CN101817769B - Carbamido peptide aminopeptidase N inhibitor and application thereof - Google Patents
Carbamido peptide aminopeptidase N inhibitor and application thereof Download PDFInfo
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Abstract
The invention provides a carbamido peptide aminopeptidase N inhibitor and application thereof. The invention provides the superactive peptide aminopeptidase N inhibitor, thereby being capable of curing the disease that the activity or the express of the aminopeptidase N is abnormal. Specifically, the invention relates to a peptide compound with the structures of general formulas (I), (II) or (III), and further relates to various optical isomers thereof, a pharmaceutically acceptable salt, a solvate and a prodrug. The invention further relates to a drug composite of the peptide compound which comprises the structures of the general formulas (I), (II) or (III) and use therefore for preparing the drug.
Description
Technical field
The present invention relates to a kind of carbamido peptide aminopeptidase N inhibitor and its production and use, belong to technical field of chemistry.
Background technology
Aminopeptidase N (APN, CD13) be the II of gang type film in conjunction with glycoprotein, molecular weight is about 150Kd, belongs to the Gluzincins subtribe of zine ion dependency metalloprotease and Aminopeptidase M 1 family, form with homodimer is present in cytolemma, participates in the degraded of substrate N terminal amino acid.Aminopeptidase N is distributed widely in the myelocyte in GM-SCF and each stage of growth; At non-hemocyte, be distributed in the stroma cell of hemocytopoietic organ, tumor vascular endothelial cell, various epithelial cells comprise renal proximal tubules epithelial cell, bile duct epithelial cell and intestinal brush border epithelial cell etc.; Also be distributed in the surface of inoblast, mesenchymal cell tumour cell etc.; Also there is a spot of solubility APN to exist in the serum.APN participates in the physiological regulation of body, and in the hemocyte differentiation, blood vessel takes place, and plays an important role in a plurality of physiological and pathological regulated and control networks such as cell proliferation and apoptosis and immunomodulatory.Studies have shown that Aminopeptidase N plays an important role in tumour generation, development, Invasion and Metastasis, apoptosis, tumor-blood-vessel growth and virus infection.
1) Aminopeptidase N is at the tumor cell surface high level expression.This enzyme degradable extracellular matrix, thus tumor cell invasion and transfer promoted.Extracellular matrix plays important effect in keeping the conduction of cell connection stability and intercellular signal.Degradation of extracellular matrix can also promote growth of tumor propagation (Sato Y, Biol.Pharm.Bull., 2004,27 (6): 772-776 by promoting the release that is present in somatomedin wherein; Saiki, I.; Et al.Int.J.Cancer., 1993,54,137; Menrad A., Speicher D., Wacker J., et al.Cancer Res., 1993,53 (6): 1450-1455).2) Aminopeptidase N can stimulate vascular endothelial cell release tumor capillary blood vessel to form correlation factor, promotes the tumour cell vasculogenesis.APN can make things convenient for endotheliocyte invasion its hetero-organization on every side at new vessel endotheliocyte and inferior endotheliocyte high expression level.This also is the substance of vasculogenesis, and vasculogenesis is the first step of tumor growth and transfer.3) APN has also participated in the inflammatory reaction that the T lymphocyte relies on simultaneously in granulocyte and lymphocytic cell surface great expression; Can also be expressed in the antigen presenting cell surface, degraded immunologic active material (as interleukin-8); The T cell that major histocompatibility complex II type (MHC-II) the Adhesion Antigen determinant of the processing of participation antigen and cell surface relies on is to the identification of antigen, reduced the recognition capability of T cell to its antigen, scavenger cell and NK cell have been weakened simultaneously to identification and the kill capability of tumour cell, immunity of organisms is descended, thereby promoted the propagation of tumour cell, and suppressed its apoptosis.4) Aminopeptidase N is as the acceptor on human corona virus HCoV-229E and Transmissible gastroenteritis virus (TGEV) surface, in upper respiratory tract infection (as: SARS) and acute enteritis, play an important role, and its relevant (Delmas of activity with enzyme that plays a role, B., et al.Nature, 1992,357,417; Yeager, C.L.; Et al.Nature, 1992,357,420).APN has also participated in the inflammatory reaction of T lymphocyte dependence and the process that the HIV virion enters host cell.Studies show that the Aminopeptidase N activity is higher than healthy volunteer (Shen W, Li B, et al.Blood, 2000,96 (8), 2887 far away in patient's body of infected by HIV; Shipp MA, et al.Blood, 1993,82 (4), 1052).5) Aminopeptidase N participates in the degraded of endogenous analgesic matter endorphin and enkephalin, thereby causes the excessive release of P material, causes pain.6) Aminopeptidase N degraded Angiotensin, adjusting (Mitsui, the T. of participation body blood pressure; Et al.Biol.Pharm.Bull., 2004,27,768.).
Since more than ten years, very rapid to the research and development of APN inhibitor, but have only a unique marketed drug---ubenimex up to now.The APN inhibitor is as the inhibitor of peptase, and great majority are the analogue of peptide or peptide, and is relatively more responsive to the degraded of body endoenzyme; In addition because control tumor growth propagation and regulation of apoptosis network are very huge and complicated, for example by signal transduction in the body of multiple growth factor receptor tyrosine kinase or by thereby the activation compensatory of integrin receptor being promoted tumor growth propagation, suppress its apoptosis, this also is the great majority non-cytotoxicity target type antitumor drug that comprises the APN inhibitor at the reason place that clinical stage is had one shot.In addition, the inhibitor clinical or Aminopeptidase N that preclinical study is more mostly is natural product at present, for example ubenimex (Ubenimex) has the class dipeptides structure that contains beta-amino acids as one, be used for leukemic treatment as immunostimulant at present, be from the nutrient solution of the netted streptomycete of olive (Streptomyces olivorecticuli), to separate to obtain, complete synthesis costing dearly, thereby it is limited to originate.
Carbamido peptide compound designed among the present invention finds in being directed to the Aminopeptidase N screening active ingredients, and it is active similar or be better than the ubenimex of present unique listing for several drug molecules.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of carbamido peptide aminopeptidase N inhibitor and its production and use is provided.
Technical scheme of the present invention is:
Have general formula (I), (II) or class peptide compounds (III), with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug:
Wherein,
R
1Be hydrogen, substituting group on the various natural or alpha-non-natural amino acid α carbon, these amino acid comprise: various a-amino acids such as glycine, L-Ala, Xie Ansuan, phenylalanine, Isoleucine, leucine, methionine(Met), Methionin, ornithine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, Serine, Threonine, Histidine, tryptophane, arginine, halfcystine, citrulline, proline(Pro), oxyproline, tyrosine etc.; Various beta-amino acids such as β-An Jibingsuan, beta-amino phenylpropionic acid etc.; Gamma-amino acid such as γ-An Jidingsuan etc., the glycine of D-amino acid such as D type, L-Ala, Xie Ansuan, phenylalanine, Isoleucine, leucine, methionine(Met), Methionin, ornithine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, Serine, Threonine, Histidine, tryptophane, arginine, halfcystine, citrulline, proline(Pro), oxyproline, tyrosine etc.; Other amino acid such as various δ-amino acid etc.
R
1' be hydrogen, substituting group on the various natural or alpha-non-natural amino acid α carbon, these amino acid comprise: various a-amino acids such as glycine, L-Ala, Xie Ansuan, phenylalanine, Isoleucine, leucine, methionine(Met), Methionin, ornithine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, Serine, Threonine, Histidine, tryptophane, arginine, halfcystine, citrulline, proline(Pro), oxyproline, tyrosine etc.; Various beta-amino acids such as β-An Jibingsuan, beta-amino phenylpropionic acid etc.; Gamma-amino acid such as γ-An Jidingsuan etc., the glycine of D-amino acid such as D type, L-Ala, Xie Ansuan, phenylalanine, Isoleucine, leucine, methionine(Met), Methionin, ornithine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, Serine, Threonine, Histidine, tryptophane, arginine, halfcystine, citrulline, proline(Pro), oxyproline, tyrosine etc.; Other amino acid such as various δ-amino acid etc.
R
2Be hydrogen, C1-12 aliphatic chain alkyl, aromatic base, arylalkyl, heteroaryl, heteroarylalkyl; Optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, guanidine radicals, carboxyl, halogen C1-12 alkyl, C1-12 alkoxyl group, C1-12 alkyl, C1-12 cycloalkyl, aryl, heteroaryl, or aryl C1-12 alkyl;
X is the hydroxamic acid base, carboxyl; Or C1-12 aliphatic chain alkoxyl group, fragrant oxygen base, alkoxy aryl, heteroaryloxy, heteroaryl alkoxyl group, C1-12 aliphatic chain alkylamino radical, aromatic amino, aryl alkylamino radical, assorted aryl amine, heteroaryl alkylamino radical; Optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, guanidine radicals, carboxyl, halogen C1-12 alkyl, C1-12 alkoxyl group, C1-12 alkyl, C1-12 cycloalkyl, aryl, heteroaryl, aryl C1-12 alkyl;
Y is hydrogen, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl; Various protecting groups for the protection of amino amino, as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), fluorenylmethyloxycarbonyl, 2-xenyl-2-third oxygen carbonyl, phthalimide-based, p-toluenesulfonyl, trityl, formyl radical, ethanoyl or trifluoroacetyl group etc.
Above-mentioned formula (I) or (II) in the carbon shown in the * have the S configuration.
Preferably, above-mentioned carbamido peptide compound (I), (II) or (III) specifically comprise following compound:
Preferably, above-mentioned carbamido peptide compound (I) is one of following compounds:
1a:2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
2a:(2S)-2-methyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
3a:(2S)-2-sec.-propyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
4a:(2S)-2-(2-methyl)-propyl group-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
5a:(2S)-2-(1-methyl)-propyl group-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
6a:(2S)-2-benzyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
7a:(2S)-2-(methylthio group)-ethyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
8a:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
1b:2-(3-benzyl urea groups)-N-hydroxyl acetamide,
2b:(2S)-2-methyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
3b:(2S)-2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
4b:(2S)-2-(2-methyl)-propyl group-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
5b:(2S)-2-(1-methyl)-propyl group-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
6b:(2S)-2-benzyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
7b:(2S)-2-(methylthio group)-ethyl-2-(3-benzyl tertiary butyl urea groups)-N-hydroxyl acetamide,
8b:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-benzyl tertiary butyl urea groups)-N-hydroxyl acetamide,
1c:2-(3-styroyl urea groups)-N-hydroxyl acetamide,
2c:(2S)-2-methyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
3c:(2S)-2-sec.-propyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
4c:(2S)-2-(2-methyl)-propyl group-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
5c:(2S)-2-(1-methyl)-propyl group-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
6c:(2S)-2-benzyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
7c:(2S)-2-(methylthio group)-ethyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide or
8c:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-styroyl urea groups)-N-hydroxyl acetamide.
Preferably, above-mentioned carbamido peptide compound (II) is one of following compounds:
1f:2-[3-(1-hydroxyl amino formyl radical-3-methyl-butyl)-urea groups]-the 4-methylvaleric acid,
2f:2-[3-(1-hydroxyl amino formyl radical-3-methyl-butyl)-urea groups]-the 3-phenylpropionic acid,
3f:2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-the 4-methylvaleric acid,
4f:2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-the 3-phenylpropionic acid,
1g:2-[3-(1-hydroxyl amino formyl radical-3-methyl-butyl)-urea groups]-4-methylvaleric acid oxyamide,
2g:2-[3-(1-hydroxyl amino formyl radical-3-methyl-butyl)-urea groups]-3-phenylpropionic acid oxyamide,
3g:2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-4-methylvaleric acid oxyamide or
4g:2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-3-phenylpropionic acid oxyamide.
Preferably, above-mentioned carbamido peptide compound (III) is one of following compounds:
1d:6-benzyloxycarbonyl amino-2-(3-carboxymethyl urea groups)-caproic acid,
2d:(2S, 2 ' S)-6-benzyloxycarbonyl amino-2-[3-(2-methyl)-carboxymethyl urea groups]-caproic acid,
3d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-ethyl)-urea groups]-caproic acid,
4d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-2-methyl-propyl)-urea groups]-caproic acid,
5d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-3-methyl butyl)-urea groups]-caproic acid,
6d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-2-methyl butyl)-urea groups]-caproic acid,
7d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-2-benzyl)-urea groups]-caproic acid,
8d:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(1-carboxyl-3-methylthio group propyl group)-urea groups]-caproic acid,
1e:(2S, 1 ' S)-6-benzyloxycarbonyl amino-2-[3-(5-benzyloxycarbonyl amino-1-carboxyl-amyl group)-urea groups]-caproic acid,
2e:(3 ' S)-[5-hydroxyl amino carbonyl-5-(3-hydroxyl amino carbonyl methyl-urea groups)-amyl group]-benzyl carbamate,
3e:(3 ' S, 1 " S)-5-hydroxyl amino carbonyl-5-[3-(1-hydroxyl amino carbonyl ethyl)-urea groups]-amyl group }-benzyl carbamate,
4e:(3 ' S, 1 " S)-5-hydroxyl amino carbonyl methyl-5-[3-(1-hydroxyl amino carbonyl-2-methyl)-propyl group urea groups]-amyl group }-benzyl carbamate,
5e:(3 ' S, 1 " S)-5-hydroxyl amino carbonyl methyl-5-[3-(1-hydroxyl amino carbonyl-3-methyl)-butyl urea groups]-amyl group }-benzyl carbamate,
6e:(3 ' S, 1 " S)-5-hydroxyl amino carbonyl methyl-5-[3-(1-hydroxyl amino carbonyl-2-styroyl urea groups]-amyl group }-benzyl carbamate,
7e:(3 ' S, 1 " S)-5-hydroxyl amino carbonyl methyl-5-[3-(1-hydroxyl amino carbonyl-3-methylthio group)-propyl group urea groups]-amyl group }-benzyl carbamate,
8e:(3 ' S, 1 " S)-5-[3-(5-benzyloxycarbonyl amino-1-hydroxyl amino carbonyl-amyl group)-urea groups]-5-hydroxyl amino carbonyl-amyl group }-benzyl carbamate,
1h:(2S)-6-carbobenzoxy-(Cbz)-2-(3-methoxycarbonyl methyl-urea groups) methyl caproate,
2h:(2S, 2 ' S)-6-carbobenzoxy-(Cbz) 2-[3-2-(methoxycarbonyl ethyl)-urea groups] methyl caproate,
3h:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-methoxycarbonyl-2-methyl-propyl)-urea groups] methyl caproate,
4h:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-methoxycarbonyl-3-methyl butyl)-urea groups] methyl caproate,
5h:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-methoxycarbonyl-2-methyl butyl)-urea groups] methyl caproate,
6h:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-methoxycarbonyl-2-phenylethyl)-urea groups] methyl caproate,
7h:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-methoxycarbonyl-3-methylthio group propyl group)-urea groups] methyl caproate,
1i:(2S)-6-carbobenzoxy-(Cbz)-2-(3-carbobenzoxy-(Cbz) methyl-urea groups) benzyl hexanoate,
2i:(2S, 2 ' S)-6-carbobenzoxy-(Cbz) 2-[3-2-(carbobenzoxy-(Cbz) ethyl)-urea groups] benzyl hexanoate,
3i:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-carbobenzoxy-(Cbz)-2-methyl-propyl)-urea groups] benzyl hexanoate,
4i:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-carbobenzoxy-(Cbz)-3-methyl butyl)-urea groups] benzyl hexanoate,
5i:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-carbobenzoxy-(Cbz)-2-methyl butyl)-urea groups] benzyl hexanoate,
6i:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-carbobenzoxy-(Cbz)-2-phenylethyl)-urea groups] benzyl hexanoate or
7i:(2S, 1 ' S)-6-carbobenzoxy-(Cbz)-2-[3-(1-carbobenzoxy-(Cbz)-3-methylthio group propyl group)-urea groups] benzyl hexanoate.
In above-claimed cpd, most preferably: one of 4b, 5b, 6b, 7b, 4c, 6c, 4d, 4e.
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises above-mentioned general formula (I), (II) or (III) class peptide compounds and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
In addition, the present invention comprises that also a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises above-mentioned general formula (I), (II) or (III) class peptide compounds and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
These class peptide compounds are in the application of the medicine of prevention or the treatment mammalian diseases relevant with Aminopeptidase N activity or abnormal expression.Described related mammalian disease with Aminopeptidase N activity or abnormal expression comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer's venereal disease disease, periodontopathy, epidermolysis bullosa, leukemia etc.Therefore, the invention still further relates to and contain (I), (II) or (III) pharmaceutical composition of structural compounds.
Detailed Description Of The Invention
Used definition and term
Term and definition implication used herein is as follows:
" substituting groups on the various natural or alpha-non-natural amino acid α carbon ": refer to 20 kinds of natural amino acids, the non-natural a-amino acid, beta-amino acids, gamma-amino acid, δ-amino acid, D-amino acid etc., and still belong to amino acid whose derivative, preferred natural a-amino acid is as phenylalanine, Isoleucine, leucine, methionine(Met).
" halogen ", or " halogen " comprises fluorine, chlorine, bromine or iodine.
" cycloalkyl " is replacement or unsubstituted, saturated or undersaturated cyclic alkyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkyl, preferably contain 2-10 atom.Assorted alkyl can be direct-connected or side chain, replacement or unsubstituted.
" aryl " refers to the aromatic carbocyclic group, and preferred aromatic ring contains 6-10 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.
" cycloalkyloxy " is replacement or unsubstituted, saturated or undersaturated cyclic alkoxy, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" cycloalkanes amido " is replacement or unsubstituted, saturated or undersaturated ring-type alkylamino radical, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" assorted alkoxyl group " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkoxyl group, preferably contain 2-10 atom.Assorted alkoxyl group can be direct-connected or side chain, replacement or unsubstituted.
" assorted alkylamino radical " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkylamino radical, preferably contain 2-10 atom.Assorted alkylamino radical can be direct-connected or side chain, replacement or unsubstituted.
" aryloxy " refers to aromatic carbocyclic oxygen base group, and preferred aromatic ring contains 6-10 carbon atom.
" aryl amine " refers to the aromatic carbocyclic amine groups, and preferred aromatic ring contains 6-10 carbon atom.
" heteroaryloxy " is aromatic heterocycle oxygen base, can be monocycle or bicyclic radicals.
" assorted aryl amine " is the aromatic heterocycle amido, can be monocycle or bicyclic radicals.
" aroyl " refers to that the aromatic carbon ring end is connected with the group of carbonyl.Preferred aromatic ring contains 6-10 carbon atom.
" cycloalkanes acyl group " is replacement or unsubstituted, and saturated or undersaturated annular termination is connected with the group of carbonyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" 4-hetaroylpyrazol " is the group that the aromatic heterocycle end is connected with carbonyl, can be monocycle or bicyclic radicals.Preferable heteroaryl comprises, thienyl for example, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkyl, preferably contain 2-10 atom.Assorted alkyl can be direct-connected or side chain, replacement or unsubstituted.
" aryl " refers to the aromatic carbocyclic group.Preferred aromatic ring contains 6-10 carbon atom.
" cycloalkyl " is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" pharmacy acceptable salt " refer to formula (I), (II) or (III) compound have curative effect and nontoxic salt form.It can form cationic salts by arbitrary basic group (as amino).A lot of such salt known in the art.The cationic salts that forms at any acidic-group (as carboxyl), or at the anion salt of any basic group (as amino) formation.It is known in the art that these salt have many, comprises salt and the organic salt (as amine salt) of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium) as cationic salts.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge provides.In addition, those of skill in the art can get certain salt according to solubleness, stability, easy preparation etc. and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
" solvate " is the title complex that solute (as aminopeptidase N inhibitor) and solvent (as water) are combined to form.Referring to J.Honig etc., The Van Nostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents of not disturbing aminopeptidase N inhibitor (solvent known to for example water, ethanol, acetic acid, the N, dinethylformamide, dimethyl sulfoxide (DMSO) and this those skilled in the art or that determine easily).
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. have defined the form of The compounds of this invention or all possible steric isomer of its physiological derivative.Unless indication is arranged in addition, the chemical name of The compounds of this invention comprises the mixture of all possible stereochemical form, affiliated mixture comprises all diastereomers and the enantiomorph of basic structure molecule, and the single isomeric forms of the The compounds of this invention of substantially pure, namely wherein contain and be lower than 10%, preferably be lower than 5%, particularly be lower than 2%, most preferably be lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in the scope of the present invention.
Formula (I), (II) or (III) the class peptide compounds can also other protected form or the form of derivative exist, these forms will be apparent to those skilled in the art, and all should be contained in the scope of the present invention.
Aforesaid substituting group self also can be replaced by one or more substituting groups.Such substituting group is included in C.Hansch and A.Leo, those substituting groups of listing among the Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituted comprises, alkyl for example, thiazolinyl, alkoxyl group, hydroxyl, the oxygen base, nitro, amino, aminoalkyl group (as aminomethyl etc.), cyano group, halogen, carboxyl, carbonylic alkoxy (as carbonyl oxyethyl group etc.), sulfenyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl (as piperidyl, morpholinyl, pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combination.
The preparation method of described compound, reactions steps and reaction formula are as follows:
The preparation method of compound (I) is as follows:
Be raw material with optics amino acid, through esterification protection carboxyl, carry out condensation by triphosgene and connect corresponding amine in succession, again methyl esters is obtained target compound through respective reaction; Perhaps original with corresponding amine flavor, be converted into isocyanic ester via triphosgene in succession, again with the amino acid whose methyl esters condensation of optics, then methyl esters is obtained target compound through respective reaction.
Synthetic route:
The preparation method of compound (II) is as follows:
Be raw material with optics amino acid, through esterification protection carboxyl, carry out condensation by triphosgene in succession, connect another carboxyl through the optics amino acid of esterification protection, the protecting group that needs are taken off is taken off then, again methyl esters is obtained target compound through respective reaction.
Synthetic route:
The preparation method of compound (III) is as follows:
Be that raw material is amino through tertbutyloxycarbonyl protection in succession with carbobenzoxy-(Cbz) Methionin; with various alcohol, phenol, amine condensation; slough tertbutyloxycarbonyl; carry out condensation join dependency group by triphosgene again; slough carbobenzoxy-(Cbz) then; or continue to carry out condensation with corresponding acyl chlorides or acid anhydrides, or go up other amino protecting group, obtain target compound.
Synthetic route:
Above-mentioned R
1, R
1', R
2, X, Y such as above-mentioned general formula (I), (II) or class peptide compounds (III) define;
Reagent in the above-mentioned reaction formula and reaction conditions: (a) Acetyl Chloride 98Min., anhydrous methanol refluxes (b) triphosgene, saturated sodium bicarbonate aqueous solution, methylene dichloride, 0 ℃, (c) as used be various above-mentioned amine, triethylamine, methylene dichloride, (d) azanol potassium, anhydrous methanol, 25 ℃, (e) triphosgene, toluene refluxes, (f) as used be above-mentioned various amino acid methyl ester hydrochloride, triethylamine, methylene dichloride, (g) as used be above-mentioned various amino acid methyl ester hydrochloride, triethylamine, methylene dichloride, (h) tosic acid, phenylcarbinol, 90 ℃, (i) as used be above-mentioned various amino acid methyl ester hydrochloride, triethylamine, methylene dichloride, (j) palladium/carbon, hydrogen, anhydrous methanol, 30 ℃, (k) as used be above-mentioned various amino acid methyl ester hydrochloride, triethylamine, methylene dichloride, (l) preparation carboxylic acid: 1mol/L sodium hydroxide, methyl alcohol, 25 ℃; Preparation hydroxamic acid: azanol potassium, anhydrous methanol, 25 ℃, (m) (Boc)
2O, aqueous sodium hydroxide solution, tetrahydrofuran (THF), room temperature; (n) as used be above-mentioned various alcohol, phenol or amine, EDCI, HOBt; methylene dichloride, room temperature, (o) HCl ethyl acetate saturated solution; room temperature, (p) triethylamine, methylene dichloride; room temperature, (q) palladium/carbon, hydrogen; anhydrous methanol, 30 ℃, (r) as used be the corresponding acyl chlorides of above-mentioned various acyl group or acid anhydrides.
The concrete operations step of described compound will be described in detail in an embodiment.
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine synthetic route according to the ABC of this area; as the selective reaction thing, solvent and temperature, thus can improve yield with the generation of avoiding side reaction by using various GPF (General Protection False bases.These conventional guard methods can be referring to for example T.Greene, Protecting Groups in OrganicSynthesis.
Obviously, above-mentioned route is that stereoselectivity is synthetic, also can prepare its optically active class peptide compounds by above-mentioned route.For example each seed amino acid of raw material is replaced with its optical isomer (D configuration).Those skilled in the art can obtain various other isomer of this type of carbamido peptide derivative easily, and can be by conventional separation means purifying, as chirality salt or chirality chromatography column etc.
Aminopeptidase N suppresses active test description in Lejczak, and .Biochemistry such as B are in 1989,28,3549.Substrate L-leucyl-p-N-methyl-p-nitroaniline is degraded by Aminopeptidase N, be created in the p-N-methyl-p-nitroaniline that 405nm has absorption, and the size of the concentration of p-N-methyl-p-nitroaniline and enzymic activity is proportionate.Determine the content of p-N-methyl-p-nitroaniline by the optical density that detects the 405nm place, thereby determine the activity of aminopeptidase, reflect that indirectly inhibitor suppresses the size of degree to enzymic activity.
General formula (I), (II) or class peptide compounds (III) external presses down enzyme test proves that such peptide compounds is a kind of carbamido peptide aminopeptidase N inhibitor.Carbamido peptide of the present invention spatially is complementary with the avtive spot of Aminopeptidase N, has therefore shown the higher enzymic activity that presses down external.
The aminopeptidase N inhibitor ubenimex that has gone on the market is used for the treatment of leukemia for many years clinically, and can be used as the immunomodulator use.The compounds of this invention is as the application of carbamido peptide aminopeptidase N inhibitor.In the medicine for preparing prevention or the treatment mammalian diseases relevant with the active unconventionality expression of Aminopeptidase N, have broad application prospects.According to prior art, described related mammalian disease with the active unconventionality expression of Aminopeptidase N comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer venereal disease disease, periodontopathy, epidermolysis bullosa and leukemia.
The pharmaceutical composition that contains The compounds of this invention:
Part derivative of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such idic acid and salt inorganic or that organic bases forms.
Compound of the present invention can form hydrate or solvate.The one skilled in the art known with compound formed hydrate or form the method for solvate when in solution, concentrating with appropriate organic solvent during with the water freeze-drying.
The present invention comprises the medicine that contains the therapeutic dose The compounds of this invention and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, and glucose, water, glycerine, ethanol and their binding substances are hereinafter discussed in more detail.If desired, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can for, for example, solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise that one or more may be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with shape and the size compression of needs in tablet.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
Typical liquid vehicle comprises syrup, peanut oil, and sweet oil, water, etc.Liquid vehicle is for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-conditioning agent.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, and oils (for example fractionated coconut oil and peanut oil) ethylene glycol for example) and their derivative.The carrier that is used for administered parenterally can also be grease such as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes the interior perfusion of passages through which vital energy circulates.This compound can also be with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate etc.When preparation is used for when oral, (phospholipid and 1,2-propylene glycol are concentrated, A.Nattermann ﹠amp to generally acknowledge PHOSALPG-50; Cie.GmbH) 0.01% tween 80 in is used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.
Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension in the liquid suspension of ampoule or bottle or non-water.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in the aqueous solution of organic or inorganic alkali.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester etc.
Various release systems are known and can be for the administrations of compound or other various preparations that these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, etc.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (preferred usually) oral route.Compound can be by administration easily any or that other is suitable, for example by injecting or bolus injection, by epithelium or the mucous membrane circuit (for example, oral mucosa, rectum and intestinal mucosa, etc.) absorb or the support by carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.For different, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
The present invention contains as the design of above-mentioned general formula (I), (II) or compound (III) and has adopted class peptide and isostere layout strategy.Class peptide and isostere strategy have been widely used in design and development field antiviral, antitumor drug, its structure is formed the structure that is similar to peptide by natural or alpha-non-natural amino acid and non-peptide group, but overall conformation is different from natural peptide material again, on the one hand, the class peptide has the intrinsic activity of substrate, the activity of inhibitory enzyme be can come by the active centre of identification enzyme, selectivity and usefulness to target site improved simultaneously; In addition, class peptide and natural peptide matters exist structural difference and are difficult for by the peptide enzyme liberating, and biologically stable and availability are improved, and the long action time of compound.
Particularly, the present invention is raw material with optical purity amino acid, and by the selective protection carboxyl, through the synthetic key intermediate of steps such as replacement, condensation, deprotection, purpose all is for the avidity that strengthens compound and enzyme or acceptor and metabolic stability.
The present invention designs the aminopeptidase N inhibitor that a synthetic class has the brand new parent nucleus, and but in vitro tests shows its acellular cytotoxic activity but embodies remarkable vitro enzymic activity, is expected to become the anticancer drug candidate of a class non-cytotoxicity class.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited thereto.
Synthesizing of embodiment 1. The compounds of this invention (I)
1. so that (2S)-2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide (3b) is example:
1) preparation of benzyl isocyanate ester (1)
The 1.16g benzylamine is dissolved in the toluene solution 80mL that splashes into the 2.22g triphosgene under the solution room temperature that 20mL toluene obtains, after 4 hours, evaporate to dryness toluene obtains yellow oil product benzyl isocyanate ester (1) with this reaction solution backflow, need not to be further purified, can be directly used in next step.
2) preparation of 2-(3-benzyl urea groups)-2-sec.-propyl methyl acetate (2)
Dichloromethane solution with benzyl isocyanate ester (1) under the ice bath splashes in the dichloromethane solution that contains 2.51g L-valine methyl ester hydrochloride and 2.12g triethylamine, after dripping off this reaction solution is at room temperature stirred, after 1 hour, the evaporate to dryness methylene dichloride, after residue is dissolved in ethyl acetate, with 1N hydrochloric acid and saturated common salt water washing, use the dried over mgso organic phase.Get yellow oil 2-(3-benzyl urea groups)-2-sec.-propyl methyl acetate (2), need not to be further purified, can be directly used in next step.
3) NH
2The preparation of OK
The saturated absolute methanol solution of 140mL KOH is added drop-wise in the absolute methanol solution that 240mL contains 46.7g (670mmol) oxammonium hydrochloride, and temperature is lower than 40 ℃ in the control, dropwise, and the cooling reaction solution, filtering white KCl precipitation, the airtight preservation of gained filtrate is standby.
4) (2S)-preparation of 2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide (3b)
2-(3-benzyl urea groups)-2-sec.-propyl methyl acetate (2) is added in the above-mentioned 30mL azanol potassium methanol solution stirring at room, TLC monitoring process.After reaction is finished, remove methyl alcohol under reduced pressure, residue is dissolved in 1N hydrochloric acid, and adjusting pH is 1-2, adds ethyl acetate extraction, with saturated common salt water washing organic phase, drying.Obtaining product crude product (2S)-2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide (3b) is the off-white color solid, column chromatography for separation (sherwood oil: ethyl acetate=2: 1), obtain white solid (2S)-2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide (3b) 2.47g, overall yield 68%.mp＝180-183℃。ESI-MS?m/z：265.3[M+H]
+。1H-NMR(300MHz，DMSO-d6)：δ10.61(s，1H)，δ8.80(s，1H)，δ7.33-7.19(m，5H)，δ6.50(t，1H，J＝6.0Hz)，δ6.16(d，1H，J＝9.3Hz)，δ4.20(d，2H，J＝6.0Hz)，δ3.87(dd，1H，J＝7.2Hz，9.3Hz)，δ1.85-1.74(m，1H)，δ0.85(d，6H，6.9Hz)。
Synthesizing of embodiment 2. The compounds of this invention (III)
Be example with (2S)-6-carbobenzoxy-(Cbz)-2-(3-methoxycarbonyl methyl-urea groups) methyl caproate (1h):
1) preparation of N6-carbobenzoxy-(Cbz)-L-lysine methyl ester hydrochloride (3)
To slowly be added dropwise to the 50mL anhydrous methanol under the 2.35g Acetyl Chloride 98Min. ice bath, dropwise back stirring at room half hour, then 2.80g N6-carbobenzoxy-(Cbz)-L-Methionin is once added, then reaction mixture slowly is heated to backflow, after 1 hour, evaporate to dryness methyl alcohol obtains white solid compound N 6-carbobenzoxy-(Cbz)-L-lysine methyl ester hydrochloride (3), need not to be further purified, can be directly used in next step reaction.
2) preparation of N6-carbobenzoxy-(Cbz)-L-lysine methyl ester-1-isocyanic ester (4)
Above-mentioned steps 1) the N6-carbobenzoxy-(Cbz) that obtains in-L-lysine methyl ester hydrochloride (3) adds in 40mL saturated sodium bicarbonate solution and the 40mL methylene dichloride, once adds the 1.00g triphosgene under the ice bath while stirring.Ice bath vigorous stirring 15min, separatory, water layer dichloromethane extraction three times merge organic layer, drying.Solvent evaporated obtains compound N 6-carbobenzoxy-(Cbz)-L-lysine methyl ester-1-isocyanic ester (4), need not purifying, can be directly used in next step reaction.
3) preparation of glycine methyl ester hydrochloride (5)
To slowly be added dropwise to the 50mL anhydrous methanol under the 2.35g Acetyl Chloride 98Min. ice bath, dropwise back stirring at room half hour, then the 0.75g glycine is once added, then reaction mixture slowly is heated to backflow, after 1 hour, evaporate to dryness methyl alcohol obtains white solid compound glycine methyl ester hydrochloride (5), need not to be further purified, can be directly used in next step reaction.
4) (2S)-preparation of 6-carbobenzoxy-(Cbz)-2-(3-methoxycarbonyl methyl-urea groups) methyl caproate (1h)
Above-mentioned steps 3) glycine methyl ester hydrochloride that obtains in (5) stirs in the 20mL methylene dichloride with the 1.01g triethylamine, drip the dichloromethane solution of 10mLN6-carbobenzoxy-(Cbz)-L-lysine methyl ester-1-isocyanic ester (4) under the ice bath, dropwised the back stirring at room one hour, the evaporate to dryness methylene dichloride, residue is dissolved in after the ethyl acetate hydrochloric acid and the saturated common salt water washing with 1N, dry organic phase then.Obtain yellow oil (2S)-6-carbobenzoxy-(Cbz)-2-(3-methoxycarbonyl methyl-urea groups) methyl caproate (1h) crude product after the solvent evaporated, column chromatography for separation (sherwood oil: ethyl acetate=1: 4), obtain white solid (2S)-6-carbobenzoxy-(Cbz)-2-(3-methoxycarbonyl methyl-urea groups) methyl caproate (1h) 1.48g, overall yield 39%.ESI-MS?m/z：410.2[M+H]
+。1H-NMR(600MHz，CDCl
3)：δ7.36-7.26(m，5H)，δ5.13-5.04(m，3H)，δ4.48-4.44(m，2H)，δ3.73(s，3H)，δ3.71(s，3H)，δ3.21-3.17(m，2H)，δ1.81-1.35(m，6H).
Synthesizing of embodiment 3 The compounds of this invention (II)
With 2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-3-phenylpropionic acid oxyamide (4g) is example:
1) preparation of phenylalanine methyl ester hydrochloride (6)
To slowly be added dropwise to the 100mL anhydrous methanol under the 4.24g Acetyl Chloride 98Min. ice bath, dropwise back stirring at room half hour, then the 2.98g phenylalanine is once added, then reaction mixture slowly is heated to backflow, after 1 hour, evaporate to dryness methyl alcohol obtains white solid compound phenylalanine methyl ester hydrochloride (6), need not to be further purified, can be directly used in next step reaction.
2) preparation of phenylalanine methyl ester-1-isocyanic ester (7)
Above-mentioned steps 1) phenylalanine methyl ester hydrochloride that obtains in (6) 1.90g adds in 40mL saturated sodium bicarbonate solution and the 40mL methylene dichloride, once adds the 1.00g triphosgene under the ice bath while stirring.Ice bath vigorous stirring 15min, separatory, water layer dichloromethane extraction three times merge organic layer, drying.Solvent evaporated obtains compound phenylalanine methyl ester-1-isocyanic ester (7), need not purifying, can be directly used in next step reaction.
3) 2-[3-1-(methoxycarbonyl-2-phenyl-ethyl)-urea groups]-preparation of 3-phenylpropionic acid methyl esters (8)
Above-mentioned steps 1) phenylalanine methyl ester hydrochloride that obtains in (6) 1.90g and 1.01g triethylamine stir in the 20mL methylene dichloride, drip the dichloromethane solution of phenylalanine methyl ester-1-isocyanic ester (7) under the ice bath, dropwised the back stirring at room one hour, the evaporate to dryness methylene dichloride, residue is dissolved in after the ethyl acetate hydrochloric acid and the saturated common salt water washing with 1N, dry organic phase then.Obtain yellow oil 2-[3-1-(methoxycarbonyl-2-phenyl-ethyl)-urea groups after the solvent evaporated]-3-phenylpropionic acid methyl esters (8) crude product, need not to be further purified, can be directly used in next step reaction.
4) 2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-preparation of 3-phenylpropionic acid oxyamide (4g)
With 2-[3-1-(methoxycarbonyl-2-phenyl-ethyl)-urea groups]-3-phenylpropionic acid methyl esters (8) adds in the above-mentioned 30mL azanol potassium methanol solution stirring at room, TLC monitoring process.After reaction is finished, remove methyl alcohol under reduced pressure, residue is dissolved in 1N hydrochloric acid, and adjusting pH is 1-2, separates out white precipitate, will precipitate with after the ethyl acetate washing vacuum-drying.Obtain product 2-[3-(1-hydroxyl amino formyl radical-2-phenyl-ethyl)-urea groups]-3-phenylpropionic acid oxyamide (4g) is white solid 1.89g, overall yield 54%.ESI-MS?m/z：386.2[M+H]
+。1H-NMR(300MHz，DMSO-d6)：δ10.71(s，1H)，δ10.56(s，1H)，δ8.93(s，1H)，δ8.81(s，1H)，δ7.32-7.07(m，10H)，δ6.38-6.35(m，2H)，δ4.05-4.18(m，2H)，δ2.84-2.51(m，4H).
Embodiment 4 target compounds suppress the activity test (In vitro) of Aminopeptidase N
Test principle and detailed test procedure are referring to CN 1974554A cyclin imide peptidyl metalloprotease inhibitor and application thereof, and experimental result sees Table 1.
The external enzyme test result that presses down of table 1.
aNA＝not?available
Last table test data shows that the inhibition activity of compound 4b, 5b, 6b, 7b, 4c, 6c, 4d, the Aminopeptidase N of 4e all is better than the positive control drug ubenimex, has the excellent development prospect.
Claims (4)
1. the compound that leads to formula I:
Wherein,
R
1Be hydrogen, substituting group on the various natural or alpha-non-natural amino acid α carbon, these amino acid are: L-Ala, Xie Ansuan, phenylalanine, Isoleucine, leucine, methionine(Met), Methionin, ornithine, aspartic acid, l-asparagine, L-glutamic acid, glutamine, Serine, Threonine, Histidine, tryptophane, arginine, halfcystine, citrulline, proline(Pro), oxyproline, tyrosine; β-An Jibingsuan, beta-amino phenylpropionic acid; γ-An Jidingsuan;
R
2Be hydrogen, C1-12 aliphatic chain alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, guanidine radicals, carboxyl.
2. compound is characterized in that it being one of following compound:
1a:2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
2a:(2S)-2-methyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
3a:(2S)-2-sec.-propyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
4a:(2S)-2-(2-methyl)-propyl group-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
5a:(2S)-2-(1-methyl)-propyl group-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
6a:(2S)-2-benzyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
7a:(2S)-2-(methylthio group)-ethyl-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
8a:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-tertiary butyl urea groups)-N-hydroxyl acetamide,
1b:2-(3-benzyl urea groups)-N-hydroxyl acetamide,
2b:(2S)-2-methyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
3b:(2S)-2-sec.-propyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
4b:(2S)-2-(2-methyl)-propyl group-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
5b:(2S)-2-(1-methyl)-propyl group-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
6b:(2S)-2-benzyl-2-(3-benzyl urea groups)-N-hydroxyl acetamide,
7b:(2S)-2-(methylthio group)-ethyl-2-(3-benzyl tertiary butyl urea groups)-N-hydroxyl acetamide,
8b:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-benzyl tertiary butyl urea groups)-N-hydroxyl acetamide,
1c:2-(3-styroyl urea groups)-N-hydroxyl acetamide,
2c:(2S)-2-methyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
3c:(2S)-2-sec.-propyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
4c:(2S)-2-(2-methyl)-propyl group-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
5c:(2S)-2-(1-methyl)-propyl group-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
6c:(2S)-2-benzyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide,
7c:(2S)-2-(methylthio group)-ethyl-2-(3-styroyl urea groups)-N-hydroxyl acetamide or
8c:(2S)-2-[4-(N-carbobenzoxy-(Cbz))-amino butyl]-2-(3-styroyl urea groups)-N-hydroxyl acetamide.
3. the preparation method of the described compound of claim 1 is characterized in that:
Be raw material with optics amino acid, through esterification protection carboxyl, carry out condensation by triphosgene and connect corresponding amine in succession, again methyl esters is obtained target compound through respective reaction; Be raw material with corresponding amine perhaps, be converted into isocyanic ester via triphosgene in succession, again with the amino acid whose methyl esters condensation of optics, then methyl esters is obtained target compound through respective reaction;
Synthetic route:
R wherein
1, R
2Class peptide compounds as the logical formula I of claim 1 defines;
Reagent in the above-mentioned reaction formula: (a) Acetyl Chloride 98Min., anhydrous methanol, (b) triphosgene refluxes, saturated sodium bicarbonate aqueous solution, methylene dichloride, 0 ℃ (c) is used to be various above-mentioned amine, triethylamine, methylene dichloride (d) azanol potassium, anhydrous methanol, 25 ℃ of (e) triphosgene, toluene, backflow (f) is used to be above-mentioned various amino acid methyl ester hydrochloride, triethylamine, methylene dichloride.
4. pharmaceutical composition comprises compound and one or more pharmaceutically acceptable carriers or the vehicle of claim 1 or 2.
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