CN112851635A - Cyclic sulfones compound and preparation method, application and pharmaceutical composition thereof - Google Patents
Cyclic sulfones compound and preparation method, application and pharmaceutical composition thereof Download PDFInfo
- Publication number
- CN112851635A CN112851635A CN201911189434.XA CN201911189434A CN112851635A CN 112851635 A CN112851635 A CN 112851635A CN 201911189434 A CN201911189434 A CN 201911189434A CN 112851635 A CN112851635 A CN 112851635A
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- Prior art keywords
- compound
- amino
- pharmaceutically acceptable
- hydroxy
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- -1 Cyclic sulfones compound Chemical class 0.000 title claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 14
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- 108010018951 Interleukin-8B Receptors Proteins 0.000 claims abstract description 21
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- 201000010099 disease Diseases 0.000 claims abstract description 11
- 230000001404 mediated effect Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 163
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
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- 229940124803 CXCR2 antagonist Drugs 0.000 abstract description 7
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 77
- 230000015572 biosynthetic process Effects 0.000 description 51
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- 235000002639 sodium chloride Nutrition 0.000 description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
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- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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Abstract
The invention belongs to the technical field of pharmacy, and relates to a cyclic sulfone compound, a preparation method, application and a pharmaceutical composition thereof. The cyclic sulfone compound is represented by a formula (I), is a CXCR2 antagonist, and can be used for preventing and/or treating CXCR2 receptor-mediated diseases.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and relates to a CXCR2 antagonist as well as a preparation method and application thereof.
Background
Chemokines are low molecular weight (mostly 8-10kDa) proteins capable of chemotactic cells for directed movement, consisting of 70-100 amino acids. Chemokines are classified into four major classes, CXC, CC, C, and CX3C, depending on the number of highly conserved cysteine residues at the N-terminus of their peptide chains and their relative positions. Studies have shown that chemokines can be released from many inflammatory and structural cells upon stimulation and act through chemokine receptors of the G protein-coupled receptor (GPCR) superfamily. Among these, the chemokine receptor CXCR2 is expressed on a variety of cells including neutrophils, macrophages, vascular endothelial cells, oligodendrocyte precursor cells, myeloid-derived suppressor cells, and tumor cells, and functions in conjunction with CXC chemokines containing the glutamate-leucine-arginine motif (+ ELR), such as interleukin-8 (IL-8 or CXCL8) or growth-related oncogenes (GRO α, β, γ or CXCL1,2,3) (see Zarbock et al, Front. Immunol.,3:1 (2012); Ley et al, am. J Physiol-Reg I283: R7-R28 (2002); Kurareva et al, curr. Opin. Pharmacol.30:27 (2016)).
Binding of the CXCR2 receptor to its ligand induces many different cellular responses, playing an important role in a variety of diseases such as inflammation, tumors, and the central nervous system. Blocking or eliminating CXCR2 can significantly reduce leukocyte recruitment, tissue injury, and mortality in models of inflammatory diseases, such as chronic obstructive pulmonary disease, acute lung injury, asthma, and atherosclerosis. Currently, some small molecule compounds, such as Danirixin, AZD5069 and Navarixin, etc., as CXCR2 antagonists, have been tested in clinical trials for diseases such as chronic obstructive pulmonary disease, asthma, etc. (see Neamati et al, therapeutics, 7:1543 (2017)).
Studies have shown that + ELR chemokines have angiogenic properties, such as high expression of CXCR2 ligands including Growth regulating oncogenes GRO-alpha, GRO-beta, GRO-gamma, and IL-8, etc., and binding to CXCR2 expressed on the surface of vascular endothelial cells, neutrophils in peripheral blood vessels and activating angiogenesis, promoting tumor Growth in colorectal cancer models (see Damme et al, Cytokine Growth F. R., 22: 345 (2011)).
Bone Marrow Derived Suppressor Cells (MDSCs) overexpress CXCR2 in the tumor microenvironment. Multiple studies have demonstrated that MDSCs play a crucial role in protecting tumors from cytotoxic T cell-mediated antitumor effects and in inhibiting the efficacy of immune checkpoint blockade. Apoptosis protein-1 (PD-1) and infiltration of MDSCs by T cells are key factors in tumor immune escape, and numerous studies have shown that blocking CXCR2 can prevent migration of neutrophils and myelosuppressive cells from the bone marrow to the tumor site, increase infiltration of T cells in tumors and increase the efficacy of PD-1/PD-L1 inhibitors in mouse tumor models (see Mackall et al Sci. Transl. Med., 6: 237 (2014); Sansom et al Cancer Cell,29:832 (2016)). CXCR2 antagonists may also directly inhibit the proliferation of tumor cells. Studies have shown that treatment of human melanoma cells with a CXCR2 small molecule antagonist results in a significant decrease in cell proliferation and a dose-dependent relationship after 72 hours of treatment with a CXCR2 antagonist compared to the control (see Li et al med. clin-barcelona,152:425 (2019)).
In addition, CXCR2 is highly expressed on Oligodendrocytes (OPCs) in the Central Nervous System (CNS) and affects neutrophil-mediated demyelination and OPC-mediated myelin repair, while exerting peripheral functions to promote demyelination and affect CNS mechanisms to impair remyelination, so CXCR2 has also become a potential target for recent treatment of central nervous system diseases such as multiple sclerosis, brain injury diseases, and alzheimer's disease (see Lane et al j.virol.,93: e00240-19 (2019); McLarno et al j.neuroillum., 12: 144 (2015)).
In view of the key role of CXCR2 in pathogenesis of various diseases, the invention provides a CXCR2 antagonist and a preparation method thereof, which can be used for treating or preventing various diseases mediated by CXCR 2.
Disclosure of Invention
The technical problem solved by the invention is to provide a novel CXCR2 antagonist, a preparation method, a pharmaceutical composition and an application thereof, and the antagonist has stronger antagonistic activity on a chemokine receptor CXCR2, so that the antagonist has a prevention and/or treatment effect on a CXCR2 receptor mediated disease.
In order to solve the technical problem, the invention provides the following technical scheme:
in one aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R1、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl.
Preferably, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R1Selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl;
R2selected from hydrogen, fluorine, chlorine;
R3selected from hydrogen, chlorine, bromine.
In particular, preferred compounds according to the invention are the following:
on the other hand, the technical scheme of the invention also provides a preparation method of the compound.
A compound represented by the formula (1) was prepared by the method-1:
R1、R2and R3Each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
(1) Taking the compound A as a starting material, and preparing a compound B through acylation reaction;
(2) preparing a compound C from the compound B through cyclization and chlorosulfonylation;
(3) carrying out reduction reaction on the compound C to prepare a compound D;
(4) reacting the compound D with chloropropionic acid to prepare a compound E;
(5) preparing a compound F from the compound E through intramolecular acylation reaction;
(6) carrying out oxidation reaction on the compound F to prepare a compound G;
(7) preparing a compound H from the compound F through a ring opening reaction;
(8) reacting compound H with isocyanate to prepare the compound or pharmaceutically acceptable salt thereof.
A compound represented by the formula (1) was prepared by the method-2:
R1、R2and R3Each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
(1) Carrying out reduction reaction on the compound G to prepare a compound I;
(2) preparing a compound J from the compound I through intramolecular dehydration reaction;
(3) preparing a compound K from the compound J through a ring-opening reaction;
(4) reacting compound H with an isocyanate to prepare the compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof.
A compound represented by the formula (1) was prepared by the method-3:
R1、R2and R3Each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
(1) Reacting the compound L with aniline to prepare a compound M;
(2) reacting compound M with compound K to prepare a compound, a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof.
Preparation of a Compound represented by the formula (1) by Process-4:
R1、R2and R3Each independently selected from hydrogen and halogenPlain, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
(1) Preparing a compound N from the compound K through a reduction reaction;
(2) reacting compound N with an isocyanate to prepare the compound, a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof.
Preparation of a Compound represented by the formula (1) by Process-5:
R1、R2and R3Each independently selected from hydrogen, halogen, C1-3 alkyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl
(1) Reacting compound N with compound M to prepare the compound, a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof.
In a further aspect of the present invention there is provided a pharmaceutical composition comprising said compound, a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient; preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients for preventing and/or treating inflammatory diseases, tumors, autoimmune diseases or neurological diseases, other than the compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and/or treating inflammatory diseases, tumors, autoimmune diseases or neurological diseases.
In yet another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the compounds, stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier or excipient; preferably, the pharmaceutical formulation is selected from the following pharmaceutical dosage forms: parenteral formulations, such as injection solutions or suspensions; enterally, e.g., orally, such as tablets or capsules; formulations for topical administration, for example lotions, gels, ointments, creams, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.
In still another aspect, the present invention also provides a use of the compound, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of an inflammatory disease, a tumor, an autoimmune disease, or a neurological disease. In other words, the present invention provides a method for preventing and/or treating an inflammatory disease, a tumor, an autoimmune disease or a neurological disease, which comprises administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of the compound, a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
Some of the terms used in the present invention are defined below, and other undefined terms have meanings well known to those skilled in the art.
Halogen means fluorine, chlorine, bromine or iodine.
"optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with halogen" means that halogen may, but need not, be present, and the description includes the case where alkyl is substituted with halogen and the case where alkyl is not substituted with halogen.
The compounds of the invention may contain one or more chiral centers, which exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof (e.g., racemic mixtures), are within the scope of the present invention.
The compounds of the present invention include geometric isomers thereof. For example, if the compounds of the present invention contain double bonds or fused rings, these compounds may exist as geometric isomers, and their cis, trans forms and mixtures of cis and trans forms are included in the scope of the present invention.
The compounds of the present invention include tautomers thereof. Tautomers refer to structural isomers of different energies that are interconverted via a low energy barrier.
The compounds of the present invention also include isotopically-labeled compounds thereof, in which one or more atoms are replaced by atoms naturally found to have the same atomic number, but a different atomic mass or mass number. Examples include, but are not limited to: hydrogen isotope2H and3h; carbon isotope11C、13C and14c; isotope of chlorine36Cl; isotopes of fluorine18F; iodine isotope123I and125i; isotope of nitrogen13N and15n; oxygen isotope15O、17O and18o; isotope of phosphorus32Isotopes of P and sulfur35S。
Various hydrates and solvates of the compound or salt thereof of the present invention and polymorphic forms thereof (polymorphisms) are also included in the scope of the present invention.
Prodrugs of the compounds described herein are also included within the scope of the invention. Some derivatives of the compounds described in the present invention have weak pharmacological activity or no pharmacological activity themselves, but when these derivatives are administered into or onto the body, they may be converted into the compounds described in the present invention having pharmacological activity by means of, for example, hydrolytic cleavage, and the like, and these derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, vol.14, ACS Symposium Series (t.higuchi and w.stella) and Bioreversible Carriers in Drug Design, Pergamon Press,1987(ed.e.b.roche, American Pharmaceutical Association).
The compounds of the present invention include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts are salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are described in detail in j.pharma.sci.,1977,66,1-19 by Berge et al, which is incorporated herein by reference. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic bases, or inorganic and organic acids, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, dihydrogenphosphate, metaphosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprylate, or a mixture thereof, Citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.
When used as a medicament, the compounds of the present invention are generally administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions of the compounds of the present invention and a pharmaceutically acceptable carrier, diluent or excipient are also included within the scope of the present invention. As used herein, carriers, adjuvants, excipients include any and all solvents, diluents or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. In Remington: the Science and Practice of Pharmacy, 21stedition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. 1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparationThe contents of which are hereby incorporated by reference.
The compositions of the present invention may be administered by any route suitable for the condition to be treated. In particular by administration in the form: parenterally, e.g., in the form of injectable solutions or suspensions; enterally, e.g., orally, e.g., in tablet or capsule form; topically, for example in the form of a lotion, gel, ointment or cream or in the form of a nasal or suppository. Topical application is, for example, application to the skin. Another form of topical administration is to the eye.
The pharmaceutical compositions may be administered in solid, semi-solid, liquid or gaseous form, or may be in a dry powder, such as lyophilized form. Pharmaceutical compositions can be packaged in a form convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the route of administration. Implantable sustained release formulations, as well as transdermal formulations, are also contemplated.
Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.
The compounds of the present invention may be used alone or in combination with other therapeutic agents for the treatment of the diseases or conditions described herein, such as cancer. In certain embodiments, the compounds of the present invention are combined in a pharmaceutical combination formulation, or as a combination therapy in a dosing regimen, with a second compound having anti-hyperproliferative properties or for the treatment of a hyperproliferative disease, such as cancer. The second compound of the pharmaceutical combination or dosing regimen preferably has complementary activities to the compounds of the present invention such that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of the present invention are combined with other anti-tumor agents. The anti-tumor medicine comprises: alkylating agents including, but not limited to, cyclophosphamide, mechlorethamine, melphalan, cinchonine, carmustine; platinoids including but not limited to carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors including, but not limited to, topotecan, camptothecin, topotecan, irinotecan; antibiotics, including but not limited to, anthracyclines, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; anti-microtubule or anti-mitotic agents including, but not limited to, paclitaxel, vinorelbine, docetaxel, doxorubicin; antimetabolites including, but not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine (mecaptoprine), thioguanine, and gemcitabine; antibodies, including but not limited to herceptin, bevacizumab; hormones, including but not limited to letrozole (letrozole), vorozole (vorazole), tamoxifen, toremifene, fulvestrant, flutamide, nilutamide, triptorelin; kinase inhibitors, EGFR kinase inhibitors, including but not limited to gefitinib (gefitinib), erlotinib (erlotinib), lapatinib (lapatinib), afatinib (afatinib); VEGFR inhibitors including, but not limited to, Sorafenib (Sorafenib), regrafenib (Regorafenib), Sunitinib (Sunitinib), Cabozantinib (Cabozantinib), Pazopanib (Pazopanib), vandetanib (vandetanib), axitinib (axitinib); ALK inhibitors including, but not limited to, Crizotinib (Crizotinib), ceritinib (ceritinib), Alectinib; Bcr-Abl inhibitors, including but not limited to Imatinib (Imatinib), panatinib (Ponatinib), Nilotinib (Nilotinib), Dasatinib (Dasatinib); BTK inhibitors, including but not limited to Ibrutinib (Ibrutinib); B-RAF inhibitors, including but not limited to Vemurafenib (Vemurafenib); cyclin-dependent kinase CDK4/6 inhibitors, Palbociclib (Palbociclib); mTOR inhibitors, including but not limited to rapamycin (rapamycin), everolimus (everolimus); sirtuin inhibitors, including but not limited to vorinostat (vorinostat); PD1/PDL1 antibody, Keytruda (Pembrolizumab), Opdivo (Nivolumab).
In yet another aspect, the invention also provides the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the manufacture of a medicament for the prevention and/or treatment of a CXCR2 receptor mediated disease, wherein the CXCR2 receptor mediated disease comprises chronic obstructive pulmonary disease, asthma, cystic fibrosis, cancer, arthritis, psoriasis, inflammatory bowel disease, pain, multiple sclerosis, alzheimer's disease, parkinson's disease.
The beneficial technical effects are as follows: the compounds of the invention show significant antagonistic activity against CXCR2 in an in vitro test.
Detailed Description
The following are specific examples of the present invention, which further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
Preparation method
The compounds of the present invention may be synthesized according to the synthetic schemes herein and/or by techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthetic methods.
In one general synthetic approach, compounds of formula (I) were prepared according to method-1.
Method-1
Compounds 1,2
R1Cl or Me
R2Either Cl or F
Specifically, in the method-1, the polysubstituted diaryl urea derivative of the invention is described in the invention. Can be prepared by 8-step reaction. For example, compound A is used as a starting material, and compound B is prepared through acylation reaction; preparing a compound C from the compound B through cyclization and chlorosulfonylation; carrying out reduction reaction on the compound C to prepare a compound D; reacting the compound D with chloropropionic acid to prepare a compound E; preparing a compound F from the compound E through intramolecular acylation reaction; carrying out oxidation reaction on the compound F to prepare a compound G; preparing a compound H from the compound F through a ring opening reaction; reacting the compound H with isocyanate to prepare the polysubstituted diaryl urea derivative.
In another general synthetic method, a compound of formula (I) is prepared according to method-2.
Method-2
Compound 4,6-15
R1=F,Cl,Br,Me,CF3Or H
R2F, Cl or H
R3Cl, Me or H
Specifically, in Synthesis Process-2, the polysubstituted diaryl urea derivative of the invention can be prepared by a 10-step reaction. For example, compound G can be prepared by a 6-step reaction using compound A as a starting material, using method-1; carrying out reduction reaction on the compound G to prepare a compound I; preparing a compound J from the compound I through intramolecular dehydration reaction; preparing a compound K from the compound J through a ring-opening reaction; reacting the compound H with isocyanate to prepare the polysubstituted diaryl urea derivative.
In another general synthetic method, a compound of formula (I) is prepared according to method-3.
Method-3
Compounds 23 to 27
R1Cl, Br or Me
R2F, Cl or H
Specifically, in the synthesis method-3, the polysubstituted diaryl squaramide derivative provided by the invention can be prepared through 11-step reaction. For example, compound K is prepared by a 9-step reaction using compound a as a starting material, using method-1 and method-2; taking the compound L as another starting material, and preparing a compound M by reacting the compound L with aniline; the compound M reacts with the compound K to prepare the polysubstituted diaryl squaramide derivative.
In another general synthetic method, a compound of formula (I) is prepared according to method-4.
Method-4
Compound 3,5,16-22
R1=F,Cl,Br,Me,CF3Or H
R2F, Cl or H
R3Me or H
Specifically, in Synthesis Process-4, the polysubstituted diaryl urea derivative of the invention can be prepared by an 11-step reaction. For example, compound K is prepared by a 9-step reaction using compound a as a starting material, using method-1 and method-2; preparing a compound N from the compound K through a reduction reaction; the compound N reacts with isocyanate to prepare the polysubstituted diaryl urea derivative.
In another general synthetic method, a compound of formula (I) is prepared according to method-5.
Method-5
Compounds 28 to 32
R1Cl, Br or Me
R2H, F or Cl
Specifically, in Synthesis Process-5, the polysubstituted bisaryl squarylide of the invention described herein can be prepared by a 12-step reaction. For example, compound K is prepared by a 10-step reaction using method-1, method-2 and method-4, starting with compound a; by the method-3, a compound M is prepared by reacting a compound L with aniline, wherein the compound L is used as another starting material; the compound N and the compound M react to prepare the polysubstituted diaryl squaramide derivative.
The compounds of the present invention may be synthesized according to one or more of the synthetic schemes herein and/or by techniques well known in the art. One skilled in the art will recognize that the synthetic methods of certain embodiments described in detail herein can be readily adapted to synthesize other embodiments. In some embodiments, the compounds described herein may be prepared by an appropriate combination of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as alfa aesar (china) chemical limited, or are readily prepared using synthetic methods commonly used in the art.
1H NMR spectra were recorded on instruments operated at 400MHz or 500 MHz.1H NMR spectra were obtained as a solution (reported in ppm) using CDCl3(7.26ppm) or DMSO-d6(2.50ppm) or internal tetramethylsilane (0.00ppm) as reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants given are in hertz (Hz).
In the following preparations and examples, "Me" means methyl, "Et" means ethyl, "Boc" means t-butyloxycarbonyl, "PE" means petroleum ether, "EtOAc" means ethyl acetate, "MeOH" means methanol, "DMSO-d6"refers to deuterated dimethylsulfoxide," DCM "refers to dichloromethane," rt "refers to room temperature," mL "refers to mL," mmol "refers to millimole," μ M "refers to micromole," nM "refers to nanomole," and "deg.C" refers to degrees Celsius.
Example 1: synthesis of 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxo-4-thiochromanon-7-yl) urea (Compound 1)
Step 1: synthesis of N- (3-chlorophenyl) pivaloamide
Placing 58.8g of 3-chloroaniline in a 1L eggplant-shaped bottle, adding 300mL of LDCM, and adding 96.5mL of Et under vigorous stirring3And N, after the temperature of the reaction liquid is reduced to 0 ℃, slowly dropwise adding 68.4mL of PivCl, gradually heating to room temperature after dropwise adding, and reacting for 1 hour. Adding water to quench the reaction, extracting twice with dichloromethane, combining organic phases, washing once with saturated salt solution, drying and evaporating to obtain a light yellow solid, performing ultrasonic treatment with a mixed solution of EA/PE (1: 10), and filtering to obtain a white solid 93.7g, 96% yield).
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.84(t,J=2.0Hz,1H),7.59(ddd,J=8.2,1.9,0.8Hz,1H),7.31(t,J=8.1Hz,1H),7.08(ddd,J=8.0,2.1,0.9Hz,1H),1.22(s,9H).
MS(ESI+)m/z 212.1[M+H]+。
Step 2: synthesis of 2- (tert-butyl) benzo [ d ] oxazole-7-sulfonyl chloride
Placing 30g of N- (3-chlorphenyl) pivalic amide into a 2L eggplant-shaped bottle, adding 300mL of LTHF, replacing argon with the reaction liquid, cooling to-78 ℃, slowly dropwise adding 150mL (2.5M) of N-butyllithium, heating to-20 ℃ within 45 minutes after dropwise adding, reacting for 2 hours, cooling to-78 ℃ again, and dropwise adding 75mL of SO2Cl2The reaction was carried out at-78 ℃ for 2 hours and warmed to room temperature overnight. Adding water to quench the reaction, washing with water, extracting with EA twice, combining organic phases, drying with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, loading by a wet method, and performing column chromatography separation (PE: EA is 1:30) to obtain 22.1g of crude product, which is directly used for the next reaction.
And step 3: synthesis of 2- (tert-butyl) benzo [ d ] oxazole-7-thiophenol
22.1g of 2- (tert-butyl) benzo [ d ] oxazole-7-sulfonyl chloride was placed in a 1L eggplant-shaped bottle, and 400mL of toluene and 65g of triphenylphosphine were added thereto, followed by refluxing for 5 hours. The reaction is stopped, the toluene is evaporated, EA is added into the mixture for ultrasonic treatment to precipitate a white solid, the white solid is filtered, and the filtrate is evaporated to dryness to obtain 18.0 g of crude 2- (tert-butyl) benzo [ d ] oxazole-7-thiophenol which is directly used for the next reaction.
And 4, step 4: synthesis of 3- ((2- (tert-butyl) benzo [ d ] oxazol-7-yl) thio) propanoic acid
18.0 g of 2- (tert-butyl) benzo [ d]The oxazole-7-thiophenol crude product was placed in a 500mL eggplant-shaped bottle, 180mL of ethanol and 16mL of 10% KOH aqueous solution were added, and after stirring at room temperature for 10 minutes, 3.56 g of chloropropionic acid and 4.56 g of K were added2CO3And refluxed overnight. After completion of the reaction, the solvent was evaporated, 200mL of water was added to the mixture, the aqueous phase (300mL × 2) was extracted with EA, the organic phase of the two extractions was discarded, the pH of the aqueous phase was adjusted to 1, the aqueous phase was extracted with EA (300mL × 2), the organic phase was dried with saturated saline, and purified by column chromatography after drying over anhydrous sodium sulfate (PE: EA ═ 3:1) to obtain 8.3g of a pale yellow solid (total yield: 21% in steps 2 to 4).
1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),7.57(dd,J=7.2,1.7Hz,1H),7.35–7.27(m,2H),3.27(t,J=7.0Hz,2H),2.57(t,J=7.0Hz,2H),1.43(s,9H).
MS(ESI+)m/z 280.1[M+H]+.
And 5: synthesis of 2- (tert-butyl) -7, 8-dihydro-6-hydro-thiopyran [7,8-d ] oxazol-6-one
2.0 g of 3- ((2- (tert-butyl) benzo [ d ] oxazol-7-yl) thio) propionic acid are placed in a 100mL round bottom flask, added in portions to 20mL of concentrated sulfuric acid at 0 ℃ in order to dissolve them as far as possible and left to stand overnight at room temperature. The reaction solution was slowly poured into ice water, and after stirring well, the aqueous phase (150 mL. times.2) was extracted with EA and discarded. And adding NaOH aqueous solution into the organic phase to adjust the pH value to be 10, extracting twice by using EA, combining the organic phases, washing by using saturated sodium chloride water, drying by using anhydrous sodium sulfate, and evaporating to obtain a target product, wherein 1.85g of light yellow solid is directly used for the next reaction, and the yield is 99%.
1H NMR(400MHz,DMSO-d6)δ7.98(d,J=8.5Hz,1H),7.50(d,J=8.4Hz,1H),3.45(dd,J=7.2,5.6Hz,2H),2.98–2.93(m,2H),1.44(s,9H).
MS(ESI+)m/z 262.1[M+H]+.
Step 6: synthesis of 2- (tert-butyl) -7, 8-dihydro-6-hydro-thiopyran [7,8-d ] oxazol-6-one-9, 9-dioxide
1.3g of 2- (tert-butyl) -7, 8-dihydro-6-hydro-thiopyran [7,8-d ] oxazol-6-one was placed in a 250mL eggplant-shaped bottle, 70mL of methylene chloride was added thereto, the temperature was lowered to 0 ℃ and then 1.72g of m-CPBA was added in portions and reacted at ordinary temperature for 2 hours. After the reaction is stopped, the reaction solution is directly concentrated and subjected to column chromatography separation and purification to obtain 1.2g of white solid, wherein the yield is 82%.
1H NMR(400MHz,DMSO-d6)δ8.13(d,J=8.4Hz,1H),8.02(d,J=8.4Hz,1H),4.19–4.14(m,2H),3.33–3.28(m,2H),1.48(s,9H).
MS(ESI+)m/z 294.1[M+H]+.
And 7: synthesis of 4-amino-8-hydroxy thiochroman-4-one-1, 1' -dioxide
1.2g of 2- (tert-butyl) -7, 8-dihydro-6H-thiochromen [7,8-d ] oxazol-6-one 9, 9-dioxide was placed in a 500mL jar flask, 108mL of 1, 4-dioxane and 20mL of water were added, 2.9mL of concentrated sulfuric acid was slowly dropped under vigorous stirring, and the reaction was refluxed for 48 hours. Stopping the reaction, directly concentrating the reaction solution to dryness, adding 100mL of water, adjusting the pH value to 6 by using a 4N sodium hydroxide aqueous solution, extracting an aqueous phase (200mL multiplied by 2) by using dichloromethane, combining organic phases, washing by using saturated sodium chloride water, drying by using anhydrous sodium sulfate, and drying to dryness to obtain a crude product which is brown oily matter and is directly used for the next reaction.
And 8: synthesis of 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1' -dioxo-4-oxothiochromen-7-yl) urea
100mg of 7-amino-8-hydroxythiochroman-4-one 1, 1-dioxide is put into a 100mL eggplant-shaped bottle, 20mL of dichloromethane is added, 82.8mg of 2, 3-dichlorophenyl isocyanate is added under stirring at room temperature, reaction is carried out for 3 hours at room temperature, the reaction solution is precipitated and becomes turbid, filtration is carried out, and filter cakes (10mL multiplied by 2) are washed twice by dichloromethane, so that 120mg of target product is obtained, and the yield is 67%.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.42(s,1H),8.31(d,J=8.7Hz,1H),8.06(t,J=4.9Hz,1H),7.47(d,J=7.5Hz,1H),7.34(d,J=0.8Hz,1H),7.33(d,J=0.5Hz,1H),3.91–3.85(m,2H),3.15–3.09(m,2H).
MS(ESI+)m/z 415.1[M+H]+.
Example 2: synthesis of 1- (3-fluoro-2-methylphenyl) -3- (8-hydroxy-1, 1-dioxo-4-oxothiochromen-7-yl) urea (Compound 2)
The title compound was prepared according to the method of step 8 of example 1 from 7-amino-8-hydroxythiochroman-4-one 1, 1-dioxide and 2 methyl-3-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.32(s,1H),9.01(s,1H),8.43–8.33(m,1H),7.64(d,J=8.2Hz,1H),7.60(d,J=8.7Hz,1H),7.19(dd,J=15.1,8.1Hz,1H),6.90(t,J=8.8Hz,1H),4.03–3.92(m,2H),3.20–3.12(m,2H),2.17(d,J=1.9Hz,3H).
MS(ESI+)m/z 379.1[M+H]+.
Example 3: synthesis of 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxathiochroman-7-yl) urea (Compound 3)
Step 1: synthesis of 2- (tert-butyl) -6-hydroxy-7, 8-dihydro-6-hydro-thiochroman [7,8-d ] oxazole 9, 9-dioxide.
Dissolving 1.18 g of 2- (tert-butyl) -7, 8-dihydro-6-hydro-thiopyran [7,8-d ] oxazole-6-one-9, 9-dioxide in 20mL of methanol, cooling to 0 ℃, adding 304mg of sodium borohydride, stirring for 5 minutes, adding water to quench the reaction, extracting an organic phase with ethyl acetate, and drying saturated saline to obtain 2- (tert-butyl) -6-hydroxy-7, 8-dihydro-6-hydro-thiochroman [7,8-d ] oxazole 9, 9-dioxide which is directly used for the next reaction.
MS(ESI+)m/z 296.1[M+H]+.
Step 2: synthesis of 2- (tert-butyl) -8 hydro-thiochromene [7,8-d ] oxazole 9, 9-dioxide.
885mg of 2- (tert-butyl) -6-hydroxy-7, 8-dihydro-6-hydro-thiochroman [7,8-d ] oxazole 9, 9-dioxide was dissolved in 30mL of toluene, 30mg of p-toluenesulfonic acid was added thereto, and the mixture was refluxed at 130 ℃ for 24 hours and purified by column chromatography to give 690mg of 2- (tert-butyl) -8-hydro-thiochromene [7,8-d ] oxazole 9, 9-dioxide.
MS(ESI+)m/z 278.1[M+H]+.
And step 3: synthesis of 2- (tert-butyl) -7, 8-dihydro-6 h-thiochroman [7,8-d ] oxazole 9, 9-dioxide.
500mg of 2- (tert-butyl) -8H-thiochromene [7,8-d ] oxazole 9, 9-dioxide was dissolved in 20mL of methanol, and 500mg of palladium on carbon was added thereto, followed by stirring overnight at room temperature under hydrogen. After filtration of the palladium on carbon, the solvent was evaporated to dryness to give 498mg of 2- (tert-butyl) -7, 8-dihydro-6 h-thiochroman [7,8-d ] oxazole 9, 9-dioxide, which was used directly in the next reaction.
MS(ESI+)m/z 280.1[M+H]+.
And 4, step 4: synthesizing 7-amido-8-hydroxy thiochroman 1, 1-dioxide.
The title compound was synthesized from 2- (tert-butyl) -7, 8-dihydro-6 hydro-thiochroman [7,8-d ] oxazole 9, 9-dioxide according to the method of step 7 in example 1.
MS(ESI+)m/z 214.1[M+H]+.
And 5: synthesis of 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea.
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2, 3-dichlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.26(d,J=8.0Hz,1H),8.96(s,1H),8.09(dd,J=7.5,2.4Hz,1H),7.73(d,J=8.3Hz,1H),7.35–7.30(m,3H),6.82(d,J=8.4Hz,1H),3.44–3.39(m,2H),2.90(t,J=6.1Hz,2H),2.24–2.15(m,2H).
MS(ESI+)m/z 401.1[M+H]+.
Example 4: synthesis of 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 4)
Step 1: synthesis of 7-amino-8-hydroxy-2-hydro-thiochromene 1, 1-dioxide.
The title compound was synthesized from 2- (tert-butyl) -8 hydro-thiochromene [7,8-d ] oxazole 9, 9-dioxide according to the method of step 7 in example 1.
MS(ESI+)m/z 212.1[M+H]+.
Step 2: 1- (2, 3-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2, 3-dichlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.38(s,1H),9.24(s,1H),8.19(d,J=8.4Hz,1H),8.09(dd,J=6.8,3.0Hz,1H),7.36–7.29(m,2H),6.99(d,J=8.4Hz,1H),6.72(d,J=10.4Hz,1H),6.09(dt,J=10.0,4.9Hz,1H),4.26(dd,J=4.8,1.6Hz,2H).
MS(ESI+)m/z 399.1[M+H]+.
Example 5: synthesis of 1- (3-fluoro-2-methylphenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 5)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-methyl-3-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.90(s,1H),8.65(s,1H),7.72(d,J=8.4Hz,1H),7.62(d,J=8.2Hz,1H),7.17(dd,J=15.1,8.1Hz,1H),6.87(t,J=8.9Hz,1H),6.81(d,J=8.4Hz,1H),3.45–3.38(m,2H),2.90(t,J=6.0Hz,2H),2.24–2.14(m,5H).
MS(ESI+)m/z 365.1[M+H]+.
Example 6: synthesis of 1- (3-fluoro-2-methylphenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 6)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2 methyl-3-fluorophenyl isocyanate.
1H NMR(500MHz,DMSO-d6)δ9.65(s,1H),8.96(s,1H),8.80(s,1H),8.18(d,J=8.4Hz,1H),7.62(d,J=8.2Hz,1H),7.14(dd,J=15.2,7.8Hz,1H),6.94(d,J=8.4Hz,1H),6.84(t,J=8.9Hz,1H),6.67(d,J=10.3Hz,1H),6.03(dt,J=9.9,4.8Hz,1H),4.21(d,J=3.7Hz,2H),2.12(s,3H).
MS(ESI+)m/z 363.1[M+H]+.
Example 7: synthesis of 1- (4-bromophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 7)
The title compound was synthesized according to the method of step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 4-bromophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.63(s,1H),8.55(s,1H),8.23(d,J=8.4Hz,1H),7.60–7.40(m,4H),6.98(d,J=8.4Hz,1H),6.71(d,J=10.4Hz,1H),6.07(dt,J=10.0,4.8Hz,1H),4.25(dd,J=4.7,1.2Hz,2H).
MS(ESI+)m/z 409.1[M+H]+.
Example 8: synthesis of 1- (2-fluorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 8)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.38(s,1H),9.06(s,1H),8.24(d,J=8.3Hz,1H),8.14(t,J=8.1Hz,1H),7.27–7.20(m,1H),7.14(t,J=7.5Hz,1H),7.07–6.95(m,2H),6.72(d,J=10.1Hz,1H),6.13–6.03(m,1H),4.25(d,J=3.8Hz,2H).
MS(ESI+)m/z 349.1[M+H]+.
Example 9: synthesis of 1- (2-bromophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 9)
The title compound was synthesized according to the method of step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-bromophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.31(s,1H),8.94(s,1H),8.18(d,J=8.4Hz,1H),7.95(dd,J=8.2,1.4Hz,1H),7.62(dd,J=8.0,1.3Hz,1H),7.39–7.32(m,1H),7.08–6.94(m,2H),6.71(d,J=10.3Hz,1H),6.08(dt,J=10.0,4.8Hz,1H),4.25(dd,J=4.8,1.4Hz,2H).
MS(ESI+)m/z 409.1[M+H]+.
Example 10: synthesis of 1- (2-chlorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 10)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-chlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.32(s,1H),9.09(s,1H),8.19(d,J=8.1Hz,1H),8.08(d,J=8.0Hz,1H),7.46(d,J=7.6Hz,1H),7.30(t,J=7.3Hz,1H),7.06(t,J=7.2Hz,1H),6.98(d,J=8.1Hz,1H),6.71(d,J=10.0Hz,1H),6.12–6.05(m,1H),4.25(s,2H).
MS(ESI+)m/z 365.1[M+H]+.
Example 11: synthesis of 1- (2-trifluoromethylphenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 11)
The title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-trifluoromethylphenyl isocyanate according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.24(s,1H),8.91(s,1H),8.20(d,J=8.4Hz,1H),7.83(d,J=8.2Hz,1H),7.69(d,J=8.0Hz,1H),7.65(t,J=7.8Hz,1H),7.32(t,J=7.6Hz,1H),6.97(d,J=8.5Hz,1H),6.71(dt,J=10.2,1.5Hz,1H),6.08(dt,J=10.0,4.9Hz,1H),4.25(dd,J=4.8,1.7Hz,2H).
MS(ESI+)m/z 399.1[M+H]+.
Example 12: synthesis of 1- (2-methyl-3-chlorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 12)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-methyl-3-chlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.97(s,1H),8.89(s,1H),8.21(d,J=8.4Hz,1H),7.74–7.68(m,1H),7.20–7.16(m,2H),6.97(d,J=8.4Hz,1H),6.71(d,J=10.3Hz,1H),6.10–6.03(m,1H),4.25(dd,J=4.8,1.4Hz,2H),2.31(s,3H).
MS(ESI+)m/z 379.1[M+H]+.
Example 13: synthesis of 1- (2, 4-dichlorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 13)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2, 4-dichlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.34(s,1H),9.17(s,1H),8.19(d,J=8.4Hz,1H),8.13(d,J=8.9Hz,1H),7.62(d,J=2.4Hz,1H),7.38(dd,J=9.0,2.4Hz,1H),6.98(d,J=8.4Hz,1H),6.72(d,J=10.4Hz,1H),6.08(dt,J=10.0,4.8Hz,1H),4.25(dd,J=4.8,1.3Hz,2H)
MS(ESI+)m/z 399.1[M+H]+.
Example 14: synthesis of 1- (4-methylphenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 14)
The title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 4-methylphenyl isocyanate following the procedure of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.97(s,1H),8.68(s,1H),8.21(d,J=8.4Hz,1H),7.77(d,J=8.0Hz,1H),7.16(dd,J=17.4,7.7Hz,2H),6.98(dd,J=7.1,5.4Hz,2H),6.71(d,J=10.3Hz,1H),6.06(dt,J=10.0,4.9Hz,1H),4.25(dd,J=4.7,1.2Hz,2H),2.26(s,3H)
MS(ESI+)m/z 345.1[M+H]+.
Example 15: synthesis of 1- (2-chloro-3-fluorophenyl) -3- (8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) urea (Compound 15)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 2-chloro-3-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6))δ9.65(s,1H),9.37(s,1H),9.24(s,1H),8.20(d,J=8.4Hz,1H),7.98(dt,J=8.5,1.3Hz,1H),7.34(td,J=8.4,6.5Hz,1H),7.10–7.05(m,1H),6.98(d,J=8.5Hz,1H),6.72(dt,J=10.3,1.6Hz,1H),6.12–6.05(m,1H),4.25(dd,J=4.9,1.7Hz,2H).
MS(ESI+)m/z 383.1[M+H]+.
Example 16: synthesis of 1- (2-fluorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 16)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.10(d,J=1.9Hz,1H),8.81(s,1H),8.11(td,J=8.3,1.6Hz,1H),7.79(d,J=8.4Hz,1H),7.24(ddd,J=11.6,8.2,1.4Hz,1H),7.14(t,J=7.8Hz,1H),7.06–6.98(m,1H),6.82(d,J=8.4Hz,1H),3.46–3.37(m,2H),2.90(t,J=6.1Hz,2H),2.25–2.17(m,2H).
MS(ESI+)m/z 351.1[M+H]+.
Example 17: synthesis of 1- (2-bromophenyl) -3- (8-hydroxy-1, 1-dioxochroman-7-yl) urea (Compound 17)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-bromophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.14(s,1H),8.63(s,1H),7.98(dd,J=8.3,1.5Hz,1H),7.70(d,J=8.3Hz,1H),7.62(dd,J=8.0,1.4Hz,1H),7.37–7.31(m,1H),7.02–6.97(m,1H),6.82(d,J=8.4Hz,1H),3.44–3.39(m,2H),2.90(t,J=6.0Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 411.1[M+H]+.
Example 18: synthesis of 1- (2-chlorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 18)
The title compound was synthesized from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-chlorophenyl isocyanate according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.07(d,J=31.9Hz,1H),8.79(s,1H),8.08(dd,J=8.3,1.5Hz,1H),7.72(d,J=8.3Hz,1H),7.46(dd,J=8.0,1.4Hz,1H),7.33–7.26(m,1H),7.10–7.01(m,1H),6.82(d,J=8.4Hz,1H),3.45–3.38(m,2H),2.90(t,J=6.1Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 367.1[M+H]+.
Example 19: synthesis of 1- (2-chlorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 19)
The title compound was synthesized from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-trifluoromethylphenyl isocyanate according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.08(s,1H),8.63(s,1H),7.87(d,J=8.2Hz,1H),7.74(d,J=8.4Hz,1H),7.69(d,J=7.9Hz,1H),7.64(t,J=7.8Hz,1H),7.31(t,J=7.6Hz,1H),6.82(d,J=8.4Hz,1H),3.50–3.38(m,2H),2.90(t,J=6.1Hz,2H),2.25–2.16(m,2H).
MS(ESI+)m/z 401.1[M+H]+.
Example 20: synthesis of 1- (2-methyl-3-chlorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 20)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-methyl-3-chlorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.77(s,1H),8.66(s,1H),7.74–7.66(m,2H),7.19–7.16(m,2H),6.81(d,J=8.4Hz,1H),3.46–3.36(m,2H),2.90(t,J=6.1Hz,2H),2.30(s,3H),2.26–2.13(m,2H).
MS(ESI+)m/z 381.1[M+H]+.
Example 21: synthesis of 1- (4-methylphenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 21)
The title compound was synthesized from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 4-methylphenyl isocyanate according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.80(s,1H),8.45(s,1H),7.73(d,J=7.3Hz,1H),7.69(d,J=8.3Hz,1H),7.19(d,J=7.5Hz,1H),7.15(t,J=7.8Hz,1H),6.98(td,J=7.4,1.1Hz,1H),6.81(d,J=8.4Hz,1H),3.47–3.38(m,2H),2.90(t,J=6.1Hz,2H),2.25(s,3H),2.23–2.15(m,2H).
MS(ESI+)m/z 347.1[M+H]+.
Example 22: synthesis of 1- (2-chloro-3-fluorophenyl) -3- (8-hydroxy-1, 1-dioxothiochroman-7-yl) urea (Compound 22)
The title compound was synthesized according to the procedure for step 8 of example 1 from 7-amino-8-hydroxythiochroman 1, 1-dioxide and 2-chloro-3-fluorophenyl isocyanate.
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.15(s,1H),8.93(s,1H),7.99(dt,J=8.5,1.2Hz,1H),7.75(d,J=8.4Hz,1H),7.33(td,J=8.4,6.5Hz,1H),7.09–7.03(m,1H),6.83(d,J=8.4Hz,1H),3.45–3.40(m,2H),2.91(t,J=6.1Hz,2H),2.21(dt,J=12.0,6.1Hz,2H).
MS(ESI+)m/z 385.1[M+H]+.
Example 23: synthesis of 3- ((2, 3-dichlorophenyl) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 23)
Step 1: synthesis of 3, 4-diethoxy cyclobut-3-ene-1, 2-dione
3, 4-dihydroxy-3-ene-1, 2-dione (140mmol) was dissolved in dichloromethane 200mL, after addition of 16 drops of DMF oxalyl chloride (2.2 equiv.) was added dropwise in an ice bath, the reaction was refluxed overnight, monitored by TLC for completion of the reaction, and concentrated to give a crude product which was used directly in the next step.
Step 2: and (3) synthesizing 3- ((2, 3-dichlorophenyl) amino) -4-ethoxy cyclobut-3-ene-1, 2-diketone.
Dissolving 3, 4-diethoxy cyclobut-3-ene-1, 2-dione (13.3mmol) in dichloromethane (50mL), cooling to zero, dropwise adding a 2, 3-dichloroaniline (13.3mmol) solution dissolved in dichloromethane (25mL), reacting at zero for 3 hours, adding water (100mL) into the reaction solution for quenching, extracting the water phase (75mL multiplied by 3) of the reaction solution by dichloromethane, combining organic phases, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, and purifying by column chromatography to obtain the target product 3- ((2, 3-dichlorophenyl) amino) -4-ethoxy cyclobut-3-ene-1, 2-dione.
And step 3: synthesis of 3- ((2, 3-dichlorophenyl) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione
Dissolving 7-amino-8-hydroxy-2H-thiochromene 1, 1-dioxide in tetrahydrofuran (15mL), adding 3- ((2, 3-dichlorophenyl) amino) -4-ethoxy cyclobut-3-ene-1, 2-dione (0.24mmol), refluxing for 48h, concentrating, adding dichloromethane (10mL), precipitating with ultrasound, and filtering to obtain the title compound.
1H NMR(500MHz,DMSO-d6)δ8.15(s,1H),7.69(s,1H),7.51(d,J=7.5Hz,1H),7.43–7.34(m,2H),6.72(s,1H),6.63(d,J=9.6Hz,1H),6.03(s,1H),4.12(s,2H).
MS(ESI+)m/z 451.1[M+H]+.
Example 24: synthesis of 3- ((3-fluoro-2-methylphenyl) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 24)
Step 1: 3-Ethyl-4- ((3-fluoro-2 methylphenyl) amino) cyclobut-3-ene-1, 2-dione was synthesized from 3, 4-diethoxycyclobut-3-ene-1, 2-dione and 3-fluoro-2-methylaniline according to the method of step 2 in example 21.
Step 2: the title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 3-ethyl-4- ((3-fluoro-2 methylphenyl) amino) cyclobut-3-ene-1, 2-dione according to the method of step 3 in example 21.
1H NMR(500MHz,DMSO-d6)δ9.92(s,1H),9.87(s,2H),7.78(d,J=8.3Hz,1H),7.24(dd,J=14.6,7.7Hz,1H),7.18(d,J=8.0Hz,1H),7.03(d,J=8.3Hz,1H),6.99(t,J=8.8Hz,1H),6.74(d,J=10.3Hz,1H),6.13(dt,J=9.9,4.8Hz,1H),4.27(d,J=3.6Hz,2H),2.26(s,3H).
MS(ESI+)m/z 415.1[M+H]+.
Example 25: synthesis of 3- ((2-chloro) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 25)
Step 1: 3-Ethyl-4- ((2-chlorophenyl) amino) cyclobut-3-ene-1, 2-dione was synthesized from 3, 4-diethoxycyclobut-3-ene-1, 2-dione and 2-chloroaniline according to the procedure in step 2 of example 21.
Step 2: the title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 3-ethyl-4- ((2-chlorophenyl) amino) cyclobut-3-ene-1, 2-dione according to the procedure in step 3 of example 21.
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),10.13(s,1H),9.96(s,1H),7.77(d,J=8.3Hz,1H),7.54(ddd,J=7.8,6.2,1.4Hz,2H),7.40–7.35(m,1H),7.21–7.16(m,1H),7.05(d,J=8.4Hz,1H),6.75(d,J=10.4Hz,1H),6.14(dt,J=10.0,4.8Hz,1H),4.28(dd,J=4.8,1.6Hz,2H).
MS(ESI+)m/z 417.1[M+H]+.
Example 26: synthesis of 3- ((2-chloro-3-fluoro) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 26)
Step 1: 3-Ethyl-4- ((2-chloro-3-fluorophenyl) amino) cyclobut-3-ene-1, 2-dione was synthesized from 3, 4-diethoxycyclobut-3-ene-1, 2-dione and 2-chloro-3-fluoroaniline according to the procedure in step 2 of example 21.
Step 2: the title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 3-ethyl-4- ((2-chloro-3-fluorophenyl) amino) cyclobut-3-ene-1, 2-dione according to the method of step 3 in example 21.
1H NMR(400MHz,DMSO-d6)δ10.19(d,J=8.4Hz,2H),9.96(s,1H),7.75(d,J=8.3Hz,1H),7.46–7.36(m,2H),7.24–7.17(m,1H),7.05(d,J=8.3Hz,1H),6.75(d,J=10.4Hz,1H),6.14(dt,J=10.0,4.8Hz,1H),4.28(dd,J=4.9,1.5Hz,2H).
MS(ESI+)m/z 435.1[M+H]+.
Example 27: synthesis of 3- ((2-bromo) amino) -4- ((8-hydroxy-1, 1-dioxo-2 hydro-thiochromen-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 27)
Step 1: 3-Ethyl-4- ((2-bromophenyl) amino) cyclobut-3-ene-1, 2-dione was synthesized from 3, 4-diethoxycyclobut-3-ene-1, 2-dione and 2-bromoaniline according to the method of step 2 in example 21.
Step 2: the title compound was synthesized from 7-amino-8-hydroxy-2 hydro-thiochromene 1, 1-dioxide and 3-ethyl-4- ((2-bromophenyl) amino) cyclobut-3-ene-1, 2-dione according to the method of step 3 in example 21.
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),10.01(s,1H),9.93(s,1H),7.78(d,J=8.3Hz,1H),7.69(dd,J=8.0,1.3Hz,1H),7.47–7.37(m,2H),7.12(ddd,J=8.0,7.3,1.8Hz,1H),7.05(d,J=8.4Hz,1H),6.75(dd,J=8.8,1.7Hz,1H),6.14(dt,J=10.0,4.9Hz,1H),4.28(dd,J=4.9,1.7Hz,2H).
MS(ESI+)m/z 461.1[M+H]+.
Example 28: synthesis of 3- ((2-chloroamino) -4- ((8-hydroxy-1, 1-dioxo-thiochroman-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 28)
The title compound was synthesized according to the procedure for step 3 of example 21 from 7-amino-8-hydroxy-thiochroman 1, 1-dioxide and 3-ethyl-4- ((2-chlorophenyl) amino) cyclobut-3-ene-1, 2-dione.
1H NMR(500MHz,DMSO-d6)δ10.09(s,1H),9.84(s,1H),7.59(d,J=8.0Hz,1H),7.51(d,J=7.9Hz,2H),7.36(t,J=7.6Hz,1H),7.15(t,J=7.5Hz,1H),6.77(s,1H),3.40(s,2H),2.91(s,2H),2.21(s,2H).
MS(ESI+)m/z 419.1[M+H]+.
Example 29: synthesis of 3- ((2-chloro-3-fluoroamino) -4- ((8-hydroxy-1, 1-dioxo-thiochroman-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 29)
The title compound was synthesized from 7-amino-8-hydroxy-thiochroman 1, 1-dioxide and 3-ethyl-4- ((2-chloro-3-fluorophenyl) amino) cyclobut-3-ene-1, 2-dione according to the procedure in step 3 of example 21.
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.91(s,1H),7.48(dd,J=13.1,8.3Hz,2H),7.40(dd,J=14.3,8.1Hz,1H),7.18(t,J=8.5Hz,1H),6.87(d,J=8.4Hz,1H),3.47–3.42(m,2H),2.95–2.90(m,2H),2.25–2.15(m,2H).
MS(ESI+)m/z 437.1[M+H]+.
Example 30: synthesis of 3- ((2-methyl-3-fluoroamino) -4- ((8-hydroxy-1, 1-dioxo-thiochroman-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 30)
The title compound was synthesized from 7-amino-8-hydroxy-thiochroman 1, 1-dioxide and 3-ethyl-4- ((2-methyl-3-fluorophenyl) amino) cyclobut-3-ene-1, 2-dione according to the procedure in step 3 of example 21.
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.71(s,1H),7.51(d,J=8.3Hz,1H),7.27–7.17(m,2H),7.00–6.94(m,1H),6.85(d,J=8.4Hz,1H),3.46–3.40(m,2H),2.97–2.89(m,2H),2.26(s,3H),2.24–2.14(m,2H).
MS(ESI+)m/z 417.1[M+H]+.
Example 31: synthesis of 3- ((2-bromoamino) -4- ((8-hydroxy-1, 1-dioxo-thiochroman-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 31)
The title compound was synthesized from 7-amino-8-hydroxy-thiochroman 1, 1-dioxide and 3-ethyl-4- ((2-bromophenyl) amino) cyclobut-3-ene-1, 2-dione according to the method of step 3 in example 21.
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.74(s,1H),7.67(dd,J=8.0,1.3Hz,1H),7.52(d,J=8.3Hz,1H),7.47(dd,J=8.1,1.6Hz,1H),7.42–7.38(m,1H),7.13–7.08(m,1H),6.87(d,J=8.4Hz,1H),3.47–3.42(m,2H),2.95–2.91(m,2H),2.24–2.16(m,2H).
MS(ESI+)m/z 463.1[M+H]+.
Example 32: synthesis of 3- ((2, 3-dichloroamino) -4- ((8-hydroxy-1, 1-dioxo-thiochroman-7-yl) amino) cyclobut-3-ene-1, 2-dione (Compound 32)
The title compound was synthesized from 7-amino-8-hydroxy-thiochroman 1, 1-dioxide and 3-ethyl-4- ((2, 3-dichlorophenyl) amino) cyclobut-3-ene-1, 2-dione according to the procedure in step 3 of example 21.
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),10.00(s,1H),9.91(s,1H),7.54(dd,J=7.4,2.1Hz,1H),7.49(d,J=8.4Hz,1H),7.43–7.34(m,2H),6.87(d,J=8.4Hz,1H),3.46–3.41(m,4H),2.92(t,J=6.0Hz,2H),2.26–2.16(d,J=5.8Hz,2H).
MS(ESI+)m/z 453.1[M+H]+.
Evaluation of pharmacological Activity
Experimental example 1: CXCR2 antagonistic activity assay
(1) Cell treatment: the PathHunter cell line was recovered, passaged and expanded. Cells were plated in a white-bottomed 384-well plate, 20. mu.l per well, and incubated at 37 ℃ for detection.
(2) And (3) detection of antagonistic activity: cells and antagonist were pre-incubated before agonist was added at the EC80 concentration. The sample stock was diluted with detection buffer to 5 times the concentration of the sample to be tested (5X sample). Mu.l of 5X sample was added to the cells and incubated at 37 ℃ or room temperature for 30 minutes. The solvent concentration was 1%. Mu.l of 6 × EC80 agonist in test buffer was added to the cells and incubated at 37 ℃ or room temperature for 90 to 180 minutes.
(3) Signal detection: the assay was performed after 1 hour incubation at room temperature with the addition of 12.5. mu.l or 15. mu.l (50% v/v) PathHunter assay reagent in one portion. After generation of the signal by Perkinelmer envision, the plate was read to detect the chemiluminescent signal.
(4) And (3) data analysis: compound activity was analyzed using CBIS data analysis software (chemlinnovation, CA). Percent compound inhibition was calculated using the formula:% inhibition 100% X (1- (average RLU of test samples-average RLU of solvent control)/(average RLU of EC80 control-average RLU of solvent)). The results are shown in Table 1:
table 1: results of CXCR2 antagonistic Activity test
Summary of pharmacological activity:
the compounds of the present invention all exhibit antagonist activity against CXCR2, where the IC of compounds 1,2,3, 4, 5, 6, 8, 9, 10, 14, 15, 17, 18, 22, 23, 24, 25, 26, 27, 3150The value is less than 1. mu.M.
Claims (7)
4. a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and/or excipient.
5. The pharmaceutical composition of claim 4, further comprising a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4 or 5, for the manufacture of a medicament for the prevention and/or treatment of a CXCR2 receptor mediated disease.
7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4 or 5, for the manufacture of a medicament for the prevention and/or treatment of chronic obstructive pulmonary disease, asthma, cystic fibrosis, cancer, arthritis, psoriasis, inflammatory bowel disease, pain, multiple sclerosis, alzheimer's disease, parkinson's disease.
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