CN1127510C - Prodrugs of thrombin inhibitors - Google Patents

Prodrugs of thrombin inhibitors Download PDF

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Publication number
CN1127510C
CN1127510C CN96180024A CN96180024A CN1127510C CN 1127510 C CN1127510 C CN 1127510C CN 96180024 A CN96180024 A CN 96180024A CN 96180024 A CN96180024 A CN 96180024A CN 1127510 C CN1127510 C CN 1127510C
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pab
aze
cgl
expression
compound
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CN1209139A (en
Inventor
T·安顿松
D·古斯塔夫松
K·-J·霍夫曼
J·－E·奈斯特伦
H·泽伦森
M·瑟伦
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AstraZeneca AB
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AstraZeneca AB
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Abstract

The compounds provided by formula (I): R<1>O(O)C-CH2-(R)Cgl-Aze-Pab-R<2>, wherein R<1> and R<2> have meanings given in the description, which are useful as prodrugs of inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

The prodrug of thrombin inhibitors
Invention field
The present invention relates to the pharmaceutically acceptable prodrug of pharmaceutically active compound, specifically, these active compounds are competitive inhibitors of trypsin-like serine protease, particularly zymoplasm, the present invention relates to the prodrug as medicine, the route of synthesis that comprises their medicinal compositions and produce them.
Background
Blood coagulation is the main process that participates in hemostasis (promptly preventing damaged blood vessels to lose blood) and thrombosis (promptly form clot in blood vessel, cause the blood vessel infraction sometimes).
Solidify the result of the enzymatic reaction that is a series of complexity.A final step in this serial reaction is that the proenzyme thrombogen is converted into the organized enzyme zymoplasm.
Known zymoplasm plays an important role in solidifying.It activates thrombocyte, causes platelet aggregation; Fibrinogen is converted into fibrin monomer, and latter's spontaneous polymerization is the fibrinogen polymkeric substance; And activating Hageman factor I, the latter makes these crosslinked polymers again, forms insoluble fibrin.In addition, thrombin activation factor V and blood coagulation factor VIII cause producing zymoplasm by thrombogen " positive regeeration ".
Expect the formation of effective thrombin inhibitors by suppressing hematoblastic gathering and fibrinogen and crosslinked, show anticoagulating active.In addition, expectation strengthens anticoagulating active by suppressing positive feedback mechanism.
Prior art
Claesson (Blood Coagul.Fibrin. (1994) 5,411) has described the exploitation of low molecular weight thrombin inhibitor.
Blomb_ck etc. (J.Clin.Lab.Invest.24, supplementary issue 107,59, (1969)) have reported based on being positioned at the Fibrinogen A α chain restriction enzyme site thrombin inhibitors of aminoacid sequence on every side.In the aminoacid sequence of discussing, it is effective inhibitors that these authors propose tripeptide sequence Phe-Val-Arg.
Subsequently at for example United States Patent (USP) 4,346,078; International Patent Application WO 93/11152, WO94/29336, WO93/18060 and WO95/01168; With low-molecular-weight peptidyl thrombin inhibitors is disclosed in european patent application 648780,468231,559046,641779,185390,526877,542525,195212,362002,364344,530167,293881,686642 and 601459.
Recently, thrombin inhibitors based on peptide derivant is disclosed in european patent application 0699317 and International Patent Application WO 95/23609, WO95/35309, WO96/25426 and WO94/29336.
Particularly, back one application discloses peptide derivant R aOOC-CH 2-(R) Cgl-Aze-Pab-H, wherein R aExpression H, benzyl or C 1-6Alkyl.
Although known these active compounds show significant antithrombin activity, the pharmacodynamic properties of improving behind their oral and parenteral admins is useful.Wish that improved pharmacodynamic properties example comprises:
(a) provide the gastrointestinal absorption of improvement, so that reduce the variability between the individual interior and/or individuality relevant with these active compound bioavailabilities;
(b) this plasma concentration time plot is flattened (promptly reduce the peak in the plasma concentration in dosing interval/paddy than), so as to reduce to drop on outside the treatment at interval risk and because the too high side effect that causes of concentration peak (for example hemorrhage) and because the too low side effect that causes of concentration peak (for example thrombosis); And
(c) increase action time of these active compounds.
In addition, oral and parenteral is given may be because the partial concn height with the active enzyme thrombin inhibitor, causes bad local hemorrhage (for example in enteric cavity or subcutaneous).
At last, the oral active enzyme thrombin inhibitor that also can suppress trypsinase and other serine protease in gi tract may show the other side effect (for example suppressing trypsinase in enteric cavity) that comprises maldigestion.
Although in International Patent Application WO 94/29336, disclose some N-carbobenzyloxy derivative yet, do not mention these derivatives and can be used as prodrug as the above-mentioned active compound of thrombin inhibitors.In fact, WO94/29336 does not mention the suitable drug precursor of these active compounds.
We find by give with according to compound of the present invention, can address the above problem, although these compounds itself are non-activities, oral and/metabolism in vivo during parenteral admin, form the active enzyme thrombin inhibitor that comprises above-mentioned those compounds.
Specification sheets of the present invention
According to the present invention, provide formula I compound or its pharmacy acceptable salt (hereinafter referred to as " The compounds of this invention ")
R 1O (O) C-CH 2-(R) Cgl-Aze-Pab-R 2I is R wherein 1Expression-R 3Or-A 1C (O) N (R 4) R 5Or-A 1C (O) OR 4A 1Expression C 1-5Alkylidene group; R 2(it replaces a hydrogen atom in the amidino groups unit of Pab-H) expression OH, C (O) OR 6, C (O) OR 7Or C (O) OCH (R 8) OC (O) R 9R 3Expression H, C 1-10Alkyl or C 1-3(this back one group can randomly be used C to the alkane phenyl 1-6Alkyl, C 1-6Alkoxyl group, nitro or halogen replace); R 4And R 5Represent H, C independently 1-6Alkyl, phenyl, 2-naphthyl, or work as R 1Expression-A 1C (O) N (R 4) R 5The time, represent pyrrolidyl or piperidyl with the nitrogen-atoms that connects them; R 6Expression C 1-17(they all can randomly use C for alkyl, phenyl or 2-naphthyl 1-6Alkyl or halogen replace); R 7Expression 2-naphthyl, phenyl, C 1-3(back three kinds of groups can randomly be used C to the alkane phenyl 1-6Alkyl, C 1-6Alkoxyl group, nitro or halogen replace) or C 1-12(back one group can randomly be used C to alkyl 1-6Alkoxyl group, C 1-6Acidic group or halogen replace); R 8Expression H or C 1-4Alkyl; And R 9Expression 2-naphthyl, phenyl, C 1-6Alkoxyl group or C 1-8(back one group can randomly be used halogen, C to alkyl 1-6Alkoxyl group or C 1-6Acidic group replaces); Condition is to work as R 1Expression R 3, R 3Expression benzyl, methyl, ethyl, normal-butyl or n-hexyl and R 2Expression C (O) OR 7The time, R so 7Do not represent benzyl.
The compounds of this invention may show tautomerism.All tautomeric forms and composition thereof all are included in the scope of the present invention.
The compounds of this invention also can contain one or more asymmetric c atoms, therefore can show optics and/or diastereo-isomerism.All diastereomers can adopt the routine techniques of chromatogram for example or fractional crystallization to separate.The routine techniques that can adopt fractional crystallization for example or HPLC separates various steric isomers by separating racemic mixture or other mixture of these compounds.Perhaps, can under the condition that does not cause racemize or epimerization, react by making suitable optical activity starting material, or by for example deriving with homochiral acid, use ordinary method (for example chromatogram on HPLC, the silica gel) to separate the diastereomer derivative subsequently, prepare required optical isomer.All steric isomers all are included in the scope of the present invention.
According to of the present invention more on the one hand, provide above-mentioned qualification but no strings formula I compound as the purposes of prodrug.
R 3, R 4, R 5, R 6, R 7And R 9The alkyl that can represent can be linear, or when the carbon atom of enough numbers, can be side chain, ring-type or part cyclic, can be saturated or unsaturated, can insert oxygen and/or replaces or end-blocking with OH, and condition is that this OH group does not connect sp 2Carbon atom or the carbon atom adjacent with Sauerstoffatom.
We are meant such as CH " part cyclic alkyl " 2The group of Ch and so on.
R 8That can represent and can be used for replacing R 3, R 6And R 7Alkyl can be linear, or when the carbon atom of enough numbers, can be side chain, can be saturated or unsaturated and/or insert oxygen.
R 3And R 7The moieties of the alkane phenyl that can represent can be linear, or when the carbon atom of enough numbers, can be side chain and/or saturated or unsaturated.
A 1The alkylidene group that can represent can be linear, or when the carbon atom of enough numbers, can be side chain and/or saturated or unsaturated.
R 9That can represent and can be used for replacing R 3, R 7And R 9Alkoxyl group can be linear, or when the carbon atom of enough numbers, can be side chain and/or saturated or unsaturated.
Can be used for replacing R 7And R 9Acidic group can be linear, or when the carbon atom of enough numbers, can be side chain and/or saturated or unsaturated.
This specification sheets end has listed abbreviation.
Provide the formula I compound of above-mentioned qualification more on the one hand according to of the present invention, other condition is:
(a) R 1Do not represent-A 1C (O) OR 4
(b) R 4And R 5Dependently represent H;
(c) work as R 2Expression OC (O) R 6The time, R 6Do not represent C 1-17Alkyl.
Provide formula I compound more on the one hand according to of the present invention, wherein:
(a) R 1Expression-A 1C (O) OR 4
(b) R 4And R 5Represent H independently;
(c) work as R 2Expression OC (O) R 6The time, R 6Expression C 1-17Alkyl.
Work as R 1Expression-A 1C (O) N (R 4) R 5The time, preferred The compounds of this invention comprises those compounds, wherein: A 1Expression C 1-3Alkylidene group; R 4Expression H or C 1-6Alkyl; R 5Represent C independently 1-6Alkyl or C 4-6Cycloalkyl; Or those compounds, wherein R 4And R 5Represent pyrrolidyl together.
Work as R 1Expression-A 1C (O) OR 4The time, preferred The compounds of this invention comprises those compounds, wherein: A 1Expression C 1-5Alkylidene group; R 4Expression C 1-6Alkyl.
Work as R 1Expression R 3The time, preferred The compounds of this invention comprises those compounds, wherein R 3Expression H, C 1-10Alkyl (this back one group can be linear, or when the carbon atom of enough numbers, can be side chain and/or part ring-type or cyclic) or C 1-3Alkane phenyl (back one group can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain).
Preferred The compounds of this invention comprises those compounds, wherein R 2Expression OH, OC (O) R 6(wherein, under latter event, R 6Optional phenyl or the C that replaces of expression 1-17Alkyl (back one group can be linear, or when the carbon atom of enough numbers, can be side chain, ring-type or part cyclic and/or saturated or undersaturated)), C (O) OR 7(wherein, under latter event, R 7Phenyl, C that expression randomly replaces 1-12Alkyl (back one group can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain, ring-type or part cyclic and/or saturated or undersaturated) or C 1-3Alkane phenyl (back one group can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain) or C (O) OCH (R 8) OC (O) R 9(wherein under latter event, R 8Expression H or methyl, and R 9Expression phenyl or C 1-8Alkyl (back one group can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain and/or ring-type or part cyclic)).
Preferred The compounds of this invention comprises those compounds, wherein: R 1Expression H, linear C 1-10Alkyl, side chain C 3-10Alkyl, part ring-type C 4-10Alkyl, C 4-10Cycloalkyl, can choose the linear C of replacement wantonly 1-3The alkane phenyl, can choose the side chain C of replacement wantonly 3The alkane phenyl ,-A 1C (O) N (R 4) R 5(wherein under latter event, A 1Expression C 1-3Alkylidene group, R 4Expression H or C 1-3Alkyl, R 5Expression C 2-6Alkyl or C 5-6Cycloalkyl, or R 4And R 5Represent pyrrolidyl together) or-A 1C (O) OR 4(wherein under latter event, A 1Expression C 1-5Alkylidene group, and R 4Expression C 1-4Alkyl); R 2Expression OH, OC (O) R 6(wherein under latter event, R 6Expression can be chosen the phenyl of replacement, linear C wantonly 1-4Alkyl, side chain C 3-4Alkyl and cis octadecyl), C (O) OR 7(wherein under latter event, R 7Expression can be chosen replacement wantonly and/or can choose undersaturated linear C wantonly 1-4Alkyl maybe can be chosen replacement wantonly and/or can choose undersaturated side chain C wantonly 3-4Alkyl, the phenyl that can choose replacement wantonly maybe can be chosen the linear C of replacement wantonly 1-3The alkane phenyl maybe can be chosen the side chain C of replacement wantonly 3The alkane phenyl) or C (O) OCH (R 8) OC (O) R 9(wherein, under latter event, R 8Expression H or methyl, and R 9Expression phenyl, C 5-7Cycloalkyl, linear C 1-6Alkyl, side chain C 3-6Alkyl or part ring-type C 7-8Alkyl).
Particularly preferred The compounds of this invention comprises those compounds, wherein: R 1Represent linear C 1-6Alkyl, C 6-10Cycloalkyl maybe can be chosen the linear C of replacement wantonly 1-3The alkane phenyl; R 2Expression OH, OC (O) R 6(wherein under latter event, R 6Represent linear C 1-3Alkyl or side chain C 3Alkyl), C (O) OR 7(wherein under latter event, R 7Expression can be chosen the linear C of replacement wantonly 1-4Alkyl maybe can be chosen the side chain C of replacement wantonly 3-4Alkyl, can choose the linear C of replacement wantonly 1-3Alkane phenyl or side chain C3 alkane phenyl) or C (O) OCH (R 8) OC (O) R 9(wherein under latter event, R 8Expression H, and R 9Expression C 5-7Cycloalkyl, linear C 1-6Alkyl or part ring-type C 7-8Alkyl).
Work as R 1Expression R 3, and R 4Expression can be chosen the C of replacement wantonly 1-3During the alkane phenyl, preferably can choose substituting group wantonly and comprise C 1-6Alkyl (especially methyl).
Work as R 2Expression C (O) OR 7, and R 7Expression can be chosen the C of replacement wantonly 1-12During alkyl, preferred optional substituting group comprises halogen (especially chlorine) and C 1-6Alkoxyl group (especially methoxyl group).
Work as R 2Expression C (O) OR 7, and R 7When expression can be chosen the phenyl of replacement wantonly, preferably can choose substituting group wantonly and comprise C 1-6Alkyl (especially methyl), C 1-6Alkoxyl group (especially methoxyl group) and halogen (especially chlorine).
Work as R 2Expression C (O) OR 7, and R 7Expression can be chosen the C of replacement wantonly 1-3During the alkane phenyl, preferably can choose substituting group wantonly and comprise nitro.
Preferred The compounds of this invention comprises the compound of embodiment 1-68.
Preferred The compounds of this invention comprises:
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
nPrOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
tBuOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOEt；
EtOOCCH 2-(R)Cgl-Aze-Pab-COO-nBu；
PrlC(O)CH 2CH 2CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
ChNHC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(nPr) 2NC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH(CH 3)OOCCH 3；
MeOOCCH 2-(R)Cgl-Aze-Pab-OOCPh；
MeOOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OH；
BnOOCCH 2-(R)Cgl-Aze-Pab-OH；
nPrOOCCH 2-(R)Cgl-Aze-Pab-Z；
nPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
iPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
tBuOOCCH 2-(R)Cgl-Aze-Pab-OH；
(nPr) 2NCOCH 2OOCCH 2-(R)Cgl-Aze-Pab-OH；
ChNHCOCH 2OOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OAc；
HOOCCH 2-(R)Cgl-Aze-Pab-OH；
HOOCCH 2-(R)Cgl-Aze-Pab-O-cis-Oleyl；
Cyclooctyl-OOCCH 2-(R)Cgl-Aze-Pab-Z；
tBuCH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(2-Me)BnOOCCH 2-(R)Cgl-Aze-Pab-Z；
ChCH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
ChOOCCH 2-(R)Cgl-Aze-Pab-Z；
PhC(Me) 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(Me) 2CHC(Me) 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
ChCH 2OOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
(2-Me)BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-Me)；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-Me)；
BnOOCCH 2-(R)Cgl-Aze-Pab-COO-nBu；
iPrOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
EtOOCCH 2-(R)Cgl-Aze-Pab-COO-iBu；
BnOOCCH 2-(R)Cgl-Aze-Pab-COO-nPr；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCh；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCH 2Ch；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH(Me)OOCPh；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCPh；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOCH(Me)OAc；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OAc；
tBuOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OAc；
MeOOC-C(＝CHEt)CH 2-OOCCH 2-(R)Cgl-Aze-Pab-Z；
Men-OOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe);and
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CCl 3.
Particularly preferred The compounds of this invention comprises:
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CCl 3；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOnBu；
nPrOOCCH 2-(R)Cgl-Aze-Pab-Z；
Cyclooctyl-OOCCH 2-(R)Cgl-Aze-Pab-Z；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCh；
MeOOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OH；
nPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
iPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
BnOOCCH 2-(R) Cgl-Aze-Pab-OH; With
EtOOCCH 2-(R) Cgl-Aze-Pab-OAc. preparation
According to the present invention, the method for preparation I compound also is provided, this method comprises:
(a) by with corresponding formula I compound (R wherein 2Expression OC (O) R 6, and R 6Be defined as above) with alkoxide base (for example a kind of alkali metal alcoholates) for example under room temperature, in the presence of suitable organic solvent (for example THF), react preparation I compound (R wherein 2Expression OH).
(b) by with corresponding formula I compound (R wherein 2Expression C (O) OR 7, and R 7Be defined as above) with azanol or its acid salt for example under room temperature, in the presence of appropriate base (for example salt of wormwood or triethylamine) and suitable organic solvent (for example THF or EtOH), react, prepare its Chinese style I compound (R 2Expression OH).
(c) by with following corresponding formula II compound and formula III compound for example between room temperature and comparatively high temps (for example 40 ℃), in the presence of appropriate base (for example salt of wormwood) and suitable organic solvent (for example THF, DMF or acetonitrile), react, preparation I compound
H-(R) Cgl-Aze-Pab-R 2II is R wherein 2Be defined as above,
R 1O (O) C-CH 2-L 1III is L wherein 1The expression leavings group, for example halogenide (for example bromide) or alkylsulfonate (for example trifluoromethyl sulfonic acid), and R 1Be defined as above.
(d) by with corresponding formula I compound (R wherein 1Expression C 1-10Alkyl or C 1-3Alkane phenyl, and R 2Expression OH or C (O) OR 7) with suitable alkali (for example alkali metal alcoholates or alkali metal hydroxide) for example under room temperature, in the presence of suitable organic solvent (for example water and MeOH), react preparation I compound (R wherein 1Expression H, R 2Expression OH or C (O) OR 7, and R 7Limit above).
(e) by with corresponding formula I compound (R wherein 2Expression OH) with following formula IV compound for example under room temperature, in the presence of appropriate base (for example triethylamine, pyridine or DMAP) and suitable organic solvent (for example methylene dichloride or THF), react preparation I compound (R wherein 2Expression OC (O) R 6, and R 6Be defined as above):
R 6C(O)-O-C(O)R 6 IV
R 6C (O) Hal V wherein Hal represents Cl or Br, and in both cases, R 6All be defined as above.
(f) by with following corresponding formula VI compound and appropriate acid (for example TFA) for example under room temperature, in the presence of suitable organic solvent (for example methylene dichloride), react, prepare wherein R 1Expression H, R 2Expression OC (O) R 6, and R 6The formula I compound that is defined as above,
P 1O (O) C-CH 2-(R) Cgl-Aze-Pab-R 2VI is P wherein 1Represent sour unstable ester protecting group (for example tBu or Bn), and R 2Expression OC (O) R 6, R wherein 6Be defined as above.
(g) by the transesterification of following corresponding formula VII compound under the well-known condition of those skilled in the art, preparation I compound, wherein R 1Expression R 3, R 3Expression C 1-10Alkyl or C 1-3The alkane phenyl, R 2Expression OH or C (O) OR 7, and R 7Be defined as above,
R 1AO (O) C-CH 2-(R) Cgl-Aze-Pab-R 2VII is R wherein 1aRepresent the non-C that is forming 1-10Alkyl or C 1-3Alkane phenyl, and R 2Be defined as above or for another unstable alkyl substituent.
By will be with following formula VIII compound in the protection of going down of the well-known condition of those skilled in the art, can preparation formula II compound,
Boc-(R) Cgl-Aze-Pab-R 2VIII is R wherein 2Be defined as above.
Can be with being similar to formula I compound mentioned above (R wherein 1Expression R 3, and R 3Expression C 1-10Alkyl or C 1-3The alkane phenyl) preparation method, preparation formula VI and VII compound.
Can be by will be for example under room temperature with following formula IX compound and Boc-(R) Cgl-Aze-Pab-OH, in the presence of suitable coupling system (for example EDC), appropriate base (for example DMAP) and suitable organic solvent (for example methylene dichloride or acetonitrile), react, preparation formula VIII compound
H-Pab-R 2IX is R wherein 2Be defined as above.
Can be by with corresponding formula VIII compound (R wherein 2Expression C (O) OR 7Or C (O) OCH (R 8) OC (O) R 9) with azanol or its acid salt for example under room temperature, in the presence of appropriate base (for example salt of wormwood or triethylamine) and suitable organic solvent (for example THF and EtOH), react preparation formula VIII compound (R wherein 2Expression OH).
Can by with Boc-(R) Cgl-Aze-Pab-H with following formula X compound for example under the room temperature or be lower than under the room temperature, in the presence of appropriate base (for example NaOH) and appropriate organic solvent (for example THF), react preparation formula VIII compound (R wherein 2Expression C (O) OR 7Or C (O) OCH (R 8) OC (O) R 9),
L 2C (O) OR 2aX is L wherein 2Expression leavings group (for example halogen or phenates), R 2aExpression R 7Or-CH (R 8) OC (O) R 9, and R 7, R 8And R 9Limit as mentioned.
Perhaps can be by with corresponding formula VIII compound (R wherein 2Expression OH) with the formula IV that above limits or the formula V compound that above limits for example under room temperature, in the presence of appropriate base (for example triethylamine, pyridine or DMAP) and suitable organic solvent (for example methylene dichloride or THF), react, prepare wherein R 2Expression C (O) OR 6Formula VIII compound.
Perhaps can by with Boc-(R) Cgl-Aze-Pab-H with following formula XI compound for example under room temperature, in the presence of appropriate organic solvent (for example THF), react preparation formula VIII compound (R wherein 2Expression OC (O) R 6),
R 6C (O)-O-O-C (O) R 6XI is R wherein 6Be defined as above.
Can be by with corresponding formula VIII compound (R wherein 2Expression OC (O) R 6, and R 6Limit as mentioned) with appropriate base (for example alkali metal alcoholates) for example under room temperature, in the presence of appropriate organic solvent (for example THF), react, prepare wherein R 2The formula VIII compound of expression OH.
Formula IX compound is well-known in the document, maybe can adopt to be similar to those method preparations mentioned above.For example can by with the derivative of H-Pab-H or its protection and the formula X compound that above limits for example under room temperature, in the presence of appropriate base (for example NaOH) and suitable organic solvent (for example THF), react preparation formula IX compound, wherein R 2Expression C (O) OR 7Or C (O) OCH (R 8) OC (O) R 9, and R 7, R 8And R 9Limit as mentioned.
By H-Pab-H or its shielded derivative and Boc-Cgl-Aze-OH are for example reacted by the above-mentioned method that is used for formula VIII, can prepare Boc-(R) Cgl-Aze-Pab-H.
Perhaps can be by will be with following formula XII compound in the protection of going down of the well-known condition of those skilled in the art, preparation Boc-(R) Cgl-Aze-Pab-H,
Boc-(R) Cgl-Aze-Pab-P 2XII is P wherein 2Expression Boc adjacent blocking group.
Formula III, IV, V, X, XI and XII compound or commercially available are well-known in the document, perhaps can adopt known technology (for example hereinafter described) to obtain.
Can adopt routine techniques, The compounds of this invention is separated from its reaction mixture.
One skilled in the art will recognize that in aforesaid method, the functional group of intermediate compound may need to protect with blocking group.
The functional group that wishes protection comprises hydroxyl, amino, amidino groups and carboxylic acid.Suitable hydroxy-protective group comprises trialkylsilkl and diaryl silyl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl) and THP trtrahydropyranyl.Suitable carboxylic acid protective group comprises C 1-6Alkyl ester or benzyl ester.Suitable amino and amidino groups blocking group comprise tert-butyl ester base or carbobenzoxy.That amidino groups nitrogen can or singly be protected or two protections.
Can remove blocking group according to the well-known technology of all those skilled in the art as mentioned below.
At Protective Groups in Organic Chemistry; J W F McOmie edits; Plenum Press (1973) and Protective Groups in Organic synthesis; the 2nd edition; TW Green and P G M Wutz have described the usage of blocking group comprehensively among the Wiley-Interscience (1991).Medical science and pharmaceutical use
The compounds of this invention is useful, because their metabolism in vivo form the compound with pharmacological activity.Therefore they are designated as medicine, particularly prodrug.
Specifically,, for example prove in following test that they are metabolism in vivo, form the potential thrombin inhibitors although The compounds of this invention itself is a non-activity to zymoplasm.
" The compounds of this invention itself is a non-activity to zymoplasm " is meant in the mensuration of following test A, the IC that they show 50The TT value is greater than 1 μ M.
Therefore expect that The compounds of this invention needing in those diseases of Trombin inhibiting can be used for.
Therefore, in animal blood that comprises the people and tissue, need The compounds of this invention in thrombosis and hypercoagulable treatment processing and/or the preventive treatment.
Known hypercoagulability can cause thromboembolic disease.
The thromboembolic disease that can mention comprises heredity or the acquired defective of activated protein C resistance such as factor V sudden change (factor V Leiden) and Antithrombin III, PROTEIN C, Protein S, heparin cofactor II.Known other disease relevant with hypercoagulability and thromboembolic disease comprises circulation anti-phospholipid antibody (Lupus antithrombotics), homocysteine blood (homocysteinemi), heparin-induced thrombocytopenia and the defective in the fibrinolysis.Therefore, in treatment processing and these diseases of preventive treatment, need The compounds of this invention.
Not having in that nonconforming excessive zymoplasm is arranged in the treatment of diseases of hypercoagulability illness also needs The compounds of this invention, and these diseases are neurodegenerative disease for example, such as the AlzheimerShi disease.
The special disease state that can mention comprises that treatment is handled and/or preventive treatment venous thrombosis and pulmonary infarction, artery thrombosis (for example in myocardial infarction, unstable angor, form) based on thrombotic apoplexy and peripheral arterial thrombosis and usually during artery fibrillation from the atrium or in wall myocardial infarction thoroughly afterwards from the systemic embolism of left ventricle.
In addition, the expection The compounds of this invention is in thrombolysis, prevent to use practicality in the obstruction (being thrombosis) again through tube chamber plasty (PTA) and coronary bypass-forming operation operation back through skin; Generally preventing again after micrurgy and vascular surgery has practicality in the thrombosis.
Other indication comprises the dissemination blood vessel blood coagulation that treatment is handled and/or preventive treatment is caused by bacterium, multiple wound, poisoning or arbitrary other mechanism; When the antithrombotics that blood and inside and outside come thing surface (such as blood vessel graft, stent vascular transplantation sheet fixed mould, vessel catheter, machinery and biological pseudovalve or any other medical treatment device) to carry out when contacting is handled; With such as adopting pump oxygenator (heat-lung machine) during the operation on vessels of heart or in hemodialysis, the antithrombotics that carries out when blood contacts with external medical treatment device is handled.
Zymoplasm except that effect to coagulation process, a large amount of cells of also known activation (such as neutrophil, inoblast, endotheliocyte and smooth muscle cell).Therefore, The compounds of this invention also can be used to treat handle and/or preventive treatment is specially sent out property and adult respiratory distress syndrome, with the pulmonary fibrosis behind radiotherapy or the chemotherapeutic treatment, septic shock, septicemia, inflammatory reaction, include, but is not limited to oedema, the acute or chronic arterial such as coronary artery disease is atherosis, the weight behind cerebral arterial disease, peripheral arterial disease, reperfusion injury and the percutaneous transluminal angioplasty (PTA) is narrow.
The The compounds of this invention that suppresses trypsinase and/or zymoplasm also can be used for treating pancreatitis.
According to of the present invention more on the one hand, provide need the treatment of diseases of Trombin inhibiting method, this method comprise to the formula I compound that is defined as above or its pharmacy acceptable salt of suffering from this disease or easily suffering from the patient treatment significant quantity of this disease.
The compounds of this invention usually with pharmaceutically acceptable dosage form per os, cheek, rectum, skin, nose, tracheae, segmental bronchus, by any other parenteral approach or by sucking, with the medicinal preparations form administration, this medicinal preparations comprises acquisition as free alkali or as the prodrug of pharmaceutically acceptable non-toxicity organic or inorganic acid salt.According to described imbalance and patient to be treated and route of administration, described composition can with the dosage that changes give with.
The compounds of this invention also can in conjunction with the arbitrary antithrombotics with different mechanism of action and/or with its co-administered, antithrombotics such as anti-platelet agents acetylsalicylic acid, ticlopidine, clopidogrel, thromboxan acceptor and/or synthetase inhibitors, fibrin-ferment original receptor antagonist, prostacyclin mimetics and phosphodiesterase inhibitor and adp receptor (P2T) antagonist.
At thrombotic disease, particularly in the treatment of myocardial infarction, The compounds of this invention can also combine and/or therewith administration with antithrombotics (thromolytics), these antithrombotics such as tissue plasminogen activator (natural or reorganization), streptokinase, urokinase, prourokinase, a kind of isolating streptokinase plasminogen activators complex body (ASPAC), animal sialisterium plasminogen activators or the like.
Therefore, provide a kind of medicinal preparations more on the one hand, go back preparation and comprise formula I compound or its pharmacy acceptable salt that above limits with pharmaceutically acceptable auxiliary, diluent or carrier blended according to of the present invention.
In the mankind's treatment was handled, the oral per daily dose that The compounds of this invention is suitable was about 0.001-100mg/kg body weight, and the suitable per daily dose of parenteral admin is the 0.001-50mg/kg body weight.
The advantage of The compounds of this invention is, with following formula: compound, particularly R wherein aThe compound of expression H is compared, and they can have all specified as mentioned those improved pharmacodynamic properties behind oral and parenteral admin:
R aO (O) C-CH 2-(R) Cgl-Aze-Pab-H R wherein aLimit as mentioned.
The compounds of this invention is a non-activity to zymoplasm, trypsinase and other serine protease.These compounds are still non-activity in gi tract thus, and the potential problem complexity that therefore can avoid oral activated antithrombotics own to be experienced is such as the hemorrhage and maldigestion that is suppressed by trypsinase to cause.
In addition, adopt The compounds of this invention can avoid with parenteral give with the association of active enzyme thrombin inhibitor or parenteral give with the active enzyme thrombin inhibitor after local hemorrhage.
The advantage that The compounds of this invention also may have is, they are more effective than compound well known in the prior art, and toxicity is lower, action time is longer, and field of activity is wider, and the side effect of generation is littler, be easier to absorb, or they can have other useful pharmacological property.Biological test Test A The mensuration of thrombin clotting time (TT)
(T6769, Sigma Chem Co., final concentration are the damping fluid of 100 μ l pH74 of 1.4NIH unit/ml) and the insulation of 100 μ l inhibitor solutions 1 minute will to contain human thrombin.Then, add the normal Citrate trianion human plasma that 100 μ l merge, (KC10 Amelung) upward measures time of coagulation in automatic gear.
To map to inhibitor concentration in the time of coagulation of second, determine IC by interpolation technique 50TT.
IC 50The inhibitor concentration of TT for the human plasma thrombin clotting time is doubled. Test B Thrombin time in the external test blood plasma
With clear-headed rat detect oral or parenteral give with The compounds of this invention after the inhibition of zymoplasm, these rats were equipped with the conduit that is used for getting from carotid artery blood in 1 or 2 day before experiment.On experiment same day, give and be dissolved in ethanol: Solutol TM: this compound of water (5: 5: 90), at the set time blood sampling, pack into and contain in the plastics tubing of 1 part of sodium citrate solution (0.13mol/L) and 9 parts of blood.These pipes are centrifugal, to obtain to contain hardly hematoblastic blood plasma.This blood plasma is used for by following mensuration thrombin time.
100 μ l Citrate trianion rat plasmas are with the dilution of the salt brine solution of 100 μ l0.9%, contain the damping fluid of 100 μ l pH74 of human thrombin (T6769, Sigma Chem Co., the U.S.), the beginning clotting of plasma by adding.Upward measure time of coagulation in automatic gear (KC10, Amelung, Germany).
Make the thrombin time and active enzyme thrombin inhibitor HO (O) C-CH that is dissolved in the salt solution of the Citrate trianion rat plasma of merging by use 2(R) typical curve that interrelates of the concentration known of Cgl-Aze-Pab-H (referring to International Patent Application WO 94/29336) is estimated the concentration of above-mentioned active enzyme thrombin inhibitor in the rat plasma.
Active enzyme thrombin inhibitor HO (O) C-CH in this rat 2(R) on the basis of the estimation plasma concentration of Cgl-Aze-Pab-H (prolongation of supposition thrombin time is caused by above-claimed cpd), utilize trapezoidal rule and data infinitely extrapolated, calculate oral and/or parenteral give with this prodrug after this area under a curve (AUCpd).
Oral or parenteral give with this prodrug after, following calculated activity thrombin inhibitors HO (O) C-CH 2(R) bioavailability of Cgl-Aze-Pab-H:
[(AUCpd/ dosage)/(AUC activity, iv/ dosage] * 100 are the AUC activity here, and iv represents to give as stated above clear-headed rat intravenous injection HO (O) C-CH 2(R) AUC that obtains behind the Cgl-Aze-Pab-H. Test C Thrombin time in the external test urine
By thrombin time in the external test urine, estimates oral or parenteral to and be dissolved in ethanol: Solutol TM: drain active enzyme thrombin inhibitor HO (O) C-CH in urine behind the The compounds of this invention in the water (5: 5: 90) 2(R) amount of Cgl-Aze-Pab-H (prolongation of supposing this thrombin time is caused by above-claimed cpd).
The rat that will regain consciousness places metabolic cage, makes urine and the ight soil of collecting respectively behind oral The compounds of this invention 24 hours.Following urine to collection is measured this thrombin time.
The normal Citrate trianion human plasma (100 μ l) that merges is incubated 1 minute with this spissated rat urine or its salt water diluent.Then, by giving and damping fluid (pH7.4; 100 μ l) human thrombin in (T6769, Sigma Chem Co.) causes the clotting of plasma.At automatic gear (KC10; Amelung) upward measure this time of coagulation.
Make the thrombin time and active enzyme thrombin inhibitor HO (O) C-CH that is dissolved in the concentrated rat urine (or its salt water diluent) of the normal Citrate trianion human plasma of merging by use 2(R) typical curve that interrelates of the concentration known of Cgl-Aze-Pab-H is estimated the concentration of above-mentioned active enzyme thrombin inhibitor in the rat urine.By the gross production that the estimation mean concns with above-mentioned activity inhibitor in the urine multiply by rat urine in 24 hours, can calculate the amount (AMOUNTpd) of this activity inhibitor of excretory in this urine.
Oral or the parenteral of following calculating give with prodrug should after, active enzyme thrombin inhibitor HO (O) C-CH 2(R) bioavailability of Cgl-Aze-Pab-H:
[(AMOUNTpd/ dosage)/(AMOUNT activity, iv/ dosage] * 100 are the AMOUNT activity here, and iv represents to give clear-headed rat intravenous injection HO (O) C-CH by above-mentioned 2(R) behind the Cgl-Aze-Pab-H in urine the excretory amount. Test DBy HO (O) C-CH in the LC-MS mensuration urine 2(R) Cgl-Aze-Pab-H
As described below, oral or parenteral is given and is dissolved in ethanol by the LC-MS assay determination: Solutol TM: drain this active enzyme thrombin inhibitor HO (O) C-CH in urine behind the The compounds of this invention of water (5: 5: 90) 2(R) amount of Cgl-Aze-Pab-H.
By described in the above method C, carry out zooscopy.Collect urine sample, before analysis that it is freezing in-20 ℃.
Analyze HO (O) C-CH of urine sample in accordance with the following methods 2(R) Cgl-Aze-Pab-H content:
The urine sample that to thaw is mixed, and is centrifugal in whizzer as needs.With 1.0ml methyl alcohol activation solid phase extractions pipe (Analytichem Bond Elut.No.1210-2059), use the 1.0ml acetonitrile: water (50: 50) is regulated, and regulates with 1.0ml0.1% formic acid then.Mark (20 μ mol/L) in the 50 μ l work is added in each extraction tube.For the urine standard, add 50 μ l standardized solution.200 μ l samples (or for the urine standard, adding blank urine) are added in each pipe, after this by gravity or gentle vacuum sucking-off.Using the 1.0ml acetonitrile: before ammonium acetate (2mmol/L) (35: the 65) wash-out, (2mmol/L) washes out residual urine with the 1.0ml ammonium acetate.The elutriant of collecting is transferred in the automatic sampling bottle.30 these extracts of μ l are expelled to LC post (Hypersil BDS-C18; 3 μ m; 75mm * 4.0mm internal diameter; Hewlett-Packard No.7992603-354), with ammonium acetate buffer (13mmol/L), with 0.75ml/ minute wash-out with 40% acetonitrile and 0.1% formic acid.Tell this effluent, make to enter in the mass spectrometric electron spray(ES) of P-E Sciex API-3 (electrospray) ion source with 30 μ l/min.HO (O) C-CH 2-(R) Cgl-Aze-Pab-H and HO (O) C-CH 2-(R) retention time of Cgl-Pro-Pab-H (interior mark) is all near 1.5 minutes.M/z430.2 and 444.2 times, differentiate their molion ((M+H) of monitoring respectively with unit mass +).The urine standard has two levels, and one at the quantitation limit place, is used for based on HO (O) C-CH 2(R) Cgl-Aze-Pab-H calibrates with this interior mark peak area ratio.Check the rectilinearity of this method in 0.050-20 μ mol/L scope.The relation conefficient that changes is 1-2% under 1-20 μ mol/L, and is 7% under 0.50 μ mol/L.The quantitative limit is 0.050 μ mol/L.
By total urine turnout in 24 hours be multiply by HO in the urine (O) C-CH 2(R) the mensuration concentration of Cgl-Aze-pab-H can be calculated the amount (AMOUNTpd) of this activity inhibitor of excretory in this urine.By described in the above method C, calculate the bioavailability of this active enzyme thrombin inhibitor then.
By following examples explanation the present invention.
Embodiment General experimental procedure
Write down mass spectrum having on three sections quadrupole mass spectrometers of Finnigan MAT TSQ700 of electrospray interface.
Add on 400 and 500 spectrometers at BRUKER ACP300 and Varian UNITY and to measure 1H NMR and 13C NMR, operation 1The H frequency is respectively 300.13,399.96 and 499.82MHz, and operation 13The C frequency is respectively 75.46,100.58 and 125.69MHz.With the report chemical shift of δ unit. Preparing raw material
According to method described in the International Patent Application WO 94/29336, preparation Boc-(R) Cgl-Aze-Pab-H, Boc-(R) Cgl-Aze-Pab-H * HCl, H-(R) Aze-Pab-Z, H-(R) Aze-Pab-Z * HCl, Bn-OOCCH 2-(R) Cgl-Aze-Pab-Z, Boc-(R) Cgl-Aze-Pab-Z, Boc-(R) Cgl-Aze-OH and Pab-Z * HCl. Embodiment 1EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2(i) Boc-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2
In 0 ℃ with allyl chlorocarbonate (1.7g; 14mmol) be added drop-wise to and contain Boc-(R) Cgl-Aze-Pab-H (6.1g; THF 13mmol) (125ml) and 2M NaOH (70ml; In solution 140mmol).Behind 0 ℃ of stirring 1h, reaction mixture is concentrated, add entry (100ml), (3 * 100ml) extract the water of generation with methylene dichloride.The organic phase that merges is concentrated, produce the 6.4g crude product, the latter is by adopting EtOAc: THF: Et 3N (68: 29: 3) carries out purifying as the flash chromatography of eluent.Concentrate the subtitle compounds that produces 5.8g (81%) white solid. 1H NMR (500MHz, CDCl 3): δ 8.19 (bt, 1H), 7.78 (d, 2H), 7.26 (d, 2H), 6.02-5.92 (m, 1H), 5.32 (d, J=17Hz, 1H), 5.18 (d, J=10Hz, 1H), 5.06 (d, J=7Hz, 1H), 4.82 (bs, 1H), 4.61 (d, J=6Hz, 2H), 4.58-4.48 (m, 1H), 4.38-4.27 (m, 2H), 4.14-4.03 (m, 1H), 3.77-3.68 (m, 1H), 2.60-0.90 (m, 24H). 13C NMR (125MHz, CDCl 3) carbonyl and amidine signal: δ 172.70,170.74,168.02,164.54,155.98. is H-(R) Cgl-Aze-Pab-COOCH (ii) 2CH=CH 2* 2TFA
In 0 ℃ TFA (15ml) adding is contained Boc-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2(2.03g; 3.65mmol, from above step (i)) methylene dichloride (15ml) solution in.This reaction mixture concentrates the subtitle compounds that produces the 2.8g white solid with it after surrounding temperature stirs 3h. 1H?NMR(500MHz，MeOH(d4))：δ7.80(d，2H)，7.57(d，2H)，6.02(m，1H)，5.45(d，J＝17Hz，1H)，5.33(d，J＝10Hz，1H)，5.91-4.80(m，3H)，4.56(s，2H)，4.38(bq，J＝8Hz，1H)，3.71(d，J＝7Hz，1H)，2.76-2.60(m，1H)，2.35-2.20(m，1H)，1.9-1.0(m，11H).(iii) EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2
With H-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2* 2TFA (649mg; 0.95mmol, from above step (ii)), K 2CO 3(656mg 4.8mmol), the mixture of water (0.1ml) and THF (10ml) stirs 2h in 40 ℃, adds then and contains ethyl bromoacetate (190mg; 1.14mmol) THF (1ml). stir 4h and after stirring 14h under the surrounding temperature in 40 ℃, this reaction mixture filtered, concentrate and by adopting EtOAc: THF: Et 3N (68: 29: 3) produces the title compound of 244mg (47%) white solid as the purification by flash chromatography of eluent. 1H NMR (400MHz, CDCl 3): δ 8.46 (bt, 1H), 7.81 (d, 2H), 7.35 (d, 2H), and 6.08-5.94 (m, 1H), 5.35 (d, J=18Hz, 1H), 5.23 (d, J=11Hz, 1H), 4.93 (dd, J=6and9Hz, 1H), 4.66 (d, 2H), 4.62-4.38 (the AB part of ABX-spectrum), 4.16-4.04) (m, 4H), 3.20 (d, 2H), 2.86 (d, 1H), and 2.64-2.45 (m, 2H), 2.0-1.0 (m 17H). 13C NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.33,172.24,170.72,168.19,164.35. Embodiment 2NPrOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2
According to the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2* 2TFA (503mg; 0.74mmol, (ii) referring to above embodiment 1) and acetic acid n-propyl bromide (160mg, 0.88mmol) preparation title compound, the white solid of generation 277mg (68%). 1H-NMR (400MHz, CDCl 3): δ 8.48 (bt, 1H), 7.83 (d, 2H), 7.35 (d, 2H), 6.76 (broad peaks, 1H), 6.02 (m, 1H), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.94 (t, 1H), 4.67 (dd, 2H), 4.49 (the AB part of ABX-spectrum, 2H), 4.12 (m, 2H), 3.98 (t, 2H), 3.24 (the AB-system, 2H), 2.87 (d, 1H), 2.52 (m, 2H), 1.99 (bd, 2H), 1.80-1.50 (m, 7H), 1.61 (q, 2H), 1.30-1.10 (m, 2H), 1.00 (qd, 2H), 0.90 (t, 3H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.4,172.3,170.7,167.9,164.5 Embodiment 3TBuOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2
According to the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2* 2TFA (285mg; 0.42mmol, (ii) referring to above embodiment 1) and the positive butyl ester of bromoacetic acid (96mg, 0.50mmol) preparation title compound, the white solid of generation 93mg (39%). 1H NMR (500MHz, CDCl 3): δ 8.50 (bt, 1H), 7.81 (d, 2H), 7.36 (d, 2H), and 6.07-5.97 (m, 1H), 5.36 (d, J=16Hz, 1H), 5.22 (d, J=10Hz, 1H), 4.93 (dd, J=9and6Hz, 1H), 4.76 (d, J=6Hz, 2H), 4.57-4.46 (m, 2H), 4.18-4.04 (m, 2H), 3.19-3.08 (AB-spectrum, J AB=20Hz, 2H), 2.86 (d, J=8Hz, 1H), 2.72-2.53 (m, 2H), 2.0-0.9 (m, 23H). 13C NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.28,171.53,170.76,167.81,164.1. Embodiment 4EtOOCCH 2-(R) Cgl-Aze-Pab-COOEt (i) Boc-(R) Cgl-Aze-Pab-COOEt
According to the described step of embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab-H (600mg; 1.3mmol) and Vinyl chloroformate (150mg; 1.4mmol) the preparation subtitle compounds, the white solid of generation 240mg (34%). 1H-NMR (300MHz, CDCl 3): δ 9.37 (bs, 1H), 8.16 (bs, 1H), 7.72 (d, 2H), 7.18 (d, 2H), 5.17 (d, 1H), 4.73 (t, 1H), 4.47 (dd, 1H), 4.27 (m, 2H), 4.06 (q, 2H), 3.66 (t, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 1.4-1.8 (m, 7H), 1.22 (s, 9H), 1.3-0.8 (m, 7H). 13C-NMR (75MHz, CDCl 3) carbonyl and amidine signal: δ 172.6,170.7,167.9,164.8,156.0 (ii) H-(R) Cgl-Aze-Pab-COOEt * 2HCl
In 0 ℃, in 5 minutes, the hydrogenchloride adding is contained Boc-(R) Cgl-Aze-Pab-COOEt (240mg; 0.44mmol, from above step (i)) EtOAc (20ml) solution in.This reaction mixture concentrates generation 225mg (100%) white solid with it behind 0 ℃ of stirring 1h. 1H-NMR (300MHz, D 2O): δ 7.85 (d, 2H), 7.61 (d, 2H), 4.98 (dd, 1H), 4.60 (s, 1H), 4.44 (p, 5H), 3.90 (d, 1H), 2.73 (m, 1H), 2.37 (m, 1H), 2.0-1.65 (m, 9H), 1.39 (t, 3H), 1.4-1.1 (m, 7H), 0.98 (m, 1H). 13C-NMR (75MHz, D 2O) carbonyl and amidine signal: δ 172.7,169.4,166.8,154.3. is EtOOCCH (iii) 2-(R) Cgl-Aze-Pab-COOEt
According to embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-COOEt * 2HCl (160mg; 0.31mmol, (ii) from above step) and ethyl bromoacetate (52.5mg; 0.31mmol) the preparation title compound.The pale yellow powder of output: 100mg (61%). 1H-NMR (300MHz, CDCl 3): δ 8.48 (bt, 1H), 7.81 (d, 2H), 7.38 (d, 2H), 4.51 (the AB part of ABX-spectrum, 2H), 4.21 (q, 2H), 4.15-4.05 (m, 4H), 3.21 (the AB-spectrum, 2H), 2.86 (d, 1H), 2.68 (m, 1H), 2.53 (m, 1H), 1.96 (bd, 2H), 1.90-1.70 (m, 12H), 1.35 (t, 3H), 1.22 (t, 6H), 1.30-0.95 (m, 2H). 13C-NMR (75MHz, CDC1 3) carbonyl and amidine signal: δ 175.5,172.2,170.7,167.6,164.9 Embodiment 5EtOOCCH 2-(R) Cgl-Aze-Pab-COO-nPr (i) Boc-(R) Cgl-Aze-Pab-COO-nPr
According to the described step of above embodiment 1 (i), with Boc-(R) Cgl-Aze-Pab-H (6.0g; 13mmol) with chloroformic acid n-propyl (1.57ml; 14mmol) preparation subtitle compounds, output is 5.4g (76%). 1H-NMR (400MHz, CDCl 3): δ 8.25 (bt, 1H), 7.82 (d, 2H), 7.31 (d, 2H), 5.09 (bd, 1H), 4.87 (dd, 1H), 4.58 (dd, 1H), 4.39 (dd, 2H), 4.14 (q, 1H), 4.10 (t, 2H), 3.79 (t, 1H), 2.54 (dm, 2H), 2.21 (s, 1H), 1.87-1.55 (m, 8H), 1.33 (s, 9H), 1.45-1.0 (m, 4H), 0.99 (t, 3H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 172.7,170.6,167.8,165.0,155.9. is (ii) H-(R) Cgl-Aze-Pab-COO-nPr * 2TFA
According to the (ii) described step of embodiment 1, with 2.1g (3.7mmol) Boc-(R) Cgl-Aze-Pab-COO-nPr (from above step (i)) preparation subtitle compounds.Output is 3.7g. 1H-NMR (400MHz, MeOH-d 4): δ 7.77 (d, 2H), 7.60 (d, 1H), 4.86 (dd, 1H), 4.56 (the AB part of ABX-spectrum, 2H), 4.33 (m, 4H), 3.72 (d, 1H), 3.30 (m, 1H), 2.68 (m, 1H), 2.28 (m, 1H), 1.9-1.7 (m, 9H), 1.4-1.1 (m, 6H), 1.02 (t, 3H). 13C-NMR (100MHz, MeOH-d 4) carbonyl and amidine signal: δ 172.7,169.3,168.0,161.4. is EtOOCCH (iii) 2-(R) Cgl-Aze-Pab-COO-nPr
According to embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-COO-nPr * 2TFA (472mg; 0.69mmol, (ii) from above step) and ethyl bromoacetate (138mg; 0.83mmol) the preparation title compound, produce the O.22mg white solid of (58%). 1H-NMR (400MHz, CDCl 3): δ 8.46 (bt, 1H), 7.82 (d, 2H), 7.32 (d, 2H), 4.92 (dd, 1H), 4.49 (the AB part of ABX-spectrum, 2H), 4.10 (m, 6H), 3.23 (the AB-spectrum, 2H), 2.80 (dm, 2H), 1.98 (bd, 2H), 1.74 (q, 2H), 1.63 (dd, 2H), 1.52 (m, 1), 1.21 (t, 3H), 1.20-1.10 (m, 2H), 0.98 (t, 3H). 13C-NMR (100MHz, CDCl3) carbonyl and amidine signal δ 175.3,172.2,170.7,167.6,164.8. Embodiment 6MeOOCCH 2-(R) Cgl-Aze-Pab-COO-nPr according to above embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-COO-nPr * 2TFA (365mg; 0.53mmol, (ii) referring to above example 5) and methyl bromoacetate (98mg; 0.64mmol) the preparation title compound, the white solid of generation 114mg (41%). 1H-NMR (500MHz, CDCl 3): δ 8.44 (bt, 1H), 7.82 (d, 2H), 7.32 ((d, 2H), 7.04 (broad peak 1H), 4.92 (dd, 1H), 4.49 (the AB parts of ABX-spectrum), 4.12 (m, 2H), 4.10 (t, 2H), 3.63 (s, 3H), 3.24 (s, 2H), 2.87 (d, 1H), 2.65 (m, 1H), 2.52 (m, 1H), 2.01 (broad peak, 1H), 1.96 (bd, 2H), 1.75 (q, 4H), 1.63 (bdd, 1H), 1.53 (m, 1H), 1.3-1.1 (m, 5H), 0.99 (t, 3H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.3,172.5,170.7,167.7,165.0. Embodiment 7EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH 2OMe (i) Boc-(R) Cgl-Aze-Pab-COOCH 2CH 2OMe
According to the described step of above EXAMPLE l (i), by Boc-(R) Cgl-Aze-Pab-H (6.0g; 13mmol) with chloroformic acid 2-methoxyl group ethyl ester (1.94g; 14mmol) preparation subtitle compounds.Output is 3.9g (34%). 1H-NMR (400MHz, CDCl 3): δ 8.24 (bt, 1H), 7.83 (d, 2H), 7.31 (d, 2H), 5.08 (bd, 1H), 4.87 (dd, 1H), 4.58 (dd, 1H), 4.39 (dd, 2H), 4.30 (t, 2H), 4.15 (m, 1H), 3.79 (bt, 1H), 3.68 (t, 2H), 3.40 (s, 3H), 2.65-2.45 (m, 2H), 2.20 (broad peak, 1H), 1.9-1.55 (m, 6H), 1.34 (s, 9H), 1.3-0.95 (m, 6H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 172.7,170.7,167.8,164.6,155.9. is H-(R) Cgl-Aze-Pab-COOCH (ii) 2CH 2OMe * 2TFA
According to above embodiment 1 described step (ii), with 1.71gBoc-(R) cgl-Aze-pab-COOCH 2CH 2OMe (from above step (i)) prepares subtitle compounds.Output is 1.89g (88%). 1H-NMR (400MHz, MeOH-d4): δ 7.77 (d, 2H), 7.59 (d, 2H), 4.85 (dd, 1H), 4.56 (d, 2H), 4.49 (m, 2H), 4.37 (m, 1H), 4.28 (m, 1H), 3.70 (m, 3H), 3.37 (s, 3H), 2.68 (m, 1H), 2.28 (m, 1H), 1.9-1.7 (m, 7H), 1.4-1.1 (m, 6H). 13(154.6. is EtOOCCH (iii) for 100MHz, MeOH-d4) carbonyl and amidine signal: δ 172.7,169.3,168.0 for C-NMR 2-(R) Cgl-Aze-Pab-COOCH 2CH 2OMe
According to above embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-COOCH 2CH 2OMe * 2TFA (487mg; 0.69mmol, (ii) from above step) and ethyl bromoacetate (138mg; 0.83mmol) the preparation title compound, producing crude product, the latter is by adopting THF: methylene dichloride (3: 1) carries out purifying as the flash chromatography of eluent.Output is the white powder of 0.13mg (34%). 1H-NMR (400MHz, CDCl 3): δ 8.46 (bt, 1H), 7.83 (d, 2H), 7.32 (d, 2H), 7.21 (broad peaks, 1H), 4.92 (dd, 1H), 4.49 (the AB part of ABX-spectrum, 2H), 4.30 (t, 2H), 4.12 (q, 2H), 4.07 (q, 2H), 3.68 (t, 1H), 3.40 (s, 3H), 3.24 (s, 2H), 2.62 (m, 1H), 2.52 (m, 1H), 2.07 (broad peak, 1H), 1.97 (bd, 1H), 1.8-1.5 (m, 5H), 1.3-1.1 (m, 6H), 1.05-0.95 (m, 2H). 13C-NMR (100MHz, CDC1 3) carbonyl and amidine signal: δ 175.3,172.2,170.7,167.8,164.6. Embodiment 8MeOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH 2OMe
According to above embodiment 1 (iii) described in step, by H-(R) cgl-Aze-pab-COOCH 2CH 2OMe * 2TFA (490mg; 0.7mmol, (ii) referring to above embodiment 7) and methyl bromoacetate (128mg; 0.84mmol) the preparation title compound, producing crude product, the latter is by adopting THF: methylene dichloride (3: 1) carries out purifying as the flash chromatography of eluent.Output is the white powder of 155mg (41%). 1H-NMR (400MHz, CDCl 3): δ 8.44 (t, 1H), 7.83 (d, 2H), 7.31 (d, 2H), 4.92 (dd, 1H), 4.49 (the AB part of ABX-spectrum, 2H), 4.30 (t, 2H), 4.13 (m, 2H), 3.68 (t, 2H), 3.63 (s, 3H), 3.39 (s, 3H), 3.25 (s, 2H), 2.87 (d, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 1.96 (bd, 1H), 1.8-1.5 (m, 6H), 1.3-1.1 (m, 5H), 1.00 (q, 2H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.2,172.6,170.7,167.8,164.5. Embodiment 9EtOOCCH 2-(R) Cgl-Aze-Pab-COO-nBu (i) Boc-(R) Cgl-Aze-Pab-COO-nBu
According to the described step of embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab-H (1.01g; 2.1mmol) and butyl chloroformate (0.32g; 2.4mmol) the preparation subtitle compounds.After stirring 1.5h under the surrounding temperature, this reaction mixture is concentrated, and with three parts of dichloromethane extractions.The organic phase of He Binging washes with water then, passes through Na 2SO 4Dry and concentrated, the subtitle compounds of generation 1.0g (83%) white powder. 1H-NMR (300MHz, CDCl 3): δ 9.81-9.31 (bs, 1H), 8.36-8.20 (m, 1H), 7.35 (d, 2H), 7.84 (d, 2H), 6.78-6.43 (bs, 1H), 5.05-4.82 (m, 2H), 4.69-4.15 (m, 3H), 4.15-4.08 (m, 3H), 3.86-3.70 (m, 1H), 2.68-2.42 (m, 2H), 1.92-0.88 (m, 25H). 13C-NMR (125MHz, CDCl 3) carbonyl and amidine signal: δ 172.5,170.7,167.9,164.9,156.0.FAB-MS:(m+1)=572 (m/z) (ii) H-(R) Cgl-Aze-Pab-COO-nBu * 2HCl
According to the (ii) described step of embodiment 4, by Boc-(R) Cgl-Aze-Pab-COO-nBu (2.5g; 4.4mmol, from above step (i)) and the preparation subtitle compounds, the white powder of generation 2.4g (100%). 1H-NMR (300MHz, MeOH-d4): δ 7.78-7.60 (m, 2H), 4.66-4.49 (m, 2H), 0.98 (t, 2H), and 4.49-4.35 (m, 3H), 4.35-4.22 (m, 1H), 3.75 (d, 1H), and 1.92-1.67 (m, 8H), 1.56-1.07 (m, 8H). one of them proton signal is by CD 3The OH signal is covered 13(154.7MS (m+1)=472 (m/z) is EtOOCCH (iii) for 100MHz, MeOH-d4) carbonyl and amidine signal: δ 172.7,169.3,167.9 for C-NMR 2-(R) Cgl-Aze-Pab-COO-nBu
According to embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-COO-nBu * 2HCl (400mg; 0.74mmol) and ethyl bromoacetate (147mg; 0.88mmol) the preparation title compound.This product produces the white solid of 290mg (70%) by carrying out purifying with methylene dichloride and EtOH (gradient 0.1%=＞12.8%) as the flash chromatography of eluent. 1H-NMR (300MHz, CDCl 3): δ 9.70-9.36 (bs, 1H), 8.47 (t, 1H), 7.81 (d, 2H), 7.32 (d, 2H), 7.07-6.73 (bs, 1H), 4.97-4.87 (dd, 1H), 4.62-4.35 (m, 2H), 4.20-3.98 (m, 6H), 3.27-3.12 (m, 2H), 2.84 (s, 1H), 2.70-2.40 (m, 2H), 2.03-0.85 (m, 22H) 13C-NMR (75MHz, CDCl 3) carbonyl and amidine signal: δ 175.3,172.3,170.8,167.9,165.0FAB-MS:(m+1)=558 (m/z) Embodiment 10PrlC (O) CH 2CH 2CH 2OOCCH 2-(R) Cgl-Aze-Pab-Z (i) PrlC (O) CH 2CH 2CH 2OH
With gamma-butyrolactone (4.0g; 46.5mmol) and tetramethyleneimine (6.6g; 92.8mmol) mixture under room temperature, stir 2.5h.This product of vacuum concentration, the yellow oil product of generation 14.5g (100%). 1H-NMR(300MHz，MeOH-d4)：δ3.58(t，2H)，3.50(t，2H)，3.40(t，2H)，2.42(t，2H)，2.06-1.75(m，6H)(ii)PrlC(O)CH 2CH 2CH 2OOCCH 2Br
In 0 ℃ with bromoacetyl bromide (4.0ml; 45.8mmol) be added drop-wise to and contain PrlC (O) CH 2CH 2CH 2OH (7.2g; 45.8mmol; From above step (i)) and DMAP (5.6g; 45.8mmol) the mixture of methylene dichloride in.After stirring 1.5h under the room temperature, add in addition 1 part of bromoacetyl bromide (1.0ml, 11.4mmol) and DMAP (1.4g 11.4mmol), reacts backflow 1.5h.Add entry, use dichloromethane extraction 3 times.This organic phase Na 2SO 4Dry and concentrated, the yellow oil product of generation 10.3g (81%). 1H-NMR(400MHz，CDCl 3)：δ4.15(t，2H)，3.75(s，2H)，3.40-3.31(m，4H)，2.30(t，2H)，1.98-1.83(m，4H)，1.81-1.73(m，2H)(iii) PrlC(O)CH 2CH 2CH 2OOCCH 2-(R)Cgl-Aze-Pab(Z)
According to embodiment 1 (iii) described in step, by H-(R) Cgl-Aze-Pab-Z (6g; 10.4mmol) and PrlC (O) CH 2CH 2CH 2OOCCH 2Br (3.5g; 12.4mmol; From above step (ii)) preparation title compound.This crude product is by using heptane: EtOAc: Virahol (1: 2: 2) carries out purifying as the flash chromatography of eluent, produces 4.2g, and the latter adopts by preparation type RPLC then, with the 0.1M NH that contains 44% acetonitrile 4OAc carries out purifying as eluent, produces the white solid product of 2.64g (36%). 1H-NMR (500MHz, CDCl 3): δ 9.80-9.22 (bs, 1H), 8.36 (t, 1H), 7.96-7.58 (m, 3H), 7.45 (d, 2H), 7.37-7.22 (m, 5H), 5.20 (s, 2H), 4.95-4.88 (dd, 1H), 4.72-4.29 (m, 2H), 4.15-4.04 (m, 2H), 4.04-3.88 (m, 2H), 3.40 (t, 2H), 3.34 (t, 2H), 3.28-3.17 (m, 2H), 2.85 (d, 1H), 2.67-2.48 (m, 1H), 2.23 (t, 2H), 2.14-0.93 (m, 18H). 13C-NMR (125MHz, CDCl 3) carbonyl and amidine signal: δ 175.3,172.4,170.9,170.4,168.2,164.6FAB-MS:(m+1)=703 (m/z) Embodiment 11ChNHC (O) CH 2OOCCH 2-(R) Cgl-Aze-Pab-Z (i) ChNHC (O) CH 2OH
With hexahydroaniline (9.9g; 99.8mmol) and 2,5-dioxy-1,4-diox (3.0g; 25.9mmol) mixture stir 2.5h in 100 ℃.This product is concentrated, produce the brown solid product of 8.1g (100%). 1H-NHR(500MHz，MeOH-d4)：δ3.92(s，2H)，3.75-3.65(m，1H)，1.90-1.58(m，5H)，1.43-1.07(m，5H)。Wherein two protons are by CD 3The OH signal is covered. 13C-NHR (125MHz, MeOH-d4) amidine and carbonyl signal: δ 174.0,62.5,33.7,26.5,26.1,26.0.One of them carbon signal is by CD 3The OH signal is covered.(ii)ChNHC(O)CH 2OOCCH 2Br
With bromoacetyl bromide (4.0ml; 45.8mmol) be added drop-wise in 0 ℃ and contain ChNHC (O) CH 2OH (8.0g; 50.9mmol; From above step (i)) and DMAP (6.2g; 50.9mmol) the mixture of methylene dichloride (80ml) in.After stirring 1.5h under the room temperature, add another part bromoacetyl bromide (1.0ml, 11.4mmol) and DMAP (1.4g, 11.4mmol), with this reaction mixture refluxed 1.5h.Add entry, this water is with three parts of dichloromethane extractions.This organic phase washes with water, uses Na 2SO 4Dry and concentrated, the brown solid product of generation 10.3g (73%). 1H?NMR(400MHz，CDCl 3)：δ6.12-6.00(bs，1H)，4.62(s，2H)，3.90(s，2H)，3.84-3.76(m，1H)，1.95-1.86(m，2H)，1.75-1.65(m，2H)，1.65-1.56(m，1H)，1.43-1.29(m，2H)，1.24-1.10(m，3H).(iii) ChNHC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z
According to the similar step of embodiment 1 described in (iii), by H-(R) Cgl-Aze-Pab-Z (6g; 10.4mmol) and ChNHC (O) CH 2OOCCH 2Br (3.5g; 12.4mmol; From above step (ii)) beginning, the preparation title compound.This crude product is by using heptane: EtOAc: Virahol (5: 2: 2) carries out purifying as the flash chromatography of eluent, concentrates subsequently, then by preparation type RPLC, adopts the 0.1M NH that contains 50% acetonitrile 4OAc is as eluent.Concentrate the white solid product that produces 2.6g (36%) with lyophilize. 1H-NMR (500MHz, CDCl 3): δ 9.78-9.25 (bs, 1H), 7.90 (t, 1H), 7.78 (d, 2H), 7.44 (d, 2H), 7.38-7.24 (m, 5H), 6.66 (t, 1H), 5.20 (s, 2H), 4.90-4.83 (dd, 1H), 4.60-4.45 (m, 2H), and 4.18-3.93 (m, 4H), 3.73-3.62 (m, 1H), (d, 1H), 3.23,3.44 (AB, 2H), 2.87,2.65-2.08 (m, 3H), 1.98-0.93 (m, 22H) 13C-NMR (125MHz, CDCl 3) carbonyl and amidine signal: δ 175.1,171.7,170.7,168.8,166.1,164.4FABMS:(m+1)=703 (m/z) Embodiment 12(nPr) 2NC (O) CH 2OOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCC (CH 3) 3(i) (nPr) 2NC (O) CH 2OH
With 2,5-dioxy-1,4-diox (2.02g; 17.4mmol) and di-n-propylamine (5ml; 36.5mmol) mixture in 50 ℃ the heating 1h, in 90 ℃ the heating 66h.Add toluene, remove excessive di-n-propylamine with final vacuum.Residue contains 10% methyl alcohol by employing methylene dichloride carries out purifying as the flash chromatography of eluent, produces the required compound of 4.18g (66%). 1H?NMR(300MHz，CDCl3)：δ4.1(d，2H)，3.65(t，1H)，3.25-3.35(m，2H)，2.9-3.0(m，2H)，1.45-1.6(m，4H)，0.8-0.95(m，6H)(ii)(nPr) 2NC(O)CH 2OOCCH 2Br
To contain (nPr) 2NC (O) CH 2OH (0.743g; 4.7mmol; From above step (i)) DCC (0.951g; 4.6mmol) and bromoacetic acid (0.704g; 5.1mmol) the mixture of methylene dichloride (15ml) under room temperature, stir 1.5h.By removing by filter precipitation, and vacuum is removed this solvent from filtrate. and the Kugelrohr distillation of this residue produces the required compound of 0.66g (50%). 1H NMR (300MHz, CDCl3): δ 4.8 (s, 2H), 4.0 (s, 2H), 3.2-3.3 (m, 2H), 3.05-3.15 (m, 2H), 1.5-1.7 (m, 4H), 0.8-1.0 (dt, 6H) (iii) PIVALIC ACID CRUDE (25) ylmethyl 4-nitrophenyl carbonate
With PIVALIC ACID CRUDE (25) silver (7.5g; 25mmol) with iodomethyl 4-nitrophenyl carbonate (Alexander etc., J.Med.Chem., (1988) 31,318; 799g; Mixture 25mmol) is backflow 2h in benzene (50ml).Vacuum is removed benzene, and this residue is dissolved in the toluene.By the hyflo filtration and by adopting toluene to carry out purifying, provide 4.00g (54%) subtitle compounds as the flash chromatography of eluent. 1H NMR (300MHz; CDCl 3): δ 8.25 (d, 2H), 7.40 (d, 2H), 5.85 (s, 2H), 1.2 (s, 2H) 13C NMR (75MHz, CDCl 3) (iv) Boc-(R) Cgl-Aze-Pab-COOCH of carbonyl and amidine signal: δ 176.77,155.06 2OOCC (CH 3) 3
Under room temperature, will contain valeryl methyl 4-nitrophenyl carbonate (1.18g; 4mmol; Methylene dichloride from above step (iii)) (20ml) solution adds and contains Boc-(R) Cgl-Aze-Pab-H (1.88g; 4mmol) and triethylamine (0.66ml; 4.75mmol) methylene dichloride (20ml) solution in.Behind the 1h, use the EtOAc instead of methylene chloride, this mixture carries out purifying by adopting EtOAc as the flash chromatography of eluent, produces the subtitle compounds of 1.27g (50%). 1H?NMR(300MHz，CDCl 3)：δ9.5(bs，1H)，8.25(t，1H)，7.8(d，2H)，7.3(d，2H)，7.0(bs，1H)，5.0-4.8(m，2H)，4.65-4.5(m，1H)，4.5-4.3(m，2H)，4.2-4.05(m，1H)，3.75(t，1H)，2.7-2.4(m，2H)，1.9-1.45(m，5H)，1.45-0.8(m，24H)(v) H-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3
With Boc-(R) Cgl-Aze-Pab-COOCH 2OOCC (CH 3) 3(327mg; 0,52mmol; From above step (iv)) be dissolved in the mixture of methylene dichloride (5ml) and TFA (1.2ml).Behind the 2h, with this reaction mixture vacuum concentration, add acetonitrile, vacuum is removed this solvent again, produces the subtitle crude product, and the latter need not be further purified and be used for next step.(vi) (nPr) 2NC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3
Will from above step (residue v) with contain (nPr) 2NC (O) CH 2OOCCH 2Br (150mg; 0.53mmol; From above step (ii)) and K 2CO 3(480mg; 3.5mmol) in THF (5ml), mix, and in 40 ℃ of heating 3h.This reaction mixture is filtered and the simmer down to crude product, and the latter produces the title product of 78mg (21%) by preparation type RPLC purifying. 1H NMR (300MHz, CDCl 3): δ 9.3-9.6 (bs, 1H), 8.5 (m, 1H), 7.95-8.15 (bs, 1H), and 7.85-7.95 (d, 2H), 7.2-7.3 (d, 2H), 5.8 (s, 2H), 4.8-4.9 (dd, 1H), 4.5-4.7 (m, 3H), and 4.0-4.4 (m, 3H), 2.8-3.4 (m, 5H), 2.2-2.7 (m, 3H), 1.75-1.3 (m, 9H), 1.3-1.0 (m, 14H), 1.0-0.7 (m, 7H). 13C NMR (75MHz, CDCl3) carbonyl and amidine signal: δ 177.24,175.30,171.85,170.79,168.78,165.82,163.14. Embodiment 13EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCC (CH 3) 3
(step is similar vi), by crude product Boc-(R) Cgl-Aze-Pab-COOCH to above embodiment 12 2OOCC (CH 3) 3(0.41g; 0.65mmol; From above embodiment 12 (iv)), adopt acetonitrile (10ml), the preparation title compound as solvent.After stirred overnight under the room temperature, vacuum is removed this solvent, and this residue is distributed between EtOAc and water.Water is with EtOAc extraction 3 times, with the organic phase drying (Na that merges 2SO 4), vacuum is removed this solvent.This residue process is adopted the flash chromatography of methylene chloride as eluent.Lyophilize from Glacial acetic acid, the title compound of generation 84mg (21%). 1H NMR (300MHz, CDCl3): δ 9.9 (bs, 1H), 8.5 (t, 1H), 7.35 (d, 2H), 5.85 (s, 2H), 5.90 (dd, 2H), and 4.6-4.35 (m, 2H), 4.15-4.0 (m, 4), 3.2 (s, 2H), 2.85 (d, 1H), (2.7-2.45 m, 2), and 2.0-1.9 (m, 2H), 1.8-1.45 (m, 5H), 1.3-0.9 (m, 18H). 13C NMR (75MHz, CDC13) carbonyl and amidine signal: δ 177.23,175.48,172.29,170.80,168.85,163.14. Embodiment 14EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH (CH 3) OOCCH 3(i) Boc-(R) Cgl-Aze-Pab-COOCH (CH 3) OOCCH 3
Under room temperature, will contain Boc-(R) Cgl-Aze-Pab-H (6.38g; 13.5mmol), 1-acetoxyl ethyl 4-nitrophenyl carbonate (Alexander etc., J.Med.Chem., (1988) 31,318) (3.05g; 12mmol) and triethylamine (1.95ml; Methylene dichloride 14mmol) (40ml) solution stirring 16h adds EtOAc then.The solution that produces is concentrated a little, and use Na 2CO 3The aqueous solution (10%) washing, with its simmer down to crude product, the latter carries out purifying by adopting EtOAc as the flash chromatography of eluent, produces the subtitle compounds of 5.59g (77%). 1H NMR (300MHz, CDCl 3): δ 9.5 (bs, 1H), 8.25 (t, 1H), 7.85 (d, 2H), 7.35 (d, 2H), 6.95 (q, 1H), 6.7 (bs, 1H), 5.0-4.85 (m, 2H), 4.65-4.5 (m, 1H), and 4.5-4.25 (m, 2H), 4.2-4.05 (m, 1H) 3.75 (t, 1H), 2.65-2.45 (m, and 2H) 2.05 (s, 3H), 1.9-1.45 (m, 11H), 1.45-0.8 (m, 12H). 13(75MHz, CDCl3) carbonyl and amidine signal: δ 172.61,170.80,169.54,168.91,162.50,156.02. be H-(R) Cgl-Aze-Pab-COOCH (CH (ii) for C NMR 3) OOCCH 3
(step v) is by Boc-(R) Cgl-Aze-Pab-COOCH (CH according to above embodiment 12 3) OOCCH 3(2.21g; 3.68mmol; From above step (i)) preparation subtitle crude product.(iii) EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH (CH 3) OOCCH 3Will be from above step crude product H-(R) Cgl-Aze-Pab-COOCH (CH (ii) 3) OOCCH 3Be dissolved in the methylene dichloride (150ml).This mixture 10%Na 2CO 3Solution washing, this organic phase K 2CO 3Dry also filtration.To contain K 2CO 3(756mg; 5.5mmol) and (O-trifyl)-hydroxyethanoic acid ethyl ester (790mg; Methylene dichloride 33mmol) (5ml) adds in the solution of this generation.This reaction mixture stirred under room temperature 5-10 minute, then vacuum concentration.This residue is dissolved among the EtOAc, and the mixture of generation filters by C salt.Filtrate through adopting the flash chromatography of EtOAc as eluent, then by HPLC, is produced the title compound of 475mg (22%). 1H NMR (300MHz, CDCl3): δ 9.5 (bs, 1H), 8.3 (t, 1H), 7.7 (d, 2H), 7.2 (d, 2H), 6.85 (q, 1H), 4.8 (t, 1H), 4.45-4.25 (m, 2H), 4.1-3.85 (m, 4H), 3.1 (s, 2H), 2.75 (s, 1H), 2.5-2.3 (m, 2H), 1.95 (s, 3H), 1.9-1.8 (m, 1H), 1.7-1.25 (m, 8H), 1.25-1.75 (m, 8H). 13C NMR (75.5MHz, CDCl3) carbonyl and amidine signal: δ 175.26,172.34,170.81,169.49,168.80,162.43. Embodiment 15MeOOCCH 2-(R) Cgl-Aze-Pab-OOCPh (i) Boc-(R) Cgl-Aze-Pab-OOCPh
In 20 ℃ in 45 minutes, will be dissolved in the dibenzoyl peroxide (556mg of THF (10ml); 2.3mmol) be added drop-wise to and contain Boc-(R) Cgl-Aze-Pab-H (1.0g; 2.1mmol) and Na 2HPO 4(18.7g; In THF 105mmol) (45ml) solution.Behind 20 ℃ of stirring 24h, this reaction mixture is concentrated, the crude product process preparation type RPLC that produces.Produce the subtitle compounds of 124mg (10%) white solid. 1H-NMR (500MHz, CDCl 3): δ 8.26 (m, 1H), 8.09 (m, 2H), 7.72 (m, 2H), 7.59 (m, 1H), 7.48 (m, 2H), 7.36 (d, 2H), 5.13 (s, 2H), 4.87-4.98 (m, 2H), 4.54-4.61 (m, 1H), and 4.33-4.47 (m, 2H), 4.13-4.19 (m, 1H), 3.81 (t, 1H), 2.53-2.63 (m, 2H) .1.73-1.86 (m.3H), 1.66-1.72 (m, 2H), 1.36 (s, 9H), 0.968-1.28 (m, 6H). 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 172.7,170.6,163.9,157.0,155.9.LC-MS:m/z592 (M+H +); M/z614 (M+Na +). (ii) H-(R) Cgl-Aze-Pab-OOCPh
In 20 ℃ TFA (6ml) adding is contained Boc-(R) Cgl-Aze-Pab-OOCPh (600mg; 1.01mmol; From above step (i)) methylene dichloride (18ml) solution in.After stirring 14h, this reaction mixture is concentrated, the crude product that produces is distributed between EtOAc:0.1M NaOH.Be separated, with organic layer drying (Na 2SO 4) and evaporation.Output: 480mg (96%) white solid. 1H-NMR(400MHz，MeOH-d4)：δ8.18(m，2H)，7.77(m，2H)，7.64(m，1H)，7.52(m，2H)，7.43(d，2H)，4.75-4.81(m，1H)，4.50(s，2H)，4.18-4.34(m，2H)，3.12(d，1H)，2.57-2.68(m，1H)，2.23-2.33(m，1H)，1.88-1.96(m，1H)，1.73-1.84(m，2H)，1.59-1.71(m，2H)，1.45-1.57(m，1H)，0.80-1.34(m，5H)LC-MS：m/z492(M+H +)；m/z514(M+Na +)(iii) MeOOCCH 2-(R)Cg1-Aze-Pab-OOCPh
In 20 ℃ with methyl bromoacetate (177mg; 1.16mmol) add and to contain H-(R) Cgl-Aze-Pab-OOCPh (480mg; 0.97mmol; From above step (ii)), K 2CO 3(270mg; In acetonitrile 2mmol) (5ml) solution.This reacts on 20 ℃ and stirs 4h.This reaction mixture is filtered and concentrates, produce crude product, the latter produces the title compound of 269mg (49%) white solid by preparation type RPLC purifying. 1H-NMR (500MHz, CDCl 3): δ 8.43 (m, 1H, NH), 8.09 (m, 2H), 7.69 (m, 2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.27 (s, 2H), 4.93 (dd, 1H), 4.59 (dd, 1H), 4.40 (dd, 1H), 4.12 (m, 2H), 3.65 (s, 3H), 2.87 (d, 1H), 2.72-2.63 (m, 1H), 2.55-2.48 (m, 1H), 1.96 (m, 1H), 1.74 (m, 2H), 1.67 (d, 1H), 1.59 (d, 1H), and 1.56-1.50 (m, 1H), 1.29-1.08 (m, 4H), 1.04-0.94 (m, 1H) 13C-NMR (100MHz, CDCl 3) carbonyl and amidine signal: δ 175.1,172.5,170.6,164.0,157.1LC-MS:m/z564 (M+H +) Embodiment 16MeOOCCH 2-(R) Cgl-Aze-Pab-OH
Under 20 ℃, with KOMe (1.6ml; 0.29M; 0.46mmol) add and to contain MeOOCCH 2-(R) Cgl-Aze-Pab-OC (O) Ph (260mg; 0.46mmol; In THF (4.6ml) solution referring to above embodiment 15 (iii)).Stir after 15 minutes, this mixture is concentrated and process preparation type RPLC.Produce the title compound of 109mg (52%) white solid. 1H-NMR (500MHz, MeOH-d4): δ 7.59 (d, 2H), 7.34 (d, 2H), 4.83 (s, 2H), 4.82-4.76 (m, 1H), 4.48 (d, 1H), 4.33 (d, 1H), 4.15-4.30 (m, 2H), 3.64 (s, 3H), 3.04 (d, 1H), 2.57 (m, 1H), 2.26 (m, 1H), 1.95 (m, 1H), 1.75 (m, 2H), 1.58-1.70 (m, 2H), 1.53 (m, 1H), 1.31-1.10 (m, 4H), 1.04 (m, 1H) 13C-NMR (100MHz, MeOH-d4): carbonyl and amidine signal: δ 175.9,174.3,172.7,155.2LC-MS:m/z460 (M+H +), m/z482 (M+Na +) Embodiment 17EtOOCCH 2-(R) Cgl-Aze-Pab-OH
To EtOOCCH 2-(R) Cgl-Aze-Pab-C (O) OCH (CH 3) OOCCH 3(184mg; 0.31mmol; Referring to above embodiment 14 (iii)) add hydrochloric azanol (120ml in the solution; 1.72mmol) and triethylamine (0.8ml; 5.7mmol) EtOH (95%; 4.0ml), and this mixture stirred under room temperature 4 days.This mixture is concentrated, and this crude product is through preparation type RPLC.Produce the title compound of 85mg (58%). 1H-NMR (300MHz, CD 3OD): δ 7.6 (d, 2H), 7.35 (d, 2H), 4.75-4.85 (m, 1H), 4.4-4.55 (m, 2H), 4.0-4.35 (m, 4H), 3.35 (d, 2H), 3.05 (d, 1H), 2.5-2.65 (m, 1H), 2.2-2.35 (m, 1H), 1.9-2.05 (m, 1H), 1.4-1.85 (m, 5H), 0.85-1.35 (m, 8H) 13C-NMR (75.5MHz, CD 3OD): carbonyl and amidine signal: δ 175.97,173.91,172.72,155.23LC-MS:(m+1)=474 (m/z) Embodiment 18BnOOCCH 2-(R) Cgl-Aze-Pab-OH
With BnOOCCH 2-(R) Cgl-Aze-Pab-Z (1.0g; 1.52mmol) add hydrochloric azanol (320ml; 4.59mmol) and triethylamine (1.7ml; 12.24mmol) EtOH solution in.This reaction mixture is stirred 40h, concentrate then.This crude product adopts the 0.1M NH that contains 50% acetonitrile by preparation type RPLC 4OAc carries out purifying as eluent, produces the title compound of 0.34g (42%).LC-MS:(m+1)=536 (m/z) Embodiment 19NPrOOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (700mg; 1.2mmol) and acetic acid n-propyl bromide (268mg; 1.45mmol) the preparation title compound.Output is 259mg (35%).FAB-MS:(m+1)=606 (m/z) Embodiment 20NPrOOCCH 2-(R) Cgl-Aze-Pab-OH
Similar with step described in the embodiment 18, by nPrOOCCH 2-(R) Cgl-Aze-Pab-Z (182mg; 0.3mmol; Referring to above embodiment 19) the preparation title compound.This crude product adopts the 0.1M NH that contains 40% acetonitrile by preparation type RPLC 4OAc carries out purifying as eluent, produces the required compound of 74mg (51%).LC-MS:(m+1)=488 (m/z) Embodiment 21IPrOOCCH 2-(R) Cgl-Aze-Pab-OH
Similar with step described in the embodiment 18, by iPrOOCCH 2-(R) Cgl-Aze-Pab-Z (590mg; 0.7mmol; Referring to following examples 39) the preparation title compound.Output is 110mg (32%).LC-MS:(m+1)=488 (m/z) Embodiment 22TBuOOCCH 2-(R) Cgl-Aze-Pab-OH
Similar with step described in the embodiment 18, by tBuOOCCH 2-(R) Cgl-Aze-Pab-Z (738mg; 1.2mmol; Referring to following examples 37) the preparation title compound.Output is 290mg (48%).LC-MS:(m+1)=502 (m/z) Embodiment 23(nPr) 2NCOCH 2OOCCH 2-(R) Cgl-Aze-Pab-OH (i) HOOCCH 2-(R) Cgl (Boc)-Aze-Pab-O-Boc
To contain HOOCCH 2-(R) Cgl-Aze-Pab-OH (670mg; 1.5mmol; Referring to following examples 28), (Boc) 2O (654mg; 3mmol) and DMAP (92mg; 0.75mmol) THF: the solution of water (10: 1) stirs 2h under room temperature.This reaction mixture is concentrated, and by preparation type RPLC purifying.Lyophilize produces the subtitle compounds of 112mg (12%) white solid.LC-MS：(m-1)＝643(m/z)(ii) (nPr) 2NCOCH 2OOCCH 2-(R)Cgl(Boc)-Aze-Pab-O-Boc
To contain HOOCCH 2-(R) Cgl-Aze-Pab-O-Boc (100mg; 0.15mmol; Referring to
To contain (nPr) 2NCOCH 2-(R) Cgl (Boc)-Aze-Pab-O-Boc (20mg; 0.025mmol) TFA: methylene dichloride (1: 1) solution stirred under room temperature 5 minutes.This reaction mixture is concentrated and lyophilize from acetonitrile and water, produce the title compound of 5mg (34%).LC-MS:(m+1)=587 (m/z) Embodiment 24ChNHCOCH 2OOCCH 2-(R) Cgl-Aze-Pab-OH
Similar with step described in the embodiment 18, by ChNHCOCH 2OOCCH 2-(R) Cgl-Aze-Pab-Z (118mg; 0.17mmol; Referring to above embodiment 11 (ii)) preparation title compound.Output is 1.8mg.LC-MS:(m+1)=585 (m/z) Embodiment 25MeNHCOCH 2OOCCH 2-(R) Cgl-Aze-Pab-OH
Similar with step described in the embodiment 18, by MeNHCOCH 2-(R) Cgl-Aze-Pab-Z (81mg; 0.12mmol; Referring to following examples 36) the preparation title compound.Output is 10mg (16%).LC-MS:(m+1)=517 (m/z) Embodiment 26EtOOCCH 2-(R) Cgl-Aze-Pab-OAc (i) H-(R) Cgl-Aze-Pab-OAc
Similar with method described in following examples 27 (step (i), (ii) and (iii)), replace propionic anhydride with diacetyl oxide, the preparation subtitle compounds.LC-MS：(m+1)＝430(m/z)(ii) EtOOCCH 2-(R)Cgl-Aze-Pab-OAc
With above embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-OAc (370mg; 0.6mmol) and ethyl bromoacetate (105mg; 0.63mmol) the preparation title compound.Output is 67mg (22%).LC-MS:(m+1)=516 (m/z) Embodiment 27EtOOCCH 2-(R) Cgl-Aze-Pab-OC (O) Et (i) Boc-(R) Cgl-Aze-Pab-OH
With Boc-(R) Cgl-Aze-Pab-Z (1.0g; 1.52mmol) add in the EtOH solution of hydrochloric azanol and triethylamine.This reaction mixture was stirred under room temperature 40 hours, then it is concentrated.This crude product is by preparation type RPLC purifying.LC-MS：(m+1)＝488(m/z)(ii) Boc-(R)Cgl-Aze-Pab-OC(O)Et
To contain Boc-(R) Cgl-Aze-Pab-OH (500mg; 0.91mmol; From above step (i)) and the solution of propionic anhydride (3.5ml) under room temperature, stirred 45 minutes, concentrate then.This crude product adopts the 0.1M NH that contains 50% acetonitrile by preparation type RPLC 4OAc carries out purifying as eluent, produces the subtitle compounds of 266mg (54%).LC-MS：(m+1)＝544(m/z)(iii) H-(R)Cgl-Aze-Pab-OC(O)Et
With embodiment 1 (ii) described in step similar, by Boc-(R) Cgl-Aze-Pab-OC (O) Et (238mg; 0.44mmol; From above step (ii)) preparation subtitle compounds.Output is 290mg (100%).LC-MS：(m+1)＝444(m/z)(iv) EtOOCCH 2-(R)Cgl-Aze-Pab-OC(O)Et
In 0 ℃ with EtOOCCH 2OSO 2CF 3(105mg; 0.45mmol, by containing the preparation of triflicanhydride and hydroxyethanoic acid ethyl ester) and be added drop-wise to H-(R) Cgl-Aze-Pab-OOCEt (300mg; 0.45mmol; From above step (iii)) and K 2CO 3(308mg; 2.23mmol) methylene dichloride molten (6ml) liquid in.After under the room temperature this reaction mixture being stirred 1h, this reaction mixture of water, citric acid and water washing is dried (Na 2SO 4) and concentrate.This crude product adopts the 0.1M NH that contains 45% acetonitrile by preparation type RPLC 4OAc carries out purifying as eluent, produces the title compound of 63mg (27%).LC-MS:(m+1)=530 (m/z) Embodiment 28HOOCCH 2-(R) Cgl-Aze-Pab-OH (i) tBuOOCCH 2-(R) Cgl-Aze-Pab-OOCPh
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-OOCPh (250mg; 0.5mmol; Referring to above embodiment 15 (ii)) and bromo-acetic acid tert-butyl (119mg; 0.6mmol) the preparation subtitle compounds.Output is 211mg (69%).LC-MS：(m+1)＝606(m/z)(ii) HOOCCH 2-(R)Cgl-Aze-Pab-OOCPh
With embodiment 1 (ii) described in step similar, by tBuOOCCH 2-(R) Cgl-Aze-Pab-OOCPh (233mg; 0.3mmol; From above step (i)) the preparation subtitle compounds.Output is 65mg (37%).LC-MS：(m+1)＝550(m/z)(iii) HOOCCH 2-(R)Cgl-Aze-Pab-OH
To contain HOOCCH 2-(R) Cgl-Aze-Pab-OOCPh (60mg; 0.1mmol; From above step (ii)) and KOMe (0.2M; 0.2mmol) THF (10ml) and the solution of methyl alcohol (1.5ml) under room temperature, stirred 5 minutes.This reaction mixture is concentrated and lyophilize from water and acetonitrile, produce 28mg (63%) title compound.LC-MS:(m+1)=446 (m/z) Embodiment 29HOOCCH 2-(R) Cgl-Aze-Pab-O-cis octadecyl (i) tBuOOCCH 2-(R) Cgl (Boc)-Aze-Pab-Z
To contain tBuOOCCH 2-(R) Cgl-Aze-Pab-Z (1.7g; 2.8mmol; Referring to following examples 37), (Boc) 2O (672mg; 3.08mmol) and DMAP (68mg; 0.56mmol) THF (30ml) solution under room temperature, stir 24h.Add extra (Boc) in 5 ℃ 2O (305mg; 14mmol).Behind 24h, this reaction mixture concentrated and by preparation type RPLC purifying the required compound of generation 587mg (30%).EC-MS：(m+1)＝720(m/z)(ii) tBuOOCCH 2-(R)Cgl(Boc)-Aze-Pab-OH
Similar with step described in the embodiment 18, by tBuOOCCH 2-(R) Cgl (Boc)-Aze-Pab-Z (580mg; 0.8mmol; From above step (i)) the preparation subtitle compounds.Output is 341mg (71%).EC-MS:(m+1)=602 (m/z) (iii) tBuOOCCH 2-(R) Cgl (Boc)-Aze-Pab-O-cis octadecyl
To contain tBuOOCCH 2-(R) Cgl (Boc)-Aze-Pab-OH (340mg; 0.56mmol; From above step (ii)), cis octadecyl chlorine (170mg; 0.56mmol) and triethylamine (62mg; 0.61mmol) dichloromethane solution stirred 5 minutes.This reaction mixture concentrated and by preparation type RPLC purifying generation 326mg (67%) subtitle compounds.EC-MS:(m+1)=867 (m/z) (iv) HOOCCH 2-(R) Cgl-Aze-Pab-O-cis octadecyl
With embodiment 1 (ii) described in step similar, by tBuOOCCH 2-(R) Cgl (Boc)-Aze-Pab-O-cis octadecyl (223mg; 0.25mmol; From above step (iii)) preparation title compound.LC-MS:(m+1)=710 (m/z) Embodiment 30Ring octyl group-OOCCH 2-(R) Cgl-Aze-Pab-Z (i) Bromoacetic acid ring monooctyl ester
To encircle octanol (1.3g; 10mmol) and DMAP (0.3g) be dissolved in the methylene dichloride, add bromoacetyl chloride (1ml then; 12mmol).After stirring 18h, this reaction mixture Na 2CO 3The aqueous solution (2M) and HCl (1M) washing, dry, concentrated and employing sherwood oil: methylene dichloride (50: 50) produces 1.8g (72%) subtitle compounds by purification by flash chromatography.(ii) encircle octyl group-OOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (703mg; 1.2mmol) and bromoacetic acid ring monooctyl ester (363mg; 1.46mmol; From above step (i)) the preparation title compound.Output is 379mg (46%).FAB-MS:(m+1)=674 (m/z) Embodiment 31TBuCH 2OOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (2.5g; 4.3mmol) and bromoacetic acid tertiary butyl methyl esters (1.08g; 5.2mmol) the preparation title compound.Output is 1.87g (69%).FAB-MS:(m+1)=634 (m/z) Embodiment 32(2-Me) BnOOCCH 2-(R) Cgl-Aze-Pab-Z (i) Bromoacetic acid methyl benzyl ester
Similar with step described in the embodiment 30 (i), by 2-xylyl alcohol (5g; 41mmol) and bromoacetyl chloride (12.6g; 80mmol) preparation subtitle compounds.Output is 8.2g (82%).(ii) (2-Me)BnOOCCH 2-(R)Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (580mg, 1mmol) and bromoacetic acid 2-methyl benzyl ester (290mg; 1.2mmol; From above step (i)) the preparation title compound.Output is 30mg (4.5%).LC-MS:(m+1)=668 (m/z) Embodiment 33ChCH 2OOCCH 2-(R) Cgl-Aze-Pab-Z
To contain BnOOCCH 2-(R) Cgl-Aze-Pab-Z (1.41g; 1.7mmol) and the solution of the triethylamine (474 μ l) of cyclohexyl methyl alcohol (6ml) and methylene dichloride (3ml) refluxed 4 days.Handle this reaction mixture, produce crude product, the latter is by adopting methylene dichloride: methyl alcohol (95: 5) carries out purifying as the flash chromatography of eluent, produces the title compound of 801mg (71%).FAB-MS:(m+1)=660 (m/z) Embodiment 34ChOOCCH 2-(R) Cgl-Aze-Pab-Z (i) The bromoacetic acid cyclohexyl
Similar with step described in the embodiment 32 (i), by hexalin (1g; 10mmol) and bromoacetyl chloride (1ml; 12mmol) preparation subtitle compounds.(ii) ChOOCCH 2-(R)Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (2.5g; 4.32mmol) and bromoacetic acid cyclohexyl (1.5g; 5.2mmol) the preparation title compound.Output is 1.7g (60%).FAB-MS:(m+1)=646 (m/z) Embodiment 35PhC (Me) 2OOCCH 2-(R) Cgl-Aze-Pab-Z (i) Bromoacetic acid 2-phenyl-2-propyl ester
Similar with step described in the embodiment 30 (i), by 2-phenyl-2-propyl alcohol (3g; 22mmol) and bromoacetyl chloride (4.16g, 26mmol) preparation subtitle compounds.Output is 12g (44%).(ii) PhC(Me) 2OOCCH 2-(R)Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (1.2g; 2.2mmol) and bromoacetic acid 2-phenyl-2-propyl ester (640mg; 2.5mmol; From above step (i)) the preparation title compound.Output is 1.3g (86%). 1H-NMR (500MHz; CDCl 3) δ 9.3 (br s, 1H), 8.35 (t, 1H), 7.75 (d, 2H), 7.45 (d, 2H), 7.30-7.05 (m, 10H or11H), 5.15 (s, 2H), 4.78 (t, 1H), 4.40-4.30 (the AB part of ABX-spectrum, 2H), 3.95 (q, 1H), 3.74 (q, 1H), 3.27-3.19 (the AB spectrum, 2H), 2.72 (d, 1H), 2.43 (q, 2H), 1.93 (br d, 1H), 1.75-1.60 (m, 9H or10H), 1.54 (d, 1H), 1.49-1.40 (m, 1H), 1.25-1.0 (m, 4H), 0.92 (q, 1H) Embodiment 36MeNHCOCH 2OOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (1.0g; 1.7mmol) and MeNHCOCH 2OOCCH 2Br (440mg; 2mmol; Similar with step described in the above embodiment 11 (step (i), (ii) and (iii)), adopt methylamine displaced loop hexylamine to be prepared) the preparation title compound.Output is 380mg (35%).FAB-MS:(m+1)=635 (m/z) Embodiment 37TBuOOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z * 2HCl (500mg; 1.0mmol) and bromo-acetic acid tert-butyl (231mg; 1.2mmol) the preparation title compound.Output is 420mg (69%).LC-MS:(m+1)=620 (m/z) Embodiment 38(Me) 2CHC (Me) 2OOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z (787mg; 1.4mmol) and bromoacetic acid 2,3-dimethyl-2-butyl ester (364mg; 1.63mmol) the preparation title compound.Output is 590mg (67%).FAB-MS:(m+1)=648 (m/z) Embodiment 39IPrOOCCH 2-(R) Cgl-Aze-Pab-Z
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-Z (700mg; 1.2mmol) and isopropyl acetate bromide (262mg; 1.5mmol) the preparation title compound.Output is 225mg (31%).FAB-MS:(m+1)=606 (m/z) Embodiment 40BnOOCCH 2-(R) Cgl-Aze-Pab-COOPh (4-OMe) is (i) Boc-(R) Cgl-Aze-Pab-COOPh (4-OMe)
Similar with the described step of embodiment 1 (i), prepare subtitle compounds by Boc-(R) Cgl-Aze-Pab-H and chloroformic acid 4-methoxyl group phenyl ester.FAB-MS：(m+1)＝622(m/z)(ii) H-(R)Cgl-Aze-Pab-COOPh(4-OMe)×2HCl
With embodiment 4 (ii) described in step similar, by Boc-(R) Cgl-Aze-Pab-COOPh (4-OMe) (from above step (i)) preparation subtitle compounds.(iii) BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOPh (4-OMe) * 2HCl (85mg; 0.16mmol; From above step (iii)) and benzyl acetate bromide (90mg; 0.2mmol) the preparation title compound.Output is 60mg (56%).FAB-MS:(m+1)=670 (m/z) Embodiment 41ChCH 2OOCCH 2-(R) Cgl-Aze-Pab-COOPh (4-OMe)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOPh (4-OMe) (554mg; 0.64mmol; Referring to above embodiment 40 (ii)) and bromoacetic acid cyclohexyl methyl esters (165mg; 0.7mmol) the preparation title compound.Output is 34mg (8%).FAB-MS:(m+1)=676 (m/z) Embodiment 42(2-Me) BnOOCCH 2-(R) Cgl-Aze-Pab-COOPh (4-OMe)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOPh (4-OMe) (522mg; 1mmol; Referring to above embodiment 40 (ii)) and bromoacetic acid 2-(methyl) benzyl ester (365mg; 1.5mmol) the preparation title compound.Output is 158mg (23%).LC-MS:(m+1)=684 (m/z) Embodiment 43EtOOCCH 2-(R) Cgl-Aze-Pab-COOPh (4-Me) is (i) Boc-(R) Cgl-Aze-Pab-COOPh (4-Me)
Similar with the described step of embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab (1.96g; 4.56mmol) and 4-tolyl-chloro-formic ester (850mg; 4.99mmol) the preparation subtitle compounds.Output is 1.39g (55%).FAB-MS：(m+1)＝606(m/z)(ii) H-(R)Cgl-Aze-Pab-COOPh(4-Me)
With embodiment 4 (ii) described in step similar, by Boc-(R) Cgl-Aze-Pab-COOPh (4-Me) (388mg; 0.64mmol; From above step (i)) the preparation subtitle compounds.Output is 293mg (91%).FAB-MS：(m+1)＝506(m/z)(iii) EtOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-Me)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOPh (4-Me) (288mg; 0.6mmol; From above step (ii)) and ethyl bromoacetate (114mg; 0.7mmol) the preparation title compound.Output is 81mg (24%).FAB-MS:(m+1)=592 (m/z) Embodiment 44BnOOCCH 2-(R) Cgl-Aze-Pab-COOPh (4-Me)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOPh (4-Me) (272mg; 0.54mmol; Referring to above embodiment 43 (ii)) and benzyl acetate bromide (147mg; 0.6mmol) the preparation title compound.Output is 107mg (31%).FAB-MS:(m+1)=654 (m/z) Embodiment 45BnOOCCH 2-(R) Cgl-Aze-Pab-COO-nBu
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COO-nBu * 2HCl (400mg; 0.74mmol; Referring to above embodiment 9 (ii)) and benzyl acetate bromide (210mg; 0.88mmol) the preparation title compound.Output is 220mg (48%).FAB-MS:(m+1)=620 (m/z) Embodiment 46IPrOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2CH=CH 2* 2TFA (456mg; 0.67mmol; Referring to above embodiment 1 (ii)) and isopropyl acetate bromide (145mg; 0.8mmol) the preparation title compound.Output is 294mg (79%).FAB-MS:(m+1)=556 (m/z) Embodiment 47EtOOCCH 2-(R) Cgl-Aze-Pab-COO-iBu (i) Boc-Pab-COO-iBu
In 0 ℃ with isobutyl chlorocarbonate (270mg; 2.2mmol) add and to contain Boc-Pab-H (500mg; 2.0mmol; By Pab-Z and (Boc) 2O preparation (forming Boc-Pab-z), hydrogenation makes on Pd/C then) and triethylamine (400mg; 4.0mmol) methylene dichloride (10ml) solution in.After stirring 5h, add entry.With organic phase drying (Na 2SO 4) and concentrate, produce the subtitle compounds of 530mg (76%). 1H-NMR(500MHz，CDCl 3)δ9.5(bs，1H)，7.82(d，2H)，7.31(d，2H)，6.6(bs，1H)，5.0(bs，1H)，4.33?(bd，2H)，3.93(d，2H)，2.04(m，1H)，1.45(s，9H)，0.97(d，6H)(ii) H-Pab-COO-iBu×2HCl
With embodiment 4 (ii) described in step similar, by Boc-Pab-COO-iBu (520mg; 1.5mmol; From above step (i)) the preparation subtitle compounds.Output is 430mg (88%). 1H-NMR(500MHz，MeOD)δ7.89(d，2H)，7.75(d，2H)，4.30(s，2H)，4.17(d，2H)，2.11-2.05(m，1H)，1.02(d，6H)(iii) Boc-(R)Cgl-Aze-Pab-COO-iBu
With EDC (270mg; 1.4mmol) add contain Boc-(R) Cgl-Aze-OH (480mg; 1.4mmol), H-Pab-COO-iBu * 2HCl (430mg; 1.3mmol; From above step (ii)) and DMAP (650mg; 5.3mmol) the solution of acetonitrile (20ml) in.After stirring 3 days under the room temperature, this reaction mixture is concentrated, among the water-soluble then and EtOAc.This organic phase NaHCO 3(aq) washing and dry (Na 2SO 4), concentrate and, produce 510mg (52%) subtitle compounds by adopting EtOAc to carry out purifying as the flash chromatography of eluent.(iv) H-(R)Cgl-Aze-Pab-COO-iBu×2HCl
With embodiment 4 (ii) described in step similar, by Boc-(R) Cgl-Aze-Pab-COO-iBu (500mg; 0.88mmol; From above step (iii)) preparation subtitle compounds.Output is 360mg (87%).(v) EtOOCCH 2-(R)Cgl-Aze-Pab-COO-iBu
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COO-iBu * 2HCl (290mg; 0.53mmol; From above step (iv) and ethyl bromoacetate (110mg; 0.64mmol) the preparation title compound.Output is 140mg (47%).FAB-MS:(m+1)=558 (m/z) Embodiment 48BnOOCCH 2-(R) Cgl-Aze-Pab-COO-nPr
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COO-nPr * 2TFA (902mg; 1.3mmol; Referring to above embodiment 5 (ii)) and benzyl acetate bromide (362mg; 1.6mmol) the preparation title compound.Output is 199mg (25%). 1H-NMR:(400MHz; CDCl 3) δ 8.43 (bs, 1H), 7.78 (d, 2H), 7.38-7.27 (m, 7H), 5.05 (s, 2H), 4.90 (dd, 1H), 4.56-4.39 (the AB part 2H of ABX-spectrum), 4.12-4.03 (m, 3H), 3.98-3.91 (q, 1H), 3.33-3.22 (AB-composes 2H), 2.85 (d, 1H), and 2.65-0.94 (m, 19H) Embodiment 49EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCCh (i) EtSCOOCH 2OOCCh
In 0 ℃ with NaOH (9.1ml; 10M; 68mmol) add sulfur acid hydrogen TBuA (15.6g; 45.6mmol) and hexahydrobenzoic acid (5.85mg; In dichloromethane solution 46mmol).Stir after 5 minutes, this reaction mixture is filtered, use washed with dichloromethane, be dissolved in the toluene, it is concentrated, and be dissolved among the THF, produce [Bu 4N] +[OOCCh] -With EtSCOOCH 2Cl (4g; 25.9mmol; Referring to Folkmann and Lumd, J.Synthesis, (1990), 1159) under room temperature, add and contain [Bu 4N] +[OOCCh] -THF solution in.After stirring 12h under the room temperature, this reaction mixture is concentrated, and, produce 2.57g (40%) subtitle compounds by purification by flash chromatography. 1H-NMR (400MHz, CDCl 3) characteristic peak δ 5.80 (s, 2H, O-CH 2-O), 2.85 (q, 2H, CH 2-S) (ii) ClCOOCH 2OOCCh
With SO 2Cl 2(31.8g; 23.6mmol) add EtSCOOCH in 0 ℃ 2OOCCh (2.9g; 11.8mmol; From above step (i)) in.Stir after 30 minutes, this reaction mixture is concentrated, produce the required compound of 1.82g (70%). 1H-NMR (500MHz, CDCl 3) characteristic peak δ 5.82 (s, 2H, O-CH 2-O) (iii) Boc-(R) Cgl-Aze-Pab-COOCH 2OOCCh
Similar with embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab-H (750mg; 1.59mmol) and ClCOOCH 2OOCCh (460mg; 2.1mmol; From above step (ii)) preparation subtitle compounds.This crude product is by preparation type RPLC purifying.Output is 355mg (9%).FAB-MS：(m+1)＝656(m/z)(iv) H-(R)Cgl-Aze-Pab-COOCH 2OOCCh×2TFA
With embodiment 1 (ii) described in step similar, by Boc-(R) Cgl-Aze-Pab-COOCH 2OOCCh (from above step (iii)) prepares subtitle compounds.(v)? EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCh
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2OOCCh * 2TFA (193mg; 0.35mmol; From above step (iv)) and Trifluoroacetic Acid Ethyl Ester (83mg; 0.35mmol) the preparation title compound.Output is 87mg (39%). 1H-NMR (400MHz, CDCl 3) δ 8.48 (t br, 1H), 7.83 (d, 2H), 7.37 (d, 2H), 5.86 (s, 2H), 4.95 (dd, 1H), 4.15-4.39 (the AB part 2H of ABX-spectrum), 4.18-4.05 (m, 5H), 3.26-3.17 (AB composes 2H), 2.87 (d, 1H), 2.75-0.95 (m, 29H) Embodiment 50EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCCH 2Ch
Similar with embodiment 49 described steps, replace hexahydrobenzoic acid to begin by cyclohexyl acetic acid, the preparation title compound.Output is 74mg (17%).FAB-MS:(m+1)=656 (m/z) Embodiment 51EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH (Me) OOCPh
Similar with embodiment 49 described steps, by EtSCOOCH (CH 3) Cl (adopt Folkmann etc., J.Synthesis, (1990), 1159 described steps are by ClCOCH (CH 3) Cl and EtSH preparation) replacement EtSCOOCH 2Cl begins, the preparation title compound.Output is 70mg (23%).FAB-MS:(m+1)=650 (m/z) Embodiment 52EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCPh
Similar with embodiment 49 described steps, replace hexahydrobenzoic acid to prepare title compound with phenylformic acid.Output is 50mg (39%). 1H-NMR (300MHz, CDCl 3) δ 9.73-9.25 (s br, 1H), 8.45 (t, 1H), 8.05 (d, 2H), 7.83 (d, 2H), 7.60-7.10 (m, 6H), 6.10 (s, 2H), 4.96-4.84 (dd, 1H), 4.62-4.30 (ABX, 2H), 4.20-3.93 (m, 4H), 3.25 (s, 2H), 2.84 (d, 1H), 2.73-2.41 (m, 2H), 2.41-0.87 (m, 15H) 13C-NMR (300MHz, CDCl 3, carbonyl and amidine signal) and δ 163.1,165.3,169.0,170.8,172.3,175.5 Embodiment 53BnOOCCH 2-(R) Cgl-Aze-Pab-COOCH (Me) OAc
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH (CH 3) OC (O) CH 3(108mg; 0.21mmol; Referring to above embodiment 14 (ii)) and benzyl acetate bromide (36 μ l; 0.23mmol) the preparation title compound.Output is 41mg (30%).FAB-MS:(m+1)=650 (m/z) Embodiment 54EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OAc (i) H-(R) Cgl-Aze-Pab-COOCH 2OAc * 2TFA
Similar with step described in the embodiment 14 (step (i) and (ii)), adopt acetoxyl methyl 4-nitrophenyl carbonate (with embodiment 12 (iii) described in step similar, adopt silver acetate to replace PIVALIC ACID CRUDE (25) silvery to be equipped with) the preparation subtitle compounds.The subtitle compounds that handle to produce need not be further purified and be used for next step.(ii) EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OAc
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOC-H 2OAc * 2TFA (0.83mmol; From above step (i)) and ethyl bromoacetate (2.2mmol) preparation title compound.Output is 286mg.FAB-MS:(m+1)=574 (m/z) Embodiment 55TBuOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OAc
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2OAc * 2TFA (0.313mmol; Referring to above embodiment 54 (i)) and bromo-acetic acid tert-butyl (73mg; 0.376mmol) the preparation title compound.Output is 156mg (83%).FAB-MS:(m+1)=602 (m/z) Embodiment 56BnOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOC-tBu
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2OOC-tBu (379mg; 0.71mmol; Referring to above embodiment 12 (v)) and benzyl acetate bromide (135 μ l; 0.85mmol) the preparation title compound.Output is 146mg (30%).FAB-MS:(m+1)=678 (m/z) Embodiment 57EtOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2CCl 3(i) Boc-(R) Cgl-Aze-Pab-COOCH 2CCl 3
Similar with step described in the embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab-H (1.0g; 2.12mmol), 2M NaOH (11.7mmol) and trichloroethyl chloroformate (494mg; 2.33mmol) the preparation subtitle compounds.Output is 1.08g (79%).(ii) H-(R)Cgl-Aze-Pab-COOCH 2CCl 3
Similar with the (ii) described step of embodiment 1, by Boc-(R) Cgl-Aze-Pab-COOCH 2CCl 3(1.04g; 1.607mmol; From above step (i)) the preparation subtitle compounds.Output is 143g (99%). 1H-NMR：(500MHz；CD 3OD)δ7.79(d，2H)，7.61(d，2H)，5.10(s，2H)，4.87-4.81(m，2H)，4.63-4.52(q，2H)，4.41-4.34(m，1H)，4.30-4.24(m，1H)，3.72(d，1H)，2.72-2.63(m，1H)，2.32-2.25(m，1H)，1.88-1.10(m，14H)(iii) EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CCl 3
Similar with the (ii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COOCH 2CCl 3(400mg; 0.52mmol; From above step (iii)) and ethyl bromoacetate (95mg; 0.57mmol) the preparation title compound.Output is 8mg (23%). 1H-NMR:(500MHz; CDCl 3) δ 8.47 (bt, 1H), 7.83 (d, 2H), 7.48 (bs, 1H), 7.3 1 (d, 2H), 4.92 (dd, 1H), 4.85 (s, 2H), 4.58-4.39 (the AB part of ABX-spectrum, 2H), 4.16-4.06 (m, 4H), 3.24 (s, 2H), 4.87 (d, 1H), 2.65-2.59 (m, 1H), 2.56-2.48 (m, 1H), 2.10-0.95 (m, 16H) Embodiment 58MeOOC-C (=CEt) CH 2OOCCH 2-(R) Cgl-Aze-Pab-Z (i) MeOOC-C (=CH) C (OH) Et
With propionic aldehyde (10.1g; 0.174mol) be added drop-wise to and contain methyl acrylate (10g; 0.116mol) and 1,4-diazabicyclo [2,2,2] octane (1.3g; 0.0116mol) solution in.This reaction mixture was stirred under room temperature 14 days.Add ethyl acetate (150ml).This organic phase water and salt water washing, dry (Na 2SO 4), filter and concentrate, produce required compound.Output is 15.5g (93%). 1H-NMR：(400MHz；CDCl 3)δ6.24(s，1H)，5.81(s，1H)，4.34(t，1H)，3.78(s，3H)，2.82(bs，1H)，1.69(m，2H)，0.95(t，3H)(ii)MeOOC-C(＝CEt)CH 2Br
In 0 ℃ HBr (6.5ml ,～48%) is added drop-wise to MeOOC-C (=CH) C (OH) Et (3g; 20.8mmol; From above step (i)) in.After 5 minutes, drip H 2SO 4(dense H 2SO 46ml).Under room temperature, this reaction mixture was stirred 12 hours.Separate two-phase, dilute with ether on the upper strata.This ether phase water and NaHCO 3Solution washing, dry (Na 2SO 4And charcoal) also concentrates.This residue is purified by flash chromatography.Output is 1.7g (40%). 1H-NMR：(400MHz；CDCl 3)δ6.97(t，3H)，4.23(s，2H)，3.8(s，3H)，2.32(m，2H)，1.13(t，3H)(iii) tBuOOCCH 2-(R)Cgl-Aze-Pab-Z
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-Z (2.1g; 3.6mmol) and bromo-acetic acid tert-butyl (780mg; 4.0mmol) the preparation subtitle compounds.Output is 1.73g (78%).(iv) HOOCCH 2-(R)Cgl-Aze-Pab-Z
To contain tBuOOCCH 2-(R) dichloromethane solution of Cgl-Aze-Pab-Z (from above step (iii)) and TFA stirs 3h under room temperature.This reaction mixture is concentrated and (dense from water and HCl; Lyophilize 10eq).(v) MeOOC-C(＝CEt)CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z
To contain HOOCCH 2-(R) Cgl-Aze-Pab-Z (263mg; 0.41mmol; From above step (iv)), NaOH (1M; 1.239mmol) and the solution lyophilize of water (4ml).Add DMF (5ml), drip MeOOC-C (=CEt) CH in 0 ℃ then 2Br (103mg; 0.496mmol; From above step (ii)).This reaction mixture stirs 24h under room temperature,, wash dry (Na with water with toluene (5ml) dilution 2SO 4) and concentrate.This residue is by adopting EtOAc: methyl alcohol (95: 5) carries out purifying as the flash chromatography of eluent.Output is 95mg (33).FAB-MS:(m+1)=690 (m/z) Embodiment 59MenOOCCH 2-(R) (i) MenOOCCH of Cgl-Aze-Pab-COOPh (4-OMe) 2Br
Similar with the described step of embodiment 30 (i), by MenOH (10mmol) and bromoacetyl chloride (12mmol) preparation subtitle compounds.Output is 1.5g (54%).(ii) MenOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COOPh (4-OMe) (521mg; 1mmol; Referring to above embodiment 40 (ii)) and MenOOCCH 2Br (416mg; 1.5mmol; From above step (i)) the preparation title compound.Output is 36mg (5%).FAB-MS:(m+1)=718 (m/z) Embodiment 60TBuOOCCH 2-(R) Cgl-Aze-Pab-COOnPr
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COO-nPr (575mg; 0.837mmol; Referring to above embodiment 5 (ii)) and bromo-acetic acid tert-butyl (196mg; 1.01mmol) the preparation title compound.Output is 110mg (23%).LC-MS:(m+1)=572 (m/z) Embodiment 61MenOOCCH 2-(R) Cgl-Aze-Pab-Z
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-Z (0.7g; 1.21mmol) and MenOOCCH 2Br (0.4g; 1.45mmol; Referring to above embodiment 59 (i)) the preparation title compound.Output is 0.33g (38%).FAB-MS:(m+1)=702 (m/z) Embodiment 62BnOOCCH 2-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (i) Boc-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2)
Similar with step described in the embodiment 1 (i), by Boc-(R) Cgl-Aze-Pab-H (1.03g; 2.18mmol), 2M NaOH (24ml) and chloroformic acid 4-NO 2-benzyl ester (518mg; 2.4mmol) the preparation subtitle compounds.Output is 1.32g (93%).FAB-MS：(m+1)＝651(m/z)(ii) H-(R)Cgl-Aze-Pab-COO-Bn(4-NO 2)
Similar with the (ii) described step of embodiment 4, by Boc-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (1.32g; 2.03mmol; From above step (i)) the preparation subtitle compounds.Output is 1.0g (79%).FAB-MS：(m+1)＝551(m/z)(iii) BnOOCCH 2-(R)Cgl-Aze-Pab-COO-Bn(4-NO 2)
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (0.5g; 0.80mmol; From above step (ii)) and benzyl acetate bromide (220mg; 0.90mmol) the preparation title compound.FAB-MS:(m+1)=699 (m/z) Embodiment 63EtOOCCH 2-(R) Cgl-Aze-Pab-Bn (4-NO 2)
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (211g; 0.38mmol; Referring to above embodiment 62 (ii)) and ethyl bromoacetate (47 μ l; 0.42mmol) the preparation title compound.Output is 44mg (18%). 1H-NMR:(300MHz; CDCl3) δ 9.55 (bs, 1H), 8.50 (bt, 1H), 8.20 (d, 2H), 7.80 (d, 2H), 7.60 (d, 2H), 7.35 (d, 2H), 6.87 (bs, 1H), 4.95 (dd, 1H), and 4.65-4.40 (the AB part of ABX-spectrum, 2H), 4.18-4.04 (m, 5H), 3.27-3.15 (the AB spectrum, 2H), 2.87 (d, 1H), 2.75-2.60 (m, 1H), 2.57-2.45 (m, 1H), 2.00-0.95 (m, 16H). Embodiment 64PrlC (O) CH 2OOCCH 2-(R) Cgl-Aze-Pab-Z (i) PlC (O) CH 2OH
With 2,5-dioxy-1,4-diox (2.0g; 17mmol) and tetramethyleneimine (8ml; Mixture backflow 1h 97mmol).Remove excessive tetramethyleneimine by evaporation.Output is 4.4g (99%).FAB-MS：(m+1)＝130(m/z)(ii)PrlC(O)CH 2OOCCH 2Br
In 0 ℃ with bromoacetyl bromide (0.63g; 3.1mmol) be added drop-wise to and contain PrlC (O) CH 2OH (0.4g; 3.1mmol; From above step (i)) DMF (15ml) solution in.This reaction mixture stirs 3h in 0 ℃ of stirring 1.5h under room temperature.Add bromoacetyl bromide (0.63g again; 3.1mmol), this reaction mixture is heated to 80 ℃, it is stirred 12h and concentrated under room temperature.Output is 320mg (41%).FAB-MS：(m+1)＝252(m/z)(iii) PrlC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z
Similar with the (iii) described step of embodiment 1, by H-(R) Cgl-Aze-Pab-Z (580mg; 1mmol) and PrlC (O) CH 2OOCCH 2Br (300mg; 1.2mmol; From above step (ii)) preparation title compound.Output is 400mg (60/).FAB-MS (m+1)=675 (m/z) 1H-NMR:(500MHz; CDCl3) δ 9.66-9.42 (bs, 1H), 8.64-8.56 (m, 1H), 8.03-7.93 (d, 2H), 7.89-7.66 (bs, 1H), 7.45 (d, 2H), 7.45-7.25 (m, 5H), 5.20 (s, 2H), 4.98-4.92 (dd, 1H), 4.82-4.74 (m, 1H), 4.62,4.58 (the AB spectrum, 2H), 4.26-4.05 (m, 3H), 3.47-3.16 (m, 6H), 2.95 (d, 1H), 2.78-2.68 (m, 1H), and 2.54-2.42 (m, 1H), 2.03-1.95 (m, 16H) Embodiment 65(2-Me) BnOOCCH 2-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2)
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (500g; 0.80mmol; Referring to above embodiment 62 (ii)) and bromoacetic acid 2-(methyl) benzyl ester (234mg; 0.96mmol; Referring to above embodiment 32 (i)) the preparation title compound.Output is 528mg (92%). 1H-NMR:(400MHz, CDCl 3) δ 9.34 (bs, 1H), 8.38 (t, 1H), 8.09 (d, 2H), 7.72 (d, 2H), 7.48 (d, 2H), 7.37 (bs, 1H), 7.23 (d, 2H), 7.17-7.05 (m, 4H), 5.18 (s, 2H), 5.00 (s, 2H), 4.81 (dd, 1H), 4.45-4.34 (the AB part of ABX-spectrum, 2H), 4.04-3.97 (q, 1H), 3.93-3.86 (q, 1H), 3.27-3.17 (the AB spectrum, 2H), 2.79 (d, 1H), 2.54-2.35 (m, 2H), 2.22 (s, 3H), 1.91-1.84 (bd, 1H), 1.71-1.39 (m, 5H), 1.19-0.84 (m, 4H). Embodiment 66MeOOCCH 2-(R) Cgl-Aze-Pab-COOEt
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COOEt (350mg; 0.69mmol; Referring to embodiment 4 (ii)) and methyl bromoacetate (126mg; 0.83mmol) the preparation title compound.Output is 188mg (53%).LC-MS:(m+1)=516 (m/z) Embodiment 67(nPr) 2NC (O) CH 2OOCCH 2-(R) Cgl-Aze-Pab-COO-Bn (4-NO 2) (i) (nPr) 2NC (O) CH 2OOCCH 2Cl
With (nPr) 2NC (O) CH 2OH (244mg; 1.53mmol; Referring to above embodiment 12 (i)) and bromoacetyl chloride (270mg; 1.72mmol) mixture under room temperature, stirred 12 hours.This mixture is injected NaHCO 3In the aqueous solution, use dichloromethane extraction.This organic phase KHSO 4The aqueous solution (0.2M) and salt water washing, dry and concentrated.FAB-MS：(m+1)＝237(m/z) 1H-NMR：(400MHz，CDCl 3)δ4.82(s，2H)，4.22(s，2H)，3.31-3.26(t，2H)，3.10-3.15(t，2H)，1.68-1.52(m，2H)，1.97-0.86(m，6H)(ii) (nPr) 2NC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-COO-Bn(4-NO 2)
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COOBn (4-NO 2) (343mg; 0.62mmol; Referring to above embodiment 62 (ii)) and (nPr) 2NC (O) CH 2OOCCH 2Cl (160mg; 0.68mmol; From above step (i)) the preparation title compound.Output is 89mg (19%).FAB-MS:(m+1)=750 (m/z) Embodiment 68(2-Me) BnOOCCH 2-(R) Cgl-Aze-Pab-COOCH 2OOCtBu
With embodiment 1 (iii) described in step similar, by H-(R) Cgl-Aze-Pab-COOCH 2OOCtBu (380mg; 0.71mmol; Referring to above embodiment 12 (ii)) and bromoacetic acid 2-(methyl) benzyl ester (215mg; 0.88mmol; Referring to above embodiment 32 (i)) the preparation title compound.Output is 37mg (7.5%).FAB-MS:(m+1)=692 (m/z) Embodiment 69
The compound of embodiment 1-68 is all tested in above test A, finds all to show the IC that is higher than 1.0 μ M 50The TT value (promptly with show 0.01 μ M IC 50The activity inhibitor HOOC-CH of TT 2-(R) Cgl-Aze-Pab-H compares, and they are own to the zymoplasm non-activity). Embodiment 70
The compound of embodiment 1-68 is all tested in, two in above test B, C and/or D or the Total Test, find them or as free acid and/or as its one or more esters, the oral and/or parenteral bioavailability of the rat that shows is all with activity inhibitor HOOC-CH 2-(R) Cgl-Aze-Pab-H is the same.In rat, form HOOC-CH in supposition 2-(R) on the basis of Cgl-Aze-Pab-H, according to formula described in test B and/or the test C, calculate this bioavailability when suitable.Abbreviation Ac=ethanoyl aq=water solution A ze=S-azetidine-2-formic acid Boc=tert-butyl ester base (Boc) 2O=two-tert-butyl group two carbonic ester Bn=benzyl Bu=butyl Cgl=Cyclohexylglycine Ch=cyclohexyl DCC=dicyclohexylcarbodiimide DMAP=N, N-dimethyl aminopyridine EDC=hydrochloric acid 1-(3-dimethylaminopropyl)-h=hour HCl=hydrochloric acid of 3-ethyl carbodiimide Et=ethyl EtOH=ethanol EtOAc=ethyl acetate H-Pab-H=1-amidino groups-4-amino toluene H-Pab-Z=4-aminomethyl-1-(N-carbobenzoxy group amidino groups) benzene HPLC=high performance liquid chromatography K2CO 3Anhydrous potassium carbonate Me=methyl Men (1R, 2S, 5R)-_ basic Pab-OH=4-aminomethyl-benzamidoxime (4-aminomethyl-1-(amino-oxyimino first
Base) benzene Piv (aloyl)=2,2-dimethyl ethanoyl Pr=propyl group Prl=N-pyrrolidyl RPLC=RPLC TFA=trifluoroacetic acid THF=hydrogen furans Z=carbobenzoxy
Prefix n, s, i and t have its implication commonly used: just, different, Zhong Heshu.That prefix s, d, t, q and b in the NHR spectrum refers to respectively is unimodal, doublet, triplet, quartet and broad peak.If not statement in addition, then giving tacit consent to amino acid whose stereochemistry is (S) type.

Claims (45)

1. formula I compound or its pharmacy acceptable salt,
R 1O (O) C-CH 2-(R) Cgl-Aze-Pab-R 2I is R wherein 1Expression-R 3Or-A 1C (O) N (R 4) R 5Or-A 1C (O) OR 4A 1Expression C 1-5Alkylidene group; R 2A hydrogen atom in the amidino groups unit of replacement Pab-H, it represents OH, OC (O) R 6, C (O) OR 7Or C (O) OCH (R 8) OC (O) R 9R 3Expression H, C 1-10Alkyl or C 1-3The alkane phenyl, back one group can randomly be used C 1-6Alkyl, C 1-6Alkoxyl group, nitro or halogen replace; R 4And R 5Represent H, C independently 1-6Alkyl, phenyl, 2-naphthyl, or work as R 1Expression-A 1C (O) N (R 4) R 5The time, represent pyrrolidyl or piperidyl with the nitrogen-atoms that connects them; R 6Expression C 1-17Alkyl, phenyl or 2-naphthyl, they all can randomly use C 1-6Alkyl or halogen replace; R 7Expression 2-naphthyl, phenyl, C 1-3The alkane phenyl, they can randomly use C 1-6Alkyl, C 1-6Alkoxyl group, nitro or halogen replace, or expression C 1-12Alkyl, it can randomly use C 1-6Alkoxyl group, C 1-6Acidic group or halogen replace; R 8Expression H or C 1-4Alkyl; And R 9Expression 2-naphthyl, phenyl, C 1-6Alkoxyl group or C 1-8Alkyl, back one group can randomly be used halogen, C 1-6Alkoxyl group or C 1-6Acidic group replaces; Condition is to work as R 1Expression R 3, R 3Expression benzyl, methyl, ethyl, normal-butyl or n-hexyl, and R 2Expression C (O) OR 7The time, R so 7Do not represent benzyl.
2. the formula I compound of claim 1 qualification is wherein worked as R 1Expression-A 1C (O) N (R 4) R 5The time, A 1Expression C 1-3Alkylidene group.
3. the formula I compound that limits in the claim 1 or 2 is wherein worked as R 1Expression-A 1C (O) N (R 4) R 5The time, R 4Expression H or C 1-6Alkyl.
4. the formula I compound that limits in the claim 1 or 2 is wherein worked as R 1Expression-A 1C (O) N (R 4) R 5The time, R 5Expression C 1-6Alkyl or C 4-6Cycloalkyl.
5. the formula I compound that limits in the claim 1 or 2 is wherein worked as R 1Expression-A 1C (O) N (R 4) R 5The time, R 4And R 5Represent pyrrolidyl together.
6. the formula I compound that limits in the claim 2, wherein A 1Expression C 1-3Alkylidene group, R 4Expression H or C 1-3Alkyl, R 5Expression C 2-6Alkyl or C 5-6Cycloalkyl, or R 4And R 5Represent pyrrolidyl together.
7. the formula I compound of claim 1 qualification is wherein worked as R 1Expression-A 1C (O) OR 4The time, A 1Expression C 1-5Alkylidene group.
8. claim 1 or the 7 formula I compounds that limit are wherein worked as R 1Expression-A 1C (O) OR 4The time, R 4Expression C 1-6Alkyl.
9. the formula I compound that limits of claim 7, wherein A 1Expression C 1-5Alkylidene group, and R 4Expression C 1-4Alkyl.
10. the formula I compound of claim 1 qualification is wherein worked as R 1Expression R 3The time, R 3Expression H, C 1-10Alkyl or C 1-3Alkane phenyl, wherein C 1-10Alkyl can be linear, or when the carbon atom of enough numbers, can be side chain and/or part ring-type or cyclic, C 1-3The alkane phenyl can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain.
11. claimed compound in claim 1 or the claim 10, wherein R 1Expression H, linear C 1-10Alkyl, side chain C 3-10Alkyl, part ring-type C 4-10Alkyl, C 4-10Cycloalkyl, can choose the linear C of replacement wantonly 1-3The alkane phenyl, can choose the side chain C of replacement wantonly 3The alkane phenyl.
12. claimed compound in the claim 11, wherein R 1Represent linear C 1-6Alkyl, C 6-10Cycloalkyl maybe can be chosen the linear C of replacement wantonly 1-3The alkane phenyl.
13. the formula I compound that limits in claim 1 or 2, wherein R 2Expression OH.
14. the formula I compound that limits in claim 1 or 2 is wherein worked as R 2Expression OC (O) R 6The time, R 6Optional phenyl or the C that replaces of expression 1-17Alkyl, back one group can be linear, or when the carbon atom of enough numbers, can be side chain, ring-type or part cyclic and/or saturated or undersaturated.
15. claimed compound in the claim 14, wherein R 6Expression can be chosen the phenyl of replacement, linear C wantonly 1-4Alkyl, side chain C 3-4Alkyl and cis octadecyl.
16. claimed compound in the claim 15, wherein R 6Represent linear C 1-3Alkyl or side chain C 3Alkyl.
17. the formula I compound that limits in claim 1 or 2 is wherein worked as R 2Expression C (O) OR 7The time, R 7Optional phenyl, the C that replaces of expression 1-12Alkyl or C 1-3Alkane phenyl, wherein C 1-12Alkyl can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain, ring-type or part cyclic and/or saturated or undersaturated, C 1-3The alkane phenyl can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain.
18. claimed compound in the claim 17, wherein R 7Expression can be chosen replacement wantonly and/or can choose undersaturated linear C wantonly 1-4Alkyl maybe can choose wantonly replace and/can choose undersaturated side chain C wantonly 3-4Alkyl, the phenyl that can choose replacement wantonly maybe can be chosen the linear C of replacement wantonly 1-3The alkane phenyl maybe can be chosen the side chain C of replacement wantonly 3The alkane phenyl.
19. claimed compound in the claim 18, wherein R 7Expression can be chosen the linear C of replacement wantonly 1-4Alkyl maybe can be chosen the side chain C of replacement wantonly 3-4Alkyl, can choose the linear C of replacement wantonly 1-3Alkane phenyl or side chain C 3The alkane phenyl.
20. the formula I compound that limits in claim 1 or 2 is wherein worked as R 2Expression C (O) OCH (R 8) OC (O) R 9The time, R 8Expression H or methyl.
21. the formula I compound that limits in claim 1 or 2 is wherein worked as R 2Expression C (O) OCH (R 8) OC (O) R 9The time, R 9Expression phenyl or C 1-8Alkyl, back one group can randomly be substituted, and can be linear, or when the carbon atom of enough numbers, can be side chain and/or ring-type or part cyclic.
22. the formula I compound that limits in the claim 20, wherein R 8Expression H or methyl, and R 9Expression phenyl, C 5-7Cycloalkyl, linear C 1-6Alkyl, side chain C 3-6Alkyl or part ring-type C 7-8Alkyl.
23. claimed compound in the claim 22, wherein R 8Expression H, and R 9Expression C 5-7Cycloalkyl, linear C 1-6Alkyl or part ring-type C 7-8Alkyl.
24. claimed compound in claim 1 or 2 is wherein worked as R 1Expression R 3, and R 3Expression can be chosen the C of replacement wantonly 1-3During the alkane phenyl, described optional substituting group is C 1-6Alkyl
25. claimed compound in the claim 24, wherein said substituting group is a methyl.
26. claimed compound in claim 1 or 2 is wherein worked as R 2Expression C (O) OR 7, and R 7Expression can be chosen the C of replacement wantonly 1-12During alkyl, the described substituting group of choosing wantonly is selected from halogen and C 1-6Alkoxyl group.
27. claimed compound in the claim 26, wherein said substituting group is selected from chlorine and methoxyl group.
28. claimed compound in claim 1 or 2 is wherein worked as R 2Expression C (O) OR 7, and R 7When expression can be chosen the phenyl of replacement wantonly, the described substituting group of choosing wantonly was selected from C 1-6Alkyl, C 1-6Alkoxyl group and halogen.
29. claimed compound in the claim 28, wherein said substituting group is selected from methyl, methoxyl group and chlorine.
30. claimed compound in claim 1 or 2 is wherein worked as R 2Expression C (O) OR 7, and R 7Expression can be chosen the C of replacement wantonly 1-3During the alkane phenyl, the described substituting group of choosing wantonly is a nitro.
31. claimed compound in the claim 1, wherein
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
nPrOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
tBuOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOEt；
EtOOCCH 2-(R)Cgl-Aze-Pab-COO-nBu；
PrlC(O)CH 2CH 2CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
ChNHC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(nPr) 2NC(O)CH 2OOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCC(CH 3) 3；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH(CH 3)OOCCH 3；
MeOOCCH 2-(R)Cgl-Aze-Pab-OOCPh；
MeOOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OH；
BnOOCCH 2-(R)Cgl-Aze-Pab-OH；
nPrOOCCH 2-(R)Cgl-Aze-Pab-Z；
nPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
iPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
tBuOOCCH 2-(R)Cgl-Aze-Pab-OH；
(nPr) 2NCOCH 2OOCCH 2-(R)Cgl-Aze-Pab-OH；
ChNHCOCH 2OOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OAc；
HOOCCH 2-(R)Cgl-Aze-Pab-OH；
HOOCCH 2-(R)Cgl-Aze-Pab-O-cis-Oleyl；
Cyclooctyl-OOCCH 2-(R)Cgl-Aze-Pab-Z；
tBuCH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(2-Me)BnOOCCH 2-(R)Cgl-Aze-Pab-Z；
ChCH 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
ChOOCCH 2-(R)Cgl-Aze-Pab-Z；
PhC(Me) 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
(Me) 2CHC(Me) 2OOCCH 2-(R)Cgl-Aze-Pab-Z；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
ChCH 2OOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
(2-Me)BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-Me)；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-Me)；
BnOOCCH 2-(R)Cgl-Aze-Pab-COO-nBu；
iPrOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CH＝CH 2；
EtOOCCH 2-(R)Cgl-Aze-Pab-COO-iBu；
BnOOCCH 2-(R)Cgl-Aze-Pab-COO-nPr；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCh；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCH 2Ch；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH(Me)OOCPh；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCPh；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOCH(Me)OAc；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OAc；
tBuOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OAc；
MeOOC-C(＝CHEt)CH 2-OOCCH 2-(R)Cgl-Aze-Pab-Z；
Men-OOCCH 2-(R)Cgl-Aze-Pab-COOPh(4-OMe)；and
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CCl 3。
32. the compound that claim 1 is claimed, it is
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2CCl 3；
BnOOCCH 2-(R)Cgl-Aze-Pab-COOnBu；
nPrOOCCH 2-(R)Cgl-Aze-Pab-Z；
Cyclooctyl-OOCCH 2-(R)Cgl-Aze-Pab-Z；
EtOOCCH 2-(R)Cgl-Aze-Pab-COOCH 2OOCCh；
MeOOCCH 2-(R)Cgl-Aze-Pab-OH；
EtOOCCH 2-(R)Cgl-Aze-Pab-OH；
nPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
iPrOOCCH 2-(R)Cgl-Aze-Pab-OH；
33. the formula I compound that claim 1 limits, wherein extra condition is R 1Do not represent-A 1C (O) OR 4
34. the formula I compound that claim 1 limits, wherein extra condition is R 4And R 5Dependently represent H.
35. the formula I compound that claim 1 limits, wherein extra condition is to work as R 2Expression OC (O) R 6The time, R 6Do not represent C 1-17Alkyl.
36. the formula I compound that claim 1 limits, wherein R 1Expression-A 1C (O) OR 4
37. the formula I compound that claim 1 limits is wherein worked as R 4And R 5Represent H independently.
38. the formula I compound that claim 1 limits is wherein worked as R 2Expression OC (O) R 6The time, R 6Expression C 1-17Alkyl.
39. medicinal preparations, it comprise with each of pharmaceutically acceptable auxiliary, diluent or carrier blended claim 1-38 in the formula I compound or its pharmacy acceptable salt that limit.
40. as the formula I compound or its pharmacy acceptable salt that limit in each of the claim 1-38 of medicine.
41. the formula I compound that limits in each of claim 1-38 or the purposes of its pharmacy acceptable salt promptly need the purposes of the active ingredient in the drug manufacture of disease of Trombin inhibiting as treatment.
42. claimed purposes in the claim 41, wherein said disease is a thrombosis.
43. the formula I compound that limits in each of claim 1-38 or the purposes of its pharmacy acceptable salt, the purposes of the active ingredient in promptly producing as blood anticoagulant.
44. it is that limit in the claim 1 but do not have the purposes of formula I compound provisory as prodrug.
45. the method for preparation I compound, this method comprises:
(a) for R 2The formula I compound of expression OH is with R 2Expression OC (O) R 6And R 6React as corresponding formula I compound and alkoxide base that claim 1 limits;
(b) for R 2The formula I compound of expression OH is with R 2Expression C (O) OR 7And R 7Corresponding formula I compound and azanol or its acid addition salt reaction as claim 1 qualification;
(c) with following corresponding formula II compound and the reaction of formula III compound,
H-(R)Cgl-Aze-Pab-R 2 II
R wherein 2Limit as claim 1,
R 1O(O)C-CH 2-L 1 III
L wherein 1Expression leavings group, and R 1Limit as claim 1;
(d) for R 1Expression H and R 2Expression OH or C (O) OR 7Formula I compound, with corresponding formula I compound, wherein R 1Expression C 1-10Alkyl or C 1-3Alkane phenyl, and R 2Expression OH or C (O) OR 7, with alkali reaction;
(e) for R 2Expression OC (O) R 6Formula I compound, with R 2The corresponding formula I compound of expression OH with following formula IV compound reaction,
R 6C(O)-O-C(O)R 6 IV
R 6C(O)Hal V
Wherein Hal represents Cl or Br, and in both cases, R 6All limit as claim 1.
(f) for R wherein 1Expression H, and R 2Expression OC (O) R 6, and R 6As the formula I compound of claim 1 qualification, with following corresponding formula VI or formula V compound and acid-respons,
P 1O (O) C-CH 2-(R) Cgl-Aze-Pab-R 2VI is P wherein 1Represent sour unstable ester protecting group, and R 2Expression OC (O) R 6, R wherein 6Limit as claim 1;
(g) for R wherein 1Expression R 3, R 3Expression C 1-10Alkyl and C 1-3The alkane phenyl, R 2Expression OH or C (O) OR 7, and R 7Formula I compound as claim 1 limits carries out transesterification with following corresponding formula VII compound,
R 1aO (O) C-CH 2-(R) Cgl-Aze-Pab-R 2VII is R wherein 1aRepresent the non-C that is forming 1-10Alkyl or C 1-3The unstable alkyl substituent of alkane phenyl or another selection, and R 2Limit as claim 1.
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WO1994029336A1 (en) * 1993-06-03 1994-12-22 Astra Aktiebolag New peptide derivatives
WO1995035309A1 (en) * 1994-06-17 1995-12-28 Basf Aktiengesellschaft New thrombin inhibitors, their preparation and use
WO1996016671A1 (en) * 1994-12-02 1996-06-06 Astra Aktiebolag New antithrombotic formulation, process for its manufacturing, and use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994029336A1 (en) * 1993-06-03 1994-12-22 Astra Aktiebolag New peptide derivatives
WO1995035309A1 (en) * 1994-06-17 1995-12-28 Basf Aktiengesellschaft New thrombin inhibitors, their preparation and use
WO1996016671A1 (en) * 1994-12-02 1996-06-06 Astra Aktiebolag New antithrombotic formulation, process for its manufacturing, and use thereof

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