CN101168560A - N-substituted peptide amide, pharmaceutical composition and use thereof - Google Patents

N-substituted peptide amide, pharmaceutical composition and use thereof Download PDF

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CN101168560A
CN101168560A CNA2006101139708A CN200610113970A CN101168560A CN 101168560 A CN101168560 A CN 101168560A CN A2006101139708 A CNA2006101139708 A CN A2006101139708A CN 200610113970 A CN200610113970 A CN 200610113970A CN 101168560 A CN101168560 A CN 101168560A
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lys
arg
tyr
asp
val
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CN101168560B (en
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王德心
张莉
杜冠华
龚喜
杨潇骁
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Institute of Materia Medica of CAMS
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The invention discloses a kind of novel peptidyl amine compound, the production method of the compound, the pharmaceuticals composition containing the compound, and the application of the compound in precaution and/or remedy for immune hypofunction related illnesses.

Description

The N-substituted peptide amide, its pharmaceutical composition and purposes
Technical field
The present invention is the N-substituted peptide amide of the new promotion immunologic function of a class, immune two-ways regulation, relates to peptide and organic molecule field.
Background technology
Reported in literature and various countries a large amount of clinical practice proof TP-5 has immune two-ways regulation function.Can induce and promote T lymphocyte and subgroup differentiation, maturation and the activation of human body; Regulate the lymphocytic ratio of T, make CD 4 +/ CD 8 +Be tending towards normal; Increase multiple lymphokine, as the secretion of a., r Interferon, rabbit, interleukin-22 and interleukin-13; Strengthen NK cell viability etc.But TP-5 metabolism in vivo is too fast, and the transformation period is 30 seconds shortcoming for this reason only
Summary of the invention
Metabolism is fast in vivo at TP-5 in the prior art, and the transformation period is 30 seconds shortcoming for this reason only, the invention provides a kind of
For solving technical problem of the present invention, adopt following technical scheme:
At Asp 3And Val 4The place changes the Ida and the β-Ala of non-natural structure into;
Introduce the different amide structures that replace at C-terminal;
At Tyr 5Carboxyl terminal introduce the Aca-Phe-Met fragment;
Make the TP-5 two strandsization.
The general structure of The compounds of this invention is:
R 1-X 1-X 2-X 3-X 4-Tyr-R 2
Wherein arginyl, valyl and tyrosyl remain unchanged.And lysyl in the former TP-5 molecule and aspartoyl also remain unchanged in most modification, only change to some extent in the discrete synthetics.
See following description for details:
X 1Be selected from arginyl (Arg), lysyl (Lys), guanidine-nitro arginyl (Arg (NO 2));
X 2Be selected from lysyl (Lys), arginyl (Arg), N-methyl glycyl (Sar), D-alanyl (D-Ala);
X 3Be selected from aspartoyl (Asp), glutamy (Glu), iminodiethanoic acid list acyl (Ida);
X 4Be selected from valyl (Val), and leucyl (Leu), β-alanyl (β-Ala), Cys;
R 1Be selected from H, Cys;
R 2Be selected from NH 2, NHMe, NHEt, NHBu, NH (CH 2) 2OH (Gol), NH (CH 2) 2NH (CH 2) 2OH, NHC (CH 3) 2CH 2OH, Aca-Phe-Met-R ' [R ' be selected from NHEt, Gol, NH (CH 2) 2NH (CH 2) 2OH and NHC (CH 3) 2CH 2OH], Lys-NHR (R=H, C 1～10Alkyl).
The method for preparing The compounds of this invention also is provided according to the present invention.At first adopt classical solid-phase peptide synthesis strategy, with chloromethyl resin (substitution value: 1mmol/g, degree of crosslinking: 1%, granularity: the 100-200 order) be solid phase carrier, finish the assembling of target sequence through method progressively.
Condensing agent is a N-hydroxybenzotriazole (HOBt) and the molar mixture that waits of dicyclohexylcarbodiimide (DCC), or O-benzotriazole-N, N, N ', N '-tetramethyl-hexafluoro phosphonium salt (HBTU) and HOBt and NMM (N-methylmorpholine) etc. molar mixture.All monitor condensation level after per step condensation with the triketohydrindene hydrate color reaction.
Wherein all with Boc protection a-amino, two amino acid whose protection forms are in addition: Fmoc-Lys (Boc)-OH and Fmoc-Asp (OtBu)-OH for Tyr, Val and Arg.
Boc and tBu protecting group are removed by 3.5N HCl/HOAc, and the Fmoc protecting group removes with 20% piperidines/DMF.
Carry out ammonia with different amine compound respectively after the peptide chain sequence assembling is finished and separate, finish from solid phase carrier and discharge the peptide amide product.Crude product carries out purifying through quick filtering layer of C-18 and solvent recrystallization (or reprecipitation).All end product is all through ESI-MS analytical proof structure.
Therefore the present invention also relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, make any formulation that is suitable for human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in the administration unit, the effective constituent The compounds of this invention can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also the effective constituent The compounds of this invention particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of The compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.1-100mg/Kg body weight, and more preferably the 1-60mg/Kg body weight most preferably is the 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Pharmacological evaluation proves that compound of the present invention can prevent and/or treat the illness relevant with immunologic hypofunction, as the medicine or the formula constituent of chronic hepatitis B, various primary or Secondary cases T cell defect (as children's innate immunity defective disease), the low disease of various cellular immune function (as severe viral hepatitis, severe upper respiratory tract infection, intractable oral cavity ulcer etc.), tumour patient and HIV the infected's aspects such as assisting therapy.
Advantage of the present invention
The various substituted amide structures of compound C-terminal of the present invention have overcome the TP-5 primary structure can not resist the shortcoming of carboxypeptidase degraded, has exempted the Degradation of the interior carboxypeptidase of body to modification, thereby has improved the little peptide compounds of this class stability in vivo.
Increased the speed that molecular weight delays to be eliminated in vivo in the terminal two strandsization of introducing tripeptides section and TP-5 main chain of C-.
Biological activity test of the present invention proves that our modification promotes the transcellular specific activity TP-5 of T to be significantly improved, and shows it is the good immunomodulator of a class.
Simple and feasible on the preparation method, with low cost.
This compounds is expected to be used for clinically the prevention and the medicine of panimmunity defective illness
In a word, this law people's peptide compounds has stronger biologically stable and immunoregulatory activity.Term:
The abbreviation of protecting group abbreviation and reagent, solvent is respectively in the raw material:
Boc: tert-butoxy carbonyl,
Fmoc: fluorenes methoxy carbonyl acyl,
TBu: the tertiary butyl,
Aca: the omega-amino-caproic acid,
Ida: iminodiethanoic acid list acyl,
Gol: glycinol,
DMF: dimethyl formamide,
DCM: methylene dichloride,
THF: tetrahydrofuran (THF),
TEA: triethylamine,
HOAc: acetate
Arg: arginyl,
Lys: lysyl,
Arg (NO 2): guanidine-nitro arginyl,
Sar:N-methyl glycyl,
The D-Ala:D-alanyl,
Asp: aspartoyl,
Glu: glutamy,
Ida: iminodiethanoic acid list acyl,
Val: valyl,
Leu: leucyl,
β-Ala: β-alanyl
Embodiment
The following examples further specify the present invention, but do not limit the present invention in any way.
Embodiment 1
H-Arg-Lys-Asp-Val-Tyr-Gol2HCl's (I) is synthetic
At first adopt classical solid-phase peptide synthesis strategy, with chloromethyl resin (substitution value: 1mmol/g, degree of crosslinking: 1%, granularity: the 100-200 order) be solid phase carrier, finish the assembling of target sequence through method progressively.Wherein all with Boc protection a-amino, two amino acid whose protection forms are in addition: Fmoc-Lys (Boc)-OH and Fmoc-Asp (OtBu)-OH for Tyr, Val and Arg.All monitor condensation level after per step condensation with the triketohydrindene hydrate color reaction.After all condensation is finished, with monoethanolamine (Gol)/H 2(2: 1: 3, v/v) solution mixed with the peptide resin of full guard and shakes 30h O/DMF.The filtrate of collecting is mixed with the distilled water of proper volume, then under reduced pressure by the C-18 filtering layer, uses the distilled water gradation drip washing C-18 filtering layer (removing excessive Gol and DMF) of an amount of volume after all filtering again.Drain back anhydrous diethyl ether drip washing.Use at last HOAc-EtOH (1: 2, v/v) eluted product, the filtrate of collection gets solid residue through concentrating under reduced pressure.The latter through the EtOAc-sherwood oil grind powdered product.The latter removes Boc and tBu protecting group through 3.5N HCl/HOAc, concentrates after Et 2O grind end product I,
Total recovery is 88.7%,
Its structure is by the ESI-MS analytical proof, and the molecule peak is 723.4 (M+H).
Synthetic route is as follows:
Figure A20061011397000091
Embodiment 2
H-Arg-Lys-Asp-Val-Tyr-NH (CH 2) 2NH (CH 2) 2OH2HCl's (II) is synthetic
The solid phase synthesis of peptide chain-ordering is identical with example I, gets difference and is that ammonia is separated usefulness
H 2N (CH 2) 2NH (CH 2) 2OH is an amine component.
Other concrete reaction conditionss and example I are also together.
The yield of II is 87.5%,
The analytical results of its ESI-MS is 766.3 (M+H).
Embodiment 3
H-Arg-Lys-Asp-β Ala-Tyr-NHEt's (III) is synthetic
In the solid phase synthesis of peptide chain-ordering, second at C-end replaces original with Boc-β-Ala-OH
Boc-Val-OH, all the other conditions and example I all with.In addition, with the another difference of example I be before ammonia is separated, to remove Boc and tBu protecting group in advance, promptly obtain free product III after ammonia is separated:
Figure A20061011397000101
H-Arg-Lys-Asp-β.Ala-Tyr-NHEt(III)
The yield of III is 93.6%, and the result of its ESI-MS is: 679.4 (M+H).
Embodiment 4
Synthetic and the biological activity of H-Arg-Lys-Ida-Val-Tyr-NHEt (IV)
Solid phase synthesis condition and ammonia separate condition and to implement 3 identical.
The yield of IV is 91.9%,
The analytical results of its ESI-MS is 707.4 (M+H).
Embodiment 5
H-Arg-Lys-Asp-β-Ala-Tyr-Aca-Phe-Met-NHEt's (V) is synthetic
Solid phase synthesis, ammonia separate condition and aftertreatment identical with embodiment 3,
The yield of V is 78.7%,
Its ESI-MS result is 1071.6 (M+H).
Embodiment 6
H-Arg-Lys-Asp--Ala-Tyr-Aca-Phe-Met-NHCH (CH 3) 2Synthesizing (VI)
Solid phase synthesis, ammonia separate condition and aftertreatment identical with embodiment 5,
The yield of VI is 75.3%,
ESI-MS result is 1084.6 (M+H).
Embodiment 7
Synthetic and the biological activity of H-Lys-Arg-Asp-Val-Tyr-NHEt (VII)
Solid phase synthesis, ammonia separate condition and aftertreatment identical with embodiment 3,
The yield of VII is 88.2%,
ESI-MS result is 707.5 (M+H).
Embodiment 8
H-Lys-Arg-Ida-Val-Tyr-NHCH 3(VIII) synthetic and biological activity
This synthetic amino acid that all adopts the Boc protection, its condensation reaction and ammonolysis reaction are identical with embodiment 7.
The yield of VIII is 76.3%,
ESI-MS result is 693.4 (M+H).
Embodiment 9
Synthesizing (IX)
This synthesizes at first uses Boc-Lys (Boc)-OH at K 2CO 3Reach under the KI catalysis and the chloromethyl resin bonding.Carry out two parallel TP-5 sequence assembling of key after removing two Boc protecting groups on the lysyl.Reaction conditions is identical with embodiment 1.It is identical with embodiment 3 that ethamine is separated condition.Synthetic route is as follows:
Figure A20061011397000112
The yield of product IX is 90.1%,
The result of its ESI-MS is 1482.8 (M+H).
Embodiment 10
Figure A20061011397000121
Synthetic
The solid-phase peptide synthesis condition is identical with embodiment 9, and the condensation of final step halfcystine is a raw material with Boc-Cys (Acm)-OH.After finishing, condensation uses I 2/ HOAc-DMF condition removes the Acm protecting group, and finishes the bonding of disulfide linkage.It is identical with embodiment 3 that ammonia is separated condition, and synthetic route is as follows:
Figure A20061011397000122
The yield of product X is 89.3%,
The result of its ESI-MS is 1630.7 (M+H).
Pharmacological evaluation
Peptide prod of the present invention is measured as follows to the LT isoreactivity that influences of T:
1, experiment in vitro
Get 10 of BALB/c mouse, according to a conventional method, the aseptic mouse spleen of getting shreds grinding, crosses 200 order steel meshes, and the serum-free RPMI-1640 is washed once, centrifugal 5 minutes of 1500rpm.Adopt two pair salt methods of steaming to destroy red corpuscle, and remove fatty tissue, recentrifuge.Cell precipitation is white corpuscle, and transferring cell concn with complete RPMI-1640 is 5*10 6Plant in 96 orifice plates in/ml100 μ l/ hole, adds Con A (final concentration 5 μ g/ml) or LPS (final concentration 5 μ g/ml) simultaneously, sample 10 μ l/ holes.Other establishes blank hole (not adding inductor), and negative control hole (adds inductor
But do not add sample), 37 ℃, 5%CO 2Hatch 72h, cultivate and finish preceding 4h, add MTT100 μ l (final concentration 5 μ g/ml), after cultivation finishes, measure 540nm OD value, and by following formula calculating lymphocyte transformation rate.
The experiment in vitro result is as shown in table 1:
Table 1 partial synthesis peptide is to the LT influence of T
Figure A20061011397000132
Experiment in experimental example 2, the body
Get 80 of BALB/c mouse, be divided into normal control group, model (endoxan) control group, the positive (TP-5,0.22 μ mol/kg) control group and various N-substituted peptide amide (0.22 μ mol/kg) experimental group.Except that normal group, all the other each groups are all used the modeling of endoxan 100mg/Kg abdominal injection.Modeling begins administration, intraperitoneal injection, every 0.2ml next day.Continuous 7 days, to weigh next day after the last administration, the aseptic mice spleen survey T/B lymphocyte transformation rate of getting is got thymus gland and spleen is weighed, and blood sampling carry out white blood cell count(WBC).Concrete operation is as follows:
(1) to the influence of thymus gland and spleen weight
Get mouse thymus and spleen, and compare, calculate thymus index and index and spleen index with body weight
(2) to the LT influence of T/B
According to a conventional method, the aseptic mouse spleen of getting shreds grinding, crosses 200 order steel meshes, and serum-free 1640 is washed once, centrifugal 5 minutes of 1500rpm.Adopt two pair salt methods of steaming to destroy red corpuscle, and remove fatty tissue, recentrifuge.Cell precipitation is white corpuscle, and transferring cell concn with complete RPMI-1640 is 5*10 6Plant in 96 orifice plates in/ml100 μ l/ hole, adds Con A (final concentration 5 μ g/ml) or LPS (final concentration 5 μ g/ml) simultaneously, 100 μ l/ holes.Other establishes blank hole (not adding inductor), 37 ℃, 5%CO 2Hatch 72h, cultivate and finish preceding 4h, add MTT100 μ l (final concentration 5 μ g/ml), after cultivation finishes, measure 540nm OD value, and by following formula calculating lymphocyte stimulation indices.
Stimulation index=experimental port OD value/control wells OD value
(3) the Cytometric influence of dialogue
Adopt anticoagulation, with leukocyte count in the note blood on the white blood cell count(WBC) instrument.
(4) statistics: experimental data is represented with X ± sd, relatively adopts the t check between group.
Experimental result is as shown in table 2 in the body:
Table 2 partial synthesis peptide (dosage: activity in vivo 0.22 μ mol/kg)
*P＜0.05， **P＜0.01
From external, intravital experimental result as can be seen, intramolecular Arg of TP-5 and Lys two residues are exchanged, do not influence former activity; With still keeping original activity behind the Val among non-natural amino acid Ida replacement TP-5.Because Ida is not the protein source acidic amino acid, in vivo can be effectively to the degraded of protease inhibitor, so the peptide compounds that contains the Ida structure among the present invention is expected to have stronger biologically stable and immunoregulatory activity.

Claims (6)

1. a compounds is characterized in that, their chemical structure of general formula is:
R 1-X 1-X 2-X 3-X 4-Tyr-R 2
X 1Be selected from arginyl (Arg), lysyl (Lys), guanidine-nitro arginyl (Arg (NO 2));
X 2Be selected from lysyl (Lys), arginyl (Arg), N-methyl glycyl (Sar), D-alanyl (D-Ala);
X 3Be selected from aspartoyl (Asp), glutamy (Glu), iminodiethanoic acid list acyl (Ida);
X 4Be selected from valyl (Val), and leucyl (Leu), β-alanyl (β-Ala), Cys;
R 1Be selected from H, Cys;
R 2Be selected from NH 2, NHMe, NHEt, NHBu, NH (CH 2) 2OH (Gol), NH (CH 2) 2NH (CH 2) 2OH, NHC (CH 3) 2CH 2OH, Aca-Phe-Met-R ' [R ' be selected from NHEt, Gol, NH (CH 2) 2NH (CH 2) 2OH and NHC (CH 3) 2CH 2OH], Lys-NHR (R=H, C 1～10Alkyl).
2. according to claim 1 compound, it is characterized in that, comprise following compound
H-Arg-Lys-Asp-Val-Tyr-Gol
H-Arg-Lys-Asp-Val-Tyr-NH(CH 2) 2NH(CH 2) 2OH
H-Arg-Lys-Asp-β-Ala-Tyr-NHEt
H-Arg-Lys-Ida-Val-Tyr-NHEt
H-Arg-Lys-Asp-β-Ala-Tyr-Aca-Phe-Met-NHEt
H-Arg-Lys-Asp-β-Ala-Tyr-Aca-Phe-Met-NHCH(CH 3) 2
H-Lys-Arg-Asp-Val-Tyr-NHEt
H-Lys-Arg-Ida-Val-Tyr-NHCH 3
H-Lys-Arg-Asp-Cys-Tyr-OH
Figure A2006101139700002C1
3. a pharmaceutical composition is characterized in that, contain medicine effective dose as described arbitrary compound of claim 1-2 and pharmaceutical carrier.
4. according to the pharmaceutical composition of claim 3, it is characterized in that described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
5. arbitrary compound among the claim 1-2 prevents and/or treats application in the illness relevant with immunologic hypofunction in preparation.
6. according to the application of claim 5, it is characterized in that the illness that described immunologic hypofunction is relevant comprises chronic hepatitis B, primary or Secondary cases T cell defect disease, viral hepatitis, respiratory tract severe infection, intractable oral cavity ulcer, postoperative weakness, tumour and AIDS.
CN200610113970A 2006-10-23 2006-10-23 N-substituted peptide amide, pharmaceutical composition and use thereof Expired - Fee Related CN101168560B (en)

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DE2938420A1 (en) * 1979-09-22 1981-04-09 Hoechst Ag, 6000 Frankfurt NEW PEPTIDES AND METHOD FOR THEIR PRODUCTION
US4298523A (en) * 1980-06-17 1981-11-03 Ortho Pharmaceutical Corporation Methods and compositions for preparation of H-ARG-X-Z-Y-TYR-R
US4505853A (en) * 1983-11-18 1985-03-19 Ortho Pharmaceutical Corporation Enzyme-resistant immunomodulatory peptides
US4629723A (en) * 1984-06-27 1986-12-16 Ortho Pharmaceutical Corporation Potent thymopentin analogs

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Address after: 210029 No. 8 Julong North Road, Sinpo District, Jiangsu, Lianyungang

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Granted publication date: 20120905

Termination date: 20181023