 32H 32N 6O 71.5H 2O:C, 60.08; H, 5.51; N, 113.14. measured value: C, 59.77; H, 5.46; N, 12.98.
Embodiment 17
(±)-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-1-(tert-butoxycarbonyl)-7-(4-hydroxyl-ethyl acetylene-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-the 1-methyl acetate
Under ar gas environment with 3-butine-1-alcohol (65mg, 0.93mmol), two (triphenylphosphine) Palladous chloride. (II) (5mg, 0.007mmol), triphenylphosphine (10mg, 0.038mmol) and Copper diiodide (10mg, 0.052mmol) (I) add to (±)-2,3,4,5-tetrahydrochysene-1-(tert-butoxycarbonyl)-7-iodo-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (obtains by embodiment 7c; 440mg is 0.94mmol) in the solution in triethylamine (34ml).With described reactant mixture reflux 4 hours, pass through celite then _Filter concentrated filtrate.With residue through purification by silica gel column chromatography (4: 20: 20: 56 methanol/ethyl acetate/hexanes/ch) obtain target compound (390mg, 94%) into weak yellow liquid:
TLC?R f(5％MeOH∶Cl 2CH 2)0.37； 1H?NMR(400MHz,CDCl 3)δ?7.34(dd,J=1.8,8.1Hz,1H),7.31(d,J=1.8Hz,1H),7.13(d,J=8.1?Hz,1H),5.15-5.23(m,1H),4.75(d,J=14.4Hz,1H),3.68(d,J=14.4Hz,1H),3.63-3.67(m,2H),3.59(s,3H),3.04,(s,3H),2.88(dd,J=5.5,15.2Hz,1H),2.45(t,J=6.4Hz,2H),2.26(dd,J=9.5,15.2Hz,1H),2.04(br?s,1H),1.34(br?s,9H)；MS(ES)m/e417[M+H] +.
B) (±)-1-(tert-butoxycarbonyl)-7-(4-hydroxyl fourth-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-the 1-methyl acetate
10%Pd/C (40mg) is added to (±)-1-(tert-butoxycarbonyl)-7-(4-hydroxyl-ethyl acetylene-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-2-methyl acetate (370mg, 0.89mmol) in the solution in ethanol (20ml), in (50psi) under the room temperature hydrogen environment described mixture of jolting on the Parr device.After 12 hours, pass through celite _Filter described reactant, concentrated filtrate obtains the target compound (350mg, 94%) into weak yellow liquid:
TLC R f(4: 20: 20: 56MeOH/EtOAc/ hexane/Cl 2CH 2) 0.55; 1H NMR (400MHz, CDCl 3) δ 7.10-7.19 (m, 3H), 5.59-5.77 (m, 1H), 4.85 (d, J=15.0Hz, 1H), 3.68-3.60 (m, 5H), 3,12 (s, 3H), 2.85 (dd, J=5.4,15.3Hz, 1H), 2.65 (t, J=6.4Hz, 2H), 2.34 (dd, J=10.0,15.3Hz, 1H), 1.30-1.78 (m, 13H); MS (ES) m/e 421[M+H] +.
C) (±)-1-(tert-butoxycarbonyl)-7-(4-carboxyl fourth-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-the 1-methyl acetate
In 0 ℃ to (±)-1-(tert-butoxycarbonyl)-7-(4-hydroxyl fourth-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-2-methyl acetate (350mg, 0.82mmol) add 2 in the solution in dichloromethane, 2,6,6-tetramethyl oxo piperidinium chloride (J.Org.Chem.1985,50,3930-3931; 220mg, 1.1mmol).Under 0 ℃ of ar gas environment, described mixture was stirred 2 hours.Add 2-methyl-2-butene (1ml), then add the NaClO of prepared fresh 2Solution (0.76g, 6.7mmol), NaH 2PO 4.H 2O (0.78g, 5.68mmol) and water (25ml).Remove ice bath, be absorbed in described mixture in the ethyl acetate and order 0.05M hydrochloric acid and salt water washing.Dry (magnesium sulfate), concentrate and through silica gel column chromatography (5% acetic acid was in 4: 20: 20: 56 methanol/ethyl acetate/hexanes/ch) obtain target compound (350mg, 98%):
TLC R f(5%AcOH was at 4: 20: 20: 56MeOH/EtOAc/ hexane/Cl 2CH 2) 0.32; 1H NMR (400MHz, CDCl 3) δ 7.13-7.18 (m, 3H), 5.60-5.69 (m, 1H), 4.83 (d, J=14.2Hz, 1H), 3.76 (d, J=14.2 Hz, 1H), 3.66 (s, 3H), 3.12 (s, 3H), 2.93 (dd, J=4.5,15.3Hz, 1H), 2.67 (t, J=7.3Hz, 2H), 2.36 (t, J=7.3Hz, 2H), 2.30-2.34 (m, 1H), 1.95 (q, J=7.3Hz, 2H), 1.34 (s, 9H); MS (ES) m/e 435[M+H] +.
D) (±)-1-(tert-butoxycarbonyl)-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-the 2-methyl acetate
With the carbonochloridic acid isobutyl ester (97mg 0.8mmol) adds to (±)-1-(tert-butoxycarbonyl)-7-(4-carboxyl fourth-1-yl)-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-the 2-methyl acetate (350mg, 0.8mmol) and Et 3(81mg is 0.8mmol) in the mixture of the stirring in anhydrous THF (8ml) and freezing (10 ℃) for N.After 10 minutes, add 1,2-phenylenediamine (1.43g, 0.9mmol) solution in THF (2ml).Under room temperature, continue to stir to spend the night, then evaporating solvent.Residue is dissolved in the ethyl acetate, order sodium bicarbonate aqueous solution and the described solution of salt water washing.Dry (magnesium sulfate) also concentrates the generation faint yellow solid.It is dissolved in the glacial acetic acid (5ml), described reactant is heated to 60 ℃.After 3 hours, cool off described mixture, concentrate,, use dichloromethane extraction with the neutralization of 2.5N sodium hydroxide.Dry (magnesium sulfate) concentrates and obtains target compound (200mg, 50%) through silica gel column chromatography (1-5% ethanol/methylene gradient): TLC R f(4: 20: 20: 56 methanol/ethyl acetate/dichloromethane) 0.18;
1H NMR (400MHz, CDCl 3) δ 7.57-7.61 (m, 2H), 7.15-7.28 (m, 4H), 7.08 (s, 1H), 5.60-5.55 (m, 1H), 4.75-4.88 (m, 1H), 3.71 (d, J=14.2Hz, 1H), 3.70 (s, 3H), 3.10 (s, 3H), 2.94 (dd, J=4.2,15.3Hz, 1H), 2.85-2.90 (m, 2H), and 2.73-2.79 (m, 2H), 2.32-2.36 (m, 1H), 2.15-2.23 (m, 1H), 1.34 and 1.55 (br s, rotamer, 9H); MS (ES) m/e 507[M+H] +.
E) (±)-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with Lithium hydrate (17mg, 0.17mmol) add to (±)-1-(tert-butoxycarbonyl)-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1, the 4-benzodiazepine _-(200mg is 0.395mmol) in the solution in methanol (2ml) and water (3ml) for the 2-methyl acetate.Under room temperature, described reactant mixture was stirred 4 hours.Be acidified to pH4 and concentrate the generation white solid with dilute hydrochloric acid.In 0 ℃ of mixture that it is dissolved in dichloromethane (10ml) and the trifluoroacetic acid (5ml), with described reactant remain in 0 ℃ 30 minutes.Evaporating solvent also grinds residue and ether through ODS flash chromatography purification (10-18% contain 0.1%TFA acetonitrile/water gradient).Concentrate the target compound (75mg, 48%) that also lyophilization obtains colourless powder: 1H
NMR((400MHz,CDCl 3)δ7.58-7.61(m,2H),7.37-7.39(m,2H),6.79(d,J=8.2
Hz,1H),6.68(s,1H),6.39(d,J=8.2Hz,1H),5.18(d,J=16.8?Hz,1H),4.77(dd,J
=7.0,7.5Hz,1H),3.63(d,J=16.8Hz,1H),3.03-3.19(m,3H),2.97(s,3H),2.83
(dd,J=7.0,16.4Hz,1H),2.52-2.56(m,2H),2.08-2.12(m,2H)；MS(ES)m/e
393.0[M+H] +. value of calculation C 22H 24N 4O 3C 2HF 3O 20.5H 2O:C, 55.92; H,
5.08N, 10. measured value: C56.16; H, 4.92; N, 10.88.
Embodiment 18
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) methyl of 4-[(benzimidazolyl-2 radicals-yl)] aminobutyronitrile
With 4-bromo butyronitrile (0.37g, 2.4989mmol) add to 2-amino methyl benzimidazole dihydrochloride (0.5g, 2.2717mmol) and sodium bicarbonate (0.67g is 7.951mmol) in the stirred mixture in dry DMF (10ml).Under room temperature, stirred 24 hours, concentrate described mixture.Be absorbed in residue in the water and use dichloromethane extraction.Through the dried over mgso organic extract, concentrate and obtain being brown oil target compound (0.15g, 35%) through silica gel rapid column chromatography purification (5% ethanol/methylene):
1HNMR(250MHz,DMSO-d 6)δ1.82(m,2H),2.45(t,J=4Hz,2H),2.85(t,J=4Hz,2H),4.11(s,2H),7.14(m,2H),7.50(m,2H).
B) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(4-cyano group propyl group) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With EDC (0.265g 0.8906mmol) adds to the methyl of 4-[(benzimidazolyl-2 radicals-yl)] aminobutyronitrile (0.159g, 0.7422mmol), 2,3,4,5-tetrahydrochysene-7-carboxyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.217g, 0.7422mmol), HOBt.H 2O (0.120g, 0.8906mmol) and i-Pr 2(0.192g is 1.4844mmol) at anhydrous CH for NEt 3In the stirred mixture among the CN (7ml).After stirring 48 hours under the room temperature, concentrate described mixture.Be absorbed in residue in the water and use dichloromethane extraction.The order with saturated sodium bicarbonate and salt water washing organic layer, through dried over mgso, the simmer down to brown oil.Obtain target compound (0.261g, 74%) through flash chromatography on silica gel purification (3% ethanol/methylene) into the canescence foam:
1H?NMR(250MHz,DMSO-d 6)：δ1.95(m,2H),2.66(dd,J=16.4,3.5Hz,1H),2.78(dd,J=16.4,3.5Hz,1H),2.85(t,J=8.7Hz,2H),3.45(t,J=8.7?Hz,2H),3.60(s,3H),3.80(d,J=16Hz,1H),4.52(s,2H),4.84(d,J=2.9?Hz,2H),5.15(m,1H),5.48(d,J=16Hz,1H),6.40(d,J=3.5Hz,1H),6.54(d,J=8.3Hz,1H),7.25(m,4H)；,7.50(m,1H),7.62(m,1H).
C) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(4-cyano group propyl group) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With 2.5N sodium hydroxide (0.7ml, 1.6433mmol) add to (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(4-cyano group propyl group) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.261g is 0.5478mmol) in the solution of the stirring in methanol (5rml) for the 2-methyl acetate.Under room temperature, stir and spend the night, concentrate described mixture.Residue is absorbed in the water, described solution is acidified to pH=4 with 6NHCl.Filter white solid and drying and obtain target compound (0.21g, 81%):
1H?NMR(250MHz,DMSO-d 6)：δ1.95(m,2H),2.66(dd,J=16.4,3.5Hz,1H),2.78(dd,J=16.4,3.5Hz,1H),2.85(t,J=8.7Hz,2H),3.45(t,J=8.7Hz,2H),3.80(d,J=16?Hz,1H),4.52(s,2H),4.84(d,J=2.9Hz,2H),5.15(m,1H),5.48(d,J=16Hz,1H),6.40(d,J=3.5Hz,1H),6.54(d,J=8.3Hz,1H),7.25(m,4H),7.50(m,1H),7.62(m,1H).
D) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with Ra/Ni with (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(4-cyano group propyl group) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-1-acetic acid (0.200g, 0.4325mmol) the mixture hydrogenation of ammonium hydroxide (1ml, 30% solution) in methanol (5ml) 24 hours.Filter to remove catalyst, concentrated filtrate also obtains target compound (0.100g, 33%) into pale solid through reversed phase chromatography (10% acetonitrile/water that contains 0.1%TFA): 1H NMR (400MHz, DMSO-d 6) δ 1.45 (m, 2H), 1.72 (m, 2H), 2.54 (dd, J=16.4,3.5Hz, 1H), 2.70 (m, 2H), 2.75 (dd, J=16.4,3.5Hz, 1H), 2.95 (s, 3H), 3.65 (t, J=8.7Hz, 2H), 3.85 (d, J=16Hz, 1H), 5.05 (s, 2H), 5.15 (m, 1H), 5.48 (d, J=16Hz, 1H), 6.65 (d, J=8.3Hz, 1H), 7.20 (m, 2H), 7.61 (m, 2H), 7.75 (s, 2H), 7.85 (m, 2H); IR (KBr) 3425,3000,3100,1728,1675,1630,1625,1613 cm -1MS (ES) m/e 479 (M+H). value of calculation C 25H 30N6O 42CF 3CO 2H:C, 49.30; H, 4.56; N, 11.89. measured value: C, 49.22; H, 4.89; N, 11.84.
Embodiment 19
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(2-cyano methyl) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) [(benzimidazolyl-2 radicals-yl) methyl] aminoacetonitriles
According to the step of embodiment 18 (A), but replace 4-bromo butyronitrile to be prepared as the target compound (0.15g, 35%) of pale solid with the bromo acetonitrile:
1H?NMR(250MHz,DMSO-d 6)：δ3.71(s,2H),3.98(s,2H),7.14(m,2H),7.50(m,2H).
B) (S)-2,3,4, methyl-N-(2-cyano methyl) amino of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the step of embodiment 18 (b), but replacing the methyl of 4-[(benzimidazolyl-2 radicals-yl) with [(benzimidazolyl-2 radicals-yl) methyl] aminoacetonitriles] aminobutyronitrile is prepared as the target compound (0.487g, 66%) of canescence foam:
1H?NMR(250MHz,DMSO-d 6)δ2.66(dd,J=16.4,3.5Hz,1H),2.78(dd,J=16.4,3.5Hz,1H),2.92(s,2H),3.60(s,3H),3.80(d,J=16?Hz,1H),4.52(s,2H),4.84(d,J=2.9Hz,2H),5.15(m,1H),5.48(d,J=16Hz,1H),6.40(d,J=3.5Hz,1H),6.54(d,J=8.3Hz,1H),7.25(m,4H),7.50(m,2H),7.62(m,2H).
C) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(2-cyano methyl) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Step according to embodiment 18 (c), with (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(2-cyano methyl) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate, and make product recrystallization in ethanol obtain target compound (0.420g, 89%) into white solid:
1H NMR (400MHz, DMSO-d 6) δ 2.66 (dd, J=16.4,3.5Hz, 1H), 2.78 (dd, J=16.4,3.5Hz, 1H), 2.92 (s, 2H), 3.80 (d, J=16Hz, 1H), 4.52 (s, 2H), 4.84 (d, J=2.9Hz, 2H), 5.15 (m, 1H), 5.48 (d, J=16Hz, 1H), 6.40 (d, J=3.5Hz, 1H), 6.54 (d, J=8.3Hz, 1H), 7.25 (m, 4H), 7.50 (m, 1H), 7.62 (m, 1H); MS (ES) m/e 465 (M+H) +. value of calculation C 23H 22N 6O 42HCl:C, 53.19; H, 4.66; N, 16.18; Measured value: C, 52.98; H, 4.43; N, 16.53.
Embodiment 20
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (R)-2-trifyl dimethyl succinate
With trifluoromethanesulfanhydride anhydride (10.0g, 35.7164mmol) drop to D-malic acid dimethyl ester (5.5g, 33.9213mmol), (2.82g is 35.7164mmol) in the mixed liquor of the stirring in anhydrous methylene chloride (55ml) cooling (0 ℃) for anhydrous pyridine.In 0 ℃ stir 4 hours after, described mixture of water quenching and stratum disjunctum.Order dilute hydrochloric acid and salt water washing organic layer also concentrate the target compound (8.50g, 96%) that obtains to white solid through dried over mgso:
1HNMR(250MHz,CDCl 3：δ3.10(d,J=5.8Hz,2H),3.74(s,3H),3.78(s,3H),5.52(t,J=5.8Hz,1H).
B) D-(2-cyano-phenyl) malic acid dimethyl ester
Under room temperature with the 2-aminobenzonitrile (0.5g, 4.2323mmol), 2, the 6-di-tert-butyl pyridine (0.85g, 4.4439mmol) and (R)-mixture of 2-trifyl dimethyl succinate in 2: 1 hexane/chloroform (25ml) stirred 76 hours.Concentrate described mixture, be absorbed in residue in the water and use ethyl acetate extraction.Order is with 10% hydrochloric acid and salt water washing organic extract, and is through dried over mgso, concentrated and obtain target compound (0.886g, 80%) into yellow solid through flash chromatography on silica gel purification (10% ethyl acetate/hexane):
1HNMR(250MHz,CDCl 3)δ2.95(d,J=5.8Hz,1H),3.74(s,3H),3.78(s,3H),4.60(m,1H),5.28(d,J=5.8Hz,1H),6.73(d,J=8.5Hz,1H),6.80(t,J=8.5Hz,1H),7.47(m,2H).
C) (S)-2,3,4,5-tetrahydrochysene-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
(10.75g 41.0006mmol) (uses NH at methanol with D-(2-cyano-phenyl) malic acid dimethyl ester under 55psi with Ra/Ni 3(g) presaturation is 10 minutes, and 100ml) hydrogenation is 48 hours.Filter to remove catalyst, concentrated filtrate also obtains target compound (5.03g, 53%) into pale solid through flash chromatography on silica gel purification (40% ethyl acetate/hexane):
1HNMR(250MHz,CDCl 3)δ2.65(dd,J=16.3,7.6Hz,1H),2.99(da,16.3,5.9Hz,1H),3.74(s,3H),3.95(dd,J=16,6.9Hz,1H),4.79(m,1H),4.95(dd,J=16,5.3Hz,1H),6.55(t,J=5.3Hz,1H),6.65(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),6.97(d,J=7.6Hz,1H),7.15(d,J=7.6Hz,1H).
D) (S)-2,3,4,5-tetrahydrochysene-7-bromo-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with (S)-2,3,4,5-tetrahydrochysene-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (5.03g, 21.4746mmol) and n-Bu 4NBr 3(10.35g, 21.4746mmol) mixture in chloroform (100ml) stirred 3 hours, concentrated described mixture then.Residue is absorbed in the water, stirs, filter the target compound (5.61g, 83%) that obtains to pale solid:
1H?NMR(250MHz,CDCl 3)δ2.74(dd,J=16.3,7.6Hz,1H),3.05(dd,J=16.3,5.9Hz,1H),3.75(s,3H),4.05(dd,J=16,6.9Hz,1H),4.73(t,J=5.9Hz,1H),4.86(dd,J=16,5.3Hz,1H),6.68(d,J=7.6Hz,1H),6.75(t,J=5.3Hz,1H),7.14(s,1H),7.25(d,J=7.6?Hz,1H).
E) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-the N-methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
To (S)-2,3,4,5-tetrahydrochysene-7-bromo-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (1.5g, 4.77905mmol), 2-(methylamino methyl) benzimidazole dihydrochloride (2.24g, 9.5809mmol), triphenylphosphine (1.26g, 4.7905mmol), n-Bu 3(6.21g is 33.5333mmol) with (Ph for N 3P) 4(1.10g 0.9581mmol) charged into argon and carbon monoxide 10 minutes to Pd in the mixture in N-methyl 2-Pyrrolidone (20ml).Under the carbon monoxide environment, described mixture was heated 8 hours at 100-105 ℃ then.Cool off described mixture and be acidified to pH=2 with 6N HCl.With the described solution of ethyl acetate extraction, discard ethyl acetate layer.With in 30% sodium hydroxide and water layer and use dichloromethane extraction.Through the dried over mgso organic extract, concentrate and obtain target compound (1.62g, 80%) into pale solid through flash chromatography on silica gel purification (5% ethanol/methylene):
1HNMR(250MHz,DMSO-d 6)：δ2.65(dd,J=16.3,7.6Hz,1H),2.81(dd,J=16.3,5.9Hz,1H),3.05(s,3H),3.60(s,3H),3.75(dd,J=16.3,6.9Hz,1H),4.78(s,2H),4.95(m,1H),5.05(dd,J=16,5.3Hz,1H),6.20(d,J=5.9Hz,1H),6.55(d,J=7.6Hz,1H),7.25(m,4H),7.55(m,2H),8.21(t,J=5.3Hz,1H).
F) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
According to the step of embodiment 18 (c), with (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-the N-methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate obtains the target compound (0.060g, 57%) into pale solid:
1H NMR (400MHz, DMSO-d 6) δ 2.52 (dd, J=16.3,7.6Hz, 1H), 2.84 (dd, J=16.3,5.9Hz, 1H), 3.20 (s, 3H), 3.75 (dd, J=16.3,6.9Hz, 1H), 4.95 (t, J=5.9Hz, 1H), 5.05 (dd, J=16,5.3Hz, 1H), 5.10 (s, 2H), 6.59 (d, J=7.6Hz, 1H), 7.12 (s, 1H), 7.20 (d, J=7.6Hz, 1H), 7.48 (m, 2H), 7.69 (m, 2H), 7.90 (d, J=5.3Hz, 1H); IR (KBr) 3600-3100,3100-2800,1681,1613,1601,1485,1445,1314,830,764,742 cm -1MS (ES) m/e 422 (M+H) +. value of calculation C 21H 21N 5O 4: C, 61.91; H, 5.20; N, 17.19. measured value: C, 61.57; H, 5.32; N, 17.29.
Embodiment 21
(S)-2,3,4,5-tetrahydrochysene-7-[[[[1-(2-hydroxyethyl) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) methyl of 2-[[(benzimidazolyl-2 radicals-yl)] amino] ethyl acetate
Under room temperature with 2-amino methyl benzimidazole dihydrochloride hydras (4.0g, 18.1736mmol), sodium bicarbonate (7.63g, 90.868mmol) and the 2-bromoethyl acetate (4.55g, 27.2603mmol) mixture in dry DMF (60ml) stirred 24 hours, concentrated then.Be absorbed in residue in the water and use dichloromethane extraction.Through the dried over mgso organic extract, obtain target compound (0.50g, 12%) into brown oil through flash chromatography on silica gel purification (5% ethanol/methylene):
1H?NMR(250MHz,CDCl 3)δ1.95(s,3H),3.48(s,2H).4.50(m,4H),7.25(m,2H),7.35(m,1H),7.73(m,1H).
B) (S)-2,3,4,5-tetrahydrochysene-7-[[[[1-(2-acetoxyl group ethyl) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the step of embodiment 18 (b), but with 2-[[(benzimidazolyl-2 radicals-yl] methyl] amino] ethyl acetate replaces 4-[(benzimidazolyl-2 radicals-yl] methyl] aminobutyronitrile is prepared as the target compound (0.251g, 78.5%) of white solid: 1H NMR (250MHz, CDCl 3) δ 1.95 (s, 3H), 2.66 (dd, J=16.4,3.5Hz, 1H), 2.95 (s, 3H), 3.05 (dd, J=16.4,3.5Hz, 1H), 3.60 (d, J=16Hz, 1H), 3.75 (s, 3H), 4.45 (d, J=5.9Hz, 2H), 4.62 (s, 2H), 4.92 (t, J=5.9Hz, 2H), 5.10 (m, 1H), 5.40 (d, J=16Hz, 1H), 6.49 (d, J=8.3Hz, 1H), 7.32 (m, 3H), 7.60 (m, 2H), 7.71 (m, 1H), 8.15 (t, J=5.3Hz, 1H).
C) (S)-2,3,4,5-tetrahydrochysene-7-[[[[1-(2-hydroxyethyl) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With 1.0N LiOH (1.4ml, 1.425mmol) add to (S)-2,3,4,5-tetrahydrochysene-7-[[[[1-(2-acetoxyl group ethyl) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.241g is 0.475mmol) in the part suspension of the stirring in THF (5ml) for the 2-methyl acetate.Under room temperature, stir and spend the night, concentrate described mixture.Be absorbed in residue in the water and be acidified with acetic acid to pH=4.Filter pale solid and grind the target compound (0.16g, 75%) that obtains to white solid with acetone:
1H NMR (400MHz, DMSO-d 6): δ 2.54 (dd, J=16.4,3.5Hz, 1H), 2.95 (s, 3H), 3.05 (dd, J=16.4,3.5Hz, 1H), 3.60 (d, J=16Hz, 1H), 4.45 (d, J=5.9Hz, 2H), 4.62 (s, 2H), 4.92 (t, J=5.9Hz, 2H), 5.10 (m, 1H), 5.40 (d, J=16Hz, 1H), 6.49 (d, J=8.3Hz, 1H), 7.32 (m, 3H), 7.60 (m, 2H), 7.71 (m, 1H), 8.15 (t, J=5.3Hz, 1H); MS (ES) m/e452 (M+H) +. value of calculation C 23H 25N 5O 50.75H 2O:C, 59.71; H, 5.72; N, 15.14. measured value: C, 59.65, H, 5.70; N, 14.88.
Embodiment 22
(S)-2,3,4,5-tetrahydrochysene-7-[[N-(benzimidazolyl-2 radicals-yl] methyl-N-[[4-(2-carboxylbenzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) methyl of 4-[[(benzimidazolyl-2 radicals-yl)] amino] the butyl benzene dicarboximide
In 100-110 ℃ with 2-amino methyl benzimidazole dihydrochloride hydras (22.10g, 100.7269mmol), sodium bicarbonate (42.40g, 503.6347mmol) and 4-bromo butyl benzene dicarboximide (34.10g, 120.8723mmol) mixture heated in dry DMF (250mg) 6 hours, cool off then and concentrate.Be absorbed in residue in the water and use dichloromethane extraction.Through the dried over mgso organic extract, concentrate and obtain target compound (10.8g, 31%) into brown foam through flash chromatography on silica gel purification (5% ethanol/methylene):
1H?NMR(250MHz,CDCl 3)δ1.65(m,2H),1.85(m,2H),2.75(t,J=8.9Hz,2H),3.78(t,J=8.9?Hz,2H),4.17(s,2H),7.20(m,2H),7.60(m,2H),7.72(m,2H),7.88(m,2H).
B) (±)-2,3,4,5-tetrahydrochysene-7-[[N-(benzimidazolyl-2 radicals-yl] methyl-N-[[4-(Phthalimide base) butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With EDC (1.50g, 5.0525mmol) add to the methyl of 4-[[(benzimidazolyl-2 radicals-yl)] amino] butyl benzene dicarboximide (1.75g, 5.0525mmol), (±)-2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (1.61g, 4.2104mmol), HOBt.H 2O (0.69g, 5.0525mmol) and i-Pr 2(1.10g is 8.4209mmol) at anhydrous CH for NEt 3In the stirred mixture among the CN (30ml).After stirring 24 hours under the room temperature, concentrate described mixture.Be absorbed in residue in the water and use dichloromethane extraction.Order is with saturated sodium bicarbonate and salt water washing organic extract, and is through dried over mgso, concentrated and obtain target compound (2.85g, 95%) into yellow foam through flash chromatography on silica gel purification (5% ethanol/methylene): 1H NMR (250MHz, DMSO-d 6) δ 1.60 (m, 2H), 2.65 (m, 2H), 2.85 (dd, J=16.4,3,5Hz, 1H), 3.55 (m, 4H), 3.65 (s, 3H), 4.00 (d, J=16.0Hz, 1H), 4.18 (q, J=8.9Hz, 2H), 4.75 (s, 2H), 5.15 (m, 1H), 5.45 (d, J=16.0 Hz, 1H), 6.23 (d, J=5.3Hz, 1H), 6.57 (d, J=7.6Hz, 1H), 7.20 (m, 7H), 7.55 (m, 4H), 7.90 (m, 4H).
C) (±)-tetrahydrochysene-7-[[N-(benzimidazolyl-2 radicals-yl] methyl-N-(the amino butyl of 4-) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (±)-2,3,4,5-tetrahydrochysene-7-[[N-(benzimidazolyl-2 radicals-yl] methyl-N-[[4-(Phthalimide base) butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.50g, 0.7015mmol) and hydrazine (0.07g, 2.1045mmol) mixture in methanol (5ml) refluxed 6 hours, cooled off then and concentrated.Residue is absorbed in the water, is acidified to pH=2, filter and remove white solid with 6N HCl.Discard this solid.Use ethyl acetate extraction filtrate, discard ethyl acetate layer.Alkalize water layer to pH=9 and use chloroform extraction with sodium carbonate.Also concentrate the target compound (0.41g, 89%) that obtains to pale solid through the dried over mgso organic layer:
1H?NMR(250MHz,DMSO-d 6)δ1.47(m,2H),1.75(m,2H),2.65(m,5H),2.85(dd,J=16.3,5.9Hz,1H),3.65(s,7H),4.05(d,J=16.0Hz,1H),5.05(s,2H),5.15(m,1H),5.45(d,J=16,1H),6.65(d,J=7.6Hz,1H),7.25(m,6H),7.41(s,1H),7.60(m,2H),7.85(m,2H).
D) (±)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(2-carboxylbenzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
With 1.0N LiOH (1.2ml) add to (±)-tetrahydrochysene-7-[[N-(benzimidazolyl-2 radicals-yl] methyl-N-(4-amino butyl) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(0.34g is 0.47mmol) in the solution of the stirring in THF for the 2-methyl acetate.After stirring under the room temperature is spent the night, concentrate described mixture, with acetic acid residue is acidified to pH=4.Cross filter solid and grind the target compound (0.130g, 39%) that obtains to white solid with acetone:
1HNMR (400MHz, DMSO-d 6) δ 1.47 (m, 2H), 1.75 (m, 2H), 2.54 (dd, J=16.3,3.5Hz, 1H), 2.65 (m, 2H), 2.85 (dd, J=16.3,5.9Hz, 1H), 3.20 (m, 2H), 3.75 (m, 4H), 4.05 (d, J=16.0Hz, 1H), 5.05 (s, 2H), 5.15 (m, 1H), 5.45 (d, J=16,1H), 6.65 (d, J=7.6Hz, 1H), 7.25 (m, 6H), 7.41 (s, 1H), 7.60 (m, 2H), 7.85 (m, 2H); IR (KBr) 3400,3326,3100-3000,1721,1637,1626,1616,1607,1300,750,694 cm -1MS (ES) m/e717 (M+H) +. value of calculation C 40H 38N 6O 83H 2O:C, 63.56; H, 5.87; N, 11.12. measured value: C, 63.56; H, 5.83; N, 11.04.
Embodiment 23
(±)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With EDC (0.25g, 0.8424mmol) add to (±)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(Phthalimide base) butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.409g, 0.702mmol), 4-azido salicylic acid-N-hydroxyl succinamide ester (0.194g, 0.702mmol) and i-Pr 2NEt (0.272g, 2.106mmol) anhydrous CH at 2: 1 3In the stirred mixture among the CN/DMF (10ml).After stirring 24 hours under the room temperature, concentrate described mixture.Residue is absorbed in the water, filters the target compound (0.204g, 39%) that also obtains after drying to pale solid: 1H NMR (250MHz, DMSO-d 6) δ 1.40 (m, 2H), 1.75 (m, 2H), 2.65 (m, 3H), 2.75 (dd, J=16.3,5.9Hz, 1H), 3.20 (m, 2H), 3.51 (m, 4H), 3.65 (m, 3H), 3.95 (d, J=16Hz, 1H), 4.79 (s, 2H), 5.12 (m, 1H), 5.37 (d, J=16 Hz, 1H), 6.20 (s, 1H), 6.55 (m, 3H), 7.20 (m, 8H), 7.55 (m, 3H), 7.85 (d, J=7.6Hz, 1H), 7.98 (s, 1H), 8.75 (s, 1H).
B) (±)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 22 (d); with (±)-2; 3; 4; 5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1; the 4-benzodiazepine _-saponification of 2-methyl acetate obtains the target compound (0.100g, 50%) into white solid: 1H NMR (400MHz, DMSO-d 6) δ 1.40 (m, 2H), 1.75 (m, 2H), 2.65 (m, 3H), 2.75 (dd, J=16.3,5.9 Hz, 1H), 3.20 (m, 2H), 3.51 (m, 4H), 3.95 (d, J=16Hz, 1H), 4.79 (s, 2-H), 5.12 (m, 1H), 5.37 (d, J=16Hz, 1H), 6.20 (s, 1H), 6.55 (m, 3H), 7.20 (m, 8H), 7.55 (m, 3H), 7.85 (d, J=7.6Hz, 1H), 7.98 (s, 1H), 8.75 (s, 1H); MS (ES) m/e 730 (M+H) +. value of calculation C 39H 39N 9O 62.5H 2O:C, 60.46; H, 5.72; N, 16.27. measured value: C, 60.46; H, 5.43; N, 15.90.
Embodiment 24
2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)-N-[[[(+)-biological acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(2RS)-preparation of acetic acid
A) 2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)-N-[[[(+)-biological acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(2RS)-methyl acetate
To (±)-tetrahydrochysene-7-[[N-(methyl-N-(amino butyl) amino of benzimidazolyl-2 radicals-yl)] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.40g, 0.6865mmol), (+)-biotin (0.17g, 0.6865mmol), HOBtH 2O (0.11g, 0.8239mmol) and i-Pr 2(0.18g is 1.3730mmol) in 1: 2 DMF/CH for NEt 3Add in the mixture of CN (12mL) EDC (0.25g, 0.8239mmol).After stirring 24 hours under the room temperature, mixture is concentrated.Residue is water-soluble and use CHCl 3Extraction.Use saturated NaHCO in order 3With salt water washing organic extract liquid, use dried over mgso, concentrate, through flash chromatography on silica gel (10%MeOH/CH 2Cl 2) purification promptly gets yellow cystose target compound (0.24g, 44%): 1HNMR (250MHz, DMSO-d 6) δ 1.30 (m, 2H), 1.60 (m, 4H), 2.05 (t, J=8.9Hz, 2H); , 2.60 (m, 3H), 2.68 (dd, J=16.3,5.9Hz, 1H), 3.10 (m, 4H), 3.45 (m, 2H), 3.60
(m,2H),3.65(s,3H),4.01(d,J=16Hz,1H),4.12(t,J=8.9Hz,1H),4.30(t,J=8.9Hz,1H),4.78(s,2H),5.10(m,1H),5.45(d,J=16Hz,1H),6.20(d,J=5.3Hz,1H),6.40(d,J=8.9Hz,2H),6.55(d,J=7.6Hz,1H),7.25(m,9H),7.45(m,1H),7.55(m,1H),7.70(t,J=8.6Hz,1H).
B) 2,3,4,5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)-N-[[[(+)-biological acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(2RS)-acetic acid
1.0NLiOH (0.44ml) is added 2; 3; 4; 5-tetrahydrochysene-7-[[N-(methyl of benzimidazolyl-2 radicals-yl)-N-[[[(+)-biological acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1; the 4-benzodiazepine _-(2RS)-(0.24g is 0.2967mmol) in 1: in the solution of the stirring of 2THF/MeOH (6mL) for methyl acetate.After stirring under the room temperature is spent the night, mixture is concentrated.Residue is water-soluble, and is acidified to pH=4 with AcOH.With linen solid filtering, grind the target compound (0.160g, 68%) that promptly gets to white solid with hot acetone:
1H NMR (400MHz, DMSO-d 6) d 1.30 (m, 2H), 1.60 (m, 4H), 2.05 (t, J=8.9 Hz, 2H), 2.60 (m, 3H), 2.68 (dd, J=16.3,5.9 Hz, 1H), 3.10 (m, 4H), 3.45 (m, 2H), 3.60 (m, 2H), 4.01 (d, J=16Hz, 1H), 4.12 (t, J=8.9Hz, 1H), 4.30 (t, J=8.9Hz, 1H), 4.78 (s, 2H), 5.10 (m, 1H), 5.45 (d, J=16Hz, 1H), 6.20 (d, J=5.3Hz, 1H), 6.40 (d, J=8.9Hz, 2H), 6.55 (d, J=7.6Hz, 1H), 7.25 (m, 9H), 7.45 (m, 1H), 7.55 (m, 1H), 7.70 (t, J=8.6Hz, 1H); MS (ES) m/e 795 (M+H) +. value of calculation C 42H 50N 8O 6S1.75H 2O:C, 61.04; H, 6.52; N, 13.56. measured value: C, 60.89; H, 6.24; N, 13.31.
Embodiment 25
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 24 (b), with (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate promptly gets the target compound (0.250g, 80%) into pale solid: 1H NMR (400MHz, DMSO-d 6) δ 1.37 (m, 2H), 1.62 (m, 2H), 2.52 (dd, J=3.5Hz, 1H), 2.64 (m, 2H), 2.75 (dd, J=16.3,5.9Hz, 1H), 3.51 (m, 4H), 3.91 (d, J=16Hz, 1H), 4.98 (s, 2H), 5.05 (m, 1H), 5.37 (d, J=16Hz, 1H), 6.53 (d, J=7.9Hz, 2H), 7.17 (m, 7H), 7.52 (m, 1H), 7.62 (s, 1H), 7.78 (m, 1H); IR (KBr): 3386,3100-3000,1647,1613,1403,740,699cm -1MS (ES) m/e 569 (M+H) +. value of calculation C 32H 36N 6O 42.75H 2O:C, 62.18; H, 6.77; N, 13.60. measured value: C, 62.11; H, 6.68; N, 13.57.
Embodiment 26
(±)-2; 3; 4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 3-iodo-4-azido salicylic acid-N-hydroxy-succinamide ester
With iodine (0.510g, 1.9913mmol) add 4-azido salicylic acid-N-hydroxy-succinamide ester (0.500g, 1.8103mmol) and Silver Trifluoroacetate (0.44g is 1.9931mmol) in CHCl 3In the stirred mixture (10mL).Under room temperature, stir and spend the night, will react and filter to remove solid precipitation.Use H in order 2O, saturated NaHCO 3With the saline wash filtrate, then through dried over mgso.Concentrate and promptly get the solid target compound of lilac (0.703g, 97%):
1H?NMR(250MHz,CDCl 3)δ2.98(s,4H),6.83(d,J=7.6Hz,1H),8.05(d,J=7.6Hz.1H).
B) methyl of (±)-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to embodiment 22 (b) flow process, but replace the methyl of 4-[[(benzimidazolyl-2 radicals-yl) with 3-iodo-4-azido salicylic acid-N-hydroxy-succinamide ester] amino] butyl phthalimide, prepare and be the foamy target compound of yellow (0.312g, 56%):
1H?NMR(250MHz,DMSO-d 6)δ1.42(m,?2H),1.60(m,2H),2.52(dd,J=16.3,3.5Hz,1H),2.63(m,?2H),2.79(dd,J=16.3,5.9Hz,1H),3.25(s,2H),3.55(m,6H),3.65(s,3H),3.95(d,J=16Hz,1H),4.75(s,2H),5.02(m,1H),5.35(d,J=16?Hz,1H),6.14(d,J=5.3?Hz,1H),6.52(d,J=7.9?Hz,1H),6.86(d,J=7.9Hz,1H),7.25(m,10H),7.51(s,2H),7.90(d,J=7.9Hz,1H),9.01(s,1H).
C) methyl of (±)-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 22 (c); with the methyl of (±)-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate.Through the silica gel rapid column chromatography (0.5,0.5,9.5AcOH/MeOH/CH 2Cl 2) purification promptly gets the target compound (0.170g, 58%) of pale solid:
1H NMR (400MHz, DMSO-d 6) δ 1.42 (m, 2H), 1.60 (m, 2H), 2.52 (dd, J=16.3,3.5Hz, 1H), 2.63 (m, 2H), 2.79 (dd, J=16.3,5.9Hz, 1H), 3.25 (s, 2H), 3.55 (m, 6H), 3.95 (d, 16,1H), 4.75 (s, 2H), 5.02 (m, 1H), 5.35 (d, J=16Hz, 1H), 6.14 (d, J=5.3Hz, 1H), 6.52 (d, J=7.9Hz, 1H), 6.86 (d, J=7.9Hz, 1H), 7.25 (m, 10H), 7.51 (s, 2H), 7.90 (d, J=7.9Hz, 1H), 9.01 (s, 1H); MS (ES) m/e 856 (M+H) +IR (KBr): 3360,3100-3000,2116,1704,1643,1610,1586,1477,1305,1274,766,700cm -1. value of calculation C 39H 38IN 9O 64.5H 2O:C, 50.01; H, 5.06; N, 13.46. measured value C, 50.19; H, 5.01; N, 13.12.
Embodiment 27
The methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-preparation of 1H-benzimidazolyl-2 radicals-glycine
A) methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1H-benzimidazolyl-2 radicals-methyl aminoacetate
Under room temperature with diisopropylethylamine (1,1ml, 6.48mmol) add to 5-carboxyl-benzimidazolyl-2 radicals-methyl aminoacetate (0.24g, 0.96mmol), 2-(methylamino methyl) benzimidazole is two-trifluoro-acetate (0.56g, 1.44mmol), HOBt.H 2O (0.19g, 1.44mmol) and EDC (0.28g is 1.44mmol) in the solution of the stirring in dry DMF (8ml).After 23 hours, wash with 5% sodium bicarbonate (30ml) and saline (30ml) with dichloromethane (100ml) described reactant mixture of dilution and order.Dry (magnesium sulfate) concentrates and obtains target compound (0.16g, 42%) into pale solid: MS (ES) m/e393.0 (M+H) through silica gel column chromatography (10% ethanol/methylene) +
B) methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1-benzimidazolyl-2 radicals-glycine
Under room temperature with 1.0N LiOH (1.0ml, 1.0mmol) drop to the methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-(0.16g is 0.41mmol) in the mixture in THF (10ml) and water (10ml) for 1H-benzimidazolyl-2 radicals-methyl aminoacetate.After 1 hour, cool off to small size and on ice bath, use 1.0N AcOH (1.0ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.Collect solid, use cold water washing, air drying obtains the target compound (0.15g, 100%) into pale solid: MS (ES) m/e 379.2 (M+H) +
Embodiment 28
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.94ml, 5.4mmol) add to (±)-7-carboxyl-4-(3, the 3-dimethylbutyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-2-acetic acid (0.39g, 1.08mmol), 2-(methylamino methyl) benzimidazole is two-trifluoro-acetate (0.42g, 1.08mmol), HOBt.H 2O (0.22g, 1.62mmol) and EDC (0.31 g is 1.62mmol) in the solution of the stirring in dry DMF (8ml).After 23 hours, with dichloromethane (100ml) the described reactant mixture of dilution and order with 5% sodium bicarbonate (2 * 25ml) and saline (25ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.39g, 71%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 506.4 (M+H) +
B) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (1.0ml, 1.0mmol) drop to (±)-2,3,4, the methyl of 5-tetrahydrochysene 7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-mixture of 2-methyl acetate (0.38g, 0.75mmol)) in THF (10ml) and water (10ml) in.After 50 minutes, cool off to small size and on ice bath, use 1.0N AcOH (2.5ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.Collect solid, use cold water washing, air drying obtains the target compound (0.27g, 73%) into white solid: MS (ES) m/e 492.2 (M+H) +
Embodiment 29
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.79ml, 4.56mmol) add to (±)-7-carboxyl-4-(3, the 3-dimethylbutyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-2-acetic acid (0.33g, 0.91mmol), 2-(amino methyl) benzimidazole dihydrochloride hydras (0.3g, 1.36mmol), HOBt.H 2O (0.18g, 1.36mmol) and EDC (0.26g is 1.36mmol) in the solution of the stirring in dry DMF (8ml).After 20 hours, with dichloromethane (70ml) the described reactant mixture of dilution and order with 5% sodium bicarbonate (2 * 20ml) and saline (20ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.25g, 56%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 492.4 (M+H) +
B) (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (1.0ml, 1.0mmol) drop to (±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-mixture of 2-methyl acetate (0.24g, 0.49mmol)) in THF (8ml) and water (8ml) in.2.5 after hour, cool off to small size and on ice bath, use 1.0N AcOH (1.2ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.Collect described solid, use cold water washing, air drying obtains the target compound (0.25g, 109%) into white solid: MS (ES) m/e 478.2 (M+H) +
Embodiment 30
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.53ml, 3.0mmol) add to (±)-7-carboxyl-4-(3, the 3-dimethylbutyl)-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.22g, 1.0mmol), 2-(methylamino) methyl-4-azepine benzimidazole oxalic acid methyl ester (0.29g, 1.0mmol), HOBtH 2O (0.12g, 0.91mmol) and EDC (0.17g is 0.91mmol) at anhydrous CH 3In the solution of the stirring among the CN (12ml).After 21 hours, reactant mixture is concentrated, with dichloromethane (100ml) dilution, and order with 5% sodium bicarbonate (2 * 20ml) and saline (20ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.147g, 48%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 507.4 (M+H) +
B) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (0.69ml, 0.69mmol) drop to (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-mixture of 2-methyl acetate (0.14g, 0.276mmol)) in THF (8ml) and water (8ml) in.After 2 hours, cool off to small size and on ice bath, use 1.0N AcOH (0.69ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.Collect solid, use cold water washing, air drying obtains the target compound (0.074g, 54%) into white solid: MS (ES) m/e 493.2 (M+H) +
Embodiment 31
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.27ml, 1.53mmol) add to (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-2-methyl acetate trifluoroacetate (0.14g, 0.34mmol), the 2-[[1-[(benzimidazolyl-2 radicals-yl) methyl] benzimidazole] methyl] amine two (trifluoroacetate) (0.17g, 0.34mmol), HOBtH 2O (0.064g, 0.48mmol) and EDC (0.091g is 0.48mmol) in the solution of the stirring in dry DMF (10ml).After 22 hours, reactant mixture is concentrated, with dichloromethane (70ml) dilution, and order with 5% sodium bicarbonate (2 * 30ml) and saline (20ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.080g, 43%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 552.2 (M+H) +
B) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (0.36ml, 0.36mmol) drop to (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.08g is 0.14mmol) in the mixture in THF (5ml) and water (4ml) for the 2-methyl acetate.After 2 hours, cool off to small size and on ice bath, use 1.0N AcOH (0.69ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.The solution lyophilization is obtained crude product (0.086g) into white powder.Through the C-18 Bond (0%-20%CH that contains 0.1%TFA 3CN/H 2The O eluting) purification obtains the target compound into white powder: MS (ES) m/e 538.2 (M+H) +
Embodiment 32
(S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.22ml, 1.29mmol) add to (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-2-methyl acetate trifluoroacetate (0.075g, 0.26mmol), two [(benzimidazolyl-2 radicals-yl) methyl] amine three (trifluoroacetate) (0.16g, 0.26mmol), HOBt.H 2O (0.05g, 0.36mmol) and EDC (0.069g is 0.36mmol) at anhydrous CH 3In the solution of the stirring among the CN (10ml).After 17 hours, reactant mixture is concentrated, with dichloromethane (80ml) dilution, and order with 5% sodium bicarbonate (2 * 20ml) and saline (20ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.05g, 36%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 552.2 (M+H) +
B) (S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (0.23ml, 0.23mmol) drop to (S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-mixture of 2-methyl acetate (0.05g, 0.09mmol)) in THF (6ml) and water (4ml) in.After 1 hour, cool off to small size and on ice bath, use 1.0N AcOH (0.3ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.Collect the gained solid, use cold water washing, air drying obtains the target compound (0.048g, 98%) into white solid: MS (ES) m/e 538.2 (M+H) +
Embodiment 33
±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenethyl)-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenethyl)-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with diisopropylethylamine (0.3ml, 1.74mmol) add to (±)-7-carboxyl--3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.11g, 0.29mmol), two [(benzimidazolyl-2 radicals-yl) methyl] amine three (trifluoroacetate) (0.18g, 0.29mmol), HOBtH 2O (0.058g, 0.43mmol) and EDC (0.083g is 0.43mmol) at anhydrous CH 3In the solution of the stirring among the CN (l2ml).After 21 hours, reactant mixture is concentrated, with dichloromethane (100ml) dilution, and order with 5% sodium bicarbonate (2 * 20ml) and saline (20ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.13g, 70%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 642.2 (M+H) +
B) (±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0N LiOH (0.6ml, 0.6mmol) drop to (±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenethyl)-1H-1, the 4-benzodiazepine _-(0.13g is 0.20mmol) in the mixture in THF (5ml) and water (5ml) for the 2-methyl acetate.After 18 hours, cool off to small size and on ice bath, use 1.0N AcOH (0.6ml) neutralization then at concentrated described reactant mixture on the Rotary Evaporators.The solution lyophilization is obtained crude product (0.092g, 77%) into white powder.(gradient contains the 5%-30%CH of 0.1%TFA through the ODS chromatography 3CN/H 2O) obtain target compound: MS (ES) m/e628.2 (M+H) into white powder +
Embodiment 34
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] preparation of amino-4-pentyne ethyl ester
A) (±)-4-acetenyl-2-aza cyclo-butanone
(9.0g, (the 0.5M THF solution of 31ml is in solution 0.55mmol) 69.7mmol) slowly to add to acetenyl chlorination magnesium with 4-acetoxyl group-2-aza cyclo-butanone in 0 ℃.1.5 after hour, add 1.0N HCl (100ml), mixture is dissolved among the EtOAc (300ml), and uses 1.0N HCl (100ml), saturated NaHCO in order 3(100ml) and saline (100ml) washing.Dry (magnesium sulfate) and concentrated promptly getting are the solid target compound of light brown (4.57g, 69%): MS (ES) m/e 96.0 (M+H) +
B) (±)-3-amino-4-pentyne ester ethyl ester
With (±)-4-acetenyl-2-aza cyclo-butanone (1.3g, 13.68mmol), the mixture heated of EtOH (54ml) and dense HCl (6ml) refluxed 18 hours.Reactant is cooled to room temperature, with saturated NaHCO 3Transfer pH to 8.0.(3 * 70ml) extractive reactions are with the EtOAc layer of saline (50ml) washing merging with EtOAc.Dry (magnesium sulfate) also concentrates the target compound (1.06g, 55%) that promptly gets to brown liquid: MS (ES) m/e 141.9 (M+H) +
C) [[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] methyl succinate
In the time of 0 ℃ with 3-carbomethoxy propionyl chloride (0.6g, 4.0mmol) add 2-amino-ethyl benzimidazole diacetin (1.13g, 4.0mmol) and diisopropylethylamine (2.59g is 20mmol) in anhydrous CH 2Cl 2In the solution of stirring (45ml).After stirring 1.5 hours under the room temperature, use CH 2Cl 2(50ml) with reactant mixture dilution and order water (30ml), 5% sodium bicarbonate (30ml) and saline (30ml) washing.Dry (magnesium sulfate) concentrates and obtains target compound (0.2g, 18%) into yellow solid: MS (ES) m/e276.4 (M+H) through silica gel column chromatography (8% ethanol/methylene) +
D) [[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinic acid
Will [[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] methyl succinate (0.2g, 0.73mmol), 1.0N NaOH (1.82ml, 1.82mmol) and the mixture of MeOH (10ml) under room temperature, stirred 24 hours, be concentrated into dried then.Add water (5ml), with 1.0N HCl (1.82ml) neutralization, gained solution promptly gets crude product target compound (0.23g) into pale powder through lyophilization: MS (ES) m/e 261.9 (M+H) +
E) (±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-pentinoic acid ethyl ester
Under room temperature with diisopropylethylamine (0.32ml, 1.83mmol) add (±)-3-amino-4-pentinoic acid ethyl ester (0.12g, 0.88mmol), [[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinic acid (0.19g, 0.73mmol), HOBtH 2O (0.15g, 1.1mmol) and EDC (0.21g is 1.1mmol) in anhydrous CH 3In the solution of the stirring among CN (15ml) and the DMF (3ml).After 23 hours, reactant mixture is concentrated, use CH 2Cl 2(100ml) with reactant mixture dilution and order with 5% sodium bicarbonate (2 * 25ml) and saline (25ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.07g, 25%) into white solid through silica gel column chromatography (7% ethanol/methylene): MS (ES) m/e 385.4 (M+H) +
Embodiment 35
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] preparation of amino-4-pentinoic acid
A) (±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-pentinoic acid
Under room temperature with 1.0N LiOH (0.78ml, 0.78mmol) be added drop-wise to (±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] (0.12g is 0.31mmol) in THF (5ml), H for amino-4-pentinoic acid ethyl ester 2O (5ml) and CH 3In the mixture of CN (1ml).After 3 hours, on Rotary Evaporators, reactant mixture is concentrated into small size, in ice bath, cools off, use 1.0NAcOH (0.78ml) neutralization then.The solution lyophilization is obtained crude product (0.167g) into white powder.Through the ODS chromatography (10%CH that contains 0.1%TFA 3CN/H 2O) obtain target compound: MS (ES) m/e 357.1 (M+H) into white powder +
Embodiment 36
(±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-preparation of 4-pentinoic acid (SB-237554)
A) (4-azepine benzimidazole-2-yl) methyl butyrate
In 0 ℃ with triethylamine (319ml 22.9mmol) is added to 2, the 3-diamino-pyridine (2.5g, 22.9mmol) and 4-(chloroformyl) methyl butyrate (3.77g is 22.9mmol) in the mixture of anhydrous THF (50ml).After 16 hours, under vacuum condition, reactant is concentrated into dried in stirring at room.Residue is dissolved in the glacial acetic acid (25ml) and in 110 ℃ of heating.After 93 hours, reaction is cooled to room temperature, and under vacuum, concentrates.Water (40ml) and CH 2Cl 2(40ml), mixture is neutralized to pH7 with 5N NaOH with the dilution of dark-brown residue.CH is further used in layering, aqueous layer 2Cl 2(2 * 100ml) extractions.Use 5% sodium bicarbonate (2 * 30ml) and the organic facies that merges of saline (30ml) washing in order.Dry (magnesium sulfate) concentrates and obtains target compound (0.47,9%): MS (ES) m/e 220.0 (M+H) through silica gel column chromatography (7% ethanol/methylene) +
B) (4-azepine benzimidazole-2-yl) butanoic acid
With (4-azepine benzimidazole-2-yl) methyl butyrate (0.47g, 2.13mmol), the mixture of 1.0NNaOH (6ml) and MeOH (10ml) stirred under room temperature 5.5 hours, was concentrated into dried then.Water (2ml) dilutes residue, and neutralizes with 1.0N HCl (0.73ml).Collect the gained solid, air drying promptly gets the target compound (0.32g, 73%) into yellow powder: MS (ES) m/e 206.0 (M+H) +
C) glycyl (±)-3-[[(N-tert-butoxycarbonyl)] amino]-the 4-ethyl valerate
Under room temperature with diisopropylethylamine (0.92ml, 5.32mmol) be added to (±)-3-amino-4-pentinoic acid ethyl ester (0.3g, 2.13mmol), Boc-Gly (0.56g, 3.19mmol), HOBtH 2O (0.43g, 3.19mmol) and EDC (0.61g is 3.19mmol) in anhydrous CH 3In the solution of the stirring among the CN (15ml).After 34 hours, reactant mixture is concentrated, use CH 2Cl 2(70ml) with reactant mixture dilution and order with 5% sodium bicarbonate (2 * 15ml) and saline (15ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (0.5g, 79%) into colorless oil through silica gel column chromatography (1: 1 EtOAc/ hexane): MS (ES) m/e 299.2 (M+H) +D) amino (±)-3-[(glycyl)]-4-ethyl valerate trifluoroacetate
With TFA (5ml) and CH 2Cl 2Solution (15ml) is in room temperature property adding (±) next time-3-[[(N-tert-butoxycarbonyl) glycyl] amino]-4-pentinoic acid ethyl ester (0.5g, 1.68mmol) in.After 30 minutes, solution concentrates on Rotary Evaporators, and residue (reconcentration is removed remaining TFA) in toluene obtains the target compound (0.55g, 106%) of light yellow pulpous state: MS (ES) m/e 199.2 (M+H) +
E) (±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-4-pentinoic acid ethyl ester
Under room temperature with diisopropylethylamine (0.94ml 5.43mmol) is added to (±)-3-[(glycyl) amino]-4-ethyl valerate trifluoroacetate (0.55g, 1.76mmol), (4-azepine benzimidazole-2-yl) butanoic acid (0.32g, 1.55mmol), HOBtH 2O (0.31g, 2.33mmol) and EDC (0.45g is 2.33mmol) in anhydrous CH 3In the solution of the stirring among the CN (15ml).After 64 hours, reactant mixture is concentrated, use CH 2Cl 2(100ml) with reactant mixture dilution and order with 5% sodium bicarbonate (2 * 25ml) and saline (25ml) wash.Dry (magnesium sulfate) concentrates and through silica gel column chromatography (7%MeOH/CH 2Cl 2) obtain target compound (0.11g, 18%) into white solid: MS (ES) m/e 3 86.4 (M+H) +
F) (±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-the 4-pentinoic acid
Under room temperature with 1.0N LiOH (0.71ml 0.71mmol) is added drop-wise to (±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-(0.11g is 0.285mmol) in THF (5ml), H for 4-pentinoic acid ethyl ester 2O (5ml) and CH 3In the mixture of CN (1ml).After 2 hours, on Rotary Evaporators, reactant mixture is concentrated into small size, in ice bath, cools off, use 1.0N AcOH (0.70ml) neutralization then.The solution lyophilization is obtained crude product (0.1g, 100%) into white powder.Through the ODS chromatography (5%CH that contains 0.1%TFA 3CN/H 2O) obtain target compound: MS (ES) m/e 358.4 (M+H) into white powder +
Embodiment 37
(S)-2,3,4 methyl, 5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl)] methylamino] carbonyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) D-malic acid dimethyl ester-O-trifluoromethanesulfonic acid
Under 0 ℃ of ar gas environment with D-malic acid dimethyl ester (12.96g, 80mmol) and pyridine (6.8ml, 84mmol) drips of solution in anhydrous methylene chloride (50ml) adds to trifluoromethanesulfanhydride anhydride (14.2ml, 84mmol) in anhydrous methylene chloride (40ml) (in flame-dried flask).Stirred 30 minutes in 0 ℃ of mixture, under room temperature, stirred 4 hours then the Huang Juse of generation.By adding the described reactant of entry (50ml) quenching, stratum disjunctum.Order water (3x) and salt water washing organic layer.Dry (magnesium sulfate) also concentrates the target compound (22.45g, 95%) that obtains to pale solid: MS (ES) m/e 295 (M+H) +
B) N-(2-cyano-phenyl)-D-aspartic acid dimethyl ester
Under 0 ℃ of ar gas environment with D-malic acid-O-trifluoromethanesulfonic acid dimethyl ester (22.4g, 76.2mmol) solution in chloroform (40ml) and hexane (40ml) adds to the 2-aminobenzonitrile (9.0g in flame-dried flask, 76.2mmol) and 2, in the solution of 6-di-tert-butyl pyridine in chloroform (50ml) and hexane (50ml).In 0 ℃ the mixture that produces was stirred 30 minutes, under room temperature, stirred 3 days then.Vacuum is removed solvent and residue is placed ethyl acetate and order 5%HCl (10x) and salt water washing.Dry (magnesium sulfate) concentrates and obtains to clarifying the target compound (12.3g, 62%) of grease through flash chromatography on silica gel purification (12% ethyl acetate/hexane): MS (ES) m/e 263.3 (M+H) +
C) (S)-2,3,4,5-tetrahydrochysene-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under the room temperature hydrogen environment (balloon) with N-(2-cyano-phenyl)-D-aspartic acid dimethyl ester (12g, 45.7mmol), Et 3N (7.64ml, 54.84mmol) and the mixture of Raney-Ni (46g, weight in wet base are used methanol prewashing) in methanol (200ml) stirred 2 days.Filter and remove catalyst and use methanol (3x) washing.Concentrate and obtain target compound (7.93g, 74%): MS (ES) m/e 235.3 (M+H) into white solid through flash chromatography on silica gel purification (0-5% ethanol/methylene) +
D) (S)-2,3,4,5-tetrahydrochysene-7-bromo-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
(5.16g 10.7mmol) adds to (S)-2,3 step by step with tetrabutylammonium tribromide under room temperature, 4,5-tetrahydrochysene-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (2.5g, 10.7mmol) in the solution in chloroform (50ml), under room temperature, described mixture was stirred 2 days.Add entry (30ml) then, separate organic layer and order water and salt water washing.Dry (magnesium sulfate) concentrates and obtains target compound (1.99g, 60%) into white solid through flash chromatography on silica gel purification (0-5% ethanol/methylene): MS (ES) m/e 313.0 (M+H) +
E) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under 110 ℃ of carbon monoxide environment, will contain (S)-2,3,4,5-tetrahydrochysene-7-bromo-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (624mg, 2mmol), 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride (695mg, 2.8mmol), DIEA (1.8ml, 10mmol) and (Ph 3P) 2PdCl 2(126mg is 0.18mmol) the mixture heated of NMP (22ml) 48 hours.(high vacuum) removed solvent and residue obtained target compound (170mg, 19.5%) into faint yellow solid through flash chromatography on silica gel purification (0.5-5% ethanol/methylene) on Rotary Evaporators: MS (ES) m/e 473.5 (M+H) +
F) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Under room temperature with 1.0M LiOH (0.6ml, 0.6mmol) drop to (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-(170mg is 0.39mmol) in the solution in methanol (5ml) and THF (5ml) for the 2-methyl acetate.Stir the mixture that generates also concentrated in 20 hours.Residue is soluble in water, (use the 5%CH that contains 0.1%TFA with the 30%TFA acidify and through the ODS chromatography 3CN/H 2The O eluting).Concentrated and lyophilization obtains the target compound into pale powder:
[α] n 25-74.5°(c=1,CH 3OH)；MS(ES)m/e?423.2(M+H) +.
Value of calculation C 21H 22N 6O 42 TFA1.75H 2O:C, 44.03; H, 4.06; N, 12.32. measured value: C, 44.33; H, 4.04; N, 12.28.
Embodiment 38
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4,5-tetrahydrochysene-7-iodo-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Pyridine-ICl complex: (8.5ml 105mmol) makes temperature maintenance 10-15 ℃ in the solution in anhydrous methylene chloride (20ml) under 5 ℃ of ar gas environments iodine monochloride (100ml, the 1M solution in dichloromethane) slowly to be added to pyridine.In 5-10 ℃ described mixture was stirred 20 minutes, adds hexane (50ml) then, in cryostat with described mixture restir 30 minutes.Draw solid collected by filtration, order hexane and petroleum ether, drying obtains being the solid reagent of yellow crystal (22.5g).
With pyridine-ICl complex (1.27g, 5.28mmol) substep add to (S)-2,3,4,5-tetrahydrochysene-3-oxo-1H-1, the 4-benzodiazepine _-(1.18g is 4.8mmol) in the solution in dichloromethane (20ml) and methanol (20ml) for the 2-methyl acetate.Under room temperature, the mixture that produces was stirred 40 minutes, add 1M sodium bisulfate (20ml) then.Draw solid collected by filtration and wash with ether.Drying obtains the target compound (1.72g, quantitative) into pale solid: MS (ES) m/e361.2 (M+H) +
B) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Following in 110 ℃ of carbon monoxide environment with (S)-2,3,4,5-tetrahydrochysene-7-iodo-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (1.08g, 3mmol), 2-amino methyl benzimidazole dihydrochloride hydras (924mg, 4.2mmol), DIEA (6.2ml, 15mmol) and (Ph 3P) 2PdCl 2(211mg is 0.3mmol) the mixture heated of NMP (30ml) 3 hours.(high vacuum) removed solvent and residue obtained target compound (530mg, 44%) into pale solid through flash chromatography on silica gel purification (0-7% ethanol/methylene) on Rotary Evaporators: MS (ES) m/e 408.1 (M+H) +
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
C) according to the method for embodiment 37 (f), but with (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate replaces (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate is prepared as the target compound (66%) of white powder:
[α] n 25-145.3 ° of (c=1, CH 3OH); MS (ES) m/e 394.2 (M+H) +. value of calculation
C 20H 19N 5O 42TFA0.125H 2O:C, 46.22; H, 3.43; N, 11.23. measured value: C, 46.13; H, 3.78; N, 11.49.
Embodiment 39
(±)-N-[2-(amino methyl)-4-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl] phenyl] preparation of aspartic acid
A) (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under room temperature with EDC (130mg, 0.75mmol) add to (±)-2,3,4,5-tetrahydrochysene-7-carboxyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (190mg, 0.68mmol), 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride (169mg, 0.68mmol), HOBt.H 2O (101mg, 0.75mmol) and DIEA (0.39ml is 2.24mmol) in the solution in dry DMF.After 20 hours, go up to concentrate described reactant, residue is obtained target compound (260mg, 88%) into white solid through silica gel column chromatography (1-6.5% ethanol/methylene): MS (ES) m/e 437.5 (M+H) at Rotary Evaporators (high vacuum) +
B) methyl (±)-N-[2-(amino methyl)-4-[[[(4-azepine-5-tolimidazole-2-yl)] methylamino] carbonyl] phenyl] aspartic acid
Method according to embodiment 37 (f), but with (±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate replacement (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate is prepared as the target compound (66%) of white powder:
MS(ES)m/e441.2(M+H) +.
Value of calculation C 21H 24N 6O 52TFA2.25H 2O:C, 42.08; H, 4.38; N, 11.78. measured value: C, 42.01; H, 4.18; N, 11.55.
Embodiment 40
(S)-2,3,4 methyl, 5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the method for embodiment 38 (b), but replace 2-amino methyl benzimidazole dihydrochloride hydras to be prepared as amber solid target compound (63%): MS (ES) m/e 423 (M+H) with 2-(amino methyl) 4-azepine-5-tolimidazole dihydrochloride +
B) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Method according to embodiment 37 (f), but with (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate replacement (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate is prepared as the target compound (50%) of white powder:
MS (ES) m/e 409.2 (M+H) +. value of calculation C 20H 20N 6O 41.75TFA.H 2O:C, 45.09; H, 3.82; N, 3.45. measured value: C, 45.18; H, 4.10; N, 13.58.
Embodiment 41
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-preparation of 2-acetas
A) 4-fluoro-3-[[2-(pyridin-3-yl] ethyl] amino] t-butyl perbenzoate
With 4-fluoro-3-ar-Toluic acid tert-butyl ester (3.83g, 18.22mmol), NBS (3.578,20.24mmol), benzoyl peroxide (0.228,0.91mmol) and carbon tetrachloride (90ml) reflux.After 16 hours, described reactant of cooling and filtration in frozen water, concentrated filtrate.Make the residue short silicagel column (20% ethyl acetate/hexane) of flowing through remove the baseline material, and concentrated filtrate.Residue is dissolved among the THF (90ml), add rapidly 3-(2-amino-ethyl) pyridine (6.97g, 57mmol).The gentle heat absorption of this additive reaction.Spend the night described reactant stirring concentrated then.Wash with 1.0N sodium hydroxide (30ml), water (30ml) and saline (30ml) with ether (100ml) dilution residue and order.Dry (magnesium sulfate) concentrates and obtains target compound (2.58g, 59%) into yellow oil: MS (ES) m/e331 (M+H) through silica gel column chromatography (10% ethanol/methylene) +
B) (S)-and 4-fluoro-3-[2-azepine-4-(benzyloxycarbonyl) amino-3,6-dioxo-6-methoxyl group-2-[2-(pyridin-3-yl) ethyl] hexyl] t-butyl perbenzoate
Under room temperature with DCC (1.86g, 9mmol) add to 4-fluoro-3-[[2-(pyridin-3-yl] ethyl] the aminobenzoic tert-butyl acrylate (and 2.7g, 8.18mmol), N-Cbz-L-aspartic acid β-methyl ester (J.Am.Chem.Soc.1957,79,5967; 2.53g, 9mmol) and HOBt.H 2(1.2g is 9mmol) in the solution in dry DMF (10ml) for O.After 24 hours, with ether (25ml) described mixture of dilution and filtration.Filtrate is concentrated into dried, with ether (50ml) dilution residue and water (2 * 10ml) and saline (10ml) wash.Dry (magnesium sulfate) concentrates and obtains target compound (2.4g, 49%) into colorless oil: MS (ES) m/e594 (M+H) through silica gel column chromatography (dichloromethane) +
C) (S)-and 4-fluoro-3-[4-amino-2-azepine-3,6-dioxo-6-methoxyl group-2-[2-(pyridin-3-yl) ethyl] hexyl] t-butyl perbenzoate
(50psi) jolting (S) under the room temperature hydrogen environment-4-fluoro-3-[2-azepine-4-(benzyloxycarbonyl) amino-3,6-dioxo-6-methoxyl group-2-[2-(pyridin-3-yl) ethyl] hexyl] t-butyl perbenzoate (2.4g, 4mmol), 10%Pd/C (184mg, 0.17mmol) and the mixture of methanol (17ml).1.5 after hour, pass through celite _Filter described reactant and concentrated.Obtain target compound (1.1g, 59%) through silica gel column chromatography (10% methanol in 1: 1 ethyl acetate/chloroform in): MS (ES) m/e 460 (M+H) into colorless oil +
D) (S)-2,3,4,5-tetrahydrochysene-7-(tert-butoxycarbonyl)-4-[2-(pyridin-3-yl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
Under 120-125 ℃ of ar gas environment, in oil bath, heat (S)-4-fluoro-3-[4-amino-2-azepine-3,6-dioxo-6-methoxyl group-2-[2-(pyridin-3-yl) ethyl] hexyl] t-butyl perbenzoate (0.64g, 1.39mmol) solution in anhydrous DMSO (5.7ml).17.5 after hour, described reactant of cooling and water (12ml) dilution in frozen water.(3 * 20ml) extract described mixture, the ethyl acetate layer that water (10ml) and saline (10ml) washing merge with ethyl acetate.Dry (magnesium sulfate) concentrates, and obtains subdiaphanous solid target chemical compound (0.15g, 33%) through silica gel column chromatography (9: 1 methylene chloride): MS (ES) m/e 440 (M+H) +
E) (S)-2,3,4,5-tetrahydrochysene 7-carboxyl-4-[2-(pyridin-3-yl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
4M HCl/ dioxane (0.5ml) is added to (S)-2,3,4,5-tetrahydrochysene 7-(tert-butoxycarbonyl)-4-[2-(pyridin-3-yl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-(0.18g's 2-methyl acetate 4.1mmol) in the solution in anhydrous methylene chloride (5ml) and under room temperature spends the night described reactant stirring.Vacuum concentration, then (reconcentration obtains target compound (0.12g, 65%) in 3 * 10ml): MS (ES) m/e 384 (M+H) at toluene +
F) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-2,3,4,5-tetrahydrochysene-7-carboxyl-4-[2-(pyridin-3-yl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (0.12g, 0.26mmol) and the mixture of thionyl chloride (15ml) refluxed 1 hour.The Fructus Citri tangerinae color solution concentration that produces is extremely done residual yellow Fructus Citri tangerinae color foam.Be dissolved in it in dichloromethane (10ml) and under 0 ℃ of ar gas environment, drop to and contain 2-amino methyl benzimidazole dihydrochloride hydras (0.058g, 0.26mmol), pyridine (0.72g, 9.1mmol) and triethylamine (0.55g, 5.46mmol) solution in dichloromethane (15ml).Stir described reactant mixture down in the room temperature ar gas environment then.25.5 after hour, in described reactant mixture, add dichloromethane (200ml) and 5% sodium bicarbonate (50ml) obtains faint yellow precipitation, it filtered and air drying obtains target compound (0.030g, 22% productive rate): MS (ES) m/e 513 (M+H) +
G) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-the 2-acetas
Under room temperature with 1.0 LiOH (0.57ml, 0.57mmol) drop to (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-(0.030g is 0.059mmol) in the mixture in THF (4ml) and water (5ml) for the 2-methyl acetate.With the light brown yellow solution stirring that produces 21.5 hours, on Rotary Evaporators, concentrate then.Residue is obtained crude product product into yellow powder through lyophilization.Through preparation property HPLC (PRP-1 _Post, gradient elution contains the 10-20% acetonitrile/water of 0.1%TFA) obtain target compound (0.010g, 34% productive rate):
MS (ES) m/e 499 (M+H) +. value of calculation C 22H 26N 6O 43C 2HF 3O 23HCl3 H 2O:C, 37.41; H, 3.41; N, 7.52. measured value: C, 37.6; H, 3.52; N, 7.52.
Embodiment 42
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-ethyl acetate
A) (S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate
In ethanol (200ml), feed hydrogen chloride gas 10 minutes, add (S)-2,3 then, 4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid (2.00g, 4.5mmol).Under room temperature, described reactant was stirred 24 hours, on Rotary Evaporators, be concentrated into dried then.Residue reconcentration in toluene (2x) is removed residual ethanol, then through silica gel column chromatography (gradient, 7% ethanol/methylene (1L), 10% ethanol/methylene then).The residue that produces is dissolved in the ethanol, adds the ether sedimentation solid.Collect solid and obtain target compound into white solid with the ether washing:
MS (ES) m/e 450.2 (M+H) +. value of calculation C 24H 27N 5O 41.5H 2O:C, 60.49; H, 6.35; N, 14.70. measured value: C, 60.41; H, 6.27; N, 14.38.
Embodiment 43
4-[[[3-(propyl group of 1H-benzimidazolyl-2 radicals-yl)] amino] carbonyl] preparation of piperidines-1-acetic acid
A) 2-[3-(N-tert-butoxycarbonyl) aminopropyl] benzimidazole
Under 0 ℃ of ar gas environment with the carbonochloridic acid isobutyl ester (10.2ml, 79mmol) solution in THF (25ml) adds to 4-(tert-butoxycarbonyl) aminobutyric acid (Organic Synthesis1984,63,160; 13.5g, 0.066mmol) and triethylamine (11ml is 80mmol) in the solution in THF (50ml).0.5 after hour, in the suspension of the white that produces, drip 1,2-phenylenediamine (7g, 64.8mmol) solution in THF (50ml).Described reactant was stirred 18 hours, filter then, filtrate simmer down to semisolid.It is dissolved in the acetic acid (100ml) and in 70 ℃ with described solution heating 18 hours.Concentrate described reactant mixture, reconcentration is several times in toluene with residue.Obtain target compound (6.0g, 33%) through the flash chromatography on silica gel purification: MS (ES) m/e 276 (M+H) +
B) 2-(3-aminopropyl) benzimidazole dihydrochloride
Under room temperature with 2-[3-(N-tert-butoxycarbonyl) aminopropyl] benzimidazole (and 1.2g, 4.3mmol) and the solution stirring of dioxane (20ml) in dichloromethane (25ml) of 4M HCl 18 hours.The suspension that filters the white that produces obtains target compound (1.07g, 97%).
C) 4-[[[3-(propyl group of 1H-benzimidazolyl-2 radicals-yl)] amino] carbonyl] piperidines-1-ethyl acetate
(0.76g, 3mmol) mixture heated in thionyl chloride (10ml) refluxed 15 minutes, was concentrated into dried then with 4-carboxyl piperidines-1-ethyl acetate hydrochloride (Yellin ' s SB 223913 CIP).From toluene after the evaporation for several times, with residue and 2-(3-aminopropyl) benzimidazole dihydrochloride (0.77g, 3mmol) and DIEA (3ml) be dissolved among the DMF (25ml).After 18 hours, described reactant mixture is allocated between ethyl acetate (50ml) and 5% sodium bicarbonate (100ml), with ethyl acetate (2 * 50ml) extractions.The organic extract that order water and saturated nacl aqueous solution washing merge is then through dried over mgso.Concentrate and obtain target compound (40mg, 3%) through flash chromatography on silica gel purification (6% ethanol/methylene).
B) 4-[[[3-(propyl group of benzimidazolyl-2 radicals-yl)] amino] carbonyl] piperidines-1-acetic acid
Under room temperature with the 1N sodium hydroxide solution (0.4ml, 0.4mmol) add to 4-[[3-(the propyl group amino of 1H-benzimidazolyl-2 radicals-yl)] carbonyl] (40mg is 0.1mmol) in the solution of the stirring in methanol (10ml) for piperidines-1-ethyl acetate.After 18 hours, with acetic acid (1ml) described mixture of neutralization and the concentrated methanol of removing.With XAD-2 post on the aqueous solution, water (500ml) eluting is used 20%CH then 3CN/H 2The O eluting.Component and lyophilization that collection contains product obtain target compound (9mg, 25%):
MS(ES)m/e?345.2?[M+H] +.
Value of calculation C 18H 24N 4O 30.75H 2O:C, 60.40; H, 7.18; N, 15.65. measured value: C60.48; H, 7.16; N, 15.40.
Embodiment 44
4-[[[3-(benzimidazolyl-2 radicals-yl] propyl group] amino] carbonyl] preparation of phenylacetic acid
A) 4-[[[3-(benzimidazolyl-2 radicals-yl] propyl group] amino] carbonyl]-1-phenylacetic acid ethyl ester
With 2-(4-carboxyl phenyl) ethyl acetate (Yellin ' s SB 223913 CIP) (0.5g, 2.4mmol), 2-(3-aminopropyl) benzimidazole dihydrochloride (0.7g, 2.8mmol), HOBt.H 2O (0.36g, 2.6mmol), EDC (0.5g, 2.6mmol) and DIEA (1.5ml, 8.8mmol) the mixture fast warming in DMF (15ml) and under room temperature, stirring 18 hours.Described reactant mixture is allocated between ethyl acetate (50ml) and 5% sodium bicarbonate (100ml), with ethyl acetate (2 * 50ml) extractions.The organic extract that order water and saturated nacl aqueous solution washing merge is then through dried over mgso.The solid of residue of evaporation ground with ether obtains target compound (0.56g, 66%):
MS (ES) m/e 366.0[M+H] +Value of calculation C 21H 23N 3O 30.25H 2O:C, 68.18; H, 6.40; N, 11.36. measured value C, 68.16; H, 6.26; N, 11.36.
B) 4-[[[3-(benzimidazolyl-2 radicals-yl] propyl group] amino] carbonyl] phenylacetic acid
Under room temperature with the 1N sodium hydroxide solution (6ml, 6mmol) add to 4-[[[3-(1H-benzimidazolyl-2 radicals-yl] propyl group] amino] carbonyl]-(0.38g is 1mmol) in the solution of the stirring in methanol (15ml) for 1-phenylacetic acid ethyl ester.After 4 hours, the solid that produces with acetic acid (6ml) described mixture of neutralization and filtration obtains target compound (77mg, 22%): MP 108-110 ℃; MS (ES) m/e 345.2[M+H] +. value of calculation C 19H 19N 3O 30.6H 2O:C, 65.54; H, 5.85; N, 12.07. measured value: C, 65.63; H, 5.65; N, 11.95.
Embodiment 45
(S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl] methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 3,4-diaminourea three is fluoridized benzene
4-amino-3-nitrotrimethylolmethane is fluoridized benzene, and (3.7070g 17.98mmol) is dissolved in the methanol, adds the 10%Pd/C of catalytic amount.In reactant, feed hydrogen and stirring under room temperature hydrogen (balloon).After 24 hours, described reactant is passed through celite _Filter, vacuum evaporation filtrate obtains target compound (3.0878g, 98%).This material uses without identifying.
B) 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5-trifluoro methyl benzimidazole
With the Cbz-sarcosine (3.9950g 17.13mmol) is dissolved among the anhydrous THF, add the carbonochloridic acid isobutyl ester (2.5ml, 19.27mmol), then add triethylamine (5.0ml, 35.95mmol).Make blended anhydride form 30 minutes under room temperature, add to 3 then, 4-diaminourea three is fluoridized benzene, and (3.0818g is 7.53mmol) in the solution in anhydrous THF.In room temperature after following 20 hours, the described reactant of vacuum evaporation.Make residue be allocated between ethyl acetate and the 1.0N sodium bicarbonate stratum disjunctum.Use the ethyl acetate extraction water layer, the organic layer that dry (magnesium sulfate) merges filters and vacuum evaporation.Make residue reconcentration in toluene, be dissolved in then in the glacial acetic acid (125ml).In 110 ℃ described solution was heated 24 hours, then vacuum evaporation acetic acid.Make residue reconcentration from toluene, be adsorbed in then and also go up anhydrous silica gel flash chromatography post on the silica gel.Obtain target compound (2.9397g, 47.2%) with 1: 1 chloroform/ether eluting:
TLC?R f(1∶1?CH 2Cl 2/Et 2O)0.57；MS(ES)m/e?364.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ8.0-7.2(m,9H),5.05(s,2H),4.84(s,2H),3.07(s,3H).
C) 2-(methylamino methyl)-5-trifluoro methyl benzimidazole
With 2-[N-(benzyloxycarbonyl)-N-methyl] (2.9397g 8.09mmol) is dissolved in the methanol amino methyl-5-trifluoro methyl benzimidazole, adds the 10%Pd/C of catalytic amount.In reactant, feed hydrogen and stirring under room temperature hydrogen (balloon).After 5 hours, described reactant is passed through celite _Filter the residual brown oil of vacuum concentration evaporated filtrate.400MHz NMR analyzes and shows that the Cbz protecting group still exists, and therefore makes residue experience reaction condition again.After 18 hours, pass through celite _Filter removal catalyst and vacuum evaporation filtrate and obtain target compound (1.7809g, 96%):
1H?NMR(250MHz,CDCl 3)δ7.76-7.32(m,4H),4.32(s,2H),2.59(s,3H).
D) (S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl] methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(179.2mg 0.61mmol) claims in the 100ml round-bottomed flask 2-methyl acetate.Add acetonitrile (10ml), then add HOBt.H 2O (97.9mg, 0.72mmol) and EDC (149.3mg, 0.78mmol).After all solids dissolving, add 2-(methylamino methyl)-5-trifluoro methyl benzimidazole (186.1mg, 0.81mmol) solution in acetonitrile and diisopropylethylamine (0.25mg, 1.44mmol).After following 24 hours, the described reactant of vacuum evaporation obtains target compound (308.1mg, 100%) with residue through silica gel column chromatography (3% methanol/chloroform) in room temperature:
TLC?R f(5％MeOH/CHCl 3)0.21； 1H?NMR(250MHz,CDCl 3)δ7.83-7.16(m,7H),5.37(d,1H),5.05-4.70(m,3H),2.96(m,3H),3.72(s,3H),3.16(s,2H),2.11(s,3H)；MS(ES)m/e?504.0(M+H) +.
E) (S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl] methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid
With (S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl] methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-(308.1mg 0.61mmol) is dissolved in the methanol (5ml) the 2-methyl acetate, adds entry (5ml), then add the 1.0N sodium hydroxide (2.0ml, 2.0mmol).In room temperature after following 24 hours, with 1.0N hydrochloric acid (2.0ml) the described reactant that neutralizes.Under room temperature, the mixture of off-white color was stirred 15 minutes dilute with water then, collecting precipitation on agglomerating glass funnel.In vacuum desiccator, the white powder dried overnight obtained target compound (268.0mg, 90%):
MS (ES) m/e490.2 (M+H) +. value of calculation C 23H 22N 5O 4F 32.25H 2O0.25HCl:C, 51.24; H, 5.00; N, 12.99. measured value: C, 51.44; H, 4.96; N, 12.45.
Embodiment 46
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl] methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-4,7-dimethoxy benzo imidazoles
According to the method for embodiment 45 (b), with 1,2-diaminourea-3, the 6-dimethoxy benzene replaces 3, and 4-diaminourea three is fluoridized benzene and is prepared target compound:
MS(ES)m/e?356.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ7.34(s,5H),6.54(d,2H),5.18(s,2H),4.65(s,2H),3.95(s,3H),3.86(s,3H),3.03(s,3H).
B) 4,7-dimethoxy-2-(methylamino methyl) benzimidazole
With 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-4, (186.5mg 0.53mmol) is dissolved in the methanol 7-dimethoxy benzo imidazoles, adds the 10%Pd/C of catalytic amount.In reactant, feed hydrogen and stirring under room temperature hydrogen (balloon).After 20 hours, described reactant is passed through celite _Filter, vacuum evaporation filtrate obtains target compound (96.9mg, 83%):
1H?NMR(250MHz,CDCl 3)δ6.52(s,2H),3.94-3.86(m,6H),2.36(s,3H).
C) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl] methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(112.3mg 0.38mmol) claims in the 100ml round-bottomed flask 2-methyl acetate.Add acetonitrile, then add HOBt.H 2O (62.3mg, 0.46mmol) and EDC (120.0mg, 0.63mmol).After all solids dissolving, and the adding diisopropylethylamine (0.1ml, 0.57mmol), then add and contain diisopropylethylamine (0.1ml, 0.57mmol) 4,7-dimethoxy-2-(methylamino methyl) benzimidazole (96.8mg, 0.44mmol) solution in acetonitrile.In room temperature after following 2.5 days, the described reactant of vacuum evaporation.With residue once, obtain target compound (152.0mg, 80.0%) through silica gel column chromatography (chloroform, 5% methanol/chloroform then) then with the toluene revaporization:
TLC?R f(5％MeOH/CHCl 3)0.35；MS(ES)m/e?496.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ7.25(m,2H),6.56(s,2H),5.36(d,1H),3.91(s,6H),3.70(s,3H),3.08(s,3H).
D) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl] methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Method according to embodiment 45 (e) makes (S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl] methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate obtains target compound (110.0mg, 74%):
MS (ES) m/e 482.2 (M+H) +. value of calculation C 24H 27N 5O 60.75H 2O:C, 58.23; H, 5.80; N, 14.15. measured value: C, 58.26; H, 5.59; N, 13.90.
Embodiment 47
(S)-2,3,4 methyl, 5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 1,2-diaminourea-3-methylbenzene
According to the flow process of embodiment 45 (a), but (3.0204g 19.98mmol) replaces 4-amino-3-nitro-trifluoromethyl toluene, preparation target compound (2.4815g) with 2-methyl-6-nitroaniline.Can use without evaluation.
B) 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-4-tolimidazole
(4.6466g 19.92mmol) is dissolved among the anhydrous THF in the 100ml round-bottomed flask with the Cbz-sarcosine.Add triethylamine (3.0ml, 21.57mmol), add then the carbonochloridic acid isobutyl ester (2.8ml, 21.59mmol).The white reaction mixture stirs 0.5hr in RT, at-20 to-30 ℃ it is added to 1 then, and 2-diaminourea-3-methylbenzene (2.4815g) is in the solution of anhydrous THF.After 20 minutes, reactant is warmed to RT, under this temperature, stirs 16hr.With the reactant liquor evaporation, residue is at EtOAc and 1.0N NaHCO under vacuum 3The middle distribution.Layering is with EtOAc extraction water solution layer.Dry (MgSO 4) organic extract liquid that merges, filter, evaporate under the vacuum.Residue concentrates in toluene again, and exsiccant solid is dissolved in ice AcOH (150ml).Solution in 110 ℃ of heating 18hr, is concentrated in fine vacuum then.Residue concentrates in toluene again, and it is absorbed on the silica gel, places on the dry silica gel flash chromatography post.With 1: 1CH 2Cl 2/ Et 2O eluting pillar promptly gets target compound (3.1586g, 51%):
MS(ES)m/e?310.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ7.35-7.01(m,10H),5.00(s,2H),4.72(s,2H),2.99(s,3H),2.55(s,3H).
C) 4-methyl-2-(methylamino methyl) benzimidazole
Flow process according to embodiment 45 (c), but with 2-[N-(benzyloxycarbonyl]-the N-methyl] amino methyl-4-tolimidazole replaces 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5-trifluoro methyl benzimidazole, preparation target compound (2.9916g, quantitative values) 1H NMR (250MHz, CDCl 3) 87.36-7.01 (m, 4H), 4.01 (s, 2H), 2.52 (s, 3H), 2.41 (s, 3H).
D) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(188.5mg 0.64mmol) weighs and places the 100ml round-bottomed flask 2-methyl acetate.Add CH 3CN is sequentially added into HOBt.H then 2O (103.5mg, 0.77mmol), EDC (149.3mg, 0.78mmol) and diisopropylethylamine (0.15ml, 0.86mmol).After 15 minutes, (273.8mg is 1.56mmol) in CH to add 4-methyl-2-(methylamino methyl) benzimidazole 3Solution among the CN.Add CH 2Cl 2(5ml) dissolve some material.Behind following 18 hours of the RT, reactant is concentrated, residue on silica gel through chromatography (5%MeOH/CHCl 3) after obtain target compound (307.3mg, quantitatively):
MS(ES)m/e?450.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ7.23-7.03(m,7H),6.41(br?s,1H),5.33(d,J=16.3Hz,1H),3.69(s,3H),3.46(s,3H),3.10(s,3H).
E) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 45 (e), with (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl) methyl] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (307.3mg, 0.68mmol) saponification promptly gets target compound (243.9mg, 82%):
MS (ES) m/e 436.2 (M+H) +. value of calculation C 23H 25N 5O 42.75H 2O:C, 56.96; H, 6.34; N, 14.44: measured value: C, 56.72; H, 6.27; N, 14.26.
Embodiment 48
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 2-amino-4,6-dimethyl-3-nitropyridine
With 2-amino-4, (5.55g 45.43mmol) weighs and places the 500ml round-bottomed flask 6-lutidines.Flask is cooled to-78 ℃.Add concentrated sulphuric acid (25ml, 450mmol), add then concentrated nitric acid (3.5ml, 56.0mmol).Mixture becomes the solid frozen material.Remove cryostat, reactant is warmed to RT.Exothermic reaction has been carried out in the effusion that is accompanied by nitrous oxide gas after about 15 minutes, and reactant becomes peony.Reactant in 85-90 ℃ of heating 3 hours, is cooled to room temperature then, with the frozen water dilution, with 6N NaOH (160ml) neutralization.With EtOAc (3X) extraction water solution, use MgSO 4The dry EtOAc layer that merges filters, and evaporates under the vacuum.With silica gel adsorption gained orange colour solid, place on the dry silica gel post through flash chromatography.With 1: 1 CHCl 3/ Et 2O eluting pillar promptly gets target compound (1.0650g, 14%): MS (ES) m/e168.0 (M+H) +
B) 2,3-dioxy base-4,6-lutidines
According to the flow process of embodiment 45 (a), with 2-amino-4, (1.0650g 6.37mmol) replaces 4-amino-3-nitro-trifluoromethyl toluene to 6-dimethyl-3-nitropyridine, preparation target compound (836.1mg, 95.7%).Can use without evaluation.
C) 4-azepine-2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5, the 7-dimethylbenzimidazole
According to the flow process of embodiment 45 (b), with 2,3-diaminourea-4, (836.1mg 6.09mmol) replaces 3 to the 6-lutidines, and 4-two-5 amido benzotrifluoride is through silica gel column chromatography (3%MeOH/CHCl 3) target compound (1.2273g, 62%): MS (ES) m/e 325.0 (M+H) +
D) 4-azepine-2-(methylamino methyl)-5, the 7-dimethylbenzimidazole
Flow process according to embodiment 45 (c), with 4-azepine-2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5, the 7-dimethylbenzimidazole (1.2273g 3.78mmol) replaces 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5-trifluoro methyl benzimidazole, through Et 2After grinding, O obtains target compound into white powder.This material can use without evaluation.
E) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate is (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(175.0mg 0.60mmol) weighs and places the 100ml round-bottomed flask 2-methyl acetate.Add CH 3CN (10ml) is sequentially added into HOBt.H then 2O (115.9mg, 0.86mmol), EDC (124.9mg, 0.65mmol) and diisopropylethylamine (0.13ml, 0.75mmol).Add 4-azepine-2-(methylamino methyl)-5, the 7-dimethylbenzimidazole (144.5mg, 0.76mmol) and diisopropylethylamine (0.13ml is 0.75mmol) in CH 3Suspension among the CN stirs reactant under room temperature.After 22 hours, reactant is evaporated residue and toluene coevaporation under vacuum.Through silica gel column chromatography (3%MeOH/CHCl 3(1L), 5%MeOH/CHCl then 3) promptly get target compound (76.9mg, 28%): MS (ES) m/e 465.2 (M+H) +F) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(76.9g 0.17mmol) is dissolved in MeOH (5ml) and H to the 2-methyl acetate 2Among the O (5ml), and adding 1.0N NaOH (0.5ml, 0.5mmol).Behind following 24 hours of the RT, with 1.0N HCl (0.5ml) neutralization reactant, evaporating solvent under the vacuum.Through ODS chromatography (gradient: the 10%%CH that contains 0.1%TFA 3CN/H 2O (500ml), contain the 15%%CH of 0.1%TFA 3CN/H 2O (500ml), contain the 30%%CH of 0.1%TFA 3CN/H 2O (500ml) obtains residue, and it and toluene are steamed once altogether, and is dry under the fine vacuum.The gained residue is dissolved in MeOH (5ml), and uses Et 2The O precipitation.Collect white solid with sintered glass funnel, place the vacuum desiccator dried overnight promptly to get target compound (52.0mg, 68%): HPLC (ODS post, 1.5ml/min, gradient: the 5-50%CH that contains 0.1%TFA 3CN/H 2O)
t R12.38min; MS (ES) m/e 451.2 (M+H) +. value of calculation C 23H 6N 6O 41H 2O1CF 3CO 2H:C, 51.55; H, 5.02; N, 14.43: measured value: C, 51.34; H, 5.00; N, 14.41.
Embodiment 49
(S)-2,3,4,5-tetrahydrochysene-7-[[[(5, the methyl of 6-difluoro benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 1,2-diaminourea-4,5-two fluorobenzene
According to the flow process of embodiment 45 (a), with 4, (2.0g 11.49mmol) replaces 4-amino-3-nitro-trifluoromethyl toluene to 5-two fluoro-2-nitroanilines, the preparation target compound.Can use without evaluation.
B) 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5,6-difluoro benzimidazole
According to the flow process of embodiment 47 (b), with 1,2-diaminourea-4,5-two fluorobenzene replace 1,2-diaminourea-3-methylbenzene, the AcOH cyclisation step is carried out rather than 110 ℃ at 80 ℃, is prepared into target compound (1.3767g, 36%);
TLC?R f(1∶1?CH 2Cl 2/Et 2O)0.42；MS(ES)m/e?332.0(M+H) +; 1HNMR(250MHz,CDCl 3)δ7.50-7.14(m,8H),5.13(s,2H),4.61(s,2H),3.06(s,3H).
C) 5,6-two fluoro-2-(methylamino methyl) benzimidazole
Flow process according to embodiment 46 (b), with 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-5,6-difluoro benzimidazole (1.3767g, 4.16mmol) replacement 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-4,7-dimethoxy benzo imidazoles, the preparation target compound (875.6mg, quantitatively): MS (ES) m/e 198.0 (M+H) +
D) (S)-2,3,4,5-tetrahydrochysene-7-[[[(5, the methyl of 6-difluoro benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(415.7mg 1.42mmol) is dissolved in CH to the 2-methyl acetate 3CN adds HOBt.H then 2O (209.3mg, 1.55mmol) and EDC (314.9mg, 1.64mmol).After 5 minutes, (0.25ml 1.64mmol), produces a clarifying colourless solution to add diisopropylethylamine.Add 5, (284.5g is 1.44mmol) in CH for 6-two fluoro-2-(methylamino methyl) benzimidazole 3Solution among the CN.After 30 minutes, reactant becomes slight muddiness, therefore adds more diisopropylethylamine (0.25ml), and reactant is clarified colourless again.After 24 hours, reactant is evaporated under vacuum.Residue and toluene coevaporation once, through silica gel column chromatography (CHCl 3(0.25L), 2%MeOH/CHCl then 3(1.5L), 5%MeOH/CHCl then 3) promptly get (456.8mg, 68%) of target compound:
MS(ES)m/e?472.2(M+H) +； 1H?NMR(250MHz,CDCl 3)δ7.34-7.08(m,6H),6.44(brs,1H),5.39(d,J=16.2?Hz,1H),3.70(s,3H),3.14(s,3H),2.96(s,3H).
E) (S)-2,3,4,5-tetrahydrochysene-7-[[[(5,6-difluoro benzimidazolyl-2 radicals-ylmethyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With (S)-2,3,4,5-tetrahydrochysene-7-[[[(5, the methyl of 6-difluoro benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(456.8mg 0.97mmol) is dissolved in MeOH (10ml) and H to the 2-methyl acetate 2Among the O (10ml).(3.0ml 3.0mmol), stirs reactant down in RT to add 1.0N NaOH.After 18 hours, with 1.0N HCl (3.0ml) neutralization reactant.A kind of white precipitate forms, and it is collected in the sintered glass filter, and is dry in the vacuum desiccator.Through ODS chromatography (gradient: the 10%CH that contains 0.1%TFA 3CN/H 2O (500ml), contain the 18%CH of 0.1%TFA then 3CN/H 2O (500ml), contain the 25%CH of 0.1%TFA then 3CN/H 2O (500ml)) obtains residue, once with itself and toluene coevaporation.The gained residue is dissolved among the small size MeOH, uses Et 2The O precipitation promptly gets the target compound (330.9mg) into white surplus toner end, HPLC (ODC post; 1.5ml/min; The gradient 5-50%CH that contains 0.1%TFA 3CN/H 2O) t R=14.12min; MS (ES) m/e 458.2 (M+H) +C 22H 21N 5O 4F 22.5H 2The value of calculation of O: C, 52.57; H, 5.22; N, 13.94: measured value: C, 52.76; H, 5.15; N, 13.67.
Embodiment 50
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-aminomethyl phenyl and imidazoles-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carboxyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(228.8mg 0.78mmol) is dissolved in CH to the 2-methyl acetate 3CN is sequentially added into HOBtH then 2O (154.2mg, 1.14mmol), EDC (179.4mg, 0.94mmol) and diisopropylethylamine (0.50ml, 0.94mmol).(125.4mg is 0.77mmol) in CH to add 2-(amino methyl)-4-azepine-5-tolimidazole dihydrochloride 3Solution among the CN/DMF stirs reactant down in RT.After 24 hours, reactant is evaporated under vacuum, residue and toluene coevaporation are once.Through silica gel column chromatography (CHCl 3(0.25L) 3%MeOH/CHCl then 3(0.5L) 5%MeOH/CHCl then 3) promptly get target compound (159.9mg, 48%): MS (ES) m/e437.2 (M+H) +
B) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 48 (f), with (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (159.9mg 0.37mmol) promptly gets target compound behind saponification and the purification:
MS (ES) m/e 423.39 (M+H) +. value of calculation
C 21H 22N 6O 40.5H 2O1.25TFA:C, 52.64; H, 5.02; N, 16.74. measured value: C, 52.65; H,
5.02；N.16.74.
Embodiment 51
(S)-2,3,4,5-tetrahydrochysene-4-methyl-7-[[[(4-nitrobenzophenone and imidazoles-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 2-[N-(tert-butoxycarbonyl)-N-methyl] amino methyl-4-nitrobenzimidazole
(2.0320g 10.74mmol) is dissolved in anhydrous THF, is cooled to-15 ℃ in dry ice/acetone batch with the Boc-sarcosine.The adding triethylamine (5.0ml, 3.6375mmol), and then adding carbonochloridic acid isobutyl ester (1.5ml, 11.56mmol).0.5 after hour, mixture is added to 1 in-20 ℃, (1.3047g 10.77mmol) in the solution of anhydrous THF, is warmed to RT with reactant to 2-diaminourea-3-Nitrobenzol.After 24 hours, reactant is evaporated under vacuum, residue is at EtOAc and 1.0N NaHCO 3Between distribute.Layering is with EtOAc extraction water solution layer.With the organic facies drying (MgSO that merges 4), filter vacuum drying.Residue is dissolved among the ice AcOH (100ml), and solution is heated to 75 ℃.After 24 hours, reactant is evaporated residue and toluene coevaporation (2X) under vacuum.Product is adsorbed on the silica gel (the gradient: CHCl of flash chromatography on dried silicagel column 3(0.51), 2%MeOH/CHCl then 3(1L), 2%MeOH/CHCl then 3) to obtain target compound (2.2089g, 75%):
1HNMR(250MHz,CDCl 3)δ8.10(dd,2H),7.40-7.32(m,1H),4.69(s,2H),3.02(s,3H),1.54(s,9H).
B) 2-(methylamino methyl)-4-nitrobenzimidazole
In in dioxane, handling 2-[N-(tert-butoxycarbonyl)-N-methyl with 4N HCl under the room temperature] and amino methyl-4-nitrobenzimidazole (2.2089g, 8.05mmol).After the adding, can generate the white solid precipitation immediately.After 4 hours, reactant evaporates under vacuum, and residue grinds the target compound (1.639g) that promptly gets to white solid in ether.It can use without identifying.
C) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-nitrobenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate
According to the flow process of embodiment 49 (d), replace 5 with 2-(methylamino methyl)-4-nitrobenzimidazole, 6-two fluoro-2-(methylamino methyl) benzimidazole, the preparation target compound (292.9mg, quantitatively): MS (ES) m/e 481.2 (M+H) +
D) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-nitrobenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 45 (e), with (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-nitrobenzimidazole-2-yl) methyl] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate (292.9mg, 0.61mmol) saponification promptly gets target compound (211.0mg, 68%):
MS (ES) m/e467.4 (M+H) +. value of calculation C 22H 22N 6O 62.5H 2O:C, 52.12; H, 5.27; N, 16.58: measured value: C, 52.07; H, 4.97; N, 16.40.
Embodiment 52
(S)-2,3,4 methyl, the amino benzimidazole of 5-tetrahydrochysene-7-[[[(4--2-yl)] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) (S)-2,3,4, the amino benzimidazole of 5-tetrahydrochysene-7-[[[(4--2-yl) methyl] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-nitrobenzimidazole-2-yl) methyl] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(108.7mg 0.21mmol) is dissolved among the MeOH 2-acetic acid, adds the 10%Pd/C of catalytic amount.In reactant, feed H 2, then at H 2Under the air bag environment in stirring at room.After 20 hours, pass through Celite _Remove by filter catalyst, filtrate is evaporated under vacuum.The gained solid is dissolved in methanol, uses Et 2O precipitation, dry in vacuum desiccator, and through the ODS chromatography purification (gradient: contain 0.1%TFA water 500ml, contain the 5%CH of 0.1%TFA 3CN/H 2O 500ml, contain the 10%CH of 0.1%TFA 3CN/H 2O 500ml, contain the 15%CH of 0.1%TFA 3CN/H 2O 500ml, contain the 20%CH of 0.1%TFA 3CN/H 2O 500ml, contain the 25%CH of 0.1%TFA 3CN/H 2O 500ml, contain the 30%CH of 0.1%TFA 3CN/H 2O 500ml).Products therefrom and toluene coevaporation once grind with ether then and promptly get target compound (34.7mg):
MS (ES) m/e437.5 (M+H) +Value of calculation C 22H 24N 6O 41.5H 2O1.5TFA:C, 47.32; H, 4.53; N.13.24: measured value: C, 47.35, H, 4.86; N.13.61.
Embodiment 53
2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-preparation of acetic acid
A) 2-[1 (R)-[N-(benzyloxycarbonyl)-N-methyl] amino-ethyl] benzimidazole
According to the flow process of embodiment 47 (b), with Cbz-N-methyl D-alanine replaced C bz-sarcosine, with 1, the 2-phenylenediamine replaces 1,2-diaminourea-3-methylbenzene, the AcOH cyclisation step is carried out rather than 110 ℃ preparation target compound: MS (ES) m/e 310.2 (M+H) in 80 ℃ +
B) 2-[1 (R)-(methylamino ethyl)] benzimidazole
Flow process according to embodiment 46 (b), with 2-[1 (R)-[N-(benzyloxycarbonyl)-N-methyl] amino-ethyl] benzimidazole replacement 2-[N-(benzyloxycarbonyl)-N-methyl] amino methyl-4,7-dimethoxy benzo imidazoles, preparation target compound (276.0mg, 48%): MS (ES) m/e 176.2 (M+H) +
C) 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the flow process of embodiment 49 (d), with 2-[1 (R)-(methylamino ethyl)] benzimidazole replacement 5,6-two fluoro-2-(methylamino methyl) benzimidazole, preparation target compound (203.5mg, 90%): MS (ES) m/e 450.5 (M+H) +
D) 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
According to the flow process of embodiment 49 (e), with 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-ethyl acetate saponification and promptly get target compound (179.3mg, 75%) through the ODS chromatography:
MS (ES) m/e 4365 (M+H) +. value of calculation
C 23H 25N 5O 40.75H 2O0.75TFA:C, 55.01; H, 5.14; N, 13.10; Measured value: C, 54.98; H, 5.42; N, 12.75.
Embodiment 54
(S)-2,3,4 methyl, 5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-ethyl acetate
A) (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate
With (S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid (0.5g) is dissolved in EtOH, and solution is cooled to 0 ℃ in ice bath.In solution, be blown into HCl gas until saturated, with the flask Rubber Diaphragm Seal, remove ice bath then.Reactant was stirred 20 hours in RT, then evaporating solvent under the vacuum.Residue and toluene (3X) coevaporation three times is dissolved in EtOH then, uses Et 2The O precipitation.Collect solid with sintered glass funnel, promptly get target compound (483.9mg) with the vacuum desiccator dried overnight:
MS (ES) m/e 451.4 (M+H) +. value of calculation C 23H 26N 6O 4HCl1.375H 2O:C, 53.98; H, 5.86; N, 16.42. measured value: C, 54.00; H, 5.82; N, 16.42.
Embodiment 55
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-preparation of acetic acid
A) 2-[1 (S)-[N-(tert-butoxycarbonyl)-N-methyl] amino-ethyl] benzimidazole
According to the flow process of embodiment 51 (a), replace the Boc-sarcosine with Boc-N-methyl-L-alanine, with 1, the 2-phenylenediamine replaces 1, and 2-diaminourea-3-Nitrobenzol is from CHCl 3Recrystallization is prepared into target compound (1.7792g, 65%) in the hexane: MS (ES) m/e 276.4 (M+H) +
B) 2-[1 (S)-(methylamino ethyl)] benzimidazole
Flow process according to embodiment 51 (b), with 2-[1 (S)-[N-(tert-butoxycarbonyl)-N-methyl] amino-ethyl] benzimidazole replacement 2-[N-(tert-butoxycarbonyl)-N-methyl] amino methyl]-the 4-nitrobenzimidazole, the preparation target compound can use without evaluation.
C) (S)-2,3,4, the ethyl of 5-tetrahydrochysene-7-[[[(1S)-(benzo miaow quinoline-2-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the flow process of embodiment 49 (d), with 2-[1 (S)-(methylamino ethyl)] benzimidazole replacement 5,6-two fluoro-2-(methylamino methyl) benzimidazole is prepared into target compound (414.7mg, 88%): MS (ES) m/e 450.2 (M+H) +
D) 2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
Flow process according to embodiment 45 (e), with 2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate promptly gets target compound (117.2mg): MS (ES) m/e 436.2 (M+H) +. value of calculation C 23H 25N 5O 40.75H 2O0.75TFA:C, 55.05; H, 5.14; N, 13.10; Measured value: C, 55.14; H, 5.38; N, 13.04.
Embodiment 56
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-preparation of acetic acid
A) 2-[1 (S)-(tert-butoxycarbonyl) amino-ethyl] benzimidazole
According to the flow process of embodiment 51 (a), replace the Boc-sarcosine with the Boc-L-alanine, with 1, the 2-phenylenediamine replaces 1,2-diaminourea-3-Nitrobenzol, preparation target compound (714.7mg, 25%): MS (ES) m/e 262.4 (M+H) +
B) 2-[1 (S)-(amino-ethyl)] benzimidazole
According to the flow process of embodiment 51 (b), with 2-[1 (S)-(tert-butoxycarbonyl) amino-ethyl] benzimidazole replacement 2-[N-(tert-butoxycarbonyl)-N-methyl] amino methyl-4-nitrobenzimidazole, the preparation chemical compound can use without evaluation.
C) 2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
According to the flow process of embodiment 49 (d), with 2-[1 (S)-(amino-ethyl)] benzimidazole replacement 5,6-two fluoro-2-(methylamino methyl) benzimidazole, preparation target compound (270.7mg, 80%): MS (ES) m/e 436.0 (M+H) +
D) 2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
According to the flow process of embodiment 45 (e), with 2,3,4,5-tetrahydrochysene-7-[[[(1S)-(benzimidazolyl-2 radicals-yl] ethyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-saponification of 2-methyl acetate promptly gets target compound (158.1mg, 61%):
MS (ES) m/e 422.0 (M+H) +. value of calculation C 22H 23N 5O 41.75H 2O:C, 58.37; H, 5.90; N, 15.46; Measured value: C58.17; H, 5.77; N, 15.08.
Embodiment 57
2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-preparation of acetic acid
A) 2-[1 (R)-(benzyloxycarbonyl) amino-ethyl] benzimidazole
According to the flow process of embodiment 47 (b), with Cbz-D-alanine replaced C bz-sarcosine, with 1, the 2-phenylenediamine replaces 1,2-diaminourea-3-methylbenzene, and the AcOH cyclisation step is carried out but not 110 ℃ in 80 ℃, preparation target compound (1.14559,43%): MS (ES) m/e 296.4 (M+H) +
B) 2-(1 (R)-amino-ethyl) benzimidazole
Flow process according to embodiment 46 (b), with 2-[1 (R)-(benzyloxycarbonyl) amino-ethyl] benzimidazole replacement 2-[N-(benzyloxycarbonyl)-N-methyl] amino-ethyl-4,7-dimethoxy benzo imidazoles, preparation target compound (258.1mg, 93%): MS (ES) m/e 161.9 (M+H) +
C) 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-methyl acetate
According to the flow process of embodiment 49 (d), and usefulness 2-((1R)-amino-ethyl] benzimidazole replacement 5,6-two fluoro-2-(methylamino methyl) benzimidazole, preparation target compound (263.6mg, 84%): MS (ES) m/e 436.3 (M+H) +
D) 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
According to the flow process of embodiment 49 (e), with 2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-the methyl acetate saponification promptly gets target compound (125.0mg, 49%):
MS (ES) m/e 422.0 (M+H) +. value of calculation C 22H 23N 5O 40.5H 2O1.25HCl:C, 55.51; H, 5.35; N, 14.71. measured value: C, 55.70; H, 5.47; N, 14.53.
Embodiment 58
(S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) 2-carbonyl ethyoxyl imidazo [1,2a] pyridine
(4g 42.50mmol) is dissolved in MeOH (50ml) with the 2-aminopyridine.(8.3g 42.50mmol), stirs reactant 2 hours in 70 ℃ to add ethyl bromide acetone.Remove and desolvate, solution neutralizes with 1M NaOH.With EtOAc extractive reaction thing, the EtOAc layer that the salt water washing merges.Dry (MgSO 4), filter, concentrate, through silica gel rapid column chromatography (2%MeOH/Cl 2CH 2) obtain the target compound (4.5g, 56%) of faint yellow solid:
1H?NMR(400MHz,CDCl 3)δ1.43(t,J=7Hz,3H),4.45(q,J=7Hz,2H),6.86(t,J=6.6Hz,1H),7.24(t,J=6.6Hz,1H).
B) 2-hydroxymethyl imidazo [1,2a] pyridine
(0.5g 2.81mmol) is dissolved among the anhydrous THF, adds solutions of lithium aluminium hydride (1.0M of 0.5ml is in THF) then with 2-carbonyl ethyoxyl imidazo [1,2a] pyridine in 0 ℃.Reactant is warmed to RT and stirred 1 hour.Add H 2O (0.2ml) adds 15%NaOH (0.2ml) then, adds H at last again 2O (0.6ml).Solids removed by filtration and with hot THF (2 * 100ml) with hot CHCl 3(4 * 100ml) washings.Merging filtrate and cleaning mixture, dry (MgSO 4).Filter the back removal of solvent under reduced pressure, residue is through silica gel rapid column chromatography (5%MeOH/Cl 2CH 2) purification obtains the target compound (0.1g, 25%) of weak yellow liquid: 1HNMR (400MHz, CDCl 3) δ 4.85 (s, 2H), 6.76 (t, J=6.8Hz, 1H), 7.15 (t, J=6.8Hz, 1H), 7.53 (s, 1H), 7.54 (d, J=6.7Hz, 1H), 8.1 (d, J=6.7Hz, 1H) .MS (ES) m/e149 (M+H) +.
C) 2-chloromethyl imidazo [1,2a] pyridine
(0.4ml, (0.4g is 2.7mmol) in CHCl 3.2mmol) to be added to 2-hydroxymethyl imidazo [1,2a] pyridine with thionyl chloride in 0 ℃ 3In the solution (30ml).After RT stirs 1 hour down, pour suspension into ice, 10%NaHCO 3And CHCl 3Mixture in.CHCl is used in layering 3Aqueous phase extracted.Merge organic extract liquid, dry (MgSO 4).After the filtration, decompression removes to desolvate down and promptly gets target compound (0.4g, 89%):
1H?NMR(400?MHz,CDCl 3)δ4.7(s,2H),6.7(t,1H),7.2(t,1H),7.5(d,1H),7.6(s,1H),8.0(d,1H)；MS(ES)m/e?167(M+H) +.
D) 2-(methylamino methyl) imidazo [1,2a] pyridine
(317mg, 2mmol) in the solution of EtOH (5ml), reactant mixture stirred 2 hours in 0 ℃ in 0 ℃ fresh concentrated methylamine (15ml) to be added to 2-chloromethyl imidazo [1,2a] pyridine.Remove and to desolvate, (C-18 silica gel contains the H of 0.1%TFA to residue through the reversed phase column chromatography purification 2O).Lyophilization promptly gets the target compound (461mg, 87%) into white solid:
1H?NMR(250?MHz,CDCl 3)δ2.5(s,3H),4.0(s,2H),6.7(t,1H),7.2(t,1H),7.5(d,1H),7.6(s,1H),8.1(d,1H).MS(ES)m/e?162(M+H) +.
E) (S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-methyl acetate
With (S)-7-carbonyl-4-methyl-3-oxo-2,3,4,5-tetrahydrochysene-1H-1, the 4-benzodiazepine _-(828.2mg 2.83mmol) is dissolved in CH to the 2-methyl acetate 3CN is sequentially added into HOBt.H 2O (398.1mg, 2.92mmol), EDC (562.9mg, 2.94mmol) and diisopropylethylamine (1ml, 5.74mmol).After solid dissolving, add 2-(methylamino methyl) imidazo [1,2a] pyridine (460.7mg, 2.86mmol) and diisopropylethylamine (1.5ml is 8.61mmol) in CH 3Solution among the CN stirs reactant down in RT.After 24 hours, reactant is concentrated residue and toluene (2X) coevaporation.The gained residue is through silica gel column chromatography (5%MeOH/CHCl 3) obtain target compound (694.6mg, 56%): MS (ES) m/e 436.4 (M+H) +
F) (S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
With (S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(663.4mg 1.52mmol) is dissolved in MeOH (10ml) to the 2-methyl acetate.Add H 2O (10ml), (5ml 5.0mmol), stirs reactant down in RT to add 1.0NNaOH then.After 20 hours, with 1.0 NHCl (5ml) neutralization reactant, solution evaporates under vacuum.Residue is through ODS chromatography purification (gradient: the H that contains 0.1%TFA 2O 500ml contains the 5%CH of 0.1%TFA 3CN/H 2O500ml contains the 10%CH of 0.1%TFA 3CN/H 2O 500ml contains the 15%CH of 0.1%TFA 3CN/H 2O 500ml contains the 20%CH of 0.1%TFA 3CN/H 2O 500ml), and then through ODS chromatography (gradient: contain the water 250ml of 0.1%TFA, contain the 10%CH of 0.1%TFA then once 3CN/H 2O 1.5L contains the 20%CH of 0.1%TFA then 3CN/H 2O1L).Merge the part that contains pure products, concentrate.Residue and toluene coevaporation are dissolved in MeOH then, use Et 2O precipitates again and promptly gets target compound (96.4mg):
MS(ES)m/e?421.9(M+H) +.
Value of calculation C 22H 23N 5O 40.25H 2OTFA:C, 53.38; H, 4.57; N, 12.97. measured value: C, 53.68; H, 4.97; N, 12.94.
Embodiment 59
(±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-preparation of 2-acetic acid
A) N-(carbonyl benzyloxy)-N-(methyl) acetonitrile
Under RT with Cbz chlorine (7.40ml, 49.3mmol) slowly add to N methylamino acetonitrilehydrochlorate (5.0g, 46.92mmol) and triethylamine (13.4ml is 96.2mmol) in the solution of dichloromethane (200ml).Reactant was stirred 18 hours down in RT, with 1N HCl, water and saline purging compound.With organic layer drying (MgSO 4), concentrated obtaining to clarifying buttery target compound (6.97g, 73%).
B) N-(carbonyl benzyloxy)-amino thioacetamide of N-(methyl)
With hydrosulfuric acid be blown into N-(carbonyl benzyloxy)-N-(methyl) acetonitrile (15g, 73.5mmol) and triethylamine (30.75ml is 220.6mmol) in the solution of DMF (250ml).After 20 minutes,, reactant is stirred 18h down in RT with the flask sealing.Then reactant is poured into 2N NaHCO 3(1L), use dichloromethane extraction.With the organic facies that water/saline of 1: 1 (5X) washing merges, dry (MgSO 4), concentrate and obtain yellow oil, (gradient: the 40-50% ethyl acetate/hexane) purification promptly gets the target compound (12.26g, 70%) into white solid: MS (ES) m/e 239.0 (M+H) through flash chromatography on silica gel with it +
C) N-(carbonyl benzyloxy)-N-methyl-S-(methyl) acetyl group sulfo-imino-ester (acetothioimidate)
(17.66ml, (6.75g is 28.36mmol) in the solution of acetone (100ml) 283.6mmol) to add to N-(carbonyl benzyloxy)-amino thioacetamide of N-(methyl) with iodomethane under RT.In the dark solution was stirred 3 hours down in RT, the gained sedimentation and filtration is promptly got target compound (9.63g, 89%) into white solid: MS (ES) m/e 253.4 (M+H) +
D) (±)-2-amino-3, the 3-dimethoxy-butane
Sodium cyanoborohydride is added to 3,3-dimethoxy-2-butanone (1.32g, 10mmol) and ammonium acetate (1.1g 100mmol) transfers to 6 with the methoxide acid solution with pH in the solution of methanol (30ml), reactant is stirred down in RT spend the night, and concentrates.Residue is water-soluble, transfers to pH 5 with the HCl aqueous solution.Gained solution extracts with ether (3X), water-soluble liquid phase Na 2CO 3Alkalize to pH 10 the reuse extracted with diethyl ether.With organic layer drying (MgSO 4), concentrate the target compound (1.1g, 83%) that promptly gets to clarified oil: MS (ES) m/e 134.2 (M+H) +
E) N-(carbonyl benzyloxy)-N-(methyl-(4,5-dimethyl-1H-imidazoles-2-yl) methylamine
With (±)-2-amino-3,3-dimethoxy-butane (1.05g, 7.89mmol) and N-(carbonyl benzyloxy)-N-methyl-S-(methyl) acetyl thio imino-ester (2.0g, 5.26mmol) in the solution of methanol (30ml) in 60 ℃ of heating 2 hours, concentrate and obtain yellow oil.Thick oil is dissolved in 6N Hcl (30ml), stirred 1 hour in RT.With the NaOH aqueous solution above-mentioned solution is alkalized to pH12, use dichloromethane extraction then.With the organic facies drying (MgSO that merges 4), concentrate brown oil, obtain target compound (0.590g, 41%) through flash chromatography on silica gel (4% ethanol/methylene) purification: MS (ES) m/e 274.0 (M+H) into clarified oil +
F) N-methyl-(4,5-dimethyl-1H-imidazoles-2-yl) methylamine
With (0.35g, methanol 1.28mmol) (15ml) solution and the glacial acetic acid (5ml) that contains 10%Pd/C (0.035g) (45psi) jolting 6 hours in the H2 environment of N-(carbonyl benzyloxy)-N-methyl-(4,5-dimethyl-1H-imidazoles-2-yl) methylamine.Reactant is filtered, and concentrated filtrate promptly gets brown buttery target compound (0.22g, 86%): MS (ES) m/e 140 (M+H) +, it promptly can be used for next step without being further purified.
G) (±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1 H-1, the 4-benzodiazepine _-the 2-methyl acetate
With N-methyl-(4,5-dimethyl-1H-imidazoles-2-yl) methylamine (0.20g, 1.1mmol) and (±)-7-carboxyl-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-methyl acetate (0.320g, 1.1mmol) (0.287ml, 1.65mmol) solution under the existence stirs under room temperature in DIEA.Adding EDC (0.316g, 1.65mmol), and then adding DMAP (0.013g, 0.11mmol).Mixture stirred 18 hours down in RT, concentrated and obtained oil, and (gradient: the 0.5-2% ethanol/methylene) purification promptly gets and clarifies buttery target compound (0.060g, 9%): MS (ES) m/e 414.2 (M+H) through flash chromatography on silica gel +
H) (±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid
1N NaOH (3eq) is added to (±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(0.06g is in solution 0.145mmol) for the 2-methyl acetate, mixture was stirred 5 hours down in RT, concentrate.Residue is water-soluble, with 50% acetic acid pH is transferred to 5.With solution concentration, promptly get target compound (0.050g, 86%) through MPLC (ODS-AQ contains 10% acetonitrile/water of 0.1%TFA, in 220nm place ultraviolet determination) purification: MS (ES) m/e 400.2 (M+H) into white solid +
Embodiment 60
3-[(3-[2-(ethyl of benzimidazolyl-2 radicals-yl)] isoxazoline-5 (RS)-yl] acetyl group] amino-3 (R, S)-preparation of methylpropanoic acid
A) 4-(benzimidazolyl-2 radicals-yl)-1-butylene
According to the general flow of preparation 4 among the P50256-1, replace the Boc-sarcosine with the 4-penetenoic acid, the preparation target compound.
B) 4-(1-tosyl benzimidazolyl-2 radicals-yl)-1-butylene
Sodium hydride is added to 4-carefully, and (benzimidazolyl-2 radicals-yl)-1-butylene (50mmol) and 4-toluene sulfochloride (55mmol) are in the solution of anhydrous THF (200ml).Reactant is stirred under RT reacts completely, use saturated NH then 4Cl (200ml) quenching extracts mixture with EtOAc.With the organic extract liquid drying (MgSO that merges 4) and concentrate, residue promptly gets target compound with the silica gel column chromatography purification.
C) 4-(1-tosyl benzimidazolyl-2 radicals-yl)-1-butyraldehyde
(1-tosyl benzimidazolyl-2 radicals-yl)-1-butylene (40mmol) is in CH ozone to be blown into 4-in the time of-78 ℃ 2Cl 2Until generating the blueness that continues, in solution, be blown into argon then and remove redundant ozone (160ml) and in the solution of MeOH (40ml).Add anhydrous dimethyl base thioether (excessive), reactant is warmed to RT.Reactant is stirred under RT reacts completely, concentrate then, residue promptly gets target compound through silica gel column chromatography.
D) 4-(1-tosyl benzimidazolyl-2 radicals-yl)-1-butyl aldoxime
Oxammonium hydrochloride. (33mmol) is added to 4-in 0 ℃, and (1-tosyl benzimidazolyl-2 radicals-yl)-1-butyraldehyde (30mmol) and anhydrous sodium acetate (66mmol) are in the solution of MeOH (150ml).With reactant in 0 ℃ of stirring until fully, concentrate, residue is at H 2Distribute between O and the EtOAc.The EtOAc aqueous layer extracted is used in layering.Use 5%NaHCO in order 3The organic layer that washing merges with saturated brine, dry (MgSO 4), concentrate target compound.
E) 4-(1-tosyl benzimidazolyl-2 radicals-yl)-1-fourth oxime acyl chlorides
According to the flow process of embodiment 1 (b) among the WO 95/14682, and usefulness 4-(1-tosyl benzimidazolyl-2 radicals-yl)-1-butyl aldoxime replacement 4-cyano group benzo oxime, the preparation target compound.
F) [3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] and isoxazole miaow-5 (R, S)-yl] tert-butyl acetate
According to the flow process of the embodiment 1 (d) of WO 95/14682, (1-tosyl benzimidazolyl-2 radicals-yl)-1-fourth oxime acyl chlorides replaces 4-cyano group benzene oxime acyl chlorides, replaces the 3-M Cr with the 3-butenoic acid tert-butyl ester, the preparation target compound with 4-.
G) [3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] and isoxazoline-5 (R, S)-yl] acetic acid
To add in the 4M HCl in the dioxane (10ml) at 0 ℃ [3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] tert-butyl acetate (5mmol) is in CH 2CH 2In the solution (40ml).Reactant is stirred down until fully in RT, concentrate then and obtain target compound.
H) 3-[[3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] acetyl group] amino-3 (R, S)-the methylpropanoic acid ethyl ester
Under RT, EDC (1.2mmol) is added to [3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] acetic acid (1mmol), 3 (R, S)-aminobutyric acid ethyl ester (1.2mmol), HOBtH 2O (1.2mmol) and diisopropylethylamine (4mmol) are in anhydrous CH 3In the solution of CN (5ml).Reactant is stirred down until fully in RT, concentrate then, promptly get target compound through the silica gel column chromatography purification.
I) 3-[[3-[2-(ethyl of benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] acetyl group] amino-3 (R, S)-methylpropanoic acid
With 1.0 N LiOH (2.5mmol) add to 3-[3-[2-(ethyl of 1-tosyl benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] acetyl group] amino-3 (R, S)-methylpropanoic acid ethyl ester (0.5mmol) is in the solution of THF (2.5ml).Reactant is stirred down until fully, then with 1.0N HCl neutralization in RT.With solution concentration, residue promptly gets target compound through the reversed phase chromatography purification.
Embodiment 61
3-{3, the methyl of 4-dihydro-8-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _-preparation of 4-propanoic acid
A) 2-amino-4-iodo-benzoic acid
Equal J.Org.Chem.1986 according to Sasson, 51, the method for 2880-2883 obtains 4-iodo-2-nitrobenzoic acid with the oxidation of 4-iodo-2-Methylnitrobenzene, with ferrum and acetic acid nitryl group reduced then, thus the preparation target compound.
B) 4-iodo-isatoic acid acid anhydride
By an addition funnel, with solution in the toluene solution (80ml) of 1.93M phosgene slowly be added to 2-amino-4-iodo-benzoic acid (26.3g, 0.1mol), (10.6g is 0.1mol) and in the churned mechanically ice-cold solution of water (250ml) for sodium carbonate.After 2 hours, by the isolated by filtration precipitated product, water (200ml), 1: 1 methanol mixture (300ml) and ether (200ml) washing solid in order.Vacuum press dry the dry target compound that gets.
C) N-(2-amino-4-iodobenzene formoxyl)-Beta-alanine benzyl ester
With 4-iodo-isatoic acid acid anhydride (5.0g, 0.0173mol), Beta-alanine benzyl ester toluene fulfonate (5.85g, 0.0173mol) and dimethyl aminopyridine (0.5g, 0.0041mmol) solution of the electromagnetic agitation in pyridine (35ml) in 80 ℃ the heating 2 hours.Reactant mixture is chilled to RT, vacuum concentration.The gained residue is dissolved in ethyl acetate (100ml), and use in order 10% copper sulfate (2 * 50ml), saturated sodium bicarbonate (1 * 50ml) and saline (1 * 50ml) washing.Dry (Na 2SO 4), filter, concentrate, silica gel column chromatography (1: 1 EtOAc/ hexane) target compound.
D) N-(4-iodo-2-methylamino benzoyl)-Beta-alanine benzyl ester
With N-(2-amino-4-iodobenzene formoxyl)-Beta-alanine benzyl ester (2.0mmol), 2, the 6-lutidines (0.35ml, 3.0mmol) and methyl iodide (0.19ml, 3.0mmol) solution of the electromagnetic agitation in DMF (15ml) in 50 ℃ the heating 15 hours.Reactant mixture is cooled to RT, vacuum concentration.The gained residue is dissolved in ethyl acetate (75ml), and use in order 10% citric acid (1 * 50ml), saturated sodium bicarbonate (1 * 50ml) and saline (1 * 50ml) washing.Dry (Na 2SO 4), filter, concentrate, silica gel column chromatography (gradient 35-65%EtOAc/ hexane) target compound.
E) 3-[3,4-dihydro-8-iodo-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _]-the 4-benzyl propionate
Under ar gas environment with alpha-brominated acetyl bromide (0.09ml; 1.04mmol) slowly add to N-(4-iodo-2-methylamino benzoyl)-Beta-alanine benzyl ester (0.305g in the solution of dichloromethane (2ml); 0.69mmol) and triethylamine (0.144g is 1.04mmol) in the solution of the electromagnetic agitation of cold (30 ℃) of methylene (3ml).Reactant mixture is warmed to RT and stirred 2 hours.With mixture with dichloromethane (40ml) dilution, and use in order 10% citric acid (1 * 50ml) and saturated sodium bicarbonate (1 * 50ml) washing, the drying (Na 2SO 4), filtration, vacuum concentration.The gained residue is dissolved in DMF (3ml), and (25mg 1.04mmol) is cooled to 0 ℃ slurry in DMF (2ml) to add sodium hydride by addition funnel.Stir after 24 hours, pour mixture the ice-cold solution of 10% citric acid (50ml) into, with ethyl acetate (3 * 40ml) extractions.With saturated sodium bicarbonate (extract that 1 * 50ml) washing merges, dry (Na 2SO 4), filter and concentrate.Silica gel column chromatography (gradient 40-70%EtOAc/ hexane) gets target compound.
F) 3-[3, the methyl of 4-dihydro-8-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _]-the 4-benzyl propionate
Under the CO environment with 3-[3,4-dihydro-8-iodo-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _]-4-benzyl propionate (2mmol), 2-(methylamino methyl) benzimidazole dihydrochloride (3mmol), DIEA (1.8ml, 10mmol) and (Ph 3P) 2PdCl 2(140mg is 0.2mmol) in the mixture heated to 110 of N-N-methyl-2-2-pyrrolidone N-(20ml) ℃ and kept 3 hours.Then mixture is concentrated, residue promptly gets target compound through flash chromatography on silica gel
G) 3-[3, the methyl of 4-dihydro-8-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _]-the 4-propanoic acid
With 3-[3, the methyl of 4-dihydro-8-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1-methyl-2,5-dioxo-1H-1, the 4-benzodiazepine _]-4-benzyl propionate (2mmol) and the mixture of 10%Pd/C (0.02g) in methanol (100ml) be at H 2Hydrogenation is 6 hours in the environment (50psi).Remove by filter catalyst, the filtrate vacuum concentration is promptly got target compound
Embodiment 62
The methyl of 3-{4H-imidazo [1,2a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-preparation of 4-propanoic acid
A) N-(2-amino-4-iodobenzene formoxyl)-Beta-alanine ethyl ester
(0.5g, 0.0041mol) solution of the electromagnetic agitation in pyridine (35ml) was in 80 ℃ of heating 2 hours with 4-iodo-isatoic acid acid anhydride (0.0173mol), Beta-alanine carbethoxy hydrochloride (0.0173mol) and dimethyl aminopyridine.Reactant mixture is cooled to RT and vacuum concentration gained residue is dissolved in ethyl acetate (100ml), and use in order 10% copper sulfate (2 * 50ml), saturated NaHCO 3(1 * 50ml) and saline (1 * 50ml) washing.Dry (Na 2SO 4), filter, concentrate.And must target compound through silica gel column chromatography (1: 1 EtOAc/ hexane).
B) 3-[3,4-dihydro-8-iodo-2,5-dioxo-1H-1, the 4-benzodiazepine _]-the 4-ethyl propionate
Under ar gas environment with alpha-brominated acetyl bromide (0.09ml; 1.04mmol) solution in dichloromethane (2ml) slowly adds to N-(2-amino-4-iodobenzene formoxyl)-Beta-alanine ethyl ester (0.69mmol) and triethylamine (0.144g is 1.04mmol) in the solution of the magnetic agitation of cold (30 ℃) of dichloromethane (3ml).Reactant mixture is warmed to RT and stirred 2 hours.With dichloromethane (40ml) diluted mixture thing, and the order with 10% citric acid (1 * 50ml) with saturated NaHCO 3(1 * 50ml) washing, dry (Na 2SO 4), filtration, vacuum concentration.The gained residue is dissolved in DMF (3ml), and (25mg is 1.04mmol) in the slurry of DMF (2ml) to add to the sodium hydride that is chilled to 0 ℃ by addition funnel.Stir after 2 hours, pour mixture the ice-cold solution (50ml) of 10% citric acid into, with ethyl acetate (3 * 40ml) extractions.Use saturated NaHCO 3(extract that 1 * 50ml) washing merges, dry (Na 2SO 4), filtration, vacuum concentration, promptly get target compound through silica gel column chromatography.
C) 3-[3,4-dihydro-8-iodo-2-thioketone-5-oxo-1H-1, the 4-benzodiazepine _]-the 4-ethyl propionate
Under RT and nitrogen environment, Lawesson ' s reagent (1.0g) is added to 3-[3,4-dihydro-8-iodo-2,5-dioxo-1H-1, the 4-benzodiazepine _]-(1.0g 2.49mmol) in the solution of THF (10ml), heats reactant 2 hours in 50 ℃ the 4-ethyl propionate.Reactant mixture is cooled to RT and vacuum concentration.Silica gel column chromatography (gradient 40-60%EtOAc/ hexane) gets target compound.
D) 3-[4H-imidazo [1,2-a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-iodo]-the 4-ethyl propionate
In RT 2N NaOH (1.2ml) is added to 3-[3,4-dihydro-8-iodo-2-thioketone-5-oxo-1H-1, the 4-benzodiazepine _]-the 4-ethyl propionate (0.95g, 2.27mmol), the hydrogen sulfate TBuA of methyl iodide (0.2g) and catalytic amount is in CH 2Cl 2(10ml) and H 2In the two phase liquid of the vigorous stirring among the O (10ml).After 2 hours, CH is used in layering 2Cl 2(2 * 25ml) washing water layers.With the organic extract liquid drying (Na that merges 2SO 4), filtration, vacuum concentration.The residue that obtains is dissolved in toluene (10ml), and (0.23g handles 1moleq) with propargyl amine (0.64ml, 4 times excessive) and pyridine hydrochloride.With reactant reflux 6 hours, be cooled to RT then.Concentrate and make target compound through silica gel column chromatography (EtOAc).
E) methyl of 3-[4H-imidazo [1,2-a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-the 4-ethyl propionate
Under the CO environment with 3-[4H-imidazo [1,2-a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-iodo]-4-ethyl propionate (2mmol), 2-(methylamino methyl) benzimidazole (3mmol), DIEA (1.8ml, 10mmol) and (Ph 3P) 2Pd/Cl 2(140mg, 0.2mmol) mixture heated to 110 in N-N-methyl-2-2-pyrrolidone N-(20ml) ℃ and keeping 3 hours.Then mixture is concentrated, residue promptly gets target compound through flash chromatography on silica gel.
F) methyl of 3-[4H-imidazo [1,2-a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-the 4-propanoic acid
With the methyl of 3-[4H-imidazo [1,2-a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-ethyl propionate (54mmol), LiOHH 2The solution of O (0.79mmol) THF (5ml) and water (2ml) stirs down in RT and spends the night.Mixture is concentrated, and residue is water-soluble, and gained solution neutralizes with 3N HCl.Collecting precipitation and vacuum drying promptly get target compound.
Embodiment 63
4-[4-(2-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-preparation of 1-Piperidineacetic acid
A) 4-[4-[(tert-butoxycarbonyl)]-the 1-piperazinyl]-the 1-ethyl piperidine
Equal the method for EPA0542363 A2 according to Porter, pass through NaCNBH 3Reduction amination is from the 1-piperazine carboxylic acid tert-butyl ester (Aldrich) and 4-oxo-1-Piperidineacetic acid (Porter etc., EPA 0542363 A2) preparation target compound.B) 4-(1-piperazinyl)-1-ethyl piperidine
With the 4-[4-[(tert-butoxycarbonyl)]-the 1-piperazinyl]-1-ethyl piperidine and 4M HCl/ dioxy ring six alkane are in CH 2Cl 2In solution stirred 18 hours down in RT.Reactant mixture is concentrated the hydrochlorate that promptly gets target compound.C) benzimidazole 2-[2-chloroethyl)]
With 2-benzimidazole ethanol and thionyl chloride in CH 2Cl 2In vlil 2 hours.The mixture evaporation is promptly got target compound.D) 4-[4-[2-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the 1-ethyl piperidine
With 4-(1-piperazinyl)-1-ethyl piperidine, 2-[2-chloroethyl)] benzimidazole and the solution of DIEA in DMF stirred under room temperature 18 hours.Mixture is concentrated and promptly get target compound through chromatography purification.E) 4-[4-[2-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the 1-Piperidineacetic acid
With 4-[4-[2-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-1-ethyl piperidine and the solution of 1.0N NaOH in MeOH stirs down in RT.After 18 hours, mixture neutralizes with AcOH, and by XAD-2 post desalination, lyophilization promptly gets target compound.
Embodiment 64
1-hydroxyl-4-[4-[3-(propyl group of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-preparation of Cyclohexaneacetic acid
A) 1-hydroxyl-4-[4-[2-(propyl group of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the Cyclohexaneacetic acid tert-butyl ester
1-hydroxyl-4-(1-piperazinyl)-Cyclohexaneacetic acid tert-butyl ester (EPA 0537980 A1), 2-(3-bromopropyl) benzimidazole (J.Org.Chem.1962,27,2165) and the solution of DIEA in DMF were stirred 18 hours down in RT.Mixture is concentrated and promptly get target compound through chromatography purification.
B) 1-hydroxyl-4-[4-[2-(propyl group of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-Cyclohexaneacetic acid
With 1-hydroxyl-4-[4-[2-(propyl group of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the Cyclohexaneacetic acid tert-butyl ester and 4M HCl/-two-oxygen ring six alkane are in CH 2Cl 2In stir down in RT.After 18 hours, the mixture evaporation is promptly got target compound.
Embodiment 65
N-[3-[1-[2-(2-benzimidazolyl) ethyl] carbonyl] piperidyl] carbonyl]-preparation of Beta-alanine
Equal the flow process of embodiment 1 among the WO 95/25091 according to Beavers, replace N with (2-benzimidazolyl) propanoic acid α-Boc-D-lys (Cbz)-OH, the preparation target compound.
Embodiment 66
The methyl of 2-[(benzimidazolyl-2 radicals-yl)]-5-[2-(carboxyl-2-ethyl) amino] carbonyl]-2, the preparation of 3-dihydro-3-oxo-1H-iso-indoles
According to preparation 1-12 (Hartman etc., EP 0540334-A1) preparation 1-H-iso-indoles-5-Methanamide, 2,3-dihydro-N-(2-carboxyl-ethyl)-2-[2-(piperidyl) ethyl]-flow process of 3-oxo, replace Boc-4-piperidines-2-ethamine with 2-(amino methyl) benzimidazole (Aldrich), thereby, the preparation target compound.
Embodiment 67
The preparation of [3 (R)-[2-(ethyl of benzimidazolyl-2 radicals-yl)]-2-oxo-piperidine base] acetyl group-3 (R)-methyl-Beta-alanine
A) 4-(methyl butyrate of benzimidazolyl-2 radicals-yl)
According to the flow process of embodiment 36 (a), with 1, the 2-diaminobenzene replaces 2,3-diamino-pyridine, preparation target compound.
B) 4-(butanoic acid of benzimidazolyl-2 radicals-yl)
According to the flow process of embodiment 36 (b), 4-(benzimidazole 2-yl) methyl butyrate saponification is promptly got target compound.
C) [3 (R)-[2-(ethyl of benzimidazolyl-2 radicals-yl)]-2-oxo-piperidine base] acetyl group-3 (R)-methyl-Beta-alanine
According to the flow process of (J.Med.Chem.1995,38,3332) such as Duggan, (benzimidazolyl-2 radicals-yl) butanoic acid replaces (N-Boc-piperidin-4-yl) butanoic acid, the preparation target compound with 4-.
Embodiment 68
4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino]-acetyl group] preparation of phenoxyacetic acid
4-[2-(Boc-methylamino) acetyl group] phenol
With the bicarbonate di tert butyl carbonate (5.96g, 27.3mmol) in 1, the solution in the 4-dioxane (25ml) is added drop-wise to 4-[2-(methylamino) acetyl group in 0 ℃] the phenolate hydrochlorate (5.0g, 24.8mmol), 1,4-dioxane (30ml), H 2(25ml is in mixture 25mmol) for O (25ml) and 1.0N NaOH.After 24 hours, with the reactant temperature to RT and stirred 1.5 hours.(25ml 25mmol), with reactant restir 0.5 hour under RT, concentrates to add more 1.0N NaOH.Residue is used 1.0M NaHSO with EtOAc (80ml) dilution 4Mixture is acidified to pH2.The gained mixture extracts with EtOAc, uses H 2The organic layer that the O washing merges, dry (MgSO 4).Filter and concentrate and promptly get target compound (6.49g, 99%):
1H?NMR(250?MHz,CDCl 3)δ6.70-8.05(m,4H),4.53(s,2H),2.98(s,3H),1.50(s,9H).
B) 4-[2-(Boc-methylamino) acetyl group] phenoxyacetic acid benzyl ester
Under ar gas environment with embodiment 68 (a) chemical compound (5.04g, 19.0mmol) and K 2CO 3(2.63g, 19.0mmol) mixture in acetone (100ml) refluxes and stirred 1 hour.Mixture is cooled to RT, and adding monobromo-acetic acid benzyl ester (5.23g, 22.8mmol).With reactant reflux 18 hours, cool off then and filter.Use the washing with acetone filter cake, filtrate is concentrated.Residue is dissolved in CH 2Cl 2(300ml), use H in order 2O (50ml) and saline (50ml) washing.Dry (Na 2SO 4), concentrate, obtain target compound (7.28g, 93%) through flash chromatography (silica gel, 1: 3 EtOAc/ hexane): 1H NMR (250MHz, CDCl 3) δ 6.85-7.95 (m, 9H), 5.23 (s, 2H), 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 (d, 9H).
C) 4-[2-(methylamino) acetyl group] phenoxyacetic acid benzyl ester hydrochloride
With embodiment 68 (b) chemical compound (7.26g, 17.57mmol) and 4M HCl in 1, the mixture in the 4-dioxane (150ml) stirred under room temperature 1 hour.Concentrate and use Et 2O grinds the target compound (5.93g, 97%) that promptly gets to white powder:
1H?NMR(250?MHz,CD 3OD)δ7.05-8.00(m,9H),5.23(s,2H),4.88(s,2H),4.65(s,2H),2.80(s,3H).
D) 4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group] phenoxyacetic acid benzyl ester
Embodiment 68 (c) chemical compound (1mmol), 2-(benzimidazolyl) acetic acid (1mmol), EDC (1.5mmol) and the mixture of DIEA (3mmol) in DMF (25ml) are stirred down in RT.Pour mixture into 5%NaHCO 3In and extract with EtOAc.Wash organic facies with water, dry (MgSO 4) concentrate.Residue gets target compound through chromatography (silica gel).
E) 4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group] the phenoxyacetic acid ester
With embodiment 68 (d) chemical compound (1mmol) and 1N NaOH (1.5ml) in CH 3Stir among the OH (20ml) and concentrate.Residue is water-soluble, uses CH 2Cl 2Extraction transfers to pH 5 with rare HCl with water and promptly gets target compound.
Embodiment 69
4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group]-1, the preparation of the inferior benzene dioxy of 2-base oxalic acid
A) 4-[2-(Boc-methylamino) acetyl group]-1, the 2-dihydroxy benzenes
Flow process according to embodiment 68 (a); with Stryphnasal (Serturner). (5.0g 23.0mmol) replaces 4-[2-(methylamino) acetyl group] the phenolate hydrochlorate, through flash chromatography (silica gel; 1: 1 EtOAc/ hexane) makes target compound (1.2g, 19%): MS (ES) m/e 282.2[M+H] +
B) 4-[2-(Boc-methylamino) acetyl group]-1, the inferior benzene dioxy of 2-base oxalic acid dimethyl ester
According to the flow process of embodiment 68 (b), (0.9g 3.2mmol) replaces embodiment 68 (a) chemical compound with embodiment 69 (a) chemical compound, with monobromo-acetic acid methyl ester (1.23g, 8.0mmol) replace monobromo-acetic acid benzyl ester, prepare target compound (1.11g, 81%): MS (ES) m/e 426.2[M+H] +
C) 4-[2-(methylamino) acetyl group]-1, the inferior benzene two ethoxyacetic acid dimethyl ester hydrochlorates of 2-
According to the flow process of embodiment 68 (c), usefulness embodiment 69 (b) chemical compound (1.11g 2.6mmol) replaces embodiment 68 (b) chemical compound, the preparation target compound (1.1g, quantitatively): MS (ES) m/e326.0[M+H] +
D) 4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group]-1, the inferior benzene dioxy of 2-base oxalic acid dimethyl ester
According to the flow process of embodiment 68 (d), replace embodiment 68 (c) chemical compound with embodiment 69 (c) chemical compound, make target compound.
E) 4-[[[[2-(benzimidazole) methyl] carbonyl] methylamino] acetyl group]-1, the inferior benzene dioxy of 2-base oxalic acid
According to the flow process of embodiment 68 (e), replace embodiment 68 (d) chemical compound with embodiment 69 (d) chemical compound, make target compound.
Embodiment 70
The N-[3-[[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl]-preparation of Beta-alanine
A) methyl N-[3-[[[(2-benzimidazolyl)] carbonyl] amino] benzoyl]-Beta-alanine benzyl ester
(Alig etc., EPA372486) (1mmol), (2-benzimidazolyl) acetic acid (1mmol), EDC (1.5mmol) and the mixture of DIEA (3mmol) in DMF (25ml) stir down in RT with N-(3-amino benzoyl)-Beta-alanine benzyl ester.Pour mixture into 5%NaHCO 3In and extract with EtOAc.Wash the organic facies of merging with water, dry (MgSO 4) and concentrate.Residue promptly gets target compound through chromatography (silica gel).
B) methyl N-[3-[[[(2-benzimidazolyl)] carbonyl] amino] benzoyl]-Beta-alanine
With embodiment 70 (a) chemical compound (1mmol) and 1N NaOH (1.5ml) in CH 3Mixture among the OH (20ml) stirs, and concentrates.Residue is water-soluble, uses CH 2The Cl extraction transfers to pH5 with rare HCl with water and promptly gets target compound.
Embodiment 71
[[1-[N-[[(2-benzimidazolyl) methyl] carbonyl] the cheese acyl group]-the 4-piperidyl] the oxygen base] preparation of acetic acid
A) [[the 1-[N-[[(2-benzimidazolyl) methyl] carbonyl] the cheese acyl group]-the 4-piperidyl] the oxygen base] tert-butyl acetate
With [(1-cheese acyl group-4-piperidyl) oxygen base] tert-butyl acetate (Alig etc., EPA 372486) (1mmol), (2-benzimidazolyl) acetic acid (1mmol), EDC (1.5mmol) and the mixture of DIEA (3mmol) in DMF (25ml) stir down in RT.Pour mixture into 5%NaHCO 3, and extract with EtOAc.Wash the organic facies of merging with water, dry (MgSO 4) and concentrate.Residue promptly gets target compound through chromatography (silica gel).
B) [[the 1-[N-[[(2-benzimidazolyl) methyl] carbonyl] the cheese acyl group]-the 4-piperidyl] the oxygen base] acetic acid
With embodiment 71 (a) chemical compound (1mmol) and CF 3CO 2H is in CH 2Cl 2In mixture stir and concentrate and promptly get target compound.
Embodiment 72
(S)-and the 4-[[[(2-benzimidazolyl) methyl] carbonyl] glycyl]-preparation of 3-methoxycarbonyl methyl-2-oxo piperazine-1-acetic acid
Equal flow process (embodiment 59) among the EP 0529858 according to Sugihara, replace 4-amidino groups benzoate hydrochlorate, make target compound with (2-benzimidazolyl) acetic acid.
Embodiment 73
(3S, 5S)-5-[[4-[(2-benzimidazolyl) methyl] phenyl] the oxygen methyl]-preparation of 3-carboxymethyl-2-Pyrrolidone
A) methyl 4-[(2-benzimidazolyl)] phenol
According to the general flow of Wahlgren and Addison (J.Heterocycl.Chem.1989,26,541-543), replace 2-(hydroxyl) phenylacetic acid with 4-(hydroxyl) phenylacetic acid, make target compound.
B) (3S, 5S)-the 5-[[4-[(2-benzimidazolyl) methyl] phenyl] the oxygen ylmethyl]-the 3-[(tert-butoxycarbonyl) methyl]-2-Pyrrolidone
According to the flow process (Australian Patent Application AU-A-86926/91, embodiment 51) of Himmelsbach etc., replace 4 '-cyano group-3 '-fluoro-4-hydroxyl with embodiment 73 (a) chemical compound) xenyl, obtain target compound.
C) (3S, 5S)-the 5-[[4-[(2-benzimidazolyl) methyl] phenyl] the oxygen methyl]-3-carboxymethyl-2-Pyrrolidone
Use CH 2Cl 2In CF 3CO 2H Processing Example 73 (b) chemical compound promptly gets target compound.
Embodiment 74
The 1-[(2-benzimidazolyl) methyl]-3-[4-(2-carboxyethyl) phenyl]-preparation of 4-methoxyl group-3-pyrrolidone-2-ketone
According to the flow process (EP 0567968) of Linz etc., replace the 4-cyano-aniline with (2-benzimidazolyl) methylamine, obtain target compound.
Embodiment 75
2-[6-(the methylamino carbonyl of benzimidazolyl-2 radicals-yl)]-1,2,3, the 4-tetrahydro isoquinolyl] preparation of acetic acid
A) 6-methoxyl group-1,2,3, the 4-tetrahydroisoquinoline
Method (J.Med.Chem.1987,30,2208-2216) preparation 6-methoxyl group-1,2,3,4-tetrahydroisoquinoline according to D.J.Sall and G.L.Grunewald.
B) 2-[6-methoxyl group-1,2,3, the 4-tetrahydroisoquinoline] ethyl acetate
With embodiment 75 (a) chemical compound (1.1mmol), chloracetic acid ethyl ester (1.17mmol) and potassium carbonate (1.17mmol) solution stirring 18 hours in acetonitrile (10ml).Then with mixture at EtOAc and H 2Distribute in the mixture of O.The organic facies rotary evaporation is become oil, obtain target compound through the silica gel column chromatography purification.
C) 2-[6-hydroxyl-1,2,3, the 4-tetrahydroisoquinoline] ethyl acetate
With embodiment 75 (b) chemical compound (0.249g, 1.0mmol) and Boron tribromide (1M is in CH 2Cl 2In, 1.0ml, 1.0mmol, solution ml) stirred 12 hours in RT then in-70 ℃ of stirrings 2 hours.The solution rotating evaporation is become oil.Residue is dissolved in EtOAc.Water (1X), 5%NaHCO 3(2X), water (1X) washing EtOAc.With EtOAc in Mg 2SO 4Last dry, filter, rotary evaporation obtains target compound.
D) 2-[6-trifluoromethyl sulfonyloxy-1,2,3, the 4-tetrahydro isoquinolyl] ethyl acetate
With embodiment 75 (c) chemical compound (0.235g, 1.0mmol), three fluorosulfonic anhydride (0.23ml, 1.1mmol) and Et 3(0.32ml is 1.5mmol) in CH for N 2Cl 2Solution stirring (5ml) 8 hours.Above-mentioned solution rotating evaporation is become oil.Residue is dissolved in EtOAc.Use 5%NaHCO 3(2X), water (1X) washing EtOAc.Use Na 2SO 4With the EtOAc drying, filter, rotary evaporation promptly gets target compound.
E) 2-[6-carboxyl-1,2,3, the 4-tetrahydro isoquinolyl] ethyl acetate
Under the carbon monoxide environment, with embodiment 75 (d) chemical compound (0.367g, 1.0mmol), palladium diacetate (II) (0.022g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.34ml, 2.5mmol), the solution stirring of NMP (5ml) in ammonium carbonate (10%) aqueous solution 8 hours.This solution rotating is flashed to oil.Residue promptly gets target compound through the silica gel column chromatography purification.
F) ethyl-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3,4-tetrahydro isoquinolyl] acetic acid
With embodiment 75 (e) chemical compound (0.263g, 1.0mmol), (2-benzimidazolyl) acetic acid compound (0.34g, 1.0mmol), EDC (0.191g, 1.0mmol), HOBtH 2O (0.151g, 1.0mmol) and triethylamine (0.235ml, 2.0mmol) solution stirring in DMF (7ml) is 8 hours.This solution rotating is flashed to oil.Residue promptly gets target compound through the silica gel column chromatography purification.
G) 2-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3, the 4-tetrahydro isoquinolyl] acetic acid
With embodiment 75 (f) chemical compound (0.42g, 1.0mmol) in the 1N sodium hydrate aqueous solution (1.5ml, 1.5mmol) and the solution stirring in the ethanol (5ml) 8 hours.This solution rotating is flashed to oil.Residue gets target compound through the silicagel column purification.
Embodiment 76
2-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1-oxo-1,2,3,4-tetrahydro isoquinolyl] preparation of acetic acid
A) 6-methoxyl group-1-oxo-1,2,3, the 4-tetrahydroisoquinoline
According to the method for D.J.Sall and G.L.Grunewald etc. (J.Med.Chem. (1987), 30,2208-2216), preparation 6-methoxyl group-1-oxo-1,2,3,4-tetrahydroisoquinoline.
B) 2-[6-methoxyl group-1-oxo-1,2,3, the 4-tetrahydroisoquinoline] ethyl acetate
Mixture heated in THF (5ml) refluxed 1 hour with embodiment 76 (a) chemical compound (0.39mmol) and NaH (0.17g, 0.43mmol, 60% oily decentralized photo), was cooled to room temperature then.(0.43mmol) is added in the said mixture with the chloracetic acid ethyl ester, and this mixture was stirred 1 hour.Also (2 * 15ml) washings merge organic layer, water (10ml) washing, rotary evaporation one-tenth oil with EtOAc in mixture water (10ml) quenching.Residue promptly gets target compound through the silica gel column chromatography purification.
C) 2-[6-hydroxyl-1-oxo-1,2,3, the 4-tetrahydro isoquinolyl] ethyl acetate
With embodiment 76 (b) chemical compound (0.263g, 1.0mmol) and Boron tribromide (1M solution is in CH 2Cl 2In, solution 1.1ml) stirred 4 hours in RT then in-70 ℃ of stirrings 2 hours.This solution rotating is flashed to oil.Residue is dissolved in EtOAc.Water (1X), 5%NaHCO 3(2X), water (1X) washing EtOAc.Through MgSO 4Dry EtOAc filters and promptly gets target compound through rotary evaporation.
D) 2-[6-trifluoromethyl sulfonyloxy-1-oxo-1,2,3, the 4-tetrahydro isoquinolyl] ethyl acetate
(3.4mmol, ml) solution in pyridine (5ml) was warmed to room temperature 1 hour in 0 ℃ of cooling with it with embodiment 76 (c) chemical compound (3.4mmol) and three fluorosulfonic anhydride.Water (5ml) is the said mixture quenching, and with EtOAc (2 * 7ml) washings.Merge organic layer, water (7ml) washing, rotary evaporation becomes oil.Residue promptly gets target compound through the silica gel column chromatography purification.
E) 2-[6-carboxyl-1-oxo-1,2,3, the 4-tetrahydro isoquinolyl] ethyl acetate
Under the carbon monoxide environment, with embodiment 76 (d) chemical compound (0.23g, 1.0mmol), palladium diacetate (II) (0.026g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.0mmol), the solution stirring of NMP (7ml) in ammonium carbonate solution (10%) 8 hours.This solution rotating is flashed to oil.Residue gets target compound through silica gel column chromatography.
F) ethyl-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3,4-tetrahydro isoquinolyl] acetic acid
With embodiment 76 (e) chemical compound (0.34g, 1.0mmol), 2-(benzimidazolyl) acetic acid compound (0.43g, 1.0mmol), EDC (0.191g, 1.0mmol), HOBtH 2O (0.15g, 1.0mmol) and triethylamine (0.234ml, 2.3mmol) solution stirring in DMF (8ml) is 8 hours.This solution rotating is flashed to oil.Residue promptly gets target compound through the silica gel column chromatography purification.
Selectable, with embodiment 76 (d) chemical compound (0.23g, 1.0mmol), palladium diacetate (II) (0.026g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.25ml, 2.1mmol), (0.31g, 1.0mmol) solution in ammonium carbonate (10%) aqueous solution stirred 8 hours under the carbon monoxide environment for NMP (7ml) and intermediate A chemical compound.This solution rotating is flashed to oil.Residue gets target compound through the silica gel column chromatography purification.
G) 2-[6-((benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3, the 4-tetrahydro isoquinolyl] acetic acid
With embodiment 76 (f) chemical compound (0.25g, 1.0mmol) in the 1N sodium hydrate aqueous solution (1.5ml, 1.5mmol) and the solution stirring in the ethanol (8ml) 8 hours.Solution becomes oil through rotary evaporation.Residue gets target compound through silica gel purification.
Embodiment 77
2-[6-((benzimidazolyl-2 radicals-yl) methyl carbonylamino) tetrahydronaphthalene] preparation of acetic acid
A) 5-amino-tetrahydronaphthalene-2-tert-butyl acetate
Prepare 5-amino-tetrahydronaphthalene-2-tert-butyl acetate according to (EO 0635492 for flow process 12 and embodiment 28, A-D part, Jan.25,1995) described methods such as M.J.Fisher
B) 2-[6-((benzimidazolyl-2 radicals-yl) methyl carbonylamino) tetrahydronaphthalene] acetas
With embodiment 77 (a) chemical compound (0.261g, 1.0mmol), 2-(amino methyl) benzimidazole (0.256g, 1.0mmol), EDC (0.191g, 1.0mmol), I-hydroxybenzotriazole hydrate (0.152g, 1.0mmol) and triethylamine (0.234ml, 2.1mmol) solution stirring in DMF (5ml) is 8 hours.This solution becomes oil through rotary evaporation.Residue gets target compound through silica gel column chromatography.
With the crude product esteramides (0.32g, 1.0mmol) and the solution stirring of trifluoroacetic acid (5ml) in dichloromethane (5ml) 1 hour.This solution rotating is flashed to oil.Residue Et 2O handles.Filtering also, vacuum drying promptly gets target compound.
Embodiment 78
2-[6-((benzimidazolyl-2 radicals-yl) methylamino carbonyl) tetrahydronaphthalene] preparation of acetic acid
A) 5-hydroxyl-tetrahydronaphthalene-2-ethyl acetate
(EP 0635492, flow process 6 and embodiment 20, A-D part, method P71), preparation chemical compound ethyl-5-hydroxyl-tetrahydronaphthalene-2-acetic acid according to M.J.Fisher etc.
B) 5-trifluoromethyl sulfonyloxy-tetrahydronaphthalene-2-ethyl acetate
(0.321g is 1.0mmol) in CH with embodiment 78 (b) chemical compound 2Cl 2Solution (10ml) is cooled to 0 ℃.The adding trifluoromethanesulfanhydride anhydride (0.125ml, 1.1mmol).With above-mentioned solution stirring 2 hours.Solution rotating is flashed to oil.Residue is dissolved in EtOAc.Water (1X), 5%NaHCO 3, water (1X) washing EtOAc.With the dry EtOAc of MgSO4, filter.The filtrate rotary evaporation is promptly got target compound.
C) 6-carboxyl-tetrahydronaphthalene-2-ethyl acetate
Under the carbon monoxide environment, with embodiment 78 (c) chemical compound (0.26g, 1.0mmol), palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.245ml, 2.1mmol), the solution stirring of NMP (10ml) in ammonium carbonate (10%) aqueous solution 8 hours.This solution rotating is flashed to oil.Residue promptly gets target compound through the silica gel column chromatography purification.
D) [6-((benzimidazolyl-2 radicals-yl) methylamino carbonyl)-tetrahydronaphthalene-ethyl acetate
With embodiment 78 (c) chemical compound (0.34g, 1.0mmol), (2-benzimidazolyl) acetic acid compound (0.32g, 1.0mmol), EDC (0.191g, 1.0mmol), HOBtH 2O (0.152g, 1.0mmol) and triethylamine (0.23ml, 2.1mmol) solution stirring in DMF (6ml) is 8 hours.Above-mentioned solution rotating is flashed to oil.Residue gets target compound through the silica gel column chromatography purification.
Selectable, with embodiment 78 (b) chemical compound (0.34g, 1.0mmol), palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.1mmol), (0.32g, 1.0mmol) solution in ammonium carbonate solution (10%) stirred 8 hours under the carbon monoxide environment for NMP (10ml) and intermediate A chemical compound.Above-mentioned solution rotating is flashed to oil.Residue gets target compound through silica gel column chromatography.
E) 2-[6-((benzimidazolyl-2 radicals-yl) methylamino carbonyl)-tetrahydronaphthalene-2-acetic acid
With embodiment 78 (d) chemical compound (0.31g, 1.0mmol) in the 1N sodium hydrate aqueous solution (1.5ml, 1.5mmol) and the solution stirring in the ethanol (5ml) 8 hours.This solution rotating is flashed to grease.Residue obtains target compound through silica gel column chromatography.
Embodiment 79
2-[5-((benzimidazolyl-2 radicals-yl) methyl carbonylamino)-benzofuran]-preparation of propanoic acid
A) ethyl 1-carboxyl methoxyl group-4-nitrosalicylaldehyde
With 1-hydroxyl-4-nitrosalicylaldehyde (Aldrich) (0.167g, 1.0mmol), bromoethyl acetate (0.166g, 1.0mmol), potassium carbonate (0.276g, 2.0mmol) and sodium iodide (0.015g, 0.1mmol) solution in THF (10ml) is heated to 80 ℃ and kept 24 hours.Above-mentioned solution rotating is flashed to grease, and residue obtains target compound through silica gel column chromatography.
B) ethyl 2-carboxyl-5-nitrobenzofuran
With embodiment 79 (a) chemical compound (0.229g, 1.0mmol), (0.152g, 1.0mmol) solution in ethanol (10ml) at room temperature stirred 18 hours DBU.Above-mentioned solution rotating is flashed to grease, handle this residue with EtOH (10ml).In solution, be blown into HCl gas 2 minutes, refluxed 5 hours.Above-mentioned solution rotating is flashed to grease.Add EtOAc and water (2X), 5% citric acid (2X), water (1X), 5%NaHCO 3(2X) and water (1X) washing.The EtOAc rotary evaporation is obtained target compound.
C) ethyl 2-(2-carboxyl) ethylidene-5-nitrobenzofuran
With DiBAL (1.0M in THF, 1.0ml, 1.0mmol) Processing Example 79 (b) chemical compound (0.235g, 1.0mmol) cold soln in THF (5ml) (78 ℃).Above-mentioned solution in-78 ℃ of stirrings 30 minutes, was stirred 3 hours down in RT.With this solution CH 3COOH (3ml) handles, and water (2ml) is handled then.This solution rotating is flashed to grease and removes acetic acid with the methylbenzene azeotropic processing.Drying obtains crude product aldehyde in the vacuum.
((0.224g, 1.0mmol) solution in THF (5ml) is 1 hour 1.0mmol) to handle phosphonate ester for 60% suspension in mineral oil, 0.04g with sodium hydride at 0 ℃.(0.235g 1.0mmol) is added in this solution with above-mentioned aldehyde.Under room temperature, stirred this solution 18 hours.Solution rotating is flashed to grease, obtain target compound through this residue of silica gel column chromatography purification.
D) 2-[5-amino-benzofuranyl] the propanoic acid tert-butyl ester
(0.261g, 1.0mmol) (0.026g, ethanol 10%wt) (5ml) solution was in 45psi hydrogenation 1 hour in containing the palladium charcoal with embodiment 79 (c) chemical compound.This solution is become grease by diatomite filtration and with the filtrate rotary evaporation.Obtain target compound through silica gel column chromatography.
E) 2-[5-((the methyl carbonylamino-benzofuran of benzimidazolyl-2 radicals-yl)]-propanoic acid
With embodiment 79 (d) chemical compound (0.263g, 1.0mmol), EDC (0.191g, 1.0mmol), I-hydroxybenzotriazole hydrate (0.150g, 1.0mmol), 2-(amino methyl) benzimidazole compound (0.234g, 1.0mmol) and triethylamine (0.288ml, 2.0mmol) solution stirring in DMF (5.0ml) is 18 hours.Above-mentioned solution is become grease and this residue is got target compound through silica gel column chromatography through rotary evaporation.
With the crude product ester (0.263g, 1.0mmol) solution in MeOH (3.0ml) with 1NNaOH (1.5ml, 1.5mmol) and water (2ml) processing.Above-mentioned solution was stirred 18 hours under RT.This solution rotating is flashed to grease and promptly gets target compound with the reversed phase chromatography purification.
Embodiment 80
2-[5-((benzimidazolyl-2 radicals-yl) methyl carbonylamino)-2,3-dihydro-benzofuran]-preparation of propanoic acid
A) 2-[5-amino-2,3-dihydro-benzofuranyl] ethyl propionate
In the chromatography purification of embodiment 79 (d) chemical compound, also can obtain target compound.
B) 2-[5-(6-aminopyridine base-2-methyl carbonylamino)-benzofuran]-propanoic acid
With embodiment 80 (a) chemical compound (0.263g, 1.0mmol), EDC (0.191g, 1.0mmol), I-hydroxybenzotriazole hydrate (0.15g, 1.0mmol), 2-(amino methyl) benzimidazole compound (0.32g, 1.0mmol) and triethylamine (0.288ml, 2.0mmol) solution stirring in DMF (5.0ml) is 18 hours.Above-mentioned solution is become grease and this residue is got target compound through silica gel column chromatography through rotary evaporation.
(0.290g, 1.0mmol) (1.2ml 1.2mmol) handled 18 hours the solution in MeOH (5.0ml) with 1NNaOH with the crude product ester.Above-mentioned solution was stirred 18 hours under RT.This solution rotating is flashed to grease and promptly gets target compound with the reversed phase chromatography purification.
Embodiment 81
2-[5-(6-aminopyridine base-2-methylamino carbonyl)-benzofuran]-preparation of propanoic acid
A) 2-ethoxy carbonyl-5-(tert-butyl group-dimethyl silane oxygen base)-benzofuran
2-ethoxy carbonyl-5-(hydroxyl)-benzofuran (is equaled EP0655439 by M.L.Denny, 31,5, flow preparation described in 95) (0.206g, 1.0mmol), the tert-butyl group-dimetylsilyl chlorine (0.23ml, 1.0mmol) and imidazoles (0.34g, 1.0mmol) solution stirring in THF is 4 hours.Above-mentioned solution rotating is flashed to grease.Adding EtOAc also washes with water.The EtOAc rotary evaporation is promptly got target compound.
B) 2-hydrogen carbonyl-5-(t-butyldimethylsilyloxy base)-benzofuran
With DiBAL (1.0M in THF, 1.0ml, 1.0mmol) Processing Example 81 (a) chemical compound (0.35g, 1.0mmol) cold (78 ℃) solution in THF (5ml).Above-mentioned solution in-78 ℃ of stirrings 30 minutes, was stirred 3 hours down in RT.With this solution CH 3COOH (3ml) handles, and water (2ml) is handled then.Above-mentioned solution rotating is flashed to grease and removes acetic acid with the methylbenzene azeotropic processing.Drying obtains target compound in vacuum.
C) 2-[5-(tert-butyl group-dimethyl silane oxygen base)-benzofuran]-ethyl acrylate
(0.224g, 1.0mmol) (60% suspension in mineral oil, 0.04g 1.0mmol) handled 1 hour in 0 ℃ the solution in THF (5ml) with sodium hydride with the phosphine ester.(0.235g 1.0mmol) is added in the above-mentioned solution with above-mentioned aldehyde.This solution was stirred 18 hours in RT.Above-mentioned solution rotating is flashed to grease, this residue is obtained target compound through the silica gel column chromatography purification.
D) 2-[-5-(hydroxyl)-benzofuran]-propanoic acid-2-ethyl ester
With embodiment 81 (c) chemical compound (0.234g, 1.0mmol) and 10% palladium charcoal (0.023g, the 10%wt) hydrogenation 1 hour under 50psi of the mixture in EtOH (5ml).Obtain above-mentioned ester (0.169g, 56%) by diatomite filtration and through concentrating.
(0.34g, (0.140g, 1.0mmol) solution in THF (10ml) stirred 18 hours in RT the tetraethyl ammonium of fluoridizing 1.0mmol) with above-mentioned crude product.Above-mentioned solution rotating flashed to grease and through the silica gel column chromatography purification.
E) 2-[-5-(trifluoromethyl sulfonyloxy)-benzofuran]-propanoic acid-2-ethyl ester
With trifluoromethyl sulfonic acid anhydride (0.21ml, 1.1mmol) in 0 ℃ of Processing Example 81 (d) chemical compound (0.366g, 1.0mmol) and Et 3(0.23ml is 1.5mmol) in CH for N 2Cl 2Solution (10ml).After 2 hours above-mentioned solution rotating is flashed to grease.Residue is dissolved in EtOAc.Water (1X), 5%NaHCO in order 3(2x), water (1X) washing EtOAc.With EtOAc through MgSO 4Dry also filtration.The filtrate rotary evaporation is promptly got target compound.
F) 2-[5-(carboxyl)-benzofuran]-propanoic acid-2-ethyl ester
With embodiment 81 (e) chemical compound (0.366g, 1.0mmol), palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.1mmol), NMP (7ml) in sodium bicarbonate aqueous solution (10%, the 6ml) solution stirring in.This solution rotating is flashed to grease.Residue promptly gets target compound through the silica gel column chromatography purification.
G) 2-[5-(6-(6-aminopyridine base-2-methylamino carbonyl) benzofuran]-propanoic acid-2-ethyl ester
With embodiment 81 (f) chemical compound (0.366g, 1.0mmol), (2-benzimidazolyl) acetic acid compound (0.23g, 1.0mmol), EDC (0.191g, 1.0mmol), HOBt (0.152g, 1.0mmol) and triethylamine (0.235g, 2.1mmol) solution stirring in DMF (8ml) is 8 hours.This solution rotating is flashed to grease.Residue obtains target compound through silica gel column chromatography.
Selectable, with embodiment 81 (e) chemical compound (0.366g, 1.0mmol), palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.1mmol), (0.32g, 1.0mmol) (10%, 10ml) solution in stirred 8 hours under the carbon monoxide environment in ammonium carbonate solution for NMP (10ml) and intermediate A chemical compound.Above-mentioned solution rotating is flashed to grease.Residue gets target compound through silica gel column chromatography.
H) 2-[5-(6-(6-aminopyridine base-2-methylamino carbonyl)-benzofuran]-propanoic acid
(0.366g, 1.00mmol) solution stirring in 1N NaOH aqueous solution (1.5ml.1.5mmol) and ethanol (8ml) is 8 hours with embodiment 81 (g) chemical compound.Above-mentioned solution rotating is flashed to grease.Residue is through silica gel column chromatography place target compound.
Embodiment 82
2-[5-((benzimidazolyl-2 radicals-yl) methylamino carbonyl)-2,3-dihydro-benzofuran]-preparation of propanoic acid
A) 2-[5-(hydroxyl)-2,3-dihydro-benzofuran]-propanoic acid-2-tert-butyl ester
Chromatography purification also obtains this target compound among the embodiment 81 (d).
B) 2-[5-(trichloromethyl sulfonyloxy)-2,3-dihydro-benzofuran]-propanoic acid-2-tert-butyl ester
With embodiment 82 (a) chemical compound (0.28g, 1.0mmol) and Et 3(0.23ml is 2.1mmol) in CH for N 2Cl 2(0.15ml 1.1mmol) handled 2 hours cold soln (5ml) with trifluoromethyl sulfonic acid anhydride.Above-mentioned solution rotating is flashed to grease.Residue is dissolved in EtOAc.Water (1X), 5%NaHCO 3(2X), water (1X) washing EtOAc is through MgSO 4Drying is filtered, and filtrate obtains target compound through rotary evaporation.
C) 2-[5-(carboxyl)-2,3-dihydro-benzofuran]-propanoic acid-2-tert-butyl ester
With embodiment 82 (b) chemical compound (0.24g, 1.0mmol),, palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.1mmol), the solution of NMP (8ml) in sodium bicarbonate aqueous solution (10ml, 10%) stirred 8 hours down in RT.Above-mentioned solution rotating is flashed to grease.Residue gets target compound through silica gel column chromatography.
D) 2-[5-(6-(6-aminopyridine base-2-methylamino carbonyl)-2,3-Dihydrobenzofuranes]-propanoic acid-2-tert-butyl ester
With embodiment 82 (c) chemical compound (0.366g, 1.0mmol), (2-benzimidazolyl) acetic acid compound (0.23g, 1.0mmol), EDC (0.191g, 1.0mmol), HOBt (0.152g, 1.0mmol) and triethylamine (0.23g, 2.1mmol) solution stirring in DMF (8ml) is 8 hours.This solution rotating is flashed to grease.Residue obtains target compound through silica gel column chromatography.
Selectable, with embodiment 82 (b) chemical compound (0.366g, 1.0mmol), palladium diacetate (II) (0.023g, 0.1mmol), triphenylphosphine (0.262g, 1.0mmol), diisopropylamine (0.23ml, 2.1mmol), (0.23g, 2.1mmol) (10%, 10ml) solution in stirred 8 hours under the carbon monoxide environment in ammonium carbonate solution for NMP (10ml) and intermediate A chemical compound.Above-mentioned solution rotating is flashed to grease.Residue gets target compound through silica gel column chromatography.
E) 2-[5-(6-(and benzimidazolyl-2 radicals-yl)-methylamino carbonyl]-2,3-dihydro-benzofuran]-propanoic acid
(0.37g, 1.0mmol) (1.5ml, 1.5mmol) solution stirring in aqueous solution and the ethanol (8ml) is 8 hours in 1N NaOH with embodiment 82 (d) chemical compound.Above-mentioned solution rotating is flashed to grease.Residue is through silica gel column chromatography place target compound.
Embodiment 83
The methyl of 1-[(1H-benzimidazolyl-2 radicals-yl)]-the 3-{4-[(2-ethoxy carbonyl) ethyl] phenyl }-3-oxo-imidazolidine
A) 2-aminomethyl-1,2-ptoluene-sulfonyl-benzimidazole
With 2-tolimidazole (1mmol), p-toluenesulfonyl chloride (1.05mmol) and Et 3The solution stirring of N (1.05mmol) in water (2ml) and THF (1ml) 4 hours.Said mixture is concentrated and water (10ml) dilution by rotary evaporation.(2 * 15ml) wash above-mentioned solution with EtOAc.Merge organic layer, water (5ml) washs and obtains grease through rotary evaporation.
With the top grease of mentioning (2-methyl isophthalic acid-ptoluene-sulfonyl-benzimidazole) (1mmol) and N-bromosuccinimide (1.05mmol) in CCl 4Solution (10ml) refluxed 18 hours.A kind of white solid is precipitated out from above-mentioned solution when cooling.With above-mentioned solid filtering, use CCl 4Grind and under vacuum drying obtain a kind of solid.
With Boc 2NH (1mmol) and the solution stirring of potassium hydroxide (1mmol) in ethanol (5ml) 1 hour.Add absolute ether (15ml) and said mixture filtered the salt that obtains to white solid.With aforementioned solid 2-bromomethyl-1-ptoluene-sulfonyl benzimidazole (1mmol) and (Boc) 2N -K +(mmol) solution in THF (10ml) stirred 18 hours in 60 ℃.The mixture rotary evaporation is become a grease.
With 2-[two-(tert-butoxycarbonyl) amino methyl]-1-ptoluene-sulfonyl benzimidazole (1mmol) is in TFA (1.1mmol) and CH 2Cl 2In solution stirring 1 hour.Above-mentioned solution rotating is flashed to grease and obtains target compound through chromatography purification.
B) 2-[4-(2-hydroxyethyl amino) phenyl] ethyl propionate
Flow process (EP 0587134 for embodiment V, P44, Sept, 8,1993) according to F.Himmelsbach etc. prepares this chemical compound.Wherein glycolaldehyde dimer (Aldrich) (mmol) is added to 2-(4-aminophenyl) methyl propionate 1 (1mmol) in acetonitrile solution (pH6-7) solution (ml), adds sodium cyanoborohydride (1.1mmol) then and said mixture was stirred 1 hour.This mixture rotary evaporation is become grease.Residue is dissolved in the mixture of frozen water and ethyl acetate.With washing with water layer and with ethyl acetate among the 4NNaOH.Above-mentioned organic facies rotary evaporation is become grease.The solution of this grease in ethyl acetate promptly gets target compound through silica gel column chromatography.
C) methyl of N-[(1-ptoluene-sulfonyl-1H-benzimidazolyl-2 radicals-yl)]-N '-hydroxyethyl-N '-and the 4[(2-ethoxy carbonyl) ethyl] phenyl }-urea
(EP 0587134, Sept.8,1993 and EP0612741 according to the flow process of F.Himmelsbach etc., Feb, 21,1994) prepare this chemical compound, wherein the solution of embodiment 83 (a) chemical compound (1mmol) photoreactive gas (1.1mmol) in THF (20ml) was stirred 20 minutes in-20 ℃.Embodiment 83 (b) chemical compound (1.0mmol) is added in the above-mentioned solution and the gained mixture stirred and the gained solution rotating evaporated in 18 hours.With 5% citric acid, wash the solution of residue in ethyl acetate with water then.The organic facies rotary evaporation is become grease.The solution of this grease in ethyl acetate is obtained target compound through the silicagel column purification.
D) N 1-[(1-ptoluene-sulfonyl-1H-benzimidazolyl-2 radicals-yl) methyl]-N 3-the 4[(2-ethoxy carbonyl) and ethyl] phenyl }-2-oxo-imidazolidine
Flow process (embodiment III according to F.Himmelsbach etc., EP 0587134, Sept, 8,1993 and EP 0612741, Feb, 21,1994) prepare this chemical compound, wherein embodiment 83 (c) chemical compound (1mmol), mesyl chloride (1.2mmol) and the solution of triethylamine (1.2mmol) in dichloromethane (5ml) were stirred 1 hour in 0 ℃.Said mixture is distributed in the mixture of water and dichloromethane.Merge organic layer and through anhydrous sodium sulfate drying and rotary evaporation.
Vlil in acetone (5ml) is 3 hours with above-mentioned residue and sodium iodide (1.1mmol).And rotary evaporation becomes grease.Two (trimethyl silyl) potassium azide (1.2mmol) are added to above-mentioned residue in the solution of DMF (5ml), are cooled to 0 ℃.With 30 minutes this solution is warmed to room temperature, rotary evaporation becomes grease.Residue is distributed in the mixture of water and dichloromethane.Merge organic facies and through anhydrous sodium sulfate drying, rotary evaporation.The solution of grease in ethyl acetate obtains target compound through the silicagel column purification.
E) N 1-[(1H-benzimidazolyl-2 radicals-yl) methyl]-N 3-the 4-[(2-carboxyl) and ethyl] phenyl }-2-oxo-imidazolidine
(1.2ml, 1.2mmol) solution stirring in is 18 hours in THF (5ml) and 1N NaOH with embodiment 83 (d) chemical compound (1mmol).With obtaining target compound with said mixture and through the silicagel column purification in the concentrated hydrochloric acid.
Embodiment 84 non-intestinal type unit composition
The formulation preparation of the chemical compound 20mg of a kind of embodiment 1 that contains promising sterilization dry powder is as follows: the 20mg chemical compound is dissolved in the 15ml distilled water.The multiple dose that above-mentioned solution is filled into 25ml under aseptic condition is pacified in the bottle and lyophilization.Duplicate and be used for vein or intramuscular injection by adding the 5% glucose powder of 20ml in water (D5W).Therefore determine dosage according to volume injected.Be added to the dilution of finishing among the D5W of another volume subsequently by quantitative volume and be used for injection, or be added to quantitative dosage in another device as be used to disperse this medicine to instil in bottle or the bag or other defeated-injection body system for use in IV with this dosage unit.
Embodiment 85 peroral dosage form unit composition
Prepare the capsule that is used for oral administration by mixing and grinding 50ml embodiment 1 chemical compound with 75mg lactose and 5mg magnesium stearate.Above gained powder is sieved and be filled in the hard capsule.
Embodiment 86 peroral dosage form unit composition
By being mixed with 10% gelatin solution and granulate, 20mg sucrose, 150mg calcium sulphate dihydrate and 50mg embodiment 1 chemical compound prepare the tablet that is used for oral administration.Wet granular is sieved, dry mixes with 10mg starch, 5mg Pulvis Talci and 3mg stearic acid; Be pressed into tablet.
Above the description full disclosure how to prepare and use the present invention.Then, the present invention is not limited only to embodiment described above here, but comprises its all modification in the following claim scope.Here the various lists of references of being quoted to magazine, patent and other publication have comprised the present situation of this area and have here introduced and do further reference.

Claims (52)

1. the chemical compound of formula I or (II) or (III) or (IV) or (V) or its pharmaceutically acceptable salt: Or
Figure A9618011300022
Or
Figure A9618011300023
Or
Figure A9618011300024
Or
Figure A9618011300025
Wherein:
W is-(CHR g) b-V '-or phenyl;
A is the fibrinogen deceptor antagonists template;
V ' is CONR 21Or NR 21CO;
G is NR e, S or O;
R gBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl or Ar-C 0-6Alkyl;
R 21Be Het-(CH 2) 0-6-U '-(CH 2) 1-6-, C 3-7Cycloalkyl-(CH 2) 0-6-U '-(CH 2) 1-6-or Ar-(CH 2) 0-6-U '-(CH 2) 1-6-;
U ' is CONR fOr NR fCO;
R fBe H, C 1-6Alkyl or Ar-C 1-6Alkyl;
R eBe H, C 1-6Alkyl, Ar-C 1-6Alkyl, Het-C 1-6Alkyl, C 3-7Cycloalkyl-C 1-6Alkyl, (CH 2) qOH or (CH 2) kCO 2R g
K is 0,1 or 2;
Q is 1 or 2;
B is 0,1 or 2;
R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2Or R bAnd R cIn conjunction with forming 5 yuan or 6 yuan of fragrance or non-aromatic carbocyclic or heterocycle, optionally be selected from halogen, CF by 3 of as many as 3, C 1-4Alkyl, OR f, S (O) kR f, COR f, CO 2R fOH, NO 2, N (R f) 2, CO (NR f) 2And CH 2N (R f) 2Or the substituent group of methylene-dioxy replaces.
2. the chemical compound of claim 1, wherein said fibrinogen deceptor antagonists template A is following formula or its pharmaceutically acceptable salt:
Figure A9618011300031
A 1To A 5Form 7 yuan of rings of come-at-able replacement, described ring can be saturated or unsaturation, optional 2 hetero atoms that are selected from O, S and N of as many as that contain, and wherein S and N are optional oxidized;
D 1To D 4Form 6 yuan of rings of come-at-able replacement, can choose wantonly and contain 2 nitrogen-atoms of as many as;
R is at least one and is selected from R 7, Q-C 1-4Alkyl, Q-C 2-4Alkenyl, Q-C 2-4The substituent group of alkynyl, optional by one or more=O, R 11Or R 7Replace;
R *Be H, Q-C 1-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 3-4Oxo alkenyl, Q-C 3-4Oxo alkynyl, Q-C 2-4Alkynyl, C 3-6Cycloalkyl, Ar or Het, optional by one or more R 11Replace;
Q is H, C 3-6Cycloalkyl, Het or Ar;
R 7For-COR 8,-COCR ' 2R 9,-C (S) R 8,-S (O) mOR ' ,-S (O) mNR ' R " ,-PO (OR ') ,-PO (OR) ' 2,-B (OR ') 2,-NO 2And Tet;
R 8For-OR ' ,-NR ' R " ,-NR ' SO 2R ' ,-NR ' OR ' ,-OCR ' 2C (O) OR ' ,-OCR ' 2OC (O)-R ' ,-OCR ' 2C (O) NR ' 2, CF 3Or AA;
R 9For-OR ' ,-CN ,-S (O) rR ', S (O) mNR 2' ,-C (O) R ' C (O) NR ' 2Or-CO 2R ';
R 11For H, halogen ,-OR 12,-CN ,-NR ' R 12,-NO 2,-CF 3, CF 3S (O) r-,-CO 2R ' ,-CONR ' 2, Q-C 0-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 2-6Alkynyl, Q-C 0-6Alkoxyl-, Q-C 0-6Alkyl amino or Q-C 0-6Alkyl-S (O) r-;
R 12For R ' ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR 15,-S (O) mR ' or S (O) mNR ' 2
R 13For R ' ,-CF 3,-SR ' or-OR ';
R 14For R ' ,-C (O) R ', CN, NO 2, SO 2R ' or C (O) OR 15
R 15Be H, C 1-6Alkyl or Ar-C 0-4Alkyl;
R ' is H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R " be R ' ,-C (O) R ' or-C (O) OR 15
R " ' be R " or AA2;
AA1 is the aminoacid by its amino connection, and its carboxyl is optional protected, the aminoacid of AA2 for connecting by its carboxyl, and its amino is optional protected;
M is 1 or 2;
N is 0 to 3;
P is 0 or 1; With
T is 0 to 2.
3. the chemical compound of claim 2, wherein
A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S (O) x
A 2Be CR 2R 2 ', CR 2, NR 2
A 3Be CR 3R 3 ', CR 3, NR 3, N, O or S (O) x
A 4Be CR 4R 4 ', CR 4, NR 4, N;
A 5Be CR 5R 5 ', CR 5, NR 5, N, O or S (O) x
D 1-D 4Be CH or N;
R 1And R 1 'Be R *Or R, or be=O together;
R 2And R 2 'Be R *, R or be=O;
R 3And R 3 'Be R *, R or be=O;
R 4And R 4 'Be R *, R or be=O;
R 5And R 5 'Be R *, R or be=O;
X is 0,1 or 2.
4. the chemical compound of claim 2, wherein A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S; A 2Be CR 2R 2 ', NR 2Or CR 2A 3Be CR 3R 3 'A 4Be CR 4R 4 ', CR 4, NR 4Or N; A 5Be CR 5R 5 ', CR 5, NR 5, N or O; D 1And D 4Be CH; D 2Or D 3Be CH 6R 2Or R 4Be R; R 3, R 3 'And R 5, R 5 'For=O or R *, H.
5. the chemical compound of claim 2, wherein
A 1Be CHR 1 ', CR 1, NR ", N or S; A 2Be CR 2Or CR 2R 2 'A 3Be CR 3R 3 'A 4Be CR 4R 4 'Or NR 4A 5Be CR 5R 5 'D 1-D 4Be CH.
6. the chemical compound of claim 2, wherein
A 1Be CR 1, A 2Be CR 2, A 3Be C=O, A 4Be NR 4And A 5Be CHR 5
7. the chemical compound of claim 2, wherein
A 1Be NR 1, A 2Be CHCR 2, A 3Be CR 3R 3 ', A 4Be NR 4And A 5Be C=O.
8. the chemical compound of claim 2, wherein
A 1And A 4Be C=O, A 2Be NR 2, A 3Be CHR 3 ', and A 5Be NR 5
9. the chemical compound of claim 2, wherein
A 1Be NR 1, A 2Be CHR 2, A 3Be C=O, A 4Be NR ', and A 5Be CHR 5
10. the chemical compound of claim 2, for:
Figure A9618011300061
11. the chemical compound of claim 2, for
Figure A9618011300062
12. the chemical compound of claim 11, wherein:
R 1Be H or C 1-4Alkyl; R 2, R 2 'For H ,-CH 2CO 2H; R 5R 5 'Be H, H.
13. formula (X XI) or (X XII) chemical compound or its pharmaceutically acceptable salt:
Figure A9618011300071
Or
Figure A9618011300072
Wherein:
B is-(CHR g) a-U-(CHR g) b-V-or phenyl or
Figure A9618011300073
A is the fibrinogen deceptor antagonists template; U and V do not exist or are CO, CR g 2, C (=CR g 2), S (O) k, O, NR g, CR gOR g, CR g(OR k) CR g 2, CR g 2CR g(OR k), C (O) CR g 2, CR g 2C (O), CONR iNR iCOOC (O), C (O) O, C (S) O, OC (S), C (S) NR g, NR gC (S), S (O) 2NR g, NR gS (O) 2, N=N, NR gNR g, NR gCR g 2, NR gCR g 2, CR g 2O, OCR g 2, C ≡ C or CR g=CR gG is NR e, S or O; R gBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl or Ar-C 0-6Alkyl; R kBe R g,-C (O) R gOr-C (O) OR fR iBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl, Het-(CH 2) 0-6-U '-(CH 2) 1-6-, C 3-7Cycloalkyl-(CH 2) 0-6-U '-(CH 2) 1-6-or Ar-(CH 2) 0-6-U '-(CH 2) 1-6-or be selected from halogen, CN, NR by one to three g 2, OR g, SR g, CO 2R g, CON (R g) 2The C that replaces 1-6Alkyl; R fBe H, C 1-6Alkyl or Ar-C 1-6Alkyl; R eBe H, C 1-6Alkyl, Ar-C 1-6Alkyl, Het-C 1-6Alkyl, C 3-7Cycloalkyl-C 1-6Alkyl, (CH 2) qOH or (CH 2) kCO 2R gU ' is CONR fOr NR fCO; K is 0,1 or 2; Q is 1 or 2; A is 0,1 or 2; B is 0,1 or 2; R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2Or R bAnd R cIn conjunction with forming 5 yuan or 6 yuan of fragrance or non-aromatic carbocyclic or heterocycle, optionally be selected from halogen, CF by 3 of as many as 3, C 1-4Alkyl, OR f, S (O) kR f, COR f, CO 2R fOH, NO 2, N (R f) 2, CO (NR f) 2And CH 2N (R f) 2Or the substituent group of methylene-dioxy replaces.
14. the chemical compound of claim 13, wherein said fibrinogen deceptor antagonists template A is following formula or its pharmaceutically acceptable salt:
Figure A9618011300081
Wherein:
A 1To A 5Form 7 yuan of rings of come-at-able replacement, described ring can be saturated or unsaturation, can choose wantonly and contain 2 hetero atoms that are selected from O, S and N of as many as, and wherein S and N can choose wantonly oxidized;
D 1To D 4Form 6 yuan of rings of come-at-able replacement, optional 2 nitrogen-atoms of as many as that contain;
R is at least one and is selected from R 7, Q-C 1-4Alkyl, Q-C 2-4Alkenyl, Q-C 2-4The substituent group of alkynyl, optional by one or more=O, R 11Or R 7Replace;
R *Be H, Q-C 1-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 3-4Oxo alkenyl, Q-C 3-4Oxo alkynyl, Q-C 2-4Alkynyl, C 3-6Cycloalkyl, Ar or Het can choose wantonly by one or more R 11Replace;
Q is H, C 3-6Cycloalkyl, Het or Ar;
R 7For-COR 8,-COCR ' 2R 9,-C (S) R 8,-S (O) mOR ' ,-S (O) mNR ' R " ,-PO (OR ') ,-PO (OR) ' 2,-B (OR ') 2,-NO 2And Tet;
R 8For-OR ' ,-NR ' R " ,-NR ' SO 2R ' ,-NR ' OR ' ,-OCR ' 2C (O) OR ' ,-OCR ' 2OC (O)-R ' ,-OCR ' 2C (O) NR ' 2, CF 3Or AA;
R 9For-OR ' ,-CN ,-S (O) rR ', S (O) mNR ' ,-C (O) R ' C (O) NR ' 2Or-CO 2R ';
R 11For H, halogen ,-OR 12,-CN ,-NR ' R 12,-NO 2,-CF 3, CF 3S (O) r-,-CO 2R ' ,-CONR ' 2, Q-C 1-6Alkyl, Q-C 1-6Oxoalkyl group, Q-C 2-6Alkenyl, Q-C 2-6Alkynyl, Q-C 0-6Alkoxyl, Q-C 1-6Alkyl amino or Q-C 0-6Alkyl-S (O) r-;
R 12For R ' ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR 15,-S (O) mR ' 2Or S (O) mNR ' 2
R 13For R ' ,-CF 3,-SR ' or-OR ';
R 14For R ' ,-C (O) R ', CN, NO 2, SO 2R ' or C (O) OR 15
R 15Be H, C 1-6Alkyl or Ar-C 0-4Alkyl;
R ' is H, C 1-6Alkyl, C 3-7Cycloalkyl-C 0-4Alkyl or Ar-C 0-4Alkyl;
R " be R ' ,-C (O) R ' or-C (O) OR 15
R " ' be R " or AA2;
AA1 is the aminoacid by its amino connection, and its carboxyl is optional protected, the aminoacid of AA2 for connecting by its carboxyl, and its amino is optional protected;
M is 1 or 2;
N is 0 to 3;
P is 0 or 1; With
T is 0 to 2.
15. the chemical compound of claim 14, wherein
A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S (O) x
A 2Be CR 2R 2 ', CR 2, NR 2
A 3Be CR 3R 3 ', CR 3, NR 3, N, O or S (O) x
A 4Be CR 4R 4 ', CR 4, NR 4Or N;
A 5Be CR 5R 5 ', CR 5, NR 5, N, O or S (O) x
D 1-D 4Be CH or N;
R 1And R 1 'Be R *Or R, or be=O together;
R 2And R 2Be R *, R or be=O;
R 3And R 3Be R *, R or be=O;
R 4And R 4 'Be R *, R or be=O;
R 5And R 5Be R *, R or be=O;
X is 0,1 or 2.
16. the chemical compound of claim 14, wherein A 1Be CR 1R 1 ', CR 1, NR 1, N, O or S; A 2Be CR 2R 2 ', NR 2Or CR 2A 3Be CR 3R 3 'A 4Be CR 4R 4 ', CR 4, NR 4Or N; A 5Be CR 5R 5 ', CR 5, NR 5, N or O; D 1And D 4Be CH; D 2Or D 3Be CH 6R 2Or R 4Be R; R 3, R 3' and R 5, R 5 'For=O or R *, H.
17. the chemical compound of claim 14, wherein A 1Be CHR 1, CR 1, NR ", N or S; A 2Be CR 2Or CR 2R 2 'A 3Be CR 3R 3 'A 4Be CR 4R 4 'Or NR 4A 5Be CR 5R 5 'D 1-D 4Be CH.
18. the chemical compound of claim 14, wherein A 1Be CR 1, A 2Be CR 2, A 3Be C=O, A 4Be NR 4And A 5Be CHR 5
19. the chemical compound of claim 14, wherein A 1Be NR 1, A 2Be CHCR 2, A 3Be CR 3R 3 ', A 4Be NR 4And A 5Be C=O.
20. the chemical compound of claim 14, wherein
A 1And A 4Be C=O, A 2Be NR 2, A 3Be CHR 3 ', and A 5Be NR 5
21. the chemical compound of claim 14, wherein A 1Be NR 1, A 2Be CHR 2, A 3Be C=O, A 4Be NR ' and A 5Be CHR 5
22. the chemical compound of claim 14, for:
Figure A9618011300111
23. the chemical compound of claim 14, for
Figure A9618011300112
24. the chemical compound of claim 23, wherein:
R 1Be H or C 1-4Alkyl; R 2, R 2 'For H ,-CH 2CO 2H; R 5R 5 'Be H, H.
25. be selected from following chemical compound or its pharmaceutically acceptable salt:
The methyl of 5-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-1H-benzimidazolyl-2 radicals-glycine;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(5-trifluoro methyl benzimidazole-2-yl) methyl] methylamino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4,7-dimethoxy benzo imidazoles-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-tolimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[N-(methyl-N-(2-cyano methyl) amino of benzimidazolyl-2 radicals-yl)] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(4-phthalimido butyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
4-[[[3-(propyl group of benzimidazolyl-2 radicals-yl)] amino] carbonyl] piperidines-1-acetic acid;
4-[[[3-(propyl group of benzimidazolyl-2 radicals-yl)] amino] carbonyl] phenylacetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5,7-dimethylbenzimidazole-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-[2-(3, the 4-methylenedioxyphenyl) ethyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-acetamide;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[[1-[(benzimidazolyl-2 radicals-yl)] benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine benzimidazole-2-yl) methyl] methylamino] carbonyl]-4-(3, the 3-dimethylbutyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[2-(acetyl group of benzimidazolyl-2 radicals-yl)] amino]-5-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(5, the methyl of 6-difluoro benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[two [(benzimidazolyl-2 radicals-yl) methyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-4-methyl-7-[[[(4-nitrobenzimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-4-(2,2, the 2-trifluoroethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
The methyl of (±)-4-[4-[[[(1H-benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-the 3-phenylbutyric acid;
(±)-3-[[[4-(4-azepine benzimidazole-2-yl) bytyry] glycyl] amino]-the 4-valeric acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[[(1-(2-hydroxyethyl) benzimidazolyl-2 radicals-yl] methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-(2-methoxy ethyl)-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the amino benzimidazole of 5-tetrahydrochysene-7-[[[(4--2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid, [(2,2-dimethyl-2-methoxyl group acetyl group) oxygen base] methyl ester;
2,3,4,5-tetrahydrochysene-7-[[[((1R)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
(±)-N-[2-(amino methyl)-4-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl] phenyl] aspartic acid;
(±)-2,3,4, the luxuriant and rich with fragrance imidazoles of 5-tetrahydrochysene-4-methyl-3-oxo-7-[[[(-2-yl) methyl] amino] carbonyl]-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[3-(phenyl of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
The methyl of (±)-4-[4-[[[(benzimidazolyl-2 radicals-yl)] methylamino] carbonyl] phenyl]-3-(dimethylamino carbonyl) butanoic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-[2-(pyridin-3-yl) ethyl]-1H-1, the 4-benzodiazepine _-the 2-acetas;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] methylamino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(2-carboxylbenzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-2-hydroxy benzoyl) amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-the 2-ethyl acetate;
2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[[(±) the biotin acyl group] amino] butyl] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-(2RS)-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(imidazo (1,2a) pyridine-2-yl) methyl] methylamino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(S)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-5-[[2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-the 2-yl] methyl] tetrazolium;
(S)-2,3,4,5-tetrahydrochysene-7-[[[(4-azepine-5-tolimidazole-2-yl) methyl] amino] carbonyl]-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4,5-tetrahydrochysene-7-[3-(propyl group of benzimidazolyl-2 radicals-yl)]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-(the amino butyl of 4-) amino] carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[[(benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-(N-hydroxyl) acetamide;
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-pentinoic acid ethyl ester;
(±)-3-[[[2-(ethyl of benzimidazolyl-2 radicals-yl)] amino] succinyl group] amino-4-pentinoic acid;
(±)-2,3,4, the methyl of 5-tetrahydrochysene-7-[[N-[(benzimidazolyl-2 radicals-yl)]-N-[[4-(4-azido-3-iodo-2-hydroxy benzoyl) amino] butyl] amino carbonyl]-3-oxo-4-(2-phenylethyl)-1H-1, the 4-benzodiazepine _-2-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1S)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid;
2,3,4,5-tetrahydrochysene-7-[[[(1R)-(ethyl of benzimidazolyl-2 radicals-yl)] amino] carbonyl]-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-(2S)-acetic acid; With
(±)-7-[[[(4,5-dimethyl-1H-imidazoles-2-yl) methyl] methylamino] carbonyl]-2,3,4,5-tetrahydrochysene-4-methyl-3-oxo-1H-1, the 4-benzodiazepine _-2-acetic acid.
26. be selected from following chemical compound or its pharmaceutically acceptable salt:
3-[[3-[2-(ethyl of benzimidazolyl-2 radicals-yl)] isoxazoline-5 (R, S)-yl] acetyl group] amino-3 (R, S)-methylpropanoic acid;
3{3, the methyl of 4-dihydro-8-[[[((benzimidazolyl-2 radicals-yl)) methylamino] carbonyl]-1-methyl-2,5-dioxo 1H-1, the 4-benzodiazepine _-the 4-propanoic acid;
The methyl of 3-{4H-imidazoles [1,2a] [1,4] benzodiazepine _-5 (6H)-1-methyl-6-oxo-9-[[[(benzimidazolyl-2 radicals-yl)) methylamino] carbonyl]-the 4-propanoic acid;
4-[4-[2-(ethyl of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the 1-Piperidineacetic acid;
1-hydroxyl-4-[4-[3-(propyl group of 1H-benzimidazolyl-2 radicals-yl)]-the 1-piperazinyl]-the 1-Cyclohexaneacetic acid;
N-[3-[1-[[2-(2-benzimidazolyl) ethyl] carbonyl] piperidyl] carbonyl]-Beta-alanine;
The methyl of 2-[(benzimidazolyl-2 radicals-yl)]-5-[2-(carboxy ethyl) amino] carbonyl]-2,3-dihydro-3-oxo-1H-iso-indoles;
[3 (R)-[2-(ethyl of benzimidazolyl-2 radicals-yl)]-2-oxo-piperidine base] acetyl group-3 (R)-methyl-Beta-alanine;
4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group] phenoxyacetic acid;
4-[[[[2-(benzimidazolyl) methyl] carbonyl] methylamino] acetyl group]-1, the inferior benzene dioxy of 2-base oxalic acid;
The N-[3-[[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl]-Beta-alanine;
[[the 1-[N-[[(2-benzimidazolyl) methyl] carbonyl] tyrosyl-]-the 4-piperidyl] the oxygen base] acetic acid;
(S)-and the 4-[[[(2-benzimidazolyl) methyl] carbonyl] glycyl]-3-methoxycarbonyl methyl-2-oxo piperazine-1-acetic acid;
(3S, 5S)-the 5-[[4-[(2-benzimidazolyl) methyl] phenyl] the oxygen ylmethyl]-3-carboxyl N-methyl-2-2-pyrrolidone N-;
The 1-[(2-benzimidazolyl) methyl]-3-[4-(2-carboxy ethyl) phenyl]-4-methoxyl group-3-pyrroline-2-one;
2-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3, the 4-tetrahydro isoquinolyl] acetic acid;
2-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1-oxo-1,2,3, the 4-tetrahydro isoquinolyl] acetic acid;
2-[6-(benzimidazolyl-2 radicals-yl) methyl carbonylamino)-1,2,3, the 4-tetralyl] acetic acid;
2-[6-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-1,2,3, the 4-tetralyl] acetic acid;
2-[5-(benzimidazolyl-2 radicals-yl) methyl carbonylamino)-benzofuran] propanoic acid;
2-[5-(benzimidazolyl-2 radicals-yl) methyl carbonylamino)-2,3-dihydro-benzofuran] propanoic acid;
2-[5-(6-aminopyridine base-2-methylamino carbonyl)-benzofuran]-propanoic acid;
2-[5-(benzimidazolyl-2 radicals-yl) methylamino carbonyl)-2,3-dihydro-benzofuran]-propanoic acid; Or
The methyl of 1-[(1H-benzimidazolyl-2 radicals-yl)]-the 3-{4[(2-ethoxy carbonyl) ethyl] phenyl }-3-oxo-imidazolidine.
27. Pharmaceutical composition, it comprises any one the chemical compound in pharmaceutically acceptable carrier and the claim 1 to 26.
28. suppress the method for Vitronectic receptor in mammal, it comprises the formula I of the claim 1 that gives effective dose or the chemical compound of (II) or (III) or (IV) or (V).
29. the method for claim 28, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 10 times of fibrinogen deceptor Ki.
30. the method for claim 28, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 30 times of fibrinogen deceptor Ki.
31. the method for claim 28, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 100 times of fibrinogen deceptor Ki.
32. the treatment of claim 28 is the method for the disease that is absorbed as an inducement again of bone wherein.
33. the method for claim 28 treatment osteoporosis, inflammation, restenosis or atherosclerosis.
34. suppress the method for Vitronectic receptor in mammal, it comprises the chemical compound of the defined formula of the claim 13 that gives effective dose (X XI) or (X XII).
35. the method for claim 34, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 10 times of fibrinogen deceptor Ki.
36. the method for claim 34, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 30 times of fibrinogen deceptor Ki.
37. the method for claim 34, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 100 times of fibrinogen deceptor Ki.
38. the treatment of claim 34 is the method for the disease that is absorbed as an inducement again of bone wherein.
39. the method for claim 34 treatment osteoporosis, inflammation, restenosis or atherosclerosis.
40. suppress the method for Vitronectic receptor in mammal, it comprises the chemical compound of the claim 25 that gives effective dose.
41. the method for claim 40, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 10 times of fibrinogen deceptor Ki.
42. the method for claim 40, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 30 times of fibrinogen deceptor Ki.
43. the method for claim 40, wherein said chemical compound suppresses Vitronectic receptor, and its Ki that suppresses Vitronectic receptor is that described chemical compound suppresses more than 100 times of fibrinogen deceptor Ki.
44. the treatment of claim 40 is the disease method that is absorbed as an inducement again of bone wherein.
45. the method for treatment osteoporosis, inflammation, restenosis or the atherosclerosis of claim 40.
46. the application of the chemical compound of any one in the claim 1 to 26 in drug manufacture.
47. the chemical compound of any one in the claim 1 to 26 suppresses the application in the drug manufacture of Vitronectic receptor in the mammal of needs.
48. the chemical compound of any one in the claim 1 to 26 is application in the drug manufacture of disease of an inducement at the treatment bone resorption.
49. the application of the chemical compound of any one in the claim 1 to 26 in the drug manufacture of treatment osteoporosis, inflammation, restenosis or atherosclerosis.
50. prepare the method for formula I or (II) or (III) or (IV) or (V) chemical compound or its pharmaceutically acceptable salt:
Figure A9618011300201
Or or or
Figure A9618011300202
Or
Figure A9618011300205
Wherein:
W is-(CHR g) b-V '-or phenyl;
A is the fibrinogen deceptor antagonists template;
V ' is CONR 21Or NR 21CO;
G is NR e, S or O;
R gBe H, C 1-6Alkyl, Het-C 0-6Alkyl, C 3-7Cycloalkyl-C 0-6Alkyl or Ar-C 0-6Alkyl;
R 21Be Het-(CH 2) 0-6-U '-(CH 2) 1-6-, C 3-7Cycloalkyl-(CH 2) 0-6-U '-(CH 2) 1-6-or Ar-(CH 2) 0-6-U '-(CH 2) 1-6-;
U ' is CONR fOr NR fCO;
R fBe H, C 1-6Alkyl or Ar-C 1-6Alkyl;
R eBe H, C 1-6Alkyl, Ar-C 1-6Alkyl, Het-C 1-6Alkyl, C 3-7Cycloalkyl-C 1-6Alkyl, (CH 2) qOH or (CH 2) kCO 2R g
K is 0,1 or 2;
Q is 1 or 2;
B is 0,1 or 2;
R bAnd R cIndependently be selected from H, C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl or C 3-6Cycloalkyl-C 0-6Alkyl, halogen, CF 3, OR f, S (O) kR f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2N (R f) 2Or R bAnd R cIn conjunction with forming 5 yuan or 6 yuan of fragrance or non-aromatic carbocyclic or heterocycle, optionally be selected from halogen, CF by 3 of as many as 3, C 1-4Alkyl, OR f, S (O) kR f, COR f, CO 2R fOH, NO 2, N (R f) 2, CO (NR f) 2And CH 2N (R f) 2Or the replacement of the substituent group of methylene-dioxy, described method comprises:
(ⅰ) formula I chemical compound, make formula (a) chemical compound and formula (I b) chemical compound reaction of I:
Figure A9618011300211
L " A (I b) wherein:
R b, R c, R fDefined identical with above-mentioned formula I with A, its active functional group group is protected; With
L ' and L " be quilt-SnBu for being reflected at group or the L ' that W partly forms amido link 3The phenyl that replaces, L " be halogen;
After this remove any blocking group, the optional pharmaceutically acceptable salt that forms; Or
(ⅱ) formula II chemical compound, make formula (a) chemical compound and formula (I b) chemical compound reaction of II:
Figure A9618011300212
L " A (I-b) wherein:
R b, R c, G is defined identical with formula I with A, its active functional group group is protected; With
L ' and L " be quilt-SnBu for being reflected at group or the L ' that W partly forms amido link 3The phenyl that replaces, L " be halogen;
After this remove any blocking group, the optional pharmaceutically acceptable salt that forms; Or
(ⅲ) formula III chemical compound, make formula (a) chemical compound and formula (I b) chemical compound reaction of III:
Figure A9618011300221
L "-A (I b) wherein:
R b, R c, R eDefined identical with formula I with A, its active functional group group is protected; With
L ' and L " be quilt-SnBu for being reflected at group or the L ' that W partly forms amido link 3The phenyl that replaces, L " be halogen;
After this remove any blocking group, the optional pharmaceutically acceptable salt that forms; Or
(ⅳ) formula IV chemical compound, make formula (a) chemical compound and formula (I b) chemical compound reaction of IV:
Figure A9618011300222
L " A (I b) wherein:
R g, R eDefined identical with formula I with A, its active functional group group is protected; With
L ' and L " be quilt-SnBu for being reflected at group or the L ' that W partly forms amido link 3The phenyl that replaces, L " be halogen; After this remove any blocking group, the optional pharmaceutically acceptable salt that forms; Or (V) formula (V) chemical compound, make formula (a) chemical compound and formula (I b) chemical compound reaction of V:
L " A (I b) wherein:
R g, R e, defined identical with A with formula I, its active functional group group is protected; With
L ' and L " be quilt-SnBu for being reflected at group or the L ' that W partly forms amido link 3The phenyl that replaces, L " be halogen;
After this remove any blocking group, the optional pharmaceutically acceptable salt that forms.
51. the method for preparation formula (X XI) chemical compound:
Figure A9618011300232
Wherein A is defined identical with claim 13 with B, and described method comprises makes formula (XX V) chemical compound and the reaction of formula (XX VI) chemical compound:
Figure A9618011300233
L 4-A (XX VI) is wherein:
A is defined identical with claim 13, and its active function groups is protected; And L 3And L 4It is the group that forms covalent bond at the B partial reaction; After this remove the group and the optional pharmaceutically acceptable salt that forms of any protection.
52. the method for preparation formula (X XI) chemical compound:
Figure A9618011300241
Wherein A, B are defined identical with claim 13 with G, and described method comprises makes formula (XX VII) chemical compound and the reaction of formula (XX VIII) chemical compound: L 6-A (XX VIII) is wherein: A and G are with above-mentioned defined identical, and its active function groups is protected; And L 5And L 6It is the group that forms covalent bond at the B partial reaction; After this remove the group and the optional pharmaceutically acceptable salt that forms of any protection.
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