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WO2011011965A1 - Antagoniste de l’hormone de libération de l’hormone lutéinisante ayant la structure de l'hydantoïne - Google Patents

Antagoniste de l’hormone de libération de l’hormone lutéinisante ayant la structure de l'hydantoïne Download PDF

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WO2011011965A1
WO2011011965A1 PCT/CN2010/001078 CN2010001078W WO2011011965A1 WO 2011011965 A1 WO2011011965 A1 WO 2011011965A1 CN 2010001078 W CN2010001078 W CN 2010001078W WO 2011011965 A1 WO2011011965 A1 WO 2011011965A1
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aph
phe
xaa
pro
group
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刘克良
周宁
高永清
周文霞
张永祥
程军平
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中国人民解放军军事医学科学院毒物药物研究所
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Publication of WO2011011965A1 publication Critical patent/WO2011011965A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C07D233/78—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61P15/16—Masculine 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
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P5/06—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
    • 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
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior 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
    • 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
    • A61P5/26—Androgens
    • 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
    • A61P5/30—Oestrogens
    • 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
    • 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
    • A61P5/34—Gestagens
    • 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
    • A61P5/36—Antigestagens
    • 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

Definitions

  • the present invention relates to a decapeptide derivative having a luteinizing hormone releasing hormone receptor antagonistic activity, which inhibits pituitary secretion of gonadotropin and inhibits gonadal secretory hormone action, a preparation method thereof, a pharmaceutical composition containing the same, and the same
  • a decapeptide derivative having a luteinizing hormone releasing hormone receptor antagonistic activity which inhibits pituitary secretion of gonadotropin and inhibits gonadal secretory hormone action
  • a preparation method thereof a pharmaceutical composition containing the same, and the same
  • a pharmaceutical composition containing the same for the treatment of prostate cancer, endometrial cancer, reproductive-related sex hormone-related diseases, contraception, and the like. Background technique
  • LHRH Luteinizing hormone releasing hormone
  • LH Luteinizing hormone releasing hormone
  • FSH follicle stimulating hormone
  • LHRH The primary structure of LHRH is as follows:
  • LHRH antagonists can inhibit the release of LH by blocking the action of LHRH, and thus can be used for the treatment of sex hormone related diseases such as prostate cancer.
  • LHRH antagonists Compared with agonists, LHRH antagonists have the advantages of rapid speed, no overshoot, rapid recovery after drug withdrawal, and strong controllability of serum androgen levels. It is expected that LHRH antagonists are superior to agonists in the treatment of prostate cancer, are more acceptable to patients, and have greater application prospects than agonists.
  • LHRH antagonists Although there are many LHRH antagonists currently developed, as a peptide drug, most of them still have shortcomings such as low bioavailability, short half-life in vivo, and high dry dose of histamine, which limits the clinical use of LHRH antagonists. Applications. In addition, similar to other peptide drugs, LHRH antagonist drugs are also difficult to absorb by oral administration. The currently marketed LHRH antagonist drugs are administered parenterally.
  • the decapeptide derivative of the formula (I) or a stereoisomer thereof can be used as a medicament for the treatment of prostate cancer, endometrial cancer, contraception, and other diseases related to sex hormone-dependent diseases.
  • another object of the present invention is to provide a use of the compound of the formula (I), and a process for the preparation of the compound of the formula (I).
  • the first aspect of the invention provides a compound of formula (I):
  • the carboxyl group, the amide group, the phosphoric acid group, the sulfonyl group may be one or p each independently bonded to any one of R 2 , R 3 and R 4 , and t, n and p may each independently be an integer of 0-6. For example, 0, 1, 2, 3, 4, or 5;
  • a heterocycloalkyl group is a cyclic group having from 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O and S, etc. in the ring structure; the aryl group is unsubstituted or independently a mono- or di- or tri-substituted 4, 5, 6, or 7-membered monocyclic or bicyclic aromatic group selected from the group consisting of a nitro group, a carboxy group, or a C C4 alkyl group, such as a phenyl group or a naphthyl group.
  • the heterocyclic group may be unsubstituted or monosubstituted or disubstituted with a substituent independently selected from halogen, nitro, carboxy or d-alkyl, containing from 1 to 5 independently selected from N, O and S. a 4, 5, 6, or 7 membered monocyclic or bicyclic aromatic group of a hetero atom such as pyrrolyl, furyl, pyridyl or the like;
  • Y is selected from the following structures (i), (ii), (iii), (iv) or (v):
  • Each m is independently an integer from 0 to 6, for example 0, 1, 2, 3, or 4;
  • X is selected from hydrogen or from 1 to 4 substituents independently selected from the group consisting of halogen (eg, chlorine, fluorine, bromine) , iodine), decyl, ethyl, propyl, isopropyl, n-propyl, Ac-, NH 2 CO-, NTA -, CAM-, NDN -, CEC -, heptanoyl, lauryl, palmitoyl, Butyryl, nicotinyl, decanoyl, piperidinyl, morpholinyl;
  • halogen eg, chlorine, fluorine, bromine
  • iodine iodine
  • B is selected from the group consisting of NH 2 , -OH, -NR 19 R 20 , -NHNR 19 R 20 ; wherein Ri 9 and R 2 are .
  • Ri 9 and R 2 are independently selected from one another: H -, substituted or unsubstituted dC ⁇ straight or branched alkyl, substituted or unsubstituted C 2 -C 30 straight or branched alkenyl or alkynyl, substituted or unsubstituted d-Cso straight or branched alkoxy, substituted or unsubstituted d-Cso straight or branched alkylthio, substituted or unsubstituted d-o straight or branched alkylamino, cycloalkyl or Cycloalkenyl (CH 2 ) q -, aryl (CH 2 ) q -, heterocyclyl (CH 2 ) q -, or Y, such as C 3 -C 8 cycl
  • Xaa 3 is D-Phe or D-Pal
  • Xaa s , Xaa 6 and Xaa 8 are each independently selected from L or D type Phe (NAM), Phe(NNM), Phe(NOM), Aph(Ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, Gln, Asn, Lys, Ilys, Orn, Iorn, Cit, Aph(Hor ), Mph, Phe(COOH), Phe(CAM), Pal, Aph (Lauryl), Aph (palm base), Aph (butyryl), Aph (nicotinoyl), Aph (decanoyl), Uph (two Base, Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), ILys;
  • Xaa 5 , Xaa 6, or Xaa 8 is the following structure:
  • Q is selected from the group consisting of H, -NR 21 R 22 , -NHC(0)NR 21 R 22 , -C(0)NR 21 R 22 , -NH-C(0)R 23 , R 43 0-NR 24 -C( 0)-, R 25 R 26 P(0)- , R 27 N(R 28 N)P(0)- , R 29 O(R 30 N)P(O)- ,
  • W is selected from -COOH, -CONH 2 , -N(iPr) 2 , -NR 35 R 36 , -NHC(NR 37 )NR 38 R 39 , -NHC(O)NR 40 R" , -NH-C(0 ) R 42 , or Q;
  • r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;
  • R 21 -R 43 are independently selected from each other: H, HC(O)-, R, C(0)-, R!RiNCiO)-, wherein, 1 ⁇ and respectively are 11, substituted or unsubstituted dC ⁇ straight A chain or branched alkyl group, a substituted or unsubstituted c 2 -c 30 straight or branched alkenyl or alkynyl group, a substituted or unsubstituted ( ⁇ ⁇ straight or branched alkoxy group, substituted or unsubstituted d-Cso linear or branched alkylthio, cycloalkyl or cycloalkenyl (CH 2 ) n -, aryl (CH 2 ) n -, heterocyclyl (CH 2 ) n -, or Y, for example C 3 -C 3 .cycloalkyl or cycloalkenyl (CH 2 ) n -, C 3 -C 3
  • Xaa 7 is Lcu, Acc 5 or Acc 6 .
  • Xaa 3 is D-Phe or D-Pal
  • Xaa 5 , Xaa 6 and Xaa 8 are each independently selected from Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Amp, Uph, Arg, of L or D type.
  • Xaa 5 , Xaa 6 Xaa 8 is the following structure:
  • Q is selected from H, -NR 21 R 22 , -NHG(0)NR 21 R 22 > -C(0)NR 21 R 22 , -NH-C(0)R 2 3 , R"0-NR 24 -C (0)-, R 25 R 26 P(0)- , R 27 N(R 28 N)P(0)- , R 29 O(R 30 N)P(O)- ,
  • W is selected from -COOH, -CONH 2 , -N(iPr) 2 , -NR 35 R 36 , -NHC(NR 37 )NR 38 R 39 , -NHC(O)NR 40 R" , -NH-C(0 ) R 42 , or Q;
  • r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;
  • R 21 -R 43 are independently selected from each other: H, HC(O)-, RiC(O)-, R!R 2 NC(0)-, wherein 1 ⁇ and are respectively 11, substituted or unsubstituted dC 3 .
  • a mono- or di-substituted 4, 5, 6, or 7-membered monocyclic or bicyclic aromatic group such as phenyl, which is unsubstituted or independently substituted with a substituent selected from a steroid, a nitro group, a carboxy group or a dC 4 alkyl group. Or naphthyl or the like; the heterocyclic group may be unsubstituted or independently selected from! a 4, 4, 5, 6, or 7-membered mono- or di-substituted substituent containing 1-5 independently selected from N, O, and S, etc., of a substituent of a nitro group, a carboxy group, or a -C4 alkyl group.
  • a monocyclic or bicyclic aromatic group such as pyrrolyl, furyl, pyridyl, etc.; each n is independently 0, 1, 2, 3, or 4;
  • Xaa 7 is Leu, Acc 5 or Acc 6 .
  • B is NH 2 ;
  • Xaa 3 is D-Phe or D-Pal
  • Xaa 5 , Xaa 6 and Xaa 8 are each independently selected from D type Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, Gin, Asn, Lys, Ilys, Orn, lorn, Cit, Aph(Hor), Mph, Phe(COOH)> Phe(CAM), Pal, Aph (Lauryl), Aph (palm base), Aph (butyryl), Aph (nicotinoyl), Aph (decanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), ILys;
  • Xaa 7 is Lcu, Acc 5 or Acc 6 .
  • X is selected from hydrogen or 1 to 2 substituents independently selected from the group consisting of chlorine, fluorine, decyl, and ethyl;
  • B is NH 2 ;
  • Xaa 3 is D-Phe or D-Pal
  • Xaa 5 is selected from the group consisting of Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac),
  • Xaa 6 is selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO),
  • D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (different) propyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (decanoyl) ), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop, D-PaK D-Pro, D-Amp> D-Phe, D-Arg, D-GIu> D-Asp, D-Phe(COOH), D-Phe(CAM), D-Aph (Lauryl), D-Aph (Palm-based), D-Aph (nicotinoyl), D-Aph (de
  • Xaa 7 is Leu, Acc 5 or Acc 6 ;
  • Xaa 8 is Arg, ILys, IOrn, Asn, Gln.
  • R is One embodiment of the compounds of formula (I) according to any one of the first aspect of the present invention, wherein B is NH 2.
  • Xaa 5 is selected from the group consisting of Phe (NAM), Phe (NNM) > Phe (NOM), Mop, Aph, Uph, Gln , Asn, Aph (Hor).
  • Xaa 6 is selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO), D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (two Butyl-Cbm), D-Aph(Ac), D-Aph (n-butyryl), D-Aph (decanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe ( AM), D-Phe (NNM), D-Phe (NOM), D-Mop.
  • B is NH 2 ;
  • Xaa 3 is D-Phe or D-Pal
  • Xaa 5 is selected from the group consisting of Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph,
  • Xaa 6 is selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO),
  • D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (two Butyl-Cbm), D-Aph(Ac), D-Aph (n-butyryl), D-Aph (decanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe ( NAM), D-Phe (NNM), D-Phe (NOM), D-Mop;
  • Xaa 7 is Leu
  • Xaa 8 is Arg.
  • B is NH 2 ;
  • Xaa is D-Phe
  • Xaa is Mop
  • D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac ), D-Aph (n-butyryl), D-Aph (decanoyl), D-Uph, D-Aph,
  • Xaa is Leu
  • Xaa is Arg.
  • a compound of formula (I) according to any one of the first aspects of the invention which is selected from the group consisting of:
  • p s -D-Aph 6 (pipera 3 ⁇ 4J ⁇ -CO)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2 , NHC-D-Pal 3 -Ser 4 -M.
  • p s -D-Aph 6 (indole-CO)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2 , NHC-D-Pal 3 -Ser 4 -M.
  • a compound of formula (I) according to any one of the first aspects of the invention which is selected from the group consisting of:
  • NHC is: A compound of formula (I) according to any one of the first aspects of the invention, which is selected from the group consisting of
  • the NHC is:
  • a compound of formula (I) according to any one of the first aspects of the invention which is selected from the group consisting of: 1, NHC-D-Phe 3 -Ser 4 -Mop 5 -D-Aph 6 (diethyl-Cbm)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2
  • NHC-D-Phe 3 -Ser 4 -Mop s -D-Aph 6 (morpholinyl-CO)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2
  • NHC-D-Phe 3 -Ser 4 -Mop 5 -D-Aph 6 (Ac)-Leu 7 -Arg 8 -Pro 9 -D-Ala 10 -NH 2
  • the NHC is:
  • a second aspect of the invention relates to a process for the preparation of a compound of formula (I) according to the invention, which comprises the steps of:
  • step b) then reacting the reactant of step b) with an excess of carbonyldiimidazole (abbreviated as CDI) until the ninhydrin test is negative;
  • CDI carbonyldiimidazole
  • step d) The resin obtained in step d) is placed in a reactor of an HF cutter, anisole is added, the HF cutter is evacuated, and the reactor is cooled with liquid nitrogen to add liquid HF at -10 to 10.
  • the reaction is carried out under C (for example, at about 0 ° C), the HF is removed by an oil pump, and the solid is precipitated by adding chilled anhydrous diethyl ether.
  • the suspension is transferred to a sand core funnel and washed three times with a small amount of cooled anhydrous ether. Rinse with an aqueous acetic acid solution (for example, 10%) until the resin no longer adheres to each other, collect the washing liquid, and dry, that is,
  • X, Z, B, Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , and Xaa 8 are as defined for the compound of formula (I) according to any one of the first aspects of the invention.
  • a third aspect of the invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of formula (I) according to any one of the first aspects of the invention, and an optional medicament An acceptable carrier or excipient.
  • the fourth aspect of the invention provides the use of the compound of the formula (I) according to any one of the first aspects of the invention for the preparation of a medicament.
  • a fourth aspect of the invention provides the use of a compound of formula (I) according to any one of the first aspects of the invention for the manufacture of a medicament for antagonizing luteinizing hormone releasing hormone (LHRH).
  • LHRH antagonizing luteinizing hormone releasing hormone
  • a fourth aspect of the invention provides the use of a compound of formula (I) according to any one of the first aspects of the invention for the manufacture of a medicament for antagonizing a luteinizing hormone releasing hormone (LHRH) receptor.
  • LHRH luteinizing hormone releasing hormone
  • a fourth aspect of the invention provides the compound of formula (I) according to any one of the first aspects of the invention for use in the preparation of a gonadotropin-secreting hormone (e.g., luteinizing hormone (LH) and/or follicle stimulating hormone (FSH). ))
  • a gonadotropin-secreting hormone e.g., luteinizing hormone (LH) and/or follicle stimulating hormone (FSH).
  • a fourth aspect of the invention provides the use of a compound of formula (I) according to any one of the first aspects of the invention for the manufacture of a medicament for inhibiting a gonadotropin-like hormone such as estrogen, progesterone and/or testosterone. .
  • a fourth aspect of the present invention provides the compound of the formula (I) according to any one of the first aspects of the invention for use in the treatment and/or prevention of a sex hormone related disease (such as a sex hormone related cancer such as prostate cancer or endometrial cancer). , breast cancer) or other drugs whose sex hormones depend on related diseases or symptoms or drugs used for contraception.
  • a sex hormone related disease such as a sex hormone related cancer such as prostate cancer or endometrial cancer.
  • breast cancer breast cancer
  • drugs whose sex hormones depend on related diseases or symptoms or drugs used for contraception.
  • a fourth aspect of the invention also provides the use of a compound of formula (I) according to any one of the first aspects of the invention for the manufacture of a medicament for reducing histamine release, anti-inflammatory, or anti-allergic response.
  • any aspect of the invention or any one of the aspects of the invention is equally applicable to any of the other aspects or any of the other aspects, as long as they do not contradict each other, of course, when applied to each other If necessary, the corresponding features can be appropriately modified.
  • the “any” refers to any of the aspects of the first aspect of the invention; when otherwise mentioned in a similar manner, Have the same meaning.
  • halogen or “halo” as used herein refers to fluoro, chloro, bromo, and iodo.
  • hydrocarbyl as used in the present invention includes alkyl, alkenyl and alkynyl groups. These alkyl, alkenyl and alkynyl groups have their specified number of carbon atoms and may be linear or branched.
  • formula (I) decapeptide derivative stereoisomer as used in the present invention is meant to include its corresponding D- or L-stereo configuration.
  • the group moiety R has two chiral carbon atoms, which may be independently of each other in a D-configuration or an L-configuration; preferably, they are all D-configuration.
  • Acyl means H-CO- or alkyl-CO-, wherein said alkyl group is as described herein.
  • acylamino is acyl-NH- wherein acyl is as defined herein.
  • Alkoxycarbonyl means an alkyl-O-CO- group wherein the alkyl group is as described herein.
  • alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • alkyl refers to an aliphatic hydrocarbon group which may be a straight or branched chain having a specified number of carbon atoms, especially from about 1 to about 15 carbon atoms, optionally one or more Halogen atom substitution. In particular, an alkyl group having from 1 to about 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • the "lower alkyl group” which is a component of a group or a lower decyloxy group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group means that it may have a chain in a straight chain or a branched chain.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 3-pentyl, heptyl, octyl, decyl, Mercapto and dodecyl.
  • alkyl group substituted by one or more of the facet atoms include a trifluoromethyl group.
  • the alkyl group may also be independently selected from halogen, nitro, amino, by 1, 2, 3 or 4 Substituted by a substituent of a hydroxyl group, a carboxyl group, a dC 4 alkyl group or a dC 4 alkoxy group or a dC 4 alkylthio group.
  • alkenyl means a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond in the same chain having the indicated number of carbon atoms, especially from about 2 to about 15 carbon atoms. Preferred are alkenyl groups having from 2 to about 12 carbon atoms in the chain; and more preferably from 2 to about 6 carbon atoms (e.g., from 2 to 4 carbon atoms) in the chain.
  • branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight chain; herein is meant a linear alkenyl chain.
  • “Lower alkenyl” means that the chain contains from about 2 to about 4 carbon atoms which may be straight or branched.
  • Exemplary alkenyl groups include ethenyl, propylalkenyl, n-butenyl, isobutenyl, 3-methylbut-2-alkenyl, n-pentenyl, heptanoyl, Octenyl, cyclohexylbutenyl and anthracenyl.
  • the alkenyl group may be substituted by 1, 2, 3 or 4 independently from a steroid, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a d-alkyl group or a dC 4 alkoxy group or a C4 alkylthio group. Substituted.
  • Alkoxy means an alkyl-O- group wherein the alkyl group is as described herein.
  • alkoxy group include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptyloxy.
  • Alkylthio means an alkyl-S- group wherein the alkyl group is as described herein.
  • Alkenyloxy means an alkenyl-O- group in which alkenyl is as defined above.
  • the alkenyloxy group exemplified includes an allyloxy group.
  • Alkenylthio means an alkenyl-S- group in which alkenyl is as defined above.
  • Halogen includes fluorine, chlorine, bromine and hydrazine, preferably fluorine, chlorine, bromine, more preferably fluorine and chlorine, still more preferably chlorine.
  • alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon oxime bond which may be a straight or branched chain having a specified number of carbon atoms, especially from about 2 to about 15 carbon atoms. Having from 2 to about 12 carbon atoms in the chain; and more preferably from 2 to about 6 carbon atoms (e.g., from 2 to 4 carbon atoms) in the chain.
  • alkynyl groups include ethynyl, propynyl, n-butynyl, Isobutynyl, 3-methylbutan-2-yl and n-pentynyl.
  • Alkynyl may be independently selected from the group consisting of a aryl group, a nitro group, an amino group, a hydroxy group, and a carboxy group. Substituted by a C C4 alkyl or dC decyloxy group or a C C4 alkylthio group
  • Aroyl means an aryl-CO- group wherein the aryl group is as described herein. Show Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Aroylamino is an aroyl-NH- group in which the aroyl group is as defined above.
  • Aryl as a group or a component of a group represents: (i) an optionally substituted monocyclic or polycyclic aromatic carbocyclic moiety of from about 6 to about 14 carbon atoms, such as phenyl or naphthyl. Or (ii) an optionally substituted partially saturated polycyclic aromatic carbocyclic moiety wherein the aryl group and the cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, fluorenyl Or a dihydroindenyl ring.
  • an aryl group may be substituted by one or more (eg, 2, 3, 4, 5) aryl substituents, which may be the same or different, wherein "aryl substituent" includes, for example, an acyl group. , acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkoxy , arylalkoxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or acid bioisosteres) ), cyano, halogen, heteroaroyl, heteroaryl, heteroarylalkoxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoro
  • Arylalkoxy means an arylalkyl group wherein the arylalkyl group is as defined above.
  • exemplary arylalkoxy groups include benzyloxy and 1- or 2-naphthylmethoxy.
  • Arylalkylthio means an arylalkyl-S- group in which the arylthio group is as defined above.
  • An exemplary arylalkylthio group is benzylthio.
  • Aryloxy means an aryl-O- group in which the aryl group is as defined above.
  • exemplary aryloxy groups include phenoxy and naphthyloxy, each of which is optionally substituted.
  • Cycloalkenyl means a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having the indicated number of carbon atoms, especially from about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexyldecyl and cycloheptenyl.
  • the cycloalkenyl group may be substituted by 1, 2, 3 or 4 substituents independently selected from halogen, nitro, amino, hydroxy, carboxy, d-alkyl or dC 4 alkoxy.
  • Cycloalkyl means having the indicated number of carbon atoms, especially from about 3 to about 10 carbon atoms A saturated monocyclic or bicyclic ring system, optionally substituted with oxygen.
  • Exemplary monocyclic cycloalkyl rings include C 3 -8 cyclodecyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of a genino, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a dC alkyl group or a C C4 alkoxy group.
  • a heterocyclic group is a compound having one or more (e.g., 2, 3, 4, 5) heteroatoms in its ring structure.
  • Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).
  • the heterocyclic group may especially be aromatic (i.e., heteroaryl), saturated or partially saturated.
  • Preferred monocyclic heterocyclic groups of the present invention include 5- and 6-membered monocyclic heterocyclic groups. These heterocyclic and heteroaromatic compounds may be further substituted by the following groups: aryl, alkyl, alkoxy, haloalkyl, alkoxy, nitro, cyano, alkyl, alkylamino Or phenyl.
  • Examples of preferred aromatic 5- or 6-membered heterocyclic groups of the invention include 1,3,2,4- or 1,3,4,5-bisoxadiazole, dioxazinyl, dioxazinyl. 1,2,3-, 1,2,4-. 1,3,2- or 1,3,4-dioxazolyl, 1,3,2,4- or 1,3,4,5 -dithiadiazolyl , dithiatriazinyl, dithiaffinyl, 1,2,3-dithiazolyl, 2- or 3-furanyl, furazyl, 1-, 2- or 4-imidazole Base, isoxazolyl, isothiazole-3-, -4- or 5-yl, isoxazole-3-, -4- or 5-yl, 1,2,3- 1,2,4- , 1,2,5- or 1,3,4-oxadiazol-3-, -4- or 5-yl, oxazinyl, oxatriazinyl, 1,2,3,4- or 1,2,3,5-oxatriazoly
  • the most preferred aromatic heterocyclic group of the present invention includes furan-2-yl, furan-3-yl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2- or 3-pyridyl, and 1- or 2-thienyl.
  • Examples of preferred saturated or partially saturated 5- or 6-membered heterocyclic groups of the invention include 1,3,5,6,2-dioxadiazinyl, 1,2,3,4,5- or 1,2, 3,5,4-dioxadiazolyl, dioxoalkyl, 1,3-dioxolyl, 1,3,5,6,2-dithiazinyl, 1,2, 3,4,5- or 1,2,3,5,4-dithiadiazolyl, 2-isoimidazolyl, isopyrrolyl, isotazolyl, 1,2,3- or 1,2,4 -isotriazolyl, morpholinyl, oxadiazinyl, 1,2,4-, 1,2,6-, 1,3,2-, 1,3,6- or 1,4,2-anthracene Azinyl, piperazinyl, homopiperazinyl, piperidinyl, 1,2-, 1,3- or 1,4-pyranyl, and 1,2,3-pyrrolidinyl.
  • Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 7 membered rings containing one or more heteroatoms or a heteroatom-containing group selected from the group consisting of 0, S and NNiR 2 and optionally The ground is replaced by oxygen; (ii) a partially saturated polycyclic heteroatom-containing carbocyclic moiety wherein the aryl (or heteroaryl) ring is optionally substituted by one or more "aryl substituents", respectively, and The cycloalkyl groups are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, dihydroindolyl, and pyridolinyl).
  • brackets "( )” are used in the group representing the present invention, for example, the bracket “( )” used in "Aph (decanoyl)", and the contents thereof do not refer to the contents outside the brackets. , but means that the group in parentheses is connected to the part outside the brackets, such as the above
  • the compound of the formula (I) and its stereoisomers and physiologically acceptable salts thereof exhibit not only good effects in animal antiandrogen secretion experiments, but also exhibit lower histamine dry doses in in vitro assays. Therefore, it can be used as a hormonal agent for animals, preferably for mammals, especially humans.
  • the invention therefore also relates to an effective amount of at least one compound of the formula (I) and/or its stereoisomers or physiologically acceptable salts thereof, as well as conventional pharmaceutical excipients or auxiliaries (ie pharmaceutically acceptable) A pharmaceutical composition of the accepted excipient or adjuvant).
  • the "conventional pharmaceutical excipient or adjuvant” herein includes any or all solvents, dispersion media, coatings, antibacterial or antifungal agents, isotonic and sustained release agents, and similar physiologically compatible preparations, suitable for intravenous injection. , intramuscular, subcutaneous, or other modes of administration.
  • the active compound may be coated to protect the compound from acid or other natural conditions and inactivated, depending on the mode of administration.
  • physiologically acceptable salt or “non-physiologically acceptable salt” as used in the present invention refers to a salt or a combination thereof which retains the expected physiological activity of the parent compound without causing any unexpected toxic side effects.
  • An acid salt a benzoate, a pamoate, an alginate, an oxime sulfonate, a naphthalene sulfonate, and the like.
  • the cation according to the salt may be: an inorganic salt such as a potassium salt, a lithium salt, a zinc salt, a copper salt, a cerium salt, a cerium salt or a calcium salt, and may also be an organic salt such as a trialkylammonium salt.
  • an inorganic salt such as a potassium salt, a lithium salt, a zinc salt, a copper salt, a cerium salt, a cerium salt or a calcium salt
  • organic salt such as a trialkylammonium salt.
  • the compound of the formula (I) of the present invention and a stereoisomer thereof or a pharmaceutical composition containing the same can be administered in any manner known per se, such as oral, intramuscular, subcutaneous, etc., for administration of a pharmaceutical form such as a tablet, a capsule, or a mouth.
  • a pharmaceutical form such as a tablet, a capsule, or a mouth.
  • various biodegradable or biocompatible carriers well known in the art can be widely used.
  • the carrier examples include, for example, a saline-based solution and various buffered aqueous solutions, ethanol or other polyols, liposomes, polylactic acid, vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and the like.
  • the dose of the compound of the formula (I) of the present invention and its stereoisomers depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, sensitivity and individual response of the patient or animal, The specific compound used, the route of administration, the number of administrations, and the desired therapeutic effect.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three, four dosage forms.
  • the single maximum dose will generally not exceed 30 mg/kg body weight, for example 0.0001-30 mg/Kg, such as 0.0005-20 mg/Kg, such as 0.001-10 mg/Kg, such as 0.005-10 mg/Kg, such as 0.005-5 mg/Kg, such as 0.01-5 mg. /Kg, for example 0.05-2 mg/Kg body weight.
  • a single dose of 30 mg/Kg or more or 0.0001 mg/Kg or less may also be used.
  • the present inventors have found that the compound of the formula (I) having the group moiety R of the present invention has a good biological activity for inhibiting testosterone release in rats, and the octapeptide fragment not comprising the R group is not detected to inhibit testosterone in rats. The biological activity released.
  • the present invention provides a general and/or specific description of the materials and test methods used in the tests. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. It will be apparent to those skilled in the art that, hereinafter, the materials and methods of operation of the present invention are well known in the art unless otherwise stated.
  • the solid phase synthesis carrier MBHA resin used in the examples is Tianjin Nankai Synthetic Co., Ltd.; DCC:, HOBT, BOP. DIEA and Boc-protected natural amino acids by Shanghai Jill Biochemical Co., Ltd. and Chengdu Kaitai New Technology Co., Ltd., Boc - Protected non-natural amino acids are provided by our laboratory, except as indicated.
  • Example 1 Synthesis of Compound 1
  • Boc-D-Nal was inserted into the peptide chain
  • the N-terminal Boc was removed with 4M HCl/Diox, neutralized.
  • a 3-fold excess of CDI was added for 0.5 h, and excess CDI was washed away with DCM.
  • the triketone was tested for condensation. If it was positive, it was negative until it was negative.
  • the reaction was carried out for 4 h at room temperature, and the resin was washed with methanol and DCM, and the reaction was completed.
  • the above peptide resin was placed in a reactor of an HF cutter, and 1.0 mL of anisole was added. After installation, the system of the HF cutter was evacuated, the reactor was cooled with liquid nitrogen, transferred to about 10 mL of liquid HF, and reacted at 0 C for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, solidified by adding anhydrous ethyl ether, and the suspension was transferred to a sand core funnel.
  • the weight of the animal was previously referred to as the body weight of the animal.
  • the blood was collected from the posterior venous plexus of the capillary.
  • the serum testosterone content was determined by chemiluminescence method.
  • the testosterone content and body weight were randomly divided into groups. Each group of 4 animals was injected subcutaneously in a single dose. After 500 ⁇ 8 of the compound, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, the venous plexus of the ball was centrifuged at 5000 rpm for 8 min, and the separated serum was chemiluminescence (Beckman Coulter, USA)
  • the company's Access Immunoassay System chemiluminometer measures serum testosterone levels. The results are shown in Table 2.
  • the serum testosterone content is usually less than 1.5n g / ml, which is considered to have a therapeutic effect, and the duration of the animal in the range of serum testosterone content generally reflects the biological activity maintenance time of the test sample.
  • the compounds of the examples prepared in the present invention can provide a serum testosterone content within the range required for effective treatment.
  • the serum testosterone content has a great relationship with various diseases which the compound of the formula (I) of the present invention can treat, and it is generally considered that the serum testosterone content range can be used for the treatment of the present invention under the conditions of the test.
  • Various diseases of the invention for example, prostate cancer, endometrial cancer, breast cancer and other diseases that are dependent on sex hormones (see, for example, Bernhard Kutscher et al, Angew Chem Int Ed Engl, 1997, 36, 2148-2161; and Andrew V Schally, Peptides, 1999) , 20, 1247-1262, these documents are incorporated herein by reference.
  • Real face example 2 Determination of the ability of rat peritoneal mast cells to release histamine

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Abstract

L'invention porte sur un dérivé décapeptide de la formule (I) qui posséde la structure de l'hydantoïne, sur un procédé de préparation de celui-ci, sur une composition pharmaceutique contenant le dérivé décapeptide et sur l'application de celle-ci lors de la préparation du médicament. Le dérivé décapeptide est un antagoniste de l’hormone de libération de l’hormone lutéinisante (LHRH) qui a une activité antagoniste du récepteur LHRH et des actions d'inhibition de la sécrétion de gonadotrophines de la glande pituitaire et de la sécrétion d'hormones stéroïdes de la glande sexuelle. Formule (I), R-Xaa3-Ser-Xaa5- Xaa6- Xaa7- Xaa8-Pro-D-Ala-B
PCT/CN2010/001078 2009-07-29 2010-07-16 Antagoniste de l’hormone de libération de l’hormone lutéinisante ayant la structure de l'hydantoïne WO2011011965A1 (fr)

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CN104418936B (zh) * 2013-08-20 2018-06-05 中国人民解放军军事医学科学院毒物药物研究所 Lhrh拮抗剂衍生物及其药物用途

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WO1994014841A1 (fr) * 1992-12-18 1994-07-07 Abbott Laboratories Antagonistes de lhrh comprenant des restes d'aminoacyle modifies en position 5 et 6
CN1781935A (zh) * 2004-12-01 2006-06-07 中国人民解放军军事医学科学院毒物药物研究所 新的lhrh拮抗剂
CN1965809A (zh) * 2005-11-16 2007-05-23 中国人民解放军军事医学科学院毒物药物研究所 Lhrh拮抗剂类物质的注射用缓释微球及其制备方法
CN101037472A (zh) * 2006-03-14 2007-09-19 中国人民解放军军事医学科学院毒物药物研究所 具有低组胺释放作用的lhrh拮抗剂
WO2008147556A2 (fr) * 2007-05-25 2008-12-04 Ipsen Pharma S.A.S. Ligands de récepteurs de la mélanocortine modifiés au moyen d'hydantoïne

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ATE305008T1 (de) * 1999-10-15 2005-10-15 Neurocrine Biosciences Inc Gonadotropin freisetzenden hormon rezeptor antagonisten und ihre verwandten verwendungen
MX2007005765A (es) * 2004-11-23 2007-07-19 Wyeth Corp Antagonistas del receptor de la hormona que libera gonadotropina.

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Publication number Priority date Publication date Assignee Title
US4476116A (en) * 1982-12-10 1984-10-09 Syntex (U.S.A.) Inc. Polypeptides/chelating agent nasal compositions having enhanced peptide absorption
WO1994014841A1 (fr) * 1992-12-18 1994-07-07 Abbott Laboratories Antagonistes de lhrh comprenant des restes d'aminoacyle modifies en position 5 et 6
CN1781935A (zh) * 2004-12-01 2006-06-07 中国人民解放军军事医学科学院毒物药物研究所 新的lhrh拮抗剂
CN1965809A (zh) * 2005-11-16 2007-05-23 中国人民解放军军事医学科学院毒物药物研究所 Lhrh拮抗剂类物质的注射用缓释微球及其制备方法
CN101037472A (zh) * 2006-03-14 2007-09-19 中国人民解放军军事医学科学院毒物药物研究所 具有低组胺释放作用的lhrh拮抗剂
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Publication number Priority date Publication date Assignee Title
US10087221B2 (en) 2013-03-21 2018-10-02 Sanofi-Aventis Deutschland Gmbh Synthesis of hydantoin containing peptide products

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