CA2402193A1 - Novel lhrh-antagonists, production and use thereof as medicament - Google Patents
Novel lhrh-antagonists, production and use thereof as medicament Download PDFInfo
- Publication number
- CA2402193A1 CA2402193A1 CA002402193A CA2402193A CA2402193A1 CA 2402193 A1 CA2402193 A1 CA 2402193A1 CA 002402193 A CA002402193 A CA 002402193A CA 2402193 A CA2402193 A CA 2402193A CA 2402193 A1 CA2402193 A1 CA 2402193A1
- Authority
- CA
- Canada
- Prior art keywords
- xxx
- lys
- compound according
- nle
- tyr
- 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.)
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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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- 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
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- 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
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Reproductive Health (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to peptides, comprising an N-methylated amino acid component and an improved water solubility. According to the invention, medicaments containing the said peptides can be used for treatment of hormon e- dependant tumours and hormone-influenced non-malignant disease states.</SDOA B>
Claims (16)
1. Compounds of the general formula I
A-Xxx 1-Xxx 2-Xxx 3-Xxx 4-Xxx 5-Xxx 6-Xxx 7-Xxx 8-Xxx 9-Xxx 10-NH2 (I) in which A is an acetyl group, Xxx 1 is D-Na1 (2), Xxx 2 is D-Cpa, Xxx 3 is D-Pa1 (3), Xxx 4 is Ser, Xxx 5 is N-Me-Tyr, Xxx 6 is D-Cit, D-Hci or D-[~-N'-4-(4-amidinophenyl)-amino-1,4-dioxobutyl]Lys (abbreviation: D-Lys(B)), Xxx 7 is Leu or Nle, Xxx 8 is Arg or Lys(iPr), Xxx 9 is Pro and Xxx l0 is D-Ala or Sar, with the proviso that if Xxx 6 is D-Lys(B), then Xxx 7 is Nle, if Xxx 6 is D-Cit, then Xxx 7 is Nle and Xxx 10 is D-Ala, or if Xxx 6 is D-He i, then Xxx 7 is Leu and Xxx 10 is D-Ala, and their salts with pharmaceutically acceptable acids.
A-Xxx 1-Xxx 2-Xxx 3-Xxx 4-Xxx 5-Xxx 6-Xxx 7-Xxx 8-Xxx 9-Xxx 10-NH2 (I) in which A is an acetyl group, Xxx 1 is D-Na1 (2), Xxx 2 is D-Cpa, Xxx 3 is D-Pa1 (3), Xxx 4 is Ser, Xxx 5 is N-Me-Tyr, Xxx 6 is D-Cit, D-Hci or D-[~-N'-4-(4-amidinophenyl)-amino-1,4-dioxobutyl]Lys (abbreviation: D-Lys(B)), Xxx 7 is Leu or Nle, Xxx 8 is Arg or Lys(iPr), Xxx 9 is Pro and Xxx l0 is D-Ala or Sar, with the proviso that if Xxx 6 is D-Lys(B), then Xxx 7 is Nle, if Xxx 6 is D-Cit, then Xxx 7 is Nle and Xxx 10 is D-Ala, or if Xxx 6 is D-He i, then Xxx 7 is Leu and Xxx 10 is D-Ala, and their salts with pharmaceutically acceptable acids.
2. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7 -Arg 8-Pro 9-Sar 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7 -Arg 8-Pro 9-Sar 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
3. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B)6-Nle 7-Arg 8-Pro 9-D-Ala 10-NH2, or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B)6-Nle 7-Arg 8-Pro 9-D-Ala 10-NH2, or a salt with pharmaceutically acceptable acids thereof.
4. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7-Lys(iPr) 8-Pro 9-Sar 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7-Lys(iPr) 8-Pro 9-Sar 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
5. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Phe(4-Cl) 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Phe(4-Cl) 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Lys(B) 6-Nle 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
6. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Cit 6-Nle 7-Arg 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Cit 6-Nle 7-Arg 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
7. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Hci 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Hci 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
8. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Cit 6-Nle 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa 2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Cit 6-Nle 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
9. Compound according to Claim 1 having the formula:
Ac-D-Nal(2) 1-D-Cpa2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Hci 6-Leu 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
Ac-D-Nal(2) 1-D-Cpa2-D-Pal(3) 3-Ser 4-N-Me-Tyr 5-D-Hci 6-Leu 7-Lys(iPr) 8-Pro 9-D-Ala 10-NH2 or a salt with pharmaceutically acceptable acids thereof.
10. Compounds according to one of Claims 1 to 9, in which the salt is an acetate, trifluoroacetate or embonate.
11. Compounds according to one of Claims 1 to 10 for use as medicament.
12. Pharmaceutical preparation, comprising at least one compound according to one of Claims 1 to 10, and customary vehicles and excipient.
13. Process for the preparation of compounds of the general formula I according to Claim 1 and one of Claims 2 to 9, in which fragments from units Xxx 10 provided with suitable protective groups, in which m is an integer from 1 to 10 and Xxx 1 is acetylate, are synthesized on a solid phase or in solution according to customary processes, then the fragments are linked to a solid phase by segment coupling and after conclusion of the coupling the compounds of the general formula I
are removed from the solid phase using customary processes with amidation on the unit Xxx 10.
are removed from the solid phase using customary processes with amidation on the unit Xxx 10.
14. Use of the compounds according to Claims 1 to 10 for the production of medicament for the treatment of hormone-dependent tumors, in particular prostate carcinoma, breast cancer or uterine myoma, and for non-malignant indications whose treatment necessitates LH-RH hormone suppression, such as endometriosis, benign prostate hyperplasia (BPH) or for the treatment of female or male fertility disorders, in mammals, in particular in humans.
15. Process for the production of pharmaceutical preparations according to Claim 12, where at least one compound according to one of Claims 1 to 10 is mixed with the customary vehicles and excipient and formulated as a medicament.
16. Process for the treatment of hormone-dependent tumors in particular prostate carcinoma, breast cancer or uterine myoma, and non-malignant disorders whose treatment necessitates LH-RH
hormone suppression, such as endometriosis, benign prostate hyperplasia (BPH), and in the treatment of female or male fertility disorders, in mammals, in particular in humans, by administration of an efficacious dose of least one compound according to Claims 1 to 10.
hormone suppression, such as endometriosis, benign prostate hyperplasia (BPH), and in the treatment of female or male fertility disorders, in mammals, in particular in humans, by administration of an efficacious dose of least one compound according to Claims 1 to 10.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/525,007 | 2000-03-14 | ||
| US09/525,007 US6627609B1 (en) | 1999-03-17 | 2000-03-14 | LHRH antagonists having improved solubility properties |
| PCT/EP2001/002719 WO2001068676A2 (en) | 2000-03-14 | 2001-03-12 | Lhrh-antagonists, production and use thereof as medicament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2402193A1 true CA2402193A1 (en) | 2002-09-09 |
| CA2402193C CA2402193C (en) | 2010-05-18 |
Family
ID=24091545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2402193A Expired - Lifetime CA2402193C (en) | 2000-03-14 | 2001-03-12 | Novel lhrh-antagonists, production and use thereof as medicament |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP1268522B1 (en) |
| JP (1) | JP3805679B2 (en) |
| KR (1) | KR100607396B1 (en) |
| CN (2) | CN1443195A (en) |
| AT (1) | ATE408619T1 (en) |
| AU (2) | AU2001260110B2 (en) |
| BG (1) | BG107121A (en) |
| BR (1) | BR0109279A (en) |
| CA (1) | CA2402193C (en) |
| DE (1) | DE50114335D1 (en) |
| DK (1) | DK1268522T3 (en) |
| ES (1) | ES2312435T3 (en) |
| HR (1) | HRP20020810A2 (en) |
| HU (1) | HUP0300222A3 (en) |
| IL (1) | IL151647A0 (en) |
| MX (1) | MXPA02008870A (en) |
| NO (1) | NO20024363L (en) |
| NZ (1) | NZ521273A (en) |
| PL (1) | PL357999A1 (en) |
| PT (1) | PT1268522E (en) |
| RU (1) | RU2248982C9 (en) |
| SK (1) | SK14332002A3 (en) |
| UA (1) | UA79070C2 (en) |
| WO (1) | WO2001068676A2 (en) |
| ZA (1) | ZA200207248B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100340572C (en) * | 2004-12-01 | 2007-10-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel LHRH antagonist |
| CN101037472B (en) * | 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 | LHRH antagonist with low-histamine releasing function |
| AU2009206212B2 (en) | 2008-01-24 | 2014-01-16 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Lytic domain fusion constructs and methods of making and using same |
| CN101597321B (en) * | 2008-06-03 | 2013-04-24 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with long-acting low-histamine release side effect |
| WO2010142060A1 (en) * | 2009-06-11 | 2010-12-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Lhrh antagonist with long potency and low histamine releasing effect |
| IL238323B2 (en) | 2012-10-30 | 2023-11-01 | Esperance Pharmaceuticals Inc | Antibody/drug conjugates and methods of use |
| CN104418936B (en) * | 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 antagonist derivative and its medicinal usage |
| FR3024612B1 (en) * | 2014-08-04 | 2018-03-09 | Alstom Transp Tech | POWER SUPPLY MODULE OF A MOTOR BLOCK, TRACTION SYSTEM AND ELECTRIC VEHICLE |
| RU2585367C1 (en) * | 2014-11-05 | 2016-05-27 | Наталья Владимировна Спиридонова | Method of treating infertility in females suffering from uterine myoma |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5110904A (en) | 1989-08-07 | 1992-05-05 | Abbott Laboratories | Lhrh analogs |
| US5140009A (en) | 1988-02-10 | 1992-08-18 | Tap Pharmaceuticals, Inc. | Octapeptide LHRH antagonists |
| US5300492A (en) | 1988-02-10 | 1994-04-05 | Tap Pharmaceuticals | LHRH analogs |
| IL101074A (en) | 1991-03-14 | 1997-09-30 | Salk Inst For Biological Studi | GnRH ANALOGS AND THEIR PREPARATION |
| AU1371892A (en) | 1991-04-25 | 1992-12-21 | Romano Deghenghi | Luteinizing hormone releasing hormone antagonist peptides |
| US5698522A (en) | 1992-12-04 | 1997-12-16 | Abbott Laboratories | 6-position modified decapeptide LHRH antagonists |
| DK0683792T3 (en) | 1992-12-18 | 2002-01-14 | Abbott Lab | LHRH antagonists with modified aminoacyl residues at positions 5 and 6 |
| IL108509A0 (en) | 1993-02-22 | 1994-05-30 | Salk Inst For Biological Studi | GnRH antagonist peptides |
| DE4320201A1 (en) * | 1993-06-18 | 1995-01-12 | Asta Medica Ag | Use of Cetrorelix and other nona and decapeptides for the manufacture of a medicament for combating AIDS and for growth stimulation |
| DE19544212A1 (en) | 1995-11-28 | 1997-06-05 | Asta Medica Ag | New LH-RH antagonists with improved effects |
| DE19911771B4 (en) | 1999-03-17 | 2006-03-30 | Zentaris Gmbh | LHRH antagonist, process for its preparation and its use |
-
2001
- 2001-03-12 AU AU2001260110A patent/AU2001260110B2/en not_active Ceased
- 2001-03-12 DE DE50114335T patent/DE50114335D1/en not_active Expired - Fee Related
- 2001-03-12 EP EP01933682A patent/EP1268522B1/en not_active Expired - Lifetime
- 2001-03-12 AU AU6011001A patent/AU6011001A/en active Pending
- 2001-03-12 KR KR1020027012059A patent/KR100607396B1/en active IP Right Grant
- 2001-03-12 RU RU2002127786/04A patent/RU2248982C9/en active
- 2001-03-12 PL PL01357999A patent/PL357999A1/en unknown
- 2001-03-12 MX MXPA02008870A patent/MXPA02008870A/en active IP Right Grant
- 2001-03-12 CA CA2402193A patent/CA2402193C/en not_active Expired - Lifetime
- 2001-03-12 PT PT01933682T patent/PT1268522E/en unknown
- 2001-03-12 ES ES01933682T patent/ES2312435T3/en not_active Expired - Lifetime
- 2001-03-12 CN CN01807543A patent/CN1443195A/en active Pending
- 2001-03-12 AT AT01933682T patent/ATE408619T1/en not_active IP Right Cessation
- 2001-03-12 SK SK1433-2002A patent/SK14332002A3/en not_active Application Discontinuation
- 2001-03-12 WO PCT/EP2001/002719 patent/WO2001068676A2/en active IP Right Grant
- 2001-03-12 BR BR0109279-0A patent/BR0109279A/en not_active IP Right Cessation
- 2001-03-12 CN CNB2006100817821A patent/CN100500692C/en not_active Expired - Fee Related
- 2001-03-12 DK DK01933682T patent/DK1268522T3/en active
- 2001-03-12 IL IL15164701A patent/IL151647A0/en unknown
- 2001-03-12 HU HU0300222A patent/HUP0300222A3/en unknown
- 2001-03-12 JP JP2001567766A patent/JP3805679B2/en not_active Expired - Lifetime
- 2001-03-12 NZ NZ521273A patent/NZ521273A/en unknown
- 2001-12-03 UA UA2002108075A patent/UA79070C2/en unknown
-
2002
- 2002-09-10 ZA ZA200207248A patent/ZA200207248B/en unknown
- 2002-09-12 NO NO20024363A patent/NO20024363L/en not_active Application Discontinuation
- 2002-09-18 BG BG107121A patent/BG107121A/en unknown
- 2002-10-10 HR HRP20020810 patent/HRP20020810A2/en not_active Application Discontinuation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20210312 |