CN101987865B - Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure - Google Patents
Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure Download PDFInfo
- Publication number
- CN101987865B CN101987865B CN200910165535.3A CN200910165535A CN101987865B CN 101987865 B CN101987865 B CN 101987865B CN 200910165535 A CN200910165535 A CN 200910165535A CN 101987865 B CN101987865 B CN 101987865B
- Authority
- CN
- China
- Prior art keywords
- ala
- pro
- nhc
- ser
- arg
- 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
- 0 CC(C)(C)OC(N(*)C(Cc1cc2ccccc2cc1)C(NC(Cc1ccccc1)C(C)=O)=O)=O Chemical compound CC(C)(C)OC(N(*)C(Cc1cc2ccccc2cc1)C(NC(Cc1ccccc1)C(C)=O)=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
- C07D233/78—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/34—Gestagens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Biochemistry (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Gynecology & Obstetrics (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
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
Technical field
The present invention relates to have luteinizing hormone-releasing hormone receptor antagonist activity, there is the decapeptide derivative that suppresses the effect of pituitary gonad-stimulating hormone, the effect of inhibition glandular secretion steroid hormone, its preparation method, containing their pharmaceutical composition and their purposes in treatment prostate cancer, carcinoma of endometrium, sexual hormoue dependence relative disease, the contraception etc. relevant with reproduction.
Background technology
Luteinizing hormone-releasing hormone (below can referred to as LHRH) is one of peptide hormone of being secreted by hypothalamus, its Main Function is to promote that hypophysis synthesizes and discharges lutropin (LH) and follicular stimulating hormone (FSH), excites Development in Puberty and regulates reproduction, fertility and sexual hormoue correlated process.LHRH is made up of ten amino-acid residues, and C-end contains amide structure.The primary structure of LHRH is as follows:
p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
Lhrh antagonist, therefore can be for sexual hormoue relative disease as the treatment of the diseases such as prostate cancer by the release of blocking-up LHRH effect and then inhibition LH.Compared with agonist, lhrh antagonist have effective speed fast, without after upper punch phenomenon, drug withdrawal, recover fast, to advantages such as the horizontal controllability of serum androgen are strong.Can expect, the curative effect of lhrh antagonist treatment prostate cancer is better than agonist, is more easily accepted by patient, has larger application prospect than agonist.
Although the lhrh antagonist of developing is at present existing a lot, as a kind of peptide medicament, great majority still exist bioavailability low, and Half-life in vivo is short, and the high weak point of histamine release amount has limited lhrh antagonist application clinically.In addition, similar to other peptide medicament, lhrh antagonist medicine is also difficult to pass through oral absorption.The lhrh antagonist medicine of listing is all non-oral administration at present.
Therefore, still wish to provide the effective lhrh antagonist with novel structure.
Summary of the invention
The object of this invention is to provide the effective lhrh antagonist with novel structure.The inventor has now found that a kind of decapeptide derivative after deliberation, and it is with following formula (I) compound:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or its salt without physiology toxicity, not only thering is action time and lower histamine release side effect in good LHRH antagonistic activity, longer body, part of compounds even also has Orally active.Therefore formula (I) decapeptide derivative or its steric isomer can be used as the purposes of medicine for prostate cancer, carcinoma of endometrium, contraception and other sexual hormoue dependence treating correlative diseases.For this reason, another object of the present invention is to provide the purposes of described formula (I) compound, and the preparation method of described formula (I) compound.
For this reason, first aspect present invention provides formula (I) compound:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or the acceptable salt of physiology, wherein,
wherein,
Z is selected from H, R
1r
2n-(CR
3r
4)
t-C (O)-, R
1c (O)-, R
2o-NR
1-C (O)-, R
1-, R
1oS (O
2)-; Wherein, R
1, R
2, R
3and R
4can be respectively independently of each other H, contain or do not contain replacement or the unsubstituted C of carboxyl, amide group, phosphate, alkylsulfonyl etc.
1-C
30straight chain or branched-chain alkyl, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl, replace or unsubstituted C
1-C
30straight chain or branched alkoxy, replace or unsubstituted C
1-C
30straight chain or branched alkane sulfenyl, replace or unsubstituted C
1-C
30straight chain or branched alkane amido, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyloxy base, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl sulfenyl, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl amido, cycloalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-, 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,
Carboxyl, amide group, phosphate, alkylsulfonyl can be one or p and be connected to independently respectively R
1, R
2, R
3and R
4any one carbon atom on, t, n and p can be respectively independently for the integer of 0-6 is for example 0,1,2,3,4, or 5;
Heterocyclylalkyl is in its ring structure, to contain 1-5 (preferably 1-3) heteroatomic cyclic group independently selected from N, O and S etc.; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4the substituting group of alkyl is monosubstituted or two replace 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 of alkyl is monosubstituted or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or the Bicyclic group independently selected from N, O and S etc., as pyrryl, and furyl, pyridyl etc.;
Y is selected from following structure (i), (ii), (iii), (iv) or (v):
Each m is the integer of 0-6 independently, for example, be 0,1,2,3, or 4;
X is selected from hydrogen or 1～4 independently selected from following substituting group: halogen (for example chlorine, fluorine, bromine, iodine), methyl, ethyl, propyl group, sec.-propyl, n-propyl, Ac-, NH
2cO-, NTA-, CAM-, NDN-, CEC-, oenanthyl, lauryl, palmityl, butyryl radicals, nicotinoyl, nonanoyl, piperidyl, morpholinyl;
B is selected from NH
2,-OH ,-NR
19r
20,-NHNR
19r
20; Wherein R
19and R
20be selected from independently of each other: H-, replaces or unsubstituted C
1-C
30straight chain or branched-chain alkyl, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl, replace or unsubstituted C
1-C
30straight chain or branched alkoxy, replace or unsubstituted C
1-C
30straight chain or branched alkane sulfenyl, replace or unsubstituted C
1-C
30straight chain or branched alkane amido, cycloalkyl or cycloalkenyl (CH
2)
q-, aryl (CH
2)
q-, heterocyclic radical (CH
2)
q-, or Y, for example C
3-C
8cycloalkyl or cycloalkenyl (CH
2)
q-, C
3-C
8heterocyclylalkyl or cycloalkenyl (CH
2)
q-, aryl (CH
2)
q-, heterocyclic radical (CH
2)
q-, or Y, each q is the integer of 0-6 independently, for example, be 0,1,2,3, or 4; Wherein, Heterocyclylalkyl is in its ring structure, to contain 1-5 (preferably 1-3) heteroatomic cyclic group independently selected from N, O and S etc.; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4the substituting group of alkyl monosubstituted or dibasic 4,5,6 or 7 yuan of monocycles or Bicyclic group, as phenyl or naphthyl etc.; Heterocyclic radical can be unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4the substituting group of alkyl is monosubstituted or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or the Bicyclic group independently selected from N, O and S etc., as pyrryl, and furyl, pyridyl etc.;
Xaa
3for D-Phe or D-Pal;
Xaa
5, Xaa
6and Xaa
8be selected from independently of one another the Phe (NAM) of L or D type, 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), Aph (palmityl), Aph (butyryl radicals), Aph (nicotinoyl), Aph (nonanoyl), Uph (diethyl), Uph (diη-propyl), Aph (piperidyl-CO), Aph (morpholinyl-CO), Uph (di-isopropyl), Aph (Hor), ILys,
Or
Xaa
5, Xaa
6or Xaa
8for following structure:
II (D-or L-type) III (D-or L-type)
Wherein,
Q is selected from H ,-NR
21r
22,-NHC (O) NR
21r
22,-C (O) NR
21r
22,-NH-C (O) R
23, R
43o-NR
24-C (O)-, R
25r
26p (O)-, R
27n (R
28n) P (O)-, R
29o (R
30n) P (O)-, R
31o (R
32o) P (O)-, R
33oS (O
2)-, R
34-or Y;
Be selected from-COOH of W ,-CONH
2,-N (iPr)
2,-NR
35r
36,-NHC (NR
37) NR
38r
39,-NHC (O) NR
40r
41,-NH-C (O) R
42, or Q;
R is the integer of 0-6, as 0,1, and 2,3,4,5 or 6;
R
21-R
43be selected from 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
30straight chain or branched-chain alkyl, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl, replace or unsubstituted C
1-C
30straight chain or branched alkoxy, replace or unsubstituted C
1-C
30straight 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
30cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
30heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-; Wherein Heterocyclylalkyl is in its ring structure, to contain 1-5 (preferably 1-3) heteroatomic cyclic group independently selected from N, O and S etc.; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4the substituting group of alkyl monosubstituted 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 of alkyl is monosubstituted or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or the Bicyclic group independently selected from N, O and S etc., as pyrryl, and furyl, pyridyl etc.; Each n is 0,1,2,3 independently, or 4;
Xaa
7for Leu, Acc
5or Acc
6.
According to formula (I) compound described in first aspect present invention any one, wherein said group part R has following configuration:
Wherein, the definition of Z and X is with the definition in formula (I) compound described in first aspect present invention any one.
Formula (I) compound according to described in first aspect present invention any one:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or the acceptable salt of physiology, wherein,
wherein,
Z is H;
X is selected from hydrogen or 1～4 independently selected from following substituting group: chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, n-propyl;
B is selected from NH
2,-OH;
Xaa
3for D-Phe or D-Pal;
Xaa
5, Xaa
6and Xaa
8be selected from independently of one another the Phe (NAM) of L or D type, 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), Aph (palmityl), Aph (butyryl radicals), Aph (nicotinoyl), Aph (nonanoyl), Uph (diethyl), Uph (diη-propyl), Aph (piperidyl-CO), Aph (morpholinyl-CO), Uph (di-isopropyl), Aph (Hor), ILys,
Or
Xaa
5, Xaa
6or Xaa
8for following structure:
II (D-or L-type) III (D-or L-type)
Wherein,
Q is selected from H ,-NR
21r
22,-NHC (O) NR
21r
22,-C (O) NR
21r
22,-NH-C (O) R
23, R
43o-NR
24-C (O)-, R
25r
26p (O)-, R
27n (R
28n) P (O)-, R
29o (R
30n) P (O)-, R
31o (R
32o) P (O)-, R
33oS (O
2)-, R
34-or Y;
Be selected from-COOH of W ,-CONH
2,-N (iPr)
2,-NR
35r
36,-NHC (NR
37) NR
38r
39,-NHC (O) NR
40r
41,-NH-C (O) R
42, or Q;
R is the integer of 0-6, as 0,1, and 2,3,4,5 or 6;
R
21-R
43be selected from 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
30straight chain or branched-chain alkyl, replace or unsubstituted C
2-C
30straight chain or branched-chain alkenyl or alkynyl, replace or unsubstituted C
1-C
30straight chain or branched alkoxy, replace or unsubstituted C
1-C
30straight 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
30cycloalkyl or cycloalkenyl (CH
2)
n-, C
3-C
30heterocyclylalkyl or cycloalkenyl (CH
2)
n-, aryl (CH
2)
n-, heterocyclic radical (CH
2)
n-; Wherein Heterocyclylalkyl is in its ring structure, to contain 1-5 (preferably 1-3) heteroatomic cyclic group independently selected from N, O and S etc.; Aryl is unsubstituted or is independently selected from halogen, nitro, carboxyl or C
1-C
4the substituting group of alkyl monosubstituted 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 of alkyl is monosubstituted or dibasic, contain 1-5 heteroatomic 4,5,6 or 7 yuan of monocycles or the Bicyclic group independently selected from N, O and S etc., as pyrryl, and furyl, pyridyl etc.; Each n is 0,1,2,3 independently, or 4;
Xaa
7for Leu, Acc
5or Acc
6.
Formula (I) compound according to described in first aspect present invention any one:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or the acceptable salt of physiology, wherein,
wherein,
Z is H;
X is selected from hydrogen or 1～4 independently selected from following substituting group: chlorine, fluorine, bromine, methyl, ethyl, propyl group;
B is NH
2;
Xaa
3for D-Phe or D-Pal;
Xaa
5, Xaa
6and Xaa
8be selected from independently of one another the Phe (NAM) of D type, 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), Aph (palmityl), Aph (butyryl radicals), Aph (nicotinoyl), Aph (nonanoyl), Uph (diethyl), Uph (diη-propyl), Aph (piperidyl-CO), Aph (morpholinyl-CO), Uph (di-isopropyl), Aph (Hor), ILys,
Xaa
7for Leu, Acc
5or Acc
6.
Formula (I) compound according to described in first aspect present invention any one:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or the acceptable salt of physiology, wherein,
wherein,
Z is H;
X is selected from hydrogen or 1～2 independently selected from following substituting group: chlorine, fluorine, methyl, ethyl;
B is NH
2;
Xaa
3for D-Phe or D-Pal;
Xaa
5be selected 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);
Xaa
6be selected from D-Aph (diethyl-Cbm), D-Aph (piperidyl-CO), D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (di-isopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (positive butyryl radicals), 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 (diη-propyl), D-Uph (di-isopropyl), D-Aph (Hor),
Xaa
7for Leu, Acc
5or Acc
6;
Xaa
8for Arg, ILys, IOrn, Asn, Gln.
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein R is
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein B is NH
2.
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein Xaa
3for D-Phe or D-Pal.
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein Xaa
5be selected from Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph, Uph, Gln, Asn, Aph (Hor).
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein Xaa
6be selected from D-Aph (diethyl-Cbm), D-Aph (piperidyl-CO), D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (di-isopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (positive butyryl radicals), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop.
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein Xaa
7for Leu.
In an embodiment of the formula described in first aspect present invention any one (I) compound, wherein Xaa
8for Arg.
Formula (I) compound according to described in first aspect present invention any one:
R-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B
Formula (I)
Or its steric isomer or the acceptable salt of physiology, wherein,
B is NH
2;
Xaa
3for D-Phe or D-Pal;
Xaa
5be selected from Phe (NAM), Phe (NNM), Phe (NOM), Mop, Aph, Uph, Gln, Asn, Aph (Hor);
Xaa
6be selected from D-Aph (diethyl-Cbm), D-Aph (piperidyl-CO), D-Aph (morpholinyl-CO), D-Aph (morpholinyl-CO), D-Aph (di-isopropyl-Cbm), D-Aph (dipropyl-Cbm), D-Aph (dibutyl-Cbm), D-Aph (Ac), D-Aph (positive butyryl radicals), D-Aph (nonanoyl), D-Uph, D-Aph, D-Gln, D-Asn, D-Phe (NAM), D-Phe (NNM), D-Phe (NOM), D-Mop,
Xaa
7for Leu;
Xaa
8for Arg.
According to formula (I) compound described in first aspect present invention any one, it is selected from:
1, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
2, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
3, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
4, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
5, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
6, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
7、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
8, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(positive butyryl radicals)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
9, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(nonanoyl)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
10、NHC-D-Phe
3-Ser
4-Mop
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
11、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
12、NHC-D-Phe
3-Ser
4-Mop
5-D-Gln
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
13、NHC-D-Phe
3-Ser
4-Mop
5-D-Asn
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
14、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NAM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
15、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NNM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
16、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NOM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
17、NHC-D-Phe
3-Ser
4-Aph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
18、NHC-D-Phe
3-Ser
4-Uph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
19、NHC-D-Phe
3-Ser
4-Phe(NAM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
20、NHC-D-Phe
3-Ser
4-Phe(NNM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
21、NHC-D-Phe
3-Ser
4-Phe(NOM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
22、NHC-D-Phe
3-Ser
4-Gln
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
23、NHC-D-Phe
3-Ser
4-Asn
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
24、NHC-D-Phe
3-Ser
4-Aph(Hor)
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
25, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
26, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
27, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
28, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
29, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
30, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
31、NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
32, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(positive butyryl radicals)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
33, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(nonanoyl)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
34、NHC-D-Pal
3-Ser
4-Mop
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
35、NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
36、NHC-D-Pal
3-Ser
4-Mop
5-D-Gln
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
37、NHC-D-Pal
3-Ser
4-Mop
5-D-Asn
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
38、NHC-D-Pal
3-Ser
4-Mop
5-D-Phe(NAM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
39、NHC-D-Pal
3-Ser
4-Mop
5-D-Phe(NNM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
40、NHC-D-Pal
3-Ser
4-Mop
5-D-Phe(NOM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
41、NHC-D-Pal
3-Ser
4-Aph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
42、NHC-D-Pal
3-Ser
4-Uph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
43、NHC-D-Pal
3-Ser
4-Phe(NAM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
44、NHC-D-Pal
3-Ser
4-Phe(NNM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
45、NHC-D-Pal
3-Ser
4-Phe(NOM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
46、NHC-D-Pal
3-Ser
4-Gln
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
47、NHC-D-Pal
3-Ser
4-Asn
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
48、NHC-D-Pal
3-Ser
4-Aph(Hor)
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2，
Wherein, NHC is:
In the structural formula of above 48 particular compound, the Arabic numerals that the upper right corner of each amino acid abbreviations indicates are the relative position for representing that this amino acid connects at this concrete short peptide compound amino acid only.For example, for compound 1, NHC-group part is wherein equivalent to comprise two amino acid, " the D-Phe in this compound 1
3-" be equivalent to the 3rd amino acid of this short peptide compound 1.
According to formula (I) compound described in first aspect present invention any one, it is selected from:
1, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
2, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
3, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
4, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
5, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
6, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
7、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
8, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(positive butyryl radicals)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
9, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(nonanoyl)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
10、NHC-D-Phe
3-Ser
4-Mop
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
11、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2，
Wherein, NHC is:
According to formula (I) compound described in first aspect present invention any one, it is selected from:
1, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
2, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
3, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
4, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
5, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
6, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
7、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2，
Wherein, NHC is:
According to formula (I) compound described in first aspect present invention any one, it is selected from:
1, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
2, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
3, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
7、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2，
Wherein, NHC is:
Second aspect present invention relates to the method for preparing formula of the present invention (I) compound, and it comprises the following steps:
A) taking mbha resin as solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of formula (I) compound described in first aspect any one, by Boc solid-phase polypeptide synthetic operation method, makes R '-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B-MBHA resin, wherein R ' is
B) with HCl, the solution in dioxane (for example solution of 4M HCl/ dioxane) removes Boc, neutralization reactant;
C) then make step reactant b) react with excessive carbonyl dimidazoles (referred to as CDI), be negative until triketohydrindene hydrate detects;
D) add DIEA/DCM, (for example at room temperature) reaction at 10～50 DEG C, with methyl alcohol and/or DCM cleaning resin;
E) making steps d) gained resin is placed in the reactor of HF cutting device, add methyl-phenoxide, HF cutting device is vacuumized, use cooled with liquid nitrogen reactor, add liquid HF, (for example approximately 0 DEG C at) reaction at-10 to 10 DEG C, take HF away with oil pump, add freezing anhydrous diethyl ether to make solid precipitation, then suspension is transferred in sand core funnel, with a small amount of cooling anhydrous diethyl ether washing three times, no longer mutually adhere to for example, rinsing with acetic acid aqueous solution (10%) to resin again, collect washings, dry, obtain
Wherein, X, Z, B, Xaa
3, Xaa
5, Xaa
6, Xaa
7, and Xaa
8definition with the definition of formula (I) compound described in first aspect present invention any one.
According to the method for second aspect present invention, wherein the Boc solid-phase polypeptide synthetic operation method of step described in a) is can for example, referring to document (, Huang Weide, Chen Changqing work, polypeptide is synthetic, Science Press, 1985).
Third aspect present invention provides a kind of pharmaceutical composition, and it comprises formula (I) compound described in the first aspect present invention any one that treats and/or prevents significant quantity and optional pharmaceutically acceptable carrier or vehicle.
Fourth aspect present invention provides formula (I) compound described in first aspect present invention any one in the purposes of preparing in medicine.
Specifically, fourth aspect present invention provides the purposes of formula (I) compound in the medicine for the preparation of antagonism luteinizing hormone-releasing hormone (LHRH) described in first aspect present invention any one.
Fourth aspect present invention also provides formula (I) compound described in the first aspect present invention any one purposes in the medicine for the preparation of antagonism luteinizing hormone-releasing hormone (LHRH) acceptor.
Fourth aspect present invention also provides formula (I) compound described in first aspect present invention any one in for example, purposes for the preparation of suppressing in the medicine of pituitary gonad-stimulating hormone (lutropin (LH) and/or follicular stimulating hormone (FSH)).
Fourth aspect present invention also provides formula (I) compound described in the first aspect present invention any one purposes in for example, medicine for the preparation of inhibition glandular secretion steroid hormone (oestrogenic hormon, progestogen and/or testosterone).
Fourth aspect present invention also provides formula (I) compound described in first aspect present invention any one relying on the medicine of relative disease or symptom or the purposes for the medicine of practising contraception for the preparation for the treatment of and/or preventing sexual hormoue relative disease (as sexual hormoue associated cancer, as prostate cancer, carcinoma of endometrium, mammary cancer) or other sexual hormoue.
Fourth aspect present invention also provides formula (I) compound described in first aspect present invention any one in the purposes for the preparation of reducing in the medicine of histamine release, anti-inflammatory or anti-allergic.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Term used herein " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.
The term " alkyl " adopting in the present invention comprises alkyl, thiazolinyl and alkynyl.These alkyl, thiazolinyl and alkynyl have its carbon atom specifying number, and can be straight chain or can be side chain.
Term used herein " formula (I) decapeptide derivative steric isomer " refers to and comprises its corresponding D-or L-steric configuration.
In formula of the present invention (I) compound, in group part R wherein, there are 2 chiral carbon atoms, they can be to be D-form or L-configuration independently of each other; Preferably, they are D-form.
Except as otherwise noted, the term using in this application has following implication.
" acyl group " refers to 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 " refers to alkyl-O-CO-group, and wherein said alkyl is as described herein.
Exemplary alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.
Unless otherwise indicated, " alkyl " refers to it can is to have the particularly aliphatic hydrocarbyl of approximately 15 carbon atoms of about 1-of carbon atom specifying number in the chain of straight or branched, and it is optionally replaced by one or more halogen atoms.Particularly there are 1-approximately 6 carbon atoms, for example alkyl of 1-4 carbon atom.Refer to it can is the aliphatic hydrocarbyl in the chain of straight or branched with approximately 4 carbon atoms of 1-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.Exemplary 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 being replaced by one or more halogen atoms comprises trifluoromethyl.Alkyl can also be by 1,2,3 or 4 independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C
1-C
4alkyl or C
1-C
4alkoxyl group or C
1-C
4the substituting group of alkylthio replaces.
" alkenyl " refers to that contain carbon-to-carbon double bond has the particularly aliphatic hydrocarbyl of the straight or branched of approximately 15 carbon atoms of about 2-of carbon atom specifying number in chain simultaneously.In preference chain, there is the alkenyl of approximately 12 carbon atoms of 2-; More preferably in chain, there are approximately 6 carbon atoms of 2-(for example 2-4 carbon atom).In this and whole text, " side chain " used refers to that one or more low alkyl groups are connected on straight chain as methyl, ethyl or propyl group; Refer to straight-chain alkenyl chain at this." low-grade alkenyl " refers in chain and contains approximately 4 carbon atoms of 2-of having an appointment, and it can be straight or branched.Example chain thiazolinyl comprise second alkenyl, the third alkenyl, positive fourth alkenyl, isobutyl alkenyl, 3-methyl fourth-2-alkenyl, positive penta alkenyl, heptan alkenyl, pungent alkenyl, cyclohexyl fourth alkenyl and the last of the ten Heavenly stems alkenyl.Alkenyl can be by can be by 1,2,3 or 4 independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C
1-C
4alkyl or C
1-C
4alkoxyl group or C
1-C
4the substituting group of alkylthio replaces.
" alkoxyl group " refers to alkyl-O-group, and wherein said alkyl is as described herein.Alkoxyl group example comprise difluoro-methoxy, methoxyl group, trifluoromethoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan oxygen base.
" alkylthio " refers to alkyl-S-group, and wherein said alkyl is as described herein.
" alkenyl oxy " refers to alkenyl-O-group, and wherein alkenyl defines as above.Alkenyl oxy for example comprises allyloxy.
" alkenyl thio " refers to alkenyl-S-group, and wherein alkenyl defines as above.
" halogen " comprises fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine, more preferably fluorine and chlorine, more more preferably chlorine.
" alkynyl " refers to and contains carbon-to-carbon three key simultaneously it can be to have the particularly aliphatic hydrocarbyl of approximately 15 carbon atoms of about 2-of carbon atom specifying number in the chain of straight or branched.Preferred alkynyl has approximately 12 carbon atoms of 2-in chain; More preferably in chain, there are approximately 6 carbon atoms of 2-(for example 2-4 carbon atom).Example alkynyl comprises ethynyl, proyl, positive butynyl, isobutyl alkynyl, 3-methyl fourth-2-alkynyl and positive pentynyl.Alkynyl can be by 1,2,3 or 4 independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C
1-C
4alkyl or C
1-C
4alkoxyl group or C
1-C
4the substituting group of alkylthio replaces
" aroyl " refers to aryl-CO-group, and wherein said aryl is as described herein.Example aroyl comprises benzoyl and 1-and 2-naphthoyl.
" aroylamino " is aroyl-NH-group, and wherein aroyl defines as above.
" aryl " represents as the integral part of a group or group: (i) optional substituted monocycle or the polycyclic aromatic isocyclic part of approximately 14 carbon atoms of about 6-, as phenyl or naphthyl; Or (ii) the polycyclic aromatic isocyclic part of optional substituted fractional saturation, wherein aryl and cycloalkyl or cycloalkenyl form ring texture, for example tetralyl, indenyl or indane basic ring together with condensing.Unless otherwise defined, aryl can be by one or more (as 2, 3, 4, 5) aryl substituent replacement, it can be identical or different, wherein " aryl substituent " comprises, for example, acyl group, amido, alkoxyl group, alkoxy carbonyl, alkylenedioxy group, alkyl sulfinyl, alkyl sulphonyl, alkylthio, aroyl, aroylamino, aryl, alkoxy aryl, aryl-alkoxy carbonyl, alkylthio-aryl, aryloxy, aryloxycarbonyl, aryl sulfinyl, aryl sulfonyl, arylthio, carboxyl (or sour bioisoster bioisoster), cyano group, halogen, 4-hetaroylpyrazol, heteroaryl, 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 providing in the present invention.
" alkoxy aryl " refers to arylalkyl-O-group, and wherein said arylalkyl is described above.Exemplary alkoxy aryl comprises benzyloxy and 1-or 2-naphthalene methoxyl group.
" alkylthio-aryl " refers to arylalkyl-S-group, and wherein said arylalkyl is described above.Example alkylthio-aryl is benzylthio-.
" aryloxy " refers to aryl-O-group, and wherein aryl is described above.Exemplary aryloxy comprises phenoxy group and naphthyloxy, and it is optionally substituted separately.
" cycloalkenyl " refer to contain at least one carbon-to-carbon double bond and have the carbon atom that specifies number particularly approximately 10 carbon atoms of about 3-non-aromatic monocyclic or encircle ring system more.Exemplary monocycle cycloalkenyl comprises ring penta alkenyl, hexamethylene alkenyl and ring alkenyl in heptan.Cycloalkenyl can be by 1,2,3 or 4 independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C
1-C
4alkyl or C
1-C
4the substituting group of alkoxyl group replaces.
" cycloalkyl " refers to have particularly saturated monocycle or the dicyclo ring system of approximately 10 carbon atoms of about 3-of carbon atom specifying number, and optionally replaced by oxygen.Exemplary monocyclic cycloalkyl ring comprises C
3-8cycloalkyl ring, as cyclopropyl, cyclopentyl, cyclohexyl and suberyl.Cycloalkyl can be by 1,2,3 or 4 independently selected from halogen, nitro, amino, hydroxyl, carboxyl, C
1-C
4alkyl or C
1-C
4the substituting group of alkoxyl group replaces.
Heterocyclic radical is in its ring structure, to have one or more (as 2,3,4,5) heteroatomic compound.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).Heterocyclic radical can be aromatics (namely heteroaryl), 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, sulfanyl, alkylamino or phenyl.
The preferred aromatics 5-of the present invention or 6-unit heterocyclic radical example comprise 1,3,2,4-or 1,3,4,5-bis-oxadiazolyl, Er Evil triazinyl, dioxazine base, 1,2,3-, 1,2,4-, 1,3,2-or 1,3,4-bis-oxazolyl, 1,3,2,4-or 1,3,4,5-dithiadiazole base, two thiophene triazinyls, dithiazine base, 1,2,3-dithiazole base, 2-or 3-furyl, furazan base, 1-, 2-or 4-imidazolyl, iso indazolyl, isothiazole-3-,-4-or-5-base, isoxazole-3-,-4-or-5-base, 1,2,3-, 1,2,4-, 1,2,5-or 1,3,4-oxadiazole-3-,-4-or-5-base, Evil tetrazine base, Evil triazinyl, 1,2,3,4-or 1,2,3,5-oxatriazole base, oxazole-2-,-4-or-5-base, 2-or 3-pyrazinyl, 1-, 3-or 4-pyrazolyl, 3-or 4-pyridazinyl, 2-, 3-or 4-pyridyl, 2-, 4-or 5-pyrimidyl, 1-, 2-or 3-pyrryl, 1,2,3,4-or 2,1,3,4-tetrazyl, thiadiazoles-3-,-4-or-5-base, thiazole-2-,-4-or-5-base, 2-or 3-thienyl, 1,2,3-, 1,2,4-or 1,3,5-triazines base, with 1,2,3-, 1,2,4-, 2,1,3-or 4,1,2-triazolyl.The most preferred aromatic heterocyclic radical of the present invention comprises furans-2-base, furans-3-base, 2-, 4-or 5-imidazolyl, 3-, 4-or 5-isoxazolyl, 1-, 2-or 3-pyridyl and 1-or 2-thienyl.
The preferred saturated or fractional saturation 5-of the present invention or 6-unit heterocyclic radical example comprise 1, 3, 5, 6, 2-bis-oxadiazine base, 1, 2, 3, 4, 5-or 1, 2, 3, 5, 4-bis-oxadiazolyl, alkyl dioxin, 1, 3-dioxane penta alkenyl, 1, 3, 5, 6, 2-bis-thiadiazine bases, 1, 2, 3, 4, 5-or 1, 2, 3, 5, 4-dithiadiazole base, the different imidazolyl of 2-, different pyrryl, different tetrazyl, 1, 2, 3-or 1, 2, the different triazolyl of 4-, morpholinyl, oxadiazine base, 1, 2, 4-, 1, 2, 6-, 1, 3, 2-, 1, 3, 6-or 1, 4, 2-oxazinyl, piperazinyl, homopiperazine base, piperidyl, 1, 2-, 1, 3-or 1, 4-pyranyl, with 1, 2, 3-pyrrolidyl.
" Heterocyclylalkyl " refers to: (i) cycloalkyl of about 3-7 person's ring, it contains one or more heteroatomss or is selected from O, S and NR
1r
2containing heteroatom group and can optionally being replaced by oxygen; (ii) many rings of fractional saturation are containing heteroatoms isocyclic part, wherein aryl (or heteroaryl) ring, optionally replaced by one or more " aryl substituent " respectively, and Heterocyclylalkyl condenses and forms ring texture (example of this type of group comprises chromanyl, dihydro benzo furyl, indolinyl and pyrindolinyl) together.
In the time representing group of the present invention, use bracket " () "; the bracket " () " for example using in " Aph (nonanoyl) "; content in it does not refer to the content outside this bracket is further described; and refer to that the group in bracket is connected with the part outside bracket, for example above-mentioned " Aph (nonanoyl) " refers to " 4-nonanoyl-amido phenylalanine ".
The preparation of the compounds of this invention adopts solid phase synthesis process; taking mbha resin as carrier, Boc-protects strategy, and DCC/HOBT or BOP/DIEA are condensation reagent; HCl/ dioxane is deprotecting regent, after having reacted, with liquid HF, decapeptide derivative is cut down from mbha resin.
According to the present invention, formula (I) compound and steric isomer thereof and its physiologically acceptable salt not only demonstrate good result in animal androgen antagonist secretion experiment, and demonstrate lower histamine release amount in measuring in vitro, therefore can be used as amcinonide for animal, be preferred for Mammals, particularly people.
Therefore the present invention also relates at least one formula (I) compound of effective dose and/or the pharmaceutical composition of its steric isomer or its physiologically acceptable salt and conventional medicine vehicle or assistant agent (being pharmaceutically acceptable vehicle or assistant agent) that contain as activeconstituents.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 applicable to intravenous injection, intramuscular injection, subcutaneous injection, or other administering mode.According to the mode of administration, active compound dressing can be avoided to acid or the impact of other natural condition and inactivation with protection compound.
Term used herein " the acceptable salt of physiology " or " without the salt of physiology toxicity " refer to that can retain parent compound expects physiologically active and can not produce the salt of any unexpected toxic side effect or their composition.For example: hydrochloride, hydrobromate, vitriol, phosphoric acid salt, nitrate, and acetate, oxalate, tartrate, succinate, malate, benzoate, embonate, alginates, mesylate, naphthalenesulfonate etc.Can be again according to the positively charged ion containing in salt: sylvite, lithium salts, zinc salt, mantoquita, barium salt, bismuth salt, the inorganic salt such as calcium salt, also can be organic salts such as trialkyl ammonium salts.
Formula of the present invention (I) compound and steric isomer thereof or the pharmaceutical composition that contains it can be with known any mode administrations, as oral, muscle, subcutaneous etc., form of administration is tablet, capsule, buccal tablet, chewable tablet, elixir, suspensoid, transdermal agent, micro-capsule embedding medium, implants, syrup etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For unit form of administration is made to tablet, can be widely used 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) compound and steric isomer thereof depends on many factors, for example to prevent or treat character and the severity of disease, the sex of patient or animal, age, body weight, susceptibility and individual reaction, particular compound used, route of administration, administration number of times and the desired result for the treatment of reaching etc.Above-mentioned dosage can single dose form or be divided into several, for example two, three, four dosage form administrations.Single maximal dose is generally no more than 30mg/Kg body weight, for example 0.0001-30mg/Kg, for example 0.0005-20mg/Kg, for example 0.001-10mg/Kg, for example 0.005-10mg/Kg, for example 0.005-5mg/Kg, for example 0.01-5mg/Kg, for example 0.05-2mg/Kg body weight.But, in some cases, the single dosage more than also can using 30mg/Kg body weight or below 0.0001mg/Kg.
The inventor finds, formula (I) compound with group part R of the present invention has the biological activity that in good inhibition rat body, testosterone discharges, and the octapeptide fragment that does not comprise R group does not detect and suppresses the biological activity that in rat body, testosterone discharges.
The abbreviation using in the present invention has implication below:
NHC is:
Ac ethanoyl,
Acc
5alpha-amino group cyclopentyl carboxylic acid,
Acc
6alpha-amino group cyclohexane carboxylic acid,
Ala L-Ala,
Amp 4-aminomethyl-phenylalanine,
Arg arginine,
Aph 4-amino-benzene L-Ala,
Aph (Ac) 4-acetamido phenylalanine,
Aph (DMe) 4-(N, N-dimethyl)-amino-benzene L-Ala,
Aph (oenanthyl) 4-oenanthyl-amino-benzene L-Ala,
Aph (lauryl) 4-lauroyl-amido phenylalanine,
Aph (palmityl) 4-palmityl-amido phenylalanine,
Aph (butyryl radicals) 4-butyryl-amido phenylalanine,
Aph (nicotinoyl) 4-nicotinoyl-amido phenylalanine,
Aph (nonanoyl) 4-nonanoyl-amido phenylalanine,
Uph (diethyl) 4-(N, N-bis-bases-urea groups) phenylalanine,
Uph (diη-propyl) 4-(N, N-n-propyl-urea groups) phenylalanine,
Aph (piperidyl-CO) 4-(piperidine formyl amido) phenylalanine,
Aph (morpholinyl-CO) 4-(morpholine formamido-) phenylalanine,
Uph (di-isopropyl) 4-(N, N-di-isopropyl urea groups) phenylalanine,
Uph (diethyl) 4-(N, N-diethyl urea groups) phenylalanine,
Aph (Hor) 4-whey amide group phenylalanine,
Asn l-asparagine,
Asp aspartic acid,
Boc tertbutyloxycarbonyl,
BOP benzotriazole-1-oxygen-tri-(dimethylamino) phosphorus phosphofluoric acid,
CAM carboxymethyl,
CEC carboxylic ethanoyl,
Cpa 4-chlorophenylalanine,
CPC carboxyl propionyl group,
DCC dicyclohexylcarbodiimide,
DIEA diisopropylethylamine,
Gln glutamine,
Glu L-glutamic acid,
HOBt I-hydroxybenzotriazole,
IPr sec.-propyl,
Leu leucine,
Lys Methionin,
Phe (COOH) carboxyphenylalanine,
Phe (CAM) carboxymethyl phenylalanine,
Ilys sec.-propyl Methionin,
Iorn sec.-propyl ornithine,
MBHA phenylamino methyl resin,
Mob β-piperonyl L-Ala,
Mop morpholine methyl phenylalanine,
Mph piperonyl L-Ala,
Nal naphthylalanine,
Pal 3-pyrazoleahtnine,
Phe phenylalanine,
RP-HPLC RPLC,
Pro proline(Pro),
Ser Serine,
TEA triethylamine,
Ureido urea groups,
Uph is to urea groups phenylalanine,
Phe (NAM) 4-((N, N-bis-propyloics) aminomethyl) phenylalanine,
Phe (NA
bm) 4-((N, N-bis-carbobenzoxy-(Cbz) methyl) aminomethyl) phenylalanine,
Phe (NNM) 4-((N, N-diamino acyl methyl) aminomethyl) phenylalanine,
Phe (NN
tBum) 4-((N, the tertiary fourth aminoacyl of N-bis-methyl) aminomethyl) phenylpropyl alcohol ammonia
Acid,
Phe (NOM) 4-((N, N-dihydroxy ethyl) aminomethyl) phenylalanine,
Phe (NO
bm) 4-((N, N-bis-benzyloxy ethyls) aminomethyl) phenylalanine.
Embodiment
Further illustrate the present invention below by specific embodiment and experimental example, still, should be understood to, these embodiment and experimental example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
Embodiment solid-phase synthesized carrier mbha resin used is the synthetic responsibility of Tianjin Nankai company limited product; The natural amino acid of DCC, HOBT, BOP, DIEA and Boc-protection is by gill biochemical corp, Shanghai and Chengdu Kai Tai New Technology Co., Ltd. product, and the alpha-non-natural amino acid of Boc-protection provides by this laboratory is synthetic except explanation.
embodiment 1: compound 1 synthetic
NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
Taking 63mg mbha resin (0.04mmol) as solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the Boc solid-phase peptide synthesis (reference: Huang Weide of standard, Chen Changqing work, polypeptide is synthetic, Science Press, 1985) the synthetic Boc-D-Nal of operation
1-D-Cpa
2-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2-mbha resin.
After Boc-D-Nal access peptide chain, remove the Boc of N end with 4M HCl/Diox, neutralization, after washing finishes, add 3 times of excessive CDI, reaction 0.5h, wash away excessive CDI with DCM, triketohydrindene hydrate detects condensation effect, and the positive is reacted again if, until be negative, add 10%DIEA/DCM, after room temperature reaction 4h, with methyl alcohol and DCM cleaning resin, reaction finishes.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added 1.0mL methyl-phenoxide, after installing, the system of HF cutting device is evacuated, use cooled with liquid nitrogen reactor, proceed to the liquid HF of about 10mL, in 0 DEG C of reaction 40 minutes.Take HF away with oil pump, take off reactor, add freezing anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cooling anhydrous diethyl ether washing three times, then rinse to resin and no longer mutually adhere to 10% acetic acid aqueous solution, collect washings, after lyophilize the white dry powder of 50.6mg, slightly peptide yield 93.5%.Obtain sterling through RP-HPLC purifying, pure peptide yield 14.3%.ESI-MS:1484.6 (theoretical value: 1484.1).
embodiment 2～48: compound 2～48 synthetic
Use is similar to the method synthetic compound 2～48 of embodiment 1.The structure of compound 2～48 is respectively referring to above.The various raw materials used of synthetic compound 2～48 are purchased from Chengdu Cheng Nuo Science and Technology Ltd. and Compositech Inc. of Nankai, or synthetic voluntarily by the inventor.
Synthetic result is summarized as follows table 1:
Table 1
| Compound N o. | Thick peptide yield/% | Pure peptide yield % | The poor * of ESI-MS |
| 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 is poor " represents the absolute value of theoretical value of ESI-MS and the difference of measured value, that is: ESI-MS poor=| theoretical value-measured value |.
experimental example 1: suppress testosterone effect experiment in rat body:
Before experiment, claim the weight of animals, the blood sampling of glass capillary ball rear vein beard, after separation of serum, use chemiluminescence determination Testosterone Content in Serum, press testosterone concentration and body weight random packet, every group of 4 animals, respectively at after disposable excessive subcutaneous injection testing compound 500 μ g 1,2,4,6,8,10,12,16,20,24 hour, the blood sampling of ball rear vein beard, the centrifugal 8min of 5000rpm, the chemoluminescence method for serum that separation is obtained (the Access Immunoassay System of Beckman Coulter company of U.S. Chemiluminescence Apparatus) is measured Testosterone Content in Serum.The results are shown in Table 2.
Table 2
| Compound number a | Suppress the testosterone effect time (hour) b |
| 2 | 8-12 |
| 3 | 8-16 |
| 7 | 6-8 |
| 1，5 | 4-6 |
| 4 | 2-4 |
| 6 | 6-8 |
| 13～21 | Respectively do for oneself 4～6 hours |
| 24～33 | Respectively do for oneself 4～6 hours |
| 42～48 | Respectively do for oneself 4～6 hours |
A: while not indicating especially, be subcutaneous administration, 500ug/kg;
B: Testosterone Content in Serum is lower than the time length of 1.5ng/ml.
Under this experiment condition, conventionally Testosterone Content in Serum, lower than 1.5ng/ml, is thought and is had result for the treatment of, and the time length length of animal within the scope of this Testosterone Content in Serum has reflected that the biological activity of test sample holds time conventionally.
From table 2 result, each compound of the prepared embodiment of the present invention can make Testosterone Content in Serum reach in the needed scope of effective treatment.
In addition, it should be noted that, the various diseases that Testosterone Content in Serum and formula of the present invention (I) compound can be treated has great relation, it has been generally acknowledged that being issued to described Testosterone Content in Serum scope at this test conditions can be used for the treatment of various diseases of the present invention.Various diseases that the sexual hormoue such as such as prostate cancer, carcinoma of endometrium, mammary cancer relies on (for example, referring to, Bernhard Kutscher et al, Angew Chem Int Ed Engl, 1997,36,2148-2161; And Andrew V Schally, Peptides, 1999,20,1247-1262, these documents are incorporated to herein by reference).
experimental example 2: the ability of impelling rat peritoneal mast cells to discharge histamine is measured
5 male rat broken end sacrificed by exsanguination, the cold PBS 15mL/ of abdominal injection only, after opening abdominal cavity, sucking-off peritoneal fluid is to ice bath centrifuge tube, centrifugal 10 minutes of 1500rpm, repeated washing once merges sedimentation cell afterwards, appropriate amount of buffer solution is made to single cell suspension, count number of nucleated cells with after 20 times of white corpuscle diluted.Get above-mentioned cell suspension and add respectively 37 DEG C of different sample sizes to hatch 15 minutes, boil rear ice bath termination reaction.After centrifugal, get supernatant, the Chemiluminescence Apparatus of producing with BMG company is in EX340nm, and EM460nm measures fluorescence intensity, calculates the release percentage of histamine according to fluorescence intensity, and calculates the EC of each medicine
50.Result shows, compound 1～48 all shows that having the lower rat peritoneal mast cells that impels discharges the ability of histamine, thereby shows that these compounds can be used as the medicine of anti-allergic.
Claims (12)
1. following compound, or its steric isomer or the acceptable salt of physiology, it is selected from:
1, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
2, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
3, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
4, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
5, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
6, NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
7、NHC-D-Phe
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
13、NHC-D-Phe
3-Ser
4-Mop
5-D-Asn
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
14、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NAM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
15、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NNM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
16、NHC-D-Phe
3-Ser
4-Mop
5-D-Phe(NOM)
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
17、NHC-D-Phe
3-Ser
4-Aph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
18、NHC-D-Phe
3-Ser
4-Uph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
19、NHC-D-Phe
3-Ser
4-Phe(NAM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
20、NHC-D-Phe
3-Ser
4-Phe(NNM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
21、NHC-D-Phe
3-Ser
4-Phe(NOM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
24、NHC-D-Phe
3-Ser
4-Aph(Hor)
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
25, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(diethyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
26, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(piperidyl-CO)-Leu
7-Arg
8-pro
9-D-Ala
10-NH
2
27, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(morpholinyl-CO)-Leu
7-Arg
8-pro
9-D-Ala
10-nH
2
28, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(di-isopropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
29, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(dipropyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
30, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(dibutyl-Cbm)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
31、NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(Ac)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
32, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(positive butyryl radicals)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
33, NHC-D-Pal
3-Ser
4-Mop
5-D-Aph
6(nonanoyl)-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
42、NHC-D-Pal
3-Ser
4-Uph
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
43、NHC-D-Pal
3-Ser
4-Phe(NAM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
44、NHC-D-Pal
3-Ser
4-Phe(NNM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
45、NHC-D-Pal
3-Ser
4-Phe(NOM)
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
46、NHC-D-Pal
3-Ser
4-Gln
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
47、NHC-D-Pal
3-Ser
4-Asn
5-D-Mop
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2
48, NHC-D-Pal
3-Ser
4-Aph (Hor)
5-D-Uph
6-Leu
7-Arg
8-Pro
9-D-Ala
10-NH
2, wherein, NHC is:
。
2. the method for the compound of preparation claim 1, it comprises the following steps:
A) taking mbha resin as solid phase carrier, BOP/DIEA is condensing agent, and the aminoacid sequence of compound according to claim 1, by Boc solid-phase polypeptide synthetic operation method, makes R '-Xaa
3-Ser-Xaa
5-Xaa
6-Xaa
7-Xaa
8-Pro-D-Ala-B-MBHA resin, wherein R ' is
B) with HCl, the solution in dioxane removes Boc, neutralization reactant;
C) then make step reactant b) react with excessive carbonyl dimidazoles (referred to as CDI), be negative until triketohydrindene hydrate detects;
D) add DIEA/DCM, reaction at 10～50 DEG C, with methyl alcohol and/or DCM cleaning resin;
E) making steps d) gained resin is placed in the reactor of HF cutting device, adds methyl-phenoxide, HF cutting device is vacuumized, use cooled with liquid nitrogen reactor, add liquid HF, reaction at-10 to 10 DEG C, take HF away with oil pump, add freezing anhydrous diethyl ether to make solid precipitation, then suspension is transferred in sand core funnel, with a small amount of cooling anhydrous diethyl ether washing three times, rinse to resin and no longer mutually adhere to acetic acid aqueous solution again, collect washings, dry, obtain
Wherein, X, Z, B, Xaa
3, Xaa
5, Xaa
6, Xaa
7, and Xaa
8definition with the definition of compound described in claim 1.
3. the method for claim 2, wherein step b) the described HCl solution in dioxane be the solution of 4M HCl/ dioxane.
4. the method for claim 2, wherein steps d) described 10～50 DEG C be room temperature.
5. the method for claim 2, wherein step e) described-10 to 10 DEG C be 0 DEG C.
6. the method for claim 2, wherein step e) described acetic acid aqueous solution be 10% acetic acid aqueous solution.
7. a pharmaceutical composition, it comprises compound and optional pharmaceutically acceptable carrier or vehicle described in the claim 1 that treats and/or prevents significant quantity.
8. the purposes of compound in the medicine for the preparation of antagonism luteinizing hormone-releasing hormone (LHRH) described in claim 1.
9. the purposes of compound in the medicine for the preparation of antagonism luteinizing hormone-releasing hormone (LHRH) acceptor described in claim 1.
10. the purposes of compound in the medicine for the preparation of inhibition pituitary lutropin (LH) and/or follicular stimulating hormone (FSH) described in claim 1.
The purposes of compound in the medicine for the preparation of inhibition glandular secretion oestrogenic hormon, progestogen and/or testosterone described in 11. claims 1.
Described in 12. claims 1, compound is for the preparation for the treatment of and/or preventing the medicine of prostate cancer, carcinoma of endometrium, mammary cancer or the purposes for the medicine of practising contraception.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910165535.3A CN101987865B (en) | 2009-07-29 | 2009-07-29 | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure |
| PCT/CN2010/001078 WO2011011965A1 (en) | 2009-07-29 | 2010-07-16 | Luteinising hormone releasing hormone antagonist with hydantoin structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910165535.3A CN101987865B (en) | 2009-07-29 | 2009-07-29 | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101987865A CN101987865A (en) | 2011-03-23 |
| CN101987865B true CN101987865B (en) | 2014-07-30 |
Family
ID=43528719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910165535.3A Expired - Fee Related CN101987865B (en) | 2009-07-29 | 2009-07-29 | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101987865B (en) |
| WO (1) | WO2011011965A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE034308T2 (en) | 2013-03-21 | 2018-02-28 | Sanofi Aventis Deutschland | Synthesis of hydantoin containing peptide products |
| 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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001029044A1 (en) * | 1999-10-15 | 2001-04-26 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| WO2006058012A2 (en) * | 2004-11-23 | 2006-06-01 | Wyeth | Gonadotropin releasing hormone receptor antagonists |
| CN101037472A (en) * | 2006-03-14 | 2007-09-19 | 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4476116A (en) * | 1982-12-10 | 1984-10-09 | Syntex (U.S.A.) Inc. | Polypeptides/chelating agent nasal compositions having enhanced peptide absorption |
| DK0683792T3 (en) * | 1992-12-18 | 2002-01-14 | Abbott Lab | LHRH antagonists with modified aminoacyl residues at positions 5 and 6 |
| CN100340572C (en) * | 2004-12-01 | 2007-10-03 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel LHRH antagonist |
| CN1965809A (en) * | 2005-11-16 | 2007-05-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained-release microsphere of LHRH antagonist for injection and preparation process thereof |
| RU2450017C2 (en) * | 2007-05-25 | 2012-05-10 | Ипсен Фарма С.А.С. | Hydantoin modified melanocortin receptor ligands |
-
2009
- 2009-07-29 CN CN200910165535.3A patent/CN101987865B/en not_active Expired - Fee Related
-
2010
- 2010-07-16 WO PCT/CN2010/001078 patent/WO2011011965A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001029044A1 (en) * | 1999-10-15 | 2001-04-26 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| WO2006058012A2 (en) * | 2004-11-23 | 2006-06-01 | Wyeth | Gonadotropin releasing hormone receptor antagonists |
| CN101037472A (en) * | 2006-03-14 | 2007-09-19 | 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 |
Non-Patent Citations (2)
| Title |
|---|
| 21羟化酶缺陷的药物治疗进展;刘冬年;《国外医学.内分泌学分册》;20021025;第22卷(第05期);301-303 * |
| 刘冬年.21羟化酶缺陷的药物治疗进展.《国外医学.内分泌学分册》.2002,第22卷(第05期),301-303. |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011011965A1 (en) | 2011-02-03 |
| CN101987865A (en) | 2011-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU619221B2 (en) | Effective antagonists of the luteinizing hormone releasing hormone which release negligible histamine | |
| TW479062B (en) | LH-RH peptide analogues, their uses and pharmaceutical compositions containing them | |
| JP6495899B2 (en) | Hormone secretion regulator and composition containing the same | |
| EP4309741A1 (en) | Cyclic compound having inhibitory effect selective for kras but not for hras and nras | |
| CN102459313A (en) | High penetration prodrug compositions of peptides and peptide-related compounds | |
| US20240148694A1 (en) | Treatment of androgen deprivation therapy associated symptoms | |
| CN101987865B (en) | Antagonist of luteinizing hormone releasing hormone (LHRH) containing hydantoin structure | |
| EP3151849B1 (en) | Peptides as oxytocin agonists | |
| CN101037472B (en) | LHRH antagonist with low-histamine releasing function | |
| JP2020528070A (en) | A long-acting palmitic acid-bound GnRH derivative and a pharmaceutical composition containing the same. | |
| CN101597321B (en) | LHRH antagonist with long-acting low-histamine release side effect | |
| WO2023214576A1 (en) | Cyclic compound having selective kras inhibitory effect on hras and nras | |
| AU2018209236B2 (en) | Novel compounds (immunorhelins) | |
| CN102675418B (en) | Lhrh antagonist derivative, Preparation Method And The Use | |
| CA2412899C (en) | Medicinal preparations for treating sex hormone-dependent diseases | |
| Joseph et al. | Antiestrogenic and anticancer activities of peptides derived from the active site of alpha‐fetoprotein | |
| US10167326B2 (en) | Alpha-fetoprotein “ring and tail” peptides | |
| CN104418936B (en) | Lhrh antagonist derivative and its medicinal usage | |
| WO2024101402A1 (en) | Pharmaceutical composition containing cyclic compound having selective kras inhibitory effect against hras and nras | |
| WO2024101386A1 (en) | Cyclic compound having selective kras inhibitory effect on hras and nras | |
| WO2014005513A1 (en) | Cyclopeptide lhrh antagonist derivatives and pharmacal use thereof | |
| WO2002000688A1 (en) | Peptide compound and pharmaceutical compositions and medicines containing the same as the active ingredient |
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 |
Granted publication date: 20140730 Termination date: 20150729 |
|
| EXPY | Termination of patent right or utility model |