CN102276698B - MC4-R cyclopeptide agonist and application thereof - Google Patents

MC4-R cyclopeptide agonist and application thereof Download PDF

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CN102276698B
CN102276698B CN201010196955.0A CN201010196955A CN102276698B CN 102276698 B CN102276698 B CN 102276698B CN 201010196955 A CN201010196955 A CN 201010196955A CN 102276698 B CN102276698 B CN 102276698B
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刘克良
冯思良
贾启燕
梁远军
孟庆斌
韩寒
许笑宇
魏晓莉
郑建全
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Abstract

The invention belongs to the field of pharmaceutical chemical engineering and relates to a cyclic peptide shown as a formula (1), or stereoisomers thereof, or physiological-toxicity-free salts thereof. The compounds have MC4-R (Melanocortin 4 Receptors) excitation activity. The invention also relates to a medicinal composition containing the compounds and application of the compounds to preparation of medicaments for treating obesity or sexual dysfunction and other diseases.

Description

A kind of MC4-R cyclic peptide agonist and uses thereof
Technical field
The invention belongs to field of medicine and chemical technology, relate to the Cyclopeptide derivatives shown in formula (1) or its steric isomer or its salt without physiology toxicity; These compounds have MC4-R agonist activity.The invention still further relates to the pharmaceutical composition and the purposes of these compounds in the medicine of the diseases such as preparation treatment obesity or sexual dysfunction that contain these compounds.
R-Xaa1-encircles (Xaa2-Xaa3-Xaa4-Arg-Trp-Xaa5)-Z formula (1)
Background technology
Along with society and the variation of mode of life, some diseases for example obesity or sexual dysfunction all highlights day by day.Wherein, obesity is one of well-known factor that causes the common diseases such as arteriosclerosis, hypertension, heart trouble and I type i diabetes, and sexual dysfunction also badly influences patient's physical and mental health and happy family life.
It is only the probability that slight obesity will increase diseases such as suffering from diabetes, hypertension, yet be used for the treatment of in the market fat active drug and only have a few, for example sibutramine (Sibutramine) and orlistat (Orlistat), and all there is the shortcoming of drug withdrawal bounce-back; The first-line drug of the treatment of sexual dysfunction is the phosphodiesterase inhibitors such as Virga, but this type of medicine is invalid to female patient, and the response of some patients were report fades away.Therefore the research and development of the medicine of new treatment obesity and sexual dysfunction are necessary and the task of top priority, have very wide prospect.
α-MSH is a kind of endogenous line style tridecanoic peptide that comes from proopiomelanocortin (POMC).As far back as the 1950's, people are discovery just, and the maincenters such as dog, monkey, cat and rabbit are given after α-MSH to cause its heat, and its mechanism of action is to produce modulability behavior effect by acting on MC4-R.Research shows, MC4-R agonist has potential using value (Van PL at aspects such as treatment obesity and sexual dysfunctions, Martin W J, Howard A D, et al..A role for the melanocortin 4 receptor in sexual function, Proceedings of the National Academy of Sciences of the UnitedStates of America, 2002,99 (17): 11381-11386; Martin W J, Macintyre D E.Melanocortin receptors and erectile function.European Urology, 2004,45 (6): 706-713.).
α-MSH is a wire tridecanoic peptide, and C end is amide structure, and N holds acetylize.The primary structure of α-MSH is as follows:
Ac-Ser 1-Tyr 2-Ser 3-Met 4-Glu 5-His 6-Phe 7-Arg 8-Trp 9-Gly 10-Lys 11-Pro 12-Val 13-NH 2
People studied discovery afterwards, and the minimum bioactive sequence of α-MSH is His 6-Phe 7-Arg 8-Trp 9.Round this pharmacophore, people design and have synthesized a series of these compounds, comprise linear peptides and cyclic peptide, aspect treatment obesity and sexual dysfunction, are having certain effect.Wherein, the ring seven peptide MC4-R agonist PT-141 (Bremelanotide) of U.S. Palatin company exploitation is carrying out II phase clinical study (Palatin Technologies Inc., PRESS RELEASE on Febrary 16,2010.).Because the transformation period is short or the reason such as toxic side effect large (as causing elevation of blood pressure), this compounds does not also have a kind of listing at present.Therefore,, when maintenance is active, the transformation period, the reduction toxic side effect that suitably improve compound are very important.
Summary of the invention
One aspect of the present invention relates to the Cyclopeptide derivatives shown in formula (1) or its steric isomer or its salt without physiology toxicity,
R-Xaa1-encircles (Xaa2-Xaa3-Xaa4-Arg-Trp-Xaa5)-Z formula (1)
Wherein,
R is selected from H-, R 1c (O)-, R 1r 2c (O)-, R 1r 2nC (O)-, Biotin-, tertbutyloxycarbonyl (Boc) and the overgrown with weeds methoxycarbonyl (Fmoc) shown in formula (2), wherein, R 1and R 2respectively independently selected from H, halogen, replacement or unsubstituted C 1-C 6straight chain or branched-chain alkyl, replacement or unsubstituted C 2-C 6straight chain or branched-chain alkenyl or alkynyl, replacement or unsubstituted C 1-C 6straight chain or branched alkoxy, replacement or unsubstituted C 1-C 6straight chain or branched alkane sulfenyl, replacement or unsubstituted C 2-C 6straight chain or branched-chain alkenyl or alkynyloxy base, replacement or unsubstituted C 2-C 6straight chain or alkenyl thio or alkynes sulfenyl, C 3-C 8cycloalkyl, C 3-C 8cycloalkenyl group, C 6-C 14aryl, heteroaryl and C 3-C 8heterocyclic radical;
Figure GSA00000140116200031
formula (2)
Z is-OH or-NR 3r 4, R wherein 3, R 4be H-, R independently of one another 1-, R 1r 2c (O)-, R 1r 2nC (O)-, R wherein 1and R 2definition with noted earlier;
Xaa1 is selected from leucine residue (Leu), Isoleucine residue (Ile), nor-leucine residue (Nle) and structure-NH-(CH of L or D type 2) n1-CO-, wherein, the integer that n1 is 1-5;
Xaa2 is selected from the structure shown in formula (the 3)-Shi (6) of L or D type, and wherein n2-n5 is respectively independently selected from the integer of 1-5;
Figure GSA00000140116200032
formula (3)
Figure GSA00000140116200033
formula (4)
Figure GSA00000140116200034
formula (5) formula (6)
Xaa3 is the His of L or D type or the structure shown in formula (7), wherein, and R 5be selected from R 1,-NR 1r 2,-NHC (O) NR 1r 2,-C (O) NR 1r 2, and-NH-C (O) R 1, R wherein 1and R 2definition with noted earlier;
Figure GSA00000140116200036
formula (7)
Xaa4 is D type
Figure GSA00000140116200037
wherein, R 6be selected from R 1,-NR 1r 2,-NHC (O) NR 1r 2,-C (O) NR 1r 2, and-NH-C (O) R 1, R wherein 1and R 2definition with noted earlier;
Xaa5 is selected from the structure shown in formula (the 8)-Shi (11) of L or D type, and wherein n6-n9 is respectively independently selected from the integer of 1-5;
Figure GSA00000140116200041
formula (8)
Figure GSA00000140116200042
formula (9)
Figure GSA00000140116200043
formula (10)
Figure GSA00000140116200044
formula (11).
Cyclopeptide derivatives shown in formula (1) or its steric isomer or its salt without physiology toxicity have good MC4-R agonist activity, have good stability simultaneously.Therefore the Cyclopeptide derivatives shown in formula (1) or its steric isomer or its salt without physiology toxicity can be used as medicine for the treatment of obesity and relative disease and sexual dysfunction.Wherein, " ring " represents by amido linkage (CO-NH-) or disulfide linkage (S-S-) Cheng Huan.
In one embodiment of the invention, described R is Biotin-, Xaa2 is that the structure shown in formula (3) or formula (4) and Xaa5 are the structure shown in formula (8) or formula (9), or Xaa2 is that the structure shown in formula (5) or formula (6) and Xaa5 are the structure shown in formula (10) or formula (11).
In one embodiment of the invention, described R is selected from H-, R 1c (O)-, R 1r 2c (O)-, tertbutyloxycarbonyl (Boc) and overgrown with weeds methoxycarbonyl (Fmoc), Xaa2 is that the structure shown in formula (3) and Xaa5 are the structure shown in formula (9), or Xaa2 is that the structure shown in formula (4) and Xaa5 are the structure shown in formula (8) or formula (9), or Xaa2 is that the structure shown in formula (5) and Xaa5 are the structure shown in formula (11), or Xaa2 is that the structure shown in formula (6) and Xaa5 are the structure shown in formula (10) or formula (11).
In one embodiment of the invention, described R 5for H.
In one embodiment of the invention, described R is ethanoyl (AC-) or Biotin-, and Z is-NH 2, Xaa1 is L-Nle or Aca, and Xaa2 is L-Asp, L-Cys, L-hCys, NAsp or NhCys, and Xaa5 is L-Lys, L-Cys, L-hCys, NLys or NhCys, and Xaa3 is L-His or L-Tal, Xaa4 is D-Phe or D-Cpa.
In one embodiment of the invention, described Cyclopeptide derivatives is selected from following compound:
(1) Ac-Nle-ring (Asp-His-DPhe-Arg-Trp-NLys)-NH 2
(2) Ac-Nle-ring (NAsp-His-DPhe-Arg-Trp-Lys)-NH 2
(3) Ac-Nle-ring (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2
(4) Ac-Nle-ring (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2
(5) Ac-Nle-ring (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2
(6) Ac-Nle-ring (NhCys-His-DPhe-Arg-Trp-NhCys)-NH 2
(7) Ac-Nle-ring (Asp-His-DCpa-Arg-Trp-NLys)-NH 2
(8) Ac-Nle-ring (NAsp-His-DCpa-Arg-Trp-Lys)-NH 2
(9) Ac-Nle-ring (NAsp-His-DCpa-Arg-Trp-NLys)-NH 2
(10) Ac-Nle-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2
(11) Ac-Nle-ring (NhCys-His-DCpa-Arg-Trp-Cys)-NH 2
(12) Ac-Nle-ring (NhCys-His-DCpa-Arg-Trp-NhCys)-NH 2
(13) Biotin-Nle-ring (Asp-His-DPhe-Arg-Trp-NLys)-NH 2
(14) Biotin-Nle-ring (NAsp-His-DPhe-Arg-Trp-Lys)-NH 2
(15) Biotin-Nle-ring (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2
(16) Biotin-Nle-ring (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2
(17) Biotin-Nle-ring (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2
(18) Biotin-Nle-ring (NhCys-His-DPhe-Arg-Trp-NhCys)-NH 2
(19) Biotin-Nle-ring (Asp-His-DCpa-Arg-Trp-NLys)-NH 2
(20) Biotin-Nle-ring (NAsp-His-DCpa-Arg-Trp-Lys)-NH 2
(21) Biotin-Nle-ring (NAsp-His-DCpa-Arg-Trp-NLys)-NH 2
(22) Biotin-Nle-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2
(23) Biotin-Nle-ring (NhCys-His-DCpa-Arg-Trp-Cys)-NH 2
(24) Biotin-Nle-ring (NhCys-His-DCpa-Arg-Trp-NhCys)-NH 2
(25) Biotin-Nle-ring (Asp-His-DPhe-Arg-Trp-Lys)-NH 2
(26) Biotin-Nle-ring (Cys-His-DPhe-Arg-Trp-Cys)-NH 2
(27) Biotin-Nle-ring (hCys-His-DPhe-Arg-Trp-Cys)-NH 2
(28) Biotin-Nle-ring (Cys-His-DPhe-Arg-Trp-hCys)-NH 2
(29) Biotin-Nle-ring (hCys-His-DPhe-Arg-Trp-hCys)-NH 2
(30) Biotin-Nle-ring (Asp-His-DCpa-Arg-Trp-Lys)-NH 2
(31) Biotin-Nle-ring (Cys-His-DCpa-Arg-Trp-Cys)-NH 2
(32) Biotin-Nle-ring (hCys-His-DCpa-Arg-Trp-Cys)-NH 2
(33) Biotin-Nle-ring (Cys-His-DCpa-Arg-Trp-hCys)-NH 2
(34) Biotin-Nle-ring (hCys-His-DCpa-Arg-Trp-hCys)-NH 2
(35) Ac-Nle-ring (Asp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(36) Ac-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(37) Ac-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(38) Ac-Nle-ring (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(39) Ac-Nle-ring (NhCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(40) Ac-Nle-ring (NhCys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(41) Ac-Nle-ring (Asp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(42) Ac-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(43) Ac-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(44) Ac-Nle-ring (Cys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(45) Ac-Nle-ring (NhCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(46) Ac-Nle-ring (NhCys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(47) Biotin-Nle-ring (Asp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(48) Biotin-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(49) Biotin-Nle-ring (NAsp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(50) Biotin-Nle-ring (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(51) Biotin-Nle-ring (NhCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(52) Biotin-Nle-ring (NhCys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(53) Biotin-Nle-ring (Asp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(54) Biotin-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(55) Biotin-Nle-ring (NAsp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(56) Biotin-Nle-ring (Cys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(57) Biotin-Nle-ring (NhCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(58) Biotin-Nle-ring (NhCys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(59) Biotin-Nle-ring (Asp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(60) Biotin-Nle-ring (Cys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(61) Biotin-Nle-ring (hCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(62) Biotin-Nle-ring (Cys-Tal-DPhe-Arg-Trp-hCys)-NH 2
(63) Biotin-Nle-ring (hCys-Tal-DPhe-Arg-Trp-hCys)-NH 2
(64) Biotin-Nle-ring (Asp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(65) Biotin-Nle-ring (Cys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(66) Biotin-Nle-ring (hCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(67) Biotin-Nle-ring (Cys-Tal-DCpa-Arg-Trp-hCys)-NH 2
(68) Biotin-Nle-ring (hCys-Tal-DCpa-Arg-Trp-hCys)-NH 2
(69) Ac-Aca-ring (Asp-His-DPhe-Arg-Trp-NLys)-NH 2
(70) Ac-Aca-ring (NAsp-His-DPhe-Arg-Trp-Lys)-NH 2
(71) Ac-Aca-ring (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2
(72) Ac-Aca-ring (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2
(73) Ac-Aca-ring (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2
(74) Ac-Aca-ring (NhCys-His-DPhe-Arg-Trp-NhCys)-NH 2
(75) Ac-Aca-ring (Asp-His-DCpa-Arg-Trp-NLys)-NH 2
(76) Ac-Aca-ring (NAsp-His-DCpa-Arg-Trp-Lys)-NH 2
(77) Ac-Aca-ring (NAsp-His-DCpa-Arg-Trp-NLys)-NH 2
(78) Ac-Aca-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2
(79) Ac-Aca-ring (NhCys-His-DCpa-Arg-Trp-Cys)-NH 2
(80) Ac-Aca-ring (NhCys-His-DCpa-Arg-Trp-NhCys)-NH 2
(81) Biotin-Aca-ring (Asp-His-DPhe-Arg-Trp-NLys)-NH 2
(82) Biotin-Aca-ring (NAsp-His-DPhe-Arg-Trp-Lys)-NH 2
(83) Biotin-Aca-ring (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2
(84) Biotin-Aca-ring (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2
(85) Biotin-Aca-ring (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2
(86) Biotin-Aca-ring (NhCys-His-DPhe-Arg-Trp-NhCys)-NH 2
(87) Biotin-Aca-ring (Asp-His-DCpa-Arg-Trp-NLys)-NH 2
(88) Biotin-Aca-ring (NAsp-His-DCpa-Arg-Trp-Lys)-NH 2
(89) Biotin-Aca-ring (NAsp-His-DCpa-Arg-Trp-NLys)-NH 2
(90) Biotin-Aca-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2
(91) Biotin-Aca-ring (NhCys-His-DCpa-Arg-Trp-Cys)-NH 2
(92) Biotin-Aca-ring (NhCys-His-DCpa-Arg-Trp-NhCys)-NH 2
(93) Biotin-Aca-ring (Asp-His-DPhe-Arg-Trp-Lys)-NH 2
(94) Biotin-Aca-ring (Cys-His-DPhe-Arg-Trp-Cys)-NH 2
(95) Biotin-Aca-ring (hCys-His-DPhe-Arg-Trp-Cys)-NH 2
(96) Biotin-Aca-ring (Cys-His-DPhe-Arg-Trp-hCys)-NH 2
(97) Biotin-Aca-ring (hCys-His-DPhe-Arg-Trp-hCys)-NH 2
(98) Biotin-Aca-ring (Asp-His-DCpa-Arg-Trp-Lys)-NH 2
(99) Biotin-Aca-ring (Cys-His-DCpa-Arg-Trp-Cys)-NH 2
(100) Biotin-Aca-ring (hCys-His-DCpa-Arg-Trp-Cys)-NH 2
(101) Biotin-Aca-ring (Cys-His-DCpa-Arg-Trp-hCys)-NH 2
(102) Biotin-Aca-ring (hCys-His-DCpa-Arg-Trp-hCys)-NH 2
(103) Ac-Aca-ring (Asp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(104) Ac-Aca-ring (NAsp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(105) Ac-Aca-ring (NAsp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(106) Ac-Aca-ring (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(107) Ac-Aca-ring (NhCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(108) Ac-Aca-ring (NhCys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(109) Ac-Aca-ring (Asp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(110) Ac-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(111) Ac-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(112) Ac-Aca-ring (Cys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(113) Ac-Aca-ring (NhCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(114) Ac-Aca-ring (NhCys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(115) Biotin-Aca-ring (Asp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(116) Biotin-Aca-ring (NAsp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(117) Biotin-Aca-ring (NAsp-Tal-DPhe-Arg-Trp-NLys)-NH 2
(118) Biotin-Aca-ring (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(119) Biotin-Aca-ring (NhCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(120) Biotin-Aca-ring (NhCys-Tal-DPhe-Arg-Trp-NhCys)-NH 2
(121) Biotin-Aca-ring (Asp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(122) Biotin-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(123) Biotin-Aca-ring (NAsp-Tal-DCpa-Arg-Trp-NLys)-NH 2
(124) Biotin-Aca-ring (Cys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(125) Biotin-Aca-ring (NhCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(126) Biotin-Aca-ring (NhCys-Tal-DCpa-Arg-Trp-NhCys)-NH 2
(127) Biotin-Aca-ring (Asp-Tal-DPhe-Arg-Trp-Lys)-NH 2
(128) Biotin-Aca-ring (Cys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(129) Biotin-Aca-ring (hCys-Tal-DPhe-Arg-Trp-Cys)-NH 2
(130) Biotin-Aca-ring (Cys-Tal-DPhe-Arg-Trp-hCys)-NH 2
(131) Biotin-Aca-ring (hCys-Tal-DPhe-Arg-Trp-hCys)-NH 2
(132) Biotin-Aca-ring (Asp-Tal-DCpa-Arg-Trp-Lys)-NH 2
(133) Biotin-Aca-ring (Cys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(134) Biotin-Aca-ring (hCys-Tal-DCpa-Arg-Trp-Cys)-NH 2
(135) Biotin-Aca-ring (Cys-Tal-DCpa-Arg-Trp-hCys)-NH 2
(136) Biotin-Aca-ring (hCys-Tal-DCpa-Arg-Trp-hCys)-NH 2
Preferably, the present invention is selected from compound 1,2,3,4,5,10,14,16,17,20,23,25,27,30,32,36,38,39,42,45,48,54,69,70,71,72,73,78,82,84,85,88,91,93,95,98,100,104,106,107,110,112,113,116 and 122 above.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains any above-mentioned Cyclopeptide derivatives or its steric isomer or its salt without physiology toxicity, and optionally, it can also contain pharmaceutically acceptable carrier or auxiliary material.
An also aspect of the present invention relates to above-mentioned Cyclopeptide derivatives or its steric isomer or its salt without physiology toxicity as the purposes of MC4-R agonist.
Also aspect of the present invention relates to above-mentioned Cyclopeptide derivatives or its steric isomer or its salt without physiology toxicity and treats and/or prevents the purposes in the medicine of obesity, hypertension, atherosclerosis, heart trouble or type ii diabetes in preparation.
Also aspect of the present invention relates to above-mentioned Cyclopeptide derivatives or its steric isomer or its salt without physiology toxicity and treats and/or prevents the purposes in the medicine of sexual dysfunction in preparation.
Also aspect of the present invention relates to the method for the sexual dysfunction of a kind for the treatment of or assisting therapy and/or prevention Mammals (comprising people), and the method comprises Cyclopeptide derivatives of the present invention or its steric isomer or its salt without physiology toxicity or the pharmaceutical composition of the present invention of using significant quantity.
Also aspect of the present invention relates to a kind of method of obesity, hypertension, atherosclerosis, heart trouble or the type ii diabetes for the treatment of or assisting therapy and/or prevention Mammals (comprising people), and the method comprises Cyclopeptide derivatives of the present invention or its steric isomer or its salt without physiology toxicity or the pharmaceutical composition of the present invention of using significant quantity.
The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.
The compounds of this invention of word " significant quantity " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound adopting, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with adopted particular compound; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.
Below the invention will be further described.
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.
In the present invention, all amino acid configurations, except being labeled as D-type, are L-type.
In the present invention, unless otherwise indicated, term " alkyl " refers to it can is in the chain of straight or branched, to have the aliphatic hydrocarbyl of approximately 1 to approximately 15 carbon atoms, and it is optionally replaced by one or more halogen atoms.Particularly there are approximately 6 carbon atoms of 1-.Example alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, 3-amyl group, heptyl, octyl group, nonyl, decyl and dodecyl.The examples of alkyl 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.
Term " 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.
Term " halogen " comprises fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine.
Term " cycloalkyl " refers to saturated monocycle or the dicyclo ring system of approximately 10 carbon atoms of about 3-, optionally by oxygen, is replaced.Example 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.
Term " aryl " is 6-14 unit's monocycle or Bicyclic group, and as phenyl or naphthyl, it is not substituted or is independently selected from halogen, nitro, carboxyl or C 1-C 4the substituting group of alkyl is monosubstituted or two replace or three replace;
Term " heteroaryl " is for containing 1-5 independently selected from heteroatomic 4-10 unit's monocycle or the Bicyclic group of N, O and S, and as pyrryl, furyl, pyridyl etc., it is not substituted or is independently selected from halogen, nitro, carboxyl or C 1-C 4the substituting group of alkyl is monosubstituted or two replace;
Term " heterocyclic radical " is in its ring structure, to contain 1-5, preferred 1-3 the heteroatomic non-aromatic ring-type group independently selected from N, O and S, and as pyranyl, piperidyl etc., it is not substituted or is independently selected from halogen, nitro, carboxyl or C 1-C 4the substituting group of alkyl is monosubstituted or two replace or three replace.
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment solid-phase synthesized carrier mbha resin used and PAM resin are the synthetic responsibility of Tianjin Nankai company limited product; The natural amino acid of DCC, HOBT, BOP, DIEA and protection is by gill biochemical corp, Shanghai and Chengdu Cheng Nuo new technology limited liability company product, and the alpha-non-natural amino acid of protection provides by this laboratory is synthetic except explanation.
The abbreviation of using in the present invention has implication below:
Ac ethanoyl
Aca hexosamine residue
Asp asparagicacid residue
Arg arginine residues
Boc tertbutyloxycarbonyl
BOP benzotriazole-1-oxygen-tri-(dimethylamino) phosphorus phosphofluoric acid
Cpa tetrachlorobenzene alanine residue
Cys cysteine residues
DCC dicyclohexylcarbodiimide
DIEA diisopropylethylamine
Fmoc fluorenylmethyloxycarbonyl
Fpa P-fluoropnenylalanine residue
HCys homocysteine residue
HOBt I-hydroxybenzotriazole
His histidine residues
Lys lysine residue
Mbha resin phenylamino methyl resin
α-MSH α-melanocyte-stimulatinghormone
Mtal 2-amino-3-(2-methylthiazol base-4-) propionic acid residue
NAsp N-carboxy ethyl glycine residue
NCys N-mercapto methyl glycine residue
NhCys N-mercaptoethyl glycine residue
NLys N-aminobutyl glycine residue
Nle nor-leucine residue
PAM resin methylol phenylacetamidomethyl resin
Phe phenylalanine residue
RP-HPLC RPLC
Tal 2-amino-3-(thiazolyl-4-) propionic acid residue
Trp tryptophan residue
Embodiment 1: compd A c-Nle-encircles (Asp-His-DPhe-Arg-Trp-NLys)-NH 2(1) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the Fmoc solid-phase peptide synthesis (reference: Huang Weide of standard, Chen Changqing work, polypeptide is synthetic, Science Press, 1985) the synthetic Ac-Nle-ring of operation (Asp-His-DPhe-Arg-Trp-NLys)-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the liquid HF of 0.5mL methyl-phenoxide and about 10mL, in 0 ℃ of reaction 40 minutes.With oil pump, take HF away, take off reactor, add cold anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cold anhydrous diethyl ether washing three times, then use 10% acetic acid aqueous solution 150mL by product wash-out, after lyophilize white fluffy solids crude peptide 212mg.Used 10% acetic acid/water 50mL to dissolve, through the anti-phase middle pressure chromatogram purification of C18, eluent is 20%-30% acetonitrile/1% acetic acid/water, and freeze-drying obtains pure peptide 14.7mg, and HPLC purity is 91.7%, yield 7%.ESI-MS：1024.0(MW1024)。
Embodiment 2: compd A c-Nle-encircles (NAsp-His-DPhe-Arg-Trp-Lys)-NH 2(2) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-ring of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation (NAsp-His-DPhe-Arg-Trp-Lys)-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the liquid HF of 0.5mL methyl-phenoxide and about 10mL, in 0 ℃ of reaction 40 minutes.With oil pump, take HF away, take off reactor, add cold anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cold anhydrous diethyl ether washing three times, then use 10% acetic acid aqueous solution 150mL by product wash-out, after lyophilize white fluffy solids crude peptide 196mg.Used 10% acetic acid/water 50mL to dissolve, through the anti-phase middle pressure chromatogram purification of C18, eluent is 20%-30% acetonitrile/1% acetic acid/water, and freeze-drying obtains pure peptide 10.2mg, and HPLC purity is 95.4%, yield 5%.ESI-MS：1024.0(MW1024)。
Embodiment 3: compd A c-Nle-encircles (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2(3) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-ring of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation (NAsp-His-DPhe-Arg-Trp-NLys)-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the liquid HF of 0.5mL methyl-phenoxide and about 10mL, in 0 ℃ of reaction 40 minutes.With oil pump, take HF away, take off reactor, add cold anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cold anhydrous diethyl ether washing three times, then use 10% acetic acid aqueous solution 150mL by product wash-out, after lyophilize white fluffy solids crude peptide 196mg.Used 10% acetic acid/water 50mL to dissolve, through the anti-phase middle pressure chromatogram purification of C18, eluent is 20%-30% acetonitrile/1% acetic acid/water, and freeze-drying obtains pure peptide 10.5mg, and HPLC purity is 91.6%, yield 5%.ESI-MS：1024.0(MW1024)。
Embodiment 4: compd A c-Nle-encircles (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2(4) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-Cys-His-DPhe-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 176mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 14.4mg, HPLC purity 93.5%, yield 7%.ESI-MS：1017.7(MW1017)。
Embodiment 5: compd A c-Nle-encircles (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2(5) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-NhCys-His-DPhe-Arg-Trp-Cys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 185mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 16.1mg, HPLC purity 96.2%, yield 8%.ESI-MS：1017.6(MW1017)。
Embodiment 6: compd A c-Nle-encircles (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2(10) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-Cys-His-DCpa-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 192mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 11.1mg, HPLC purity 94.2%, yield 5%.ESI-MS：1050.8(MW1051)。
Embodiment 7: compd B iotin-Nle-encircles (Asp-His-DPhe-Arg-Trp-Lys)-NH 2(25) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Biotin-Nle-ring of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation (Asp-His-DPhe-Arg-Trp-Lys)-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the liquid HF of 0.5mL methyl-phenoxide and about 10mL, in 0 ℃ of reaction 40 minutes.With oil pump, take HF away, take off reactor, add cold anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cold anhydrous diethyl ether washing three times, then use 10% acetic acid aqueous solution 150mL by product wash-out, after lyophilize white fluffy solids crude peptide 210mg.Used 10% acetic acid/water 50mL to dissolve, through the anti-phase middle pressure chromatogram purification of C18, eluent is 20%-30% acetonitrile/1% acetic acid/water, and freeze-drying obtains pure peptide 12.7mg, and HPLC purity is 94.8%, yield 5%.ESI-MS：1208.0(MW1208)。
Embodiment 8: compd A c-Nle-encircles (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2(38) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Nle-Cys-Tal-DPhe-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 201mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 12.4mg, HPLC purity 95.6%, yield 6%.ESI-MS：1033.8(MW1034)。
Embodiment 9: compd A c-Aca-encircles (NAsp-His-DPhe-Arg-Trp-NLys)-NH 2(71) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Biotin-Nle-ring of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation (Asp-His-DCpa-Arg-Trp-Lys)-mbha resin.
Above-mentioned peptide resin is put into the reactor of HF cutting device, added the liquid HF of 0.5mL methyl-phenoxide and about 10mL, in 0 ℃ of reaction 40 minutes.With oil pump, take HF away, take off reactor, add cold anhydrous diethyl ether to be settled out solid, then suspension is transferred in sand core funnel.With a small amount of cold anhydrous diethyl ether washing three times, then use 10% acetic acid aqueous solution 150mL by product wash-out, after lyophilize white fluffy solids crude peptide 210mg.Used 10% acetic acid/water 50mL to dissolve, through the anti-phase middle pressure chromatogram purification of C18, eluent is 20%-30% acetonitrile/1% acetic acid/water, and freeze-drying obtains pure peptide 15.7mg, and HPLC purity is 92.1%, yield 6%.ESI-MS：1023.9(MW1024)。
Embodiment 10: compd A c-Aca-encircles (Cys-His-DPhe-Arg-Trp-NhCys)-NH 2(72) synthesize.
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Aca-Cys-His-DPhe-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 201mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 15.1mg, HPLC purity 93.6%, yield 7%.ESI-MS：1016.7(MW1017)。
Embodiment 11: compd A c-Aca-encircles (NhCys-His-DPhe-Arg-Trp-Cys)-NH 2(73) synthesize.
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Aca-NhCys-His-DPhe-Arg-Trp-Cys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 192mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 15.6mg, HPLC purity 94.8%, yield 7%.ESI-MS：1016.9(MW1017)。
Embodiment 12: compd A c-Aca-encircles (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2(78) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Aca-Cys-His-DCpa-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 185mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 10.8mg, HPLC purity 94.8%, yield 5%.ESI-MS：1051.7(MW1051)。
Embodiment 13: compd A c-Aca-encircles (Cys-Tal-DPhe-Arg-Trp-NhCys)-NH 2(106) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Aca-Cys-Tal-DPhe-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 185mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 10.5mg, HPLC purity 97.1%, yield 5%.ESI-MS：1034.9(MW1035)。
Embodiment 14: compd A c-Aca-encircles (Cys-Tal-DCpa-Arg-Trp-NhCys)-NH 2(112) synthesize
The 390mg mbha resin (0.54mmol/g) of take is solid phase carrier, BOP/DIEA is condensing agent, according to the aminoacid sequence of compound, by the synthetic Ac-Aca-Cys-Tal-DCpa-Arg-Trp-NhCys-MBHA resin of the Fmoc solid-phase peptide synthesis of standard (reference is with embodiment 1) operation.
After peptide resin is dry, use anhydrous hydrogen fluoride cracking, through freeze-drying, obtain the thick peptide 207mg of linear precursor, add water 100mL and dissolve, 10% ammoniacal liquor adjust pH to 8.4, solution is slightly pink.Under room temperature magnetic agitation, add Tripotassium iron hexacyanide 100mg, solution yellowing.HPLC monitors reaction process, and about 10min reaction completes.Add the about 10g of anionite-exchange resin, after the about 20min of stirring at room, solution is yellow to disappear; Filter washing 20mL * 2 time.Merge the aqueous solution, directly carry out middle pressure separation and purification, freeze-drying, finally pure peptide 13.7mg, HPLC purity 96.4%, yield 6%.ESI-MS：1067.8(MW1068)。
Embodiment 15: receptor-binding activity evaluation test
Experimental technique: radioligand receptor binding methods
Material: the membranin that is rich in MC4-R that rat cerebral tissue extracts; [ 125i]-NDP-α-MSH， PerkinElmer company.
Experimental principle: the highly sensitive feature of utilizing high affinity, specificity, saturability, reversibility and the radionuclide measurement of binding of receptor and ligand, acceptor is combined under certain condition with its tagged ligand, when reaction reaches balance or in different time point termination reactions, separated free and tagged ligand that be combined with receptor-specific, measure respectively the radioactivity of the two, calculate its concentration.
Parameter: in conjunction with inhibition percentage, in conjunction with inhibition percentage=(competitive binding-non-specific binding)/(total binding-non-specific binding) * 100%.
Higher to the combination activity of acceptor in conjunction with the higher expression compound of inhibition percentage.
Screening compound: select 10nM and two concentration of 100nM, with the positive contrast of PT-141, each given the test agent repeats 3 times.Table 1 has provided the higher compound result of inhibiting rate.Can see, in 100nM level, having 11 compound inhibiting rates to reach 50%; In 10nM level, there are 5 compound inhibiting rates to reach 50%, PT-141 is suitable with positive control, has shown higher receptor-binding activity.
Table 1 receptor-binding activity evaluation result
Figure GSA00000140116200211
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.

Claims (5)

1. Cyclopeptide derivatives or its steric isomer or its salt without physiology toxicity, wherein, described Cyclopeptide derivatives is selected from following compound:
(10) Ac-Nle-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2, and
(78) Ac-Aca-ring (Cys-His-DCpa-Arg-Trp-NhCys)-NH 2.
2. a pharmaceutical composition, it contains Cyclopeptide derivatives claimed in claim 1 or its steric isomer or its salt without physiology toxicity, and pharmaceutically acceptable carrier or auxiliary material.
3. Cyclopeptide derivatives claimed in claim 1 or its steric isomer or its salt without physiology toxicity are as the purposes of MC4-R agonist.
4. Cyclopeptide derivatives claimed in claim 1 or its steric isomer or its salt without physiology toxicity treat and/or prevent the purposes in fat medicine in preparation.
5. Cyclopeptide derivatives claimed in claim 1 or its steric isomer or its salt without physiology toxicity treat and/or prevent the purposes in the medicine of sexual dysfunction in preparation.
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US11332499B2 (en) 2018-08-16 2022-05-17 Regents Of The University Of Minnesota Cyclic peptides and methods of use thereof
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