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 it

Info

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
Application number
IL41313A
Other versions
IL41313A0 (en
Original Assignee
Harrison Ltd
Mckenna A
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US00226508A external-priority patent/US3835108A/en
Application filed by Harrison Ltd, Mckenna A filed Critical Harrison Ltd
Publication of IL41313A0 publication Critical patent/IL41313A0/en
Publication of IL41313A publication Critical patent/IL41313A/en

Links

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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (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
IL41313A 1972-02-15 1973-01-17 Preparation of the lh-and fsh-releasing hormone and compositions containing it IL41313A (en)

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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE454879B (en) * 1982-06-29 1988-06-06 Astra Laekemedel Ab ALFA-BROMODYTHYL CARBONATE AND ITS USE AS INTERMEDIATE IN PENICILLIN G PREPARATION

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS528831B2 (en) * 1971-10-04 1977-03-11

Also Published As

Publication number Publication date
IL48514A0 (en) 1976-01-30
IL41313A0 (en) 1973-03-30
FR2181730B1 (en) 1977-07-15
JPS4886868A (en) 1973-11-15
SE403772B (en) 1978-09-04
GB1425513A (en) 1976-02-18
NZ169577A (en) 1984-09-28
FR2181730A1 (en) 1973-12-07
CA1025441A (en) 1978-01-31
GB1425511A (en) 1976-02-18
GB1425512A (en) 1976-02-18
IL48514A (en) 1976-08-31
JPS5729462B2 (en) 1982-06-23
DE2307010C2 (en) 1986-08-21
CH589608A5 (en) 1977-07-15
DE2307010A1 (en) 1973-08-23

Similar Documents

Publication Publication Date Title
AU675274B2 (en) Reduced size LHRH analogs
CA1263500A (en) Gnrh antagonists ii
ES2260833T3 (en) MODIFIED GNRH ANTAGONISTS IN POSITIONS 5 AND 6.
US4689396A (en) GnRH antagonists V
EP0973801B1 (en) GnRH ANTAGONISTS
US4565804A (en) GnRH Antagonists VI
JPH03501969A (en) An effective antagonist of the hormone-releasing luteinizing hormone that releases negligible amounts of histamine.
PT984982E (en) LH-RH PEPTIDIC ANALOGS ITS USES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4661472A (en) GnRH antagonists IX
CA1302650C (en) Gnrh antagonists viii
US3835108A (en) Process for preparing the releasing hormone of luteinizing hormone(lh)and of follicle stimulating hormone(fsh),salts and compositions thereof,and intermediates therefor
KR920004824B1 (en) Process for the preparing lh/rh antagonist peptides
JPS6022720B2 (en) Peptide and its production method
HU186877B (en) Process for preparing new hormone antagonists releasing luteinizing hormone and acid addition salts thereof
EP0063423B1 (en) Gnrh antagonists
US4619914A (en) GNRH antagonists IIIB
US4740500A (en) GnRH antagonists VIII
US3888838A (en) Decapeptide having luteinizing hormone (lh)-and follicle stimulating hormone (fsh)-releasing activity, salts and compositions thereof, a process for preparing same, and intermediates therefor
US4083967A (en) Nona- and decapeptides
IL41313A (en) Preparation of the lh-and fsh-releasing hormone and compositions containing it
EP0122712A2 (en) GnRH antagonists
IE58287B1 (en) Spiro-heteroazolones for treatment of diabetes complications
KITAGAWA et al. Alternative Synthesis of Substance P
MXPA99011169A (en) Lh-rh peptide analogues, their uses and pharmaceutical compositions containing them