IL41313A - Preparation of the lh-and fsh-releasing hormone and compositions containing it - Google Patents
Preparation of the lh-and fsh-releasing hormone and compositions containing itInfo
- Publication number
- IL41313A IL41313A IL41313A IL4131373A IL41313A IL 41313 A IL41313 A IL 41313A IL 41313 A IL41313 A IL 41313A IL 4131373 A IL4131373 A IL 4131373A IL 41313 A IL41313 A IL 41313A
- Authority
- IL
- Israel
- Prior art keywords
- ester
- carboxy
- treating
- isolating
- prolyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims 18
- 108700012941 GNRH1 Proteins 0.000 title claims 4
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 title claims 4
- 238000000034 method Methods 0.000 claims 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 36
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 32
- 239000002253 acid Substances 0.000 claims 22
- 150000001875 compounds Chemical class 0.000 claims 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 18
- 239000004471 Glycine Substances 0.000 claims 16
- 150000007530 organic bases Chemical class 0.000 claims 16
- 125000005907 alkyl ester group Chemical group 0.000 claims 13
- 239000003054 catalyst Substances 0.000 claims 13
- 229910000510 noble metal Inorganic materials 0.000 claims 13
- 150000002148 esters Chemical class 0.000 claims 12
- 150000003839 salts Chemical class 0.000 claims 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 10
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims 9
- 229910052739 hydrogen Inorganic materials 0.000 claims 8
- 239000001257 hydrogen Substances 0.000 claims 8
- 239000012442 inert solvent Substances 0.000 claims 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 8
- 239000011707 mineral Substances 0.000 claims 8
- 239000002904 solvent Substances 0.000 claims 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 239000008194 pharmaceutical composition Substances 0.000 claims 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 6
- 150000008282 halocarbons Chemical class 0.000 claims 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 5
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims 5
- 229910052763 palladium Inorganic materials 0.000 claims 5
- OHCMNYPOVOHMJR-BZSNNMDCSA-N (2s)-2-[[(2s)-3-(1h-imidazol-5-yl)-2-[[(2s)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)NC(=O)[C@H]1NC(=O)CC1)C1=CNC=N1 OHCMNYPOVOHMJR-BZSNNMDCSA-N 0.000 claims 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims 4
- -1 aralkyl ester Chemical class 0.000 claims 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims 4
- 229960002429 proline Drugs 0.000 claims 4
- 239000007787 solid Substances 0.000 claims 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 3
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical group [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims 2
- WVISONSNWGLKSK-YFKPBYRVSA-N (2s)-2-(carboxyamino)-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(O)=O WVISONSNWGLKSK-YFKPBYRVSA-N 0.000 claims 2
- WUEPMEXUMQVEGN-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;2,2,2-trifluoro-n-[2-[2-[(2,2,2-trifluoroacetyl)amino]ethylamino]ethyl]acetamide Chemical compound OC(=O)C(F)(F)F.FC(F)(F)C(=O)NCCNCCNC(=O)C(F)(F)F WUEPMEXUMQVEGN-UHFFFAOYSA-N 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 2
- 229930182821 L-proline Natural products 0.000 claims 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 229960000583 acetic acid Drugs 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- 150000004292 cyclic ethers Chemical class 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 150000004702 methyl esters Chemical class 0.000 claims 2
- 230000020477 pH reduction Effects 0.000 claims 2
- 238000007911 parenteral administration Methods 0.000 claims 2
- 238000004810 partition chromatography Methods 0.000 claims 2
- 229960004799 tryptophan Drugs 0.000 claims 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims 1
- VNFJIBZRKDALBZ-UHFFFAOYSA-N 2-amino-n-tert-butylacetamide Chemical compound CC(C)(C)NC(=O)CN VNFJIBZRKDALBZ-UHFFFAOYSA-N 0.000 claims 1
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 claims 1
- 229920002307 Dextran Polymers 0.000 claims 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 claims 1
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 1
- 208000035752 Live birth Diseases 0.000 claims 1
- 101100091501 Mus musculus Ros1 gene Proteins 0.000 claims 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 239000003957 anion exchange resin Substances 0.000 claims 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 1
- TYQYRKDGHAPZRF-INIZCTEOSA-N benzyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)OCC1=CC=CC=C1 TYQYRKDGHAPZRF-INIZCTEOSA-N 0.000 claims 1
- HBBRVEMMVUOSTL-UHFFFAOYSA-N butyl n-aminocarbamate Chemical compound CCCCOC(=O)NN HBBRVEMMVUOSTL-UHFFFAOYSA-N 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 230000012173 estrus Effects 0.000 claims 1
- 239000012362 glacial acetic acid Substances 0.000 claims 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 230000002267 hypothalamic effect Effects 0.000 claims 1
- 238000002513 implantation Methods 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 229960003136 leucine Drugs 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 230000007257 malfunction Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical group Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 claims 1
- 230000016087 ovulation Effects 0.000 claims 1
- 230000001817 pituitary effect Effects 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 239000000829 suppository Substances 0.000 claims 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 claims 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
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0825—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp 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
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (3)
1. AHP-5792-1-C1 We claim: lo A process for preparing the LH- and FSH-releasing hormone, a decapeptide of the formula I H- Pyr - His - Trp - Ser - Tyr - Gly - Leu - Arg - Pro - Gly - KHn (I.) in the form of its hydrochloride salt$ which comprises treating the hexapeptide fl-.N-[N-[U-[N-( 5-oxo-L-prolyl) -L-histidyl] -L-trypto-phyl]-L-seryl]-L-tyrosyl]glyclne hydrazide trifl oroacetate in an anhydrous inert solvent with a strong mineral acid and an organic nitrite at a temperature within the range of from about -30°C to about -10°C, making the mixture alkaline by addition of a strong organic base, adding a solution of N-[N-[N-(N- L-leucyl)-L-arginyl]-L-prolyl]glycinamide diacetate in an anhydrous inert solvent, agitating the mixture at a temperature v/ithin the range from about -30°C to about 0°C, and isolating the decapeptide of formula I. as its hydrochloride salt.
2. A .process as claimed in Claim 1 in which the decapeptide of formula I is purified by partition chromatography and is isolated in substantially pure form as the diacetate salt.
3. , A process as claimed in Claim 2 in which the decapeptide of formula I is purified by partition chromatography on a chemically modified cross-linked dextran using the lower phase of a n-butanol-acetic acid-water mixture as solvent,, - o A process as claimed in Claim 1 in which the hydrochloride ealt of the decapeptide of formula I is treated with a strongly basic anion exchange resin in the form of its salt with a pharmaceutically acceptable acid and the corresponding salt of the decapeptide is isolated. 5· A process as claimed in Claim 1 in which the hydrochloride salt of the decapeptide of fonsula I is treated with a sparingly water-soluble acid and the corresponding sparingly water-soluble salt of the decapeptide is separated. AHP-5792-1-C1
6. A process as claimed in Claim 5 in which the sparingly water-soluble acid is taesikc, alginic, or pamoie acid. γβ A process as claimed in Claim 1 in which the anhydrous inert solvent is dimethylformamide or a mixture of dimethylformamide and dimethylsulfoxide. go A process as claimed in Claim 1 in which the strong mineral acid is hydrogen chloride. o,„ A process as claimed in Claim 1 in which the strong organic base is triethylamine. 2.0 · process as claimed in Claim 1 in which the organic nitrite is _t-butyl nitrite or isoamyl nitrite.
11. A process as claimed in Claim 1 %n which the hexapeptide N-[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl] - L-tryptophyl]-L-sery33-L-tyrosyl] lycine hydrazide trifluoroacetate is prepared by treating a Bolution of N-[N-(5-oxo-L-prolyl)-L-histidyl]- L-tryptophan hydrazide in an inert anhydrous solvent with a strong mineral acid and an organic nitrite at a temperature of from about -30°C to about -20°C, making the mixture alkaline by addition of a strong organic base, adding a solution of N-(N-L~Deryl-L-tyroeyl)glyclnQ 2-carboxyhydrazide t-butyl ecter in an inert anhydrous solvent, agitating the mixture at a temperature within the range from about -30°C to about 0°C to obtain K-[N-[N-lN-iN-(5-oxo=L-prolyl)-L-histidyl]- L-tryptophyl] -L-seryl]-L-tyrosyl] lycine 2-carboxyhydrazide t-butyl ester; treating said last-named compound with trifluoroacetic acid, and isolating the hexapeptide named above . 12· A process as claimed in Claim 11 in which the anhydrous inert solvent is dimethylformamide or a mixture of AHP-5792-1-C1 13, A process as claimed in Claim 11 in which the strong mineral acid is hydrogen chloride. Ik. A process as claimed in Claim 11 in which the strong organic base is triethylamine.
15. A process as claimed in Claim 11 in which the organic nitrite is t-butyl nitrite or isoarayl nitrite.
16. A process as claimed in Claim 11 in which the N-[N-(5-oxo-L-prolyl)-L-histidyl3-L-tryptophan hydrazide is prepared by treating a solution of N-(5-oxo-L-prolyl)-L-histidine hydrazide in an inert anhydrous solvent with a strong mineral acid and an organic nitrite at a temperature of from about -30°C to about -20°C, making the mixture alkaline b^ addition of a strong organic base, adding a solution of a lower alkyl or aralkyl ester of L-tryptophan in an inert anhydrous solvent, agitating the mixture at a temperature within the range from about -30°C to about 0?C, and isolating the corresponding N-[N-(5-oxo-L-prolyl) -L-histidyl]-L-tryptophan lower alkyl or aralkyl ester*, treating said last-named compound with hydrazine hydrate, and isolating N-[N-(5-oxo-L-prolyl)-L-histidyl3- L-tryptophan hydrazide. 17„ A process as claimed in Claim 16 in which the anhydrous inert solvent is dimethylformamide or a mixture of dimethylformamide and dimethylsulfoxide.
18. Λ process as claimed in Claim 16 in which the strong mineral acid is hydrogen chloride.
19. A process as claimed in Claim 16 in which the strong organic base is triethylamine. AHP-5? 2-i- 20, Λ process as claimed in Claim lb in which the organic nitrite is t-butyl nitrite or isoamyl nitrite. 21, A process as claimed in Claim 16 in which the ester of L-tryptophan is the benzyl ester. 22, A process as claimed in Claim 11 in which the N-(N-L-seryl-L-tyrosyl) lycine 2-carboxyhydrazide t_-butyl ester is prepared by treating a lower alkyl ester of N-[0-benzyl-N-carboxy-L-tyrosyl[]glycine -benzyl ester with an aqueous alkali raetal hydroxide followed by acidification of the mixture and' isolating N-[0-benzyl-N-carboxy-L-tyrosyl3glycine N-benzyl ester; treating said last-named compound in solution in an anhydrous ether or cyclic ether first v/ith ethyl chloroforraate and then with t-butyl carbazate, and isolating N-[0-benzyl-N-carboxy-L-tyrosyl] glycine N-benzyl ester 2-carboxyhydrazide ^-butyl ester; treating said last-named compound with hydrogen and a noble metal catalyst and isolating N-L-tyrosylglycine 2-carboxyhydrazide t—butyl ester; adding said last-named compound in solution in a halogenated hydrocarbon to an activated ester of N-carboXy-L-seryl N-benzyl ester, keeping the mixture at about 0°C for several days, and isolating N-[N~(N-carboxy-L-seryl)-L-tyrosyl]glycine N-benzyl ester 2-carboxyhydrazide t-butyl ester; treating said last-named compound with hydrogen and a noble metal catalyst , and isolating N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester, 23, A process as claimed in Claim 22 in which the lower alkyl ester of N-[0-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester is the methyl ester. AHP-5792-1-C1 2^ . Λ process as claimed in Claim 22 in which the noble metal catalyst is palladium. 5* A process as claimed in Claim 22 in which the halogenated hydrocarbon is chloroform.
26. A process as claimed in Claim 22 in which the activated ester of N-carboxy-L-seryl N-benzyl ester is the 2,^-dinitrophenyl ester. 27· · A process as claimed in Claim 1 in which the hexapeptid N-[ -[N-[N-[N-( 5-oxo-L-prolyl)-L-histidyl] -L-tryptophyl] -L-seryl]-L-tyrosyl3glycine hydrazide trifluoroacetate is prepared by treating N-[N-(5~oxo-L-prolyl)-L-histidyl]-L-tryptophan benzyl ester with hydrogen and a noble metal catalyst, and isolating N_[N-( 5-oxo-L-prolyl)-L-histidyl]-L-tryptophan; treating said last-named compound in solution in an anhydrous inert solvent with K-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide _t-butyl ester and dicyclohexylcarbodiimide at a temperature within the range of about 0°C to room temperature, and isolating fi._[N-[N-[N-[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophyl]-L-serylJ-L-tyrosyl]glycine 2-carboxyhydrazide t-butyl ester; treating said last-named compound with trifluoroacetic acid, and isolating the hexapeptide named above.
28. A process as claimed in Claim 27 in which the noble metal catalyst is palladium. 29· A process as claimed in Claim 27 in which the inert solvent is dimethylformamide. AHP-5792-1-C!
30. A process as claimed in Claim 2? in which the N_[N-(5-oxo-L-prolyl)-L-histidyl]-L-tryptophan benzyl ester is prepared by treating a solution of N-(5-oxo-L-prolyl)-L-histidine hydrazide in an inert anhydrous solvent with a strong mineral acid and an organic nitrite at a temperature of from about -30°C to about -20°C, making the mixture alkaline by addition of a strong organic base, adding a solution of L-tryptophan benzyl ester in an inert anhydrous solvent , agitating the mixture at a temperature within the range from about - 0°C to about 0°G, and isolating the corresponding N-[N-(5-oxo-L-prolyl)-L-histidyl] -L-tryptophan benzyl ester0 31¾ A process as claimed in Claim 30 in which the anhydrous inert solvent is dimethylformamide or a mixture of dimethylformamide and dimethylsulfoxide.
32. A process as claimed in Claim 30 in which the strong mineral acid is hydrogen chloride. 33» A process as claimed in Claim 30 in which the strong organic base is triethylamine. 3 . A process as claimed in Claim 30 in which the organic nitrite is _t-butyl nitrite or isoamyl nitrite.
35. T A process as claimed in Claim 27 in which the N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t.-butyl ester is prepared by treating a lower alkyl ester of N-[0-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester with an aqueous alkali metal hydroxide followed by acidification of the mixture and isolating N-[O-benzyl-N-carbox -L-t ros 1] lycine N-benzyl ester; treating said last-named compound in solution in an anhydrous ether or cyclic ether first with ethyl chlorofornate AHP~5792-1-Ci and then with butyl carbazate, and isolating N-[0-benzyl-N-carboxy-L-tyrosyl] glycine N-benzyl ester 2-carboxyhydrazide t-butyl ester; treating said last-named compound with hydrogen and a noble metal catalyst and isolating N-L-tyrosylglycine 2-carboxyhydrazide t-butyl ester; adding said last-named compound in solution in a halogenated hydrocarbon to an activated ester of N-carboxy-L-seryl N-benzyl ester, keeping the mixture at about 0°C for several days, and isolating N-[N-carboxy-L-seryl)-L-tyrosyl]glycine N-benzyl ester 2-carboxyhydrazide t-butyl ester; treating said last-named compound with hydrogen, and a noble metal catalyst, and isolating N-(N-L-seryl-L-tyrosyl)glycine 2-carboxyhydrazide t-butyl ester.
36. A process as claimed in Claim 35 in which the lov/er alkyl ester of N-[0-benzyl-N-carboxy-L-tyrosyl]glycine N-benzyl ester is the methyl ester.
37. A process as claimed in Claim 35in which the noble metal catalyst is palladium.
38. A process as claimed in Claim 35 in which the halogenated hydrocarbon is chloroform.
39. A process as claimed in Claim 35 in which the activated ester of N-carboxy-L-seryl N-benzyl ester is the 2,^-dinitrophenyl ester. ^O. A process as claimed in Claim 1 in which N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]glycinamide diacetate is prepared by treating N-carboxy-L-proline N-benzyl ester in solution in a halogenated hydrocarbon at about 0°C with a glycine lov/er alkyl ester acid addition salt in the presence AKP-5792-1-C1 of a strong organic base and of dicyclohexylcarbodiimide followed by treatment with ammonia, and isolating 2-[(N-carboxy- L-prolyl)aminoJacetamide N-benzyl ester; treating said last-named compound with hydrogen and a noble metal catalyst, and isolating 2-[(L-prolyl)amino3acetamide ; treating said last-named compound in solution in dimethylformamide and in the presence of a strong organic base with a N-carboxy- Q N -nitro-L-arginine N-lower alkyl ester and N-hydroxysuccinimide and dicyclohexylcarbodiimide at a temperature within the range of from about -20°C to room temperature, and isolating the corresponding N-lower alkyl ester of N-[N-(N-carboxy- N -nitro-L-arginyl)-L-prolyl]glycinamide; treating said last-named compound v/ith a strong acid, and separating the corresponding salt G of N-[N-(N -nitro-L-arginyl) -L-prolylUglycinamide ; treating said last-named compound in solution in dimethylformamide with an activated ester of N-carboxy-L-leucine N-benzyl ester in the presence of a strong organic base at a temperature within the range of from about 0°C to room temperature, and isolating N-[N-[N-(N-carboxy~L-leucyl)-N -nitro-L-arginyl]-L-prolylDglycinamide N-benzyl ester; treating said last-named compound in solution in glacial' acetic acid with hydrogen and a noble metal catalyst, and isolating N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl3glycinamide diacetate. hi, A process as claimed in Claim ho in which the halogenated hydrocarbon is chloroform. ^2. A process as claimed in Claim hO in which the glycine lower alkyl ester acid addition salt is glycine ethyl ester hydrochloride. h'>, A process as claimed in Claim hO in which the strong organic base is triethylamine. ΑΗΡ-5792~1-01 k . A process as claimed in Claim kO in which the noble metal catalyst is palladium.
45. A process as claimed in Claim kO in which the G N-lower alkyl ester of N-carboxy-N -nitro-L-arginine is the Q N-t-butyl ester, md N-[N-(N-carboxy-N -nitro-L-arginyl) -L-prolyj.]-glycinamide N-t_~butyl ester is obtained. ½, process as claimed in Claim ho n which the strong acid is hydrogen chloride or trifluoroacetic acid. " , Λ process as claimed in Claim 0 in which the activated ester of N-carboxy-L-le cine N-benzyl ester is the 2,^,5-trichlorophenyl ester. 'f8. A process as claimed in Claim 1 in which N-[N-[N-(N-L-leucyl)-L-arginyl]-L-prolyl]glycinamide diacetate is prepared by treating a lower alkyl ester acid addition salt of L-proline in solution in an anhydrous strongly polar G solvent with N-carboxy-N -nitro-L-arginine N-t-butyl- ester in the presence of a strong organic base and of dicyclohexylcarbodiimide at a temperature within the range of from about -20°C to room temperature, followed by treatment with an aqueous alkali metal hydroxide, and isolating M-(N-carboxy-N -nitro-L-arginyl)-L-proline N-t-butyl ester; treating said last-named compound in solution in dimethylformamide with an acid addition salt of a glycine lower alkyl ester in the presence of a strong organic base and of dicyclohexylcarbodiimide at a temperature within the range of from about 0°C to room temperature, followed by treatment with ammonia, and isolating N-[N-(N-carboxy-N -nitro-L-arginyl) -L-prolyl]glycinamide N-t-butyl ester; treating said last-nar:3d compound with a strong acid, and separating the corresponding ealt of H-CN-(WG-nitro-I*=arginyl)-L-prolyl]glycinamide; treating said last-named compound in 41313/2 solution in dimethylformamide with an activated ester of N-carboxy-L-.leucine N-benzyl ester in the presence of a strong organic base at a temperature within the range of from about 0°C to room temperature, and isolating N-[N-[N-(N-carboxy- L-leucyl)- -nitro-L-arginylD-L-prolylDglycinamide N-benzyl ester; treating said last-named compound in solution in glacial acetic acid with hydrogen and a noble metal catalyst, and isolating H-[N-[N-( -L-leucyl)-L-arginyl3-L-prolyl]glycinarnide diacetate. Λ process as claimed in Claim 8 in which the lower alkyl ester acid addition salt of L-proline is L-proline methyl ester hydrochloride.
50. A process as claimed in Claim 48.in which the strong organic base is triethylamine. ;
51. A process as claimed in Claim 48 in which the aqueous alkali metal hydroxide is sodium hydroxide.
52. A process as claimed in Claim 48 in which the acid addition salt of a glycine lower alkyl ester is glycine ethyl ester hydrochloride.
53. A process as claimed in Claim 48 in which the strong acid is hydrogen chloride or .trifluoroacetic acid0 . A process as claimed in Claim 48 in which the noble metal catalyst is palladium.
55. A process as claimed in Claim in which the activated ester of N-carboxy-L-leucine N-benzyl ester is the 2,4,5-trichlorophenyl ester. 41413/2
56. A pharmaceutical composition for nasal or parenteral administration v/hich comprises a pharmaceutically acceptable liquid carrier and the decapeptide of formula I when prepared by the process of Claim 1„
57. A pharmaceutical composition for parenteral, sublingual, or vaginal administration which comprises a pharmaceutically acceptable solid carrier and the decapeptide of formula I:when prepared by the process of Claim 1<>
58. A pharmaceutical composition for nasal or vaginal insufflation which comprises a pharmaceutically acceptable finely divided solid carrier and the finely divided decapeptide of formula I when prepared by the process of Claim 1.
59. A pharmaceutical composition for vaginal administration as a suppository which comprises a pharmaceutically acceptable semi-solid carrier and the decapeptide of formula I when prepared by the process of Claim 1. 60· A pharmaceutical composition for parenteral administration which comprises the decapeptide of fornmla I when prepared by the process of Claim 1 microencapsulated in a pharmaceutically acceptable coating material. ' 41313/2
61. A pharmaceutical composition for administration by implantation which comprises a pharmaceutically acceptable solid carrier or container and the decapeptide of formula I when prepared by the process of Claim 1.
62. A pharmaceutical composition for intravaginal administration which comprises a pharmaceutically acceptable container and the decapeptide of formula I when prepared by the process of Claim 1.
63. The method of synchronizing ovulation and estrus, of increasing the number of live births, and of inducing puberty in non-human animals which comprises administering the decapeptide of formula I when prepared by the process of Claim 1.
64. The method of distinguishing between hypothalamic and pituitary malfunctions or lefsions in the human female which comprises administering the decapeptide of formula I when prepared by the process of Claim 1, and observing the subsequent levels of LH. ND:ed
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US00226508A US3835108A (en) | 1972-02-15 | 1972-02-15 | Process for preparing the releasing hormone of luteinizing hormone(lh)and of follicle stimulating hormone(fsh),salts and compositions thereof,and intermediates therefor |
| US24346572A | 1972-04-12 | 1972-04-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL41313A0 IL41313A0 (en) | 1973-03-30 |
| IL41313A true IL41313A (en) | 1976-08-31 |
Family
ID=26920599
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL48514A IL48514A (en) | 1972-02-15 | 1973-01-17 | Hexapeptide intermediate for the preparation of the lh-and fsh-releasing hormone |
| IL41313A IL41313A (en) | 1972-02-15 | 1973-01-17 | Preparation of the lh-and fsh-releasing hormone and compositions containing it |
| IL48514A IL48514A0 (en) | 1972-02-15 | 1975-11-21 | Hexapeptide intermediate for the preparation of the lh-and fsh-releasing hormone |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL48514A IL48514A (en) | 1972-02-15 | 1973-01-17 | Hexapeptide intermediate for the preparation of the lh-and fsh-releasing hormone |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL48514A IL48514A0 (en) | 1972-02-15 | 1975-11-21 | Hexapeptide intermediate for the preparation of the lh-and fsh-releasing hormone |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5729462B2 (en) |
| CA (1) | CA1025441A (en) |
| CH (1) | CH589608A5 (en) |
| DE (1) | DE2307010C2 (en) |
| FR (1) | FR2181730B1 (en) |
| GB (3) | GB1425513A (en) |
| IL (3) | IL48514A (en) |
| NZ (1) | NZ169577A (en) |
| SE (1) | SE403772B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL68992A (en) * | 1982-06-29 | 1991-06-10 | Astra Laekemedel Ab | Alpha-bromo diethyl carbonate and process for the preparation of ethoxycarbonyloxy esters of penicillanic acids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS528831B2 (en) * | 1971-10-04 | 1977-03-11 |
-
1973
- 1973-01-17 IL IL48514A patent/IL48514A/en unknown
- 1973-01-17 NZ NZ169577A patent/NZ169577A/en unknown
- 1973-01-17 IL IL41313A patent/IL41313A/en unknown
- 1973-02-13 DE DE2307010A patent/DE2307010C2/en not_active Expired
- 1973-02-14 GB GB3217475A patent/GB1425513A/en not_active Expired
- 1973-02-14 FR FR7305151A patent/FR2181730B1/fr not_active Expired
- 1973-02-14 GB GB718073A patent/GB1425511A/en not_active Expired
- 1973-02-14 GB GB3217675A patent/GB1425512A/en not_active Expired
- 1973-02-14 CH CH210773A patent/CH589608A5/xx not_active IP Right Cessation
- 1973-02-14 SE SE7302099A patent/SE403772B/en unknown
- 1973-02-15 CA CA163,972A patent/CA1025441A/en not_active Expired
- 1973-02-15 JP JP1884473A patent/JPS5729462B2/ja not_active Expired
-
1975
- 1975-11-21 IL IL48514A patent/IL48514A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH589608A5 (en) | 1977-07-15 |
| FR2181730A1 (en) | 1973-12-07 |
| IL41313A0 (en) | 1973-03-30 |
| GB1425511A (en) | 1976-02-18 |
| JPS5729462B2 (en) | 1982-06-23 |
| SE403772B (en) | 1978-09-04 |
| FR2181730B1 (en) | 1977-07-15 |
| CA1025441A (en) | 1978-01-31 |
| NZ169577A (en) | 1984-09-28 |
| DE2307010A1 (en) | 1973-08-23 |
| JPS4886868A (en) | 1973-11-15 |
| IL48514A (en) | 1976-08-31 |
| GB1425512A (en) | 1976-02-18 |
| DE2307010C2 (en) | 1986-08-21 |
| IL48514A0 (en) | 1976-01-30 |
| GB1425513A (en) | 1976-02-18 |
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