CN101037472B - LHRH antagonist with low-histamine releasing function - Google Patents

LHRH antagonist with low-histamine releasing function Download PDF

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CN101037472B
CN101037472B CN2006100657269A CN200610065726A CN101037472B CN 101037472 B CN101037472 B CN 101037472B CN 2006100657269 A CN2006100657269 A CN 2006100657269A CN 200610065726 A CN200610065726 A CN 200610065726A CN 101037472 B CN101037472 B CN 101037472B
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nal
arg
leu
ala
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CN101037472A (en
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刘克良
周宁
林凡程
周文霞
张永祥
程军平
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Institute of Pharmacology and Toxicology of AMMS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Abstract

The invention relates to decapeptide derivative which has LHRH receptor antagonism activity, an effect of inhibiting pituitary to excrete gonadotrophic hormone, an effect of inhibiting the gonad to excrete steroid hormone and has a lower histamine releasing effect, its producing method, the drug combination and its drug applications for treating the sex hormone correlated disease such as prostate cancer and the disease correlated to the anti-histamine or reducing histamine release.

Description

Luteinizing hormone-releasing hormone antagonist with low histamine release effect
Technical field
The present invention relates to the decapeptide derivative that has the LHRH receptor antagonist activity and have lower histamine release side effect, contain their pharmaceutical composition and the described decapeptide derivative purposes that relies on the medicine of relative disease for the preparation for the treatment of prostate cancer and other sexual hormoue.
Background technology
LHRH (luteinizing hormone-releasing hormone) is by one of peptide hormone of hypothalamus secretion, its Main Function is to promote that hypophysis is synthetic and discharge lutropin (LH) and follicular stimulating hormone (FSH), excites Development in Puberty and regulates reproduction, fertility and sexual hormoue correlated process.LHRH is comprised of ten amino-acid residues, and the C-end contains 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 is by the release of blocking-up LHRH effect and then inhibition LH, therefore can be used for the treatment of the diseases such as sexual hormoue associated cancer such as prostate cancer, existing unique lhrh antagonist class medicine that has gone on the market is cetrorelix (Cetrorelix), is mainly used to control ovary excitement and LH fluctuation.Compare with agonist, lhrh antagonist have produce effects speed fast, without recover after upper punch phenomenon, the drug withdrawal fast, to advantages such as the horizontal controllability of serum androgen are strong.Can expect, the curative effect of lhrh antagonist treatment prostate cancer is better than agonist, is easilier accepted by the patient, has the application prospect larger than agonist.
Histamine is a kind of inflammatory mediator of finding the earliest, by generating after the l-histidine decarboxylation for extensively being present in a kind of autacoid in the tissue.Major storage was in the particle of mastocyte and basophilic granulocyte after histamine generated, and transformation reactions or other materializations stimulate and impel mast cell degranulation, discharge histamine.Histamine can cause transformation reactions in vivo, and the generation of many inflammation is all relevant therewith.Its tip that can excite nerve causes skin rubefaction and itch; Can make the smooth muscle contraction of Various Tissues, especially bronchial smooth muscle causes bronchial asthma; Also can cause the arteriole diastole, cause the contrafluxion oedema, suffer a shock when serious.
Most drug more or less can cause the side reaction of histamine release in vivo, thereby the lhrh antagonist of exploitation is exactly can cause anaphylactoid generation owing to can cause excessive histamine release at present, therefore fails clinically well to be used.So, keeping on the basis of greater activity, how further modifying lhrh antagonist just becomes a important step in the lhrh antagonist drug research to falling its low histamine release effect.
Before this, the inventor has had been found that some have the long-acting antagonist of LHRH receptor antagonist activity (referring to Chinese patent application No.200510115056.2).Purpose of the present invention then is on the basis of original long-acting lhrh antagonist, further seeks the lhrh antagonist with lower histamine release effect.
Summary of the invention
The inventor has now found that to have the decapeptide derivative of following formula (I) through research:
R-β-D-Nal-D-Cpa-Xaa 3-Ser-Xaa 5-Xaa 6-Leu-Xaa 8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or physiologically acceptable salt are when having good LHRH antagonistic activity, also have lower histamine release side effect, so formula (I) decapeptide derivative or its steric isomer or physiologically acceptable salt can be used as medicine and are used for the treatment that prostate cancer and other sexual hormoue rely on relative disease.
Therefore, first aspect of the present invention relates to formula (I) decapeptide derivative or its steric isomer or physiologically acceptable salt,
R-β-D-Nal-D-Cpa-Xaa 3-Ser-Xaa 5-Xaa 6-Leu-Xaa 8-Pro-D-Ala-B
Formula (I)
Wherein,
R be H-, HC (O)-, HOOC (CH 2) m-, HOOC (CH 2) mC (O)-, R 1C (O)-, R 1R 2NC (O)-, R 2O-NR 1-C (O)-, R 1R 2P (O)-, R 1N (R 2N) P (O)-, R 1O (R 2N) P (O)-, R 1O (R 2O) P (O)-, R 1-, R 1OS (O 2)-,
R wherein 1And R 2Be H independently of one another, optional replacement or the unsubstituted C that contains carboxyl, amido, phosphate, alkylsulfonyl 1-C 6The straight or branched alkyl replaces or unsubstituted C 2-C 6Straight or branched alkenyl or alkynyl replace or unsubstituted C 1-C 6The straight or branched alkoxyl group replaces or unsubstituted C 1-C 6The straight or branched alkylthio replaces or unsubstituted C 1-C 6The straight or branched alkylamino replaces or unsubstituted C 2-C 6Straight or branched alkenyl oxy or alkynyloxy base replace or unsubstituted C 2-C 6Straight or branched alkenyl thio or alkynyl sulfenyl replace or unsubstituted C 2-C 6Straight or branched alkenyl amino or alkynyl are amino, C 3-C 8Cycloalkyl-(CH 2) n-or cycloalkenyl group-(CH 2) n-, C 3-C 8Heterocyclic radical-(CH 2) n-or heterocycloalkenyl-(CH 2) n-, C 6-C 14Aryl-(CH 2) n-, C 3-C 8Heteroaryl-(CH 2) n-, C 3-C 8Heterocyclylalkyl-(CH 2) n-or Y, and described carboxyl, amido, phosphate, alkylsulfonyl independently of one another with 1 or n be connected to R 1Or R 2Any one carbon atom on;
B can be-OH ,-NR 19R 20,-NHNR 19R 20Or Y;
Y can be following structure (i), (ii), and (iii), (iv) or (v):
Figure S06165726920060316D000031
Figure S06165726920060316D000041
R wherein 3-R 20Be H-, replacement or unsubstituted C independently of one another 1-C 6Straight chain or branched-chain alkyl replace or unsubstituted C 2-C 6Straight or branched alkenyl or alkynyl replace or unsubstituted C 1-C 6The straight or branched alkoxyl group replaces or unsubstituted C 1-C 6The straight or branched alkylthio replaces or unsubstituted C 1-C 6The straight or branched alkylamino, C 3-C 8Cycloalkyl-(CH 2) n-or cycloalkenyl group-(CH 2) n-, C 3-C 8Heterocyclic radical-(CH 2) n-or heterocycloalkenyl-(CH 2) n-, C 6-C 14Aryl-(CH 2) n-, C 3-C 8Heteroaryl-(CH 2) n-, C 3-C 8Heterocyclylalkyl-(CH 2) n-or Y;
Substituting group in described " replacement or unsubstituted " is selected from halogen, nitro, carboxyl, alkylsulfonyl, phosphate, sulfydryl, hydroxyl, amide group, guanidine radicals, urea groups, imidazolyl, amino, ester group etc. and contains heteroatomic group;
Xaa 3Be D-Phe or D-Pal,
Xaa 5, Xaa 6And Xaa 8Be any among Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Glu, Asp, Gin, Asn, Lys, Ilys, Orn, Iorn or the Mph of L or D type independently of one another;
Perhaps
Xaa 5, Xaa 6Or Xaa 8Be following structure:
Figure S06165726920060316D000042
II (D-or L-type) III (D-or L-type)
Wherein,
Q is-H-NR 21R 22,-NHC (O) NR 21R 22,-C (O) NR 21R 22,-NH-C (O) R 23, R 2O-NR 24-C (O)-, R 25R 26P (O)-, R 27N (R 28N) P (O)-, R 29O (R 30N) P (O)-, R 31O (R 32O) P (O)-, R 33OS (O 2)-, R 34-or Y;
W is-COOH-CONH 2,-N (iPr) 2,-NR 35R 36,-NHC (NR 37) NR 38R 39,-NHC (O) NR 40R 41,-NH-C (O) R 42Or Q;
R wherein 21-R 42Be independently of one another H-, HC (O)-, R 1C (O)-, R 1R 2NC (O)-, R 1And R 2Described as defined above;
Each m and n are the integer of 0-6 independently of one another, for example 0,1,2,3,4,5 or 6.
Second aspect of the present invention relates to the method for preparing the compounds of this invention, and described method comprises that utilizing solid phase synthesis process to synthesize partly is connected on formula (I) decapeptide derivative or its steric isomer suc as formula (I) defined decapeptide derivative and with Y and B.
The 3rd aspect of the present invention relates to the pharmaceutical composition that contains at least a above-mentioned formula (I) decapeptide derivative, its steric isomer or their physiologically acceptable salt and one or more pharmaceutically acceptable carrier or vehicle.
The 4th aspect of the present invention relates to the compounds of this invention for the preparation of the purposes of the medicine for the treatment of the disease relevant with sexual hormoue or illness (such as sexual hormoue associated cancer, for example prostate cancer).
The 5th aspect of the present invention relates to the compounds of this invention for the preparation of the purposes of the medicine (for example oestrogenic hormon, progestogen and/or testosterone) of medicine, inhibition pituitary gonad-stimulating hormone (for example LH and/or FSH) and the inhibition glandular secretion steroid hormone of lhrh antagonist, antagonism LHRH acceptor.
The 6th aspect of the present invention relates to the compounds of this invention and pharmaceutical composition thereof for the preparation of the histamine release effect with reduction and/or has the purposes of the medicine of anti-inflammatory, anti-allergic.
According to one embodiment of the invention, the present invention relates to have following formula decapeptide derivative or its steric isomer or the physiologically acceptable salt of (I):
R-β-D-Nal-D-Cpa-Xaa 3-Ser-Xaa 5-Xaa 6-Leu-Xaa8-Pro-D-Ala-B
Formula (I)
Wherein,
R be H-, HC (O)-, HOOC (CH 2) m-, HOOC (CH 2) mC (O)-, R 1C (O)-, R 1R 2NC (O)-, R 2O-NR 1-C (O)-, R 1R 2P (O)-, R 1N (R 2N) P (O)-, R 1O (R 2N) P (O)-, R 1O (R 2O) P (O)-, R 1-, R 1OS (O 2)-,
R wherein 1And R 2Be H independently of one another, optional replacement or the unsubstituted C that contains carboxyl, amido, phosphate, alkylsulfonyl 1-C 6The straight or branched alkyl replaces or unsubstituted C 2-C 6Straight or branched alkenyl or alkynyl replace or unsubstituted C 1-C 6The straight or branched alkoxyl group replaces or unsubstituted C 1-C 6The straight or branched alkylthio replaces or unsubstituted C 1-C 6The straight or branched alkylamino replaces or unsubstituted C 2-C 6Straight or branched alkenyl oxy or alkynyloxy base replace or unsubstituted C 2-C 6Straight or branched alkenyl thio or alkynyl sulfenyl replace or unsubstituted C 2-C 6Straight or branched alkenyl amino or alkynyl are amino, C 3-C 8Cycloalkyl-(CH 2) n-or cycloalkenyl group-(CH 2) n-, C 3-C 8Heterocyclic radical-(CH 2) n-or heterocycloalkenyl-(CH 2) n-, C 6-C 14Aryl-(CH 2) n-, C 3-C 8Heteroaryl-(CH 2) n-, C 3-C 8Heterocyclylalkyl-(CH 2) n-or Y, and described carboxyl, amido, phosphate, alkylsulfonyl independently of one another with 1 or n be connected to R 1Or R 2Any one carbon atom on;
B can be-OH ,-NR 19R 20,-NHNR 19R 20Or Y;
Y can be following structure (i), (ii), and (iii), (iv) or (v):
Figure S06165726920060316D000061
Figure S06165726920060316D000071
R wherein 3-R 20Be H-, replacement or unsubstituted C independently of one another 1-C 6Straight chain or branched-chain alkyl replace or unsubstituted C 2-C 6Straight or branched alkenyl or alkynyl replace or unsubstituted C 1-C 6The straight or branched alkoxyl group replaces or unsubstituted C 1-C 6The straight or branched alkylthio replaces or unsubstituted C 1-C 6The straight or branched alkylamino, C 3-C 8Cycloalkyl-(CH 2) n-or cycloalkenyl group-(CH 2) n-, C 3-C 8Heterocyclic radical-(CH 2) n-or heterocycloalkenyl-(CH 2) n-, C 6-C 14Aryl-(CH 2) n-, C 3-C 8Heteroaryl-(CH 2) n-, C 3-C 8Heterocyclylalkyl-(CH 2) n-or Y;
Substituting group in described " replacement or unsubstituted " is selected from halogen, nitro, carboxyl, alkylsulfonyl, phosphate, sulfydryl, hydroxyl, amide group, guanidine radicals, urea groups, imidazolyl, amino, ester group etc. and contains heteroatomic group;
Xaa 3Be D-Phe or D-Pal,
Xaa 5, Xaa 6And Xaa 8Be any among Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Glu, Asp, Gln, Asn, Lys, Ilys, Orn, Iorn or the Mph of L or D type independently of one another;
Perhaps
Xaa 5, Xaa 6Or Xaa 8Be following structure:
Figure S06165726920060316D000072
II (D-or L-type) III (D-or L-type)
Wherein,
Q is-H-NR 21R 22,-NHC (O) NR 21R 22,-C (O) NR 21R 22,-NH-C (O) R 23, R 2O-NR 24-C (O)-, R 25R 26P (O)-, R 27N (R 28N) P (O)-, R 29O (R 30N) P (O)-, R 31O (R 32O) P (O)-, R 33OS (O 2)-, R 34-or Y;
W is-COOH-CONH 2,-N (iPT) 2,-NR 35R 36,-NHC (NR 37) NR 38R 39,-NHC (O) NR 40R 41,-NH-C (O) R 42Or Q;
R wherein 21-R 42Be independently of one another H-, HC (O)-, R 1C (O)-, R 1R 2NC (O)-, R 1And R 2Described as defined above;
Each m and n are the integer of 0-6 independently of one another, for example 0,1,2,3,4,5 or 6.
According to the present invention, term used herein " formula (I) decapeptide derivative steric isomer " refers to its corresponding D-or L-steric configuration.
According to a preferred embodiment of the invention, wherein, R is H-, Ac-, NH 2CO-, NTA-, CAM-, NDN-, CEC-.
According to a preferred embodiment of the invention, wherein B is-NH 2
According to a preferred embodiment of the invention, Xaa wherein 5Be Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Gln, Asn, Glu, Asp, Phe (COOH), Phe (CAM);
According to a preferred embodiment of the invention, Xaa wherein 6Be D-Pal, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Aph (Ac), D-Mop, D-Phe, D-Aph, D-Uph, D-Arg, D-Gln, D-Asn, D-Glu, D-Asp, D-Phe (COOH), D-Phe (CAM); Preferably, Xaa 8Be Arg, ILys, IOrn, Asn, Gln.
The further preferred embodiment according to the present invention, the compounds of this invention are selected from following decapeptide or its steric isomer or physiologically acceptable salt:
(1)Ac-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Arg 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(2)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Arg 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(3)NH 2CO-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Arg 5-D-Pal 6-Leu 7-Arg 8-Pro 9 -D-Ala 10-NH 2
(4)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(5)D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(6)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(7)Ac-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(8)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(9)NH 2CO-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(10)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(11)D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(12)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(13)Ac-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(14)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(15)NH 2CO-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Asn 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(16)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(17)D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(18)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(19)Ac-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(20)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(21)NH 2CO-D-Nal 1-D-Cpa 2-D-Pal 3-Ser 4-Mph 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(22)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(23)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(24)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(25)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(26)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(27)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(28)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(29)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(DMe) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(30)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(31)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(32)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-A la 10-NH 2
(33)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(34)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(35)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(36)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(DMe) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(37)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(38)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(39)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(40)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(41)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(42)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(43)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(44)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(DMe) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(45)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(46)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(47)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(48)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(49)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(50)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(51)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(52)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(DMe) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(53)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(54)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(55)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(56)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(57)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(58)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(59)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(60)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(DMe) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(61)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe 6-Leu 7-Arg 8-Pro 9- D-Ala 10-NH 2
(62)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(63)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(64)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(65)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(66)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(67)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(68)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(DMe) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(69)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(70)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(71)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(72)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(73)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(74)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(75)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(76)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(DMe) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(77)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(78)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(79)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(80)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(81)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(82)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(83)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(84)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(DMe) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(85)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(86)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(87)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(88)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(89)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(90)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8 -Pro 9-D-Ala 10-NH 2
(91)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(92)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(DMe) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(93)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(94)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(95)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(96)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(97)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(98)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(99)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(100)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph(DMe) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(101)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Leu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(102)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Tyr 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(103)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Lys 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(104)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Glu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(105)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(106)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(107)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Leu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(108)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Tyr 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(109)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Lys 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(110)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Glu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(111)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(112)Ac-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(113)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Leu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(114)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Tyr 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(115)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Lys 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(116)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Glu 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(117)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(118)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Asn 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(119)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-P ro 9-D-Ala10-NH 2
(120)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(COOH) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(121)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(CAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(122)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(COOH) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(123)NTA-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(CAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(124)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(COOH) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(125)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(CAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(126)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(COOH) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(127)NDN-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(CAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(128)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(129)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(130)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(131)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(CAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(132)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(COOH) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(133)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(134)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NNM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(135)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(NOM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(136)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(CAM) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(137)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Phe(COOH) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(138)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(139)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 3-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(140)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(141)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(CAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(142)CAM-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(COOH) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(143)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(144)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NNM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(145)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(NOM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(146)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(CAM) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(147)CEC-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Phe(COOH) 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(148)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Aph 6-Leu 7-Arg 8-P ro 9-D-Ala 10-NH 2
(149)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(150)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(151)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(152)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(153)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(154)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(155)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph(Ac) 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(156)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2
(157)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Uph 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2。
More preferably, the compounds of this invention is selected from above-claimed cpd 1,6,7,12,13,19,23,24,25,26,27,28,38,39,40,41,42,43,62,63,64,65,66,67,72,73,78,79,80,81,82,83,86,88,89,96,105,106,117,120,121,122,123,124,128,129,133,134,143,149,152,156.
The abbreviation of using among the present invention has following implication:
The Ac-ethanoyl
The Ala-L-Ala,
The Arg-arginine,
Aph-4-amino-benzene L-Ala
Aph (Ac)-4-acetamido phenylalanine
Aph (DMe)-4-(N, N-dimethyl)-amino-benzene L-Ala
The Asn-l-asparagine
The Asp-aspartic acid
The Boc-tertbutyloxycarbonyl,
BOP-benzotriazole-1-oxygen-three (dimethylamino) phosphorus phosphofluoric acid,
The CAM-carboxymethyl
CEC-carboxylic ethanoyl
The Cpa-4-chlorophenylalanine,
The CPC-carboxyl propionyl group
The DCC-dicyclohexylcarbodiimide,
The DIEA-diisopropylethylamine,
The Gln-glutamine
Glu-L-glutamic acid
The Gly-glycine
The His-Histidine
The HOBt-1-hydroxybenzotriazole,
The iPr-sec.-propyl
The Leu-leucine,
Lys-Methionin
Phe (COOH)-carboxyphenylalanine
Phe (CAM)-carboxymethyl phenylalanine
ILys-sec.-propyl Methionin
IOrn-sec.-propyl ornithine
MBHA-phenylamino methyl resin,
Mob-β-piperonyl L-Ala
Mop-morpholine methyl phenylalanine,
Mph-piperonyl L-Ala
The Nal-naphthylalanine,
NAM-imine oxalic acid dibenzyl ester
NTA-N, N-diacetoxyl glycyl
NDN-N, N-diacetylamino glycyl
The Orn-ornithine
The Pal-3-pyrazoleahtnine
The p-Glu-Pyrrolidonecarboxylic acid
The Phe-phenylalanine,
The RP-HPLC-RPLC
The Pro-proline(Pro),
The Ser-Serine,
The Trp-tryptophane
Tyr-tyrosine
The TEA-triethylamine,
The Ureido-urea groups
Uph-is to the urea groups phenylalanine
Phe (NAM)-4-((N, N-diacetoxyl) aminomethyl) phenylalanine
Phe (NA BM)-4-((N, N-oxalic acid carbobenzoxy) aminomethyl) phenylalanine
Phe (NNM)-4-((N, N-diacetylamino) aminomethyl) phenylalanine
Phe (NOM)-4-((N, N-diethyl alcohol radical) aminomethyl) phenylalanine
Except as otherwise noted, the term that uses in this application has following implication.
Among the present invention, all amino acid configurations are the L-type except being labeled as the D-type.
" acyl group " refers to H-CO-or alkyl-CO-, and wherein said alkyl is as described herein.
" amido " is acyl group-NH-, and wherein acyl group as defined herein.
" alkoxy carbonyl " refers to alkyl-O-CO-, and alkyl wherein as defined herein.
Unless otherwise indicated, " alkyl " refers to it can is to have approximately the approximately aliphatic hydrocarbyl of 15 carbon atoms of 1-in the chain of straight or branched, and it is randomly replaced by one or more halogen atoms.Particularly have 1-approximately 6 carbon atoms, for example alkyl of 1-4 carbon atom.Refer to it to be to have the approximately aliphatic hydrocarbyl of 4 carbon atoms of 1-in the chain of straight or branched as " low alkyl group " of the integral part of a group or lower alkoxy, lower alkylthio, low alkyl group sulfinyl or low alkyl group alkylsulfonyl, unless otherwise indicated.The example alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, 3-amyl group, heptyl, octyl group, nonyl, decyl and dodecyl.The examples of alkyl that is replaced by one or more halogen atoms comprises trifluoromethyl.Alkyl can also be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1,2,3 or 4 1-C 4Alkyl or C 1-C 4Alkoxyl group or C 1-C 4The substituting group of alkylthio replaces.
" alkenyl " refers to contain carbon-to-carbon double bond and has simultaneously approximately the approximately aliphatic hydrocarbyl of the straight or branched of 15 carbon atoms of 2-in the chain.Has the approximately alkenyl of 12 carbon atoms of 2-in the preference chain; More preferably have approximately 6 carbon atoms (for example 2-4 carbon atom) of 2-in the chain.Used " side chain " refers to that one or more low alkyl groups such as methyl, ethyl or propyl group are connected on the straight chain in this and whole text; Refer to the straight-chain alkenyl chain at this." low-grade alkenyl " refers to contain in the chain approximately 4 carbon atoms of 2-of having an appointment, and it can be straight or branched.The example chain thiazolinyl comprise second alkenyl, the third alkenyl, positive fourth alkenyl, isobutyl alkenyl, 3-methyl fourth-2-alkenyl, positive penta alkenyl, heptan alkenyl, hot alkenyl, cyclohexyl fourth alkenyl and the last of the ten Heavenly stems alkenyl.Alkenyl can be able to be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1,2,3 or 4 1-C 4Alkyl or C 1-C 4Alkoxyl group or C 1-C 4The substituting group of alkylthio replaces.
" alkoxyl group " refers to alkyl-O-group, and wherein said alkyl is as described herein.The alkoxyl group example comprise difluoro-methoxy, methoxyl group, trifluoromethoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.
" alkylthio " refers to alkyl-S-group, and wherein said alkyl is as described herein.
" alkenyl oxy " refers to alkenyl-O-group, and wherein alkenyl as defined above.Alkenyl oxy for example comprises allyloxy.
" alkenyl thio " refers to alkenyl-S-group, and wherein alkenyl as defined above.
" halogen " comprises fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine, bromine.
" alkynyl " refers to contain carbon-to-carbon three key, and it can be to have approximately the approximately aliphatic hydrocarbyl of 15 carbon atoms of 2-in the chain of straight or branched simultaneously.Preferred alkynyl has approximately 12 carbon atoms of 2-in chain; More preferably have approximately 6 carbon atoms (for example 2-4 carbon atom) of 2-in the chain.The example alkynyl comprises ethynyl, proyl, positive butynyl, isobutyl alkynyl, 3-methyl fourth-2-alkynyl and positive pentynyl.Alkynyl can be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1,2,3 or 4 1-C 4Alkyl or C 1-C 4Alkoxyl group or C 1-C 4The substituting group of alkylthio replaces
" aroyl " refers to aryl-CO-group, and wherein said aryl is as described herein.The example aroyl comprises benzoyl and 1-and 2-naphthoyl.
" aroylamino " is aroyl-NH-group, and wherein aroyl as defined above.
" aryl " is as the representative of the integral part of a group or group: (i) about approximately optional substituted monocycle or the polycyclic aromatic isocyclic part of 14 carbon atoms of 6-, such as phenyl or naphthyl; Or (ii) the polycyclic aromatic isocyclic part of optional substituted fractional saturation, wherein aryl and cycloalkyl or cycloalkenyl condense and consist of ring texture together, for example tetralyl, indenyl or indane basic ring.Unless otherwise defined; aryl can be by one or more (such as 2; 3; 4; 5) the aryl substituent replacement; it can be identical or different; wherein " aryl substituent " comprises; for example; acyl group; amido; alkoxyl group; alkoxy carbonyl; alkylenedioxy group; the alkyl sulfinyl; alkyl sulphonyl; alkylthio; aroyl; aroylamino; aryl; alkoxy aryl; aryl-alkoxy carbonyl; alkylthio-aryl; aryloxy; aryloxycarbonyl; the aryl sulfinyl; aryl sulfonyl; arylthio; carboxyl (or sour bioisoster bioisoster); cyano group; halogen; 4-hetaroylpyrazol; heteroaryl; the heteroaryl alkoxyl group; heteroaroylamino; heteroaryloxy; hydroxyl; nitro; trifluoromethyl; alkyl; for example be selected from halogen; nitro; cyano group, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Alkylthio, C 1-C 4Alkyl sulphinyl, C 1-C 4Alkyl sulphonyl, carboxyl, C 1-C 4Carbalkoxy, amino, C 1-C 4Alkylamino, C 1-C 4Dialkyl amido or C 1-C 4Alkyl-carbonyl-amino.Group in " aryl substituent " has the definition that provides among the present invention.
" alkoxy aryl " refers to arylalkyl-O-group, and wherein said arylalkyl as mentioned above.The example alkoxy aryl comprises benzyloxy and 1-or 2-naphthalene methoxyl group.
" alkylthio-aryl " refers to arylalkyl-S-group, and wherein said arylalkyl as mentioned above.The example alkylthio-aryl is benzylthio-.
" aryloxy " refers to aryl-O-group, and wherein aryl as mentioned above.The example aryloxy comprises phenoxy group and naphthyloxy, and it is optional being substituted separately.
" cycloalkenyl group " refer to contain at least one carbon-to-carbon double bond and have about 3-approximately 10 carbon atoms non-aromatic monocyclic or encircle ring system more.Example monocycle cycloalkenyl comprises cyclopentenyl, cyclohexenyl and cycloheptenyl.Cycloalkenyl group can be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1,2,3 or 4 1-C 4Alkyl or C 1-C 4The substituting group of alkoxyl group replaces.
" cycloalkyl " refers to contain saturated monocycle or the dicyclo ring system of 3-10 carbon atom, randomly replaced by oxygen.Example monocyclic cycloalkyl ring comprises C 3-8Cycloalkyl ring is such as cyclopropyl, cyclopentyl, cyclohexyl and suberyl.Cycloalkyl can be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1,2,3 or 4 1-C 4Alkyl or C 1-C 4The substituting group of alkoxyl group replaces.
" heterocyclic radical " refers to contain 5-14 ring members and have monocycle or the dicyclic compound of one or more (such as 2,3,4,5) heteroatomic saturated or fractional saturation in its ring structure.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).The preferred monocyclic heterocycles base of the present invention comprises 5-and 6-unit monocyclic heterocycles base.These heterogeneous ring compounds also can further be replaced by following radicals: halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, nitro, cyano group, sulfanyl, alkylamino or phenyl.
" heteroaryl " refers to the heterogeneous ring compound of aromatics.These heteroaryls also can further be replaced by following radicals: halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, nitro, cyano group, sulfanyl, alkylamino or phenyl.
The preferred aromatics 5-of the present invention or 6-unit heterocyclic radical example comprise 1,3,2,4-or 1,3,4,5-Er oxadiazolyl Er Evil triazinyl dioxazine base, 1,2,3-, 1,2,4-, 1,3,2-or 1,3,4-Er oxazolyl, 1,3,2,4-or 1,3,4,5-dithiadiazole base, two thiophene triazinyls, the dithiazine base, 1,2,3-dithiazole base, 2-or 3-furyl, the furazan base, 1-, 2-or 4-imidazolyl, iso indazolyl, isothiazole-3-,-4-or-5-base isoxazole-3-,-4-or-5-base, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazole-3-,-4-or-5-base Evil tetrazine base Evil triazinyl, 1,2,3,4-or 1,2,3,5-oxatriazole base oxazole-2-,-4-or-5-base, 2-or 3-pyrazinyl, 1-, 3-or 4-pyrazolyl, 3-or 4-pyridazinyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 1-, 2-or 3-pyrryl, 1,2,3,4-or 2,1,3, the 4-tetrazyl, thiadiazoles-3-,-4-or-5-base, thiazole-2-,-4-or-5-base, 2-or 3-thienyl, 1,2,3-, 1,2,4-or 1,3, the 5-triazinyl, with 1,2,3-, 1,2,4-, 2,1,3-or 4,1,2-triazolyl.The most preferred aromatic heterocyclic radical of the present invention comprises furans-2-base, furans-3-base, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-or 3-pyridyl and 1-or 2-thienyl.
The preferred saturated or fractional saturation 5-of the present invention or 6-unit heterocyclic radical example comprise 1,3,5,6,2-Er oxadiazine base, 1,2,3,4,5-or 1,2,3,5,4-Er oxadiazolyl alkyl dioxin, 1,3-dioxa cyclopentenyl, 1,3,5,6,2-, two thiadiazine bases, 1,2,3,4,5-or 1,2,3,5,4-dithiadiazole base, the different imidazolyl of 2-, different pyrryl, different tetrazyl, 1,2,3-or 1,2, the different triazolyl of 4-, morpholinyl oxadiazine base, 1,2,4-, 1,2,6-, 1,3,2-, 1,3,6-or Isosorbide-5-Nitrae, the 2-oxazinyl, piperazinyl, the homopiperazine base, piperidyl, 1,2-, 1,3-or Isosorbide-5-Nitrae-pyranyl, with 1,2,3-pyrrolidyl.
" Heterocyclylalkyl " refers to: (i) the about cycloalkyl of 3-7 person ring, it contains one or more heteroatomss or is selected from O, S and NR 1R 2Contain heteroatom group and can randomly be replaced by oxygen; (ii) many rings of fractional saturation contain the heteroatoms isocyclic part, wherein aryl (or heteroaryl) encircles, randomly replaced by one or more " aryl substituent " respectively, and Heterocyclylalkyl condenses and consists of ring texture together, the example of this type of group comprises chromanyl, dihydro benzo furyl, indolinyl.
Can adopt following methods to prepare the compounds of this invention:
(1) utilize solid phase synthesis process, take mbha resin as carrier, Boc-protects strategy, and DCC/HOBT or BOP/DIEA are condensation reagent, and the HCl/ dioxane is deprotecting regent, with liquid HF the decapeptide derivative is cut down from mbha resin after having reacted;
(2) will partly be connected on above-mentioned formula (I) decapeptide derivative or its steric isomer suc as formula (I) defined Y and B.
Structure and derivative thereof shown in above-mentioned synthesis type (I) the employed formula II of decapeptide derivative and the formula III, such as Boc-Phe (NAM), Boc-Phe (CAM), Boc-Phe (NNM), Boc-Phe (NOM) etc. can be passed through Boc-p-CH 2Cl-Phe (synthesize and see embodiment 1) and NAM, cyano group (reacted cyan-hydrolysis can be obtained carboxyl), NNM, NOM etc. are synthetic under triethylamine catalysis, Boc-p-urea groups-Phe, NTA and NDN synthetic sees embodiment, CAM can be connected on the peptide chain by the amino reaction of bromoacetic acid and polypeptide, and CPC, CEC can be connected on the peptide chain with amino reaction of polypeptide by malonic acid monoester or oxalic acid monoesters;
Thus, the invention still further relates to compound or derivatives thereof, for example Boc-Phe (NAM), Boc-Phe (CAM), Boc-Phe (COOH), Boc-Phe (NNM), Boc-Phe (NOM), Boc-p-urea groups-Phe, NTA, CAM, NDN, CEC and derivative thereof shown in formula II, III and the Y part.
Further, the invention still further relates to compound or derivatives thereof shown in formula II, III and the Y part for example Boc-Phe (NAM), Boc-Phe (CAM), Boc-Phe (COOH), Boc-Phe (NNM), Boc-Phe (NOM), Boc-p-urea groups-Phe, NTA, CAM, NDN, CEC and derivative thereof for the preparation of the purposes with the medicine that reduces histamine release effect, anti-inflammatory, anti-allergic.
According to the present invention, formula (I) decapeptide derivative and steric isomer thereof and physiologically acceptable salt not only demonstrate good result in animal androgen antagonist secretion experiment, and in external test, demonstrate lower histamine release amount, therefore can be used as hormone medicine and be used for animal, be preferred for Mammals, particularly the people.
Therefore the present invention also relates to and containing as at least a formula (I) the decapeptide derivative of the effective dose of activeconstituents and/or the pharmaceutical composition of its steric isomer or physiologically acceptable salt and one or more conventional medicine carriers or vehicle.
Term used herein " physiologically acceptable salt " refers to keep parent compound expection physiologically active and can not produce the salt of any unexpected toxic side effect or their composition.For example: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, nitrate, and acetate, oxalate, tartrate, succinate, malate, benzoate, embonate, alginates, mesylate, naphthalenesulfonate etc.Can be again according to the positively charged ion that contains in the salt: sylvite, lithium salts, zinc salt, mantoquita, barium salt, bismuth salt, the inorganic salt such as calcium salt also can be such as organic salts such as trialkyl ammonium salts.
Formula of the present invention (I) decapeptide derivative and steric isomer thereof or contain its pharmaceutical composition can be with known any mode administration, such as oral, muscle, subcutaneous etc., form of administration such as tablet, capsule, buccal tablet, chewable tablet, elixir, suspensoid, transdermal agent, micro-capsule embedding medium, implants, syrup etc.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be widely used various biodegradable or physiologically acceptable carrier well known in the art.About the example of carrier, such 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.
The dosage of formula of the present invention (I) decapeptide derivative or its steric isomer depends on many factors, for example to prevent or treat character and the severity of disease, the sex of patient or animal, age, body weight, susceptibility and individual reaction, used particular compound, route of administration, administration number of times and the desired result for the treatment of that reaches etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, three, four dosage form administrations.Single maximal dose generally is no more than the 10mg/Kg body weight, 0.001-10mg/Kg for example, and preferred 0.01-5mg/Kg, better dosage range is the 0.5-2mg/Kg body weight.But, in some cases, also may use the single dosage that the 10mg/Kg body weight is above or 0.001mg/Kg is following.
Embodiment
Below example and biological activity test be used for further specifying the present invention, but and do not mean that any limitation of the invention.
The used solid-phase synthesized carrier mbha resin of embodiment is the synthetic responsibility company limited of Tianjin Nankai product; The natural amino acid of DCC, HOBT, BOP, DIEA and Boc-protection is by the triumphant safe new technology in Shanghai gill biochemical corp and Chengdu limited liability company product, and the alpha-non-natural amino acid of Boc-protection synthesizes by this laboratory voluntarily except explanation is.
Embodiment 1:Boc-p-CH 2Cl-Phe's is synthetic
Ac-Phe (p-CH 2Cl)-(this laboratory prepares according to ordinary method Phe-OEt, 5g, 17.6mmol) boil off hydrochloric acid and dioxane after in 40mL concentrated hydrochloric acid and 100mL dioxane, refluxing 10 hours, obtain solid and directly under ice bath, add 50mL methyl alcohol without separation and purification, after TEA transfers pH to 9, add again 35.2mmol (3.9mL), then add 4.6g (Boc) 2O (21.1mmol), stirring at room 12 hours is revolved methyl alcohol, and the aqueous solution transfers pH to acid, ethyl acetate extraction, ester layer washing twice, anhydrous sodium sulfate drying.Concentrated ester layer, oily matter ethyl acetate-sherwood oil recrystallization behind column chromatography gets the 2.7g white crystal, total recovery 49.1%.TLC detects: chloroform: methyl alcohol: HOAc (20:1:0.5), Rf=0.6.
Embodiment 2:Boc-Phe (NA BSynthesizing M)
Boc-p-CH 2Cl-Phe (this laboratory prepares according to ordinary method) (1.75g, 5mmol) with imine oxalic acid dibenzyl ester (1.88g, 6mmol, according to synthetic below with reference to the described method of document: Huang Weide, the Chen Changqing work, polypeptide is synthetic, Science Press, 1985, p47) place the 100ml round-bottomed flask, add the 50mL dissolve with ethanol.After adding TEA (1.69mL, 12mmol) under the ice bath, stirring at room 72 hours is revolved ethanol, and the aqueous solution transfers pH to alkalescence, and again water transfer phase pH is extremely acid after the ether washing, ethyl acetate extraction, and washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrated ester layer, solid gets white crystal 1.80g with ethyl acetate-sherwood oil recrystallization, productive rate 61%.TLC detects: chloroform: methyl alcohol: HOAc (20:1:0.5), Rf=0.7.
Embodiment 3:Boc-p-NH 2(PhOCO)-Phe synthetic
Boc-p-NH 2-Phe (1.40g, 5mmol is according to synthetic below with reference to the described method of document: Theobald, P., Porter J., Rivier C., et al, J.Med.Chem., 1991,34,2395-2402) place the 150mL round-bottomed flask, add 30mL water, the aqueous sodium carbonate of 9.8mL10%, make it to dissolve rear adding 30mL Isosorbide-5-Nitrae-dioxane.Add carbonyl phenoxy acyl chlorides (0.63mL, 5mmol) under the ice bath.React and revolve Isosorbide-5-Nitrae-dioxane after 1 hour, the citric acid acidifying is to acid.Ethyl acetate extraction, ester layer be water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrated ester layer is through the 1.3g of column chromatography white crystal, productive rate 65%.M.p.260 ℃ (decomposition), TLC detects: chloroform: methyl alcohol: acetic acid (9:1:0.5), Rf=0.8.
Embodiment 4:Boc-p-urea groups-Phe's is synthetic
Boc-p-NH 2(PhOCO)-Phe (1.15g.2.87mmol) is dissolved in the 40mL anhydrous methanol, logical NH under the ice bath 31 hour.Revolve methyl alcohol, the gained solid 0.80g white solid of methyl alcohol-ether recrystallization, productive rate 86%.M.p.175-178 ℃, TLC detects: chloroform: methyl alcohol: acetic acid (9:1:0.5), Rf=0.8.
Embodiment 5 (PhCH 2O0CCH 2) 2NCH 2COOH's (NTA) is synthetic
Imine oxalic acid dibenzyl ester (28.8mmol, 9g) places the 100ml round-bottomed flask with bromoacetic acid (14.4mmol, 2.0g), adds the 50mL dissolve with ethanol.After adding TEA (10mL, 72mmol) under the ice bath, stirring at room 72 hours is revolved ethanol, and the aqueous solution transfers pH to alkalescence, and again water transfer phase pH is extremely acid after the ether washing, ethyl acetate extraction, and washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrated ester layer, oily matter get 2g oily matter, yield 44.4% behind column chromatography.TLC detects: chloroform: methyl alcohol: HOAc (20:1:0.5), Rf=0.3.
Embodiment 6:PhOCO-Nal-OCH 3Synthetic
Nal-OCH 3HCl (23.3mmol, 6.18g) be dissolved in the 100mL water, add l0% aqueous sodium carbonate 50mL (51.26mmol) and 100mL dioxane under the ice bath, be added dropwise to carbonyl phenoxy acyl chlorides 2.91mL (23.3mmol), stirring at room was revolved dioxane after 2 hours, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrated ester layer, solid gets white crystal 7.13g with ethyl acetate-sherwood oil recrystallization, productive rate 91.4%.TLC detects: ethyl acetate: sherwood oil (1:3), Rf=0.7.m.p.79-80℃
Embodiment 7: tBu-urea groups-Nal-OCH 3Synthetic
PhOCO-Nal-OCH3 (6mmol, 2.13g) be dissolved in the 60mL ethyl acetate, add TERTIARY BUTYL AMINE (60mmol, 9.6mL), stirring at room was revolved ethyl acetate after 15 hours, added 40mL water, the 1N hcl acidifying is to PH=2, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrated ester layer, solid gets white crystal 1.4g with ethyl acetate-sherwood oil recrystallization, productive rate 71.1%.TLC detects: ethyl acetate: sherwood oil (1:3), Rf=0.3.m.p.154-155℃
Embodiment 8: tBu-urea groups-Nal-OH's is synthetic
TBu-Ureido-Nal-OCH3 (1.4g, 4.3mmol) be dissolved in the 14mL methyl alcohol, add 2NNaOH aqueous solution 14mL under the ice bath, stirring at room after 5 hours the 1N hcl acidifying to PH=7, revolve methyl alcohol, the 1N hcl acidifying is to PH=2, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrated ester layer, solid gets white solid 1.1g with ethyl acetate-sherwood oil recrystallization, productive rate 82.1%.TLC detects: chloroform: methyl alcohol: HOAc (20:1:0.5), Rf=0.3.m.p.161-163℃
Embodiment 9D-N αSynthesizing of-tertbutyloxycarbonyl-4-(N, N-dimethyl)-amino-benzene L-Ala [D-Boc-Aph (DMe)-OH]
0.9g (3.2mmol) D-Boc-Aph-OH is dissolved in the 30mL dehydrated alcohol, adds the Pd-C of 0.3g10%, the formaldehyde of 0.8mL37%～40% (9.8mmol), and logical hydrogen catalytic hydrogenation is saturated to inhaling hydrogen.Remove by filter Pd-C, solution is spin-dried for into oily.Column chromatography gets the 0.6g white solid.Rf=0.59 (chloroform: methyl alcohol: acetic acid, 20:1:0.5), productive rate 60.85%.m.p.：50-53℃
Embodiment 10N, N-diacetylamino Padil (NDN) synthetic
(PhCH 2OOCCH 2) 2NCH 2COOH (NTA) (10mmol) is dissolved in the 50mL methyl alcohol, and logical ammonia is to saturated, and placement is spent the night, solvent evaporated, water-soluble, the citric acid acidifying, n-butanol extraction is spin-dried for solvent and gets white solid NDN1.5g, Rf=0.30 (propyl carbinol: acetic acid: water, 3:1:1), productive rate 79.37%.m.p.：180-182℃
Embodiment 11: compound (6) synthetic
Take 63mg mbha resin (0.04mmol) as solid phase carrier, BOP/DIEA is condensing agent, aminoacid sequence according to compound, Boc solid-phase peptide synthesis (reference: Huang Weide by standard, the Chen Changqing work, polypeptide is synthetic, Science Press, 1985) the synthetic Ac-D-Nal of operation 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Pal 6-Leu 7-Arg 8-Pro 9-D-Ala 10-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the 1.0mL methyl-phenoxide, the system with the HF cutting device after installing is evacuated, and uses the cooled with liquid nitrogen reactor, changes the approximately liquid HF of 10mL over to, in 0 ℃ of reaction 40 minutes.Take HF away with oil pump, take off reactor, add freezing anhydrous diethyl ether and be settled out solid, again suspension is transferred in the sand core funnel.With the anhydrous diethyl ether of a small amount of cooling washing three times, wash to resin with 10% acetic acid aqueous solution again and no longer mutually adhere to, collect washings, after the lyophilize the white dry powder of 50.6mg, peptide yield 91.5% slightly.Get sterling through the RP-HPLC purifying, pure peptide yield 12.8%.ESI-MS:1386.0 (theoretical value 1384.5).
Embodiment 12: suppress the testosterone effect experiment in the rat body:
Claim the weight of animals before the experiment, the blood sampling of glass capillary ball rear vein beard, use the chemiluminescence determination Testosterone Content in Serum behind the separation of serum, press testosterone concentration and body weight random packet, every group of 4 animals, respectively at behind the disposable excessive injection testing compound aqueous solution (500 μ g/kg) 8,16,24 hours, the blood sampling of ball rear vein beard, the centrifugal 8min of 5000rpm measures Testosterone Content in Serum with the serum that separation obtains with chemoluminescence method (the Access Immunoassaysystem of U.S. Beckman coulter company Chemiluminescence Apparatus)
Embodiment 13: the ability of impelling rat peritoneal mast cells to discharge histamine is measured
5 male rat broken end sacrificed by exsanguination, the cold PBS15mL/ of abdominal injection only, the sucking-off peritoneal fluid is to the ice bath centrifuge tube after opening the abdominal cavity, centrifugal 10 minutes of 1500rpm, repeated washing once merges sedimentation cell afterwards, appropriate amount of buffer solution is made single cell suspension, count number of nucleated cells with after 20 times of the white corpuscle diluted.Get above-mentioned cell suspension and add respectively 37 ℃ of different sample sizes and hatched 15 minutes, boil rear ice bath termination reaction.Get supernatant after centrifugal, use the Chemiluminescence Apparatus of BMG company production in EX340nm, EM460nm measures fluorescence intensity, calculates the release percentage of histamine according to fluorescence intensity, and calculates the EC of each medicine 50, EC 50Be worth greatlyr, then histamine release side effect is lower.
According to the method described above, activity and histamine release measurement result see the following form 1.
Table 1. pharmacologically active and histamine release measurement result
Compound number Suppress the testosterone effect time in the rat body (hour) Histamine release is measured EC 50 (μg/mL)
Cetrorelix 8 6.25
1 8 4.73
38 48 16.8
46 32 158.9
62 32 13.17
63 32 15.92
65 48 30.13
72 8 77.30
73 8 13.4
78 32 17.62
79 32 13.42
86 8 19.41
88 8 35.4
89 8 254.7
96 8 14.37
105 48 46.16
149 8 15.90
152 8 14.68
156 24 53.39

Claims (5)

1. following compound:
(38)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2，
(78)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2，
(79)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Mop 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2，
(149)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Aph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2，
(152) NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Uph 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2, and
(156)NH 2CO-D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Gln 5-D-Aph(Ac) 6-Leu 7-Arg 8-Pro 9-D-Ala 10-NH 2，
Or its physiologically acceptable salt.
2. pharmaceutical composition, it contains compound and one or more pharmaceutically acceptable carrier or the vehicle of at least a claim 1.
3. the compound of claim 1 is for the preparation of the purposes for the treatment of with the medicine of sexual hormoue relative disease or illness, and wherein said is and the sexual hormoue associated cancer that wherein said and sexual hormoue associated cancer is prostate cancer with sexual hormoue relative disease or illness.
4. the compound of claim 1 discharges or reduces the purposes of the medicine of histamine release for the preparation of antihistamine.
5. the compound of claim 1 is for the preparation of the purposes of the medicine of inhibition glandular secretion steroid hormone, and wherein said steroid hormone is testosterone.
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