CN1706833A - Formyl peptide-like acceptor-1 regulator and its prepn and use - Google Patents
Formyl peptide-like acceptor-1 regulator and its prepn and use Download PDFInfo
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- CN1706833A CN1706833A CNA2004100249345A CN200410024934A CN1706833A CN 1706833 A CN1706833 A CN 1706833A CN A2004100249345 A CNA2004100249345 A CN A2004100249345A CN 200410024934 A CN200410024934 A CN 200410024934A CN 1706833 A CN1706833 A CN 1706833A
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Abstract
The present invention provides one kind of substituted quinazoline-4-ketone compounds shown in the general expression, and their preparation process and application as formyl peptide-like acceptor-1 regulator in medicine for diminishing inflammation, immunoregulating and resisting infection.
Description
Technical field
The present invention relates to class formyl peptides sample acceptor-a 1 (Formyl Peptide Receptor Like-1, FPRL1) conditioning agent, refer to that specifically a class can be used as the substituted quinazoline ketone derivatives small molecules organic compound of non-peptide class FPRL1 receptor modulators, it influences the chemotactic and the activation of neutrophil leukocyte as formyl peptides sample acceptor-1 (FPRL1) conditioning agent, brings into play regulating effect at body in the non-specific and specificity inflammation reaction.
Background technology
The chemoattractant of histocyte and microorganisms such as N-formyl peptides (fMLF) can cause the exosmosing of neutrophil leukocyte, chemotactic and activation, signal transduction pathway performance physiological effect by certain comprises chemotaxis, inflammatory reaction, immunomodulatory and anti-virus infection etc.Infecting in early days, but this class chemoattractant enhancing body nonspecific immune response ability, and pathogenic micro-organism is also removed in antagonism; But its high-caliber continuous expression then causes acute or chronic inflammation, and the pathologic process with other cytokine fellowship infectious diseases, allergic disorder and some immunological diseases works the mischief to body.Therefore, chemoattractant and associated receptor are as pharmaceutically-active novel targets, for many treatments with human diseases of high morbidity and mortality ratio provide new research direction.
The fMLF of synthetic is first found exogenous formyl peptide receptor (Formyl Peptide Receptor, FPR) agonist.Studies show that fMLF can stimulate neutrophil leukocyte to cause a series of physiological change such as cell shape changes, taxis moves, adheres to vessel wall, phagocytosis, release superoxide anion and take off the particle reaction.Other evidence show that fMLF can activate nuclear factor NF-κ B, impels secretion inflammatory factors such as phagocytic cell, starts the nonspecific immune response of body when resisting the pathogenic micro-organism invasion.Actively to the anti-infective while, a large amount of superoxide anions and proteolytic ferment that phagocytic cell produces can damage healthy tissues, as idiopathic pulmonary fibrosis (the Nicholls JM that causes because of acute lung injury, Leo LM, Kam C L, et al.Lung pathology of fatal severe acute respiratiory syndrome.Lancet, 2003,361 (9371): 1773-8).In addition, fMLF can also stimulate a series of cytokines of monocytes such as IL-1, IL-6 and IL-8 etc., in immunne response, bring into play transmission information, raise T cell and antigen presentation function by the latter's chain reaction, activation antigen specificity helper T cell 1 and 2 (Th1 and Th2), the immunological effect of generation anti-virus infection.Except that the FPR acceptor, the FPR homoreceptor of also having found two humanizeds so far is FPRL1 and FPRL2 (Formyl Peptide Receptor Like-2) acceptor, but relevant receptor structure, signal transduction pathway and pathophysiological mechanism research remain to be carried out in a deep going way.
Can discern bacterium source property chemotactic substance in view of formyl peptide receptor itself, it can not be ignored the effect in anti-infective at body.The mouse that knocks out the FPR acceptor gene is easier in infectation of bacteria than normal mouse of the same race, when using fMLF at stimulated in vitro knock out mice neutrophilic granulocyte, and its chemotactic miopragia; After in body, injecting fMLF, its migration ability disappearance (Gao JL in peripheral blood, Lee EJ, Murphy PM.Impaired antibacterial host defense in mice lacking theN-formylpeptide receptor.J Exp Med.1999 Feb 15; 189 (4): 657-62).Newest research results shows, with FPR homologous FPRL1 high expression level in neutrophilic granulocyte and monocyte surface, in body specificity and nonspecific inflammation reaction, bring into play important effect.
The FPRL1 acceptor belongs to Toxins, pertussis sensitive G i protein linked receptor, and it and FPR all are positioned at human chromosome 19q13.3.FPRL1 acceptor and FPR acceptor have 69% homology on aminoacid sequence, except that being present in neutrophilic granulocyte and monocyte, in liver cell, dendritic cell, stellate cell, microgliacyte, bone-marrow-derived lymphocyte and T lymphocyte etc., expression is arranged all.The part of known FPRL1 acceptor structurally has diversity; agonist comprises the formylated peptide quasi-molecule of above-mentioned N-; the lipid Lipoxin A4 (LXA4) that when inflammatory reaction and tissue injury, produces; helicobacter pylori excretory polypeptide Hp (2-20); the lipopolysaccharides of bacterium (Bae YS; Park JC; He R; et al.Differential signalingof formyl peptide receptor-like 1 by Trp-Lys-Tyr-Met-Val-Met-CONH2 or lipoxin A4 inhuman neutrophils.Mol Pharmacol; 2003; 64 (3): 721-30; Betten A; Bylund J; CristopheT; et al.A proinflammatory peptide from Helicobacter pylori activates monocytes toinduce lymphocyte dysfunction and apoptosis.J Clin Invest; 2001; 108 (8): 1221～8; Bylund J; Karlsson A; Boulay F; et al.Lipopolysaccharide-induced granulemobilization and priming of the neutrophil response to Helicobacter pylori peptideHp (2-20); which activates formyl peptide receptor-like 1.Infect Immun; 2002; 70 (6): 2908-14); inflammation acute reaction associated protein is (as amyloid serum protein A; amyloid-beta 1-42; HIV-1 coat protein fragment; viral protein etc.) (Su SB; Gong W; Gao JL; et al.A seven-transmembrane; Gprotein-coupled receptor; FPRL1; mediates the chemotactic activity of serum amyloidA for human phagocytic cells.J Exp Med; 1999; 189 (2): 395～402; Le Y; Gong W; TiffanyHL; et al.Amyloid (beta) 42 activates a G-protein-coupled chemoattractant receptor; FPR-like-1.J Neurosci; 2001; 21 (2): RC123; Le Y; Yazawa H; Gong W; et al.Theneurotoxic prion peptide fragment PrP (106-126) is a chemotactic agonist for the Gprotein-coupled receptor formyl peptide receptor-like 1.J Immunol; 2001,166 (3): 1448-51) etc.Discover that Cathelicidin C end check hydrolysis products LL-37 has anti-microbial effect and can weaken the activity of endotoxin that bacterium produces, it is via the function of FPRL1 receptor activation neutrophilic granulocyte, monocyte and T cell performance opposing bacterium; It can also recruit phagocyte and immunocyte migration to inflammation part except that antibiotic, the immune emergency reaction of enhancing body.FPRL1 has accumulated certain experiment basis as the potential drug treatment target spot of anti-AIDS and amyloid pathology.Simultaneously, based on also several famous laboratories expansion of immunoregulation druge screening study of FPRL1 receptor stimulant and antagonist, report as yet so far and find specific FPRL1 acceptor organic molecule part in the world.
Summary of the invention
The objective of the invention is to design the conditioning agent of the substituted quinazoline ketone derivatives small molecules formyl peptides sample acceptor-1 novel with synthesizing a class;
Another object of the present invention is to provide the method for this compounds of preparation;
A further object of the present invention just provides the conditioning agent of such compound as formyl peptides sample acceptor-1, the application in anti-inflammatory, immunomodulatory and anti-infectives.
The concrete structure of class formyl peptides sample acceptor-1 conditioning agent of the present invention is general formula (A):
Ar wherein
1, Ar
2Independently be phenyl or substituted-phenyl separately, wherein the substituting group in the substituted-phenyl be selected from arbitrarily in the following groups one, two or three: alkyl; Hydroxyl; Sulfydryl; Formamyl; Methanoyl (amine) base; Contain the substituted alkoxy or alkylamino radical or the alkane sulfydryl that comprise halogen atom, alkoxyl group or hydroxyl; Contain the replacement alkanoyloxy or alkyl amide or alcoxyl (amine) carbonyl that comprise halogen atom, alkoxyl group or hydroxyl; Alkyl, C that oxygen or amine or sulphur replace
2-C
6Thiazolinyl, phenyl, benzyl, thienyl, C
2-C
6Enoyl-, benzoyl; Contain any one that comprises alkoxyl group, alkylamino radical, two or three benzoyl, benzyl acyl group, Thenoyl, aminoacyl methyl (NH that group replaces
2COCH
2); C
2-C
6Thiazolinyl oxygen (amine) carbonyl; Benzene oxygen (amine) carbonyl; Benzyloxy (amine) carbonyl; Thiophene oxygen (amine) carbonyl; Aminoacyl methyl oxygen (amine) carbonyl; Aminoacyl methyl acyl-oxygen (amine) base; Alkoxyl group; Alkylamino radical; Cycloalkyloxy; The cycloalkanes amido; Amido; Amide group; Carbalkoxy; Cycloalkoxycarbonyl; Alkanoyloxy; Alkyl amide; Urea groups; Urylene; Alkyloyl; Nitro; Carboxyl; Aldehyde radical.
Wherein X is O, S.
The preferred substituted quinazoline ketone derivatives of the present invention has following structure type:
1. work as Ar
1For
X wherein
1Be one of following any group:
R
1Be H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2) time,
Ar
2For
X wherein
2Be one of following any group:
R
2Be H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps Ar
2For
X wherein
1, X
2Be one of following any group:
R wherein
3, R
4Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps substituting group replaces Ar in the ortho position each other
2For
X wherein
1, X
2Be one of following any group:
R wherein
5, R
6Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2).
2. work as Ar
1For
X wherein
1, X
2Be one of following any group:
R wherein
7, R
8Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2) time,
Ar
2For
X wherein
2Be one of following any group:
R wherein
2Be following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps Ar
2For
X wherein
1, X
2Be one of following any group:
R wherein
3, R
4Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps substituting group replaces Ar in the ortho position each other
2For
X wherein
1, X
2Be one of following any group:
R wherein
5, R
6Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2).
The invention also discloses the preparation method of this compounds, concrete processing step is as follows:
Wherein intermediate compound I makes by following method: with ortho-nitrophenyl formyl chloride (or adjacent nitro thiobenzoyl chlorine) and aminocompound is starting raw material, earlier in containing the dichloromethane solution of triethylamine coupled reaction taking place, then makes the adjacent aminocompound of intermediate with zinc/Glacial acetic acid as going back original reagent.
Ar wherein
1, Ar
2Be phenyl or substituted-phenyl independently of one another, wherein the substituting group in the substituted-phenyl be selected from arbitrarily in the following groups one, two or three: alkyl; Hydroxyl; Sulfydryl; Formamyl; Methanoyl (amine) base; Contain the substituted alkoxy or alkylamino radical or the alkane sulfydryl that comprise halogen atom, alkoxyl group or hydroxyl; Contain the replacement alkanoyloxy or alkyl amide or alcoxyl (amine) carbonyl that comprise halogen atom, alkoxyl group or hydroxyl; Alkyl, C that oxygen or amine or sulphur replace
2-C
6Thiazolinyl, phenyl, benzyl, thienyl, C
2-C
6Enoyl-, benzoyl, contain any one that comprise alkoxyl group, alkylamino radical, two or three benzoyl, benzyl acyl group, Thenoyl, aminoacyl methyl (NH that group replaces
2COCH
2); C
2-C
6Thiazolinyl oxygen (amine) carbonyl; Benzene oxygen (amine) carbonyl; Benzyloxy (amine) carbonyl; Thiophene oxygen (amine) carbonyl; Aminoacyl methyl oxygen (amine) carbonyl; Aminoacyl methyl acyl-oxygen (amine) base; Alkoxyl group; Alkylamino radical; Cycloalkyloxy; The cycloalkanes amido; Amido; Amide group; Carbalkoxy; Cycloalkoxycarbonyl; Alkanoyloxy; Alkyl amide; Urea groups; Urylene; Alkyloyl; Nitro; Carboxyl; Aldehyde radical.
Compound I and Compound I I obtain general formula (A) compound through cyclization, and Compound I and II carry out ring-closure reaction at N in the mixed solvent of dinethylformamide, N,N-dimethylacetamide or above-mentioned solvent and Glacial acetic acid.Sometimes reaction needed heating condition.Reaction times decides according to concrete reactant.Usually come the performance level of tracking and measuring reaction with TLC, the general post-treating method that adopts comprised that suction filtration, concentration of reaction solution eliminate solvent, extraction, column chromatography for separation etc. after reaction finished.Final product (A) detects proof with NMR.
The synthetic method of substituted quinazoline ketone heterocyclic structural unit is consulted Tetraheron Letters 1997,38 (49): 8445-8448 among the present invention.
Description of drawings
Fig. 1 is fMLF (FPR acceptor high-affinity part), the WKYMVm (W-pep that uses different concns respectively; FPR and FPRL1 receptor stimulant), MMK1 (specificity FPRL1 receptor stimulant) and C1 stimulate people's neutrophilic granulocyte to detect the secretion of beta-glucosidase enzyme.Result's demonstration is the dose-dependently relation by the secretory volume of post-stimulatory cell beta-glucuronidase and administration concentration.The effect of C1 and MMK1 are close as seen from the figure, but MMK1 has stronger avidity.
Fig. 2 is the RBL-2H3 cell that the WKYMVm (W-pep) that uses different concns respectively, MMK1, C1 and fMLF stimulate transfection humanized FPRL1 acceptor.Above-mentioned part can strengthen cell beta-glucosidase enzyme excretory activity.FMLF does not induce the receptor-mediated degranulation via FPRL1 as the agonist of FPR acceptor.Wherein WKYMVm is the most potent agonist, and C1 and MMK1's is similar in the effect detection result, but MMK1 surpasses C1 on intensity.Corresponding EC
50Value is respectively: C1:1.88 * 10
-6M; MMK1:7.17 * 10
-8M; WKYMVm:2.29 * 10
-8M.
Fig. 3. detect β-hexosaminidase secretion activity that fMLF, WKYVMm (W-pep), MMK1 and C1 act on the RBL-2H3 cell of expressing FPRL1 (left side) or FPR (right side) acceptor.The result shows that MMK1 and C1 optionally activate and express FPRL1 recipient cell β-hexosaminidase Secretory Pathway, but the secretion of expressing FPR recipient cell β-hexosaminidase is not then had influence.Find that relatively the fMLF selectively acting is in the FPR acceptor but not the FPRL1 acceptor; WKYVMm all has stirring effect to FPR and FPRL1 acceptor, all causes degranulation on the cell of expressing above-mentioned two kinds of acceptors.
Fig. 4. adopt Fluo-3 as fluorescent indicator detect C1 cause in transfection FPRL1 (on) and the effect that flows of FPR (descending) intracellular Ca2+.WKYVMm (W-pep) is the agonist (positive control) of FPR and FPRL1 acceptor.The intracellular Ca2+ stream that C1 causes is consistent with WKYVMm on usefulness, but on the intensity than WKYVMm a little less than 1000 times.Contrast finds that C1 is the weak agonist of FPR acceptor, only can trigger faint calcium current by the FPR acceptor.
Fig. 5. use Toxins, pertussis (PTX) to handle (100ng/ml, 16 hours) in advance to the RBL-2H3 cell of transfection FPRL1 acceptor, give WKYMVm (W-pep subsequently; On) or C1 (descending).Not with showing that Toxins, pertussis is handled with purple.Both inductive calcium current reactions of results suggest are by Toxins, pertussis sensitive G protein (Gi) is mediated.
To trigger extracellular, downstream signal transduction associated kinase (Extracellular Signal RelatedKinase, phosphorylation Erk) behind Fig. 6 .FPRL1 receptor activation.Use the RBL-2H3 cell of 3 kinds of ligand stimulation transfection FPRL1 acceptors respectively, ligand concentration and action time are as shown in Figure 6.The result shows that Compound C 1, WKYMVm (W-pep) and MMK1 all can be behind receptor activation make Erk that phosphorylation take place in 2-5 minute and reach the peak of reaction.But the effect of three kinds of parts has strength difference, Compound C 1 than other two parts a little less than 1000 times.
Can find out that from above-mentioned experiment compound provided by the present invention has to the FPRL1 acceptor that the chemotactic neutrophil(e) granule is thin consumingly Born of the same parents' function has with the ALI of the initiations such as active chronic inflammation such as systemic inflammatory reaction syndrome and idiopathic pulmonary fibrosis The pathology of the common sense of participation infectious diseases of substantial connection and other cell factor, allergic disease and some immunity diseases Process helps to intervene above-mentioned pathology process to the adjusting of its function, in the hope of the effectively development of the control state of an illness. Up to now, state Inside and outside find that not yet the FPRL1 acceptor is had bioactive organic micromolecule compound. It is true to learn functional experiment by associated biomolecule The general formula compound (A) that card is invented is a species specificity FPRL1 receptor stimulating agent, can be at anti-inflammatory, anti-infective and immune Be applied in the regulating drug.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) is dissolved in the N,N-dimethylacetamide that 10ml contains 5% Glacial acetic acid, adds 0.25g 4-methoxybenzaldehyde, 80 ℃ of following reacting by heating 24 hours.After reaction finishes, remove reaction solvent, get product 2-(4-methoxyl group-phenyl)-2 with column chromatography separation method, 3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C1).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.41(m，2H)，1.67(m，2H)，3.73(s，3H)，3.99(t，2H)，6.11(s，1H)，6.75(m，2H)，6.91(m，4H)，7.33-7.68(m，6H)。
Embodiment 2:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.30g 2; the 4-dimethoxy benzaldehyde contains the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; in the reaction in 24 hours of 50 ℃ of following reacting by heating; obtain product 2-(2; 4-dimethoxy-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C2).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.42(m，2H)，1.68(m，2H)，3.59(s，3H)，3.72(s，3H)，4.00(t，2H)，6.40(s，1H)，6.52(m，2H)，6.73(m，2H)，6.94-7.02(m，3H)，7.28(t，1H)，7.48(m，1H)，7.65(m，2H)。
Embodiment 3:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.27g 4-dimethylaminobenzaldehyde contain the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 60 ℃ of following reacting by heating 24 hours; obtain product 2-(4-dimethylamino-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C3).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.42(m，2H)，1.68(m，2H)，2.84(s，6H)，4.00(t，2H)，6.04(s，1H)，6.68-6.79(m，4H)，6.92(m，2H)，7.17-7.30(m，4H)，7.61(m，2H)。
Embodiment 4:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.32g 2; the 4-dichlorobenzaldehyde contains the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 100 ℃ of following reacting by heating 24 hours; obtain product 2-(2; 4-two chloro-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C4).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.42(m，2H)，1.69(m，2H)，4.00(t，2H)，6.58(s，1H)，6.78(m，1H)，6.99(m，2H)，7.35(m，1H)，7.53-7.80(m，7H)，7.93(m，1H)。
Embodiment 5:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.22g 4-tolyl aldehyde contain the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 80 ℃ of following reacting by heating 24 hours; obtain product 2-4-methyl-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C5).
1HNMR(300MHz，DMSO-d
6)δ0.91(t，3H)，1.40(m，2H)，1.68(n，2H)，2.31(m，3H)，3.99(t，2H)，6.11(s，1H)，6.78(m，2H)，6.94(m，2H)，7.18-7.35(m，6H)，7.58(m，2H)。
Embodiment 6:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.19g phenyl aldehyde contain the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 50 ℃ of following reacting by heating 24 hours; obtain product 2-phenyl-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C6).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.40(m，2H)，1.67(m，2H)，3.99(t，2H)，6.15(s，1H)，6.82-7.00(m，4H)，7.46(m，4H)，7.58-7.69(m，5H)。
Embodiment 7:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.22g 4-hydroxy benzaldehyde contain the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 70 ℃ of following reacting by heating 24 hours; get product 2-(4-hydroxyl-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C7).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.39(m，2H)，1.66(m，2H)，3.99(t，2H)，6.04(s，1H)，6.73-6.91(m，6H)，7.22(m，1H)，7.30(m，2H)，7.58(m，2H)，7.67(m，1H)。
Embodiment 8:
0.30g N-(4-butoxy-benzoyl)-2-amino-benzoyl hydrazine (1) and 0.28g piperonylaldehyde contain the N of 5% Glacial acetic acid at 10ml; in the N-N,N-DIMETHYLACETAMIDE; 100 ℃ of following reacting by heating 24 hours; get product 2-(3; 4-methylene-dioxy-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one (C8).
1HNMR(300MHz，DMSO-d
6)δ0.92(t，3H)，1.44(m，2H)，1.68(m，2H)，4.01(t，2H)，6.00(s，2H)，6.07(s，1H)，6.75-6.91(m，6H)，7.03(m，1H)，7.27(m，2H)，7.68(m，2H)。
Embodiment 9: biological activity test
1. experiment material and instrument
The RBL-2H3 cell strain of cell strain: RBL-2H3 and expression FPR or FPRL1 acceptor; Foetal calf serum (GIBCO/BRL); DMEM substratum (GIBCO/BRL); Cytochalasin B (Sigma, St.Louis, MO); Anti-phosphorylation Erk antibody and anti-Erk antibody (Cell Signaling Technologies); P-Nitrophenyl-N-acetyl-β-D-glucosamide (Sigma, St.Louis, MO); 4-Methylumbelliferyl β-D-glucuronide hydrate (Sigma, St.Louis, MO); Fluo3/AM (Molecular Probes, Eugene, OR); Toxins, pertussis (List Laboratories, Campbell, CA); G418 (Invitrogen, Carlsbad, CA); The Forma CO2gas incubator (Forma, USA); PTI Spectrofluorometer (Photon Technology International, Lawrenceville, NJ); SpectroMax 340 Plate Reader (MolecularDynamics, Sunnyvale, CA).
2. experimental technique
2.1 cell cultures
The RBL-2H3 cell cultures is in the DMEM substratum that contains 10% foetal calf serum and 2mM L-glutamine.With LipofectAmine FPR or FPRL1 receptor plasmid are changed over to wherein, select 4-5 week, select the cell clone of stably express acceptor with G418 (400ng/ml).
2.2 separation neutrophilic granulocyte
The peripheral blood of taking healthy donor is with reference to Ulmer and Flad (Ulmer ﹠amp; Flad, 1979) method of describing is carried out the Percoll gradient centrifugation.The separation efficiency of neutrophilic granulocyte is about 97%, and survival rate is greater than 98%.It is resuspended in the RPMI1640 substratum of serum-free, and cell density is 2 * 10
6Individual/ml.The donor sample number of the required hemocyte of repeated experiments is no less than 3 examples.
2.3 detect the release of beta-glucosidase enzyme
The neutrophilic granulocyte that separation is obtained is resuspended among the HBSS that contains 10 μ M Cytochalasin B, and cell density is 6.25 * 10
6Individual/ml (0.5 * 10
6Individual/80 μ l), hatched on ice 15 minutes, place 37 ℃ to place again 15 minutes.After the preincubation, get 80 μ l cell suspensions and mix with the damping fluid that 80 μ l contain the different concns agonist respectively, place to be placed in 10 minutes in 37 ℃ and stop taking off particle reaction, cleer and peaceful cell in the centrifugation on ice.Beta-glucosidase enzyme quantivative approach: cleer and peaceful 20 μ l 10mM 4-Methylumbelliferyl β-D-glucuronide hydrates on the 20 μ l were hatched under 37 ℃ 15 minutes in containing the 0.1M sodium acetate soln (pH4.0) of 0.1%Triton X-100.Add 300 μ l and contain stop buffer (pH10.4) termination reaction of 50mM Glycine and 5mM EDTA.Under 365nm excitation wavelength and 460nm emission wavelength, detect fluorescent reaction with the PTI spectrofluorometer immediately.Total beta-glucosidase enzyme amount records from contain 0.1%Triton X-100 cell pyrolysis liquid in the cell.The result represents with the per-cent that beta-glucosidase enzyme content in the supernatant accounts for total Polyglucosidase content in the cell.
2.4 detect the release of β-hexoside enzyme
Cell inoculation is after 24 orifice plates are cultivated 48 hours, if Toxins, pertussis treatment group and non-Toxins, pertussis treatment group, wherein the Toxins, pertussis treatment group is given the Toxins, pertussis of 100ng/ml, hatch after 18 hours cell is simply washed, then cell and the 10 μ M Cytochalasin B that are dissolved in the HBSS (HBSS-HB) of 20mM HEPES (pH7.4) and 0.2%BSA were hatched 15 minutes on ice altogether, hatched 15 minutes at 37 ℃ times and 1mM P-nitrophenyl-N-aeetyl-β-D-glucosamide at last.Behind the flushing cell, after 10 minutes, place termination on ice to take off the particle reaction culture plate in 37 ℃ of stimulations with the agonist that illustrates dosage.The β of emiocytosis-hexoside enzyme quantivative approach: with the P-nitrophenyl-N-acetyl-β-D-glucosamide of cleer and peaceful 10 μ l 1mM on the 20 μ l in 37 ℃ hatch 1 hour after, add 200 μ l 0.1M Na
2CO
3With 0.1M NaHCO
3(pH10) termination reaction is with the light absorption value at SpectroMax 340 Plate Reader mensuration 405nm place.Total β-hexoside enzyme amount records from 0.1%Triton X-100 cell pyrolysis liquid in the cell.The result represents with the per-cent that β in the supernatant-hexoside enzyme content accounts for total β-hexoside enzyme content in the cell.
2.5 calcium current is measured
Under 37 ℃, hatched 1 hour with no trysinization liquid collecting cell and 4 μ M Fluo-3/AM.The Toxins, pertussis treatment group is given the Toxins, pertussis pre-treatment 18 hours of 100ng/ml.After the cell flushing, counting, each calcium current is measured and is needed 5 * 10
5Individual cell.Use the PTI spectrofluorometer to detect excitation wavelength and be fluorescent absorption value under the 525nm as 488nm and emission wavelength.
2.6 detect the activation of cell signalling associated kinase Erk
Use 3 kinds of parts (WKYVMm, MMK1 and Compound C 1) to stimulate the RBL-2H3 cell of transfection FPRL1 acceptor respectively, ligand concentration and action time are as shown in Figure 6.At each time point collecting cell, carry out electrophoresis after the cracking and detect the Erk phosphorylation with Western Blot method respectively, find two band: p44 (Erk1) and p42 (Erk2) with anti-phosphorylation Erk antibody.Anti-Erk antibody detects non-phosphorylating Erk in the equivalent cell pyrolysis liquid in contrast.
3. experiment conclusion
(1) Compound C 1 has identical biological activity with FPRL1 receptor selective agonists MMK1 (small peptide), but the intensity of C1 effect a little less than.The exciting strength ratio WKYVMm of C1 reduces by 1000 times in the calcium current experiment;
(2) take off that confirmation Compound C 1 is the receptor selective agonists of FPRL1 in the experiment of particle experiment and calcium current;
(3) intracellular Ca2+ of Compound C 1 initiation is flowed through by protein mediated to Toxins, pertussis sensitive G i, and FPRL1 acceptor and the coupling mutually of Toxins, pertussis sensitive G i albumen are described.
(4) Compound C 1 activate behind the FPRL1 acceptor can the triggering signal transduction pathway in the Erk phosphorylation reaction.
4. reference
Ulmer，A.J.，and?Flad，H.D.(1979)J.Immunol.Methods?30，1-10.
Claims (7)
1. class general formula (A) formyl peptides sample acceptor-1 conditioning agent:
Ar wherein
1, Ar
2Be phenyl or substituted-phenyl independently of one another, wherein the substituting group in the substituted-phenyl be selected from arbitrarily in the following groups one, two or three: alkyl; Hydroxyl; Sulfydryl; Formamyl; Methanoyl (amine) base; Contain the substituted alkoxy or alkylamino radical or the alkane sulfydryl that comprise halogen atom, alkoxyl group or hydroxyl; Contain the replacement alkanoyloxy or alkyl amide or alcoxyl (amine) carbonyl that comprise halogen atom, alkoxyl group or hydroxyl; Alkyl, C that oxygen or amine or sulphur replace
2-C
6Thiazolinyl, phenyl, benzyl, thienyl, C
2-C
6Enoyl-, benzoyl, contain any one that comprise alkoxyl group, alkylamino radical, two or three benzoyl, benzyl acyl group, Thenoyl, aminoacyl methyl (NH that group replaces
2COCH
2); C
2-C
6Thiazolinyl oxygen (amine) carbonyl; Benzene oxygen (amine) carbonyl; Benzyloxy (amine) carbonyl; Thiophene oxygen (amine) carbonyl; Aminoacyl methyl oxygen (amine) carbonyl; Aminoacyl methyl acyl-oxygen (amine) base; Alkoxyl group; Alkylamino radical; Cycloalkyloxy; The cycloalkanes amido; Amido; Amide group; Carbalkoxy; Cycloalkoxycarbonyl; Alkanoyloxy; Alkyl amide; Urea groups; Urylene; Alkyloyl; Nitro; Carboxyl; Aldehyde radical;
X is O, S.
2. formyl peptides sample acceptor-1 conditioning agent according to claim 1 is characterized in that:
Work as Ar
1For
X wherein
1Be one of following any group:
R
1Be H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2) time,
Ar
2For
X wherein
2Be one of following any group:
R
2Be H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps Ar
2For
X wherein
1, X
2Be one of following any group:
R wherein
3, R
4Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps substituting group replaces Ar in the ortho position each other
2For
X wherein
1, X
2Be one of following any group:
R wherein
5, R
6Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2).
3. formyl peptides sample acceptor-1 conditioning agent according to claim 1 is characterized in that:
Work as Ar
1For
X wherein
1, X
2Be one of following any group:
R wherein
7, R
8Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2) time,
Ar
2For
X wherein
2Be one of following any group:
R wherein
2Be following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps Ar
2For
X wherein
1, X
2Be one of following any group:
R wherein
3, R
4Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2);
Perhaps substituting group replaces Ar in the ortho position each other
2For
X wherein
1, X
2Be one of following any group:
R wherein
5, R
6Independent separately is following any one substituting group: H; Alkyl; Contain the substituted alkyl that comprises halogen atom, alkoxyl group or hydroxyl; C
2-C
6Thiazolinyl; Phenyl; Benzyl; Thienyl; Aminoacyl methyl (NH
2COCH
2).
4. formyl peptides sample acceptor-1 conditioning agent according to claim 1, described compound is selected from:
1) 2-(4-methoxyl group-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
2) 2-(2,4-dimethoxy-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
3) 2-(4-dimethylamino-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
4) 2-(2,4-two chloro-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
5) 2-4-methyl-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
6) 2-phenyl-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
7) 2-(4-hydroxyl-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one
8) 2-(3,4-methylene-dioxy-phenyl)-2,3-dihydro-3-(4-butoxy-benzamide)-1H-quinazoline-4-one.
5. the preparation method of formyl peptides sample acceptor-1 conditioning agent as claimed in claim 1 is characterized in that compound is to make by following steps:
1) preparation of midbody compound I
With ortho-nitrophenyl formyl chloride (or adjacent nitro thiobenzoyl chlorine) and aminocompound is starting raw material, in containing the dichloromethane solution of triethylamine coupled reaction takes place earlier, then makes the adjacent aminocompound of intermediate with zinc/Glacial acetic acid as going back original reagent;
Ar wherein
1, Ar
2Be phenyl or substituted-phenyl independently of one another, wherein the substituting group in the substituted-phenyl be selected from arbitrarily in the following groups one, two or three: alkyl; Hydroxyl; Sulfydryl; Formamyl; Methanoyl (amine) base; Contain the substituted alkoxy or alkylamino radical or the alkane sulfydryl that comprise halogen atom, alkoxyl group or hydroxyl; Contain the replacement alkanoyloxy or alkyl amide or alcoxyl (amine) carbonyl that comprise halogen atom, alkoxyl group or hydroxyl; Alkyl, C that oxygen or amine or sulphur replace
2-C
6Thiazolinyl, phenyl, benzyl, thienyl, C
2-C
6Enoyl-, benzoyl, contain any one that comprise alkoxyl group, alkylamino radical, two or three benzoyl, benzyl acyl group, Thenoyl, aminoacyl methyl (NH that group replaces
2COCH
2); C
2-C
6Thiazolinyl oxygen (amine) carbonyl; Benzene oxygen (amine) carbonyl; Benzyloxy (amine) carbonyl; Thiophene oxygen (amine) carbonyl; Aminoacyl methyl oxygen (amine) carbonyl; Aminoacyl methyl acyl-oxygen (amine) base; Alkoxyl group; Alkylamino radical; Cycloalkyloxy; The cycloalkanes amido; Amido; Amide group; Carbalkoxy; Cycloalkoxycarbonyl; Alkanoyloxy; Alkyl amide; Urea groups; Urylene; Alkyloyl; Nitro; Carboxyl; Aldehyde radical;
2) Compound I and Ar
2CHO is at N, and dinethylformamide, N,N-dimethylacetamide or at N in the mixed solvent of dinethylformamide, N,N-dimethylacetamide and Glacial acetic acid, carry out ring-closure reaction and make under heating,
Ar wherein
1, Ar
2Independently be phenyl or substituted-phenyl separately, wherein the substituting group in the substituted-phenyl be selected from arbitrarily in the following groups one, two or three: alkyl; Hydroxyl; Contain the substituted alkoxy or the alkylamino radical that comprise halogen atom, alkoxyl group or hydroxyl; Contain the replacement alkanoyloxy or the alkyl amide that comprise halogen atom, alkoxyl group or hydroxyl; The alkyl that oxygen or amine or sulphur replace, contain the substituted alkyl, the C that comprise halogen atom, alkoxyl group or hydroxyl
2-C
6Thiazolinyl, phenyl, benzyl, C
2-C
6Enoyl-, benzoyl, contain any one that comprise alkoxyl group, alkylamino radical, two or three benzoyl, benzyl acyl group, Thenoyl, aminoacyl methyl (NH that group replaces
2COCH
2); Alkoxyl group; Alkylamino radical; Cycloalkyloxy; The cycloalkanes amido; Amido; Amide group; Carbalkoxy; Cycloalkoxycarbonyl; Alkanoyloxy; Alkyl amide; Urea groups; Urylene; Alkyloyl; Nitro; Carboxyl; Aldehyde radical;
X is O, S.
6. the preparation method of formyl peptides sample acceptor-1 conditioning agent according to claim 5, it is characterized by ring-closure reaction need carry out under 50～100 ℃ heating condition.
7. the described formyl peptides sample of claim 1 acceptor-1 conditioning agent is used in preparation anti-inflammatory, immunomodulatory and anti-infectives.
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| CNB2004100249345A CN100506802C (en) | 2004-06-04 | 2004-06-04 | Formyl peptide-like acceptor-1 regulator and its Preparation and use |
| PCT/CN2005/000736 WO2005118559A1 (en) | 2004-06-04 | 2005-05-26 | A type of formyl peptide receptor-like 1 regulator, preparation method and use thereof |
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| CNB2004100249345A CN100506802C (en) | 2004-06-04 | 2004-06-04 | Formyl peptide-like acceptor-1 regulator and its Preparation and use |
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| WO (1) | WO2005118559A1 (en) |
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| CN103880761A (en) * | 2014-03-25 | 2014-06-25 | 天津大学 | Method for synthesizing 4(3H)-quinazolinone derivative by using cyclization elimination one-pot method |
| CN104114541A (en) * | 2011-11-10 | 2014-10-22 | 阿勒根公司 | 2,5-dioxoimidazolidin-1-yl-3-phenylurea derivatives as formyl peptide receptor like-1 (FPRL-1) receptor modulators |
| CN105384698A (en) * | 2015-10-20 | 2016-03-09 | 陕西科技大学 | Synthetic method for quinazolinone FPR2 formyl peptide receptor agonist |
| CN105705484A (en) * | 2013-11-21 | 2016-06-22 | 阿勒根公司 | Phenylcarbamate derivatives as formyl peptide receptor modulators |
| CN105814019A (en) * | 2013-11-28 | 2016-07-27 | 杏林制药株式会社 | Urea derivative or pharmacologically acceptable salt thereof |
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| SG11201406629VA (en) | 2012-04-16 | 2014-11-27 | Allergan Inc | (2-ureidoacetamido)alkyl derivatives as formyl peptide receptor 2 modulators |
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| DE2232532A1 (en) * | 1972-07-03 | 1974-01-31 | Hoechst Ag | BIS-N-HETEROCYCLIC COMPOUNDS WITH CHEMOTHERAPEUTIC PROPERTIES AND METHOD FOR THEIR PRODUCTION |
| DE19501481A1 (en) * | 1995-01-19 | 1996-07-25 | Bayer Ag | 2,8-disubstituted quinazolinones |
| JP3486752B2 (en) * | 1995-08-30 | 2004-01-13 | 株式会社大塚製薬工場 | Method for producing quinazolin-4-one derivative |
| AUPR201600A0 (en) * | 2000-12-11 | 2001-01-11 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivative |
| TW200306839A (en) * | 2002-02-06 | 2003-12-01 | Novartis Ag | Quinazolinone derivatives and their use as CB agonists |
-
2004
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| CN105705484A (en) * | 2013-11-21 | 2016-06-22 | 阿勒根公司 | Phenylcarbamate derivatives as formyl peptide receptor modulators |
| CN105705484B (en) * | 2013-11-21 | 2018-09-14 | 阿勒根公司 | Carbanilate derivative as formyl peptide receptor conditioning agent |
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| CN103880761A (en) * | 2014-03-25 | 2014-06-25 | 天津大学 | Method for synthesizing 4(3H)-quinazolinone derivative by using cyclization elimination one-pot method |
| CN105384698A (en) * | 2015-10-20 | 2016-03-09 | 陕西科技大学 | Synthetic method for quinazolinone FPR2 formyl peptide receptor agonist |
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| WO2005118559A1 (en) | 2005-12-15 |
| CN100506802C (en) | 2009-07-01 |
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