CN1148391A - Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamido-naphthalene derivatives - Google Patents
Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamido-naphthalene derivatives Download PDFInfo
- Publication number
- CN1148391A CN1148391A CN96190152A CN96190152A CN1148391A CN 1148391 A CN1148391 A CN 1148391A CN 96190152 A CN96190152 A CN 96190152A CN 96190152 A CN96190152 A CN 96190152A CN 1148391 A CN1148391 A CN 1148391A
- Authority
- CN
- China
- Prior art keywords
- imino
- methyl
- pyrrolylcarbonyl
- carbonyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
A compound of formula (II) wherein R is an acidic group; m is an integer of 1 to 3; n is zero or an integer of 1 to 3; A is an enzymatically hydrolyzable spacer; and X is a biologically active compound; or a pharmaceutically acceptable salt thereof, for use as an antiproliferative, in particular anti-tumor and anti-angiogenic agent, and anti-inflammatory agent, is provided..
Description
The present invention relates to improve the method for the system biological drug effect of bioactive compounds, polypyrrole formamido group naphthoic acid derivative and their preparation method contain their pharmaceutical composition and their application in treatment.
The be affected strong influence of different parameters of their biological drug effects of the result of treatment of all medicines.For example, for some cytotoxic agent very likely such as Paclitaxel
, also being considered to taxol and camptothecin analogues, extremely low solvability forces the clinician to use vehicle such as ethanol and has remarkable toxic Cremofor in water
, and adopt very long transfusion time.Therefore, in treatment, need and this quasi-molecule can be dissolved in aqueous medium, particularly under physiological condition and/or with activity form, slowly discharge medicine, rather than reach the system of peak value and common toxic concentration rapidly.And strong protein binding also can prevent active substance metabolism inefficacy and very fast drainage.
Therefore, as first purpose, the present invention relates to improve the method for the biological drug effect of bioactive compounds system X, this method comprises to be provided and following formula (I) carrier group bonded active compound X or its pharmaceutically acceptable salt:
Wherein R is an acidic-group; M is integer 1-3; N is 0 or integer 1-3; But A is the spacer of enzymatic hydrolysis.
Another object of the present invention provides new compound shown in the formula (II) and pharmaceutically acceptable salt thereof,
R wherein, X, m, n and A as above define.
A further object of the present invention provides the pharmaceutical composition that contains at least a formula as the therapeutic activity agent (II) compound or its pharmaceutically acceptable salt (definition as above) and pharmaceutically acceptable carrier and/or thinner.
Formula (I) or (II) the bioactive compounds X in the compound for example, can be the taxane compounds, Comptothecin compounds, epipodophyllotoxin compound, anthracycline compound, distamycin compound, the ceramide compound, benzoyl carbinol, tetrahydrochysene S and hydrocortisone; Or their pharmaceutically acceptable salt.If at compound (I) or (II), partly there are two or more acidic-groups to exist at naphthalene, then they can be identical or different, and are preferably identical, for example, choose from following groups: sulfonic acid, carboxylic acid and phosphonic acids.The R substituting group can be in each of naphthalene nucleus or simultaneously on two aryl moieties.
Formula (I) but or (II) the spacer A of the enzymatic hydrolysis in the compound can be that for example: a)-Y-CO-, wherein Y is C
1-C
6Alkylidene group or C
2-C
6Alkylene group, divalence C
3-C
5Cycloalkyl or phenylene; Or b) amino-acid residue or peptide spacer preferably are selected from
β Ala, Gly, Phe-Gly; Phe-Phe-, Leu-Gly, Val-Ala; Phe-Ala, Leu-Phe, Leu-Ala; Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly; Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Phe-Gly; Phe-Leu-Gly-Phe, Gly-Phe-Leu-Gly-Phe, Gly-β Ala; Phe-Gly-β Ala, Phe-Phe-β Ala, Leu-Gly-β Ala; Val-Ala-β Ala, Phe-Ala-β Ala, Leu-Phe-β Ala; Leu-Gly-β Ala, Phe-Leu-Gly-β Ala, Phe-Phe-Leu-β Ala; Leu-Leu-Gly-β Ala; Phe-Tyr-Ala-β Ala, Phe-Gly-Phe, Phe-Phe-Gly-β Ala; Phe-Leu-Gly-Phe-β Ala, Gly-Phe-Leu-Gly-Phe-β Ala and amino caproyl.
For example, for β Ala, spacer is-HN-CH
2-CH
2-CO-, and for glycerine, spacer is-HN-CH
2-CO-.
According to top definition, obviously, in said compound, there is the amino or a hydroxyl that can be spaced apart the acyl group acidylate of basic A at least to compounds X; Therefore, provide-the HN-CO-A-X group for formula (II) compound of definition here.
The taxane compound is, for example, taxol, 7-shows taxol, taxotere, or 7-epitaxotere.
Comptothecin compounds is, for example, and camptothecine or 9-amino-camptothecin.
Epipodophyllotoxin compound is, for example, and etoposide.
Anthracycline compound is that for example, Zorubicin is shown erythromycin (epirubicin), darubicin, 4 '-iododoxorubicin, methoxyl group morpholino-Zorubicin and daunorubicin.
The distamycin compound is, for example, the tallimustine-amidoxim, it is 3-(1-methyl-4-(1-methyl-4-(1-methyl-4-(4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group) pyrroles-2-formamido group) pyrroles-2-formamido group) pyrroles-2-formamido group) propionyl (propion) amidoxim.
The ceramide compound is, for example, and C
2-C
30Ceramide compound, i.e. N-(C
2-C
30)-acyl group-D-sphingosine, particularly C
14-ceramide, i.e. (2S-3R-4E)-1,3-dihydroxyl-2-tetradecanoyl-amido-4-octadecylene.
Alkylidene group or alkylene group can be straight or brancheds.
C
1-C
6The preferred C of alkylidene group
1-C
4Alkyl typically is-CH
2-,-CH
2-CH
2-and-CH
2-CH
2-CH
2-, especially preferably-CH
2-CH
2-.
C
2-C
6The preferred C of alkylene group chain
2-C
6The alkylene group chain, typically be-CH=CH-or-CH=CH
2-CH
2-, especially preferably suitable-or anti--CH=CH-.
Typical divalence C
3-C
5Cycloalkyl is a cyclopropyl.
Typical divalence phenylene is 1, the 2-phenylene.
The present invention also comprises the pharmaceutically acceptable salt of formula (II) compound.
Formula of the present invention (I) or (II) example of the pharmaceutically acceptable salt of compound comprise they and mineral alkali, as sodium hydroxide, potassium, the salt that calcium and ammonium form, or they and organic bases are as Methionin, arginine, N-methyl-glycosamine, triethylamine, trolamine, dibenzylamine, methylbenzylamine, two-(2-ethyl-hexyl)-amine, piperidines, N-ethylpiperidine, N, N-diethylamino-ethylamine, N-ethylmorpholine, β-phenylethylamine, N-benzyl-β-phenylethylamine, N-benzyl-N, the salt that N-dimethyl-amine and other acceptable organic amine form.
The invention described above formula (II) compound comprises all possible isomer, particularly steric isomer, typically is diastereomer, and their mixture.
The present invention also comprises metabolite and the metabolic precursor thereof or the bioprecursor (prodrug just) of formula (II) compound.
That is, the present invention includes different but be used for being transformed directly or indirectly in vivo behind the human body compound of an accepted way of doing sth (II) compound with above-mentioned formula (II) structural formula of compound.
Preferred compounds of the invention are following formula (II) compound, wherein R is a sulfonic group; M is 2 or 3; N is 1 or 2; A is-Y '-CO-that wherein Y ' is selected from-CH
2-CH
2-,-CH=CH-and cyclopropyl or 1,2-phenylene; Or amino-acid residue, or be selected from β-Ala, Gly, the peptide spacer of Leu-Gly and Phe-Leu-Gly; X is selected from taxol, and 7-shows taxol, table erythromycin, taxotere, tallimustine-amidoxim, N-(C
2-C
30)-acyl group-D-sphingosine, camptothecine, 9-amino-camptothecin, etoposide, Zorubicin, methoxyl group-morpholino-Zorubicin, benzoyl carbinol, tetrahydrochysene S and hydrocortisone, and pharmaceutically acceptable salt.
The specific examples of the preferred compound of formula of the present invention (II) has: N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 ' (7-table) taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 ' (7-table) taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 '-taxotere; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxotere; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-3 '-etoposide; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-3 '-etoposide; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-3 '-Zorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-3 '-Zorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-6-alanyl-21-tetrahydrochysene S; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-21-hydrocortisone; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-20-camptothecine; 6-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-20-(9-amino) camptothecine; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-3 '-etoposide; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-14-(3 '-methoxyl group morpholino)-Zorubicin; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-1-benzoyl carbinol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-21-hydrocortisone; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-2 '-taxol; 3-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid)))-propionyl-3 '-N-daunorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-20-O-camptothecine; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-phenyl alanyl-leucyl-glycyl-20-O-camptothecine; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-O-benzoyl carbinol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-β-alanyl-O-benzoyl carbinol; 21-(N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-hydrocortisone; N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-the O-tallimustine-amidoxim; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; And pharmaceutically acceptable salt, particularly sodium salt.
The carrier group of formula defined above (I) is that formula (II) compound combines with bioactive compounds X defined above, for example, can obtain by any method of the preparation of narrating below formula of the present invention (II) compound.
Formula of the present invention (II) compound and salt thereof for example, can obtain by following method: a) with formula (III) compound
Wherein, R, m and n definition are as above reacted with formula (IV) compound or derivatives thereof,
X-CO-Y-COOH (IV) wherein, X defines as above, Y is C
1-C
6Alkylidene group or C
2-C
6The alkylene group chain, divalence C
3-C
5Cycloalkyl or phenylene obtain formula (II) compound, and wherein A is-Y-CO-, and the Y definition is the same; Or b) with formula V compound or its reactive derivatives
Wherein, R, Y, m and n definition are as above reacted with formula (VI) compound,
X (VI) wherein, X defines as above, obtains formula (II) compound, wherein A is-Y-CO-, Y definition is the same; Or c) with formula (VII) compound
Wherein, R, m and n define as above, and Z is a leavings group, with the reaction of formula (VIII) compound,
X-A ' H (VIII) wherein, X defines as above, A ' is amino-acid residue or the peptide spacer of A, obtains formula (II) compound, wherein A is amino-acid residue or peptide spacer; Or d) with formula (IX) compound or its reactive derivative,
Wherein, R, m and n define as above, and A ' is amino-acid residue or the peptide spacer of A, with the reaction of formula (VI) compound,
X (VI) wherein, X defines as above, obtains formula (II) compound, wherein A is amino-acid residue or peptide spacer; And, if desired, can be with the salinization of formula (II) compound; And/or, if desired, formula (II) compound is dissociated out from its salt; And/or, if desired, from their mixture, isolate the isomer of formula (II) compound.
Formula (IV), (V) and (IX) reactive derivatives of compound for example can be, for example, the acyl group isourea that obtains with the dicyclohexyl carbodiimide situ reaction; Or according to currently known methods, for example, the low alkyl group with suitable is typically C
1-C
4Alkyl, the mixed anhydride that the formyl halide reaction obtains; Or by reacting the imidazolidine derivative that obtains with carbonyl dimidazoles.
Leavings group Z in formula (VII) compound for example can be the 1-N-imidazolyl.
Method a), b), c) and d) all relate to acylation reaction, they are the similar approach that can implement with well known method.Similarly, can prepare its free cpds from the salt of formula (II) according to currently known methods, from its isomer of mixture separation of formula (II).
Method a) and c) be the acylation reaction of aminocompound, and method b) and d) be the acylation reaction of oxy-compound and aminocompound.
Typically; according to method a), b), c) and d); amino acylation reaction can be about 10 in about 100 ℃ of temperature ranges; organic, aprotonic solvent such as dimethyl formamide are in methyl-sulphoxide or the N,N-DIMETHYLACETAMIDE; if desired; at organic bases such as 4-Dimethylamino pyridine, triethylamine, xylidine or pyridine carry out under existing.
Typically; according to method b) and d); the acylation reaction of hydroxyl can be about 5 in about 110 ℃ of temperature ranges; at organic solvent such as dimethyl formamide; in methyl-sulphoxide or the N,N-DIMETHYLACETAMIDE, if desired, at organic bases such as triethylamine; the 4-Dimethylamino pyridine, pyridine or xylidine carry out under existing.
If (VI), (VIII), (IX) and (X) there is the group that may disturbance reponse carries out in formula (IV) in the compound, then can be with its protection before reaction, after reaction finishes with its deprotection.For example, can be with known routine techniques in the chemistry of peptides with hydroxyl, amino and/or carboxy protective and deprotection then.
For n wherein is 1,2 or 3 formula (III) compound, can recognize from WO91/10649, also can obtain according to the described method in there.Wherein n is that 0 formula (III) compound both can be known in the art, also can obtain with currently known methods.In a word, they all are commercial prods.
Formula (IV) compound can typically have succinyl oxide by formula (VI) compound of definition here and suitably acylating agent such as acid anhydride, Tetra hydro Phthalic anhydride, or have only suitable dicarboxylic acid that a carboxyl is activated such as propanedioic acid or toxilic acid reaction to obtain.
The formula V compound can obtain with suitable acylation reaction by formula (III) compound of definition here, for example, and those acylating agents of acidylate formula (VI) compound of mentioning during above-mentioned preparation formula (IV) compound.
Wherein Z for example is the formula V compound of 1-N-imidazolyl, can be according to currently known methods, and through type (III) compound and carbonylic imidazole reaction obtain.
Formula (VIII) or (IX) compound can be according to known method in the chemistry of peptides, through type (VI) or (III) compound and suitable activated amino acid or reactive polypeptide obtain respectively.Activated amino acid or peptide can obtain by known method in the chemistry of peptides.
Formula (VI) compound is (for example, the taxane compound) well known in the prior art and be disclosed in JACS 93,2325 (1971) and Proc.Am.Assoc.Cancer.Res., 31, p.417 (1990).
7-table-taxol is to learn from Tetrahedron Letters 34,6845 (1993).Taxotere is disclosed in US4, and 814,470.
7-table-taxotere is the taxotere derivative, i.e. phenylpropionic acid, and β-[[(1,1-dimethyl oxyethyl group) carbonyl] amino]-Alpha-hydroxy-, 12 β-(acetoxyl)-12-(benzoyloxy)-2a, 3,4,4a, 5,6,9,10,11,12,12a, 12 β-ten dihydro-4,6,11-trihydroxy--4a, 8,13,13-tetramethyl--5-oxygen-7,11-methylene radical-1H-ring ten [3,4] benzene [12-b] oxet-9-base ester, [2aR-[2a α, 4 α, 4a β, 6 β, 9 α (α R
*, β S
*), 11 α, 12 α, 12a α, 12b α]]-compound, have following chemical formula:
Wherein t.Bu refers to the tertiary butyl; Ac. refer to acyl group; Ph refers to phenyl.
Formula (X) compound can pass through taxotere at organic aprotonic solvent such as toluene, in benzene or the dimethylbenzene, at alkaline reagents such as diazabicyclo hendecene or Na
2CO
3Exist down, reflux obtained in about 6-9 hour.
Camptothecine can be from J.A.C.S.88, and 3888-3890 learns in (1967).9-aminocamptothecin is disclosed in J.Med.Chem.36,2689-2700 (1993).
Etoposide for example, is disclosed in US4,564,675.
Zorubicin for example, is disclosed in Tetrahedron Letters, 1007 (1969).
Daunorubicin for example, is disclosed in Nature 201,706 (1964).
Table erythromycin for example, is disclosed in J.Med.Chem.18,703 (1975).
Darubicin for example, is disclosed in Investigational New Drugs 4,85 (1986).
4 '-iododoxorubicin for example, is disclosed in Cancer Research 47,4001 (1987).
Methoxyl group morpholino-Zorubicin is from US4, and 672,057 learn.
Benzoyl carbinol is from DE4, and 203,116 learn.
Tetrahydrochysene S is a commodity compound, 3 α, and 5 beta-tetrahydros-aldosterone also are considered to the tetrahydrochysene hydrocortisone.
Hydrocortisone for example, is disclosed in J.A.C.S.72, and 5793 (1950).
Formula (II) compound and pharmaceutically acceptable salt thereof are defined as " The compounds of this invention " and " activeconstituents " of the present invention here.Pharmacology
Formula of the present invention (II) is poly--and pyrroyl amino naphthalenes acid derivative has more valuable biological property than related compound X defined above.Really, The compounds of this invention generally has higher systems biology activity than the related compound X that exists in its chemical structure.And the acidity that exists in the The compounds of this invention is poly--and the amino naphthoic acid structure of pyrroyl provides at physiologically acceptable solvent such as sterilized water or Cremophor EL
The mid x/y correlation x/y compounds X has better deliquescent new compound.
Really, known compound X such as taxol and camptothecine are in fact water insoluble.On the contrary, for example, the present invention contains taxol or contains Comptothecin compounds such as FCE29142, and FCE28284 and FCE28855 are then water-soluble.
Therefore, under physiological condition, The compounds of this invention has the advantage that the better healing instrument is provided than related compound X.
Formula (II) new compound and salt thereof can be used as antiproliferative, in particular as antitumor and anti-angiogenic agent, and as antiphlogistic.
Therefore, they can be used to improve treatment for cancer.Particularly they can be used for improving and suffer from leukemia such as myeloblastic leukemia, lymphoma, sarcoma, neuroblastoma, wilms' tumor, or bladder, mammary gland, lung, Tiroidina, colon, prostate gland, skin, brain, the patient's of the malignant tumour of liver or ovary the state of an illness.
The following example A, B, C and D provide the biological activity test data of some representational compounds of the present invention, and are compared with the activity data of reference compound.
The chemical name of all FCE compounds will partly provide in the chemical experiment of this specification sheets in the following tabulation.The external drug cell toxicity test of embodiment A
With 2 * 10 of exponential growth
4/ mlB16-F10 mouse melanoma cells and 1 * 10
5/ ml L1210 murine leukemia cell is inoculated in the RPMI1640 medium that is supplemented with 10% heat-killed foetal calf serum and 2mM glutamine in 24 hole flat boards (Costar).The test compound that adds scalar concentration after the inoculation immediately, i.e. taxol or FCE compound.Cultivate and use coulter counter records cell quantity after 72 hours, estimate cytostatic situation with this.Use in triplicate culture for every kind of test compound concentration.The antiproliferative activity of test compound is calculated by dose response curve, and uses IC
50(ratio of the culture of handling and untreated contrast cell growth inhibiting is 50% dosage) expression.The results are shown in following Table I.
Table I
*Have R=SO
3All compounds of H
* 1)B16-F10 mouse melanoma cells was handled in 72 hours
2)72 hours Processing Example B of L1210 murine leukemia cell taxol, FCE29142, FCE28721 and FCE28746 activity in vivo
| FCE * | ??m | ??n | ????A | Cytotoxicity IC 50 |
| ??X＝ | ||||
| ??28284 | ????2 | ????2 | β alanyl-2 ' | ?????5±1 1) |
| ??28403 | ????2 | ????2 | Propionyl-2 ' | ?????19±9 1) |
| ??28721 | ????3 | ????2 | β alanyl-2 ' | ?????6±1 1) |
| ??28722 | ????3 | ????2 | Propionyl-2 ' | ?????8±1 1) |
| ??28745 | ????2 | ????1 | β alanyl-2 ' | ?????6±0 1) |
| ??28746 | ????3 | ????1 | β alanyl-2 ' | ?????4±1 1) |
| ??28842 | ????3 | ????1 | β alanyl-2 ' | ?????17±4 1) |
| ??29142 | ????3 | ????1 | Phe-Leu-Gly-2′ | ?????5±0.2 1) |
| Reference | ?????35±3 1) | |||
| ??X＝ | ||||
| ??28855 | ????3 | ????2 | The β alanyl | ?????11±1 2) |
| Reference | ?????15±3 2) | |||
The purpose of these experiments is comparison taxols, FCE29142, FCE28721 and FCE28746 solvability and the activity in acceptable solvent biologically.For this reason, select mouse lung cancer M109 for use, because former clinical preceding data have shown that taxol has good activity to this model.Material and method mouse
The female mouse of BALB/c that obtains from Charles River Italy.These mouse are 8-10 age in week before the experiment.Medicine
Because therefore limited water-soluble of taxol be dissolved in it and contain 50% polyoxyethylated castor oil (Cremophor EL
) and 50% alcoholic acid carrier in, be diluted to required concentration with 5% glucose solution then.Solution is a bit muddy, observes precipitation after the short period of time and forms.
On the contrary, FCE29142, FCE28721 and FCE28746 dissolve readily in Cremophor
In+the ethanol, and gained solution (above 2 hours) for a long time keeps limpid.Tumour
By the transplanting of intramuscular (i.m.) series M109 mouse cancer is kept in vivo.In experiment, 5 * 10
5Individual cell is arrived in the BALB/c mouse body by intramuscular injection.
Calculate the survival time of mouse, activity is represented with T/C%.
T.I.%=is with respect to the inhibition per-cent (%) of control group tumor growth.
TOX=dies from toxic number of mice.
When mouse dies from before the control group, or when body weight obviously reduces and/or observes spleen and/or liver size and reduce mensuration TOX.Administration
At M109, taxol, FCE29142, FCE28721 and FCE28746 are intravenous injections (i.v.) in per 1,5,9 day.Gained the results are shown in Table II.
The Table II activity in vivo
| ????FCE | ????????????????????????????M109?im | |||
| ??mg/kg??1，5，9iv | ????TI％ | ????T/C％ | ????Tox | |
| ????28721 | ????28 ????42 ????62 | ????64 ????92 ????100 | ????99 ????108 ????＞200 | ????0/10 ????0/8 ????0/8 |
| ????28746 | ????58 ????70 | ????96 ????100 | ????139 ????177 | ????0/8 ????0/8 |
| ????29142 | ????67 | ????100 | ????＞200 | ????0/8 |
| Taxol | ????33 | ????98 | ????156 | ????0/10 |
Table II shows that the FCE compound is not increasing the active increase owing to the survival time increases under the toxic situation than taxol.The active hyperplasia ability of Embodiment C acyl sphingosine derivative in endotheliocyte measured
(BAEC) cultivates in being added with the DMEM of 10%FCS with bovine aortic endothelial cells, measures before the 20th subculture in vitro separately then.Behind the inoculating cell 24 hours, cell was handled 48 hours with test compound.When finishing, experiment measures cell survival rate with the MTT assay method.The cell motility is measured
According to people such as Mc Carthy described (J.Cell Biol 1986,102:179-188), with measuring chemotaxis with the poly-carbonating strainer in 8 μ m apertures and with the improved Boyden coyote hole that gelatin (100 μ g/ml are in 0.1% acetate) covers.The cell of exponential growth is separated, and before mensuration, contained in the serum medium and kept 1 hour at 37 ℃.Pack at the top coyote hole and to contain 5 * 10
4The DMEM that is added with 1%FCS of individual cell.24 hours substratum that are suitable for the human melanoma cell series of A375/M of concentrated 10 times are added to the coyote hole middle and lower part, bottom that is with or without test compound.Cultivate 4 hours after filters at 37 ℃ and dye, and write down the quantity of migrating cell with image analyzer with Diff Quick.Cell adhesion power is measured
Index growthing cell is by trypsinized, and contains in the serum medium at 37 ℃ and to keep 1 hour, so that carry out chemotactic assay.Then they are suspended in the medium that contains 1%FCS again, and are seeded in the 24 hole flat boards that are coated with gelatin with the density of 30,000 cells/well.Test compound is added in each hole, and cell is at 37 ℃ 5%CO
2The middle processing 4 hours.Cultivate when finishing, wash this flat board twice with DMEM+10%FCS.Reclaim and use coulter counter records cell count after 48 hours, gained the results are shown in Table III.
Table III
The anti-angiogenesis activity CAM of embodiment D benzoyl carbinol derivative measures
| Effect IC to BAEC cell proliferation 50(μM) | |
| ????FCE29604 | ????29 |
| The C14-acyl sphingosine | ????＞100 |
| Effect IC to BAEC cell A375/M inductive motility 50(μM) | |
| ????FCE29604 | ????28 |
| The C14-acyl sphingosine | ????＞100 |
| Effect IC to BAEC cell adhesion power 50(μM) | |
| ????FCE29604 | ????＜25 |
| The C14-acyl sphingosine | ????＞100 |
At the 3rd day that grows the chicken embryo is shifted out from their shell, be placed in the elasticity petri plate and remain on 37 ℃ of 3%CO
2Test compound was mixed in the methylcellulose gum culture dish in the 5th day, be put into the CAMs top of growth then.In 48 hours, detect the avascular area (diameter 4mm) of representing capillary vessel degeneration area with stereoscopic microscope.BFGF-gel foam implant
With gel foam (Upjohn, USA) cut into inch strips (about 7 * 10 * 10mm), and suck saturation capacity in the bFGF of 0.1%PBS/BSA solution (20 μ g/ml).The contrast sponge is made with identical method and floods with 0.1%PBS/BSA.After the anesthesia, cutting the long dorsomeson skin incision of 1cm afterbody to occipital crest 3-4cm.Sponge is inserted in the subcutaneous pouch, uses stample gun skin suture then.Intravenous injection in the 1st day treatment.After 15 days, mouse is put to death and sponge is taken out in operation, and make sample and be used for histological examination.Gained the results are shown in Table IV.
Table IV
| Effect to CAM mensuration | |||
| Compound | Dosage (nm/ sheet) | Active (positive CAMs) % | Toxicity (dead embryo %) |
| ??FCE29378 | ????3700 | ????100 | ????0 |
| Benzoyl carbinol | ????1850 | ????75 | ????0 |
| Effect to the bFGF-gel foam | |||
| Compound | Dosage (mg/kg) | Blood vessel restraining effect (%) | |
| ????FCE29378 | ????24 | ????85 | |
| Benzoyl carbinol | ????200 | ????0 | |
Table IV shows for CAM to be measured, and compares FCE29378 with benzoyl carbinol and shows not increasing under the toxic situation and increased activity.But, in the bFGF-gel foam is measured, have only FCE29378 to show suitable activity, though and benzoyl carbinol does not have activity fully with higher dosetest yet.
Because different clinical symptom, the treatment plan that Mammals is adopted must be fit to pathological type, also will consider route of administration usually, compound, the form of administered compound and patient's age, body weight and physical condition.
The compounds of this invention such as FCE28284, FCE28403 and FCE29142 are applicable to that the dosage level of grownup's administration can be from every dose of about 50mg to about 1000mg, every day 1-3 time, preferred every dose of about 100-500mg, every day 1-3 time.Certainly, these dosage regimens can be regulated to reach optimum therapeuticing effect.
As mentioned above, the present invention also comprises the pharmaceutical composition that contains at least a formula (II) compound and pharmaceutically acceptable carrier or thinner.Certainly, the character of said composition will be by desired route of administration decision.
These compositions can be made preparation with composition commonly used with usual manner.For example, The compounds of this invention can water-based or oily solution, or suspension, tablet, pill, capsule, syrup, drops or suppository form administration.
Therefore, for oral administration, contain the preferred sugar-coat of pharmaceutical composition or the film coated tablet of The compounds of this invention, pill or gelatine capsule contain active substance and thinner such as lactose, glucose, sucrose, mannitol, Sorbitol Powder, Mierocrystalline cellulose; Lubricant such as silicon-dioxide, talcum, stearic acid, Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol; Perhaps, they also can contain tackiness agent such as starch, gelatin, methylcellulose gum, carboxymethyl cellulose, Sudan Gum-arabic, yellow work glue, polypropylene pyrrolidone; Depolymerizing agent such as starch, alginic acid, alginate, glycerite of starch acid sodium; Effervescent mixture; Staining agent; Sweeting agent; Wetting agent such as Yelkin TTS, polysorbate, lauryl sulfate ester; In a word, nontoxic and material no pharmaceutical activity may be used to pharmaceutical preparation.
Said pharmaceutical preparation can be with currently known methods as mixing granulation, compressing tablet, sugar coating or the preparation of coating clothing.
Liquid dispersant for oral use can be, for example, and syrup, emulsion and suspension.
Syrup can contain carrier, for example, and sucrose or be mixed with glycerine and/or the sucrose of mannitol and/or Sorbitol Powder.
Suspension and emulsion can contain carrier, for example, and natural gum, agar, sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose, or polyvinyl alcohol.
The suspension or the solution that are used for intramuscularly can contain pharmaceutically acceptable carrier when containing active compound, as sterilized water, and sweet oil, ethyl oleate, Cremophor EL
, dibasic alcohol such as propylene glycol, and, if desired, an amount of Xylotox.
The solution that is used for intravenous injection or transfusion can contain carrier, for example, and Cremophor EL
, sterilized water or preferably, they can be the sterilized water normal isotonic saline solution.Suppository also can contain pharmaceutically acceptable carrier when containing active compound, as theobroma oil, and polyoxyethylene glycol, Vykamol Sorbitol 8B tensio-active agent or Yelkin TTS.
Following embodiment is unrestricted the present invention in order to explanation.Embodiment 1N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-β-alanyl-2 '-taxol [FCE28284]
(press J.Nat.Prod.51 to 2 ' (β-alanyl) taxol formate (291mg=0.3mmol), 298 (1988) described preparations) add 4-Dimethylamino pyridine (36mg=0.3mmol) and 4-(imidazolyl-carbonyl imino--N-methyl-4 in dimethyl formamide (20ml) solution, 2-pyrrolylcarbonyl-imino-(N-methyl-4,2-pyrrolylcarbonyl-imino-))-1,7-naphthalene disulfonic acid disodium salt (246mg=0.3mmol), whole then at room temperature the stirring 7 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 3: 1 mixture is made eluent, obtains the 362mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ 0.98 (s, 3H, 17), 1.01 (s, 3H, 16), 1.48 (s, 3H, 19), 1.4-1.9 (m, 3H, CH
2-14+6 β), 1.79 (s, 3H, 18), 2.09,2.21 (two-s, 6H, CH
3CO-4+CH
3CO-10), 2.30 (m, 1H, 6 α), 2.60 (m, 2H, OCOCH
2CH
2NH), 3.30 (m, 2H, OCOCH
2CH
2NH), 3.57 (d, J=7.3Hz, 1H, 3), 3.81,3.84 (two-s, 6H, 2-NCH
3), 3.9-4.2 (m, 3H, CH
2-20+7), 4.63 (s, 1H, OH-1), 4.90 (m, 2H, 5+OH-7), 5.33 (d, J=8.5Hz, 1H, 2 '), 5.40 (d, J=7.3Hz, 1H, 2), 5.53 (t, J=8.5Hz, 1H, 3 '), 5.82 (m, 1H, 13), 6.07 (t, J=6.0Hz, 1H, CONHCH
2CH
2), 6.28 (s, 1H, 10), 6.77 (d, J=1.7Hz, 1H, pyrroles), 6.94 (d, J=1.7Hz, 1H, pyrroles), 7.1-8.0 (m, 21H, 3-
+ 2H
Pyrroles+2 "+3 "+6 "+5 "), 8.22 (s, 1H, NHCONHCH
2CH
2), 9.17 (d, J=1.8Hz, 1H, 8 "), 9.25 (d, J=8.5Hz, 1H, NH-4 '), 9.86,10.01 (two-s, 2H, 2-pyrroles CONH).
Can obtain following compounds: β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-2 '-taxol [FCE28721] with similar approach; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-alanyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-2 ' (7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-alanyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-alanyl-3 '-etoposide; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene disulfonic acid disodium salt)))-alanyl-3 '-etoposide; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-alanyl-3 '-Zorubicin; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-3 '-Zorubicin; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-alanyl-21-tetrahydrochysene S; And β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-alanyl-21-hydrocortisone.Embodiment 24-(imidazolyl-carbonyl-imino--N-methyl-4,2-pyrrolylcarbonyl imino-(N-methyl-4,2-pyrrolylcarbonyl imino-))-1, the 7-naphthalene disulfonic acid disodium salt
With compound 4-(amino-N-methyl-4,2-pyrrolylcarbonyl-imino-(N-methyl-4,2-pyrrolylcarbonyl imino-)-1,7-naphthalene disulfonic acid disodium salt hydrochloride (628mg=1mmol) is dissolved in dimethyl formamide (70ml) and the triethylamine (0.14ml=1mmol).Above-mentioned solution was added drop-wise to N in 3 hours, in dimethyl formamide (40ml) solution of N '-carbonyl dimidazoles (648mg=4mmol), and whole at room temperature the stirring 2 hours.Vacuum evaporating solvent is to doing, and residuum is handled with acetone (200ml), and restir 1 hour also filters, and obtains title compound (740mg).
1H-NMR (200MHz; DMSO-d
6) δ: 3.86,3.90 (two-s, 6H, 2-NCH
3), 7.0-7.4 (m, 5H, 4H pyrroles
), 7.50 (d, J=7.9Hz, 1H, 3), 7.6-8.1 (m, 4H, 6+5+2+
), 8.36 (s, 1H,
), 9.20 (s, 1H, 8), 10.05,10.09,10.3 8 (3-CONH) .F.A.BMS:m/z 662, M-Na for three-s, 3H; 594. embodiment 3 β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-2 ' taxol [FCE28403]
(press J.Med.Chem.32 to 2 ' succinyl taxol (165mg=0.173mmol); the described preparation of 788-792 (1989)) adds N in dimethyl formamide (15ml) solution; N ' dicyclohexyl carbodiimide (71mg=0.345mmol), and with mixture stirring 1 hour.Add compound 4-(amino-N-methyl-4 again, 2-pyrrolylcarbonyl-imino-(N-methyl-4,2-pyrrolylcarbonyl imino-)-1,7-naphthalene disulfonic acid disodium salt hydrochloride (155mg=0.247mmol) and 4-Dimethylamino pyridine (30mg=0.247mmol), and whole at room temperature the stirring 20 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 3: 1 mixture is made eluent, obtains the 180mg title compound.
1H-NMR (400MHz, DMSO ,-d
6) δ: 0.98 (S, 3H, 17), 1.01 (S, 3H, 16), 1.47 (S, 3H, 19), 1.4-1.9 (m, 3H, CH
2-14+6 β), 1.76 (S, 3H, 18), 2.08,2.23 (two-s, 6H, CH
3CO-4+CH
3CO-10), 2.30 (m, 1H, 6 α), 2.5-2.8 (m, 4H, OCOCH
2CH
2CO), 3.56 (d, J=7.0Hz, 1H, 3), 3.82,3.84 (three-s, 6H, 2-NCH
3), 3.9-4.2 (m, 3H, CH
2-20+7), 4.61 (s, 1H, OH-1), 4.9 (m, 1H, OH-7+5), 5.35 (d, J=9.0Hz, 1H, 2 '), 5.39 (d, J=7.0Hz, 1H, 2), 5.53 (t, J=9.0Hz, 1H, 3 '), 5.81 (m, 1H, 13), (6.27 s, 1H, 10), 6.85 (d, J=1.7Hz, 1H, the pyrroles), 7.1-8.0 (m, 22H, 3H-pyrroles+3-
+ 2 "+3 "+5 "+6 "), 9.18 (d, J=1.5Hz, 8 "), 9.23 (d, J=9.0Hz, 1H, NH-4 '), 9.92,9.96,10.02 (three-s, 3H, 3-CONH).
Can obtain following compounds: β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-2 '-taxol [FCE28722] with similar approach; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-2 ' (7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-20-camptothecine; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-20-(9-amino) camptothecine; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-3 '-etoposide; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-14-(3 '-methoxyl group morpholino)-Zorubicin; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-propionyl-1-benzoyl carbinol; And β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)))-propionyl-21-hydrocortisone.Embodiment 47-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrroles-carbonyl (N-methyl-4,2-pyrrolylcarbonyl imino-))-1,3,5-naphthalene trisulfonic acid trisodium salt
With compound 7-(4-amino-N-methyl-2-pyrrolylcarbonyl-imino-(N-methyl-4,2-pyrrolylcarbonyl imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt hydrochloride (800mg=1.096mmol) is dissolved in dimethyl formamide (80ml) and triethylamine (0.15ml=1.096mmol).In 3 hours, this drips of solution is added to N, and N '-carbonyl dimidazoles (736mg=4, in dimethyl formamide 384mmol) (60ml) solution, whole then at room temperature the stirring 4 hours.Vacuum evaporating solvent is to doing, and residuum is handled with acetone (250ml), and restir 1 hour also filters, and obtains title compound (830mg).
1H-NMR (200MHz; DMSOd
6) δ: 3.88,3.89 (two is unimodal, 6H, 2-NCH
3); (7.0-7.4 m, 5H, 2-pyrroles+1H imidazoles); (7.79 s, 1H, imidazoles); (8.2-8.4 m, 3H, 6+2+1H imidazoles); 8.9-9.2 (m, 2H, 8+4); 10.04,10.22,10.38 (three is unimodal, 3H, 3-CONH).
Obtain following compounds with similar approach: 4-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl-imino-)-1,7-naphthalene disulfonic acid disodium salt.
1H-NMR (200MHz, DMSO-d
6) δ: 3.88 (s, 3H, NCH
3); (7.07 m, 1H, imidazoles); 7.23,7.29 (two doublets, J=1.9Hz, 2H, pyrroles); (7.48 d, J=7.7Hz, 1H, 3); (7.71 dd, J=7.8Hz, J=1.8Hz, 1H, 6); (7.80 t, J=1.3Hz, 1H, imidazoles); (7.89 d, J=7.8Hz, 1H, 5); (7.97 d, J=7.7Hz, 1H, 2); (8.36 m, 1H, imidazoles); (9.19 d, J=l.8Hz, 1H, 8); 10.06 10.41 (two is unimodal, 2H, 2-CONH) .7-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl-imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt.
1H-NMR (200MHz, DMSO-d
6) δ: 3.91 (s, 3H, NCH
3); (7.06 m, 1H, imidazoles); 7.23,7.26 (two doublets, J=1.9Hz, 2H, pyrroles); (7.80 t, J=1.5Hz, 1H, imidazoles); (8.2-8.4 m, 3H, 6+2+1H imidazoles); 9.0,9.11 (two multiplets, 2H, 8+4); 10.23 10.37 (two is unimodal, 2H, 2-CONH) .8-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl-imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt.Embodiment 5N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))-β-alanyl-2 '-taxol [FCE28721]
In dimethyl formamide (8ml) solution of 2 ' (β-alanyl) taxol formate (97mg=0.1mmol), add 4-Dimethylamino pyridine (12mg=0.1mmol) and 7-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl (N-methyl-4,2-pyrrolylcarbonyl imino-))-1,3,5-naphthalene trisulfonic acid trisodium salt (95mg=0.12mmol), whole then at room temperature the stirring 12 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 1: 1 mixture is made eluent, obtains the 90mg title compound.
1H-NMR (400 MHz, DMSO-d
6) δ: 0.99 (s, 3H, 17); (1.01 s, 3H, 16); (1.49 s, 3H, 19); 1.80s, 3H, 18); 1.5-1.9 (m, 3H, CH
2-14+61H β); 2.09 2.22 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); (2.30 m, 1H, 6 α); 2.60 (m, 2H, NHCH
2CH
2CO); 3.30 (m, 2H, NHCH
2CH
2CO); (3.58 d, J=7.3Hz, 1H, 3); 3.81 3.88 (two is unimodal, 6H, 2-NCH
3); 3.98,4.01 (two doublets, J=8.5Hz, 2H, CH
2-20); (4.11 m, 1H, 7); 4.62 (s, 1H, OH-1); 4.89 (m, 2H, 5+OH-7); 5.34 (d, J=8.5Hz, 1H, 2 '); (5.41 d, J=7.3Hz, 1H, 2); 5.5 (dd, J=8.5Hz, J=8.5Hz, lH, 3 '); (5.83 m, 1H, 13); 6.06 (m, 1H, NHCONHCH
2); (6.29 s, 1H, 10); 6.72,6.94 (two doublets, J=1.8Hz, 2H, pyrroles); 7.19,7.33 (two doublets, J=1.5Hz, 2H, pyrroles); 7.1,8.0 (m, 15H, 3-Ph); 8.20 (s, 1H, NHCONHCH
2); (8.30 d, J=1.8Hz, 1H, 2 "); (8.37 d, J=2.4Hz, 1H, 6 "); 9.00,9.15 (two multiplets, 2H, 8 "+4 "); (9.22 d, J=8.5Hz, 1H, NH-4 '); 9.77,10.17 (two is unimodal, 2H, 2-CONH). embodiment 6 β-(4-carbonyl imido acyl; the N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl; 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))) propionyl-2 '-taxol [FCE28722]
Add N in dimethyl formamide (10ml) solution of 2 '-succinyl--taxol (95mg=0.1mmol), N ' dicyclohexyl carbodiimide (41mg=0.2mmol) stirs whole mixture 1 hour then.Add compound 7-(4-amino, N-methyl-2-pyrrolylcarbonyl-(4-imino-, N-methyl again, 2-pyrrolylcarbonyl imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt hydrochloride (80mg=0.11mmol) and 4-Dimethylamino pyridine (18mg=0.15mmol), and stirring at room 20 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 1: 1 mixture is made eluent, obtains the 120mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ: 0.98 (s, 3H, 17); (1.00 s, 3H, 16); (1.47 s, 3H, 19); (1.76 s, 3H, 18); 2.08 2.23 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); 1.4-2.4 (m, 4H, CH
2-14+CH
2-6); 2.5-2.8 (m, 4H, COCH
2CH
2CO); (3.56 d, J=7.0Hz, 1H, 3); 3.82 3.87 (two is unimodal, 6H, 2-NCH
3); 3.9-4.2 (m, 3H, 7+CH
2-20); 4.61 (s, 1H, OH-1); 4.90 (m, 2H, OH-7+5); 5.35 (d, J=8.5Hz, 1H, 2 '); (5.39 d, J=7.0Hz, 1H, 2); 5.53 (dd, J=8.5Hz, J=8.5Hz, 1H, 3 '); (5.81 m, 1H, 13); (6.27 s, 1H, 10); 6.81,7.34 (two doublets, J=1.5Hz, 2H, pyrroles); 7.15,7.18 (two doublets, J=1.7Hz, 2H, pyrroles); 7.1-8.0 (m, 15H, 3Ph); (8.29 d, J=1.7Hz, 1H, 6 "); (8.37 d, J=2.0Hz, 1H, 2 "); 8.97,9.13 (two multiplets, 2H, 8 "+4 "); 9.23 (d, J=8.5Hz, 1H, 4 '); 9.92,9.93,10.21 (three is unimodal, 3H, 3-CONH). embodiment 7N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt))-β-alanyl-2 '-taxol [FCE28745]
In dimethyl formamide (25ml) solution of 2 ' (β-alanyl) taxol formate (291mg=0.3mmol), add 4-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl imino-)-1,7-naphthalene disulfonic acid disodium salt (286mg=0.5mmol), whole then stirring at room 20 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 2: 1 mixture is made eluent, obtains the 250mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ: 0.99 (s, 3H, 17); (1.01 s, 3H, 16); (1.48 s, 3H, 19); 1.4-1.9 (m, 3H, CH
2-14+6 β); (1.80 s, 3H, 18); 2.09 2.23 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); (2.31 m, 1H, 6 α); 2.60 (m, 2H, OCOCH
2CH
2NH); 3.2-3.5 (m, 2H, OCOCH
2CH
2NH); (3.58 d, J=7.3Hz, 1H, 3); 3.79 (s, 1H, NCH
3); 3.9-4.2 (m, 3H, CH
2-20+7); 4.64 (s, 1H, OH-1); 4.91 (m, 2H, 5+OH-7); 5.34 (d, J=8.5Hz, 1H, 2 '); (5.40 d, J=7.3Hz, 1H, 2); 5.54 (dd, J=8.5Hz, J=8.5Hz, 1H, 3 '); (5.82 m, 1H, 13); 6.09 (t, J=6.0Hz, 1H, OCOCH
2CH
2NH); (6.29 s, 1H, 10); (6.93-7.02 two doublets, J=1.9Hz, 2H, pyrroles); (7.1-8.0 m, 19H, 3-ph+3 "+6 "+5 "+2 "); 8.26 (s, 1H, NHCONHCH
2); (9.18 d, J=1.8Hz, 1H, 8 "); (9.25 d, J=8.5Hz, 1H, NH-4 '); 9.88 (s, 1H, the pyrroles-CONH).
Can obtain following compounds: N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))-β-alanyl-2 '-taxol [FCE28746] with similar approach.
1H-NMR (400MHz, DMSO-d
6) δ: 0.99 (s, 3H, 17); (1.01 s, 3H, 16); (1.48 s, 3H, 19); (1.80 s, 3H, 18); 1.4-1.9 (m, 3H, CH
2-14+6 β); 2.09 2.23 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); (2.30 m, 1H, 6 α); 2.60 (m, 2H, OCOCH
2CH
2NH); 3.2-3.5 (m, 2H, OCOCH
2CH
2NH); (3.58 d, J=7.0Hz, 1H, 3); 3.83 (s, 3H, NCH
3); 3.9-4.2 (m, 3H, CH
2-20+7); 4.64 (s, 1H, OH-1); 4.90 (m, 2H, 5+OH-7); 5.34 (d, J=8.5Hz, 1H, 2 '); (5.40 d, J=7.0Hz, 1H, 2); 5.54 (dd, J=8.5Hz, J=8.5Hz, 1H, 3 '); (5.82 m, 1H, 13); 6.12 (m, 1H, OCOCH
2CH
2NH); (6.29 s, 1H, 10); 6.91,7.01 (two doublets, J=1.8Hz, 2H, pyrroles); 7.1-8.0 (m, 15H, 3-Ph); 8.22 (s, 1H, NHCONHCH
2); (8.26 d, J=1.8Hz, 1H, 2 "); (8.34 d, J=2.3Hz, 1H, 6 "); 8.94,9.10 (two multiplets, 2H, 8 "+4 "); (9.27 d, J=8.5Hz, 1H, NH-4 '); 10.02 (s, 1H .N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))-β-alanyl-the 2 '-taxol [FCE28842] of pyrroles-CONH).
1H-NMR (400MHz, DMSO-d
6) δ: 1.00 (s, 3H, 17); (1.02 s, 3H, 16); (1.49 s, 3H, 19); (1.81 s, 3H, 18); 1.4-1.9 (m, 3H, CH
2-14+6 β); 2.10 2.24 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); (2.2-2.4 m, 1H, 6 α); 2.60 (m, 2H, OCOCH
2CH
2NH); 3.1-3.3 (m, 2H, OCOCH
2CH
2NH); (3.59 d, J=7.2Hz, 1H, 3); 3.82 (s, 3H, NCH
3); 3.9-4.2 (m, 3H, CH
2-20+7); 4.65 (s, 1H, OH-1); 4.93 (m, 2H, 5+OH-7); 5.34 (d, J=8.5Hz, 1H, 2 '); (5.41 d, J=7.2Hz, 1H, 2); 5.54 (dd, J=8.5Hz, J=8.5Hz, 1H, 3 '); (5.83 m, 1H, 13); 6.02 (t, J=6.0Hz, 1H, OCOCH
2CH
2NH); (6.30 s, 1H, 10); 6.95,7.03 (two doublets, J=1.7Hz, 2H, pyrroles); (7.1-8.1 m, 17H, 3-Ph+7 "+6 "); 8.34 (s, 1H, NHCONHCH
2); (8.61 d, J=2Hz, 1H, 2 "); (9.27 d, J=8.5Hz, 1H, NH-4 '); (9.37 d, J=2.0Hz, 1H, 4 "); 12.20 (s, 1H, the pyrroles-CONH). embodiment 8N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)) phenyl alanyl-leucyl-glycyl-2 '-taxol [FCE29142]
In 2 ' (phenyl alanyl-leucyl-glycyl) taxol (351mg=0.3mmol) dimethyl formamide (20ml) solution (WO94/00156), add 4-Dimethylamino pyridine (36mg=0.3mmol) and 8-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt (333mg=0.5mmol), whole then stirring at room 20 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 2: 1 mixture is made eluent, obtains the 331mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ: 0.81 (d, J=6.5Hz, 3H, δ-Leu); 0.84 (d, J=6.5Hz, 3H, δ '-Leu); (0.99 s, 3H, 17); (1.01 s, 3H, 16); (1.48 s, 3H, 19); (1.79 s, 3H, 18); 1.4-1.9 (m, 6H, CH
2-14+6 β+γ Leu+ β, β ' is Leu); 2.09 2.21 (two is unimodal, 6H, CH
3CO-4+CH
3CO-10); (2.32 m, 1H, 6 α); (2.81 dd, J=7.9Hz, J=13.7Hz, 1H, β Phe); 2.99 (dd, J=4.1Hz, J=13.7Hz, 1H, β ' is Phe); (3.57 d, J=8.2Hz, 1H, 3); 3.78 (s, 3H, NCH
3); 3.8-4.2 (m, 5H, α, α ' Gly+CH
2-20+7); (4.38 m, 1H, α Leu); (4.48 m, 1H, α Phe); 4.61 (s, 1H, OH-1); 4.90 (m, 2H, OH-7+5); (5.40 m, 2H, 2 '+2); 5.51 (dd, J=8.5Hz, J=8.5Hz, 1H, 3 '); (5.84 m, 1H, 13); 6.03 (d, J=7.9Hz, 1H, NH-Phe); (6.29 s, 1H, 10); (6.91-7.00 two doublets, J=1.9Hz, 2H, 3 +5 ); (7.1-8.1 m, 22H, 4ph+6 "+7 "); 8.15 (d, J=8.5Hz, 1H, NH-Leu); 8.39 (t, J=6.0Hz, 1H, NH-Gly); (8.50 s, 1H, NH-4 ); (8.60 d, J=2.0Hz, 1H, 7 "); 9.26 (d, J=8.2Hz, 1H, NH-4); (9.36 d, J=2.0Hz, 1H, 4 "); 12.18 (s, 1H, NH-8 "). embodiment 93 '-N-succinyl-daunorubicin
With daunorubicin (100mg, 0.177mmol) and succinyl oxide (21.2mg 0.212mmol) is dissolved in the anhydrous methylene chloride (20ml), add then triethylamine (123 μ l, 0.885mmol), and whole under room temperature and nitrogen, the stirring 2.5 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: methyl alcohol is that 7: 3 mixture is made eluent, obtains the 120mg title compound.Embodiment 103-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))) propionyl-3 '-N-daunorubicin [FCE28854]
(87mg, 0.139mmol) and 1, (22.5mg 0.139mmol) is dissolved in the dimethyl formamide (10ml) the 1-carbonyl dimidazoles, and wholely stirs 8 hours under room temperature and nitrogen with compound 3 '-N-succinyl-daunorubicin.Add compound 7-(amino-N-methyl-4,2-pyrrolylcarbonyl imino--(N-methyl-4,2-pyrrolylcarbonyl imino-))-1 again, 3-naphthalene disulfonic acid disodium salt hydrochloride (109mg, 0.139mmol) and the 4-Dimethylamino pyridine (18.3mg 0.15mmol), and stirs whole mixture and spends the night.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of LiChroprep RP-8 post purifying, and water: acetonitrile is that 4: 1 mixture is made eluent, obtains the 57mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ: 1.12 (d, J=6.6Hz, 3H, CH
3-6 '); 1.42 (dd, J=4.5Hz, J=12.1Hz, 1H, 2 ' eq); 1.84 (m, 1H, 2 ' ax); 2.1-2.3 (m, 2H, CH
2-8); 2.25 (s, 1H, COCH
3); 2.3-2.5 (m, 4H, COCH
2CH
2CO); 2.92,2.98 (two doublets, J=18.2Hz, 2H, CH
2-10); 3.40 (m, 1H, 4 '); 3.86 3.80 (two is unimodal, 6H, 2-NCH
3); 3.97 (s, 3H, OCH
3); 3.95 (m, 1H, 3); 4.17 (q, J=6.6Hz, 1H, 5 '); (4.73 d, J=5.9Hz, 1H, OH-4 '); (4.93 m, 1H, 7); 5.22 (d, J=3.1Hz, 1H, 1 '); 5.54 (s, 1H, OH-9); 6.81,7.12,7.14,7.31 (four doublets, J=1.7Hz, 4H, pyrroles); (7.60 d, J=8.0Hz, 1H, NH-3 '); (7.64 m, 1H, 3); (7.90 m, 4H, 1+2+5 "+6 "); (8.00 d, J=1.8Hz, 1H, 4 "); (8.22 d, J=1.8Hz, 1H, 2 "); (8.90 d, J=1.8Hz, 1H, 8 "); 9.81,9.90,10.21 (three is unimodal, 3H, 3-CONH); 13.29 14.04 (two is unimodal, 2H, OH-6+OH-11) .F.A.B MS:m/z1178, M
--Na embodiment 1120-O-(carbobenzoxy-(Cbz)-β-alanyl) camptothecine
With carbobenzoxy-(Cbz)-Beta-alanine (3.2g, 14.34mmol) and the 4-Dimethylamino pyridine (3.5g 28.68mmol) is dissolved in the anhydrous chloroform (30ml), drip in nitrogen and when stirring oxalyl chloride (1.24ml, 14.34mmol).After 45 minutes, under the situation of ingress of air not, above-mentioned crude product mixture is added to camptothecine (2.5g, 7.17mmol) and the 4-Dimethylamino pyridine (875mg, 7.17mmol) 1, in 2-ethylene dichloride (100ml) suspension, whole then under nitrogen, the stirring 2 hours.Reaction soln dilutes with methylene dichloride (100ml), and water (200ml) washing.Separate organic phase, drying, removal of solvent under reduced pressure.Residuum obtains the 3.47g title compound from ethanol (150ml) recrystallization.
1H-NMR (200MHz; DMSO d
6) δ: 0.95 (t, 3H, CH
3CH
2); 2.15 (q, 2H, CH
3CH
2); 2.75 (m, 2H, NHCH
2CH
2COO); 3.3 (m, 2H, NHCH
2CH
2COO); 5.0 (s, 2H, PhCH
2); 5.25 (s, 2H, CH
2-5); 5.5 (s, 2H, CH
2-17); (7.1 s, 1H, 14); 7.2-7.4 (m, 6H, Ph+NH); (7.7 m, 1H, 10); (7.85 m, 1H, 11); 8.15 (m, 2H, 12+9); (8.65 s, 1H, 7). embodiment 1220-O-(β-alanyl) camptothecine formate
(3.0g adds 5%Pd/C (1.0g) in methyl alcohol 5.42mmol) (170ml) and formic acid (100ml) solution, and is whole then 40 ℃ of stirrings 4 hours to 20-O-(carbobenzoxy-(Cbz)-β-alanyl) camptothecine.Filter reaction mixture, vacuum evaporating solvent obtains the 2.5g title compound to doing.
1H-NMR (200MHz; DMSO d
6) δ: 0.95 (t, 3H, CH
3CH
2); 2.15 (q, 2H, CH
3CH
2); 2.7-3.1 (m, 4H, NHCH
2CH
2COO); 5.3 (s, 2H, CH
2-5); 5.5 (s, 2H, CH
2-17); (7.15 s, 1H, 14); (7.7 m, 1H, 10); (7.85 m, 1H, 11); 8.15 (m, 2H, 12+9); 8.3 (bs, 1H, HCO
2H); (8.7 s, 1H, 7). embodiment 13N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-β-alanyl-20-O-camptothecine [FCE28855]
With compound 20-O-(β-alanyl) camptothecine formate (200mg, 0.43mmol) and 4-(imidazolyl-carbonyl-imino--N-methyl-4,2-pyrrolylcarbonyl imino-(N-methyl-4,2-pyrrolylcarbonyl imino-))-1,7-naphthalene disulfonic acid disodium salt (354mg, 0.516mmol) be dissolved in dimethyl formamide (10ml), wholely then under room temperature and nitrogen, stirred 8 hours.Removal of solvent under reduced pressure, residuum is handled with methylene dichloride (30ml), stirs 30 minutes, filters and obtains crude product.At the enterprising circumstances in which people get things ready for a trip spectrum of LiChroprepRP-8 post purifying, eluent system is the gradient of A to B with it, and A is a water, and B is a water: acetonitrile (85: 15) obtains the 165mg title compound.
1H-NNR (400MHz; DMSO d
6) δ: 0.9 (t, J=7.4Hz, 3H, CH
3CH
2); 2.16 (q, J=7.4Hz, 2H, CH
3CH
2); 2.73 (m, 2H, NHCH
2CH
2COO); 3.30 (m, 2H, NHCH
2CH
2COO); 3.76 3.84 (two is unimodal, 6H, 2-NCH
3); 5.30 (s, 2H, CH
2-5); 5.49 (s, 2H, CH
2-17); 6.03 (t, J=6.0Hz, 1H, NHCH
2CH
2COO); 6.68,6.86,7.18,7.35 (four doublets, J=1.7Hz, 4H, pyrroles); (7.10 s, 1H, 14); 7.49 (d, J=7.8Hz, 1H, 3 '); (7.68 m, 2H, 10+6 '); (7.81 m, 1H, 11), 7.89 (d, J=8.8Hz, 1H, 5 '); 7.96 (d, J=7.8Hz, 1H, 2 '); 8.09 (m, 2H, 12+9); 8.19 (s, 1H, CH
2NHCONH); (8.68 s, 1H, 7); 9.18 (d, J=1.5Hz, 1H, 8 '); 8.79 10.00 (two is unimodal, 2H, 2-CONH) .F.A.B MS:m/z991, M
--2Na+H; 1013, M
--Na
Can obtain following compounds: N-(4-carbonyl imino-with similar approach, the N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid disodium salt)))-phenyl alanyl-leucyl-glycyl-20-O-camptothecine.Embodiment 14O-(N-trityl-phenyl alanyl-leucyl-glycyl) benzoyl carbinol
To phenacylate (408mg, add 4-dimethylamino-pyridine (244mg in pyridine 3mmol) (20ml) solution, 2mmol) (1398mg, 2mmol), and whole backflow was stirred 6 hours with N-trityl-phenyl alanyl-leucyl-glycyl-4-nitrophenyl ester.Reaction mixture dilutes with ethyl acetate, with dilute hydrochloric acid (0.5N) and water washing, anhydrous sodium sulfate drying.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and eluent is an ethyl acetate: hexane 1: 1 obtains the 930mg title compound.Embodiment 15O-(phenyl alanyl-leucyl-glycyl) benzoyl carbinol
Compound O-(N-trityl-phenyl alanyl-leucyl-glycyl) benzoyl carbinol (930mg) is dissolved in the mixture of Glacial acetic acid (110ml) and water (25ml), whole then stirring at room 1.5 hours.Vacuum evaporating solvent is to doing, and residuum is dissolved in ethyl acetate, with dilution with toluene and evaporation, obtains the 606mg title compound again.
1H-NMR (200MHz, CDCl
3): δ 0.89,0.91 (two doublets, J=6.1Hz, 6H, δ+δ ｀-Leu); 1.4-1.8 (m, 3H, β+β ｀+γ-Leu); 2.72 (dd, J=9.0,13.6Hz, 1H, β-Phe); 3.20 (dd, J=4.0,13.6Hz, 1H, β ｀-Phe); 3.68 (dd, J=4.0,9.0Hz, 1H, α-Phe); 4.0-4.4 (m, 2H, α+α ｀-Gly); 4.52 (m, 1H, α-Leu); 5.37 (s, 2H, COOCH
2); 7.0-8.0 (m, 12H, 2-Ph+NH-Leu+NH-Gly). embodiment 16N-(4-carbonyl imino-; the N-methyl; 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)) phenyl alanyl-leucyl-glycyl-O-benzoyl carbinol [FCE29378]
In dimethyl formamide (100ml) solution of O-(phenyl alanyl-leucyl-glycyl) benzoyl carbinol (600mg), add 4-Dimethylamino pyridine (160mg) and 8-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl imino-)-1; 3; 5-naphthalene trisulfonic acid trisodium salt (1068mg), whole then stirring at room 20 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: 2: 1 wash-outs of methyl alcohol obtain the 702mg title compound.
1H-NMR (400MHz, DMSO-d
6) δ: 0.83,0.87 (two d, J=6.6Hz, 6H, δ+δ ｀-Leu); 1.4-1.7 (m, 3H, β+β ｀+γ-Leu); 2.80 (dd, J=7.7,13.5Hz, 1H, β-Phe); 3.1 (dd, J=4.8,13.5Hz, 1H, β ｀-Phe); 3.80 (s, 3H, NCH
3); 3.9-4.1 (m, 2H, α+α ｀-Gly); 4.38 (m, 1H, α-Leu); 4.47 (m, 1H, α-Phe); 5.50,5.53 (two d, J=17.3Hz, 2H, COOCH
2CO); 6.03 (d, J=8.1Hz, 1H, NH-Phe); 6.91,7.01 (two d, J=1.6Hz, 2H, 3 '+5 '); 7.1-8.0 (m, 10H, 2-Ph); 8.00,8.05 (two d, J=8.3Hz, 2H, 6+7); 8.18 (d, J=8.4 Hz, 1H, NH-Leu); 8.37 (t, J=5.9Hz, 1H, NH-Gly); (8.49 s, 1H, NH-4 '); (8.60 d, J=2.0Hz, 1H, 2); (9.36 d, J=2.0Hz, 1H, 4); 12.18 (s, 1H, NH-1).
Can obtain following compounds: N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)) phenyl alanyl-leucyl-glycyl-β-third chlorine acyl-O-benzoyl carbinol with similar approach.Embodiment 1721-(N-trityl-phenyl alanyl-leucyl-glycyl) hydrocortisone
To hydrocortisone (362mg, add 4-Dimethylamino pyridine (122mg in pyridine 1mmol) (15ml) solution, 1mmol) and N-trityl-phenyl alanyl-leucyl-glycyl-4-nitrophenyl ester (769mg 1.1mmol), wholely then stirred 3 hours at 100 ℃.Reaction mixture dilutes with ethyl acetate, with dilute hydrochloric acid (0.5N) and water washing, and uses anhydrous sodium sulfate drying.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use ethyl acetate: 3: 1 wash-outs of hexane obtain the 750mg title compound.
1H-NMR (400MHz, DMSO-d
6): δ 0.75 (s, 3H, 18); 0.83,0.86 (two d, J=6.4 Hz, 6H, δ+δ ｀-Leu); (1.35 s, 3H, 19); 2.76 (d, J=8.8Hz, NH-Phe); 3.40 (m, 1H, α-Phe); 3.7-4.0 (m, 3H, α-Leu+ α, α ｀-Gly); (4.24 m, 1H, 11); 4.31 (d, J=3.8Hz, 1H, OH-11); 4.74,5.13 (two d, J=17.6Hz, 2H, CH
2-21); 5.39 (s, 1H, OH-17); (5.54 s, 1H, 4); 7.0-7.4 (m, 20H, 4-Ph); 7.65 (d, J=7.6Hz, 1H, NH-Leu); 8.18 (t, J=6.0Hz, 1H, NH-Gly). embodiment 1821-(phenyl alanyl-leucyl-glycyl) hydrocortisone
With the mixture of the Glacial acetic acid (115ml) of 21-(N-trityl-phenyl alanyl-leucyl-glycyl) hydrocortisone (750mg) and water (25ml) stirring at room 3 hours.Vacuum evaporating solvent is dissolved in methyl alcohol to doing with residuum, with dilution with toluene and evaporation.Residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use ethyl acetate: 5: 1 wash-outs of methyl alcohol obtain the 400mg title compound.F.A.B.MS:m/z678, M-H.
1H-NMR (400MHz, DMSO-d
6): δ 0.74 (s, 3H, 18); 0.83,0.85 (two d, J=6.2Hz, 6H, δ+δ ｀-Leu); (1.34 s, 3H, 19); 2.61 (dd, J=8.5,13.5Hz, 1H, β-Phe); 2.93 (dd, J=4.4,13.5Hz, 1H, β ｀-Phe); 3.42 (dd, J=4.4,8.5Hz, 1H, α-Phe); 3.87 (dd, J=6.0,17.6Hz, 1H, α-Gly); 3.96 (dd, J=6.0,17.6Hz, 1H, α ｀-Gly); (4.25 m, 1H, 11); 4.36 (m, 2H, OH-11+ α-Leu); 4.76,5.13 (two d, J=17.6Hz, 2H, CH
2-21); 5.42 (s, 1H, OH-17); (5.54 s, 1H, 4); 7.1-7.3 (m, 5H, Ph); 7.95 (d, J=7.8Hz, 1H, NH-Leu); 8.38 (t, J=6.0Hz, 1H, NH-Gly). embodiment 1921-(N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)) phenyl alanyl-leucyl-glycyl) hydrocortisone [FCE29603]
To 21-(phenyl alanyl-leucyl-glycyl) hydrocortisone (400mg, 0.59mmol) dimethyl formamide (30ml) solution in add 4-Dimethylamino pyridine (72mg, 0.59mmol) and 8-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt (609mg, 0.915mmol), whole then stirring at room 6 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: 2: 1 wash-outs of methyl alcohol obtain the 390mg title compound.F.A.B.MS:m/z1010, M-H (as free acid).
1H-NMR (400MHz, DMSO-d
6): δ 0.76 (s, 3H, 18); 0.83,0.87 (two d, J=6.6Hz, 6H, δ+δ ｀-Leu); (1.34 s, 3H, 19); 2.80 (dd, J=8.0,13.9Hz, 1H, β-Phe); 3.00 (dd, J=4.4,13.9Hz, 1H, β ｀-Phe); 3.80 (s, 3H, NCH
3); 3.87 (dd, J=17.6,6.1Hz, 1H, α-Gly); 4.00 (dd, J=17.6,6.1Hz, 1H, α ｀-Gly); (4.24 m, 1H, 11); 4.35 (m, 2H, OH11+ α-Leu); 4.46 (m, 1H, α-Phe); 4.77,5.14 (two d, J=17.6Hz, 2H, CH
2-21); 5.43 (s, 1H, OH-17); (5.54 s, 1H, 4); 6.02 (d, J=7.7Hz, 1H, NH-Phe); 6.90,7.00 (two d, J=1.8Hz, 2H, 3 '+5 '); 7.1-7.3 (m, 5H, Ar-Phe); 8.00,8.04 (two d, J=8.4Hz, 2H, 6 "+7 "); 8.16 (d, J=8.4Hz, 1H, NH-Leu); 8.31 (t, J=6.1Hz, 1H, NH-Gly); (8.48 s, 1H, CONH-4 '); (9.61 d, J=1.8Hz, 1H, 2 "); (9.38 d, J=1.8Hz, 1H, 4 "); 12.17 (s, 1H, CONH-8 "). embodiment 20Tallimustine amidoxim
500mgtallimustine (is pressed J.Med.Chem.32, the described method preparation of 774-778) 20mlDMF solution is 60 ℃ of heating, and handle with the 1M DMF of 0.68ml azanol, from hydroxylamine hydrochloride (70mg), obtain in 10% water of 0.139ml triethylamine and 1mlDMF.After 30 minutes, add the 1M DMF of 1 equivalent azanol.To doing, (methylene dichloride: methyl alcohol 85: 15), obtain the 400mg title compound is white solid to residuum with purification by flash chromatography with solution evaporation.F.A.B.MS:m/z713, M+H; 244.
1H-NMR (200MHz, DMSO-d
6): δ 2.20 (m.2H); 3.32 (m, 2H); 3.79 (s, 3H); 3.83 (s, 3H); 3.85 (s, 3H); 3.90-3.70 (m, 8H); 5.40 (bs, 2H); 6.82 (m, 2H); 6.83 (d, J=1.7Hz, 1H); 7.4 (d, J=1.7Hz, 1H); 7.6 (d, J=1.7Hz, 1H); 7.17 (d, 1.7Hz, 1H); 7.23 (d, 1.7Hz, 1H); 7.28 (d, J=1.7Hz, 1H); 7.83 (m, 2H); 7.87 (t, J=5.7Hz, 1H); 8.82 (s, 1H); 9.86 (s, 1H); 9.92 (s, 1H); Embodiment 21O-(N-trityl-phenyl alanyl-leucyl-glycyl) tallimustine amidoxim
To tallimustine amidoxim (250mg, 0.35mmol) dimethyl formamide (9ml) solution in add 4-Dimethylamino pyridine (48mg, 0.35mmol) and N. trityl-phenyl alanyl-leucyl-glycyl-4-nitrophenyl ester (315mg, 0.45mmol), whole then stirring at room 4 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: 28: 2 wash-outs of methyl alcohol obtain the 357mg title compound.Embodiment 22O-(phenyl alanyl-leucyl-glycyl) tallimustine amidoxim
With the mixture of the Glacial acetic acid (28ml) of O-(N-trityl-phenyl alanyl-leucyl-glycyl) tallimustine amidoxim (314mg) and water (6.5ml) stirring at room 1 hour.Vacuum evaporating solvent is to doing, and residuum is dissolved in methyl alcohol, with dilution with toluene and evaporation, obtains the thick compound of 254mg.F.A.B.MS:m/z1031, M+H; 697, M-(O-GlyLeu-Phe)+2H; 336; 261; 244.
1H-NMR (400MHz, DMSO-d
6): δ 0.83,0.86 (two doublets, J=6.4Hz, 6H, δ+δ '-Leu); 1.3-1.5 (m, 3H, β+β '+γ-Leu); 2.31 (t, J=7.5Hz, 2H, CONHCH
2CH
2); 2.63 (dd, J=13.3,8.2Hz, 1H, β-Phe); 2.94 (dd, J=13.3,4.4Hz, 1H, β '-Phe); 3.2-3.4 (m, 3H, CONHCH
2CH
2+ α-Phe); 3.6-4.0 (m, 19H, 3-NCH
3+ α, α '-Gly+N (CH
2CH
2Cl)
2); 4.36 (m, 1H, α-Leu); 6.45 (bs, 2H, NH
2); (6.7-7.4 m, 13H, 6H pyrroles+Ar-Phe+2H Ph); 7.85 (m, 2H, Ph); 8.03 (m, 2H, NH-Leu+CONHCH
2CH
2); 8.33 (t, J=5.9Hz, 1H, NH-Gly); 9.91,9.95,10.02 (three is unimodal, 3H, 3-CONH). embodiment 23N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt)) phenyl alanyl-leucyl-glycyl)-the O-tallimustine amidoxim
To O-(phenyl alanyl-leucyl-glycyl) tallimustine amidoxim (254mg, 0.246mmol) dimethyl formamide (30ml) solution in add 4-Dimethylamino pyridine (30mg, 0.246mmol) and 8-(4-(imidazolyl-carbonyl-imino-)-N-methyl-2-pyrrolylcarbonyl imino-)-1,3,5-naphthalene trisulfonic acid trisodium salt (172mg, 0.258mmol), whole then 50 ℃ of stirrings 4 hours.Vacuum evaporating solvent is to doing, and residuum is at the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column purifying, and use methylene dichloride: 7: 3 wash-outs of methyl alcohol obtain the 240mg title compound.F.A.B.MS:m/z1561, M-H (as free acid).
1H-NMR (400MHz.DMSO-d
6): δ 0.83,0.87 (two doublets, J=6.6Hz, 6H, δ+δ '-Leu); 1.4-1.7 (m, 3H, β+β '+γ-Leu); 2.31 (t, J=7.5Hz, 2H, CONHCH
2CH
2); 2.81 (dd, J=13.7,8.0Hz, 1H, β-Phe); 3.00 (dd, J=13.7,4.4Hz, 1H, β '-Phe); 3.3-3.5 (m, 2H, CONHCH
2CH
2); 3.7-4.1 (m, 22H, 4-NCH
3+ α, α '-Gly+N (CH
2CH
2Cl)
2); 4.35 (m, 1H, α-Leu); 4.45 (m, 1H ,+α-Phe); 6.2 (d, J=7.7Hz, 1H, NH-Phe); 6.45 (bs, 2H, NH
2); (6.7-7.3 m, 15H, 8H pyrroles+Ar-Phe+2H Ph); 7.84 (m, 2H, Ph); 7.9-8.1 (m, 3H, CONHCH
2CH
2+ 6+7); 8.18 (d, J=8.4Hz, 1H, NH-Leu); 8.25 (t, J=5.9Hz, 1H, NH-Gly); (8.47 s, 1H, NH-4 '); (8.61 d, J=2.6Hz, 1H, 2); (9.37 d, J=2.6Hz, 1H, 4); 9.88,9.92,10.0,12.2 (four are unimodal, 4H, 4-CONH). embodiment 247-(imidazolyl-carbonyl-imino--N-methyl-4,2-pyrrolylcarbonyl imino-)-1,3-naphthalene disulfonic acid di-potassium
Under nitrogen and room temperature, within an hour to the N that stirs, N '-carbonyl dimidazoles (1.48g, 9.14mmol) dimethyl formamide (5ml) solution in drip 7-(4-amino-N-methyl-2-pyrrolylcarbonyl imino-)-1,3-naphthalene disulfonic acid di-potassium (458mg, dimethyl formamide 0.914mmol) (5ml) solution.3.5 after hour, the concentrating under reduced pressure reaction mixture adds acetone (100ml) then to 3ml.Leach solid precipitation and use washing with acetone, obtaining the 476mg title compound is pink powder.
1H-NMR (200MHz, DMSO-d
6): δ 3.95 (s, 3H); 7.1 (m, 1H); 7.25 (d, 1H); 7.3 (d ' 1H); 7.8 (t, 1H); 7.9 (m, 2H); 8.0 (m, 1H); 8.25 (d, 1H); 8.4 (m, 1H); 8.95 (bs, 1H); 10.3 (bs ' 1H); 10.4 (bs ' 1H). embodiment 25N-myristoyl imidazoles
To tetradecanoic acid (1.0g divides small quantities of N of adding in ethyl acetate 4.38mmol) (10ml) solution, N '-carbonyl dimidazoles (697g, 4.3mmol).Whole at room temperature stir 2 hours after, CO
2Release stops, and observes the white crystalline solid precipitation.Leach solid,, obtain the 566mg title compound with ethyl acetate (a few ml) washing and dry.
1H-NMR (200MHz ' DMSO-d
6): δ 0.85 (t, 3H); 1.1-1.4 (m, 20H); 1.55-1.75 (m, 2H); 3.0 (t, 2H); 7.05 (m ' 1H); 7.7 (t, 1H); 8.4 (m, 1H). embodiment 26 (2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene (C
14-ceramide)
To (2S, 3R, 4E)-1,3-dihydroxyl-2-amino-4-octadecylene (D-ceramide, Fluka, 100mg, 0.334mmol) methylene dichloride (15ml) solution in a collection of adding 93mgN-myristoyl imidazoles (0.334mmol), whole then stirring at room 90 hours.Removal of solvent under reduced pressure, residuum are carried out purification by flash chromatography on silicagel column, use CH
2Cl
2: EtOH95: 5 wash-outs, obtaining the 148mg title compound is white solid.
1H-NMR (200MHz ' CDCl
3): δ 0.75-0.95 (m ' 6H); 1.1-1.5 (m, 40H); 1.5-1.7 (m, 4H); 1.95-2.1 (m ' 2H); 2.2 (t, 2H); 2.7-2.8 (m, 2H); 3.6-3.8 (m, 1H); 3.85-4.0 (m, 2H); 4.25-4.35 (m, 1H); 5.45-5.6 (m, 1H); 5.7-5.85 (m, 1H); 6.2 (d, 1H). embodiment 271-O-(N-trityl-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene
Under nitrogen and room temperature, to (the 2S that stirs, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene (142mg, 0.28mmol) and 4-Dimethylamino pyridine (68mg, 0.56mmol) anhydrous 1, drip in 2-ethylene dichloride (50ml) solution N-trityl-phenyl alanyl-leucyl-glycyl-right-nitrophenyl ester (195mg, 0.28mmol) 1,2-diamino ethane (10ml) solution, and whole stirring 4 days.Removal of solvent under reduced pressure, residuum are carried out purification by flash chromatography on silicagel column, use sherwood oil: 1: 1 wash-out of ethyl acetate, obtaining the 106mg title compound is water white oil.Embodiment 281-O-(phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene
In the mixture of acetate (10ml) and water (2ml), add 1-O-(N-trityl-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene (106mg, 0.1mmol), and whole stirring at room 3 hours.Removal of solvent under reduced pressure, residuum are carried out purification by flash chromatography on silicagel column, use EtOAc: EtOH85: 15 wash-outs, obtaining the 65mg title compound is white solid.
1H-NMR (200MHz, CDCl
3): δ 0.8-1.0 (m, 12H); 1.1-2.1 (three groups of multiplets, 52H); 2.25 (t ' 2H); 2.75 (dd ' 1H); 3.2 (dd, 1H); 3.7 (dd, 1H); 3.8-4.25 (m, 5H); 4.3-4.5 (m, 2H); 5.4-5.5 (m, 1H); 5.65-5.85 (m, 1H); 6.5 (d, 1H); 6.95 (t, 1H); 7.15-7.4 (m, 5H); 7.75 (d, 1H). embodiment 291-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl (7-imino--1,3-naphthalene disulfonic acid di-potassium)) phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene [FCE29604A]
With compound 1-O-(phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene (65mg, 0.078mmol) be dissolved in anhydrous dimethyl formamide (10ml), and a collection of adding 7-(imidazolyl-carbonyl imino--N-methyl-4,2-pyrrolylcarbonyl imino-)-1,3-naphthalene disulfonic acid di-potassium (59.5mg, 0.1mmol).Whole stirring at room 2 hours.Removal of solvent under reduced pressure, residuum are carried out purification by flash chromatography on silicagel column, use CH
2Cl
2: MeOH3: 1, be 2: 1 wash-outs then, obtaining the 56mg title compound is white solid.F.A.B.MS:m/z1276, M-2K+H.
1H-NMR (400MHz, DMSO-d
6): δ 0.8-0.9 (m, 12H, δ, δ '-Leu+2-CH
3(CH
2)
11CH
2); 1.1-1-4 (m, 44H, 2-CH
3(CH
2)
11CH
2); 1.4-1.7 (m, 3H, beta, gamma, γ '-Leu); 1.92 (m, 2H, CH
2-6); 2.03 (t, J=7.5Hz, 2H, CH
2CONH-2); 2.82 (dd, J=13.8,7.9Hz, 1H, β-Phe); 3.01 (dd, J=13.8,4.7Hz, 1H, β '-Phe); 3.7-3.9 (m, 4H, α, α '-Gly+2+3); 4.0-4.3 (m, 2H, CH
2-1); 4.36 (m, 1H, α-Leu); 4.50 (m, 1H, α-Phe); 5.00 (d, J=5.3Hz, 1H, OH-3); (5.34 dd, J=6.4,15.5Hz, 1H, 4); (5.56 dt, J=15.5,6.4Hz, 1H, 5); 6.10 (d, J=7.8Hz, 1H, NH-Phe); 6.85-6.9 (two doublets, J=1.8Hz, 2H, 3A+5A); 7.1-7.3 (m, 5H, Ar-Phe); 7.54 (d, J=8.8Hz, 1H, NH-2); 7.84 (d, J=9.1Hz, 1H, 5B); 7.89 (dd, J=9.1,2.0Hz, 1H, 6B); 8.00 (d, J=1.8Hz, 1H, 4B); 8.1-8.3 (m, 3H, 2B+NHGly+NHLeu); 8.31 (s, 1H, NH
A); 8.83 (d, J=2.0Hz, 1H, 8B); 10.02 (s, 1H, NH
B).
Can obtain following compounds: 1-O-(N-(4-carbonyl imino-with similar approach, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid disodium salt))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; And 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid trisodium salt))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene.Embodiment 307-table-taxotere
In toluene (100ml) solution of taxotere (200mg), add 1,8-(diazabicyclo) [5.4.0] 11-7-alkene (4mg), and whole reflux temperature stirring 8 hours.Solution dilutes with ethyl acetate, the rare HCl of organic phase, water and salt water washing.Dry also evaporation is then with silica gel chromatography purifying (ethyl acetate: hexane 3: 1), obtain the 140mg title compound.
1H-NMR (CDCl
3) δ: 3.6 (m, 1H, 7 β). embodiment 31 β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-alanyl-2 '-taxol
With β-(4-carbonyl imino-, the N-methyl, 2-pyrrolylcarbonyl-(4-imino-, the N-methyl, 2-pyrrolylcarbonyl-(4-imino--1, the 7-naphthalene disulfonic acid disodium salt)))-and the water of alanyl-2 '-taxol: ethanol (9: 1) solution is at the enterprising circumstances in which people get things ready for a trip spectrum of Amberlite IR-120 (H) post purifying, and water: ethanol (9: 1) is made eluent.Vacuum evaporated solution obtains title compound to doing.Embodiment 32 intravenous fluid 1-10mg/ml
The intravenous (IV) drug preparation can be made by 500mg compound F 17-hydroxy-corticosterone CE28284 is dissolved in the water for injection (100ml).
Before the transfusion, can be according to standard practice with the solution dilution that obtains, store and/or carry in the equipment of glass, polypropylene, polyolefine or polyethylene-lined.
Use similar approach, also can prepare the intravenous (IV) drug preparation that contains 1-10mg/ml compound F 17-hydroxy-corticosterone CE29142 or compound F 17-hydroxy-corticosterone CE28855.
Claims (11)
1. formula (II) compound and pharmaceutically acceptable salt thereof:
Wherein R is an acidic-group; M is integer 1-3; N is 0 or integer 1-3; But A is the spacer of enzymatic hydrolysis; X is a bioactive compounds.
2. according to formula (II) compound of claim 1, wherein R is selected from sulfonic acid, the acidic-group of carboxylic acid and phosphoric acid.
3. according to formula (II) compound of claim 1, wherein X is the taxane compound, the distamycin compound; the ceramide compound, Comptothecin compounds, epipodophyllotoxin compound; anthracycline compound, benzoyl carbinol, the compound of tetrahydrochysene S and hydrocortisone.
4. according to formula (II) compound of claim 1, but wherein the spacer A of enzymatic hydrolysis is: a)-Y-CO-, wherein Y is C
1-C
6Alkylidene group or C
2-C
6The alkylene group chain, divalence C
3-C
5Cycloalkyl or phenylene; Or b) amino-acid residue or peptide spacer are selected from β Ala, Gly; Phe-Gly, Phe-Phe-, Leu-Gly; Val-Ala, Phe-Ala, Leu-Phe; Leu-Ala, Phe-Leu-Gly, Phe-Phe-Leu; Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe; Phe-Phe-Gly, Phe-Leu-Gly-Phe, Gly-Phe-Leu-Gly-Phe; Gly-β Ala, Phe-Gly-β Ala, Phe-Phe-β Ala; Leu-Gly-β Ala, Val-Ala-β Ala, Phe-Ala-β Ala; Leu-Phe-β Ala, Leu-Gly-β Ala, Phe-Leu-Gly-β Ala; Phe-Phe-Leu-β Ala, Leu-Leu-Gly-β Ala, Phe-Tyr-Ala-β Ala; Phe-Gly-Phe; Phe-Phe-Gly-β Ala, Phe-Leu-Gly-Phe-β Ala, Gly-Phe-Leu-Gly-Phe-β Ala and amino caproyl.
5. according to formula (II) compound of claim 1, wherein R is a sulfonic group; M is 2 or 3; N is 1 or 2; A is-Y '-CO-that wherein Y ' is selected from-CH
2-CH
2-,-CH=CH-and cyclopropyl or 1,2-phenylene; Or amino-acid residue, or be selected from β-Ala, Gly, the peptide spacer of Leu-Gly and Phe-Leu-Gly; X is a taxol, and 7-shows taxol, table erythromycin, taxotere, camptothecine, 9-amino-camptothecin, etoposide, Zorubicin, methoxyl group-morpholino-Zorubicin, benzoyl carbinol, tallimustine-amidoxim, N-(C
2-C
30)-acyl group-D-sphingosine, tetrahydrochysene S and hydrocortisone, and pharmaceutically acceptable salt.
6. following compounds or its pharmaceutically acceptable salt, particularly sodium salt: N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 ' (7-table) taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 ' (7-table) taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-2 '-taxotere; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-2 '-taxotere; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-3 '-etoposide; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-3 '-etoposide; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-3 '-Zorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-3 '-Zorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-21-tetrahydrochysene S; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-β-alanyl-21-hydrocortisone; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-(7-table) taxol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-2 '-taxotere; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-20-camptothecine; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-20-(9-amino) camptothecine; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-3 '-etoposide; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-14-(3 '-methoxyl group morpholino)-Zorubicin; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-propionyl-1-benzoyl carbinol; β-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid)))-propionyl-21-hydrocortisone; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3,5-naphthalene trisulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-β-alanyl-2 '-taxol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-2 '-taxol; 3-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid)))-propionyl-3 '-N-daunorubicin; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-β-alanyl-20-O-camptothecine; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino-, N-methyl, 2-pyrrolylcarbonyl-(4-imino--1,7-naphthalene disulfonic acid)))-phenyl alanyl-leucyl-glycyl-20-O-camptothecine; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-O-benzoyl carbinol; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl-β-alanyl-O-benzoyl carbinol; 21-(N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-hydrocortisone; N-(4-carbonyl imino-, N-methyl, 2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-the O-tallimustine-amidoxim; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-acetylaminohydroxyphenylarsonic acid 4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-exanoyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(7-imino--1,3-naphthalene disulfonic acid))-β-alanyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene; 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-myristoyl amino-4-octadecylene; And 1-O-(N-(4-carbonyl imino-, N-methyl-2-pyrrolylcarbonyl-(8-imino--1,3,5-naphthalene trisulfonic acid))-phenyl alanyl-leucyl-glycyl)-(2S, 3R, 4E)-1,3-dihydroxyl-2-stearyl amino-4-octadecylene.
7. the preparation method of formula (II) compound or its salt of a claim 1 definition, this method comprises: a) with formula (III) compound
Wherein, R, m and n definition are reacted with formula (IV) compound with claim 1,
X-CO-Y-COOH (IV) wherein, X defines with claim 1, Y is C
1-C
6Alkylidene group or C
2-C
6Alkylene group, divalence C
3-C
5Cycloalkyl or phenylene obtain formula (II) compound, and wherein A is-Y-CO-; Or b) with formula V compound or its reactive derivatives
Wherein, R, m and n definition are with claim 1, and Y defines as above, with the reaction of formula (VI) compound,
X (VI) wherein, X defines with claim 1, obtains formula (II) compound, wherein A is-Y-CO-; Or c) with formula (VII) compound
Wherein, R, m and n definition are with claim 1, and Z is a leavings group, with the reaction of formula (VIII) compound,
X-A ' H (VIII) wherein, X defines with claim 1, A ' is as amino-acid residue or the peptide spacer of the A of claim 4 definition, obtains formula (II) compound, wherein A is amino-acid residue or peptide spacer; Or d) with formula (IX) compound,
Wherein, R, m and n definition are with claim 1, and A ' is amino-acid residue or the peptide spacer as the A of claim 4 definition, with the reaction of formula (VI) compound,
X (VI) wherein, X defines with claim 1, obtains formula (II) compound, wherein A is amino-acid residue or peptide spacer; And, if desired, can be with the salinization of formula (II) compound; And/or, if desired, formula (II) compound is dissociated out from its salt; And/or, if desired, from their mixture, isolate the isomer of formula (II) compound.
8. a pharmaceutical composition contains pharmaceutically acceptable carrier and/or thinner, and as formula (II) compound or its pharmaceutically acceptable salt of at least a claim 1 definition of activeconstituents.
9. formula (II) compound of claim 1 definition or its pharmaceutically acceptable salt is as antiproliferative, particularly antitumor and anti-angiogenic agent, and the purposes of antiphlogistic.
10. method of improving bioactive compounds system X bioavailability, this method comprise provides such and following carrier group bonded active compound X or its pharmaceutically acceptable salt,
R wherein, m, n and A definition are with claim 1.
11. method according to claim 10; wherein compounds X is to be selected from the taxane compound; the distamycin compound; the ceramide compound, Comptothecin compounds, epipodophyllotoxin compound; anthracycline compound; benzoyl carbinol, the compound of tetrahydrochysene S and hydrocortisone, or their pharmaceutically acceptable salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9504065.5A GB9504065D0 (en) | 1995-03-01 | 1995-03-01 | Poly-pyrrolecarboxamidonaphthalenic acid derivatives |
| GB9504065.5 | 1995-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1148391A true CN1148391A (en) | 1997-04-23 |
Family
ID=10770421
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96190152A Pending CN1148391A (en) | 1995-03-01 | 1996-02-08 | Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamido-naphthalene derivatives |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0758339A1 (en) |
| JP (1) | JPH10504319A (en) |
| KR (1) | KR970702868A (en) |
| CN (1) | CN1148391A (en) |
| AR (1) | AR002280A1 (en) |
| AU (1) | AU696470B2 (en) |
| CA (1) | CA2189358A1 (en) |
| EA (1) | EA000006B1 (en) |
| FI (1) | FI964331A (en) |
| GB (1) | GB9504065D0 (en) |
| HU (1) | HUP9603305A3 (en) |
| IL (1) | IL117193A0 (en) |
| MX (1) | MX9605089A (en) |
| NO (1) | NO964610D0 (en) |
| NZ (1) | NZ302267A (en) |
| PL (1) | PL317094A1 (en) |
| WO (1) | WO1996026950A1 (en) |
| ZA (1) | ZA961636B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933569A (en) * | 2022-04-07 | 2022-08-23 | 澳门科技大学 | Sphingolipid compound, liposome containing sphingolipid compound and application |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6492335B1 (en) * | 1996-09-30 | 2002-12-10 | Bayer Aktiengesellschaft | Glycoconjugates from modified camptothecin derivatives (20-O-linkage) |
| DE19640969A1 (en) * | 1996-10-04 | 1998-04-16 | Bayer Ag | 20-0 linked glycoconjugates from camptothecin |
| ID23424A (en) * | 1997-05-14 | 2000-04-20 | Bayer Ag | GLIKOKONJUGUS OF 20 (S) -CAMPTOTESIN |
| GB9713733D0 (en) * | 1997-06-27 | 1997-09-03 | Pharmacia & Upjohn Spa | Poly-branched polycarboxamido compounds |
| GB9713732D0 (en) * | 1997-06-27 | 1997-09-03 | Pharmacia & Upjohn Spa | Substituted triazinic compounds |
| US6485514B1 (en) * | 1997-12-12 | 2002-11-26 | Supergen, Inc. | Local delivery of therapeutic agents |
| US6288072B1 (en) * | 1999-12-29 | 2001-09-11 | Monroe E. Wall | Camptothecin β-alanine esters with topoisomerase I inhibition |
| US6350756B1 (en) | 2001-01-18 | 2002-02-26 | California Pacific Medical Center | Camptothecin derivatives |
| US6855720B2 (en) | 2001-03-01 | 2005-02-15 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
| US6403604B1 (en) | 2001-03-01 | 2002-06-11 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
| WO2002100832A1 (en) | 2001-06-13 | 2002-12-19 | Genesoft Pharmaceuticals, Inc. | Isoquinoline compounds having antiinfective activity |
| EP1534725A2 (en) * | 2002-05-16 | 2005-06-01 | Glycomimetics, Inc. | Compounds and methods for inhibiting selectin-mediated function |
| WO2003101998A1 (en) | 2002-06-03 | 2003-12-11 | California Pacific Medical Center | Nitrogen-based homo-camptothecin derivatives |
| WO2004012736A1 (en) | 2002-08-02 | 2004-02-12 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
| WO2004039318A2 (en) | 2002-10-25 | 2004-05-13 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
| EP1587529A4 (en) | 2002-12-10 | 2009-08-12 | Oscient Pharmaceuticals Corp | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
| PL1934236T3 (en) | 2005-09-02 | 2013-04-30 | Glycomimetics Inc | Heterobifunctional pan-selectin inhibitors |
| US7875602B2 (en) | 2005-10-21 | 2011-01-25 | Sutter West Bay Hospitals | Camptothecin derivatives as chemoradiosensitizing agents |
| WO2009126556A1 (en) | 2008-04-08 | 2009-10-15 | Glycomimetics, Inc. | Pan-selectin inhibitor with enhanced pharmacokinetic activity |
| WO2011163568A1 (en) * | 2010-06-24 | 2011-12-29 | University Of Kansas | Conjugates comprising an n-oxime bond and associated methods |
| WO2012037034A1 (en) | 2010-09-14 | 2012-03-22 | Glycomimetics, Inc. | E-selectin antagonists |
| ES2655443T7 (en) | 2011-12-22 | 2021-03-22 | Glycomimetics Inc | E-selectin antagonist compounds |
| EP2928476B1 (en) | 2012-12-07 | 2018-02-14 | GlycoMimetics, Inc. | Compounds, compositions and methods using e-selectin antagonists for mobilization of hematopoietic cells |
| HUE045542T2 (en) | 2014-12-03 | 2019-12-30 | Glycomimetics Inc | Heterobifunctional inhibitors of e-selectins and cxcr4 chemokine receptors |
| CA3009836A1 (en) | 2016-01-22 | 2017-07-27 | Glycomimetics, Inc. | Glycomimetic inhibitors of pa-il and pa-iil lectins |
| US11291678B2 (en) | 2016-03-02 | 2022-04-05 | Glycomimetics, Inc | Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin |
| JP2019524791A (en) | 2016-08-08 | 2019-09-05 | グリコミメティクス， インコーポレイテッド | Combinations of T cell checkpoint inhibitors with inhibitors of E-selectin or inhibitors of CXCR4 or with heterobifunctional inhibitors of both E-selectin and CXCR4 |
| AU2017341065B2 (en) | 2016-10-07 | 2023-04-06 | Glycomimetics, Inc. | Highly potent multimeric E-selectin antagonists |
| EP3596096A1 (en) | 2017-03-15 | 2020-01-22 | GlycoMimetics, Inc. | Galactopyranosyl-cyclohexyl derivatives as e-selectin antagonists |
| EP3381897A1 (en) | 2017-03-27 | 2018-10-03 | Leadiant Biosciences SA | Derivatives of the disodium 2,2'-{carbonylbis[imino-3,1-phenylenecarbonylimino(1-methyl-1h-pyrrole-4,2-diyl)carbonylimino]}dinaphthalene-1,5-disulfonate salt and related compounds as heparanase inhibitors for the treatment of cancer |
| WO2019108750A1 (en) | 2017-11-30 | 2019-06-06 | Glycomimetics, Inc. | Methods of mobilizing marrow infiltrating lymphocytes and uses thereof |
| AU2018395417B2 (en) | 2017-12-29 | 2023-07-13 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
| JP7455064B2 (en) | 2018-03-05 | 2024-03-25 | グリコミメティクス， インコーポレイテッド | Methods of treating acute myeloid leukemia and related conditions |
| US11845771B2 (en) | 2018-12-27 | 2023-12-19 | Glycomimetics, Inc. | Heterobifunctional inhibitors of E-selectin and galectin-3 |
| WO2021118927A1 (en) | 2019-12-13 | 2021-06-17 | Insideoutbio, Inc. | Methods and compositions for targeted delivery of nucleic acid therapeutics |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9000644D0 (en) * | 1990-01-11 | 1990-03-14 | Erba Carlo Spa | New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds |
| GB9216962D0 (en) * | 1992-08-11 | 1992-09-23 | Erba Carlo Spa | Therapeutically active naphthalenesulfonic-pyrrolecarboxamido derivatives |
| GB9304589D0 (en) * | 1993-03-05 | 1993-04-21 | Erba Carlo Spa | Biologically active ureido derivatives useful as antimetastic agents |
| GB9307948D0 (en) * | 1993-04-16 | 1993-06-02 | Erba Carlo Spa | Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease |
| GB9403909D0 (en) * | 1994-03-01 | 1994-04-20 | Erba Carlo Spa | Ureido derivatives of naphthalenephosphonic acids and process for their preparation |
-
1995
- 1995-03-01 GB GBGB9504065.5A patent/GB9504065D0/en active Pending
-
1996
- 1996-02-08 EA EA199600104A patent/EA000006B1/en not_active IP Right Cessation
- 1996-02-08 PL PL96317094A patent/PL317094A1/en unknown
- 1996-02-08 CN CN96190152A patent/CN1148391A/en active Pending
- 1996-02-08 MX MX9605089A patent/MX9605089A/en unknown
- 1996-02-08 NZ NZ302267A patent/NZ302267A/en unknown
- 1996-02-08 CA CA002189358A patent/CA2189358A1/en not_active Abandoned
- 1996-02-08 AU AU48698/96A patent/AU696470B2/en not_active Ceased
- 1996-02-08 JP JP8525980A patent/JPH10504319A/en active Pending
- 1996-02-08 HU HU9603305A patent/HUP9603305A3/en unknown
- 1996-02-08 WO PCT/EP1996/000528 patent/WO1996026950A1/en not_active Application Discontinuation
- 1996-02-08 EP EP96904024A patent/EP0758339A1/en not_active Withdrawn
- 1996-02-20 IL IL11719396A patent/IL117193A0/en unknown
- 1996-02-29 AR ARP960101576A patent/AR002280A1/en unknown
- 1996-02-29 ZA ZA961636A patent/ZA961636B/en unknown
- 1996-10-28 FI FI964331A patent/FI964331A/en unknown
- 1996-10-31 NO NO964610A patent/NO964610D0/en unknown
- 1996-11-01 KR KR1019960706263A patent/KR970702868A/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114933569A (en) * | 2022-04-07 | 2022-08-23 | 澳门科技大学 | Sphingolipid compound, liposome containing sphingolipid compound and application |
| WO2023193341A1 (en) * | 2022-04-07 | 2023-10-12 | 澳门科技大学 | Sphingolipid compound, liposome containing sphingolipid compound, and application |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA961636B (en) | 1996-09-06 |
| HUP9603305A2 (en) | 1997-08-28 |
| CA2189358A1 (en) | 1996-09-06 |
| MX9605089A (en) | 1997-12-31 |
| KR970702868A (en) | 1997-06-10 |
| PL317094A1 (en) | 1997-03-17 |
| AR002280A1 (en) | 1998-03-11 |
| AU4869896A (en) | 1996-09-18 |
| NO964610L (en) | 1996-10-31 |
| NZ302267A (en) | 1997-10-24 |
| EP0758339A1 (en) | 1997-02-19 |
| FI964331A (en) | 1996-11-01 |
| WO1996026950A1 (en) | 1996-09-06 |
| FI964331A0 (en) | 1996-10-28 |
| NO964610D0 (en) | 1996-10-31 |
| EA199600104A1 (en) | 1997-09-30 |
| EA000006B1 (en) | 1997-12-30 |
| IL117193A0 (en) | 1996-06-18 |
| JPH10504319A (en) | 1998-04-28 |
| AU696470B2 (en) | 1998-09-10 |
| HUP9603305A3 (en) | 1998-01-28 |
| GB9504065D0 (en) | 1995-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1148391A (en) | Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamido-naphthalene derivatives | |
| US10106581B2 (en) | Cyclic peptidomimetic compounds as immunomodulators | |
| JP4451660B2 (en) | Paclitaxel solvate | |
| KR20160081898A (en) | 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators | |
| CN102348718B (en) | Deoxyactagardine derivatives | |
| EP2612857B1 (en) | Chemical synthesis and anti-tumor and anti-metastatic effects of dual functional conjugate | |
| CN1712399B (en) | Production and use for taxol and muramic acyl dipeptide conjugate substance of immune reinforcer | |
| WO2009124468A1 (en) | Anthracycline antibiotic derivatives with high activity, preparation methods and uses thereof | |
| KR920002141B1 (en) | Dimeric epipodo phyllotoxin glucoside derivatives | |
| JP4554606B2 (en) | Novel cytotoxic depsipeptide | |
| CN110152013B (en) | Pectin-adriamycin conjugate and preparation method and application thereof | |
| CN113307838B (en) | Hybrid molecular compound and application thereof in treating tumors | |
| CN110418653B (en) | Pectin-adriamycin conjugate and preparation method and application thereof | |
| CN101029034A (en) | Polyenic taxol soluble derivative, its preparation and use | |
| WO1995025728A1 (en) | Taxane derivatives with antitumor activity | |
| JP2002526540A (en) | Cytotoxic alkaloids (halitulin) | |
| TR201816372T4 (en) | Ethoxyketone compounds for enzyme inhibition. | |
| CN102485735B (en) | 6-fructosamine-4-arylamidoquinazoline derivative and purpose thereof | |
| CN108976201B (en) | 3R-indolylmethyl-6S-aromatic amino acid modified piperazine-2, 5-dione, and synthesis, activity and application thereof | |
| JPH11180997A (en) | Novel antitumor compound | |
| CN1296047C (en) | Caloporoside derivatives, methods for prodn. thereof and their use | |
| CN109734692B (en) | Chrysin leucine derivative with EGFR kinase inhibitory activity | |
| CN110669100B (en) | Metronidazole serine-asparagine dipeptide compound and preparation and application thereof | |
| CN101215276B (en) | N,N'-substituted phenylpropylamino acid phenylpropylaminoalcohols esters derivatives and preparation method thereof | |
| CN108929315B (en) | 3R-indolylmethyl-6S-methionine modified piperazine-2, 5-dione, and synthesis, activity and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |