CN1370147A - Novel integrin alpha V\ beta3 inhibitors - Google Patents

Novel integrin alpha V\ beta3 inhibitors Download PDF

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CN1370147A
CN1370147A CN00811950A CN00811950A CN1370147A CN 1370147 A CN1370147 A CN 1370147A CN 00811950 A CN00811950 A CN 00811950A CN 00811950 A CN00811950 A CN 00811950A CN 1370147 A CN1370147 A CN 1370147A
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amino
base
phenyl
compound
medicament
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A·荣茨克
O·沙德特
S·古德曼
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Merck Patent GmbH
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Merck Patent GmbH
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

The invention relates to novel compounds of formula (I) which are biologically active when present as ligands of the integrin alpha<v>beta<3>: X-Y-Z-R<1>-CH2-R<2>(R<4>)-CH2-CO-R<5> wherein the meaning of X, Y, Z, R<1>, R<2>, R<4> and R<5> is given in Claim 1. The invention also relates to the physiologically acceptable salts and solvates of said compounds.

Description

Novel integral protein α vβ 3Inhibitor
The present invention relates to the novel cpd of formula I
X-Y-Z-R 1-CH 2-R 2(R 4)-CH 2-CO-R 5In the I formula
X is H 2N-C (=NH)-, H 2N-C (=NH)-NH-, A-C (=NH)-and NH-, Het 1-or Het 1-NH-,
Wherein this primary amine groups group also can provide with usual amino protecting group,
Y is
One, two, three or four methylene group can use N, O and/or S to replace in the formula,
Z be do not exist ,-O-,-NH-,-NA-,-CH (OH)-,-CH (OA)-,-CHA-,-CA 2-or-S-,
R 1Be not have replacement or F is arranged, Cl, Br, A, OA, OCF 3Or CN one replaces, two replacement or trisubstituted phenylenes,
R 2Be N, CH or CA,
R 3Be H, F, Cl, Br, A, OA or OCF 3,
R 4Be that F is arranged, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH 2, CONHA, CONA 2Or NO 2One replaces or polysubstituted phenyl, naphthyl or Het 2,
R 5Be OH, OA, NH 2, NHA or NA 2,
Het 1Be a kind of monocyclic or dicyclic heterocycle that 1～4 N atom is arranged, this heterocycle can be that nothing replaces or NH is arranged 2One replacement or dibasic,
Het 2Be a kind of aromatic series monocyclic or dicyclic heterocycle that 1～3 N, O and/or S atom are arranged, this heterocycle can be that nothing replaces or F be arranged, Cl, Br, A, OA, SA, OCF 3,-CO-A, CN, COOA, CONH 2, CONHA, CONA 2Or NO 2One replacement or dibasic,
Aryl is that nothing replaces or Hal is arranged, A, OA, OH, CO-A, CN, COOA, COOH, CONH 2, CONHA, CONA 2Or NO 2One replaces or polysubstituted phenyl or naphthyl,
A is the alkyl that 1～12 C atom is arranged,
N is 1,2,3,4,5 or 6,
M, o are 0,1,2,3,4,5 or 6 independently of one another under each situation,
Its prerequisite is R 4Being not equal to one has A or the monobasic phenyl or naphthyl of aryl,
And physiologically acceptable salt and solvate.
The present invention be based upon find to have the novel cpd of valuable performance, especially those can be used on the basis of compound this purpose that medicament produces.
Have been found that formula I compound and salt thereof have very valuable pharmacology performance and good tolerability.They especially can work as the integral protein inhibitor, particularly can suppress α vThe interaction of integral protein acceptor and part.These compounds are at integral protein α vβ 3And α vβ 5Situation under demonstrate specific activity.These compounds are as acceptor α vβ 3Adhesion receptor antagonists very high reactivity is especially arranged.This effect can be with people such as J.W.Smith at J.Biol, and the method described in the Chem.265,11008-11013 and 12267-12271 (1990) is confirmed.
Having confirmed 3-(4-fluorophenyl)-4-{4-(3-(pyridine-2-base amino) propoxy-) phenyl experimentally } butyric acid is to vitronectin and acceptor α vβ 3Adherent restraining effect.
At Curr.Opin.Cell.Biol.5, in 864 (1993), B.Felding-Habermann and D.A.Cheresh have described integral protein as miscellaneous phenomenon and syndromic adhesion receptor, especially about acceptor α vβ 3Importance.
In EP 0820988, integral protein α has been described vβ 3Other inhibitor.Vitronectic receptor antagonist has also been described in WO97/24124 and in EP 0820991.
P.C.Brooks, R.A.Clark and D.A.Cheresh have described the vasculogenesis source to the interactional dependency between blood vessel integral protein and the extracellular matrix protein at Science 264 among the 569-71 (1994).
P.C.Brooks.A.M.Montgomery, M.Rosenfeld, R.A.Reisfeld, T.-Hu, G.Klier and D.A.Cheresh be at Cell 79,1157-64 (1994) thus in described a kind of cyclic peptide and suppressed the possibility that this interaction starts the apoptosis (apoptosis) of angiogenic vascular cell.
Can prevent also that according to compound of the present invention thereby viable cell from also can prevent the adherent experimental evidence of tumour cell to matrix protein matter to the proteinic adhesion of corresponding matrix, can test with a kind of cell adhesion provides, this test is to carry out with the method that is similar to people such as F.Mitjans (J.CellScience 108,2825-2838 (1995)).
At J.Clin.Invest.96, among the 1815-1822 (1995), people such as P.C.Brooks have described cancer control and have used α with handling with tumor promotion vascularization disease vβ 3Antagonistic.
Therefore, can be used as the medicinal activity compound, be particularly useful for handling neoplastic disease, osteoporosis, Gorham and be used to suppress vascularization according to formula I compound of the present invention.
Can block the integral protein acceptor and,, can prevent that tumour cell from passing through to shift diffusion as the GPIIb/IIIa antagonistic such as the interactional formula I compound between the last Fibrinogen part of fibrinogen deceptor (glycoprotein iib/iiia).This point confirms by following observation: tumour cell causes that by tumour cell and hematoblastic interaction microagglomerate (microthrombus) formation takes place to the diffusion of vascular system from local tumor.This tumour cell is to screen by the protection in this microagglomerate, is that immune cell is unacquainted.This microcoacervation is known from experience and is attached on the vessel wall, therefore, and the convenient further infiltration of tumour cell in this tissue.Because the formation of this microthrombus is to transmit by the fibrinogen deceptor that Fibrinogen is attached on the activated blood platelet.Thereby the GPIIb/IIIa antagonistic can be considered as effective transfer inhibitor.
Except that the combination of Fibrinogen, fibronectin and the hematoblastic fibrinogen deceptor of von Willebrand factor pair, formula I compound also can suppress further adhesivity albumen for example vitronectin, collagen protein and laminine to the combination of the lip-deep corresponding acceptor of various different cell types.Specifically, they can prevent the formation of platelet thrombus, thereby can be used for handling thrombosis, palsy, cardiac infarction, inflammation and arteriosclerosis.
The performance of these compounds also can be confirmed with the method for describing among the EP-A1-0462960.Also can confirm Fibrinogen and fibrinogen deceptor bonded are suppressed with the method that provides among the EP-A1-0381033.
Method (Nature 4832,927-929,1962) with Born can be at external confirmation platelet aggregation inhibitor effect.By means of with WO 95/32710 similar osteoclast absorption test, can confirm the inhibition of The compounds of this invention to bone resorption.
Therefore, the present invention relates to can be used as production usefulness, the physiologically acceptable salt of the medicament that the integral protein inhibitor uses according to the formula I compound of claim 1 and/or its.The invention particularly relates to control with medicament that formula I compound and/or its pathologic vessels according to claim 1 form disease, tumour, osteoporosis, inflammation and infection produces and uses acceptable salt.
The pharmaceutical active compounds that the compound of formula I can be used as among people doctor and the animal doctor is used to prevent and/or treat thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, neoplastic disease, molten osteopathy is osteoporosis for example, hypercalcemia, pathologic vessels forms case such as inflammation, the ophthalmology disease, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubescent glaucoma, ulcerative colitis, Crohn disease, atherosclerosis, psoriasis, postangioplasty restenosis, viral infection, bacterial infection, fungal infection, acute renal failure, with in wound healing, help agglutination.
Formula I compound can be used as the operation that anti-microbial active matter is used for using biomaterial, implant, conduit or schrittmacher.At this, their anti-Putrefactions.Infection and Immunity (infect with immunity), the process of describing among the 2851-2855 (1988) just can confirm the effect of its antimicrobial acivity with people such as P.Valentin-Weigund.
The present invention also relates to for example alcohol adduct of the hydrate of these compounds and solvate.
The invention further relates to according to the formula I compound of claim 1 and the preparation technology of salt thereof, it is characterized in that
A) by handling, formula I compound is discharged from its functional derivatives with a kind of solvolysis agent, reductive agent or hydrogenolysis agent, or
B) make radicals X and/or R 5Change into another kind of radicals X and/or R 5, its method for example is
I) by reacting, make amino group change into guanidino group with a kind of amidination agent,
Ii) make the ester hydrolysis,
Iii), make hydroxyamidines change into amidine by hydrogenation,
And/or make a kind of alkali or the acid of formula I change into one of its salt.
Formula I compound has a chiral centre, therefore can exist with many stereoisomer forms.All these forms (for example D and L shaped formula) and composition thereof (for example DL form) all is included among the formula I.
So-called prodrug derivatives is also included within according in the compound of the present invention, promptly uses such as alkyl or carboxyl groups, carbohydrate or oligopeptides modification, can be cracked into the formula I compound according to active compound of the present invention in vivo rapidly.
More than and below the abbreviation representative mentioned: Ac acetyl group BOC tertbutyloxycarbonyl CBZ or Z benzyloxycarbonyl group DCCI dicyclohexyl carbodiimide DMF dimethyl formamide EDCI N-ethyl-N; N '-(dimethylaminopropyl) carbodiimides Et ethyl Fmoc 9-fluorenylmethyloxycarbonyl HOBt I-hydroxybenzotriazole Me methyl Mtr 4-methoxyl group-2; 3,6-trimethylbenzene sulfonyl HONSu N-hydroxy-succinamide OBut tert-butyl ester Oct caprylyl OMe methyl esters OEt ethyl ester POA phenoxy group acetyl group TFA trifluoroacetic acid Trt trityl (trityl group)
To what whole invention all was suitable for be, repeatedly the group of Chu Xianing for example A all can be identical or different, promptly be independent of each other.
A is an alkyl, have 1,2,3,4,5,6,7,8,9,10,11 or 12 C atoms, and better be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the sec-butyl or the tertiary butyl, also can be amyl group in addition, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, the 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3, the 3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-, 1,2,2-trimethylammonium propyl group, heptyl, octyl group, nonyl or decyl, undecyl or dodecyl.A also can be the alkyl that has halogen to replace, and better is CF 3
X better is, for example, pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, basic amino, the benzimidazolyl-2 radicals-Ji amino, 4 of imidazoles-2-, the basic amino of 5-glyoxalidine-2-, 2-aminooimidazole-5-base amino, 2-aminopyridine-6-base amino, 2-aminooimidazole-5-base or 2-aminopyridine-6-base.
Y better is, for example, and ethylidene, propylidene or butylidene.
Z better is, for example, and O.
R 1Better be, for example, 1, the 4-phenylene.
R 2Better be, for example, CH or N, especially CH.
R 4Better be for example, to have F one to replace or polysubstituted phenyl.
R 5Better be, for example, OH.
Het 1Better be 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl, these are that nothing replaces or A, NHA and/or NH are arranged 2One replacement or dibasic, further be preferably 1,2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolines base, 2-, 4-, 5-, 6-, 7-or 8-quinazoline, 1H-imidazo [4,5-b] pyridine-2-base or 1,8-naphthyridine-7-base.
Heterocyclic radical also can be partial hydrogenation or complete hydrogenant.
Therefore, Het 1Also can be, for example, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl, 2,5-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl, 1-, 2-or 3-pyrrolidyl, tetrahydrochysene-1-,-2-or-the 4-imidazolyl, 4,5-glyoxalidine-2-base, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrazolyl, tetrahydrochysene-1-,-3-or-the 4-pyrazolyl, 1,4-dihydro-1-,-2-,-3-or-the 4-pyridyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-or-the 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, six hydrogen-1-,-3-or-the 4-pyridazinyl, six hydrogen-1-,-2-,-4-or-the 5-pyrimidyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-the 8-quinolyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-8-isoquinolyl or 1,2,3,4-tetrahydrochysene-1,8-naphthyridine-7-base.
Hydrogenant or partially hydrogenated Het 1Group can also have=NH or the replacement of carbonyl oxygen base.
Het 2Better be 2,3-, 2,4-, 2,5-or 3,4-thienyl, 2,3-, 2,4-, 2,5-or 3,4-pyrryl, 2,4-, 2,5-or 4,5-imidazolyl, 2,3-, 2,4-, 2,6-or 3,5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5-or 5,6-pyrimidyl.These are that nothing replaces or F, Cl, Br, A, OA or OCF are arranged 3-replace.
N better is 2,3,4,5 or 6, and n is especially extraordinary to be 3,4 or 5.
M and o are 0,1 or 2 in each case independently of one another better, and they are especially extraordinary to be 0.
" one or many " replacement has meant one, two, three or four replacements.
Aryl is not have to replace; better-as noted-be monobasic phenyl; good especially is phenyl; adjacent; between or p-methylphenyl; adjacent; between or to ethylphenyl; adjacent; between or to the propyl group phenyl; adjacent; between or the p-isopropyl phenyl; adjacent; between or to tert-butyl-phenyl; adjacent; between or to cyano-phenyl; adjacent; between or p-methoxyphenyl; adjacent; between or to ethoxyl phenenyl; adjacent; between or to fluorophenyl; adjacent; between or to bromophenyl; adjacent; between or rubigan; adjacent; between or to the methylthio group phenyl; adjacent; between or to the methanesulfinyl phenyl; adjacent; between or to the methylsulfonyl phenyl; adjacent; between or p-aminophenyl; adjacent; between or to the methylamino phenyl; adjacent; between or to dimethylaminophenyl; adjacent; between or p-nitrophenyl; adjacent; between or to acetylphenyl; adjacent; between or to the methoxycarbonyl phenyl; adjacent; between or to aminocarbonyl-phenyl; further be preferably 2; 3-; 2; 4-; 2; 5-; 2; 6-; 3; 4-or 3; the 5-difluorophenyl; 2; 3-; 2; 4-; 2; 5-; 2; 6-; 3; 4-or 3; the 5-dichlorophenyl; 2; 3-; 2; 4-; 2; 5-; 2; 6-; 3; 4-or 3; the 5-dibromo phenyl; 2-chloro-3-methyl-; 2-chloro-4-methyl-; 2-chloro-5-methyl-; 2-chloro-6-methyl-; 2-methyl-3-chloro-; 2-methyl-4-chloro-; the 2-methyl-5-chloro-; 2-methyl-6-chloro-; 3-chloro-4-methyl-; 3-chloro-5-methyl-or 3-methyl-4-chloro-phenyl-; 2-bromo-3-methyl; 2-bromo-4-methyl; 2-bromo-5-methyl; 2-bromo-6-methyl; 2-methyl-3-bromo-; 2-methyl-4-bromo-; 2-methyl-5-bromo-; 2-methyl-6-bromo-; 3-bromo-4-methyl-; 3-bromo-5-methyl-or 3-methyl-4-bromophenyl; 2; 4-or 2; the 5-dinitrophenyl; 2; 5-or 3; the 4-Dimethoxyphenyl; 2; 3; 4-; 2; 3; 5-; 2; 3; 6-; 2; 4; 6-or 3; 4; the 5-trichlorophenyl; 2; 4; 6-tri-tert phenyl; 2; the 5-3,5-dimethylphenyl; to iodophenyl; 4-fluoro-3-chloro-phenyl-; 4-fluoro-3; the 5-3,5-dimethylphenyl; 2-fluoro-4-bromophenyl; 2; 5-two fluoro-4-bromophenyls; 2; 4-two chloro-5-aminomethyl phenyls; 3-bromo-6-p-methoxy-phenyl; 3-chloro-6-p-methoxy-phenyl; 2-methoxyl group-5-aminomethyl phenyl; 2; 4,6-triisopropyl phenyl.
Amino protecting group better is formyl radical, ethanoyl, propionyl, butyryl radicals, phenylacetyl, benzoyl, toluoyl, POA, methoxycarbonyl, ethoxycarbonyl, 2; 2,2-trichloro-ethoxycarbonyl, BOC, 2-iodine ethoxycarbonyl, CBZ (carbobenzoxy-(Cbz)), 4-methoxyl group benzyloxy carbonyl, FMOC, Mtr or benzyl.
Therefore, the invention particularly relates at least a formula I compound that one of above pointed better implication is arranged in those groups of wherein being mentioned.Some preferably compound group can represent that these have implication pointed among the formula I corresponding to formula I and wherein more not detailed specified group with following minor Ia～Im, but wherein
In a), X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, basic amino, the benzimidazolyl-2 radicals-Ji amino, 4 of imidazoles-2-, the basic amino of 5-glyoxalidine-2-, 2-aminooimidazole-5-base amino, 2-aminopyridine-6-base amino, 2-aminooimidazole-5-base or 2-aminopyridine-6-base;
At b) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4;
At c) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4;
At d) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O;
At e) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH;
At f) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be that F, Cl, Br, OA, OCF are arranged 3,-CO-A, CN, COOA, CONH 2Or NO 2One replaces or polysubstituted phenyl;
At g) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be that F, Cl, Br, OA or OCF are arranged 3One replaces or polysubstituted phenyl,
R 5Be OA or OH;
At h) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be to have F one to replace or polysubstituted phenyl,
R 5Be OA or OH;
At i) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be to have Hal, A or aryl one to replace or polysubstituted phenyl,
R 5Be OA or OH,
Prerequisite is R 4Be not equal to A or the monobasic phenyl or naphthyl group of aryl are arranged;
At k) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be the phenyl that has Hal and aryl to replace,
R 5Be OA or OH,
Prerequisite is R 4Be not equal to A or the monobasic phenyl or naphthyl group of aryl are arranged;
1) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-the 2-base is amino, benzimidazolyl-2 radicals-Ji amino or 4,5-glyoxalidine-2-base is amino,
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be the phenyl that has Hal and aryl to replace,
R 5Be OA or OH,
Aryl is that Hal, A, OA, CF are arranged 3, CN or NO 2One replacement, two replaces or trisubstd phenyls,
Prerequisite is R 4Be not equal to A or the monobasic phenyl or naphthyl group of aryl are arranged;
At m) in, X is pyrimidine-2--amino, pyridine-2-base amino, imidazoles-1-base, imidazoles-amino, the benzimidazolyl-2 radicals-Ji amino, 4 of 2-base, the basic amino of 5-glyoxalidine-2-, 2-aminooimidazole-5-base amino, 2-aminopyridine-6-base amino, 2-aminooimidazole-5-base or 2-aminopyridine-6-base
Y is-(CH 2) n-,
N is 2,3 or 4,
Z is O,
R 2Be N or CH,
R 4Be to have Hal, A or aryl one to replace or polysubstituted phenyl,
R 5Be OA or OH,
Prerequisite is R 4Be not equal to A or the monobasic phenyl or naphthyl group of aryl are arranged.
Formula I compound with and preparation be with known method preparation itself originally with initiator, for example as the above (classic for example of document, as Houben-Weyl, Methodender organischen Chemie (organic chemistry method), Georg-Thieme-Verlag, the Stuttgart), promptly known and be applicable under the reaction conditions of the reaction of being mentioned and prepare.In this case, we are also can utilization itself known but in this mutation of not mentioning in more detail.
If wish, this initial substance also can original position generate, and therefore, they needn't be separated from reaction mixture, but further react immediately to provide formula I compound.
Formula I compound better can be by handling with a kind of solvolysis agent or hydrogenolysis agent, formula I compound being discharged obtain from one of its functional derivatives.
Solvolysis preferably or hydrogenolysis initial substance are that those are originally corresponding to formula I but do not contain one or more free amine groups and/or oh group and contain corresponding protected amino and/or oh group person; better be that those do not have the H atom that is connected with the N atom and the person that has the amino protecting group; especially those do not have the HN group and have R ' N group (wherein R ' is an amino protecting group) person and/or those do not have hydroxyl hydrogen atom and the person that has the hydroxyl protecting group; for example, those corresponding to formula I but not have group-COOH and have group-COOR " (wherein R " be hydroxyl protecting group) person.
In the molecule of this initial substance, also have many identical or different protected amino and/or oh group and exist.If the blocking group that exists differs from one another, then they can optionally remove under many circumstances.
" amino protecting group " this expression generally knows, and relates to be applicable to that protection (or blocking-up) amino avoids chemical reaction but the group that taken place on other position can remove easily after the desirable chemical reaction in this molecule.Such group specifically, is not have acyl group, aryl, aralkyl oxygen methyl or the aralkyl that replaces or replacement is arranged.Because amino protecting group removes afterwards in desired response (or reaction sequence), thereby its character and size were unimportant originally; Yet being preferably those has 1～20,1～8 C atom person especially." carboxyl groups " this expression will be understood on the broad sense that interrelates with technology of the present invention.It comprises from aliphatics, araliphatic, aromatic series or heterocycle family carboxylic acid or sulfonic acid deutero-carboxyl groups, and comprises carbalkoxy, aryloxy carbonyl, aralkoxycarbonyl group especially particularly.Such carboxyl groups example is formyl radical or alkanoyl for example ethanoyl, propionyl, butyryl radicals; The virtue alkanoyl is phenylacetyl for example; Aroyl is benzoyl or toluyl for example; Virtue oxygen alkanoyl is POA for example; Carbalkoxy is methoxycarbonyl, ethoxycarbonyl, 2,2 for example, 2-trichloro-ethoxycarbonyl, BOC, 2-iodine ethoxycarbonyl; Aralkoxycarbonyl is CBZ (" carbobenzoxy-(Cbz) "), 4-methoxyl group benzyloxy carbonyl, Fmoc for example; Arylsulfonyl is Mtr for example.Amino protecting group is BOC and Mtr preferably, also has CBZ, Fmoc, benzyl, formyl radical and ethanoyl in addition.
The removing of amino protecting group-Yin employed protecting group different-can such as with strong acid, more handy TFA or cross chloric acid but also can with other strong inorganic acid for example hydrochloric acid or sulfuric acid, strong organic carboxyl acid for example trichoroacetic acid(TCA) or sulfonic acid for example Phenylsulfonic acid or tosic acid carry out.The existence of another kind of inert solvent is possible, but is not always necessary.The inert solvent that is suitable for better is an organic solvent, and for example carboxylic acid such as acetate, ethers such as tetrahydrofuran (THF) Huo diox, amides such as DMF, halogenated hydrocarbon such as methylene dichloride also can be alcohols for example methyl alcohol, ethanol or Virahol in addition, can also be water.The above mixture of mentioning solvent also is suitable for.TFA does not better add further solvent with excessive use, crosses chloric acid is then crossed chloric acid with acetate and 70% form of mixtures uses in 9: 1.Between more about 0 ℃ and about 50 ℃ of the scission reaction temperature; This reaction is (room temperature) between 15 and 30 ℃ more fortunately.
Group B OC, OBut and Mtr better can such as with TFA in methylene dichloride or with removing in 15～30 ℃ in about 3～5N HCl Zai diox, the Fmoc group can with a kind of secondary amine for example about 5～50% intensity solution of dimethylamine, diethylamine or piperidines in DMF, remove in 15～30 ℃.
The blocking group that the available hydrogen solution removes (for example CBZ or benzyl) can be such as removing by handling with hydrogen under the existence of a kind of catalyzer (for example a kind of noble metal catalyst such as palladium, more a kind of carrier for example charcoal on).Here the solvent of Shi Yonging be already pointed out those, especially such as alcohols such as methyl alcohol or ethanol or amides such as DMF.Usually, hydrogenolysis be the temperature between about 0～100 ℃ and about 1～200 the crust between pressure, more fortunately 20～30 ℃ and 1～10 the crust carry out.The hydrogenolysis of CBZ group is used such as 5～10%Pd/C in methyl alcohol, or with ammonium formiate (without hydrogen) with Pd/C in methyl alcohol/DMF at 20～30 ℃, just can carry out smoothly.
The inert solvent that is suitable for is such as hydro carbons for example hexane, sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbon is trieline, 1 for example, 2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohols is methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol for example; Ethers is diethyl ether, diisopropyl ether, tetrahydrofuran (THF) (THF) Huo diox for example; Gylcol ether is ethylene glycol-methyl ether or an ether (methylcyclohexane or ethyl cellosolve), glycol dimethyl ether (diglyme) for example; Ketone is acetone or butanone for example; Amides is ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF) for example; Nitrile is acetonitrile for example; The sulfoxide class is dimethyl sulfoxide (DMSO) (DMSO) for example; Dithiocarbonic anhydride; Carboxylic-acid is formic acid or acetate for example; Nitro-compound is Nitromethane 99Min. or oil of mirbane for example; The ester class is ethyl acetate for example; Water; Or the mixture of the solvent of mentioning.
And then, also can make a kind of ester hydrolysis of formula I.Better, this be by solvolysis as already pointed out or hydrogenolysis, for example with LiOH in methyl alcohol, with NaOH or KOH in diox/water between 0～60 ℃, the temperature between 10～40 ℃ is carried out more fortunately.
Cyano group to the conversion of amidino groups group be by with such as azanol reaction, subsequently a kind of catalyzer for example Pd/C in the presence of carry out with hydrogen reduction N-hydroxyamidines.
And then, can be by as the above, removing protecting group with solvent solution or hydrogenolysis method, or make by solvent or hydrogenolysis and discharged by the amino of usual protecting group protection, and replace usual amino protecting group with hydrogen.
In order to prepare its X is H 2N-C (=NH)-and the formula I compound of NH-, handle a kind of suitable aminocompound with a kind of amidineization agent.The agent of a kind of amidineization preferably is 1-amidino groups-3 (DPEN), and this compound especially adopts with its nitrate form.This reaction more a kind of inert solvent or solvent mixture be for example in water/diox, between 0～120 ℃, more fortunately under the temperature between 60～120 ℃, for example carries out under the situation of triethylamine or ethyl diisopropylamine adding a kind of alkali.
For a kind of amidine of preparation formula I (X=-C (=NH)-NH 2), can in a kind of nitrile (X=CN) of formula I, add ammonia.This interpolation better divides a plurality of stages to carry out: a) use H 2S changes into a kind of thioamides to this nitrile in a kind of known mode own, uses for example CH of a kind of alkylating agent again 3I changes into corresponding S-alkylimide monothioester, again with NH 3Reaction provides amidine; B) in the presence of HCl with a kind of alcohol for example ethanol make this nitrile change into corresponding imide ester, handle with hydrogen again; Or c) makes the reaction of this nitrile and two (trimethyl silyl) amination lithium, make its product hydrolysis then.
And then be preferably, in a kind of inert solvent, with a kind of reductive agent for example phosphorus trichloride such as making the reduction of a kind of hydroxyl heterocycle, thereby formula I compound is discharged from its oxidized form precursor.
And then; free amine group can be with a kind of acyl chlorides or acid anhydrides with the usual way acidylate, perhaps with a kind of do not have replace or have replace alkane halogen, more a kind of inert solvent for example among methylene dichloride or the THF and/or a kind of alkali for example triethylamine or pyridine in the presence of, alkylation under the temperature between-60 ℃～+ 30 ℃.
The alkali of formula I can be used a kind of acid, such as by a kind of inert solvent for example in the ethanol normal this alkali change into relevant acid salt, evaporation subsequently with normal reaction that should acid.Concerning this reaction, especially those can produce the acid of acceptable salt on the physiology in the acid that is suitable for.Therefore, can be with mineral acid sulfuric acid for example, nitric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid such as ortho-phosphoric acid, thionamic acid, can use organic acid in addition, especially aliphatic, alicyclic, araliphatic, the monobasic or the polycarboxylic acid of aromatic or heterocycle family, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid or ethyl sulfonic acid, ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene monosulfonic acid and disulfonic acid, lauryl sulfate.The salt that generates with unacceptable acid on the physiology is picrate for example, can be used for the separation of formula I compound and/or refining.
On the other hand, the acid of formula I can be accepted one of metal-salt or ammonium salt by changing on its physiology with a kind of alkali reaction.Here possible salt is sodium salt, sylvite, magnesium salts, calcium salt and ammonium salt especially, substituted ammonium salt is arranged in addition in addition, for example diformazan ammonium salt, two b ammonium salts or diisopropyl ammonium salt, an alcohol salt, di-alcohol ammonium salt or diisopropanol ammonium salt, cyclohexyl ammonium salt, dicyclohexyl ammonium salt, dibenzyl second di-ammonium salts, and then also have the salt that generates with arginine or Methionin.
Formula I compound contains one or more chiral centres, therefore, can exist with racemic modification form or optically active form form.Resulting racemic modification can with known method itself mechanically or chemical mode be separated into enantiomorph.Be preferably,, generate diastereomer from this raceme mixture by reacting with a kind of optically active resolving agent.The agent of disassembling that is suitable for is acid such as optically-active, for example the tartrate of D type and L type, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid or various opticity camphorsulfonic acid beta camphor sulfonic acid for example.It also is favourable disassembling by means of the enantiomorph of optically active resolving agent (for example dinitrobenzoyl phenylglycocoll) packed column; The eluent that is suitable for is the mixture such as hexane/isopropyl alcohol/acetonitrile, and its volume ratio is such as 82: 15: 3.
Certainly, utilize active initial substance,, also can obtain the optically-active compound of formula I according to the above method.
The present invention not only comprises the compound of being mentioned, and comprising mixture and preparation, the latter can influence other pharmaceutically active compounds or adjuvant according to the basic pharmacological action of compound of the present invention in desired mode except that containing according to also containing these compounds of the present invention.These can be used as therapeutical agent, diagnostic reagent or reagent.They to the mode of human body or animals administer can be partial or general, per os, through intravenous, through endoperitoneal, through intramuscular, through subcutaneous, through skin, intranasal, through cheek or through ionotherapy, they comprise the prescription of following dosage forms: suspension liquor, emulsion agent or solution, liposome agent, ointment, paste, biodegradable polymers agent, nanoparticle agent, tablet, capsule, pill, granule, powder, suction with aerosol, intranasal in drops or sprays.These product innovations also can make up other technology, and for example surgical operation, irradiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy can also make up other medicament.Such medicament can come from such as cardiovascular field, central nervous system field or oncology.They can oncology pharmacy, for example angiogenesis inhibitor or cytostatic agent, group alkylating agent chemotherapy, microbiotic, metabolic antagonist, biotechnological formulation and immunomodulator, hormone and antagonistic thereof, yperite derivative, alkaloid and other, wherein, these materials can have lower molecular weight or high molecular.They can be lipid, carbohydrate or protein-based.Also can be included in has cell kinase, toxin, fused protein, monoclonal antibody and a vaccine in the middle of these.
Therefore, the present invention relates to the compound of the chemical formula that defines in above, following and claims, comprise its physiologically acceptable salt, as medicament, diagnostic reagent or reagent.
The invention particularly relates to corresponding medicament as inhibitor and be used for control indirectly or directly based on α vβ 3The disease of integral protein expression of receptor, therefore, under the dyspoietic situation of pathologic vessels, be used to control thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, inflammation, infection, also can be used to influence wound healing process.
The present invention also relates to corresponding pharmaceutical preparation, wherein contain at least a medicament and appropriate carriers and/or the vehicle of formula I.
The present invention and then relate to according to compound of claims and this specification sheets and/or the purposes that its physiologically acceptable salt is used to produce a kind of medicament, this medicament can be used for control indirectly or directly based on α vβ 3The disease of integral protein expression of receptor, therefore, especially under the dyspoietic situation of pathologic vessels, be used to control thrombosis, heart embolism, coronary heart disease, arteriosclerosis, tumour, osteoporosis, inflammation, infection, also can be with influencing wound healing process.Can be used as medicament according to medicament of the present invention or the pharmaceutical preparation that comprises this medicament and be used for people doctor or animal doctor.The carrier that is suitable for be suitable for through intestines (for example per os) or non-through enteral administration or topical application or be suitable for suck that Sprayable is used and also not with the organic substance or the inorganic substance of this novel cpd reaction, for example for example lactose or starch, Magnesium Stearate, talcum, mineral jelly (Vaseline) of water, vegetables oil, benzylalcohol, aklylene glycol, polyoxyethylene glycol, vanay, gelatin, carbohydrate.Tablet, pill, coated tablet, capsule, powder, granule, syrup, juice agent or drops be used for peroral administration, suppository is particularly useful for the per rectum administration, solution, better oil base or group water solution agent, suspend liquor, emulsion agent or implant is used for non-ly through enteral administration in addition, and ointment, creme or powder are used for topical application.These novel cpds also can be freeze dried, and resulting lyophilized products can be used for such as producing injection formulations.Pointed preparation can be sterilized and/or can be contained vehicle for example antiseize paste, sanitas, stablizer and/or wetting agent, emulsifying agent, the salt that is used to influence osmotic pressure, buffer material, tinting material, drug flavoring and/or one or more further active compounds, for example one or more VITAMIN.
For as the administration of a kind of suction sprays, can use and contain dissolving or be suspended in a kind of propelling agent or propellant mixture (CO for example 2The sprays of the active compound or chloro-fluoro-carbon kind).Better, this active compound uses with the micron form at this, can also have can tolerate on another or the multiple physiology solvent for example ethanol exist.Sucking solution can be by means of usual sucker administration.
Usually, according to material of the present invention can be similar to other known, commercial preparation that gets (for example described in the US-A-4472305), better with between the about 0.05～500mg of every dosage device, the dosed administration between 0.5～100mg especially.Between the more about 0.01～20mg/kg body weight of per daily dose.Yet, each patient's concrete dosage depends on the factor of all kinds, for example, the effect that depends on the specific compound that adopts, depend on age, body weight, overall health and sex, depend on recipe, depend on administration time and approach, also depend on discharge rate, medicine combination and this treatment at the seriousness of specified disease.Better right and wrong are through enteral administration.
More than and below, temperature is all ℃ to provide.
HPLC analyzes (retention time Rt) and carries out in order to following system:
3 μ m silicas rod post, 210 seconds 20～100% water/acetonitrile/0.01% trifluoroacetic acid gradient elution, 2.2ml/ minute fluence rate detects at 220nm.
Mass spectroscopy (MS): EI (Electron Impactionization) M +
FAB (fast atom bombardment(FAB)) (M+H) +
Embodiment 1
3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyro-synthetic
835mg Mg is suspended among the absolute THF of 5ml.Drip the solution of a kind of 2.0g 4-benzyloxy benzyl chloride in the 5ml absolute thf then.Add finish after, muddy solution adds the solution of a kind of 1.73g 2-cyano group-3-(4-fluorophenyl) ethyl propenoate in the 10ml absolute toluene then stirring at room 1 hour, mixture refluxed 16 hours.Remove solvent, and after usual aftertreatment, obtain 4-(4-benzyloxy phenyl)-2-cyano group-3-(4-fluorophenyl) ethyl butyrate (" AA ").
8.27g " AA " is suspended in the mixture of a kind of 80ml acetate and the dense HCl of 80ml, then, this mixture refluxed 16 hours.After usual aftertreatment, obtain 4-(4-hydroxy phenyl)-3-(4-fluorophenyl) butyric acid (" AB ").
The solution of a kind of 1.0g " AB " in the absolute methyl alcohol of 10ml is handled with the 0.4ml thionyl chloride, and stirring at room 16 hours.After usual aftertreatment, obtain 4-(4-hydroxy phenyl)-3-(4-fluorophenyl) methyl-butyrate (" AC ").
The pure and mild 1.23g polymkeric substance of third-1-is in conjunction with in the suspension of triphenyl phosphine (about 3mmol/g loads) in the absolute THF of 17ml 0.62ml the diethylazodicarboxylate is added drop-wise to a kind of 0.4g " AC ", 0.5g 3-(1-pyridone-2-base is amino), and this mixture stirred 16 hours subsequently.Filter and remove after the solvent, residue is refining with HPLC.Obtain 3-(4-fluorophenyl)-4-{4-(3-(1-pyridone-2-base is amino) propoxy-) phenyl } methyl-butyrate (" AD ").
The solution of a kind of 0.45g " AD " in the 30ml chloroform is handled with the 0.59g phosphorus trichloride, at room temperature stirs 2 hours, and further stirs 2 hours under refluxing.After usual aftertreatment, residue is handled with the 0.2g lithium hydroxide in 15ml methyl alcohol, at room temperature stirs 16 hours.Remove after the solvent, residue is handled with the 0.66ml trifluoroacetic acid, and is refining with HPLC.Obtain 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } the butyric acid trifluoroacetate.
Figure A0081195000221
3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } α that causes of butyric acid vβ 3The test-results that suppresses
IC 50Value can make and suppress 50% concentration (nmol/l) with corresponding isolated receptor bonded vitronectin, for vitronectin provides (people's such as Smith method, J.Biol.Chem.265,12267-71,1990) in conjunction with test.
IC 50α vβ 3：10。
Pharmacology data confirms according to compound of the present invention acceptor α vβ 3Antagonistic activity.
In the mode of similar the above synthetic schemes, obtained following compound:
3-(4-fluorophenyl)-4-{4-[2-(pyrimidine-2--amino) oxyethyl group] phenyl } the butyric acid trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[3-(pyrimidine-2--amino) propoxy-] phenyl } the butyric acid trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[4-(pyrimidine-2--amino) butoxy] phenyl } the butyric acid trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[2-(pyridine-2-base is amino) oxyethyl group] phenyl } the butyric acid trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[4-(pyridine-2-base is amino) butoxy] phenyl } the butyric acid trifluoroacetate;
3-(4-fluorophenyl)-4-{4-[3-(imidazoles-1-yl) propoxy-] phenyl } butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(4,5-dihydro-1H-imidazoles-2-base is amino) propoxy-] phenyl } butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(imidazoles-2-base is amino) propoxy-] phenyl } butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(benzimidazolyl-2 radicals-Ji amino) propoxy-] phenyl } butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridine-6-base is amino) propoxy-] phenyl } butyric acid;
3-(4-fluorophenyl)-4-{4-[3-(2-aminooimidazole-5-base is amino) propoxy-] phenyl } butyric acid.
Embodiment 2
Synthesizing of (4-fluorophenyl-{ 4-(3-(pyridine-2-base is amino) propoxy-) benzyl } amino) acetate
40.0g the 4-hydroxy benzaldehyde is dissolved under a kind of protective gas atmosphere among the absolute THF of 400ml, solution is handled with 55.1g dihydropyrane and 13.7g tosic acid pyridine, in stirred overnight at room temperature.Remove solvent with rotatory evaporator, residue carries out aftertreatment with usual way, obtains colorless oil 4-(tetrahydropyrans-2-base oxygen) phenyl aldehyde (" BA ").
The solution of a kind of 2.0g " BA " in the absolute methyl alcohol of 20ml is handled with 1.17g 4-fluoroaniline, stirs 3 hours at 60 ℃.Add the 0.79g sodium cyanoborohydride in room temperature, reaction soln refluxed 16 hours.Remove solvent, usual aftertreatment and chromatography refining after, obtain colourless liquid shape 4-fluorophenyl-(4-(tetrahydropyrans-2-base oxygen) benzyl) amine (" BB ").
8.0g " BB " and 10.36g methyl bromoacetate are at a kind of N 2Be dissolved under the atmosphere among the absolute THF of 100ml, handle, refluxed 16 hours with 12.0g salt of wormwood.Remove solvent, usual aftertreatment and chromatography refining after, obtain colorless solid shape { [4-fluorophenyl]-[4-(tetrahydropyrans-2-base oxygen) benzyl] amino } methyl acetate (" BC ").
The solution of a kind of 0.5g " BC " in 25ml methyl alcohol and 5ml methylene dichloride is handled with the dense HCl of 2.76ml, at room temperature stirs 5 minutes.Remove after solvent and the usual aftertreatment, residue is dissolved in the absolute THF of 16ml and 0.47g 3-(1-pyridone-2-base the is amino) third-1-alcohol, use the triphenyl phosphine (about 3mmol/g loads) of 1.17g polymkeric substance to handle then, drip the 0.62ml diethylazodicarboxylate then.This suspension at room temperature stirred 16 hours then.Filter and remove after the solvent, residue is refining with HPLC.Obtain (4-[3-(1-pyridone-2-base is amino) propoxy-] benzyl }-(4-fluorophenyl) amino) methyl acetate (" BD ").
The solution of a kind of 0.44g " BD " in the 30ml chloroform is handled with the 0.57g phosphorus trichloride, at room temperature stir 2 hours, under refluxing, further stirred 2 hours.After the usual aftertreatment, residue is handled with the 0.27g lithium hydroxide in 15ml methyl alcohol, at room temperature stirs 16 hours.Remove after the solvent, add the 0.66ml trifluoroacetic acid, mixture is refining with HPLC.Obtain ((4-fluorophenyl)-and 4-[3-(pyridine-2-base is amino) propoxy-] benzyl } amino) acetate two (trifluoroacetate).
Figure A0081195000241
Obtain following compounds similarly:
((4-fluorophenyl)-and 4-[2-(pyrimidine-2--amino) oxyethyl group] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[3-(pyrimidine-2--amino) propoxy-] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[4-(pyrimidine-2--amino) butoxy] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[2-(pyridine-2-base is amino) oxyethyl group] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[4-(pyridine-2-base is amino) butoxy] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[3-(imidazoles-1-yl) propoxy-] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[3-(4,5-dihydro-1H-imidazoles-2-base is amino) propoxy-] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[3-(imidazoles-2-base is amino) propoxy-] benzyl } amino) acetate,
((4-fluorophenyl)-and 4-[3-(benzimidazolyl-2 radicals-Ji amino) propoxy-] benzyl } amino) acetate.
Embodiment 3
Obtain following compound in the mode that is similar to embodiment 1
3-((3-chloro-4-phenyl) phenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
Figure A0081195000251
3-(2-bromophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(3, the 4-dichlorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(4-bromophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(2, the 3-dichlorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(2,4 dichloro benzene base)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(3-bromophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(2, the 6-difluorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
3-(3, the 5-dichlorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid.
Following examples relate to pharmaceutical preparation:
Embodiment A: injection medicine bottle
A kind of 100g 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } butyric acid and the solution of 5g Sodium phosphate dibasic in 3 liters of bi-distilled waters are adjusted to pH6.5, sterilising filtration, are filled in the injection medicine bottle with 2NHCl, freeze-drying under aseptic condition, sterile seal.Each injection medicine bottle contains the 5mg active compound.
Embodiment B: suppository
A kind of 20g 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl butyric acid melts with the mixture of 100g soybean lecithin and 1400g theobroma oil, in the impouring model, make it to cool off.Each suppository contains the 20mg active compound.
Embodiment C: solution
A kind of 1g 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } butyric acid, 9.38g NaH 2PO 42H 2O, 28.48g Na 2HPO 412H 2O and 0.1g benzalkonium chloride are prepared a kind of solution with the 940ml bi-distilled water.This solution is adjusted to pH 6.8, supplies 1 liter, is sterilized with irradiation.This solution can use with eye drops form.
Embodiment D: ointment
500mg 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } butyric acid mixes with 99.5g Vaseline under aseptic condition.
Embodiment E: tablet
A kind of 1kg 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } mixture of butyric acid, 4kg lactose, 1.2kg yam starch, 0.2kg talcum and 0.1kg Magnesium Stearate is with a kind of usual way compressing tablet, provide tablet, make each sheet contain the 10mg active compound.
Embodiment F: coated tablet
To be similar to the mode compressed tablets of embodiment E, then with a kind of Drug coating of forming by sucrose, yam starch, talcum, tragakanta and tinting material with the usual way dressing.
Embodiment G: capsule
2kg 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } butyric acid is filled in the hard gelatin capsule with usual way, makes each capsule contain the 20mg active compound.
Embodiment H: ampulla
A kind of 1kg 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl } solution sterilization of butyric acid in 60 liters of bi-distilled waters filters, is filled in the ampoule, freeze-drying under aseptic condition, sterile seal.Each ampoule contains the 10mg active compound.
Example I: suck sprays
14g 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base amino) propoxy-] phenyl butyric acid is dissolved in 10 liters of grades and oozes in the NaCl solution, with this filled with solution to there being the commercial of pump mechanism to get in the automiser spray.This solution can be sprayed in oral cavity or the nasal cavity.One puff spraying (approximately 0.1ml) is corresponding to the dosage of about 0.14mg.

Claims (10)

1. the compound of formula I
X-Y-Z-R 1-CH 2-R 2(R 4)-CH 2-CO-R 5In the I formula
X is H 2N-C (=NH)-, H 2N-C (=NH)-NH-, A-C (=NH)-and NH-, Het 1-or Het 1-NH-,
Wherein this primary amine groups group also can provide with usual amino protecting group,
Y is
Figure A0081195000021
One, two, three or four methylene group can use N, O and/or S to replace in the formula,
Z be do not exist ,-O-,-NH-,-NA-,-CH (OH)-,-CH (OA)-,-CHA-,-CA 2-or-S-,
R 1Be not have replacement or F is arranged, Cl, Br, A, OA, OCF 3Or CN one replaces, two replacement or trisubstituted phenylenes,
R 2Be N, CH or CA,
R 3Be H, F, Cl, Br, A, OA or OCF 3,
R 4Be that F is arranged, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH 2, CONHA, CONA 2Or NO 2One replaces or polysubstituted phenyl, naphthyl or Het 2,
R 5Be OH, OA, NH 2, NHA or NA 2,
Het 1Be a kind of monocyclic or dicyclic heterocycle that 1～4 N atom is arranged, this heterocycle can be that nothing replaces or NH is arranged 2One replacement or dibasic,
Het 2Be a kind of aromatic series monocyclic or dicyclic heterocycle that 1～3 N, O and/or S atom are arranged, this heterocycle can be that nothing replaces or F be arranged, Cl, Br, A, OA, SA, OCF 3,-CO-A, CN, COOA, CONH 2, CONHA, CONA 2Or NO 2One replacement or dibasic,
Aryl is that nothing replaces or Hal is arranged, A, OA, OH, CO-A, CN, COOA, COOH, CONH 2, CONHA, CONA 2Or NO 2One replaces or polysubstituted phenyl or naphthyl,
A is the alkyl that 1～12 C atom is arranged,
N is 1,2,3,4,5 or 6,
M, o are 0,1,2,3,4,5 or 6 independently of one another under each situation,
Its prerequisite is R 4Being not equal to one has A or the monobasic phenyl or naphthyl of aryl,
And physiologically acceptable salt and solvate.
2. according to the compound of claim 1
A) 3-(4-fluorophenyl)-4-{4-[3-(pyridine-2-base is amino) propoxy-] phenyl } butyric acid,
B) 3-(4-fluorophenyl)-4-{4-[3-(2-aminopyridine-6-base is amino) propoxy-] phenyl } butyric acid,
C) 3-(4-fluorophenyl)-4-{4-[3-(2-aminooimidazole-5-base is amino) propoxy-] phenyl } butyric acid,
And physiologically acceptable salt and solvate.
3. according to the formula I compound of claim 1 and the preparation technology of salt thereof, it is characterized in that
A) by handling, formula I compound is discharged from its functional derivatives with a kind of solvolysis agent, reductive agent or hydrogenolysis agent, or
B) make radicals X and/or R 5Change into another kind of radicals X and/or R 5, its method for example is
I) by reacting, make amino group change into guanidino group with a kind of amidination agent,
Ii) make the ester hydrolysis,
Iii), make hydroxyamidines change into amidine by hydrogenation,
And/or make a kind of alkali or the acid of formula I change into one of its salt.
As medicament according to the formula I compound of claim 1 with according to compound and the physiologically acceptable salt and the solvate of claim 2.
5. according to the medicament of claim 4, be used for control based on α as a kind of inhibitor vβ 3The disease of integral protein receptor expression and pathology function.
6. according to the medicament of claim 5, be used to control thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, fibrosis, inflammation, infection, psoriasis, also can be used to influence wound healing process.
7. pharmaceutical preparation comprises according at least a medicament of one of claim 5 and 6 and comprises carrier and/or vehicle suitably the time, and comprises other active compound suitably the time.
8. the purposes that is used to produce medicament according to compound and/or its physiologically acceptable salt of claim 1 and 2, described medicament can be used for control based on α vβ 3The disease of integral protein receptor expression and pathology function.
9. according to the purposes of claim 8, be used to produce a kind of medicament, this medicament can be used for controlling the pathologic process that is subjected to the vasculogenesis support or expands because of vasculogenesis.
10. according to the purposes of claim 8, be used to produce a kind of medicament, this medicament can be used for controlling thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, fibrosis, inflammation, infection, psoriasis, also can be used to influence wound healing process.
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