CN101987865A - Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure - Google Patents

Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure Download PDF

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CN101987865A
CN101987865A CN2009101655353A CN200910165535A CN101987865A CN 101987865 A CN101987865 A CN 101987865A CN 2009101655353 A CN2009101655353 A CN 2009101655353A CN 200910165535 A CN200910165535 A CN 200910165535A CN 101987865 A CN101987865 A CN 101987865A
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phe
xaa
pro
nhc
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CN101987865B (en
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刘克良
周宁
高永清
周文霞
张永祥
程军平
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to an antagonist of luteinizing hormone releasing hormone (LHRH) containing a hydantoin structure, and particularly relates to a decapeptide derivative which has LHRH receptor antagonism activity, can inhibit hypophysis from secreting gonadotropin and inhibit sexual gland from secreting steroid hormone and is shown in the formula (I): R-Xaa<3>-Ser-Saa <5>-Xaa<6>-Xaa<7>-Xaa<8>-Pro-D-Ala-B, wherein the definition of each symbol is in the specification. The invention also relates to a preparation method of compounds as shown in the formula (1), a pharmaceutical composition containing the compounds and applications of the compounds in preparing medicaments.

Description

Luteinizing hormone releasing hormone antagonist containing hydantoin structure
Technical Field
The invention relates to decapeptide derivatives with luteinizing hormone releasing hormone receptor antagonistic activity, the effects of inhibiting gonadotropin secretion of pituitary gland and inhibiting steroid hormone secretion of gonad, a preparation method thereof, a pharmaceutical composition containing the decapeptide derivatives and application of the decapeptide derivatives in treatment of prostatic cancer, endometrial cancer, sex hormone dependence related diseases related to reproduction, contraception and the like.
Background
Luteinizing hormone-releasing hormone (hereinafter, abbreviated as LHRH) is one of peptide hormones secreted from hypothalamus, and its main functions are to promote synthesis of pituitary gland and release Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), stimulate pubertal development and regulate reproduction, fertility and sex hormone-related processes. LHRH consists of ten amino acid residues, the C-terminus containing an amide structure. The primary structure of LHRH is as follows:
p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
LHRH antagonists inhibit the release of LH by blocking the action of LHRH, and thus can be used for the treatment of sex hormone-related diseases such as prostate cancer. Compared with an agonist, the LHRH antagonist has the advantages of high effect taking speed, no phenomenon of upward flushing, quick recovery after stopping administration, strong controllability on serum androgen level and the like. It is expected that the curative effect of the LHRH antagonist on the prostate cancer is better than that of the agonist, the LHRH antagonist is more easily accepted by patients, and the LHRH antagonist has larger application prospect than that of the agonist.
Although a lot of LHRH antagonists are developed at present, most of LHRH antagonists serving as peptide drugs still have the defects of low bioavailability, short in-vivo half-life, high histamine release amount and the like, and the clinical application of the LHRH antagonists is limited. In addition, like other peptide drugs, LHRH antagonist drugs are also difficult to be absorbed orally. Currently marketed LHRH antagonist drugs are all administered by non-oral routes.
Therefore, it would be desirable to be able to provide effective LHRH antagonists with novel structures.
Disclosure of Invention
It is an object of the present invention to provide effective LHRH antagonists having novel structures. The present inventors have studied to find a decapeptide derivative which is a compound of the following formula (I):
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer thereof or a physiologically nontoxic salt thereof, not only has good LHRH antagonistic activity, longer in-vivo action time and lower side effect of histamine release, but also has oral activity as part of the compound. Therefore, the decapeptide derivative shown in the formula (I) or the stereoisomer thereof can be used as a medicine for treating prostatic cancer, endometrial cancer, contraception and other sex hormone dependence related diseases. To this end, a further object of the present invention is to provide the use of the compounds of formula (I), and a process for the preparation of the compounds of formula (I).
To this end, a first aspect of the invention provides a compound of formula (I):
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure B2009101655353D0000021
wherein,
z is selected from H, R1R2N-(CR3R4)t-C(O)-、R1C(O)-、R2O-NR1-C(O)-、
R1-、R1OS(O2) -; wherein R is1、R2、R3And R4Independently of each other, may be H, substituted or unsubstituted C with or without carboxyl, amido, phosphate, sulfonyl, or the like1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, substituted or unsubstituted C1-C30Straight or branched alkylamino, substituted or notSubstituted C2-C30Straight or branched alkenyl or alkynyloxy, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynylthio, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynylamino, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, e.g. C3-C8Cycloalkyl or Cycloalkenyl (CH)2)n-，C3-C8Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-or Y; wherein,
the carboxyl, the amido, the phosphate and the sulfonyl can be one or p and are respectively and independently connected to R1、R2、R3And R4T, n and p may each independently be an integer of 0 to 6, such as 0, 1, 2, 3, 4, or 5;
heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S and the like in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-, di-, or tri-substituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like;
y is selected from the following structures (i), (ii), (iii), (iv) or (v):
Figure B2009101655353D0000041
each m is independently an integer from 0 to 6, such as 0, 1, 2, 3, or 4;
x is selected from hydrogen or 1-4 substituents independently selected from: halogen (e.g. chloro, fluoro, bromo, iodo), methyl, ethyl, propyl, isopropyl, n-propyl, Ac-, NH2CO-, NTA-, CAM-, NDN-, CEC-, heptanoyl, lauryl, palmityl, butyryl, nicotinoyl, nonanoyl, piperidinyl, morpholinyl;
b is selected from NH2、-OH、-NR19R20、-NHNR19R20(ii) a Wherein R is19And R20Independently of one another, from: h-, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, substituted or unsubstituted C1-C30Straight or branched alkylamino, cycloalkyl or Cycloalkenyl (CH)2)q-, aryl (CH)2)q-, heterocyclic radical (CH)2)q-, or Y, e.g. C3-C8Cycloalkyl or Cycloalkenyl (CH)2)q-，C3-C8Heterocycloalkyl or Cycloalkenyl (CH)2)q-, aryl (CH)2)q-, heterocyclic radical (CH)2)qOr Y, each q is independently an integer from 0 to 6, for example 0, 1, 2, 3, or 4; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S and the like in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4Alkyl substituent mono-or di-substituted, containing 1-5 heteroatoms independently selected from N, O and S4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic groups of a nucleus, such as pyrrolyl, furyl, pyridyl and the like;
Xaa3is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Phe (nam), Phe (nnm), Phe (nom), Aph (ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, gin, Asn, Lys, illys, Orn, ion, Cit, Aph (Hor), Mph, Phe (COOH), Phe (cam), Pal, Aph (lauryl), Aph (palmityl), Aph (butyryl), Aph (nicotinyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), Ilys;
or
Xaa5、Xaa6Or Xaa8The structure is as follows:
Figure B2009101655353D0000051
wherein,
q is selected from H, -NR21R22、-NHC(O)NR21R22、-C(O)NR21R22、-NH-C(O)R23、R43O-NR24-C(O)-、R25R26P(O)-、R27N(R28N)P(O)-、R29O(R30N)P(O)-、R31O(R32O)P(O)-、R33OS(O2)-、R34-or Y;
w is selected from-COOH, -CONH2、-N(iPr)2、-NR35R36、-NHC(NR37)NR38R39、-NHC(O)NR40R41、-NH-C(O)R42Or Q;
r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6; r21-R43Independently of one another, from: H. HC (O) -, R1C(O)-、R1R2NC (O) -, wherein R1And R2Each is H, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, or Y, e.g. C3-C30Cycloalkyl or Cycloalkenyl (CH)2)n-，C3-C30Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S, etc. in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or disubstituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like; each n is independently 0, 1, 2, 3, or 4;
Xaa7is Leu, Acc5Or Acc6。
A compound of formula (I) according to any one of the first aspect of the invention wherein the moiety R has the following configuration:
Figure B2009101655353D0000071
wherein Z and X are as defined for a compound of formula (I) according to any one of the first aspect of the invention.
A compound of formula (I) according to any one of the first aspect of the invention:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure B2009101655353D0000072
wherein,
z is H;
x is selected from hydrogen or 1-4 substituents independently selected from: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, n-propyl;
b is selected from NH2、-OH；
Xaa3Is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Phe (nam), Phe (nnm), Phe (nom), Aph (ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, gin, Asn, Lys, illys, Orn, ion, Cit, Aph (Hor), Mph, Phe (COOH), Phe (cam), Pal, Aph (lauryl), Aph (palmityl), Aph (butyryl), Aph (nicotinyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), Ilys;
or
Xaa5、Xaa6Or Xaa8The structure is as follows:
Figure B2009101655353D0000081
wherein,
q is selected from H, -NR21R22、-NHC(O)NR21R22、-C(O)NR21R22、-NH-C(O)R23、R43O-NR24-C(O)-、R25R26P(O)-、R27N(R28N)P(O)-、R29O(R30N)P(O)-、R31O(R32O)P(O)-、R33OS(O2)-、R34-or Y;
w is selected from-COOH, -CONH2、-N(iPr)2、-NR35R36、-NHC(NR37)NR38R39、-NHC(O)NR40R41、-NH-C(O)R42Or Q;
r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;
R21-R43independently of one another, from: H. HC (O) -, R1C(O)-、R1R2NC (O) -, wherein R1And R2Each is H, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, or Y, e.g. C3-C30Cycloalkyl or Cycloalkenyl (CH)2)n-，C3-C30Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S, etc. in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or disubstituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like; each n is independently 0, 1, 2, 3, or 4;
Xaa7is Leu, Acc5Or Acc6。
A compound of formula (I) according to any one of the first aspect of the invention:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure B2009101655353D0000091
wherein,
z is H;
x is selected from hydrogen or 1-4 substituents independently selected from: chlorine, fluorine, bromine, methyl, ethyl, propyl;
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Each independently selected from Phe (nam), Phe (nnm), Phe (nom), Aph (ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, gin, Asn, Lys, illys, Orn, Cit, Aph (Hor), Mph, Phe (COOH), Phe (cam), Pal, Aph (lauryl), Aph (palmityl), Aph (butyryl), Aph (nicotinyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), Ilys;
Xaa7is Leu, Acc5Or Acc6。
A compound of formula (I) according to any one of the first aspect of the invention:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure B2009101655353D0000101
wherein,
z is H;
x is selected from hydrogen or 1-2 substituents independently selected from: chlorine, fluorine, methyl, ethyl;
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5selected from Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, Gln, Asn, Phe (COOH), Phe (CAM), Aph (hor);
Xaa6selected from D-Aph (diethyl-Cbm), D-Aph (piperidyl-CO), D-Aph (morpholinyl-CO) and D-Aph (morpholine)group-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop, D-Pal, D-Pro, D-Amp, D-Phe, D-Arg, D-Glu, D-Asp, D-Phe (COOH), (D-Phe (CAM), D-Aph (lauryl), D-Aph (palmityl), D-Aph (nicotinoyl), D-Aph (nonanoyl), D-Uph (diethyl), D-Uph (di-n-propyl), D-Uph (diisopropyl), D-Aph (hor);
Xaa7is Leu, Acc5Or Acc6；
Xaa8Arg, ILys, IOrn, Asn, Gln.
In one embodiment of the compounds of formula (I) according to any of the first aspect of the invention, wherein R is
Figure B2009101655353D0000111
In one embodiment of the compounds of formula (I) according to any of the first aspect of the present invention, wherein B is NH2。
In one embodiment of the compounds of formula (I) as described in any of the first aspect of the invention, wherein Xaa3Is D-Phe or D-Pal.
In one embodiment of the compounds of formula (I) as described in any of the first aspect of the invention, wherein Xaa5Selected from Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph, Uph, Gln, Asn, Aph (Hor).
In one embodiment of the compounds of formula (I) as described in any of the first aspect of the invention, wherein Xaa6Selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), and D-Mop.
In one embodiment of the compounds of formula (I) as described in any of the first aspect of the invention, wherein Xaa7Is Leu.
In one embodiment of the compounds of formula (I) as described in any of the first aspect of the invention, wherein Xaa8Is Arg.
A compound of formula (I) according to any one of the first aspect of the invention:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure B2009101655353D0000121
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5selected from Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph, Uph, Gln, Asn, Aph (Hor);
Xaa6selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop;
Xaa7is Leu;
Xaa8is Arg.
A compound of formula (I) according to any one of the first aspect of the invention, selected from:
1、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
2、NHC-D-Phe3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
3、NHC-D-Phe3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
4、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
5、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
6、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
7、NHC-D-Phe3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2
8、NHC-D-Phe3-Ser4-Mop5-D-Aph6(n-butyryl) -Leu7-Arg8-Pro9-D-Ala10-NH2
9、NHC-D-Phe3-Ser4-Mop5-D-Aph6(nonanoyl) -Leu7-Arg8-Pro9-D-Ala10-NH2
10、NHC-D-Phe3-Ser4-Mop5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
11、NHC-D-Phe3-Ser4-Mop5-D-Aph6-Leu7-Arg8-Pro9-D-Ala10-NH2
12、NHC-D-Phe3-Ser4-Mop5-D-Gln6-Leu7-Arg8-Pro9-D-Ala10-NH2
13、NHC-D-Phe3-Ser4-Mop5-D-Asn6-Leu7-Arg8-Pro9-D-Ala10-NH2
14、NHC-D-Phe3-Ser4-Mop5-D-Phe(NAM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
15、NHC-D-Phe3-Ser4-Mop5-D-Phe(NNM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
16、NHC-D-Phe3-Ser4-Mop5-D-Phe(NOM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
17、NHC-D-Phe3-Ser4-Aph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
18、NHC-D-Phe3-Ser4-Uph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
19、NHC-D-Phe3-Ser4-Phe(NAM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
20、NHC-D-Phe3-Ser4-Phe(NNM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
21、NHC-D-Phe3-Ser4-Phe(NOM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
22、NHC-D-Phe3-Ser4-Gln5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
23、NHC-D-Phe3-Ser4-Asn5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
24、NHC-D-Phe3-Ser4-Aph(Hor)5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
25、NHC-D-Pal3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
26、NHC-D-Pal3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
27、NHC-D-Pal3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
28、NHC-D-Pal3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
29、NHC-D-Pal3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
30、NHC-D-Pal3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
31、NHC-D-Pal3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2
32、NHC-D-Pal3-Ser4-Mop5-D-Aph6(n-butyryl) -Leu7-Arg8-Pro9-D-Ala10-NH2
33、NHC-D-Pal3-Ser4-Mop5-D-Aph6(nonanoyl) -Leu7-Arg8-Pro9-D-Ala10-NH2
34、NHC-D-Pal3-Ser4-Mop5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
35、NHC-D-Pal3-Ser4-Mop5-D-Aph6-Leu7-Arg8-Pro9-D-Ala10-NH2
36、NHC-D-Pal3-Ser4-Mop5-D-Gln6-Leu7-Arg8-Pro9-D-Ala10-NH2
37、NHC-D-Pal3-Ser4-Mop5-D-Asn6-Leu7-Arg8-Pro9-D-Ala10-NH2
38、NHC-D-Pal3-Ser4-Mop5-D-Phe(NAM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
39、NHC-D-Pal3-Ser4-Mop5-D-Phe(NNM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
40、NHC-D-Pal3-Ser4-Mop5-D-Phe(NOM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
41、NHC-D-Pal3-Ser4-Aph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
42、NHC-D-Pal3-Ser4-Uph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
43、NHC-D-Pal3-Ser4-Phe(NAM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
44、NHC-D-Pal3-Ser4-Phe(NNM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
45、NHC-D-Pal3-Ser4-Phe(NOM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
46、NHC-D-Pal3-Ser4-Gln5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
47、NHC-D-Pal3-Ser4-Asn5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
48、NHC-D-Pal3-Ser4-Aph(Hor)5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2Wherein NHC is:
Figure B2009101655353D0000141
in the above 48 specific compound formulae, the arabic numerals indicated in the upper right corner of each amino acid abbreviation are used only to indicate the relative position of the amino acid linkage in the specific short peptide compound. For example, for Compound 1, where the NHC-group moiety is equivalent to comprising two amino acids, -D-Phe-in Compound 13- "is the amino acid number 3 corresponding to the short peptide compound 1.
A compound of formula (I) according to any one of the first aspect of the invention, selected from:
1、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
2、NHC-D-Phe3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
3、NHC-D-Phe3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
4、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
5、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
6、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
7、NHC-D-Phe3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2
8、NHC-D-Phe3-Ser4-Mop5-D-Aph6(n-butyryl) -Leu7-Arg8-Pro9-D-Ala10-NH2
9、NHC-D-Phe3-Ser4-Mop5-D-Aph6(nonanoyl) -Leu7-Arg8-Pro9-D-Ala10-NH2
10、NHC-D-Phe3-Ser4-Mop5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
11、NHC-D-Phe3-Ser4-Mop5-D-Aph6-Leu7-Arg8-Pro9-D-Ala10-NH2，
Wherein NHC is:
a compound of formula (I) according to any one of the first aspect of the invention, selected from:
1、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
2、NHC-D-Phe3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
3、NHC-D-Phe3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
4、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
5、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
6、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
7、NHC-D-Phe3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2Wherein NHC is:
Figure B2009101655353D0000161
a compound of formula (I) according to any one of the first aspect of the invention, selected from:
1、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cb)m)-Leu7-Arg8-Pro9-D-Ala10-NH2
2、NHC-D-Pbe3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
3、NHC-D-Phe3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
7、NHC-D-Phe3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2Wherein NHC is:
a second aspect of the present invention relates to a process for the preparation of a compound of formula (I) according to the invention, comprising the steps of:
a) using MBHA resin as a solid phase carrier and BOP/DIEA as a condensing agent, preparing R' -Xaa according to the Boc solid phase polypeptide synthesis operation method of the amino acid sequence of the compound of the formula (I) in any one of the first aspect3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B-MBHA resin, wherein R is
Figure B2009101655353D0000171
b) Boc removal with HCl in dioxane (e.g. 4M HCl/-dioxane solution), neutralization of the reaction;
c) then reacting the reactant of step b) with an excess of carbonyldiimidazole (abbreviated as CDI) until ninhydrin detection is negative;
d) adding DIEA/DCM, reacting at 10-50 deg.C (for example, room temperature), washing the resin with methanol and/or DCM;
e) placing the resin obtained in the step d) into a reactor of an HF cutting instrument, adding anisole, vacuumizing the HF cutting instrument, cooling the reactor by liquid nitrogen, adding liquid HF, reacting at-10 to 10 ℃ (for example, at about 0 ℃), pumping off HF by an oil pump, adding frozen anhydrous ether to precipitate a solid, transferring the suspension into a sand core funnel, washing with a small amount of cooled anhydrous ether for three times, washing with an acetic acid aqueous solution (for example, 10%) until the resins are not adhered to each other, collecting a washing solution, and drying to obtain the resin composition,
wherein, X, Z, B, Xaa3、Xaa5、Xaa6、Xaa7And Xaa8Is as defined for the compound of formula (I) according to any one of the first aspect of the invention.
The method according to the second aspect of the invention, wherein the Boc solid phase polypeptide synthesis protocol described in step a) is described in the literature (e.g. huang dade, chen chang qing, polypeptide synthesis, scientific press, 1985).
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of formula (I) as described in any one of the first aspects of the invention, and optionally a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, the invention provides the use of a compound of formula (I) as described in any one of the first aspects of the invention in the manufacture of a medicament.
In particular, in a fourth aspect, the present invention provides the use of a compound of formula (I) as defined in any one of the first aspects of the invention in the manufacture of a medicament for antagonising Luteinizing Hormone Releasing Hormone (LHRH).
The fourth aspect of the present invention also provides the use of a compound of formula (I) as defined in any one of the first aspects of the present invention in the manufacture of a medicament for antagonising the Luteinizing Hormone Releasing Hormone (LHRH) receptor.
The fourth aspect of the present invention also provides the use of a compound of formula (I) according to any one of the first aspect of the present invention in the manufacture of a medicament for inhibiting the secretion of gonadotropins, such as Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH), by the pituitary.
The fourth aspect of the present invention also provides the use of a compound of formula (I) as described in any one of the first aspects of the present invention in the manufacture of a medicament for use in inhibiting secretion of a steroid hormone (e.g. an estrogen, a progestin and/or a testosterone) from the gonads.
The fourth aspect of the present invention also provides the use of a compound of formula (I) as described in any one of the first aspect of the present invention in the manufacture of a medicament for the treatment and/or prophylaxis of sex hormone related diseases (such as sex hormone related cancers, e.g. prostate cancer, endometrial cancer, breast cancer) or other sex hormone dependent diseases or conditions, or for contraception.
The fourth aspect of the present invention also provides the use of a compound of formula (I) as defined in any one of the first aspects of the present invention in the manufacture of a medicament for reducing histamine release, anti-inflammatory, or anti-allergic response.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine, and iodine.
The term "hydrocarbyl" as used herein includes alkyl, alkenyl and alkynyl groups. These alkyl, alkenyl and alkynyl groups have the indicated number of carbon atoms and may be straight-chain or may be branched.
The term "stereoisomers of decapeptide derivatives of formula (I)" as used herein is meant to include the corresponding D-or L-configuration thereof.
In the compounds of the formula (I) according to the invention, in which the radical moiety R has 2 chiral carbon atoms, they may, independently of one another, be in the D-or L-configuration; preferably, they are both in the D-configuration.
Unless otherwise indicated, terms used in the present application have the following meanings.
"acyl" refers to H-CO-or alkyl-CO-, wherein the alkyl is as described herein.
"acylamino" is acyl-NH-wherein acyl is as defined herein.
"alkoxycarbonyl" refers to an alkyl-O-CO-group, wherein the alkyl is as described herein.
Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
Unless otherwise specified, "alkyl" refers to an aliphatic hydrocarbon group having the specified number of carbon atoms in the chain, which may be straight or branched, particularly from about 1 to about 15 carbon atoms, which is optionally substituted with one or more halogen atoms. Particularly alkyl groups having from 1 to about 6 carbon atoms, for example from 1 to 4 carbon atoms. "lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means an aliphatic hydrocarbon group having from 1 to about 4 carbon atoms in the chain which may be straight or branched, unless otherwise specified. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl, and dodecyl. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl. The alkyl group can also be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1, 2, 3 or 41-C4Alkyl or C1-C4Alkoxy or C1-C4And (3) substituent substitution of alkylthio.
"alkenyl" means a straight or branched chain aliphatic hydrocarbon group containing a carbon-carbon double bond with the indicated number of carbon atoms in the chain, particularly from about 2 to about 15 carbon atoms. Alkenyl groups having from 2 to about 12 carbon atoms in the chain are preferred; and more preferably from 2 to about 6 carbon atoms in the chain (e.g., from 2 to 4 carbon atoms). "branched" as used herein and throughout this text means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight chain; by which is meant a linear alkenyl chain. "lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butylalkenyl, isobutenyl, 3-methylbut-2-enyl, n-pentylenyl, heptenyl, octenyl, cyclohexylbutylalkenyl, and decylalkenyl. Alkenyl may be substituted with 1, 2, 3 or 4 substituents independently selected from halogen, nitro, amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Alkoxy or C1-C4And (3) substituent substitution of alkylthio.
"alkoxy" refers to an alkyl-O-group, wherein the alkyl is as described herein. Examples of alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptyloxy.
"alkylthio" refers to an alkyl-S-group, wherein the alkyl is as described herein.
"alkenyloxy" refers to an alkenyl-O-group, wherein alkenyl is as defined above. Exemplary alkenyloxy groups include allyloxy.
"alkenylthio" refers to an alkenyl-S-group, wherein alkenyl is as defined above.
"halogen" includes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine, more preferably fluorine and chlorine, still more preferably chlorine.
"alkynyl" refers to an aliphatic hydrocarbon group having the indicated number of carbon atoms in the chain, particularly from about 2 to about 15 carbon atoms, containing a carbon-carbon triple bond, which may also be straight or branched. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably from 2 to about 6 carbon atoms in the chain (e.g., from 2 to 4 carbon atoms). Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, 3-methylbut-2-ynyl, and n-pentynyl. Alkynyl can be independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C by 1, 2, 3 or 41-C4Alkyl or C1-C4Alkoxy or C1-C4Substituent substitution of alkylthio
"aroyl" refers to an aryl-CO-group, wherein the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1-and 2-naphthoyl.
"aroylamino" is an aroyl-NH-group, wherein aroyl is as defined above.
"aryl" as a group or component of a group represents: (i) an optionally substituted monocyclic or polycyclic aromatic carbon ring portion of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated polycyclic aromatic carbon ring portion wherein the aryl and cycloalkyl or cycloalkenyl are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl, or indanyl ring. Unless otherwise defined, an aryl group can be substituted with one or more (e.g., 2, 3, 4, 5) aryl substituents, which can be the same or different, where "aryl substituent" includes, for example, acyl, amido, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkoxy, arylalkoxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxyl (or acid bioisostere, etc.), cyano, halogen, heteroaroyl, heteroaryl, heteroarylalkoxy, heteroaroylamino, heteroaryloxy, hydroxyl, nitro, trifluoromethyl, alkyl, e.g., selected from halo, amino, heteroaryloxy, hydroxyl, nitro, trifluoromethyl, alkyl, and the likeElement, nitro, cyano, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylthio radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, carboxyl, C1-C4Alkoxycarbonyl, amino, C1-C4Alkylamino radical, C1-C4Dialkylamino or C1-C4An alkylcarbonylamino group. The groups in the "aryl substituents" have the definitions given herein.
"arylalkoxy" refers to an arylalkyl-O-group, wherein the arylalkyl group is as described above. Exemplary arylalkoxy groups include benzyloxy and 1-or 2-naphthylmethoxy.
"arylalkylthio" refers to an arylalkyl-S-group wherein the arylalkyl group is as described above. An exemplary arylalkylthio group is benzylthio.
"aryloxy" refers to an aryl-O-group, wherein aryl is as described above. Exemplary aryloxy groups include phenoxy and naphthoxy, each of which is optionally substituted.
"cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having the indicated number of carbon atoms, particularly from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl can be substituted by 1, 2, 3 or 4 independently selected from halogen, nitro, amino, hydroxy, carboxy, C1-C4Alkyl or C1-C4Substituent of alkoxy.
"cycloalkyl" means a saturated monocyclic or bicyclic ring system having the indicated number of carbon atoms, particularly from about 3 to about 10 carbon atoms, optionally substituted with oxygen. Exemplary monocyclic cycloalkyl rings include C3-8Cycloalkyl rings, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl may be substituted with 1, 2, 3 or 4 substituents independently selected from halogen, nitro, amino, hydroxy, carboxy, C1-C4Alkyl orC1-C4Substituent of alkoxy.
Heterocyclyl is a compound having one or more (e.g. 2, 3, 4, 5) heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S). The heterocyclyl group may in particular be aromatic (i.e. heteroaryl), saturated or partially saturated. Preferred monocyclic heterocyclic groups of the present invention include 5-and 6-membered monocyclic heterocyclic groups. These heterocycles and heteroaromatics may furthermore be substituted by the following groups: halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, sulfanyl, alkylamino or phenyl.
Examples of preferred aromatic 5-or 6-membered heterocyclic groups of the present invention include 1, 3, 2, 4-or 1, 3, 4, 5-di
Figure B2009101655353D0000221
Oxadiazolyl and oxadiazolylTriazinyl, di
Figure B2009101655353D0000223
Ash radical, 1, 2, 3-, 1, 2, 4-, 1, 3, 2-or 1, 3, 4-di
Figure B2009101655353D0000224
Azolyl, 1, 3, 2, 4-or 1, 3, 4, 5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1, 2, 3-dithiazolyl, 2-or 3-furyl, furazanyl, 1-, 2-or 4-imidazolyl, isoindolyl, isothiazol-3-, -4-or-5-yl, isothiazolyl
Figure B2009101655353D0000225
Oxazole-3-, -4-or-5-yl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-or 1, 3, 4-
Figure B2009101655353D0000226
Diazol-3-, -4-or-5-yl,
Figure B2009101655353D0000227
Tetrazine group,
Figure B2009101655353D0000228
Triazinyl, 1, 2, 3, 4-or 1, 2, 3, 5-A triazolyl group,
Figure B2009101655353D00002210
Oxazol-2-, -4-or-5-yl, 2-or 3-pyrazinyl, 1-, 3-or 4-pyrazolyl, 3-or 4-pyridazinyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidinyl, 1-, 2-or 3-pyrrolyl, 1, 2, 3, 4-or 2, 1, 3, 4-tetrazolyl, thiadiazol-3-, -4-or-5-yl, thiazol-2-, -4-or-5-yl, 2-or 3-thienyl, 1, 2, 3-, 1, 2, 4-or 1, 3, 5-triazinyl, and 1, 2, 3-, (meth) acrylic acid ester, 1, 2, 4-, 2, 1, 3-or 4, 1, 2-triazolyl. Most preferred aromatic heterocyclic groups for use herein include furan-2-yl, furan-3-yl, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isoheterocyclylAzolyl, 1-, 2-or 3-pyridyl, and 1-or 2-thienyl.
Examples of preferred saturated or partially saturated 5-or 6-membered heterocyclic groups of the present invention include 1, 3, 5, 6, 2-bis
Figure B2009101655353D00002212
Diazinyl, 1, 2, 3, 4, 5-or 1, 2, 3, 5, 4-bisOxadiazolyl and oxadiazolyl
Figure B2009101655353D00002214
Alkyl, 1, 3-dioxolanenyl, 1, 3, 5, 6, 2-dithiadiazinyl, 1, 2, 3, 4, 5-or 1, 2, 3, 5, 4-dithiadiazolyl, 2-isoimidazolyl, isopyrrolyl, isotetrazolyl, 1, 2, 3-or 1, 2, 4-isotriazolyl, morpholinyl, heterocycloalipentadienyl, heterocycloagularyl, heterocycloazolyl, heterocycloa,Diazinyl, 1, 2, 4-, 1, 2, 6-, 1, 3, 2-, 1, 3, 6-or 1, 4, 2-
Figure B2009101655353D00002216
Oxazinyl, piperazinyl, homopiperazinyl, piperidinyl, 1, 2-, 1, 3-, or 1, 4-pyranyl, and 1, 2, 3-pyrrolidinyl.
"heterocycloalkyl" means: (i) cycloalkyl of about 3 to 7 membered ring containing one or more heteroatoms or selected from O, S and NR1R2And may be optionally substituted with oxygen; (ii) partially saturated polycyclic heteroatom-containing carbocyclic moieties in which the aryl (or heteroaryl) rings are each optionally substituted with one or more "aryl substituents" and the heterocycloalkyl groups are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl, and pyridindolinyl).
The use of the parenthesis "()" in the context of a group of the present invention, such as that used in "Aph (nonanoyl)", where the content within the parenthesis does not indicate further description of the content outside the parenthesis, but rather indicates that the group within the parenthesis is attached to the portion outside the parenthesis, such as the aforementioned "Aph (nonanoyl)" indicates "4-nonanoyl-aminophenylalanine".
The preparation of the compound adopts a solid-phase synthesis method, MBHA resin is used as a carrier, a Boc-protection strategy, DCC/HOBT or BOP/DIEA is used as a condensation reagent, HCl/dioxane is used as a deprotection reagent, and the decapeptide derivative is cut from the MBHA resin by liquid HF after the reaction.
According to the present invention, the compounds of formula (I) and stereoisomers and physiologically acceptable salts thereof not only show good effects in animal antiandrogen secretion experiments, but also show low histamine release amounts in vitro assays, and thus can be used as hormonal agents for animals, preferably for mammals, especially humans.
The present invention therefore also relates to pharmaceutical compositions containing as active ingredient an effective dose of at least one compound of formula (I) and/or its stereoisomers or physiologically acceptable salts thereof, in association with customary pharmaceutical excipients or adjuvants, i.e. pharmaceutically acceptable excipients or adjuvants. As used herein, "conventional pharmaceutical excipients or adjuvants" include any and all solvents, dispersion media, coatings, antibacterial or antifungal agents, isotonic and sustained release agents, and similar physiologically compatible preparations suitable for intravenous, intramuscular, subcutaneous, or other modes of administration. Depending on the mode of administration, the active compound may be coated to protect the compound from inactivation by acids or other natural conditions.
The term "physiologically acceptable salt" or "physiologically nontoxic salt" as used herein refers to a salt or a combination thereof which retains the desired physiological activity of the parent compound without any unexpected toxic or side effects. For example: hydrochloride, hydrobromide, sulfate, phosphate, nitrate, and acetate, oxalate, tartrate, succinate, malate, benzoate, pamoate, alginate, methanesulfonate, naphthalenesulfonate, and the like. Depending on the cation contained in the salt, it may in turn be: inorganic salts such as potassium salt, lithium salt, zinc salt, copper salt, barium salt, bismuth salt, calcium salt, and organic salts such as trialkylammonium salt.
The compound of formula (I) and its stereoisomers or pharmaceutical compositions containing it of the present invention may be administered in any known manner, such as orally, intramuscularly, subcutaneously, etc., in dosage forms such as tablets, capsules, buccal tablets, chewable tablets, elixirs, suspensions, transdermal agents, microencapsulated formulations, implants, syrups, etc. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to formulate a unit dosage form into a tablet, a wide variety of biodegradable or biocompatible carriers well known in the art can be used. As examples of the carrier, there may be mentioned saline-based and various aqueous buffer solutions, ethanol or other polyhydric alcohols, liposomes, polylactic acid, vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and the like.
The dosage of the compounds of formula (I) and stereoisomers thereof of the present invention will depend upon a variety of factors such as the nature and severity of the condition to be prevented or treated, the sex, age, weight, sensitivity and individual response of the patient or animal, the particular compound employed, the route of administration, the number of administrations and the therapeutic effect desired. The above dosage may be administered in a single dosage form or divided into several, e.g., two, three, four dosage forms. The single maximum dose will generally not exceed 30mg/Kg body weight, for example 0.0001 to 30mg/Kg, for example 0.0005 to 20mg/Kg, for example 0.001 to 10mg/Kg, for example 0.005 to 5mg/Kg, for example 0.01 to 5mg/Kg, for example 0.05 to 2 mg/Kg. However, in some cases, a single dose of 30mg/Kg body weight or more, or 0.0001mg/Kg or less, may also be used.
The present inventors have found that the compounds of formula (I) having the moiety R of the group of the present invention have a good biological activity of inhibiting testosterone release in rats, whereas the octapeptide fragment not comprising the R group has no detectable biological activity of inhibiting testosterone release in rats.
The abbreviations used in the present invention have the following meanings:
Figure B2009101655353D0000251
NHC is:
the acetyl group Ac has a function of,
Acc5alpha-aminocyclopentylcarboxylic acid,
Acc6alpha-aminocyclohexyl-carboxylic acid,
ala-alanine, which is a basic amino acid of the peptide,
amp 4-aminomethyl-phenylalanine,
the amino acid sequence of Arg and arginine,
aph 4-aminophenylalanine, or a pharmaceutically acceptable salt thereof,
aph (Ac) 4-acetamidophenylalanine,
aph (DME) 4- (N, N-dimethyl) -aminophenylalanine,
aph (heptanoyl) 4-heptanoyl-aminophenylalanine,
aph (lauryl) 4-lauroyl-aminophenylalanine,
aph (palmityl) 4-palmitoyl-aminophenylalanine,
aph (butyryl) 4-butyryl-aminophenylalanine,
aph (nicotinoyl) 4-nicotinoyl-aminophenylalanine,
aph (nonanoyl) 4-nonanoyl-aminophenylalanine,
uph (diethyl) 4- (N, N-diethyl-ureido) phenylalanine,
uph (di-N-propyl) 4- (N, N-N-propyl-ureido) phenylalanine,
aph (piperidinyl-CO) 4- (piperidinecarboxamido) phenylalanine,
aph (morpholinyl-CO) 4- (morpholinocarboxamido) phenylalanine,
uph (diisopropyl) 4- (N, N-diisopropyl ureido) phenylalanine,
uph (diethyl) 4- (N, N-diethylureido) phenylalanine,
aph (hor) 4-lactamylphenylalanine,
the dosage of Asn-asparagine is the same as that of Asn-asparagine,
an Asp group of aspartic acid, an aspartic acid,
a Boc-t-butyloxycarbonyl group,
BOP benzotriazole-1-oxy-tris (dimethylamino) phosphonium hexafluorophosphate,
the carboxymethyl group of the CAM is a group,
the CEC carboxyl acetyl group is a carboxyl acetyl group,
cpa 4-chlorophenylalanine, which is a pharmaceutically acceptable salt thereof,
the CPC-carboxypropionyl group is shown,
DCC dicyclohexyl carbodiimide (DCC-dicyclohexyl carbodiimide),
the reaction product of DIEA (diethylhexyl Ether) diisopropylethylamine,
(ii) a group of Gln-glutamines,
the glutamic acid of Glu,
HOBt 1-hydroxybenzotriazole,
the isopropyl group of iPr is introduced,
leu-leucine-containing amino acids, and the amino acids,
lys lysine is added to the reaction mixture of lysine and lysine,
phe (COOH) carboxyphenylalanine,
phe (CAM) of the group of carboxymethylphenylalanine,
the amino acid sequence of Ilys-isopropyl lysine,
the amino acid of the Iorn isopropyl ornithine,
the MBHA phenyl amino methyl resin is prepared by the following steps of,
(ii) Mob beta-piperonyl alanine,
the amino acid sequence of the Mop morpholine methyl phenylalanine,
the amino acid Mph of piperonyl alanine,
the content of Nal-naphthylalanine is shown in the specification,
(ii) Pal 3-pyridylalanine,
a Phe-phenylalanine amino acid, a phenylalanine amino acid,
RP-HPLC reversed-phase high performance liquid chromatography,
pro-proline, in the form of a Pro,
a serine having a sequence of Ser (serine),
TEA was added to the triethylamine in the presence of TEA,
the urea-group of Ureido,
uph a source of para-ureido-phenylalanine,
phe (NAM) 4- ((N, N-dicarboxyethyl) aminomethyl) phenylalanine,
Phe(NABm) 4- ((N, N-dibenzyloxycarbonylmethyl) aminomethyl) phenylalanine,
phe (NNM) 4- ((N, N-diaminoylmethyl) aminomethyl) phenylalanine,
Phe(NNtBum) 4- ((N, N-di-tert-butylaminomethyl) aminomethyl) phenylalanine,
phe (NOM) 4- ((N, N-dihydroxyethyl) aminomethyl) phenylalanine,
Phe(NOBm) 4- ((N, N-dibenzyloxyethyl) aminomethyl) phenylalanine.
Detailed Description
The present invention is further illustrated by the following specific examples and experimental examples, but it should be understood that these examples and experimental examples are for illustrative purposes only and are not to be construed as limiting the present invention in any way.
The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.
The solid phase synthesis carrier MBHA resin used in the examples is a product of Tianjin Nankai Synthesis responsibility Co., Ltd; DCC, HOBT, BOP, DIEA and Boc-protected natural amino acids were produced by Gill Biochemical and Chengdu Kaitai New technology, Inc. of Shanghai and Boc-protected unnatural amino acids were provided synthetically in this laboratory except for the description.
Example 1: synthesis of Compound 1
NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
Boc-D-Nal was synthesized using 63mg of MBHA resin (0.04mmol) as a solid phase support and BOP/DIEA as a condensing agent according to the amino acid sequence of the compound by standard Boc solid phase peptide synthesis methods (ref: Huang Vid, Chen Hei Qing, peptide Synthesis, scientific Press, 1985)1-D-Cpa2-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2-MBHA resin.
After the Boc-D-Nal is connected into a peptide chain, removing Boc at the N end by using 4M HCl/Diox, neutralizing, after washing is finished, adding 3 times of excessive CDI, reacting for 0.5h, washing off the excessive CDI by using DCM, detecting condensation effect by ninhydrin, if the reaction is positive and the reaction is carried out again until the reaction is negative, adding 10% DIEA/DCM, reacting for 4h at room temperature, washing the resin by using methanol and DCM, and finishing the reaction.
Putting the peptide resin into a reactor of an HF cutter, adding 1.0mL of anisole, vacuumizing the system of the HF cutter after the peptide resin is installed, cooling the reactor by liquid nitrogen, transferring into about 10mL of liquid HF, and reacting for 40 minutes at 0 ℃. The HF was pumped off with an oil pump, the reactor was removed, frozen anhydrous ether was added to precipitate a solid, and the suspension was transferred to a sand core funnel. Washing with small amount of cooled anhydrous ether for three times, washing with 10% acetic acid water solution until the resins are not adhered to each other, collecting washing solution, and freeze drying to obtain 50.6mg white dry powder with crude peptide yield of 93.5%. Purifying by RP-HPLC to obtain pure product with pure peptide yield of 14.3%. ESI-MS: 1484.6 (theoretical value: 1484.1).
Examples 2 to 48: synthesis of Compounds 2 to 48
Compounds 2-48 were synthesized using a method similar to that of example 1. The structures of compounds 2 to 48 are as described above. The various raw materials used for synthesizing the compounds 2 to 48 are purchased from Ducheng Nuo science and technology Co., Ltd and Nankai Synthesis science and technology Co., Ltd, or synthesized by the present inventors.
The results of the synthesis are summarized in table 1 below:
TABLE 1
Compound No. Crude peptide yield/% Yield of pure peptide% ESI-MS difference
2～10 88.2～95.6 9.8～16.2 0.2～0.6
11～20 89.3～92.5 10.2～15.7 0.3～0.8
21～30 87.8～94.3 9.5～15.1 0.2～0.7
31～50 85.1～94.8 9.4～14.9 0.1～0.7
"ESI-MS difference" means the absolute value of the difference between the theoretical value and the measured value of ESI-MS, namely: ESI-MS difference is | theoretical value-measured value |.
Experimental example 1: experiment of inhibiting testosterone in rats:
weighing animal weight before experiment, collecting blood in venous plexus behind glass capillary ball, separating serum, measuring serum testosterone content by chemiluminescence method, randomly grouping according to testosterone content and weight, collecting 4 animals in each group, injecting compound to be measured 500 μ g once and excessively subcutaneously for 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, collecting blood in venous plexus behind ball, centrifuging at 5000rpm for 8min, and measuring serum testosterone content by chemiluminescence method (Access immunology System chemiluminescence apparatus of Beckman Coulter company, USA). The results are shown in Table 2.
TABLE 2
Compound numberinga Testosterone inhibiting action time (hours)b
2 8-12
3 8-16
7 6-8
1，5 4-6
4 2-4
6 6-8
13～21 Each for 4 to 6 hours
24～33 Each for 4 to 6 hours
42～48 Each for 4 to 6 hours
a: when not specially noted, the medicine is subcutaneously administrated, 500 ug/kg;
b: serum testosterone levels were below 1.5ng/ml for a sustained period.
Under the present experimental conditions, a serum testosterone level of less than 1.5ng/ml is generally considered therapeutically effective, and the duration of the animal in this range of serum testosterone levels generally reflects the duration of the biological activity of the test sample.
As can be seen from the results in Table 2, the compounds of the examples prepared in accordance with the present invention provide serum testosterone levels within the range required for effective treatment.
Furthermore, it is to be noted that serum testosterone levels are strongly related to the various diseases which the compounds of formula (I) according to the invention are able to treat, and it is generally considered that reaching said range of serum testosterone levels under the conditions of the test is useful for the treatment of the various diseases according to the invention. Such as prostate cancer, endometrial cancer, breast cancer, and the like (see, for example, Bernhard Kutscher et al, Angew Chem Int Ed Engl, 1997, 36, 2148-.
Experimental example 2: determination of the ability to promote histamine release from mast cells in the abdominal cavity of rats
The 5 male rats are killed by decapitation and are injected with 15 mL/cold PBS in the abdominal cavity, the abdominal cavity liquid is sucked out to an ice bath centrifuge tube after the abdominal cavity is opened, the centrifugation is carried out for 10 minutes at 1500rpm, the precipitation cells are merged after the repeated washing is carried out once, a proper amount of buffer solution is prepared into single cell suspension, and the number of nucleated cells is counted after the single cell suspension is diluted by 20 times of leukocyte diluent. The cell suspension is added with different sample amounts and incubated at 37 ℃ for 15 minutes, and the reaction is stopped after boiling in ice bath. After centrifugation, the supernatant was collected, the fluorescence intensity was measured by a chemiluminescence apparatus manufactured by BMG corporation at EX340nm, EM460nm, the percentage of histamine release was calculated from the fluorescence intensity, and the EC of each drug was calculated50. The results show that the compounds 1-48 have lower capacity of promoting rat abdominal mast cells to release histamine, so that the compounds can be used as anti-allergic drugs.

Claims (15)

1. A compound of formula (I):
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure F2009101655353C0000011
wherein,
z is selected from H, R1R2N-(CR3R4)t-C(O)-、R1C(O)-、R2O-NR1-C(O)-、R1-、R1OS(O2) -; wherein R is1、R2、R3And R4Independently of each other, may be H, substituted or unsubstituted C with or without carboxyl, amido, phosphate, sulfonyl, or the like1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, substituted or unsubstituted C1-C30Straight or branched alkylamino, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyloxy, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynylthio, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynylamino, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, e.g. C3-C8Cycloalkyl or Cycloalkenyl (CH)2)n-，C3-C8Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-or Y; wherein,
the carboxyl, the amido, the phosphate and the sulfonyl can be one or p and are respectively and independently connected to R1、R2、R3And R4T, n and p may each independently be an integer of 0 to 6, such as 0, 1, 2, 3, 4, or 5;
heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S and the like in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4Alkyl substituent mono-or di-substitutedOr a trisubstituted 4, 5, 6, or 7 membered monocyclic or bicyclic aromatic group, such as phenyl or naphthyl and the like; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like;
y is selected from the following structures (i), (ii), (iii), (iv) or (v):
Figure F2009101655353C0000021
Figure F2009101655353C0000031
each m is independently an integer from 0 to 6, such as 0, 1, 2, 3, or 4;
x is selected from hydrogen or 1-4 substituents independently selected from: halogen (e.g. chloro, fluoro, bromo, iodo), methyl, ethyl, propyl, isopropyl, n-propyl, Ac-, NH2CO-, NTA-, CAM-, NDN-, CEC-, heptanoyl, lauryl, palmityl, butyryl, nicotinoyl, nonanoyl, piperidinyl, morpholinyl;
b is selected from NH2、-OH、-NR19R20、-NHNR19R20(ii) a Wherein R is19And R20Independently of one another, from: h-, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, substituted or unsubstituted C1-C30Straight or branched alkylamino, cycloalkyl or Cycloalkenyl (CH)2)q-, aryl (CH)2)q-, heterocyclic radical (CH)2)q-, or Y, e.g. C3-C8Cycloalkyl or Cycloalkenyl (CH)2)q-，C3-C8Heterocycloalkyl or Cycloalkenyl (CH)2)q-, aryl (CH)2)q-, heterocyclic radical (CH)2)qOr Y, each q is independently an integer from 0 to 6, for example 0, 1, 2, 3, or 4; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S and the like in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like;
Xaa3is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Phe (nam), Phe (nnm), Phe (nom), Aph (ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, gin, Asn, Lys, illys, Orn, ion, Cit, Aph (Hor), Mph, Phe (COOH), Phe (cam), Pal, Aph (lauryl), Aph (palmityl), Aph (butyryl), Aph (nicotinyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), Ilys;
or
Xaa5、Xaa6Or Xaa8The structure is as follows:
Figure F2009101655353C0000041
wherein,
q is selected from H, -NR21R22、-NHC(O)NR21R22、-C(O)NR21R22、-NH-C(O)R23、R43O-NR24-C(O)-、R25R26P(O)-、R27N(R28N)P(O)-、R29O(R30N)P(O)-、R31O(R32O)P(O)-、R33OS(O2)-、R34-or Y;
w is selected from-COOH, -CONH2、-N(iPr)2、-NR35R36、-NHC(NR37)NR38R39、-NHC(O)NR40R41、-NH-C(O)R42Or Q;
r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;
R21-R43independently of one another, from: H. HC (O) -, R1C(O)-、R1R2NC (O) -, wherein R1And R2Each is H, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, or Y, e.g. C3-C30Cycloalkyl or Cycloalkenyl (CH)2)n-，C3-C30Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S, etc. in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or disubstituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4Alkyl substituent mono-or di-substituted, containing 1-5A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group of a heteroatom independently selected from N, O and S, etc., such as pyrrolyl, furanyl, pyridyl, etc.; each n is independently 0, 1, 2, 3, or 4;
Xaa7is Leu, Acc5Or Acc6。
2. A compound of formula (I) according to claim 1, wherein said moiety R has the following configuration:
Figure F2009101655353C0000051
wherein Z and X are as defined in claim 1.
3. The compound of claim 1 of formula (I):
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure F2009101655353C0000061
wherein,
z is H;
x is selected from hydrogen or 1-4 substituents independently selected from: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, n-propyl;
b is selected from NH2、-OH；
Xaa3Is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, Gln, Asn, Lys, Ilys, Orn, Iorn, Cit, Aph (Hor), Mph, Phe (COOH), Phe (CAM), Pal, Aph (lauryl), each independently selected from the group consisting of L and DAph (palmityl), Aph (butyryl), Aph (nicotinoyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (hor), ILys;
or
Xaa5、Xaa6Or Xaa8The structure is as follows:
Figure F2009101655353C0000062
wherein,
q is selected from H, -NR21R22、-NHC(O)NR21R22、-C(O)NR21R22、-NH-C(O)R23、R43O-NR24-C(O)-、R25R26P(O)-、R27N(R28N)P(O)-、R29O(R30N)P(O)-、R31O(R32O)P(O)-、R33OS(O2)-、R34-or Y;
w is selected from-COOH, -CONH2、-N(iPr)2、-NR35R36、-NHC(NR37)NR38R39、-NHC(O)NR40R41、-NH-C(O)R42Or Q;
r is an integer from 0 to 6, such as 0, 1, 2, 3, 4, 5 or 6;
R21-R43independently of one another, from: H. HC (O) -, R1C(O)-、R1R2NC (O) -, wherein R1And R2Each is H, substituted or unsubstituted C1-C30Straight or branched alkyl, substituted or unsubstituted C2-C30Straight or branched alkenyl or alkynyl, substituted or unsubstituted C1-C30Straight or branched alkoxy, substituted or unsubstituted C1-C30Straight or branched alkylthio, cycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-, or Y, e.g. C3-C30Cycloalkyl radicalsOr Cycloalkenyl (CH)2)n-，C3-C30Heterocycloalkyl or Cycloalkenyl (CH)2)n-, aryl (CH)2)n-, heterocyclic radical (CH)2)n-; wherein heterocycloalkyl is a cyclic group having 1 to 5 (preferably 1 to 3) heteroatoms independently selected from N, O, S, etc. in its ring structure; aryl being unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or disubstituted with a substituent for an alkyl group, such as phenyl or naphthyl; the heterocyclic group may be unsubstituted or independently selected from halogen, nitro, carboxyl or C1-C4A 4-, 5-, 6-, or 7-membered monocyclic or bicyclic aromatic group which is mono-or di-substituted with a substituent for alkyl and which contains 1 to 5 heteroatoms independently selected from N, O, S and the like, such as pyrrolyl, furyl, pyridyl and the like; each n is independently 0, 1, 2, 3, or 4;
Xaa7is Leu, Acc5Or Acc6。
4. A compound of formula (I) according to claim 3:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure F2009101655353C0000081
wherein,
z is H;
x is selected from hydrogen or 1-4 substituents independently selected from: chlorine, fluorine, bromine, methyl, ethyl, propyl;
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5、Xaa6and Xaa8Each independently selected from Phe (NAM), Phe (NNM) in form D) Phe (nom), Aph (ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, gin, Ash, Lys, Ilys, Orn, Iorn, ionn, Cit, Aph (Hor), Mph, Phe (COOH), Phe (cam), Pal, Aph (lauryl), Aph (palmityl), Aph (butyryl), Aph (nicotinyl), Aph (nonanoyl), Uph (diethyl), Uph (di-n-propyl), Aph (piperidinyl-CO), Aph (morpholinyl-CO), Uph (diisopropyl), Aph (Hor), Ilys;
Xaa7is Leu, Acc5Or Acc6。
5. A compound of formula (I) according to claim 3:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure F2009101655353C0000091
wherein,
z is H;
x is selected from hydrogen or 1-2 substituents independently selected from: chlorine, fluorine, methyl, ethyl;
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5selected from Phe (NAM), Phe (NNM), Phe (NOM), Aph (Ac), Mop, Phe, Aph, Amp, Uph, Arg, Pro, Glu, Asp, Gln, Asn, Phe (COOH), Phe (CAM), Aph (hor);
Xaa6selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop, D-Pal, D-Pro, D-Amp, D-Phe, D-Arg, D-Glu, D-Asp, D-Phe (COOH), D-Phe (CAM), (CAM), D-Aph (lauryl), D-Aph (palmityl), D-Aph (nicotinoyl), D-Aph (nonanoyl)) D-Uph (diethyl), D-Uph (di-n-propyl), D-Uph (diisopropyl), D-Aph (hor);
Xaa7is Leu, Acc5Or Acc6；
Xaa8Arg, ILys, IOrn, Asn, Gln.
6. A compound of formula (I) according to claim 3:
R-Xaa3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B
formula (I)
Or a stereoisomer or physiologically acceptable salt thereof, wherein,
Figure F2009101655353C0000101
b is NH2；
Xaa3Is D-Phe or D-Pal;
Xaa5selected from Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph, Uph, Gln, Asn, Aph (Hor);
Xaa6selected from the group consisting of D-Aph (diethyl-Cbm), D-Aph (piperidinyl-CO), D-Aph (morpholinyl-CO), D-Aph (diisopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (n-butyryl), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Ph e (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop;
Xaa7is Leu;
Xaa8is Arg.
7. A compound of formula (I) according to claim 3, selected from:
1、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
2、NHC-D-Phe3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
3、NHC-D-Phe3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
4、NHC-D-Phe3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
5、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
6、NHC-D-Phe3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
7、NHC-D-Phe3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2
8、NHC-D-Phe3-Ser4-Mop5-D-Aph6(n-butyryl) -Leu7-Arg8-Pro9-D-Ala10-NH2
9、NHC-D-Phe3-Ser4-Mop5-D-Aph6(nonanoyl) -Leu7-Arg8-Pro9-D-Ala10-NH2
10、NHC-D-Phe3-Ser4-Mop5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
11、NHC-D-Phe3-Ser4-Mop5-D-Aph6-Leu7-Arg8-Pro9-D-Ala10-NH2
12、NHC-D-Phe3-Ser4-Mop5-D-Gln6-Leu7-Arg8-Pro9-D-Ala10-NH2
13、NHC-D-Phe3-Ser4-Mop5-D-Asn6-Leu7-Arg8-Pro9-D-Ala10-NH2
14、NHC-D-Phe3-Ser4-Mop5-D-Phe(NAM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
15、NHC-D-Phe3-Ser4-Mop5-D-Phe(NNM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
16、NHC-D-Phe3-Ser4-Mop5-D-Phe(NOM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
17、NHC-D-Phe3-Ser4-Aph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
18、NHC-D-Phe3-Ser4-Uph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
19、NHC-D-Phe3-Ser4-Phe(NAM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
20、NHC-D-Phe3-Ser4-Phe(NNM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
21、ＮHC-D-Phe3-Ser4-Phe(NOM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
22、NHC-D-Phe3-Ser4-Gln5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
23、NHC-D-Phe3-Ser4-Asn5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
24、NHC-D-Phe3-Ser4-Aph(Hor)5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
25、NHC-D-Pal3-Ser4-Mop5-D-Aph6(diethyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
26、NHC-D-Pal3-Ser4-Mop5-D-Aph6(piperidinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
27、NHC-D-Pal3-Ser4-Mop5-D-Aph6(morpholinyl-CO) -Leu7-Arg8-Pro9-D-Ala10-NH2
28、NHC-D-Pal3-Ser4-Mop5-D-Aph6(diisopropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
29、NHC-D-Pal3-Ser4-Mop5-D-Aph6(dipropyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
30、NHC-D-Pal3-Ser4-Mop5-D-Aph6(dibutyl-Cbm) -Leu7-Arg8-Pro9-D-Ala10-NH2
31、NHC-D-Pal3-Ser4-Mop5-D-Aph6(Ac)-Leu7-Arg8-Pro9-D-Ala10-NH2
32、NHC-D-Pal3-Ser4-Mop5-D-Aph6(n-butyryl) -Leu7-Arg8-Pro9-D-Ala10-NH2
33、NHC-D-Pal3-Ser4-Mop5-D-Aph6(nonanoyl) -Leu7-Arg8-Pro9-D-Ala10-NH2
34、NHC-D-Pal3-Ser4-Mop5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2
35、NHC-D-Pal3s-Ser4-Mop5-D-Aph6-Leu7-Arg8-Pro9-D-Ala10-NH2
36、NHC-D-Pal3-Ser4-Mop5-D-Gln6-Leu7-Arg8-Pro9-D-Ala10-NH2
37、NHC-D-Pal3-Ser4-Mop5-D-Asn6-Leu7-Arg8-Pro9-D-Ala10-NH2
38、NHC-D-Pal3-Ser4-Mop5-D-Phe(NAM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
39、NHC-D-Pal3-Ser4-Mop5-D-Phe(NNM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
40、NHC-D-Pal3-Ser4-Mop5-D-Phe(NOM)6-Leu7-Arg8-Pro9-D-Ala10-NH2
41、NHC-D-Pal3-Ser4-Aph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
42、NHC-D-Pal3-Ser4-Uph5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
43、NHC-D-Pal3-Ser4-Phe(NAM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
44、NHC-D-Pal3-Ser4-Phe(NNM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
45、NHC-D-Pal3-Ser4-Phe(NOM)5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
46、NHC-D-Pal3-Ser4-Gln5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
47、NHC-D-Pal3-Ser4-Asn5-D-Mop6-Leu7-Arg8-Pro9-D-Ala10-NH2
48、NHC-D-Pal3-Ser4-Aph(Hor)5-D-Uph6-Leu7-Arg8-Pro9-D-Ala10-NH2Wherein NHC is:
Figure F2009101655353C0000121
8. a process for the preparation of a compound of formula (I) according to any one of claims 1 to 7, comprising the steps of:
a) using MBHA resin as a solid phase carrier and BOP/DIEA as a condensing agent, preparing R' -Xaa according to the Boc solid phase polypeptide synthesis operation method of the amino acid sequence of the compound of the formula (I) in any one of the first aspect3-Ser-Xaa5-Xaa6-Xaa7-Xaa8-Pro-D-Ala-B-MBHA resin, wherein R is
Figure F2009101655353C0000131
b) Boc removal with HCl in dioxane (e.g. 4M HCl/dioxane solution), neutralization of the reaction;
c) then reacting the reactant of step b) with an excess of carbonyldiimidazole (abbreviated as CDI) until ninhydrin detection is negative;
d) adding DIEA/DCM, reacting at 10-50 deg.C (for example, room temperature), washing the resin with methanol and/or DCM;
e) placing the resin obtained in the step d) into a reactor of an HF cutting instrument, adding anisole, vacuumizing the HF cutting instrument, cooling the reactor by liquid nitrogen, adding liquid HF, reacting at-10 to 10 ℃ (for example, at about 0 ℃), pumping off HF by an oil pump, adding frozen anhydrous ether to precipitate a solid, transferring the suspension into a sand core funnel, washing with a small amount of cooled anhydrous ether for three times, washing with an acetic acid aqueous solution (for example, 10%) until the resins are not adhered to each other, collecting a washing solution, and drying to obtain the resin composition,
wherein, X, Z, B, Xaa3、Xaa5、Xaa6、Xaa7And Xaa8As defined for compounds of formula (I) as claimed in any one of claims 1 to 7.
9. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 7 and optionally a pharmaceutically acceptable carrier or excipient.
10. Use of a compound of formula (I) according to any one of claims 1 to 7 in the manufacture of a medicament for antagonising Luteinizing Hormone Releasing Hormone (LHRH).
11. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 in the manufacture of a medicament for antagonising the Luteinizing Hormone Releasing Hormone (LHRH) receptor.
12. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 in the manufacture of a medicament for inhibiting the secretion of gonadotropins (e.g. Luteinizing Hormone (LH) and/or Follicle Stimulating Hormone (FSH)) by the pituitary.
13. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 in the manufacture of a medicament for inhibiting the secretion of steroid hormones (such as oestrogen, progestogen and/or testosterone) from the gonads.
14. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 in the manufacture of a medicament for the treatment and/or prophylaxis of sex hormone related diseases (such as sex hormone related cancers, such as prostate, endometrial, breast cancer) or other sex hormone dependent diseases or conditions, or for contraception.
15. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 in the manufacture of a medicament for reducing histamine release, anti-inflammatory, or anti-allergic response.
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