CN104418936A - LHRH antagonist derivative and medicinal application thereof - Google Patents
LHRH antagonist derivative and medicinal application thereof Download PDFInfo
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- CN104418936A CN104418936A CN201310363034.2A CN201310363034A CN104418936A CN 104418936 A CN104418936 A CN 104418936A CN 201310363034 A CN201310363034 A CN 201310363034A CN 104418936 A CN104418936 A CN 104418936A
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- aph
- cpa
- cbm
- pro
- ilys
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- COLNVLDHVKWLRT-UHFFFAOYSA-N NC(Cc1ccccc1)C(O)=O Chemical compound NC(Cc1ccccc1)C(O)=O COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
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
- A61P13/08—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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P5/28—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention relates to a decapeptide derivative having an LHRH receptor antagonistic activity and particularly relates to a compound represented as the formula (I). The invention also relates to a preparation method of the compound, a medicinal composition comprising the compounds, and applications of the compounds in preparation of a drug having an effect of inhibiting secretion of gonadotropin by hypophysis, a drug having the effect of inhibiting the secretion of steroid hormone by gonad, and a drug for treating prostate cancer, endometrial cancer, a sex hormone dependant disease relative to reproduction and a drug for contraception and the like. The formula (I) is described as follows: R-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)-Aaa7-Ilys-Pro-Aaa10-NH2.
Description
Technical field
The present invention relates to the decapeptide derivative with LHRH receptor antagonist activity, the invention still further relates to the preparation method of described decapeptide derivative, containing their pharmaceutical composition, and they have the purposes suppressed in the medicine of pituitary gonad-stimulating hormone effect, the medicine of inhibition glandular secretion steroid hormone effect and treatment prostate cancer, carcinoma of endometrium, medicine such as the sexual hormoue relevant with reproduction dependence relative disease, contraception etc. in preparation.
Background technology
LHRH(luteinizing hormone-releasing hormone) be one of peptide hormone secreted by hypothalamus, its Main Function promotes that hypophysis synthesizes and discharges lutropin (LH) and follicular stimulating hormone (FSH), excites Development in Puberty and regulate Sheng Zhi ﹑ fertility and sexual hormoue correlated process.LHRH is made up of ten amino-acid residues, and C-end is containing amide structure.The primary structure of LHRH is as follows:
p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
Lhrh antagonist, by blocking the release of LHRH effect and then suppression LH, therefore may be used for the treatment of sex hormone related condition as diseases such as prostate cancers.Compared with agonist, lhrh antagonist have effective speed fast, without recovering after upper punch phenomenon, drug withdrawal soon, to advantages such as serum androgen controlled level are strong.Can expect, the curative effect of lhrh antagonist treatment prostate cancer is better than agonist, is more easily easily accepted by the patient, has larger application prospect than agonist.
Although the lhrh antagonist developed at present is existing a lot, as a kind of peptide medicament, great majority still exist that bioavailability is low, and Half-life in vivo is short, the high weak point of histamine release amount, limits lhrh antagonist application clinically.Indivedual bibliographical information, the lhrh antagonist of high density self can be assembled when subcutaneous administrations, form amyloid fiber shape aggregate, and peptide molecule from aggregate end slow releasing, thus can have effect (Maji, the S.K. of slowly-releasing, D.Schubert, et al. " Amyloid as a depot for theformulation of long-acting drugs. " PLoS Biology, 2008,6 (2): 240-252).This aggregate is a stable bank only comprising polypeptide drugs, has the weave construction of high-sequential.Found by the common structure analyzing lhrh antagonist, they have a hydrophobic N end and a hydrophobic C end mostly, and the region intermediate that hydrophilic (middle 3 ~ 6), and this structure is by amphipathic based on secondary structure of β-pleated sheet structure formation.（Struthem,R.S.;Tanaka,G.;Koerber,S.C.;Solmajer,T.;Baniak,E.L.;Gierasch.L.M.;Vale,W.;Rivier,J.;Hagler,A.T.Design ofBiologically Active,conformationally Constrained GnRH Antagonists.proteins:Structure,Function Genet.1990,8,295-304.）。This secondary structure amphipathic may be that such polypeptide can the molecular basis of self-assembly.
Lhrh antagonist is combined with hair fastener form with acceptor, 7 is not the critical sites with receptors bind, and 7 are just in time positioned at hydrophilic and hydrophobic intersection, therefore, object of the present invention is exactly replace lhrh antagonist 7 amino acids with the amino acid of different structure, keep former activated while, by changing peptide chain length and sterically hindered, reach and regulate aggregate accumulation shape and release rate, thus reach slow release effect in various degree, obtain New-type long-acting lhrh antagonist analogue.
Summary of the invention
The present inventor is through unremitting effort and a large amount of experimental studies, be surprisingly found out that, compound shown in formula (I) or its steric isomer or its salt without physiological-toxicity, not only there is good LHRH antagonistic activity, and the aggregate of different shape can be self-assembled in vitro, therefore there is action time in longer body, the effect of slowly-releasing can be reached, this completes the present invention.
R-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)-Aaa
7-Ilys-Pro-Aaa
10-NH
2
Formula (I)
First aspect present invention relates to the compound shown in formula (I), or its steric isomer or its salt without physiological-toxicity,
R-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)-Aaa
7-Ilys-Pro-Aaa
10-NH
2
Formula (I)
Wherein, R is Ac, Cbm or R
1;
Wherein R
1for-CO(CH
2)
ncH
3;
N can be 0,1,2,3,4,5 or 6;
Aaa
7for Thr, Phe, Met, Ile, Val, Tyr, Nle, Nleu, β-Leu, Acc
3, Acc
5, Acc
6, Clpa, Mle, Cpa or following structure:
Wherein X is C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkyl acyl or halogen; .
Aaa
10for D-Ala, D-Val, Sar or C
α-Me-Ala.
In embodiments of the invention, R is Ac or Cbm.
In embodiments of the invention, Aaa
7for Thr, Ile, Nle, Nleu, β-Leu, Acc
3, Acc
5or Acc
6.
In embodiments of the invention, Aaa
10for D-Ala.
In specific embodiment of the invention scheme, described compound or its steric isomer or its salt without physiological-toxicity, it is selected from following compound:
(1)Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Ile
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（2）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Val
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（3）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Nle
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（4）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
6)
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（5）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Met
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（6）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Phe
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（7）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
5)
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（8）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Nleu)
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（9）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-βLeu
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（10）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
3)
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（11）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Thr
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（12）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Clpa
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（13）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(m)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（14）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(p)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（15）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(o)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（16）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Mle
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（17）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Cpa
7-Ilys
8-Pro
9-D-Ala
10-NH
2
（18）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Leu
7-Ilys
8-Pro
9-D-Val
10-NH
2
（19）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Leu
7-Ilys
8-Pro
9-Sar
10-NH
2
Preferably, the compounds of this invention is selected from compound (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11).
More preferably, the compounds of this invention is selected from compound (1), (2), (4), (7), (10), (11).
In the present invention, (the 1) ~ numbering of (19) and the numbering of representation compound.
The invention still further relates to compound described in any one of first aspect present invention or its steric isomer or its preparation method without the salt of physiological-toxicity; it comprises employing solid phase synthesis process; take mbha resin as carrier; Boc-or Fmoc-Preservation tactics; DIC/HOBT or HBTU/DIEA is condensation reagent; HCl/ dioxane or piperidines/DMF are deprotecting regent, are cut down by decapeptide derivative after having reacted with liquid HF from mbha resin.
The invention still further relates to pharmaceutical composition, it contains compound described in any one of at least one first aspect present invention or its steric isomer or its salt without physiological-toxicity, and optional pharmaceutically acceptable carrier or vehicle.
The invention still further relates to compound described in any one of first aspect present invention or its steric isomer or its salt without physiological-toxicity for the preparation of prevention or therapeutic humoral relative disease or for the purposes in the medicine of practising contraception.
In the present invention, described sex hormone related condition comprises sexual hormoue associated cancer, precocious puberty, hyperplasia of prostate, endometriosis, menoxenia (as amenorrhoea, dysfunctional uterine bleeding or ovulation failure) or Infertility etc.
In the present invention, described sexual hormoue associated cancer comprises prostate cancer, carcinoma of endometrium, mammary cancer or ovarian cancer etc.
In embodiments of the invention, described medicine is sustained release preparation.
The invention still further relates to compound described in any one of first aspect present invention or its steric isomer or its salt without physiological-toxicity for the preparation of the purposes suppressed in the medicine of pituitary gonad-stimulating hormone (such as LH and/or FSH) and/or inhibition glandular secretion steroid hormone (such as oestrogenic hormon, progestogen and/or testosterone).
In embodiments of the invention, described medicine is sustained release preparation.
The invention still further relates to prevention or the method for therapeutic humoral relative disease or contraception, described method comprises to the compound of any one of first aspect present invention of experimenter's prevention in need or treatment significant quantity or its steric isomer or its step without the salt of physiological-toxicity.
In the present invention, described sex hormone related condition comprises sexual hormoue associated cancer, precocious puberty, hyperplasia of prostate, endometriosis, menoxenia (as amenorrhoea, dysfunctional uterine bleeding or ovulation failure) or Infertility etc.
In the present invention, described sexual hormoue associated cancer comprises prostate cancer, carcinoma of endometrium, mammary cancer or ovarian cancer etc.
The invention still further relates to and suppress pituitary gonad-stimulating hormone (such as LH and/or FSH) and/or the method for inhibition glandular secretion steroid hormone (such as oestrogenic hormon, progestogen and/or testosterone), described method comprises to the compound of any one of first aspect present invention of experimenter's prevention in need or treatment significant quantity or its steric isomer or its step without the salt of physiological-toxicity.
Except as otherwise noted, the term used in this application has following implication.
In the present invention, all amino acid configuration, except being labeled as D-type, are L-type.
In the present invention, term used " steric isomer " refers to its corresponding D-or L-steric configuration.
In the present invention, described C
1-6alkyl refers to comprise and specifies number the straight chain of carbon atom and the saturated hydrocarbyl of side chain, is such as methyl, ethyl usually, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, 3-amyl group, hexyl etc.Term " alkyl " also comprises cycloalkyl, i.e. ring-type C
3-C
6alkyl, as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferably, term used herein " alkyl " refers to comprise and specifies number the straight chain of carbon atom and the chain-like alkyl of side chain.
In the present invention, described C
1-6alkoxyl group refers to C
1-6allcyl-O-groups, wherein said C
1-6alkyl is C as herein described
1-6alkyl.Examples of alkoxy comprise methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan oxygen base.
In the present invention, described C
1-6alkyl acyl refers to C
1-6alkyl-CO-, wherein said C
1-6alkyl is as described herein.
In the present invention, described halogen is fluorine, chlorine, bromine or iodine.
According to the present invention, described compound and steric isomer thereof not only have good LHRH antagonistic activity with its salt without physiological-toxicity, and the aggregate of different shape can be self-assembled in vitro, therefore there is action time in longer body, the effect of slowly-releasing can be reached, for the preparation of sustained release preparation.Therefore the compounds of this invention can be used as amcinonide for animal, is preferred for Mammals, particularly people.
Therefore the present invention also relates to containing compound of the present invention and/or its steric isomer or its pharmaceutical composition without physiological-toxicity salt and conventional pharmaceutically acceptable carrier or vehicle.Here " pharmaceutically acceptable carrier or vehicle " comprises any one or all solvents, dispersion medium, dressing, antiseptic-germicide or anti-mycotic agent, isotonic and sustained release dosage, and similar physiology compatibility agent, with applicable intravenous injection, intramuscular injection, subcutaneous injection, or other administering mode, as oral administration.According to the mode of administration, can by active compound dressing with protect compound from acid or the impact of other natural condition inactivation.
Term used herein " salt without physiological-toxicity " refers to and can retain parent compound expection physiologically active and can not produce salt or their composition of any unexpected toxic side effect.Such as: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, nitrate, and acetate, oxalate, tartrate, succinate, malate, benzoate, embonate, alginates, mesylate, naphthalenesulfonate etc.Positively charged ion according to containing in salt can be again: sylvite, lithium salts, zinc salt, mantoquita, barium salt, bismuth salt, and the inorganic salt such as calcium salt also can be the organic salts such as such as trialkyl ammonium salts.
Compound of the present invention and steric isomer thereof, can with known any mode administration without physiological-toxicity salt or the pharmaceutical composition containing it, as oral, muscle, subcutaneous etc., form of administration is tablet, capsule, buccal tablet, chewable tablet, elixir, suspensoid, transdermal agent, micro-capsule embedding medium, implants, syrup etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.In order to unit dosage forms for administration is made tablet, various biodegradable or physiologically acceptable carrier well known in the art can be widely used.About the example of carrier, as saline based and various aqueous buffer solution, ethanol or other polyvalent alcohol, liposome, poly(lactic acid), vinyl-acetic ester, polyanhydride, polyglycolic acid, collagen, poe etc.
Compound of the present invention or its steric isomer or its dosage without physiological-toxicity salt depend on many factors, such as to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight, susceptibility and individual reaction, particular compound used, route of administration, administration number of times and desired by the result for the treatment of etc. that reaches.Above-mentioned dosage can single dose form or be divided into several, such as two, three, four dosage forms for administration.Single maximal dose is generally no more than 30mg/Kg body weight, such as 0.001-30mg/Kg, preferred 0.01-5mg/Kg, and better dosage range is 0.5-2mg/Kg body weight.But, in some cases, the single dosage of more than 30mg/Kg body weight or below 0.001mg/Kg also may be used.
The abbreviation used in the present invention has implication below:
Ac-ethanoyl
Ala-L-Ala,
Aph-4-amino phenylalanine
Boc-tertbutyloxycarbonyl,
Cpa-fenclonine,
DIEA-diisopropylethylamine,
HOBt-1-hydroxybenzotriazole,
Hor-dihydroorotate,
Leu-leucine,
ILys-sec.-propyl Methionin
MBHA-phenylamino methyl resin,
Nal-naphthylalanine,
Nleu-nor-leucine
C
α-Me-Ala-C
α-methyl-alanine
Pal-3-pyrazoleahtnine,
Phe-phenylalanine,
RP-HPLC-RPLC
Pro-proline(Pro),
Ser-Serine,
(p) Mph-to methylphenylalanine,
(p) Cpa-fenclonine,
Sar-nitrogen methylglycine,
Accompanying drawing explanation
The transmission electron microscope picture of Fig. 1 compound (4), (7), (10)
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturers suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment solid-phase synthesized carrier mbha resin used is Tianjin Nankai synthesis responsibility company limited product; The natural amino acid of DIC, HOBT, HBTU, DIEA and Boc-protection or Fmoc-protection is by gill biochemical corp, Shanghai and Chengdu Cheng Nuo New Technology Co., Ltd. product, and the alpha-non-natural amino acid of Boc-or Fmoc-protection provides by the synthesis of this laboratory except explanation.
Embodiment 1: the synthesis of decapeptide derivative
With 1g mbha resin (0.96mmol) for solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the Boc solid-phase peptide synthesis (reference: Huang Weide, Chen Changqing work, Peptide systhesis of standard, Science Press, 1985), first synthesize Leu
7-Ilys(Cbz)
8-Pro
9-D-Ala
10-mbha resin.Synthesize example with compound (1): according to standard Boc strategy successively with the protected amino acid unit of 6 and the Boc-Aph(Fmoc of 5) condensation; the same remove Fmoc protecting group after; add the vitamin B13 of 2mmol or other unit that will modify, 2mmolHBTU, 2mmolDIEA; react triketohydrindene hydrate after 4-10 hour to detect; after reacting completely; remaining amino acid is connected successively again according to standard Boc strategy; put into the reactor of HF cutting device; the same process; 1.47g white dry powder is obtained, thick peptide yield 93.5% after lyophilize.Chromatogram purification is pressed to obtain sterling in warp, pure peptide yield 12.1%.ESI-MS:[M+2H] 810.6(theoretical value: 1620.2).
Prepared compound (2) ~ (19) according to the method described above, the Mass Spectrometric Identification result of compound is as shown in table 1
The mass spectroscopy result of table 1 compound
Embodiment 2: suppress testosterone effect and histamine release EC in rat body
50determination experiment
Testosterone effect experiment is suppressed: before experiment, claim the weight of animals in rat body, glass capillary ball rear vein beard is taken a blood sample, chemiluminescence determination Testosterone Content in Serum is used after separation of serum, by testosterone concentration and body weight random packet, often organize 4 animals, respectively at after disposable subcutaneous injection 2mg/kg testing compound 8,16,24 hours etc., ball rear vein beard is taken a blood sample, the centrifugal 8min of 5000rpm, measures Testosterone Content in Serum by being separated the serum chemoluminescence method (Beckman Coulter company of U.S. AccessImmunoassay System Chemiluminescence Apparatus) obtained.
Histamine release EC
50measuring method: compound PBS damping fluid is made into 2.0 μ g/mL respectively, 20.0 μ g/mL, 200 μ g/mL mother liquors are for subsequent use.5 SD male rats are put to death pneumoretroperitoneum and are injected cold PBS, and cut open the chest sucking-off peritoneal fluid low-temperature centrifugation, and repeated washing once merges sedimentation cell afterwards, adds appropriate PBS and make single cell suspension, white corpuscle diluted, get its part (about containing 2 × 10
6individual cell) add in some centrifuge tubes, then compound stock solutions is added respectively, concentration is made into the full retting conditions pipe of 0(), 0.1,0.3,1.0,3.0,10.0,30.0,100.0 μ g/mL, hatch 15min in 37 DEG C of water-baths, full retting conditions pipe boils 5min, ice bath stopped reaction, 4 DEG C, after the centrifugal 5min of 1500rpm, get supernatant liquor chemical luminescence detector and measure fluorescence intensity at EX340nm and EM460nm wavelength place, correlation formula according to instrument calculates histamine release percentage automatically, draws the EC of each compound
50.EC
50be worth larger, show that sample causes the ability of histamine release more weak.
According to the method described above, determination of activity the results are shown in Table 2.
Table 2 compound suppresses the evaluation result of rat TESTO secretion
Testosterone Content in Serum measurement result shows, lhrh antagonist of the present invention is after amino acid modified 7 different by structure, the activity of original antagonist can be kept, effective reduction Testosterone Content in Serum (implication that testosterone concentration reduces: as compared to the testosterone concentration in rat body before blank group rat and administration, all have the remarkable reduction on statistical significance.）；
Histamine release EC
50measurement result shows, compound of the present invention has low histamine releasing activity, effectively can reduce the side effect that histamine release causes.
Embodiment 3: transmission electron microscope method observes the morphology of the aggregate
By compound dissolution of the present invention at 1ml, the N.F,USP MANNITOL of 5%, in the sodium azide aqueous solution of 0.01%, be configured to the solution of 1mg/ml, be placed on incubated at room 4 hours, get 5 μ L mother liquors and be diluted to 50 μ L, be configured to 50 μMs, drop on the copper mesh of carbon supporting film, precipitation 5min, the phospho-wolframic acid dyeing 1min of 2%, HITACH transmission electron microscope observing, picture amplifies 70,000 ~ 80,000.
Transmission electron microscope observing finds, the compounds of this invention defines amyloid fiber or vesica shape aggregate, as shown in Figure 1.
Embodiment 4: aggregate dialysis experiment
Hatch the solution (N.F,USP MANNITOL of 5% of the 400 μ L the compounds of this invention of 18 days, in the sodium azide aqueous solution of 0.01%, be configured to the solution of 1mg/ml), adding molecular weight cut-off is in the dialysis tubing of 3.5KDa, be the mother liquor (N.F,USP MANNITOL of 5% of 9mL outside pipe, the sodium azide aqueous solution of 0.01%), note not allowing the both sides of film have bubble, in order to measure the outer strength of solution of pipe, get the outer solution 250 μ L of pipe and be diluted to 500 μ L, spectrophotofluorometer exciting light is at 280nm, and utilizing emitted light is at 290nm ~ 500nm, exciting light slit is 5nm, and utilizing emitted light slit is 10nm.
According to the method described above, determine the release of each compound, as shown in table 3.Find the rate of release of compound and the sterically hindered relevant of 7 amino acids.To the compound of same state of aggregation, 7 steric hindrances are larger, and the rate of release of aggregate is faster.Therefore, the aggregate of the compounds of this invention, regulates accumulation shape and depolymerization speed by the structure changing 7 amino acids, thus realizes slow releasing function in various degree.
The release of table 3 aggregate
Wherein Degarelix is a kind of commercial gonadotropin releasing hormone for prostate cancer therapy (GnRH) blocker.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (10)
1. the compound shown in formula (I), or its steric isomer or its salt without physiological-toxicity,
R-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)-Aaa
7-Ilys-Pro-Aaa
10-NH
2
Formula (I)
Wherein, R is Ac, Cbm or R
1;
Wherein R
1for-CO(CH
2)
ncH
3;
N can be 0,1,2,3,4,5 or 6;
Aaa
7for Thr, Phe, Met, Ile, Val, Tyr, Nle, Nleu, β-Leu, Acc
3, Acc
5, Acc
6, Clpa, Mle, Cpa or following structure:
Wherein X is C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkyl acyl or halogen; .
Aaa
10for D-Ala, D-Val, Sar or C
α-Me-Ala.
2. the compound of claim 1 or its steric isomer or its salt without physiological-toxicity, it is selected from following compound:
(1)Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Ile
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（2）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Val
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（3）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Nle
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（4）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
6)
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（5）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Met
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（6）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Phe
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（7）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
5)
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（8）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Nleu)
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（9）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-βLeu
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（10）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(Acc
3)
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（11）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Thr
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（12）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Clpa
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（13）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(m)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（14）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(p)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（15）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-(o)Mph
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（16）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Mle
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（17）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Cpa
7-Ilys
8-Pro
9-D-Ala
10-NH
2；
（18）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Leu
7-Ilys
8-Pro
9-D-Val
10-NH
2；
（19）Ac-D-Nal
1-D-Cpa
2-D-Pal
3-Ser
4-Aph（Hor）
5-D-Aph（Cbm）
6-Leu
7-Ilys
8-Pro
9-Sar
10-NH
2。
3. pharmaceutical composition, it contains compound described in any one of at least one claim 1-2 or its steric isomer or its salt without physiological-toxicity, and optional pharmaceutically acceptable carrier or vehicle.
4. the pharmaceutical composition of claim 3, it is sustained release preparation.
5. the compound described in any one of claim 1-2 or its steric isomer or its salt without physiological-toxicity are for the preparation of prevention or therapeutic humoral relative disease or for the purposes in the medicine of practising contraception.
6. the purposes of claim 5, wherein said sex hormone related condition comprises sexual hormoue associated cancer, precocious puberty, hyperplasia of prostate, endometriosis, menoxenia (as amenorrhoea, dysfunctional uterine bleeding or ovulation failure) or Infertility.
7. the purposes of claim 6, wherein said sexual hormoue associated cancer comprises prostate cancer, carcinoma of endometrium, mammary cancer or ovarian cancer etc.
8. the purposes of any one of claim 5-7, wherein said medicine is sustained release preparation.
9. the compound described in any one of claim 1-2 or its steric isomer or its salt without physiological-toxicity are for the preparation of the purposes suppressed in the medicine of pituitary gonad-stimulating hormone (such as LH and/or FSH) and/or inhibition glandular secretion steroid hormone (such as oestrogenic hormon, progestogen and/or testosterone).
10. the purposes of claim 9, wherein said medicine is sustained release preparation.
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|---|---|---|---|
| CN201310363034.2A CN104418936B (en) | 2013-08-20 | 2013-08-20 | Lhrh antagonist derivative and its medicinal usage |
| PCT/CN2014/083865 WO2015024450A1 (en) | 2013-08-20 | 2014-08-07 | Lhrh antagonist derivative and pharmaceutical use thereof |
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|---|---|---|---|
| CN201310363034.2A CN104418936B (en) | 2013-08-20 | 2013-08-20 | Lhrh antagonist derivative and its medicinal usage |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114460179A (en) * | 2020-11-09 | 2022-05-10 | 深圳市健翔生物制药有限公司 | Method for measuring in-vitro release degree of degarelix acetate for injection |
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| CN1061605A (en) * | 1990-11-10 | 1992-06-03 | 天津市计划生育研究所 | The synthetic method of luteinizing hormone-releasing hormone antagonistic analogs, product and application |
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| US5968895A (en) * | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
| EP0882736A1 (en) * | 1997-06-02 | 1998-12-09 | Laboratoire Theramex S.A. | LH-RH peptide analogues, their uses and pharmaceutical compositions containing them |
| CN101037472B (en) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with low-histamine releasing function |
| CN101597321B (en) * | 2008-06-03 | 2013-04-24 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with long-acting low-histamine release side effect |
| CN101987865B (en) * | 2009-07-29 | 2014-07-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure |
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2013
- 2013-08-20 CN CN201310363034.2A patent/CN104418936B/en not_active Expired - Fee Related
-
2014
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| CN1061605A (en) * | 1990-11-10 | 1992-06-03 | 天津市计划生育研究所 | The synthetic method of luteinizing hormone-releasing hormone antagonistic analogs, product and application |
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| CN114460179A (en) * | 2020-11-09 | 2022-05-10 | 深圳市健翔生物制药有限公司 | Method for measuring in-vitro release degree of degarelix acetate for injection |
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| CN104418936B (en) | 2018-06-05 |
| WO2015024450A1 (en) | 2015-02-26 |
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