CN100340572C - Novel LHRH antagonist - Google Patents
Novel LHRH antagonist Download PDFInfo
- Publication number
- CN100340572C CN100340572C CNB2005101150562A CN200510115056A CN100340572C CN 100340572 C CN100340572 C CN 100340572C CN B2005101150562 A CNB2005101150562 A CN B2005101150562A CN 200510115056 A CN200510115056 A CN 200510115056A CN 100340572 C CN100340572 C CN 100340572C
- Authority
- CN
- China
- Prior art keywords
- phe
- arg
- nal
- leu
- ala
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The present invention relates to decapeptide derivatives which have the activity of antagonizing an LHRH receptor, the effects of inhabiting the secretion of pituitary gonadotrophin and the effect of inhabiting sex gland steroid hormone, a preparation process thereof, a medical composition containing the decapeptide derivatives and an application of the decapeptide derivatives for treating prostate carcinoma and procreation related sex hormone dependence relevant diseases.
Description
Technical field
The present invention relates to have the decapeptide derivative of LHRH receptor antagonist activity, the preparation method of alpha-non-natural amino acid contains their pharmaceutical composition and they are in the purposes for the treatment of prostate cancer and other sexual hormoue dependence 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
Because LH and FSH excretory reduce the effect that can directly have influence on its target organ, can suppress follicular development and ovulation to ovary, oestrogenic hormon and progestogen are generated reduce; Testis is then suppressed the generation of sperm, the secretion of testosterone is lowered.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, 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 bigger application prospect than agonist by the patient.
Though the lhrh antagonist that is developed at present is existing a lot, as a kind of peptide medicament, great majority still exist bioavailability low, transformation period weak point in the body, and the high weak point of histamine release amount has limited lhrh antagonist application clinically.Therefore, LHRH is carried out structure of modification, increase stability, improve the bioavailability of lhrh antagonist, prolong the interior action period of its body and increase biological activity very necessary enzyme or non-enzyme environment.
The objective of the invention is to seek new lhrh antagonist.
Summary of the invention
The inventor has now found that formula (I) decapeptide derivative after deliberation
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 the toxic salt of its no physiology, have good LHRH antagonistic activity, so formula (I) decapeptide derivative or its steric isomer can be used as medicine and are used for the purposes that prostate cancer and other sexual hormoue rely on treating correlative diseases.
First aspect present invention relates to compound, and it comprises the no physiology toxicity salt of formula (I) decapeptide derivative or its steric isomer or its,
R-β-D-Nal-D-Cpa-Xaa
3-Ser-Xaa
5-Xaa
6-Leu-Xaa
8-Pro-D-Ala-B
Formula (I)
Wherein
R can be: H-, HC (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
1C (O)-, R
1R
2NC (O)-, wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyloxy base replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl sulfenyl, cycloalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y, for example C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y,
Wherein, preferably, Heterocyclylalkyl is for containing the heteroatomic cyclic group that 1-5 (preferred 1-3) is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or two replaces or trisubstituted 4,5,6 or 7 yuan of monocycles or Bicyclic groups, as phenyl or or naphthyl etc.; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc., as pyrryl, furyl, pyridyl etc.; Each n is the integer of 0-6 independently, as 0,1,2,3, or 4;
Y can be structure (i), (ii), (iii), (iv) or (v):
Each m is the integer of 0-6 independently, for example is 0,1,2,3, or 4;
B can be-OH ,-NR
19R
20,-NHNR
19R
20Or Y;
R
3-R
20Can be respectively independently of each other: H-, HC (O)-, R
1C (O)-, R
1R
2NC (O)-, wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, cycloalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y, for example C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y;
Wherein, preferably, Heterocyclylalkyl is for containing the heteroatomic cyclic group that 1-5 (preferred 1-3) is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group, as phenyl or or naphthyl etc.; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc., as pyrryl, furyl, pyridyl etc.; Each n is 0,1,2,3 independently, or 4;
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, Gln, Asn or the Mph of L or D type independently of one another;
Perhaps
Xaa
5, Xaa
6Or Xaa
8Also can be following structure:
Wherein,
Q is-H-NR
21R
22,-NHC (O) NR
21R
22,-C (O) NR
21R
22,-NH-C (O) R
23, or Y;
W is-CH
2N (iPr)
2,-CH
2NR
24R
25,-NHC (NR
26) NR
24R
25,-NHC (O) NR
24R
25,-NH-C (O) R
27, or Q;
Z is-NHC (NR
28) NHR
29, or Q;
R
21-R
28Can be respectively independently of each other: H-, HC (O)-, R
1C (O)-, R
1R
2NC (O)-, wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, cycloalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y, for example C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-,
Wherein, preferably, Heterocyclylalkyl is for containing the heteroatomic cyclic group that 1-5 (preferred 1-3) is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group, as phenyl or or naphthyl etc.; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc., as pyrryl, furyl, pyridyl etc.; Each n is 0,1,2,3 independently, or 4.
In The compounds of this invention, particularly preferably be, R is-H, Ac, NH
2CO-, NTA, NDN.
In The compounds of this invention, particularly preferably be, B is-NH
2
Preferably, Xaa
5Be Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Gln, Asn, Mph, Leu, Lys, Tyr or Aph (DMe);
Preferably, Xaa
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 or D-Aph (DMe);
Preferably, Xaa
8Be Arg.
The invention still further relates to the method for preparing The compounds of this invention, comprise: preparation formula (II), (III) or (IV) shown in compound and derivative thereof, preparation compound Y and B and derivative thereof and compound Y and B be connected on above-mentioned formula (I) decapeptide derivative or its steric isomer.
The invention still further relates to and can be used for intermediate for preparing The compounds of this invention and preparation method thereof.Particularly, the present invention relates to formula (II), (III) or (IV) shown in compound or derivatives thereof, for example Boc-Phe (NA
BM), Boc-p-NH
2(PhOCO)-Phe,
tBu-Ureido-Nal-OH, Boc-p-ureido-Phe, (PhCH
2OOCCH
2)
2NCH
2COOH, PhOCO-Nal-OCH
3,
tBu-Ureido-Nal-OCH
3, and D-Boc-Aph (DMe)-OH, and preparation method thereof.
The invention still further relates to the pharmaceutical composition that contains at least a above-mentioned formula (I) decapeptide derivative or its steric isomer or salt and pharmaceutically acceptable carrier or vehicle.
The invention still further relates to The compounds of this invention and be used for the treatment of purposes in the medicine of sexual hormoue relative disease (as the sexual hormoue associated cancer, as prostate cancer) in preparation.
The invention still further relates to the purposes of The compounds of this invention in treatment prostate cancer and other sexual hormoue dependence relative disease or symptom.
The invention still further relates to the purposes of The compounds of this invention antagonism LHRH, the purposes of antagonism LHRH acceptor, the purposes that suppresses hypophysis secretion gonad-stimulating hormone (for example LH and/or FSH), and the purposes of inhibition glandular secretion steroid hormone (for example oestrogenic hormon, progestogen and/or testosterone).
The invention still further relates to the purposes that The compounds of this invention is used for antagonism LHRH, antagonism LHRH acceptor in preparation, suppresses 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).
The invention still further relates to formula (II), (III) or (IV) shown in compound or derivatives thereof, for example Boc-Phe (NA
BM), Boc-p-NH
2(PhOCO)-Phe,
tBu-Ureido-Nal-OH and Boc-p-ureido-Phe.
Term used herein " formula (I) decapeptide derivative steric isomer " is meant its corresponding D-or L-steric configuration.
According to the preferred embodiments of the invention, The compounds of this invention is selected from following decapeptide or its steric isomer or does not have the toxic salt of physiology:
(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
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-uMop
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
More preferably, The compounds of this invention is selected from compound 1,6,7,12,13,19,23,24,25,26,27,28,38,39,40,41,42,43,62,63,64,65,66,67,78,79,80,81,82,83,105,106,117.
Description of drawings
There is not figure.
Embodiment
The abbreviation of Shi Yonging in 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) phosphofluoric acid,
The Cpa-4-chlorophenylalanine,
The DCC-dicyclohexylcarbodiimide,
The DIEA-diisopropylethylamine,
The Gln-glutamine
Glu-L-glutamic acid
The HOBt-1-hydroxybenzotriazole,
The iPr-sec.-propyl
The Leu-leucine,
Lys-Methionin
MBHA-phenylamino methyl resin,
Mob-β-piperonyl L-Ala
Mop-morpholine methyl phenylalanine,
Mph-piperonyl L-Ala
The Nal-naphthylalanine,
NBM-imine oxalic acid dibenzyl ester
NTA-N, N-diacetoxyl glycyl
NDN-N, N-diacetylamino glycyl
The Pal-3-pyrazoleahtnine,
The Phe-phenylalanine,
The RP-HPLC-RPLC
The Pro-proline(Pro),
The Ser-Serine,
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.
" acyl amino " is acyl group-NH-, and wherein acyl group as defined herein.
" alkoxy carbonyl " is meant alkyl-O-CO-group, and wherein said alkyl is as described herein.
The example alkoxy carbonyl comprises methoxyl group-and ethoxy carbonyl.
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.Or
" 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 " 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 ring penta alkenyl, hexamethylene alkenyl and ring alkenyl in heptan.Cycloalkenyl 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 the saturated monocycle or the dicyclo ring system of about 10 carbon atoms of about 3-, 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 to have one or more (as 2,3,4,5) heteroatomic compound in its ring structure.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).Heterocyclic radical can be aromatics (heteroaryl just), saturated or fractional saturation especially.The preferred monocyclic heterocycles base of the present invention comprises 5-and 6-unit monocyclic heterocycles base.These heterocycles and heteroaromatics 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, 1,3-dioxane penta alkenyl, 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 (example of this type of group comprises chromanyl, dihydro benzo furyl, indolinyl and pyrindolinyl).
The preparation method of The compounds of this invention
The preparation of The compounds of this invention can be adopted solid phase synthesis process; with the mbha resin is carrier, and Boc-protects strategy, and DCC/HOBT or BOP/DIEA are condensation reagent; 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.The amino acid of Boc protection is commercially available, and is perhaps synthetic according to method or the methods known in the art of embodiment.The compounds of this invention also can adopt other method known in the art to prepare.
On the other hand, the invention still further relates to and can be used for intermediate for preparing The compounds of this invention and preparation method thereof.
The present invention relates to Boc-p-CH in one embodiment
2Cl-Phe and preparation method thereof.
The present invention relates to Boc-Phe (NA in another embodiment
BM) and preparation method thereof.
The present invention relates to Boc-p-NH in another embodiment
2(PhOCO)-Phe and preparation method thereof.
The present invention relates to Boc-p-ureido-Phe and preparation method thereof in another embodiment.
The present invention relates to (PhCH in another embodiment
2OOCCH
2)
2NCH
2COOH and preparation method thereof.
The present invention relates to PhOCO-Nal-OCH in another embodiment
3And preparation method thereof.
The present invention relates in another embodiment
tBu-Ureido-Nal-OCH
3And preparation method thereof.
The present invention relates in another embodiment
tBu-Ureido-Nal-OH and preparation method thereof.
The present invention relates to D-N in another embodiment
α-tertbutyloxycarbonyl-4-(N, N-dimethyl)-amino-benzene L-Ala [D-Boc-Aph (DMe)-OH] and preparation method thereof.
These compounds can also can prepare according to methods known in the art according to the described preparation of embodiment.
According to the present invention, formula (I) decapeptide derivative and steric isomer thereof and its no physiology toxicity salt demonstrate good result in animal androgen antagonist secretion experiment, and therefore can be used as amcinonide is used for animal, is 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 its no physiology toxicity salt and conventional medicine vehicle or assistant agent.Here " conventional medicine vehicle or assistant agent " comprises any or all solvents, dispersion medium, dressing, antiseptic-germicide or anti-mycotic agent, Deng oozing and slowly-releasing reagent, and similar physiology compatibility agent, to be fit to intravenous injection, intramuscular injection, subcutaneous injection, or other parenteral administration mode is good.According to the mode of administration, the active compound dressing can be avoided acid or the influence of other natural condition and inactivation with the protection compound.
Term used herein " the toxic salt of no physiology " 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 this 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 except that explanation is to be provided.
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 (as the preparation of embodiment 1 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 9.8mL 10%, 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-ureido-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
3L 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 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-Ureido-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-Ureido-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 9 D-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 0.3g 10%, 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: acetate, 20: 1: 0.5), productive rate 60.85%.m.p.：50-53℃
Embodiment 10: 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 5: 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 Immunoassay System of U.S. Beckman Coulter company Chemiluminescence Apparatus)
According to the method described above, determination of activity the results are shown in following table.
The pharmacologically active result
| The compound sequence number | Antagonistic activity | |||||
| 8 hours | 16 hours | 24 hours | 32 hours | 48 hours | 72 hours | |
| 1 | + | - | ||||
| 6 | + | + | - | |||
| 7 | + | - | ||||
| 12 | + | + | - | |||
| 13 | + | + | - | |||
| 19 | + | + | - | |||
| 23 | + | + | + | + | + | - |
| 24 | + | + | + | + | - | - |
| 38 | + | + | + | + | - | - |
| 39 | + | + | + | + | - | - |
| 40 | + | + | + | - | ||
| 62 | + | + | + | + | - | |
| 63 | + | + | + | + | - | |
| 64 | + | + | + | + | - | |
| 65 | + | + | + | + | + | - |
| 66 | + | + | + | + | + | |
| 67 | + | + | + | + | - | |
| 78 | + | + | + | + | + | - |
| 79 | + | + | + | + | - | |
| 81 | + | + | + | + | + | - |
| 82 | + | + | + | + | - | |
| 83 | + | + | + | + | + | + |
| 105 | + | + | + | + | + | - |
| 117 | + | + | + | + | + | - |
+: antagonistic activity is medium-: do not show antagonistic activity
Claims (23)
1, compound or its steric isomer shown in the formula (I), or the toxic salt of its no physiology,
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)-, R
1C (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)-or R
1R
2NC (O)-,
Wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y,
Wherein, Heterocyclylalkyl is for containing 1-5 heteroatomic cyclic group that is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc.; Each n is 0,1,2,3 independently, or 4;
Y is structure (i), (ii), (iii), (iv) or (v):
Each m is 0,1,2,3 independently, or 4;
B is-OH-NR
19R
20,-NHNR
19R
20Or Y;
R
3-R
20Be independently of each other H-, HC (O)-, R
1C (O)-or R
1R
2NC (O)-,
Wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, or Y,
Wherein, Heterocyclylalkyl is for containing 1-5 heteroatomic cyclic group that is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group; Heterocyclic radical is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc.; Each n is 0,1,2,3 independently, or 4;
Xaa
3Be D-Phe;
Xaa
5, Xaa
6And Xaa
8Be any among Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Gln, Asn or the Mph of L or D type independently of one another; Perhaps
Xaa
5, Xaa
6Or Xaa
8Be following structure independently of each other:
(II) (D-or L-type) (III) (D-or L-type)
(IV) (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, or Y;
W is-CH
2N (iPr)
2,-CH
2NR
24R
25,-NHC (NR
26) NR
24R
25,-NHC (O) NR
24R
25, perhaps-NH-C (O) R
27
Z is-NHC (NR
28) NHR
29, or Q;
R
21-R
28Can be respectively independently of each other: H-, HC (O)-, R
1C (O)-or R
1R
2NC (O)-,
Wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-,
Wherein, Heterocyclylalkyl is for containing the heteroatomic cyclic group that 1-5 (preferred 1-3) is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc.; Each n is 0,1,2,3 independently, or 4.
2, the compound of claim 1, wherein Xaa
5, Xaa
6Or Xaa
8Be following structure independently of each other:
(II) (D-or L-type) (III) (D-or L-type)
(IV) (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, or Y;
W is-CH
2N (iPr)
2,-CH
2NR
24R
25,-NHC (NR
26) NR
24R
25,-NHC (O) NR
24R
25, perhaps-NH-C (O) R
27
Z is-NHC (NR
28) NHR
29, or Q;
R
21-R
28Can be independently of each other H-, HC (O)-, R
1C (O)-, R
1R
2NC (O)-, wherein, R
1And R
2Be respectively H, replace or unsubstituted C
1-C
6Straight chain or branched-chain alkyl replace or unsubstituted C
2-C
6Straight chain or branched-chain alkenyl or alkynyl replace or unsubstituted C
1-C
6Straight chain or branched alkoxy replace or unsubstituted C
1-C
6Straight chain or branched alkane sulfenyl, C
3-C
8Cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
8Heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-,
Wherein, Heterocyclylalkyl is for containing 1-5 heteroatomic cyclic group that is independently selected from N, O and S etc. in its ring structure; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replaces or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4The substituting group list of alkyl replace or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or Bicyclic group that is independently selected from N, O and S etc.; Each n is 0,1,2,3 independently, or 4.
3. according to the compound of claim 1 or 2, wherein, Heterocyclylalkyl is for containing 1-3 heteroatomic cyclic group that is independently selected from N, O and S etc. in its ring structure.
4. according to the compound of claim 1 or 2, wherein, aryl is phenyl or naphthyl.
5. according to the compound of claim 1 or 2, wherein, heterocyclic radical is a pyrryl, furyl, or pyridyl.
6. according to the compound of claim 1, wherein, R is-H, Ac, NH
2CO-, NTA-or NDN-.
7. according to the compound of claim 1, wherein, B is-NH
2
8. according to the compound of claim 1, wherein, Xaa
5Be Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Uph, Arg, Gln, Asn, Mph, Leu, Lys, Tyr or Aph (DMe).
9. according to the compound of claim 1, wherein, Xaa
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 or D-Aph (DMe).
10. according to the compound of claim 1, wherein, Xaa
8Be Arg.
11, according to the compound of claim 1, it is selected from following decapeptide derivative:
(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
(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
(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
(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
(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
(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
(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
(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
(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
(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。
12, according to the compound of claim 2, it is selected from following decapeptide derivative:
(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)
3-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
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
13, according to the compound of claim 1, it is selected from compound 6,12,23,24,25,26,27,28,38,39,40,41,42,43,62,63,64,65,66,67,78,79,80,81,82,83,105,106,117.
14, each compound of claim 1-13 is used for the treatment of purposes in the medicine of sexual hormoue relative disease in preparation.
15, according to the purposes of claim 14, wherein, the sexual hormoue relative disease is the sexual hormoue associated cancer.
16. according to the purposes of claim 15, wherein, the sexual hormoue associated cancer is a prostate cancer.
17, pharmaceutical composition, it contains each compound and pharmaceutically acceptable carrier or vehicle of at least a claim 1-13.
18, the pharmaceutical composition of claim 17, wherein said compound is selected from the compound in claim 11 or 12.
19, the pharmaceutical composition of claim 17, wherein said compound is selected from compound 6 and 12.
20, claim 1 Chinese style (II), (III) or (IV) shown in the compound or derivatives thereof, wherein said derivative is selected from: Boc-Phe (NA
BM), Boc-p-NH
2(PhOCO)-Phe,
tBu-Ureido-Nal-OH and Boc-p-ureido-Phe, (PhCH
2OOCCH
2)
2NCH
2COOH, PhOCO-Nal-OCH
3,
tBu-Ureido-Nal-OCH
3, D-Boc-Aph (DMe)-OH.
21, each compound of claim 1-13 is used for antagonism LHRH, antagonism LHRH acceptor in preparation, suppresses the purposes of the medicine of hypophysis secretion gonad-stimulating hormone and/or inhibition glandular secretion steroid hormone.
22. the purposes of claim 21, wherein, described medicine is used to suppress hypophysis secretion LH and/or FSH.
23. the purposes of claim 21, wherein, described medicine is used for inhibition glandular secretion oestrogenic hormon, progestogen and/or testosterone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101150562A CN100340572C (en) | 2004-12-01 | 2005-11-25 | Novel LHRH antagonist |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410096458.8 | 2004-12-01 | ||
| CN200410096458 | 2004-12-01 | ||
| CNB2005101150562A CN100340572C (en) | 2004-12-01 | 2005-11-25 | Novel LHRH antagonist |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1781935A CN1781935A (en) | 2006-06-07 |
| CN100340572C true CN100340572C (en) | 2007-10-03 |
Family
ID=36772598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005101150562A Expired - Fee Related CN100340572C (en) | 2004-12-01 | 2005-11-25 | Novel LHRH antagonist |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100340572C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101037472B (en) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with low-histamine releasing function |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101597321B (en) * | 2008-06-03 | 2013-04-24 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with long-acting low-histamine release side effect |
| WO2010142060A1 (en) * | 2009-06-11 | 2010-12-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Lhrh antagonist with long potency and low histamine releasing effect |
| CN101987865B (en) * | 2009-07-29 | 2014-07-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure |
| CN103524599B (en) * | 2012-07-05 | 2016-04-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyclic peptide lhrh antagonist derivative and pharmaceutical use thereof |
| CN104418936B (en) * | 2013-08-20 | 2018-06-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Lhrh antagonist derivative and its medicinal usage |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348462A (en) * | 1999-03-17 | 2002-05-08 | 赞塔里斯股份公司 | Novel LHRH-antagonists with improved solubility characteristics |
| CN1443195A (en) * | 2000-03-14 | 2003-09-17 | 赞塔里斯股份公司 | LHRH-antagonists, production and use thereof as medicament |
-
2005
- 2005-11-25 CN CNB2005101150562A patent/CN100340572C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1348462A (en) * | 1999-03-17 | 2002-05-08 | 赞塔里斯股份公司 | Novel LHRH-antagonists with improved solubility characteristics |
| CN1443195A (en) * | 2000-03-14 | 2003-09-17 | 赞塔里斯股份公司 | LHRH-antagonists, production and use thereof as medicament |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101037472B (en) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | LHRH antagonist with low-histamine releasing function |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1781935A (en) | 2006-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1052731C (en) | Compounds with growth hormone releasing properties | |
| CN1055700C (en) | Therapeutic peptide derivatives | |
| CN1166597C (en) | Nitrogenous group conversion method | |
| CN1113895C (en) | Growth-hormone secretagogues | |
| CN100340572C (en) | Novel LHRH antagonist | |
| CN1084743C (en) | Muscarinic antagonists | |
| CN1147260A (en) | Neurokinine (tachykinine) antagonists | |
| CN1119434A (en) | Phenoxyphenylacetic acid derivatives | |
| CN1208412A (en) | Antagonists of gonadotropin releasing hormone | |
| CN86101850A (en) | N, the manufacture method and the purposes of N '-dialkyl group guanidine radicals dipeptides | |
| CN1968948A (en) | Processes for preparing gonadotropin releasing hormone receptor antagonists | |
| CN1046727C (en) | HIV protease inhibitors | |
| CN1300281A (en) | Compounds with growth hormone releasing properties | |
| CN1491942A (en) | Non humidity suction stable crystalline form of N-[N-N-(4-piperidine-4-yl)-N-ethyl glycyl) compound | |
| CN1180358A (en) | Bridged indoles as matrix metalloprotease inhibitors | |
| CN1047084A (en) | Dipeptidase derivant with enzyme inhibition | |
| CN1856305A (en) | Pyridine derivatives and use thereof as urotensin II antagonists | |
| CN1173951C (en) | Substituted 1,3-diaryl-2-pyridine-2-yl-3-(pyridine-2-ylamino)-propanol derivatives, methods for their production, pharmaceutical compositions containing the same and their use | |
| CN1157224C (en) | Novel amide derivs. as growth hormone secretagogues | |
| CN1575282A (en) | Lactam compound | |
| CN101037472A (en) | LHRH antagonist with low-histamine releasing function | |
| CN1167437A (en) | Method of using triaryl-ethylene derivatives in the treatment and prevention of osteoporosis | |
| CN1054857C (en) | Motilin-like polypeptides with gastrointestinal motor stimulating activity | |
| CN1227259C (en) | Propanolamine derivs. linked with bile acid used for treating disorders of lipid metabolism | |
| CN1051914A (en) | The peptide class |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071003 Termination date: 20151125 |