CN1281451A - Benzamine derivatives - Google Patents

Benzamine derivatives Download PDF

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Publication number
CN1281451A
CN1281451A CN98812087A CN98812087A CN1281451A CN 1281451 A CN1281451 A CN 1281451A CN 98812087 A CN98812087 A CN 98812087A CN 98812087 A CN98812087 A CN 98812087A CN 1281451 A CN1281451 A CN 1281451A
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methyl
phenyl
oxazolidine
ylmethyl
amino
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D·多施
H·朱拉塞克
H·伍尔兹格
J·甘特
W·梅德斯基
H·P·布赫斯塔勒
S·安扎利
S·贝尔诺塔特－达尼洛夫斯基
G·梅策尔
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Merck Patent GmbH
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The invention relates to novel compounds of formula (I) wherein X, Y, W, R1, R2, R3 and R4 have the meaning cited in Claim 1. The inventive compounds are inhibitors of coagulation factor Xa and can be used in prophylaxis and/or therapy for thromboembolic diseases.

Description

Benzamine derivatives
The present invention relates to formula I compound and its salt Wherein
R 1Be-C (=NH)-NH 2, this group can be replaced by the following groups list :-COA ,-CO-[C (R 5) 2] m-Ar ,-COOA ,-amino protecting group of OH or a routine,
Figure 9881208700122
Or
R 2Be H, A, OR 5, N (R 5) 2, NO 2, CN, Hal, NR 5COA, NHCOAr, NHSO 2A, NHSO 2Ar, COOR 5, CON (R 5) 2, CONHAr, COR 5, COAr, S (O) nA or S (O) nAr,
R 3Be R 5Or-[C (R 5) 2] m-COOR 5,
R 3Can also be-CO-N-to form five-ring thus, wherein R with X 3Be-C=O and X are N,
R 4Be A, cycloalkyl ,-[C (R 5) 2] mAr ,-[C (R 5) 2] mHet or-CR 5=CR 5-Ar,
R 5Be H, A or benzyl,
X is O, NR 5Or CH 2,
Y is O, NR 5, N[C (R 5) 2] m-Ar, N[C (R 5) 2] m-Het, N[C (R 5) 2] m-COOR 5, N[C (R 5) 2] m-COOR 5,
Figure 9881208700131
Figure 9881208700132
N[C (R 5) 2] m-CON (R 5) 2, N[C (R 5) 2] m-CONR 5Ar or N[C (R 5) 2] m-CONAr 2,
W be a key ,-SO 2-,-CO-,-COO-or-CONR 5-,
A is the alkyl with 1-20 carbon atom, one of them or two CH 2Base can be by O or S atom or quilt-CR 5=CR 5-group substitutes, and/or 1-7 wherein H atom can substitute by F,
Ar is naphthyl or phenyl, they be unsubstituted or by following groups single, double or three replacements: R 1, A, Ar, OR 5, N (R 5) 2, NO 2, CN, Hal, NHCOA, NHCOAr ', NHSO 2A, NHSO 2Ar ', COOR 5, CON (R 5) 2, CONHAr ', COR 5, COAr ', S (O) nA or S (O) nAr,
Ar ' is naphthyl or phenyl, and they can be unsubstituted or single, double or trisubstituted by following groups: R 1, A, OR 5, N (R 5) 2, NO 2, CN, Hal, NHCOA, COOR 5, CON (R 5) 2, COR 5Or S (O) nA,
Het is saturated or undersaturated monocycle or bicyclic heterocycle system, this ring system contains one, two, three or four identical or different heteroatoms, for example nitrogen, oxygen and sulphur, and this ring system is unsubstituted or is replaced or polysubstituted by following groups is single: Hal, A, Ar ', OR 5, COOR 5, CN, N (R 5) 2, NO 2, NHCOA, NHCOAr ' and/or ketonic oxygen,
Hal is F, Cl, Br or I,
M is 0,1,2,3 or 4,
N is 0,1 or 2.
The present invention also provides optical activity form, racemic modification, diastereomer and hydrate and the solvate of these compounds.
Valuable based on having found to have, be particularly useful for preparing the new compound of medicinal property and finished the present invention.
Present inventor's discoverable type I compound and salt thereof have very useful pharmacological property and good tolerability.Specifically, they have factor Xa rejection characteristic, therefore can be used for antagonism and prevention thromboembolic disorders, for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication.
Aromatic Amidine derivatives with anti thrombotic action for example can be known from EP 0540051 B1.The annular guanidine of treatment thromboembolic disease also is recorded in, for example among the WO 97/08165.Have the active aromatic heterocycle of factor Xa inhibitor, for example can from WO 96/10022, know.
The antithrombotic of The compounds of this invention form and anticoagulation owing to activation blood coagulating protein enzyme, the known restraining effect that is called factor, perhaps owing to other are activated serine protease, for example restraining effect of factor VII a, factor or zymoplasm.
Xa factor is one of proteolytic enzyme that participates in complicated blood clotting process.X a factor catalysis thrombogen is to the conversion of zymoplasm.Zymoplasm is cracked into fibrin monomer with Fibrinogen, and this monomer is crosslinked subsequently, and thrombosis is played the essence effect.The activation of zymoplasm can cause the generation of thromboembolic disorders.The scleroproein that Trombin inhibiting can suppress to relate in the thrombosis forms.
To the restraining effect of zymoplasm can, for example by G.F.Cousins etc. in " circulation " (Circulation) 1996,94, the method for describing among the 1705-1712 is measured.
Therefore, supressor X a can prevent thrombosis.
Formula I compound of the present invention and salt thereof are intervened the blood clotting process and are therefore suppressed thrombosis by supressor X a.
Formula I compound of the present invention also has the function as the inhibitor of the serum prothrombin conversion accelerator (SPCA) a factor, the IX a factor and zymoplasm in the blood coagulation chain.
The compounds of this invention can be measured by method in the conventional external or body the restraining effect of factor and anti-freezing and anti-thrombus activity.A kind of suitable method is, for example J.Hauptmann etc. is at " thrombosis and hemostasis " (Thrombosis and Haemostasis) 63, the method for 220-223 (1990) record.
The restraining effect of Xa factor also can, for example by T.Hara etc. in " thrombosis and hemostasis " (Thromb.Haemostas.) 71, the method for describing among the 314-319 (1994) is measured.
With after tissue factor combines, the endogenic reaction part that blood clotting factor VII a causes the blood clotting chain also makes factor X activation be factor Xa.Therefore the inhibition of factor VII a is stoped the formation of factor Xa, stoped the formation of thrombus subsequently.
The compounds of this invention can adopt in the conventional external and body method to measure to the restraining effect of factor VII a and anti-freezing and anti-thrombus activity.The inhibiting ordinary method of a kind of mensuration factor VII a is, for example H.F.Ronning etc. puts down in writing among the 73-81 in " thrombosis research " (ThrombrosisResearch) 1996,84.
Formula I compound can medicament forms be applied to the people and uses with the veterinary drug form, especially for antagonism and prevention thromboembolic disorders, for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication.
The invention provides formula I compound and salt thereof, the formula I compound of preparation claim 1 and the method for salt thereof also are provided, be characterised in that
A) they obtain by dissociating with one of solvolysis or their functional derivatives of hydrogenolysis agent treated:
ⅰ) dissociate amidino groups by Qi oxadiazole derivative of hydrogenolysis Cong,
ⅱ) by with solvolysis or hydrogenolysis agent treated, replace conventional amino protecting group with hydrogen, perhaps the amino with the protection of GPF (General Protection False base dissociates out, or
B) be preparation,
R wherein 1Be
Figure 9881208700151
Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700153
Or
Figure 9881208700154
W is-SO 2-or-CO-,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700161
R wherein 1Be
Figure 9881208700162
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is Or
Figure 9881208700164
And R 2And R 5Such as claim 1 definition,
With the reaction of formula III compound, R 4-W-L III
Wherein W is-SO 2-or-CO-,
R 4Such as claim 1 definition,
And L is Cl, Br, I or free or reactive functional group deutero-OH group, perhaps
C) be wherein R of preparation 1Be
Figure 9881208700171
Or
Figure 9881208700172
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is O,
W is a key,
And R 2And R 4Such as claim 1 definition,
With formula II compound,
R wherein 1Be Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is O,
And R 2Such as claim 1 definition,
With the reaction of formula IV compound, R 4-W-OH IV
Wherein W is a key,
And R 4Such as claim 1 definition,
Perhaps d) be preparation
R wherein 1Be
Figure 9881208700181
Or
Figure 9881208700182
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
W is a key,
R 4Be-[C (R 5) 2] mAr or-[C (R 5) 2] mHet,
M is 0,
And R 2Such as claim 1 definition,
With formula V compound
R wherein 1Be
Figure 9881208700191
Or
Figure 9881208700192
R 3With X be together-CO-N-, form 5 yuan of rings thus,
L is Cl, Br, I or free or reactive functional groups deutero-OH base,
And R 2Define as claim,
With the reaction of formula VI compound, R 4-W-Y-H VI
Wherein W is a key,
Y is
R 4Be-[C (R 5) 2] mAr or-[C (R 5) 2] mHet,
M is 0,
Perhaps e) be preparation,
R wherein 1Be
Figure 9881208700194
Or
Figure 9881208700195
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700201
Or
Figure 9881208700202
W is-CONH-,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700203
R wherein 1Be
Figure 9881208700204
Or
Figure 9881208700205
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700206
Or
Figure 9881208700211
And R 2And R 5Such as claim 1 definition,
With the reaction of formula VII compound, R 4-N=C=O VII
Wherein
R 4Such as claim 1 definition,
Perhaps f) be preparation,
R wherein 1Be
Figure 9881208700212
Or
Figure 9881208700213
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
W is SO 2,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700214
R wherein 1Be
Figure 9881208700221
Or
Figure 9881208700222
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
And R 2And R 5Such as claim 1 definition,
With the reaction of formula VIII compound, R 4-SO 2-L VIII
Wherein
L is Cl, Br, I or free or reactive functional group deutero-OH group,
And R 4Such as claim 1 definition,
Perhaps g) be preparation,
Wherein
X be NH and
R 3Be H,
And R 1, R 2, R 4, Y and W such as claim 1 definition,
These compounds can obtain by being dissociated by their De oxazolidone derivatives with solvolysis or hydrogenolysis agent treated,
Perhaps h) for preparing wherein R 1Be-C (=NH)-NH 2Formula I compound,
Cyano group is converted into corresponding amidino groups,
Perhaps
ⅰ) in formula I compound, can be by following method for example with one or more group Y, R 1, R 2, R 3And/or R 4Be converted into one or more radicals R 1, R 2, R 3And/or R 4:
ⅰ) hydrolysis of ester group is a carboxyl,
ⅱ) reduction nitro,
ⅲ) acidylate amino,
And/or
K) alkali or the acid with the formula I is converted into its salt.
For various groups for several times, for example R occurring 5, its implication separately is independent of each other.
Except as otherwise noted, in context, group or parameter L, W, X, Y, R 1 2, R 2, R 3, R 4, R 5, m and n have the implication that the formula I provides to the III.
Solvate is an addition compound, for example with organic inert solvent, as with alcohols, for example addition compound of methyl alcohol, ethanol or propyl alcohol.
In the superincumbent structural formula, A has 1-20, the straight or branched alkyl of preferred 1,2,3,4,5,6,7,8,9,10,11 or 12 carbon atom.A is methyl preferably; Also have ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl; Can also be amyl group, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2, the 2-dimethyl propyl, 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-or 1,2,2-trimethylammonium propyl group, heptyl, octyl group, nonyl or decyl.
A can also be, for example, and trifluoromethyl, pentafluoroethyl group, allyl group or crot(on)yl.
OR 5Be OH, OA or benzyloxy, OA is methoxyl group, oxyethyl group, propoxy-, butoxy or hexyloxy preferably.
Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl preferably.Cycloalkyl can also be that for example, bicyclic terpene is as the 3-menthyl; Especially preferably camphor-10-base.
COR 5Be acyl group, preferably formyl radical, ethanoyl, propionyl can also be butyryl radicals, pentanoyl or caproyl.
Hal is F, Cl or Br preferably, but also can be I.
R 2Preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl group, oxyethyl group, propoxy-, nitro, amino, methylamino-, dimethylamino, ethylamino, diethylin, kharophen, sulfonamido, methanesulfonamido, phenylsulfonamido, methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, phenyl sulfinyl, phenyl sulfonyl, cyano group, carboxyl, methoxycarbonyl, ethoxycarbonyl can also be acyl group or benzoyl.
R 2Especially preferably H.
R 3Preferably A, benzyl, CH 2COOH or CH 2COOA, but H particularly.
R 4Preferably, for example, A, cycloalkyl, Ar, CH 2Ar, CH 2CH 2Ar, CH 2Het, CH 2CH 2Het or CH=CH-Ar.
R 5Be H, A or benzyl, but H especially.
X is O, NH, NA or N-benzyl, can also be CH 2
R 3Be-CO-N-to form 5 yuan of rings thus together with X.
Y preferably, for example O, NH, N-methyl, N-ethyl, N-Ar, N-CH 2-Ar, N-Het, N-CH 2-Het, N-COOA, N-CH 2-COOA, N-CH 2-COOH, N-CH 2-COO benzyl,
NCH 2-CONH 2, NCH 2-CONHA, NCH 2-CONA 2, NCH 2-CONR 5Ar or NCH 2-CONAr 2
W preferably, for example, key ,-SO 2-or-CO-, can also be-COO-or-CONH-.
The preferably unsubstituted phenyl or naphthyl of Ar; also preferably by for example following groups one; two or trisubstituted naphthyl or phenyl: A; fluorine; chlorine; bromine; iodine; hydroxyl; methoxyl group; oxyethyl group; propoxy-; butoxy; pentyloxy; hexyloxy; benzyloxy; the benzene oxyethyl group; methylthio group; ethylmercapto group; methylsulfinyl; the ethyl sulfinyl; methyl sulphonyl; ethylsulfonyl; the phenyl sulfinyl; phenyl sulfonyl; nitro; amino; methylamino-; ethylamino; dimethylamino; diethylin; formamido group; kharophen; propionamido; butyrylamino; methanesulfonamido; ethanesulfonamido; third sulfonamido; the fourth sulfonamido; phenylsulfonamido; (4-tolyl) sulfonamido; the carboxyl methoxyl group; the carboxyl oxyethyl group; the methoxycarbonyl methoxyl group; the methoxycarbonyl oxyethyl group; the hydroxyl methoxyl group; hydroxyl-oxethyl; methoxy ethoxy; carboxyl; methoxycarbonyl; ethoxycarbonyl; cyano group; the phenyl amino formyl radical; acyl group or benzoyl can also be xenyls.
Therefore, Ar preferably, for example; adjacent-; between-or right-tolyl, adjacent-; between-or right-ethylbenzene base, adjacent-; between-or right-propyl group phenyl; adjacent-; between-or right-isopropyl phenyl, adjacent-; between-or right-tert-butyl-phenyl, adjacent-; between-or right-hydroxy phenyl; adjacent-; between-or right-nitrophenyl, adjacent-; between-or right-aminophenyl, adjacent-; between-or right-(N-methylamino-) phenyl; adjacent-; between-or right-acetylamino phenyl, adjacent-; between-or right-p-methoxy-phenyl, adjacent-; between-or right-ethoxyl phenenyl; adjacent-; between-or right-carboxyl phenyl; adjacent-; between-or right-methoxycarbonyl phenyl, adjacent-; between-or right-(N, N-dimethylamino) phenyl; adjacent-; between-or right-(N-ethylamino) phenyl; adjacent-; between-or right-(N, N-diethylin) phenyl, adjacent-; between-or right-acetyl phenyl; adjacent-; between-or right-formylphenyl; adjacent-; between-or right-fluorophenyl, adjacent-; between-or right-bromophenyl, adjacent-; between-or right-chloro-phenyl-; adjacent-; between-or right-methylsulfonyl phenyl; adjacent-; between-or right-(phenylsulfonamido) phenyl, adjacent-; between-or right-(methanesulfonamido) phenyl, adjacent-; between-or right-methylthio group phenyl; also preferably 2; 3-; 2,4-; 2,5-; 2; 6-; 3; 4-or 3,5-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; 2,4-or 2,5-dinitrophenyl; 2; 5-or 3,4-Dimethoxyphenyl, 3-nitro-4-chloro-phenyl-; 3-amino-4-chloro-; 2-amino-3-chloro-; 2-amino-4-chloro-; 2-amino-5-chloro-or 2-amino-6-chloro-phenyl-; 2-nitro-4-N, the N-dimethylamino-or 3-nitro-4-N, the N-dimethylamino phenyl; 2; the 3-diamino-phenyl, 2,3; 4-; 2; 3,5-; 2,3; 6-; 2; 4,6-or 3,4; the 5-trichlorophenyl; 2,4, the 6-trimethoxyphenyl; 2-hydroxyl-3; the 5-dichlorophenyl, right-iodophenyl, 3; 6-two chloro-4-aminophenyls; 4-fluoro-3-chloro-phenyl-, 2-fluoro-4-bromophenyl, 2; 5-two fluoro-4-bromophenyls; 3-bromo-6-p-methoxy-phenyl, 3-chloro-6-p-methoxy-phenyl, 3-chloro-4-acetylamino phenyl; 3-fluoro-4-p-methoxy-phenyl; 3-amino-6-aminomethyl phenyl, 3-chloro-4-acetylamino phenyl or 2,5-dimethyl-4-chloro-phenyl-.
Ar is extremely preferably unsubstituted or by following groups one, two or trisubstd phenyl: amino, OR 5, Hal, CN, a 1-10 carbon atom alkyl, CF 3, CH 3SO 2, OCF 3, kharophen ,-C (=NH)-NH 2, methoxycarbonyl or ethoxycarbonyl, also preferably by the monobasic naphthyl of following groups: the alkoxyl group of Hal, a dimethylamino or 1-6 carbon atom, and unsubstituted biphenyl group.
Ar ' especially; for example, phenyl or naphthyl, also preferably adjacent-; between-or right-tolyl; adjacent-; between-or right-ethylbenzene base; adjacent-; between-or right-propyl group phenyl, adjacent-; between-or right-isopropyl phenyl, adjacent-; between-or right-tert-butyl-phenyl; adjacent-; between-or right-hydroxy phenyl; adjacent-; between-or right-nitrophenyl, adjacent-; between-or right-aminophenyl, adjacent-; between-or right-(N-methylamino-) phenyl; adjacent-; between-or right-acetylamino phenyl; adjacent-; between-or right-p-methoxy-phenyl, adjacent-; between-or right-ethoxyl phenenyl, adjacent-; between-or right-carboxyl phenyl; adjacent-; between-or right-methoxycarbonyl phenyl; adjacent-; between-or right-(N, N-dimethylamino) phenyl, adjacent-; between-or right-(N-ethylamino) phenyl; adjacent-; between-or right-(N; the N-diethylin) phenyl, adjacent-; between-or right-acetyl phenyl, adjacent-; between-or right-formylphenyl; adjacent-; between-or right-fluorophenyl; adjacent-; between-or right-bromophenyl, adjacent-; between-or right-chloro-phenyl-, adjacent-; between-or right-methylsulfonyl phenyl.
Het preferably, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl, 1,2,3-triazoles-1-preferably also,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3-oxadiazole-4-or-the 5-base, 1,2,4-oxadiazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 4-or 5-pseudoindoyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzoisoxazole base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzo-2,1,3-oxadiazole 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-quinazolyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo [1,4] oxazinyl, also preferably 1,3-benzo dioxolane-5-base, 1,4-benzodioxane-6-base, 2,1,3-diazosulfide-4-or-5-base or 2,1,3-Ben Bing oxadiazole-5-base.
Heterocyclic group can be a hydrogenant partially or completely.
Het also can be, for example, 2,3-dihydro-2-,-3-,-4-or-the 5-furyl, 2,5-dihydro-2-,-3-,-4-or-the 5-furyl, tetrahydrochysene-2-or-the 3-furyl, 1,3-dioxolane-4-base, tetrahydrochysene-2-or-the 3-thienyl, 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, 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, 2-, 3-or 4-morpholinyl, tetrahydrochysene-2-,-3-or-the 4-pyranyl, 1,4-dioxane base, 1,3-dioxane-2-,-4-or-the 5-base, 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-the 8-isoquinolyl, 2-, 3-, 5-, 6-, 7-or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, in addition preferably 2, the 3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy phenyl, 3,4-ethylenedioxy phenyl, 3,4-(difluoro methylene-dioxy) phenyl, 2,3-Dihydrobenzofuranes-5-or-the 6-base, 2,3-(2-oxo-methylene-dioxy) phenyl or 3,4-dihydro-2H-1,5-benzo two oxa--6-or-the 7-base, also preferably 2,3-dihydro benzo furyl or 2,3-dihydro-2-oxo-furyl.
Het is unsubstituted or single or polysubstituted by following groups: Hal, A, Ar ', COOR 5, CN, N (R 5) 2, NO 2, Ar-CONH-CH 2" many " are meant two, three, four or five.
Het especially preferably thiazole-2-,-4-or-the 5-base, thiophene-2-or-the 5-base, chroman-6-base, pyridine-2-,-3-or-the 4-base, pyrimidine-2-or-the 5-base, thionaphthene-2-base, 1,3-benzo dioxolane-4-or-the 5-base, 1,4-benzodioxane-5-or-the 6-base, 2,1,3-diazosulfide-4-or-the 5-base, they are unsubstituted or single or polysubstituted by following groups: Hal, A, phenyl, OR 5, COOR 5, CN, N (R 5) 2, NO 2, NHCOA, NHCO phenyl and/or ketonic oxygen.
Formula I compound can have one or more chiral centres, therefore can exist by various stereoisomer forms.Formula I compound comprises these all forms.
So at least one that the invention provides above-mentioned group wherein has those formula I compounds of a kind of preferred meaning that provides above.The available following structure division I a corresponding to the formula I of some preferred compound group represents wherein do not have the further concrete group that limits to have the implication that provides in the formula I to I i, but
In I a, R 2Be H;
In I b, R 3Be R 5Or-(CH 2) m-COOR 5
In I c, R 4Be A, cycloalkyl ,-(CH 2) mAr ,-(CH 2) mHer or-CH=CH-Ar;
In I d, Y is O, NR 5, N (CH 2) m-Ar, N (CH 2)-Het, N (CH 2) m-COOR 5,
Figure 9881208700271
In I e, A is the alkyl with 1-20 carbon atom, one or two CH wherein 2Group can be substituted by-CH=CH-group and/or 1-7 H atom can be substituted by F;
In I f, Ar is unsubstituted or by following groups one, two or trisubstituted naphthyl or phenyl: R 1, A, phenyl, OR 5, N (R 5) 2, NO, CN, Hal, NHCOA, NHCO phenyl, NHSO 2A, NHSO 2Phenyl, COOR 5, CON (R 5) 2, CONH phenyl, COR 5, CO phenyl, S (O) nA or S (O) nAr;
In I g, Ar ' is a phenyl;
In I h, Het be thiazole-2-,-4-or-the 5-base, thiophene-2-or-the 5-base, chroman-6-base, pyridine-2-,-3-or-the 4-base, pyrimidine-2-or-the 5-base, thionaphthene-2-base, 1,3-benzo dioxolane-4-or-the 5-base, 1,4-benzodioxane-5-or-6-base or 2,1,3-diazosulfide-4-or-the 5-base, they are unsubstituted or single or polysubstituted by following groups: Hal, A, phenyl, OR 5, COOR 5, CN, N (R 5) 2, NO 2, NHCOA, NHCO phenyl and/or ketonic oxygen;
In I i, R 1Be-C (=NH)-NH 2, this group also can be replaced by the following groups list :-COA ,-CO-(CH 2) m-Ar ,-COOA or OH,
Or
Figure 9881208700281
R 2Be H,
R 3Be R 5Or-(CH 2) m-COOR 5,
R 3With X can also be together-CO-N-, form 5 yuan of rings thus,
R 4Be A, cycloalkyl ,-(CH 2) mAr ,-(CH 2) mHet or-CH=CH-Ar,
R 5Be H, A or benzyl,
X is O, NR 5Or CH 2,
Y is O, NR 5, N (CH 2) m-Ar, N (CH 2) m-Het, N (CH 2) m-COOR 5,
Figure 9881208700291
NCH 2-CONH 2, NCH 2-CONHA, NCH 2-CONA 2, NCH 2-CONR 5Ar or NCH 2-CONAr 2, W be a key ,-SO 2-,-CO-,-COO-or-CONH-, A is the alkyl with 1-20 carbon atom, one of them or two CH 2Can by-
The CH=CH-group substitutes and/or 1-7 H atom can be substituted by F,
Ar is unsubstituted or by following groups one, two or trisubstd phenyl: NH 2, OR 5, Hal, CN, alkyl, CF with 1-10 carbon atom 3, CH 3SO 2, OCF 3, kharophen ,-C (=NH)-NH 2, methoxycarbonyl or ethoxycarbonyl, can also be by mono-substituted naphthyl of Hal, dimethylamino or methoxyl group or unsubstituted biphenyl group.
Het be thiazole-2-,-4-or-the 5-base, thiophene-2-or-the 5-base, chroman-6-base, pyridine-2-,-3-or-the 4-base, pyrimidine-2-or-the 5-base, thionaphthene-2-base, 1,3-benzo dioxolane-4-or-the 5-base, 1,4-benzodioxane-5-or-6-base or 2,1,3-diazosulfide-4-or-the 5-base, they are unsubstituted or single or polysubstituted by following groups: Hal, A, phenyl, OR 5, COOR 5, CN, N (R 5) 2, NO 2, NHCOA, NHCO phenyl and/or ketonic oxygen.
Formula I compound can be by the method preparation of previously known with the raw material that synthesizes them, for example the method for describing in the document is (as standard method, referring to, as Houben-Weyl, Methodender organischen Chemie[organic chemistry method], Georg-Thieme-Verlag, Stuttgart), specifically known and be suitable for carrying out under the reaction conditions of above-mentioned reaction.In these reactions, available various variations are previously knowns, are not described in detail at this.
If desired, can form raw material on the spot, they need not be separated from reaction mixture like this, just can directly further react, and obtain formula I compound.
Formula I compound preferably obtains by dissociating with solvolysis or their functional group derivant of hydrogenolysis agent treated.
The preferred feedstock that is used for solvolysis or hydrogenolysis is those corresponding formula I compounds that comprise corresponding protected amino and/or hydroxyl (replacing one or more free amine groups and/or hydroxyl); preferably have amino protecting group those compounds of (replacing and N atom bonded H atom); especially preferably have R '-N group those compounds of (replacing the HN group); wherein R ' is an amino protecting group; and/or those have those compounds of hydroxyl protecting group (the H atom that replaces hydroxyl); for example have-COOR " (replace-COOH) corresponding formula I compound, wherein R " be hydroxyl protecting group.
Preferred raw material also comprises can be converted into corresponding amidino compounds De oxadiazole derivative.
By for example with cyano compound and azanol reaction, again with phosgene, dialkyl carbonate, chloro-formic ester, N, N '-carbonyl dimidazoles or acetic anhydride Yin Ru oxadiazole group.
In raw molecule, can there be several identical or different protected amino and/or hydroxyls.If the protecting group that exists differs from one another, optionally cracking is removed in many cases.
Term " amino protecting group " is usually known, relates to the group that is suitable in chemical reaction protection (blocking-up) amino but is easy to remove behind the required chemical reaction that carries out in other positions of molecule.Specifically, typically these groups are acyl group, aryl, aralkoxy methyl or aralkyl unsubstituted or that replace.Because amino protecting group is removed after required reaction (or response procedures), therefore their character and size are not strict with; But preferably has 1-20, especially the group of 1-8 carbon atom.Term " acyl group " should be interpreted as broad sense in the method for the invention.It comprises by aliphatic series, araliphatic, fragrance or heterocyclic carboxylic acid or sulfonic acid deutero-acyl group, specifically carbalkoxy, aryloxy carbonyl and at first be aralkoxycarbonyl.The example of this class acyl group comprises alkanoyl, as ethanoyl, propionyl or butyryl radicals; The virtue alkanoyl is as phenylacetyl; Aroyl, for example benzoyl or toluyl; The aryloxy alkanoyl is as POA; Carbalkoxy, as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, BOC (tertbutyloxycarbonyl), 2-iodo ethoxycarbonyl; Aralkoxycarbonyl is as CBZ (" carbobenzoxy "), 4-methoxyl group benzyloxy carbonyl, FMOC; Aryl sulfonyl is as Mtr.Preferred amino protecting group is BOC and Mtr, also has CBZ, Fmoc, benzyl and ethanoyl.
Term " hydroxyl protecting group " is usually known, relates to the group that is suitable for protecting hydroxyl in chemical reaction but is easy to remove behind the required chemical reaction that carries out in other positions of molecule.Typical these groups are above-mentioned unsubstituted or aryl, aralkyl or acyl groups of replacing, can also be alkyl.Because amino protecting group is removed after required reaction (or response procedures), therefore their character and size are not strict with; But preferably has 1-20, especially the group of 1-10 carbon atom.Especially, the example of hydroxyl protecting group is benzyl, p-nitrophenyl formyl radical, p-toluenesulfonyl, the tertiary butyl and ethanoyl, and the benzyl and the tertiary butyl are particularly preferred.
According to the protecting group that adopts, formula I compound can use from dissociating of its functional group derivant, and for example strong acid carries out, and is to use TFA or perchloric acid easily, but also can use other strong inorganic acids, for example hydrochloric acid or sulfuric acid; Strong organic carboxyl acid is as trichoroacetic acid(TCA); Perhaps sulfonic acid is as Phenylsulfonic acid or tosic acid.May but always do not need other inert solvents to exist.Suitable inert solvent is organic solvent preferably, and carboxylic acid for example is as acetate; Ethers is as tetrahydrofuran (THF) Huo diox; Amides is as DMF; Halogenated hydrocarbon is as methylene dichloride; Maybe can also be alcohols, for example methyl alcohol, ethanol or Virahol; And water.Also can use the mixture of above-mentioned solvent.TFA is preferably with excessive use, and need not to add other solvents, and perchloric acid is that 9: 1 the acetate and the form of mixtures of 70% perchloric acid are used with ratio.At about 0 ℃ to 50 ℃, preferably 15-30 ℃ (room temperature) under carry out easily by this reaction for the cracked temperature of reaction.
Group B OG, OBut and Mtr preferably use TFA in methylene dichloride under 15-30 ℃, perhaps remove with about 3-5N HCl cracking in the Zai diox; The FMOC group can be removed with dimethylamine, diethylamine or the piperidines cracking of about 5-50% down in 15-30 ℃ in DMF.
The protecting group that can remove by hydrogenolysis (for example Qi oxadiazole derivative of CBZ, benzyl or Cong dissociate amidino groups) can, for example, in the presence of catalyzer (as noble's metal catalyst, as easily at the palladium on upholder such as the carbon), handle cracking and remove with hydrogen.The suitable solvent of this reaction is above-mentioned those, and especially, alcohols for example is as methyl alcohol or ethanol; Perhaps amides is as DMF.Hydrogenolysis is usually under about 0 ℃ to 100 ℃, under about 1-200 bar pressure, preferably carries out under 20-30 ℃ and 1-10 crust.Can for example use 10% Pd/C in methyl alcohol easily, perhaps use ammonium formiate (replacement hydrogen) with Pd/C in methyl alcohol/DMF in 20-30 ℃ of following hydrogenolysis CBZ group.
Formula I compound
R wherein 1Be Or
R 2With X be together-CO-N-, form 5 yuan of rings thus,
Y is Or
Figure 9881208700324
W is-SO 2-or-CO-,
And R 2And R 4Such as claim 1 definition,
Can be preferably by formula II compound and the reaction of formula III compound be obtained.
In formula III compound, L is Cl, Br, I or the reactive OH group of modifying preferably, Acibenzolar for example, acyl imidazoles (imidazolide) or have the alkylsulfonyloxy (preferred mesyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl sulfonyloxy or tolysulfonyl oxygen base) of 6-10 carbon atom.
This reaction is carried out in the presence of acid binding agent in inert solvent usually, described acid binding agent is alkali metal hydroxide, carbonate or supercarbonate or alkaline earth metal hydroxides, carbonate or supercarbonate preferably, perhaps the faintly acid salt of other basic metal or alkaline-earth metal, preferred potassium, sodium, calcium or caesium.Add organic bases, for example triethylamine, xylidine, pyridine or quinoline or excessive formula II amine component or the alkyl derivative of formula III also are useful.According to the condition that adopts, the reaction times can be from several minutes to 14 days, and temperature of reaction is between 0 ℃ and 150 ℃, usually between 20 ℃ to 130 ℃.
Suitable inert solvent is that for example, hydro carbons is as hexane, sherwood oil, benzene, toluene or dimethylbenzene; Hydrochloric ether, trichloroethane, 1 for example, 2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohols, for example methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, the trimethyl carbinol; Ethers, for example ether, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox; Glycol ethers, for example ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); Ketone, for example acetone or butanone; Amides, for example ethanamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone (NMP) or dimethyl formamide (DMF); Nitrile, for example acetonitrile; Sulfoxide class, for example dimethyl sulfoxide (DMSO) (DMSO); Dithiocarbonic anhydride; Carboxylic-acid, for example formic acid or acetate; Nitro-compound, for example Nitromethane 99Min. or oil of mirbane; Ester class, for example ethyl acetate; The perhaps mixture of described solvent.
The raw material of formula II and formula III is normally known.Yet those new compounds can be by the method preparation of previously known.
Formula I compound
R wherein 1Be Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is O,
W is a key,
And R 2And R 4Such as claim 1 definition,
Can be preferably by in inert solvent, in the presence of for example triphenylphosphine and azoethane dicarboxylic ester, be that formula II compound and the formula IV compound of O carries out Mitsunobu and react and obtain with Y wherein.
Wherein Y is that the raw material of the formula II raw material of O and formula IV is normally known.Yet those new compounds can be by the method preparation of previously known.
Formula I compound
R wherein 1Be Or
Figure 9881208700342
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700343
W is a key,
R 4Be-[C (R 5) 2] mAr or-[C (R 5) 2] mHet,
M is 0,
And R 2Such as claim 1 definition,
Can be preferably by formula V compound and the reaction of formula VI compound be obtained.
In formula V compound, L is Cl, Br, I or the reactive OH group of modifying preferably, Acibenzolar for example, acyl imidazoles or have the alkylsulfonyloxy (preferred mesyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl sulfonyloxy or tolysulfonyl oxygen base) of 6-10 carbon atom.
The reaction of formula V compound and formula VI compound preferably in inert solvent and above shown in temperature under carry out.
The raw material of formula V and formula VI is normally known.Yet those new compounds can be by the method preparation of previously known.
Formula I compound
R wherein 1Be Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is Or
Figure 9881208700352
W is-CONH-,
And R 2And R 4Such as claim 1 definition,
Can preferably pass through formula II compound
R wherein 1Be Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is Or
W is-CONH-,
And R 2And R 5Such as claim 1 definition,
Obtain with the reaction of formula VII compound.
Wherein W be-these formula II compounds of CONH-and the reaction of formula VII compound preferably in inert solvent and above shown in temperature under carry out.
Wherein W be-the formula II raw material of CONH-and the raw material of formula VII are normally known.Yet those new compounds can be by the method preparation of previously known.
Formula I compound
R wherein 1Be Or
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
W is SO 2,
And R 2And R 4Such as claim 1 definition,
Can preferably pass through formula II compound
R wherein 1Be
Figure 9881208700363
Or
Figure 9881208700364
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
And R 2And R 5Such as claim 1 definition,
Obtain with the reaction of formula VIII compound.
In formula VIII compound, L is Cl, Br, I or the reactive OH group of modifying preferably, Acibenzolar for example, acyl imidazoles or have the alkylsulfonyloxy (preferred mesyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl sulfonyloxy or tolysulfonyl oxygen base) of 6-10 carbon atom.
Wherein Y is N[C (R 5) 2] m-COOR 5Formula II compound and the reaction of formula VIII compound preferably in inert solvent and above carry out under the temperature that provides.
Formula I compound, wherein
X be NH and
R 3Be H,
And R 1, R 2, R 4, Y and W such as claim 1 definition,
Can obtain by dissociating with solvolysis or their De oxazolidone derivatives of hydrogenolysis agent treated.This is reflected at as carrying out under the condition of describing in " protecting group is removed ".
R wherein 1Be-C (=NH)-NH 2Formula I compound also can obtain by corresponding cyano compound.
Cyano group carries out to the conversion of amidino groups is following: by with, azanol reaction for example, subsequently at catalyzer, for example the existence of Pd/C is narrowed with hydrogen reduction N-hydroxyl down.
Be the amidine of preparation formula I (R wherein 1Be-C (=NH)-NH 2), also ammonia can be added to the nitrile (R of formula I 1=CN) in.Adding preferably divides several steps to carry out according to the mode of previously known: a) use H 2S is converted into thioamides with nitrile, again with alkylating reagent for example methyl iodide thioamides is converted into corresponding S-alkyl-imino-monothioester, obtain amidine with ammonia react then; B) in the presence of HCl, nitrile with alcohol for example Ethanol Treatment be converted into corresponding imino esters, then with itself and ammonia react; Perhaps c) with the reaction of nitrile and two (trimethyl silyl) Lithamide, then with the product hydrolysis.
In addition; can following a kind of formula I compound be changed into another kind of formula I compound: by acidylate amino or with nitroreduction for amino (for example inert solvent for example in methyl alcohol or the ethanol through Raney nickel or Pd/ carbon catalytic hydrogenation), with one or more group Y, R 1, R 2, R 3And/or R 4Be converted into one or more group Y, R 1, R 2, R 3And/or R 4
Ester can be hydrolyzed in 0 ℃-100 ℃ in water, water-THF or water-diox with acetate or sodium hydroxide or potassium hydroxide.
Also can be according to ordinary method, with acyl chlorides or acid anhydrides acidylate free amine group; Perhaps with alkylogen unsubstituted or that replace, easily inert solvent for example among methylene dichloride or the THF and/or alkali for example triethylamine or pyridine in the presence of carry out alkylation between in-60 to+30 ℃.
The alkali usable acid of formula I is converted into relevant acid salt, and for example by the described alkali and the acid of equivalent are for example reacted in the ethanol at inert solvent, evaporation subsequently transforms.The acid that can obtain physiological acceptable salt is particularly suitable for this reaction.For this reason, can use mineral acid, sulfuric acid for example, nitric acid, haloid acid is (as spirit of salt, Hydrogen bromide), phosphoric acid (as ortho-phosphoric acid), thionamic acid, or organic acid, especially aliphatic, alicyclic, araliphatic, aromatics or heterocyclic monobasic or polycarboxylic acid, 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-sulfonic acid or naphthalene disulfonic acid and lauryl sulfate.The salt of the unacceptable acid of physiology, for example picrate can be used for separating and purifying formula I compound.
On the other hand, formula I compound available bases (as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood) is converted into corresponding metal salt, especially basic metal or alkaline earth salt, perhaps is converted into corresponding ammonium salt.
Also can use the acceptable organic bases of physiology, for example thanomin.
Because the molecular structure of formula I compound of the present invention, they can be chiralitys, so can exist with various enantiomeric forms.Therefore, they can racemic modification or the existence of optical activity form.
Because the racemic modification of The compounds of this invention and/or the pharmaceutical activity of steric isomer may be different, therefore be to use enantiomorph ideally.In these cases, can adopt chemistry known in the art or physical method that end product or intermediate are separated into enantiomeric compounds, perhaps their enantiomeric form can be used to synthesize.
Under the situation of racemic amines, this mixture and the reaction of optical activity separation agent can be formed diastereomer.Suitable separation agent is; for example; optical activity acid is as amino acid (as N-benzoyl proline(Pro) or N-benzenesulfonyl proline(Pro)) or various optically active camphorsulfonic acid of the tartrate of R-or S-configuration, diacetyl tartrate, dibenzoyl tartaric acid, mandelic acid, oxysuccinic acid, lactic acid, suitable N-protected.It also is useful by optical activity separation agent (for example dinitrobenzoyl phenylglycocoll, cellulose triacetate or other sugared derivatives or be fixed in the chirality methyl acrylate derivative polymkeric substance of silica gel) enantiomorph being carried out chromatographic separation.The solvent of this method of being suitable for is water-based or alcohol solvent mixture, and for example ratio is hexane/isopropyl alcohol/acetonitrile of 82: 15: 3.
The purposes that the present invention also provides formula I compound and/or its physiological acceptable salt to be used for useful in preparing drug formulations is especially passed through the purposes of approach useful in preparing drug formulations non-chemically.For this reason, they and at least a solid, liquid and/or semi-solid carrier or assistant agent suitable formulation can be made,, one or more other active compounds can be added if suitable.
The present invention also provides pharmaceutical preparation, and they contain at least a formula I compound and/or a kind of its physiologically acceptable salt.
These preparations can be used as human medicine or veterinary drug.The available carrier be suitable for gi tract (for example oral), non-stomach and intestine or topical and not with the organic or inorganic material of new compound of the present invention reaction, for example water, vegetables oil, benzylalcohol, alkanediol class, polyethylene glycols, triacetin, gelatin, sugar (as lactose or starch), Magnesium Stearate, talcum and Vaseline, tablet, pill, coated tablet, capsule, pulvis, granule, syrup, juice agent or drops especially can be used for oral; Suppository can be used for rectal administration; Solution, preferred oiliness or aqueous solution also have suspension, emulsion or implant to can be used for parenteral introduction, and ointment, creme or pulvis can be used for topical.New compound of the present invention can also be by freeze-drying, and the obtained freeze-drying thing can be used for preparing injection.Above-mentioned preparation can be sterilization and/or contain assistant agent, the for example salt of lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, adjusting osmotic pressure, buffer substance, pigment, perfume compound and/or several other active compounds, for example one or more VITAMIN.
Formula I compound and their physiological acceptable salt can be used for antagonism and prevention thromboembolic disorders, for example thrombosis, myocardial infarction, atherosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication.
For this reason, the dosage of material of the present invention is preferably the about 1-500 milligram of per unit dosage, especially 5-100 milligram usually.Every day, dosage was preferably approximately O.02-10 milligram/kg body weight.But, every patient's concrete dosage depends on multiple different factor, the activity of the particular compound of Shi Yonging for example, age, body weight, healthy state, sex, diet, administration time and approach, administration time and approach, and excretion rate, the severity of the combined utilization of medicine and the disease for the treatment of.The preferred oral administration.
Above and all temperature hereinafter all degree centigrade to provide.In the following embodiments, " conventional aftertreatment " be meant: add entry; If desired, pH is transferred to 2-10; According to the structural formula of end product, if desired, mixture with ethyl acetate or dichloromethane extraction, is separated organic phase, through dried over sodium sulfate and evaporation, resistates is through silica gel chromatography and/or recrystallization.Measure R with silica gel fValue; Moving phase: ethyl acetate/methanol 9: 1.Mass spectrum (MS): EI (electron impact ionization) M +FAB (fast atom bombardment) (M+H) +Embodiment 1
With 100 milligrams of 3-[4-(5-methyl-[1,2,4] phenyl-oxadiazoles-3-yl)]-5-piperazine-1-base Jia Ji oxazolidine-2-ketone (" A ") [can be by following reaction acquisition: with 3-[4-(5-methyl-[1,2,4] oxadiazole-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl methanesulfonates and 1-tert-butoxycarbonyl-piperazine and sodium bicarbonate react in acetonitrile; After sloughing the BOC base with the HCl/ diox, handle with sodium hydroxide solution] and 110 milligram 2,4,6-trichlorobenzene SULPHURYL CHLORIDE solution and 400 milligrams of 4-Dimethylamino pyridines on polystyrene in 10 milliliters of methylene dichloride mix and were incorporated in stirring at room 18 hours.Filter this mixture and, obtain 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl except that desolvating]-5-[4-(2,4,6-trichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, FAB 586/588.Similarly, with " A " and the reaction of 4-xenyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-biphenyl sulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-styryl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-styryl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-nitrobenzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-oil of mirbane alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2, the reaction of 5-dimethoxy benzene sulfonyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(2,5-dimethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-naphthalic sulfonic chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-chloro-4-fluorobenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-chloro-4-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-cyano group benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-cyano group benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 5-nitro-2-Methyl benzenesulfonyl chlorine reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(5-nitro-2-Methyl benzenesulfonyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of benzyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-benzyl alkylsulfonyl piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of decyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-decyl alkylsulfonyl piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-trifluoromethyl benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(2-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-chloro-4-fluorobenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-chloro-4-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 4-chloro-2, the reaction of 5-dimethyl benzene SULPHURYL CHLORIDE obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-chloro-2,5-dimethyl benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-fluorobenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 4-dibromobenzene SULPHURYL CHLORIDE obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-dibromobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-chlorobenzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-chlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2, the reaction of 6-two chloro phenylsulfonyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2,6-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 4-two chloro phenylsulfonyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 5-two chloro phenylsulfonyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,5-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-naphthoyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-naphthoyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the methylsulfonyl chloride reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-methylsulfonyl piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-methylsulfonyl benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-methylsulfonyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-nitrobenzyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-nitrobenzyl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (4-methoxycarbonyl-3-methoxythiophene-2-yl) SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((4-methoxycarbonyl-3-methoxythiophene-2-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-trifluoromethyl benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(3-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-trifluoromethoxy benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (1S)-(camphor-10-yl) SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((1S)-(camphor-10-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (1R)-(camphor-10-yl) SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((1R)-(camphor-10-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (2,2,5,7,8-pentamethyl-chroman-6-yl) SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((2,2,5,7,8-pentamethyl-chroman-6-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-isopropyl benzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-tert.-butylbenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-tert.-butylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-butylbenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3,5-dinitrobenzene-4-anisole SULPHURYL CHLORIDE reaction obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,5-dinitrobenzene-4-anisole alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the ethyl sulfonyl chloride reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-ethylsulfonyl piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-nitrobenzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-oil of mirbane alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-trifluoromethoxy benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(2-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2, the reaction of 4-dinitrophenyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2,4-dinitrobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of sec.-propyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-sec.-propyl alkylsulfonyl piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-ethylbenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-ethylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-bromo-2-trifluoromethoxy benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-bromo-2-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2,3, the reaction of 4-trifluoro-benzene SULPHURYL CHLORIDE obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2,3,4-trifluoro-benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 4-difluoro chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-difluoro benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2,2, the reaction of 2-trifluoro ethyl sulfonyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2,2,2-trifluoro ethylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3-nitro-4-toluene sulfonyl chloride reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-nitro-4-tosyl group) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2-nitro-6-chlorobenzene sulfonyl chloride reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-nitro-6-chlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2,5-dimethoxy benzene excess acetyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(2,5-dimethoxy phenylacetyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 4-dichlorobenzoyl chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-dichloro-benzoyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-fluorobenzoyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-fluoro benzoyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-trifluoromethoxy Benzoyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-trifluoromethoxy benzoyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-pyridine formyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-pyridine formyl radical) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-thionaphthene formyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-thionaphthene formyl radical) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 4-chlorobenzene excess acetyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-chloro acetyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 1-naphthoyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(1-naphthoyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of (1,3-benzo dioxolane-5-yl) formyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-((1,3-benzo dioxolane-5-yl) formyl radical) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 3-nitrobenzoyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3-nitro benzoyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-xenyl formyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-xenyl formyl radical) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of cyclopentyl formyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(cyclopentyl formyl radical) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of [5-chloro-1-(4-tolyl)-1H-pyrazoles-4-yl] SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-{4-[5-chloro-1-(4-tolyl)-1H-pyrazoles-4-yl] alkylsulfonyl } piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-chlorobenzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 5,7, the reaction of 7-trimethylammonium-2-(1,3,3-trimethylammonium butyl) octyl group SULPHURYL CHLORIDE obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(5,7,7-trimethylammonium-2-(1,3,3-trimethylammonium butyl) octyl group alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-butoxy-5-(1, the 1-dimethyl propyl) benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-butoxy-5-(1, the 1-dimethyl propyl) benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-butoxy-5-(1,1,3, the 3-tetramethyl butyl) benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-butoxy-5-(1,1,3, the 3-tetramethyl butyl) benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 2-nitro-4-trifluoromethyl benzene sulfonyl chloride reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(2-nitro-4-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-bromo-2-ethylbenzene SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-bromo-2-ethylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-trifluoromethyl benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-trifluoromethyl benzene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3, the reaction of 4-difluoro chloride obtains
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-difluoro benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 1-naphthyl SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(1-naphthyl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-anisole SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-anisole alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-toluene sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-tosyl group) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-third SULPHURYL CHLORIDE, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-third alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 6-chloro-2-naphthalic sulfonic chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 2-(naphthalene-1-yl) ethyl sulfonyl chloride, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-(naphthalene-1-yl) ethylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone; With the isobutyl chlorocarbonate reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-the 5-[4-isobutyl boc] piperazine-1-ylmethyl] oxazolidine-2-ketone.
Embodiment 2
With 100 milligrams of 3-[4-(5-methyl-[1; 2,4] phenyl-oxadiazoles-3-yl)]-5-[4-(2,4; 6-trichlorophenyl alkylsulfonyl) 15 ml methanol solution of piperazine-1-ylmethyl] oxazolidine-2-ketone are with after 100 milligrams of Raney nickels and an acetate mix, room temperature hydrogenation 8 hours.Filtration catalizer also removes and desolvates.Obtain 4-{2-oxo-5-[4-(2,4,6-trichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 546/548.
Similarly, the compound that is obtained by embodiment 1 obtains following Benzamine derivatives by hydrogenation.
4-{2-oxo-5-[4-(4-biphenyl sulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 520;
4-{2-oxo-5-[4-(2-benzene ethylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 472;
4-{2-oxo-5-[4-(2-amino phenyl sulfonyl acyl group) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 459;
4-{2-oxo-5-[4-(2,5-dimethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 504;
4-{2-oxo-5-[4-(2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 494;
4-{2-oxo-5-[4-(2-chloro-4-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 496;
4-{2-oxo-5-[4-[(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) alkylsulfonyl] piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 522;
4-{2-oxo-5-[4-(2-cyano group benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 469;
4-{2-oxo-5-[4-(5-amino-2-methyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 473;
4-{2-oxo-5-[4-benzyl alkylsulfonyl piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 458;
4-{2-oxo-5-[4-alkylsulfonyl in last of the ten Heavenly stems piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 508;
4-{2-oxo-5-[4-(2-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 512;
4-{2-oxo-5-[4-(3-chloro-4-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 496;
4-{2-oxo-5-[4-(4-chloro-2,5-dimethyl benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 506;
4-{2-oxo-5-[4-(2-fluorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 462;
4-{2-oxo-5-[4-(3,4-dibromobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 600/602/604;
4-{2-oxo-5-[4-(3-chlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 478;
4-{2-oxo-5-[4-(2,6-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 512;
4-{2-oxo-5-[4-(3,4-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 512;
4-{2-oxo-5-[4-(3,5-dichlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 512;
4-{2-oxo-5-[4-(2-naphthoyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 458;
4-{2-oxo-5-[4-methylsulfonyl piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 382;
4-{2-oxo-5-[4-(2-methylsulfonyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 522;
4-{2-oxo-5-[4-(2-aminobenzyl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 473;
4-{2-oxo-5-[4-((4-methoxycarbonyl-3-methoxythiophene-2-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 538;
4-{2-oxo-5-[4-(3-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 512;
4-{2-oxo-5-[4-(4-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 528;
4-{2-oxo-5-[4-(((1S)-camphor-10-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 518;
4-{2-oxo-5-[4-(((1R)-camphor-10-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 518;
4-{2-oxo-5-[4-((2,2,5,7,8-pentamethyl-chroman-6-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 570;
4-{2-oxo-5-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 486;
4-{2-oxo-5-[4-(4-tert.-butylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate;
4-{2-oxo-5-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 500;
4-{2-oxo-5-[4-(3,5-diamino-4-anisole alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 504;
4-{2-oxo-5-[4-ethylsulfonyl piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 396;
4-{2-oxo-5-[4-(4-oil of mirbane alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 459;
4-{2-oxo-5-[4-(2-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 528;
4-{2-oxo-5-[4-(2,4-diaminobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 474;
Different third alkylsulfonyl piperazine of 4-{2-oxo-5-[4--1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 410;
4-{2-oxo-5-[4-(4-ethylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 472;
4-{2-oxo-5-[4-(4-bromo-2-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzyl narrows, acetate, FAB 606/608;
4-{2-oxo-5-[4-(2,3,4-trifluoro-benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 498;
4-{2-oxo-5-[4-(3,4-difluoro benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 480;
4-{2-oxo-5-[4-(2,2,2-trifluoro ethylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 450;
4-{2-oxo-5-[4-(3-amino-4-Methyl benzenesulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 473;
4-{2-oxo-5-[4-(2-amino-6-chlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 585;
4-{2-oxo-5-[4-(2,5-dimethoxy phenylacetyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 482;
4-{2-oxo-5-[4-(3,4-dichloro-benzoyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 476;
4-{2-oxo-5-[4-(3-fluoro benzoyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 426;
4-{2-oxo-5-[4-(4-trifluoromethoxy benzoyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 492;
4-{2-oxo-5-[4-(3-pyridine formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 409;
4-{2-oxo-5-[4-(2-thionaphthene formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 463;
4-{2-oxo-5-[4-(4-chloro acetyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 456;
4-{2-oxo-5-[4-(1-naphthoyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 458;
4-{2-oxo-5-[4-((1,3-benzo dioxolane-5-yl) formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzyl narrows, acetate, FAB 452;
4-{2-oxo-5-[4-(3-amino benzoyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 423;
4-{2-oxo-5-[4-(4-xenyl formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 484;
4-{2-oxo-5-[4-(cyclopentyl formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 400;
4-{2-oxo-5-[4-(5-chloro-1-(4-aminomethyl phenyl)-1H-pyrazoles-4-yl) alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 558;
4-{2-oxo-5-[4-(4-chlorobenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 478;
4-{2-oxo-5-[4-(5,7,7-trimethylammonium-2-(1,3,3-trimethylammonium butyl) octyl group alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 620;
4-{2-oxo-5-[4-(2-butoxy-5-(1, the 1-dimethyl propyl) benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 586;
4-{2-oxo-5-[4-(2-butoxy-5-(1,1,3, the 3-tetramethyl butyl) benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 628;
4-{2-oxo-5-[4-(2-amino-4-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate;
4-{2-oxo-5-[4-(4-bromo-2-ethylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 550/552;
4-{2-oxo-5-[4-(4-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 512;
4-{2-oxo-5-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 528;
4-{2-oxo-5-[4-(isobutoxy formyl radical) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, acetate, FAB 404;
Similarly, with 3-[3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-piperazine-1-base Jia Ji oxazolidine-2-ketone and reaction of 6-chloro-2-naphthalic sulfonic chloride, hydrogenation subsequently makes following compounds:
3-{2-oxo-5-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, 118 ℃ of fusing points.
Similarly, with 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-piperazine-1-base Jia Ji oxazolidine-2-ketone and 6-methoxyl group-2-naphthalic sulfonic chloride reaction, hydrogenation subsequently makes following compounds:
4-{2-oxo-5-[4-(6-methoxyl group-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine.
Similarly, with 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-piperazine-1-base Jia Ji oxazolidine-2-ketone and reaction of 2-fluorobenzyl chloride, hydrogenation subsequently makes following compounds:
4-{2-oxo-5-[4-(2-luorobenzyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine.
Embodiment 3
With 100 milligrams of 3-[4-(5-methyl-[1; 2; 4]-and oxadiazole-3-yl) phenyl]-5-[4-(2,4,6-trichlorophenyl alkylsulfonyl) piperazine-1-ylmethyl] 8 ml methanol solution of oxazolidine-2-ketone and 3 milliliters of 1N aqueous sodium hydroxide solutions mix and are incorporated in 60 ℃ and stirred 48 hours.After conventional aftertreatment, obtain 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenylamino]-1-[4-(2,6-two chloro-4-anisole alkylsulfonyls) piperazine-1-yl] propane-2-alcohol, FAB556/558.
Similarly, by 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3,4-difluoro benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(3-fluoro-4-anisole alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(1-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(1-naphthalene sulfonyl base) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-trifluoromethyl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenylamino]-1-[4-(4-trifluoromethyl benzenesulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-biphenyl sulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-biphenyl sulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(3-trifluoromethyl benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenylamino]-1-[4-(3-trifluoromethyl benzenesulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-(4-trifluoromethoxy benzenesulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenylamino]-1-[4-(4-trifluoromethoxy benzenesulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-anisole alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-anisole alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-tosyl group) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-tosyl group) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-styryl alkylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(2-styryl alkylsulfonyl) piperazine-1-yl] propane-2-alcohol; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(2-(naphthalene-1-yl) ethylsulfonyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenylamino]-1-[4-(2-(naphthalene-1-yl) ethylsulfonyl) piperazine-1-yl] propane-2-alcohol;
Similarly, by 4-{2-oxo-3-[4-(6-methoxyl group-2-naphthalene sulfonyl base) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, obtain
4-{2-hydroxyl-3-[4-(6-methoxynaphthalene-2-alkylsulfonyl) piperazine-1-yl] third amino benzamidine, diacetin, FAB 498 and
By 4-{2-oxo-5-[4-(2-luorobenzyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzamidine, obtain
4-{2-hydroxyl-3-[4-(2-luorobenzyl) piperazine-1-yl] third amino } benzamidine, acetate, FAB 386.
Embodiment 4
With 60 milligrams of 3-[4-(5-methyl-[1; 2; 4]-and oxadiazole-3-yl) phenylamino]-1-[4-(2,6-two chloro-4-anisole alkylsulfonyls) piperazine-1-yl] 5 ml methanol solution of propane-2-alcohol mix with 50 milligrams of Raney nickels and an acetate, room temperature hydrogenation 8 hours.Filtration catalizer also removes and desolvates.Obtain 4-{3-[4-(2,6-two chloro-4-anisole alkylsulfonyls) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 516/518.
Similarly, the propane of being listed by embodiment 3-2-alcohol derivate obtains following compounds by hydrogenation:
4-{3-[4-(3-fluoro-4-anisole alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 466;
4-{3-[4-(1-naphthalene sulfonyl base) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 468;
4-{3-[4-(4-trifluoromethyl benzenesulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 486;
4-{3-[4-(4-biphenyl sulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 494;
4-{3-[4-(3-trifluoromethyl benzenesulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 486;
4-{3-[4-(4-trifluoromethoxy benzenesulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 502;
4-{3-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 460;
4-{3-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 474;
4-{3-[4-(4-anisole alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 448;
4-{3-[4-(4-tosyl group) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 432;
4-{3-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 460;
4-{3-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 502;
4-{3-[4-(2-styryl alkylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzyl narrows, acetate, FAB 446;
4-{3-[4-(2-(naphthalene-1-yl) ethylsulfonyl) piperazine-1-yl]-2-hydroxyl third amino } benzamidine, acetate, FAB 496.
Embodiment 5
With the heating 40 hours under refluxing of 200 milliliters of acetonitrile solutions of 10.0 gram { 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylates, 6.73 gram 4-BOC-amino piperidines and 8.5 gram sodium bicarbonates.Carry out conventional aftertreatment, obtain 5-(4-BOC-amino piperidine-1-ylmethyl)-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone.
With TFA cracking BOC group in methylene dichloride, obtain 5-(4-amino piperidine-1-ylmethyl)-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone (" B ").
Be similar to embodiment 1,, obtain " B " and the reaction of (3-methoxyl group-4-methoxycarbonyl thiophene-2-yl) SULPHURYL CHLORIDE
N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-(3-methoxyl group-4-methoxycarbonyl thiophene-2-yl) sulphonamide With the benzene sulfonyl chloride reaction, obtain
N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-benzsulfamide; With 3, the reaction of 4-dimethoxy benzene sulfonyl chloride obtains
3,4-dimethoxy-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-benzsulfamide; With the butyl sulfochlorides reaction, obtain
N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-butyl sulfonamide; With 2,4, the reaction of 6-trimethylbenzene chloride obtains
2,4,6-trimethylammonium-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-benzsulfamide; With the reaction of styryl SULPHURYL CHLORIDE, obtain
Styryl-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl) sulphonamide; With the reaction of 2-methyl sulphonyl benzene sulfonyl chloride, obtain
2-methyl sulphonyl-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-benzsulfamide; With the reaction of 4-xenyl SULPHURYL CHLORIDE, obtain
4-xenyl-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl) sulphonamide; With 5-dimethylamino-1-naphthalic sulfonic chloride reaction, obtain
5-dimethylamino-N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-the 1-naphthalene sulfonylamide; With the reaction of 1-naphthalic sulfonic chloride, obtain
N-(1-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } piperazine-4-yl)-the 1-naphthalene sulfonylamide.
By being similar to the hydrogenation of embodiment 2, obtain following compounds by these compounds
4-{5-[4-((3-methoxyl group-4-methoxycarbonyl thiophene-2-yl) sulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 552;
4-{5-[4-(phenylsulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 458;
4-{5-[4-(3,4-dimethoxy phenylsulfonamido) piperidines-1-ylmethyl]-2-oxygen is for oxazolidine-3-yl } and benzamidine, acetate, FAB 518;
4-{5-[4-(fourth sulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 438;
4-{5-[4-(2,4,6-Three methyl Benzene sulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 500;
4-{5-[4-(benzene ethanesulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 486;
4-{5-[4-(2-methyl sulphonyl benzenesulfonyl amino) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 536;
4-{5-[4-(4-xenyl sulfonamido) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 533;
4-{5-[4-(5-dimethylamino-1-naphthalene sulfonyl amino) piperidinyl-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 551;
4-{5-[4-(1-naphthalene sulfonyl amino) piperidines-1-ylmethyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 458.
Embodiment 6
With 10.0 gram { 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylates, 7.4 gram N, the heating 40 hours under refluxing of 400 milliliters of acetonitrile solutions of N '-dimethyl-ethylenediamine and 8.5 gram sodium bicarbonates.Carry out conventional aftertreatment, obtain 5-{[methyl-(2-methylamino-ethyl) amino] methyl }-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone (" C ")
Be similar to embodiment 1, with " C "
With 2,4, the reaction of 6-trichlorobenzene SULPHURYL CHLORIDE obtains
2,4,6-three chloro-N-methyl-N-[2-(methyl-{ 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen for oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide With the reaction of 2-trifluoromethoxy benzene sulfonyl chloride, obtain
2-trifluoromethoxy-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With 2,4, the reaction of 6-trichlorobenzene SULPHURYL CHLORIDE obtains
2,4,6-three chloro-N-methyl-N-[2-(methyl-{ 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen for oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-trifluoromethyl benzene sulfonyl chloride, obtain
4-trifluoromethyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-isopropyl benzene SULPHURYL CHLORIDE, obtain
4-sec.-propyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-propylbenzene SULPHURYL CHLORIDE, obtain
4-propyl group-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-acetylsulphanilyl chloride, obtain
4-acetylaminohydroxyphenylarsonic acid N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 2-naphthalic sulfonic chloride, obtain
N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 2-naphthalene sulfonylamide; With the reaction of 3-trifluoromethyl benzene sulfonyl chloride, obtain
3-trifluoromethyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-diazole-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-chloro-3-nitrobenzene sulfonyl chloride, obtain
4-chloro-3-nitro-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of styryl SULPHURYL CHLORIDE, obtain
N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the styryl sulphonamide; With the reaction of benzyl SULPHURYL CHLORIDE, obtain
4-trifluoromethyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the benzyl sulphonamide; With the toluene sulfonyl chloride reaction, obtain
4-methyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-anisole SULPHURYL CHLORIDE, obtain
4-methoxyl group-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 1-naphthalic sulfonic chloride, obtain
N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 1-naphthalene sulfonylamide; With the reaction of 4-xenyl SULPHURYL CHLORIDE, obtain
N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 4-biphenyl sulfonamides; With 3, the reaction of 4-difluoro chloride obtains
3,4-two fluoro-N-methyl-N-[2-(methyl-{ 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen for oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-amylbenzene SULPHURYL CHLORIDE, obtain
4-amyl group-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-butylbenzene SULPHURYL CHLORIDE, obtain
4-butyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 4-methyl sulphonyl benzene sulfonyl chloride, obtain
4-methyl sulphonyl-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-benzsulfamide; With the reaction of 6-chloro-2-naphthalic sulfonic chloride, obtain
6-chloro-N-methyl-N-[2-(methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 2-naphthalene sulfonylamide;
By being similar to the hydrogenation of embodiment 2, obtain following compounds by these compounds
The 4-{5-[(methyl-and 2-[methyl-(2,4,6-trichlorobenzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 548/550
4-{5-[(methyl-{ 2-[methyl-(2-trifluoromethoxy benzenesulfonyl) amino] ethyl } amino) methyl)-2-oxygen is for oxazolidine-3-yl } benzamidine, acetate, FAB 530;
4-{5-[(methyl-{ 2-[methyl-(4-trifluoromethyl benzenesulfonyl) amino] ethyl } amino) methyl)-2-oxygen is for oxazolidine-3-yl } benzamidine, acetate, FAB 514;
The 4-{5-[(methyl-and 2-[methyl-(4-isopropyl benzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 488;
The 4-{5-[(methyl-and 2-[methyl-(4-propylbenzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 488;
The 4-{5-[(methyl-and 2-[methyl-(4-P-acetamido benzene sulfonyl base) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 503;
The 4-{5-[(methyl-and 2-[methyl-(2-naphthalene sulfonyl base) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 496;
4-{5-[(methyl-{ 2-[methyl-(3-trifluoromethyl benzenesulfonyl) amino] ethyl } amino) methyl)-2-oxygen is for oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 514;
The 4-{5-[(methyl-and 2-[methyl-(3-amino-4-chlorobenzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 495;
The 4-{5-[(methyl-and 2-[methyl-(benzene ethylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 474;
The 4-{5-[(methyl-and 2-[methyl-(benzyl alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 460;
The 4-{5-[(methyl-and 2-[methyl-(4-tosyl group) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 460;
The 4-{5-[(methyl-and 2-[methyl-(4-anisole alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 476;
The 4-{5-[(methyl-and 2-[methyl-(1-naphthalene sulfonyl base) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 496;
The 4-{5-[(methyl-and 2-[methyl-(4-biphenyl sulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 522;
The 4-{5-[(methyl-and 2-[methyl-(3,4-difluoro benzenesulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 516;
The 4-{5-[(methyl-and 2-[methyl-(4-amylbenzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 516;
The 4-{5-[(methyl-and 2-[methyl-(4-butylbenzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 502;
The 4-{5-[(methyl-and 2-[methyl-(4-methylsulfonyl benzenesulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 502;
The 4-{5-[(methyl-and 2-[methyl-(6-chloro-2-naphthalene sulfonyl base) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine, trifluoroacetate, FAB 530.
Be similar to embodiment 3 and 4, by 6-chloro-N-methyl-N-[2-(methyl-{ 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 2-naphthalene sulfonylamide obtains compound;
4-{3-(2-[(6-chloro-2-naphthalene sulfonyl base) and methylamino-] ethyl } methylamino-)-2-hydroxyl third amino } benzamidine, acetate, FAB 504
Figure 9881208700621
And by 7-methoxyl group-N-methyl-N-[2-(methyl-{ 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino) ethyl]-the 2-naphthalene sulfonylamide obtains compound:
4-{3-(2-[(7-methoxyl group-2-naphthalene sulfonyl base) and methylamino-] ethyl } methylamino-)-2-hydroxyl third amino } benzamidine, acetate, FAB 500.
Be similar to embodiment 3, cracking following compounds De oxazolidine ring:
The 4-{5-[(methyl-and 2-[methyl-(4-biphenyl sulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine,
4-{5-[(methyl-{ 2-[methyl-(4-isopropyl benzene alkylsulfonyl) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl benzamidine and
The 4-{5-[(methyl-and 2-[methyl-(1-naphthalene sulfonyl base) amino] ethyl } amino) methyl)-2-Yang Dai oxazolidine-3-yl } benzamidine,
Obtain following compounds respectively:
4-{3-(the 2-[(4-biphenyl sulfonyl) and methylamino-] ethyl } methylamino-)-2-hydroxyl third amino } benzamidine, diacetin, EI 460 (M +-NH 2);
4-{3-(2-[(4-isopropyl benzene alkylsulfonyl) and methylamino-] ethyl } methylamino-)-2-hydroxyl third amino } benzamidine, diacetin, EI 461; With
4-{3-(2-[(1-naphthalene sulfonyl base) and methylamino-] ethyl } methylamino-)-2-hydroxyl third amino } benzamidine, diacetin, EI 469.
Embodiment 7
(10.6g{3-[4-5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } heating 40 hours under refluxing of the 50ml acetonitrile solution of methyl mesylate, 3.17g sodiumazide.Carry out conventional aftertreatment, obtain 5-azido-methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone.The 7.7g triazo-compound is suspended in the glycol dimethyl ether, adds the 3.6ml trimethyl phosphite, this mixture was stirred 1.5 hours under refluxing.After adding 4.9ml half concentrated hydrochloric acid, this makes mixture boiling 3 hours.Carry out conventional aftertreatment, obtain 5-aminomethyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone, hydrochloride.
This compound is suspended in the methylene dichloride, mixes with alkaline ion exchanger and stirred 2 hours.Behind deionizing exchanger and the solvent, obtain 5-aminomethyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone (" D ").
Be similar to embodiment 1, with " D " and 3, the reaction of 4-difluoro chloride obtains
3,4-two fluoro-N-{3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-anisole SULPHURYL CHLORIDE, obtain
4-methoxyl group-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-chloro-3-nitrobenzene sulfonyl chloride, obtain
4-chloro-3-nitro-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the butyl sulfochlorides reaction, obtain
N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } butyl sulfonamide; With the reaction of 3-trifluoromethyl benzene sulfonyl chloride, obtain
3-trifluoromethyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 2-naphthalic sulfonic chloride, obtain
N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide.
Be similar to embodiment 2, obtain following compounds by the above-mentioned sulphonamide of hydrogenation:
4-{5-[(3,4-difluoro phenylsulfonamido) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 411;
4-{5-[(4-anisole sulfonamido) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 405;
4-{5-[(3-amino-4-chlorobenzene sulfonamido) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 424;
4-{5-[(butyl sulfonamido) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 355;
4-{5-[(3-trifluoromethyl phenylsulfonamido) methyl]-2-oxygen is for oxazolidine-3-yl } and benzamidine, acetate, FAB 443;
4-{5-[(2-naphthalene sulfonyl amino) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 425.
Embodiment 8
Be similar to embodiment 3 and 4,
By 3,4-two fluoro-N-{3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-(3,4-difluoro phenylsulfonamido)-2-hydroxyl third amino } benzamidine, acetate, FAB385
Figure 9881208700651
By 4-methoxyl group-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-(4-anisole sulfonamido)-2-hydroxyl third amino } benzamidine; By 4-chloro-3-nitro-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-(3-amino-4-chlorobenzene sulfonamido)-2-hydroxyl third amino } benzamidine; By N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } butyl sulfonamide, obtain
4-{3-(butyl sulfonamido)-2-hydroxyl third amino } benzyl narrows, acetate, FAB 329; By 3-trifluoromethyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-(3-trifluoromethyl phenylsulfonamido)-2-hydroxyl third amino } benzamidine, acetate, FAB 417; By N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-2-third sulphonamide, obtain
4-{3-(third sulfonamido)-2-hydroxyl third amino } benzamidine, acetate, FAB 391.
Embodiment 9
With 30.0g{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl methyl mesylate and the solution of 300ml aqueous methylamine solution in 300ml THF under pressure in 80 ℃ of heating 18 hours.Carry out conventional aftertreatment, obtain 5-methylamino-methyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] oxazolidine-2-ketone (" E ").
Be similar to embodiment 1,, obtain " E " and butyl sulfochlorides reaction
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } butyl sulfonamide; With the reaction of 4-isopropyl benzene SULPHURYL CHLORIDE, obtain
4-sec.-propyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 3-trifluoromethyl benzene sulfonyl chloride, obtain
3-trifluoromethyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of styryl SULPHURYL CHLORIDE, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } the styryl sulphonamide; With the reaction of 2-naphthalic sulfonic chloride, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide; With the reaction of 4-propylbenzene SULPHURYL CHLORIDE, obtain
4-propyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-anisole SULPHURYL CHLORIDE, obtain
4-methoxyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With 2,4, the reaction of 6-trimethylbenzene chloride obtains
2,4,6-trimethylammonium-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the Benzoyl chloride reaction, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzamide; With the reaction of 2-naphthoyl chloride, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthoamide; With the reaction of cyclohexyl methylsulfonyl chloride, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } the cyclohexyl methane amide; With the reaction of 4-xenyl formyl chloride, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 4-biphenyl carboxamides; With the reaction of 4-chloro-benzoyl chloride, obtain
4-chloro-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzamide; With the reaction of 4-(1, the 1-dimethyl propyl) benzene sulfonyl chloride, obtain
4-(1, the 1-dimethyl propyl)-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With 3, the reaction of 4-difluoro chloride obtains
3,4-two fluoro-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-tert.-butylbenzene SULPHURYL CHLORIDE, obtain
The 4-tertiary butyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-trifluoromethyl benzene sulfonyl chloride, obtain
4-trifluoromethyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 4-amylbenzene SULPHURYL CHLORIDE, obtain
4-amyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide; With the reaction of 1-naphthalic sulfonic chloride, obtain
N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 1-naphthalene sulfonylamide;
Be similar to embodiment 2, obtain following compounds:
5-{5-[((butyl alkylsulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 369
Figure 9881208700681
5-{5-[((4-sec.-propyl alkylsulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 431;
The 5-{5-[((3-trifluoromethyl sulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine, acetate, FAB 457;
5-{5-[((benzene ethylsulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzyl narrows, acetate, FAB 417;
5-{5-[((2-naphthalene sulfonyl base) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[((4-propylbenzene alkylsulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[((4-anisole alkylsulfonyl) methyl methylamino-)]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[((2,4,6-Three methyl Benzene alkylsulfonyl) methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[(benzoyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[(2-naphthoyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[(cyclohexyl formyl radical methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[(4-xenyl formyl radical methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine;
5-{5-[(4-chlorobenzene formacyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine.
Similarly, obtain 5-fourth aminomethyl-3-[4-(5-methyl-[1 by { 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylate and butylamine, 2,4] phenyl] oxazolidine-2-ketone (" E-1 ")-oxadiazoles-3-yl).
With " E-1 "
With the reaction of 6-chloro-2-naphthalic sulfonic chloride, obtain
6-chloro-N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide;
With the reaction of 4-xenyl SULPHURYL CHLORIDE, obtain
N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 4-biphenyl sulfonamides;
With the reaction of 2-naphthalic sulfonic chloride, obtain
N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide.
Embodiment 10
Be similar to embodiment 3 and 4, by N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } butyl sulfonamide, obtain
4-{3-[(butane-1-alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine
Figure 9881208700691
By 4-sec.-propyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-isopropyl benzene alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 405; By 3-trifluoromethyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(3-trifluoromethyl benzenesulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 431; By N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } the styryl sulphonamide, obtain
4-{3-[(styroyl alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine; By N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide, obtain
4-{3-[(2-naphthalene sulfonyl base) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB413; By 6-chloro-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide, obtain
4-{3-[(6-chloro-2-naphthalene sulfonyl base) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 447; By 4-propyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-propylbenzene alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 405; By 4-methoxyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-anisole alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 393; By 2,4,6-trimethylammonium-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(2,4,6-Three methyl Benzene alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 405; By 5-{5-[(benzoyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, obtain
4-{3-(benzoyl methylamino-)-2-hydroxyl third amino } benzamidine; By 5-{5-[(2-naphthoyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, obtain
4-{3-(2-naphthoyl methylamino-)-2-hydroxyl third amino } benzamidine; By 5-{5-[(cyclohexyl formyl radical methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, obtain
4-{3-(cyclohexyl formyl methylamino-)-2-hydroxyl third amino } benzamidine; By 5-{5-[(4-xenyl formyl radical methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, obtain
4-{3-(4-xenyl formyl methylamino-)-2-hydroxyl third amino } benzamidine; By 5-{5-[(4-chlorobenzene formacyl methylamino-) methyl]-2-Yang Dai oxazolidine-3-yl } benzamidine, obtain
4-{3-(4-chlorobenzoyl methylamino-)-2-hydroxyl third amino } benzamidine; By 4-(1, the 1-dimethyl propyl)-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-(1, the l-dimethyl propyl) benzenesulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 433; By 3,4-two fluoro-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(3-fluoro-4-anisole alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 411; By the 4-tertiary butyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-tert.-butylbenzene alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 419; By 4-trifluoromethyl-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-trifluoromethyl benzenesulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 431; By 4-amyl group-N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } benzsulfamide, obtain
4-{3-[(4-amylbenzene alkylsulfonyl) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 433; By N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 1-naphthalene sulfonylamide, obtain
4-{3-[(1-naphthalene sulfonyl base) methylamino-]-2-hydroxyl third amino } benzyl narrows acetate, FAB4l3; By 6-chloro-N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide, obtain
4-{3-[(6-chloro-2-naphthalene sulfonyl base) fourth amino]-2-hydroxyl third amino } benzamidine; By N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 4-biphenyl sulfonamides, obtain
The 4-{3-[(4-biphenyl sulfonyl) fourth amino]-2-hydroxyl third amino } benzamidine; By N-butyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-the 2-naphthalene sulfonylamide, obtain
4-{3-[(2-naphthalene sulfonyl base) fourth amino]-2-hydroxyl third amino } benzamidine; By N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-(7-methoxyl group-2-naphthyl) sulphonamide, obtain
4-{3-[(7-methoxyl group-2-naphthalene sulfonyl base) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 443; By N-methyl-N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-(6-methoxyl group-2-naphthyl) sulphonamide, obtain
4-{3-[(6-methoxyl group-2-naphthalene sulfonyl base) methylamino-]-2-hydroxyl third amino } benzamidine, acetate, FAB 443.
Embodiment 11
10.9g 3-(4-cyano-phenyl)-5-Qiang Jia Ji oxazolidine-2-ketone (" F "), 5.9g 3-cyanophenol, 26.2g triphenylphosphine and the solution of 13.1g diethyl azodiformate in 250ml THF were stirred 4 hours under protective atmosphere.Carry out conventional aftertreatment, obtain 3-(4-cyano-phenyl)-5-[(3-cyano-benzene oxygen) methyl] oxazolidine-2-ketone.
8.5g dicyano compound, 5.5g oxammonium hydrochloride and the solution of 11.2g yellow soda ash in 130mlDMF were stirred 3 hours down in 60 ℃.Carry out conventional aftertreatment, obtain 3-(4-N-hydroxyl amidino groups phenyl)-5-[(3-N-hydroxyamidines phenoxyl) methyl] oxazolidine-2-ketone.
Be similar to embodiment 2,, obtain 3-(4-narrows basic phenyl)-5-[(3-amidino groups phenoxy group by this compound by hydrogenation) methyl] oxazolidine-2-ketone, diacetin, fusing point 159-160 ℃, FAB 354.
Similarly, with " F " and 4 '-xenol-4-formonitrile HCN reaction, with oxammonium hydrochloride reaction and reduction, obtain compound again
3-(4-amidino groups phenyl)-5-[(4 '-amidino groups-4-biphenylyloxy) methyl] oxazolidine-2-ketone, diacetin, fusing point 214-224 ℃; With the reaction of 4-cyanophenol, with oxammonium hydrochloride reaction and reduction, obtain compound again
3-(4-amidino groups phenyl)-5-[(4-amidino groups phenoxy group) methyl] oxazolidine-2-ketone, diacetin, 164 ℃ of fusing points (decomposition); With the reaction of 4-cyano group-N-(ethoxycarbonyl) benzsulfamide, obtain compound
N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-N-ethoxycarbonyl-4-cyano group benzsulfamide, diacetin, FAB 489.
Embodiment 12
With 400mg{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylate, 240mg phenylpiperazine and the solution of 120mg sodium bicarbonate in the 10ml acetonitrile is in 80 ℃ of heating 18 hours.Carry out conventional aftertreatment, obtain 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-(4-phenylpiperazine-1-ylmethyl) oxazolidine-2-ketone.
By being similar to the hydrogenation of embodiment 2, obtain 4-[2-oxo-5-(4-phenylpiperazine-1-ylmethyl) oxazolidine-3-yl] benzamidine, acetate, FAB 380.
Similarly, with " A " and the reaction of 5-brooethyl benzo [2,1,3] thiadiazoles, obtain compound
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(benzo [2,1,3] thiadiazoles-5-ylmethyl) piperazine-1-ylmethyl] oxazolidine-2-ketone.
By being similar to the hydrogenation of embodiment 2, obtain 4-[2-oxo-5-(4-benzo [2,1,3] thiadiazoles-5-ylmethyl) piperazine-1-ylmethyl) oxazolidine-3-yl] benzamidine, acetate, FAB512.
Similarly, will 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylate and 2-piperazine-1-yl pyrimidines reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(pyrimidine-2-base) piperazine-1-ylmethyl] oxazolidine-2-ketone, with the benzyl diethylenediamine reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-benzyl diethylenediamine-1-ylmethyl] oxazolidine-2-ketone, with the reaction of (benzo [2, l, 3] thiadiazoles-5-yl) piperazine, obtain compound
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(benzo [2,1,3] thiadiazoles-5-yl) piperazine-1-ylmethyl] oxazolidine-2-ketone.
Be similar to embodiment 3 and 4, De oxazolidone Huan is with the oxadiazole ring for the cracking following compounds: by 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(pyrimidine-2-base) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-[2-hydroxyl-3-(4-pyrimidine-2-base piperazine-1-yl) third amino] benzamidine, acetate, FAB 356; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-benzyl diethylenediamine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-[2-hydroxyl-3-(4-benzyl diethylenediamine-1-yl) third amino] benzyl narrows, acetate, FAB 368; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(benzo [2,1,3] thiadiazoles-5-yl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-[2-hydroxyl-3-(4-(benzo [2,1,3] thiadiazoles-5-yl) piperazine-1-yl) third amino] benzamidine, trifluoroacetate, FAB 412.By 4-[3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(3, the 5-dimethoxy-benzyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-[2-hydroxyl-3-(4-(3, the 5-dimethoxy-benzyl) piperazine-1-yl) third amino] benzamidine, FAB 428.
Similarly, 3-[3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-yl } methyl mesylate and 4-piperazine-1-yl pyridines reaction, obtain
3-[3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(pyridin-4-yl) piperazine-1-ylmethyl] oxazolidine-2-ketone, this compound is converted into through hydrogenation
3-[2-oxo-5-(4-(pyridin-4-yl) piperazine-1-ylmethyl) oxazolidine-3-yl] benzamidine, acetate, FAB 38l, fusing point 152-165 (decomposition).
Embodiment 13
Solution stirring in the 10ml methylene dichloride is 4 hours with 200mg " A " and 66mg butyl isocyanate.Add 400mg aminomethyl polystyrene, with this mixture restir 12 hours.Remove polystyrene and solvent, obtain 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl through conventional aftertreatment]-5-[4-butyl formamyl piperazine-1-ylmethyl] oxazolidine-2-ketone.
Similarly, with " A " and the reaction of cyclic isocyanate polyhexamethylene, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(cyclohexyl carboxyamide base) piperazine-1-ylmethyl] oxazolidine-2-ketone; With 4-methoxyphenyl isocyanate reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(4-methoxyphenyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone; With the reaction of 4-phenylfluoroform based isocyanate, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-5-[4-[N-(4-fluoroform phenyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone; With 4-chloro-phenyl-isocyanate reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(4-chloro-phenyl-) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone; With 3-carbethoxy phenyl isocyanate reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(3-carbethoxy phenyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone; With 1-naphthyl isocyanate reaction, obtain
3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(naphthalene-1-base formamyl) piperazine-1-ylmethyl] oxazolidine-2-ketone.
By being similar to the hydrogenation of embodiment 2, by 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(4-methoxyphenyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{2-oxo-5-{4-[N-(4-p-methoxy-phenyl) formamyl] piperazine-1-ylmethyl } oxazolidine-3-yl } benzamidine, acetate, FAB 453
Figure 9881208700751
By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(4-trifluoromethyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{2-oxo-5-{4-[N-(4-trifluoromethyl) formamyl] piperazine-1-ylmethyl } oxazolidine-3-yl } benzamidine, acetate, FAB 473; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(4-chloro-phenyl-) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{2-oxo-5-{4-[N-(4-chloro-phenyl-) formamyl] piperazine-1-ylmethyl } oxazolidine-3-yl } benzamidine, acetate, FAB 457; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-((butyl formamyl piperazine-1-ylmethyl) oxazolidine-2-ketone obtains 4-5-
4-{2-oxo-5-(4-butyl formamyl piperazine-1-ylmethyl) oxazolidine-3-yl } benzamidine, acetate, FAB 403; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-[N-(3-carbethoxy phenyl) formamyl] piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{2-oxo-5-{4-[N-(3-carbethoxy phenyl) formamyl] piperazine-1-ylmethyl } oxazolidine-3-yl } benzamidine, acetate, FAB 495; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(naphthalene-1-base formamyl) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{2-oxo-5-[4-(naphthalene-1-base formamyl) piperazine-1-ylmethyl] oxazolidine-3-yl } benzyl narrows, acetate, FAB 403.
Be similar to embodiment 3 and 4, by 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-(4-fourth formamyl piperazine-1-ylmethyl) oxazolidine-2-ketone obtains 5-
4-{3-(4-fourth formamyl piperazine-1-yl)-2-hydroxyl third amino) benzamidine, acetate, FAB 377; By 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-5-[4-(cyclohexyl carboxyamide base) piperazine-1-ylmethyl] oxazolidine-2-ketone, obtain
4-{3-(4-cyclohexyl carboxyamide base piperazine-1-yl)-2-hydroxyl third amino } benzamidine, acetate, FAB 403
Figure 9881208700761
Embodiment 14
With the heating 18 hours under refluxing of the mesylate of 1 equivalent { 3-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenyl]-2-oxo oxazolidine-5-yl } methyl mesylate, 3 equivalent glycine benzyl esters and the solution of 3 equivalent sodium bicarbonates in acetonitrile.Conventional aftertreatment, obtain 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino } acetate benzyl ester (" G ").
Be similar to embodiment 1,, obtain " G " and 6-chloro-naphthalene-2-base SULPHURYL CHLORIDE reaction
N-[6-chloro-naphthalene-2-base alkylsulfonyl]-N-[3-(4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } the acetate benzyl ester.
By being similar to the hydrogenation of embodiment 2, obtain
N-[6-chloronaphthalene-2-base alkylsulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino acetate, acetate, FAB 517 and
N-[6-chloronaphthalene-2-base alkylsulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } the acetate benzyl ester.
Similarly, with " G " and naphthalene-2-base SULPHURYL CHLORIDE reaction, hydrogenation subsequently obtains
N-[naphthalene-2-base alkylsulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } acetate, acetate, FAB 483 With the reaction of 4-anisole SULPHURYL CHLORIDE, hydrogenation subsequently obtains
N-[4-anisole alkylsulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } acetate, acetate, FAB 453; With the reaction of styryl SULPHURYL CHLORIDE, hydrogenation subsequently obtains
N-[styryl alkylsulfonyl]-N-[3-(4-aminophenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } the acetate benzyl ester, acetate, FAB 549; With the reaction of 4-xenyl SULPHURYL CHLORIDE, hydrogenation subsequently obtains
The N-[4-biphenyl sulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } acetate, acetate, FAB 509; With the reaction of 4-propylbenzene SULPHURYL CHLORIDE, hydrogenation subsequently obtains
N-[4-propylbenzene alkylsulfonyl]-N-[3-(4-amidino groups phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] amino } the acetate benzyl ester, acetate, FAB 565.
Embodiment 15
Solution in methyl alcohol stirred 4 hours under refluxing with 4-Oxyranyle HOMOVERATRONITRILE and BOC-piperazine.Conventional aftertreatment obtains 4-[2-hydroxyl-3-(4-BOC-piperazine-1-yl) propoxy-] benzonitrile.With the oxammonium hydrochloride reaction, obtain N-hydroxyl-4-[2-hydroxyl-3-(4-Boc-piperazine-1-yl) propoxy-subsequently] benzamidine.Use acetic anhydride acylation subsequently, obtain 2-acetoxyl group-1-(4-BOC-piperazine-1-yl)-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenoxy group] propane.After removing the BOC group with hydrochloric acid De dioxane solution,, obtain 2-acetoxyl group-1-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-yl with the reaction of 4-propylbenzene SULPHURYL CHLORIDE]-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenoxy group] propane.Be similar to the reaction of embodiment 3 and 4, obtain
4-{2-hydroxyl-3-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-yl] propoxy-} benzamidine
Obtain following compounds similarly:
3-{2-hydroxyl-3-[4-(4-xenyl formyl radical) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 459; 3-{2-hydroxyl-3-[4-(6-chloro-2-naphthalene sulfonyl base) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 503;
3-{2-hydroxyl-3-[4-(2-naphthalene sulfonyl base) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 469;
3-{2-hydroxyl-3-[4-(4-propylbenzene alkylsulfonyl) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 461;
3-{2-hydroxyl-3-[4-(4-isopropyl benzene alkylsulfonyl) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 461;
3-{2-hydroxyl-3-[4-(4-anisole alkylsulfonyl) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 449;
3-{2-hydroxyl-3-[4-(4-butylbenzene alkylsulfonyl) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 399;
3-{2-hydroxyl-3-[4-benzoyl-piperazine-1-yl] propoxy-} benzamidine, acetate, FAB383;
3-{2-hydroxyl-3-[4-(7-methoxyl group-2-naphthalene sulfonyl base) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 499;
3-{2-hydroxyl-3-[4-(3, the 5-dimethoxy-benzyl) piperazine-1-yl] propoxy-} benzamidine, acetate, FAB 429;
3-{2-hydroxyl-3-[4-(4-biphenyl sulfonyl) piperazine-1-yl] propoxy-} benzamidine, diacetin, FAB 495;
3-{2-hydroxyl-3-[4-(naphthalene-2-ylmethyl) piperazine-1-yl] propoxy-} benzamidine, diacetin, FAB 419;
3-(2-hydroxyl-3-[4-(2-naphthoyl) piperazine-1-yl] propoxy-} benzamidine, diacetin, FAB 433;
3-{2-hydroxyl-3-[4-(4-xenyl-4-ylmethyl) piperazine-1-yl] propoxy-} benzamidine, diacetin, FAB 445.
Embodiment 16
With 10.0g 3-Oxyranyle HOMOVERATRONITRILE (" H ") and 7.1g 3-cyanophenol and 173mg cesium fluoride 130 ℃ of fusions.Carry out conventional aftertreatment, obtain 11.8g 1,3-two-(3-cyano-benzene oxygen)-2-hydroxy propane.With the oxammonium hydrochloride reaction, obtain 1,3-two-[3-(N-hydroxyl amidino groups) phenoxy group]-2-hydroxyl-propane subsequently.Be similar to embodiment 2 and carry out hydrogenation, obtain 1,3-two-(3-amidino groups phenoxy group)-2-hydroxyl-propane, diacetin, FAB 329
Figure 9881208700801
Similarly, obtain
1,3-two-(4-amidino groups phenoxy group)-2-hydroxyl-propane, diacetin, FAB 329
With
1-(3-amidino groups phenoxy group)-3-(4-amidino groups phenoxy group)-2-hydroxyl-propane.
Similarly, with " H " and following phenol reactant: the 4-chlorophenol, the 4-methylphenol, phenol, the 4-methoxyphenol, the 4-cyclohexylphenol and subsequently with oxammonium hydrochloride reaction and hydrogenation, obtain following compounds:
1-(3-amidino groups phenoxy group)-2-hydroxyl-3-(4-chlorophenoxy)-propane,
1-(3-amidino groups phenoxy group)-2-hydroxyl-3-(4-methylphenoxy)-propane,
1-(3-amidino groups phenoxy group)-2-hydroxyl-3-phenoxypropane,
1-(3-amidino groups phenoxy group)-2-hydroxyl-3-(4-methoxyl group phenoxy group)-propane,
1-(3-amidino groups phenoxy group)-2-hydroxyl-3-(4-cyclohexyl phenoxy group)-propane.
Embodiment 17
With 1 equivalent N-{3-[4-(5-methyl-[1,2,4] phenyl-oxadiazoles-3-yl)]-2-Yang Dai oxazolidine-5-ylmethyl }-(6-chloro-2-naphthyl) sulphonamide (" I ") [can pass through 5-aminomethyl-3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) reaction of phenyl] oxazolidine-2-ketone and 6-chloro-2-naphthalic sulfonic chloride obtains], 1.1 equivalent N, N '-dimethyl chloride ethanamide and the solution of 1.1 normal cesium carbonates in DMF were stirring at room 12 hours.Carry out conventional aftertreatment, obtain 2-((6-chloro-2-naphthalene sulfonyl base)-{ 3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl } amino]-N, N '-N,N-DIMETHYLACETAMIDE.
Be similar to embodiment 3 and 4 and react, obtain 2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino]-N, N '-N,N-DIMETHYLACETAMIDE
Figure 9881208700811
Similarly, with " I " and following compounds: N, N '-diethylchloro-acetamide, N, N '-dipropyl chlor(o)acetamide, N-phenyl-chloride ethanamide, N, N '-phenylbenzene chlor(o)acetamide and ethyl chloroacetate reaction also are similar to embodiment 3 and 4 Kai Lie oxazolidone Huan subsequently with the oxadiazole ring obtains following compounds:
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino]-N, N '-diethyl acetamide,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino]-N, N '-Valpromide,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino]-phenyl acetanilide,Phenacetylaniline,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino]-N, N '-phenylbenzene ethanamide,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(6-chloro-2-naphthalene sulfonyl base) amino] acetate, acetate, FAB 491.
Similarly, with N-{3-[4-(5-methyl-[1,2,4] phenyl-oxadiazoles-3-yl)]-2-Yang Dai oxazolidine-5-ylmethyl }-(4-isopropyl phenyl) sulphonamide and N, N '-dimethyl chloride ethanamide, N, N '-diethylchloro-acetamide, N, N '-dipropyl chlor(o)acetamide, N-phenyl-chloride ethanamide, N, N '-phenylbenzene chlor(o)acetamide, bromotoluene, butyl iodide, 4-chloromethyl-2-methylthiazol, 4-methoxy-benzyl bromine, ethyl chloroacetate, 4-neoprene acid ethyl ester, 3-chloromethyl benzoic acid ethyl ester, 4-chloromethyl benzoic acid ethyl ester, 3,5-dimethoxy-benzyl bromine, 4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) bromotoluene, 3-(5-methyl-[1,2,4] bromotoluene and 2-fluoro benzyl bromide reaction-oxadiazoles-3-yl), and be similar to embodiment 3 and 4 Kai Lie oxazolidone Huan subsequently with the oxadiazole ring obtains following compounds:
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-sec.-propyl alkylsulfonyl) amino]-N, N '-N,N-DIMETHYLACETAMIDE,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-sec.-propyl alkylsulfonyl) amino]-N, N '-diethyl acetamide,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-sec.-propyl alkylsulfonyl) amino]-N, N '-Valpromide,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-sec.-propyl alkylsulfonyl) amino]-phenyl acetanilide,Phenacetylaniline,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-sec.-propyl alkylsulfonyl) amino]-N, N '-phenylbenzene ethanamide,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl) benzyl amino] third amino } benzamidine, acetate, FAB 481,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl) fourth amino] third amino } benzamidine, acetate, FAB 447,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl) (2-methylthiazol-4-ylmethyl) amino] third amino } benzamidine, acetate, FAB 502,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl) (4-methoxy-benzyl) amino] third amino } benzamidine, acetate, FAB 511,
2-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-isopropyl benzene alkylsulfonyl) amino] acetate, acetate, FAB 449,
4-[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-isopropyl benzene alkylsulfonyl) amino] butyric acid, diacetin, FAB 477,
3-{[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-isopropyl benzene alkylsulfonyl) amino] methyl } phenylformic acid, diacetin, FAB 525,
4-{[[3-(4-amidino groups phenyl amino)-2-hydroxypropyl]-(4-isopropyl benzene alkylsulfonyl) amino] methyl } phenylformic acid, diacetin, FAB 525
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl)-(3, the 5-dimethoxy-benzyl) amino] third amino } benzamidine, diacetin, FAB 541,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl)-(4-amidino benzyl) amino] third amino } benzamidine, triacetate, FAB 523,
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl)-(3-amidino benzyl) amino] third amino benzamidine, triacetate, FAB 523 and
4-{ (2-hydroxyl)-3-[(4-isopropyl benzene alkylsulfonyl)-(2-luorobenzyl) amino] third amino } benzamidine, diacetin, FAB 499.
Similarly, with " I " and iodoethane, bromotoluene, 4-methoxy-benzyl bromine, 2-brooethyl naphthalene, 4-chloromethyl-2-methylthiazol and the reaction of 4-methoxy-benzyl chlorine also are similar to embodiment 3 and 4 Kai Lie oxazolidone Huan subsequently with the oxadiazole ring obtains
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl) ethylamino]-2-hydroxyl third amino } benzamidine
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl) benzyl amino]-2-hydroxyl third amino } benzamidine,
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl)-(4-methoxy-benzyl) amino]-2-hydroxyl third amino } benzamidine,
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl)-(naphthalene-2-ylmethyl) amino]-2-hydroxyl third amino } benzamidine,
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl)-(2-methylthiazol-4-ylmethyl) amino]-2-hydroxyl third amino benzamidine, diacetin, FAB 544 and
4-{3-[(6-chloro-2-naphthyl alkylsulfonyl)-(4-methoxy-benzyl) amino]-2-hydroxyl third amino } benzamidine, diacetin, FAB 553.
Similarly, with N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl }-(4-p-methoxy-phenyl) sulphonamide and butyl iodide reaction, be similar to embodiment 3 and 4 Kai Lie oxazolidone Huan subsequently with the oxadiazole ring obtains
4-{3-[(4-anisole alkylsulfonyl) fourth amino]-2-hydroxyl third amino } benzamidine, acetate, FAB 435.
Similarly, with N-{3-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl]-2-Yang Dai oxazolidine-5-ylmethyl-(2-naphthyl) sulphonamide with
Butyl iodide and
Iodoethane
Reaction is similar to embodiment 3 and 4 Kai Lie oxazolidone Huan subsequently with the oxadiazole ring obtains
4-{3-[(2-naphthalene sulfonyl base) fourth amino]-2-hydroxyl third amino benzamidine, acetate, FAB455 and
4-{3-[(2-naphthalene sulfonyl base) ethylamino]-2-hydroxyl third amino } benzamidine, acetate, FAB427.
Embodiment 18
Be similar to embodiment 11,, obtain following compounds suitable cyano compound and oxammonium hydrochloride reaction:
3-(3-N-hydroxyl amidino groups phenyl)-5-[(4-N-hydroxyamidines phenoxyl) methyl] oxazolidine-2-ketone, fusing point 201-205 ℃,
3-(3-N-hydroxyl amidino groups phenyl)-5-[(3-N-hydroxyamidines phenoxyl) methyl] oxazolidine-2-ketone,
3-(4-N-hydroxyl amidino groups phenyl)-5-[(3-N-hydroxyl amidino groups benzyloxy) methyl] oxazolidine-2-ketone,
3-(3-N-hydroxyl amidino groups phenyl)-5-[(3-N-hydroxyl amidino groups benzyloxy) methyl] oxazolidine-2-ketone.
Be similar to embodiment 2, obtain following compounds by hydrogenation:
3-(3-amidino groups phenyl)-5-[(4-amidino groups phenoxy group) methyl] oxazolidine-2-ketone, diacetin, fusing point 150-166 ℃ (decomposition), FAB 354;
3-(3-amidino groups phenyl)-5-[(3-amidino groups phenoxy group) methyl] oxazolidine-2-ketone, diacetin, fusing point 312-318 ℃;
3-(4-amidino groups phenyl)-5-[(3-amidino groups benzyloxy) methyl] oxazolidine-2-ketone, triacetate, fusing point 189-205 ℃ (decomposition), FAB 368;
3-(3-amidino groups phenyl)-5-[(3-amidino groups benzyloxy) methyl] oxazolidine-2-ketone, triacetate, fusing point 204-222 ℃ (decomposition), FAB 368.
Embodiment 19
Be similar to embodiment 16,, with oxammonium hydrochloride reaction and hydrogenation, obtain 4-[3-hydroxyl-4-(3-amidino groups phenoxy group) butyl subsequently 4-Oxyranyle ethyl benzonitrile and the reaction of 3-cyanophenol] benzamidine, diacetin, FAB 327
Figure 9881208700861
Embodiment 20
Under nitrogen, be added to 10.0g 3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenol among the 50ml DMF after, add down the 2.6g sodium hydride at 0 ℃ subsequently.Add the 5.1ml epoxy bromopropane, this mixture was stirring at room 24 hours.Carry out conventional aftertreatment, obtain 5-methyl-3-(3-Oxyranyle p-methoxy-phenyl)-[1,2,4]-oxadiazoles.
8.0g oxyethane based compound is dissolved in the 400ml methyl alcohol, feeds 6 hours ammonias.With this mixture restir 16 hours, remove desolvate after, obtain 1-amino-3-[3-(5-methyl-[1,2,4]-oxadiazole-3-yl) phenoxy group] propane-2-alcohol (" AB ").With 500mg " AB " and 434mg 4-anisole SULPHURYL CHLORIDE and 2.0g polymerization DMAP (1.6mmol Dimethylamino pyridine/g resin) in the 5ml pyridine stirring at room 24 hours.The filtering resin is also handled filtrate routinely, obtains N-{2-hydroxyl-3-[3-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenoxy group] propyl group }-the 4-methoxybenzenesulphoismide.
By being similar to the hydrogenation of embodiment 2, obtain
3-[2-hydroxyl-3-(4-anisole sulfonamido) propoxy-] benzamidine, acetate, FAB380
Similarly, with " AB " and 4-isopropyl benzene SULPHURYL CHLORIDE, the 2-naphthalic sulfonic chloride, 6-chloro-2-naphthalic sulfonic chloride, 7-methoxyl group-2-naphthalic sulfonic chloride, reaction and hydrogenation subsequently obtain following compounds:
3-[2-hydroxyl-3-(4-isopropyl benzene sulfonamido) propoxy-] benzamidine, acetate, FAB392;
3-[2-hydroxyl-3-(2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB 400;
3-[2-hydroxyl-3-(6-chloro-2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB434;
3-[2-hydroxyl-3-(7-methoxyl group-2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB 430;
Similarly, with 1-amino-3-[4-(5-methyl-[1,2,4] phenoxy group-oxadiazoles-3-yl)] propane-2-alcohol and 4-anisole SULPHURYL CHLORIDE, 4-isopropyl benzene SULPHURYL CHLORIDE, 2-naphthalic sulfonic chloride, 6-chloro-2-naphthalic sulfonic chloride, 7-methoxyl group-2-naphthalic sulfonic chloride, reaction and hydrogenation subsequently obtain following compounds:
4-[2-hydroxyl-3-(4-anisole sulfonamido) propoxy-] benzamidine, acetate, FAB380;
4-[2-hydroxyl-3-(4-isopropyl benzene sulfonamido) propoxy-] benzamidine, acetate, FAB392;
4-[2-hydroxyl-3-(2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB 400;
4-[2-hydroxyl-3-(6-chloro-2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB434;
4-[2-hydroxyl-3-(7-methoxyl group-2-naphthalene sulfonyl amino) propoxy-] benzamidine, acetate, FAB 430.
Embodiment 21
10.71ml sodium methylate (intensity is 30% methanol solution) is added in the 30ml methyl alcohol, under nitrogen atmosphere, adds 4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) aniline, and this mixture was stirred 10 minutes at 45 ℃.This mixture is added in the suspension of 480mg Paraformaldehyde 96 and 20ml methyl alcohol subsequently, and this mixture was stirred 2 hours at 60 ℃.This mixture and 440mg sodium borohydride mix and are incorporated in 60 ℃ of stirrings 1 hour then.This mixture mixes (at every turn) with 1.44g Paraformaldehyde 96,3.1g sodium methylate and 220mg sodium borohydride subsequently, and this married operation repeats more than twice.
After a few hours, this mixture is with the 1N sodium hydroxide hydrolysis and carry out conventional aftertreatment.Obtain 1.93g N-methyl-4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) aniline crude product.
1.35g 4-(5-methyl-[1,2,4]-oxadiazoles-3-yl)-methylphenylamine and the solution of 1.0ml epoxy chloropropane in 5m ethanol and 3.5ml water were seethed with excitement 12 hours under refluxing.Carry out conventional aftertreatment, obtain 0.4g N-methyl-N-oxyethane methyl-4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) aniline.0.39g N-methyl-N-oxyethane methyl-4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) aniline and the solution of 30ml methylamine (intensity is 33% ethanolic soln) in 10ml ethanol were stirred 15 hours in 65 ℃.Carry out conventional aftertreatment, obtain 0.44g 1-methylamino--3-{ methyl-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] amino propane-2-alcohol (" BC ").
With 100mg " BC " and 87mg 4-isopropyl phenyl SULPHURYL CHLORIDE and 300mg polymerization DMAP (1.6mmol Dimethylamino pyridine/g resin) in the 5ml methylene dichloride stirring at room 16 hours.The filtering resin is handled filtrate routinely.Obtain 109mg N-(2-hydroxyl-3-{ methyl-[4-(5-methyl-[1,2,4]-oxadiazoles-3-yl) phenyl] amino } propyl group)-4-sec.-propyl-N-methyl benzenesulfonamide.
By being similar to the hydrogenation of embodiment 2, obtain
4-(2-hydroxyl-3-[(4-isopropyl benzene alkylsulfonyl)-the N-methylamino-] propyl group }-the N-methylamino-) benzamidine, acetate, FAB 419
Figure 9881208700891
Similarly, with " BC " and the reaction of 2-naphthalic sulfonic chloride, hydrogenation subsequently obtains
4-(2-hydroxyl-3-[(naphthalene-2-base alkylsulfonyl)-the N-methylamino-] propyl group }-the N-methylamino-) benzamidine, diacetin, FAB 427.
The following example relates to pharmaceutical preparation:
Embodiment A: injection
With 2N hydrochloric acid the active compound and the solution of 5g Sodium phosphate dibasic in 3 liters of distilled waters of 100g formula I is transferred to pH6.5, carry out sterilising filtration then, the injection bottle that will be full of this solution freeze-drying and in sealed under aseptic conditions under aseptic condition.Every injection bottle contains the 5mg active compound.
Embodiment B: suppository
Mixture fusion with active compound and the 100g soybean lecithin and the 1400g theobroma oil of 20g formula I in the impouring mould, makes its cooling.Every rose suppository contains the 20mg active compound.
Embodiment C: solution
Preparation 1g formula I active compound, 9.38g two hypophosphite monohydrate sodium dihydrogens, 28.48g disodium hydrogen phosphate dodecahydrate and the solution of 0.1g benzalkonium chloride in the 940ml distilled water.PH is transferred to 6.8, add to 1L and radiation sterilization.This solution can be used as eye drop.
Embodiment D: ointment
500g formula I active compound is mixed under aseptic condition with 99.5g Vaseline.
Embodiment E: tablet
1kg formula I active compound, 4kg lactose, 1.2kg potato starch, 0.2kg talcum and 0.1kg Magnesium Stearate are suppressed in flakes according to a conventional method, made every to contain the 10mg active compound.
Embodiment F: coating tablet
Be similar to the embodiment E compressed tablets, then with ordinary method, with the dressing material package clothing of sucrose, potato starch, talcum, xanthan gum and pigment composition.
Embodiment G: capsule
In a conventional manner, fill hard gelatin capsule, make every rose capsule contain the 20mg active compound with 2kg formula I active compound.
Embodiment H: ampoule
The solution of 1kg formula I active compound in the 60L distilled water is carried out sterilising filtration, this solution is filled in the ampoule, freeze-drying and under aseptic condition in sealed under aseptic conditions.Per ampoule contains the 10mg active compound.

Claims (9)

1, formula I compound and its salt Wherein
R 1Be-C (=NH)-NH 2, this group can be replaced by the following groups list :-COA ,-CO-[C (R 5) 2] m-Ar ,-COOA ,-amino protecting group of OH or a routine,
Figure 9881208700022
R 2Be H, A, OR 5, N (R 5) 2, NO 2, CN, Hal, NR 5COA, NHCOAr, NHSO 2A, NHSO 2Ar, COOR 5, CON (R 5) 2, CONHAr, COR 5, COAr, S (O) nA or S (O) nAr,
R 3Be R 5Or-[C (R 5) 2] m-COOR 5,
R 3Can also be-CO-N-to form five-ring thus, wherein R with X 3Be-C=O and X are N,
R 4Be A, cycloalkyl ,-[C (R 5) 2] mAr ,-[C (R 5) 2] mHet or-CR 5=CR 5-Ar,
R 5Be H, A or benzyl,
X is O, NR 5Or CH 2,
Y is O, NR 5, N[C (R 5) 2] m-Ar, N[C (R 5) 2] m-Het, N[C (R 5) 2] m-COOR 5,
N[C (R 5) 2] m-CON (R 5) 2, N[C (R 5) 2] m-CONR 5Ar or N[C (R 5) 2] m-CONAr 2,
W be a key ,-SO 2-,-CO-,-COO-or-CONR 5-,
A is the alkyl with 1-2O carbon atom, one of them or two CH 2Base can be by O or S atom or quilt-CR 5=CR 5-group substitutes, and/or 1-7 wherein H atom can substitute by F,
Ar is naphthyl or phenyl, and they are unsubstituted or single, double or trisubstituted by following groups: R 1, A, Ar, OR 5, N (R 5) 2, NO 2, CN, Hal, NHCOA, NHCOAr ', NHSO 2A, NHSO 2Ar ', COOR 5, CON (R 5) 2, CONHAr ', COR 5, COAr ', S (O) nA or S (O) nAr,
Ar ' is naphthyl or phenyl, and they can be unsubstituted or single, double or trisubstituted by following groups: R 1, A, OR 5, N (R 5) 2, NO 2, CN, Hal, NHCOA, COOR 5, CON (R 5) 2, COR 5Or S (O) nA,
Het is saturated or undersaturated monocycle or bicyclic heterocycle system, this ring system contains one, two, three or four identical or different heteroatoms, for example nitrogen, oxygen and sulphur, and this ring system is unsubstituted or is replaced or polysubstituted by following groups is single: Hal, A, Ar ', OR 5, COOR 5, CN, N (R 5) 2, NO 2, NHCOA, NHCOAr ' and/or ketonic oxygen,
Hal is F, Cl, Br or I,
M is 0,1,2,3 or 4,
N is 0,1 or 2.
2, according to the compound of claim 1,
A) 4-{3-[4-(2,6-two chloro-4-anisole alkylsulfonyls) piperazine-1-yl]-2-hydroxypropyl amino } benzamidine;
B) methylamino-4-{3-[(4-isopropyl benzene alkylsulfonyl)]-2-hydroxypropyl amino } benzamidine;
C) 4-{3-[4-(1-naphthyl benzenesulfonyl) piperazine-1-yl]-2-hydroxypropyl amino } benzamidine;
D) methyl] oxazolidine-2-ketone 3-(4-amidino groups phenyl)-5-[(3-amidino groups phenoxy group)
With their salt.
3, the formula I compound of preparation claim 1 and the method for salt thereof are characterised in that
A) they obtain by dissociating with one of solvolysis or their functional derivatives of hydrogenolysis agent treated:
ⅰ) dissociate amidino groups by Qi oxadiazole derivative of hydrogenolysis Cong,
ⅱ) dissociate out by the amino that substitutes conventional amino protecting group with solvolysis or hydrogenolysis agent treated with hydrogen or the GPF (General Protection False base is protected,
B) be preparation,
R wherein 1Be
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700042
W is-SO 2-or-CO-,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700051
R wherein 1Be
Figure 9881208700052
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700053
And R 2And R 5Such as claim 1 definition,
With the reaction of formula III compound,
R 4-W-L Ⅲ
Wherein W is-SO 2-or-CO-,
R 4Such as claim 1 definition,
And L is Cl, Br, I or free or reactive functional group deutero-OH group,
Perhaps
C) be preparation
R wherein 1Be
Figure 9881208700061
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is O,
W is a key,
And R 2And R 4Such as claim 1 definition,
With formula II compound,
R wherein 1Be
Figure 9881208700063
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is O
And R 2Such as claim 1 definition,
With the reaction of formula IV compound,
R 4-W-OH?Ⅳ
Wherein W is a key,
And R 4Such as claim 1 definition,
Perhaps
D) be preparation
R wherein 1Be
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
W is a key,
R 4Be-[C (R 5) 2] mAr or-[C (R 5) 2] mHet,
M is 0,
And R 2Such as claim 1 definition,
With formula V compound
Figure 9881208700073
R wherein 1Be
R 3With X be together-CO-N-, form 5 yuan of rings thus,
L is Cl, Br, I or free or reactive functional groups deutero-OH base,
And R 2Define as claim,
With the reaction of formula VI compound, R 4-W-Y-H VI
Wherein W is a key,
Y is
R 4Be-[C (R 5) 2] mAr or-[C (R 5) 2] mHet,
M is 0,
Perhaps
E) be preparation,
R wherein 1Be
Figure 9881208700082
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
Figure 9881208700083
W is-CONH-,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700091
R wherein 1Be
Figure 9881208700092
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is
And R 2And R 5Such as claim 1 definition,
With the reaction of formula VII compound, R 4-N=C=O VII
Wherein
R 4Such as claim 1 definition,
Perhaps
F) be preparation,
R wherein 1Be
R 3With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
W is SO 2,
And R 2And R 4Such as claim 1 definition,
With formula II compound
Figure 9881208700102
R wherein 1Be
Figure 9881208700103
R 1With X be together-CO-N-, form 5 yuan of rings thus,
Y is N[C (R 5) 2] m-COOR 5,
And R 2And R 5Such as claim 1 definition,
With the reaction of formula VIII compound, R 4-SO 2-L VIII
Wherein
L is Cl, Br, I or free or reactive functional group deutero-OH group,
And R 4Such as claim 1 definition,
Perhaps
G) be preparation,
Wherein
X be NH and
R 3Be H,
And R 1, R 2, R 4, Y and W such as claim 1 definition,
These compounds can obtain by being dissociated by their De oxazolidone derivatives with solvolysis or hydrogenolysis agent treated,
Perhaps
H) for preparing wherein R 1Be-C (=NH)-NH 2Formula I compound,
Cyano group is converted into corresponding amidino groups,
Perhaps
ⅰ) in formula I compound, can be by following method for example with one or more group Y, R 1, R 2, R 3And/or R 4Be converted into one or more radicals R 1, R 2, R 3And/or R 4:
ⅰ) hydrolysis of ester group is a carboxyl
ⅱ) reduction nitro
ⅲ) acidylate amino,
And/or
K) alkali or the acid with the formula I is converted into its salt.
4, the method for useful in preparing drug formulations is characterised in that the formula I compound of claim 1 and/or a kind of its physiologically acceptable salt and at least a solid, liquid, semi-solid carrier or assistant agent is made suitable formulation.
5, pharmaceutical preparation is characterised in that formula I compound and/or a kind of its physiologically acceptable salt of comprising at least a claim 1.
6, be used to prevent and treat formula I compound and its physiologically acceptable salt of the claim 1 of thrombosis, myocardial infarction, atherosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication.
7, as formula I medicine and its physiologically acceptable salt of the claim 1 of inhibitors of coagulation factor Xa.
8, the formula I compound of claim 1 and/or its physiologically acceptable salt are used to prepare the purposes of medicine.
9, the formula I compound of claim 1 and its physiologically acceptable salt application in control thrombosis, myocardial infarction, atherosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication.
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