LV10106B - Products and their application of method for design and synthesis of enteinizing hormone releasing hormone antagonists - Google Patents
Products and their application of method for design and synthesis of enteinizing hormone releasing hormone antagonists Download PDFInfo
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- LV10106B LV10106B LVP-92-175A LV920175A LV10106B LV 10106 B LV10106 B LV 10106B LV 920175 A LV920175 A LV 920175A LV 10106 B LV10106 B LV 10106B
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- d3pal3
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000015572 biosynthetic process Effects 0.000 title claims abstract 8
- 238000003786 synthesis reaction Methods 0.000 title claims abstract 8
- 239000005557 antagonist Substances 0.000 title claims description 6
- 239000005556 hormone Substances 0.000 title description 11
- 229940088597 hormone Drugs 0.000 title description 11
- 239000003488 releasing hormone Substances 0.000 title 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 claims abstract description 30
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims abstract 4
- 230000002513 anti-ovulatory effect Effects 0.000 claims abstract 3
- 229960001340 histamine Drugs 0.000 claims abstract 2
- 101100109397 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-8 gene Proteins 0.000 claims description 16
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 10
- 101100260702 Mus musculus Tinagl1 gene Proteins 0.000 claims description 10
- 101150088826 arg1 gene Proteins 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 239000002474 gonadorelin antagonist Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 3
- 102100024304 Protachykinin-1 Human genes 0.000 claims description 3
- 101800003906 Substance P Proteins 0.000 claims description 3
- -1 aromatic amino acids Chemical class 0.000 claims description 2
- 238000010276 construction Methods 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 3
- 150000001413 amino acids Chemical class 0.000 claims 2
- 201000009273 Endometriosis Diseases 0.000 claims 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 claims 1
- 102000009151 Luteinizing Hormone Human genes 0.000 claims 1
- 108010073521 Luteinizing Hormone Proteins 0.000 claims 1
- 108090000189 Neuropeptides Proteins 0.000 claims 1
- 102000003797 Neuropeptides Human genes 0.000 claims 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 claims 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 claims 1
- 239000003433 contraceptive agent Substances 0.000 claims 1
- 230000002254 contraceptive effect Effects 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 230000002124 endocrine Effects 0.000 claims 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 claims 1
- 208000000509 infertility Diseases 0.000 claims 1
- 230000036512 infertility Effects 0.000 claims 1
- 231100000535 infertility Toxicity 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- IDVFNSHOEYLXJD-UHFFFAOYSA-N liberine Chemical compound O=C1N(C)C(OC)=NC2=C1NC(=O)N2C IDVFNSHOEYLXJD-UHFFFAOYSA-N 0.000 claims 1
- 229940040129 luteinizing hormone Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000002028 premature Effects 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 210000004994 reproductive system Anatomy 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 abstract description 3
- 125000002038 D-arginyl group Chemical group N[C@@H](C(=O)*)CCCNC(=N)N 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 230000003578 releasing effect Effects 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 101150004094 PRO2 gene Proteins 0.000 description 6
- 101150043784 Reg3b gene Proteins 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IARMVHGFNATOQB-HOTGVXAUSA-N (2s)-2-[[(2s)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical class C1=CC=CC2=CC(C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CC=C21 IARMVHGFNATOQB-HOTGVXAUSA-N 0.000 description 3
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960003699 evans blue Drugs 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 101000740205 Homo sapiens Sal-like protein 1 Proteins 0.000 description 2
- 101100491597 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-6 gene Proteins 0.000 description 2
- 240000008881 Oenanthe javanica Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100037204 Sal-like protein 1 Human genes 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000745 gonadal hormone Substances 0.000 description 2
- 239000003667 hormone antagonist Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CIBMHJPPKCXONB-UHFFFAOYSA-N propane-2,2-diol Chemical compound CC(C)(O)O CIBMHJPPKCXONB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ANCPORHKTCOJHE-ZAJCDATESA-N (2s)-2-amino-3-(2,3,7,7a-tetrahydro-1h-indol-3-yl)propanoic acid Chemical compound C1C=CC=C2C(C[C@H](N)C(O)=O)CNC21 ANCPORHKTCOJHE-ZAJCDATESA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- MRHCSNNEUHXNIC-UHFFFAOYSA-N 9-benzylpurin-6-amine Chemical compound C1=NC=2C(N)=NC=NC=2N1CC1=CC=CC=C1 MRHCSNNEUHXNIC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100011375 Caenorhabditis elegans egl-4 gene Proteins 0.000 description 1
- 101100455752 Caenorhabditis elegans lys-3 gene Proteins 0.000 description 1
- 101100533230 Caenorhabditis elegans ser-2 gene Proteins 0.000 description 1
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 1
- 101100315627 Caenorhabditis elegans tyr-3 gene Proteins 0.000 description 1
- 101100149883 Candida albicans (strain SC5314 / ATCC MYA-2876) SOU2 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 1
- 102100038796 E3 ubiquitin-protein ligase TRIM13 Human genes 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 101000664589 Homo sapiens E3 ubiquitin-protein ligase TRIM13 Proteins 0.000 description 1
- 206010071119 Hormone-dependent prostate cancer Diseases 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OTXBNHIUIHNGAO-UWVGGRQHSA-N Leu-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN OTXBNHIUIHNGAO-UWVGGRQHSA-N 0.000 description 1
- CZCIKBSVHDNIDH-UHFFFAOYSA-N Nalpha-methyl-DL-tryptophan Natural products C1=CC=C2C(CC(NC)C(O)=O)=CNC2=C1 CZCIKBSVHDNIDH-UHFFFAOYSA-N 0.000 description 1
- 101100042258 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) sem-1 gene Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- DRKAXLDECUGLFE-ULQDDVLXSA-N Pro-Leu-Phe Chemical compound CC(C)C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O DRKAXLDECUGLFE-ULQDDVLXSA-N 0.000 description 1
- GXXTUIUYTWGPMV-FXQIFTODSA-N Ser-Arg-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O GXXTUIUYTWGPMV-FXQIFTODSA-N 0.000 description 1
- TYYLDKGBCJGJGW-WMZOPIPTSA-N Trp-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=C(O)C=C1 TYYLDKGBCJGJGW-WMZOPIPTSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- JFIOVJDNOJYLKP-UHFFFAOYSA-N bithionol Chemical compound OC1=C(Cl)C=C(Cl)C=C1SC1=CC(Cl)=CC(Cl)=C1O JFIOVJDNOJYLKP-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000026234 pro-estrus Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 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
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Claims (9)
- LV 10106 LUTEINIZĒJOŠĀ HORMONA LIBERĪNA ANTAGONISTU KONSTRUĒŠANAS UN SINTĒZES PRODUKTI UN TO IZMANTOŠANA IZGUDROJUMA FORMULA 5 1. Luteinizējošā hormona liberina (LHRH) antagonistu konstruēšanas un sintēzes metode, kā izejas sastāvu ņemot augstiedarbigu LHRH antagonistu [NAc-D2Na!1, DpCIPhe2, D3Pal3, Ser4, Tyr5, DArg1, Leu2 3, Arg1, Pro4, DAIa10]NH2 (II) un modificējot molekulas (II) sārmaino un 10 lipofīlo daļu, lai iegūtu jaunu LHRH antagonistu, kuram vienlaicīgi ir augsta antiovulārā aktivitāte (AOA) un zema histamīnizdalošā aktivitāte (HRA), kas pamatojas uz tās topoloģisko līdzību ar neiropeptīda, vielas P molekulu.
- 2. Konstruēšanas un sintēzes metode, saskaņā ar 1. punktu, kurTyr5-DArg1-Arg1 C-gals un aromātisko aminoskābju N-gals molekulā (II) tiek pielāgots un aizvietots.
- 3. Konstruēšanas un sintēzes metode, saskaņā ar 1. un 2. punktiem, 20 kur piemērota sārmaina grupa tiek ievadīta pozīcijā 2, 3, 5, 6, 8 un sintētiska aminoskābe tiek ievadīta iepriekšminētajās pozīcijās.
- 4. Konstruēšanas un sintēzes metode, saskaņā ar 1. punktu, kur DArg1 molekulā (II) ir aizvietots ar D3Pal ar piemērotu bāziskumu, lai 25 iegūtu analogu (III): [NAc-D2Na|1, DpCIPhe2, D3Pal3, Ser4, Tyr5, D3Pal1, Leu3, Arg1, Pro4, DAIa1ū]NH2.
- 5. Konstruēšanas un sintēzes metode, saskaņā ar 1. un 4. punktiem, kur Tyr5 molekulā (III) ir aizvietots ar Arg5, lai iegūtu analogu (IV): [NAc-30 D2Nal1, DpCIPhe2, D3Pal3, Ser4, Arg5, D3Pal1, Leu3, Arg1, Pro4, DAIa10]NH2. 1 35 [NAc-D2Nal1, DpCIPhe2, DPhe.3, Ser4, Arg5, D3Pal1, Leu3, Arg1, Pro4, 2 Konstruēšanas un sintēzes metode, saskaņā ar 5 punktu, 3 kur D3Pal3 molekulā (IV) ir aizvietots ar DPhe3, lai iegūtu analogu (V): 4 DAIa10]NH2. 2
- 7. Konstruēšanas un sintēzes metode, saskaņā ar 4. punktu, kur D3Pal3 molekulā (III) ir aizvietots ar DPhe8, lai iegūtu analogu (V): [NAc-D2Na|1, DpCIPhe2, DPhe3, Ser4, Tyr5, D3Pal8, Leu7, Arg8, Pro9, DAIa10]NH2·
- 8. Sastāvs, saskaņā ar 1. punktu, kurš izteikts ar formulu [NAc-D2Na|1, AA2, AA3, Ser4, AA5, AA8, Leu7, AA8, Pro9, DAIa10]-NH2, kurā AA ir dabiskas vai sintētiskas aminoskābes ar formulu D- vai L-ArAla, kurun R’2N-, RR'N-: kurā r· = CH3'* CH3CH2-, C3H7-, C4H9-, H-; r = CH3-; CH3CH2-, C3H7-, C4H9-, H-. LV 10106
- 9. LHRH antagonisti, saskaņā ar 8. punktu, AA2 = D-pCIPhe, D-ArAla, Dphe, Ar-Ala, DXCH2Phe; AA3 = D3Pal, Ar-Ala, D-ArAla, DPhe, D-XCH2Phe; AA5 = Arg, DMap, Pip, Tyr, Pal, Mop, Tep, Map, Phe, Eap, Pap, 5 Bap, DMop; AA8 = D3Pal, D-Ar-Ala, D-XCH2Phe; AA8 = Pip, Mop, Tep, Map, Eap, Pap, Bap, Arg, kurāun R’2N-, RR'N-: kurā 35 R' = CH3-, CH3CH2-, C3H7-, C4H9-, H-; R = CH3-, CH3CH2-, C3H7-, C4H9-, H-. 4
- 10. LHRH antagonistu, saskaņā ar 8, vai 9. punktu, izmantošana, kur sastāvs, kā peptidu zāļu līdzeklis, normāla injekciju šķīduma, injicējamu kapsulu un citu farmaceitisku sastāvu formā tiek izmantots vairošanās endokrinoloģiskās sistēmas traucējumu, ieskaitot 5 endometriozi, priekšlaicīgo bērnu pubertāti, prostātas vēzi un krūšu dziedzera vēzi, ārstēšanai un kā vīriešu, tā sieviešu kontracepcijas līdzeklis dzimstības regulēšanai vai arī neauglības diagnostikai un ārstēšanai. 10 11. [N-AC-D2NaM, P-CI-D-Phe2, D3Pal3, Ser* MopS, D3Pal6, Leu7, Arg8, Pro9, D-Ala10]NH2 · 12. [N-AC-D-2Nal1, D-Phe2, D3Pal3, Ser*, Mop8, D3Pal8, Leu7, Arg8, Pro9,D-Ala1Ū]NH2. 15 13. [N-AC-D-2Na|1, P-Cl-D-Phe2, D3Pal3, Ser* Arg8, D3Pal8, Leu7, Pap8,Pro9,D-Ala10]NH2. 20
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN90108955A CN1036343C (zh) | 1990-11-10 | 1990-11-10 | 新促黄体生成素释放激素拮抗类似物的制备方法 |
| PCT/EP1991/002110 WO1992008733A1 (en) | 1990-11-10 | 1991-11-08 | Lhrh-antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LV10106A LV10106A (lv) | 1994-05-10 |
| LV10106B true LV10106B (en) | 1995-04-20 |
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| LVP-92-175A LV10106B (en) | 1990-11-10 | 1992-10-27 | Products and their application of method for design and synthesis of enteinizing hormone releasing hormone antagonists |
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| Country | Link |
|---|---|
| EP (1) | EP0564466B1 (lv) |
| KR (1) | KR100244624B1 (lv) |
| CN (1) | CN1036343C (lv) |
| AT (1) | ATE149520T1 (lv) |
| AU (1) | AU662496B2 (lv) |
| CA (1) | CA2095932C (lv) |
| CZ (1) | CZ284168B6 (lv) |
| DE (1) | DE69125024T2 (lv) |
| DK (1) | DK0564466T3 (lv) |
| EE (1) | EE03141B1 (lv) |
| ES (1) | ES2100965T3 (lv) |
| FI (1) | FI933156A0 (lv) |
| GR (1) | GR3023389T3 (lv) |
| HR (1) | HRP920585B1 (lv) |
| IE (1) | IE913915A1 (lv) |
| LT (1) | LT3971B (lv) |
| LV (1) | LV10106B (lv) |
| NO (1) | NO931697L (lv) |
| NZ (1) | NZ240505A (lv) |
| PH (1) | PH31178A (lv) |
| PL (1) | PL170564B1 (lv) |
| PT (1) | PT99458B (lv) |
| RU (1) | RU2123499C1 (lv) |
| SI (1) | SI9111779B (lv) |
| SK (1) | SK281319B6 (lv) |
| UA (1) | UA41300C2 (lv) |
| WO (1) | WO1992008733A1 (lv) |
| YU (1) | YU48831B (lv) |
| ZA (1) | ZA918847B (lv) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69330838T2 (de) * | 1992-12-18 | 2002-04-25 | Abbott Laboratories, Abbott Park | Lhrh antagonisten mit modifizierten aminoacylresten an den positionen 5 und 6 |
| DE4305225A1 (de) * | 1993-02-19 | 1994-08-25 | Asta Medica Ag | Neues Herstellverfahren für Cetrorelix Lyophilisat |
| US6828415B2 (en) | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
| DE4338015A1 (de) * | 1993-11-08 | 1995-05-11 | Asta Medica Ag | Verwendung von D-glucopyranuronsäuren und deren Derivaten zum Einbau in pharmakologisch wirksame Peptide und deren Salze |
| US5843901A (en) * | 1995-06-07 | 1998-12-01 | Advanced Research & Technology Institute | LHRH antagonist peptides |
| DE19544212A1 (de) * | 1995-11-28 | 1997-06-05 | Asta Medica Ag | Neue LH-RH-Antagonisten mit verbesserter Wirkung |
| US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
| DE19911771B4 (de) * | 1999-03-17 | 2006-03-30 | Zentaris Gmbh | LHRH-Antagonist, Verfahren zu seiner Herstellung und seiner Verwendung |
| CN101037472B (zh) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | 具有低组胺释放作用的促黄体生成素释放激素拮抗剂 |
| CN102675418B (zh) * | 2011-03-15 | 2016-04-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Lhrh拮抗剂衍生物、其制备方法及用途 |
| CN103524599B (zh) * | 2012-07-05 | 2016-04-20 | 中国人民解放军军事医学科学院毒物药物研究所 | 环肽lhrh拮抗剂衍生物及其药物用途 |
| CN104418936B (zh) * | 2013-08-20 | 2018-06-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Lhrh拮抗剂衍生物及其药物用途 |
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| US4801577A (en) * | 1987-02-05 | 1989-01-31 | Syntex (U.S.A.) Inc. | Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists |
| US4851385A (en) * | 1987-07-15 | 1989-07-25 | Indiana University Foundation | LHRH antagonist analogs having low histamine-release activity |
-
1990
- 1990-11-10 CN CN90108955A patent/CN1036343C/zh not_active Expired - Lifetime
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1991
- 1991-11-07 NZ NZ240505A patent/NZ240505A/xx not_active IP Right Cessation
- 1991-11-07 ZA ZA918847A patent/ZA918847B/xx unknown
- 1991-11-08 DE DE69125024T patent/DE69125024T2/de not_active Expired - Lifetime
- 1991-11-08 WO PCT/EP1991/002110 patent/WO1992008733A1/en not_active Ceased
- 1991-11-08 SI SI9111779A patent/SI9111779B/sl not_active IP Right Cessation
- 1991-11-08 IE IE391591A patent/IE913915A1/en not_active Application Discontinuation
- 1991-11-08 ES ES91919435T patent/ES2100965T3/es not_active Expired - Lifetime
- 1991-11-08 CZ CZ93848A patent/CZ284168B6/cs not_active IP Right Cessation
- 1991-11-08 AU AU88612/91A patent/AU662496B2/en not_active Ceased
- 1991-11-08 UA UA94030668A patent/UA41300C2/uk unknown
- 1991-11-08 AT AT91919435T patent/ATE149520T1/de not_active IP Right Cessation
- 1991-11-08 PH PH43428A patent/PH31178A/en unknown
- 1991-11-08 RU RU93004994A patent/RU2123499C1/ru not_active IP Right Cessation
- 1991-11-08 DK DK91919435.7T patent/DK0564466T3/da active
- 1991-11-08 CA CA002095932A patent/CA2095932C/en not_active Expired - Lifetime
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- 1991-11-08 PT PT99458A patent/PT99458B/pt not_active IP Right Cessation
- 1991-11-08 KR KR1019930701418A patent/KR100244624B1/ko not_active Expired - Fee Related
- 1991-11-08 SK SK453-93A patent/SK281319B6/sk unknown
- 1991-11-08 YU YU177991A patent/YU48831B/sh unknown
-
1992
- 1992-09-29 HR HR920585A patent/HRP920585B1/xx not_active IP Right Cessation
- 1992-10-27 LV LVP-92-175A patent/LV10106B/en unknown
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1993
- 1993-05-10 PL PL91295427A patent/PL170564B1/pl unknown
- 1993-05-10 NO NO93931697A patent/NO931697L/no not_active Application Discontinuation
- 1993-07-09 FI FI933156A patent/FI933156A0/fi not_active Application Discontinuation
- 1993-12-03 LT LTIP1513A patent/LT3971B/lt not_active IP Right Cessation
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1994
- 1994-10-25 EE EE9400178A patent/EE03141B1/xx not_active IP Right Cessation
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1997
- 1997-05-09 GR GR970401042T patent/GR3023389T3/el unknown
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