CN101037472A - LHRH antagonist with low-histamine releasing function - Google Patents

LHRH antagonist with low-histamine releasing function Download PDF

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CN101037472A
CN101037472A CNA2006100657269A CN200610065726A CN101037472A CN 101037472 A CN101037472 A CN 101037472A CN A2006100657269 A CNA2006100657269 A CN A2006100657269A CN 200610065726 A CN200610065726 A CN 200610065726A CN 101037472 A CN101037472 A CN 101037472A
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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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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

Lhrh 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, the pharmaceutical composition and the described decapeptide derivative that contain them are used to prepare the purposes that treatment prostate cancer and other sexual hormoue rely on the medicine of relative disease.
Background technology
LHRH (luteinizing hormone-releasing hormone) is by one of hypothalamus excretory peptide hormone, its main effect is to promote that hypophysis is synthetic and discharge lutropin (LH) and follicular stimulating hormone (FSH), excites and grows pubescence and adjusting reproduction, fertility and sexual hormoue correlated process.LHRH is made up 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 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, supreme recover after phenomenon, the drug withdrawal fast, to advantages such as the horizontal controllability of serum androgen are strong.Can expect that the curative effect of lhrh antagonist treatment prostate cancer is better than agonist, easilier be accepted to have the application prospect bigger than agonist by the patient.
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.Histamine mainly is stored in the particle of mastocyte and basophilic granulocyte after generating, 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 multiple tissue, 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 in the hope of 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 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 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), (iii), (iv) or (v):
Figure A20061006572600191
Figure A20061006572600201
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 A20061006572600202
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 2Definition as mentioned 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 purposes that The compounds of this invention is used to prepare the medicine for the treatment of disease relevant with sexual hormoue or illness (as sexual hormoue associated cancer, for example prostate cancer).
The 5th aspect of the present invention relates to medicine that The compounds of this invention is used to prepare lhrh antagonist, antagonism LHRH acceptor, suppresses the purposes of the medicine (for example oestrogenic hormon, progestogen and/or testosterone) of hypophysis secretion gonad-stimulating hormone (for example LH and/or FSH) and inhibition glandular secretion steroid hormone.
The 6th aspect of the present invention relates to The compounds of this invention and pharmaceutical composition is used to prepare histamine release effect with reduction and/or the purposes with 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-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 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 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), (iii), (iv) or (v):
Figure A20061006572600221
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 A20061006572600232
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 2Definition as mentioned 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 " is meant 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-Ala 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 2-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-Pro 9-D-Ala 10-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 4-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-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
(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 that being labeled as the D-type.
" acyl group " is meant 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 " is meant alkyl-O-CO-, and alkyl wherein as defined herein.
Unless otherwise indicated, " alkyl " is meant it can is the aliphatic hydrocarbyl that has about 15 carbon atoms of about 1-in the chain of straight or branched, and it is randomly replaced by one or more halogen atoms.Particularly have about 6 carbon atoms of 1-, for example the alkyl of 1-4 carbon atom.Be meant it to be the aliphatic hydrocarbyl that has about 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 " is meant and contains the aliphatic hydrocarbyl that has the straight or branched of about 15 carbon atoms of about 2-in the carbon-to-carbon double bond while chain.The alkenyl that has about 12 carbon atoms of 2-in the preference chain; More preferably have about 6 carbon atoms of 2-(for example 2-4 carbon atom) in the chain.Used " side chain " is meant 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; Be meant the straight-chain alkenyl chain at this." low-grade alkenyl " is meant and contains about 4 carbon atoms of the 2-that has an appointment in the chain, and it can be a straight or branched.The example chain thiazolinyl comprise second alkenyl, 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 " is meant 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 " is meant alkyl-S-group, and wherein said alkyl is as described herein.
" alkenyl oxy " is meant alkenyl-O-group, and wherein the alkenyl definition as above.Alkenyl oxy for example comprises allyloxy.
" alkenyl thio " is meant alkenyl-S-group, and wherein the alkenyl definition as above.
" halogen " comprises fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine, bromine.
" alkynyl " is meant and contains carbon-to-carbon three key simultaneously it can be the aliphatic hydrocarbyl that has about 15 carbon atoms of about 2-in the chain of straight or branched.Preferred alkynyl has about 12 carbon atoms of 2-in chain; More preferably have about 6 carbon atoms of 2-(for example 2-4 carbon atom) 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 " is meant 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 the aroyl definition as above.
" aryl " represented as the integral part of a group or group: (i) the optional substituted monocycle of about 14 carbon atoms of about 6-or polycyclic aromatic isocyclic part, as phenyl or naphthyl; Or the polycyclic aromatic isocyclic part of (ii) optional substituted fractional saturation, wherein aryl and cycloalkyl or cycloalkenyl condense and constitute ring texture together, for example tetralyl, indenyl or dihydro indenyl rings.Unless otherwise defined; aryl can be by one or more (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 " is meant 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 " is meant arylalkyl-S-group, and wherein said arylalkyl as mentioned above.The example alkylthio-aryl is a benzylthio-.
" aryloxy " is meant aryl-O-group, and wherein aryl as mentioned above.The example aryloxy comprises phenoxy group and naphthyloxy, its optional separately being substituted.
" cycloalkenyl group " is meant and contains at least one carbon-to-carbon double bond and have the non-aromatic monocyclic of about 10 carbon atoms of about 3-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 " is meant saturated monocycle or the dicyclo ring system that contains 3-10 carbon atom, randomly replaced by oxygen.Example monocyclic cycloalkyl ring comprises C 3-8Cycloalkyl ring is 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 " is meant monocycle or the dicyclic compound that contains 5-14 ring members and have one or more (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, sulfane base, alkylamino or phenyl.
" heteroaryl " is meant 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, sulfane base, alkylamino or phenyl.
Preferred aromatics 5-of the present invention or 6-unit heterocyclic radical example comprise 1,3,2,4-or 1,3,4,5-two  di azolies, two  triazinyls, two  piperazine bases, 1,2,3-, 1,2,4-, 1,3,2-or 1,3,4-two  azoles bases, 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-the 5-base, different  azoles-3-,-4-or-the 5-base, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4- diazole-3-,-4-or-the 5-base,  tetrazine base, the  triazinyl, 1,2,3,4-or 1,2,3,5- triazolyl,  azoles-2-,-4-or-the 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-the 5-base, thiazole-2-,-4-or-the 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, the 2-triazolyl.The most preferred aromatic heterocyclic radical of the present invention comprises furans-2-base, furans-3-base, 2-, 4-or the different  azoles of 5-imidazolyl, 3-, 4-or 5-base, 1-, 2-or 3-pyridyl and 1-or 2-thienyl.
Preferred saturated or fractional saturation 5-of the present invention or 6-unit heterocyclic radical example comprise 1,3,5,6,2-two  diazines, 1,2,3,4,5-or 1,2,3,5,4-two  di azolies, two  alkyl, 1, the 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, the  diazine, 1,2,4-, 1,2,6-, 1,3,2-, 1,3,6-or 1,4,2- piperazine base, piperazinyl, high piperazinyl, piperidyl, 1,2-, 1,3-or 1, the 4-pyranyl, with 1,2, the 3-pyrrolidyl.
" Heterocyclylalkyl " is meant: (i) cycloalkyl of about 3-7 person's 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 respectively by one or more " aryl substituent ", and Heterocyclylalkyl condenses and constitutes ring texture together, the example of this type of group comprises chromanyl, dihydro benzo furyl, indolinyl.
Can adopt following method to prepare The compounds of this invention:
(1) utilizing solid phase synthesis process, is carrier with the mbha resin, and Boc-protects strategy, and DCC/HOBT or BOP/DIEA are condensation reagent, and the HCl/ dioxane is a deprotecting regent, has reacted the back and with liquid HF the decapeptide derivative has been cut down from mbha resin;
(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, for example Boc-Phe (NAM), Boc-Phe (CAM), Boc-Phe (NNM), Boc-Phe (NOM) etc. can pass through Boc-p-CH shown in above-mentioned synthesis type (I) employed formula II of decapeptide derivative and the formula III 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, 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 are used to prepare the purposes with the medicine that reduces histamine release effect, anti-inflammatory, anti-allergic to the invention still further relates to compound or derivatives thereof shown in formula II, III and the Y part.
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 is 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 " is meant that can keep parent compound expects physiologically active and can not produce the salt of toxic side effect outside any expectation 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, 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 way administration, 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. for example.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 extensive use of various biodegradable or physiologically acceptable carrier well known in the art.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.
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 the 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 of treatment 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, preferable 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 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 that 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 35.2mmol (3.9mL) again, add 4.6g (Boc) then 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.Concentrate the 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.Ice bath add down TEA (1.69mL, 12mmol) after, stirring at room 72 hours is revolved ethanol, the aqueous solution transfers pH to alkalescence, after the ether washing pH of water transfer phase again to acid, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrate the 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 the back and add 30mL 1,4-dioxane.Adding carbonyl phenoxy acyl chlorides under the ice bath (0.63mL, 5mmol).React and revolve 1 after 1 hour, the 4-dioxane, 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.Concentrate the ester layer, 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, the down logical NH of 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 2OOCCH 2) 2NCH 2COOH's (NTA) is synthetic
(28.8mmol, 9g) (14.4mmol 2.0g) places the 100ml round-bottomed flask to the imine oxalic acid dibenzyl ester, adds the 50mL dissolve with ethanol with bromoacetic acid.Ice bath add down TEA (10mL, 72mmol) after, stirring at room 72 hours is revolved ethanol, the aqueous solution transfers pH to alkalescence, after the ether washing pH of water transfer phase again to acid, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrate the ester layer, oily matter gets 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, ice bath adds 10% aqueous sodium carbonate 50mL (51.26mmol) and 100mL dioxane down, 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.Concentrate the 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) is dissolved in the 60mL ethyl acetate, and the adding TERTIARY BUTYL AMINE (60mmol, 9.6mL), stirring at room was revolved ethyl acetate after 15 hours, added 40mL water, and the 1N hcl acidifying is to PH=2, ethyl acetate extraction, washing twice, the ester layer is with anhydrous sodium sulfate drying.Concentrate the 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, ice bath adds 2NNaOH aqueous solution 14mL down, 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.Concentrate the 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 0.8mL 37%～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: acetate, 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 NDN 1.5g, Rf=0.30 (propyl carbinol: acetate: water, 3: 1: 1), productive rate 79.37%.m.p.：180-182℃
Embodiment 11: compound (6) synthetic
With 63mg mbha resin (0.04mmol) is solid phase carrier, and BOP/DIEA is a condensing agent, according to the aminoacid sequence of compound, (polypeptide is synthetic for reference: Huang Weide, Chen Changqing work for the Boc solid-phase peptide synthesis of the standard of pressing, 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, add the 1.0mL methyl-phenoxide, the system with the HF cutting device after installing is evacuated, and use the cooled with liquid nitrogen reactor, changes about 10mL liquid state HF over to, reacts 40 minutes in 0 ℃.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 a small amount of refrigerative anhydrous diethyl ether washing three times, wash to resin with 10% acetic acid aqueous solution again and adhere to no longer mutually, collect washings, after the lyophilize the white dry powder of 50.6mg, peptide yield 91.5% slightly.Get pure product 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 chemiluminescence determination serum testosterone content behind the separation of serum, press testosterone concentration and body weight random packet, every group of 4 animals, respectively at the disposable excessive injection testing compound aqueous solution (500 μ g/kg) back 8,16,24 hours, the blood sampling of ball rear vein beard, the centrifugal 8min of 5000rpm measures serum testosterone content 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 the rat abdominal cavity mastocyte 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 back merges sedimentation cell, appropriate amount of buffer solution is made single cell suspension, with counting karyocyte number after 20 times of the white corpuscle diluted.Get above-mentioned cell suspension and add 37 ℃ of different sample sizes respectively and hatched 15 minutes, boil back ice bath termination reaction.Get supernatant after centrifugal, the Chemiluminescence Apparatus of using the production of BMG company is in EX340nm, and 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 greatly more, then histamine release side effect is low more.
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 (10)

1, formula (I) decapeptide derivative or its steric isomer or its 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 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 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), (iii), (iv) or (v):
Figure A2006100657260002C1
Figure A2006100657260003C1
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-or Y;
Described " replacement or unsubstituted " substituting group 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 A2006100657260004C1
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 2Definition as mentioned 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.
2, the compound of claim 1, wherein, Xaa 5, Xaa 6Or Xaa 8Be following structure independently of one another:
Figure A2006100657260004C2
II (D-or L-type) III (D-or L-type)
Wherein, the definition of Q and W is with claim 1.
3, the compound of claim 1, it is selected from following decapeptide derivative:
(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，
(31)D-Nal 1-D-Cpa 2-D-Phe 3-Ser 4-Aph 5-D-Mop 6-Leu 7-Are 8-Pro 9-D-A la 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-Ala 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-Pro 9-D-Ala 10-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 4-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-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，
(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-N，H 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 2And
(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。
4, the compound of claim 3, it is selected from compound 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.
5, pharmaceutical composition, it contains each compound and one or more pharmaceutically acceptable carrier or vehicle of at least a claim 1-4.
6, each compound of claim 1-4 be used to prepare treatment and sexual hormoue relative disease or illness, for example with the purposes of the medicine of sexual hormoue associated cancer such as prostate cancer.
7. each compound of claim 1-4 is used to prepare the purposes that antihistamine discharges or reduce the medicine of histamine release.
8. each compound of claim 1-4 is used to prepare antagonism LHRH, antagonism LHRH acceptor, suppresses the purposes of the medicine of hypophysis secretion gonad-stimulating hormone, for example LH and/or FSH and/or inhibition glandular secretion steroid hormone, for example oestrogenic hormon, progestogen and/or testosterone.
9. compound or derivatives thereof shown in formula II described in the claim 1 or the formula III, routine 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.
Claim 1 Chinese style (II), (III) or (IV) shown in the 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 are used to prepare the purposes with the medicine that reduces histamine release effect, anti-inflammatory, anti-allergic.
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WO2011011965A1 (en) * 2009-07-29 2011-02-03 中国人民解放军军事医学科学院毒物药物研究所 Luteinising hormone releasing hormone antagonist with hydantoin structure
WO2012122930A1 (en) * 2011-03-15 2012-09-20 中国人民解放军军事医学科学院毒物药物研究所 Lhrh antagonist derivative, and preparation method and applications thereof
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US5925730A (en) * 1997-04-11 1999-07-20 Ferring Bv GnRH antagonists
DE19911771B4 (en) * 1999-03-17 2006-03-30 Zentaris Gmbh LHRH antagonist, process for its preparation and its use
AU2001260110B2 (en) * 1999-03-17 2005-05-05 Zentaris Gmbh Novel LHRH-antagonists, production and use thereof as medicament
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WO2011011965A1 (en) * 2009-07-29 2011-02-03 中国人民解放军军事医学科学院毒物药物研究所 Luteinising hormone releasing hormone antagonist with hydantoin structure
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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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