HRP960585A2 - Novel peptides, their preparation and use - Google Patents
Novel peptides, their preparation and use Download PDFInfo
- Publication number
- HRP960585A2 HRP960585A2 HR08/573,422A HRP960585A HRP960585A2 HR P960585 A2 HRP960585 A2 HR P960585A2 HR P960585 A HRP960585 A HR P960585A HR P960585 A2 HRP960585 A2 HR P960585A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- nhc
- residue
- prolyl
- nhch
- Prior art date
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 2-tert-butylglycyl Chemical group 0.000 claims description 118
- 150000001875 compounds Chemical class 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 22
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000002114 valyl group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 10
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 150000007513 acids Chemical class 0.000 claims description 8
- 125000003625 D-valyl group Chemical group N[C@@H](C(=O)*)C(C)C 0.000 claims description 7
- 125000000249 D-isoleucyl group Chemical group N[C@@H](C(=O)*)[C@@H](CC)C 0.000 claims description 6
- 125000003301 D-leucyl group Chemical group N[C@@H](C(=O)*)CC(C)C 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001203 alloisoleucine group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 14
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
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- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical compound C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- 108010045552 dolastatin 15 Proteins 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000010855 food raising agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000037219 healthy weight Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Izumom se odnosi na nove peptide i njihove derivate koji u usporedbi s dolastatinom 10 i 15 (U.S. patenti br. 4,879,276 i 4,816,444) i spojevima opisanim u WO 93/23424 nude jako poboljšane terapeutske mogućnosti za liječenje neoplaziskih bolesti.
Spojevi prema ovom izumu uključuju nove peptide formule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
u kojoj
R1 je vodik, metil ili etil;
R2 je metil, ili etil; ili
R1-N-R2 zajedno tvore pirolidinski prsten;
A je ostatak valil, izoleucil, alo-izoleucil, 2-terc-butilglicil, 2-etilglicil, norleucil ili norvalil;
B je ostatak N-metil-valil, N-metil-norvalil, N-meti-leucil, N-metil-izoleucil, N-metil-2-terc-butil-glicil, N-metil- 2-etilglicil, ili N-metil-norleucil;
D je ostatak prolil, homoprolil, hidroksiprolil, ili ciazolidin-4-karbonil;
E je ostatak prolil, homoprolil, hidroksiprolil, tiazolidin-4-karbonil, trans-4-fluor-L-prolil, cis-4-fluor- L- prolil,trans- 4- klor-L-prolil ili cis-4-klor-L-prolil;
X je etil, propil, butil, izopropil, sek.butil, terc.butil, ciklopropil ili cikopentil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D-izoleucil, D-leucil, D-norvalil, 1-aminopentil-1-karbonil, ili 2,2 -dimetilglicil;
S je 0 ili 1;
K je -NH-C1-8-alkil, -NH-C3-8-alkenil, -NH-C3-8-alkinil, -NH-C6-8-cikloalkil, -NH-C1-4-alken-C3-8-cikloalkil,
C1-4-alkil-N-C1-6-alkil, u kojima ostaci jedne CH2 skupine mogu biti nadomješteni s O ili S, jedan H s fenilom ili cijano, ili 1, 2 ili H s fluorom, osim u slučaju ostatka N-metoksi-N-metilamino, N-benzilamino, ili ostatka N-metil-N-benzil-amino, ili K je
[image]
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
Posebno K može biti -NHCH3, -NHCH2CH3, -NH (CH2) 2CH3,
-NH(CH2)3CH3, -NH(CH2)4CH3, -NH (CH2) 5CH3, -NH (CH2) 6CH3,
-NHCH(CH2)7CH3, -NHCH(CH3)2, -NHCH (CH3) CH2CH3, -NHCH (CH2CH3) 2,
-NHCH(CH2CH2CH3)2, -NHC(CH3)3, -NHCH (CH2CH3) CH2CH2CH3,
-NHCH(CH3)CH(CH3)2, -NHCH (CH2CH3) CH (CH3) 2, -NHCH (CH3) C (CH3) 3,
-NH-cikloheksil, -NH-cikloheptil, -NH-ciklookstil,
-N(CH3)OCH2CH3, -N(CH3)OCH2CH2CH3, -NH (CH3)OCH (CH3) 2,
-N(CH3)O(CH2)3CH3, -N(CH3)OCH2C6H5, -NH (CH2) 2C6H5,
-NH(CH2)3C6H5, -NHCH(CH3)C6H5, -NHC (CH3) 2C6H5,
-NHC(CH3)2CH2CH3, -NHC (CH3) (CH2CH3) 2, -NHCH[CH (CH3) 2]2,
-NHC(CH3)2CN, -NHCH(CH3)CH(OH)C6H5, -NHCH2-cikloheksil,
-NHCH2C(CH3)3, -NHCH2CH (CH3) 2, -N(CH3)2, -N(CH2CH3)2,
-N(CH2CH2CH3)2, -NHCH2CF3, -NHCH (CH2F) 2, -NHCH2CH2F,
-NHCH2CH2OCH3, -NHCH2CH2SCH3, -NHCH2CHCH2, -NH-C (CH3) 2CH=CH2,
-NHC(CH3)2C=CH, -NHC(CH2CH3)2C=CH, -NHC (CH3) 2CH2CH2OH,
-NH(CH2CH2O)2CH2CH3, -NHC (CH3) 2CH (CH3) 2, -NHC (CH3) 2CH2CH2CH3,
-NHC(CH3)2CH2C6H5, -N (OCH3) CH (CH3) 2, -N (OCH3) CH2CH3,
-N (OCH3) CH2CH2CH3, -N (OCH3) CH2C6H5, -N (OCH3) C6H5, -N (CH3) OC6H5,
-NHCH[CH (CH3) 2]2, -N (OCH3) CH2CH2CH2CH3,
ili naročiti gore navedeni prstenasti sistemi.
Prednost se daje spojevima formule I u kojoj supstituenti R1, R2, A, B, D, E, X, G i s imaju slijedeća značenja:
R1 je vodik, metil ili etil, naročito metil;
R2 je metil ili etil, naročito metil;
A je valil, izoleucil, 2-terc.butilglicil, 2-etil-glicil, norleucil ili norvalil, naročito valil, izoleucil, 2-terc. butilglicil, 2-etilglicil;
B je N-metil-valil, N-metil-norvalil, N-rnetil-izoleucil, N-metil-2-terc.butilglicil, N-metil-2-etil-glicil, ili N-metil- norleucil, naročito N-metil-valil, N-metil-2-etilglicil, N-metil-norleucil, N-metil-izoleucil, ili N-metil-2-terc.butil-glicil;
D je prolil, homoprolil ili tiazolidin-4-karbonil, naročito prolil ili tiazolidin-4-karbonil;
E je prolil, homoprolil, tiazolidin-4-karbonil, trans-4-fluor-L-prolil, cis-4-fluor-L-prolil, trans-4-klor-L-prolil ili cis-4-klor-L-prolil, naročito prolil, trans-4-fluor-L-prolilf cis-4-fluor-L-prolil, trans-4-klor-prolil, ili cis-4-klor-prolil;
X je etil, propil, izopropil, sek.butil, terc.butil ili ciklopropil, naročito etil, izopropil, sek.butil ili terc.butil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D-izoleucil, D-leucil ili 2,2-dimetil-glicil;
S je 0 ili 1.
K ima ponajprije značenja:
-NH-C1-8-alkil, -NH-C6-8-cikloalkil, -NH-CH2-cikloheksil, C1-4-alkil-N-C1-6-alkil, u kojima ostaci jedne CH2 skupine mogu biti nadomješteni s O, jedan H s fenilom ili 1, 2 ili H s fluorom, osim u slučaju ostatka N-metoksi-N-metilamino, N-benzilamino, ili N-raetil-N-benzilamino, ili K je
[image]
K je ponajprije
-NHCH3, -NHCH2CH3, -NH (CH2) 2CH3, -NH (CH2) 3CH3,
-NH (CH2) 4CH3, -NH (CH2) 5CH3, -NH (CH2) 6CH3, -NH (CH2) 7CH3,
-NHCH(CH3)2, -NHCH(CH3)CH2CH3, -NHCH (CH2CH3) 2,
-NHCH(CH2CH2CH3)2, -NHC(CH3)3, -NHCH (CH2CH3) CH2CH2CH3,
-NHCH(CH3)CH(CH3)2, -NHCH (CH2CH3) CH (CH3) 2, -NHCH (CH3) C (CH3) 3,
-NH-cikloheksil, -NH-cikloheptil, -NH-ciklooktil,
-N(CH3)OCH2CH3, -N(CH3)OCH2CH2CH3, -NH (CH3)OCH (CH3) 2,
-N(OCH3)CH(CH3)2, -NH(CH3)OCH2C6H5, -NH (CH2) 2C6H5,
-NH(CH2)3C6H5, -NHCH(CH3)C6H5, -NHC (CH3) 2C6H5,
-NHC(CH3)2CH2CH3, -NHC (CH3) (CH2CH3) 2, -NHCH (CH3) CH (OH) C6H5,
-NHCH2-cikloheksil, -N(CH3)2, -N(CH2CH3)2, -N (CH2CH2CH3) 2,
-NHCH(CH2F)2, -NHC(CH3)2CH2CH2OH, -NH (CH2CH2O) 2CH2CH3,
-NHC(CH3)2CH(CH3)2, -NHC (CH3) CH=CH2, -NHC (CH3) 2CN,
-NHC(CH3)2C≡CH, -NHC(CH3)CONH2, -N (OCH3) CH2C6H5,
-NHCH[CH(CH3)2]2, -N(OCH3)CH2C6H5, -N (OCH3) CH2CH3,
-N (OCH3) CH2CH2CH3, -N (OCH3) CH2CH2CH2CH3,
[image]
Posebnu prednost se daje spojevima formule I u kojoj
R1 i R2 jesu metil;
A je ostatak valil, izoleucil ili 2-terc.butil-glicil;
B je ostatak N-metil-valil, N-metil-izoleucil, ili N-metil-2-terc.butilglicil;
D je ostatak prolil ili tiazolidin-4-karbonil;
E je ostatak prolil, cis-4-fluor-L-prolil, ili cis-4-klor-L-prolil;
X je ostatak izopropil, sek.butil, ili terc.butil;
S je 0;
K je
-NHCH(CH3)2, -NHCH (CH3) CH2CH3, -NHCH (CH2CH3) 2,
-NHCH (CH2CH2CH3) 2, -NHC (CH3) 3, -NHCH (CH2CH3) CH2CH2CH3,
-NHCH (CH3) CH (CH3) 2, -NHCH (CH2CH3) CH (CH3) 2, -NHCH (CH3) C (CH3) 3,
-NH-cikloheptil, -NH-ciklooktil, -N (CH3)OCH2CH3,
-N (CH3) OCH2CH2CH3, -NH (CH3) OCH (CH3) 2, -N (OCH3) CH (CH3) 2,
-NH (CH3)OCH2C6H5, -NH (CH2) 2C6H5, -NH (CH2) 3C6H5, -NHCH (CH3) C6H5,
-NHC (CH3) 2C6H5, -NHC (CH3) 2CH2CH3, -NHC (CH3) (CH2CH3) 2,
-NHCH (CH3) CH (OH) C6H5, -NHCH (CH2F) 2, -NHC (CH3) 2CH2CH2OH,
-NH (CH2CH2O) 2CH2CH3, -NHC (CH3) CH=CH2, -NHC (CH3) 2CH (CH3) 2,
-N (OCH3) CH2CH3, -N (OCH3) CH2CH2CH3, -N (OCH3) CH2CH2CH2CH3,
-NHC (CH3) 2CN, -NHC (CH3) 2C=CH, -NHCH[CH (CH3) 2]2,
-NHC (CH3) CONH2, -NHC (CH3) 2CH2C6H5, -N (OCH3) C6H5,
-N(OCH3)CH2C6H5,
[image]
Ovaj izum također osigurava metode za pripravu spojeva formule I, farmaceutskih sastava koji sadrže takove spojeve zajedno s farmaceutski prihvatljivim nosačem i metode za njihovu upotrebu za liječenje raka sisavaca.
Novi spojevi mogu postojati kao soli s fiziološki podnošljivim kiselinama kao što su klorovodična kiselina, limunska kiselina, vinska kiselina, mliječna kiselina, fosforna kiselina, metansulfonska kiselina, octena kiselina, mravlja kiselina, maleinska kiselina, fumarna kiselina, jabučna kiselina, sukcinska kiselina, malonska kiselina, sumporna kiselina,L-glutaminska kiselina, L-aspartinska kiselina, piruvinska kiselina, inucinska kiselina, benzojeva kiselina, glukuronska kiselina, oksalna kiselina, askorbinska kiselina i acetilglicin.
Novi spojevi mogu se pripremiti poznatim metodama kemije pepticla. Tako se peptidi mogu sastaviti sekvencijalno od amino kiselina ili povezivanjem prikladnih malih peptidnih fragmenata. Kod sekvencijalnog sastavljanja, počevši na C završetku peptidni lanac povećava se postupno svaki puta sa po jednom amino kiselinom. Kod povezivanja framenata moguće je zajedno povezati fragmente različitih duljina, i fragmenti se mogu dobiti redom sekvencijalnim sastavljanjem iz amino kiselina ili fragmentnim povezivanjem njih samih.
U obadva slučaja, kod sekvencijalnog sastavljanja i kod fragmentnog povezivanja potrebno je povezati jedinice tvorbom amidne veze. Za to su prikladne enzimske i kemijske metode.
Kemijske metode za tvorbu amidne veze opisane su u pojedinostima u Mueller, Methoden der organischen Chemie, Vol. XV/2, str. 1 do 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, str. 31 do 341 71 do 82 f Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, str. 85 do 128, John Wiley & Sons, New York, 1976; The Practice of Peptide Synthesis, M. Bodanszky, A. Bodanszky, Springer-Verlagf 1994f i u drugim standardnim radovima kemije peptida. Posebnu prednost daje se metodi azida, simetričnoj i kombiniranoj metodi anhidrida, in situ stvaranjem ili pretvorbom aktivnih estera, upotrebi uretanom zaštićenihN-karboksi anhidrida amino kiselina i tvorbi amidne veze povezivanjem reagenata, a to su naročito dicikloheksilkarbodiirnid (DCC) , diizopropil-karbodiimid (DIC), 1-etoksikarbonil-2-etoksi-1,2-dihidro-kinolin (EEDQ), pivaloilklorid, 1-etil-3- (3- dimetil-aminopropil)karbodiimid-hidroklorid (EDCI), anhidrid n-propanfosfonske kiseline (PPA), N,N-bis- (2-okso -3-oksazoldinil) -arnidofosforil klorid (BOP-C1) , brom-tris-pirolidinofosfonijev heksafluorfosfat (PyBrop), difenil fosforil azid (DPPA), Castrov reagens (BOP, PyBop), O -benzotriazolil-N,N,N N-tetrametiluronijeve soli (HBTU), O-azabenzotriazolil-N,N, N , N -tetrametiluronijeve soli (HATU), dietilfosforil cijanid (DEPCN) , 2,5-difenil-2, 3- dihidro-3-okso-4-hidroksitiofen dioksid (Steglichov reagens; HOTDO) i 1,1'-karbonildiimidazol (CDI). Reagensi za povezivanje mogu se upotrijebiti sami ili u kombinaciji s dodacima kao što su N,N-dimetil-4-amino-piridin (DMAP), N-hidroksi-benzotriazol (HOBt) , N-hidroksi-benzotriazin (HOOBt), azabenzotriazol (HOAt), N- hidroksi-sukcinimid (HOSu) ili 2-hidroksipiridin.
Budući da se normalno u enzimatskoj sintezi peptida može izbjeći rad sa zaštitnim skupinama, reverzibilna zaštita reaktivnih skupina, koje nisu uključene u tvorbu amidne veze, nužna je u kemijskoj sintezi za oba reaktanta. Za kemijsku sintezu peptida prednost imaju tri uobičajena postupka sa zaštitnim skupinama: postupci s benziloksikarbonilom (Z) , t-butoksikarbonilom (Boe) i 9-f luorenilmetoksikarbonilorn (Fmoc) .
U svakom slučaju identificirana je zaštitna skupina na alfa amino skupini jedinice produženja lanca. Detaljan pregled zaštitnih skupina za amino kiseline dao je Mueller, Methoden der organischen Chemie Vol. XV/1, str. 20 do 906, Thieme Verlag, Stuttgart, 1974. Jedinice koje se upotrebljavaju za sastavljanje peptidnog lanca mogu reagirati u otopini, u suspenziji ili metodom sličnom onoj koju je opisao Merrifield u J. Anier. Chem. Soc. 85 (1963) 2149.
Za sintezu peptida u otopini prikladna su sva otapala koja su inertna pod uvjetima reakcije, naročito voda,N, N- dimetilformamid (DMF) , dimetilsulfoksid, (DMSO) , aceto-nitril, diklormetan (DCM), etil acetat, 1,4-dioksan, tetrahidrofuran (THF), N-metil-2-pirolidon (NMP) i mješavine spomenutih otapala.
Sinteza peptida na polimernoj podlozi može se provesti u svim inertnim organskim otapalima u kojima su topivi upotrijebljeni derivati amino kiselina. Međutim, prednost se daje otapalima koja imaju dodatno svojstvo da u njima smola bubre, kao DMF, DCM, NMP, acetonitril i DMSO, i mješavine tih otapala. Po završetku sinteze, peptid se odvaja od polimerne podloge. Uvjeti pod kojima je moguće odvajanje različitih tipova smola obznanjeni su u literaturi. Reakcije odvajanja koje se općenito najčešće koriste su kiselo katalizirane i s paladijem kao katalizatorom, naročito odvajanje u tekućem bezvodnom fluorovodiku, u anhidridu trifluormetansulfonkse kiseline, u razrijeđenoj ili koncentriranoj trifluoroctenoj kiselini, odvajanje s paladijem kao katalizatorom u THF-u ili mješavini THF-DCM u prisutnosti slabe baze kao što je morfolin ili odvajanje u mješavini octene kiseline i diklormetana i trifluoretanola. Ovisno o odabranim zaštitnim skupinama, one se mogu zadržati ili također odcijepiti pod uvjetima odvajanja.
Djelomična deprotekcija peptida može tako biti korisna kad se provode određene reakcije sinteze.
Peptidi dialkilirani na N-završetku mogu se pripremiti povezivanjem odgovarajućih N,N-dialkilamino kiselina u otopini ili na polimernoj podlozi, reduktivnim alkilranjem veze smola-peptid u DMF/1% octenoj kiselini s NaCNBH3 i odgovarajućim aldehidom, hidrogeniranjem peptida u otopini u prisutnosti aldehida ili ketona i Pd/C.
Ovdje obznanjene razne amino kiseline, nastale neprirodnim putem, mogu se dobiti od komercijalnih izvora ili se mogu sintetizirati od komercijalno dostupnih materijala primjenom metoda poznatih u struci. Na primjer, aminokiselinski dogradni blokovi sa R1 i R2 jedinicama mogu se pripremiti u skladu s E. Wuensch, Houben Weyl, Meth. d. Org. Chemie, sv. XV, 1, str. 306 i dalje, Thieme Verlag Stuttgart 1974 i tamo citiranoj literaturi.
Spojevi ovog izuma mogu se upotrijebiti za inhibiciju ili za drugačiji način liječenja čvrstih tumora (tj. tumora pluća, dojke, debelog crijeva, prostate, bubrega, rektuma ili unutrašnjih tumora) ili hematoloških malignacija (tj . leukemije, limfoma) davanjem spoja sisavcima.
Naročita prednost novih spojeva je to da su oni u vrlo otporni prema enzimskoj razgradnji i mogu se dati oralno.
Lijek se može dati na bilo koji način uobičajen za farmaceutska, ponajprije onkološka sredstva, uključiv oralno, parenteralno kao subkutano, intravenski, intramuskularno i intraperitonealno.
Spojevi se mogu dati sami ili u obliku farmaceutskih sastava koji sadrže spoj formule I zajedno s farmaceutski prihvatljivim nosačem prikladnim za željeni način nadanja. Takovi farmaceutski sastavi mogu biti kombinirani proizvodi, tj. mogu također sadržavati i druge terapeutski aktivne sastojke.
Doza koja se daje sisavcima sadrži učinkovitu količinu aktivnog sastojka koji inhibira tumor, a ovisi o uobičajenim faktorima uključiv biološku aktivnost dotičnog upotrijebljenog spoja, načinu davanja, starosti, zdravstvenom stanju i tjelesnoj težini primaoca, prirodi i opsegu simptoma, učestalosti liječenja, davanju druge terapije i željenom učinku. Tipična dnevna doza bit će približno 0,05 do 50 miligrama po kilogramu tjelesne težine kod oralnog davanja ili 0,01 do 20 mg kod parenteralnog davanja.
Novi spojevi mogu se dati u čvrstim ili tekućim uobičajenim farmaceutskim oblicima, npr. neprevučene ili s filmom prevučene tablete, kapsule, puderi, granule, čepići ili otopine. Oni se proizvode na uobičajen način. U tu svrhu aktivne tvari mogu se preraditi s uobičajenim farmaceutskim pomoćnim sredstvima kao što su veziva za tablete, punila, konzervansi, sredstva za razaranje tableta, regulatori tecivosti, plastifikatori, kvasila, dispergatori, emulgatori, otapala, sastavi za potpomaganje oslobađanja, antioksidanti i/ili potisni plinovi (vidi H. Sucker i sur.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Oblici za davanje dobiveni na taj način normalno sadrže 1-90% mase aktivne tvari.
Slijedeći primjeri imaju svrhu objasniti izum. Proteinogene amino kiseline pisane su u primjerima u kraticama pri čemu se koristi poznati kod od tri slova. Ostale upotrijebljene kratice jesu: Me2Val = N,N-dimetil-valin, MeVal = N-metilvalin.
A. Opći postupak
I. Naznačeni peptidi u patentnom zahtjevu 1 su ili sintetizirani klasičnom sintezom iz otopine primjenom standardne Z- ili Boc-metodologije, kako je gore opisano, ili primjenom standardnih metoda sinteze iz čvrste faze primjenom postupka sa Boe ili Fince zaštitnom skupinom.
U slučaju sinteze iz čvrste faze N,N-dialkilpenta-ili heptapeptidne kiseline oslobađaju se iz čvrste podloge i dalje se povezuju s odgovarajućom C-terminalnom amino kiselinom u otopini. BOP-C1 i PyBrop upotrijebljeni su kao reagensi za povezivanje amino kiseline iza N-metilamino kiselina. Vremena reakcija odgovarajuće su rasla. Za reduktivno alkiliranje N-završetka peptidna smola oslobodi se zaštite na N-završetku i zatim reagira s trostrukim molarnim suviškom aldehida ili ketona u DMF/ 1%-tnoj octenoj kiselini s dodatkom 3 ekvivalenta NaCNBH3. Po završetku reakcije (Kaiserov test negativan) smola se ispere nekoliko puta s vodom, izopropanolom, DMF-om i diklormetanom.
Kod sinteze u otopini, upotreba Boc-zaštićene amino kiseline NCAs (N-terc.butiloksikarbonil-amino kiselina-N – karboksi-anhidrid), odnosno Z-zaštićene amino kiseline NCAs (N-benziloksikarbonil-amino kiselina-N- karboksi -anhidrid), ili upotreba pivaloilklorida kao sredstva za povezivanje najkorisnija je za povezivanje amino kiseline iza N-metilamino kiselina. Reduktivno alkiliranje N-završetka može se provesti npr. pomoću reakcije N-terminalno zaštićenih peptida ili amino kiselina s odgovarajućim aidehidima ili ketonima upotrebom NaCNBH3 ili vodika, Fd/C.
II. Čišćenje i karakterizacija peptida
čišćenje se provodi pomoću gel kromatografije (SEPHADEK G-10, G-15/10% HOAc, SEPHADEK LH20/MeOH), kromatografijom srednjeg pritiska (stacionarna faza: HD-SIL C-8, 20-45 mikrona, 100 angstrema; mobilna faza: gradijent s A - 0,1% TFA/MeOH, B = 0,1% TFA/voda) , ili preparativne HPLC (stacionarna faza: Waters Delta-Pak C-18, 15 mikrona, 100 angstrema; mobilna faza: gradijent s A - 0,1% TFA/MeOH, B - 0,1% TFA/voda).
Čistoća dobivenih proizvoda određena je pomoću analitičke HPLC (stacionarna faza: 100 2,1 mm VYDAC C-18, 5 l, 300 angstrema; mobilna faza: gradijent acetonitril-vode, puferiran s 0,1% TFA, 40°C) .
Karakterizacija provedena je analizom amino kiselina i pomoću masene spektroskopije bombardiranjem s brzim atomima.
B. Posebni postupci
Primjer 1
(SEQ ID NO: 1) Me2Val-Val-MeVal-Pro-Pro-NHCH(CH3) 2
a) Z-MeVal-Pro-OMe
66,25 g (250 mmolova) Z-MeVal-OH otopi se u 250 ml suhog diklormetana. Nakon dodatka 36,41 ml (262,5 mmolova) trietilamina, reakcijsku smjesu ohladi se na -25°C i doda se 32,27 ml (262,5 mmolova) pivaloil klorida. Miješa se 2,5 sata i zatim se u reakcijsku smjesu pri 0°C doda 41,89 g (250 mmolova) H-Pro-OMe x HCl u 250 ml diklormetana, neutraliziranog s 36,41 ml (262,5 mmolova) trietilamina. Miješanje se nastavi 2 sata pri -25°C i preko noći pri sobnoj temperaturi.
Reakcijsku smjesu razrijedi se s diklormetanom i temeljito ispere sa zasićenom vodenom otopinom NaHCO3 (3 x) , vodom (1 x) , 5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Ostatak (91,24 g) miješa se preko noći s petrol eterom i filtrira. Dobiveno je 62,3 g proizvoda.
b) H-MeVal-Pro-OMe
48,9 g (130 mmolova) Z-MeVal-Pro-OMe otopi se u 490 ml metanola. Nakon dodatka 10,9 ml (130 mmolova) koncentriane klorovodične kiseline i 2,43 g 10%-tnog paladij/ugljena reakcijsku smjesu se hidrogenira. Filtracijom i isparavanjem do suhog dobiveno je 36,43 g proizvoda.
c) Z-Val-MeVal-Pro-OMe
18,1 g (65 mmolova) H-MeVal-Pro-OMe, 21,6 g (78 mmolova) Z-Val-N-karboksanhidrida i 22,8 ml (130 mmolova) diizopropiletilamina miješa se u 110 ml DMF-a 2 dana pri 40°C. Nakon isparavanja DMF-a doda se diklormetan i organsku fazu se ispere sa zasićenom vodenom otopinom NaHCO3 (3 x) , vodom (1 x) , 5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobiveno je 29,3 g proizvoda kao viskoznog ulja.
d) H-Val-MeVal-Pro-OMe
29,3 g (61,6 mmolova) Z-Val-MeVal-Pro-OMe otopi se u 230 ml metanola. Nakon dodatka 1,15 g 10%-tnog paladij/ugljena reakcijsku smjesu se hidrogenira. Filtracijom i isparavanjem do suhog dobiveno je 21,96 g proizvoda.
e) Z-Val-Val-MeVal-Pro-OMe
15,29 g (61 mmol) Z-Val-OH i 21,96 g (61 mmol) H-Val-MeVal-Pro-OMe otopi se u 610 ml diklormetana i ohladi se na 0°C. Nakon dodatka 8,16 ml (73,2 mmola) N-metil-morfolina, 2,77 g (20,3 mmolova) HOBt i 11,74 g (61 mmol) EDCI reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi, razrijedi s diklormetanom i temeljito ispere sa zasićenom vodenom otopinom NaHCO3 (3 x) , vodom (1 x) , 5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobiveno je 31,96 g proizvoda.
f) Z-Val-Val-MeVal-Pro-OH
31,96 g (57 mmolova) Z-Val-Val-MeVal-Pro-OMe otopi se u 250 ml metanola. Doda se 102,6 ml 1 N otopine LiOH i smjesu se miješa preko noći pri sobnoj temperaturi. Nakon dodatka 500 ml vode, vodenu fazu se ispere tri puta s etil acetatom, namjesti na pH 2 pri 0°C i ekstrahira 3 puta s etil acetatom. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobiveno je 30,62 g željenog proizvoda kao bijele čvrste tvari.
g) Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3) 2
2 g (3,35 mmola) Z-Val-Val-MeVal-Pro-OH i 0,664 g (3,35 mmola) H-Pro-NHCH (CH3) 2 otopi se u 34 ml suhog diklormetana. Ohladi se na 0°C i doda 1,35 ral (12,1 mmolova) N-metilmorfolina, 0,114 g (0,84 mmolova) HOBt i 0,645 g (3,35 mmola) EDCI i reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi. Doda se 80 ml diklormetana i organsku fazu temeljito se ispere sa zasićenom vodenom otopinom NaHCO3 (3 x) , vodom (1 x),5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobiveno je 1,96 g proizvoda koji je bez daljnjeg čišćenja upotrijebljen u slijedećoj reakciji.
h) Me2Val-Val-MeVal-Pro-Pro-NHCH(CH3) 2
1,96 g Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 otopi se u 11 ml metanola. U atmosferi dušika doda se 0,54 g 10%-tnog Pd/C i reakcijsku smjesu hidrogenira se 4 sata pri sobnoj temperaturi. Doda se 0,86 ml (11,24 mmolova) 37%-tne vodene otopine formaldehida i 0,281 g 10%-tnog Pd/C i hidrogeniranje se nastavi još 5 sati. Filtracijom i isparavanjem otapala dobije se 2,77 g sirovog proizvoda. Za daljnje čišćenje peptid se otopi u vodi, pH se namjesti na 2 i vodenu fazu ekstrahira se tri puta s etil acetatom. Zatim se vodenu fazu namjesti na pH 8-9 i ekstrahira se četiri puta s diklormetanom. Organsku fazu se osuši preko natrijevog sulfata i dobije se 1,37 g čistog proizvoda kao bijele pjene. Spoj se dalje čisti srednje tlačnom tekućinskom kromatografijom (10 - 50% A u 10 minuta; 50 -90% A u 320 minuta). Frakcije koje sadrže proizvod se sjedine, liofiliziraju, ponovno otope u vodi i pH se namjesti na 9 sa 1N LiOH. Nakon ekstrakcije s diklormetanom organsku fazu se osuši preko natrijevog sulfata i isperi do suhog. Liofilizacijom je dobiveno 500 g čistog proizvoda koji je karakteriziran masenom spektrometrijom bombardiranjem s brzim atomima ([M+H]+ = 593) .
Primjer 2
(SEQ ID NO: 1)
Me2Val-Val-MeVal-Pro-Pro-NHC (CH3) 3
i) Z-Val-Val-MeVal-Pro-Pro-NHC (CH3) 3
2 g (3,35 mmola) Z-Val-Val-MeVal-Pro-OH i O,692 g (3,35 mmola) H-Pro-NHC (CH3) 3 otopi se u 34 ml suhog diklormetana. Kad se ohladi na 0°C doda se 1,35 ml (12,1 minolova) N-metilmorfolina, O,114 g (0,84 mmolova) HOBt-a i 0,645 g (3,35 mmola) EDCI i reakcijsku smjesu miješa se preko noći pri sobnoj temperaturi. Doda se 80 ml diklormetana i organsku fazu temeljito se ispere sa zasićenom vodenom otopinom NaHCO3 (3 x) , vodom (1 x) ,5%-tnom limunskom kiselinom (3 x) i sa zasićenom otopinom NaCl. Organsku fazu se osuši preko natrijevog sulfata i ispari do suhog. Dobiveno je 1,8 g proizvoda koji je bez daljnjeg čišćenja upotrijebljen u slijedećoj reakciji.
k) Me2Val-Val-MeVal-Pro-Pro-NHC(CH3) 3
1,8 g Z-Val-Val-MeVal-Pro-Pro-NHCH(CH3)2 otopi se u 10 ml metanola. U atmosferi dušika doda se 0,049 g 10%-tnog Pd/C i reakcijsku smjesu hidrogenira se 4 sata pri sobnoj temperaturi. Doda se 0,86 ml (11,24 mmolova) 37%-tne vodene otopine formaldehida i 0,252 g 10%-tnog Pd/C i hidrogeniranje se nastavi još 5 sati. Filtracijom i ispravanjem otapala dobije se 1,82 g sirovog proizvoda. Spoj se dalje očisti srednje tlačnom tekućinskom kromatografijom (10 - 50% A u 10 minuta; 50 - 90% A u 320 minuta). Frakcije koje sadrže proizvod se sjedine, liofiliziraju, ponovno otope u vodi i pH se namjesti sa 1N LiOH na 9. Nakon ekstrakcije s diklormetanom organsku fazu se osuši preko natrijevog sulfata i isperi do suhog. Liofilizacijom je dobiveno 547 g čistog proizvoda koji je karakteriziran masenom spektrometrijom bombardiranjem s brzim atomima ([M+H]+ = 607) .
Slijedeći spojevi pripremljeni su ili se mogu pripremiti u skladu s primjerima 1 i 2.
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Spojevi ovog izuma mogu se ocijeniti što se tiče anti-kancerogenog djelovanja konvencionalnim metodama, koje uključuju na primjer, metode opisane u nastavku.
A. Metodologija in vitro
Citotoksičnost je izmjerena primjenom standardne metodologije na adherentnim staničnim linijama kao što je ispitivanje na mikrokulturi tetrazolija (MTT, e. mickroculture tetrazolium assay). Pojedinosti ovog ispitivanja bile su objavljene (Alley, Me i al., Cancer Research 48 : 589-601, 1988). Za pripravu mikrotitarske ploče kultura upotrijebljene su eksponencijalno rastuće kulture stanica tumora kao što je HT-29 raka debelog crijeva ili LX-1 tumora pluća. U 96-jamičnu ploču (u 150 µl medija) posijano je 3000 stanica po jamici i stanice su rasle preko noći pri 37°C. Ispitni spojevi su dodani u deseterostrukom razrjeđenju varirajući od 10-4 do 10-10 M. Stanice su zatim inkubirane 72 sata. Za određivanje broja za život sposobnih stanica u svakoj jamici dodana je MTT boja (50 µl otopine od 3 mg/ml 3-(4,5-diemtiltiazol-2-il)-2, S-difeniltetrazolijevog bromida u otopini soli). Smjesa je inkubirana 5 sati pri 37°C i zatim je u svaku jamicu dodano po 50 µl od 25%-tne SDS, pH 2. Nakon inkubacije preko noći, pomoću ELISA čitača očitana je apsorbancija svake jamice kod 550 nm. Izračunate su srednje vrijednosti + /- standardno odstupanje podataka iz ponovljenih jamica pomoću formule % T/C (% za život sposobnih obrađenih stanica /kontrolnih).
[image]
Koncentracija ispitnog spoja koja daje T/C od 50% inhibicije rasta označena je kao vrijednost IC50.
B. Metodologija in vivo
Spojevi ovog izuma bili su nadalje podvrgnuti predkliničkim ispitivanjima s obzirom na djelovanje in vivo, koje je indikativno za kliničku upotrebljivost. Takovi pokusi provedeni su s bezdlakim miševima u koje je transplantirano (ksenografirano) tkivo tumora, ponajprije humanog podrijetla, što je dobro poznato u tom području. Dati miševima koji nose ksenografirani tumor ispitni spojevi bili su ocijenjeni što se tiče njihove anti-tumorske učinkovitosti.
Potanje, humani tumori dojke (MX-1) koji su rasli u atimičkim bezdlakim miševima transplantirani su u nove miševe primaoce, upotrebom fragmenata tumora koji su bili veličine približno 50 mg. Dan presađivanja bio je označen kaodan 0. Šest dana kasnije miševi, u skupina od po 5-10 miševa, obrađeni su s ispitnim spojevima datim intravenskom injekcijom. Spojevi su davani svaki drugi dan tijekom 3 tjedna dozom od 1-200 mg/kg tjelesne težine.
Promjeri tumora i tjelesne težine mjerene su dva puta ujedno. Volumeni tumora izračunati su pomoću promjera izmjerenog s Vernierovim šestarom i formule
(duljina x širina2)/2 = mm3 volumena tumora
Prosječni volumeni tumora izračunati su za svaku liječenu skupinu, a T/C vrijednosti određene su za svaku skupinu prema kontrolnim neobrađenim tumorima.
Novi spojevi imaju dobra svojstva inhibicije tumora.
Claims (9)
1. Novi peptidi formule I
R1R2N-CHX-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 je vodik, metil ili etil;
R2 je metil, ili etil; ili
RX-N-R2 zajedno tvore pirolidinski prsten;
A je ostatak valil, izoleucil, alo-izoleucil, 2-terc-butilglicil, 2-etilglicilf norleucil ili norvalil;
B je ostatak N-metil-valil, N-metil-norvalil, N-metil-leucil, N-metil-izoleucil, N-metil-2-terc-butil-glicil, N-metil-2- etilglicil, ili N-metil-norleucil;
D je ostatak prolil, homoprolil, hidroksiprolilf ili tiazolidin-4-karbonil ;
E je ostatak prolil, homoprolil, hidroksiprolil, tiazolidin-4-karbonilf trans-4-fluor-L-prolil, cis-4-fluor-L-prolil, trans -4-klor-L-prolil ili cis-4-klor-L-prolil;
X je etil, propil, butil, izopropil, sek.butil, terc.butil, ciklopropil ili cikopentil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D-izoleucil, D-leucil, D-norvalil, 1- aminopentil -1- karbonil, ili 2,2-dimetilglicil;
S je 0 ili 1;
K je -NH-C1-8-alkil, -NH-C3-8-alkenil, -NH-C3-8-alkinil, -NH-C6-8-cikloalkil, -NH-C1-4-alken-C3-8-cikloalkil,
C1-4-alkil-N-C1-6-alkil, u kojima ostaci jedne CH2 skupine mogu biti nadomješteni s O ili S, jedan H s fenilom ili cijano, ili 1, 2 ili H s fluorom, osim u slučaju ostatka N-metoksi-N-metilamino, N-benzilamino, ili ostatka N-metil-N-benzil-amino, ili K je
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
2. Novi peptidi formule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 je vodik, metil ili etil;
R2 je metil, ili etil; ili
R1-N-R2 zajedno tvore pirolidinski prsten;
A je ostatak valil, izoleucil, alo-izoleucil, 2-terc-butilqlicil, 2-etilglicil, norleucil ili norvalil;
B je ostatak N-metil-valil, N-metil-norvalil, N-metil-leucil, N-metil-izoleucil, N-metil-2-terc-butil-glicil, N- metil-2-etilglicil, ili N-metil-norleucil;
D je ostatak prolil, homoprolil, hidroksiprolil, ili tiazolidin-4-karbonil;
E je ostatak prolil, homoprolil, hidroksiprolil, tiazolidin-4-karbonil, trans-4-fluor-L-prolil, cis-4-fluor-L-prolil, trans-4- klor-L-prolil ili cis-4-klor-L-prolil;
X je etil, propil, butil, izopropil, sek.butil, terc.butil, ciklopropil ili cikopentil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D-izoleucil, D-leucil, D-norvalil, 1- aminopentil -1-karbonil, ili 2, 2-dimetilglicil;
S je 0 ili 1;
K je -NHCH3, -NHCH2CH3, -NH (CH2) 2CH3, -NH (CH2) 3CH3,
-NH (CH2) 4CH3, -NH (CH2) 5CH3, -NH (CH2) 6CH3, -NHCH (CH2) 7CH3,
-NHCH (CH3) 2, -NHCH (CH3) CH2CH3, -NHCH (CH2CH3) 2,
-NHCH (CH2CH2CH3) 2, -NHC (CH3) 3, -NHCH (CH2CH3) CH2CH2CH3,
-NHCH (CH3) CH (CH3) 2, -NHCH (CH2CH3) CH (CH3) 2, -NHCH (CH3) C (CH3) 3,
-NH-cikloheksil, -NH-cikloheptil, -NH-ciklookstil,
-N (CH3) OCH2CH3, -N (CH3) OCH2CH2CH3, -NH (CH3) OCH (CH3) 2,
-N (CH3) O (CH2) 3CH3, -N (CH3) OCH2C6H5, -NH (CH2) 2C6H5,
-NH(CH2)3C6H5, -NHCH(CH3)C6H5, -NHC (CH3) 2C6H5,
-NHC (CH3) 2CH2CH3, -NHC (CH3) (CH2CH3) 2, -NHCH[CH (CH3) 2]2,
-NHC(CH3)2CN, -NHCH(CH3)CH(OH)C6H5, -NHCH2-cikloheksil,
-NHCH2C(CH3)3, -NHCH2CH(CH3) 2, -NHCH2CF3, -NHCH (CH2F) 2,
-NHCH2CH2F, -NHCH2CH2OCH3, -NHCH2CH2SCH3, -NHCH2CHCH2,
-NH-C(CH3)2CH=CH2, -NHC (CH3) 2C≡CH, -NHC (CH2CH3) 2C≡CH,
-NHC(CH3)2CH2CH2OH, -NH (CH2CH2O) 2CH2CH3, -NHC (CH3) 2CH (CH3) 2,
-NHC(CH3)2CH2CH2CH3, -NHC (CH3) 2CH2C6H5, -N (OCH3) CH (CH3) 2,
-N(OCH3)CH2CH3, -N(OCH3)CH2CH2CH3, -N (OCH3) CH2C6H5,
-N(OCH3)C6H5, -N(CH3)OC6H5, -NHCH[CH (CH3) 2]2,
-N(OCH3)CH2CH2CH2CH3, ili K je
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
3. Novi peptidi tormule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 -je vodik, metil ili etil;
R2 je metil ili etil;
A je ostatak valil, izoleucil, 2-terc.butilglicil, 2-etil-glicil, norleucil ili norvalil;
B je ostatak N-metil-valil, N-metil-norvalil, N-metil-izoleucil, N-metil-2-terc.butilglicil, N-meti1-2-etil-glicil, ili N-metil-norleucil;
D je prolil ili tiazolidin-4-karbonilni ostatak;
E je ostatak prolil, homoprolil, tiazolidin-4-karbonil, trans-4-fluor-L-prolil, cis-4-fluor-L-prolil, trans-4- klor-L- prolil ili cis-4-klor-L-prolil;
X je etil, propil, izopropil, sek.butil, terc.butil ili ciklopropil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D~izoleucil, D-leucil ili 2,2-diinetil-glicil;
S je 0 ili 1;
K je -NH-C1-8-alkil, -NH-C6-8-cikloalkil, -NH-CH2-ciklolheksil, C1-4-alkil-N-C1-6-alkil, u kojima ostaci jedne CH2 skupine mogu biti nadomješteni s O, jedan H s fenilom ili 1, 2 ili H s fluorom, osini u slučaju ostatka N-metoksi-N-metilamino, N-benzilamino, ili N-metil-N-benzilamino, ili K je
[image]
4. Novi peptidi formule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 je metil;
R2 jesu metil;
A je valil, izoleucil ili 2-terc.butil-glicil ili etil-glicil;
B je ostatak N-metil-valil, N-metil-izoleucil, N-metil-2-terc.butilglicil, N-metil-2-etil-glicil ili N-metil-norleucil;
D je prolil ili tiazolidin-4-karbonilni ostatak;
E je ostatak prolilf trans-4-fluor-L-prolil, cis-4-fluor-L-prolil, trans-4-klor-L-prolil ili cis-4-klor-L-prolil;
X je etil, izopropil, sek.butil ili terc.butil;
G je ostatak L-2-terc.butilglicil, D-2-terc.butil-glicil, D-valil, D-izoleucil, D-leucil ili 2,2-dimetil-glicil;
S je 0 ili 1;
K je -NH-C1-8-alkil, -NH-C6-8-cikloalkil, -NH-CH2-cikloheksil, C1-4-alkil-N-C1-6-alkil, u kojima ostaci jedne CH2 skupine mogu biti nadomješteni s O, jedan H s fenilom ili 1, 2 ili H s fluorom, osim u slučaju ostatka N-metoksi-N -metilamino, N-benzilamino, ili N-metil-N-benzilamino, ili K je
[image]
[image]
5. Novi peptidi formule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 je metil;
R2 jesu metil;
A je ostatak valil, izoleucil ili 2-terc.butil-glicil ili etil-glicilni;
B je ostatak N-metil-valil, N-metil-izoleucil, N-metil-2-terc.butilglicil;
D je prolil ili tiazolidin-4-karbonilni ostatak;
E je ostatak prolil, cis-4-fluor-L-prolil ili cis-4-klor-L-prolil;
X je izopropil, sek.butil ili terc.butil;
S je 0;
K je -NHC(CH3)3, -NHCH (CH2CH3) CH (CH3) 2,
-NHCH (CH3) C (CH3) 3, -N (CH3) OCH2CH3, -N (CH3) OCH2CH2CH3,
-NH (CH3) OCH (CH3) 2, -N (CH3) O (CH2) 3CH3, -N (CH3) OCH2C6H5,
-NHC (CH3) 2C6H5, -NHC (CH3) 2CH2CH3, -NHC (CH3) (CH2CH3) 2,
--NHCH[CH (CH3) 2]2, -NHC (CH3) 2CN, -NHCH (CH3) CH (OH) C6H5,
-NH-C (CH3) 2CH=CH2, -NHC (CH3) 2C≡CH, -NHC (CH2CH3) 2C≡CH,
-NHC (CH3) 2CH2CH2OH, -NHC (CH3) 2CH (CH3) 2, -NHC (CH3) 2CH2CH2CH3,
-NHC (CH3) 2CH2C6H5, -N (OCH3) CH (CH3) 2, -N (OCH3) CH2CH3,
-N (OCH3) CH2CH2CH3, -N (OCH3) CH2C6H5, -N (OCH3) C6H5, -N (CH3) OC6H5,
-N (OCH3) CH2CH2CH2CH3, ili K je
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
6. Novi peptidi formule I
R1R2N-CHK-CO-A-B-D-E- (G) s-K I
naznačeni time, da
R1 je metil;
R2 jesu metil;
A je valilni ostatak;
B je N-metil-valilni ostatak;
D je prolilni ostatak;
E je prolilni ostatak;
X je izopropil;
S je 0;
K je -NHC(CH3)3, -NHCH (CH2CH3) CH (CH3) 2,
-NHCH (CH3) C (CH3) 3, -N (CH3) OCH2CH3, -N (CH3) OCH2CH2CH3,
-NH (CH3)O (CH2) 3CH3, -N (CH3)OCH2C6H5, -NHC (CH3) 2C6H5,
-NHC(CH3)2CH2CH3, -NHC (CH3) (CH2CH3) 2, -NHCH[CH (CH3) 2]2,
-NHC (CH3) 2CN, -NHCH(CH3)CH(OH)C6H5, -NH-C (CH3) 2CH=CH2,
-NHC(CH3)2C≡CH, -NHC(CH2CH3)2C≡CH, -NHC (CH3) 2CH2CH2OH,
-NHC(CH3)2CH(CH3)2, -NHC (CH3) 2CH2CH2CH3, -NHC (CH3) 2CH2C6H5,
-N(OCH3)CH(CH3)2, -N(OCH3)CH2CH3, -N (OCH3) CH2CH2CH3,
-N(OCH3)CH2C6H5, -N(OCH3)C6H5, -N (CH3) OC6H5,
-N (OCH3) CH2CH2CH2CH3, ili K je
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
7. Novi peptidi formule I
R1R2N-CHX-CO-A-B-D-E-(G) s-K I
naznačeni time, da
R1 je metil;
R2 jesu metil;
A je ostatak valil, izoleucil ili 2-terc.butil-qlicil;
B je ostatak N-metil-valil, N-metil-izoleucil ili N-metil-2-terc.butilglicil;
D je prolil ili tiazolidin-4-karbonilni ostatak;
E je prolilni ostatak;
X je izopropil, sek.butil ili terc.butil;
G je D-2-terc.butilglicil, D-izoleucil 2,2-dimetil-glicilni ostatak, D-valil ili L-2-terc.butilglicil;
S je 1;
K je K je -NHCH3, -NHCH2CH3, -NH (CH2) 2CH3,
-NH (CH2) 3CH3, -NH (CH2) 4CH3, -NH (CH2) 5CH3, -NHCH (CH3) 2,
-NHCH (CH3) CH2CH3, -NHCH (CH2CH3) 2, -NHC (CH3) 3,
-NH-cikloheksil, -NHC (CH3) 2CN, -NHC (CH3) 2C≡CH ili
-NHC(CH3) 2CONH2; ili K je
[image]
i njihove soli s fiziološki podnošljivim kiselinama.
8. Spojevi formule I ili njihove soli, naznačeni time, da se upotrebljavaju za liječenje bolesti.
9. Metoda ili priprava spojeva formule I prema zahtjevu 1, naznačena time, da se oni pripravljaju u skladu s poznatim metodama kemije peptida.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57342295A | 1995-12-15 | 1995-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP960585A2 true HRP960585A2 (en) | 1998-02-28 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR08/573,422A HRP960585A2 (en) | 1995-12-15 | 1996-12-12 | Novel peptides, their preparation and use |
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|---|---|
| EP (2) | EP0866800B1 (hr) |
| JP (1) | JP3939354B2 (hr) |
| KR (1) | KR100463739B1 (hr) |
| CN (1) | CN1127514C (hr) |
| AR (1) | AR004382A1 (hr) |
| AT (2) | ATE277076T1 (hr) |
| AU (2) | AU731458B2 (hr) |
| BG (1) | BG64563B1 (hr) |
| BR (1) | BR9611987A (hr) |
| CA (1) | CA2237721C (hr) |
| CO (1) | CO4750840A1 (hr) |
| CZ (1) | CZ296908B6 (hr) |
| DE (2) | DE69633457T2 (hr) |
| DK (1) | DK0866800T3 (hr) |
| ES (1) | ES2229287T3 (hr) |
| HR (1) | HRP960585A2 (hr) |
| HU (1) | HU228275B1 (hr) |
| IL (2) | IL124342A (hr) |
| MX (1) | MX9803953A (hr) |
| MY (1) | MY114327A (hr) |
| NO (1) | NO319273B1 (hr) |
| NZ (1) | NZ324691A (hr) |
| PL (1) | PL186721B1 (hr) |
| PT (1) | PT866800E (hr) |
| RU (1) | RU2182911C2 (hr) |
| SK (1) | SK285286B6 (hr) |
| TR (1) | TR199801102T2 (hr) |
| TW (1) | TW474946B (hr) |
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| ZA (1) | ZA9610510B (hr) |
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| US6143721A (en) * | 1997-07-18 | 2000-11-07 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
| US5985837A (en) * | 1998-07-08 | 1999-11-16 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
| WO2000051998A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
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| US4879276A (en) * | 1983-12-19 | 1989-11-07 | Uniroyal Chemical Ltd./Uniroyal Chemical Ltee | Method for reducing serum uric acid levels |
| US4816444A (en) * | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
| US5831002A (en) * | 1992-05-20 | 1998-11-03 | Basf Aktiengesellschaft | Antitumor peptides |
| KR100286242B1 (ko) * | 1992-05-20 | 2001-04-16 | 스타르크, 카르크 | 돌라스타틴 유도체 |
| SG67935A1 (en) * | 1992-12-16 | 1999-10-19 | Basf Ag | Novel peptides the preparation and use thereof |
| DE4415997A1 (de) * | 1994-05-06 | 1995-11-09 | Basf Ag | Neuer peptidischer Wirkstoff und dessen Herstellung |
| DE4415998A1 (de) * | 1994-05-06 | 1995-11-09 | Basf Ag | Neue Tetrapeptide, ihre Herstellung Verwendung |
| US5807984A (en) * | 1995-11-09 | 1998-09-15 | Basf Aktienegesellschaft | Oligopeptides, the preparation and use thereof |
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1996
- 1996-12-09 TW TW085115211A patent/TW474946B/zh not_active IP Right Cessation
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- 1996-12-13 MY MYPI96005266A patent/MY114327A/en unknown
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- 1996-12-13 AR ARP960105673A patent/AR004382A1/es active IP Right Grant
- 1996-12-13 ZA ZA9610510A patent/ZA9610510B/xx unknown
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1998
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- 1998-05-22 BG BG102479A patent/BG64563B1/bg unknown
- 1998-06-12 NO NO19982711A patent/NO319273B1/no not_active IP Right Cessation
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2004
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2005
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