[go: up one dir, main page]

WO1995004541A1 - Analogues de lhrh a extremite n-terminale modifiee - Google Patents

Analogues de lhrh a extremite n-terminale modifiee Download PDF

Info

Publication number
WO1995004541A1
WO1995004541A1 PCT/US1994/008678 US9408678W WO9504541A1 WO 1995004541 A1 WO1995004541 A1 WO 1995004541A1 US 9408678 W US9408678 W US 9408678W WO 9504541 A1 WO9504541 A1 WO 9504541A1
Authority
WO
WIPO (PCT)
Prior art keywords
ser
leu
pro
d4clphe
d3pal
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.)
Ceased
Application number
PCT/US1994/008678
Other languages
English (en)
Inventor
Fortuna Haviv
Timothy D. Fitzpatrick
Rolf E. Swenson
Charles J. Nichols
Nicholas A. Mort
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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 US08/103,022 external-priority patent/US5413990A/en
Priority claimed from US08/279,677 external-priority patent/US5502035A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to JP50647395A priority Critical patent/JP3662926B2/ja
Priority to EP94924100A priority patent/EP0738154A1/fr
Publication of WO1995004541A1 publication Critical patent/WO1995004541A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary 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
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • 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
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to organic compounds having biological activity, to compositions containing the compounds, and to medical methods of treatment. More particularly, the present invention concerns certain N- terminus modified deca-and undecapeptides having LHRH antagonist activity, pharmaceutical compositions containing the peptides, and a method of inhibiting LHRH activity in a mammal in need of such treatment.
  • the gonadotropins follicle stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG), are required for ovulation, spermatogenesis, and the biosynthesis of sex steroids.
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • CG chorionic gonadotropin
  • a single hypothalamic hormone, gonadotropin-releasing hormone (GnRH, also known as luteinizing hormone-releasing hormone, LHRH) is responsible for regulating the secretion of both FSH and LH in mammals.
  • LHRH The structure of LHRH was determined by A. V. Schally, et al, Science, 173: 1036-1037 (1971). Early attempts to prepare peptides having LHRH-like activity centered on the synthesis of compounds which were LHRH agonists.
  • these compounds contain nine or ten aminoacyl residues, substituting naturally-occurring or non-naturally-occurring amino acid residues at one or more positions in the natural sequence of LHRH.
  • active antagonists of LHRH have been reported which contain fewer than ten amino acid residues.
  • LHRH antagonists are useful for the treatment of a variety of conditions in which the suppression of sex steroids plays a key role including contraception, delay of puberty, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormonal-dependent tumors of the breast and ovaries, palliative treatment or remission of hormonal-dependent tumors of the prostate, the treatment of cryptoorchidism, hirsutim in women, gastric motility disorders, dysmenorrhea, and endometriosis.
  • the present invention provides, in its principle embodiment, a class of deca-and undecapeptide antagonist analogs of LHRH which have been modified at the N-terminus by addition of either an acyl functional group or an acyl functional group together with an additional aminoacyl residue.
  • the compounds of the present invention inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads.
  • peptides of the present invention have the structure:
  • X is an acyl group selected from the group consisting of (a) dihydroshikimyl, (b) 2-furoyl, (c) 3-furoyl, (d) tetrahyrofuro-2-yl, (e) tetrahydrofuro-3-yl, (f) (thien-2-yl)carbonyl, (g) (thien-3-yl)carbonyl, (h) (tetrahydrothien-2-yl)carbonyl, (i)
  • A is absent or is an aminoacyl residue selected from the group consisting of ⁇ - alanyl, D-alanyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminovaleryl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 11-aminoundecanoyl, azaglycyl, glycyl, sarcosyl, and D-seryl.
  • B is an aminoacyl residue selected from the group consisting of D-phenylalanyl, D-3-(4-chlorophenyl)alanyl, D-3-(4-fluorophenyl)alanyl, D-3- (quinolin-3-yl)alanyl, sarcosyl, glycyl, azaglycyl, D-33-diphenylalanyl, N ⁇ -methyl-D-3-(naphth-2-yl)alanyl, and D-3-(naphth-2-yl)alanyl.
  • C is an aminoacyl residue selected from the group consisting of D-3-(4-chlorophenyl)alanyl, D-33-diphenylalanyl, D-3-(4-fluorophenyl)alanyl, D-3-(naphth- 2-yl)alanyl, D-phenylalanyl, and D-3-(quinolin-3-yl)alanyl.
  • D is an aminoacyl residue selected from the group consisting of D-alanyl, D-3-(benzo[b]thien-2-yl)alanyl, glycyl, D-3-(naphth-1-yl)alanyl, D-3-(pyrid-3-yl)alanyl,
  • E is an aminoacyl residue selected from the group consisting of glycyl, L-seryl, L-homoseryl, L-seryl(O-benzyl), and N ⁇ (R 1 )-L seryl where R 1 is alkyl of from one to four carbon atoms.
  • F is an aminoacyl residue selected from the group consisting of N ⁇ (R 1 )-alanyl, N ⁇ (R 1 )-(3-(4-(3-amino-1,2,4-triazol-5-yl)amino)phenyl)alanyl, N ⁇ (R 1 )-(3- (4-((3-amino-l,2,4-triazol-5-yl)amino)methyl)phenyl)alanyl, N ⁇ (R 1 )-(3-(4-(3-amino-1,2,4-triazol-5-yl)amino)cyclohexyl)alanyl, N ⁇ (R 1 )-(3-(4- (nicotinyl)amino)cyclohexyll)alanyl, N ⁇ (R 1 )-(N- ⁇ -nicotinyl)lysyl, N ⁇ (R 1 )-(N- ⁇ -nicotiny
  • G is an aminoacyl residue selected from the group consisting of glycyl, D-citrullyl, D-homocitrullyl, ⁇ -alanyl, and an aminoacyl residue of the structure
  • X is selected from the group consisting of -(CH 2 ) n - where n is one to six and
  • Y is absent or is an aminoacyl residue selected from the group consisting of D-alanyl, L-alanyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7- aminoheptanoyl, 8-amino-octanoyl, 11-aminoundecanoyl, azaglycyl, D-3-(benzo[b]thien-2-yl)alanyl, L-3-(benzo[b]thien-2-yl)alanyl, D-3-(4-chlorophenyl)alanyl, D-cyclohexylanalyl, glycyl, D-histidyl, D-histidyl(benzyl), D-leucyl, D-3-(naphth-2-yl)alanyl, D-phenylalanyl, D-3-(pyrid-3-yl)alanyl, s
  • Z is either absent or is an aminoacyl residue selected from the group consisting of D-alanyl, L-alanyl, azaglycyl, D-cyclohexylalanyl, glycyl, D-histidyl, D-phenylalanyl, 3-((4-(3-amino-1,2,4-triazol-5-yl)amino)phenyl)alanyl, (3-(4-((3-amino-1,2,4-triazol-5-yl)amino)methyl)phenyl)alanyl, sarcosyl, D-seryl, L-seryl, and
  • R 2 is 3-amino-1,2,4-triazol-5-yl or is an acyl group selected from the group consisting of acetyl; (4-acety'lpiperazin-1-yl)carbonyl; (adamant-1-yl)carbonyl;
  • benzoyl optionally substituted with a group selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; butyryl; cycolhexylcarbonyl; dihydroshikimyl; formyl; nicotinyl; 2-furoyl; 2- and 6-hydroxynicotinyl; (indol-2-yl)carbonyl; isonicotinyl; (4-methylpiperazin-1-yl)carbonyl; (morphilin-1-yl)carbonyl; 2- and 6-methylnicotinyl; 1- and 2-naphthoyl optionally substituted with a group selected from alkyl of one to four carbon atoms, alkoxy of one to four arbon atoms, and halogen; picolyl; (piperazin-1-yl)carbonyl; propionyl, pyrazinoyl; pyridylacetyl; (pyrrolyl
  • H is an aminoacyl residue selected from the group consisting of L-leucyl; N(R 1 )-L-leucyl; glycyl; sarcosyl; prolyl; L-valyl; L-cyclohexylalanyl; and N ⁇ (R 1 )-L-cyclohexylalanyl; where R 1 is hydrogen or alkyl of from one to six carbon atoms.
  • I is an aminoacyl residue selected from the grorp consisting of L-citrullyl
  • L-homocitrullyl L-histidyl; L-(N- ⁇ -isopropyl)lysyl; L-arginyl; and N ⁇ (R 1 )-L-arginyl; L-homoarginyl; L-2-amino-6-N g -ethylguanidinohexanoyl; and L-2-amino-6-N g ,N g -diethylguanidinohexanoyl.
  • J is an aminoacyl residue selected from the group consisting of L-prolyl; 4-hydroxy-L-prolyl; L-pipecolyl; L-azetidinyl; L-2,8-tetrahydroisoquinoline-2-carbonyl, N(R 1 )-L-leucyl; sarcosyl; glycyl; and N(R 1 )-L-alanyl; where R 1 is hydrogen or alkyl of from one to six carbon atoms.
  • K is -NH(CH 2 CH 3 ) or is an aminoacyl residue selected from the group consisting of D-alanylamide, D-alanyl(OH), D-glutamyl(OH), L-glutamyl(OH), N(R 1 )-L-alanylamide, N(R ⁇ )-D-alanylamide, sarcosamide, D-serylamide, and azaglycylamide, glycylamide, where R 1 is as defined above and with the proviso that when K is -NH(CH 2 CH 3 ) then J is L-prolyl.
  • compositions for use in suppressing levels of sex hormones in a mammal comprising a sex hormone suppressing effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
  • halide refers to bromo (Br), chloro (CI), fluoro (F) or iodo (I).
  • resin refers to resins of the type commonly used in the art of synthetic peptide preparation. Examples of such resins include, but are not limited to, methyl benzhydrylamine (MB HA) or benzhydrylamine (BHA) or Merrifield resin (i.e. chloromethylated polystyrene).
  • MB HA methyl benzhydrylamine
  • BHA benzhydrylamine
  • Merrifield resin i.e. chloromethylated polystyrene
  • alkyl refers to divalent straight or branched group derived from a saturated hydrocarbon by the removal of a single hydrogen atom.
  • alkyl include, but are not limited to methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, and the like.
  • alkylene refers to a straight or branched divalent group derived from a saturated hydrocarbon by the removal of two hydrogen atoms. Examples of alkylene include -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 - and the like.
  • azetidinyl refers to the cyclic aminoacyl residue derived from azetidine-2-carboxylic acid.
  • cycloalkyl refers to a monovalent cyclic hydrocarbon group derived from a cyclic saturated hydrocarbon group by the removal of a single hydrogen atom.
  • examples of cycloalkyl groups include cyclopropyl, cycobutyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octane, and the like.
  • cycloalkylene refers to a divalent group derived from a saturated cyclic hydrocarbon by the removal to two hydrogens. Examples include
  • isonicotinyl means the acyl group derived from isonicotinic acid, i.e. pyridine-4-carboxylic acid.
  • nicotinyl denotes the acyl group derived from nicotinic acid, i.e. pyridine-3-carboxylic acid.
  • Picolinoyl refers to the acyl group derived from picolinic acid, i.e. 2- pyridinecarboxylic acid.
  • dihydroshikimyl refers to the fully saturated analog of shikimic acid.
  • Al stands for 3-(benzo[b]thien-2-yl)alanine, with "Thial” and “Thiaz” representing 3-(thien-2-yl) alanine and 3-(thiazolyl)alanine, respectively.
  • Cha represents 3-cyclohexylalanine and various amino acids derived from phenylalanine by substitution of the phenyl group are represented by abbreviations such as “D4ClPhe,” “D4FPhe,” “D4NO 2 Phe,” and “D4NH 2 Phe” which represent D- 3-(4-chlorophenyl)alanine, D-3-(4-fluorophenyl)alanine, D-3-(4-nitrophenyl)alanine, and D-3-(4-aminophenyl)alanine, respectively.
  • Cit and HCit stand for citrullyl and homocitrullyl (or L-2-amino-(6-aminocarbonylamino)hexanoic acid), respectively.
  • Cha(4AmPyz) represents a 3-((4-aminopyrazin-2-carbonyl)cyclohexyl)-alanyl aminoacyl residue.
  • DLys(Nic) or “D-Lys(N-epsilon nicotinyl)” represents a D-lysine amino acid or aminoacyl residue substituted on the epsilon nitrogen atom of the side chain by a nicotinyl acyl group.
  • DLys(Isonic),” “DLys(Shik),” “DLys(Fur),” and “DLys(THF) represent D-lysine acylated on the epsilon nitrogen atom by an isonicotinyl, shikimyl, fur-2-oyl, or tetrahydrofur-2-oyl group.
  • DLys(Isp)," “DLys(Nisp)” or “D-Lys(N-epsilon isopropyl)” stand for a lysine substituted on the epsilon amino group of the lysine side-chain by an isopropyl group.
  • Hard stands for homoarginyl or L-2-amino-6-guanidinohexanoyl).
  • HardgEt and “HargEt 2" represent L-2-amino-6-N g -ethylguanidinohexanoic acid and L-2-amino-6-N g ,N g -diethylguanidinohexanoic acid, respectively.
  • Aha represents 4-aminoheptanboic acid
  • Aca represents 6-aminocaproic acid
  • Gaba denotes 4-aminobutyric acid
  • Bala represents beta-aminoalanine or 3-aminopropionic acid.
  • D1Nal and D2Nal represent D-3-(naphth-1-yl)alanine and D-3-(naphth-2-yl)alanine, respectively.
  • D3Pal represents D-3-(pyrid-3-yl)alanine and "D3Qal” or “D3Qual” stands for D-3-(quinol-3-yl)alanine.
  • D-(4-Atza)Phe or “DAtzPhe” means D-3-(4-(3-amino-1H-1,2,4-triazol-5-yl)amino)phenyl)alanine and "D-(4-Atzame)Phe” or “D-(AtzMe)Phe” represents D-3-(4-(((3-amino-1H-1,2,4'-triazol-5-yl)amino)methyl)phenyl)alanine.
  • Sar and SarNH 2 mean sarcosine or the amide of sarcosine, respectively.
  • DLys(COdiAmpropShik) refers to a D-Lysyl(N- ⁇ -carbonyl-N',N"-diaminoprop-aneshikimyl) aminoacyl residue.
  • salts recognized in the pharmaceutical formulation arts as non-toxic and sutable for use in formulations intended for use in human and animal treatment Suitable acids and bases useful for this purpose are listed, for example, in the review article, "Pharmaceutical Salts” by S. N. Berge, etal, J. Pharm. Sci., 66: 1-19 (1977).
  • the aminoacyl residue A is absent, and the peptides of the present invention are decapapetides modified at the N- terminus with an acyl function and possess the structure
  • Preferred compounds of the present invention have the structure
  • X is an acyl group selected from the group consisting of tetrahydrofur-3-oyl, (tetrahydrothien-2-yl)carbonyl, (pyrrol-2-yl)carbonyl, prolyl, (indolin-2-yl)carbonyl, 3-(indolin-3-yl)propionyl, (dihydrobenzo[b]fur-2-yl)carbonyl, and (tetrahydropyran-2-yl)carbonyl.
  • AA 6 is an aminoacyl residue selected from the group consisting of tyrosyl, arginyl, N ⁇ -methyltyrosyl, lysyl(N-epsilon-(3'-amino-1H-1',2',4'-triazol-5-yl)), and N a -methyl-3-(4-(3'-amino-1H-1',2',4'-triazol-5-ylmethyl)phenyl)alanyl.
  • AA 7 is an aminoacyl residue selected from the group consisting of D-citrullyl, D-homocitrullyl, D-lysyl(N-epsilon nicotinyl), D-lysyl(N-epsilon glycyl nicotinyl), D-lysyl(N-epsilon azaglycyl nicotinyl), D-lysyl(N-epsilon shikimyl), D-lysyl(N-epsilon glycyl shikimyl), D-lysyl(N-epsilon azaglycyl shikimyl), D-lysyl(N-epsilon dihydroshikimyl), D-lysyl(N-epsilon glycyl dihydroshikimyl), D-lysyl(N-epsilon glyc
  • AA 9 is an aminoacyl group selected from the group consisting of lysyl(N-epsilon isopropyl), arginyl, L-(N g ,N g -diethylhomoarginyl), and homoarginyl.
  • AA 1 0 is an aminoacyl residue selected from the group consisting of D- alanylamide, and D-sarcosamide.
  • compounds of this invention have the structure:
  • X is an acyl group selected from the group consisting of tetrahydrofuro-2-yl ** AA 7 is an aminoacyl residue selected from the group consisting of D-citrullyl, D-lysyl(N-epsilon nicotinyl), D-lysyl(N-epsilon glycyl nicotinyl), D-lysyl(N-epsilon azaglycyl nicotinyl), D-lysyl(N-epsilon shikimyl), D-lysyl(N-epsilon glycyl shikimyl), D-lysyl(N-epsilon glycyl shikimyl), D-lysyl(N-epsilon azaglycyl shi
  • AA 1 0 is an aminoacyl residue selected from the group consisting of D-alanylamide, and D-sarcosamide.
  • Representative compounds of the present invention were evaluated in an in vitro test for LHRH antagonist potency (pA2).
  • the test employed the method detailed in F. Haviv, et al. J. Med. Chem., 32: 2340-2344 (1989).
  • the values of ⁇ A2 are the negative logarithms of the concentration of the particular antagonist test compound required to shift the response curve produced by the agonist leuprolide to two-fold higher concentration.
  • Leuprolide is the LHRH agonist having the structure 5-oxo- Pro 1 -His 2 -Trp 3 -Ser 4 -Tyr 5 -D-Leu 6 -Leu 7 -Arg 8 -Pro 9 -NHEt and is disclosed and claimed in United States Patent 4,005,063.
  • pA2 values of 9.5 or greater are indicative of good LHRH antagonist potency, with values of 10.0 or greater being preferred.
  • the compounds of the present invention to act as LHRH antagonists and are useful for suppressing levels of gonadotropins and androgens in mammals.
  • an amount of a compound of the invention or a pharmaceutical composition containing the antagonists, effective to suppress levels of sex hormones in a mammal is administered to the host in need of such treatment.
  • These compounds or compositions may be administered by any of a variety of routes depending upon the specific end use, including orally, parenterally (including subcutaneous, intramuscular and intraveneous administration), vaginally (particularly for contraception), rectally, buccally (including sublingually), transdermally or intranasally. The most suitable route in any given case will depend upon the use, particular active ingredient, the subject involved, and the judgment of the medical practitioner.
  • the compound or composition may also be administered by means of slow-release, depot or implant formulations as described more fully herein below.
  • the active ingredient in amounts between about 0.01 and 10 mg/kg body weight per day, preferably between about 0.1 and 5.0 mg/kg body weight per day.
  • This administration may be accomplished by a single daily administration, by distribution over several applications or by slow release in order to achieve the most effective results.
  • a further aspect of the present invention relates to pharmaceutical
  • compositions containing as active ingredient a compound of the present invention which compositions comprise such compound in admixture with a pharmaceutically acceptable, non-toxic carrier.
  • a pharmaceutically acceptable, non-toxic carrier such compositions may be prepared for use for parenteral (subcutaneous, intramuscular or intraveneous) administration, particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration, particularly in semisolid forms such as creams and suppositories; for oral or buccal administration, particularly in the form of tablets or capsules, or intranasally, particularly in the form of powders, nasal drops or aerosols.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA., 1970.
  • Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for inhalation administratiom may be solid and contain as excipients, for example, lactose, or may be aqueous or oily solutions for administration in the form of nasal drops.
  • typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • a dosage form may contain a pharmaceutically acceptable non-toxic salt of a compound of the invention which has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., N,N'-dibenzylethylened
  • the compounds of the present invention or, preferably, a relatively insoluble salt such as those just described may be formulated in a gel, for example, an aluminum monostearate gel with, e.g. sesame oil, suitable for injection.
  • Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like.
  • Another type of slow release depot formulation for injection would contain the compound or salt dispersed or encapsulated in a slow degrading, non-toxic, non- antigenic polymer such as a polylactic acid/polyglycolic acid polymer for example as described in U.S. Patent No. 3,773,919.
  • the compounds of the invention or, preferably, relatively insoluble salts such as those described above may also be formulated in cholesterol matrix pellets, particularly for use in animals. Additional slow release, depot or implant formulations, e.g. liposomes, are well known in the literature. See, for example, Sustained and Controlled Release Druq Delivery
  • the compounds of the present invention are synthesized by techniques known to those skilled in the art as, for example, by so-called "solid phase” peptide synthesis or by usual methods of solution phase chemistry.
  • solid phase peptide synthetic techniques may be found in J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, 1963 and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2., p.46, Academic Press (New York), 1973.
  • For classical solution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1, Academic Pres (New York), 1965.
  • these methods comprise the sequential addition of one or more amino acids or suitably protected amino acids to a growing peptide chain bound to a suitable resin.
  • the starting amino acids are commercially available or, where novel in the compounds of this invention, are synthesized by methods detailed below from readily available starting materials.
  • either the amino or carboxyl group of the first amino acid is protected by a suitable protecting group.
  • the protected or derivatized amino acid can then be either attached to an inert solid support (resin) or utilized in solution by adding the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected, under conditions conducive for forming the amide linkage.
  • the protecting group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is added, and so forth.
  • any remaining protecting groups are removed sequentially or concurrently, and the peptide chain, if synthesized by the solid phase method, is cleaved from the solid support to afford the final polypeptide.
  • a particularly preferred method of preparing peptides involves solid phase peptide synthesis.
  • the alpha-amino function of the amino acids is protected by an acid or base sensitive group.
  • Such protecting groups should have the properties of being stable to the conditions of peptide linkage formation, while being readily removable without destruction of the growing peptide chain or racemization of any of the chiral centers contained therein.
  • Suitable protecting groups are t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz),
  • Particularly preferred side chain protecting groups are, for side-chain amino groups as in lysine and arginine: nitro, p-toluene-sulfonyl, 4-methoxybenzene-sulfonyl, Cbz, BOC and adamantyloxycarbonyl; for tyrosine: benzyl, o-bromo- benzyloxycarbonyl, 2,6-dichlorobenzyl, isopropyl, cyclohexyl, cyclopentyl and acetyl; for serine: benzyl and tetrahydropyranyl; for histidine: benzyl, Cbz, p-toluenesulfonyl and 2,4-dinitrophenyl; for tryptophan: formyl.
  • the C-terminal amino acid is attached to a suitable solid support.
  • suitable solid supports useful for the above synthesis are those materials which are inert to the reagents and reaction conditions of the stepwise condensation-deprotection reactions, as well as being insoluble in the solvent media used.
  • Suitable solid supports are chloromethylpolystyrene-divinylbenzene polymer, hydroxymethyl-polystyrene-divinylbenzene polymer, and the like. Chloromethyl-polystyrene-1% divinylbenzene polymer is especially preferred.
  • a particularly useful support is the benzhydrylamino-polystyrene-divinylbenzene polymer described by P. Rivaille, et al, Helv. Chim. Acta., 54, 2772 ( 1971).
  • the coupling to the chloromethyl polystyrene-divinylbenzene type of resin is made by means of the reaction of the alpha-N-protected amino acid, especially the BOC-amino acid, as its cesium, tetramethylammonium, triethylammonium, 1,5-diazabicyclo-[5.4.0] undec-5-ene, or similar salt.
  • the coupling reaction is accomplished in a solvent such as ethanol, acetonitrile, N,N-dimethylformamide (DMF), and the like, with the chloromethyl resin at an elevated temperature, for example between about 40° and 60°C, for from about 12 to 48 hours.
  • a solvent such as ethanol, acetonitrile, N,N-dimethylformamide (DMF), and the like
  • Preferred reagents and reaction conditions involve the coupling of an alpha-N-BOC amino acid cesium salt with the resin in DMF at about 50°C for about 24 hours.
  • the alpha-N-BOC-amino acid is attached to the benzhydrylamine resin by means of N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC) with or without 1-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate (BOP) or bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCl), mediated coupling for from about 1 to about 24 hours, preferably about 12 hours at a temperature of between about 10° and 50°C, most preferably 25°C in a solvent such as dichloromethane or DMF, preferably dichloromethane.
  • the coupling of the carboxyl group to the N- methyl-Ser(OBzl) attached to the peptide resin requires catalysis by 4-dimethylamino
  • the coupling of successive protected amino acids can be carried out in an automatic polypeptide synthesizer as is well known in the art.
  • the removal of the alpha-N-protecting groups may be performed in the presence of, for example, a solution of trifluoroacetic acid in methylene chloride, hydrogen chloride in dioxane, hydrogen chloride in acetic acid, or other strong acid solution, preferably 50% trifluoroacetic acid in dichloromethane at about ambient temperature.
  • Each protected amino acid is preferably introduced in 0.4M concentration and approximately 3.5 molar excess and the coupling may be carried out in dichloromethane,
  • the coupling agent is normally DCC in dichloromethane but may be N,N'-di-isopropylcarbodiimide (DIC) or other carbodiimide either alone or in the presence of HOBt, N-hydroxysuccinimide, other N-hydroxyimides or oximes.
  • DIC N,N'-di-isopropylcarbodiimide
  • protected amino acid active ester e.g. p-nitrophenyl
  • N-methyl-(4-chloromethyl)phenylalanine hydrochloride is treated with di- t-butylcarbonate (1.2 equivalents) in the presence of triethylamine (1 equivalent) in THF at 0 °C for 1 hr. After work-up and purification BOC-N-methyl-(4-chloromethyl)phenylalanine is obtained.
  • BOC-N-Me-(4-chloromethyl)phenylalanine is heated under reflux for 4 to 24 hr with excess of sodium azide and catalytic amount of sodium iodide in methanol.
  • the residue is treated with dilute hydrochloric acid to pH 6 and extracted with ethyl acetate.
  • the organic extracts are dried and concentrated to yield BOC-N-methyl-(4- azidomethyl)phenylalanine.
  • This is hydrogenated over Pd/C catalyst in methanol to afford BOC-N-methyl-(4-aminomethyl)phenylalanine.
  • the last compound is treated with 9-fluorenylmethyl chlorocarbonate under basic conditions as described in page 24 of " The Practice of Peptide Synthesis" by M. Bodanszky and A. Bodanszky.
  • N-(t-butoxycarbonyl)-N-methyl-(4-FMOC-aminomethyl)phenylalanine is obtained (see Scheme 1).
  • BOC-D-(4-chloromethyl)phenylalanine is synthesized according to Preparation A described above.
  • the product is first treated with sodium azide in methanol, using analogous conditions to those previously described, and then hydrogenated to yield N-BOC-D-(4-aminomethyl)phenylalanine which is substituted with FMOC, as previously described, to afford N-(t-Butoxycarbonyl)-D-(4-FMOC-aminomethyl)Phenylalanine.
  • Atz or 3-amino-1,2,4-triazol-5-yl group can be attached to the 4-amino group of 3-(4-aminophenyl)alanine or the terminal amino group the omega-aminoalkyl side chain of any alpha,omega-diaminocarboxylic acid amino acid by the method detailed below in Scheme 2 which illustrates the process for N ⁇ -methyl-3-(4-aminophenyl)alanine.
  • the peptide-resin is washed, 3 times with methylene chloride, 3 times with DMF, and reacted with 10- to 20-fold excess of diphenylcyanocarboimidate in DMF overnight (see Scheme 2 below), washed, 3 times with methylene chloride, 3 times with DMF, and then reacted with 20- to 100-fold excess of hydrazine in DMF overnight.
  • the peptide-resin is washed, as previously described, dried over P 2 O 5 overnight, and treated with HF/anisole as above.
  • Deblocking to remove the t-BOC group from the alpha-amino function of the peptide, is carried out using a solution of 45% trifluoroacetic acid (TFA), 2.5% anisole, 2.0% dimethyl phosphite, and 50.5% methylene chloride.
  • TFA trifluoroacetic acid
  • anisole 2.0% dimethyl phosphite
  • methylene chloride 50.5%
  • Base wash to remove and neutralize the TFA used for deprotection, is carried out using a solution of 10% N-N'-diisopropylethylamine in methylene chloride.
  • the resin is washed with base three times for one minute each time after a deblocking step.
  • Coupling reaction is carried out using a 3-fold molar excess of 0.3 M DMF solution of a t-BOC protected amino acid derivative along with a 3-fold molar excess of 0.3 M methylene chloride solution of diisopropylcarbodiimide as activator.
  • the activated amino acid is then coupled to the free alpha amino group of the peptide-resin.
  • the reaction time is as described in the synthesis protocol.
  • amino protected amino acids are coupled to the resin according the following order, number, and duration of couplings:
  • the resin Upon completion of the synthesis the resin is dried overnight over P2O5 under vacuum and then treated with dry HF in the presence of anisole at 0 °C for lh to cleave the peptide from the resin. The excess of reagent is removed in vacuo. The resin is washed first with ether, then stined at room temperature with a solution of (1: 1:0.1) water/acetonitrile/acetic acid (50 ml) for 15 minutes, and filtered. The filtrate is lyophilized to give the crude peptide as a fluffy powder.
  • Amino Acid Anal 1.01 Ala; 0.99 Pro; 0.99 Lys; 1.01 Leu; 0.99 NMeTyr; 0.49Ser; 0.94 Tyr.
  • Amino Acid Analysis 1.00 Ala; 1.01 Pro; 1.04 Lys(Isp); 1.00 Leu; 0.99 Lys; 0.78 NMeTyr; 0.54 Ser; 0.993Pal; 1.06 4ClPhe; 0.99 Gly.
  • Amino Acid Analysis 1.01 Ala; 1.02 Pro; 0.99 Lys(Isp); 1.02 Leu; 0.98 Lys; 1.10 NMeTyr; 0.47 Ser; 0.983Pal; 1.02 4ClPhe; 0.98 Gly.
  • Amino Acid Analysis 1.00 Ala; 1.04 Pro; 0.94 Lys(Isp); 1.02 Leu; 0.96 Lys; 1.10 NMeTyr; 0.49 Ser; 1.00 3Pal; 1.07 4ClPhe; 0.98 Gly.
  • Amino Acid Analysis 1.00 Ala; 0.99 Pro; 0.93 Lys(Isp); 0.99 Leu; 1.03 Lys; 0.90 NMeTyr; 0.55 Ser; 0.98 3Pal; 1.004ClPhe; 1.00 Gly.
  • Example 6a N-Nicotinyl-3Aminopro ⁇ ionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-DAlaNH 2
  • the title compound was prepared by the procedure described in Example 2 for the synthesis of NicGly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-DAlaNH 2 was used but substituting BOC-DLys(N-epsilon-FMOC) instead of BOC-DLys(N-epsilon-Nicotinyl). Upon the completion of the synthesis the peptide resin was treated with 20%
  • Amino Acid Analysis 1.01 Ala; 0.98 Pro; 0.92 Lys(Isp); 0.98 Leu; 0.97 Lys; 0.65 NMeTyr; 0.45 Ser; 0.92 3Pal; 0.98 4ClPhe; 2.06 Gly.
  • the title compound was prepared by the procedure described in Example 2 for the synthesis of NicGly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon- Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-DAlaNH 2 was used but substituting BOC-DLys(N-epsilon-FMOC) instead of BOC-DLys(N-epsilon-Nicotinyl). Upon the completion of the synthesis the peptide resin was treated with 20%
  • Amino Acid Analysis 1.00 Ala; 0.98 Pro; 1.02 Lys(Isp); 0.98 Leu; 1.05 Lys; 0.97 NMeTyr; 0.53 Ser; 0.953Pal; 1.01 4ClPhe; 1.01 Gly.
  • Amino Acid Analysis 1.04 Ala; 0.97 Pro; 0.93 Lys(Isp); 0.99 Leu; 0.95 Lys; 0.86 NMeTyr; 0.50 Ser; 1.053Pal; 1.11 4ClPhe; 2.02 Gly.
  • Example 1 was used but substituting BOC-Gly for BOC-DTyr(O-2,6diCl-Bzl), BOC- DCit for BOC-DLys(N-epsilon-FMOC), BOC-Arg(Tos) for BOC-Lys(N-epsilon- CBZ,isopropyl) and the appropriate BOC-amino acids and acids for acetic acid. After workup, lyophilization and HPLC purification the following compounds were obtained:
  • Amino Acid Analysis 1.01 Ala; 1.03 Pro; 0.96 Arg; 1.04 Leu; 0.98 Cit; 0.47 Ser; 0.693Pal; 0.974ClPhe; 0.95 Gly.
  • Amino Acid Analysis 1.00 Ala; 1.01 Pro; 1.00 Arg; 1.03 Leu; 1.02 Cit; 0.86 NMeTyr; 0.44 Ser; 1.03 3Pal; 1.01 4ClPhe; 0.95 Gly.
  • Amino Acid Analysis 1.09 Ala; 1.02 Pro; 0.97 Arg; 0.94 Lys; 0.75 NMeTyr; 0.51 Ser; 1.03 3Pal; 1.094ClPhe; 0.97 Gly (Compound 107).
  • the title compound was prepared by the procedure described in Example 15 for N-Shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Gly-Nic)-Leu-Arg-Pro-DAlaNH 2 was used but coupling twice with BOC-Gly before the nicotinic acid coupling.
  • the title compound was prepared by the procedure described in Example 15 for N-Shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Gly-Shik)-Leu-Arg- Pro-DAlaNH 2 was used to synthesize Boc-Gly-D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys(Gly-Boc)-Leu-Arg-Pro-DAla-resin.
  • the peptide was cleaved with HF/anisole and lyophylized leaving the free glycine amine residues at positions 0 and 6.
  • Example 23a N-Nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Ile-Arg-Pro-DAlaNH 2 (Compound 112); R t 14.27 min; FAB Mass spec, m/e 1691 (M+H) + .
  • Amino Acid Analysis 1.04 Ala; 1.04 Pro; 1.00 Arg; 0.95 He; 0.96 Lys; 1.79 NMeTyr; 0.47 Ser; 0.99 D3Pal; 1.05 D4ClPhe; 1.01 Gly.
  • Example 25a N-Nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-DAlaNH 2 (Compound 115); R t 30.45 min; FAB Mass spec, m/e 1705 (M+H) + .
  • Amino Acid Analysis 0.99 Ala; 1.00 Pro; 1.04 Leu; 0.96 Lys; 1.06 NMeTyr; 0.54 Ser; 1.13 3Pal; 1.204ClPhe; 1.02 Gly.
  • Amino Acid Analysis 1.03 Ala; 0.99 Pro; 1.00 Leu; 0.98 Lys; 1.04 NMeTyr; 1.05 Ser; 0.973Pal; 1.044ClPhe.
  • Amino Acid Analysis 1.03 Ala; 1.03 Pro; 1.01 Leu; 0.93 Lys; 1.28 NMeTyr; 0.47 Ser; 0.973Pal; 1.044ClPhe; 0.88 Gly.
  • Amino Acid Analysis 0.98 Ala; 1.03 Pro; 1.04 Leu; 0.94 Lys; 1.15 NMeTyr; 0.49 Ser; 1.153Pal; 1.2044ClPhe; 0.97 Gly.
  • Amino Acid Analysis 1.00 Ala; 0.96 Pro; 0.96 Leu; 1.03 Lys; 0.54 Ser; 0.923Pal; 0.974ClPhe; 1.05 Gly.
  • Amino Acid Analysis 1.07 Ala; 0.99 Pro; 1.00 Leu; 0.94 Lys; 0.40 Ser; 0.983Pal; 1.044ClPhe; 1.00Gly.
  • Amino Acid Analysis 1.04 Ala; 0.99 Pro; 1.00 Leu; 0.97 Lys; 0.48 Ser; 0.99 3Pal; 1.03 4ClPhe; 0.99Gly.
  • Example 27
  • Amino Acid Analysis 1.04 Ala; 0.99 Pro; 0.99 Leu; 1.00 Lys; 1.47 NMeTyr; 0.46 Ser; 0.993Pal; 1.06 4ClPhe; 1.02Gly.
  • Amino Acid Analysis 1.00 Ala; 1.02 Leu; 1.01 Lys; 1.07 NMeTyr; 0.43 Ser; 1.153Pal; 0.90 4ClPhe; 0.98.Gly.
  • Amino Acid Analysis 1.01 Ala; .0.98 Pro; 0.95 Arg; 1.04 Leu; 0.96 Lys; 0.90 NMeTyr; 0.55 Ser; 1.13 3Pal; 1.19 4ClPhe.
  • Amino Acid Analysis 1.02 Ala; 1.02 Pro; 0.95 Lys(Isp); 1.01 Leu; 0.93 Lys; 1.07 NMeTyr; 0.47 Ser; 1.073Pal; 1.13 4ClPhe; 1.03 Gly.
  • Amino Acid Analysis 1.00 Ala; 1.02 Pro; 0.94 Lys(Isp); 1.02 Leu; 0.87 Lys; 0.87 NMeTyr; 0.5 Ser; 0.973Pal; 1.05 CIPhe.
  • Amino Acid Analysis :0.96 Ala; 1.02 Pro; 1.6 Lys(Isp); 1.02Leu; 0.94 Lys; 1.16 NMeTyr; 0.48 Ser.
  • Amino Acid Analysis 1.04 Ala; 1.03 Pro; 0.88 Lys(Isp); 0.99 Leu; 0.94 Lys; 1.23 NMeTyr; 0.63 Ser; 0.864ClPhe.
  • Amino Acid Analysis 1.01 Ala; 1.02 Pro; 0.95Lys(Isp); 1.00 Leu; 0.96 Lys; 1.09 NMeTyr; 0.41 Ser; 1.004ClPhe.
  • the title compound was prepared by the procedure described in Example 33 was used but, instead of introducing NicAzagly after the coupling with BOC- D4ClPhe, the peptide-resin was coupled with BOC-Sar followed by nicotinic acid.
  • Amino Acid Analysis 1.00 Ala; 1.02 Pro; 0.87 Lys(Isp); 1.04 Leu; 0.95 Lys; 1.04 NMeTyr; 0.46 Ser; 1.063Pal; 1.044ClPhe.
  • Example 5 The procedure described in Example 5 is used but substituting BOC-SarNH-resin instead of BOC-DAlaNH-resin. After workup, lyophilization and HPLC purification (R)-Tetrahydrofur-2-ol-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nicotinyl)-Leu-Lys(Isp)-Pro-SarNH 2 (167) is obtained as the trifluoroacetic acid salt.
  • Example 2 The procedure described in Example 1 is used but substituting the BOC-Tyr(O-2,6diClBzl) for BOC-NMe-Tyr(O-2,6Cl-Bzl). After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser- Tyr-DLys(Nicotinyl)-Leu-Lys(Isp)-Pro-SarNH 2 (168) is obtained as the
  • Example 41 The procedure described in Example 41 is used but substituting BOC-Lys(Nic) for BOC-Tyr(O-2,6Cl-Bzl). After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys(Nic)-DLys(Nicotinyl)-Leu-Lys(Isp)-Pro-SarNH 2 (169) is obtained as the trifluoroacetic acid salt.
  • Example 41 The procedure described in Example 41 is used but substituting BOC-DCit and BOC-Arg(Tos) for BOC-DLys(Nic) and BOC-Lys(CbzJsp), respectively. After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-Arg-Pro-SarNH 2 (170) is obtained as the trifluoroacetic acid salt.
  • R,S Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-Arg-Pro-SarNH 2 (170) is obtained as the trifluoroacetic acid salt.
  • Example 41 The procedure described in Example 41 is used but substituting BOC-DHcit for BOC-DLys(Nic). After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Arg-Pro-SarNH 2 (171) is obtained as the trifluoroacetic acid salt.
  • Example 44 The procedure described in Example 44 is used but substituting BOC- Lys(Isp,Cbz) for BOC-Arg(Tos). After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys(Isp)-Pro-SarNH 2 (172) is obtained as the trifluoroacetic acid salt.
  • Example 43 The procedure described in Example 43 is used but substituting BOC- Arg(Tos) and BOC-D-4-(p-OMe-Benzoyl)Homoalanyl for BOC-Tyr(O-2,6-diClBzl) and BOC-DCit, respectively. After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Arg-D4( ⁇ OMeBzol)-Leu-Arg-Pro-SarNH 2 (173) is obtained as the trifluoroacetic acid salt.
  • Example 43 The procedure described in Example 43 is used but substituting BOC- DHarg(Et 2 ) and BOC-Hang(Et 2 ) for BOC-DCit and BOC-Arg(Tos), respectively. After workup, lyophilization and HPLC purification (R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHarg(Et 2 )-Leu-Harg(Et 2 )-Pro-SarNH 2 (174) is obtained as the trifluoroacetic acid salt.
  • R,S Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHarg(Et 2 )-Leu-Harg(Et 2 )-Pro-SarNH 2 (174) is obtained as the trifluoroacetic acid salt.
  • Example 48
  • Example 38 The procedure described in Example 38 is used but substituting BOC-NMePhe(4NFMOC) and BOC-DPhe(4NFMOC) for BOC-NMeTyr(O-2,6-ClBzl) and BOC-DLys(Nic).
  • the peptide-resin was treated with 30% piperidine in DMF for 2 hr, then washed three times with (1:1) DMF/DCM, treated with a solution of diphenyl cyanocarbonimidate (0.43 g) in DMF ( 15 mL) and the mixture was bubbled for 16 hr.
  • Example 48 The procedure described in Example 48 is used but substituting BOC-Phe(4NFMOC) for BOC-NMePhe(4NFMOC). After workup, lyophilization and
  • Example 51 The procedure described in Example 48 is used but substituting BOC- NMePhe(4Me-NFMOC) and BOC-DPhe(4Me-NFMOC) for BOC- NMePhe(4NFMOC) and BOC-DPhe(4NFMOC).
  • lyophilization and HPLC purification R,S) Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser- NMePhe(MeAtz)-DPhe(Me-Atz)-Leu-Lys(Isp)-Pro-SarNH 2 (177) is obtained as the trifluoroacetic acid salt.
  • Example 51 Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser- NMePhe(MeAtz)-DPhe(Me-Atz)-Leu-Lys(Isp)-Pro-
  • Example 48 The procedure described in Example 48 is used but substituting BOC-Lys(FMOC) and BOC-DLys(NFMOC) for BOC-NMePhe(4N-FMOC) and BOC-DPhe(4NFMOC), respectively.
  • lyophilization and HPLC purification R,S
  • Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys(Atz)-DLys(Atz)-Leu-Lys(Isp)-Pro-SarNH 2 is obtained as the trifluoroacetic acid salt.
  • Example 52a N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4C1Phe-D3Pal-Ser-Tyr-DLys(Nicotinyl)-Leu-Lys(Isp)-Pro-DAlaNH 2 (Compound 179).
  • Example 52b N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys(Nic)-DLys(Nicotinyl)-Leu-Lys(Is ⁇ )-Pro-DAlaNH 2 (Compound 180).
  • Example 52e N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys(Isp)-Pro-DAlaNH 2 (Compound 183).
  • Example 52f N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Arg-D-4(pOMeBzol)Hala-Leu-Arg-Pro-DAlaNH 2 (Compound 184).
  • Example 52g N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHarg(Et 2 )-Leu-Harg(Et 2 )-Pro-DAlaNH 2 (Compound 185).
  • Example 52h N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe(Atz)-DPhe(Atz)-Leu-Lys(Isp)-Pro-DAlaNH 2 (Compound 186).
  • Example 52j N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe(Me-Atz)-DPhe(Me-Atz)-Leu-Lys(Is ⁇ )-Pro-DAlaNH 2 (Compound 188).
  • Example 52k N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys(Atz)-DLys(Atz)-Leu-Lys(Isp)-Pro-DAlaNH 2 (Compound 189).
  • Example 31 The procedure described in Example 31 is used but substituting BOC-SarNH-resin for BOC-DAlaNH-resin and substituting the appropriate amino acids and acids at position 6. After workup, lyophilization and HPLC purification the following compounds are obtained as the trifluoroacetic acid salt:
  • Example 53a N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Azagly-2Fur)-Leu-Lys(Is ⁇ )-P ⁇ o-SarNH 2 (Compound 190).
  • Example 53b N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Azagly-Nic)-Leu-Lys(Isp)-Pro-SarNH 2 (Compound 191).
  • Example 53c N-(R,S)-Tetrahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Gly-Nic)-Leu-Lys(Isp)-Pro-SarNH 2 (Compound 192).
  • Example 55 The procedure described in Example 1 is used but substituting the appropriate BOC-amino acids for BOC-Gly, BOC-DLys-FMOC for BOC-DCit, and BOC-Sar-NH-resin for BOC-DAla-NH-resin. After workup, lyophilization and HPLC purification Nic-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-SarNH 2 is obtained as the trifluoroacetate salt.
  • Example 55 Example 55
  • Example 54 The procedure described in Example 54 is used but substituting BOC-DAlaNH-resin for BOC-SarNH-resin. After workup, lyophilization and HPLC purification N-(R,S) 4H 2 Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-DAlaNH 2 is obtained as the trifluoroacetate salt.
  • Example 55 The procedure described in Example 55 is used but substituting (R,S)-tetrahydro-2-furoic acid for nicotinic acid. After workup, lyophilization and HPLC purification N-(R,S) 4H 2 Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-SarNH 2 is obtained as the trifluoroacetate salt.
  • Example 54 The procedure described in Example 54 is used but shikimic acid for nicotinic acid. After workup, lyophilization and HPLC purification Shik-Gly-D2Nal- D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-SarNH 2 is obtained as the trifluoroacetate salt.
  • Example 54 The procedure described in Example 54 is used but substituting the appropriate BOC-amino acids and acids at positions 0, 6 and 8. After workup, lyophilization and HPLC purification Nic-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4AmAtz)-DLys(Shik)-Leu-Harg-Pro-DAlaNH 2 is obtained as the trifluoroacetate salt.
  • Example 59
  • Example 14 The procedure described in Example 14 is used but substituting BOC-3Qal for BOC-D2Nal. After workup, lyophilization and HPLC purification Nic-Gly-D3Qal- D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Shik)-Leu-Harg-Pro-DAlaNH 2 is obtained as the trifluoroacetate salt.
  • Example 54 The procedure described in Example 54 is used to obtain Nic-Gly-D2Nal- D4ClPhe-D3Pal-Ser-NMeTyr-DLys(FMOC)-Leu-Harg-P ⁇ o-SarNH-resin . This was then treated with excess of 1, 1'-N,N'-carbonyldiimidazole in DMF for 20 min. The resin was washed three times with (1: 1) DMF/DCM and the treated with excess of diaminoproprane in DMF for 1 hr. The resin was again washed as previously described and reacted with shikimic acid in DMF using two couplings of 6 hr each.
  • Example 60 The procedure described in Example 60 is used to obtain (R,S)-4H 2 Fur-Gly- D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(FMOC)-Leu-Lys(Isp)-P ⁇ o-DAlaNH-resin . This was then treated with excess of 1,1'-N,N'-carbonyldiimidazole in DMF for 20 min. The resin was washed three times with (1: 1) DMF/DCM and the treated with excess of diaminoproprane in DMF for 1 hr. The resin was again washed as previously described and reacted with shikimic acid in DMF using two couplings of 6 hr each.
  • Example 61 The procedure described in Example 61 is used but substituting SarNH-resin for BOC-DAlaNH-resin. After workup, lyophilization and HPLC purification (R,S) 4H-2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(COdiAmpropShik)-Leu-Harg-Pro-SarNH 2 is obtained as the trifluoroacetate salt.
  • Example 62 The procedure described in Example 62 is used but substituting nicotinic acid for shikimic acid. After workup, lyophilization and HPLC purification (R,S) 4H 2 Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(COdiAmpropNic)-Leu-Lys(Isp)-Pro-SarNH 2 is obtained as the trifluoroacetate salt.
  • Example 59 The procedure described in Example 59 is used but substituting BOC-cis-Cha(4Am-Prz) for BOC-NMeTyr(O-2,6-Cl-Bzl) and picolinic acid for nicotinic acid. After workup, lyophilization and HPLC purification Nic-Gly-D3Qal-D4ClPhe-D3Pal-Ser-cis-Cha(4AmPrz)-DLys(Pic)-Leu-Arg-Pro-DAlaNH 2 is obtained as the trifluoroacetate salt.
  • Example 2 The procedure described in Example 2 is used but substituting BOC-Sar-NH-resin for for BOC-DAla-NH-resin. After work-up, lyophilization, and HPLC purification the following compounds are obtained:
  • Example 65a NShikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-SarNH 2 (Compound 207).
  • Example 65b N-Dihydroshikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-SarNH 2 (Compound 208).
  • Example 65c N-2Furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-SarNH 2 (Compound 209).
  • Example 65d N-3Furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-DAlaNH 2 (Compound 210).
  • Example 65e N-Picolyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-SarNH 2 (Compound 211).
  • Example 65f N-Nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(N-epsilon-Nicotinyl)-Leu-Lys(N-epsilon-Isopropyl)-Pro-SarNH 2 (Compound 212).
  • Example 68 The procedure described in Example 1 was used but substituting (S)-tetrahydro-2-furoic acid for BOC-DTy
  • Example 69 The procedure described in Example 69 was used but substituting (R)- tetrahydro-3-furoic acid for (S)-tetrahydro-2-furoic acid. After work-up,
  • Example 71 The procedure described in Example 71 was used but substituting the appropriate acids for shikimic acid. After work-up, lyophilization, and HPLC purification the following compounds were obtained:
  • Example 72g N-Isonicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Isp)-Pro-DAlaNH 2 (Compound 23b) R t 22.71min; FAB Mass spec, m/e 1597 (M+H) + .
  • Amino Acid Analysis 1.00 Ala; 1.01 Pro; 0.93 Lys(Isp); 1.02 Leu; 0.97 Lys; 1.10 NMeTyr; 0.42 Ser; 1.02 3Pal ; 1.074ClPhe.
  • Example 75 The procedure described in Example 71 was used but substituting BOC- Lys(Nic) for BOC-NMeTyr(O-2,6-Cl-BzL
  • Example 76 The procedure described in Example 76 was used but substituting (R)-tetrahydro-2-furoic acid for (S)-tetrahydro-2-furoic acid. After work-up,
  • Amino Acid Analysis 1.02 Ala; 1.02 Pro; 0.97 Arg; 0.98 Leu; 0.94 Cit; 0.68 NMeTyr; 0.51 Ser; 1.003Pal; 1.054ClPhe.
  • Amino Acid Analysis 1.02 Ala; 1.03 Pro; 0.91 Arg; 1.04 Leu; 1.04 Cit; 0.94 NMeTyr; 0.52 Ser; 0.72 3Pal; 1.01 4ClPhe.
  • Amino Acid Analysis 1.01 Ala; 1.07 Pro; 0.97 Arg; 1.00 Leu; 0.93 Cit; 0.60 NMeTyr; 0.60 Ser; 0.93 3Pal; 0.944ClPhe.
  • Example 78 The procedure described in Example 78 was used but substituting shikimic acid for 5-oxo-tetrahydrofur-2-oyl acid, BOC-Harg(NO 2 ) for BOC-Arg(Tos), and BOC-DLys(FMOC) for BOC-DCit. With the completion of the synthesis the resin was treated with 30% piperidine in DMF, washed and coupled with shikimic acid using two- two hours coupling protocol.
  • Amino Acid Analysis 1.01 Ala; 1.00 Pro; 1.26 Lys(Isp); 1.02 Leu; 1.01 Lys; 1.02 NMeTyr; 0.42 Ser; 1.14 D3Pal; 1.25 D4ClPhe; 0.97 Gly.
  • Amino Acid Analysis 1.00 Ala; 0.99 Pro; 0.95 Lys(Isp); 1.01 Leu; 1.02 Lys; 1.00 NMeTyr; 0.42 Ser; 0.93 D3Pal; 1.10 D4ClPhe; 0.98 Gly.
  • Amino Acid Analysis 1.01 Ala; 1.01 Pro; 0.99 Lys(Isp); 1.01 Leu; 0.87 NMeTyr; 0.48 Ser; 0.99 D3Pal; 1.04 D4ClPhe; 0.98 Gly.
  • Example 92 The procedure described in Example 92 was used but substituting BOC- Tyr(O-2,6ClBzl) for BOC-NMeTyr(O-2,6ClBzl). After work-up, lyophilization, and HPLC purification N-(S)-2-Tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr- DHcit-Leu-Lys(N-epsilon-Isopropyl)-Pro-DAlaNH 2 was obtained as the
  • Example 4 The procedure described in Example 4 was used but substituting BOC-Tyr(O-2,6ClBzl), BOC-DHcit and BOC-Arg(NO 2 ) for BOC-NMeTyr(O-2,6ClBzl),
  • Example 96 The procedure described in Example 96 was used but substituting BOC-Sar for BOC-Bala. After work-up, lyophilization, and HPLC purification N-(S)-2-
  • Amino Acid Analysis 0.98 Ala; 1.00 Pro; 0.87 Lys(Isp); 1.00 Leu; 1.01 Lys; 1.02 NMeTyr; .0.42 Ser; 1.00 D3Pal; 1.08 D4ClPhe; 0.89 Sar.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pregnancy & Childbirth (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des décapeptides et des undécapeptides substitués sur l'atome d'azote N-terminal par des groupes acyle qui comprennent furo-2-yl, isonicotinyle, nicotinyle, 2-, 3- et 4-quinoléinecarbonyle, shikimyle, dihydroshikimyle, et tétrahydrofur-2-oyl qui sont des antagonistes puissants de LHRH et sont utilisés pour diminuer les taux d'hormones sexuelles chez les mammifères.
PCT/US1994/008678 1993-08-06 1994-07-29 Analogues de lhrh a extremite n-terminale modifiee Ceased WO1995004541A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP50647395A JP3662926B2 (ja) 1993-08-06 1994-07-29 Ｌｈｒｈのｎ末端改変類似体
EP94924100A EP0738154A1 (fr) 1993-08-06 1994-07-29 Analogues de lhrh a extremite n-terminale modifiee

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/103,022 US5413990A (en) 1993-08-06 1993-08-06 N-terminus modified analogs of LHRH
US08/103,022 1994-07-27
US08/279,677 US5502035A (en) 1993-08-06 1994-07-27 N-terminus modified analogs of LHRH
US08/279,677 1994-07-27

Publications (1)

Publication Number Publication Date
WO1995004541A1 true WO1995004541A1 (fr) 1995-02-16

Family

ID=26799998

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/008678 Ceased WO1995004541A1 (fr) 1993-08-06 1994-07-29 Analogues de lhrh a extremite n-terminale modifiee

Country Status (4)

Country Link
EP (1) EP0738154A1 (fr)
JP (2) JP3662926B2 (fr)
CA (1) CA2167834A1 (fr)
WO (1) WO1995004541A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5635161A (en) * 1995-06-07 1997-06-03 Abbott Laboratories Aerosol drug formulations containing vegetable oils
EP0673254A4 (fr) * 1992-12-04 1998-11-18 Abbott Lab Antagonistes de l'hormone liberant l'hormone luteinisante (lhrh) de decapeptides modifies en position 6.
RU2163910C2 (ru) * 1995-11-28 2001-03-10 Аста Медика Акциенгезельшафт Антагонисты рилизинг-фактора лютеинизирующего гормона (лг-рф) (варианты), способ их получения (варианты), фармацевтическая композиция и способ приготовления лекарственных препаратов
WO2001009173A3 (fr) * 1999-07-30 2001-08-16 Ct Nat De La Rech Scient Cnr Utilisation des acides quinique, shikimique et de leurs derives pour la preparation de ligands du recepteur du mannose
US6462062B1 (en) 2000-09-26 2002-10-08 The Procter & Gamble Company Compounds and methods for use thereof in the treatment of cancer or viral infections
US7700559B2 (en) 2003-04-04 2010-04-20 Medical Research Council Gonadotropin releasing hormone analogues conjugates with steroid hormones
US8173600B2 (en) 2004-04-30 2012-05-08 Chiesi Farmaceutici S.P.A. Caspase-2 inhibitors and their biological applications
US12371454B2 (en) 2019-11-07 2025-07-29 Chugai Seiyaku Kabushiki Kaisha Cyclic peptide compound having Kras inhibitory action

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182262A2 (fr) * 1984-11-13 1986-05-28 Syntex (U.S.A.) Inc. Nona et décapeptides analogues de LHRH utiles comme antagonistes de LHRH
US4800191A (en) * 1987-07-17 1989-01-24 Schally Andrew Victor LHRH antagonists
EP0413209A1 (fr) * 1989-08-07 1991-02-20 TAP Pharmaceuticals Inc. Analogues de LHRH

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2233652B (en) * 1986-10-13 1991-08-21 Sandoz Ltd Solid phase synthesis of peptide alcohols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0182262A2 (fr) * 1984-11-13 1986-05-28 Syntex (U.S.A.) Inc. Nona et décapeptides analogues de LHRH utiles comme antagonistes de LHRH
US4800191A (en) * 1987-07-17 1989-01-24 Schally Andrew Victor LHRH antagonists
EP0413209A1 (fr) * 1989-08-07 1991-02-20 TAP Pharmaceuticals Inc. Analogues de LHRH

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0738154A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0673254A4 (fr) * 1992-12-04 1998-11-18 Abbott Lab Antagonistes de l'hormone liberant l'hormone luteinisante (lhrh) de decapeptides modifies en position 6.
US5635161A (en) * 1995-06-07 1997-06-03 Abbott Laboratories Aerosol drug formulations containing vegetable oils
RU2163910C2 (ru) * 1995-11-28 2001-03-10 Аста Медика Акциенгезельшафт Антагонисты рилизинг-фактора лютеинизирующего гормона (лг-рф) (варианты), способ их получения (варианты), фармацевтическая композиция и способ приготовления лекарственных препаратов
WO2001009173A3 (fr) * 1999-07-30 2001-08-16 Ct Nat De La Rech Scient Cnr Utilisation des acides quinique, shikimique et de leurs derives pour la preparation de ligands du recepteur du mannose
US6462062B1 (en) 2000-09-26 2002-10-08 The Procter & Gamble Company Compounds and methods for use thereof in the treatment of cancer or viral infections
US7700559B2 (en) 2003-04-04 2010-04-20 Medical Research Council Gonadotropin releasing hormone analogues conjugates with steroid hormones
US8173600B2 (en) 2004-04-30 2012-05-08 Chiesi Farmaceutici S.P.A. Caspase-2 inhibitors and their biological applications
US12371454B2 (en) 2019-11-07 2025-07-29 Chugai Seiyaku Kabushiki Kaisha Cyclic peptide compound having Kras inhibitory action

Also Published As

Publication number Publication date
JP3662926B2 (ja) 2005-06-22
JP2005170950A (ja) 2005-06-30
EP0738154A4 (fr) 1996-04-12
CA2167834A1 (fr) 1995-02-16
EP0738154A1 (fr) 1996-10-23
JPH09501913A (ja) 1997-02-25

Similar Documents

Publication Publication Date Title
AU675274B2 (en) Reduced size LHRH analogs
US4667014A (en) Nonapeptide and decapeptide analogs of LHRH, useful as LHRH antagonists
JP3645255B1 (ja) ５位および６位で修飾されているＧｎＲＨ拮抗物質
US5110904A (en) Lhrh analogs
US4481190A (en) Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists
CA1264760C (fr) Intermediaires d'analogues nonapeptide et decapeptide de la lh-rh utiles comme inhibiteurs de la lh-rh
US5413990A (en) N-terminus modified analogs of LHRH
JP4191259B2 (ja) ＧｎＲＨ拮抗物質
US5502035A (en) N-terminus modified analogs of LHRH
PT682524E (pt) Composicoes farmaceuticas que contem a proteina bactericida indutora da permeabilidade e um agente tensioactivo
US20060281685A1 (en) Methods of treatment using novel lhrh antagonists having improved solubility properties
EP0328090A2 (fr) Analogues du LHRH
US5698522A (en) 6-position modified decapeptide LHRH antagonists
EP0683792B1 (fr) Antagonistes de lhrh comprenant des restes d'aminoacyle modifies en position 5 et 6
JP3662926B2 (ja) Ｌｈｒｈのｎ末端改変類似体
US5516759A (en) LHRH antagonists having lactam groups at the N-terminus
US5508383A (en) Cyclic peptide LHRH antagonists
EP0328089A2 (fr) Analogues des LHRH à dimension réduite
JP2672677B2 (ja) Ｌｈｒｈ同族体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2167834

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1994924100

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1994924100

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994924100

Country of ref document: EP