CN1077716A - Antiviral peptides - Google Patents

Antiviral peptides Download PDF

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CN1077716A
CN1077716A CN93103206A CN93103206A CN1077716A CN 1077716 A CN1077716 A CN 1077716A CN 93103206 A CN93103206 A CN 93103206A CN 93103206 A CN93103206 A CN 93103206A CN 1077716 A CN1077716 A CN 1077716A
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alkyl
phenyl
cycloalkyl
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C·W·格林格拉斯
S·D·A·施特里特
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Following formula: compound and pharmacologically acceptable salt thereof and bioprecursor are the inhibitor of retrovirus proteolytic enzyme, can be used for treating and preventing people's retrovirus infection.In the following formula, described in the implication such as specification sheets of each substituting group and letter.

Description

Antiviral peptides
The present invention relates to the peptide derivant that some contains heterocyclic radical, these derivatives can be used for treating or prevent people's retrovirus to infect.
Human immunodeficiency virus (HIV) is a kind of retrovirus, and it is the virulence factor of many kinds of clinical diseases, and severe patient is commonly called as the relevant syndromes with AIDS of AIDS (acquired immune deficiency syndrome (AIDS)) in these diseases.The feature that HIV infects is that immune sexual exhaustion and the central nervous system function of carrying out fallen and hindered.Serious immune deficiency patient easily suffers from far-ranging opportunistic infection (for example Pneumocystis carinii, people's cytomegalovirus or oidiomycetic infection) and cancer (as kaposi's sarcoma).HIV infected cell (CD particularly + 4Lymphocyte) in the carrying out property damage that is lost in immunologic function is an important factor.HIV is also relevant with viewed pathological phenomenon to the infection of monocyte/macrophage spectra system cell.Therefore, HIV is to CD + 4The successful infection of cell is the committed step in the pathogenic process.
HIV is a kind of retrovirus, and it is with RNA its genetic information of encoding, and after virus entered host cell, RNA then was converted into DNA.A basic step in the retrovirus replication cycle is that initial polypeptide precursor is processed into sophisticated structural protein and replication protein.This course of processing is that the proteolytic enzyme by encoding viral carries out, if lack this enzymic activity, then virus replication is obstructed.
We find that some is connected with the peptide derivant of heterocyclic radical, no matter is at cell-less measurement or in cells infected, all is the potent inhibitor of retrovirus proteolytic enzyme, and in addition, these derivatives demonstrate antiviral activity in tissue culture is measured.This activity makes these compounds can be used for treatment and the prevention retrovirus infects the particularly infection that is caused by HIV.
Therefore, the invention provides compound and pharmacologically acceptable salt and bioprecursor with following formula:
Figure 931032067_IMG5
Wherein:
R 1Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, aryl, heterocyclic radical or CONR 9R 10;
R 2Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl (C 1-C 4) alkyl, aryl (C 1-C 4) alkyl or heterocyclic radical (C 1-C 4) alkyl;
R 3Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl (C 1-C 4) alkyl, aryl (C 1-C 4) alkyl, aryl (C 2-C 4) thiazolinyl, heterocyclic radical (C 1-C 4) alkyl or heterocyclic radical (C 2-C 4) alkyl;
R 4Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, aryl or heterocyclic radical;
R 5, R 6, R 7And R 8All be H, C independently of one another 1-C 6Alkyl or C 3-C 8Cycloalkyl; Perhaps, R 5And R 6, or R 7And R 8, can connect together forms three to eight Yuans carbocyclic rings;
X is monocycle or dicyclo four to the ten element heterocycle bases that contain some ring carbon atoms and a theheterocyclic nitrogen atom, and this group is connected with the carbonyl that links to each other by theheterocyclic nitrogen atom; This group can be saturated or part is unsaturated, and, remove-(CR 7R 8) mOutside-Het the substituting group, this group can be by 4 other substituting groups replacements at the most, and substituting group all is independently selected from F, C 1-C 6Alkyl, C 3-C 8Cycloalkyl, OR 11Or NR 9R 10;
Het is imidazolyl or triazolyl, and they all can be randomly by C 1-C 6Alkyl, C 3-C 8Cycloalkyl, NR 9R 10Or CONR 9R 10Replace;
R 9Or R 10All be H, C independently 1-C 6Alkyl or C 3-C 8Cycloalkyl, perhaps, R 9And R 10Can connect together and form four to eight Yuans nitrogen heterocycles with the nitrogen-atoms that they connected;
R 11Be H, C 1-C 6Alkyl or C 3-C 8Cycloalkyl;
N and m are 0,1 or 2 independently of one another;
Any alkyl or cycloalkyl included in the above-mentioned definition all can randomly be replaced by full replacement of fluorine or part.
At R 1, R 2, R 3And R 4Above-mentioned definition in, heterocyclic radical is meant four to six element heterocycle bases, wherein contained heteroatoms is 4 nitrogen-atoms at the most, or 1 Sauerstoffatom or sulphur atom add optional 1 or 2 nitrogen-atoms.This ring can be an aromaticity, also can be all or part of saturated, can randomly be condensed by benzene, or be replaced by following groups: C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 2-C 5Alkyloyl, C 1-C 4Alkoxyl group, halogen, hydroxyl, oxygen or aryl.Preferred heterocyclic radical is pyridyl, pyrimidyl, thienyl, isoquinolyl and tetrazyl.
At R 1, R 2, R 3And R 4Above-mentioned definition in, aryl refers to that substituting group is selected from C independently of one another by the optional phenyl that replaces of 1-3 substituting group 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 1-C 4Alkoxyl group, C 2-C 5Alkyloyl, hydroxyl, halogen, by the C of all or part of replacement of fluorine 1-C 4Alkyl, by the C of all or part of replacement of fluorine 1-C 4Alkoxyl group, phenyl, phenoxy group, benzyl, benzoyl, phenyl SO 2-, pyridyl, tetrazyl, phenyltetrazole base, NR 9R 10Or CONR 9R 10; R wherein 9And R 10Limit as the front.Halogen refers to fluorine, chlorine, bromine or iodine.
Imidazolyl or triazolyl (being Het) both can connect by ring carbon atom, also can connect by theheterocyclic nitrogen atom, and both can be unsubstituted, also can coverlet replacement, two replace or three replacements.Triazolyl had both comprised that the 1,2,3-triazoles base also comprised 1,2, the 4-triazolyl.
The alkyl and the alkoxyl group that contain 3 or more a plurality of carbon atoms can be side chain or straight chain.Included any alkyl, alkoxyl group or cycloalkyl in the above-mentioned definition all can be randomly by all or part of replacement of fluorine.
Term in the above-mentioned definition " bioprecursor " is meant pharmaceutically useful, the biodegradable derivative of formula I compound, this derivative is when giving the animal or human, change into the formula I compound in vivo, the example is included in the ester derivative that forms between the free hydroxyl group of formula I compound and (for example) amino acid (as the L-Xie Ansuan).
No matter should be realized that the formula I compound has many unsymmetrical carbons, the present invention includes all possible steric isomer, be through isolating or not separated.
Of the present invention one specific and preferred aspect provides the compound with following three-dimensional chemical configuration:
Figure 931032067_IMG6
In following formula, show that with thick key table this group is positioned on the planes of molecules, show that with empty key table this group is positioned under the planes of molecules.
At R 1Definition in, aryl is preferably phenyl, heterocyclic radical is preferably trimethylene oxide-3-base or 1,1-dioxy Thietane-3-base.R 1Be preferably the tertiary butyl, sec.-propyl, trimethylene oxide-3-base or 1,1-dioxy Thietane-3-base, (CR 5R 6) nDo not exist; Perhaps, R 1Be phenyl, (CR 5R 6) be CH 2; Perhaps, R 1Be H 2NCO-, CH 3NHCO-or (CH 3) 2NCO-, (CR 5R 6) nBe CH 2Or CH(CH 3).Particularly preferably be wherein R 1Be the tertiary butyl, sec.-propyl or trimethylene oxide-3-base, n is 0 compound; R wherein most preferably 1(CR 5R 6) n-be the compound of the tertiary butyl.
At R 2Definition in, aryl is preferably phenyl, heterocyclic radical is for example pyridyl, pyrimidyl or thienyl.R 2Be preferably aryl (C 1-C 4) alkyl; Preferred especially benzyl.
At R 4Definition in, aryl is preferably phenyl, heterocyclic radical is preferably pyridyl, pyrimidyl or thienyl.R 4Be preferably C 1-C 6Alkyl; Particularly preferably be sec.-propyl and sec-butyl (Xie Ansuan or Isoleucine derivative).
Heterocyclic radical X is preferably four to six Yuans saturated or single unsaturated groups, and most preferably azetidine, tetramethyleneimine, tetrahydropyridine or piperidyl particularly preferably are piperidines.
R 7And R 8Be preferably H, m is preferably 0 or 1.
At R 3Definition in, aryl is that heterocyclic radical is for example pyridyl, pyrimidyl, isoquinolyl or thienyl as the phenyl that does not replace or replace of front defined in the term " aryl ".R 3Be preferably aryl (C 1-C 4) alkyl or aryl (C 2-C 4) thiazolinyl, most preferably on phenyl ring, chosen wantonly the benzyl that replaces, perhaps R by fluorine, chlorine, iodine, methyl, trifluoromethyl or trifluoromethoxy 3Be 3-phenyl third-2-thiazolinyl or 3-phenyl propyl.
Concrete preferred compound comprises:
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine;
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-2-(3-phenyl third-2-alkene-1-yl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(R)-2-(4-benzyl chloride base)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl-]-4-(imidazoles-1-yl) piperidines;
A second aspect of the present invention provides the application as medicine of formula I compound or pharmaceutically acceptable salt thereof or bioprecursor, especially as being used for the treatment of or prevent people's retrovirus the to infect application of medicine of (particularly HIV infection).The present invention also comprises formula I compound or pharmaceutically acceptable salt thereof or the application of bioprecursor in a kind of medicine of preparation, and this medicine is used for prevention or the treatment retrovirus infects.
The present invention also comprises a kind of pharmaceutical composition, and said composition comprises a kind of formula I compound or pharmaceutically acceptable salt thereof or bioprecursor, and a kind of acceptable diluents or carrier.
The antiviral activity of logical formula I compound utilizes the external test system to determine.For example, to protect the human T-cell be that H9 is not subjected to the carrying out property effect 7 days that HIV infects fully to the formula I compound.Undressed virus infected cell then demonstrates typical cytopathic effect, as plasmodial formation and necrocytosis.In addition, the virion right and wrong of crossing with the formula I compound treatment that virus infected cell produced are infective.
Can comprise the infection that causes by human or animal's retrovirus especially HIV-1 with the example of the infection of formula I compounds for treating or prevention.So the clinical disease that can treat or prevent comprises AIDS, the relevant syndromes of AIDS and HIV dependency dementia.These compounds also can be used to stop the carrying out of the individual disease of symptomless infection.
The formula I compound can utilize coupling and resist technology to prepare, and these technology are that the technician in chemistry of peptides field is familiar with.
This method can with the preparation formula shown in following (the I a) reaction scheme of compound illustrates:
The generalized step of reaction formula A institute is initial by being protected lactone (II).Utilize (for example) n-Butyl Lithium or hexamethyldisilane base amination lithium to make this lactone alkylation, add formula R then 3The Br compound is isolated desired isomer, obtains product (III).Handling with diluted alkaline then opens lactonic ring; generate corresponding alcohol acid, subsequently hydroxyl is protected, for example at N; make the t-butyldimethylsilyl derivative with the tert-butyldimethylsilyl chloride reaction in the dinethylformamide, protected ester with posthydrolysis and generate intermediate (IV).
Reaction formula B has illustrated intermediate (IV), and (I is compound a) with another hydrolysate (VIII) coupling production.In this process, removed the protecting group (when protecting group is tertbutyloxycarbonyl, removing) on the intermediate (V) by handling with HCl, utilize the acid amides coupling reagent to make gained compound (VI) and N-be protected amino acid Boc-NHCH(R 4) CO 2The H reaction generates intermediate (VII).Remove the N-protected base on (VII) then, make amine product (VIII) and intermediate (IV) coupling generate intermediate (IX).Remove hydroxyl protecting group X from (IX) then 1, (I is end product a) for production.Another kind method can generate intermediate (IX) by intermediate (X) and intermediate (VI) coupling.Intermediate (X) then can be prepared by intermediate (IV),, makes intermediate (IV) and carboxy protective amino acid H that is 2NCH(R 4) CO 2Basic hydrolysis is carried out in the R reaction subsequently.
Figure 931032067_IMG7
Protecting group, X ': preferred t-butyldimethylsilyl
R 1-(CR 5R 6) n: preferred tertiary butyl or benzyl.
Figure 931032067_IMG8
Acid amides coupler: as the 1-(3-dimethyl propyl)-the 3-ethyl carbodiimide
Protecting group: P, preferred tertiary butoxy carbonyl or carbobenzoxy-(Cbz);
X ', preferred t-butyldimethylsilyl
R, preferable methyl or ethyl
Reaction formula C has illustrated the method that another is alternative, and by handling the tertbutyloxycarbonyl that removes on the intermediate (XI) with acid (as trifluoroacetic acid), the carbonic acid ester derivative with formula (XII) reacts production (X III) product, wherein R subsequently 1(CR 5R 6) nGroup is not the tertiary butyl.For example, the reaction of formula (XI) product and 3-trimethylene oxide oxygen carbonyl oxygen base succinimide generates product (X III), wherein R 1Be the 3-oxetanyl, n is 0.
Figure 931032067_IMG9
X ' or be H perhaps is a protecting group, as t-butyldimethylsilyl.
Y is a group that nucleophilic substitution easily takes place, preferred succinimide oxygen base.
Required formula (V) raw material of above-mentioned steps is the documentation compound in some cases, perhaps can be prepared by the raw material that is easy to get with conventional synthesis method.For example, make the 1-(N-tertbutyloxycarbonyl)-3-hydroxy azetidine and methylsulfonyl chloride reaction, in the presence of alkali, react then with formula Het-H compound, generate required formula (V) compound, wherein X is a chlorine heterocycle butane ring.Perhaps, in the presence of ammonium acetate, make the 1-(N-carbobenzoxy-(Cbz))-4-ketone piperidines and sodium cyanoborohydride reaction, make the former be converted into the 4-aminoderivative, generate 4-(1,2,4-triazole-4-yl with the reaction of azine dimethyl formamide more subsequently) derivative.
The 1-(N-tertbutyloxycarbonyl)-the 4-keto piperidine with by the 1-(diethoxymethyl) anionic reactive of imidazoles and n-Butyl Lithium reaction generation, in the presence of alkali, handle the product that is generated then, generate N-and protected-4-imidazoles-2-base (1,2 with methylsulfonyl chloride, 5, the 6-tetrahydropyridine) intermediate.Generate corresponding N-protected-4-(imidazoles-2-yl after the catalytic hydrogenation) piperidines.Above-mentioned carbonyl compound directly reacts with heterogeneous ring compound such as imidazoles in the presence of thionyl chloride, and generating X is formula (V) compound of tetrahydro pyridyl, once more reduction back generation piperidines biology.
M is not equal to 0 formula (V) intermediate and can utilizes the method for transformation of standard to be prepared by suitable precursor among the reaction formula B, and utilizes the nucleophilic ring opening effect of (for example) epoxy group(ing) to introduce the Het group.For example, 1-(N-tertbutyloxycarbonyl)-the 4-keto piperidine in the presence of alkali with the reaction of trimethylammonium iodate blunderbuss, generate 4-spiral shell-2 '-oxyethane.The 4-hydroxyl is then eliminated in this product and imidazoles reaction, generates the 1-(N-tertbutyloxycarbonyl)-4-(imidazoles-1-yl) methyl isophthalic acid, 2,5, the 6-tetrahydropyridine, the reduction back generates corresponding piperidine derivative.
Synthetic middle naturally occurring amino acid whose N-tert.-butoxy (BOC) derivative that uses of formula (VII) compound can have been bought on market, and its hydroxysuccinimide eater also can have been bought.Can prepare (referring to for example M.J.O ' Donnell etc., J.Amer.Chem.Soc., 111:2353,1989) with standard method by the corresponding intermediate of alpha-non-natural amino acid deutero-.The formula II compound can be by the amino-aldehyde of corresponding tertbutyloxycarbonyl protection (referring to D.H.Rich etc.; J.Org.Chem.; 43:3624,1978 and Y.Hamada etc., Chem.Pharm.Bull.; 30(5): 1921; 1982) with ethyl propiolate (referring to A.H.Fray etc., J.Org.Chem., 51:4828; 1986) reaction prepares, and is reduced into 5-tertiary butyloxycarbonyl amino-4-hydroxy-6-phenyl capronate subsequently.Make its cyclisation in reflux in toluene then, generate the formula II lactone, be the mixture of diastereomer, these diastereomer available standards methods are separated.
In the specific embodiment that said synthesis route and this paper are proposed, need some hydroxyls and amino protecting group and activated carboxylic base.It will be understood by those skilled in the art that described coupling and guard method can carry out with any standard peptide synthesis method, therefore, these methods are included in the scope of the present invention.The availability that being chosen in of specific protecting group depended on necessary reagent to a great extent, it to the influence of protection compound dissolution degree, whether whether remove easily and exist may affected other groups owing to use this protecting group.Further reaction for example, is necessary in said process, specific amino to be protected and deprotection, so that can take place the amino that bears again.For specified amino, the selection of protecting group will be depended on the effect of described amino in the entire reaction formula.Can use the different various amino protecting groups of active degree.These groups are known in the art, please note following summary: people such as Bodansky " peptide is synthetic " second edition (John Wiley ﹠amp; Sons, N.Y., 1976); Greene " protecting group in the organic synthesis " (John Wiley ﹠amp; Sons, N.Y., 1981); McOmie " protecting group in the organic chemistry " (Plenum Press, N.Y., 1973); And Sheppard compiles the article (the 23.6th joint 321-339 page or leaf, Pergamon Press, N.Y., 1979) in " comprehensive organic chemistry: the synthetic and reaction of organic compound " at E.Haslam.
Representational amino protecting group includes, but is not limited to aryloxy carbonyl, as carbobenzoxy-(Cbz); The aralkyl that replaces or replace, as benzyl, trityl, diphenyl-methyl, 4-nitrobenzyl; Ben Yajiaji; Arylthio is as thiophenyl, nitrophenylsulfenyl and trichlorobenzene sulfenyl; The phosphoryl derivative, as solutions of dimethyl phosphoryl base and 0,0-dibenzyl phosphoryl; The trialkylsilkl derivative, as trimethyl silyl, and as United States Patent (USP) 4,322,341 described other protecting groups.The amino protecting group that is preferred for above-mentioned reaction scheme is a tertbutyloxycarbonyl.The method that replaces above-mentioned group on given amino is known.In general, these methods comprise: in reaction-inert solvent such as water, methylene dichloride or tetrahydrofuran (THF), make suitable aminocompound acidylate with corresponding carbonyl chlorine or acid anhydrides.When using water as solvent, there is alkali (acid acceptor) to exist, as sodium hydroxide or potassium hydroxide; In the time of with an organic solvent, then to there be tertiary amine to exist, as triethylamine or pyridine.When using aqueous solvent system, the pH of reaction generally is maintained at about pH8-10, preferred pH9.
Think the method that is suitable for the special groups that adopted with those skilled in the art, will be protected amino and be converted into the non-amino that protected.For example, there is the methylene dichloride of hydrogen chloride gas to handle, is easy to remove tertbutyloxycarbonyl with saturated.
Various hydroxyl protecting group also is known, and is described in the front and has drawn in the exhausted document.Preferred hydroxyl protecting group is a t-butyldimethylsilyl.This group can be introduced as previously mentioned, is easy to remove when at room temperature handling with the tetrahydrofuran solution of tetra-n-butyl Neutral ammonium fluoride.
The activation of carboxyl also is a method known to those skilled in the art as the means of accelerating given acylation reaction.Useful especially acid anhydrides and the Acibenzolar of being to use in the reaction scheme described herein, particularly those are by N-hydroxybenzene dicarboximide, N-hydroxy-succinamide or I-hydroxybenzotriazole deutero-ester, and all these compounds all use in peptide is synthetic.
Use the dehydration coupler to form Acibenzolar.Representational in this class coupler have: 1-cyclohexyl-3-(2-morpholino ethyl) carbodiimide, N, N '-dicyclohexylcarbodiimide, N, N '-carbonyl dimidazoles, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, oxyethyl group acetylene, diphenylethlene ketone and N-ethyl-5-phenyl-isoxazole azoles quinoline-3 '-sulphonate.Use the reaction conditions of these couplers that sufficient description is arranged in the literature.In general, these conditions comprise the temperature that adopts reaction-inert solvent and room temperature to 100 ℃ scope.Preferred above-mentioned carbodiimide reagent because these reagent allow to adopt the room temperature reaction temperature, and can make desired ester reach satisfied yield.
After coupled reaction is finished and generated end product, can remove various protecting groups with proper technology discussed above, and available ordinary method such as recrystallization method or column chromatography separation and purification formula I compound.
Above-mentioned reaction scheme can be revised, and makes it pass through suitably to select raw material, to R 1To R 8, X and Het any variant required for protection all be suitable for adopting.
So another aspect of the present invention comprises a kind of method for preparing the formula I compound, this method comprises: remove the protecting group of formula (IX) compound, isolate the formula I compound, and randomly form its pharmacologically acceptable salt.
Figure 931032067_IMG10
X wherein 1It is a hydroxyl protecting group that alternative removes.
Preferred X 1Protecting group is a t-butyldimethylsilyl, and this protecting group removes by handling with positive tetrabutyl ammonium fluoride in organic solvent (preferred tetrahydrofuran (THF)).
The new intermediate of formula (VIII), (IX), (X) also constitutes a part of the present invention.
The example of the pharmacologically acceptable salt of formula I compound has acid salt, as vitriol, hydrosulfate, phosphoric acid salt, lactic acid salt, mesylate, fumarate, Citrate trianion, succinate and gluconate.
When the patient who suffers from retrovirus (especially HIV) infection is treated, compound (I) can be used with any suitable way, for example oral, parenteral (for example subcutaneous, intravenously, intramuscular or intracutaneous), rectum, intranasal, part (comprising cheek and hypogloeeis) or vaginal approach.Can make preparation according to known routine techniques in the pharmacy industry, these preparations will contain antiviral agent of the present invention and one or more plant pharmaceutically useful carrier, and optional other treatment agent.Oral dosage form specifically comprises syrup, tablet and capsule, also can contain seasonings in these formulations except that containing inert support.Tablet can prepare by the powder of suppressing proper composition (as antiviral agent and tackiness agent, thinner, lubricant and tensio-active agent) with conventional compressing tablet or molding technology.Rectal formulation will be suppository form, and vagina preparation will be (for example) tamping, creme or foaming agent form.Parenteral administration will be sterile form, and for example the bottle injection wherein contains promising water-based or non-aqueous thinner, buffer reagent and the antioxidant that preparation and blood etc. is oozed and add.In general, the suitable dosage of the anti-retrovirus agent of formula I will be 1-50mg/kg/ days, preferred 1-25mg/kg/ days, divide six fractionated dose administrations every day at the most.Certainly, according to patient's age, body weight, disease severity and reaction, may need higher or lower dosage in some cases, and suitable treatment plan will be determined by the clinician.
The formula I compound can use with the other medicines compatibility, and wherein some medicine may strengthen the activity of formula I compound.This class medicine comprises following medicine:
(a) reverse transcriptase inhibitors replaces acyclic pyrimidine (HEPT) derivative as AZT, ddI, ddC, foscarnet, TIBO compound, dipyridodiazepinones or 6-;
(b) gp120-CD4 blocker as T 500 and solubility CD4, comprises the composition of it and toxic agents such as pseudomonal toxin;
(c) tat antagonist is as Beracilline;
(d) other retrovirus proteinase inhibitor are as Ro 31-8959;
(e) biological response modifier comprises Interferon, rabbit, interleukin-or G CFS (as GM-CSF).
Antiviral activity with following method assessment The compounds of this invention: test-compound is dissolved among the 50 μ l DMSO, and is a kind of composite salt solution of 7.2) is diluted to 1mg/ml at RPMI 1640(pH.With the concentration of 0.001,0.01,0.1,1 and 10 μ g/ml, in human T-cell system (H9), carry out anti-HIV1(III B strain) test.The contrast that meanwhile begins to handle is infected.
Infect after seven days, the tissue culture supernatant liquor carried out titration to check C8166(human T-cell system) on whether have infectious virus.Checked in the culture synplasm whether occurs in the 3rd, 5 and 7 day.The contrast of treated with medicaments is not infected and is demonstrated typical viral cytopathic effect, comprises the death of plasmodial formation and cell.The IC that is quoted 100Be culture is provided the minimum test concentrations of protection fully.Adopt this testing method, the IC of compound 100Value is in the scope of 0.1-10.0 μ g/ml.
Following EXPERIMENTAL EXAMPLE will be proposed now to be described more specifically the preparation of some raw material and formula I compound.Use Merck Kieselgel 60F 254Silica-gel plate carries out routine monitoring with tlc to the purity of compound. 1The H nuclear magnetic resonance spectrum is with Nicolet QE-300 type or Bruker AC-300 type spectrograph record, and is all consistent with the structure of being inferred in all cases.Be marked with a low ppm in chemical shift is done with tetramethylsilane and represent that main spectrum peak is represented with conventional abbreviation: s, unimodal; D, bimodal; T, triplet; M, multiplet; B, broad peak.Except as otherwise noted, specific rotation concentration with 0.1% under 25 ℃ is measured in methyl alcohol.All temperature all are degree centigrade.
The preparation of raw material and intermediate
Preparation 1
(S)-5-[(S)-1-tertiary butyloxycarbonyl amino-2-phenylethyl]-gamma-butyrolactone
A) (4S, 5S) and (4R, 5S)-5-tertiary butyloxycarbonyl amino-4-hydroxy-6-phenyl oneself-2-acetylenic acid ethyl ester
Under-25 ℃, the solution of Diisopropylamine (6.4ml) in anhydrous tetrahydro furan (25ml) is stirred under nitrogen, added the hexane solution (24.4ml) of 1.6M n-Butyl Lithium through 5 minutes, keep temperature to be lower than-20 ℃ therebetween.Under-20 ℃ after 15 minutes, solution is cooled to-70 ℃, dripped ethyl propiolate (3.8g) through 10 minutes, protect temperature to be lower than-65 ℃ therebetween.Under-70 ℃ with the yellow suspension restir of gained 20 minutes, dripped N-tertbutyloxycarbonyl-L-phenylpropyl alcohol ammonium aldehyde (6.5g then through 10 minutes, see J.R.Luly etc., J.Org.Chem., 52:1487,1987) solution in anhydrous tetrahydro furan (15ml) is handled, and still keeps temperature to be lower than-65 ℃ therebetween.Clarifying yellow solution was stirred 2 hours down in-70 ℃, use acetate (4ml) to handle then.Remove cooling bath, make mixture be warmed to-30 ℃, in the time of-30 ℃, under causus stirring, add entry (100ml) and ethyl acetate (100ml).Separate organic layer, use 1M hydrochloric acid (50ml), saturated sodium bicarbonate aqueous solution (50ml) and saturated brine (50ml) washing then successively, dry (Na 2SO 4) and evaporating solvent after obtain the oily crude product.This oily matter silica gel chromatography purifying is made eluent with ethyl acetate-hexane (1: 4).Evaporation contains the product fraction and obtains a kind of oily matter, spends the night and solidifies through placement.Obtaining title compound with ether-hexane recrystallization, is two kinds of mixture (4S, 5S: 4R, 5S) (4.3g) that diastereomer is about 2: 1.
m.p.98-99°。Measured value: C, 65.62; H, 7.42; N, 4.33.C 19H 25NO 5
Calculated value C, 65.70; H, 7.20; N, 4.03%.
N.M.R.（CDCl 3）δ＝1.30-1.39（m，3H）;1.43（s，9H）;2.90-3.11（m，2H）;3.37-3.38 and 4.16-4.19（2x brm，1H）;3.93-4.04（m，1H）;4.22-4.33（m，2H）;4.51-4.56（m，1H）;4.77-4.79 and 4.87-4.90（2 x brm，1H）;7.24-7.35（m，5H）.
B) (4S, 5S) and (4R, 5S)-5-tertiary butyloxycarbonyl amino-4-hydroxy-6-phenyl ethyl hexanoate
Above-mentioned product (1.17g) is dissolved in the ethanol (50mg), adds 5%Pd-BaSO 4Catalyzer.Make mixture at 50 pounds/inch then 2Hydrogenation is 2 hours under (344.7 kPas).Filter the final vacuum evaporating solvent, obtain the title compound (1.18g) (two kinds of mixtures that diastereomer is about 2: 1) of white solid.
M.p.125-126 ° of measured value: C, 64.91; H, 8.40; N, 3.98, C 19H 29NO 5Calculated value C, 64.95; H, 8.26; N, 3.98%.
N.M.R.(CDCl 3) δ=1.24-1.33(m, 3H); 1.39 and 1.42(2 x s, 9H); 1.72-1.95(m, 2H); 2.38-2.62(m, 2H); 2.77-2.98(m, 2H); 3.02-3.04 and 3.40-3.42(2 x m, 1H can with D 2The O exchange); 3.59-3.91(m, 2H); 4.08-4.22(m, 2H); 4.58-4.61 with d 4.86-4.89(2 x m, 1H); 7.22-7.37(m, 5H).
C) (S)-5-[(S)-1-tertiary butyloxycarbonyl amino-2-phenylethyl]-gamma-butyrolactone
To be dissolved in by γ-hydroxy ester that above-mentioned (b) obtains in 2.5% acetate-toluene (35ml), with this vlil 2 hours, cooling and vacuum-evaporation after do, resistates silica gel chromatography purifying, with ether-hexane (40: 60) wash-out, obtain title compound (0.4g).
M.p.98-99 °. measured value: C, 66.77; H, 7.78; N, 4.38.C 17H 23NO 4Calculated value: C, 66.88; H, 7.54; N, 4.59%.m/e=306(MH +).
N.M.R.（CDCl 3）δ＝1.42（s，9H）;2.11-2.19（m，2H）;2.51-2.58（m，2H）;2.87-3.02（m，2H）;4.00-4.07（m，1H）;4.47-4.52（m，1H）;4.63（d，J＝10，NH）;7.26-7.36（m，5H）.
[α] 25D-22.6°（c＝1，MeOH）.
I.R.（KBr）1775，1690，1525cm -1.
Preparation 2
(R)-the 2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-(t-butyldimethylsilyloxy base)-6-phenyl caproic acid
A) (R)-3-benzyl-(S)-5-[(S)-1-tertiary butyloxycarbonyl amino-2-phenylethyl]-gamma-butyrolactone
With hexamethyldisilane base amine (7.9ml) cold (10 ℃) solution in tetrahydrofuran (THF) (15ml), handled 3 minutes with the hexane solution (23ml) of 1.6M n-Butyl Lithium, keep temperature to be lower than 0 ℃ therebetween.After 5 minutes, solution is cooled to-70 ℃ under 0 ℃, adds (S)-5-[(S)-1-tertiary butyloxycarbonyl amino-2-phenylethyl]-solution of gamma-butyrolactone (5g) in tetrahydrofuran (THF) (38ml), keep temperature to be lower than-65 ℃ therebetween.This solution was stirred 15 minutes down at-70 ℃, added the solution of bromotoluene (1.95ml) in tetrahydrofuran (THF) (12.5ml) then through 1 minute ,-70 ℃ of following restir 10 minutes, use acetate (6.5ml) to handle then solution, remove cooling bath.Add entry (50ml) and ethyl acetate (50ml), make the warm room temperature of mixture.Separate organic layer, dry then (MgSO 4) and vacuum evaporating solvent, obtain the oily crude product.Use the silica gel chromatography purifying,, obtain clarifying buttery title compound (3.52g) with ether-hexane (50: 50) wash-out.Measured value:
C, 73.22; H, 7.50; N, 3.50.C 24H 29NO 4Calculated value C, 72.91; H, 7.34; N, 3.54%.
[α] 25 D-14°（C＝0.1%，MeOH）
N.M.R.（CDCl 3）δ＝1.37（s，9H）;1.95-2.30（m，2H）;2.79-3.20（m，5H）;3.92-4.01（m，1H），4.21-4.25（m，1H）;4.52-4.56（m，1H）;7.21-7.36（m，10H）.
B) (R)-the 2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-(t-butyldimethylsilyloxy base)-6-phenyl caproic acid
At room temperature, (1N 53.5ml) handles the product (suspension in 17.63g) Zai diox (120ml) and the water (60ml) in (a) with sodium hydroxide.Reactant was stirred 3 hours, add acetate then it is acidified to pH5.After placing 30 minutes again, leach throw out and wash with water.This solid is dissolved in ethyl acetate, dry (MgSO 4) and vacuum-evaporation, the white solid that obtains is developed with hexane, filters and drying, obtains intermediate alcohol acid (17.85g).At N, the solution in the dinethylformamide is at room temperature handled with imidazoles (29.38g) and tert-butyldimethylsilyl chloride (32.53g) with this alcohol acid.Stir after 18 hours, vacuum evaporating solvent, resistates is handled with frozen water, with 10% citric acid acidifying to pH4, and and 2 * 400ml ethyl acetate extraction.Extraction liquid merges after drying (MgSO 4), vacuum-evaporation obtains grey oily matter (29.2g).The solution of this oily matter in tetrahydrofuran (THF) (240ml) is at room temperature handled with acetate (240ml) and water (80ml).At room temperature stirred 2 hours, and stirred 18 hours down at 4 ℃, vacuum evaporated solution then, resistates distributes between water (400ml) and ethyl acetate (400ml).Tell organic layer, water (2 * 400ml), saturated brine (100ml) washing, dry (MgSO 4) the final vacuum evaporation, obtain grey oily matter, use the silica gel chromatography purifying, with ether-hexane (70: 30) wash-out, obtain the title compound (22.4g) of white glass shape.
m/e 528（MH） +
N.M.R.（DMSO-d 6）δ＝0.10（s，6H）;0.95（s，9H）;1.30（m，10H）;1.35（m，1H）;1.95（m，1H）;2.40（m，1H）;2.72（m，2H）;2.85（m，1H）;3.60（m，1H）;3.75（m，1H）;6.88（d，1H）;7.22（m，10H）.
Preparation 3
5-brooethyl isoquinoline 99.9
Under-70 ℃, and hexane solution (3.3ml) the processing 5-bromo-isoquinoline of usefulness 1.6M n-Butyl Lithium and 7-bromo-isoquinoline isomer mixture (5: 7,40: 60; 1.0g; See Glyde and Taylor, J.Chem.Soc.Perkin Trans 2: 1783,1975) solution in anhydrous tetrahydro furan (15ml).Reactant is maintained this temperature 30 minutes, add the solution of anhydrous dimethyl formamide (0.74ml) in anhydrous tetrahydro furan (5ml) then.After 15 minutes, stop reaction with ethanol (5ml) is anxious, and make reactant be warmed to intensification.Add saturated ammonium chloride solution (10ml) and ether (15ml) then successively, tell organic phase, with the saturated brine washing, dry (MgSO 4) and vacuum-evaporation.Carry out purifying with silica gel chromatography,, isolate the aldehyde that first wash-out goes out, obtain the different silicon quinoline of 5-formyl radical, be unsettled yellow solid (0.05g) with hexane-ethyl acetate (50: 50) wash-out.R f0.3(hexane-ethyl acetate 50: 50).
The solution of this product (0.88g) in anhydrous methanol (20ml) is handled down at 5 ℃ with sodium borohydride (0.53g), made the gained mixture be warmed to room temperature, and kept this temperature 1 hour.This solution with ether (20ml) dilution, is added water (10ml) then.Two-phase is separated, and water extracts with ether (20ml).Merge two parts of organic phases, with saturated nacl aqueous solution (20ml) washing, dry (MgSO 4), vacuum-evaporation obtains the 5-methylol isoquinoline 99.9 (0.37g) of yellow powder powder.
M.p.71-72 ℃. measured value: C, 75.06; H, 5.72; N, 8.66.
C 10H 9NO calculated value C, 75.45; H, 5.70; N, 8.80%.
The solution of above-mentioned product (1.11g) in glacial acetic acid (15ml) is handled with 49% hydrobromic acid aqueous solution (30ml), and the gained mixture heating up refluxed 2 hours.With the reactant vacuum concentration, resistates is suspended in the methylene dichloride, alkalizes with saturated sodium bicarbonate aqueous solution then.Two-phase is separated the water dichloromethane extraction.Organic phase merges the back washs with saturated sodium bicarbonate aqueous solution, dry (MgSO 4) 0.5 hour, vacuum-evaporation under the room temperature obtains the title product of colorless solid shape.Make this solid and methylbenzene azeotropic, directly use then (1.28g).
N.M.R.（CDCl 3）δ＝4.90（s，2H）;7.50（t，1H）;7.70（d，1H）;7.90（m，2H）;8.65（d，1H）;9.25（s，1H）.
Preparation 4
7-brooethyl isoquinoline 99.9
By the initial step of preparation 3, obtain 7-formyl radical isoquinoline 99.9 as the effusive product in back from silicagel column, and separate (0.08g) with yellow solid.R f0.25(hexane-ethyl acetate 50: 50).With the sodium borohydride reaction, obtain 7-methylol isoquinoline 99.9, m.p.129-130 ℃ as mentioned above.
The solution of hydrochloride (0.05g) in thionyl bromide (0.5ml) of above-mentioned product is heated to 60 ℃, and kept 45 minutes.Use ice-cooled reactant then, carefully add excessive water, then add ether (15ml).Add strong aqua then to pH9, tell the ether phase, wash with water and dry (MgSO 4).Add then the solution of hydrogenchloride in Virahol (0.06ml, 5.9N), the muddy suspension vacuum-evaporation at room temperature of gained.Make resistates and methylbenzene azeotropic, obtain the product hydrochloride (0.04g) of colorless solid shape.
m/e（MH） +222
N.M.R.（DMSO-d 6）δ＝5.05（s，2H）;8.10（d，1H）;8.25（d，1H）;8.30（d，1H）;8.45（s，1H）;8.65（d，1H）;9.70（s，1H）.
Preparation 5-13
Prepare following formula IV compound with preparation 2 described methods, but in step (a), use suitable substituted benzyl bromides or the different quinoline of brooethyl to make the gamma-butyrolactone alkylation, react as open loop as described in the step (b) and with tert-butyldimethylsilyl chloride subsequently.
Figure 931032067_IMG12
Preparation 14
The 1-(N-tertbutyloxycarbonyl)-3-mesyloxy azetidine
A) in methylene dichloride (40ml), stir aza-cyclobutane-3-alcohol hydrochloride (2.10g), add diisopropyl ethyl amine (2.59g), add tert-Butyl dicarbonate (4.36g) subsequently.This mixture at room temperature stirred 4 hours, vacuum evaporating solvent.Resistates is dissolved in the ethyl acetate (200ml), with 1.5M hydrochloric acid (50ml), saturated sodium bicarbonate solution (25ml) and salt solution (25ml) washing.Dry organic layer (MgSO 4), filter and vacuum-evaporation.Use the silica gel chromatography purifying,, obtain the 1-(N-tertbutyloxycarbonyl of white solid with ethyl acetate-hexane (50: 50) wash-out)-3-hydroxy azetidine (2.57g), m.p.51-53 ℃.
Measured value: C, 55.29; H, 8.70; N, 7.98.C 8H 15NO 3Calculated value C, 55.47; H, 8.73; N, 8.09%.
B) solution of above-mentioned product (1.0g) in methylene dichloride (35ml) is handled with methylsulfonyl chloride (0.75ml) and pyridine (1.5ml), and this mixture was at room temperature stirred 3 days.With solution with methylene dichloride (75ml) dilution, with aqueous citric acid solution (5%, 100ml), saturated sodium bicarbonate aqueous solution (100ml) washing, dry (MgSO 4) and vacuum-evaporation, obtain the title product (1.4g) of colorless oil.
Measured value: C, 43.00; H, 6.80; N, 5.50.C 9H 17NO 5S calculated value C, 43.03; H, 6.77; N, 5.58%.m/e 269(MH 4) +.
N.M.R.（DMSO-d 6）δ＝1.37（s，H）;3.24（s，3H）;3.88-3.96（m，2H）;4.17-4.28（m，2H）;5.25（m，1H）.
Preparation 15
The 1-(N-carbobenzoxy-(Cbz))-(R)-3-mesyloxy tetramethyleneimine
Utilize the front to prepare 4 described methods, but use triethylamine to replace pyridine as alkali, by the 1-(N-carbobenzoxy-(Cbz))-(R)-and 3-hydroxyl pyrrolidine (J.Med.Chem., 35: 1764,1992) preparation title compound, obtain the oily product.
Measured value: C, 51.60; H, 5.80; N, 4.30.C 13H 17NO 5S 1/6 H 2O calculated value C, 51.63; H, 5.78; N, 4.63%.m/e MH +300.
N.M.R.（CDCl 3）δ＝2.15（m，1H）;2.55（m，1H）;3.0（s，3H）;3.45-3.80（m，4H）;5.10（s，2H）;5.25（m，1H）;7.30（m，5H）.
Preparation 16
The 1-(N-carbobenzoxy-(Cbz))-(S)-3-is to the mesyloxy tetramethyleneimine
Under nitrogen, to the 1-(N-carbobenzoxy-(Cbz))-(R)-solution of 3-hydroxyl pyrrolidine (7.90g) in anhydrous tetrahydro furan (100ml) in, add triphenyl phosphine (13.58g).Gained solution is cooled to-30 ℃, adds toluenesulphonic acids methyl esters (10.06g), added diethyl azodiformate (10.41g) then through 0.5 hour.After 1 hour, make reactant be warmed to room temperature, and kept 65 hours.The vacuum-evaporation reactant, resistates is dissolved in methylene dichloride, washes with water, dry (MgSO 4) and vacuum-evaporation become oily.Use the silica gel chromatography purifying,, and then carry out chromatogram purification one time,, obtain golden oily product (10.22g) with hexane-ethyl acetate (80: 20 to 50: 50) wash-out with methylene chloride-methanol (98: 2 to 96: 6) wash-out.
Measured value: C, 60.59; H, 5.68; N, 3.67.C 19H 21NO 5S calculated value C, 60.78; H, 5.64; N, 3.73%.
[α] 25 D+9°（c＝0.1%，MeOH）
N.M.R.（CDCl 3）δ＝1.85-2.25（m，2H）;2.45（s，3H）;3.40-3.65（m，4H）;4.95-5.15（m，3H）;7.20-7.35（m，7H）;7.75（d，2H）.
Preparation 17
The 1-(N-tertbutyloxycarbonyl)-4-mesyloxy piperidines
According to preparation 14 described methods, by the 1-(N-tertbutyloxycarbonyl)-the 4-hydroxy piperidine prepares title compound, m.p.85-86 ℃.
Measured value: C, 47.2; H, 7.66; N, 4.91.C 11H 21NO 5S calculated value C, 47.3; H, 7.58; N, 5.02%.
N.M.R.（CDCl 3）δ＝1.5（s，9H）;1.85（m，2H）;2.0（m，2H）;3.08（s，3H）;3.35（m，2H）;3.75（m，2H）;4.9（m，1H）.
Preparation 18
The 1-(N-tertbutyloxycarbonyl)-and 3-(imidazoles-1-yl) azetidine
(60%, 0.24g) processing imidazoles (0.41g) is at N, and the solution in the dinethylformamide (30ml) at room temperature stirred this mixture 1 hour with sodium hydride.Add the 1-(N-tertbutyloxycarbonyl)-(see preparation 14,1.4g), mixture heated 3 days down in 75 ℃ 3-mesyloxy azetidine.Removal of solvent under reduced pressure is dissolved in resistates in the ethyl acetate (50ml) then, water (2 * 50ml) washings, dry (MgSO 4) and vacuum-evaporation, obtain colorless oil.Use the silica gel chromatography purifying,, obtain oily title compound (0.72g) with methylene chloride-methanol-strong aqua (93: 7: 1) wash-out.
m/e 224（MH） +
N.M.R.（DMSO-d 6）δ＝1.40（s，9H）;3.95-4.06（m，2H）;4.26-4.35（m，2H）;5.12（m，1H）;6.96（s，1H）;7.43（s，1H）;7.79（s，1H）.
Preparation 19-25
Prepare 18 described methods according to the front and prepare following formula (V) compound, but use the suitable raw material that makes by preparation 14-17, and react with unsubstituted imidazoles of suitable replacement or triazole.
Figure 931032067_IMG13
Preparation 26
(a) 1-(N-tertbutyloxycarbonyl)-and 4-(4-Methylimidazole-1-yl) piperidines
4-methylimidazole and 1-(N-tertbutyloxycarbonyl)-reaction of 4-mesyloxy piperidines, obtain two kinds of regional isomer products (regioisomeric products), use the silica gel chromatography purifying, use methylene dichloride: methyl alcohol: strong aqua (96: 3.5: 0.5) wash-out.Main isomer, R f0.47.m/e265.9（MH） +
N.M.R.（DMSO-d 6）δ＝1.43（s，9H）;1.7（dq，2H）;1.93（bd，2H）;2.07（s，3H）;2.83（m，2H）;4.05（m，3H）;6.95（s，1H）;7.55（s，1H）.
(b) 1-(N-tertbutyloxycarbonyl)-and 4-(5-Methylimidazole-1-yl) piperidines
Less important isomer, Rf 0.52.m/e265.9(MH) +
N.M.R.（DMSO-d 6）δ＝1.43（s，9H）;1.7（dq，2H）;1.9（bd，2H）;2.05（s，3H）;2.88（m，2H）;4.05（m，3H）;6.6（s，1H）;7.65（s，1H）.
Preparation 27
The 1-(N-tertbutyloxycarbonyl)-and 4-(imidazoles-2-yl)-1,2,5, the 6-tetrahydropyridine
(a) under-40 ℃ and nitrogen, stirring 1-(diethoxymethyl in anhydrous tetrahydro furan (50ml)) imidazoles (6.8g).Add n-Butyl Lithium (25ml, 1.6N hexane solution) with certain speed, make temperature keep below-35 ℃.Dripped the 1-(N-tertbutyloxycarbonyl through 10 minutes)-solution of 4-ketone-piperidines (2.65g) in anhydrous tetrahydro furan (10ml), keep temperature to be lower than-40 ℃ therebetween, the gained mixture stirred 2 hours down in-40 ℃.(50ml 0.1N) stirs 15 minutes together, adds ethyl acetate (50ml) then, and the gained mixture stirred 5 minutes with reaction mixture and hydrochloric acid.Tell organic layer, (1 * 50ml) extracts water layer with ethyl acetate.Merge organic extract liquid, (1 * 50ml) washing is washed with saturated nacl aqueous solution again with saturated sodium bicarbonate solution.Then with organic layer drying (MgSO 4) and flash to yellow oil (8.0g).Use the silica gel chromatography purifying, use ethyl acetate: methyl alcohol: strong aqua (90: 10: 1) wash-out obtains the 1-(N-tertbutyloxycarbonyl of cream-colored solid state)-4-hydroxyl-4-imidazoles-2-phenylpiperidines (2.2g).m/e 268.0（MH） +。
(b) under 0 ℃, above-mentioned product (267mg) is stirred in anhydrous dimethyl formamide (2ml) with Diisopropylamine (350ml).Once add methylsulfonyl chloride (155ml), reaction mixture was stirred 2 hours down at 0 ℃.And then gradation adding Diisopropylamine (350ml) and methylsulfonyl chloride (155ml), reaction mixture stirred under room temperature 16 hours.Gained mixture water (4ml) dilution transfers to pH9 with the 1M sodium hydroxide solution, with ethyl acetate (3 * 10ml) extractions.Merge organic extract liquid, dry (MgSO 4) and flash to jelly (260mg).Use the silica gel chromatography purifying, use methylene dichloride: methyl alcohol: strong aqua (95: 5: 1) wash-out obtains yellow gelationus title product (144mg).m/e250.1（MH） +。
N.M.R.（CDCl 3）δ＝1.46（s，9H）;2.6（bs，2H）;3.53（t，2H）;4.0（bs，2H）;6.3（m，1H）;7.0（s，2H）;9.4（bs，1H）.
Preparation 28
The 1-(N-tertbutyloxycarbonyl)-4-imidazoles-2-phenylpiperidines
The product (0.55g) of intermediate preparation 27 is dissolved in the ethanol (30ml), at 30 pounds/inch 2(2.0 crust) is down with palladium/carbon catalyst (200mg, 10%) hydrogenation.Filter catalyzer and, obtain foam (0.55g) except that desolvating.m/e 252.1（MH） +。
N.M.R.（CDCl 3）δ＝1.4（s，9H）;1.68（qd，2H）;1.95（bd，2H）;2.75（bt，2H）;2.92（bt，1H）;4.1（bd，2H）;6.9（s，2H）;8.77（bs，1H）.
Preparation 29
The 1-(N-tertbutyloxycarbonyl)-and 4-(imidazoles-1-yl) methyl isophthalic acid, 2,5, the 6-tetrahydropyridine
(a) get the 60% oily dispersion liquid of sodium hydride (4g) in anhydrous dimethyl sulfoxide (100ml), with hexane flush away fluid, then 70 ℃ of following stirring heating 1 hour.Add anhydrous tetrahydro furan (100ml), reactant is cooled to-20 ℃.Add the solution of trimethylammonium iodate blunderbuss (20.4g) in methyl-sulphoxide (80ml) then, add the 1-(N-tertbutyloxycarbonyl subsequently)-solution of 4-ketone piperidines (19.9g) in anhydrous tetrahydro furan (100ml), reactant was stirred 0.5 hour down at-10 ℃, at room temperature stirred again 1 hour.Add entry (500ml) then, with ethyl acetate (3 * 250ml) extraction mixtures.Combining extraction liquid is used the salt water washing, dry (MgSO 4) and vacuum-evaporation.Use the silica gel chromatography purifying,, obtain the 1-(N-tertbutyloxycarbonyl of colorless solid shape with hexanaphthene-ether-Virahol (60: 40: 1) wash-out) piperidines-4-spiral shell-2 '-oxyethane (19.6g).
M.p.65-66 ℃. measured value C, 62.11; H, 9.06; N, 6.55.C 11H 19NO 3Calculated value C, 61.97; H, 8.92; N, 6.57%.
(b) at nitrogen with under stirring, with the solution of oily dispersion liquid processing imidazoles (1.91g) in anhydrous acetonitrile (30ml) of 80% sodium hydride (0.84g), gained mixture heating up to 60 is ℃ until dissolving.The product (2.0g) that adds step (a) after 15 minutes is kept reaction 5 hours.After reactant at room temperature being placed spend the night, vacuum evaporating solvent, oily resistates distribute between methylene dichloride (40ml) and water (20ml).Tell organic phase, wash with water, dry (MgSO 4) and vacuum-evaporation.Use the silica gel chromatography purifying,, obtain the 1-(N-tertbutyloxycarbonyl of colourless powder shape with methylene chloride-methanol-dense 880 ammoniacal liquor (95: 4: 1) wash-out)-4-hydroxyl-4-(imidazoles-1-yl) methyl piperidine (2.13g).
Measured value C, 58.35; H, 8.30; N, 14.52.C 13H 23N 3O 3
1/10 CH 2Cl 2Calculated value C, 58.43; H, 8.07; N, 14.50%.
m/e 282（MH） +.
(c) 0-5 ℃ and stir under, with the solution of methylsulfonyl chloride (2.20ml) in anhydrous methylene chloride (10ml), treatment step (b) product (2.0g) and the solution of triethylamine (5.44ml) in anhydrous methylene chloride (80ml) make the gained mixture be warmed to room temperature and kept 14 hours.Wash reaction mixture then with water, dry (MgSO 4) and vacuum-evaporation.With silica gel chromatography purifying resistates,, obtain golden oily product (1.36g) with methylene chloride-methanol-dense 880 ammoniacal liquor (96: 4: 0 to 95: 4: 1) wash-out.
Measured value C, 59.93; H, 7.60; N, 14.79.C 13H 21N 3O 21/4 CH 2Cl 2
Calculated value C, 60.14; H, 7.61; N, 14.77%.
m/e（MH） +264
N.M.R.（CDCl 3）δ＝1.45（s，9H）;1.97（m，2H）;3.50（t，2H）;3.90（s，2H）;4.50（s，2H）;5.50（s，1H）;6.90（s，1H）;7.10（s，1H）;7.55（s，1H）.
Preparation 30
The positive butoxy carbonyl of 1-(N-)-and 4-(imidazoles-1-yl) methyl piperidine
Under 50 pounds/inch (3.5 crust) and room temperature, (0.3g) makes catalyzer with 10% palladium/charcoal, under agitation makes the solution hydrogenation of preparation 29 products (1.33g) in dehydrated alcohol (25ml) 4 hours.Then reaction mixture is filtered and vacuum-evaporation, with the methylene dichloride azeotropic.Use the silica gel chromatography purifying,, obtain colorless oil product (1.09g) with methylene chloride-methanol (96: 4) wash-out.
Measured value C, 63.08; H, 8.60; N, 15.50.C 13H 23N 3O 21/4 CH 2Cl 2Calculated value C, 63.36; H, 8.74; N, 15.84%.m/e(MH) +266
N.M.R.（CDCl 3）δ＝1.15（m，2H）;1.45（s，9H）;1.58（m，2H）;1.85（m，1H）;2.65（t，2H）;3.80（d，2H）;4.10（m，2H）;6.90（s，1H）;7.10（s，1H）;7.45（s，1H）.
Preparation 31
The 1-(N-tertbutyloxycarbonyl)-and 4-(imidazoles-1-yl)-1,2,5, the 6-tetrahydropyridine
Under-10 ℃, in anhydrous methylene chloride (30ml), stir imidazoles (8.20g), and add the solution of thionyl chloride (4.8ml) in anhydrous methylene chloride (30ml).Make the gained slurries be warmed to room temperature, drip the 1-(N-tertbutyloxycarbonyl after 2 hours)-solution of 4-ketone piperidines (6.0g) in anhydrous methylene chloride (50ml).Reaction mixture stirs and spends the night vacuum-evaporation then.In the oily resistates, add the solution of salt of wormwood (6.0g) in water (30ml), with methylene dichloride (2 * 60ml) extraction products.Combining extraction liquid and water (40ml) washing, dry (MgSO 4) and vacuum-evaporation.Use the silica gel chromatography purifying,, obtain oily product (1.0g) with ethyl acetate-methyl alcohol (100: 0 to 90: 10) wash-out.
N.M.R.（CDCl 3）δ＝1.50（s，9H）;2.55（s，2H）;3.70（t，2H）;4.05（s，2H）;5.80（s，1H）;7.10（s，2H）;7.65（s，1H）.
Preparation 32
The 1-(N-carbobenzoxy-(Cbz))-and 4-(1,2,4-triazole-4-yl) piperidines
To the 1-(N-carbobenzoxy-(Cbz))-solution of 4-ketone piperidines (5.0g) in methyl alcohol (25ml) in, add ammonium acetate (16.5g) and sodium cyanoborohydride (0.94g), mixture at room temperature stirred 24 hours.Removal of solvent under reduced pressure then, resistates distributes between ethyl acetate and 1M sodium hydroxide solution.Tell ethyl acetate layer, use dried over mgso, reduction vaporization obtains yellow oil.This resistates silica gel chromatography purifying with methylene chloride-methanol-strong aqua (95: 5: 1) wash-out, obtains the 4-amino-1-(N-carbobenzoxy-(Cbz) of yellow oily) piperidines.The solution of this product (1.5g) in toluene (20ml) is handled with dimethyl formamide azine (1.0g) and tosic acid (1.0g), and mixture heating up refluxed 24 hours.Removal of solvent under reduced pressure then, resistates silica gel chromatography purifying with methylene chloride-methanol-strong aqua (93: 7: 1) wash-out, obtains the title compound of colorless oil.
m/e（MH +）287
N.M.R.（DMSO-d 6）δ＝1.82（m，2H）;2.01（m，2H）;2.83-3.09（m，2H）;4.12（m，2H）;4.40（m，1H）;5.11（s，2H）;7.28-7.45（m，5H）;8.65（s，2H）.
Preparation 33
The 1-(N-tertbutyloxycarbonyl-(S)-valyl)-3-(imidazoles-1-yl) azetidine
With the 1-(N-tertbutyloxycarbonyl)-3-(imidazoles-1-yl) (0.72g) solution in methylene dichloride (30ml) is saturated with hydrogenchloride under 0 ℃ for azetidine (deriving from preparation 18), keeps this temperature again 1 hour.Solvent removed in vacuo, obtain amine hydrochlorate, it is dissolved in N, in the dinethylformamide (25ml), this solution is at room temperature used N-tertbutyloxycarbonyl-(S)-Xie Ansuan N-hydroxy-succinamide ester (1.01g) and N, and N-diisopropylethylamine (1.7ml) is handled).Reaction mixture at room temperature stirred 18 hours, then solvent removed in vacuo.Resistates silica gel chromatography purifying with methylene chloride-methanol-strong aqua (97: 7: 1) wash-out, obtains colourless foam shape title compound (0.79g).
m/e 323（MH） +
N.M.R.（DMSO-d 6）δ＝0.89（m，6H）;1.38（s，9H）;1.90（m，1H）∶3.61-3.78（m，1H）;3.92-4.10（m，1H）;4.24-4.80（m，3H）;5.19（m，1H）;6.98（s，1H）;7.06（dd，1H）;7.38（s，1H）;7.77（s，1H）.
Preparation 34-43
According to preparation 33 method, use the suitable intermediate that obtains by preparation 18-32, and with N-tertbutyloxycarbonyl-(S)-Xie Ansuan N-hydroxy-succinamide ester coupling, prepare following formula (VII) compound, wherein R 4Be (S)-sec.-propyl, R 7And R 8Be hydrogen.
Figure 931032067_IMG14
Preparation 44-48
According to the preparation method of preparation 33, use N-tertbutyloxycarbonyl in the coupling step-(S)-and Isoleucine N-hydroxy-succinamide ester, prepare following formula (VII) compound, wherein R 4Be sec-butyl, m is 0.
Figure 931032067_IMG15
Preparation 49
The 1-(N-tertbutyloxycarbonyl-(S)-isoleucyl-)-the 4-keto piperidine
Utilize and preparation 33 described identical methods, but use 4-keto piperidine hydrochloride hydrate (replacing 3-(imidazoles-1-yl) azetidine hydrochloride) and (S)-Isoleucine N-hydroxy-succinamide ester, the preparation title compound.m/e 313（MH） +。
[α] 25 D-16℃（c＝0.34%，MeOH）
N.M.R.（CDCl 3）δ＝0.9（m，6H）;1.2（m，1H）;1.4（s，9H）;1.6（m，1H）;1.75（m，1H）;2.5（m，4H）;3.7（m，2H）;4.15（m，2H）;4.55（m，1H）;5.2（d，2H）.
Preparation 50
N-((R)-the 2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-(t-butyldimethylsilyloxy base)-6-phenyl caproyl)-(S)-Xie Ansuan
Prepare title compound with the described method of people such as S.J.deSolms (J.Med.Chem., 34: 2852,1991).
Preparation 51
1-isocyano--3-methyl isophthalic acid-p-toluenesulfonyl-but-1-ene
With Van leusen, Schaart and Leusen(Recueil, 98(5): method 258,1979) prepares title compound by tolysulfonyl methyl isocyanide and isobutyric aldehyde.The I.R.(whiteruss) 2100cm -1
m/e 267（MH+NH 3） +
N.M.R.（CDCl 3）δ＝1.15（d，6H）;2.5（s，3H）;2.84（m，1H）;6.88（d，1H）;7.4（d，2H）;7.85（d，2H）.
Preparation 52
3-trimethylene oxide oxygen carbonyl succinimide
With oxa-ring fourth-3-alcohol (2.0g) and N, N-diisopropylethylamine (7.76g) is dissolved in the methylene dichloride (50ml), under nitrogen atmosphere, keeping under-20 ℃ the condition, above-mentioned drips of solution is being added in the solution of carbonic acid two (trichloromethyl) ester (2.69g) in methylene dichloride (100ml) through 15 minutes.Then with solution-20 ℃ of following restir 15 minutes, once add N-hydroxy-succinamide (3.45g).Make this solution be warmed to room temperature through 2 hours, then water (50ml), saturated sodium bicarbonate aqueous solution (50ml) and salt solution (25ml) washing.Then with organic layer drying (MgSO 4), filter and solvent removed in vacuo, obtain light brown oily title compound (4.65g).
N.M.R.（CDCl 3）δ＝2.83（s，4H）;4.75（m，2H）;4.90（m，2H）;5.58（m，1H）.
Embodiment 1
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine
A) 1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-t-butyldimethylsilyloxy base-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine
Under 0 ℃, make the 1-(N-tertbutyloxycarbonyl with hydrogenchloride)-(S)-valyl)-3-(imidazoles-1-yl) (made by preparation 33, the solution of 0.79g in methylene dichloride (50ml) is saturated, and keeps under this temperature 1 hour again for azetidine.Vacuum evaporating solvent obtains the amine of colorless solid shape.The solution of this product in dimethyl formamide (20ml) is added in a kind of activated ester solution for preparing in advance, the compound method of this activated ester solution is: with (R)-2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base)-6-phenyl caproic acid (derives from preparation 2,1.32g), I-hydroxybenzotriazole (0.36g), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.58g) and N, N-diisopropylethylamine (1.75ml) stirred 20 minutes in dimethyl formamide (75ml) together.Behind the restir 24 hours, solvent removed in vacuo, resistates distributes between ethyl acetate and water.Tell ethyl acetate layer, dry (MgSO 4), solvent removed in vacuo obtains colorless oil.Use the silica gel chromatography purifying,, obtain colourless foam shape title compound (1.1g) with ethyl acetate-methyl alcohol-strong aqua (90: 10: 1) wash-out.
Measured value: C, 66.04; H, 8.26; N, 9.61.C 41H 61N 5O sSi.1/2 H 2O calculated value C, 66.39; H, 8.36; N, 9.44%.
m/e 733（MH） +
[α] 25 D-6°（c＝0.29%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.12（m，6H）;0.90（m，15H）;1.25-1.29（2 x s，9H）;1.96（m，1H）;2.32-2.77（m，4H）;2.89（m，1H）;3.48-3.74（m，2H）;3.88-4.06（m，3H）;4.18-4.66（m，4H）;5.12（m，1H）;6.77（t，1H）;6.98（s，1H）;7.07-7.32（m，10H）;7.40-7.82（2 x s，1H）;7.76-7.96（2 x s，1H）;8.0-8.20（2 x d，1H）.
B) 1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl nitrogen base)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine
The product (1.19g) of step (a) is dissolved in the tetrahydrofuran (THF), at room temperature handles with the tetrahydrofuran solution of 1M tetra-n-butyl Neutral ammonium fluoride.After 48 hours, solvent removed in vacuo, product absorbs in ethyl acetate, with saturated sodium bicarbonate aqueous solution and water washing, uses MgSO 4Drying, vacuum evaporating solvent.Use the silica gel chromatography purifying,, use the ethyl acetate/hexane recrystallization then, obtain colorless solid shape product (0.52g), m.p.124-126 ℃ with methylene chloride-methanol-strong aqua (93: 7: 1) wash-out.
Measured value: C, 67.99; H, 8.01; N, 11.06.C 35H 47N 5O 5
Calculated value C, 68.05; H, 7.67; N, 11.34%.m/e 618(MH) +
[α] 25 D-3°（c＝0.14%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.80（m，6H）;1.21-1.47（m，1H）;1.27（s，9H）;1.58-1.71（m，1H）;1.81-1.98（m，1H）;2.44-2.62（m，2H）;2.68-2.92（m，3H）;3.37-3.61（m，2H）;3.85-4.02（m，2H）;4.13-4.36（m，2H）;4.41-4.56（m，2H）;5.18（m，1H）;6.43（d，1H）;6.98（s，1H）;7.05-7.30（m，10H）;7.26-7.77（2 x s，1H）;7.38-7.82（2 x s，1H）;7.88-7.98（2 x d，1H）.
Embodiment 2-10
Prepare following compounds according to embodiment 1 described general method; but in coupling step (a), use suitable formula IV to be protected carboxylic acid intermediate and suitable formula (VIII) amine, as described in step (b), remove the t-butyldimethylsilyl protecting group then.
Figure 931032067_IMG16
Figure 931032067_IMG17
Figure 931032067_IMG18
Embodiment 11
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl-(S)-valyl]-(S)-and 3-(imidazoles-1-yl) tetramethyleneimine
Adopt the method for embodiment 1, in the coupling step, use 1-(N-tertbutyloxycarbonyl-(S)-valyl)-3-(S) imidazoles-1-yl) tetramethyleneimine (preparation 36), then as embodiment 1(b) as described in remove t-butyldimethylsilyl, obtain title compound.
M.p.111-112 ℃. measured value: C, 61.90; H, 6.85; N, 9.61.
C 37H 48F 3N 5O 6Calculated value C, 62.08; H, 6.76; N, 9.78%.
m/e（MH） +716
[α] 25 D+2°（c＝0.1%，MeOH）[α] 25 365+14°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.65-0.90（m，6H）;1.15-1.35（m，10H）;1.60（m，1H）;1.85（m，1H）;2.05-2.90（m，7H）;3.20-4.10（m，6H）;4.20（m，1H）;4.55（m，1H）;4.85（m，1H）;6.40（d，1H）;6.90-6.95（2 x s，1H）;7.10-7.30（m，10H）;7.70-7.80（2 x s，1H）;7.90-8.0（2 x d，1H）.
Embodiment 12
1-[N-((S)-5-tertiary butyloxycarbonyl amino-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl-(S)-valyl]-(R)-and 3-(imidazoles-1-yl) tetramethyleneimine
Adopting aforesaid method, but with 1-(N-tertbutyloxycarbonyl-(S)-valyl-3-(R)-imidazoles-1-yl) tetramethyleneimine is initial, obtains title product, m.p.109 ℃.
Measured value: C, 61.44; H, 7.05; N, 9.71.C 37H 48F 3N 5O 62/5 H 2O
Calculated value C, 61.47; H, 6.80; N, 9.69%.m/e(MH) +716
[α] 25 D-23°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.70-0.85（m，6H）;1.15-1.40（m，10H）;1.60（m，1H）;1.85（m，1H）;2.00-2.90（m，7H）;3.25-3.70（m，5H）;3.95（m，1H）;4.20（m，1H）;4.45-4.65（m，1H）;4.75-4.95（2 x m，1H）;6.40（m，1H）;6.90（s，1H）;7.05-7.25（m，10H）;7.70-7.75（2 x s，1H）;7.90-8.05（2 x d，1H）.
Embodiment 13
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines
A) 1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-t-butyldimethylsilyloxy base-6-phenyl caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines
Utilize and the described identical method of embodiment 1 step (a), by 1-(N-tertbutyloxycarbonyl-(S)-valyl-4-imidazoles-1-phenylpiperidines with (S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-(R)-2-benzyl-6-phenyl caproic acid prepares title compound.Use the silica gel chromatography purifying,, obtain colourless foam shape product (0.71g) with ethyl acetate-methyl alcohol-strong aqua (90: 10: 1) wash-out.
Measured value: C, 67.32; H, 8.44; N, 9.22.C 43H 65N 5O 5Si.
1/4 H 2O calculated value C, 67.54; H, 8.56; N, 9.15%.
m/e 760（MH） +
N.M.R.（DMSO-d 6）δ＝0.12（m，6H）;0.91（m，15H）;1.13-1.30（m，2H）;1.26（s，9H）;1.47-1.76（m，2H）;1.89-2.08（m，4H）;2.36-2.97（m，6H）;3.50-3.75（m，2H）;3.99-4.61（m，4H）;6.79（m，1H）;6.90（d，1H）;7.07-7.29（m，11H）;7.68-7.73（2 x s，1H）;7.93-7.99（2 x d，1H）.
B) 1-[N-(R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines
With with the described identical method of embodiment 1 step b), prepare title compound by above-mentioned steps product a).Use the silica gel chromatography purifying,, use the ethyl acetate/hexane recrystallization then, obtain colorless solid shape product, m.p.121-123 ℃ (0.48g) with methylene chloride-methanol-strong aqua wash-out.
Measured value: C, 68.38; H, 7.96; N, 10.59.C 37H 51N 5O 5.1/4 H 2O
Calculated value C, 68.30; H, 7.92; N, 10.77%.
m/e 646（MH） +
[α] 25-10°（c＝0.1，MeOH）
N.M.R.（DMSO-d 6）δ＝0.77（m，6H）;1.19-1.37（m，1H）;1.28（s，9H）;1.48-1.72（m，3H）;1.82-2.04（m，3H）;2.42-2.94（m，7H）;3.38-3.60（m，2H）0;3.96-4.15（m，1H）;4.28（m，1H）;4.37-4.58（m，3H）;6.43（d，1H）;6.88（s，1H）;7.04-7.29（m，11H）;7.65-7.69（2 x s，1H）;7.84-7.88（2 x d，1H）.
Embodiment 14-37
Prepare following compounds by embodiment 13 described methods; but use suitable formula IV to be protected carboxylic acid intermediate and suitable formula (VIII) Xie Ansuan or Isoleucine derivative in coupling step (a), as described in step (b), remove the t-butyldimethylsilyl protecting group subsequently.
Figure 931032067_IMG20
Figure 931032067_IMG22
Embodiment 31
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-4-(1,2,4-triazole-4-yl) piperidines
With the catalytic hydrogenation method from the 1-(N-carbobenzoxy-(Cbz))-4-(1; 2; 4-triazole-4-yl) removes the carbobenzoxy-(Cbz) protecting group on the piperidines (preparation 32); make gained amine product and N-((R by the described method of embodiment 1 step (a))-the 2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl caproyl)-(S)-the Xie Ansuan coupling; generate 1-[N-((R)-the 2-benzyl-(S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl caproyl)-(S)-valyl]-4-(1; 2; 4-triazole-4-yl) piperidines, m/e 761(MH +).
Press the method for embodiment 1 step (b), handle above-mentioned product, generate title product with the tetra-n-butyl Neutral ammonium fluoride.
Measured value: C, 64.90; H, 7.93; N, 12.48.C 36H 50N 6O 5.H 2The O calculated value
C，65.06;H，7.83;N，12.65%.m/e 647（MH） +
[α] 25 D-9°（c＝0.12 MeOH）
N.M.R.（DMSO-d 6）δ＝0.70-0.92（m，6H）;1.15-1.41（m，10H）;1.46-1.76（m，3H）;1.81-2.16（m，3H）;2.53-2.96（m，7H）;3.38-3.64（m，2H）;3.95-4.15（m，1H）;4.27-4.61（m，4H）;6.36-6.44（m，1H）;7.01-7.12（m，10H）;7.78-7.91（m，1H）;8.54（s，1H）;8.60（s，1H）.
Embodiment 32
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl)-1,2,5,6-tetrahydropyridine tartrate
A) press embodiment 1(a) method; make (S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base)-(R)-the 2-(4-trifluoro-methoxybenzyl)-6-phenyl caproic acid with by the 1-(N-tertbutyloxycarbonyl)-4-imidazoles-2-base-(1; 2; 5; the 6-tetrahydropyridine) deprotection and the reaction of the amine that makes; generate 1-[N-((S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base)-the 6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl-(S)-valyl]-4-(imidazoles-1-yl)-1; 2; 5, the 6-tetrahydropyridine.
Measured value: C, 62.19; H, 7.39; N, 8.38.C 33H 62F 3N 5O 6Si 1/10 CH 2Cl 2
Calculated value C, 62.27; H, 7.37; N, 8.23%.
m/e 842（M） +
[α] 25 D-10°（c＝0.1%，MeOH）
N.M.R.（CDCl 3）δ＝0.10（m，6H）;0.80（d，6H）;0.90（s，9H）;1.35（s，9H）;1.20-1.95（m，5H）;2.35-2.55（m，3H）;2.70（m，2H）;3.41-4.10（m，6H）;4.55（m，1H）;4.65（d，1H）;5.60-5.80（2 x s，1H）;6.25（d，1H）;6.90-7.30（m，11H）;7.65（s，1H）.
B) press embodiment 1(b) method by with tetra-n-butyl Neutral ammonium fluoride reaction and deprotection, generate the title product of free alkali form.This product is dissolved in the dehydrated alcohol, with the solution-treated of 1-tartrate (0.14g) in dehydrated alcohol.Generate throw out after adding ether, throw out filtered and drying, obtain the 1-tartrate (0.61g) of colorless solid shape, m.p.92-152 ℃.
Measured value: C, 57.40; H, 6.64; N, 7.51.C 38H 38F 3N 5O 6.CH 16O 61/3 H 2O calculated value C, 57.11; H, 6.23; N, 7.93%.
m/e（MH） +728
[α] 25 D+6.7°（c＝0.1%，MeOH）
[α] 25 365-6.7°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.75（m，6H）;1.25（s，9H）;0.95-1.40（m，1H）;1.50（m，1H）;1.90（m，1H）;2.35-2.95（m，7H）;3.0-3.85（m，4H）;4.0（m，1H）;4.10（m，1H）;4.25（s，2H）;4.40-4.60（m，2H）;6.0（m，1H）;6.40（d，1H）;7.0（s，1H）;7.10-7.30（m，9H）;7.50（s，1H）;7.95（m，2H）.
Embodiment 33
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl-]-4-(5-isopropylimdazole-1-yl) piperidines
A) make 1-(N-tertbutyloxycarbonyl-(S)-isoleucyl-)-4-keto piperidine (preparation 49) deprotection; then with (S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl-(R)-2-(4-trifluoro-methoxybenzyl) caproic acid (preparation 10) reaction, generate 1-[N-((S)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl]-the 4-keto piperidine.
Measured value: C, 62.50; H, 8.00; N, 5.20.C 42H 62F 33O 7Si calculated value C, 62.60; H, 7.80; N, 5.20%.m/e 806.5(MH) +.[α] 25 D-5.30(c=0.1%, MeOH).
B) at 30 pounds/inch 2Under (2.0 crust), with palladium/carbon (5%, 100mg) make catalyzer, make above-mentioned product (2.0g) and ammoniacal liquor (proportion 0.88) hydrogenation 4 hours in ethanol (25ml).Filter catalyzer and evaporating solvent; obtain 2.0g colourless foam shape thing; use the silica gel chromatography purifying; use methylene dichloride: methyl alcohol: strong aqua (90: 10: 1) wash-out; after suitable fraction concentrated, obtain the 1-[N-((S of flint glass shape)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl-]-4-amino piperidine (1.53g).
C) with above-mentioned steps b) product (404mg) and 1-isocyano--3-methyl isophthalic acid-p-toluenesulfonyl-but-1-ene (derive from the preparation 51,150mg) in methyl alcohol (15ml), stirred 16 hours with diisopropylethylamine (100mg).Under 40 ℃, remove and desolvate; resistates silica gel chromatography purifying; use methylene dichloride: methyl alcohol: strong aqua (98: 2: 0.4) wash-out obtains the 1-[N-((S of flint glass shape)-5-tertiary butyloxycarbonyl amino-(S)-4-t-butyldimethylsilyloxy base-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl]-4-(5-isopropylimdazole-1-yl) piperidines (380mg).m/e 900（MH +）。
D) press embodiment 1(b) method, make above-mentioned steps c by handling with the tetra-n-butyl Neutral ammonium fluoride) the product deprotection, generate title product.
Measured value: C, 63.5; H, 7.70; N, 8.70.C 42H 58F 3N 5O 6.1/2H 2O
Calculated value C, 63.5; H, 7.48; N, 8.81%.
m/e 785.9（MH） +
N.M.R.（DMSO-d 6）δ＝0.8（m，6H）;1.05（m，1H）;1.2（m，6H）;1.3（s，9H）;1.3-2.0（m，7H）;2.5-3.0（m，6.5H）;3.2（bt，0.5H）;3.3（m，1H）;3.58（m，1H）;4.13（m，3H）;4.4-4.65（m，4H）;6.43（m，1H）;6.63（s，1H）;7.1-7.3（m，9H）;7.47，7.6（s，s，1H）;7.95（bt，1H）.
Embodiment 34
1-[N-((S)-the 4-hydroxyl-(S)-5-(trimethylene oxide-3-base oxygen carbonyl amino)-the 6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines
The product (4.0g) of embodiment 16 is dissolved in the methylene dichloride (40ml), and in ice bath, cools off.Dripped trifluoroacetic acid (10ml) through 5 minutes, solution stirred 1.5 hours down at 0 ℃.Vacuum evaporating solvent, resistates absorbs with ethyl acetate (250ml), with 1M sodium hydroxide (50ml) and salt solution (50ml) washing.With organic solution drying (MgSO 4), filter vacuum evaporating solvent.Use the silica gel chromatography purifying; with ethyl acetate-methyl alcohol-strong aqua (90: 10: 1) wash-out, obtain the 1-[N-(S of white solid)-5-amino-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines (2.98g).m/e 630（MH） +。
N.M.R.（DMSO-d 6）δ＝0.78（m，6H）;1.34-1.75（m，4H）;1.81-2.07（m，3H）;2.37-2.93（m，8H）;3.05-3.29（m，3H）;4.05-4.56（m，5H）;6.88（s，1H）;7.10-7.27（m，10H）;7.67（d，1H）;7.95（m，1H）;
B) product (0.818g) with step a) is dissolved in the methylene dichloride (30ml).Add 3-oxetanyl carbonyl oxygen base succinimide (0.344g), solution at room temperature stirred 1 hour.Then solution is washed dry (MgSO with 0.5M sodium hydroxide (15ml) and salt solution (15ml) 4), filter and vacuum-evaporation.Gained solid re-crystallizing in ethyl acetate obtains the title compound of white solid, m.p.201-203 ℃.
Measured value: C, 60.32; H, 6.22; N, 9.15; C 37H 46F 3N 5O 71/2 H 2O calculated value C, 60.15; H, 6.41; N, 9.48%.
m/e 730（MH） +
[α] 25 D+3°（c＝0.1%，MeOH），[α] 25 365+32°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.77（m，6H）;1.22-2.05（m，7H）;2.50-2.93（m，8H）;3.42-3.60（m，2H）;4.08（d，1H）;4.22-4.73（m，7H）;5.12（m，1H）;6.89（s，1H）;7.11-7.28（m，1H）;7.67（d，1H）;7.86（d，1H）.
Embodiment 35
1-[N-((S)-the 4-hydroxyl-(S)-5-(trimethylene oxide-3-base oxygen carbonyl amino)-the 6-phenyl-(R)-2-(3-phenyl third-2-thiazolinyl) caproyl)-(S)-isoleucyl]-4-(imidazoles-1-yl) piperidines
Under 0-5 ℃, with the solution of anhydrous trifluoroacetic acid (4ml) Processing Example 18 products (0.45g) in methylene dichloride (20ml) 5 hours.With the reaction solution vacuum concentration, remaining jelly and toluene (* 3) azeotropic is also dry then.Solution in methylene dichloride (25ml) is cooled to 5 ℃ with rough amine product and diisopropylethylamine (0.82ml) then, drips the solution of 3-trimethylene oxide oxygen carbonyl oxygen base succinimide (0.22g) in methylene dichloride (5ml).Make reaction solution be warmed to room temperature, kept 17 hours, wash with water then, dry (MgSO 4) and vacuum-evaporation.Use the silica gel chromatography purifying,, obtain colourless foam shape product (0.26g), m.p.157-160 ℃ with methylene chloride-methanol-strong aqua (95: 4: 1) wash-out.
Measured value: C, 66.45; H, 7.49; N, 10.22.C 38H 49N 5O 63/4H 2O
Calculated value C, 66.60; H, 7.43; N, 10.22%.
[α] 25 D+32°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.75（m，6H）;1.25-2.95（m，12H）;3.05-3.65（m，4H）;3.95-4.75（m，10H）;5.05（m，1H）;6.10（m，1H）;6.30（d，1H）;6.80-6.85（2 x s，1H）;6.95-7.35（m，11H）;7.55-7.65（2 x s，1H）;7.95（d，1H）.
Embodiment 36
1-[N-((S)-the 4-hydroxyl-(S)-the different third oxygen carbonyl amino of 5-()-the 6-phenyl-(R)-2-(3-phenyl third-2-thiazolinyl) caproyl)-(S)-isoleucyl]-4-(imidazoles-1-yl) the piperidines tartrate
Prepare title compound by embodiment 35 described methods, but use isopropyl chlorocarbonate and the reaction of amine intermediate.Use the silica gel chromatography purifying,, obtain colourless powder shape product, with ethyl acetate-hexane recrystallization with methylene chloride-methanol-strong aqua (97: 2: 1 to 95: 4: 1) wash-out.This free alkali is dissolved in the ethanol, handles with 1-tartrate.Add ether, obtain colourless powder shape tartrate, m.p.156-157 ℃.
Measured value: C, 61.60; H, 6.87; N, 8.38.C 38H 51N 5O 5C 4H 6O 61/2 H 2O
Req calculated value C, 61.75; H, 7.16; N, 8.57%.
m/e 658（MH） +
[α] 25 D+26°（c＝0.1%，MeOH）
N.M.R.（DMSO-d 6）δ＝0.75（m，6H）;1.0（m，6H）;1.25-3.65（m，14H）;3.95-4.70（m，10H）;6.10（m，1H）;6.30（d，1H）;6.65（d，1H）;6.85-6.90（2 x s，1H）;7.05-7.35（m，1H）;7.65-7.75（2 x s，1H）;7.90（d，1H）.
Embodiment 37
1-[N-((S)-5-tertiary butyloxycarbonyl amino-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl)-4-((S)-and valyl oxygen base) caproyl)-(S)-(valyl]-4-(imidazoles-1-yl) the piperidines tartrate
A) N-carbobenzoxy-(Cbz)-L-Xie Ansuan (1.03g) and dicyclohexylcarbodiimide (0.51g) are dissolved in the methylene dichloride (25ml), and this mixture was stirred 3 hours.The dicyclohexylurea (DCU) that filtering is settled out, evaporated filtrate obtain white foam shape thing.The product of this white foam shape thing and embodiment 16 is incorporated in N, in the dinethylformamide (20ml), adds 4-Dimethylamino pyridine (0.025g).Stir after 5 days under the room temperature, mixture is distributed between ethyl acetate and water.Dry organic extract liquid (MgSO 4) and evaporating solvent; use the silica gel chromatography purifying then; use ethyl acetate: methyl alcohol (0-10%) wash-out obtains the 1-[N-(S of white foam shape)-the 4-(N-carbobenzoxy-(Cbz)-(S)-valyl oxygen base)-(S)-5-tertiary butyloxycarbonyl amino-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl-(S)-valyl]-4-(imidazoles-1-yl) piperidines.
Measured value: C, 62.63; H, 6.73; N, 8.37.C 51H 65F 3N 6O 9.H 2O req calculated value C, 62.43; H, 6.88; N, 8.56%.
m/e 963（MH） +
B) above-mentioned steps product (0.95g) a) is dissolved in the dehydrated alcohol (50ml), this solution is handled with 10% palladium/carbon (0.1g), and at 60 pounds/inch 2Hydrogenation is 4 hours under (4.1 crust) and the room temperature.Behind the filtration catalizer, filtrate is evaporated to dried.Use the silica gel chromatography purifying,, obtain white foam shape product with methylene chloride-methanol-dense oxygen water (97: 3: 0.5) wash-out.This foam is dissolved in the ethyl acetate (6ml), adds the solution of tartrate (0.089g) in 10% methanol/ethyl acetate (10ml).Evaporating solvent and with ether development obtains white glass shape product (0.48g).
M.p.122 ℃. measured value C, 56.74; H, 6.78; N, 8.56.C 43H 59F 3N 6O 7: C 4H 6O 6: H 2O req calculated value C, 56.61; H, 6.77; N, 8.43%.
N.M.R.（DMSO-d 6）δ＝0.8-0.95（m，12H）;1.2（s，11H）;1.35-1.77（m，2H）;1.8-2.15（m，4H）;2.4-3.2（m，8H）;3.51（m，1H）;3.8（m，1H）;4.1（m，1H）;4.3（m，1H）;4.4-4.65（m，2H）;4.81（m，1H）;6.83（s，1H）;7.0-7.32（m，12H）;7.66（d，1H）;7.73-8.0（m，1H）.

Claims (13)

1, a kind of compound and pharmacologically acceptable salt and bioprecursor with following formula:
Figure 931032067_IMG2
Wherein:
R 1Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, aryl, heterocyclic radical or CONR 9R 10
R 2Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl (C 1-C 4) alkyl, aryl (C 1-C 4) alkyl or heterocyclic radical (C 1-C 4) alkyl;
R 3Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, C 3-C 8Cycloalkyl (C 1-C 4) alkyl, aryl (C 1-C 4) alkyl, aryl (C 2-C 4) thiazolinyl, heterocyclic radical (C 1-C 4) alkyl or heterocyclic radical (C 2-C 4) thiazolinyl;
R 4Be C 1-C 6Alkyl, C 3-C 8Cycloalkyl, aryl or heterocyclic radical;
R 5, R 6, R 7And R 8All be H, C independently of one another 1-C 6Alkyl or C 3-C 8Cycloalkyl; Perhaps, R 5And R 6, or R 7And R 8, can connect together forms three to eight Yuans carbocyclic rings;
X is monocycle or dicyclo four to the ten element heterocycle bases that contain some ring carbon atoms and a theheterocyclic nitrogen atom, and this group is connected with the carbonyl that links to each other by theheterocyclic nitrogen atom; This group can be saturated or part is unsaturated, and, remove-(CR 7R 8) mOutside-Het the substituting group, this group can be by 4 other substituting groups replacements at the most, and substituting group all is independently selected from F, C 1-C 6Alkyl, C 3-C 8Cycloalkyl, OR 11Or NR 9R 10
Het is imidazolyl or triazolyl, and they all can be randomly by C 1-C 6Alkyl, C 3-C 8Cycloalkyl, NR 9R 10Or CONR 9R 10Replace;
R 9Or R 10All be H, C independently 1-C 6Alkyl or C 3-C 8Cycloalkyl, perhaps, R 9And R 10Can connect together and form four to eight Yuans nitrogen heterocycles with the nitrogen-atoms that they connected;
R 11Be H, C 1-C 6Alkyl or C 3-C 8Cycloalkyl;
N and m are 0,1 or 2 independently of one another;
Any alkyl or cycloalkyl included in the above-mentioned definition all can randomly be replaced by full replacement of fluorine or part.
2, compound as claimed in claim 1, this compound has following three-dimensional chemical configuration:
Figure 931032067_IMG3
R wherein 1To R 8, n, m, X be defined in Het such as the front claim 1.
3, compound as claimed in claim 1 or 2, wherein R 1Be the tertiary butyl, sec.-propyl or oxetanyl, n is 0.
4, compound as claimed in claim 3, wherein R 2Be benzyl.
5, as claim 3 or 4 described compound, wherein R 4Be sec.-propyl or sec-butyl.
6, as each described compound, wherein R among the claim 3-5 3For on phenyl ring by methyl, fluorine, chlorine, iodine, CF 3Or OCF 3The optional benzyl that replaces perhaps is R 3Be 3-phenyl propyl or 3-phenyl third-2-thiazolinyl.
7, as each described compound, wherein R among the claim 3-6 5, R 6, R 7And R 8All be H.
8, as each described compound among the claim 3-7, wherein m is 0 or 1.
9, compound as claimed in claim 1, wherein said compound is:
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine;
1-[N-((R)-the 2-benzyl-(S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-2-(3-phenyl third-2-alkene-1-yl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-valyl]-4-(imidazoles-1-yl) piperidines;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(R)-2-(4-benzyl chloride base)-(S)-4-hydroxyl-6-phenyl caproyl)-(S)-valyl]-3-(imidazoles-1-yl) azetidine;
1-[N-((S)-5-(tertiary butyloxycarbonyl amino)-(S)-4-hydroxyl-6-phenyl-(R)-the 2-(4-trifluoro-methoxybenzyl) caproyl)-(S)-isoleucyl-]-4-(imidazoles-1-yl) piperidines.
10, a kind of method for preparing formula I compound as claimed in claim 1, this method comprises: remove protecting group from formula (IX) compound, isolate the formula I compound, and randomly form its pharmacologically acceptable salt
X wherein 1Be a hydroxyl protecting group that alternative removes, R 1To R 8, X and Het such as claim 1 qualification.
11, a kind of pharmaceutical composition, said composition comprise as each described formula I among the claim 1-9 or (I is compound or pharmaceutically acceptable salt thereof or bioprecursor a), and a kind of acceptable diluents or carrier.
12, (I is compound or pharmaceutically acceptable salt thereof or the application of bioprecursor in medicine a), especially the application in being used for the treatment of or preventing the medicine that people's retrovirus infects as each described formula I or formula among the claim 1-9.
13, (I a) compound or pharmaceutically acceptable salt thereof is used for the treatment of or prevents application in the medicine that people's retrovirus infects in preparation as each described formula I or formula among the claim 1-9.
CN93103206A 1992-03-25 1993-03-23 Antiviral peptides Pending CN1077716A (en)

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