CN1237978A - N (aryl/heteroaryl) amino acid derivatives, pharmaceutical compositions comprising same, and method for inhibiting 'beta'-amyloid peptide release and/or its synthesis by use of such compounds - Google Patents

Abstract

Disclosed are compounds which inhibit beta -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits beta -amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

Description

N-(aryl/hetaryl) amino acid derivative, comprise the medicinal compositions of these derivatives and suppress beta amyloid peptides and discharge and/or its synthetic method with these compounds

The mutual reference of related application

The application requires U.S. Provisional Application 60/_, _ number (the U.S. Patent application the 08/755th that this application (ⅱ) is submitted to by on November 22nd, 1996 according to 37 C.F.R. § 1.53 (b) (2), No. 334 transformations) rights and interests, it all is attached to herein as a reference this application by reference.The background of invention invention field

The present invention relates to suppress beta amyloid peptide and discharge and/or its synthetic compound, and therefore in the treatment Alzheimer, have practicality.The present invention also relates to comprise the medicinal compositions of this compounds and suppress the method that beta amyloid peptide discharges.Reference

Following publication, patent and patent application are in this application with the subscript numeric reference:

1 Glenner etc., " Alzheimer: new cerebrovascular amylaceous egg

The white purifying and the Preliminary report of evaluation ", Biochem.Biophys.Res.

Commun.,120:885-890(1984).

2 Glenner etc., " polypeptide marker of Alzheimer and diagnosis thereof are used

On the way ", the United States Patent (USP) of issuing on May 19th, 1987 the 4th, 666,829

Number.

3 Selkoe, " molecular pathology of Alzheimer " Neuron,

6:487-498(1991)。

4 Goate etc., " the amyloid that suffers from the familial Alzheimer

The separation of missense mutation in the precursor protein gene ", Nature, 349:704-

706(1990)。

5 Chartier-Harlan etc. are " in amyloid beta precursor protein gene

The early onset thereof of the Alzheimer that codon 717 sudden changes cause ",

Nature,353:844-846(1989)。

6 Murrell etc., " amyloid beta precursor protein and heredity alzheimer '

The sudden change that Mo's disease is relevant ", Science, 254:97-99 (1991).

7 Mullan etc. " may in the app gene of amyloid beta N-terminal

The pathology sudden change of Alzheimer, Nature Genet., 1:345-

347(1992)。

8 Schenk etc., " detecting the method and the composition of solubility beta amyloid peptide ",

In on May 11st, 1994 disclosed international patent application WO is disclosed

No. 94/10569.

9 Selkoe, " amyloid and Alzheimer ", Scientific

American, 2-8 page or leaf, in November, 1991.

10 Yates etc., " N, the dibasic amino acid weedicide of N-", United States Patent (USP)

Issue in number on August 10th, 3,598,859,1991.

11 Citron etc. are " in the familial Alzheimer before the amyloid beta

The body protein sudden change increases the generation of beta-protein, Nature, 360:672-674

(1992)。

12 Hansen etc. " measure the accurate with fast of cell growth and cell killing

Dye method " reexamine and further exploitation, J.Immun.Meth.,

119:203-210(1989)。

All above publications, patent and patent application all are attached to herein as a reference by reference, its degree and each independent publication, patent or patent application show specially and individually all be attached to by reference the same as a reference herein.The situation of this area

Alzheimer (AD) is a kind of degeneration encephalopathic, and its Clinical symptoms is the forfeiture of the memory of carrying out property, cognition, reasoning, judgement and emotional stability, and it causes degree of depth spirit to be degenerated (mental deterioration) gradually, finally causes death.AD is the very common reason of carrying out property mental disorder (dementia) among the elderly, it is believed that in the U.S. to be the 4th dead main medical reasons.In worldwide ethnic group and ethnic group, observe AD, and be the present and following main public health problem.Estimate that at present this disease only just influences about two to three million peoples in the U.S..AD can not cure at present.At present known do not have a therapy of effectively preventing AD or reversing its symptom and process.

The brain of suffering from the individuality of AD shows the characteristic infringement, is called (or amyloid) spot in old age, amyloid angiopathy (amyloid deposits) and neuroneme and twines in blood vessel.These a large amount of infringements, particularly amyloid spot and neuroneme are twined, and generally find in several zones to the important human brain of memory and cognitive function in suffering from the patient of AD.These infringements of the minority of more limited anatomic distribution are also found in the most of the elderlys' that do not have clinical AD brain.Amyloid spot and amyloid angiopathy also characterized the individual brain of the 21st pair of karyomit(e) trisomy (mongolism) and have the heredity cerebral hemorrhage (HCHWA-D) of Dutch type amyloidosis.At present, making a definite diagnosis usually of AD need be observed above-mentioned infringement in dying from this sick patient's cerebral tissue or in the little biopsy samples of cerebral tissue that takes out under few situation during the invasive neurosurgery.

The amyloid spot of AD and above-mentioned other disease and the distinctive main chemical composition of blood vessel amyloid deposition (amyloid angiopathy), be about 39-43 amino acid whose about 4.2 kilodaltons (kD) albumen, be called beta amyloid peptide (β AP), or be A β, A β P or β/A4 sometimes.People such as G1enner ¹Purifying beta amyloid peptide at first, and partial amino-acid series is provided.In United States Patent (USP) the 4th, 666,829 ²In the data of preceding 28 amino acid whose separating steps and sequence have been described.

Molecular biology and albumen chemical analysis show, beta amyloid peptide is the small segment of much bigger precursor protein (APP), and APP is produced by the cell in many tissues of various animals (comprising the people) usually.The understanding of gene structure to coding APP is verified, and beta amyloid peptide is downcut from APP by proteolytic enzyme, produces as peptide fragment.The beta amyloid peptide fragment downcuts and it be not immediately clear as amyloid spot sedimentary accurate biochemical mechanism cerebral tissue and cerebrovascular wall and meningovascular wall subsequently from APP.

The evidence of several respects shows, carrying out property beta amyloid peptide brain is deposited on that mechanism plays the initial stage (seminal) effect in the AD morbidity, and can the several years or many decades occur prior to cognitive symptom.Referring to for example Selkoe ³Most important evidence is such discovery, promptly in the several families of the AD with heredity decision (familial) form, the missense dna mutation of the human amino acid 717 of 770 amino acid whose isotypes of APP can find in influenced member, and do not find (Goate etc. in unaffected member ⁴Chartier-Harlan etc. ⁵With Murrell etc. ⁶), this mutant form is called Sweden's varient.Reported the Methionin of in family of Swede, finding in 1992 ⁵⁹⁵-methionine(Met) ⁵⁹⁶Become l-asparagine ⁵⁹⁵-leucine ⁵⁹⁶Two sudden change (Mullan etc. of (with reference to 695 isotypes) ⁷) genetic linkage analysis has been verified, other sudden change of some in these sudden changes and the app gene is the specific molecular reason of influenced member AD in this class family.In addition, identified the reason that sports beta amyloid peptide storage disorders HCHWA-D of amino acid 693 of 770 amino acid isotypes of APP, and in other cases, in the patient of some non-HCHWA-D, cause the phenotype of similar AD to the variation of glycine by L-Ala in amino acid 692 places.Prove that based on these sudden changes of APP in the AD case of heredity and the discovery of other sudden change the change of APP and the segmental deposition of its beta amyloid peptide can cause AD subsequently.

Although making progress aspect the pathogenesis (underlying mechanisms) of understanding AD and other beta amyloid peptide relative disease, but still need exploitation to treat the method and composition of described disease.It is desirable to, described methods of treatment is preferably based on and can suppresses beta amyloid peptide release and/or its synthetic medicine.

The present invention's general introduction

The present invention relates to find that a class suppresses beta amyloid peptide and discharges and/or its synthetic compound, so they are used in the patient that prevention AD among the easy trouble AD patient and/or treatment suffer from AD, to suppress the further deterioration of its state of an illness.This compounds with above-mentioned character is by defining with the following formula I: I is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II:

II

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group,

Halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cWith

Benzyl ring condenses and forms heteroaryl or heterocycle,

R ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen

Perhaps all be the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain 1-3 heteroaryl that is selected from following substituent replacement: alkyl, alcoxyl

Base, aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy

And thio-aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not

It is the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen

Alkyl, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the ring of hydrogen, alkyl, replacement

Alkyl, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Individual carbon atom, the optional individual heteroatomic ring that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains

Group, and optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃

Therefore, aspect an one method, the present invention relates to suppress beta-amyloid polypeptide 1-release and/or its synthetic method in the cell, this method comprises and gives the mixture of this cell with following formula I compound or formula I compound, and administered dose should be enough to suppress cell and discharge and/or synthesize beta-amyloid polypeptide 1-.

Because produce relevant in the body of beta-amyloid polypeptide 1-with the pathogeny of AD ^8,9, so formula I compound also can be used in combination with a kind of medicinal compositions, with preventative and/or therapeutic prevent and/or treat AD.Therefore, aspect other method, the present invention relates to the Preventive Method of prevention AD outbreak in the patient who develops into the AD risk is arranged, this method comprises and gives described patient a kind of medicinal compositions that described medicinal compositions comprises pharmaceutically inert carrier and a kind of above-mentioned formula I compound of significant quantity or the mixture of formula I compound.

Aspect other method, the present invention relates to a kind of therapeutic method, treatment suffers from the patient of AD, so that suppress the further deterioration of this patient's illness, this method comprises and gives described patient a kind of medicinal compositions that said composition comprises pharmaceutically inert carrier and a kind of above-mentioned formula I compound of significant quantity or the mixture of formula I compound.

In above-mentioned formula I, R ¹That the phenyl that replaces is preferably is that 4-replaces, 3,5-is dibasic or 3, the dibasic phenyl of 4-is wherein at 3 and/or 5 s' substituting group such as above-mentioned R ^bAnd R ^{B '}Definition is at 4 substituting groups such as above-mentioned R ^cDefinition.Particularly preferred 3, the dibasic phenyl of 5-comprise (as) 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-two (trifluoromethyl) phenyl and 3,5-Dimethoxyphenyl etc.Particularly preferred 3, the dibasic phenyl of 4-comprise (as) 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chloro-phenyl-, 3-chloro-4-cyano-phenyl, 3-chloro-4-iodine substituted phenyl, 3,4-methylenedioxyphenyl base etc.The phenyl that particularly preferred 4-replaces comprises (for example) 4-azido-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-cyano-phenyl, 4-ethylphenyl, 4-fluoro phenyl, 4-iodine substituted phenyl, 4-(phenylcarbonyl group) phenyl and 4-(1-oxyethyl group) ethylphenyl etc.

Other preferred R ¹Substituting group comprises (for example) 2-naphthyl, quinoline-3-base, 2-toluquinoline-6-base, benzothiazole-6-base, benzothiazole-2-base, 5-indyl, phenyl, 2-naphthyl etc.

Preferred R ²Be selected from the alkyl of 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that described substituting group is not the ortho position with aryl that is connected carbon atom or heteroaryl atom.Particularly preferred R ²Substituting group comprise (for example) methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-,-CH ₂CH ₂SCH ₃With phenyl etc.

Preferred R ³Substituting group comprises alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and sec-butyl etc.; Alkyl that replaces such as Alpha-hydroxy ethyl ,-CH ₂-cyclohexyl, benzyl, right-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-two iodos-4-hydroxybenzyl ,-CH ₂-draw diindyl-3-base, phenyl ,-(CH ₂) ₄-NH-BOC ,-(CH ₂) ₄-NH ₂,-CH ₂-(1-N-benzyl-imidazol-4 yl) ,-CH ₂-imidazol-4 yl ,-CH ₂CH ₂SCH ₃,-(CH ₂) ₄NHC (O) (CH ₂) ₄CH ₃With-(CH ₂) _yC (O) OR ⁵, wherein y is 1 or 2, R ⁵Hydrogen, methyl or the tertiary butyl, phenyl etc.

Preferred X substituting group comprises-C (O) Y group that wherein Y is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, amino-NH ₂), N-(isobutyl-) amino, N-methylamino-, N, N-dimethylamino and N-benzyl amino etc., and wherein X is-CH ₂OH etc.

The present invention also provides the new medicinal compositions that comprises medicinal inert carrier and above-mentioned formula I compound.

The particularly preferred compound that is used for method and composition of the present invention comprise (as) following compounds and pharmacy acceptable salt thereof, wherein R ²And R ³The stereochemistry of group is preferably amino acid derived by L-: N-[N-(3; the 4-dichlorophenyl) alanyl] valine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-isobutyramide N-[N-(3; the 4-dichlorophenyl) alanyl] Threonine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan ethyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan tert-butyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] valine amide N-(3; the 4-dichlorophenyl) L-Ala N-(1-hydroxy-3-methyl-2-butyl) acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N; N-dimethylformamide N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-methyl nitrosourea N-[N-(3; the 4-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] leucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Isoleucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] tryptophan methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazole-6-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(methyl esters) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-1-benzyl Histidine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] glutamic acid gamma-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] leucyl amine N-[N-(3; the 4-dichlorophenyl) alanyl] L-glutamic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-(3; 5-two iodos) L-Tyrosine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-(3-iodo) L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) glycyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N ε-(caproyl) lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanyl amine N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl]-β-Cyclohexylalanine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N; the N-dimethyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] methionine(Met) methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N; the N-dimethyl)-acid amides N-[N-(3; the 5-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Histidine methyl esters N-[N-(quinoline-3-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-benzothiazole-2-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 5-difluorophenyl) alanyl] alanine methyl ester N-[N-(3; the 5-difluorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-benzyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3; the 5-dichlorophenyl) phenyl glycyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino-hexanol N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3; the 5-dichlorophenyl) alanyl] phenylglycocoll tert-butyl ester N-[N-(3; 5-two-(trifluoromethyl) phenyl) alanyl] phenylglycocoll tert-butyl ester N-[N-(3, the 5-Dimethoxyphenyl) alanyl]-the 2-aminohexanoic acid methyl esters.

The present invention further provides new formula III compound:

III is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II:

II

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group,

Halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cWith

Benzyl ring condenses and forms heteroaryl or heterocycle,

R ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen

Perhaps all be the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain 1-3 heteroaryl that is selected from following substituent replacement: alkyl, alcoxyl

Base, aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy

And thio-aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not

It is the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen

Alkyl, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the ring of hydrogen, alkyl, replacement

Alkyl, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Individual carbon atom, the optional individual heteroatomic ring that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains

Group, and optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃, other prerequisite is not for comprising following compound known:

Work as R ¹Be phenyl, R ²Be methyl, X is-during C (O) NH Φ, so R ³Not methyl, sec.-propyl, isobutyl-; With work as R ¹Be phenyl, R ²Be methyl, X is-C (O) NH ₂The time, R so ³It or not benzyl.Preferred formula III compound comprises the compound that the I of tabulating is down listed:

III

?????R 1	????R 2	??????R 3	??????????X
				3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	??????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	?-C(O)NHCH 2CH(CH 3) 2
				3, the 4-dichlorophenyl	????-CH 3	????-CH(OH)CH 3	??????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	?????-C(O)OCH 2CH 3
				3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	?????-C(O)OC(CH 3) 3
3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	???????-C(O)NH 2
				3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	????????-CH 2OH
3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	??????-C(O)N(CH 3) 2
				3, the 4-dichlorophenyl	????-CH 3	????-CH(CH 3) 2	???????-C(O)NHCH 3
3, the 4-dichlorophenyl	????-CH 3	??????-CH 3	???????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	???????- ??CH 2CH(CH 3) 2	???????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	????-CH 2-φ	???????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	???????- ??CH(CH 3)CH 2??????CH 3	???????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	??-CH 2CH 2CH 3	???????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	??-(CH 2) 3CH 3	???????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	??-CH 2-indoles-3-base	???????-C(O)OCH 3

3, the 4-dichlorophenyl	????-CH 3	??-CH 2COOH	????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	??-CH 2C (O) the O-tertiary butyl	????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	??-(CH 2) 4-NH- ??????BOC	????-C(O)OCH 3
				Benzothiazole-6-base	????-CH 3	??-(CH 2) 3CH 3	????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	??-(CH 2) 4NH 2	????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	The P-hydroxybenzyl	????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	?????-CH 3	????-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	??-CH 2CH 2CH 3	????-C(O)OCH 3

??????R 1	?????R 2	???????R 3	???????X
				3, the 5-dichlorophenyl	????-CH 3	????-CH 2-φ	???-C(O)OCH 3
3, the 5-dichlorophenyl	????-CH 3	??-CH 2C(O)OCH 3	???-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	-CH 2-(1-N-benzyl-imidazol-4 yl)	???-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	-(CH 2) 2C (O) the O-tertiary butyl	???-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	??-CH 2CH(CH 3) 2	???-C(O)NH 2
3, the 4-dichlorophenyl	????-CH 3	??-CH 2CH 2COOH	???-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	-CH 2-(3,5-two iodos-4-hydroxy phenyl)	???-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	-CH 2-(3-iodo-4-hydroxy phenyl)	???-C(O)OCH 3
				3, the 4-dichlorophenyl	??????H	??-CH 2CH 2CH 3	???-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	???????- (CH 2) 4NC(O)(CH 2??????) 4CH 3	???-C(O)OCH 3
				3, the 4-dichlorophenyl	????-CH 3	????-CH 2-φ	???-C(O)NH 2
3, the 4-dichlorophenyl	????-CH 3	?-CH 2CH 2CH 2CH 3	???-C(O)NHCH 3
				3, the 4-dichlorophenyl	????-CH 3	??-CH 2-cyclohexyl	???-C(O)OCH 3

3, the 4-dichlorophenyl	????-CH 3	????-(CH 2) 3CH 3	??????-C(O)NH 2
				3, the 4-dichlorophenyl	????-CH 3	????-(CH 2) 3CH 3	????-C(O)N(CH 3) 2
3, the 4-dichlorophenyl	????-CH 3	???-CH 2CH 2SCH 3	??????-C(O)OCH 3
				3, the 5-dichlorophenyl	????-CH 3	??-CH 2CH 2CH 2CH 3	????-C(O)N(CH 3) 2
3, the 5-dichlorophenyl	????-CH 3	??-CH 2CH 2CH 2CH 3	??????-C(O)NH 2
				3, the 5-dichlorophenyl	????-CH 3	??-CH 2CH 2CH 2CH 3	??????-C(O)NHCH 3
3, the 5-dichlorophenyl	????-CH 3	??-CH 2-imidazol-4 yl	??????-C(O)OCH 3
				Quinoline-3-base	????-CH 3	??-CH 2CH 2CH 2CH 3	??????-C(O)OCH 3
Benzothiazole-2-base	????-CH 3	??-CH 2CH 2CH 2CH 3	??????-C(O)OCH 3
				3, the 5-difluorophenyl	????-CH 3	???????-CH 3	??????-C(O)OCH 3

??????R 1	?????R 2	??????R 3	????????X
				3, the 5-difluorophenyl	????-CH 3	-CH 2CH 2CH 2CH 3	????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	-CH 2CH 2CH 2CH 3	?????-C(O)NH 2
				3, the 4-dichlorophenyl	????-CH 3	-CH 2CH 2CH 2CH 3	???-C(O)NHCH 2-φ
3, the 4-dichlorophenyl	????-CH 3	?????-φ	??????-CH 3OH
				3, the 5-dichlorophenyl	????-φ	????-CH 3	?????-C(O)OCH 3
3, the 4-dichlorophenyl	????-CH 3	-CH 2CH 2CH 2CH 3	??????-CH 3OH
				3, the 5-dichlorophenyl	????-CH 3	?????-φ	??????-CH 2OH
3, the 5-dichlorophenyl	????-CH 3	?????-φ	???-C(O)OC(CH 3) 3
				3,5-two-(trifluoromethyl) phenyl	????-CH 3	?????-φ	???-C(O)OC(CH 3) 3
3, the 5-Dimethoxyphenyl	????-CH 3	?????- CH 2CH 2CH 2CH 3	?????-C(O)OCH 3

Detailed Description Of The Invention

As mentioned above, the present invention relates to suppress beta-amyloid polypeptide 1-and discharge and/or its synthetic method, and therefore in the treatment Alzheimer, have practicality.Yet, before describing the present invention in detail, at first define following term.Definition

Term " beta-amyloid polypeptide 1-" is meant that molecular weight is approximately 39-43 the amino acid whose peptide of 4.2kD, people such as this peptide and Glenner ¹The albumen form of describing is homotype roughly, comprises the sudden change and the posttranslational modification of normal beta-amyloid polypeptide 1-.At all events plant form, described beta-amyloid polypeptide 1-is about 39-43 the amino acid whose fragment of striding film (membrane-spanning) glycoprotein greatly, is called beta amyloid precursor protein (APP).Its 43 amino acid whose sequences are: 1Asp Ala Glu Phe Arg His Asp Ser Gly Tyr11Glu Val His His Gln Lys Leu Val Phe Phe21Ala Glu Asp Val Gly Ser Asn Lys Gly Ala31Ile Ile Gly Leu Met Val Gly Gly Val Val41Ile Ala Thr (SEQ ID NO:1) or for and its isostructural substantially sequence.

" alkyl " is meant the univalent alkyl that preferably has 1-10 carbon atom, more preferably has 1-6 carbon atom.The example of this term has such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-hexyl etc.

" alkyl of replacement " is meant a preferred 1-10 carbon atom; have 1-3 and be selected from following substituent alkyl: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; acyloxy; amino; aminoacyl; amino acyloxy; cyano group; halogen; hydroxyl; carboxyl; carboxyalkyl; cycloalkyl; the oxygen acyl amino; thiol; the thio alkoxy that replaces; aryl; heteroaryl; heterocycle; nitro and one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-cycloalkyl amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; the alkyl that replaces; cycloalkyl; aryl; asymmetric two of heteroaryl and heterocyclic different substituents replaces amine.

" alkylidene group " is meant the divalent alkyl that preferably has 1-10 carbon atom, more preferably has 1-6 carbon atom.The example of this term has such as methylene radical (CH ₂-), ethylidene (CH ₂CH ₂-), the propylidene isomer (for example-CH ₂CH ₂CH ₂-and-CH (CH ₃) CH ₂-) etc.

" alkaryl " be meant preferably in alkylene moiety, have 1-10 carbon atom, in aryl moiety, have 6-10 carbon atom-alkylidene group-aryl.The example of this class alkaryl is benzyl, styroyl etc.

" alkoxyl group " is meant " alkyl-O-" group.Preferred alkoxyl group comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.

" alkoxyl group of replacement " is meant " alkyl-O-of replacement " group, and wherein the alkyl of Qu Daiing as defined above.

" alkyl alkoxy " is meant " alkylidene group-O-alkyl " group, and alkylidene group and alkyl as above define here.This class group comprises for example methylene radical methoxyl group (CH ₂OCH ₃), ethylidene methoxyl group (CH ₂CH ₂OCH ₃), positive propylidene isopropoxy (CH ₂CH ₂CH ₂OCH (CH ₃) ₂), methylene radical tert.-butoxy (CH ₂-O-C (CH ₃) ₃) etc.

" alkylthio alkoxyl group " is meant " alkylidene group-S-alkyl " group, and wherein alkylidene group and alkyl as above define.This class group comprises that for example sulfonium methylide is for methoxyl group (CH ₂SCH ₃), ethylidene sulfo-methoxyl group (CH ₂CH ₂SCH ₃), the positive different sulfo-propoxy-of propylidene (CH ₂CH ₂CH ₂SCH (CH ₃) ₂), sulfonium methylide is for tert.-butoxy (CH ₂SC (CH ₃) ₃) etc.

" alkenyl " be meant preferably have 2-10 carbon atom, more preferably have 2-6 carbon atom and at least 1, the alkenyl in preferred 1-2 the unsaturated site of alkene.Preferred alkenyl comprises vinyl (CH=CH ₂), positive propenyl (CH ₂CH=CH ₂), pseudoallyl (C (CH ₃)=CH ₂) etc.

" alkenyl of replacement " is meant that having 1-3 as defined above is selected from following substituent alkenyl: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; acyloxy; amino; aminoacyl; amino acyloxy; cyano group; cycloalkyl; oxygen base amido; halogen; hydroxyl; carboxyl; carboxyalkyl; thiol; thio alkoxy; the thio alkoxy that replaces; aryl; heteroaryl; heterocycle; nitro; and one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-cycloalkyl; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group; with have the alkyl of being selected from; the alkyl that replaces; cycloalkyl; aryl; asymmetric two of heteroaryl and heterocyclic different substituents replaces amine.

" alkynyl group " is meant preferably have 2-10 carbon atom, more preferably have 2-6 carbon atom and have at least 1, the alkynyl group in preferred 1-2 the unsaturated site of alkynes.Preferred alkynyl group comprises ethynyl (C ≡ CH), propargyl (CH ₂C ≡ CH) etc.

" alkynyl group of replacement " is meant to have as defined above and is selected from following 1-3 substituent alkynyl group: alkoxyl group; the alkoxyl group that replaces; acyl group; amido; acyloxy; amino; aminoacyl; amino acyloxy; cyano group; cycloalkyl; the oxygen acyl amino; halogen; hydroxyl; carboxyl; carboxyalkyl; thiol; thio alkoxy; replace thio alkoxy; aryl; heteroaryl; heterocycle; nitro; and one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-naphthene amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group; with have the alkyl of being selected from; the alkyl that replaces; cycloalkyl; aryl; asymmetric two of heteroaryl and heterocyclic different substituents replaces amine.

" acyl group " be meant alkyl-C (O)-, alkyl-C (O) of replacing-, cycloalkyl-C (O)-, aryl-C (O)-, heteroaryl-C (O)-and heterocycle-C (O)-, wherein the alkyl of alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" amido " is meant-C (O) NRR group that each R is alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of hydrogen, alkyl, replacement independently here, and the alkyl of each alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" aminoacyl " is meant-NRC (O) R group that each R is alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of hydrogen, alkyl, replacement independently here, and the alkyl of each alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" acyloxy " be meant group-OC (O)-alkyl ,-alkyl of OC (O)-replacement ,-OC (O)-cycloalkyl ,-OC (O)-aryl ,-C (O) O-heteroaryl and-C (O) O-heterocycle, the alkyl of alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define here.

" amino acyloxy " be meant-NRC (O) O-alkyl ,-alkyl that NRC (O) O-replaces ,-NRC (O) O-cycloalkyl ,-NRC (O) O-aryl ,-NRC (O) O-heteroaryl and-NRC (O) O-heterocycle, here R is alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of hydrogen, alkyl, replacement, and the alkyl of each alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" oxygen amido " be meant group-OC (O) NR-alkyl ,-alkyl that OC (O) NR-replaces ,-OC (O) NR-aryl ,-OC (O) NR-heteroaryl and-OC (O) NR-heterocycle, here R is alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of hydrogen, alkyl, replacement, and the alkyl of each alkyl, replacement, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" aryl " is meant the unsaturated aromatic carbocyclic group of 6-14 carbon atom of have monocycle (for example phenyl) or a plurality of condensed ring (for example naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.

Unless definition limits in addition to aryl substituent, otherwise can randomly being selected from following substituting group with 1-3, this class aryl replaces: hydroxyl; acyl group; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amino; aminoacyl; amido; amino acyloxy; the oxygen amido; aryl; aryloxy; carboxyl; carboxyalkyl; cyano group; halogen; nitro; heteroaryl; trihalogenmethyl; thio alkoxy; the thio alkoxy that replaces; one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-naphthene amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group; and has an alkyl of being selected from; the alkyl that replaces; aryl; asymmetric two of the different substituents of heteroaryl and heterocycle etc. replaces amine etc.Preferred substituted comprises alkyl, alkoxyl group, halogen, cyano group, nitro, trihalogenmethyl and thio alkoxy.When being so replacement, such aryl is sometimes referred to as " aryl of replacement ".

" aryloxy " is meant group aryl-O-, and wherein said aryl as above defines, and comprises the aryl that also can choose replacement as defined above wantonly.

" carboxyalkyl " be meant group-C (O) O-alkyl and-alkyl that C (O) O-replaces, the alkyl of alkyl and replacement as above defines here.

" cycloalkyl " is meant the monocycle with 3-20 carbon atom or the cycloalkyl of a plurality of condensed ring (comprising and cycloalkyl ring condensed aromatic ring), and it can be randomly with 1-3 alkyl replacement.This class cycloalkyl comprises for example single ring architecture, such as cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.; Or a plurality of ring structures, such as adamantyl etc.

" cycloalkenyl group " is meant the cycloalkenyl group of 4-8 carbon atom with monocycle or a plurality of fused rings and at least one inner unsaturated point, and it can randomly replace with 1-3 alkyl.The example of suitable cycloalkenyl group comprises and for example encircles but-2-ene base, ring penta-3-thiazolinyl, ring suffering-3-thiazolinyl etc.

" halo " or " halogen " is meant fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.

" heteroaryl " is meant to have to have 1-4 heteroatomic monovalence aromatic group that is selected from oxygen, nitrogen and sulphur in 2-10 carbon atom and the ring.

Unless to heteroaryl substituting group definition restriction in addition, otherwise this class heteroaryl can randomly replace with being selected from following 1-3 substituting group: hydroxyl; acyl group; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amino; aminoacyl; amido; amino acyloxy; the oxygen amido; aryl; aryloxy; carboxyl; carboxyalkyl; cyano group; halogen; nitro; heteroaryl; trihalogenmethyl; thio alkoxy; replace thio alkoxy; one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-naphthene amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group; and has an alkyl of being selected from; the alkyl that replaces; cycloalkyl; aryl; asymmetric two of heteroaryl and heterocyclic different substituents replaces amine etc.This class heteroaryl can have monocycle (for example pyridyl or furyl) or a plurality of condensed ring (for example indolizine base or benzothienyl).Preferred heteroaryl comprises pyridyl, pyrryl and furyl.When being so replacement, such heteroaryl is sometimes referred to as " heteroaryl of replacement ".

" heterocycle " or " heterocyclic " is meant to have monocycle or a plurality of condensed ring, have in 1-12 carbon atom and the ring and have the saturated or unsaturated group of heteroatomic unit price (i.e. tie point) that 1-4 is selected from nitrogen, sulphur or oxygen.

Unless, replace otherwise this class heterocyclic radical can randomly be selected from following substituting group with 1-3: hydroxyl to heterocyclic substituent definition restriction in addition; acyl group; acyloxy; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; alkenyl; the alkenyl that replaces; alkynyl group; the alkynyl group that replaces; amino; aminoacyl; amido; amino acyloxy; the oxygen amido; aryl; aryloxy; carboxyl; carboxyalkyl; cyano group; halogen; nitro; heteroaryl; trihalogenmethyl; thio alkoxy; replace thio alkoxy; one-and two-alkylamino; one-and two-(alkyl of replacement) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group; and has an alkyl of being selected from; the alkyl that replaces; cycloalkyl; aryl; asymmetric two of heteroaryl and heterocyclic different substituents replaces amine etc.This class heterocyclic radical can have monocycle or a plurality of condensed ring.Preferred heterocycle comprises morpholino, piperidyl etc.

The example of heterocyclic radical and heteroaryl includes but not limited to furans, thiophene, thiazole oxazole, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, 2, the 3-naphthyridine, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene isoxazole phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, piperidyl, tetramethyleneimine, tetrahydrofuran base etc.

" thiol " is meant group-SH.

" thio alkoxy " is meant group-S-alkyl.

" thio alkoxy of replacement " is meant the alkyl that group-S-replaces.

" thio-aryloxy " is meant group aryl-S-, and wherein said aryl as above defines, and comprises the aryl that can choose replacement as defined above wantonly.

" sulfo-heteroaryloxy " is meant group heteroaryl-S-, and wherein said heteroaryl as above defines, and comprises the aryl that can choose replacement as defined above wantonly.

In formula I compound, R ^bAnd R ^cCan condense with phenyl ring and form heteroaryl or heterocycle.Obtain having the condensed dicyclo of following formula structure when condensing in this mode: R wherein ^{B '}Identical with above-mentioned definition, A is condensed heteroaryl or heterocyclic radical, these term definitions as above, wherein two of phenyl ring atoms are included in the total atom number that is present in heteroaryl or heterocyclic radical.The example of this type of condensed ring system comprises as indoles-5-base, indoles-6-base, sulfo-naphthalene time first-5-base, sulfo-naphthalene time first-6-base, different sulfo-naphthalene time first-5-base, different sulfo-naphthalene time first-6-base, the indoxazin-5-base, indoxazin-6-base benzoxazole-5-base benzoxazole-6-base, the anthranil-5-base, the anthranil-6-base, quinoline-6-base, quinoline-7-base, isoquinoline 99.9-6-base, isoquinoline 99.9-7-base, cinnolines-6-base, cinnolines-7-base, quinazoline-6-base, quinazoline-7-base, cumarone-5-base, cumarone-6-base, isobenzofuran-5-base, isobenzofuran-6-base etc.

" pharmacy acceptable salt " is meant the pharmacy acceptable salt of formula I compound, and described salt comprises sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium etc. derived from all organic and inorganic counter ions well known in the art as just example; And when this molecule contains an alkaline functionality, comprise the salt of organic or mineral acid, such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate etc.

The preparation of compound

By several diversified route of synthesis, and, easily prepare above-mentioned formula I compound with respect to selected concrete approach such as the easiness of compound, the market availability of raw material.

In a synthetic method, at first in molecule, introduce amino acid N H ₂CH (R ²) R of COOH or its ester ¹Group.After this, make R ¹NHCH (R ²) COOH or its ester and amine NH ₂CH (R ³) C (O) Y coupling, thereby obtain the formula I compound of X wherein for-C (O) Y.

Equally, right-C (O) Y reduces and obtains-CH ₂OH etc.

To amino acid N H ₂CH (R ²) COOH or its ester introducing R ¹Group can be finished by several approach.For example, make halogenated acetic acids and primary amine coupling can form amino acid shown in following reaction (1):

R wherein ¹And R ²As above definition, and X is preferably the halo group, as chloro or bromo.Perhaps can use not to be halogenated leavings group, as triflate, methanesulfonates, p-toluenesulfonic esters etc.In addition, in this reaction, can use 1 suitable ester.

Reaction (1) only relates under the condition that amino acid 3 is provided, with suitable halogenated acetic acids derivative 1 and 2 couplings of uncle's aryl/hetaryl amine.This reaction is by as Yates etc. ¹⁰Described, halogenated acetic acids 1 that can be by will chemical approximately calculated amount and uncle's aryl/hetaryl amine 2 mix in suitable inert solvent such as water, dimethyl sulfoxide (DMSO) (DMSO) and carry out.Excessive alkali such as the acid to produce in the cleaning reaction such as sodium bicarbonate, sodium hydroxide are used in this reaction.This reaction preferably proceeds at about 25 ℃ to about 100 ℃ and reacts completely, and is generally 1 to about 24 hours.This is reflected at U.S. Patent number 3,598, description is arranged in 859, is incorporated herein for referencial use.After reaction is finished, comprise that by ordinary method methods such as precipitation, chromatography, filtration reclaim N-aryl/N-heteroaryl amino acid.

In reaction (1), all ingredients (halogenated acetic acids 1, uncle's aryl/hetaryl amine 2 and alcohol 3) is well known in the art, and every kind of reagent can be obtained by commerce.

In another embodiment, make R by conventional N-arylation ¹Group and alanine ester (or other suitable amino acid ester) coupling.For example, stoichiometric quantity or slight excess of ammonia base acid esters are dissolved among suitable dilution agent such as the DMSO, with halogenated aromatic compound X-R ¹Coupling, wherein X is the halo group, as fluorine, chlorine or bromine, R ¹Identical with above-mentioned definition.This is reflected under excessive alkali such as the sodium hydroxide existence and carries out, so that the acid that produces in the cleaning reaction.This reaction is generally carried out finishing in about 1 to 24 hour in 15 ℃ to about 250 ℃.After reaction is finished, can comprise recovery N-arylamino acid esters such as chromatography and filtration by ordinary method.

In a further embodiment, can prepare the formula I amino acid of esterification with the suitable 2-oxo carboxylic acid ester (as pyruvate) of the method reduction amination that following reaction (2) illustrate:

R wherein ¹And R ²Identical with above-mentioned definition.

In reaction (2), the 2-oxo carboxylic acid ester 6 and the arylamine 2 of chemical approximately calculated amount mixed processing reaction solution under the condition that obtains the amine (not shown) in inert diluent such as methyl alcohol, ethanol etc.Then under the condition of routine, with suitable reductive agent such as sodium cyanoborohydride, H ₂The amine that reduction such as/palladium charcoal forms forms N-arylamino acid esters 5.In particularly preferred embodiments, reductive agent is H ₂/ palladium charcoal can be incorporated into it in initial reaction medium, can reduce by the amine that carry out on the throne in one jar of method like this, obtains N-arylamino acid esters 5.

This reaction preferably about 20 ℃ to about 80 ℃, under 1-10atm pressure, proceed to the reaction finish, be generally 1 to about 24 hours.After reaction is finished, can comprise that methods such as chromatography, filtration reclaim N-arylamino acid esters 5 by ordinary method.

The hydrolysis of carrying out ester 5 subsequently obtains the corresponding carboxylic acid derivative.

Another embodiment of preparation N-aryl amino acid comprises with amino acid whose amine groups carries out the aryl nucleophilic substitution to fluorobenzene.

Under normal condition well known in the art, make carboxylic acid derivative 5 and formula NH then ₂CH (R ³) C (O) Y (R wherein ³Identical with Y with above-mentioned definition) coupling.This coupling can obtain formula I compound.Subsequently it is modified (as reduction) and obtain other formula I compound.

When Y is ester group, can use conventional transesterify method to have the formula I compound of different ester groups with preparation.The various technology that is used for carrying out transesterify known in the art, every kind of technology uses the different ester group derived from corresponding alcohol or sulfo-alcohol to replace described ester group, can use catalyzer such as titanium isopropylate (IV) to be beneficial to the carrying out that reacts in some cases.In a kind of technology, at first in suitable dilution agent such as toluene, refined sodium or sulfo-alcoholization sodium accordingly with sodium hydride processing alcohol or sulfo-alcohol, then it is carried out transesterify.The usefulness of this technology make its be particularly suitable for using high boiling point and/expensive alcohol.

In another transesterify technology, the ester for the treatment of transesterify is placed a large amount of excessive alcohol that carries out transesterify or sulfo-alcohol.The sodium hydride that adds catalytic amount then, this reaction obtains required transesterify product fast under normal condition.Because this scheme need be used a large amount of excessive alcohol or sulfo-alcohol, therefore this method is particularly useful when described alcohol is relatively more cheap.

Transesterify provides one to obtain the substituent several different methods of different esters on above-mentioned formula I compound.Under all these situations, the pure and mild sulfo-alcohol that is used to carry out transesterify all is well known in the art, and great majority can be obtained by commerce.

Other method of preparation ester of the present invention comprises as at first ester being hydrolyzed to free acid, then carrying out the O-alkylation with haloalkyl in the presence of alkali such as salt of wormwood.

Other method of preparation provides among the embodiment below.

Wherein X is-CR ⁴R ⁴The compound of Y ' can coupling condition by the standard in peptide coupling chemistry, known under, make as amino alcohol H ₂NCHR ³CR ⁴R ⁴OH and R ¹NHCHR ²C (O) OH coupling and preparation easily, this reaction uses coupling reagent such as the carbodiimide known also can use or not use auxiliary such as N-hydroxy-succinamide, the I-hydroxybenzotriazole of knowing etc.If desired, can use blocking group with this group of protection in coupling on the Y '.When being amino, Y ' needs suitable blocking group especially.

This reaction is generally carried out in inertia aprotonic solvent such as dimethyl formamide, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF).After reaction was finished, the blocking group on can selective removal Y ' obtained required compound.

When Y ' be-OH or-during SH, the synthetic back of carrying out these groups with the chemical process of knowing transform with obtain corresponding ester (promptly-OC (OR ⁵), disulphide (promptly-SSR ⁵) and-SSC (O) R ⁵Group.For example, ester synthesis reaction only need be with suitable acid such as acetate (R under suitable enzymatic synthesis condition ⁷=methyl), carboxylic acid halides (as acyl chlorides) or anhydride reaction.

As a R ⁴When group is hydrogen, right-CHR ⁴The OH group synthesizes rear oxidation and obtains ketone derivatives.Perhaps, by making suitable keto-amine hydrochloride and amino acid whose terminal carboxyl(group) coupling can prepare this type of ketone compound.

In these synthetic methods, raw material (as L-Ala) may contain chiral centre, and therefore when using racemic raw material, the product of generation is diastereomer or R, the mixture of S enantiomorph.Perhaps, can use the chiral isomer of raw material, and if the reaction scheme of using do not make this raw material racemization, can obtain chiral product so.This type of reaction scheme can comprise that chiral centre transforms in building-up process.

Therefore, unless otherwise indicated, otherwise product of the present invention is diastereomer (if having two or more chiral centres) or R, the mixture of S enantiomorph (if having a chiral centre).Yet when the needs chiral product, this chiral product is corresponding to the L-amino acid derivative so preferably.Perhaps, chiral product can obtain by purification technique, and described technology is from R, and enantiomer separation in the S mixture is to provide one or another kind of steric isomer.This class technology is well-known in the art.

Medicinal preparations

When as medicament, formula I compound gives with the form of medicinal compositions usually.These compounds can give by all means, comprise oral, rectum, approach in skin, subcutaneous, vein, intramuscular and nose.These compounds all are effective as injectable composition and oral compositions.The mode that this compounds is known with pharmacy field prepares, and comprises at least a active compound.

The present invention also comprises medicinal compositions, and described medicinal compositions contains one or more and the pharmaceutically acceptable carrier-bound above-mentioned formula I compound as active ingredient.In preparation composition of the present invention,, dilute or wrap up with the carrier of capsule, sachet, paper or other vessel form with a kind of vehicle usually with described active ingredient and a kind of mixed with excipients.When this vehicle was used as thinner, it can be solid, semisolid or fluent material, and it can be as solvent, carrier or the medium of this active ingredient.Therefore, described composition can be for tablet, pill, pulvis, lozenge, sachet, cachet, elixir, suspension agent, emulsion, solution, syrup, aerosol (as solid or in liquid medium), contain for example pulvis of active compound ointment, soft hard-gelatin capsules, suppository, aseptic parenteral solution and the sterile packed of as many as 10% (weight).

In formulation preparation, with may need to grind this active compound before other component is mixed, so that suitable granular size to be provided.If this active compound is insoluble basically, then be ground into usually less than 200 purpose granular sizes.If this active compound is water miscible basically, then regulate granular size by grinding usually, in preparation, to provide the distribution of basic homogeneous, for example about 40 orders.

Some example of appropriate excipients comprises lactose, glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, gum arabic, calcium phosphate, sodiun alginate, tragakanta, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, sterilized water, syrup and methylcellulose gum.Described preparation can also comprise: lubricant, such as talcum powder, Magnesium Stearate and mineral oil; Wetting agent; Emulsifying agent and suspension agent; Sanitas is such as methyl benzoate and nipasol; Sweeting agent and taste-additive.Can prepare The compounds of this invention,, provide quick-release, slowly-releasing or the extended release of this active ingredient so that after adopting methods known in the art to give this patient.

Described composition is preferably with unit dosage preparation, and each dosage contains the about 100mg of the 5-that has an appointment, more commonly is the active ingredient of the about 30mg of about 10-.Term " unit dosage " is meant that being suitable as single dose is used for human subject and other mammiferous physically separated unit.Each unit contains the active substance of the predetermined amount that calculates the required result of treatment of generation and suitable pharmaceutical excipient.Preferably, use with following formula I compound with about 20% (weight) that is not higher than medicinal compositions, more preferably no higher than about 15% (weight), surplus is a medicinal inert carrier.

This active compound effectively, gives with medicinal significant quantity in very wide dosage range usually.Yet, should be appreciated that the actual administered dose of this compound will be by the doctor according to comprising that following correlative factor determines: age, body weight and the reaction of disease to be treated, the route of administration of selection, actual administered compound, individual patient, the seriousness of this patient's symptom etc.

When the solids composition of preparation such as tablet, main active ingredient is mixed with pharmaceutical excipient, form the solid preformulation composition of the homogeneous mixture that contains The compounds of this invention.When claiming that these preformulation composition are homogeneous, mean that this active ingredient is dispersed in the said composition, make said composition easily be divided into equal effective unit formulation in the Asia, such as tablet, pill and capsule.The inferior then unit dosage that is divided into the above-mentioned type of this solid preformulation thing contains for example 0.1 to about 500mg active ingredient of the present invention.

Can tablet of the present invention or coating of pill perhaps be mixed, so that the formulation that obtains prolongation effect advantage to be provided.For example, this tablet or pill can comprise an internal dose and outside dosage component, and the latter is the capsule form on the former.These two components can be separated by the enteric layers as anti-disintegration under one's belt, and make internal composition complete by entering duodenum, or delay to discharge.Can use multiple material to be used for this class enteric layers or dressing, this class material comprises the mixture of multiple polymeric acid and polymeric acid, such as shellac, hexadecanol and rhodia.

The liquid form that is used for oral or drug administration by injection in the novel composition of the present invention be can add, the aqueous solution, suitable flavoring syrup, water-based or oily suspensions and the emulsion of using the edible oil flavoring such as Semen Maydis oil, Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil and elixir and similar pharmaceutical carrier comprised.

The composition that is used for sucking or be blown into is included in solution and the suspension and the pulvis of pharmaceutically acceptable water-based or inorganic solvent or its mixture.The liquid or solid composition can contain suitable pharmaceutically acceptable vehicle mentioned above.Preferably give described composition, to be used for part or systemic effect by oral or nasal respiration approach.Composition in the solvent of preferred pharmaceutical compositions can utilize rare gas element to atomize.Atomized soln can directly suck from atomisation unit, maybe this atomisation unit can be connected to face shield (face masks tent) or intermittent type positive pressure respirator.Preferably give solution, suspension or powder composite from device per os or the intranasal that discharges said preparation in a suitable manner.

Following example of formulations illustrates medicinal compositions of the present invention.

Example of formulations 1 preparation contains the hard gelatin capsule of following component: group component

(mg/ capsule) active ingredient 30.0 starch 305.0 Magnesium Stearates 5.0 mix above component, and are filled in the hard gelatin capsule with the amount of 340mg.

Example of formulations 2 adopts following component to prepare tablet: group component

(mg/ sheet) active ingredient 25.0 Microcrystalline Celluloses 200.0 colloid silicas 10.0 stearic acid 5.0 mix above component, and compacting forms tablet, every heavy 240mg.

Example of formulations 3 preparations contain the dry powder inhaler formulations of following component: composition weight % active ingredient 5 lactose 95

This active ingredient is mixed with lactose, and mixture is added in the dry powder suction unit.

Example of formulations 4

Be prepared as follows tablet, every contains the 30mg active ingredient:

Group component

(mg/ sheet)

Active ingredient 30.0mg

Starch 45.0mg

Microcrystalline Cellulose 35.0mg

Polyvinylpyrrolidone 4.0mg

(as 10% in the sterilized water

Solution)

Sodium starch glycolate 4.5mg

Magnesium Stearate 0.5mg

Talcum powder 1.0mg

Amount to 120mg

Make active ingredient, starch and Mierocrystalline cellulose by the 20th order U.S. sieve and thorough mixing.Polyvinylpyrrolidonesolution solution is mixed with the generation pulvis, then it is passed through the 16th order U.S. sieve.So the particle that produces is in 50 ℃ of-60 ℃ of dryings, and by the 16th order U.S. sieve.Then, sodium starch glycolate, Magnesium Stearate and the talcum powder by the 30th order U.S. sieve in advance added in the particle, mix the back, produce the tablet of every heavy 120 mg in the tabletting machine compacting.

Example of formulations 5

Be prepared as follows every capsule that contains 40 mg medicines:

Group component

(mg/ capsule)

Active ingredient 40.0mg

Starch 109.0mg

Magnesium Stearate 1.0mg

Amount to 150.0mg

Active ingredient, starch and Magnesium Stearate are mixed,, and be filled in the hard gelatin capsule with the amount of 150mg by the 20th order U.S. sieve.

Example of formulations 6

Be prepared as follows the suppository that each contains the 25mg active ingredient:

Group component

Active ingredient 25mg

Saturated fatty acid glyceride to 2,000mg

Make active ingredient pass through the 60th order U.S. sieve, be suspended in the saturated fatty acid glyceride of using minimum required heat melts in advance.Then mixture is injected the suppository mold of 2.0g labelled amount, allow its cooling.

Example of formulations 7

Be prepared as follows the suspension agent that every 5.0ml contains the 50mg medicine:

Group component

Active ingredient 50.0mg

Xanthan gum 4.0mg

Xylo-Mucine (11%)

Microcrystalline Cellulose (89%) 50.0mg

Sucrose 1.75g

Sodium Benzoate 10.0mg

Correctives and tinting material are an amount of

Pure water is to 5.0ml

Active ingredient, sucrose and xanthan gum are mixed,, mix with Microcrystalline Cellulose and carboxymethylcellulose sodium solution in the previously prepared water then by the 10th order U.S. sieve.Sodium Benzoate, correctives and tinting material add while stirring with some water dilutions.Add enough water then, produce volume required.

Example of formulations 8 group components (mg/ capsule) active ingredient 15.0mg starch 407.0mg Magnesium Stearate 3.0mg amounts to 425.0mg

Active ingredient, starch and Magnesium Stearate are mixed,, and be filled in the hard gelatin capsule with the amount of 425.0mg by the 20th order U.S. sieve.

Example of formulations 9

Be prepared as follows the subcutaneous preparation of using:

Group component

Active ingredient 5.0mg

Semen Maydis oil 1ml

Example of formulations 10

Be prepared as follows topical preparation:

Group component

Active ingredient 1-10g

Emulsifying wax 30g

Whiteruss 20g

Paraffinum molle alba is to 100g

Paraffinum molle alba is heated until fusing.Add whiteruss and emulsifying wax and stirring until dissolving.Add active ingredient and continue and stir, until dispersion.Cooling mixture is until becoming solid then.

Another the preferred preparation that is used for the inventive method adopts through skin transfer device (" patch ").Can provide The compounds of this invention with the continuous or discontinuous infusion of manipulated variable with this class transdermal patch.The structure and the use of transmitting the transdermal patch of medicine are well-known in the art.Referring to the United States Patent (USP) of for example issuing on June 11st, 1,991 5,023,252, this patent is attached to herein by reference.Can make up that this class patch is used for continuously, pulse or discharge medicine on request.

Usually need or must directly or indirectly this medicinal compositions be introduced brain.Direct technology is usually directed to the useful for drug delivery intubate is placed host's ventricles of the brain, to walk around hemato encephalic barrier.At United States Patent (USP) 5,011, described being used for biological factor is transported to a this implantable transfer system of individual particular anatomical region in 472, this patent is attached to herein by reference.

The Indirection techniques of general preferred use relates to the described composition of preparation, promptly by hydrophilic medicament is converted into fat-soluble medicine, so that drug latenciation to be provided.Generally by protecting hydroxyl, carbonyl, sulfuric ester and the primary amine group that exists on this medicine, giving this medicine stronger fat-soluble, and easier in the hemato encephalic barrier transhipment, and reach latentiation.Perhaps, can instantaneously open the hypertonic solution of hemato encephalic barrier, to strengthen the release of hydrophilic drugs by endoarterial infusion.

Can be at Remington ' s pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, PA finds in the 17th edition (1985) that other is applicable to preparation of the present invention.Purposes

Compound of the present invention and medicinal compositions can be used to suppress the release of beta-amyloid polypeptide 1-and/or it is synthetic, and therefore comprises in the human Mammals Alzheimer having practicality in treatment.

As mentioned above, compound as herein described is applicable to all said medicine transfer systems.In addition, to give compound the intravital transformation period in order increasing, described compound can be made as capsule, to introduce in the lipid body cavity, to be prepared as colloid, maybe can adopt other routine techniques to prolong the plasma half-life of described compound.Can utilize various methodologies, the preparation liposome as the United States Patent (USP) 4,235,871,4,501,728 and 4,837 at for example Szoka etc., is described in 028, and these patents all are attached to herein by reference.

The amount that gives patient's compound changes with following factor: treat administered compound, such as administration purpose, the patient's of prevention or treatment state, administering mode etc.In treatment is used, give to suffer from the patient of AD with composition, administered dose is enough to suppress to small part the further outbreak of this disease and complication symptom thereof.The amount that is suitable for finishing this purpose is defined as " treatment effective dose ".To depend on the judgement of attending doctor according to some factors for the effective amount of this purposes, described factor comprises such as the degree of this patient AD or seriousness, this patient's age, body weight and general situation etc.When as therapeutical agent, best dosage range with the about 500mg/kg/ of about 0.1-days gives compound described herein.

In prophylactic application, compound there is the patient who develops into AD (for example being determined by genetic screening or family's characteristic) risk, its administered dose is enough to suppress the outbreak of this disease symptoms.The amount that is suitable for finishing this purpose is defined as " prevention effective dose ".Significant quantity for this purposes will depend on the judgement of attending doctor according to some factors, described factor such as this patient age, body weight and general situation etc.When using as prophylactic agent, best dosage range with the about 500mg/kg/ of about 0.1-days gives compound described herein.

As mentioned above, the compound that gives the patient is above-mentioned medicinal compositions form.These compositions can be sterilized by conventional sterilising technology, or can filtration sterilization.When using the aqueous solution, can pack use, also can freeze-drying use, freeze-dried preparation mixes with the sterile aqueous solvent before administration.The pH of described compound formulation is generally 3-11, and more preferably 5-9 most preferably is 7-8.Should be appreciated that, use some above-mentioned vehicle, carrier or stablizer will cause forming pharmaceutical salts.

Provide following synthetic embodiment and biology embodiment with explanation the present invention, these embodiment should not be construed as by any way and limit the scope of the invention.Unless in addition statement, otherwise all temperature are degree centigrade.

Embodiment

In following examples, below abbreviation has following implication.If a not definition of abbreviation, then it has generally accepted implication.

BOC=tert-butoxycarbonyl

Bd=wide bimodal

Bs=wide unimodal

Cbz=carbonyl benzyloxy

Cc=cubic centimetre

CDI=1,1 '-carbonyl dimidazoles

D=bimodal

Dd=double doublet

DMF=dimethyl formamide

DMSO=dimethyl sulfoxide (DMSO)

EDC=1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride

EDTA=ethylenediamine tetraacetic acid (EDTA)

Eq.=equivalent

Ether=ether

G=gram

L=liter

M=multimodal

M=volumetric molar concentration

Max=maximum

Mg=milligram

Min=minute

ML=milliliter

MM=millimolar concentration

Mmol=mmole

N=normal

Ng=nanogram

Nm=nanometer

OD=optical density(OD)

Pg=pik

PM=picomole concentration

Psi=pound/square inch

Q=four peaks

Quint=quintet

Rpm=rev/min

Rt=room temperature

S=unimodal

Sept=seven peaks

T=three peaks

THF=tetrahydrofuran (THF)

Tlc=thin-layer chromatography

μ g=microgram

μ L=microlitre

UV=ultraviolet

W/v=weight: volume

In addition, term " Aldrich " is meant the compound that is used for following method or reagent available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; Term " Bachem " is meant this compound or reagent available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance atGulph Mills, King of Prussia, PA 19406 USA; Term " Fluka " is meant described compound or reagent available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA; Term " Lancaster " is meant this compound or reagent available from Lancaster Synmesis Inc., P.O.Box 100 Windham, NH 03087USA; Term " Sigma " is meant this compound or reagent available from Sigma, P.O.Box14508, St Louis MO 63178 USA; Term " Sennchem " is meant this compound or reagent available from Senn Chemicals AG, and P.O.Box 267, CH-9157 Dielsdorf, Switzerland.

In above embodiment, all temperature are degree centigrade (unless a statement in addition), prepare specified mixture by following universal method.

Universal method A

Reduction amination

In the ethanolic soln of the arylamine in the hydrogenation flask, add 1 normal 2-oxo carboxylic acid ester (as pyruvate), then add 10% palladium charcoal (arylamine weight 25%).Under the 20psi hydrogen pressure, this reactant is hydrogenated to the tlc detection reaction finishes (30 minutes to 16 hours) on the Parr electromagnetic shaker.Then with this reaction mixture by diatomite 545 (available from AldrichChemical Company, Inc.) pad filters, and on Rotary Evaporators evaporating solvent.The crude product product is further purified by chromatography.

Universal method B

The H-heteroarylization of L-Ala

Under room temperature,, add 1 normal 2-chlorinated benzotriazole then with the DMSO solution stirring of 1.1 normal L-L-Ala and 2 normal sodium hydroxide 1 hour.With this mixture heating up to 100 ℃ 4 hours, be cooled to room temperature then and incline to ice.The pH of the aqueous solution that produces is transferred to about 2, filter and take out precipitated solid.This solid is dissolved in the 1N sodium hydroxide, filters by diatomite 545 pads.The pH of filtrate is transferred to about 2, filter and take out white precipitate, wash with water and obtain product.

Universal method C

Ester is hydrolyzed to free acid

Carry out the reaction that ester is hydrolyzed to free acid by ordinary method.Be the embodiment that two routines are taken off esterification process below.

In the mixed solution of 1: 1 methanol of carbonate (the N-arylamino acid esters for preparing by reduction amination), add the normal salt of wormwood of 2-5 as universal method A.Showed to tlc that reaction finished with this mixture heating up to 50 ℃ 0.5-1.5 hour.This reactant is cooled to room temperature, on Rotary Evaporators, removes methyl alcohol.The pH of remainder water solution is transferred to about 2, add ethyl acetate with extraction product.Then with saturated sodium-chlor washing organic phase, through dried over mgso.The solvent of removing this solution on Rotary Evaporators obtains product.

Above-mentioned amino acid ester is dissolved in dioxane/water (4: 1), and to wherein adding lithium hydroxide soluble in water (about 2 equivalents), making adding back total solvent is about 2: 1 dioxane: water.Stir this reaction mixture to reaction and finish, dioxane is removed in decompression.Dilute residue with ethyl acetate, separate each layer, with water layer alkalize to pH be 2.Return aqueous layer extracted with ethyl acetate,, filter the back decompression and remove solvent through the organism that dried over sodium sulfate merges.Residue is through conventional method purifying (as recrystallization).

The following describes a back embodiment.The methyl esters 9.27g (0.0348mol) of 3-nitrophenyl ethanoyl L-Ala is dissolved in 60ml dioxane and the 15ml water, add the lithium hydroxide be dissolved in the 15ml water (3.06g, 0.0731mol).Stir after 4 hours, dioxane is removed in decompression, dilutes residue with ethyl acetate, separates each layer, the acidifying water layer to pH be 2.(4 * 100ml) return aqueous layer extracted, through the organism that dried over sodium sulfate merges, filter the back decompression and remove solvent with ethyl acetate.Make residue recrystallization from ethyl acetate/octane-iso, obtain 7.5g (85%).C ₁₁H ₁₂N ₂O ₅Calculated value C=52.38, H=4.80, N=11.11.Analyze measured value, C=52.54, H=4.85, N=11.08.[α] ₂₃=-29.9,589nm。

Universal method D

First kind of EDC couling process

In 0 ℃, in 1: 1 mixed solution of the methylene dichloride of required acid and amino ester/acid amides, add 1.5 normal triethylamines, then add 2.0 normal hydroxybenzotriazole monohydrates, add 1.25 normal ethyl-3-(3-dimethylamino)-propyl group carbodiimide hydrochloride (EDC) then.Under room temperature this reactant stirring is spent the night, be transferred to then in the separating funnel, water, saturated sodium bicarbonate aqueous solution, 1N hydrochloric acid and saturated sodium chloride aqueous solution wash, then through dried over mgso.The solvent of this solution of evaporative removal obtains the crude product product on Rotary Evaporators.

Universal method E

Second kind of EDC couling process

Described carboxylic acid derivative is dissolved in the methylene dichloride.Order adds amino acid ester/acid amides (1eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2eq.).Placing cooling bath in the round-bottomed flask bottom makes this solution to about 0 ℃.At this moment, 1-(3-the dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) that adds 1.2eq..This solution stirring is spent the night, at N ₂Be issued to room temperature.By using saturated Na ₂CO ₃The aqueous solution, 0.1M citric acid and salt water washing organic phase are come reaction mixture, then through Na ₂SO ₄Dry.Remove to desolvate then and obtain the crude product product.Obtain purified product by the flash chromatography in suitable solvent.

Universal method F

The removal method of the BOC and the tert-butyl ester

BOC or tert-butyl ester compound are added in 1: 1 the mixed solution of methylene dichloride and trifluoroacetic acid, and be stirred to tlc and show transform and to finish, be generally 2 hours.Then this solution evaporation is extremely done, residue is dissolved in the ethyl acetate.If the compound of BOC protection then washs this solution with dilute hydrochloric acid.The pH of water is transferred to alkalescence, use ethyl acetate extraction then.If tert-butyl ester compound then washs this solution with saturated sodium bicarbonate aqueous solution.PH with water transfers to 2 then, uses ethyl acetate extraction then.No matter under which kind of situation, all wash organic phase then, through dried over mgso with saturated sodium chloride aqueous solution.The solvent of removing this solution on Rotary Evaporators obtains product.

Universal method G

The N-alkylation

In the dichloromethane solution of 3-quinolylamine, add 1.1 normal triethylamines, then add the dichloromethane solution of p-nitrophenyl SULPHURYL CHLORIDE (nosyl).Under room temperature, this reactant was stirred 5 hours, by the quinolylamine of filtering separation disulfonylization, wash then with ethyl acetate.Then this material is added in 1: 1 the mixed solution of dioxane and 1N sodium hydroxide, this solution is heated to 60 ℃, this moment, all solids all dissolved.This reactant is cooled to room temperature, pH is transferred to about 4 then.Quinolylamine by the sedimentary sulfonylation of filtering separation washes with water.Then the THF solution of this compound is added in-78 ℃ the THF suspension of sodium hydride, add the 2-ethyl bromide then.This reactant is warmed to room temperature, refluxed then 4 days.Remove the solvent in this solution on Rotary Evaporators, chromatography obtains the quinolylamine of alkylation sulfonylation.Then this product is dissolved among the DMF, adds 3 normal salt of wormwood, add 1.2 normal thiophenols subsequently.Under room temperature, this reactant stirring is spent the night.Water and this reactant of ether quenching wash organic phase with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, then through dried over mgso then.The solvent of this solution of evaporative removal obtains the crude product product on Rotary Evaporators, by chromatography it is further purified.

Universal method H

Ester/acid amides exchange

To 1 of 3 normal required amine, add 5.2 normal trimethyl aluminiums in the solution of 2-ethylene dichloride, wherein said adding is carried out under solution surface by syringe.After stirring 30 minutes under the room temperature, adding is dissolved in 1, the required ester solution of 2-ethylene dichloride.This reactant to the tlc demonstration conversion that refluxes is finished, and is generally 3 hours.Then this reactant is cooled to 0 ℃, with 10% hydrochloric acid (annotating :) quenching because meeting produces foam in adition process, so this acid should slowly add.For the product that is insoluble to aqueous acids, then described mixture is transferred in the separating funnel, separate each layer.Wash water with ethyl acetate, with saturated sodium chloride aqueous solution washing organic phase, through dried over mgso, concentrating under reduced pressure obtains the crude product product.

For the product that can be dissolved in aqueous acid, then after the reactant quenching, under reduced pressure the volume of reactant is decreased to and is about 1/3 of original volume.In the solution that produces, add 20% Seignette salt (RochelleShi salt) aqueous solution and ethyl acetate.The pH of this solution is transferred to about 13, in the water-soluble solution of aluminium salt.Separate organic phase, use the ethyl acetate extraction water.With the organic solution that saturated sodium chloride aqueous solution washing merges, through dried over mgso, concentrating under reduced pressure obtains the crude product product.

Universal method I

Ester is reduced to alcohol

The THF solution that in the anhydrous THF solution of 0 ℃ starting ester, adds 1.0 normal lithium borohydrides.Under room temperature, water quenching is then spent the night in this reactant stirring.On Rotary Evaporators, remove THF, add ethyl acetate.Separate each phase.With saturated sodium chloride aqueous solution washing organic phase, through dried over mgso, concentrating under reduced pressure obtains product.

Universal method J

The displacement of triflate

In the dichloromethane solution of R-(+)-isobutyl lactate of 0 ℃, add 1.1 normal trifluoromethanesulfanhydride anhydrides.After stirring 20 minutes under the room temperature, add 1.1 equivalents 2, the 6-lutidine continues to stir 10 minutes.Then in 0 ℃ of flask that is transferred to the methylene dichloride that contains 1 equivalent arylamine and 1 equivalent diisopropylethylamine or Nitromethane 99Min. in this solution.This reactant is remained in ambient temperature overnight, get on to desolventize at Rotary Evaporators then.Residue is dissolved in the ethyl acetate, washs successively with 5% citric acid and saturated sodium chloride aqueous solution, the solvent of removing this solution on Rotary Evaporators obtains the crude product product, through chromatography it is further purified then.

Universal method K

Form methyl esters by amino acid

Amino acid (amino acid or amino acid salts hydrochlorate) is suspended in the methyl alcohol, and is chilled to 0 ℃.In this solution, fed HCl gas 5 minutes.Make the reactant temperature to room temperature, stirred then 4 hours.Removal of solvent under reduced pressure obtains required amino acid methyl ester hydrochloride subsequently.Usually need not be further purified and use this product.

Embodiment A

N-(3, the 4-dichlorophenyl)-D, L-L-Ala synthetic

According to U.S. Patent number 3,598, the described method of 859 (being incorporated herein it all discloses for referencial use), preparation N-(3, the 4-dichlorophenyl)-D, L-L-Ala.Specifically, to 3, the 4-dichlorphenamide bulk powder (1 equivalent, add in Virahol Aldrich) (every mole 3, the about 500ml of the 4-dichlorphenamide bulk powder) solution entry (the about 0.06ml of every ml Virahol) and 2-chloropropionic acid (2 equivalents, Aldrich).This mixture is warmed to 40 ℃, and gradation adds sodium bicarbonate (0.25 equivalent) continuously then, refluxes subsequently 4-5 days.After the cooling, this mixture is inclined to water, filter to remove unreacted 3, the 4-dichlorphenamide bulk powder.With concentrated hydrochloric acid filtrate being acidified to pH is 3-4, filters the precipitation that produces, and washing and drying obtain target compound, m.p.=148-149 ℃.

Perhaps, according to above-mentioned universal method, with 3,4-dichlorphenamide bulk powder (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich) are prepared as N-(3, the 4-the dichlorophenyl)-D of oily matter, L-alanine ethyl ester.Monitor this reaction with silica gel (Rf=0.4, with 25% ethyl acetate/hexane launch), through preparation property plate layer chromatography purifying (silica gel, with 25% ethyl acetate/hexane as developping agent).

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.2(d,1?H)；6.7(d,1H)；6.4(dd,1H)；4.30(bs,1H)；4.2(q,2H)；4.1(q,1H)；1.5(d,3H)；1.3(t,3H)。

¹³C-nmr(CDCl ₃):δ=175；146.7；133；131；121；114.9；112.6；72.0；52.4；28.3；19.5。

C ₁₁H ₁₃Cl ₂NO ₂(MW=262.14; Mass spectrograph (MH ⁺) 263.

By obtaining target compound as this ester of universal method C hydrolysis.

Embodiment B

N-(3, the 5-dichlorophenyl)-D, L-L-Ala synthetic

According to U.S. Patent number 3,598, the method for 859 (or the foregoing description A), with 3,5-dichlorphenamide bulk powder (Aldrich) and 2-chloropropionic acid (Aldrich) preparation N-(3, the 5-dichlorophenyl)-D, L-L-Ala.

Embodiment C

N-(3, the 5-difluorophenyl)-D, L-L-Ala synthetic

According to U.S. Patent number 3,598, the method for 859 (or the foregoing description A), with 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich) preparation N-(3, the 5-difluorophenyl)-D, L-L-Ala.

Embodiment D

L-Xie Ansuan N, N-dimethylformamide synthetic

In the 20ml DMF stirred solution of the Cbz-L-Xie Ansuan (Bachem) of 2.51g (10mmol), add 1.46g (9mmol) CDI, this mixture was stirred 50 minutes.The 5ml THF solution that adds 6ml (12mmol) dimethyl amine (Aldrich) in this mixture stirs this reaction mixture 18 hours.Mixture is dissolved in the 100ml ethyl acetate, with 10% hydrochloric acid (3 * 40ml), (2 * 50ml) washings are through dried over mgso for 10ml salt solution and 20% salt of wormwood.Filter this mixture and concentrated, obtain Cbz-L-Xie Ansuan N, the N-dimethylformamide, under standard conditions, usefulness 10%Pd/C with its hydrogenation, is the target compound of oily matter to remove the Cbz group and to obtain as catalyzer.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=3.47(d,J=5.4Hz,1H),3.03(s,3H),2.96(s,3H),1.83(m,1H),1.60(s,2H),0.95(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H)。

¹³C-nmr(CDCl ₃):δ=175.1,56.2,37.0,35.7,32.0,19.9,16.8。

Embodiment E

Synthesizing of L-Xie Ansuan N-methyl nitrosourea

According to the described method of the foregoing description D, but replace dimethyl amine to prepare target compound with methylamine.This target compound is an oily matter.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.27(bs,1H),3.20(d,J=3.8Hz,1H),2.79(d,J=5.0Hz,3H),2.27(m,1H),1.40(bs,2H),0.96(d,J=7.1Hz,3H),0.79(d,J=6.8Hz,3H)。

¹³C-nmr(CDCl ₃):δ=175.0,60.1,30.7,25.6,19.7,15.9。

Embodiment F

Synthesizing of BOC-norleucyl-amine

In 0 ℃, in the stirring the mixture of 3.47g (15mmol) BOC-nor-leucine (Bachem), 3.44g (22.5mmol) I-hydroxybenzotriazole monohydrate and 50ml methylene dichloride, add 3.45g (1.2mmol) EDC.In 0 ℃ the mixture that produces was stirred 1 hour, in this mixture, fed ammonia 10 minutes then.Make cooling bath be warmed to room temperature, this mixture was stirred 18 hours.Mixture is evaporated to dried, grinds with 20% yellow soda ash.Filter and collect the solid that produces, wash with water and obtain 2.69g (11.7mmol, 78%) target compound.

Embodiment G

N-[3,5-two (trifluoromethyl) phenyl]-L-L-Ala synthetic

Steps A:, adopt 3,5-two (trifluoromethyl) aniline (Aldrich) and R-(+)-isobutyl lactate (Aldrich), N-[3,5-two (trifluoromethyl) phenyl according to above universal method J]-L-L-Ala isobutyl ester prepares target compound, is oily matter.Go up monitoring reaction by tlc at silica gel (Rf=0.38,10% ethyl acetate/hexane is launched).Through preparation property plate thin-layer chromatography purifying, with 10% ethyl acetate/hexane as developping agent.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.13 (s, 1H), 6.91 (s, 2H), 4.97 (d, J=8.24Hz, 1H), 4.18 (m, 1H), 3.93 (d, J=6.59Hz, 2H), 1.93 (seven peaks, J=6.71Hz, 1H), 1.49 (d, J=7.02Hz, 3H), 0.89 (d, J=6.59Hz, 6H).

¹³C-nmr(CDCl ₃):δ=174.4,147.9,133.6,133.2,132.7,132.3,129.4,125.8,122.2,1?1?8.6,112.81,112.76,111.42,111.37,111.32,111.27,111.22,72.2,52.0,32.1,28.24,28.17,23.2,19.5,19.3,19.2,18.9,14.6。

C ₁₅H ₁₇F ₆NO ₂(MW=357.30); Mass spectrum MH ⁺358.

Step B: then according to universal method C, usefulness lithium hydroxide hydrolyzing N in THF-[3,5-two (trifluoromethyl) phenyl-L-L-Ala isobutyl ester.

Embodiment H

N-(3, the 5-Dimethoxyphenyl)-D, L-L-Ala synthetic

According to U.S. Patent number 3,598, the method for 859 (or the foregoing description A), with 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich) preparation target compound.

Example I

Synthesizing of N-(3, the 4-dichlorophenyl) glycine

According to U.S. Patent number 3,598,859 method, with 3,4-dichlorphenamide bulk powder (Aldrich) and 2-Mono Chloro Acetic Acid (Aldrich) preparation N-(3, the 4-dichlorophenyl) glycine.

Embodiment J

N-(3, the 5-dichlorophenyl)-D, L-phenylglycocoll synthetic

With 3, (leq, Aldrich) (leq's 5-dichlorphenamide bulk powder Aldrich) refluxed 3 days with N-methylmorpholine (Aldrich) in ethanol with alpha-brominated phenylacetic acid methyl esters.After standard is handled, make residue recrystallization from ethyl acetate/hexane/ether/water, obtain N-(3, the 5-dichlorophenyl)-D, the L-phenyl glycine methyl ester.In methyl alcohol, obtain target compound then with 1M sodium hydroxide/this methyl esters of water hydrolysis.

Embodiment 1

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl-L-valine methyl ester synthetic

According to above universal method D (without 1N salt acid elution), adopt L-valine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl) L-Ala (deriving from the foregoing description A), the preparation target compound.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.20(m,1H),6.92-7.03(m,1H),6.69(m,1H),6.44(m,1H),4.50(m,1H),4.19(m,1H),3.78(m,1H),3.71(s,1.5H),3.65(s,1.5H),2.12(m,1H),1.50(d,J=7.0Hz,3H),0.80-0.92(m,4.5H),0.71(d,J=6.8Hz,1.5H)。

¹³C-nmr(CDCl ₃):δ=173.4,173.0,172.2,171.8,146.0,145.8,132.9,132.8,130.7,130.6,121.7,115.1,114.8,113.5,113.1,56.9,56.6,55.1,54.8,52.2,31.1,31.0,30.9,19.6,19.4,17.7,17.4。

Embodiment 2

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Xie Ansuan N-isobutyramide synthetic

According to above universal method H, adopt N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-valine methyl ester (deriving from the foregoing description 1) and isobutylamine (Aldrich), be prepared as the target compound of oily matter.Monitor this reaction (Rf=0.3,10% ethanol/methylene is as developping agent) through tlc.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.2(d,1H),7.0(m,1H),6.7(m,1H),6.4(m,1H),4.6(m,1H),4.1(m,1H),3.8(m,3H),3.6(s,3H),1.9(m,2H),1.4(d,3H),1.1(m,6H),0.9(m,6H)。

¹³C-nmr(CDCl ₃):δ=173.8,173.4,172.9,146.6,133.6,133.4,131.3,122.5,122.4,115.8,113.8,56.9,55.7,38.2,25.6,20,16,12.1。

C ₁₈H ₂₇N ₃O ₂Cl ₂(MW=388.3), mass spectrum (MH ⁺) 389.

Embodiment 3

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Threonine methyl esters synthetic

According to above universal method D (without 1N salt acid elution), adopt N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and L-threonine methyl ester hydrochloric salt (Sigma) are prepared as the target compound of oily matter.Through silica gel column chromatography purification reaction product, with 50% ethyl acetate/hexane wash-out.

The NMR data are as follows:

¹H-nmr (CDCl ₃): (d is J=6.4) with 1.17 (d, J=6.3 in δ=1.06; The 3H of 2: 1 ratios is total), 1.53 (d, J=7,3H), 2.31 (d, J=5.6) and 2.58 (d, J=4.7; 1H, 2: 1 ratio), 3.68 (s) and 3.75 (s) (3H is total, 1: 2 ratio), and 3.8-3.9 (m, 1H), 4.15-4.25 (m, 1H), and 4.3-4.25 (m, 1H), 4.3-4.45 (m, 1H), 4.5-4.6 (m, 1H), 6.4-6.5 (m, 1H), 6.65-6.7 (m, 1H), 7.4-7.55 (m, 2H).

¹³C-nmr(CDCl ₃):δ=19.96,20.23,20.39,20.49,53.23,53.28,55.35,55.59,57.5,68.13,68.21,113.72,114.20,115.42,115.60,122.26,122.35,1?31.22,131.33,133.41,133.55,146.47,146.6,171.63,171.80,174.69,174.86。

C ₁₄H ₁₈N ₂OXCl ₂(MW=349.22); Mass spectrum (MH ⁺) 349.

Embodiment 4

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl-L-Xie Ansuan ethyl ester synthetic

According to universal method D (without 1N salt acid elution), with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and L-Xie Ansuan carbethoxy hydrochloride are prepared as the target compound of oily matter.Through silica gel column chromatography purification reaction product, with 35% ethyl acetate/hexane wash-out.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=0.7-1.0 (the overlapping group of d, J=7,6H), 1.19 and 1.27 (paired t, J=7,3H), 1.5 (d, J=7,3H), 2.05-2.2 (m, 1H), 3.7-3.9 (m, 1H), 4.0-4.3 (m, 3H), 4.5-4.6 (m, 1H), 6.4-6.5 (m, 1H), 6.5-6.6 (m, 1H), 6.9-7.1 (M, 1H), 7.2-7.3 (M, 1H).

¹³C-nmr(CDCl ₃):δ=14.65,14.77,17.96,18.25,19.56,20.06,20.31,31.77,31.81,55.50,55.73,57.22,57.46,61.88,61.94,113.76,114.01,115.48,115.76,122.40,122.46,131.30,131.33,133.48,133.61,146.41,146.60,171.86,172.36,173.54,173.84。

C ₁₆H ₂₂N ₂O ₃Cl ₂(MW=361.27); Mass spectrum (MH ⁺) 361.

Embodiment 5

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl-L-Xie Ansuan tert-butyl ester synthetic

According to universal method D (without 1N salt acid elution), with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and L-Xie Ansuan tert-butyl ester hydrochloride (Sigma) are prepared as the target compound of oily matter.Through silica gel column chromatography purification reaction product, with 25% ethyl acetate/hexane wash-out.

The NMR data are as follows:

¹H-nmr (CDCl ₃): (6H), 1.36 (s) and 1.45 (s) are (9H) for the overlapping group of d, J=7 for δ=0.7-1.0,1.5-1.54 (2 d, J=7,3H), 2.0-2.2 (m, 1H), and 3.7-3.85 (m, 1H), 4.1-4.2 (m, 1H), and 4.3-4.5 (m, 1H), 6.4-6.5 (m, 1H), 6.7 (s, 1H), 6.9-7.1 (m, 1H), and 7.15-7.3 (m, 1H).

¹³C-nmr(CDCl ₃):δ=17.84,18.25,19.50,20.06,20.29,28.42,28.62,31.96,32.16,55.45,55.65,57.53,57.92,82.72,113.75,114.00,115.43,115.63,122.26,122.32,131.29,131.50,146.46,146.65,170.88,171.48,173.39,173.65。

C ₁₈H ₂₆N ₂O ₃Cl ₂(MW=389.33); Mass spectrum (MH ⁺) 389.

Embodiment 6

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl-L-valine amide synthetic

According to universal method D (without 1N salt acid elution), with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and L-valine amide hydrochloride (Sigma) are prepared as the solid target compound, and fusing point is 156-158 ℃.Through silica gel column chromatography purification reaction product, with 90: 10: 1 methylene dichloride: methyl alcohol: ammonium hydroxide wash-out.

The NMR data are as follows:

¹H-nmr (DMSO-d ₆): δ=0.6-0.9 (m, 6H), 1.2-1.4 (eclipsed d, 3H), 1.8-2.0 (m, 1H), 3.9-4.2 (m, 2H), 6.3-6.4 (m, 1H), 6.35-6.4 (m, 1H), 6.7-6.8 (m, 1H), 7.0-7.1 5 (m, 1H), 7.2-7.3 (m, 1H), 7.4 (bs, 1H), 7.8 (d is J=10) with 8.0 (d, J=10) (ratio of total 1H is 3: 2).

¹³C-nmr(DMSO-d ₆):δ=17.8,18.2,19.00,19.25,19.6,19.7,31.36,31.20,51.9,52.7,57.11,57.4,113.46,113.58,113.67,113.85,117.20,117.45,130.64,130.76,131.53,131.56,148.25,148.45,173.06,173.11,173.38,173.51。

C ₁₄H ₁₉N ₃O ₂Cl ₂(MW=331); Mass spectrum (MH ⁺) 332.

Embodiment 7

Synthesizing of N-(3, the 4-dichlorophenyl)-L-L-Ala N-(1-hydroxy-3-methyl-2-butyl) acid amides

According to universal method D (without 1N salt acid elution), with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and valerian ammonia alcohol (Sigma) are prepared as the target compound of oily matter.Through silica gel column chromatography purification reaction product, with 45: 55 ethyl acetate/hexane and 90: 10: 1 methylene dichloride: methyl alcohol: ammonium hydroxide wash-out.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆):δ=0.86(d,J=7,3H),0.91(d,J=7,3H),1.50(d,J=7,3H),1,8-2.0(m,1H),2.6(bs,1H),3.5-3.8(m,4H),4.1(bs,1H),6.45(dd,J=2.8,8.7,1H),6.7(d,J=2.8,1H),6.8(bd,1H),7.2(d,J=5,1H)。

¹³C-nmr(DMSO-d ₆):δ=19.3,20.1,20.2,29.5,55.8,57.4,64.1,113.7,115.7,122.4,131.4,133.5,146.6,174.6。

C ₁₄H ₂₀N ₂O ₂Cl ₂(MW=319.23); Mass spectrum (MH ⁺) 319.

Embodiment 8N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Xie Ansuan N, the closing of N-dimethylformamide

Become

According to universal method D, use Xie Ansuan N, N-dimethylformamide (deriving from the foregoing description D) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=145-160 ℃).

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.38 (m, 1H), 7.14 (m, 1H), 6.66 (m, 1H), 6.41 (m, 1H), 4.78 (m, 1H), 3.88 (m, 1H), 3.10 and 3.09 (s, s, 3H), 2.94 and 2.90 (s, s, 3H), 1.96 (m, 1H), 1.43 (m, 3H), 0.88 and 0.67 (m, 6H).

¹³C-nmr(CDCl ₃):δ=173.6,173.1,171.4,171.3,146.3,146.0,132.7,132.6,130.52,130.46,120.9,120.8,114.5,113.4,113.0,54.25,54.15,53.4,53.2,37.4,35.6,31.4,31.3,19.50,19.46,19.2,17.5,17.0。

C ₁₆H ₂₃N ₃O ₂Cl ₂(MW=360.29); Mass spectrum (MH ⁺) 360.

Embodiment 9N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Xie Ansuan N-methyl nitrosourea synthetic

According to universal method D, with L-Xie Ansuan N-methyl nitrosourea (deriving from the foregoing description E) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=145-160 ℃).

The NMR data are as follows:

¹H-nmr (DMSO-d ₆): δ=8.10 and 7.90 (m, 2H), 7.23 (m, 1H), 6.76 and 6.69 (m, 1H), 6.57 (m, 1H), 6.34 (m, 1H), 3.90-4.14 (m, 2H), 2.57 and 2.56 (s, s, 3H), 1.88 (m, 1H), 1.27 (m, 3H), 0.65-0.86 (m, 6H).

¹³C-nmr(DMSO-d ₆):δ=173.1,171.2,171.1,148.1,147.9,131.19,131.16,130.4,130.2,116.8,113.5,113.2,113.1,57.5,57.3,52.2,51.5,30.9,30.8,25.4,19.2,19.1,18.8,18.6,18.2,17.9。

C ₁₅H ₂₁N ₃O ₂Cl ₂(MW=346.26); Mass spectrum (MH ⁺) 346.

Embodiment 10

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-alanine methyl ester synthetic

According to universal method D (without 1N salt acid elution), with L-alanine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of oily matter.Through tlc monitoring reaction (Rf=0.24, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.1?5(m,2H),6.63(dd,1H),6.40(m,1H),4.50(m,2H),3.75(m,1H),3.67(s,1.5H),3.61(s,1.5H),1.45(d,3H),1.31(m,3H)。

¹³C-nmr(CDCl ₃):δ=173.5,173.2,173.0,172.8,146.3,146.2,132.6,130.6,130.5,121.2,114.9,114.7,113.3,113.0,54.6,54.5,52.43,52.39,47.9,47.8,19.3,19.1,17.9,17.8。

C ₁₃H ₁₆N ₂O ₃Cl ₂(MW=319.19); Mass spectrum (MH ⁺) 319.

Embodiment 11

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-L-leucine methyl esters synthetic

According to universal method D, with L-leucine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=120-132 ℃).Through tlc monitoring reaction (Rf=0.49, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.18(d,1H),6.95(bd,1H),6.69(d,1H),6.43(dd,1H),4.58(m,1H),4.32(d,1H),3.75(m,1H),3.61(s,3H),1.54(m,6H),0.90(m,6H)。

¹³C-nmr(CDCl ₃):δ=174.1,173.4,146.8,133.3,131.2,122.2,115.7,114.1,55.5,52.9,51.1,41.6,25.5,23.4,22.2,20.0。

C ₁₆H ₂₂N ₂O ₃Cl ₂(MW=361.27); Mass spectrum (MH ⁺) 361.1.

Embodiment 12

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-L-phenylalanine methyl ester synthetic

According to universal method D, with L-phenylalanine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=122-124.5 ℃).Through tlc monitoring reaction (Rf=0.47, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.21(m,4H),7.05(m,2H),6.91(d,1H),6.64(d,1H),6.38(dd,1H),4.84(q,1H),4.05(bs,1H),3.71(m,4H),3.20(m,1H),3.04(m,1H),1.37(d,3H)。

¹³C-nmr(CDCl ₃):δ=173.6,172.1,146.5,136.2,133.4,131.2,129.7,129.1,127.7,122.3,115.6,113.9,55.4,53.3,53.0,38.1,19.9。

C ₁₉H ₂₀N ₂O ₃Cl ₂(MW=395.29); Mass spectrum (MH ⁺) 395.

Embodiment 13

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Isoleucine methyl esters synthetic

According to universal method D (without 1N salt acid elution), with L-Isoleucine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=95.5-101.5 ℃).Through tlc monitoring reaction (Rf=0.62, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.21(d,1H),6.98(m,1H),6.70(m,1H),6.45(m,1H),4.55(m,1H),4.11(m,1H),3.79(m,1H),3.72(s,1.5H),3.67(s,1.5H),1.87(m,1H),1.51(d,3H),1.10(m,8H)。

¹³C-nmr(CDCl ₃):δ=1?73.8,173.4,172.9,172.4,146.6,146.4,133.6,133.4,131.30,131.28,122.5,122.4,115.8,115.4,114.1,113.8,56.9,56.8,55.7,55.5,52.8,52.7,38.3,38.2,25.6,25.5,20.2,20.0,16.05,16.03,12.1,12.0。

C ₁₆H ₂₂N ₂O ₃Cl ₂(MW=361.27); Mass spectrum (MH ⁺) 361.1.

Embodiment 14

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-(S)-2-aminovaleric acid methyl esters synthetic

According to universal method D (without 1N salt acid elution), with L-valine methyl ester hydrochloride (Sennchem) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=150-153 ℃).Through tlc monitoring reaction (Rf=0.57, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.21(d,1H),6.95(bd,1H),6.70(d,1H),6.47(dd,1H),4.57(m,1H),4.13(bd,1H),3.78(m,1H),3.67(s,3H),1.81(m,1H),1.62(m,1H),1.51(d,3H),1.30(m,2H),0.9(t,3H)。

¹³C-nmr(CDCl ₃):δ=173.8,173.0,146.6,133.4,131.3,122.4,115.7,114.1,55.6,52.9,52.4,34.8,20.2,19.2,14.2。

C ₁₅H ₂₀N ₂O ₃Cl ₂(MW=347.24); Mass spectrum (MH ⁺) 347.

Embodiment 15

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

According to universal method D (without 1N salt acid elution), with L-nor-leucine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=163-165 ℃).Through tlc monitoring reaction (Rf=0.55, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.18(d,1H,J=8.7Hz),6.99(bd,1H,J=8.2Hz),6.69(d,1H,J=2.7Hz),6.45(dd,1H,J=8.7Hz,J=2.7Hz),4.53(m,1H),4.23(d,1H,J=4.2Hz),3.77(m,1H),3.66(s,3H),1.83(m,1H),1.62(m,1H),1.48(d,3H,J=7.0Hz),1.27(m,4H),0.85(t,3H)。

¹³C-nmr(CDCl ₃):δ=173.9,173.1,146.7,133.4,131.2,122.3,11?5.7,114.1,55.5,52.9,52.6,32.4,28.0,22.8,20.1,14.4。

C ₁₆H ₂₂N ₂O ₃Cl ₂(MW=361.27); Mass spectrum (MH ⁺) 361.

Embodiment 16

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-tryptophan methyl ester synthetic

According to universal method D (without 1N salt acid elution), with L-tryptophan methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as solid target compound (mp=54-66 ℃).Through tlc monitoring reaction (Rf=0.43, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=8.1?5(bs,0.5H),7.98(bs,0.5H),7.51(d,0.5H),7.12(m,6H),6.60(d,0.5H),6.53(dd,1H),6.24(m,1H),4.88(m,1H),3.90(d,0.5H),3.70(m,4.5H),3.32(m,1H),3.22(m,1H),1.40(m,3H)。

¹³C-nmr(CDCl ₃):δ=173.8,173.6,172.8,172.4,146.4,146.3,136.6,133.3,133.2,131.2,131.1,128.2,,127.7,123.3,122.8,122.05,122.02,120.3,120.2,119.0,118.7,115.5,115.4,113.8,113.3,112.1,111.9,110.2,109.9,55.3,55.1,53.5,53.1,53.0,52.9,27.9,27.7,19.8,19.6。

C ₂₁H ₂₁N ₃O ₃Cl ₂(MW=434.33); Mass spectrum (MH ⁺) 434.

Embodiment 17N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-L-aspartic acid β-(tert-butyl ester) α-methyl esters

Synthetic

According to universal method D (without 1N salt acid elution), with L-aspartic acid β-(tert-butyl ester) α-methyl ester hydrochloride (Bachem) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A), preparation target compound.Through tlc monitoring reaction (Rf=0.56, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.52(d,0.5H),7.42(d,0.5H),7.1?3(m,1H),6.66(d,0.5H),6.60(d,0.5H),6.40(m,1H),4.76(m,1H),4.40(d,0.5H),4.31(d,0.5H),3.75(m,1H),3.69(s,1.5H),3.62(s,1.5H),2.88(m,1H),2.62(m,1H),1.47(m,3H),1.32(s,4.5H),1.21(s,4.5H)。

¹³C-nmr(CDCl ₃):δ=174.0,173.7,171.7,171.4,170.30,170.27,146.7,146.6,133.4,133.3,131.2,131.1,122.0,115.6,115.1,114.0,113.4,82.4,55.4,55.2,53.24,53.19,49.0,48.7,37.9,37.8,28.4,28.2,19.9,19.8。

C ₁₈H ₂₄N ₂O ₅Cl ₂(MW=419.31); Mass spectrum (MH ⁺) 418.

Embodiment 18

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-aspartic acid α-methyl esters synthetic

According to universal method F, remove N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-tert-butyl ester group of L-aspartic acid β-(tert-butyl ester) α-methyl esters (deriving from the foregoing description 17), obtain being solid target compound (mp=53.5-56 ℃).Through tlc monitoring reaction (Rf=0.54, with 1: 1 ethyl acetate: hexane launched).

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.59(d,1H),7.18(m,1H),6.79(d,0.5H),6.69(d,0.5H),6.58(m,0.5H),6.47(m,0.5H),4.84(m,1H),3.82(m,1H),3.73(s,1.5H),3.68(s,1.5H),3.04(m,1H),2.79(m,0.5H),2.73(m,0.5H),1.49(m,3H)。

¹³C-nmr(CDCl ₃):δ=175.7,175.6,175.14,175.07,171.1,171.0,145.0,144.6,133.6,133.5,131.44,131.40,124.2,123.4,55.9,55.4,53.8,53.7,49.05,49.00,36.1,19.2,19.1。

C ₁₄H ₁₆N ₂O ₅Cl ₂(MW=363.20); Mass spectrum (MH ⁺) 363.

Embodiment 19N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-N ε-BOC-L-lysine methyl ester synthetic

According to universal method D, with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and N ε-BOC-L-lysine methyl ester hydrochloride (Bachem) is prepared as the target compound of oily matter.Through tlc monitoring reaction (Rf=0.23, the ethyl acetate with 45%: hexane launches).

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.22(m,4H),6.63(q,1H),6.43(m,1H),4.72(t,0.5H),4.63(t,0.5H),4.53(m,1H),4.42(q,1H),3.78(m,1H),3.68(s,1.5H),3.62(d,1.5H),3.00(m,2H),1.90-1.05(m,4H),1.48(d,3H),1.42(s,9H)。

¹³C-nmr(CDCl ₃):δ=174.2,173.9,173.1,172.8,156.7,156.6,146.8,146.7,133.4,133.3,131.2,131.1,121.9,121.8,115.5,115.1,114.0,113.8,79.7,79.6,60.9,55.2,55.1,53.0,52.9,52.4,52.1,40.6,40.5,32.3,32.2,30.1,28.9,22.8,21.6,19.9,14.7。

Embodiment 20N-[N-benzothiazole-6-yl)-and D, the L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

Steps A: N-[N-benzothiazole-6-yl)-D, L-L-Ala synthetic

Under room temperature, handle the 60ml dichloromethane solution of 1 g 6-aminobenzothiazole (Lancaster) with the 0.63g pyridine, handle with the 2.1g trifluoroacetic anhydride then.Reactant was stirred 3 hours, and initial warm reaction mixture is cooled to room temperature in this process.Wash this mixture with 5% aqueous citric acid solution, use dried over mgso, remove solvent, obtain the amino benzotriazole trifluoroacetamide of 6-of quantitative yield, be cream-colored solid, it is used for next step reaction immediately.

The amino benzotriazole trifluoroacetamide of 300mg 6-is dissolved among the 35ml THF, under room temperature, adds 1.2 normal potassium hydride KHs.This solution was refluxed 5 hours, and cooling adds 18-and is preced with-6 crystal (Aldrich) and 331mg 2-ethyl bromide (Aldrich), and the mixture that produces was refluxed 36 hours.Cool off this reaction mixture, solvent is removed in decompression, and residue is dissolved in the ethyl acetate.Wash organism with water.The pH of water layer is transferred to 5, use ethyl acetate extraction.Merge organic layer, with dried over mgso and except that desolvating.The crude product material launches to obtain N-(benzothiazole-6-yl)-D, L-alanine ethyl ester (Rf=0.5) through the tlc purifying with methylene chloride (94: 4).In refluxing down, handle this material with methyl alcohol and 5 normal salt of wormwood, cool off then and remove solvent.In the water-soluble and ethyl acetate of residue.The pH of water layer is transferred to 2, use ethyl acetate extraction.Dry acetic acid ethyl ester extract is removed solvent and is obtained N-(benzothiazole-6-yl)-D, L-L-Ala.Step B:N-[N-benzothiazole-6-yl)-and D, the L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

(use DMF according to universal method D as reaction solvent, with ethyl acetate extraction and without 1N salt acid elution), with L-nor-leucine methyl ester hydrochloride (Sigma) and N-(benzothiazole-6-yl)-D, L-L-Ala (deriving from the foregoing description A), preparation target compound.Through tlc monitoring reaction (Rf=0.28, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=8.74(s,1H),7.91(s,1H,J=8.8Hz),7.15(m,1H),7.06(d,0.5H,J=2.3Hz),7.00(d,0.5H,J=2.3Hz),6.87(m,1H),4.58(m,1H),4.20(bs,2H),3.87(m,1H),3.70(s,1.5H),3.59(s,1.5H),1.30(m,10H),0.84(t,1.5H,J=6.9Hz),0.60(t,1.5H,J=6.9H)。

¹³C-nmr(CDCl ₃):δ=174.3,174.0,173.4,173.0,151.1,151.0,147.2,145.5,145.3,136.2,136.1,124.4,124.2,116.1,115.9,104.6,103.9,56.2,55.69,53.0,52.9,52.5,52.2,32.42,32.36,28.0,27.7,22.8,22.6,20.3,20.1,14.4,14.2。

C ₁₇H ₂₃N ₃O ₃S ₂(MW=349.46); Mass spectrum (MH ⁺) 350.

Embodiment 21

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-lysine methyl ester synthetic

According to universal method F, with N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-N ε-BOC-L-lysine methyl ester hydrochloride (deriving from the foregoing description 19), be prepared as the target compound of oily matter.Through flash chromatography on silica gel purification reaction product, with 89: 10: 1 methylene dichloride: methyl alcohol: ammonium hydroxide wash-out.

The NMR data are as follows:

¹H-nmr (CDCl ₃,-2 diastereomers): δ=7.21 (d, 1H), 7.09 (bd, 1H), 6.68 (q, 1H), 6.46 (m, 1H), 4.56 (m, 1H), 4.22 (bs, 1H), 3.78 (m, 1H), 3.70 (s, 1.5H), 3.67 (s, 1.5H), 2.66 (t, 1H), 2.54 (t, 1H), 1.80 (m, 1H), 1.62 (m, 1H), 1.51 (d, 1.5H), 1.50 (d, 1.5H), 1.32 (m, 2H), 1.11 (m, 1H).

¹³C-nmr (CDCl ₃,-2 diastereomers): δ=174.8,174.3,173.1,172.8,171.8,146.9,146.7,133.3,133.1,131.2,131.1,121.7,121.5,115.2,115.1,113.9,113.8,60.9,55.0,54.9,53.1,53.0,52.5,52.3,32.1,32.09,32.05,31.8,23.1,22.9,21.6,19.9,19.8 and 14.7.

C ₁₃H ₂₃N ₃O ₃Cl ₂(MW=376.28)。

Embodiment 22

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-L-Tyrosine methyl ester synthetic

According to universal method D, with L-L-Tyrosine methyl ester (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of the stereoisomer mixture of L-Ala.Through tlc monitoring reaction (Rf=0.29,10% ethanol/methylene is launched), and, use the ethanol/methylene wash-out through the flash chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.22-7.50(m,7H),6.36(dd,0.5H),6.28(dd,0.5H),4.83(m,1H),4.04(dd,1H),3.73(s,1.5H),3.70(m,1H),3.68(s,1.5H),3.14(dd,0.5H),2.97(m,1.5H),1.43(d,1.5H),1.35(d,1.5H)。

¹³C-nmr(CDCl ₃):δ=174.20,174.08,172.75,172.26,156.10,155.99,146.45,146.32,133.50,133.38,131.39,131.26,130.81,130.67,127.43,127.00,122.41,122.22,116.15,116.12,115.68,115.39,113.94,1?13.46,55.47,55.08,53.54,53.18,37.62,37.44,19.91,19.87。

C ₁₉H ₂₀N ₂O ₄Cl ₂(MW=411.28)。

Embodiment 23

N-[N-(3, the 5-dichlorophenyl)-D, L-alanyl]-L-alanine methyl ester synthetic

According to universal method D, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description B) and L-alanine methyl ester hydrochloride (Sigma) are prepared as the target compound of oily matter.Through flash chromatography on silica gel purification reaction product, the ethyl acetate/hexane wash-out with 50%.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=1.3-1.55 (have three groups bimodal, be J=7, altogether 6H) at 1.34,1.39 and 1.48 places, 3.7-3.9 (has m and unimodal at 3.67 and 3.72 places, 4H), 4.3-4.4 (m, 1H), 4.5-4.65 (m, 1H), 6.4-6.6 (m, 2H), 6.73 (s, 1H), 6.95-7.1 (m, 1H).

¹³C-nmr(CDCl ₃):δ=15.52,15.59,16.75,16.87,45.29,45.39,50.02,51.89,51.99,108.9,109.2,109.5,1?16.14,1?16.19,132.96,133.96,133.05,145.67,145.76,170.13,170.32,170.40,170.63。

C ₁₃H ₁₆N ₂O ₃Cl ₂(MW=319.19); Mass spectrum (MH ⁺) 319.

Embodiment 24

N-[N-(3,5-dioxy phenyl)-L-alanyl]-(S)-2-aminovaleric acid methyl esters synthetic

According to universal method D, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description B) and L-valine methyl ester hydrochloride (Sennchem), preparation target compound.Through silica gel column chromatography purification reaction product, the ethyl acetate/hexane wash-out with 50%.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=0.92(t,J=7,3H),1.2-1.4(m,2H),1.50(d,J=7,3H),1.5-1.7(m,1H),1.75-1.9(m,1H),3.69(s,3H),3.75-3.9(m,1H),4.2(bs,1H),4.5-4.65(m,1H),6.5(bs,2H),6.73(s,1H),6.85(bs,1H)。

¹³C-nmr(CDCl ₃):δ=14.2,19.25,20.13,34.8,52.4,53.0,55.2,112.7,119.5,136.1,148.7,173.0,173.5。

C ₁₅H ₂₀N ₂O ₃Cl ₂(MW=347.24); Mass spectrum (MH ⁺) 346.

Embodiment 25

N-[N-(3, the 5-dichlorophenyl)-L-alanyl]-L-phenylalanine methyl ester synthetic

According to universal method D, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala and L-phenylalanine methyl ester hydrochloride (Sigma), preparation target compound.Through silica gel column chromatography purification reaction product, the ethyl acetate/hexane wash-out with 50%.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=1.40(d,J=7,3H),3.10(dd,J=7,14,1H),3.23(dd,J=5,14,1H),3.74(s,3H),3.75-3.9(m,1H),4.0(bs,1H),4.8-4.95(m,1H),6.45(bs,2H),6.73(s,2H),7.0-7.2(m,2H),7.2-7.3(m,5H)。

¹³C-nrmr(CDCl ₃):δ=19.4,37.5,52.4,52.7,54.5,112.0,118.9,127.1,128.5,129.1,135.5,135.6,148.0,171.4,172.6。

C ₁₉H ₂₀N ₂O ₃Cl ₂(MW=395.29); Mass spectrum (MH ⁺) 394.

Embodiment 26N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-L-aspartic acid β-(methyl esters) α-methyl esters

Synthetic

According to universal method D (without 1N salt acid elution), with L-aspartic acid β-(methyl esters) α-methyl esters (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A), preparation target compound (mp=113.5-118 ℃).Through tlc monitoring reaction (Rf=0.29, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.47(bd,1H),7.20(m,1H),6.69(d,0.5H),6.60(d,0.5H),6.44(m,1H),4.83(m,1H),4.25(bs,0.5H),4.18(bs,0.5H),3.79(m,1H),3.72(s,1.5H),3.67(s,1.5H),3.65(s,1.5H),3.48(s,1.5H),3.00(m,1H),2.79(m,1H),1.50(m,3H)。

¹³C-nmr(CDCl ₃):δ=174.0,173.6,172.0,171.7,171.4,170.3,146.6,146.4,133.43,133.37,131.22,131.20,122.2,122.0,115.5,115.0,114.1,113.6,55.4,55.2,53.46,53.44,52.7,52.5,48.8,48.7,36.4,36.3,19.9,19.7。

C ₁₅H ₁₈N ₂O ₅Cl ₂(MW=377.23); Mass spectrum (MH ⁺) 377.

Embodiment 27N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-the closing of (N '-1-benzyl)-L-Histidine methyl esters

Become

According to universal method D (without 1N salt acid elution), be solid (Sigma) and N-(3, the 4-dichlorophenyl)-D with 1-benzyl-L-Histidine methyl ester hydrochloride, L-L-Ala (deriving from the foregoing description A), preparation target compound (mp=49-51 ℃).Through tlc monitoring reaction (Rf=0.21 launches with 5% ethanol/methylene), and with product through the flash chromatography purifying, the methyl alcohol with 5%: methylene dichloride is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=8.22(d,0.5H),7.88(d,0.5H),7.29(m,3H),7.08(m,4H),6.65(d,0.5H),6.44(m,2.5H),4.90(s,1H),4.86(s,1H),4.62(m,1H),4.47(m,1H),3.72(m,1H),3.61(s,1.5H),3.47(s,1.5H),2.95(m,2H),1.42(d,3H)。

¹³C-nmr(CDCl ₃):δ=174.0,173.9,172.4,172.0,146.9,138.1,137.9,137.6,136.7,136.5,133.1,133.0,131.0,130.9,129.6,129.5,128.84,128.79,127.74,127.71,121.1,121.0,117.3,115.3,115.1,113.9,113.6,54.9,54.8,53.2,52.9,52.8,52.7,51.3,51.2,30.2,29.8,19.8。

C ₂₃H ₂₄N ₄O ₃Cl ₂(MW=475.38); Mass spectrum (MH ⁺) 475.

Embodiment 28N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-L-L-glutamic acid β-(tert-butyl ester) α-methyl esters

Synthetic

According to universal method D (without 1N salt acid elution), with L-L-glutamic acid β-(tert-butyl ester) α-methyl ester hydrochloride (Bachem) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of oily matter.Through tlc monitoring reaction (Rf=0.52 and 0.59, with 1: 1 ethyl acetate: hexane launched), and with product through the flash chromatography purifying, with 1: 1 ethyl acetate: hexane is as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.25(m,2H),6.69(m,1H),6.45(m,1H),4.54(m,1H),3.78(m,1H),3.70(s,1.5H),3.65(s,1.5H),2.10(m,4H),1.49(d,3H),1.40(s,9H)。

¹³C-nmr(CDCl ₃):δ=174.2,173.9,172.8,172.7,172.5,172.3,146.6,146.5,133.5,133.3,131.3,131.2,122.16,122.14,115.7,115.4,114.0,113.6,81.6,81.5,55.4,55.2,53.1,53.0,52.3,51.9,32.0,31.7,28.6,27.6,27.3,20.0,19.8。

C ₁₉H ₂₆N ₂O ₅Cl ₂(MW=433.34); Mass spectrum (MH ⁺) 432.

Embodiment 29

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-L-glutamic acid α-methyl esters synthetic

According to universal method F (omit the sodium bicarbonate washing and reclaim product mutually) from ethyl acetate; remove N-[N-(3; the 4-dichlorophenyl) alanyl] tert-butyl ester base of L-glutamic acid β-(tert-butyl ester) α-methyl esters (deriving from the foregoing description 28), be provided as solid target compound (mp=42-45 ℃).Through tlc monitoring reaction (Rf=0.42 and 0.50 launches with 10% ethanol/methylene).

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.57(bs,1H),7.25(d,1H),6.75(d,1H),6.51(m,1H),4.67(m,1H),3.91(m,1H),3.76(s,1.5H),3.69(s,1.5H),2.50-2.15(m,3H),2.10-1.85(m,1H),1.51(bs,3H)。

¹³C-nmr(CDCl ₃):δ=177.98,177.73,175.17,174.94,172.64,172.26,146.60,146.45,133.52,133.33,131.41,131.27,122.32,122.28,115.68,155.47,113.98,113.59,55.37,55.17,53.35,53.29,52.20,51.85,30.68,30.26,227.29,27.18,19.86,19.77。

C ₁₅H ₁₈N ₂O ₅Cl ₂(MW=377.23)。

Embodiment 30

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-L-leucyl amine synthetic

According to universal method D, with L-leucyl amine hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A), preparation target compound.Through this compound of column chromatography purification, at first use 1: 1 ethyl acetate/hexane wash-out, use 5% ethanol/methylene wash-out then.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.32 (d, 8.6,1H), 7.1 7 (d, 8.7,1H), 6.66 (d, 2.7,1H), 6.54 (s, 1H), 6.41 (dd, 2.7,8.7,1H), 6.13 (s, 1H), 4.48 (m, 1H), 4.33 (d, 5.3,1H), 3.83 (five peaks, 6.9,1H), 1.58 (m, 3H), 1.44 (d, 7.0,3H), 0.89 (d, 6.0,3H), 0.85 (d, 5.9,3H).

¹³C-nmr(CDCl ₃):δ=174.5,173.9,146.0,132.8,130.7,121.5,114.7,113.3,54.3,51.1,40.8,24.8,22.9,21.7,19.2。

C ₁₅H ₂₁N ₃O ₂Cl ₂(MW=346.26); Mass spectrum (MH ⁺) 346.

Embodiment 31N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-(3,5-two iodos)-L-L-Tyrosine methyl ester

Synthetic

According to universal method D, with 3,5-two iodos-L-tyrosine methyl ester hydrochloride (Bachem) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of L-Ala stereoisomer mixture.Monitor this reaction (Rf=0.29, with 10% ethanol/methylene launch) and through the flash chromatography purifying, with 10% ethanol/methylene wash-out through tlc.

The NMR data are as follows:

¹H-nmr (CDCl ₃,-partial-purified diastereomer): δ=7.37 (s, 2H), 7.19 (d, 1H), 6.99 (bd, 1H), 6.65 (d, 1H), 6.40 (m, 1H), 5.78 (s, 1H), 4.73 (q, 1H), 3.72 (m, 1H), 0.70 (s, 3H).

¹³C-nmr (CDCl ₃,-two diastereomers): δ=173.86,171.87,171.41,171.37,170.90,153.48,150.74,146.37,146.30,141.01,140.09,138.39,133.50,133.45,132.14,131.62,131.34,131.28,122.80,122.62,121.82,115.89,115.78,115.72,115.47,114.54,113.79,113.21,82.97,77.08,61.01,55.69,53.32,53.28,53.18,53.14,52.97,52.90,52.76,36.37,36.15,21.67,20.20,20.11,19.76,14.79.

C ₁₉H ₁₈N ₂O ₄Cl ₂I ₂(MW=663.08); Mass spectrum (MH ⁺)=663.

Embodiment 32N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(3-iodo)-L-L-Tyrosine methyl ester synthetic

According to universal method D, with 3-iodo-L-tyrosine methyl ester hydrochloride (preparing) and N-(3 according to universal method K and with 3-iodo-L-tyrosine (Aldrich), the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of L-Ala stereoisomer mixture.Monitor this reaction (Rf=0.29, with 10% ethanol/methylene launch) and through the flash chromatography purifying, with 10% ethanol/methylene wash-out through tlc.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.37-7.20(m,3H),6.97-6.60(m,3H),6.42(dd,1.5H),6.32(dd,1.5H),5.52(bs,0.5H),5.43(bs,0.5H),4.80(m,1H),3.94(dd,1H),3.73(s,1.5H),3.70(s,1.5H),3.12(dd,0.5H),2.94(m,1.5H),1.48(d,1.5H),1.43(d,1.5H)。

¹³C-nmr(CDCl ₃):δ=173.56,171.80,171033,154.52,154.47,145.69,139.15,138.74,132.88,132.71,130.83,130.61,130.40,130.26,129.14,128.81,121.76,121.73,115.04,114.97,114.86,113.20,112.71,84.96,84.68,54.85,54.65,52.78,52.60,52.57,52.51,36.29,36.08,19.40,19.27。

C ₁₉H ₁₉N ₂O ₄Cl ₂I (MW=537.1 8); Mass spectrum (MH ⁺)=538.

Embodiment 33

According to universal method described herein and embodiment, the preparation following compounds:

N-[N-(4-chloro-phenyl-)-D, the L-alanyl]-the L-phenylalanine methyl ester

Embodiment 34

N-[N-(3, the 4-dichlorophenyl) glycyl]-(S)-2-aminovaleric acid methyl esters synthetic

According to universal method D, with N-(3, the 4-dichlorophenyl) glycine (deriving from the foregoing description I) and L-valine methyl ester hydrochloride (Sennchem), the preparation target compound.Monitor this reaction (Rf=0.32 launches with 50% ethyl acetate/hexane) and, use the ethyl acetate/hexane wash-out through tlc through the flash chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.21(d,J=8.7,1H),6.94(d,J=7.8,1H),6.68(d,J=2.6,1H),6.4(m,1H),4.6(m,2H),3.79(d,J=2.6,2H),3.71(s,3H),1.7(m,2H),1.2(m,2H),0.88(t,J=7.3,7.3,3H)。

¹³C-nmr(CDCl ₃):δ=173.3,170.2,147.2,133.6,131.2,122.2,115.0,113.6,53.0,52.3,48.8,34.8,19.2,14.1。

C ₁₄H ₁₈N ₂O ₃Cl ₂(MW=333.22); Mass spectrum (MH ⁺)=334.

Embodiment 35N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-N ε-(caproyl)-L-lysine methyl ester

Synthetic

According to universal method D, with N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-L-lysine methyl ester (deriving from the foregoing description 21) and caproic acid (Aldrich), the preparation target compound.Monitor this reaction (Rf=0.38 launches with 60% methylene dichloride/10% hexane/27% ethyl acetate/3% methyl alcohol) and through the flash chromatography purifying through tlc, with 60% methylene dichloride/10% hexane/27% ethyl acetate/3% methyl alcohol as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.70(d),7.25(m),7.15(m),6.68(m),6.42(m),5.95(bs),5.79(bs),4.70(bs),4.50(m),3.80(m),3.78(s),3.72(s),3.45(m),3.20(m),3.05(m),2.12(m),1.98(m),1.80(m),1.60(m),1.45(m),1.30(m),1.10(m)。

¹³C-nmr(CDCl ₃):δ=175.6,174.4,174.0,173.9,173.7,173.1,156.6,146.9,146.8,133.5,133.2,131.2,131.1,121.7,115.4,115.23,115.1,114.0,113.9,79.6,55.1,54.9,54.8,53.0,52.9,52.4,52.0,42.6,40.9,39.4,37.1,32.1,31.7,30.3,29.4,28.9,28.5,26.9,25.9,23.0,19.9,19.7。

C ₂₂H ₃₃N ₃O ₄Cl ₂(MW=474.43); Mass spectrum (MH ⁺)=NA.

Embodiment 36

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-phenylalanyl amine synthetic

According to universal method D, with phenylalanyl amine (Bachem) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A), preparation target compound (mp=177-179 ℃).This compound is ground purifying with chloroform.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆):δ=8.0-8.2(d,1H),7.45(m,1H),7.05-7.30(m,7H),7.65-7.72(m,1H),6.24-6.51(m,2H),4.45(m,1H),3.82(m,1H),2.95(m,1H),2.78(m,1H),1.05-1.25(m,3H)。

¹³C-nmr(CDCl ₃):δ=173.0,172.9,172.8,172.7,147.9,137.7,131.1,130.3,129.21,129.15,128.0,127.9,126.21,126.19,116.8,113.5,113.0,112.6,53.4,53.3,52.0,51.8,37.92,37.86,18.9,18.6。

C ₁₈H ₁₉N ₃O ₂Cl ₂(MW=380.23); Mass spectrum (MH ⁺)=380.

Embodiment 37N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-2-amino oneself-(N-methyl)-acid amides

Synthetic

According to universal method D, with L-nor-leucine N-methyl nitrosourea (making BOC-L-nor-leucine (Bachem) with methylamine (Aldrich) coupling, then according to the preparation of universal method F removal BOC group) and N-(3 according to universal method F, the 4-dichlorophenyl)-and D, L-L-Ala, preparation target compound.Wash this compound purifying with salt of wormwood then.

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=6.99(t,1H),6.48(d,10.8,1H),6.32(d,8.7,1H),4.09(m,1H),3.68(q,7.0,0.5H),3.59(q,7.1,0.5H),2.50(s,1.5H),2.47(s,1.5H),1.28-1.60(m,2H),1.23(t,6.5,3H),0.80-1.20(m,4H),0.68(t,6.7,1.5H),0.59(t,7.1,1.5H)。

¹³C-nmr (CD ₃OD): δ=176.6 (overlapping), 174.54,174.51,148.8,148.5,133.6,133.5,131.7,131.6,121.0,120.8,115.2,115.1,114.5,114.2,55.3,54.7,54.3,54.1,33.3 (overlapping), 29.0,28.8,26.3,26.2,23.4,23.3,19.0 (overlapping), 14.3,14.2.

C ₁₆H ₂₃N ₃O ₂Cl ₂(MW=360.29); Mass spectrum (MH ⁺)=360.

Embodiment 38 and 39N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-β-Cyclohexylalanine methyl esters synthetic

According to universal method D, with β-Cyclohexylalanine methyl esters (according to universal method K by β-Cyclohexylalanine preparation) and N-(3, the 4-dichlorophenyl)-D, the L-L-Ala is prepared as the target compound of L-Ala diastereomer, is oily matter.Monitor this reaction (Rf=0.27 (second kind isomer) and 0.30 (first kind of isomer) launch with 35% ethyl acetate/hexane) through tlc, and through the flash chromatography purifying, with 35% ethyl acetate/hexane wash-out.

NMR data following (first kind of isomer-embodiment 38):

¹H-nmr(CD ₃OD):δ=7.21(d,1H),6.81(bd,1H),6.70(d,1H),6.46(dd,1H),4.62(m,1H),4.19(d,1H),3.77(m,1H),3.65(s,3H),1.65-0.90(m,10H),1.50(d,3H)。

¹³C-nmr(CD ₃OD):δ=173.78,173.48,146.62,133.45,131.26,122.51,115.84,114.17,55.64,52.91,50.47,40.18,34.81,34.04,32.88,26.86,26.71,26.55,20.13。

NMR data following (second kind of isomer-embodiment 39):

¹H-nmr(CD ₃OD):δ=7.23(d,1H),6.83(bd,1H),6.67(d,1H),6.45(dd,1H),4.63(m,1H),4.10(d,1H),3.69(m,1H),3.72(s,3H),1.65-0.90(m,10H),1.51(d,3H)。

¹³C-nmr(CD ₃OD):δ=173.98,173.56,146.38,133.65,131.34,122.49,115.35,113.78,55.39,52.95,50.21,40.26,34.61,34.10,32.68,26.82,26.64,26.41,19.98。

C ₁₉H ₂₆N ₂O ₃Cl ₂(MW=401.34); Mass spectrum (MH ⁺)=401.

Embodiment 40

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-(S)-2-aminocaproamide synthetic

According to universal method D, with L-norleucyl-amine (according to universal method F, by BOC-L-norleucyl-amine (deriving from the foregoing description F) preparation) and N-(3, the 4-dichlorophenyl)-D, the L-L-Ala is prepared as solid target compound (mp=156-161 ℃).

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=6.49(m,1H),6.32(m,1H),1.14(m,1H),3.54-3.71(m,1H),0.80-1.62(m,9H),0.68(m,1.5H),0.58(m,1.5H)。

¹³C-nmr(CD ₃OD):δ=176.63,176.56,148.8,148.5,133.6,133.5,131.7,131.6,120.8,115.2,115.1,114.4,114.2,55.3,54.7,53.9,53.7,33.4,33.3,29.0,28.6,23.4,23.3,19.03,18.99,14.3,14.2。

C ₁₆H ₂₁N ₃O ₂Cl ₂(MW=346.26); Mass spectrum (MH ⁺) 346.

Embodiment 41N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-2-amino oneself-(N, N-dimethyl)-acyl

Synthesizing of amine

According to universal method D, with L-nor-leucine N, the N-dimethylformamide (makes BOC-L-nor-leucine (Bachem) and dimethylamine (Aldrich) coupling according to universal method E, then remove the preparation of BOC group according to universal method F) and N-(3, the 4-dichlorophenyl)-D, the L-L-Ala is prepared as solid target compound (mp=137-160 ℃).Monitor this reaction (0.20 and 0.24, launch) through tlc with the dichloromethane solution of 5% methyl alcohol, and from water this compound of deposition and purification.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=0.77 (m, 3H), 1.11 (m, 1H), 1.24 (m, 3H), 1.47 (m, 3H), 1.40-1.80 (m, 2H), 2.92 and 2.94 (two s, 3H), 3.07 (s, 3H), 3.84 (m, 1H), 4.32 (d, J=5.3Hz, 1H), 4.90 (m, 1H), 6.44 (m, 1H), 6.65 (s, 1H), 7.17 (m, 1H), 7.35 (m, 1H).

¹³C-nmr (CDCl ₃): δ=13.8,13.9,19.3,19.4,22.38,22.45,27.06,27.14,32.3,32.5,35.7 (may be overlapping), 37.0,37.1,48.6,48.8,54.3,54.5,113.1,113.5,114.4,114.7,121.1,121.3,130.6 (overlapping), 132.7,132.9,146.0,146.2,171.4,171.5,172.6,172.9.

C ₁₇H ₂₅N ₃O ₂Cl ₂(MW=374.31); Mass spectrum (MH ⁺) 374.

Embodiment 42

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-1-methionine(Met) methyl esters synthetic

According to universal method D, with L-methionine(Met) methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) is prepared as the target compound of diastereomer compound.Monitor this reaction (Rf=0.35 launches with 43% ethyl acetate/hexane) through tlc, and through this compound of flash chromatography purifying, with 43% ethyl acetate/hexane wash-out.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.21(d,2H),6.68(m,1H),6.43(m,1H),4.68(m,1H),4.21(dd,1H),3.79(m,1H),3.73(s,1.5H),3.68(s,1.5H),2.46(m,1H),2.31(t,1H),2.23-1.88(m,2H),2.06(s,1.5H),1.93(s,1.5H),1.50(d,3H)。

¹³C-nmr(CDCl ₃):δ=174.09,173.81,172.73,172.38,146.60,146.47,133.43,131.37,131.27,122.36,122.33,115.65,115.31,114.05,113.65,55.48,55.32,53.19,53.16,51.99,51.68,31.74,31.64,30.62,30.42,20.10,19.92,16.08,15.91。

C ₁₅H ₂₀N ₂O ₂Cl ₂(MW=379.31); Mass spectrum (MH ⁺) 379.

Embodiment 43N-[N-(3, the 5-dichlorophenyl)-D, L-alanyl]-(S)-2-amino oneself-(N, N-dimethyl)-acyl

Synthesizing of amine

According to universal method E, with L-nor-leucine N, the N-dimethylformamide (makes BOC-L-nor-leucine (Bachem) and dimethylamine (Aldrich) coupling according to universal method E, then remove the preparation of BOC group according to universal method F) and N-(3, the 5-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description B), the preparation target compound.Monitor this reaction (Rf=0.25-0.30 launches with 3% ethanol/methylene) through tlc, and through this compound of chromatography purification, with 3% ethanol/methylene wash-out.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=0.8-0.95 (overlapping t, 3H), 1.2-1.8 (m contains eclipsed d at 1.45 and 1.48 places, 9H, 2.95 (s, 3H), 3.10 (s, 3H), 3.8-3.9 (m, 1H), 4.3-4.4 (m, 1H), 4.8-4.95 (m, 1H), 6.45 (s, 2H), 6.6-6.7 (m, 1H).

C ₁₇H ₂₅N ₃O ₂Cl ₂(MW=374.31)。

Embodiment 44

N-[N-(3, the 5-dichlorophenyl)-D, L-alanyl]-(S)-2-aminocaproamide synthetic

According to universal method D, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description B) and L-norleucyl-amine (deriving from the foregoing description F), preparation target compound.Monitor this reaction (Rf=0.15 launches with 3% ethanol/methylene) through tlc, and through this compound of flash chromatography purifying, with 3% ethanol/methylene wash-out.

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=0.9(t,J=7,3H),1.2-1.4(m,2H),1.45(d,J=7,3H),1.5-1.7(m,1H),1.75-1.9(m,1H),3.9-4.0(m,1H),4.1-4.3(m,1H),4.3-4.4(m,1H),6.5(bs,2H),6.6(bs,1H)。

C ₁₅H ₂₁N ₃O ₂Cl ₂(MW=346.26)。

Embodiment 45N-[N-(3, the 5-dichlorophenyl)-D, L-alanyl]-(S)-2-amino oneself-(N-methyl)-acid amides

Synthetic

According to universal method D, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala and L-nor-leucine N-methyl nitrosourea (make BOC-L-nor-leucine (Bachem) and methylamine (Aldrich) coupling according to universal method E, then remove the preparation of BOC group according to universal method F), the preparation target compound.Monitor this reaction (Rf=0.25 launches with 3% ethanol/methylene) through tlc, and, launch with 3% ethanol/methylene through this compound of thin-layer chromatography purifying.

The NMR data are as follows:

¹H-nmr (CD ₃OD): δ=0.9 (t, J=7,3H), 1.2-1.4 (m, 2H), 1.45 (d, J=7,3H), 1.5-1.7 (m, 1H), 1.75-1.9 (m, 1H), 2.6-2.7 (m that has s at 2.7 places, 4H), 3.8-4.0 (m, 1H), 4.1-4.3 (m, 2H), 6.5 (bs, 2H), 6.6 (bs, 1H).

C ₁₆H ₂₃N ₃O ₂Cl ₂(MW=360.29)。

Embodiment 46

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-L-Histidine methyl esters synthetic

According to universal method D (without 1N salt acid elution), with L-Histidine methyl ester hydrochloride (Sigma) and N-(3, the 4-dichlorophenyl)-D, the L-L-Ala is prepared as solid target compound (mp=55-60 ℃).Monitor this reaction (Rf=0.52 launches with 10% ethanol/methylene) through tlc, and through this compound of flash chromatography purifying, with 50% ethyl acetate/hexane wash-out.

The NMR data are as follows:

¹H-nmr(CD ₃Cl ₃):δ=8.14(bd,J=7.02?Hz,0.5H),7.79(bd,7.57Hz,0.5H),7.33(s,1H),7.14(m,1H),6.73(s,0.5H),6.69(s,0.5H),6.59(m,1H),6.47(m,0.5H),6.37(m,0.5H),4.74(m,1H),4.33(m,1H),3.79(m,1H),3.69(s,1.5H),3.62(s,1.5H),3.05(m,2H),1.47(d,J=7.02Hz,3H)。

¹³C-nmr(CDCl ₃):δ=174.35,174.15,172.45,172.08,146.80,146.67,135.48,135.07,134.65,133.24,133.12,131.13,131.04,121.54,121.49,115.96,115.78,115.38,115.05,113.90,113.72,61.04,54.98,53.11,52.97,52.71,29.71,19.43,21.68,19.86,19.84,14.77。

C ₁₆H ₁₈N ₄O ₃Cl ₂(MW=385.25); Mass spectrum (MH ⁺) 385.

Embodiment 47

N-[N-(quinoline-3-yl)-D, L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

According to universal method G, then being hydrolyzed according to universal method C prepares N-(quinoline-3-yl)-D, L-L-Ala.Make this compound and L-nor-leucine methyl ester hydrochloride (Sigma) coupling according to universal method D then, obtain target compound into oily matter.(Rf=0.76 launches with 10% ethanol/methylene to monitor this reaction through tlc; 0.07 with 1: 1 ethyl acetate: hexane launched), and through this compound of flash chromatography purifying, with 10% ethanol/methylene as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=8.53(t,J=2.8?Hz,1H),7.95(m,1H),7.63(m,1H),7.46(m,2H),7.20(m,1H),7.10(d,J=2.75?Hz,0.5H),7.01(d,J=2.75?Hz,0.5H),4.60(m,2H),3.94(m,1H),3.71(s,1.5H),3.54(s,1.5H),1.90-0.80(m,12H)。

¹³C-nmr(CDCl ₃):δ=173.82,173.50,173.40,172.96,143.65,143.60,143.39,143.32,140.34,140.26,129.57,129.49,127.86,127.78,126.94,126.78,126.54,113.39,112.65,55.69,55.46,53.00,52.86,52.62,52.28,34.42,32.35,28.03,27.79,22.78,22.62,20.22,20.01,14.41,14.12。

C ₁₉H ₂₅N ₃O ₃(MW=343.43)。

Embodiment 48

N-[N-(benzothiazole-2-yl)-L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

According to universal method B, with 2-chloro benzo thiazole (Aldrich) and L-L-Ala (Aldrich), preparation N-(benzothiazole-2-yl)-L-L-Ala.Make this compound and L-nor-leucine methyl ester hydrochloride (Sigma) coupling according to universal method D (without 1N salt acid elution) then, obtain being solid target compound (mp=99-120 ℃).The hexane expansion), and through this product of preparation property plate layer chromatography purifying (Rf=0.42, with 1: 1 ethyl acetate:, with 1: 1 ethyl acetate: the methyl alcohol of hexane and 5: 95: methylene dichloride was as eluent in one reaction through tlc monitoring back.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.66-7.03(m,6H),4.69(m,1H),4.58(m,1H),3.72(s,1.9H),3.61(s,1.1H),1.91-1.50(m,5H),1.32-1.08(m,4H),0.87-0.65(m,3H)。

¹³C-nmr(CDCl ₃):δ=175.8,170.3,166.8,160.2,152.3,148.4,132.1,131.1,126.8,126.5,122.6,122.0,121.4,120.9,119.4,54.3,54.2,53.0,52.9,3.5,28.1,28.0,23.9,22.9,19.0,18.8,14.2。

C ₁₇H ₂₃N ₃O ₃S (MW=349.46); Mass spectrum (MH ⁺) 350.

Embodiment 49

N-[N-(3, the 5-difluorophenyl)-D, L-alanyl]-L-alanine methyl ester synthetic

According to universal method E, with L-alanine methyl ester hydrochloride (Sigma) and N-(3, the 5-difluorophenyl)-D, L-L-Ala (deriving from the foregoing description C) is prepared as solid target compound (mp=93-95 ℃).Monitor this reaction (Rf=0.4 launches with 3% ethanol/methylene) through tlc, and through this compound of flash chromatography purifying, with 3% ethanol/methylene wash-out.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=6.9(q),6.25(t),6.10(q),5.3(s),4.6(m),4.25(m),33.7-3.8(m),1.8(s),1.5(d),1.4(q),1.25(s)。

¹³C-nmr(CDCl ₃):δ=173.78,173.51,173.44,173.27,166.24,166.09,163.04,162.83,149.41,149.37,97.47,97.34,97.20,97.09,96.82,95.08,95.03,94.73,94.69,94.39,94.34,55.27,55.22,53.10,53.02,48.46,48.35,19.99,19.87,18.72,18.66。

C ₁₃H ₁₆N ₂O ₃F ₂(MW=286.3); Mass spectrum (MH ⁺) 287.

Embodiment 50

N-[N-(3, the 5-difluorophenyl)-D, L-alanyl]-(S)-2-aminohexanoic acid methyl esters synthetic

According to universal method E, with L-nor-leucine methyl ester hydrochloride (Sigma) and N-(3, the 5-difluorophenyl)-D, the L-L-Ala is prepared as solid target compound (mp=93-95 ℃).Monitor this reaction (Rf=0.6 launches with 3% ethanol/methylene) through tlc, and through this compound of flash chromatography purifying, with 3% ethanol/methylene wash-out.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=6.95(q),6.85(d),6.25(t),6.15(t),4.6(m),4.3(m),3.8(m),3.75(s),3.70(s),1.8(m),1.65(m),1.55(d),1.3(m),1.1(m),0.85(t),0.80(t)。

¹³C-nmr(CDCl ₃):δ=173.64,173.42,173.35,173.04,149.38,149.23,97.52,97.21,97.14,96.83,95.10,95.05,94.75,94.70,94.41,77.61,77.19,55.34,55.25,52.97,52.87,52.58,52.25,32.41,27.96,27.74,22.79,22.68,20.05,19.87,14.39,14.25。

C ₁₆H ₂₂N ₂O ₃F ₂(MW=328.3); Mass spectrum (MH ⁺) 329.

Embodiment 51

N-[N-(3, the 4-dichlorophenyl)-L-alanyl]-(S)-2-aminocaproamide synthetic

(use DMF according to universal method D as solvent, use ethyl acetate extraction, without 1N salt acid elution), with L-norleucyl-amine (according to universal method F, by BOC-L-norleucyl-amine (deriving from the foregoing description F) preparation) and N-(3, the 4-dichlorophenyl)-L-L-Ala (J makes 3 according to universal method, and 4-dichlorphenamide bulk powder (Aldrich) and R-(+)-isobutyl lactate (Aldrich) react, then be hydrolyzed according to universal method C), be prepared as solid target compound (mp=184-186 ℃).Monitor this reaction (Rf=0.48, with 12% ethanol/methylene launch) through tlc, and through this compound of preparation property plate layer chromatography purifying, with 12% ethanol/methylene as developping agent.

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=6.97(d,J=8.79Hz,1H),6.51(d,J=2.68Hz,1H),6.32(dd,J=8.73Hz,J=2.68Hz,1H),4.14(m,1H),3.67(q,J=6.96?Hz,1H),1.40(m,10H),0.70(m,3H)。

¹³C-nmr(CDCl ₃):δ=177.19,177.11,149.41,134.05,132.13,121.38,115.82,114.96,55.26,54.48,33.92,29.54,23.95,19.58,14.83。

C ₁₅H ₂₁N ₃O ₂Cl ₂(MW=346.26); Mass spectrum (MH ⁺) 346.

Embodiment 52N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-the closing of amino oneself (N-the benzyl)-acid amides of 2-

Become

According to above-mentioned universal method H, with N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-(S)-and 2-aminohexanoic acid methyl esters (deriving from the foregoing description 15) and benzylamine (Aldrich), be prepared as solid target compound (mp=141-146 ℃).Monitor this reaction (Rf=0.32, with 5% ethanol/methylene launch) through silica gel tlc, and through this compound of preparation property plate layer chromatography purifying, silica gel, with 5% ethanol/methylene as developping agent.

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=7.6(m,2H),7.2(m,6H),6.6(m,1H),6.3(m,1H),4.47(m,4H),3.75(m,1H),1.28(m,12H)。

¹³C-nmr(CDCl ₃):δ=174.56,174.50,172.39,172.32,146.78,146.65,138.38,133.43,133.38,131.22,129.21,128.06,121.98,121.72,121.66,115.21,115.08,113.73,113.55,54.94,54.36,53.60,53.22,43.95,33.10,32.98,28.24,27.95,22.96,22.90,19.78,19.70,14.49,14.41。

C ₂₂H ₂₇Cl ₂N ₃O ₂(MW=436.39); Mass spectrum (MH ⁺) 436.

Embodiment 53N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-2-amino-2-phenylethyl alcohol synthetic

According to above-mentioned universal method E, with N-(3, the 4-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description A) and (S)-(+)-2-phenyl glycinol (Aldrich) is prepared as solid target compound (mp=66-70 ℃).Monitor this reaction (Rf=0.25, with 5% ethanol/methylene launch) through silica gel tlc, and through this compound of rapid column chromatography purifying, silica gel, with 5% ethanol/methylene as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.4-7.1(m,6H),6.75(d,J=3Hz,1H),6.5-6.4(m,1H),5(m,1H),4.2-4.0(m,J=4Hz,1H),3.8(2H),1.7(s,1H),1.55(m,3H)。

¹³C-nmr(CDCl ₃):δ=174,146,139,134,131.8,129.5,128.5,127,123,116,114,112,67,56.5,55.5,20。

C ₁₆H ₁₈Cl ₂N ₂O ₂(MW=341); Mass spectrum (MH ⁺) 342.

Embodiment 54 and 55

N-[N-(3, the 5-dichlorophenyl)-D, L-phenyl glycyl H-alanine methyl ester synthetic

According to above-mentioned universal method E, with N-(3, the 5-dichlorophenyl)-D, L-phenylglycocoll (deriving from the foregoing description J) and L-alanine methyl ester hydrochloride (Sigma), preparation target compound.Monitor this reaction (Rf=0.95 launches with 3% ethanol/methylene) through tlc, and through this compound of recrystallization purifying from ethyl acetate, hexane and ether.Obtain the mixture of two isolating diastereomers of part

The NMR data are as follows:

¹H-nmr (CDCl ₃-75% isomer A/25% isomer B): δ=7.45-7.35 (m, 5H), 6.7 (m, 2H), 6.47 (m, 2H), 5.1-5.0 (dd, J=3Hz, 1H), 4.75 (d, J=3.5Hz, 1H), 4.65-4.5 (m, 7.2Hz, 1H), 3.75-3.68 (2s, 3: 1 ratio, 3H), 1.43-1.3 (2d, 3: 1 ratio, J=7.2Hz, 3H).

¹³C-nmr (CDCl ₃-75% isomer A/25% isomer B): δ=173.27,170.24,148.61,138.23,136.07,136.00,130.11,129.60,129.58,127.83,127.69,119.10,112.68,112.56,78.03,63.27,53.20,48.94,18.85.

¹H-nmr (CDCl ₃-25% isomer A/75% isomer B): δ=7.45-7.35 (m, 5H), 6.7 (m, 2H), 6.47 (m, 2H), 5.1-5.0 (2 * d, J=3Hz, 1H), 4.75 (d, J=3.5Hz, 1H), 4.65-4.5 (m, J=7.2 Hz, 1H), 3.75-3.68 (2s, 3: 1 ratio, 3H), 1.43-1.3 (2d, 1: 3 ratio, J=7.2Hz, 3H).

¹³C-nmr (CDCl ₃-25% isomer A/75% isomer B): δ=173.27,170.24,148.61,138.23,136.07,136.00,130.11,129.60,129.58,127.83,127.69,119.10,112.68,112.56,78.03,63.27,53.20,48.94,18.85.

C ₁₈H ₁₈N ₂O ₃Cl ₂(MW=381.26); Mass spectrum (MH ⁺) 381.

Embodiment 56

N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-2-amino-hexanol synthetic

According to above-mentioned universal method I, with N-[N-(3, the 4-dichlorophenyl)-D, L-alanyl]-(S)-2-aminohexanoic acid methyl esters (deriving from the foregoing description 15), be prepared as the target compound of oily matter.Monitor this reaction (Rf=0.16 and 0.17, with 5% ethanol/methylene launch) through silica gel tlc, and through this compound of preparation property plate layer chromatography purifying, with 5% ethanol/methylene as eluent.

The NMR data are as follows:

¹H-nmr(CD ₃OD):δ=7.20(d,1H),6.79(m,1H),6.68(dd,1H),6.43(d,1H),4.42(bd,0.6H),4.30(bd,0.4H),3.89(m,1H),3.75(m,1H),3.70-3.40(m,2H),1.60-0.95(m,9H),0.90-0.70(m,3H)。

¹³C-nmr(CD ₃OD):δ=174.42,174.17,146.06,145.96,132.89,132.85,130.74,130.69,121.64,121.49,114.98,114.70,113.14,113.08,65.42,65.11,55.00,54.76,51.69,51.48,30.67,30.59,28.16,28.00,22.48,22.36,19.44,13.92,13.82。

C ₁₅H ₂₂C ₁₂N ₂O ₂(MW=333.26); Mass spectrum (MH ⁺) 333.

Embodiment 57N-[N-(3, the 5-dichlorophenyl)-D, L-alanyl]-(S)-2-amino-2-phenylethyl alcohol synthetic

According to above-mentioned universal method E, with N-(3, the 5-dichlorophenyl)-D, L-L-Ala (deriving from the foregoing description B) and (S)-(+)-2-phenyl glycinol (Aldrich) prepares target compound.

Embodiment 58N-[N-(3,5-two aminophenyls)-L-alanyl]-the L-phenylglycocoll tert-butyl ester synthetic

According to universal method D (without 1N salt acid elution), with N-(3, the 5-dichlorophenyl)-(J makes 3 to the L-L-Ala according to universal method, 5-dichlorphenamide bulk powder (Aldrich) and R-(+)-lactic acid tert-butyl ester (Aldrich) reaction, then according to the universal method C preparation that is hydrolyzed) and L-phenylglycocoll tert-butyl ester hydrochloride (Bachem), prepare target compound.Monitor this reaction (Rf=0.39 launches with 25% ethyl acetate/hexane) through tlc, and, launch with 25% ethyl acetate/hexane through this compound of preparation property plate layer chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.55(bd,J=7.39Hz,1H),7.30(s,5H),6.73(t,J=1.68Hz,1H),6.46(d,J=1.71Hz,2H),5.45(d,J=7.45Hz,1H),4.47(d,J=5.19Hz,1H),3.82(m,1H),1.40(d,J=6.96Hz,3H),1.34(s,9H)。

¹³C-nmr(CDCl ₃):δ=173.23,169.92,148.93,137.43,136.07,129.40,128.85,127.40,119.04,112.48,83.42,57.37,54.70,28.29,19.79。

C ₂₁H ₂₄N ₂O ₃Cl ₂(MW=423.34); Mass spectrum (MH ⁺) 423.

Embodiment 59N-[N-(3,5-two (trifluoromethyl) phenyl)-L-alanyl]-the L-phenylglycocoll tert-butyl ester

Synthetic

According to universal method D, use N-[3,5-two (trifluoromethyl) phenyl]-L-L-Ala (deriving from the foregoing description G) and L-phenylglycocoll tert-butyl ester hydrochloride (Bachem), the preparation target compound.Monitor this reaction (Rf=0.46 launches with 25% ethyl acetate/hexane) through tlc.

The NMR data are as follows:

¹H-nmr(CDCl ₃):δ=7.39(d,J=7.39Hz,1H),7.29(s,5H),6.96(s,2H),5.45(d,J=7.51Hz,1H),4.69(d,J=5.31Hz,1H),3.95(m,1H),1.48(d,J=6.96Hz,3H),1.33(s,9H)。

¹³C-nmr(CDCl ₃):δ=172.7,169.9,147.9,137.3,132.8,132.4,129.42,139.34,129.31,128.9,127.4,127.2,127,122.1,113.50,113.47,112.34,112.29,112.24,83.5,57.3,54.6,28.34,28.30,28.2,19.8。

C ₂₃H ₂₄N ₂O ₃F ₆(MW=490.45)。

Embodiment 60N-[N-(3, the 5-Dimethoxyphenyl)-D, L-alanyl]-(S)-the 2-aminohexanoic acid methyl esters-close

Become

According to universal method E (, use ethyl acetate extraction) with dilute hydrochloric acid washing, usefulness N-(3, the 5-Dimethoxyphenyl)-D, L-L-Ala (deriving from the foregoing description H) and L-nor-leucine methyl ester hydrochloride (Sigma) are prepared as the target compound of faint yellow oily thing.Monitor this reaction (Rf=0.3 launches with 30% ethyl acetate/hexane) through tlc.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=0.6-0.9 (at 0.72 and 0.82 place two three peaks are arranged, J=7Hz, 3H), 1.0-1.9 (m, 9H), 3.6-3.7 (have at 3.60,3.65,3.66 and 3.67 places four unimodal, 10H), 3.7-3.8 (m, 1H), 4.6-4.7 (m, 1H), and 5.7-5.95 (m, 3H), 7.1-7.3 (m, 1H).

¹³C-nmr(CDCl ₃):δ=14.21,14.35,19.8,20.0,22.69,22.74,27.8,28.0,32.20,32.45,52.18,52.57,52.65,52.78,55.31,55.52,55.59,55.63,91.6,91.8,92.86,93.24,149.02,149.27,162.11,162.18,173.02,173.44,174.47,174.82。

C ₁₈H ₂₈N ₂O ₅(MW=352.43)。

Embodiment 61

The cell screening of the detection of the inhibitor that amyloid beta produces

In clone, measure above-mentioned multiple formula I compound, suppress the ability that amyloid beta produces to estimate them with Swedish sudden change.Cell (K293=human kidney cells system) is used in this screening assay, can be according to International Patent Publication No. W 94/10569 ⁸With Citron etc. ¹¹Described method is carried out stable transfection with this clone of amyloid precursor protein 751 (APP751) gene pairs, and described precursor protein has two sudden changes, promptly by Lys ₆₅₁Met ₆₅₂Sport Asn ₆₅₁Leu ₆₅₂(APP751 numbering).This sudden change is commonly called the Swedish sudden change, and the cell that will be called " 293 751 SWE " is with every hole 1.5-2.5 * 10 ⁴The concentration of cell adds in each hole (containing available from Sigma St.Louis, the DulbeccoShi minimum essential medium of MO+10% foetal calf serum) of Coming 96-well culture plate.For the ELISA result of (about 0.2-2.5ng/ml) acquisition amyloid beta in the setting-out line scope, the number of cell is very important.

In 37 ℃, in the incubator of 10% carbon dioxide balance after the overnight incubation, remove substratum, every hole adds substratum that 200 μ l contain formula I compound (medicine) and substitutes and carry out two hours pre-treatment, and as the preincubation cell.Preparation medicine storage liquid makes in the medicine final concentration used when handling in 100% DMSO, and the concentration of dimethyl sulfoxide (DMSO) is no more than 0.5%, in fact is generally 0.1%.

After pre-treatment finishes, remove substratum once more, replace with the fresh culture that contains medicine, cell was hatched two hours again.After the processing, in room temperature, 1200rpm, with culture plate on Beckman GPR centrifugal 5 minutes, with sedimentation cell fragment from conditioned medium.According to International Patent Publication No. W 94/10569 ⁸Described method, from each hole, get 100 μ l conditioned mediums or its proper diluent, be transferred to and use antibody 266[P.Seubert, Nature (1992) 359:325-327] wrap in advance on the ELISA culture plate of quilt, this antibody is the antibody of the amino acid/11 3-28 of beta amyloid peptide, with above-mentioned culture plate in 4 ℃ of store overnight.At second day, use traget antibody 6C6[P.Seubert, Nature (1992) 359:325-327] carry out ELISA mensuration, to detect the amount that beta amyloid peptide produces, this antibody is the antibody of directed against amyloid-beta peptide amino acid/11-16.

According to Hansen etc. ¹²The modification method of method, the cellulotoxic effect of mensuration compound.The 3-(4,5-dimethylthiazole-2-yl)-2 that adds 25 μ l in the residual cell in tissue culturing plate, 5-phenylbenzene tetrazolium bromide (MTT) (available from Sigma, St.Louis, MO) storing solution (5mg/ml), to final concentration be 1mg/ml.In 37 ℃, cell was hatched 1 hour, (50% dimethyl formamide solution of 20%w/v sodium lauryl sulphate pH4.7) stops cytoactive to add isopyknic MTT lysis buffer.Spend the night to obtain extraction fully in the room temperature jolting.At Molecular Device ' s UV _MaxMicrotiter plate is read to measure OD on the plate instrument _562nmAnd OD _650nmDifference, as the index of cells survival rate.

The result of beta amyloid peptide ELISA is fitted to typical curve, and represent with the beta amyloid peptide of ng/ml.For carrying out Cytotoxic normalization method,, and represent with the per-cent of the results of comparison that do not contain medicine with the result of these results divided by MTT.All results are the mean value and the standard deviation of at least six replications.

Measure the inhibition activity that the detection test-compound produces beta amyloid peptide with this in cell.The result of this mensuration proves that compared with the control each compound among the embodiment 1-60 all produces beta amyloid peptide has 30% inhibition at least.

Embodiment 62

Amyloid beta discharges and/or the synthetic body is interior suppresses

How this embodiment explanation detects compound of the present invention to suppressing in amyloid beta release and/or the synthetic body.In these experiments, use the PDAPP mouse [Games etc. (1995) Nature 373:523-527] at 3-5 monthly age.According to the difference of compound to be tested, usually compound is formulated as 5 or the concentration of 10mg/ml.Because the low deliquescent factor of these compounds, thus can in various solvents, prepare, as Semen Maydis oil (Safeway, South San Francisco, CA); 10% ethanol Semen Maydis oil; 2-hydroxypropyl-beta-cyclodextrin (Research Biochemicals Intemational, Natick MA) and carboxymethyl cellulose (Sigma Chemical Co., St.Louis MO).

With the subcutaneous mouse medicines of giving of No. 26 pins, after 3 hours, suffocating through carbonic acid gas makes described animal euthanasia, with 1 cc 25G 5/8 " tuberculin syringe/pin (scribbles 0.5M EDTA solution, pH8.0) carries out puncture of heart and get blood.Blood is placed Becton-Dickinson vacuum (vacutainer) pipe that contains EDTA, in 5 ℃, with 1500 * g rotation 15 minutes.Take out mouse brain then, separate and cut cortex and hippocampus, place on ice.

1. brain is measured

With the electronic pestle (Fisher of Kontes, Pittsburgh PA), with ice-cold guanidine damping fluid (5.0M Guanidinium hydrochloride, the 50mM Tris-HCl of each brain zone at 10 times of volumes, pH8.0) homogenize in is used for the hippocampus and the cortical tissue of enzyme-linked immunosorbent assay (ELISAs) with preparation.Under room temperature, homogenate was shaken on universal stage 3-4 hour gently, store the quantitative of pending amyloid beta in-20 ℃.

With ice-cold casein damping fluid [0.25% casein, phosphate buffered saline (PBS) (PBS), 0.05% sodiumazide, 20 μ g/ml press down enzyme peptide, 5mM EDTA, pH8.0,10 μ g/ml leupeptins] with 1: 10 dilution brain homogenate, therefore the final concentration of guanidine is reduced to 0.5M, then in centrifugal 20 minutes of 4 ℃, 16,000 * g.Preparation amyloid beta standard substance (1-40 or 1-42 amino acid) make to form eventually and contain 0.5M guanidine and 0.1% bovine serum albumin (BSA).

Total amyloid beta sandwich ELISA contains two monoclonal antibodies (mAb) of amyloid beta, and this sandwich ELISA is amyloid beta (aa1-40) and amyloid beta (aa1-42) quantitatively.Capture antibodies 266[P.Seubert, Nature (1992) 359:325-327] be the specific antibody of the amino acid/11 3-28 of amyloid beta.Biotinylated antibody 3D6[Johnson-Wood etc., PNAS USA (1997) 94:1550-1555] be the specific antibody of the amino acid/11-5 of amyloid beta, this antibody in mensuration with the antibody of giving a report.The biotinylated method of 3D6 according to manufacturer [pierce, Rockford IL] about the biotin labeled method of the NHS-of immunoglobulin (Ig), but with the pH of 100mM sodium bicarbonate be 8.5 damping fluid.3D6 antibody can not be discerned the precursor protein (APP) of excretory amyloid or the APP of total length, but can detect the amyloid beta class with N-terminal aspartic acid.The susceptibility lower limit of this mensuration is about 50pg/ml (11pM), the endogenous beta amyloid peptide is not shown cross reactivity at the concentration height during to 1ng/ml.

Quantitatively the sandwich ELISA configuration of amyloid beta level uses as the mAb 21F12[Johnson-Wood of capture antibodies etc., PNAS USA (1997) 94:1550-1555] (can discern the amino acid 33-42 of amyloid beta).The biotinylated 3D6 that uses in this mensuration also is a report antibody, and its susceptibility lower limit is about 125pg/ml (28pM).

Under room temperature, with 266 and 21F12 catch mABs and in 96 holes immunity culture plates (Costar, Cambidge MA), spent the night with 10 μ g/mL bag.Substratum in the sucking-off culture plate then, under room temperature, with the PBS damping fluid sealing of 0.25% human serum albumin at least 1 hour, then in 4 ℃, dry store down stand-by.Sample and standard substance are added in the culture plate, in 4 ℃ of overnight incubation.Between each step of measuring, all described culture plate is washed 3 times at least with lavation buffer solution.Under room temperature, biotinylated 3D6 (was hatched in each hole 1 hour with casein incubation buffer (0.05%Tween 20 for 0.25% casein, PBS, pH7.4) are diluted to 0.5 μ g/ml).Under room temperature, will add in each hole 1 hour with the avidin-HRP (carrier, Burlingame CA) of dilution in 1: 4000 with the casein incubation buffer.(Pierce CambridgeMA), makes its reaction 15 minutes, adds 2N sulfuric acid then and stops enzyme reaction to add chromogenic substrate SloW TMB-ELISA.With MolecularDevices Vmax (Molecular Devices, Menlo Park CA), in the difference of 450nm and 650nm place mensuration optical density, so that reaction product is carried out quantitatively.

2. blood measuring

With edta plasma at sample diluting liquid (0.2g/L sodium phosphate monohydrate (monoatomic base), 2.1 6g/L sodium phosphate heptahydrates (diacidic base), 0.5g/L Thiomersalate, 8.5g/L sodium-chlor, 0.5ml Triton X-405,6.0g/L do not contain the bovine serum albumin and the water of sphaeroprotein) in carry out 1: 1 the dilution.According to method described in the above-mentioned brain mensuration,, but replace described casein diluent with sample diluting liquid with sample and the standard substance in total amyloid beta mensuration (266 seizure/3D6 report antibody) working sample diluent.

As can be seen, those skilled in the art can carry out various modifications and change to composition and method from above-mentioned description.All are revised all in the scope that appended claim comprises.

Sequence table (1) physical data (ⅰ) applicant: ATHENA NEUROSCIENCES, INC.

ELILILLY&COMPANY

JAMES?E.AUDIA

BEVERLY?K.FOLMER

VARCHESE?JOHN

LEE?H.LATIMER

JEFFREY?S.NISSEN

WARREN?J.PORTER

EUGENE?D.PHORSETT

JING WU (ⅱ) denomination of invention: N-(aryl/hetaryl) amino acid derivative, comprise these derivatives

Medicinal compositions and suppress beta amyloid peptide with these compounds

Discharge and/or its synthetic method (ⅲ) sequence number: 1 (ⅳ) mailing address:

(A) addressee: Burns, Doane, Swecker﹠amp; Mathis, LLP

(B) street: P.O.Box 1404

(C) city: Alexandria

(D) state: Virginia

(E) country: the U.S.

(F) postcode: 22313-1404 (ⅴ) computer-reader form

(A) medium type: floppy disk

(B) computer: IBM compatible

(C) operating system: PC-DOS/MS-DOS

(D) software: PatentIn Release#1.0, the current request for data of version 1.30 (ⅵ)

(A) application number: do not issue

(B) submission date: Unassigned

(C) classification: (ⅶ) request for data formerly

(A) application number: US 08/755,334

(B) submission date: on November 22nd, 1996 (ⅷ) attorney/proxy's data

(A) name: Swiss, Gerald F.

(B) number of registration: 30,113

(C) reference/file number: 002010-057 (ⅸ) telecommunication data

(A) phone: 650-854-7400

(B) fax: the information of 650-854-8275 (2) SEQ ID NO:1:

(ⅰ) sequence signature:

(A) length: 43 amino acid

(B) type: peptide

(D) topology: linearity

(ⅱ) molecule type: peptide

(ⅹ ⅰ) sequence description: SEQ ID NO 1:Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His1 5 10Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys15 20 25Gly Ala Ile Ile Gly Leu Met Val Gly Gly Val Val Ile Ala

30??????????????????35??????????????????40Thr

Claims (77)

1. suppressing beta-amyloid polypeptide 1-in cell discharges and/or its synthetic method, this method comprises that giving this type of cell suppresses beta-amyloid polypeptide 1-release and/or the compound of its synthetic significant quantity or the mixture of compound in the cell, and wherein said compound is represented by the formula I:

I is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II:

II

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group,

Halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cWith benzene

Basic ring condenses and forms heteroaryl or heterocycle,

R ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or

The person is the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group,

Aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and sulfo-

Aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen alkane

Base, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the cycloalkanes of hydrogen, alkyl, replacement

Base, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Carbon atom, the optional individual heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains,

And optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃

2. the method for prevention AD onset in the patient that the AD initiation potential is arranged, this method comprise the medicinal compositions of the mixture that gives formula I compound that described patient comprises medicinal inert carrier and significant quantity or compound:

I is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II:

II

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group,

Halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cWith benzene

Basic ring condenses and forms heteroaryl or heterocycle,

R ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or

The person is the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group,

Aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and sulfo-

Aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen alkane

Base, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the cycloalkanes of hydrogen, alkyl, replacement

Base, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Carbon atom, the optional individual heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains,

And optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃

3. the treatment patient that suffers from AD to be suppressing the method that this patient's state of an illness further worsens, and this method comprises the medicinal compositions of the mixture that gives formula I compound that described patient comprises medicinal inert carrier and significant quantity or compound:

I is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II: II is R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group, halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cCondense formation heteroaryl or heterocycle, R with benzyl ring ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or

The person is the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group,

Aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and sulfo-

Aryloxy, prerequisite be described substituting group be connected-heteroaryl of NH group is not the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen alkane

Base, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the cycloalkanes of hydrogen, alkyl, replacement

Base, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Carbon atom, the optional individual heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains,

And optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃

4. claim 1,2 or 3 method, wherein R ¹Be phenyl, 2-naphthyl, quinoline-3-base, benzothiazole-6-base and 5-indyl.

5. claim 1,2 or 3 method, wherein R ¹Phenyl for the replacement of following formula:

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group, halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cCondense formation heteroaryl or heterocycle, R with benzyl ring ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group and thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or all be the substituting group that is not hydrogen.

6. claim 1,2 or 3 method, wherein R ¹For being selected from the 2-naphthyl that following substituting group replaces by 1-5: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group, thio alkoxy, aryl and heteroaryl at 4,5,6,7 and/or 8.

7. claim 1,2 or 3 method, wherein R ¹For containing the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group, aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and thio-aryloxy, prerequisite be described substituting group be connected-heteroaryl of NH group is not the ortho position.

8. the method for claim 7, wherein R ¹Replace for 4-, 3,5-is dibasic or 3, the dibasic phenyl of 4-.

9. the method for claim 8, wherein R ¹Be 3, the dibasic phenyl of 5-.

10. the method for claim 9, wherein said 3, the dibasic phenyl of 5-is selected from 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-two (trifluoromethyl) phenyl and 3,5-Dimethoxyphenyl.

11. the method for claim 8, wherein R ¹Be 3, the dibasic phenyl of 4-.

12. the method for claim 11 is wherein said 3, the dibasic phenyl of 4-is selected from 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chloro-phenyl-, 3-chloro-4-cyano-phenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl base.

13. the method for claim 8, wherein R ¹Phenyl for the 4-replacement.

14. the method for claim 13, the phenyl that wherein said 4-replaces is selected from 4-azido-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-cyano-phenyl, 4-ethylphenyl, 4-fluoro phenyl, 4-iodine substituted phenyl, 4-(phenylcarbonyl group) phenyl and 4-(1-oxyethyl group) ethylphenyl.

15. claim 1,2 or 3 method, wherein R ¹Be 2-toluquinoline-6-base.

16. claim 1,2 or 3 method, wherein R ²Be selected from the alkyl of 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, the alkylthio alkoxyl group and the aryl of a 1-4 carbon atom.

17. the method for claim 16, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-,-CH ₂CH ₂SCH ₃And phenyl.

18. claim 1,2 or 3 method, wherein R ³Be alkyl.

19. the method for claim 18, wherein said alkyl are methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and sec-butyl.

20. claim 1,2 or 3 method, wherein R ³Be the alkyl that replaces.

21. the method for claim 20, the alkyl of wherein said replacement be selected from the Alpha-hydroxy ethyl ,-CH ₂-cyclohexyl, benzyl, right-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-two iodos-4-hydroxybenzyl ,-CH ₂-indol-3-yl ,-(CH ₂) ₄-NH-BOC ,-(CH ₂) ₄-NH ₂,-CH ₂-(1-N-benzyl-imidazol-4 yl) ,-CH ₂-imidazol-4 yl ,-CH ₂CH ₂SCH ₃,-(CH ₂) ₄NHC (O) (CH ₂) ₃CH ₃With-(CH ₂) _yC (O) OR ⁵, wherein y is 1 or 2, R ⁵Hydrogen, methyl or the tertiary butyl.

22. claim 1,2 or 3 method, wherein X is-C (O) Y, and wherein Y is selected from alkoxyl group and thio alkoxy.

23. the method for claim 22, wherein Y is selected from following alkoxyl group: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy and tert.-butoxy.

24. claim 1,2 or 3 method, wherein X is-C (O) Y, Y is-NR ' R "; wherein R ' and R " independently be selected from alkyl, cycloalkyl, aryl, heteroaryl, the heterocycle of hydrogen, alkyl, replacement, and R ' and R " have 2-8 carbon atom in conjunction with forming, optionally also to contain 1-2 heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen, and optional by one or more alkyl or alkoxyl group replacement.

25. the method for claim 24, wherein Y is selected from amino (NH ₂), N-(isobutyl-) amino, N-methylamino-, N, N-dimethylamino and N-benzyl amino.

26. claim 1,2 or 3 method, wherein X is-CH ₂OH.

27. claim 1; 2 or 3 method; wherein said formula I compound is selected from following compounds and pharmacy acceptable salt thereof: N-[N-(3; the 4-dichlorophenyl) alanyl] valine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-isobutyramide N-[N-(3; the 4-dichlorophenyl) alanyl] Threonine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan ethyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan tert-butyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] valine amide N-(3; the 4-dichlorophenyl) L-Ala N-(1-hydroxy-3-methyl-2-butyl) acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N; N-dimethylformamide N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-methyl nitrosourea N-[N-(3; the 4-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] leucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Isoleucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] tryptophan methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazole-6-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(methyl esters) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-1-benzyl Histidine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] glutamic acid gamma-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] leucyl amine N-[N-(3; the 4-dichlorophenyl) alanyl] L-glutamic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-(3; 5-two iodos) L-Tyrosine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-(3-iodo) L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) glycyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N ε-(caproyl) lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanyl amine N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl]-β-Cyclohexylalanine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3, the 4-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] methionine(Met) methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3, the 5-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Histidine methyl esters N-[N-(quinoline-3-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-benzothiazole-2-yl)-the L-alanyl]-2-aminohexanoic acid methyl esters N-[N-(3, the 5-difluorophenyl) alanyl] alanine methyl ester N-[N-(3, the 5-difluorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl)-the L-alanyl]-S-2-aminocaproamide N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-benzyl)-acid amides N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3; the 5-dichlorophenyl) phenyl glycyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino-hexanol N-[N-(3, the 5-dichlorophenyl) alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3, the 5-dichlorophenyl)-L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3; 5-two-(trifluoromethyl) phenyl)-the L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3, the 5-Dimethoxyphenyl)-L-alanyl]-the 2-aminohexanoic acid methyl esters.

28. contain the medicinal inert carrier and the medicinal compositions of the formula I compound of significant quantity pharmaceutically:

I is wherein: R ¹Be selected from: (a) phenyl, (b) phenyl of the replacement of formula II:

II

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group,

Halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cWith benzene

Basic ring condenses and forms heteroaryl or heterocycle,

R ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group

And thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or

The person is the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 replaces

The 2-naphthyl: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group, sulphur

For alkoxyl group, aryl and heteroaryl,

(e) heteroaryl and

(f) contain the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group,

Aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and sulfo-

Aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen alkane

Base, α-diazonium alkyl-alpha-OC (O) or alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the cycloalkanes of hydrogen, alkyl, replacement

Base, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Carbon atom, the optional individual heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains,

And optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃

29. the medicinal compositions of claim 26, wherein R ¹Be phenyl, 2-naphthyl, quinoline-3-base, benzothiazole-6-base and 5-indyl.

30. the medicinal compositions of claim 26, wherein R ¹Phenyl for the replacement of following formula:

R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group, halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cCondense formation heteroaryl or heterocycle, R with benzyl ring ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group and thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or all be the substituting group that is not hydrogen.

31. the medicinal compositions of claim 26, wherein R ¹For being selected from the 2-naphthyl that following substituting group replaces by 1-5: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group, thio alkoxy, aryl and heteroaryl at 4,5,6,7 and/or 8.

32. the medicinal compositions of claim 26, wherein R ¹For containing the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group, aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and thio-aryloxy, prerequisite be described substituting group be connected-heteroaryl of NH group is not the ortho position.

33. the medicinal compositions of claim 30, wherein R ¹Replace for 4-, 3,5-is dibasic or 3, the dibasic phenyl of 4-.

34. the medicinal compositions of claim 31, wherein R ¹Be 3, the dibasic phenyl of 5-.

35. the medicinal compositions of claim 32 is wherein said 3, the dibasic phenyl of 5-is selected from 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-two (trifluoromethyl) phenyl and 3,5-Dimethoxyphenyl.

36. the medicinal compositions of claim 31, wherein R ¹Be 3, the dibasic phenyl of 4-.

37. the medicinal compositions of claim 34, wherein said 3, the dibasic phenyl of 4-is selected from 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyano-phenyl, 3-chloro-4-iodine substituted phenyl and 3,4-methylenedioxyphenyl base.

38. the medicinal compositions of claim 31, wherein R ¹Phenyl for the 4-replacement.

39. the medicinal compositions of claim 36, the phenyl that wherein said 4-replaces is selected from 4-azido-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-cyano-phenyl, 4-ethylphenyl, 4-fluoro phenyl, 4-iodine substituted phenyl, 4-(phenylcarbonyl group) phenyl and 4-(1-oxyethyl group) ethylphenyl.

40. the medicinal compositions of claim 26, wherein R ¹Be 2-toluquinoline-6-base.

41. the medicinal compositions of claim 26, wherein R ²Be selected from the alkyl of 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, the alkylthio alkoxyl group and the aryl of a 1-4 carbon atom.

42. the medicinal compositions of claim 39, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-,-CH ₂CH ₂SCH ₃And phenyl.

43. the medicinal compositions of claim 26, wherein R ³Be alkyl.

44. the medicinal compositions of claim 41, wherein said alkyl are methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and sec-butyl.

45. the medicinal compositions of claim 26, wherein R ³Be the alkyl that replaces.

46. the medicinal compositions of claim 43, the alkyl of wherein said replacement be selected from the Alpha-hydroxy ethyl ,-CH ₂-cyclohexyl, benzyl, right-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-two iodos-4-hydroxybenzyl ,-CH ₂-indol-3-yl ,-(CH ₂) ₄-NH-BOC ,-(CH ₂) ₄-NH ₂,-CH ₂-(1-N-benzyl-imidazol-4 yl) ,-CH ₂-imidazol-4 yl ,-CH ₂CH ₂SCH ₃,-(CH ₂) ₄NHC (O) (CH ₂) ₃CH ₃With-(CH ₂) _yC (O) OR ₅, wherein y is 1 or 2, R ⁵Be hydrogen, methyl or the tertiary butyl.

47. the medicinal compositions of claim 26, wherein X is-C (O) Y, and wherein Y is selected from alkoxyl group and thio alkoxy.

48. the medicinal compositions of claim 45, wherein Y is selected from following alkoxyl group: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy and tert.-butoxy.

49. the medicinal compositions of claim 26, wherein X is-C (O) Y, Y is-NR ' R "; wherein R ' and R " independently be selected from alkyl, cycloalkyl, aryl, heteroaryl, the heterocycle of hydrogen, alkyl, replacement, and R ' and R " have 2-8 carbon atom in conjunction with forming, optionally also to contain 1-2 heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen, and optional by one or more alkyl or alkoxyl group replacement.

50. the medicinal compositions of claim 47, wherein Y is selected from amino (NH ₂), N-(isobutyl-) amino, N-methylamino-, N, N-dimethylamino and N-benzyl amino.

51. the medicinal compositions of claim 26, wherein X is-CH ₂OH.

52. the medicinal compositions of claim 26; wherein said formula I compound is selected from following compounds and pharmacy acceptable salt thereof: N-[N-(3; the 4-dichlorophenyl) alanyl] valine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-isobutyramide N-[N-(3; the 4-dichlorophenyl) alanyl] Threonine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan ethyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan tert-butyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] valine amide N-(3; the 4-dichlorophenyl) L-Ala N-(1-hydroxy-3-methyl-2-butyl) acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N; N-dimethylformamide N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-methyl nitrosourea N-[N-(3; the 4-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] leucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Isoleucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] tryptophan methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazole-6-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(methyl esters) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-1-benzyl Histidine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] glutamic acid gamma-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] leucyl amine N-[N-(3; the 4-dichlorophenyl) alanyl] L-glutamic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-(3; 5-two iodos) L-Tyrosine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-(3-iodo) L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) glycyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N ε-(caproyl) lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanyl amine N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl]-β-Cyclohexylalanine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3, the 4-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] methionine(Met) methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3, the 5-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Histidine methyl esters N-[N-(quinoline-3-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-benzothiazole-2-yl)-the L-alanyl]-2-aminohexanoic acid methyl esters N-[N-(3, the 5-difluorophenyl) alanyl] alanine methyl ester N-[N-(3, the 5-difluorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl)-the L-alanyl]-S-2-aminocaproamide N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-benzyl)-acid amides N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3; the 5-dichlorophenyl) phenyl glycyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino-hexanol N-[N-(3, the 5-dichlorophenyl) alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3, the 5-dichlorophenyl)-L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3; 5-two-(trifluoromethyl) phenyl)-the L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3, the 5-Dimethoxyphenyl)-L-alanyl]-the 2-aminohexanoic acid methyl esters.

53. formula III compound:

III is wherein: R ¹Be selected from:

(a) phenyl,

(b) phenyl of the replacement of formula II:

II is R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group, halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cCondense formation heteroaryl or heterocycle, R with benzyl ring ^bAnd R ^b' independently being selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group and thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or all be the substituting group that is not hydrogen,

(c) 2-naphthyl,

(d) being selected from following substituting group at 4,5,6,7 and/or 8 by 1-5 gets

The 2-naphthyl in generation: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group,

Thio alkoxy, aryl and heteroaryl,

(e) heteroaryl and

(f) contain the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group,

Aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and sulfo-

Aryloxy, prerequisite be described substituting group with-heteroaryl that the NH group is connected is not the ortho position; R ²Be selected from the alkyl of hydrogen, a 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, alkylthio alkoxyl group, aryl, heteroaryl, the aryl of replacement and the heteroaryl of replacement of a 1-4 carbon atom, prerequisite is that aryl or the heteroaryl atom that described substituting group is connected with described carbon atom is not the ortho position; R ³Be selected from the alkyl of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, heteroaryl, replacement, the alkenyl of replacement, the alkynyl and the heterocycle of replacement; X is-C (O) Y that wherein Y is selected from:

(a) alkyl,

(b) alkyl of Qu Daiing, prerequisite are that the replacement on the alkyl of described replacement does not comprise alpha-halogen alkane

Base, α-diazonium alkyl or α-OC (O) alkyl,

(c) alkoxyl group or thio alkoxy,

(d) thio alkoxy of alkoxyl group of Qu Daiing or replacement,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocycle,

(i)-and NR ' R ", wherein R ' and R " independently be selected from alkyl, the cycloalkanes of hydrogen, alkyl, replacement

Base, aryl, heteroaryl, heterocycle, and R ' and R " have 2-8 in conjunction with forming

Carbon atom, the optional individual heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen of 1-2 that also contains,

And optional replaced and work as R by one or more alkyl or alkoxyl group ³When containing at least 3 carbon atoms, X also can be-CR ⁴R ⁴Y ', wherein each R ⁴Independently be selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, Y ' be selected from hydroxyl, amino, thiol ,-OC (O) R ⁵,-SSR ⁵,-SSC (O) R ⁵, R wherein ⁵Be selected from alkyl, cycloalkyl, aryl, heteroaryl and the heterocycle of alkyl, replacement, prerequisite is for working as R ¹Be 3,4-dichlorophenyl, R ²Be methyl, R ³For by D-phenylalanine deutero-benzyl the time, X is not-C (O) OCH so ₃, other prerequisite is not for comprising following compound known:

Work as R ¹Be phenyl, R ²Be methyl, X is-during C (O) NH Φ, so R ³Be not methyl,

Sec.-propyl, isobutyl-; With

Work as R ¹Be phenyl, R ²Be methyl, X is-C (O) NH ₂The time, R so ³It or not benzyl.

54. the compound of claim 51, wherein R ¹Be phenyl, 2-naphthyl, quinoline-3-base, benzothiazole-6-base and 5-indyl.

55. the compound of claim 51, wherein R ¹Phenyl for the replacement of following formula: R wherein ^cBe selected from acyl group, alkyl, alkoxyl group, alkyl alkoxy, azido-, cyano group, halo, hydrogen, nitro, trihalomethyl group, thio alkoxy, and R ^bAnd R ^cCondense formation heteroaryl or heterocycle, R with benzyl ring ^bAnd R ^{B '}Independently be selected from hydrogen, halo, nitro, cyano group, trihalomethyl group, alkoxyl group and thio alkoxy, prerequisite is for working as R ^cDuring for hydrogen, R so ^bAnd R ^{B '}Perhaps all be hydrogen or all be the substituting group that is not hydrogen.

56. the compound of claim 51, wherein R ¹For being selected from the 2-naphthyl that following substituting group replaces by 1-5: alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group, thio alkoxy, aryl and heteroaryl at 4,5,6,7 and/or 8.

57. the compound of claim 51, wherein R ¹For containing the heteroaryl that 1-3 is selected from following substituent replacement: alkyl, alkoxyl group, aryl, aryloxy, cyano group, halo, nitro, heteroaryl, thio alkoxy and thio-aryloxy, prerequisite be described substituting group be connected-heteroaryl of NH group is not the ortho position.

58. the compound of claim 55, wherein R ¹Replace for 4-, 3,5-is dibasic or 3, the dibasic phenyl of 4-.

59. the compound of claim 56, wherein R ¹Be 3, the dibasic phenyl of 5-.

60. the compound of claim 57 is wherein said 3, the dibasic phenyl of 5-is selected from 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-two (trifluoromethyl) phenyl and 3,5-Dimethoxyphenyl.

61. the compound of claim 56, wherein R ¹Be 3, the dibasic phenyl of 4-.

62. the compound of claim 59, wherein said 3, the dibasic phenyl of 4-is selected from 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyano-phenyl, 3-chloro-4-iodine substituted phenyl and 3,4-methylenedioxyphenyl base.

63. the compound of claim 56, wherein R ¹Phenyl for the 4-replacement.

64. the compound of claim 61, the phenyl that wherein said 4-replaces is selected from 4-azido-phenyl, 4-bromo phenyl, 4-chlorophenyl, 4-cyano-phenyl, 4-ethylphenyl, 4-fluoro phenyl, 4-iodine substituted phenyl, 4-(phenylcarbonyl group) phenyl and 4-(1-oxyethyl group) ethylphenyl.

65. the compound of claim 51, wherein R ¹Be 2-toluquinoline-6-base.

66. the compound of claim 51, wherein R ²Be selected from the alkyl of 1-4 carbon atom, the alkyl alkoxy of a 1-4 carbon atom, the alkylthio alkoxyl group and the aryl of a 1-4 carbon atom.

67. the compound of claim 64, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-,-CH ₂CH ₂SCH ₃And phenyl.

68. the compound of claim 51, wherein R ³Be alkyl.

69. the compound of claim 66, wherein said alkyl are methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and sec-butyl.

70. the compound of claim 51, wherein R ³Be the alkyl that replaces.

71. the compound of claim 68, the alkyl of wherein said replacement be selected from the Alpha-hydroxy ethyl ,-CH ₂-cyclohexyl, benzyl, right-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-two iodos-4-hydroxybenzyl ,-CH ₂-indol-3-yl ,-(CH ₂) ₄-NH-BOC ,-(CH ₂) ₄-NH ₂,-CH ₂-(1-N-benzyl-imidazol-4 yl) ,-CH ₂-imidazol-4 yl ,-CH ₂CH ₂SCH ₃,-(CH ₂) ₄NHC (O) (CH ₂) ₃CH ₃With-(CH ₂) _yC (O) OR ⁵, wherein y is 1 or 2, R ⁵Be hydrogen, methyl or the tertiary butyl.

72. the compound of claim 51, wherein X is-C (O) Y, and wherein Y is selected from alkoxyl group and thio alkoxy.

73. the compound of claim 70, wherein Y is selected from following alkoxyl group: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy and tert.-butoxy.

74. the compound of claim 51, wherein X is-C (O) Y, Y is-NR ' R "; wherein R ' and R " independently be selected from alkyl, cycloalkyl, aryl, heteroaryl, the heterocycle of hydrogen, alkyl, replacement, and R ' and R " have 2-8 carbon atom in conjunction with forming, optionally also to contain 1-2 heteroatomic cyclic group that is selected from oxygen, sulphur and nitrogen, and optional by one or more alkyl or alkoxyl group replacement.

75. the compound of claim 72, wherein Y is selected from amino (NH ₂), N-(isobutyl-) amino, N-methylamino-, N, N-dimethylamino and N-benzyl amino.

76. the compound of claim 51, wherein X is-CH ₂OH.

77. the compound of claim 51; wherein said formula I compound is selected from following compounds and pharmacy acceptable salt thereof: N-[N-(3; the 4-dichlorophenyl) alanyl] valine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-isobutyramide N-[N-(3; the 4-dichlorophenyl) alanyl] Threonine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan ethyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan tert-butyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] valine amide N-(3; the 4-dichlorophenyl) L-Ala N-(1-hydroxy-3-methyl-2-butyl) acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N; N-dimethylformamide N-[N-(3; the 4-dichlorophenyl) alanyl] Xie Ansuan N-methyl nitrosourea N-[N-(3; the 4-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] leucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] Isoleucine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] tryptophan methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N-BOC-lysine methyl ester N-[N-benzothiazole-6-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl] alanine methyl ester N-[N-(3; the 5-dichlorophenyl) alanyl]-2-aminovaleric acid methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl] phenylalanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] aspartic acid β-(methyl esters) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-1-benzyl Histidine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] glutamic acid gamma-(tert-butyl ester) α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl] leucyl amine N-[N-(3; the 4-dichlorophenyl) alanyl] L-glutamic acid α-methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-(3; 5-two iodos) L-Tyrosine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-(3-iodo) L-Tyrosine methyl ester N-[N-(3; the 5-dichlorophenyl) glycyl]-2-aminovaleric acid methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-N ε-(caproyl) lysine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl] phenylalanyl amine N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl]-β-Cyclohexylalanine methyl esters N-[N-(3; the 4-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3, the 4-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] methionine(Met) methyl esters N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N, N-dimethyl)-acid amides N-[N-(3, the 5-dichlorophenyl) alanyl]-2-aminocaproamide N-[N-(3; the 5-dichlorophenyl) alanyl]-2-amino oneself-(N-methyl)-acid amides N-[N-(3; the 4-dichlorophenyl) alanyl] Histidine methyl esters N-[N-(quinoline-3-yl) alanyl]-2-aminohexanoic acid methyl esters N-[N-benzothiazole-2-yl)-the L-alanyl]-2-aminohexanoic acid methyl esters N-[N-(3, the 5-difluorophenyl) alanyl] alanine methyl ester N-[N-(3, the 5-difluorophenyl) alanyl]-2-aminohexanoic acid methyl esters N-[N-(3; the 4-dichlorophenyl)-the L-alanyl]-S-2-aminocaproamide N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino oneself-(N-benzyl)-acid amides N-[N-(3, the 4-dichlorophenyl)-D, the L-alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3; the 5-dichlorophenyl) phenyl glycyl] alanine methyl ester N-[N-(3; the 4-dichlorophenyl) alanyl]-2-amino-hexanol N-[N-(3, the 5-dichlorophenyl) alanyl]-2-amino-2-phenylethyl alcohol N-[N-(3, the 5-dichlorophenyl)-L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3; 5-two-(trifluoromethyl) phenyl)-the L-alanyl]-L-phenylglycocoll tert-butyl ester N-[N-(3, the 5-Dimethoxyphenyl)-L-alanyl]-the 2-aminohexanoic acid methyl esters.