CN1222078A - Hydroxy-phosphinyl derivatives useful as Naaladase inhibitors - Google Patents
Hydroxy-phosphinyl derivatives useful as Naaladase inhibitors Download PDFInfo
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- CN1222078A CN1222078A CN 97195578 CN97195578A CN1222078A CN 1222078 A CN1222078 A CN 1222078A CN 97195578 CN97195578 CN 97195578 CN 97195578 A CN97195578 A CN 97195578A CN 1222078 A CN1222078 A CN 1222078A
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- propanedicarboxylic acid
- hydroxyl oxygen
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Abstract
The present disclosure relates to dipeptidase inhibitors, and more particularly, to novel phosphonate derivatives, hydroxyphosphinyl derivatives, and phosphoramidate derivatives that inhibit N-Acetylated alpha-Linked Acidic Dipeptidase (NAALADase) enzyme activity, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives to inhibit NAALADase activity, and to treat prostate diseases, especially using the compounds of the present invention for the inhibition of the growth of prostate cancer cells.
Description
Related application
The application is that application on June 17th, 1996, denomination of invention are 08/665 for " (phosphonomethyl) glutaric acid derivatives ", sequence number; the partial continuous of 776 U.S. Patent application (CIP) application; also be that December in 1996 application on the 31st, denomination of invention are 08/775 for " NAALAD activity inhibitor ", sequence number; the partial continuous application of 586 U.S. Patent application and December in 1996 application, denomination of invention on the 31st are that " phosphoramidic acid salt derivative ", sequence number are the partial continuous application of 08/778,733 U.S. Patent application.Background 1. invention fields of the present invention
The present invention relates to suppress new phosphonate derivatives, hydroxyl oxygen phosphino-derivant and the phosphoramidic acid salt derivative of enzymatic activity of the acid dipeptidase (NAALAD enzyme) of N-acetylation α-link; contain the pharmaceutical composition of this analog derivative, and utilize this analog derivative to suppress the enzymatic activity of NAALAD enzyme and the method for treatment animal prostatosis.2. the description carcinoma of prostate of prior art
In the U.S., carcinoma of prostate is the cancer of main type, and it is second main cause that the man dies from cancer.Estimate according to american association of cancer research, only just diagnosed out the new patients with prostate cancer of 317,100 examples and had 41,400 people to die from carcinoma of prostate in 1996.Between 1980 and nineteen ninety, the sickness rate of carcinoma of prostate has increased by 65%, and along with the improvement and the prediction of longer time of diagnostic test, this numeral also will continue rising.Although before the carcinoma of prostate outbreak, most men die from other disease, along with the increase in man's life-span, this disease has the more propagation time, and the mortality rate of carcinoma of prostate is estimated and can be improved more.
In 1993, there is report to think that the molecular cloning of prostate specific membrane antigen (PSMA) is the goal object of strong prostate cancer marker and radiography that is assumed to be carcinoma of prostate and cytotoxin Therapeutic Method.The PSMA antibody of PSMA antibody, particularly labelling indium-111 and labelling tritium had been disclosed and had carried out clinical trial for the diagnosis of carcinoma of prostate and treatment.PSMA is expressed in the ducts of prostate gland epithelium, and it is present in seminal fluid blood plasma, prostate fluid and the urine.In 1996, it is found that PSMA cDNA expresses to give the NAALAD enzymatic activity.The NAALAD enzyme inhibitor
Related to NAAG and NAALAD enzyme in the unusual humans and animals morbid state relevant with neurotoxicity of some and glutamate, Glu, for example people have disclosed that injection NAAG can cause that the epilepsy activity extends in Hippocampus.Nearest report, the basic horizontal of NAALAD enzymatic activity with rat of heritability epilepsy tendency continues to increase.These observed results have supported the effectiveness increase of synapse glutamate, Glu to encourage the hypothesis of the susceptibility of epilepsy, can propose the NAALAD enzyme inhibitor simultaneously antiepileptic activity can be provided.
In the ALS pathogeny be called as in the similar Animal diseases of pathology of heritability dog spinal muscular atrophy (HCSMA) and also related to NAAG and NAALAD enzyme.The result shows NAAG concentration and metabolite-NAA, glutamate, Glu and aspartate--in the cerebrospinal fluid of ALS patient and HCSMA Canis familiaris L., be enhanced 2-to 3-doubly.In addition, the NAALAD enzymatic activity significantly increases (2 to 3 times) in the myeloid tissue after death of ALS patient and HCSMA Canis familiaris L..Similarly, if NAAG metabolism increase can change the CSF level of these acidic amino acids and peptide, then the NAALAD enzyme inhibitor also can be used for suppressing the propagation of ALS clinically.
NAAG level and NAALAD enzymatic activity unusually also can particularly obtain proof at psychotic disorder brain after death in prefrontal and ambitus cerebri zone.
It is unusual that The above results shows that the NAALAD enzyme inhibitor can be used for treating glutamate, Glu.But, the objective of the invention is in surprise and unexpectedly find that noval chemical compound of the present invention is not only effective NAALAD enzyme inhibitor, and can be used for the treatment of prostatosis, particularly carcinoma of prostate effectively.Although the cancer data are relevant with prostate gland cancer cell, expection NAALAD enzyme inhibitor is used for the treatment of the cancer of other tissue that belongs to the NAALAD enzyme, described tissue such as brain, kidney and testis equally effectively.
Although had recognized that several NAALAD enzyme inhibitors, they only are used to non-clinical study.The example of this class inhibitor comprises general metallopeptidase inhibitor, as o-phenanthroline metal-chelator such as EGTA and EDTA, and peptide analogues, as Fructus Quisqualis acid and β-NAAG.Therefore be necessary to confirm more NAALAD enzyme inhibitor, particularly confirm to treat the NAALAD enzyme inhibitor of prostatosis (as carcinoma of prostate).Brief summary of the invention
The present invention relates to suppress new phosphonate derivatives, hydroxyl oxygen phosphino-derivant and the phosphoramidic acid salt derivative of enzymatic activity of the acid dipeptidase (NAALAD enzyme) of N-acetylation α-link; contain the pharmaceutical composition of this analog derivative, and utilize this analog derivative to suppress the enzymatic activity of NAALAD enzyme and treat the method for animal such as cancer class disease and the treatment disease relevant with prostatosis.
Preferred compositions of the present invention comprises the formula I chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
8Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1
X is CH
2, O or N; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
The present invention also relates to a kind of pharmaceutical composition, said composition comprises:
(ⅰ) the formula I chemical compound of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
Preferably, the formula I chemical compound exists with enzymatic activity that suppresses the NAALAD enzyme or the effective dose for the treatment of the animal prostatosis.
The invention further relates to the method for the enzymatic activity that suppresses animal NAALAD enzyme, this method comprises the formula I chemical compound that gives described animal effective dose.
At last, the present invention relates to treat the method for animal prostatosis, this method comprises the formula I chemical compound that gives described animal effective dose.The accompanying drawing summary
Fig. 1 be expression prostate cancer cell line LNCAP growth with different Fructus Quisqualis acid concentrations between bar chart.Fig. 1 has represented to utilize the Fructus Quisqualis hydrochlorate to carry out the effect of treatment in 7-days to the growth of LNCAP cell.Shown in the remarkable reduction of [3H] thymidine incorporation, it is obviously relevant with dosage that concentration is that the Fructus Quisqualis hydrochlorate of 10nM to 1 μ M demonstrates the reduction of LNCAP hyperplasia.
Fig. 2 be expression prostate cancer cell line LNCAP growth with different 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid concentration between bar chart.Fig. 2 has represented to utilize 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid to carry out the effect of treatment in 7-days to the growth of LNCAP cell.Shown in the remarkable reduction of [3H] thymidine incorporation, it is obviously relevant with dosage that concentration is that 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid of 100pM to 10nM demonstrates the reduction of LNCAP hyperplasia.
Fig. 3 is the curve chart of the response of LnCap human prostate tumor when utilizing 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid to carry out treating day.The meansigma methods of each gross tumor volume is depicted as the function curve of time after begin treatment, errors table is shown SEM.Utilize 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid to treat to cause after 6 weeks between the animal (p=0.04) of matched group and day drug administration by injection and between the animal (p=0.02) of matched group and implantation polymer and produce significant difference.
Fig. 4 utilizes animals survived percent that 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid treats and the curve chart between the natural law.With carrier contrast, Fig. 4 shows 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid of injection and polymer mixed and accepts the survival percent meansigma methods of injection 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid in the tumor higher.After this figure showed 72 days, utilizing the animal dis motility rate of polymer treatment was 88%, is 55% and utilize the animal dis motility rate that injection is treated in the tumor, and the animals of control group survival rate of utilizing carrier to treat is 32%.
Fig. 5 is the curve chart between the natural law for tumor growth and after carrying out rat Dunning cell R3327-G injection.In the time of 0 day, inject prostate gland cancer cell, 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid and the control vector of subcutaneous day injection various dose from the 1st day to the 84th day.Fig. 5 shows that the reduction of tumor growth rate is the function of 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid dosage.
Fig. 6 is that R3327-G rat prostate tumor is to utilizing the 2-[[(phenyl methyl) the hydroxyl oxygen phosphino-] methyl] the 1,3-propanedicarboxylic acid response curve for the treatment of.Will be with respect to when beginning treatment each gross tumor volume meansigma methods (V/V of representing of gross tumor volume
0) be depicted as the function of time.Utilize the 2-[[(phenyl methyl) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid treats the significant difference (p=0.02) between the animal that has obtained day injection 1 μ g medicine in matched group and the tumor after 2.5 weeks.The detailed description of the present invention's definition
" chemical compound 3 " is meant 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid, NAALAD enzyme inhibitor.
" inhibition " in the context of enzyme is meant that irreversible enzyme suppresses, and suppresses as competitiveness, uncontested property and noncompetitive.Competitive, uncontested property and noncompetitive suppress and can be distinguished the influence of the kinetics of enzyme by inhibitor.When inhibitor and enzyme are reversible competitive inhibition then takes place when combining, described combination is to carry out in the activity site and the mode of general reactant competition.Affinity between inhibitor and the enzyme can be passed through the inhibitor constant K
iMeasure described constant K
iBe defined as follows:
K
i=[E][I]/[EI]
Wherein [E] is the concentration of enzyme, and [I] is the concentration of inhibitor, and [EI] is for being reacted the concentration of formed enzyme-inhibitor coordination compound by enzyme and inhibitor.Except as otherwise noted, employed here K
iBe meant the affinity between The compounds of this invention and the NAALAD enzyme." IC50 " is meant and is used to define required compound concentrations of inhibition 50% target enzyme or the relevant term of amount.
" inhibition " in tumor growth or growth of tumour cell context can postpone by the presentation of former or secondary tumor, stop and tumor regression or the like of the alleviation of the outbreak reduction of the slower development of former or secondary tumor, former or secondary tumor, the disease second effect seriousness or reduction, tumor growth are estimated.Under opposite extreme situations, be suppressed at fully and be meant here and prevent.
" NAGG " is meant N-acetyl group-aspartyl-glutamate, Glu, and it is a kind of important brain peptide composition, and its content is suitable with main inhibitor neurotransmitter γ-An Jidingsuan (GABA).NAAG is neuronic special, is present in the synapse carrier; It discharges in several systems that are assumed to be glutamatergic and neuron produced stimulates.Some is researched and proposed NAAG and can be used as neurotransmitter and/or neuroregulator among the central nervous system, perhaps as the precursor of neurotransmitter glutamate, Glu.
" NAALAD enzyme " is meant the acid dipeptidase of N-acetylation α-link, and it is a kind of binding film metallopeptidase, NAAG catabolism can be become N-acetyl group aspartate (NAA) and glutamate, Glu:
By NAALAD enzyme catabolism NAAG
The NAALAD enzyme demonstrates high affinity, K to NAAG
m=540nM.If NAAG is a biologically active peptide, then the NAALAD enzyme can be used to the effect to synapse of NAAG is lost activity.In addition, if the NAAG function is as the glutamate, Glu precursor, then the main effect of NAALAD enzyme is the bioavailability of regulating glutamate, Glu in the synapse.
" officinal salt " be meant have required pharmaceutically active and not only do not had biological but do not have other the salt of unwanted The compounds of this invention.This salt can be the salt that forms with organic or inorganic acid, as acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cyclopentane propionate, digluconate, lauryl sulfate, esilate, fumarate, the glucose enanthate, glycerophosphate, Hemisulphate, enanthate, caproate, the hydrogen chlorate, hydrobromate, hydriodate, the 2-isethionate, lactate, maleate, mesylate, the 2-naphthalene sulfonate, nicotinate, oxalates, rhodanate, toluene fulfonate and hendecane hydrochlorate.The example of alkali salt comprises ammonium salt; Alkali metal salt is as sodium and potassium salt; Alkali salt is as calcium and magnesium salt; The salt that is become with organic base is as dicyclohexyl amine salt, N-methyl-D-glucamine salt; And the salt that is become with aminoacid, described aminoacid such as arginine and lysine.The alkalescence nitrogen-containing group can be quaternary ammoniated with reagent, and described reagent comprises the low alkyl group halides, as chloride, bromide and the iodide of methyl, ethyl, propyl group and butyl; The sulphuric acid dialkyl is as dimethyl sulfate, diethyl ester, dibutyl ester and diamyl ester; Long-chain halogenide is as decyl, lauryl, cinnamyl and stearyl chlorination thing, bromide and iodide; And aralkyl halide, as benzyl and phenethyl bromination thing.
The term relevant with tumor growth or growth of tumour cell " prevents from " to be meant if tumor or growth of tumour cell do not take place, again tumor or growth of tumour cell can not take place then, if tumor or tumor cell are grown, then tumor or tumor cell can further growths.
Term " prostatosis " is relevant with carcinoma of prostate, as adenocarcinoma or metastatic cancer, is to be the disease of feature with prostate epithelial cell misgrowth, as benign prostatic hyperplasia, and the disease that need utilize the The compounds of this invention treatment.
" PSA " is meant prostate specific antigen, and it is a kind of known prostate cancer marker.PSA is a kind of protein that is generated by prostatic cell, and generally contents level is very high in carcinoma of prostate male patient's blood.PSA and tumor trouble is relevant, and it can be used as the indicator of cancer metastasis, can be the carcinoma of prostate patient and provides parameter to the response of operation, radiation and androgen replacement therapy.
" PSMA " is meant prostate specific membrane antigen, is effective prostate cancer marker, and it is assumed to be the goal object of the radiography and the cytotoxin Therapeutic Method of carcinoma of prostate.PSMA is expressed in the ducts of prostate gland epithelium, is present in seminal fluid blood plasma, prostate fluid and the urine.It is found that PSMA cDNA expresses can give the NAALAD enzymatic activity.
Term " treatment " is meant that in order to improve the animal state of an illness directly or indirectly what carry out is any process, behavior, application or the treatment etc. of purpose with the medical treatment in animal (comprising the mankind).The compounds of this invention
The present invention relates to formula I compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1
X is CH
2, O or NR
1, R wherein
1Definition as mentioned; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
The present invention also watches described alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl attentively and can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
In preferred embodiments, this chemical compound is selected from the formula II chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
In another embodiment preferred, the R group is to be selected from aliphatic series shown in the formula II chemical compound or carbocyclic ring substituent group:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl are by carboxylic acid-substituted.
In the particularly preferred chemical compound of the present invention, R
1Be aliphatic series or carbon ring group, R
2For the ethyl and the X of carboxylic acid-substituted is CH
2, they are selected from:
2-[[methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
In the particularly preferred chemical compound of the present invention, R
1Be aliphatic series or carbon ring group, R
2For being CH by the ethyl of carboxylic acid-substituted and X
2, they are selected from:
2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] methyl] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
Although be not limited to any one concrete example, in the present invention's example very preferably, R
1Be carbocyclic ring, R
2For being CH by the ethyl of carboxylic acid-substituted and X
2, this chemical compound is:
2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid.
Other preferred The compounds of this invention comprises that wherein X is CH
2, R
1Be aliphatic series or carbocyclic ring and R
2For by the C of carboxylic acid-substituted
2-C
8The hydroxyl oxygen phosphino-derivant of alkyl or alkenyl.The example of this compounds comprises:
2-[(methyl hydroxyl oxygen phosphino-) methyl] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) methyl] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] decanedioic acid; With
2-[(benzyl hydroxyl oxygen phosphino-) methyl] decanedioic acid.
In particularly preferred The compounds of this invention, R
1Be described alkyl, alkenyl, cycloalkyl or the aryl that is replaced by heterocyclic radical, R
2For being CH by the ethyl of carboxylic acid-substituted and X
2, they are selected from:
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid.
In another embodiment preferred, the R group is the aliphatic series shown in the formula II chemical compound, carbocyclic ring or heterocyclic substituent:
Wherein
R
1Be Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group and aryl are by carboxylic acid-substituted.
In particularly preferred The compounds of this invention, R
1Be heterocyclic radical, R
2For being CH by the ethyl of carboxylic acid-substituted and X
2, they are selected from:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
Chemical compound also preferably is selected from the formula II chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be Ar
1, wherein said aryl is by carboxylic acid-substituted.
R wherein
2By aromatics or heterocyclic instantiation can be according to being provided or technology well known in the art here, easily prepare and use by those of ordinary skills.
Preferred chemical compound also can be selected from the formula III chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
In another embodiment preferred, the R group is the aliphatic series shown in the formula III chemical compound, carbocyclic ring or heterocyclic substituent:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl are by carboxylic acid-substituted.
In the particularly preferred formula III chemical compound of the present invention, R
1Be aliphatic series or carbon ring group and R
2By the ethyl of carboxylic acid-substituted, they are selected from:
2-[[methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[3-phenyl propyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(methoxy-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid; With
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid.
In particularly preferred formula III chemical compound of the present invention, R
1Be aliphatic series or carbon ring group and R
2For by the ethyl of carboxylic acid-substituted, they are selected from:
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid.
Although be not limited to any one concrete example, in the present invention's example very preferably, R
1Be carbocyclic ring, R
2For being oxygen by the ethyl of carboxylic acid-substituted and X, this chemical compound is:
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid.
Other particularly preferred The compounds of this invention comprises that wherein X is an oxygen, R
1Be aliphatic series or carbocyclic ring and R
2For by the C of carboxylic acid-substituted
2-C
9The phosphonate derivatives of alkyl or alkenyl.The example of this compounds comprises
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] decanedioic acid; With
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] decanedioic acid.
In particularly preferred The compounds of this invention, R
1Be described alkyl, alkenyl, cycloalkyl or the aryl that is replaced by heterocyclic radical, R
2For being oxygen by the ethyl of carboxylic acid-substituted and X, they are selected from:
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid:
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid.
In another embodiment preferred, R
1Be aromatics or the heterocyclic substituent shown in the formula III chemical compound:
R wherein
1Be Ar
1And R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
In particularly preferred The compounds of this invention, R
1Be heterocyclic radical, R
2For being oxygen by the ethyl of carboxylic acid-substituted and X, they are selected from:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
This chemical compound also preferably is selected from the formula III chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be Ar
1, wherein said aryl is by carboxylic acid-substituted.
R wherein
2By aromatics or heterocyclic instantiation can be according to being provided or technology well known in the art here, easily prepare and use by those of ordinary skills.
The preferred aminophosphonic acid salt compound of the present invention is selected from the formula IV chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
In preferred embodiments, the R group is aliphatic series shown in the formula IV chemical compound or carbocyclic ring substituent group:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl are by carboxylic acid-substituted.
In particularly preferred formula IV chemical compound, R
1Be aliphatic series or carbon ring group, R
2By the ethyl of carboxylic acid-substituted and NR
1Be amino, they are selected from:
2-[[methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl propyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(methoxy-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid; With
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid.
In particularly preferred formula IV chemical compound, R
1Be aliphatic series or carbon ring group, R
2For by the ethyl of carboxylic acid-substituted and NR
1Be amino, they are selected from:
2-[(benzyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] amino] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid.
Although be not limited to any one concrete example, in the present invention's example very preferably, R
1Be carbocyclic ring, R
2For being amino by the ethyl of carboxylic acid-substituted and X, this chemical compound is:
2-[(benzyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid.
Other particularly preferred The compounds of this invention comprises that wherein X is amino, R
1Be aliphatic series or carbocyclic ring and R
2For by the C of carboxylic acid-substituted
2-C
8The aminophosphonic acid salt derivative of alkyl or alkenyl.The example of this compounds comprises
2-[(methyl hydroxyl oxygen phosphino-) amino] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) amino] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) amino] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] decanedioic acid; With
2-[(benzyl hydroxyl oxygen phosphino-) amino] decanedioic acid.
In particularly preferred The compounds of this invention, R
1Be described alkyl, alkenyl, cycloalkyl or the aryl that is replaced by heterocyclic radical, R
2For being amino by the ethyl of carboxylic acid-substituted and X, they are selected from:
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid.
In another embodiment preferred, R
1Be aromatics or the heterocyclic substituent shown in the formula IV chemical compound:
Wherein
R
1Be Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl are by carboxylic acid-substituted.
In particularly preferred The compounds of this invention, R
1Be heterocyclic radical, R
2For being amino by the ethyl of carboxylic acid-substituted and X, they are selected from:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid.
This chemical compound also preferably is selected from the formula IV chemical compound:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1With
R
2Be Ar
1, wherein said aryl is by carboxylic acid-substituted.
R wherein
2By aromatics or heterocyclic instantiation can be according to being provided or technology well known in the art here, easily prepare and use by those of ordinary skills.Synthesizing of chemical compound
Utilize following general synthesis path (referring to flow process I-IX), can easily prepare The compounds of this invention by the conventional method in the organic chemistry.Precursor compound can prepare by means commonly known in the art, the method of describing in for example following document: people such as Jackson, journal of medicinal chemistry (J.Med.Chem.), 39 (2), 619-622, people such as Design.Synthesis and Biological Activity ofPotent Inhibitor of the Neuropeptidase N-Acetylated a-Linked AcidicDipeptidase and Froestl, journal of medicinal chemistry (J.Med.Chem.), 1995,38,3313-3331, Phosphinic Acid Analogues of GABA.
Utilize known method easily to prepare and contain the substituent chemical compound of R group.The further method of synthetic phosphonate ester also is described in journal of medicinal chemistry (J.Med.Chem.), and 1988,31, among the 204-212, this method also can obtain in following flow process II.
A. R '=(CH
2)
3Ph H.n-C
7H
15B. (CH
2)
4Ph I.n-C
8H
17C. (CH
2)
5Ph J.n-C
9H
19D. (CH
2)
4(P-F-Ph) K.n-C
10H
22E. (CH
2)
4-(3-pyridyl) L.CH
2(CH) (CH
3) C
4H
9F. n-C
5H
11M.CH
2(CH
3) CH (CH
3)
2G. n-C
6H
13 
N. R '=n-C
4H
9O. CH (CH
3) C
5H
11The flow process II
With above-mentioned phosphonate ester is initiation material, has many routes to can be used for preparing The compounds of this invention.Journal of medicinal chemistry (J.Med.Chem.) for example, 39, general route has been described among the 619-622 recently, this route is shown in following flow process III.
The flow process III
Another preparation route of The compounds of this invention is described in following flow process IV and the flow process V.Flow process IV and flow process V have represented with the phosphonate derivative to be the method that initiation material prepares The compounds of this invention, and the R group R group that can comprise any rational chemical substituent group and be enumerated in the description flow process II.
The flow process IV
The flow process V
Another route of preparation The compounds of this invention can allow R
1Be aromatic substituent, this route is described in the following flow process VI.
The flow process VI
Another route of preparation The compounds of this invention can allow R
2Be aromatic substituent, this route is described in the following flow process VII.
The flow process VII
Wherein X is NR
1The preparation method of The compounds of this invention be described in the following flow process VIII.
The flow process VIII
Wherein X is that the preparation method of the The compounds of this invention of oxygen is described in the following flow process IX.
Flow process IX pharmaceutical composition of the present invention
The present invention also relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) formula I, II, III or the IV chemical compound of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
In another embodiment preferred, pharmaceutical composition contains therapeutic agent further, and described therapeutic agent is selected from treatment hormone, chemotherapeutics, monoclonal antibody, anti-angiogenic formation agent, radio-labelled compound, antitumor agent and composition thereof.Treatment hormone example comprises diethylstilbestrol (DES), leuprorelin, amine fluoride, acetic acid cyproterone, ketoconazole, preferred aminoglutethimide.The example of antitumor agent comprises 5-fluorouracil, vinblastine sulfate, Estracyte, suramin and strontium-89.The chemotherapeutics example comprises buserelin, three pairs of methoxybenzene vinyl chloride, chromium phosphate, cisplatin, cyclophosphamide, dexamethasone, amycin, estradiol, estradiol valerate, conjugation and esterified estriol, estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea, melphalan, first ammonia purine, mitomycin and prednisones.
In a further preferred embodiment, the amount of existing formula I, II, III or IV chemical compound is effectively to suppress the amount of animal NAALAD enzymatic activity or treatment animal prostatosis.The method of pharmaceutical compositions
An embodiment preferred relates to pharmaceutical composition that contains The compounds of this invention or the medicine that preparation is used for the treatment of disease again.Using method ⅰ of the present invention) method of inhibition NAALAD enzymatic activity
The invention still further relates to the method that suppresses animal NAALAD enzymatic activity, comprise the chemical compound of the formula I, II, III or the IV that give described animal effective dose.ⅱ) the method for treatment prostatosis
The present invention also relates to treat the method for animal prostatosis, comprise the chemical compound of the formula I, II, III or the IV that give described animal effective dose.
In preferred embodiments, described prostatosis is disease such as the prostatic intraepithelial neoplasm formation (PIN) that carcinoma of prostate such as adenocarcinoma of prostate, benign prostatic hyperplasia or the needs relevant with prostate give The compounds of this invention.ⅲ) treatment method for cancer
Except carcinoma of prostate, the cancer of other form of available The compounds of this invention treatment comprises without restriction: the tumor that produces ACTH, acute lymphoblastic leukemia, acute nonlymphocytic leukemia, adrenocortical carcinoma, bladder cancer, the brain cancer, breast carcinoma, cervical cancer, chronic lymphocytic leukemia, chronic myelocytic leukemia, colorectal carcinoma, cutaneous T cell lymphoma, carcinoma of endometrium, the esophageal carcinoma, ewing's tumor, carcinoma of gallbladder, hairy cell leukemia, head and neck cancer, hodgkin's lymphoma, kaposi's sarcoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (little and/or non-small cell), pernicious peritoneal effusion, the malignant pleural seepage, melanoma, mesothelioma, multiple myeloma, neuroblastoma, non Hodgkin lymphoma, osteosarcoma, ovarian cancer, ovary (blastocyte) cancer, cancer of pancreas, carcinoma of penis, retinoblastoma, skin carcinoma, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, carcinoma of testis, thyroid carcinoma, chorionic carcinoma, uterus carcinoma, cancer of vagina, carcinoma vulvae and wilms' tumor.
Chemical compound of the present invention is useful especially for the cancer that treatment has the tissue of NAALAD enzyme.This tissue comprises prostate and brain, kidney and testis.
The patient who does not have late period or metastatic carcinoma for the initial stage existence, as the NAALAD enzyme inhibitor of medicine before surgery and radiotherapy as immediately initial treatment agent, and as recurrence being arranged or shifting the therapeutic agent of proceeding to treat after dangerous patient's the treatment (disease and/or surgery section according to high PSA, high Gleason scoring, local diffusion are judged from pathology proof tumor invasion).To the purpose of these patient is to suppress the growth of primary tumo(u)r potentiality transitional cell during surgery or the radiotherapy and inhibition to fail the growth of tumor cell of primary tumo(u)r of detected remnants.
Exist and be the patient of late period or metastatic carcinoma for the initial stage, as the NAALAD enzyme inhibitor of medicine can be used as continuation supplement therapy or may be as the substitute of removal hormone.The purpose that these patients are treated is the growth of tumor cell that slows down the transfer damage of untreated primary tumo(u)r and existence.
In addition, the present invention is efficacious especially in postoperative recovery process, and the present composition and method are in the probability that reduces the tumor recurrence that exfoliative cyte cause, described cell can not remove by the method for operation.ⅳ) Sickledex
The present invention also comprises the Sickledex that carries out the inventive method, and can contain chemical compound and/or the compositions that comprises The compounds of this invention.Can use radiolabeled chemical compound and monoclonal antibody so that diagnostic message is provided in the method.The example of diagnostic message and purposes comprises that the progress, targeting of the type of determining disease, specified disease are in the cell position of NAALAD enzyme inhibitor, radiolabeled chemical compound or monoclonal antibody and similar diagnostic uses well known by persons skilled in the art.Route of administration
In the method for the invention, chemical compound can pass through oral, parenteral administration with the form of the dosage particles that contains conventional avirulent pharmaceutically suitable carrier, adjuvant and excipient, comes administration by spraying suctions, part, rectum, nasal cavity, cheek, vagina administration or by the implantation Drug Storage.That the term as used herein parenteral administration comprises is subcutaneous, in the vein, intramuscular, intraperitoneal, sheath, in the ventricle, in the breastbone or intracranial injection and input technology.Preferred intrusion technology, the nervous tissue of particularly directly damaging.
Because the treatment to the central nervous system is effectively, should permeate when chemical compound of the present invention is peripherally administered and pass through blood brain barrier.Porous does not pass through approach administration effectively in the ventricle by the chemical compound of blood brain barrier.
Chemical compound also can be with the form administration of sterilization injectable formulation as sterilization injectable water or oily suspensions.These suspensions can use suitable dispersant or wetting agent and suspending agent to prepare according to technology known in the art.The sterilization injectable formulation also can be at nontoxic parenteral route acceptable diluent or injectable solution of sterilization in the solvent or the solution in suspension such as the 1,3 butylene glycol.Wherein, spendablely accept excipient and solvent is water, Ringer's solution and isoosmotic sodium chloride solution.In addition, sterilizing fixedly, oil is commonly used for solvent or suspension media.For this reason, any blended fixedly oil such as synthetic single or two glyceride can be used.Fatty acid such as oleic acid and glyceride ester derivatives thereof, the form that comprises olive oil and Oleum Ricini, particularly its polyoxyethyleneization is useful in injectable formulation.These oil solutions or suspension also can contain long-chain alcohol diluent or dispersant.
In addition, chemical compound can be with the form oral administration of capsule, tablet, waterborne suspension or solution.Tablet can contain carrier such as lactose and corn starch, and/or lubricant such as magnesium stearate.Capsule can contain diluent and comprise lactose and exsiccant corn starch.Waterborne suspension can contain and blended emulsifying agent of active component and suspending agent.Oral dosage form can further contain sweeting agent and/or aromatic and/or coloring agent.
Chemical compound can also be with the form rectally of suppository.These compositionss can be by with medicine and suitable non-stimulated at room temperature for solid but prepare for liquid makes them dissolve the mixed with excipients that discharges medicine in rectum under rectal temperature.This excipient comprises cocoa butter, Cera Flava and Polyethylene Glycol.
And, but chemical compound topical, the particularly zone of the disease for the treatment of or organ be convenient to make and be used for approachingly by the part, comprise the nervous system disease of eye, skin and intestinal lower end.
For the part is used for eyes; or eyes use; chemical compound can be formulated into etc. ooze, the micronize suspension of the sterile saline of pH regulator or, preferably be mixed with the having or the solution of preservative free such as Benasept (benzylalkonium chloride) of sterile saline of isoosmotic, pH regulator.In addition, chemical compound can be formulated into ointment, as soft petroleum ointment.
For the local skin administration, chemical compound can be formulated into the suitable ointment that contains this chemical compound, and described chemical compound is suspended or is dissolved in the mixture as one or more following materials: mineral oil, liquid paraffin, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene chemical compound, emulsive paraffin and water.In addition, chemical compound can be formulated into suitable lotion or the cream that contains this reactive compound, and described reactive compound suspends or is dissolved in the mixture of one or more following materials for example: mineral oil, Arlacel-60, polysorbate60, spermaceti alcohol ester paraffin, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The part is used for the intestinal lower end and can be made into rectal suppository preparation (seeing above) or suitable enema.
Chemical compound of the present invention can be by single dose, repeatedly divided dose or continuous infusion come administration.Since chemical compound be little, be easy to spread with metastable, they are very suitable for continuous infusion.Suction mode, particularly subcutaneous suction mode are preferred continuous infusion methods.
The compositions and methods of the invention also can use controlled-release technology.Therefore, for example, the NAALAD enzyme inhibitor can be mixed with the polymeric material that is controlled at release in several days.This class release-controlled film is known in the art.The spendable example that is usually used in the polymer of this purpose of the present invention comprises the vinyl-vinyl acetate copolymer and the degradable lactic acid-ethanol copolymer of non-degraded.Also can use some hydrogel as poly-(ethoxy first acrylate) or polyvinyl alcohol.Dosage
In treatment during above-mentioned disease, can use about 0.1mg to about 10, it is about 1 that the dosage level of 000mg order of magnitude active constituent compound, preferably about 0.1mg arrive, the dosage level of 000mg.The concrete dosage level of any given patient will change with various factors, the activity that comprises employed particular compound, patient's age, body weight, general health, sex and diet, administration time, discharge rate, the medicine of associating use is treated the order of severity and the administering mode of specified disease.In general, the external dose-effect result suitable dose that can be patient's administration provides the guidance of usefulness.Research in the animal model also is helpful, particularly helps to determine the effective dose of treatment cancer.How to determine that the proper dosage level is known in the art.
In preferred embodiments, The compounds of this invention is with the lyophilized form administration.Like this, the The compounds of this invention of 1-100mg can be with carrier and buffer agent such as mannitol and sodium phosphate lyophilizing in each bottle.Before the administration, can use the water that suppresses antibacterial that the chemical compound in the bottle is prepared again.
As mentioned above, chemical compound of the present invention can with one or more therapeutic agents (comprising chemotherapeutics) administering drug combinations.The table I provides the known middle dosage of selected chemotherapeutics.The concrete dosage of these chemotherapeutics will depend on various factors, as mentioned at described those factors of The compounds of this invention.
The table I
| Chemotherapeutics | Middle dosage |
| Asparaginase | 10,000 units |
| Bleomycin Sulphate | 15 units |
| Carboplatin | ?????50-450mg |
| Carmustine | ??????100mg |
| Cisplatin | ?????10-50mg |
| ??cladribine | ??????10mg |
| Cyclophosphamide (freeze dried) | ????100mg-2gm |
| Cyclophosphamide (non-freeze dried) | ????100mg-2gm |
| Cytosine arabinoside (freeze dried powder) | ????100mg-2gm |
| Dacarbazine | ????100-200mg |
| Actinomycin D | ??????0.5mg |
| Daunorubicin | ??????20mg |
| Diethylstilbestrol | ??????250mg |
| Amycin | ????10-150mg |
| Etidronic acid salt | ??????300mg |
| Etoposide | ??????100mg |
| Floxuridine | ??????500mg |
| Fludarabine phosphate | ??????50mg |
| Fluorouracil | ?????500mg-5gm |
| Goserelin | ??????3.6mg |
| ??granisetron?hydrochloride | ??????1mg |
| Idarubicin | ?????5-10mg |
| Ifosfamide | ?????1-3mg |
| Calcium Folinate-SF | ?????50-350mg |
| ??leuprolide | ????3.75-7.5mg |
| Chlormethine | ??????10mg |
| Medroxyprogesterone | ??????1gm |
Table 1 (continuous table)
Dosage regimen
| Melphalan | ????????50gm |
| Methotrexate | ??????20mg-1gm |
| Mitomycin | ???????5-40mg |
| Mitoxantrone | ??????20-30mg |
| ??ondansetron?hydrochloride | ????????40mg |
| ??paclitaxel | ????????30mg |
| Sodium Pamidronate | ??????30-*90mg |
| ??pegaspargase | 750 units |
| Plicamycin | ???????2,500mcgm |
| Streptozocin | ????????1gm |
| Plug is for group | ????????15mg |
| Teniposide | ????????50mg |
| Vinblastine | ????????10mg |
| Vincristine | ????????1-5mg |
| ??aldesleukin | 2,200 ten thousand units |
| ??epoetin?alfa | 2,000-10,000 unit |
| ??figrastim | ??????300-480mcgm |
| Immunoglobulin | ??????500mg-10gm |
| α-2a interferon | 3-36 1,000,000 units |
| α-2B interferon | 3-50 1,000,000 units |
| Levamisole | ????????50mg |
| Octreotide | ????1,000-5,000mcgm |
| ??sargramostim | ???????250-500mcgm |
For method of the present invention, any dosage regimen that medicine is discharged on time and according to the order of sequence all can be used and by the repetition that needs of therapeutical effect.This class scheme can comprise pretreat and/or with other therapeutic agent administering drug combinations.
Have neither the patient of the carcinoma of prostate that neither shift late period for loyalty, chemical compound of the present invention can followingly use the danger that is used to reduce transfer before (ⅰ) operation or the radiotherapy; (ⅱ) intra-operative or be used in combination with radiotherapy; And/or (ⅲ) be used to reduce the dangerous of recurrence after operation or the radiotherapy and suppress the growth of any tumors remaining cell.
For the patient of the carcinoma of prostate of suffering from late period or transfer, The compounds of this invention can be used as and continues the complementarity therapeutic agent or as the substituting agent of removing hormone, so that the growth of the tumor cell of the transfer damage of not treating primary tumo(u)r and existence of slowing down.
The inventive method is for can not being useful especially by the patient of surgical removal exfoliative cyte.Behind the surgery recovery, method of the present invention can reduce the relapse rate of the tumor that is caused by these class exfoliative cyte effectively.Unite use (ⅰ) surgical operation and radiotherapy with other Therapeutic Method
In general, surgical operation and radiotherapy were the Therapeutic Method that might cure and were hopeful to survive at least 10 years the patient who is confined to carcinoma of prostate below 70 years old for the age.
About 70% patient who is diagnosed as carcinoma of prostate recently is in this situation.About 90% among these patients (patient's sum the 65%) treatment that undergos surgery, about 10% among these patients simultaneously (patient's sum 7%) carries out radiotherapy.
The histopathological examination of surgery section shows that carrying out about 63% among the operating patient (patient's sum 40%) has the tumor of local diffusion or undetected regionality (lymph node) metastatic carcinoma when formerly diagnosing.These patient's risk of relapse are very big.In fact, about 40% will in postoperative 5 years, recur among these patients.Behind the radiotherapy even effect seldom arranged.About 80% still exists disease or recurrence or shift in back 5 years of treatment among the patient who treats as its main Therapeutic Method with radiotherapy.
At present, carry out surgical operation and radiocurable most of carcinoma of prostate patient and do not accept immediately continuation treatment.On the contrary, the antigen (" PSA ") that they often are detected prostate-specific raises, and this antigen is the leading indicator of recurrence or metastatic carcinoma.
Based on above-mentioned statistics, being worthy of consideration is used in combination the present invention with surgical operation and/or radiotherapy.(ⅱ) hormone therapy
For 10% patient who suffers from metastasized prostate cancer, removing hormone is the most effective remissive treatment.The method that removes hormone by Drug therapy and/or male castration is used to block the hormone that promotes carcinoma of prostate further growth and transfer.Simultaneously, in fact all these patients that suffer from former and metastatic tumour become irrelevant and to the treatment tolerance with hormone.Dead in the patient that about 50% loyalty has a metastatic carcinoma 3 years after initial diagnosis, and dead in this class patient of 75% 5 years after diagnosis.Proceeding supplement therapy with The compounds of this invention can be used for preventing or reverses this potential state that may shift.(ⅲ) chemotherapy
Although chemotherapy is successfully used to the cancer of some type, the chemotherapy of staying last treatment means shows small therapeutic value when the treatment carcinoma of prostate.Therefore, the probability of chemotherapy and the inventive method therapeutic alliance carcinoma of prostate is very little.Yet, when carrying out therapeutic alliance, to compare with carrying out chemotherapy separately, this class Therapeutic Method can more effectively be controlled carcinoma of prostate.(ⅳ) immunization therapy
Chemical compound of the present invention also can be united with monoclonal antibody and is used for the treatment of carcinoma of prostate.It is effective especially that this therapeutic alliance has the patient's (these patients only had 34% survival after 5 years) who relates to lymphonodi pelvini for loyalty.The example of this class monoclonal antibody is the special anti-prostate antibody of cell membrane.
The present invention also can be with using based on the immunization therapy of polyclone or monoclonal antibody derivative reagent.The preferred deutero-reagent of monoclonal antibody.These reagent are well known in the art, and comprise radiolabeled monoclonal antibody as with strontium 89 bonded monoclonal antibodies.(ⅴ) cryotherapy
Method of the present invention also can be used for the treatment of carcinoma of prostate with cryotherapy.Experimental research
Followingly prove forcefully that at the relevant experimental research that chemical compound carried out on The compounds of this invention and the structure The compounds of this invention is nontoxic and is effective to suppressing NAALAD enzymatic activity, treatment glutamate abnormality and treatment prostatosis.The toxicity in vivo of NAALAD enzyme inhibitor
In order to detect NAALAD enzyme inhibitor toxic action in vivo, give one group of injected in mice 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid (a kind of highly active NAALAD enzyme inhibitor), dosage is 1,5,10,30,100,300 and the 500mg/kg body weight.Observed mice subsequently continuously 5 days, twice of every day.The following table II shows the survival rate under each dosage level.The gained result shows that the NAALAD enzyme inhibitor is nontoxic to mice, and when hinting with the administration of treatment effective dose, similarly, The compounds of this invention should be nontoxic to the people.
The table II
The external test of NAALAD enzymatic activity
| The toxic action of NAALD enzyme inhibitor | |||||||
| Dosage (mg/kg) | ??1 | ??5 | ???10 | ???30 | ??100 | ?300 | ?500 |
| Survival rate after 5 days (%) | ?100 | ?100 | ??100 | ??100 | ??100 | ?100 | ?66.7 |
The test following compounds is to the vitro inhibition effect of NAALAD enzymatic activity.The results are shown in following table III (a), III (b) and the III (c).
The external activity of table III (a) NAALAD inhibitor
| Chemical compound | ????????K i(nM) |
| 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid 2-((phosphonomethyl)) succinic acid 2-[[(2-carboxy ethyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid | ?????0.275±0.08 ?????700.00±67.3 ?????1.89±0.19 |
2-((phosphonomethyl)) 1,3-propanedicarboxylic acid shows high-caliber NAALAD enzyme inhibition activity, K
iBe 0.27nM (table III (a)).Described inhibitor is strong more than 1000 times before the specific activity of this chemical compound.Because 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid structurally is similar to chemical compound of the present invention, the gained result hints that The compounds of this invention also should be strong NAALAD enzyme inhibitor.By comparing, 2-((phosphonomethyl)) succinic acid shows much lower NAALAD enzyme inhibition activity, and the glutamic acid analog that hint is combined on the phosphonic acids helps its NAALAD enzyme inhibition activity.The gained result also shows the 2-[[(2-carboxy ethyl) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid (having the other carboxylic acid side chain that is similar to the aspartate residue of finding among the NAAG) shows than the low NAALAD enzyme inhibition activity of 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid.
Table III (b)
Describe proof in the following table III (b) and had inhibiting other chemical compound of NAALAD enzymatic activity.The result of 9 chemical compounds in the table III (b) shows the significant K of all cpds of the present invention
iActive.The ability of these compound exhibits NAALAD enzyme inhibitor, wherein R1 comprises the aryl of aliphatic group, aryl and the replacement of aliphatic group, replacement.
The external activity of table III (b) NAALAD enzyme inhibitor
The remarkable K that The compounds of this invention also is provided by the further result that provides of table III (c)
iActive.The ability of these compound exhibits NAALAD enzyme inhibitor, wherein R1 comprises the aliphatic group that is replaced by benzyl, described benzyl is further replaced by other substituent group.
The external activity of table III (c) NAALAD enzyme inhibitor
The method of NAALAD enzymatic activity external test
Use the excrescence albumen of 30-50 μ g, 37 ℃ measure down 15 minutes from the 50nM TRIS buffer [
3H] NAAG dissociated [
3H] amount of Glu.By anion exchange liquid chromatography chromatography, substrate is separated with product.Repeat to measure so that the digestion of NAAG is no more than 20%, this is representing the range of linearity of peptidase activity.Fructus Quisqualis hydrochlorate (100 μ g) is included in the specificity of measuring with conclusive evidence in the parallel assay pipe.
The NAALAD enzyme inhibitor is to the external test of cancer effect
Referring now to attached Fig. 1 and 2, detected of the effect of NAALAD inhibitor to cancerous cell line.Handle LNCAP cell (a kind of prostate cancer cell line) with Fructus Quisqualis acid (concentration range is that 10nM is to 1 μ M) and 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid (concentration range is that 100pM is to 10nM).The 3H-thymidine of measuring under each Fructus Quisqualis acid and 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid concentration also is provided in the following table IV.Fig. 1 and 2 represents these data with figure and understand that specifically the cell of handling with the NAALAD enzyme inhibitor all reduces to some extent in the absorption of propagation and thymidine.
Table IV 3H-thymidine combination (dpm/ hole)
Dosage Fructus Quisqualis acid 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid
Contrast 4813 ± 572 4299 ± 887
10pM???????????????--??????????????????3078±1006
100pM??????????????--??????????????????2062±595
1nM?????????????3668±866??????????????1001±52
10nM????????????2137±764??????????????664±366
100nM???????????1543±312?????????????????--
1μM????????????1295±181?????????????????--
The gained result shows that LNCAP cell proliferation (measuring by 3H-thymidine binding capacity) obviously reduces with the increase of NAALAD enzyme inhibitor, and the treatment of hint The compounds of this invention cancer, particularly carcinoma of prostate can be effective.The method of external test cancer
To contain cell in RPMI 1640 media of 10% hyclone (FCS) and be coated in 24 orifice plates and allow bonding 24 hours, add Fructus Quisqualis acid (10 then
-9To 10
-6) or 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid (10
-11To 10
-8) 7 days.At the 7th day, with 3H-thymidine pulse cell 4 hours, results and mensuration radioactivity.Income value representative deal with separately 6 is the mean+/-SEM of cell hole independently.All experiments all carry out at least twice.
In order to control the non-special inhibition cytological effect of Fructus Quisqualis acid and 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid; these two kinds of reagent are being contained prostate cell line, DU145 (Carter etc., Proc.Natl.Acad.Sci.USA simultaneously; (93) estimate on non-NAALAD enzyme 749-753,1996).If handle not significantly influence of cell growth with Fructus Quisqualis acid and 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid, the NAALAD enzyme inhibition activity of these two kinds of reagent has unique effect to the inhibition cytological effect of prostate cancer cell line so.Cell line and tissue culture
Obtain the LNCAP cell from doctor WilliamNelson of Maryland Baltimore Johns Hopkins School of Medicine.DU145 obtains from U.S. typical case culture collecting center (ATCC, Rockville, Maryland).Cell is at 37 ℃, 5%CO
2Grow in/95% air, moistening heat insulating culture case, the RPMI-1640 culture medium, described culture medium is supplemented with 5% heat-inactivated hyclone, 2mM glutamine, 100 units/ml penicillin and 100 μ g/ml streptomycins (Paragon).[3H] thymidine is in conjunction with mensuration
With cell with 1 * 10
3Cell/ml concentration is suspended in the RPMI-1640 culture medium and with every hole 500 μ l and is seeded in 24 orifice plates.After the heat insulating culture 24 hours; the Fructus Quisqualis acid (Sigma) or effective NAALAD enzyme inhibitor 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid (method according to descriptions such as Jackson is synthetic, J.Med.Chem 39 (2) 619-622) of various concentration are added in the hole and with plate and put back to the heat insulating culture case.At 3,5 and 7 days, multiple new culture medium and medicine.After inoculation the 8th day, with 1 μ Ci
3Each hole of H-thymidine (New England Nuclear) pulse 4 hours.Remove culture medium then and also use saline (pH=7.4) washed twice of phosphate-buffered.Subsequently the composition in the hole is dissolved among the 0.2NNaOH of 250 μ l and transfers in the scintillation vial.Add 5ml UltimaGold (Packard) scintillation solution and use the quantitative radioactivity of Beckman LS6001 scintillation counter.The conventional method that chemical compound is synthetic
The purity of all synthetic compounds and/or evaluation are all passed through thin layer chromatography, high pressure liquid chromatography (HPLC), mass spectrum and elementary analysis and are determined.Use the Bruker spectrogrph to obtain proton magnetic resonance (PMR) (NMR) spectrum.Chemical displacement value is represented with hundred sub-very much umbers with respect to interior mark tetramethylsilane.(Analtech, Newark carry out analytical thin layer chromatography (TLC) on DE) at the silica gel G HLF plate of shop system in advance.Use the iodine platinate of UV light, phosphomolybdic acid-ethanol and/or carbonization to make the plate colour developing.At Kieselgel 60, (E Merck, Darmstadt carry out flash chromatagraphy on WestGermany) to the 230-400 order.Solvent or general reagent or HPLC level.Reaction at room temperature with in the nitrogen environment is carried out, unless note is arranged in addition.Evaporating liquid under decompression on the Buchi Rotary Evaporators.LNCaP tumor xenotransplantation mensuration and result in the body
Referring now to accompanying drawing 3 and 4, with the right side side of body portion of the subcutaneous injection male nude mouse of LNCaP Human Prostate Cancer Cells.Gross tumor volume begins that injection gives 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid (a kind of NAALAD enzyme inhibitor, 0.25 μ g/ days) in tumor every day during approximately to 50-70mm3.Comprise other group of using the silicon polymer that contains 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid, it is discharged into about 0.25 μ g/ days medicine part in the tumor.2-((phosphonomethyl)) 1,3-propanedicarboxylic acid polymer is become twice weekly.Behind the begin treatment, detect gross tumor volume 42 days.Experimental technique cell line
LNCaP is the PC-3, and this cell line builds on 1973, and from patient's peritoneal effusion, patient treated 3 months with 5-FU, amycin, methotrexate and CTX before creating cell line.This cell line is that androgen receptor is male and be used to screen cancer therapy drug as hormone antagonist.LNCaP has 1.5g NaHCO
3Growth and at 37 ℃, moistening 5%CO among the RPMI of/L, 10% hyclone (FBS) and 2mM L-glutaminate
2/ air is cultivated in the couveuse and is kept.Antibiotic is not added in the culture medium.Animal tumor model
NCr nude (nu/nu) male mice, age in 4-5 week is available from Taconie (Germantown, New York).Animal is raised in the cage of the top aseptic filtration on the ventilation cage, 4 in every cage.When animal is arrived, before using they are quarantined 4 working days.It is 35-70% that temperature remains on 72+5 and relative humidity, uses bright/dark circulation in 12 hours.Mice with aseptic, can be autoclaved, the Purina rodent that has been proved to be arbitrarily feeds.The water of drinking is by acidify and autoclaving, and the water source is recycled, deionization, UV handles and 5-μ m filters.
After the animal quarantine, side of body position, the right side subcutaneous injection of giving mice is at Matrigel
TMIn (0.1ml volume injected) 1 * 10
7The LNCaP cell.Measure tumor size and body weight twice weekly.With the vernier cursor caliper from 3 plane survey tumors, and following calculating tumor size (V): V=π (xyz)/6, wherein x, y, z deduct skin thickness for the tumor of measuring.When experiment finishes, pass through CO
2Suck disconnected then neck and put to death mice.Medicine
2-((phosphonomethyl)) 1,3-propanedicarboxylic acid is prepared in water with the concentration of 2.5mg/ml.The polymer that contains 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid can mix with 5mg 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid and 350mg siloxane glue and prepare then by 140mg NaCL is ground to form fine powder.Chemical compound is coated on the thin film and allows dry 24 hours.The sheet that this material is cut into 1-1.5mg is used for subcutaneous implantation.Therapeutic Method
Gross tumor volume is long to pre-sizing (mean tumour volume 50-70mm
3) time, mice is randomized in the treatment group, every group of 6-8 is only.All all administrations every day of treatment animal, at least 4 weeks.2-((phosphonomethyl)) 1,3-propanedicarboxylic acid is injected in the tumor every day, and the per injection volume is 0.05ml, wherein contains 0.025 μ g 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid.
The polymer (10 μ g medicine/mg polymer) that contains 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid is implanted subcutaneous.With the metafane anesthetized mice and near tumor locus, cut an osculum (＜2mm).After the implantation, clamp closure of incisions with wound.Polymer is replaced weekly twice.
After the treatment, measure tumor weekly twice for the first time, measured for 8 weeks at least.Calculate the average external volume of every group of mouse tumor on each time point.Adopt non-paired couple of tail t-test, respectively organizing of special time compared, the gained data use methods of analysis of variance (ANOVA) to analyze.
Come evaluation system toxicity by the decline for the treatment of the back body weight.If when treatment finishes or its gross tumor volume reach 1600mm
3Or earlier put to death mice during tumor ulcer.Statistical analysis
(SAS Institute Inc., Cary NC) carries out statistical analysis mentioned above to use JMP.Rat Dunning R3327 model in the body
Now referring to accompanying drawing 5 and 6, the both sides side of body portion of the subcutaneous injection homology of Dunning R3327-G prostate gland cancer cell male rat.In first research, the neoplasm growth activity of subcutaneous injection medicine every day (1,3,10 and 30mg/kg) back test 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid.Injection of 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid and measurement of tumor proceeded for 12 weeks.In second research, tumor is long to 80-290mm
3The time every day tumor in injectable drug (0.1,1,10,100 μ g) back test 2-[[(phenyl methyl) the hydroxyl oxygen phosphino-] methyl] the neoplasm growth activity of 1,3-propanedicarboxylic acid.After the beginning Drug therapy, measured gross tumor volume 42 days.Experimental technique cell line
R3327-G is by the deutero-cell line of the adenoma papilliforum of androgen sensitivity, and described adenoma is deutero-by the tumor that independently forms in the prostate.The R3327-G cell is grown in the RPMI that contains 10% hyclone (FBS), 2mML-glutamine and 10-8M dexamethasone.Culture is maintained at 37 ℃, moistening 5%CO
2In/air thermal preservation the case.Antibiotic is not added in the culture medium.
Animal tumor model
The Copenhagen male rat, age in 8-10 week, available from Harlan Sprague Dawly (Indianapolis, IN).Animal is raised by two in every cage.When animal is arrived, before using they are quarantined 4 working days.It is 35-70% that temperature remains on 72+5 and relative humidity, uses bright/dark circulation in 12 hours.Rat is arbitrarily fed with the Purina rodent and the water that have been proved to be.
After the animal quarantine, give the bilateral side of body position subcutaneous injection 1 * 10 of rat
7R3327-G cell (0.1ml volume injected).Measure tumor size and body weight twice weekly.From 3 plane survey tumors, and following calculating tumor size (V): (x * y * z)/6, wherein x, y, z deduct skin thickness for the tumor of measuring to V=π with the vernier cursor caliper.After tumor cell injection 4-5 week, tumor begins to manifest.When experiment finishes, pass through CO
2Suck and put to death rat.Medicine
2-((phosphonomethyl)) 1,3-propanedicarboxylic acid is respectively in the injection the previous day of fresh preparation in normal saline.The 2-[[(phenyl methyl) hydroxyl oxygen phosphino-] methyl] the 1,3-propanedicarboxylic acid storing solution prepares in water with the concentration of 2.5mg/ml; 10 times of serial dilutions of prepared fresh are used for injection weekly.Therapeutic Method
In the research of 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid, tumor is implanted and was begun in back 14 days to give the rat skin lower injection medicine every day and continued for 12 weeks.At the 2-[[(phenyl methyl) the hydroxyl oxygen phosphino-] methyl] in the 1,3-propanedicarboxylic acid research, long up to gross tumor volume to pre-sizing (mean tumour volume 50-70mm
3) time, give medicine.At this moment, the treatment group that rat is divided into every group of 5 rats.After this, all treatment animals all give the 2-[[(phenyl methyl in tumor every day) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid, 4 weeks of administration.
Measure tumor weekly twice.Calculate the average external volume of every group of mouse tumor on each time point.Adopt non-paired couple of tail t-test, respectively organizing of special time compared, the gained data use methods of analysis of variance (ANOVA) to analyze.For the 2-[[(phenyl methyl) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid, each gross tumor volume (V) is represented as 0 day (treatment first day) gross tumor volume (V
0) mark.For each group, use V/V
0The meansigma methods of ratio is a function construction to treat the back time.Statistical analysis
(SAS InstituteInc., Cary NC) carry out statistical analysis mentioned above to use JMP.Embodiment
The following example is used to illustrate the preferred embodiment of the use of The compounds of this invention and preparation method and the present invention is not construed as limiting.Except as otherwise noted, all percents all calculate based on final preparation 100%.Embodiment 1 preparation 2-[(methyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid flow process IV R=CH3, R1=CH2Ph methyl-neighbour-benzylphosphonic acid
Will (10.0g 77mmol) be cooled to-20 ℃ under nitrogen at the dichloromethyl phosphite ester in the 80ml absolute ether.Keep internal temperature in 0 ℃ of-10 ℃ of scope, in 1 hour, drip benzyl alcohol (23g, 213mmol) and triethylamine (10.2g, 40ml diethyl ether solution 100mmol).After adding, immediately mixture is warming to room temperature and stirs and spend the night.Filtering mixt is also used 200ml ether washing solid filter cake.Merge Organic substance and reduction vaporization and obtain the transparent and colourless liquid of 25g.By the flash chromatagraphy purification of liquid and with 1: 1 hexane/ethyl acetate gradient elution to ethyl acetate.Collect required fraction and evaporation and obtain transparent and colorless oil the adjacent benzylphosphonic acid of methyl (1, R=CH3, R1=CH2Ph, 6.5g, 50%, R0%).Rf0.1 (1: 1, hexane/ethyl acetate).
1H NMR (d6-DMSO): 7.4ppm (m, 5H), 7.1ppm (d, 1H), 5.0ppm (dd, 2H), 1.5ppm (d, 3H) 2,4-two (benzyloxycarbonyl) butyl (methyl)-neighbour-benzylphosphonic acid
Will (3.53g 20.7mmol) be cooled to-5 ℃ under nitrogen at the adjacent benzylphosphonic acid of the methyl in the 200ml dichloromethane.By syringe add triethylamine (3.2g, 32mmol), add then trimethylsilyl chloride (2.9g, 27mmol).Stir the mixture and in 1 hour, be warming to room temperature.Be added in dibenzyl 2-methylene glutarate in the 10ml dichloromethane (2,6.0g, 18.5mmol).At room temperature mixture is stirred then and spend the night.Reactant mixture is cooled to 0 ℃ and add trimethyl aluminium (2.0M is in dichloromethane for 9ml, 18mmol).Warm flask also stirred 72 hours.Transparent yellow solution is cooled to 5 ℃ also by slowly adding 5% hydrochloric acid quenching.The reactant mixture of quenching is warming to room temperature and tells organic layer.With 5% hydrochloric acid and water washing organic layer.Dry (MgSO4) organic layer and reduction vaporization and obtain the transparent faint yellow oily thing of 8g.Purification grease and with 1: 1 hexane/ethyl acetate gradient elution on silica gel to 100%7 acetoacetic esters.Collect required fraction and evaporation and to obtain clear, colorless buttery 2,4-two (benzyloxycarbonyl) butyl (methyl)-neighbour-benzylphosphonic acid (3, R=CH3, R1=CH2Ph, 0.8g, 8%).Rf0.5 (ethyl acetate).
1H?NMR(CDCL
3):7.4ppm(m,15H),5.1ppm(m,6H),3.0ppm(m,1H),2.4ppm(m,3H),1.5ppm(dd,3H)
Elementary analysis value of calculation C
28H
31O
5P0.5H
2O:C 68.01, H 6.32 measured values: C66.85, basic hydroxyl oxygen phosphino-in the H 6.352-[() methyl] 1,3-propanedicarboxylic acid
To contain 2 in the water of 100mg10% palladium on carbon at 20ml, 4-two (benzyloxycarbonyl) butyl (methyl)-neighbour-benzylphosphonic acid (0.8g, 1.6mmol) hydrogenation 4 hours under 40psi.Evaporate and the buttery 2-[(methyl of acquisition clear, colorless thickness hydroxyl oxygen phosphino-through kieselguhr backing plate filtering mixt and under fine vacuum) methyl] 1,3-propanedicarboxylic acid (4, R=CH3,0.28g, 78%).
1H?NMR(D2O):2.5ppm(m,1H),2.2ppm(t,2H),2.0ppm(m,1H),1.7ppm(m,3H),1.3ppm(d,3H)
Elementary analysis value of calculation C
7H
13O
5P0.2H
2O:C 36.92H 5.93 measured values: C37.06H 6.31 embodiment 2 preparation 2-[(butylhydroxy phosphinyls) methyl] 1,3-propanedicarboxylic acid flow process IV R=normal-butyl, R1=H
Will (25g 0.16mol) be cooled to 0 ℃ under nitrogen at the butyl phosphonic acids diethyl torak acid esters in the 60ml absolute ether.Keep internal temperature in 0 ℃, in 2 hours, drip dibutyl magnesium chloride (80ml, 0.16mol, the 2.0M solution in ether).After adding, immediately condensed white slurry is heated to 30 ℃ and kept 1 hour.Filtering suspension liquid and vapourisation under reduced pressure filtrate under nitrogen.Then transparent weak yellow liquid is added in the 15ml water and stirring at room temperature.After this add concentrated hydrochloric acid (0.5ml) again and observe exothermic reaction.Restir mixture 15 minutes is also used ethyl acetate extraction twice, each 75ml.Merge organic facies, dry (magnesium sulfate) also evaporates and acquisition clear, colorless liquid.With sodium hydroxide (40ml, 20M) treat liquid and stirring 1 hour.Then with the ether purging compound and be acidified to pH1.0.From the acidify extract, extract material requested twice with ethyl acetate, each 100ml.Merge organic facies, dry (magnesium sulfate) and reduction vaporization and obtain clear, colorless liquid butyl phosphonic acids (1, R=normal-butyl, R1=H, 10g, 51%).
1H NMR (d6-DMSO): 6.9ppm (d, 1H), 1.6ppm (m, 2H), 1.4ppm (m, 4H), 0.9ppm (t, 3H) butyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids
Will (2.0g 16mmol) be cooled to 0 ℃ under nitrogen at the butyl phosphonic acids in the 80ml anhydrous methylene chloride.(6.7g 66mmol) adds trimethylsilyl chloride (1.0M is in dichloromethane for 58ml, 58mmol) then to add triethylamine.Under 0 ℃, stirred the mixture 10 minutes and be added in dibenzyl 2-methylene glutarate (2) in the 20ml dichloromethane (6.4g, 20mmol).Remove cryostat, reactant be warming to room temperature and stir spend the night.Then mixture is cooled to 0 ℃ and carry out quenching by slow adding 5% hydrochloric acid.Tell dichloromethane layer then also with 5% hydrochloric acid and salt water washing.Dry organic layer (magnesium sulfate) and evaporation and obtain transparent light golden yellow liquid.Also use 3: 1 hexane/ethyl acetate eluting that contain 5% acetic acid through the flash chromatagraphy purification of liquid.Merge required fraction and evaporation and obtain the buttery butyl of clear, colorless [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids (3, R=normal-butyl, R1=H) (2.9g, 40%).Rf0.12 (3: 1, hexane/ethyl acetate 5% acetic acid).
1H NMR (d6-DMSO): 7.3ppm (m, 10), and 5.0ppm (s, 4H), 2.7ppm (m, 1H), 2.3ppm (y, 2H), 1.8ppm (m, 2H), 1.3ppm (m, 4H), 0.8ppm (t, 3H) 2-[(butylhydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid
To contain butyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids in the water of 0.32g 10% palladium on carbon (2.9g, 6.5mmol) hydrogenation 4.5 hours under the 40psi in the Pa Er hydrogenator at 30ml.Evaporate and the buttery 2-[(butylhydroxy of acquisition clear, colorless thickness phosphinyl through kieselguhr backing plate filtering mixt and under fine vacuum) methyl] 1,3-propanedicarboxylic acid (4, R=normal-butyl, 0.75g, 43%).
1H?NMR(D
2O):2.4ppm(m,1H),2.1ppm(t,2H),1.9ppm(m,1H),1.6ppm(m,3H),1.4ppm(m,2H),1.1ppm(m,4H),0.6ppm(t,3H)
Elementary analysis value of calculation C
10H
19O
5P0.5H
2O:C 43.64H 7.32 measured values: C43.25H 7.12 embodiment 3 preparation 2-[(benzyl hydroxyl oxygen phosphino-s) methyl] 1,3-propanedicarboxylic acid flow process IV R=CH2Ph, the R1=H benzylphosphonic acid
Will (25g 0.16mol) be cooled to 0 ℃ under nitrogen at the diethyl torak acid esters in the 100ml absolute ether.When keeping temperature to be lower than 10 ℃, in 2 hours, drip benzyl magnesium chloride (80ml, 0.16mol, the 2.0M solution in ether).Forming condensed white slurry also at room temperature stirred 1 hour.Filtering mixt and vapourisation under reduced pressure filtrate under nitrogen and obtain clear, colorless liquid.With liquid agitation and be added in the 15ml water, after this add the 0.5ml concentrated hydrochloric acid again.Observe exothermic reaction and restir 30 minutes, and after this used ethyl acetate extraction.Merge organic facies, with salt water washing, drying (magnesium sulfate) and evaporation.The transparent light golden yellow liquid of gained is added in the sodium hydroxide (50ml, 2.0M sodium hydroxide), stirred 1 hour and washs with ether.With concentrated hydrochloric acid water layer is acidified to pH1.0 and uses ethyl acetate extraction.Merge organic facies, dry (magnesium sulfate) and reduction vaporization and obtain the buttery benzylphosphonic acid of transparent light golden yellow (1, R=CH2Ph, R1=H, 8g, 32%).
1H NMR (d6-DMSO): 7.3ppm (m, 5H), 6.9ppm (d, 1H), 3.1ppm (d, 2H) benzyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids
Will (2.3g 15mmol) be cooled to 0 ℃ under nitrogen at the benzylphosphonic acid in the 150ml anhydrous methylene chloride.(6.5g, (5.8g 54mmol) keeps reaction temperature at 0 ℃ simultaneously 65mmol) to add trimethylsilyl chloride then to add triethylamine.After 30 minutes, in 5 minutes, be added in dibenzyl 2-methylene glutarate (2) in the 20ml dichloromethane (6.4g, 20mmol).Placing response thing and make it be warming to room temperature and stir and spend the night.Clear solution is cooled to 0 ℃ also to carry out quenching, drying (magnesium sulfate) and evaporation and obtains transparent yellow liquid with 5% hydrochloric acid reuse saline.Through the flash chromatagraphy purification and with contain 1: 1 hexane/ethyl acetate eluting of 10% acetic acid and obtain transparent faint yellow oily benzyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids (3, R=CH2Ph, R1=H) (2.0g, 28%).Rf0.37 (1: 1, hexane/ethyl acetate, 10% acetic acid).
1H NMR (d6-DMSO): 7.2ppm (m, 15H), 5.0ppm (s, 4H), 3.0ppm (d, 2H), 2.8ppm (m, 2H), 2.3ppm (t, 2H), 1.9ppm (m, 2H), 1.7ppm (t, 1H) 2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid
To contain benzyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids in the water of 120mg 10% palladium on carbon (0.5g, 1.0mmol) hydrogenation 6 hours under the 40psi in the Pa Er hydrogenator at 20ml.Through the kieselguhr backing plate filter and under fine vacuum evaporation and obtain the 2-[(benzyl hydroxyl oxygen phosphino-of 0.17g (57%) white solid) methyl] 1,3-propanedicarboxylic acid (4, R=CH2Ph).
1H?NMR(D
2O):7.1ppm(m,5H),2.9ppm(d,2H),2.4ppm(m,1H),2.1ppm(t,2H),1.8ppm(m,1H),1.6ppm(m,3H)
Elementary analysis value of calculation C
13H
17O
6P:C 52.00H 5.71 measured values: methyl C 51.48H 5.70 embodiment 4 preparation 2-[(phenethyl hydroxyl oxygen phosphino-s)] 1,3-propanedicarboxylic acid flow process IV R=CH2CH2Ph, R1=H phenethyl phosphonic acids
Will (15.6g 0.1mol) be cooled to 5 ℃ under nitrogen at the diethyl torak acid esters in the 100ml absolute ether.When maintaining the temperature at 0-10 ℃, in 2 hours, drip phenethyl magnesium chloride (1.0M is in THF for 100ml, 0.1mol).Form condensed white slurry and at room temperature stir and spend the night.Filtering mixt and vapourisation under reduced pressure filtrate under nitrogen and obtain clear, colorless liquid.With liquid agitation and be added in the 15ml water, after this add the 0.5ml concentrated hydrochloric acid again.Observe exothermic reaction and restir 15 minutes, and after this used ethyl acetate extraction.Merge organic facies, with salt water washing, drying (magnesium sulfate) and evaporation.The gained transparency liquid is added in the sodium hydroxide (40ml, 2.0M sodium hydroxide), stirred 1 hour and washs once with ether.With concentrated hydrochloric acid water layer is acidified to pH1.0 and uses ethyl acetate extraction.Merge organic facies, dry (magnesium sulfate) and evaporation and obtain the buttery phenethyl phosphonic acids of transparent light golden yellow (1, R=CH2CH2Ph, R1=H, 9.8g, 58%).
1H NMR (d6-DMSO): 7.2ppm (m, 5H), 6.9ppm (d, 1H), 2.8ppm (m, 2H), 1.9ppm (m, 2H) phenethyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids
Will (1.0g 5.9mmol) be cooled to-5 ℃ under nitrogen at the phenethyl phosphonic acids in the 50ml anhydrous methylene chloride.(2.3g, 23mmol), (2.2g 21mmol), keeps reaction temperature at 0 ℃ simultaneously to add trimethylsilyl chloride then to add triethylamine.After 10 minutes, in 10 minutes, be added in dibenzyl 2-methylene glutarate (2) in the 10ml dichloromethane (6.4g, 20mmol).Placing response thing and make it be warming to room temperature and stir and spend the night.Clear solution is cooled to 0 ℃ also with 5% hydrochloric acid quenching, after this separates organic layer.Obtain transparent light golden yellow liquid with salt water washing organic layer, drying (magnesium sulfate) and evaporation.Through the flash chromatagraphy purification and with contain 1: 1 hexane/ethyl acetate eluting of 5% acetic acid and obtain the buttery phenethyl of 1.2g (41%) clear, colorless [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids (3, R=CH2CH2Ph, R1=H).
1H NMR (d6-DMSO): 7.2ppm (m, 15H), 5.0ppm (s, 4H), 3.3ppm (m, 1H), 2.8ppm (m, 4H), 2.3ppm (m, 2H), 1.8ppm (m, 4H) 2-[(phenethyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid
Will 20ml contain phenethyl [2,4-two (benzyloxycarbonyl) butyl] phosphonic acids in the water of 120mg 10% palladium on carbon (1.1g, 2.2mmol) in the Pa Er hydrogenator under the 40psi hydrogenation spend the night.Through the kieselguhr backing plate filter and under fine vacuum evaporation and obtain the 2-[(phenethyl hydroxyl oxygen phosphino-of 0.8g (114%) white solid) methyl] 1,3-propanedicarboxylic acid (4, R=CH2CH2Ph).
1H?NMR(D
2O):7.2ppm(m,5H),2.7ppm(m,2H),2.5ppm(m,1H),2.3ppm(t,2H),1.9ppm(m,6H),1.5ppm(t,1H)
Elementary analysis value of calculation C
14H
19O
6P0.75H
2O, 0.5 AcOH:C 50.35H, 6.34 measured values: methyl C 50.26H 5.78 embodiment 5 preparation 2-[(3-phenylpropyl hydroxyl oxygen phosphino-s)] 1,3-propanedicarboxylic acid flow process IV R=CH2CH2CH2Ph, R1=H
Under nitrogen, the magnesium in the 20ml absolute ether is cut (2.44g 0.10mol) is added in some iodine crystal.(20.0g 0.10mol) places Dropping funnel to phenyl propyl bromide in the 80ml ether.Approximately the bromide solution of 10ml be added to magnesium cut in and begin to stir.After a few minutes, iodine is consumed and adds the phenyl propyl bromide again when keeping 35 ℃ of temperature.Finish (1.5 hours) after the adding, immediately sealed mixture and pure at 5 ℃.
(15.7g 0.1mol) is cooled to 5 ℃ to diethyl torak acid esters in the 50ml absolute ether under nitrogen.When maintaining the temperature at 0-10 ℃, in 2 hours, drip phenylpropyl magnesium chloride (100ml, 0.1mol, the 1.0M solution in ether).Form condensed white slurry and restir 30 minutes at room temperature.Filtering mixt and vapourisation under reduced pressure filtrate under nitrogen and obtain clear, colorless liquid.20ml water is added in the liquid, after this adds the 0.5ml concentrated hydrochloric acid again.Observe exothermic reaction and restir 20 minutes, and after this used ethyl acetate extraction.Merge organic facies, with salt water washing, drying (magnesium sulfate) and evaporation.The gained transparency liquid is added in the sodium hydroxide (40ml, 2.0M sodium hydroxide), stirred gained solution 1 hour and wash with ether.With concentrated hydrochloric acid water layer is acidified to pH1.0 and uses twice of ethyl acetate extraction.Merge organic facies, dry (magnesium sulfate) also evaporates and acquisition clear, colorless buttery 3-phenylpropyl phosphonic acids (1, R=CH2CH2CH2Ph, R1=H, 9.8g, 53%).
1H NMR (d6-DMSO): 7.2ppm (m, 5H), 6.9ppm (d, 1H), 2.6ppm (t, 2H), 1.7ppm (m, 2H), 1.6ppm (m, 2H) 2,4-two (benzyloxycarbonyl) butyl (3-phenylpropyl) phosphonic acids
Will (1.0g 5.4mmol) be cooled to-5 ℃ under nitrogen at the 3-phenylpropyl phosphonic acids in the 50ml anhydrous methylene chloride.(2.2g, 22mmol), (2.1g 19mmol), keeps reaction temperature at 0 ℃ simultaneously to add trimethylsilyl chloride then to add triethylamine.After 10 minutes, in 10 minutes, be added in the dibenzyl 2-methylene glutarate (2) in the 10ml dichloromethane.Reactant is warming to room temperature and stirs spend the night.Clear solution is cooled to 0 ℃ also with 5% hydrochloric acid quenching, after this separates organic layer.Obtain transparent weak yellow liquid with salt water washing organic layer, drying (magnesium sulfate) and evaporation.Obtain 2 of the transparent faint yellow oily of 1.5g (56%) through the flash chromatagraphy purification and with containing 4: 1 hexane/ethyl acetate eluting of 5% acetic acid, and 4-two (benzyloxycarbonyl) butyl (3-phenylpropyl) phosphonic acids (3, R=CH2CH2CH2Ph, R1=H).Rf 0.58 (1: 1 hexane/ethyl acetate, 5% acetic acid).
1H?NMR(d6-DMSO):7.2ppm(m,15H),5.0ppm(s,4H),2.7ppm(m,1H),2.5ppm(m,5H),2.2ppm(m,2H),1.8ppm(m,3H),1.6ppm(m,2H)
Elementary analysis: value of calculation C
29H
33O
6P1.3H
2O:C 65.48H 6.75
Measured value: methyl C 65.24H 6.392-[(3-phenylpropyl hydroxyl oxygen phosphino-)] 1,3-propanedicarboxylic acid
To contain 2 in the water of 150mg 10% palladium on carbon at 20ml, 4-two (benzyloxycarbonyl) butyl (3-phenylpropyl) phosphonic acids (1.4g, 2.8mmol) in the Pa Er hydrogenator under the 40psi hydrogenation spend the night.Through the kieselguhr backing plate filter and under fine vacuum evaporation and obtain the buttery 2-[(phenylpropyl of the faint yellow thickness of 0.8g (89%) hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid (4, R=CH2CH2CH2Ph).
1H?NMR(D
2O):7.4ppm(m,5H),2.7ppm(m,3H),2.4ppm(t,3H),1.8ppm(m,7H)
Elementary analysis:
Value of calculation C
15H
21O
6P0.75H
2O, 0.5 AcOH:C 51.23H 6.64
Measured value: hydroxyl oxygen phosphino-C 50.85H 6.02 embodiment 6 preparation 2-[[(4-methyl-benzyls)] methyl] 1,3-propanedicarboxylic acid flow process V, chemical compound 5
With hexamethyldisilane (21.1ml, 100mmol) be added to vigorous stirring the phosphonic acids ammonium (8.30g, 100mmol) in, and the gained suspension stirred 2 hours at 105 ℃.(5.00g, 27.0mmol) drips of solution is added in 0 ℃ the suspension with 4-methyl-benzyl bromide then.Mixture at room temperature stirred 19 hours.Use dichloromethane (50ml) diluted reaction mixture then and use 1N HCL (50ml) washing.Tell organic layer, dried over sodium sulfate and concentrate and obtain the 4.72g white solid.It is dissolved in (3.24g 30mmol) is added in this solution in the dichloromethane (50ml) and with benzyl alcohol.Then under 0 ℃ with 1, (6.19g 30mmol) is added in this solution and at room temperature this suspension was stirred 14 hours 3-dicyclohexylcarbodiimide (DCC).Removal of solvent under reduced pressure also is suspended in residue in the ethyl acetate.Filter gained suspension and concentrated filtrate.Obtain the 4-methyl-benzyl-neighbour-benzylphosphonic acid (2, R=4-methyl-benzyl, productive rate 34%) of 2.40g white solid: Rf0.42 (ethyl acetate) through silica gel chromatography chromatography purification residue (hexane: ethyl acetate, 4: 1 to 1: 1);
1HNMR (DMSO-d6) δ 2.30 (s, 3H), 3.29 (d, J=16.6Hz, 2H), 5.2 (m, 2H), 7.0 (d, J=543Hz, 1H), 7.1-7.2 (m, 4H), 7.3-7.4 (m, 5H).
Under 0 ℃ of temperature, sodium hydride (0.10g, 60% oil suspension) is added to 4-methyl-benzyl-neighbour-benzylphosphonic acid (2, the R=4-methyl-benzyl) (2.16g, 8.3mmol) THF (15ml) solution in, add diphenyl 2-methylene glutarate then, and mixture at room temperature stirred 4 hours.Use then among ethyl acetate (50ml) diluted reaction mixture and the impouring 1 N HCL (50ml).Tell organic layer, dried over sodium sulfate and concentrated.Through this material of silica gel chromatography chromatography purification (hexane: ethyl acetate, 4: 1 to 1: 1) and obtain 2 of 3.41g colorless oil, 4-two (benzyloxycarbonyl) butyl (4-methyl-benzyl)-neighbour-benzylphosphonic acid (4, R=4-methyl-benzyl, 70% productive rate): Rf 0.61 (ethyl acetate); 1H NMR (CDCL3) δ 1.6-1.8 (m, 1H), 1.9-2.0 (m, 2H), 2.1-2.4 (m, 6H), 2.7-2.9 (m, 1H), 3.05 (dd, J=9.0,16.8Hz, 2H), 4.8-5.1 (m, 6H), 7.0-7.1 (m, 4H), 7.2-7.4 (m, 15H).
2, (0.70g, (5%, (50psi) was with suspension jolting 18 hours 0.10g) and under hydrogen to add palladium-carbon in ethanol 1.2mmol) (30ml) solution for 4-two (benzyloxycarbonyl) butyl (4-methyl-benzyl)-neighbour-benzylphosphonic acid.Then with suspension filtration over celite backing plate and concentrating under reduced pressure.The gained residue is dissolved in distilled water (5ml), passes through AG 50W-X8 resin column (H
+Type), and lyophilization and obtain the white solid 2-[[(4-methyl-benzyl of 0.21g) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid (5, R=4-methyl-benzyl, 55% productive rate): Rf 0.62 (i-PrOH: H
2O, 7: 3);
1HNMR (D
2O) δ 1.7-1.9 (m, 3H), 2.0-2.2 (m, 1H), 2.33 (dt, J=1.7Hz, 7.4Hz, 2H), 2.55-2.70 (m, 1H), 3.12 (d, J=16.5Hz, 2H), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H).Analytical calculation value C
13H
17O
6P
*0.30H
2O:C, 52.60; H, 6.18.Measured value: C, 52.60; H, 6.28 embodiment, 7 preparation 2-[[(4-luorobenzyls) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid (R=4-luorobenzyl):
The flow process V prepares by the described method of embodiment of above wherein R=methyl-benzyl:
Rf0.64(i-PrOH∶H
2O,7∶3)；
1H?NMR(D
2O)δ1.7-1.9(m,3H),2.0-2.2(m,1H),2.3-2.4(m,2H),2.55-2.70(m,1H),3.12(d,J=16.5Hz,2H),7.0-7.1(m,2H),7.2-7.3(m,2H)。Analytical calculation value C
13H
16FO
6P
*0.25H
2O:C, 48.38; H, 5.15.Measured value: C, 48.38; H, 5.15 embodiment, 8 preparation 2-[[(4-methoxy-benzyls) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid (R=4-methoxy-benzyl):
The flow process V prepares by the described method of embodiment of above wherein R=methyl-benzyl:
Rf0.56(i-PrOH∶H
2O,7∶3)；
1H?NMR(D
2O)δ1.8-1.9(m,3H),2.0-2.2(m,1H),2.3-2.4(m,2H),2.55-2.70(m,1H),3.16(d,J=16.7Hz,2H),3.81(s,3H),6.98(d,J=8.7Hz,2H),7.25(d,J=8.7Hz,2H)。Analytical calculation value C
14H
19O
7P
*0.30H
2O:C, 50.09; H, 5.89.Measured value: C 49.98; H, 5.80 embodiment, 9 preparation 2-[[(2-luorobenzyls) the hydroxyl oxygen base] methyl] 1,3-propanedicarboxylic acid (R=2-luorobenzyl):
The flow process V prepares by the described method of embodiment of above wherein R=methyl-benzyl:
Rf0.67(i-PrOH∶H
2O,7∶3)；
1H?NMR(D
2O)δ1.8-1.9(m,3H),2.0-2.2(m,1H),2.3-2.4(m,2H),2.55-2.70(m,1H),3.28(d,J=16.6Hz,2H),7.1-7.5(m,4H)。Analytical calculation value C
13H
16FO
6P
*0.10H
2O:C, 48.79; H, 5.10.Measured value: C48.84; H, 5.14 embodiment, 10 preparation 2-[[(PFBBR) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid (R=PFBBR):
The flow process V prepares by the described method of embodiment of above wherein R=methyl-benzyl:
Rf0.69(i-PrOH∶H
2O,7∶3)；
1H?NMR(D
2O)δ1.8-2.0(m,3H),2.1-2.3(m,1H),2.3-2.5(m,2H),2.7-2.9(m,1H),3.29(d,J=15.4Hz,2H)。Analytical calculation value C
13H
12F
5O
6P
*0.45H
2O:C, 39.20; H, 3.26.Measured value: C 39.17; H, 3.28 embodiment, 11 preparation 2-[(methyl hydroxyl oxygen phosphino-s) methyl] 1,3-propanedicarboxylic acid flow process VI, chemical compound 92,4-two (benzyloxycarbonyl) butyl phosphonic acids (6)
(100g, also (155g 1.52mol) handles with triethylamine 1.52mol) to be dissolved in the 100ml chloroform with anhydrous phosphonic acids.Evaporating mixture is also transferred in 3 liters the flask, and the 75ml chloroform wherein is housed.Be cooled to 0 ℃ by the mechanical agitator agitating solution and with flask.(277g, (281g 2.58mol) handles 2.72mol) to handle clear solution reuse trimethylsilyl chloride with triethylamine.After adding trimethylsilyl chloride, in 20 minutes, drip the dibenzyl 2-methylene glutarate (2) in the 150ml chloroform immediately.Remove the low temperature bath and mixture is warming to room temperature.After 6 hours, filter the thickness slurry and filtrate is cooled to 0 ℃.Then with 5% hydrochloric acid quenching filtrate and tell organic layer.Use the chloroform extraction water layer, merge organic layer, drying (magnesium sulfate) and reduction vaporization and obtain 2 of 55g weak yellow liquid, 4-two (benzyloxycarbonyl) butyl phosphonic acids (6).Obtain the required product of 40g (7%) by the flash chromatagraphy purification of liquid and with 3: 1 hexane/ethyl acetate that contain 5% trifluoroacetic acid.Rf 0.28 (3: 1 hexane/ethyl acetate 5%TFA); 1H NMR (CDCL3): 7.3ppm (m, 10H), 7.2ppm (d, 1H), 5.12ppm (s, 2H), 2.9ppm (m, 1H), 2.4ppm (t, 2H), 2.2ppm (m, 1H), 2.0ppm (m, 3H) 2,4-two (benzyloxycarbonyl) butyl benzyl phosphonic acids (7)
With benzyl alcohol (5.3g, 49.3mmol) and dimethyl aminopyridine (0.5g) be added to 2, (19.3g is in tetrahydrofuran solution 49.4mmol) for 4-two (benzyloxycarbonyl) butyl phosphonic acids (6).(DCC, 12g 58mmol) form white precipitate to add dicyclohexylcarbodiimide.After 30 minutes, filter white suspension and reduction vaporization filtrate.By flash chromatagraphy purification clear, colorless grease and to obtain clear, colorless with 1: 1 hexane/ethyl acetate eluting buttery 2,4-two (benzyloxycarbonyl) butyl benzyl phosphonic acids (7) (11.5g, 47%).Rf.0.16 (1: 1 hexane/ethyl acetate);
1H NMR (CDCL3): 7.3ppm (m, 15H), 7.2ppm (d, 1H), 5.0ppm (m, 6H), 2.9ppm (m, 1H), 2.2ppm (m, 3H), 1.9ppm (m, 3H) 2,4-two (benzyloxycarbonyl) butyl [hydroxyl (phenyl) methyl] benzylphosphonic acid (8)
In the anhydrous THF of 5ml 2,4-two (benzyloxycarbonyl) butyl benzyl phosphonic acids (7) is added drop-wise to the sodium hydride that stirs cooling (0 ℃), and (0.09g is in 15mlTHF mixture 2.3mmol).After 15 minutes, when keeping 0 ℃ of temperature, by syringe add benzaldehyde (0.23g, 2.2mmol).After 30 minutes, water makes the mixture quenching and uses twice of dichloromethane extraction.Merge organic layer and evaporation and obtain clear, colorless grease.With grease mechanical chromatography and with 1: 1 hexane/ethyl acetate solvent system eluting on silica gel.Collect required fraction and evaporation and to obtain 0.4g (33%) clear, colorless buttery 2,4-two (benzyloxycarbonyl) butyl [hydroxyl (phenyl) methyl] benzylphosphonic acid (8).Rf.0.18 (1: 1 hexane/ethyl acetate);
1H NMR (CDCL3): 7.3ppm (m, 20H), 5.2ppm (m, 1H), 4.9ppm (m, 6H), 2.8ppm (dm, lH), 2.2ppm (m, 3H), 1.9ppm (m, 3H) 2-([hydroxyl (phenyl) methyl] hydroxyl oxygen phosphinomethyl) 1,3-propanedicarboxylic acid (9)
To contain 2 in the water of 0.10g 10% palladium on carbon at 25ml, 4-two (benzyloxycarbonyl) butyl [hydroxyl (phenyl) methyl] benzylphosphonic acid (6) (0.37g, 0.6mmol) hydrogenation 6 hours under 40psi.Mixture filters and lyophilization and obtain 2-([hydroxyl (phenyl) methyl] hydroxyl oxygen phosphinomethyl) 1,3-propanedicarboxylic acid (9) (0.14g, 70%) of white solid through the kieselguhr backing plate.
1H?NMR(D
2O):7.4ppm(m,5H),5.0ppm(d,lH),2.7ppm(m,lH),2.4ppm(m,2H),2.2ppm(m,1H),1.9ppm(m,3H)
Elementary analysis:
Value of calculation C
13H
17O
7P0.6H
2O:C 47.74 H 5.61
Measured value: C 47.73 H 5.68 embodiment 12 preparation dibenzyl-2-methylene glutarate flow process III
Under nitrogen environment, (500g 3mol) is heated to 100 ℃ with the acrylic acid benzyl ester.When keeping internal temperature to be 135-145 ℃, stop heating and drip HMPT (10g, 61mmol).After adding, immediately the mixture cool to room temperature is also added the silica gel slurry with 5: 1 hexane/ethyl acetate.Then, slurry is transferred in the post that contains a pipe dry silica gel.Wash this post with 1: 1 hexane/ethyl acetate, collect solvent and evaporation.At fine vacuum (200 μ Hg) down distillation transparent yellow liquid and the required product (212g, 42%) of distillatory clear, colorless liquid when distillatory 8g starting fraction and 180-185 ℃ when obtaining at 45 ℃.
1H NMR (CDCL
3): 7.3ppm (s, 10H); 6.2ppm (s, 1H); 5.5ppm (s, 1H); 5.2ppm (s, 2H); 5.1ppm (s, 2H); 2.6ppm (m, 4H) embodiment 13 preparation-2-[[two (benzyloxy) phosphoryls] the lining base]-1,3-propanedicarboxylic acid dibenzyl ester flow process III
Will (9.5g 36mmol) be cooled to 0 ℃ at the dibenzyl phosphite in the 350ml dichloromethane.(18.2ml, the 2.0M solution in hexane 36.4mmol) is added in the gained solution of stirring with trimethyl aluminium.After 30 minutes, in 10 minutes, be added drop-wise to 1 in the 90ml dichloromethane (6.0g, 37mmol) in.Then, the solution of clear, colorless is warming to room temperature and place to stir and spend the night.By slow adding 5% hydrochloric acid chilled mixture.Behind the restir 1.5 hours, separate organic layer and also water layer is extracted with the 100ml dichloromethane.Merge organic layer, drying (magnesium sulfate) and evaporation and obtain transparent light golden yellow liquid.Liquid is composed chromatography (4cm in the enterprising circumstances in which people get things ready for a trip of silica gel
*30cm) also with gradient (4: 1-1: 1) solvent system (hexane/ethyl acetate) eluting.Merging the fraction that contains required product also evaporates and 2 (7.1g, 42%) of generation clear, colorless liquid.Then on the Kughleror device in 0.5mmHg and 195-200 ℃ of following distillating liquid.Discard distillate and remaining light golden yellow grease is obtained 2.9g clear, colorless buttery 2 at the enterprising circumstances in which people get things ready for a trip spectrum chromatography (1: 1, hexane/ethyl acetate) of silica gel.TCL Rf0.5 (1: 1, hexane/ethyl acetate).
1H NMR (CDCL
3): 7.1-7.4 (m, 20H); 5.05 (s, 2H); 4.8-5.03 (m, 6H); 2.8 (1H); 2.22-2.40 (m, 3H); 1.80-2.02 (m, 3H) embodiment 14 preparation 2-((phosphonomethyl)) 1,3-propanedicarboxylic acid flow process III
(2.9g 4.9mmol) is added to 20ml and contains in the carbinol mixture of 0.29g (6mol) 10% palladium on carbon with the benzyl glutarate.This mixture is obtained buttery 3 (1.0g, 90%) of transparent light golden yellow thickness in the hydrogenation 24 hours under 40psi of Pa Er hydrogenator, filtration and evaporation.
1H NMR (D
2O): 2.6-2.78 (m, 1H); 2.25-2.40 (m, 2H); 1.75-2.15 (m, 4H) embodiment 15
Patient is diagnosed as prostatic adenoma.Then,, can give this patient NAALAD enzyme inhibitor by being injected directly in the tumor, described as embodiment 1-3.Behind the begin treatment, give also not give patient identical or different NAALAD enzyme inhibitor with using subdural pump intermittence ground or seriality.The expection adenoma can further not develop.Embodiment 16
Patient is diagnosed as prostatic adenoma.Then,, can give this patient NAALAD enzyme inhibitor by being injected directly in the tumor, described as embodiment 1-3.Behind the begin treatment, by implantable bioartificial compatible polymers matrix release system intermittence ground or seriality give also not give patient identical or different NAALAD enzyme inhibitor.The expection adenoma can further not develop.Embodiment 17
Patient is diagnosed as benign prostatic hyperplasia.Then,, can give this patient NAALAD enzyme inhibitor by being injected directly in the tumor, described as embodiment 1-3.Behind the begin treatment, by injection, subdural pump or polymeric matrix implant intermittence ground or seriality give also not give patient identical or different NAALAD enzyme inhibitor.Expection benign prostatic hyperplasia cell can not develop into adenoma.Embodiment 18
Patient is diagnosed as prostatic adenoma.As if adenoma do not shift.By the surgical removal adenoma.After operation finishes to recover, by pump under injection, the dura mater or by polymeric matrix implant intermittence ground or seriality ground topical administration patient NAALAD enzyme inhibitor.The expection adenoma can further not develop.Embodiment 19
Patient is diagnosed as prostate and shifts adenoma.Adenoma seemingly shifts, but surgical operation still shows it is effective therapeutic modality.By the surgical removal tumor tissues.It is as described herein to begin topical administration patient NAALAD enzyme inhibitor when approximately making a definite diagnosis, and should continue after operation.Operation keeps patient's NAALAD enzyme inhibitor level after finishing to recover by periodicity topical scheme.Careful detect the side effect that patient can not tolerate when giving the NAALAD enzyme inhibitor.The expection tumor does not further develop.If after operation, detect some former.Little tumor mass expects that its size can not increase.Embodiment 20
Patient is diagnosed as the tumor that ACTH produces.Then,, can give this patient NAALAD enzyme inhibitor by being injected directly in the tumor, described as embodiment 1-3.Behind the begin treatment, give also not give patient identical or different NAALAD enzyme inhibitor by direct injection, subdural pump or implantable bioartificial compatible polymers matrix release system.Expection can prevent or suppress the growth of tumor growth or tumor cell, and the tumor that produces ACTH can further not develop.Embodiment 21
Treat by embodiment 19 described methods, wherein patient is diagnosed as acute lymphoblastic leukemia.Embodiment 22
Treat by embodiment 19 described methods, wherein patient is diagnosed as acute nonlymphocytic leukemia.Embodiment 23
Treat by embodiment 19 described methods, wherein patient is diagnosed as the adrenocortical carcinoma of transfer or non-transfer.Embodiment 24
Treat by embodiment 19 described methods, wherein patient is diagnosed as the bladder cancer of transfer or non-transfer.Embodiment 25
Treat by embodiment 19 described methods, wherein patient's brain cancer that be transferred or non-transfer.Embodiment 26
Treat by embodiment 19 described methods, wherein patient is diagnosed as the breast carcinoma of transfer or non-transfer.Embodiment 27
Treat by embodiment 19 described methods, wherein patient is diagnosed as the cervical cancer of transfer or non-transfer.Embodiment 28
Treat by embodiment 19 described methods, wherein patient is diagnosed as the chronic lymphocytic leukemia of transfer or non-transfer.Embodiment 29
Treat by embodiment 19 described methods, wherein patient is diagnosed as the chronic myelocytic leukemia of transfer or non-transfer.Embodiment 30
Treat by embodiment 19 described methods, wherein patient is diagnosed as the colorectal carcinoma of transfer or non-transfer.Embodiment 31
Treat by embodiment 19 described methods, wherein patient is diagnosed as the cutaneous T cell lymphoma of transfer or non-transfer.Embodiment 32
Treat by embodiment 19 described methods, wherein patient is diagnosed as the carcinoma of endometrium of transfer or non-transfer.Embodiment 33
Treat by embodiment 19 described methods, wherein patient is diagnosed as the esophageal carcinoma of transfer or non-transfer.Embodiment 34
Treat by embodiment 19 described methods, wherein patient is diagnosed as the ewing's tumor of transfer or non-transfer.Embodiment 35
Treat by embodiment 19 described methods, wherein patient is diagnosed as the carcinoma of gallbladder of transfer or non-transfer.Embodiment 36
Treat by embodiment 19 described methods, wherein patient is diagnosed as the hairy cell leukemia of transfer or non-transfer.Embodiment 37
Treat by embodiment 19 described methods, wherein patient is diagnosed as the head and neck cancer of transfer or non-transfer.Embodiment 38
Treat by embodiment 19 described methods, wherein patient is diagnosed as the hodgkin's lymphoma of transfer or non-transfer.Embodiment 39
Treat by embodiment 19 described methods, wherein patient is diagnosed as the kaposi's sarcoma of transfer or non-transfer.Embodiment 40
Treat by embodiment 19 described methods, wherein patient is diagnosed as the renal carcinoma of transfer or non-transfer.Embodiment 41
Treat by embodiment 19 described methods, wherein patient is diagnosed as the hepatocarcinoma of transfer or non-transfer.Embodiment 42
Treat by embodiment 19 described methods, wherein patient is diagnosed as the pulmonary carcinoma (little and/or non-small cell) of transfer or non-transfer.Embodiment 43
Treat by embodiment 19 described methods, wherein patient is diagnosed as the pernicious peritoneal effusion of transfer or non-transfer.Embodiment 44
Treat by embodiment 19 described methods, wherein patient is diagnosed as the malignant pleural seepage of transfer or non-transfer.Embodiment 45
Treat by embodiment 19 described methods, wherein patient is diagnosed as the melanoma of transfer or non-transfer.Embodiment 46
Treat by embodiment 19 described methods, wherein patient is diagnosed as the mesothelioma of transfer or non-transfer.Embodiment 47
Treat by embodiment 19 described methods, wherein patient is diagnosed as the multiple myeloma of transfer or non-transfer.Embodiment 48
Treat by embodiment 19 described methods, wherein patient is diagnosed as the neuroblastoma of transfer or non-transfer.Embodiment 49
Treat by embodiment 19 described methods, wherein patient is diagnosed as the non Hodgkin lymphoma of transfer or non-transfer.Embodiment 50
Treat by embodiment 19 described methods, wherein patient is diagnosed as the osteosarcoma of transfer or non-transfer.Embodiment 51
Treat by embodiment 19 described methods, wherein patient is diagnosed as the ovarian cancer (and/or ovary (blastocyte) cancer) of transfer or non-transfer.Embodiment 52
Treat by embodiment 19 described methods, wherein patient is diagnosed as the cancer of pancreas of transfer or non-transfer.Embodiment 53
Treat by embodiment 19 described methods, wherein patient is diagnosed as the carcinoma of penis of transfer or non-transfer.Embodiment 54
Treat by embodiment 19 described methods, wherein patient is diagnosed as the retinoblastoma of transfer or non-transfer.Embodiment 55
Treat by embodiment 19 described methods, wherein patient is diagnosed as the skin carcinoma of transfer or non-transfer.Embodiment 56
Treat by embodiment 19 described methods, wherein patient is diagnosed as the soft tissue sarcoma disease of transfer or non-transfer.Embodiment 57
Treat by embodiment 19 described methods, wherein patient is diagnosed as the squamous cell carcinoma of transfer or non-transfer.Embodiment 58
Treat by embodiment 19 described methods, wherein patient is diagnosed as the gastric cancer of transfer or non-transfer.Embodiment 59
Treat by embodiment 19 described methods, wherein patient is diagnosed as the carcinoma of testis of transfer or non-transfer.Embodiment 60
Treat by embodiment 19 described methods, wherein patient is diagnosed as the thyroid carcinoma of transfer or non-transfer.Embodiment 61
Treat by embodiment 19 described methods, wherein patient is diagnosed as the chorionic carcinoma of transfer or non-transfer.Embodiment 62
Treat by embodiment 19 described methods, wherein patient is diagnosed as the uterus carcinoma of transfer or non-transfer.Embodiment 63
Treat by embodiment 19 described methods, wherein patient is diagnosed as the cancer of vagina of transfer or non-transfer.Embodiment 64
Treat by embodiment 19 described methods, wherein patient is diagnosed as the carcinoma vulvae of transfer or non-transfer.Embodiment 65
Treat by embodiment 19 described methods, wherein patient is diagnosed as the wilms' tumor of transfer or non-transfer.
Therefore, to carry out identical variation in many ways be conspicuous in described the present invention.Do not think that these variations have broken away from the spirit and scope of the present invention and all this class modifications are all planned to be included within the following claim scope required for protection.
Claims (60)
1. formula I compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1
X is CH
2, O or NR
1, R wherein
1Definition as mentioned; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
2. according to the chemical compound of claim 1, R wherein
1For replacing or not replacing aliphatic series or carbon ring group; And R
2For by the aliphatic group of carboxylic acid-substituted.
3. according to the chemical compound of claim 1, R wherein
1For replacing or not replacing aliphatic series or carbon ring group; And R
2For by the C of carboxylic acid-substituted
1-C
9Alkyl or alkenyl.
4. according to the chemical compound of claim 1, R wherein
1For replacing or not replacing aliphatic series or carbon ring group; And R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
5. according to the chemical compound of claim 1, R wherein
1And R
2One of be aromatics or heterocyclic group.
6. pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 1 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
7. method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 1 that gives described animal effective dose.
8. method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 1 that gives described animal effective dose.
9. method according to Claim 8, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
10. formula II compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
11. according to the chemical compound of claim 10, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
12. according to the chemical compound of claim 10, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
13. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 10 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
14. a method that suppresses the enzymatic activity of animal NAALAD enzyme, this method comprises the chemical compound of the claim 10 that gives described animal effective dose.
15. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 10 that gives described animal effective dose.
16. according to the method for claim 15, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
17. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
2-[[methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenyl propyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) methyl] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] decanedioic acid;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] decanedioic acid;
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] methyl] 1,3-propanedicarboxylic acid.
18. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture;
2-[(benzyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] methyl] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) methyl] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
19. formula II compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
R wherein
1Be Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group and aryl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
20. according to the chemical compound of claim 19, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
21. according to the chemical compound of claim 19, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
22. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 19 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
23. a method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 19 that gives described animal effective dose.
24. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 19 that gives described animal effective dose.
25. according to the method for claim 24, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
26. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
27. formula III compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
28. according to the chemical compound of claim 27, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
29. according to the chemical compound of claim 27, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
30. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 27 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
31. a method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 27 that gives described animal effective dose.
32. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 27 that gives described animal effective dose.
33. according to the method for claim 32, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
34. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
2-[[methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenyl propyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(methoxy-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] decanedioic acid;
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] decanedioic acid;
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] the oxygen base] 1,3-propanedicarboxylic acid.
35. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
2-[(benzyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) oxygen base] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid.
36. formula III compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group and aryl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
37. according to the chemical compound of claim 36, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
38. according to the chemical compound of claim 36, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
39. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 36 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
40. a method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 36 that gives described animal effective dose.
41. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 36 that gives described animal effective dose.
42. according to the method for claim 41, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
43. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] the oxygen base] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
44. formula IV compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be hydrogen, C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl; With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group, 1-naphthyl, 2-naphthyl or phenyl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
45. according to the chemical compound of claim 44, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
46. according to the chemical compound of claim 44, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
47. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 44 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
48. a method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 44 that gives described animal effective dose.
49. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 44 that gives described animal effective dose.
50. according to the method for claim 49, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
51. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
2-[[methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
2-[[butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
2-[[cyclohexyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(cyclohexyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[benzyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenylethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl propyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[phenyl butyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[(methylamino benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[[(2,3, the 4-trimethoxyphenyl) the hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(1-naphthyl) butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-naphthyl) butylhydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
2-[[(phenyl third-2-thiazolinyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] adipic acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] adipic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] 1,5-pentanedicarboxylic acid.;
2-[(benzyl hydroxyl oxygen phosphino-) amino] 1,5-pentanedicarboxylic acid.;
2-[(methyl hydroxyl oxygen phosphino-) amino] suberic acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] suberic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] Azelaic Acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] Azelaic Acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] decanedioic acid;
2-[(benzyl hydroxyl oxygen phosphino-) amino] decanedioic acid;
The 2-[[(2-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-thienyl) methyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) ethyl hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(3-thienyl) propyl hydroxy phosphinyl] amino] 1,3-propanedicarboxylic acid.
52. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
2-[(benzyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
2-[(phenyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[((hydroxyl) hydroxyl oxygen phosphino-phenyl methyl)] amino] 1,3-propanedicarboxylic acid;
2-[(butylhydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(3-phenyl propyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-fluorophenyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(methyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
2-[(phenylethyl hydroxyl oxygen phosphino-) amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methyl-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-methoxy-benzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
2-[(dihydroxy phosphinyl) amino] 1,3-propanedicarboxylic acid;
2-[[(3-benzo trifluoro) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-luorobenzyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(PFBBR) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid.
53. formula IV compound or pharmaceutically acceptable salt thereof, hydrate or its mixture:
Wherein
R
1Be Ar
1With
R
2Be C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group and aryl be by carboxylic acid-substituted,
Wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or aryl can at random be replaced by following radicals: C
3-C
8Cycloalkyl, C
3Or C
5Cycloalkyl, C
5-C
7Cycloalkenyl group, C
1-C
4Alkyl, C
1-C
4Alkenyl, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl, C
1-C
4Alkenyloxy, phenoxy group, benzyloxy or Ar
1Ar wherein
1Be selected from 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 4-indyl, 2-furyl, 3-furyl, tetrahydrofuran base, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-or 4-pyridine radicals or phenyl, they can have 1 to 5 substituent group, and this substituent group is independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl or alkenyl, C
1-C
4Alkoxyl or C
1-C
4Alkenyloxy, phenoxy group and benzyloxy.
54. according to the chemical compound of claim 53, wherein R
2For by the C of carboxylic acid-substituted
2-C
8Alkyl or alkenyl.
55. according to the chemical compound of claim 53, wherein R
2For by the C of carboxylic acid-substituted
2Alkyl or alkenyl.
56. a pharmaceutical composition, this pharmaceutical composition comprises:
(ⅰ) chemical compound of the claim 53 of treatment effective dose; With
(ⅱ) pharmaceutically suitable carrier.
57. a method that suppresses animal NAALAD enzymatic activity, this method comprises the chemical compound of the claim 53 that gives described animal effective dose.
58. a method for the treatment of the animal prostatosis, this method comprises the chemical compound of the claim 53 that gives described animal effective dose.
59. according to the method for claim 58, described prostatosis is carcinoma of prostate or benign prostatic hyperplasia.
60. be selected from following chemical compound and officinal salt thereof, hydrate or its mixture:
The 2-[[(2-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-pyridine radicals) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(tetrahydrofuran base) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(4-indyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(2-thienyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid;
The 2-[[(3-thienyl) hydroxyl oxygen phosphino-] amino] 1,3-propanedicarboxylic acid; With
The 2-[[(4-thienyl) hydroxyl oxygen phosphino-] methyl] 1,3-propanedicarboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97195578 CN1222078A (en) | 1996-06-17 | 1997-06-16 | Hydroxy-phosphinyl derivatives useful as Naaladase inhibitors |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/778,733 | 1997-05-27 | ||
| US08/775,586 | 1997-05-27 | ||
| US08/665,776 | 1997-05-27 | ||
| CN 97195578 CN1222078A (en) | 1996-06-17 | 1997-06-16 | Hydroxy-phosphinyl derivatives useful as Naaladase inhibitors |
| US08/858,985 | 1997-07-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1222078A true CN1222078A (en) | 1999-07-07 |
Family
ID=5179246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97195578 Pending CN1222078A (en) | 1996-06-17 | 1997-06-16 | Hydroxy-phosphinyl derivatives useful as Naaladase inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1222078A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111840303A (en) * | 2020-07-15 | 2020-10-30 | 天津大学 | Cytoplasmic carboxypeptidase inhibitors and uses thereof |
-
1997
- 1997-06-16 CN CN 97195578 patent/CN1222078A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111840303A (en) * | 2020-07-15 | 2020-10-30 | 天津大学 | Cytoplasmic carboxypeptidase inhibitors and uses thereof |
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