JP2003524591A - Dpiv阻害剤のプロドラッグ - Google Patents
Dpiv阻害剤のプロドラッグInfo
- Publication number
- JP2003524591A JP2003524591A JP2000555929A JP2000555929A JP2003524591A JP 2003524591 A JP2003524591 A JP 2003524591A JP 2000555929 A JP2000555929 A JP 2000555929A JP 2000555929 A JP2000555929 A JP 2000555929A JP 2003524591 A JP2003524591 A JP 2003524591A
- Authority
- JP
- Japan
- Prior art keywords
- prodrug compound
- inhibitor
- prodrug
- diabetes
- acid
- 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.)
- Granted
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 74
- 229940002612 prodrug Drugs 0.000 title claims abstract description 64
- 239000000651 prodrug Substances 0.000 title claims abstract description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 15
- 239000008103 glucose Substances 0.000 claims abstract description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 150000001413 amino acids Chemical class 0.000 claims abstract description 13
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 6
- 208000010444 Acidosis Diseases 0.000 claims abstract description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 4
- 206010027417 Metabolic acidosis Diseases 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims abstract 2
- 230000000694 effects Effects 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical group O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Chemical group OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 4
- 229960002591 hydroxyproline Drugs 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Chemical group ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 4
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
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- IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical group OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 claims description 2
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical group OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 claims description 2
- 108010016626 Dipeptides Proteins 0.000 claims description 2
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 2
- BBIXOODYWPFNDT-CIUDSAMLSA-N Ile-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(O)=O BBIXOODYWPFNDT-CIUDSAMLSA-N 0.000 claims description 2
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical group [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 claims description 2
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical group OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 claims description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- RLZXKARDPOFVNB-UHFFFAOYSA-N aziridine-1-carboxylic acid Chemical group OC(=O)N1CC1 RLZXKARDPOFVNB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012050 conventional carrier Substances 0.000 claims description 2
- KZNQNBZMBZJQJO-YFKPBYRVSA-N glyclproline Chemical compound NCC(=O)N1CCC[C@H]1C(O)=O KZNQNBZMBZJQJO-YFKPBYRVSA-N 0.000 claims description 2
- 108010077515 glycylproline Proteins 0.000 claims description 2
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- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Chemical group OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims description 2
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- 201000009104 prediabetes syndrome Diseases 0.000 claims description 2
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 abstract 1
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- 235000012333 Vitis X labruscana Nutrition 0.000 abstract 1
- 240000006365 Vitis vinifera Species 0.000 abstract 1
- 235000014787 Vitis vinifera Nutrition 0.000 abstract 1
- 208000033679 diabetic kidney disease Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 230000009471 action Effects 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 241000700157 Rattus norvegicus Species 0.000 description 5
- 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 description 5
- 238000003756 stirring Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- 230000000638 stimulation Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 3
- 102000046014 Peptide Transporter 1 Human genes 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
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- 210000004027 cell Anatomy 0.000 description 3
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- 230000006872 improvement Effects 0.000 description 3
- 108010082406 peptide permease Proteins 0.000 description 3
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- 210000002966 serum Anatomy 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108090000915 Aminopeptidases Proteins 0.000 description 2
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
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- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 102100029909 Peptide YY Human genes 0.000 description 1
- 108010088847 Peptide YY Proteins 0.000 description 1
- 102100033623 Phospholipid-transporting ATPase ABCA3 Human genes 0.000 description 1
- 102100031108 Pyroglutamyl-peptidase 1 Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100037330 Sjoegren syndrome nuclear autoantigen 1 Human genes 0.000 description 1
- 102100022076 Transmembrane protein 60 Human genes 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000001821 langerhans cell Anatomy 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108010017378 prolyl aminopeptidase Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical group 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
-
- 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
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- 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
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- 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
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
ロドラッグ化合物が提供され、そのプロドラッグ化合物が一般式A−B−C、式
中 Aがアミノ酸であり、 BがAとCの間の化学結合またはアミノ酸であり、 そして CがDP IVの安定な阻害剤である、 を有する。
はDP IV類縁酵素活性の阻害剤(エフェクター)を投与すると、DP IVお
よびDP IV様酵素による内在性の(および、又外からも投与される)インス
リン向性ペプチド胃抑制性ポリペプチド1−42(GIP1-42)およびグルカゴン様
ペプチドアミド−1 7−36(GLP-17-36)(または又GLP-17-37またはその類
縁体)の分解が減じられ、従ってそれらのペプチドホルモンまたはそれらの類縁
体の濃度の降下が減じられるか、または遅延することが見い出された。(内在性
のまたは外から導入された)インクレチンまたはそれらの類縁体の安定性によっ
てDP IVエフェクターの作用により高められた、膵臓のランゲルハンス細胞
のインクレチン受容体のインスリン向性刺激用としてのそれらの利用度を高め、
そしてとりわけ生体自体のインスリンの効果を変え、処置された生物の炭水化物
代謝の刺激を生じる。結果として、処置された生物の血清中の血清において、糖
レベルが高血糖症に特徴的なブドウ糖濃度よりも下にさがる。従って、DP I
V阻害剤によって、過剰体重、ブドウ糖尿症、高脂血症、そしてまた重症となる
代謝性アシドーシス、および血中の長引く高ブドウ糖濃度の結果である糖尿病等
の代謝異常を予防するか又は緩和することが可能である[参照:DE 196 16 486]
。
細胞の侵入を阻止することがまた実験的に可能である[参照:WAKSELMAN, M., N
GUYEN, C., MAZALEYRAT, J.-P., CALLEBAUT, C., KRUST, B., HOVANESSIAN, A.
G., CD26のDP IV活性の強力なシクロペプチド阻害剤によるCD26+
でCD26−ではない細胞のHIV−1感染の阻害、Abstract P 44 of the 24t h European Peptide Symposium 1996]。
調節できる[参照:MENTLEIN, R., DAHMS, P., GRANDT, D., KRUGER, R., ジペ
プチジルペプチダーゼIVによる神経ペプチドYおよびペプチドYYの蛋白分解
的プロセッシング、Regul. Pept. 49, 133 (1993); WETZEL, W., WAGNER, T.,
VOGEL, D., DEMUTH, H.-U., BALSCHUN, D.、CLIP断片ACTH 20−24
のレム睡眠状態の持続への影響、Neuropeptides, 31, 41 (1997)]。
られた開始を有するDP IVのエフェクターを提供することである。
ラッグ化合物を提供によって解決され、そのプロドラッグ化合物が一般式A−B
−C、式中 Aがアミノ酸であり、 BがAとCの間の化学結合またはアミノ酸であり、 および CがDP IVの安定な阻害剤である、 を有する。
マスクされていない阻害剤と比べて有意に高い活性を有している:マスクされて
いない阻害剤および本発明に記載のプロドラッグ化合物の等量を使用するとき、
75%までの耐糖能の改善がウイスターラット(Wistar rats)で得られる;表4
もまた参照。
収され、そして体の血管コンパートメント(vascular compartment)に入るという
事実に鑑みるとなおさらその改善は驚きである。従って、通常は経口的に投与さ
れた化合物の消化管における分解を抑えることのみが意図されるプロドラッグ化
合物は、阻害剤の活性の増大を導くことにならないと予想されていた。さらに、
付言すればたとえプロドラッグ化合物がそれ自体公知であっても、それらの事実
を基にして、当業者が修飾された阻害剤を、探索する理由は全くないといわなけ
ればならない;例えばPCT/US 97/09421を参照。
キシプロリン、チアゾリジンカルボン酸、デヒドロプロリン、ピペコリン酸、ア
ゼチジンカルボン酸またはアジリジンカルボン酸であり、プロリンおよびヒドロ
キシプロリンが特に好ましい。Bは好ましくは、AとCの間のペプチド結合を表
わすか、またはペプチド結合を介してAおよびCに連結される。
がって遊離されるという利点を特に有する。
れが酵素によって基A−Bおよび阻害剤Cへ開裂される。阻害剤Cは、さらなる
プロドラッグ化合物を開裂できないようにDP IV分子を阻害するであろう。
さらなるDP IV分子が存在するならば、プロドラッグ化合物は、最後のDP
IV分子が阻害されるまで開裂されるであろう(充分な量の対応するプロドラッ
グ化合物が投与されていた場合)。残りのプロドラッグ化合物は分解されず、従
ってDP IV分子の濃度が再び上昇するか、または阻害分子がDP IVによっ
て置き換えられるか、または阻害分子が***されるまで阻害剤の貯留を構成し、
そしてプロドラッグ化合物が次いで再び開裂され、従って阻害剤を遊離する。
るために必要な阻害剤を各生物が正確に遊離するであろうというさらなる利点を
有する。例えば、患者が高濃度のDP IVを有しているならば、大量の阻害剤
が遊離されるであろう;もしほんの少し上昇した濃度のDP IVしかなければ
、ほんの少しの量の阻害剤が遊離されであろう。
リジド、またはN−ジペプチジル,O−アシルヒドロキシルアミンであるプロド
ラッグ化合物が好ましい。そのような阻害剤はそれ自体、特に活性なDP IV
阻害剤であることを示している。そのような阻害剤の例として、例えばIle-Thia
、Ile-Pyr、Val-ThiaおよびVal-Pyrが挙げられる。
酸塩、コハク酸塩、酒石酸塩またはフマール酸塩等の有機塩、またはリン酸塩ま
たは硫酸塩等の無機酸基が好ましい。フマール酸塩が特に好ましい。
の新規なプロドラッグ化合物に関し、そのプロドラッグ化合物が種々の疾患、特
に糖尿病と関連する代謝性疾患の治療に使用できる。
用の開始および又作用の持続性が, 基A−Bの適切な選択によって時間的にコ
ントロールできるということにある。特に、本発明に記載のプロドラッグ化合物
から基A−Bの遊離はAのアミノ酸基の性質による:基A の定義に関して、次
の順番は、DP IV によるプロドラッグ化合物A−B−Cから基A−Bが遊離
される速度に対して見い出されている、即ちIle<Val<Phe<Pro<Ala<Gly。対応す
るPD IV 触媒遊離反応の速度定数は1s−1と100s−1の間である。
従って、正確に時間的に決まった方法でDP IV 阻害剤を遊離する手段が利用
できる:酵素が、例えばブドウ糖に富む栄養物の摂取で、直ちに作用の開始をす
るべき場合、例えば基Aとしてアミノ酸Gly をもつ化合物A−B−Cが選択され
るであろう;阻害剤の作用開始が遅くされるべき場合、例えばアミノ酸Ile が基
Aとして選択できる。従って、本発明に記載のプロドラッグ化合物によって、D
P IV 阻害剤が、特にほとんど遅滞なく、例えば摂取された栄養物とほとんど
同時に小腸の粘膜を通して輸送されることは可能である。
すとき、それは、好ましくはペプチド結合を介してAおよびCに連結する。
シルチアゾリジドの容量−効果関係の分析をすると、ウイスターラットへの活性
化合物の経口投与と非経口投与の間に差を見い出すことができる:経口投与では
、飽和が活性化合物の取り込みにおいて観察された(血清酵素の阻害に基づいて
測定)、ところが阻害剤の非経口投与では、酵素の完全な阻害が観察された。そ
れが表1に例によって示される。
び経口投与後、そしてイソロイシルチアゾリジド(Ole-Thia)用量の関数として
、基質H-Gly-Pro-pNA0.4mMに対するDP IV残存活性を阻害剤の投与30
分で決定。
することのできる本酵素、特に高濃度のDP IVがあり、そしてまた既に述べ
たように、DP IV阻害剤は消化管から定量的に吸収されるという事実に鑑み
て、DP IV阻害剤のプロドラッグ 化合物の使用はその状況においてなんらの
改善ももたらさないであろうと思われた。
れていないDP IV阻害剤と比較して糖負荷試験において明確に高い耐糖能を
もたらすことを見い出すことは極めて驚くべきことであった。その反応は特に驚
くべきであり、何故なら前に述べたように、プロドラッグが腸においてジペプチ
ジルペプチダーゼのようなそこに存在する酵素によって開裂されることが可能で
あり、従ってまさにマスクされていない阻害剤のように、標的部位への輸送に対
して、もはやなくなっている筈だからである:
れるやいなや、本発明に記載の阻害剤が遊離され、マスクされていない阻害剤が
使用されるときとまさに同じようにDP IVの阻害をする。従って、DP IV
によるプロドラッグ化合物のさらなる***が起らない;まだ分解されていないか
、又は付加的に導入されるすべてのプロドラッグ化合物並びに過剰の(即ち、D
P IVに結合していない)マスクされていない阻害剤が消化管から体の血管コ
ンパートメントへ分解されずに通過できる。そこで、それらは次いで、前に述べ
たように個々の必要に応じてDP IV阻害剤として使用できる。しかし、ある
時間の後、腸においてDP IVに結合された阻害剤が再び遊離され、血管コン
パートメントへ入る。
所望の増強を得ることも可能である。
てコントロールすることができる。
ゼは、ジペプチジルペプチダーゼIVに加えて哺乳動物の血液中に存在する。基
A−Bの適切な選択によって、どのアミノペプチダーゼがDP IV 阻害剤が遊
離するかを予め決定し、そしてどこで阻害剤の作用が起るのかを決定することが
本発明によって可能である。本発明に記載のプロドラッグ化合物または対応する
医薬組成物が従って、 DP IVの細胞特異的、組織特異的または器官特異的な
阻害において使用できる。血管コンパートメントに存在し、そして阻害剤を充分
早い速度で遊離するそれらの酵素のみが標的とされるように基A−Bを選択する
ことも可能である。
、全く驚くべき方法で、即ち 1. 阻害剤の増大した作用を達成すること; 2. 阻害剤が患者の必要に応じて遊離されること; 3. 阻害剤が時間的にコントロールされた方法でプロドラッグ化合物から遊離
されること; 4. 阻害剤がプロドラッグ化合物から遊離される部位がコントロールされるこ
と;および 5. DP IV 阻害剤の貯留が提供されること、 が可能であると言える。
に通常の担体または賦形剤と組み合わせて含むことを特徴とする、特に経口投与
のための医薬組成物がまた提供される。
例えばヒトの代謝性疾患のような、哺乳動物のDP IV活性を調節することに
よって治療できる哺乳動物の疾患の治療または予防に使用できる。
症、代謝性アシドーシス、糖尿病、糖尿病性の神経疾患および腎疾患、および糖
尿病の後遺症の治療に使用できる。
にN−ヒドロキシベンゾトリアゾール(1 eq.)およびチアゾリジン(1 eq.)と
一緒に懸濁する。当量のジシクロヘキシルカルボジイミド1M溶液を−10℃で撹
拌しながら滴加する。撹拌を−10℃で行ない、室温で一夜行なう。処理のため
、溶液を沈殿するジシクロヘキシルウレアから完全に濾別し、DMCを減圧下除去
し、得られる残渣を酢酸エチルに取る。酢酸エチル溶液を飽和重炭酸ナトリウム
溶液で少なくとも3回、飽和NaCl溶液で1回、希釈KHSO4溶液で3回そして再びN
aCl溶液で洗う。酢酸エチル層をNa2SO4で乾燥し、回転蒸発器を使用して濃縮し
、そして残こる粗生成物を酢酸エチル/ペンタンを用いて再結晶する。Boc-Pro-
Ile-Thiaが4℃で1−2日後結晶化する(収率80%)。1.1N HCl/氷酢酸の溶
液をBoc-Pro-Ile-Thia(ペプチド1 mmolに対して3 ml)に加える。撹拌を室温で
2時間行ない、無水エーテルを加え、除去できる溶液を回転蒸発器を使用して留
去する。塩酸塩が無水エーテル下4℃一夜で結晶化する。結晶をすばやく吸引濾
別し、数回無水エーテルで洗い、そして生成物をデシケーター中KOHまたは五酸
化リン上で保存する。
に冷却し、そして撹拌しながらN−メチルモルフォリン(1 eq.)およびクロロ
蟻酸イソブチルエステル(1 eq.)を続いて加える。活性化を約20分行なう。
平行して、Pro-Ile-Thia.HCl(1 eq.)をTHF 10 mlに懸濁し、−10℃に合わせ
、そしてN−メチルモルフォリン(1 eq.)を中和の目的のために加える。活性
時間が終わった後、両方の溶液を混合し、1ー2時間後室温へ温め、一夜撹拌す
る。次いで少量の水を反応混合物に加え、そしてTHFを減圧で留去する。残渣を
酢酸エチルに取り、飽和重炭酸ナトリウム溶液で少なくとも3回、飽和NaCl溶液
で1回、希釈KHSO4溶液で3回そして再びNaCl溶液で洗う。酢酸エチル層をNa2SO 4 で乾燥し、回転蒸発器を使用して濃縮し、そして生成物Boc-Gly-Pro-Ile-チア
ゾリジドを酢酸エチル/ペンタンを用いて再結晶する(収率85%)。 Bocの除
去はH-Pro-Ile-Thia/HClの合成と同様にして行なわれる(収率>95%)。
T1への親和性および輸送 種々のペプチド、DP IV阻害剤およびプロドラッグのペプチド輸送体PepT1
への親和性を放射能標識された基質D-Phe-Alaの置換によって分析した[AMASHEH
, S., WENZEL, U., WEBER, W. M., CLAUSS, W.. DANIEL, H., アフリカツメガエ
ル(Xenopus laevis)卵母細胞で発現される哺乳動物の腎ペプチド輸送体の機能の
電気生理学的分析、J. Physiol. 504, 169-174 (1997)]。例えば、テトラペプ
チド誘導体Ile-Pro-Ile-Thiaは選択されたアミノ酸誘導体と同等か、またはより
よく輸送体タンパクPepT1結合し、そして選択されたアミノ酸およびペプチドの
類縁体と比べて、同等かまたはよく輸送される(表3)。
輸送性
遊離 本発明に記載のDP IV阻害剤プロドラッグの態様によれば、標的コンパー
トメント、例えば、血液循環におけるDP IV阻害剤の遅くされた遊離がまた
可能である。 図1は、例として、本発明に記載のプロドラッグ化合物から阻害剤イソロイシ
ルチアゾリジドの遊離で生じるヒト血液DP IVの阻害、時間の関数としての
異なるコースをよる阻害を示す。血液におけるマスクされたDP IVの阻害剤
の遊離が、選ばれた場合において、DP IV自体(Pro-Pro-Ile-Thia = PPIThi
a、Gly-Pro-Ile-Thia = GPIThia)またはアミノペプチダーゼ(pGlu-Ile-Thia =
pEIThia、Pro-Ile-Thia = PIThia)によって行な割れる(図1)。同濃度のプ
ロドラッグ化合物が使用されると、DP IV阻害剤イソロイシルチアゾリジド
が血液中でプロドラッグ化合物から遊離される効率の違いがあり、活性物質の遊
離のより顕著な遅れが、Pro-Ile-Thia (PIThia)およびGly-Pro-Ile-Thia (GP
IThia)に比べてPro-Pro-Ile-Thia (PPIThia)およびpGlu-Ile-Thia (pEIThia
)の場合に示される。
ことの結果として、作用の顕著に改善されたプロフィールが経口投与によるウイ
スターラットで観察される(図2)。調べられた時間におけるDP IV阻害剤
によってもたらされた血中レベルの所望の低下が、マスクされていない活性物質
Ile-Thiaとは違って本発明に記載のプロドラッグ化合物を使用することによって
約30%強められる(表4):
載のプロドラッグの経口投与の100分での血中ブドウ糖レベルの関係
によるヒト全血中のDP IVの阻害を示す図である。
後の血清中のブドウ糖レベルを示す図である。
Claims (12)
- 【請求項1】 一般式A−B−C、式中 Aがアミノ酸であり、 BがAとCの間の化学結合またはアミノ酸であり、そして CがDP IVの安定な阻害剤である、 を有する、ジペプチジルペプチダーゼIV(DP IV)の阻害剤のプロドラッ
グ化合物。 - 【請求項2】 Bがプロリン、ヒドロキシプロリン、チアゾリジンカルボ
ン酸、デヒドロプロリン、ピペコリン酸、アゼチジンカルボン酸またはアジリジ
ンカルボン酸であることを特徴とする、請求項1に記載のプロドラッグ化合物。 - 【請求項3】 Bがプロリンまたはヒドロキシプロリンであることを特徴
とする、請求項1または2に記載のプロドラッグ化合物。 - 【請求項4】 Cがアミノアシルピロリジド、アミノアシルチアゾリジド
またはN−ジペプチジル,O−アシルヒドロキシルアミンであることを特徴とす
る、請求項1〜3のいずれかに記載のプロドラッグ化合物。 - 【請求項5】 阻害剤が塩の形で存在することを特徴とする、請求項1〜
4のいずれかに記載のプロドラッグ化合物。 - 【請求項6】 A−Bが式Ile-ProまたはGly-Proのジペプチドであること
を特徴とする、請求項1〜5のいずれかに記載のプロドラッグ化合物。 - 【請求項7】 請求項1〜6のいずれかに記載の少なくとも1つのプロド
ラッグ化合物を、任意に通常の担体または賦形剤と組み合わせて含むことを特徴
とする、特に経口投与のための医薬組成物。 - 【請求項8】 DP IVの時間的にコントロールされたインビボ阻害のた
めの医薬品の製造における、請求項1〜7のいずれかに記載のプロドラッグ化合
物または医薬組成物の使用。 - 【請求項9】 DP IVの細胞特異的、組織特異的または器官特異的な阻
害における、請求項1〜6のいずれかに記載のプロドラッグ化合物または医薬組
成物の使用。 - 【請求項10】 哺乳動物のDP IV活性を調節することによって治療で
きる哺乳動物の疾患の治療における、請求項1〜6のいずれかに記載のプロドラ
ッグ化合物または医薬組成物の使用。 - 【請求項11】 ヒトの代謝性疾患の治療における請求項9に記載の使用
。 - 【請求項12】 哺乳動物における損なわれた耐糖能、ブドウ糖尿症、高
脂血症、代謝性アシドーシス、糖尿病、糖尿病性の神経疾患および腎疾患、およ
び糖尿病の後遺症の治療における、請求項9に記載の使用。
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DE19828113A DE19828113A1 (de) | 1998-06-24 | 1998-06-24 | Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV |
DE19828113.7 | 1998-06-24 | ||
PCT/EP1999/004382 WO1999067278A1 (de) | 1998-06-24 | 1999-06-24 | Prodrugs von dp iv-inhibitoren |
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JP2003524591A true JP2003524591A (ja) | 2003-08-19 |
JP4088419B2 JP4088419B2 (ja) | 2008-05-21 |
Family
ID=7871859
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JP2000555929A Expired - Fee Related JP4088419B2 (ja) | 1998-06-24 | 1999-06-24 | Dpiv阻害剤のプロドラッグ |
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US (2) | US7084120B2 (ja) |
EP (1) | EP1087991B1 (ja) |
JP (1) | JP4088419B2 (ja) |
KR (1) | KR100529816B1 (ja) |
CN (1) | CN1245417C (ja) |
AT (1) | ATE441660T1 (ja) |
AU (1) | AU766726C (ja) |
BR (1) | BR9911468A (ja) |
CA (1) | CA2335992A1 (ja) |
DE (2) | DE19828113A1 (ja) |
HU (1) | HUP0102281A3 (ja) |
IL (1) | IL140336A0 (ja) |
NO (1) | NO20006484L (ja) |
NZ (1) | NZ508722A (ja) |
PL (1) | PL345151A1 (ja) |
RU (2) | RU2226533C2 (ja) |
WO (1) | WO1999067278A1 (ja) |
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- 1998-06-24 DE DE19828113A patent/DE19828113A1/de not_active Ceased
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1999
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- 1999-06-24 PL PL99345151A patent/PL345151A1/xx not_active Application Discontinuation
- 1999-06-24 WO PCT/EP1999/004382 patent/WO1999067278A1/de active IP Right Grant
- 1999-06-24 EP EP99932721A patent/EP1087991B1/de not_active Expired - Lifetime
- 1999-06-24 RU RU2001102058/04A patent/RU2226533C2/ru not_active IP Right Cessation
- 1999-06-24 DE DE59915073T patent/DE59915073D1/de not_active Expired - Fee Related
- 1999-06-24 JP JP2000555929A patent/JP4088419B2/ja not_active Expired - Fee Related
- 1999-06-24 AT AT99932721T patent/ATE441660T1/de not_active IP Right Cessation
- 1999-06-24 NZ NZ508722A patent/NZ508722A/en unknown
- 1999-06-24 HU HU0102281A patent/HUP0102281A3/hu unknown
- 1999-06-24 AU AU49007/99A patent/AU766726C/en not_active Ceased
- 1999-06-24 CA CA002335992A patent/CA2335992A1/en not_active Abandoned
- 1999-06-24 KR KR10-2000-7014662A patent/KR100529816B1/ko not_active IP Right Cessation
- 1999-06-24 CN CNB998076295A patent/CN1245417C/zh not_active Expired - Fee Related
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- 2000-12-19 NO NO20006484A patent/NO20006484L/no not_active Application Discontinuation
- 2000-12-22 US US09/745,776 patent/US7084120B2/en not_active Expired - Fee Related
-
2003
- 2003-12-11 US US10/735,582 patent/US7166579B2/en not_active Expired - Lifetime
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US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
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US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Also Published As
Publication number | Publication date |
---|---|
US20040171555A1 (en) | 2004-09-02 |
WO1999067278A1 (de) | 1999-12-29 |
US7084120B2 (en) | 2006-08-01 |
HUP0102281A2 (hu) | 2001-11-28 |
DE59915073D1 (de) | 2009-10-15 |
RU2226533C2 (ru) | 2004-04-10 |
KR20010071579A (ko) | 2001-07-28 |
EP1087991A1 (de) | 2001-04-04 |
RU2003136759A (ru) | 2005-05-27 |
KR100529816B1 (ko) | 2005-11-22 |
NO20006484D0 (no) | 2000-12-19 |
PL345151A1 (en) | 2001-12-03 |
AU766726B2 (en) | 2003-10-23 |
NO20006484L (no) | 2000-12-19 |
NZ508722A (en) | 2003-07-25 |
EP1087991B1 (de) | 2009-09-02 |
AU4900799A (en) | 2000-01-10 |
AU766726C (en) | 2004-08-12 |
CN1245417C (zh) | 2006-03-15 |
CN1306540A (zh) | 2001-08-01 |
US7166579B2 (en) | 2007-01-23 |
ATE441660T1 (de) | 2009-09-15 |
DE19828113A1 (de) | 2000-01-05 |
US20020049164A1 (en) | 2002-04-25 |
CA2335992A1 (en) | 1999-12-29 |
HUP0102281A3 (en) | 2001-12-28 |
JP4088419B2 (ja) | 2008-05-21 |
BR9911468A (pt) | 2001-03-20 |
IL140336A0 (en) | 2002-02-10 |
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