NOVEL ANTAGONIST COMPOUNDS FOR CHEMOKINE CXCR1 AND CXCR2 RECEPTORS AND THEIR USE IN THE TREATMENT OF

专利摘要:
The present invention relates to novel CXCR1 and CXCR2 receptor antagonist compounds to chemokines having the following general formula (I): on the pharmaceutical compositions containing these compounds as well as the use of these compounds and compositions for the treatment of pathologies mediated by chemokines, more particularly in the field of dermatology.
公开号:FR3030515A1
申请号:FR1463209
申请日:2014-12-23
公开日:2016-06-24
发明作者:Branislav Musicki；Yushma Bhurruth-Alcor
申请人:Galderma Research and Development SNC；
IPC主号:

专利说明:

[0001] Novel CXCR1 and CXCR2 receptor antagonists to chemokines, and their use in the treatment of chemokine mediated pathologies
[0002] Field of the Invention: The present invention relates to novel chemokine CXCR1 and CXCR2 receptor antagonist compounds, to pharmaceutical compositions containing these compounds and to the use of these compounds and compositions for the treatment of drug-mediated pathologies. chemokines, more particularly in the field of dermatology.
[0003] STATE OF THE ART PRIOR TO THE INVENTION Chemokines or cytokines are small, soluble proteins. Their most well-known role is the attraction and control of the activation state of the cells of the immune system. All chemokines perform their functions by binding to G protein-coupled receptors. Some chemokines are considered pro-inflammatory. The secretion of these chemokines can be induced during the immune response to promote the arrival of cells of the immune system at an infectious site. There are two types of chemokines: pro-inflammatory chemokines and constitutive chemokines. Proinflammatory (or "inducible") chemokines are produced at sites of inflammation by infiltrated tissue cells or leukocytes after contact with a pathogen. Constitutive (or "homeostatic") chemokines are produced in lymphoid organs and in some non-lymphoid organs such as skin and mucous membranes. They regulate lymphocyte trafficking and localization of lymphocytes within these organs during lymphopoiesis but also to maintain immunosurveillance. The nomenclature of these chemokine receptors is based on the group of chemokines to which its ligand belongs. Thus, the receptors corresponding to the chemokines of the CXC group are, for example, designated CXCR1, CXCR2, CXCR3, CXCR4, etc., and the receptors corresponding to the chemokines of the CC group are, for example, designated CCR1, CCR2, CCR3, etc. These receptors all have a similar tertiary structure, and they are coupled to a G protein: they are therefore part of the GPCR superfamily (G Protein Coupled Receptor). Interleukin-8 or IL-8 (also known as CXCL-8) is a member of the CXC chemokine family, which plays a key role in the recruitment of neutrophils to the site of inflammation. Two receptors, CXCR1 and CXCR2 are known to be specifically activated by IL-8. While CXCR2 binds with high affinity to IL-8 and related chemokines such as CXCL6, CXCL5, CXCL3, CXCL2 and CXCL1, CXCR1 binds only to IL-8. High levels of IL-8 and related chemokines (CXCL5, CXCL2 & CXCL1) have been described in inflammatory acne lesions (J Invest Dermatol, 2006; 126: 1071-9; Am J Pathol. 2005; 166; 6): 1691-9, Diagn Pathol, 2007 Jan 30, 2: 4). Early evidence demonstrates the expression of CXCR2 in inflammatory acne (Trivedi et al., J Invest Dermatol, 2006 126 (5): 1071-9). Thus, double antagonists of CXCR1 and CXCR2 could rapidly decrease the deleterious effects of the IL-8 inflammatory response. It is now known that many pathologies of inflammatory order are mediated by chemokines.
[0004] In the field of dermatology, there is also an unmet need to date treating the inflammatory component of pathologies of interest such as acne, rosacea or neutrophilic dermatoses, including psoriasis. However, the Applicant has discovered new compounds having an antagonistic activity with respect to the CXCR1 and CXCR2 type receptors and characterized by the presence in their structure of a functional group, of sulphoximine type, corresponding to the substructure ( la): R4 ,,) i., (la) S R5 -_, N // '0 Compared to their closest structural analogs, taken in the prior art, for example in the document W002 / 083624, and having a sulfone functional group instead of the sulfoximine functional group, these compounds have a better antagonistic activity towards the CXCR1 and CXCR2 type receptors. They also unexpectedly show better inhibition of neutrophil migration at the inflammatory site compared with their closest structural analogues, taken for example in the document W002 / 083624, which gives them an additional interest compared with the compounds already known. in the treatment of pathologies mediated by chemokines, and more particularly dermatological pathologies. SUMMARY OF THE INVENTION: A first object according to the invention relates to new CXCR1 and CXCR2 receptor antagonist compounds to chemokines, as well as their salts and enantiomers, corresponding to the following general formula (I): Rzls AB r K r Wherein the groups A and B and the substituents R3, R4, R5 are as defined hereinafter in the detailed description of the invention. A second object according to the invention relates to a pharmaceutical composition comprising an effective amount of a compound corresponding to the general formula (I) in combination with a pharmaceutically acceptable solvent or carrier. A third object according to the invention relates to a compound or a pharmaceutical composition as described above for its use as a medicament.
[0005] A fourth object according to the invention relates to a compound or a pharmaceutical composition as described above for its use in the treatment of chemokine-mediated diseases.
[0006] A fifth object according to the invention relates to a compound or a pharmaceutical composition as described above for its use in the treatment of diseases mediated by chemokines selected from the group comprising neutrophilic dermatoses, and in particular psoriasis, atopic dermatitis, acne, rosacea, asthma, chronic obstructive pulmonary diseases, adult respiratory diseases, arthritis, inflammatory bowel diseases, Crohn's disease, transplant rejection, cystic fibrosis and skin cancers. The invention also relates to a method for treating chemokine-mediated diseases comprising administering an effective amount of a compound or pharmaceutical composition as defined herein to a patient suffering from an illness. mediated by chemokines. The invention also relates to the use of a compound or pharmaceutical composition as defined herein for the preparation of a medicament for treating chemokine mediated diseases. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 represents the general synthetic scheme for preparing the compounds of general formula (I) in which R5 is hydrogen and B is (Bi). Figure 2 shows the general scheme of synthesis for preparing compounds of general formula (I) wherein R5 is different from hydrogen and B is (Bi). Unless indicated otherwise, the following definitions apply throughout the description and claims. These definitions apply regardless of whether a term is used alone or in combination with other terms. Thus, for example, the definition of the term "aryl" applies both to "aryl" as such to the "aryl" portion of the term "aryloxy" or "arylalkyl". "Alkyl" denotes a saturated linear or branched hydrocarbon chain whose number of carbon atoms is specified.
[0007] When the number of carbon atoms is not specified, it means that the alkyl chain contains from 1 to 20 carbon atoms. Preferred alkyl radicals contain 1 to 12 carbon atoms, and even more preferred are 1 to 6 carbon atoms in the chain. "Alkoxy" means an oxygen substituted by an alkyl radical as defined above, Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy radicals "Aryl" means a monocyclic or polycyclic aromatic ring system ( 2 to 3 rings) comprising from 6 to 14 carbon atoms, and preferably from 6 to 10 carbon atoms. Examples of aryl radicals that may be mentioned include the phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl and anthracenyl radicals. and fluorenyl.
[0008] The preferred aryl radicals are the phenyl radical and the naphthyl radical. The most preferred aryl radical is the phenyl radical. "Heteroaryl" means a monocyclic or polycyclic aromatic system (2 to 3 rings) comprising from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, wherein one or more of the ring atoms represent one or more of 1 to 5) heteroatom (s) selected from the group consisting of nitrogen, oxygen and sulfur. Preferred heteroaryls contain 5 or 6 ring atoms and 1 to 3 heteroatoms. The prefix aza, oxa or thia before the name of the heteroaryl root means that at least one nitrogen, one oxygen or one sulfur is present in the ring, respectively.
[0009] A nitrogen atom of a heteroaryl may be optionally oxidized to N-oxide. As examples of suitable heteroaryls, there may be mentioned the following heteroaryls: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4 triazinyl and benzothiazolyl.
[0010] The preferred heteroaryl radicals are selected from the following list: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl. Even more preferred heteroaryl radicals are pyridyl and furanyl. "Arylalkyl" denotes a radical whose aryl and alkyl portions are as defined above. As examples of arylalkyl, mention may be made of benzyl, phenethyl and naphthalenylmethyl radicals.
[0011] The bond to the structure to which it is attached is via the alkyl radical. "Heteroarylalkyl" refers to a radical whose heteroaryl and alkyl moieties are as defined above. As examples of heteroarylalkyl, mention may be made of pyridylmethyl, pyridylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl and pyrazolylethyl radicals. The bond to the structure to which it is attached is via the alkyl radical. "Cycloalkyl" refers to a non-aromatic hydrocarbon ring system having 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms, and one to three rings.
[0012] Preferred cycloalkyl radicals contain from 5 to 7 ring atoms. As examples of cycloalkyl radicals, mention may be made of cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl radicals. "Cycloalkylalkyl" denotes a radical whose cycloalkyl and alkyl portions are as defined above. As examples of cycloalkylalkyl, mention may be made of cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, norbornylmethyl and adamantylmethyl radicals.
[0013] The bond to the structure to which it is attached is via the alkyl radical. "Heterocycloalkyl" means a non-aromatic hydrocarbon ring system having from 4 to 10 carbon atoms, preferably from 5 to 10 carbon atoms, and from one to three rings, and comprising from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Preferred heterocycloalkyl radicals contain from 5 to 7 ring atoms. Exemplary heterocycloalkyl radicals include tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl and 7-oxa-bicyclo [2.2.1] heptanyl. "Fluorinated alkyl" denotes an alkyl radical as defined previously substituted with one or more fluorine atoms. As examples of fluorinated alkyl radicals, mention may be made of fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl radicals. "Perfluorinated alkyl" denotes an alkyl radical as defined above in which each hydrogen atom has been substituted with a fluorine atom. As examples of perfluorinated radicals, mention may be made of trifluoromethyl and pentafluoroethyl radicals. "Halogen" means a fluorine, chlorine, bromine or iodine atom. Preferred halogens are fluorine and chlorine atoms. "Pharmaceutically acceptable salt" refers to salts of a compound of interest that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds. The pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, hydrochloride, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate salts, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1,1'- methylene-bis- (2-hydroxy-3-naphthoate)). Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. A list of pharmaceutically acceptable salts is notably published in the review by Berge et al. (Pharm Sci 1977, 66 (1), 1-19).
[0014] Thus, a first object according to the invention concerns novel CXCR1 and CXCR2 receptor antagonist compounds for chemokines, as well as their salts and enantiomers, corresponding to the following general formula (I): ABN "NHH (I) in which: A represents OR (Al) (A2) B represents R1 ', OR (B1) (B2) with R1' and R2 ', which may be identical or different, are hydrogen, halogen, C1 to C5 alkyl unsubstituted or substituted by or more than one fluorine atom, a C1 to C5 alkoxy, OCF3, OH, CN, NR11R12, R1 and R2, which may be identical or different, represent: - a hydrogen, - a C1 to C5 alkyl, unsubstituted or substituted with one or several groups selected from F, OH, OCH3 and NR11R12; R11 and R12 having the meaning given below, it being understood that when the alkyl radical of C1 to C5 is substituted only by one or more fluorine atoms, it is is a fluorinated alkyl radical or a perfluorinated alkyl radical of Cl to C5, - alkyl of Cl C5 wherein a carbon atom is replaced by an oxygen atom or a sulfur atom, said C1 to C5 alkyl being unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the meaning given hereinafter, - a C3 to C8 cycloalkyl - a C2 to C5 alkyne, unsubstituted or substituted by one or more groups selected from F, OH, phenyl, NR11R12, R11 and R12 having the meaning given below; after, - a cycloalkyl corresponding to one of the following formulas (1), (2), (3), (4), (5) or (6) wherein R5 ', X and X' have the meanings given herein after: R5 'i ---.) <R5' / R5 'R5' 1 X R5 'X R5' I (1) (2) (3) (4) (5) (6) - an aromatic ring or heteroaromatic selected from the group consisting of the rings of the following formulas (a) to (o) wherein R7, R7a, Y and Z have the meanings given below: R7 / ei R7 z (C) (d) ( e) R7 R7 R7 R7 R7 R7 R7 R7 (h) / (i) R7 4-R7 N 1 1 (I) (N% (m) (f) (g) R7N / / 1NN (k) R7R7R7R7 (n) (o) R7 may be present several times over one cycle, and at most, as many times that there are substitutable atoms. The meanings of each substituent R7 may be the same or different. R3 represents a hydrogen, a halogen, a C1 to C5 alkyl, a C1 to C5 alkoxy, CF3, -OCF3, -OH, -NO2, -CN R4 and R5, which may be identical or different, represent: a hydrogen, a C1 to C8 alkyl, unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the meaning given below, a C1 to C8 alkyl in which a carbon atom is replaced by a nitrogen atom, an oxygen atom or a sulfur atom, said C1 to C8 alkyl being unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the significance given hereinafter, - a C3 to C8 cycloalkyl, - a C3 to C8 cycloalkyl of which one of the carbon atoms is replaced by an oxygen atom or a nitrogen atom substituted with an R7a radical, a heterocycloalkyl of 5 to 7 ring atoms, a cycloalkylalkyl, the cycloalkyl being C3 to C8 and the alkyl of C1 to C8, a phenyl, a phenyl substituted with an R7 radical, a heteroaryl, an arylalkyl, the alkyl being of Cl-05, a heteroarylalkyl, the alkyl being of Cl-05, or else R4 and R5 represent a - (CH2) - chain, - forming a ring containing from 5 to 8 atoms with the sulfur and nitrogen atoms to which they are respectively attached, one of the carbons of the ring being optionally replaced by an oxygen atom, sulfur or by a nitrogen atom substituted by a radical R8; m and R8 having the meanings given below, R5 'represents a hydrogen atom, a fluorine, an alkyl radical having 1 to 5 carbon atoms inclusive or a fluorinated or perfluorinated alkyl radical containing from 1 to 5 carbon atoms R6 represents a hydrogen atom, a -COOtBu radical or a -COOBn radical, R7 represents a hydrogen, a C1 to C3 alkyl, a halogen, -CF3, -COR9, -OR9, -NR9R10, -NO2, - CN, -SO2R9, -S (O) R9, -S (= O) (= NR9) R10 ', -SO2NR9R10, -NR9SO2R10, -NR9COR10, -NR9CO2R10, -CONR9R10, or -OO2R9, R7a represents a hydrogen or a C1 to C5 alkyl, R8 is hydrogen, -OH, -SO2R9, -COR9, -O2R9, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R9 and R10 are the same or different and are independently selected from the group consisting of hydrogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl e, or else R9 and R10 may be linked together when they are borne by the same nitrogen atom so as to form a heterocycle having between 3 and 7 members and containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen in addition to the nitrogen atom to which they are attached.
[0015] R10 'represents aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R11 and R12, which may be identical or different, represent hydrogen, C1 to C5 alkyl, C3 to C6 cycloalkyl, a chain - (CH 2) p - forming a ring containing from 4 to 6 atoms with the nitrogen atom to which they are attached, X and X ', identical or different, represent an oxygen atom, a sulfur atom, or a nitrogen atom substituted with a radical R6, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by an R8 radical, Z represents a carbon atom or a nitrogen atom, m = 3, 4, 5, or 6 and p = 3.4, or 5.
[0016] In a particularly preferred embodiment according to the invention, the compounds correspond to the general formula (I) in which: A represents (Al) B represents (B 1) R 1 represents a hydrogen, a C 1 to C 5 alkyl, unsubstituted or substituted with one or more groups selected from F, OH and OCH3, a C3-C8 cycloalkyl, a cycloalkyl of the following formula (1 ') wherein X has the meaning given below: P 15 (1') R2 represents: - an alkyl of Cl to C5, unsubstituted or substituted with one or more groups selected from F, it being understood that when the alkyl radical of Cl to C5 is substituted only by one or more fluorine atoms, it is This is a fluorinated alkyl radical or a perfluorinated alkyl radical of Cl to C5, a C1 to C5 alkyl in which a carbon atom is replaced by an oxygen atom, an alkyne of C2 to C5. , unsubstituted or substituted by one or more groups selected from fluorine and phenol nyl, an aromatic or heteroaromatic ring selected from the group consisting of the rings of the following formulas (a), (b 1) and (dl) wherein R 7 and Z have the meanings given below: ## STR2 ## R7 may be present several times on one ring, and at most as many times as there are substitutable atoms. The meanings of each substituent R7 may be the same or different, R3 represents hydrogen or chlorine, R4 and R5, which may be identical or different, represent: - a hydrogen, - a C1 to C3 alkyl, unsubstituted or substituted with a group NR11R12 , R 11 and R 12 having the meaning given below, - a C 1 to C 8 alkyl in which a carbon atom is replaced by an oxygen atom, - a pyridyl, - a piperidinyl, R 7 represents a hydrogen, an alkyl of C1 to C3 or fluorine, X is a sulfur atom, and Z is a carbon atom or a nitrogen atom.
[0017] In a more particularly preferred embodiment according to the invention, the compounds correspond to the general formula (I) in which: A represents (Al) B represents (B1) R1 represents a hydrogen, a C1 to C5 alkyl, a cycloalkyl from C3 to C8, a cycloalkyl corresponding to the following formula (1 ') wherein X has the meaning given below: R2 represents: - a C1 to C5 alkyl, unsubstituted or substituted with one or more groups selected from F, it being understood that when the alkyl radical of Cl to C5 is substituted only by one or more fluorine atoms, it is a fluorinated alkyl radical or a perfluorinated alkyl radical of Cl to C5; C1 to C5 alkyl in which a carbon atom is replaced by an oxygen atom, - an alkyne C2 to C5, unsubstituted or substituted by one or more groups selected from fluorine and phenyl, - an aromatic ring or heteroaromatic selected from the group consisting of The rings of the following formulas (a), (b 1) and (dl) in which R 7 and Z have the meanings given below: R 7 0 R 7 0 / R 7 z 0 - / (a) (b 1) (d 1) R7 can be present several times on a cycle, and at most, as many times as there are substitutable atoms. The meanings of each substituent R7 may be the same or different, R3 represents hydrogen or chlorine, R4 and R5, which may be identical or different, represent a hydrogen, a C1 to C3 alkyl or a C1 to C8 alkyl in which an atom of carbon is replaced by oxygen, R7 is hydrogen, C1 to C3 alkyl or fluorine, X is sulfur, and Z is carbon or nitrogen. The compounds of the more preferred embodiment as described above have CXCR1 receptor antagonist activities of less than 400 nM and CXCR2 receptor antagonist activities of less than 100 nM.
[0018] These compounds, in series sulfoximine, have an activity greater than that of their structurally closest analogs taken in the prior art in series sulfone as illustrated below by way of example: Table 1-the 0 :. Example 16 ## STR1 ## IC50 (nM) Migration of 356 3090 Neutrophils to IC50 (nM) In the most preferred embodiment according to the invention, the compounds correspond to the above general formula (I) in which: A represents (Al) B represents (B1) R1 represents a C1 to C5 alkyl, R2 represents: - a C1 to C5 alkyl, - an alkyne C2 to C5, substituted with one or more groups selected from fluorine and phenyl, - an aromatic or heteroaromatic ring selected from the group consisting of the rings corresponding to formulas (a), (b 1) and (dl) in which R7 and Z have the meanings given below: R7 0 R7 0 / R7 z OJ (a) (b1) (d1) R7 may be present several times over one cycle, and at most as many times as there are substitutable atoms. The meanings of each substituent R7 may be the same or different, R3 is hydrogen or chlorine, R4 and R5, the same or different, represent hydrogen or C1 to C3 alkyl, R7 is hydrogen, C1 to C3 alkyl, or a fluorine, and Z represents a carbon atom or a nitrogen atom.
[0019] The compounds of the most preferred embodiment as described above exhibit CXCR1 receptor antagonist activities of less than 50 nM and CXCR2 receptor antagonist activities of less than 20 nM. These compounds, in series sulfoximine, have an activity greater than that of their closest analogues taken in the prior art in series sulfone as illustrated below by way of example: Table 2 Cl OH 0 0 0 0 N fl / 'Cl 0 0 lei a' - H. 0H HM '/ ee N EXAMPLE 12 W002 / 083624 CXCR1 28 155 IC50 (nM) CXCR2 16 66 IC50 (nM) Migration of 82 831 neutrophils h IC50 (nM) In another embodiment according to the invention, the compounds correspond to the general formula (I) wherein: A represents (A1) B represents R1 '(B2) R1' and R2 ', which may be identical or different, represent a hydrogen, a chlorine or a fluorine, R3 represents a hydrogen or a chlorine, R4 and R5, identical or different, represent a hydrogen, an alkyl of Cl to C3. Among the more particularly preferred compounds include for example those selected from the list comprising: Compound 1: 3- (4-Chloro-2-hydroxy-3) methanesulfoxymin-phenylamino) -4- [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut -3-ene-1,2-dione Compound 2: 3-14-Chloro-2 3-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene; 1,2-dione Compound 3: 3-14-Chloro-2-hydroxy-3-methane - [(N-pyridin-4-yl) -sulfoximin] - p henylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 4: 3-14-Chloro-2-hydroxy 3-methane - [(N-pyridin-4-yl) -sulfoximin] -phenylamino} -4- (1-ethyl-propylamino) -cyclobut-3-ene-1,2-dione Compound 5: 3-14- Chloro-2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4-1 RS) - (5-methyl-furan-2-yl) - (R) -tetrahydro-thiophen-2 -yl-methyl] -amino} -cyclobut-3-ene-1,2-dione Compound 6: 1- (2-chloro-3-fluoro-phenyl) -3- (4-chloro-2-hydroxy-3- methanesulfoximinephenyl) -urea Compound 7: 1- (2-Chloro-3-fluoro-phenyl) -3-14-chloro-2-hydroxy-3-methanes - [(N-methyl) -sulfoximin] -phenyl} -urea Compound 8: 3-12-Hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut -3-ene-1,2-dione Compound 9: 3- [4-chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxyanilino] -4-ethoxy-cyclobut-3 compound 10: 3- [4-chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino] (1-ethylpropylamino) cyclobut-3-ene-1,2-dione Compound 11: 3- [4-chloro-2-hydroxy-3- [N- (2-methoxyethyl) -S-methylsulfonimidoyl] anilino] - 4 - [[(1R) -1- (5-methyl-2-furyl) propyl] amino] cyclobut-3-ene-1,2-dione Compound 12: (-) - 3-14-Chloro-2-hydroxy 3-methane- [(N-methyl) sulfoximin] phenylamino} -4-[(R) -1- (pyridin-2-yl) propylamino] cyclobut-3-ene-1,2-dione Compound 13: (+) - 3 -14-Chloro-2-hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4-[(R) -1- (pyridin-2-yl) ) -propylamino] -cyclobut-3-ene-1,2-dione Compound 14: (-) - 3-12-Hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4- [( R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 15: (-) - 3-12-Hydroxy-3-methan- [(N- methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 16: (+) - 3- 12-Hydroxy-3-methane - [(N-methyl) sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene -1,2-dione Compound 17: (+) - 3-12 3-hydroxy-methane - [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene; 1,2-dione Compound 18: (-) - 3- (2-Hydroxy-3-methane - [(N-methyl) sulfoxim] phenylamino [4- (1-ethylpropylamino) cyclobut-3-ene) 1,2-dione Compound 19: (+) - 3- (2-Hydroxy-3-methane - [(N-methyl) sulfoxim] -phenylamino- [4- (1-ethyl-propylamino] -cyclobut-3] ene-1,2-dione Compound 20: (+) - 3-14-Chloro-2-hydroxy-3-methane- [(N-methyl) sulfoximin] -phenylamino} -4- [(R) -1) Another object of the invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione. general (I) as described above in combination with a pharmaceutically acceptable solvent or carrier. A third object according to the invention relates to the compounds corresponding to the general formula (I), as well as their salts and enantiomers, or a pharmaceutical composition comprising an effective amount of a compound corresponding to the general formula (I), one of its salts or enantiomers for use as a medicament. A fourth object according to the invention relates to the compounds corresponding to the general formula (I), as well as their salts and enantiomers, or a pharmaceutical composition comprising an effective amount of a compound corresponding to the general formula (I), a of its salts or enantiomers for use in the treatment of α-chemokine mediated diseases.
[0020] Examples of c-chemokine-mediated diseases include neutrophilic dermatoses, including psoriasis, atopic dermatitis, acne, rosacea, asthma, chronic obstructive pulmonary diseases, respiratory diseases of the lungs, adults, arthritis, inflammatory bowel diseases, Crohn's disease, transplant rejection, cystic fibrosis and skin cancers. Neutrophilic dermatoses, in its broadest sense, are understood to mean the Sweet syndrome, "eccrines hydranite", SAPHO syndrome, Sneddon Wilkinson syndrome, pyoderma gangrenosum, erythema elevatum duitinum, psoriasis, psoriasis vulgaris, pustular psoriasis, palmoplantar pustulosis, exanthematous pustulosis (PEAG), pustulosis vasculitis, acro-pustulosis in children, Behcet's disease, as well as some bullous diseases such as herpes derived dermatitis , IgA neutrophilic dermatitis, Intraepidermal pustilosis IgA, Bullous pemphigoid, IgA pemphigus, Ta vasculitis, Leroy Reiter Fiellinger syndrome, Scalp pustulosis, Hallopeau continuous acrodermatitis, and dermatitis related to angioimmunoblastic lymphodenopathy, with dysmielopoesis induced by cyclophosphamide, with p-ANCA antibodies. In a preferred embodiment according to the invention, the above-mentioned pharmaceutical compound or composition is used in the treatment of dermatological diseases such as neutrophilic dermatoses, in particular psoriasis, atopic dermatitis, acne and rosacea. Another aspect of the invention relates to the use of a compound of general formula (I), as well as their salts and enantiomers or the use of a pharmaceutical composition comprising an effective amount of a compound corresponding to the general formula (I), a salt thereof and enantiomers thereof for the preparation of a medicament for the treatment of diseases of the group comprising neutrophilic dermatoses, in particular psoriasis, atopic dermatitis, acne, rosacea, asthma, chronic obstructive pulmonary diseases, adult respiratory diseases, arthritis, inflammatory bowel diseases, Crohn's disease and skin cancer. The compounds of general formula (I) of the present invention are prepared according to one of the two synthetic routes as shown in the synthetic schemes indicated in FIGS. 1 and 2. Those skilled in the art can easily deduce the experimental conditions required. for each of these two synthesis routes with reference to those used for each synthesis route as shown by examples of preparation of the compounds of formula (I) illustrated below in a non-limiting manner. By way of illustration, the following compounds, corresponding to the general formula (I) of the present invention, were prepared by following one of the two schemes presented above and in FIGS. 1 and 2. PREPARATION OF THE FORMULA COMPOUNDS (I) EXAMPLE 1 3- (4-Chloro-2-hydroxy-3-methanesulfoxymin-phenylamino) -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino-1-cyclobut - 3-ene-1,2-dione To a suspension of 3- (4-chloro-2-hydroxy-3-methanesulfoximin-phenylamino) -4-ethoxycyclobut-3-ene-1,2-dione (0.19 g, 0.51 mmol) ) in methanol (8 ml) is added a solution of (R) -1- (5-methyl-furan-2-yl) -propylan hydrochloride (0.11 g, 0.62 mmol) in methanol (1 ml) and triethylamine (85 μl, 0.62 mmol). After three days, the reaction medium is partially concentrated. Ethyl acetate and then a 1M aqueous solution of sodium dihydrogenphosphate are added. The organic phase is again washed with a 1M aqueous solution of sodium dihydrogenphosphate. The solid obtained is chromatographed on silica gel (eluent heptane / acetone, from 20% to 70% acetone). 3- (4-Chloro-2-hydroxy-3-methanesulfoxymin-phenylamino) -4 - [(R) -1- (5-methyl-furan-2-yl) propylaminecyclobut-3-ene-1,2-dione) (0.12 g, 50%) is obtained. Melting point 192 ° C. MS (ES +) m / z 438 (MH +). 1H NMR (400 MHz, DMSO-d6): δ 0.92 (td, J = 7.3, 1.5 Hz, 3H); 1.90-1.92 (m, 2H); 2.27 (s, 3H); 3.64 (s, 3H); 5.13 (q, J = 7.8 Hz, 1H); 6.06 (dd, J = 3.1, 1.3 Hz, 1H); 6.27 (t, J = 2.6 Hz, 1H); 7.02 (d, J = 8.7 Hz, 1H); 8.03 (dd, J = 8.7, 2.0Hz, 1H); 8.76 (dd, J = 9.0, 3.9Hz, 1H); 9.36 (d, J = 3.7 Hz, 1H); 11.72 (s, 2H). 3- (4-Chloro-2-hydroxy-3-methanesulfoximin-phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione To a solution of 6-amino-3-chloro-2-methanesulfoximin-phenol (0.52 g, 2.12 mmol) in ethanol (35 ml) is added 3,4-diethoxy-3-cyclobutene-1,2-dione (0.63 ml, 4.24 mmol).
[0021] The reaction medium is heated for 3 days at 60 ° C. and is then concentrated. The oil obtained is chromatographed on silica gel (eluent heptane / acetone, from 10% to 80% acetone). 3- (4-Chloro-2-hydroxy-3-methanesulfoximin-phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (0.39 g, 49%) is obtained.MS (ES +) m / z 345/347 (MH +). 6-amino-3-chloro-2-methanesulfoximinophenol To a solution of 2-tert-butyl-6-chloro-7-methanesulfoximinbenzooxazole (0.80 g, 2.79 mmol) in 1,4-dioxane (4 ml) are added water (1 ml) and sulfuric acid (0.95 ml, 17.77 mmol). The reaction medium is then heated to 100 ° C. After one hour 40 minutes, the reaction medium is cooled and hydrolysed with a 1N sodium hydroxide solution and water is added (up to pH = 6-7). The mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. 6-Amino-3-chloro-2-methanesulfoximin-phenol (0.55 g, 80%) is obtained. MS (ES +) m / z 221/223 (MH +). 2-tert-Butyl-6-chloro-7-methanesulfoximin-benzooxazole To a suspension of 2-tert-butyl-6-chloro-7-methanesulfinyl-benzooxazole (11.11 g, 40.88 mmol) 2,2,2-trifluoroacetamide ( 9.24 g, 81.76 mmol), magnesium oxide (6.59 g, 163.52 mmol) in dichloromethane (400 ml) degassed for approximately 15 minutes under nitrogen are added rhodium (II) acetate dimer (1.45 g, 3.27 mmol) and iodobenzene diacetate (20.15 g, 62.55 mmol). After 17 hours, 2,2,2-trifluoroacetamide (2.50 g, 22.12 mmol), iodobenzene diacetate (3.48 g, 10.80 mmol) and rhodium (II) acetate dimer (0.69 g, 1.56 mmol) are added. After 20 hours, the reaction medium is heated to reflux. After 45 hours, the reaction medium is filtered through Celite and is concentrated. The residue is taken up in methanol (400 ml) and potassium carbonate (28.25 g, 204.40 mmol) is added. After one hour, the reaction medium is concentrated. The residue is taken up in ethyl acetate and washed with water. The aqueous phase is again extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulphate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent heptane / ethyl acetate, 5% to 80% ethyl acetate). 2-tert-Butyl-6-chloro-7-methanesulfoximinobenzoxazole (1.76 g, 15%) is obtained. MS (ES +) m / z 287/289 (MH +). enantiomer A + enantiomer B (-) - 2-tert-Butyl-6-chloro-7-methanesulfoximin-benzooxazole (enantiomer A) (+) - 2-tert-Butyl-6-chloro-7-methanesulfoximin-benzooxazole (enantiomer B ) 2-tert-Butyl-6-chloro-7-methanesulfoximin-benzooxazole 2.5 g was separated into enantiomers by the chiral HPLC method on the column CHIRALCEL OJ 20 pm LC50 with the solvent heptane / ethanol 90:10 as the eluent. Separation gave enantiomer A (1.35 g, retention time 11.71 min, MD = -2.4 ° (c = 10 g / L, EtOH)) and enantiomer B (1.37 g, retention time 23.10 min, [ cc] D = + 3.5 ° (c = 10 g / L, EtOH)). 2-tert-butyl-6-chloro-7-methanesulfinyl-benzooxazole To a solution of 2-tert-butyl-6-chloro-7-methylsulfanyl-benzooxazole (9.78 g, 38.24 mmol) in dichloromethane (200 ml) under nitrogen is added per portion of 3-chloroperbenzoic acid (9 g, 40.15 mmol). After 24 hours, the reaction medium is hydrolysed with 2N sodium hydroxide. The organic phase is washed a second time with a 2N sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. 2-tert-Butyl-6-chloro-7-methanesulfinyl-benzooxazole (11.9 g, 100%) is obtained. MS (ES +) m / z 272/274 (MH +). 2-tert-Butyl-6-chloro-7-methylsulfanyl-benzooxazole To a suspension of 60% sodium hydride in oil (2.20 g, 55.00 mmol) in tetrahydrofuran (135 ml), under nitrogen, in a at 0 ° C., a solution of 2-tert-butyl-6-chloro-benzooxazole-7-thiol (12 g, 49.64 mmol) in tetrahydrofuran (60 ml) is added dropwise and then 15 minutes later iodomethane (9.5 ml, 152.60 mmol).
[0022] The reaction medium is then returned to ambient temperature. After 16 hours, a 1M aqueous solution of sodium dihydrogenphosphate is added as well as ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent heptane / ethyl acetate, 0% to 10% ethyl acetate). 2-tert-Butyl-6-chloro-7-methylsulfanylbenzooxazole (10.85 g, 85%) is obtained. MS (ES +) m / z 256/258 (MH +). 2-tert-Butyl-6-chloro-benzooxazole-7-thiol To a solution of 2-tert-butyl-6-chlorobenzoxazole-7-sulfonyl chloride (15.01 g, 48.70 mmol) under nitrogen in toluene (250 ml) is added a solution of triphenylphosphine (38.32 g, 146.11 mmol) in toluene (125 ml) (the reaction is exothermic). After 40 minutes, the reaction medium is hydrolysed with water (250 ml) and allowed to stir for one hour. The organic phase is then extracted twice with 1N sodium hydroxide solution (2 × 125 ml). The basic aqueous phases are combined and washed twice with toluene (2 x 125 ml). The aqueous phase is then acidified to pH = 1 with a 2N aqueous hydrochloric acid solution and then extracted twice with dichloromethane (2 × 150 ml). The organic phases are combined, dried over anhydrous sodium sulphate, filtered and concentrated. 2-tert-Butyl-6-chloro-benzooxazole-7-thiol (11.37 g, 96%) is obtained. MS (ES +) m / z 342/344 (MH +).
[0023] EXAMPLE 2 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino-4-1 (R) -1- (5-methyl-furan-2-yl) -propylaminol-cyclobutane 3-ene-1,2-dione A mixture of 3- (4-chloro-2-hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene -1,2-dione (0.16 g, 0.45 mmol) in methanol (3 ml) is added a solution of (R) -1- (5-methyl-furan-2-yl) -propylan hydrochloride (90 mg; 0.51 mmol) in methanol (1 ml) and triethylamine (70 μl, 0.50 mmol). The reaction medium is then heated to 50 ° C. After 2 hours, ethyl acetate is added and the reaction medium is washed twice with a 1M aqueous solution of sodium dihydrogenphosphate. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. The solid obtained is dried under vacuum in an oven at 50 ° C. 3- {4-Chloro-2-hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] ] -cyclobut-3-ene-1,2-dione (0.18 g; 88%) is obtained with a melting point of 131 ° C. MS (ES +) m / z 452 (MH +) 1H NMR (400 MHz, DMSO): δ 0.92 (td, J = 7.3, 1.4 Hz, 3H); 1.90-1.92 (m, 2H); 2.27 (s, 3H); 2.91 (s, 3H); 3.70 (s, 3H); 5.13 (q, J = 7.7 Hz, 1H); 6.06 (dd, J = 3.0, 1.2 Hz, 1H); 6.26 (t, J = 2.6 Hz, 1H); 6.98 (d, J = 8.7 Hz, 1H); 8.05 (dd, J = 8.7, 2.2 Hz, 1H); 8.78 (dd, J = 9.0, 3.6 Hz, 1H); 9.36 (d, J = 3.7 Hz, 1H). 3- (4-chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino) -4-ethoxycyclobut-3-ene-1,2-dione To a solution of 6-amino-3- 2-chloro-methane - [(N-methyl) -sulfoximin] -phenol (0.39 g, 1.33 mmol) in ethanol (35 ml) is added 3,4-diethoxy-3-cyclobutene-1,2- dione (0.50 ml, 3.38 mmol). The reaction medium is heated to 60 ° C. After three days, the reaction medium is concentrated. The oil obtained is chromatographed on silica gel (eluent heptane / acetone, from 20% to 50% acetone). 3- (4-Chloro-2-hydroxy-3-methane - [(N-methyl) sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (0.32 g, 67%) is obtained. MS (ES +) m / z 359/361 (MH +). 6-amino-3-chloro-2-methane-RN-methyl) -sulfoximin-1-phenol To a solution of 2-tert-butyl-6-chloro-7-methane-N-methyl-sulfoximin-benzooxazole (0.50 g 1.66 mmol) in 1,4-dioxane (2.5 ml) are added water (0.60 ml) and concentrated sulfuric acid tastefully (0.57 ml, 10.66 mmol). The reaction medium is heated at 100 ° C. for 1h30min, then 2 hours at 70 ° C. and then returned to 100 ° C. After 4 hours of reaction, concentrated sulfuric acid (0.20 ml, 3.74 mmol) is added. After 7 hours of reaction the concentrated sulfuric acid (0.40 ml, 7.48 mmol) is again added.
[0024] After 8 hours, the reaction medium is hydrolysed with water and an aqueous solution of 1N sodium hydroxide is added (up to pH = 7). The mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. 6-Amino-3-chloro-2-methane-RN-methyl) -sulfoximiephenol (0.39 g, 80%) is obtained. MS (ES +) m / z 235/237 (MH +). 2-tert-butyl-6-chloro-7-methane-N-methyl-sulfoximin-benzooxazole To a suspension of 60% sodium hydride in oil (0.12 g, 3.00 mmol) in N, N-dimethylformamide (15 ml) at 0 ° C under nitrogen is added a solution of 2-tert-butyl-chloro-7-methanesulfoximin-benzooxazole (0.74 g, 2.58 mmol) in N, N-dimethylformamide (15 ml). 20 minutes later, iodomethane (0.32 ml, 5.14 mmol) is added. The reaction medium is then returned to ambient temperature. After 3 hours 30 minutes, the reaction medium is hydrolysed with water and is extracted with ethyl acetate. The organic phase is washed again with water, dried over anhydrous sodium sulphate, filtered and concentrated. The oil obtained is chromatographed on silica gel (eluent heptane / ethyl acetate, 30% to 80% ethyl acetate). 2-tert-Butyl-6-chloro-7-methane N-methyl-sulfoximin-benzooxazole (0.51 g, 65%) is obtained. MS (ES +) m / z 301/303 (MH +). EXAMPLE 3 3-14-Chloro-2-hydroxy-3-methane-RN-pyridin-4-yl) -sulfoximin-phenylamino-4-1 (R) -1- (5-methyl-furan-2-yl) propylaminol-cyclobut-3-ene-1,2-dione To a suspension of 3- (4-chloro-2-hydroxy-3-methane-RN-pyridin-4-yl) -sulfoximinylphenylamino) -4-ethoxycyclobutane 3-ene-1,2-dione (114 mg, 0.27 mmol) and (R) -1- (5-methyl-furan-2-yl) -propylan hydrochloride (54.59 mg, 0.31 mmol) in methanol ( 3 ml) is added triethylamine (0.04 ml, 0.31 mmol). The reaction medium is heated at 60 ° C. for 24 hours. The cooled reaction medium is diluted with dichloromethane and washed twice with a 1M aqueous solution of sodium dihydrogenphosphate. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The solid obtained is taken up with methanol and crystallized with ether. The compound is chromatographed on silica gel, eluent dichloromethane methanol 95/05. 3-14-Chloro-2-hydroxy-3-methan- [(N-yridin-4-yl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-one) is obtained. y1) - propylaminecyclobut-3-ene-1,2-dione (70 mg, 48%). MS (ES +) m / z 515 (MH +). 1 H NMR (400 MHz, DMSO): δ (ppm) 0.87-0.92 (m, 3H); 1.81 (dt, J = 14.0, 7.0 Hz, 1H); 1.89-1.94 (m, 1H); 2.25 (d, J = 6.7 Hz, 3H); 3.79 (s, 3H); 5.11 (q, J = 7.6 Hz, 1H); 6.006.03 (m, 1H); 6.20 (t, J = 4.3 Hz, 2H); 6.98 (dd, J = 7.0, 2.2 Hz, 2H); 7.78 (d, J = 8.2 Hz, 1H); 8.23 (dd, J = 6.7, 4.6 Hz, 2H); 8.86 (d, J = 9.0 Hz, 1H); 9.41 (s, 1H). 3- (4-Chloro-2-hydroxy-3-methane-RN-pyridin-4-yl) -sulfoximin-1-phenylamino) -4-ethoxycyclobut-3-ene-1,2-dione To a solution of 6- amino-3-chloro-2-methane-RN-methyl) -sulfoximin] phenol (222 mg, 0.75 mmol) in ethanol (20 ml) is added 3,4-diethoxy-3-cyclobutene-1,2 -dione (0.30 ml, 2.01 mmol). The reaction medium is heated at 60 ° C overnight. The reaction medium is concentrated and taken up in ethyl acetate and then ether. 3- (4-Chloro-2-hydroxy-3-methan- [(N-yridin-4-yl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (228 mg; 72%). MS (ES +) m / z 422 (MH +) 6-Amino-3-chloro-2-methane-RN-pyridin-4-yl) -sulfoximin-1-phenol On 2-tert-butyl-6-chloro-7- (N-pyridin-4-yl) sulfoximin-benzooxazole (320 mg, 0.88 mmol) dissolved in 1,4-dioxane (5 ml) is added dropwise with sulfuric acid (0.87 ml, 16.20 mmol) diluted in water (1.28 ml) at room temperature. The reaction medium is stirred at 100 ° C. for 4 h. The pH of the medium is brought to pH = 7-8 with 1N sodium hydroxide and extraction with ethyl acetate. The organic phase is dried, filtered and concentrated. 6-Amino-3-chloro-2-methan- [(N-pyridin-4-yl) -sulfoximin] -phenol (222 mg, 84%) is obtained. MS (ES +) m / z 298 (MH +). 2-tert-Butyl-6-chloro-7- (N-pyridin-4-yl) sulfoximin-benzooxazole A mixture of 4-bromopyridine hydrochloride (848 mg, 4.36 mmol), 2-tert-butyl-chloro benzoxazole-7-sulfoximine (1.00 g, 3.49 mmol), palladium acetate (39.14 mg, 0.17 mmol), rac-2,2'bis (diphenylphosphino) -1,1'binaphthyl 97% (21.71 mg) 0.03 mmol) and cesium carbonate (2.84 g, 8.72 mmol) in toluene (12.5 ml) (degassed) is heated at 110 ° C for 40 hours. The reaction medium is taken up in water, the organic phase is extracted three times with ethyl acetate, dried and concentrated. The crude is chromatographed on silica gel, eluent dichloromethane ethyl acetate 70/30 to 40/60. 2-tert-butyl-6-chloro-7- (N-pyridin-4-yl) sulfoximin-benzooxazole (0.36 g, 28%) is obtained. MS (ES +) m / z 364 (MH +).
[0025] EXAMPLE 4 3-14-Chloro-2-hydroxy-3-methane-RN-pyridin-4-yl) -sulfoximin-1-phenylamino} -4- (1-ethylpropylamino) -cyclobut-3-ene-1 2-dione A suspension of 3- (4-chloro-2-hydroxy-3-methane- [(N-yridin-4-yl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene-1,2 -dione (114 mg, 0.27 mmol) and 1-ethylpropylamine (0.04 mL, 0.32 mmol) in methanol (3 mL) is heated at 60 ° C for 24 hours. The cooled reaction medium. The precipitate that forms is filtered and dried. The compound obtained is chromatographed on silica gel, eluent dichloromethane methanol 95/05. There is obtained 3-14-chloro-2-hydroxy-3-methane - [(N-pyridin-4-yl) -sulfoximin] phenylamino} -4- (1-ethyl-propylamino) -cyclobut-3-ene-1 2-dione (85 mg, 67%). 1 H NMR (400 MHz, DMSO): δ (ppm) 0.84-0.89 (m, 6H); 1.38-1.47 (m, 2H); 1.54-1.61 (m, 2H); 3.80 (s, 3H); 3.86 (t, J = 7.3 Hz, 1H); 6.20 (s, 1H); 6.99 (d, J = 6.8 Hz, 2H); 7.81 (d, J = 8.2 Hz, 1H); 8.24 (d, J = 6.8 Hz, 2H); 8.37 (d, J = 9.1 Hz, 1H); 9.33 (s, 1H). MS (ES +) nilz 4663 (MH +) EXAMPLE 5 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximirilphenylamino} -4 - {[(S) - (5-methyl) -2- furan-2-yl) - (R) -tetrahydro-thiophen-2-yhmethyl-aminol-cyclobut-3-ene-1,2-dione To a mixture of 3- (4-chloro-2-hydroxy-3-methane) -N-methyl-sulfoximin-1-phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (0.16 g, 0.45 mmol) in methanol (3 ml) is added a solution of C-RS) - C- (5-methyl-furan-2-yl) -C- (R) -tetrahydro-thiophen-2-yl] methylamine (0.12 g, 0.61 mmol, prepared according to the procedure described in WO 2013061004) in methanol (1 ml). After 26 hours, ethyl acetate is added and the mixture is washed twice with a 1M aqueous solution of sodium dihydrogenphosphate. The organic phase is dried over anhydrous sodium sulphate, filtered and concentrated. The solid obtained is chromatographed on silica gel (eluent heptane / acetone, from 10% to 50% acetone). The solid obtained is dried under vacuum in an oven at 50 ° C. 3-14-Chloro-2-hydroxy-3-methane- [(N-methyl) sulfoximin] -phenylamino} -4 - {[(S) - (5-methyl-furan-2-yl) - (R)) -tetrahydro-thiophen-2-yl-methyl] -amino} -cyclobut-3-ene-1,2-dione (0.14 g, 61%) is obtained with a melting point of 155 ° C. MS (ES +) m / z 510 (MH +). 1 H NMR (400 MHz, DMSO): 1.81-1.85 (m, 1H); 1.91-1.94 (m, 1H); 2.01-2.06 (m, 2H); 2.27 (s, 3H); 2.79-2.81 (m, 2H); 2.90 (s, 3H); 3.70 (s, 3H); 3.87 (dt, J = 9.6, 6.1 Hz, 1H); 5.20 (t, J = 9.6 Hz, 1H); 6.07 (d, J = 3.0 Hz, 1H); 6.30 (d, J = 3.1 Hz, 1H); 6.98 (d, J = 8.7 Hz, 1H); 8.03 (dd, J = 8.7, 3.3 Hz, 1H); 8.89 (dd, J = 9.6, 4.6 Hz, 1H); 9.41 (d, J = 4.0 Hz, 1H). EXAMPLE 6 1- (2-Chloro-3-fluoro-phenyl) -3- (4-chloro-2-hydroxy-3-methanesulfoximine-phenyl) -urea to a solution of 6-amino-3-chloro 2-methanesulfoximin-phenol (0.19 g, 0.81 mmol) in acetonitrile (1.50 ml) and N, N-dimethylformamide (0.50 ml), under nitrogen, is added a solution of 2-chloro-1-fluoro-3 isocyanato-benzene (0.15 g, 0.89 mmol) in acetonitrile (1 ml). After two hours, the reaction medium is concentrated. The residue is purified by preparative HPLC / MS (XSelect 21mm diameter C18 column, water / acetonitrile, 45% acetonitrile and then 60%) 1- (2-chloro-3-fluoro-phenyl) -3- (4- chloro-2-hydroxy-3-methanesulfoximine-phenyl) urea (0.08 g, 25.2%) is obtained at mp 203 ° C. MS (ES-) m / z 390 (MH-). 1 H NMR (400 MHz, DMSO): δ 3.63 (s, 3H); 7.00 (d, J = 8.8 Hz, 1H); 7.08 (t, J = 8.7 Hz, 1H); 7.34 (q, J = 7.6 Hz, 1H); 7.98 (d, J = 8.5 Hz, 1H); 8.28 (d, J = 8.8 Hz, 1H); 9.27 (s, 1H); 9.30 (s, 1H); 11.64 (brs, 2H).
[0026] EXAMPLE 7 1- (2-Chloro-3-fluoro-phenyl) -3-14-chloro-2-hydroxy-3-methanes-RN-methyl) -sulfoximin-1-phenyl-urea To a solution of 6 amino-3-chloro-2-methane - [(N-methyl) -sulfoximin] -phenol (0.16 g, 0.52 mmol) in acetonitrile (1.5 ml) and N, N-dimethylformamide (0.50 ml) is added a solution of 2-chloro-1-fluoro-3-isocyanato-benzene (0.12 g, 0.68 mmol) in acetonitrile (1.5 ml). After 3 hours, the reaction medium is concentrated. The residue obtained is chromatographed on silica gel (eluent heptane / ethyl acetate, from 10% to 60% ethyl acetate). 1- (2-Chloro-3-fluoro-phenyl) -3-yl-chloro-2-hydroxy-3-methanes- [(N-methyl) sulfoximiephenyl} urea (0.10 g, 45%) is obtained from melting point 107 ° C. MS (ES +) m / z 406 (MH +). 1 H NMR (400 MHz, DMSO): δ 2.92 (s, 3H); 3.68 (s, 3H); 6.99 (d, J = 8.8 Hz, 1H); 7.08 (t, J = 8.7 Hz, 1H); 7.33-7.34 (m, 1H); 7.97 (d, J = 8.5 Hz, 1H); 8.28 (d, J = 8.8 Hz, 1H); 9.27 (s, 1H); 9.30 (s, 1H); 16.33 (brs, 1H).
[0027] EXAMPLE 8 3-12-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (5-methylfuran-2-yl) -propylaminol-cyclobut-3-ene -1,2-dione To a suspension of 3- [3- (N, S-dimethylsulfonimidoyl) -2-hydroxy-anilino] -4-ethoxycyclobut-3-ene-1,2-dione (0.10 g, 0.31 mmol) in methanol (3 ml) is added at room temperature (R) -1- (5-methyl-furan-2-yl) -propylan hydrochloride (64.99 mg, 0.37 mmol) and triethylamine (51 μl; mmol). The reaction medium is heated at 60 ° C. for 1 hour 30. The reaction medium is concentrated, the crude is chromatographed on silica gel (eluent 10-60% methanol in dichloromethane). 3-12-Hydroxy-3-methane-N-methyl-sulfoximin-phenylamino-4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino} -cyclobut-3-ene-1, 2-dione (0.10 g; 77) is obtained. MS (ES +) m / z 418 (MH +) 1H NMR (DMSO-d6) δ: 9.36 (s, 1H), 8.72 (dd, J = 9.0, 2.2Hz, 1H), 8.04 (dt, J = 8.0, 1.7). Hz, 1H), 7.40 (dd, J = 8.2, 1.5 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.26 (t, J = 2.2 Hz, 1H), 6.06 (d, J = 3.6 Hz, 1H), 5.14 (q, J = 7.9 Hz, 1H), 3.46 (s, 3H), 2.83 (s, 3H), 2.27 (s, 3H), 2.02-1.81 (m, 2H), 0.93 (t , J = 7.3 Hz, 3H) 3-13- (N, S-dimethylsulfonimidoyl) -2-hydroxy-anihnol-4-ethoxy-cyclobut-3-ene-1,2-dione To a solution of 2-amino-6 (N, S-Dimethylsulfonimidoyl) phenol (0.53 g, 2.65 mmol) in ethanol (10 ml) is added at room temperature to 3,4-diethoxy-3-cyclobutene-1,2-dione (0.59 ml, 3.97 mmol). The reaction medium is heated at 60 ° C. for 24 hours. The reaction medium is filtered, 0.39 g of the expected product in the form of a yellow solid is recovered. 3- [3- (N, S-dimethylsulfonimidoyl) -2-hydroxy-anilino] -4-ethoxy-cyclobut-3-ene-1,2-dione (0.39 g, 45%) is obtained. MS (ES +) m / z 325 (MH +) 2-amino-6- (N, S-dimethylsulfonimidoyl) phenol To a solution of 2-tert-butyl-7-methane-N-methyl-sulfoximin-benzooxazole (0.57 g; 2.14 mmol) in 1,4-dioxane (8.6 ml) and water (2.28 ml) is added at room temperature sulfuric acid (2.11 ml, 39.42 mmol). The reaction medium is stirred at 100 ° C. for 4 h and then 16 h at 80 ° C. The pH of the medium is brought to pH = 7 with 10N sodium hydroxide and is then extracted with 50 ml of ethyl acetate. The organic phase is recovered and then dried with magnesium sulfate, filtered and evaporated. 2-Amino-6- (N, S-dimethylsulfonimidoyl) phenol (0.54 g) is obtained. MS (ES +) m / z 201 (MH +). 2-tert-butyl-7-methane-N-methyl-sulfoximin-benzooxazole To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfoximine (550 mg, 2.18 mmol) in N, N-dimethylformamide ( 11 ml) is added per small hydride portion of 60% sodium in the oil (105 mg, 2.62 mmol). The reaction medium is stirred for 20 minutes at room temperature and then iodomethane (258 μl, 4.14 mmol) is added. The reaction medium is then brought to ambient temperature and stirred for 20 minutes. The reaction medium is partitioned between 50 ml of water and 50 ml of ethyl acetate. The organic phase is washed twice with 20 ml of saturated sodium bicarbonate and dried over magnesium sulphate, filtered and evaporated. 2-tert-Butyl-7-methane-N-methyl-sulfoximin-benzooxazole (570 mg, 98%) is obtained. MS (ES +) m / z 267 (MH +). 2-tert-Butyl-7-methanesulfoximin-benzooxazole To a 3-degassed solution of 2-tert-butyl-6-chlorobenzooxazole-7-sulfoximine (1.00 g, 3.49 mmol) in tetrahydrofuran (18 ml) was added palladium (II) acetate (39.14 mg, 0.17 mmol), potassium fluoride (405.16 mg, 6.97 mmol) diluted in WATER (7 mL) degassed and 1,1,1,3,5,5,5-heptamethyltrisiloxane (3.10 g, 13.95 mmol) dropwise. The medium is stirred at room temperature for 1 hour. The medium is purged with nitrogen and then palladium acetate (39.14 mg, 0.17 mmol) and 1,1,1,3,5,5,5-heptamethyltrisiloxane (3.10 g, 13.95 mmol) are added and the medium is then stirred. 16h at room temperature. The medium is purged again with nitrogen and then palladium acetate (39.14 mg, 0.17 mmol), 1,1,1,3,5,5,5-heptamethyltrisiloxane (3.10 g, 13.95 mmol), potassium fluoride ( 405.16 mg, 6.97 mmol) are added and the medium is stirred for 30 minutes at room temperature. The medium is transferred to 30 ml of 3N NaOH at 0 ° C. and then stirred for 4 hours at room temperature. The medium is extracted 3 times with 50 ml of diethyl ether, the organic phases are combined and then dried over magnesium sulfate, filtered and evaporated. The crude is chromatographed on a silica column (eluent with the mixture of 0% to 70% ethyl acetate in heptane). 2-tert-butyl-7-methanesulfoximin-benzooxazole (0.57 g, 64%) is obtained. MS (ES +) m / z 254 (MH +) EXAMPLE 9 3-14-Chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino-1-4-ethoxy- cyclobut-3-ene-1,2-dione To a suspension of 3- [4-chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino] -4-ethoxy Cyclobut-3-ene-1,2-dione (180 mg, 0.43 mmol) in methanol (7.20 ml) at room temperature is added (R) -1- (5-methyl-furan-2-yl) hydrochloride propylamine (91.23 mg, 0.52 mmol) triethylamine (0.09 ml, 0.65 mmol). The reaction medium is heated at 60 ° C. for two hours. The reaction medium is concentrated, the crude is chromatographed on silica gel (5-10% methanol in dichloromethane). 344-Chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino] -4-ethoxy-cyclobut-3-ene-1,2-dione (150 mg, 64%) is got. MS (ES +) m / z 510 (MH +) 1H NMR δ (ppm) (DMSO-d6): 0.94-0.91 (3H, m), 1.85 (1H, dt, J = 14.12, 7.12Hz), 1.94 ( 1H, dd, J = 13.35, 7.62 Hz), 2.26 (3H, d, J = 4.16Hz), 2.56 (3H, s), 2.85 (2H, brs), 2.90 (1H, s). , 3.01 (1H, d, J = 12.42 Hz), 3.22 (1H, d, J = 14.18Hz), 3.36 (3H, d, J = 12.13Hz), 5.16 (1H, d, J = 8.68 Hz), 6.05 (1H, s), 6.24 (1H, d, J = 10.88Hz), 6.47 (1H, t, J = 7.18Hz), 7.99 (1H, dd, J = 14.72, 8.42Hz). ), 8.90 (1H, dd, J = 30.8, 8.83Hz), 9.40 (1H, s). 3-14-Chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino-1-4-ethoxy-cyclobut-3-ene-1,2-dione solution of 6-amino-3-chloro-2- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] phenol (190 mg, 0.65 mmol) in ethanol (5.70 ml) is added at room temperature. diethoxy-3-cyclobutene-1,2-dione (145 1..1, 0.98 mmol). The reaction medium is heated at 60 ° C. for 2 hours. The ethanol is evaporated and the residue is chromatographed on silica gel (5-10% methanol in dichloromethane). 3- [4-Chloro-3- [N- (2-dimethylaminoethyl) -5-methylsulfonimidoyl] -2-hydroxy-anilino] -4-ethoxy-cyclobut-3-ene1,2-dione (130 mg; %) is obtained. MS (ES +) m / z 418 (MH +) 6-Amino-3-chloro-2-1N- (2-dimethylaminoethyl) -S-methylsulfonimidoephenol To a solution of 2 - [[(2-tert-butyl) -6 1-chloro-1,3-benzoxazol-7-yl) methyl-oxo-sulfanylidene [amine] N, N-dimethyl-ethanamine (760 mg, 2.12 mmol) in 1,4-dioxane (11.40 ml) and water (3 ml) at room temperature is added, tastefully, concentrated sulfuric acid (2.1 ml, 39.11 mmol, 18.42 eq.). The reaction medium is stirred at 60 ° C. for 48 hours. The reaction medium is brought to pH = 8 with 10M sodium hydroxide. The product is extracted 3 times with 25 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and the solvents are evaporated. The residue obtained is chromatographed on a silica column (2-10% methanol in dichloromethane). 6-Amino-3-chloro-2- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl [henol (280 mg, 45%) is obtained. MS (ES +) m / z 292 (MH-E) 2 - [[(2-tert-Butyl-6-chloro-1,3-benzoxazol-7-yl) -methyl-oxo-sulfanylidene] amino-1-N To a suspension of 2-tert-butyl-6-chloro-benzooxazole-7-sulfoximine (2.00 g, 6.97 mmol) in toluene (10 ml) was added at room temperature (triphenylphosphanylidene) acetonitrile (6.30 g; 20.92 mmol) and 2-dimethylaminoethanol (2.10 ml, 20.92 mmol). The medium is heated for 24 hours at 120 ° C. The reaction medium is partitioned between 25 ml of water and 25 ml of ethyl acetate. The aqueous phase is reextracted again with 25 ml of ethyl acetate. The organic phases are combined and then dried over magnesium sulfate, filtered and evaporated. The crude is chromatographed on silica (2-10% methanol in dichloromethane). 2 - [[(2-tert-butyl-6-chloro-1,3-benzoxazol-7-yl) -methyl-oxosulfanylidene] amino [-N, N-dimethyl-ethanamine (1.00 g, 40%) is obtained. MS (ES +) m / z 359 (MH +).
[0028] EXAMPLE 10 3-1-4-Chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anihno-1-4- (1-ethylpropylamino) cyclobut-3-ene-1 , 2-dione A suspension of 3- [4-chloro-3- [N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino] -4-ethoxy-cyclobut-3-ene 1,2-dione (80 mg, 0.19 mmol) in methanol (3.2 ml) is added at room temperature 1-ethyl-propylamine (27 μl, 0.23 mmol). The reaction medium is heated at 60 ° C. for 48 hours. The reaction medium is concentrated, 100 mg of crude are purified by preparative HPLC. 344-chloro-34N- (2-dimethylaminoethyl) -S-methylsulfonimidoyl] -2-hydroxy-anilino] -4- (1-ethylpropylamino) cyclobut-3-ene1,2-dione (25 mg, 28%) are obtained. ). 1H NMR δ (ppm) (DMSO-d6): 0.93-0.86 (6H, m), 1.52-1.42 (2H, m), 1.67-1.57 (2H, m), 2.55 (6H, s), 2.93-2.81 (2H, m), 3.04-2.97 (1H, m), 3.22 (1H, dt, J = 13.96, 4.56Hz), 3.37 (3H, s), 3.92-3.87 (1H, m.p. m), 6.47 (1H, d, J = 8.43Hz), 8.03 (1H, d, J = 8.43Hz), 8.43 (1H, d, J = 9.05Hz), 9.33 (1H, s). MS (ES +) m / z 457 (MH +) EXAMPLE 11 / 3-1-4-Chloro-2-hydroxy-3- [N- (2-methoxyethyl) -S-methylsulfonimidoyl] anilino-1-4- [ [(1R) -1- (5-methyl-2-furybpropeaminnicyclobut-3-ene-1,2-dione) A suspension of 3- [4-chloro-2-hydroxy-3- [N- (2-methoxyethyl) S-methylsulfonimidoyl] anilino] -4-ethoxy-cyclobut-3-ene-1,2-dione (127 mg, 0.32 mmol) in methanol (5 ml) is added at room temperature of (R) -hydrochloride. 1- (5-methylfuran-2-yl) -propylan (66 mg, 0.38 mmol) and triethylamine (0.07 ml, 0.47 mmol) The reaction medium is heated at 50 ° C. for 2 hours, then it is concentrated and the crude is chromatographed on silica gel (eluent 30-60% ethyl acetate in heptane) 344-Chloro-2-hydroxy-3- [N- (2-methoxyethyl) -S-methyl-sulfonimidoyl] -anilino] 4 - [[(1R) -1- (5-methyl-2-furyl) propyl] -amino] cyclobut-3-ene-1,2-dione (85 mg, 54%) is obtained after the treatment with ether diisopropyl, MS (ES +) m / z 496 (MH +) 1H NMR δ (ppm) (DMSO-d6): 0.92 (3H, t, J = 7.29Hz), 1. 89-1.84 (1H, m), 1.95 (1H, dd, J = 13.89, 7.02Hz), 2.27 (3H, s), 3.31 (3H, m), 3.46-3.39 (2H, m). , 3.52 (2H, s), 3.68 (2H, s), 5.14 (1H, q, J = 7.65Hz), 6.06 (1H, s), 6.26 (1H, s), 7.01 (1H). , s), 8.03 (1H, d, J = 8.72Hz), 8.78 (1H, d, J = 8.82Hz), 9.36 (1H, s). 3-14-Chloro-2-hydroxy-3-1N- (2-methoxyethyl) -S-methylsulfonimidoanilino1-4-ethoxycyclobut-3-ene-1,2-dione To a solution of 6-amino-3-chloro -2-methane - [(N-2-methoxy-ethylamino) -sulfoximin] -phenol (0.50 g, 1.79 mmol) in ethanol (9.5 ml) is added at room temperature to 3,4-diethoxy-3-cyclobutene-1, 2-dione (0.40 ml, 2.69 mmol). The reaction medium is heated at 50 ° C. for 4 days. The medium is concentrated and the residue is chromatographed on silica gel (eluent 2-5% methanol in dichloromethane). 3- [4-Chloro-2-hydroxy-3- [N- (2-methoxyethyl) -N-methylsulfonimidoyl] anilinol-4-ethoxy-cyclobut-3-ene-1,2-dione (127 mg; %) is obtained. MS (ES +) m / z 403 (MH +). 6-Amino-3-chloro-2-methane - [(N-2-methoxy-ethylamino) -sulfoximin] -phenol To a solution of 2-tert-butyl-6-chloro-7-methane-N- (2- methoxy-ethylamino) -sulfoximinbenzo-oxazole (0.70 g, 2.03 mmol) in 1,4-dioxane (4.9 ml) and water (1.12 ml) is added dropwise at room temperature concentrated sulfuric acid (0.84 ml; mmol).
[0029] The reaction medium is heated at 110 ° C. for 4 hours. The reaction medium is concentrated and 28 ml of 1N sodium hydroxide are added (pH 7), then extracted with 50 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and the solvents are evaporated. 6-Amino-3-chloro-2-methane - [(N-2-methoxy-ethylamino) -sulfoximin] -phenol (0.40 g, 70%) is obtained. MS (ES +) m / z 279 (MH +). 2-tert-butyl-6-chloro-7-methane-N- (2-methoxy-ethylamino) -sulfoximin-benzooxazole To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfoximine (1.00 g; 3.49 mmol) in N, N-dimethylformamide (15 ml) is added at room temperature of 60% sodium hydride in the oil (0.21 g, 5.23 mmol). The medium is stirred for 10 minutes at room temperature and then 2-bromoethyl methyl ether (0.49 ml, 5.23 mmol) is added. The reaction medium is stirred at room temperature for 24 hours. Sodium hydride 60% in oil (21 mg, 0.52 mmol) and 2-bromoethyl methyl ether (0.07 ml, 0.70 mmol) are added to the reaction medium and the medium is stirred for 2 hours at 60 ° C. The reaction medium is partitioned between 30 ml of water and 30 ml of ethyl acetate, the organic phase is washed 3 times with 20 ml of water and then dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel (eluent 30-50% ethyl acetate in heptane). 2-tert-Butyl-6-chloro-7-methane-N- (2-methoxy-ethylamino) -sulfoximin-benzooxazole (0.70 g, 58%) is obtained. MS (ES +) m / z 345 (MH +).
[0030] EXAMPLE 12 (-) - 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylamino] 1-Cyclobut-3-ene-1,2-dione A mixture of (-) - 3- (4-chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-phenylamino) -4-ethoxy- cyclobut-3-ene-1,2-dione (216 mg, 0.60 mmol, prepared from enantiomer A, (-) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole) and (R) -1-pyridin-2-ylpropylamine hydrochloride (125 mg, 0.72 mmol) in methanol (5 ml) and in the presence of triethylamine (100 μl, 0.72 mmol) is heated at 50 ° C. for 7 hours and stirred at room temperature for 16 hours. . The solvent is evaporated and the residue is chromatographed on HP silica gel (puriFlash PF-15HP / 25g column, CombiFlash) eluted with dichloromethane / ethyl acetate (90/10 to 70/30). The solid is taken up with a little ethyl acetate, filtered and dried under vacuum at 45 ° C. (-) - 3-14-Chloro-2-hydroxy-3-methane- [(N-methyl) sulfoximin] -phenylamino} -4-1 (R) -1- (pyridin-2-yl) -propylamino ] cyclobut-3-ene-1,2-dione (156 mg, 57%) is obtained.
[0031] MS (ES +) m / z 449 (MH +); t = 5.37 min; 100%; [ ] D = -32.3 ° (c = 10 mg / ml, ethanol). 1H NMR (400 MHz, DMSO): δ (ppm) 0.85-0.89 (t, J = 7.3 Hz, 3H), 1.84-1.97 (m, 2H), 2.91 (s, 3H), 3.69 (s, 3H), 5.23-5.29 (q, J = 7.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.34-7.37 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.81-7.85 (td, J = 7.7-1.6 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 9.05-9.08 (d, J = 9.1 Hz, 1H) EXAMPLE 13 (+) - 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (pyridin-2-yl) - propylamino-1-cyclobut-3-ene-1,2-dione A mixture of (+) - 3- (4-chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-phenylamino) -4-ethoxy cyclobut-3-ene-1,2-dione (76 mg, 0.21 mmol, prepared from B ((+) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole enantiomer) and (R) 1-pyridin-2-yl-propylamine hydrochloride (44 mg, 0.25 mmol) in methanol (1.50 ml) and in the presence of triethylamine (0.04 ml, 0.25 mmol) is heated at 50 ° C. for 7 hours and stirred at room temperature. ambient for 16 hours. The solvent is evaporated and the residue is chromatographed on silica gel HP (puriFlash PF-15HP / 4G column, CombiFlash) eluted with dichloromethane / ethyl acetate (90/10 to 70/30). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (+) - 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-phenylamino} -4-1 (R) -1- (pyridin-2-yl) -propylaminol-cyclobut-3 -ene-1,2-dione (41 mg, 42%) is obtained; MS (ES +) m / z 449 (MH +); t = 5.34 min, 98.6%. 1 H NMR (400 MHz, DMSO): δ (ppm) 0.85-0.89 (t, J = 7.3 Hz, 3H), 1.84-1.99 (m, 2H), 2.91 (s, 3H), 3.69 (s, 3H), 5.23-5.29 (q, J = 7.4 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.34-7.37 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.81-7.85 (td, J = 7.7-1.6 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 9.05-9.08 (d, J = 9.1 Hz, 1H) .
[0032] EXAMPLE 14 (-) - 3-12-Hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylaminol-cyclobut-3 -ene-1,2-dione A mixture of (-) - 3- (2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene-1 2-dione (586 mg, 1.81 mmol, prepared from enantiomer A, (-) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole) and (R) -1-pyridin-2- Ylpropylamine hydrochloride (374 mg, 2.17 mmol) in methanol (10 ml) and in the presence of triethylamine (300 μl, 2.17 mmol) is heated at 50 ° C for 2 days. The solvent is evaporated and the residue is chromatographed on HP silica gel (puriFlash PF-15HP / 40G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (-) - 3-12-Hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (pyridin-2-yl) propylamino} -cyclobutane 3-ene-1,2-dione (175 mg, 23%) is obtained; MS (ES +) m / z 415 (MH +); t = 4.29 min; 98.51%; Wb = -69.4 ° (c = 8.5 mg / ml). 1 H NMR (400 MHz, DMSO): δ (ppm) 0.86-0.89 (t, J = 7.3 Hz, 3H), 1.83-1.98 (m, 2H), 2.83 (s, 3H), 3.44 (s, 3H), 5.24-5.30 (q, J = 7.3 Hz, 1H), 6.88-6.92 (t, J = 8.1 Hz, 1H), 7.34-7.39 (m, 1H), 7.41-7.43 (t, J = 6.2 Hz, 1H) , 7.81-7.86 (td, J = 7.7-1.6 Hz, 1H), 8.0-8.02 (d, J = 8.8 Hz, 1H), 8.63-8.64 (d, J = 4.2 Hz, 1H), 9.0-9.02 (d , J = 9.2 Hz, 1H). EXAMPLE 15 (-) - 3-12-Hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylaminol-cyclobut-3 -ene-1,2-dione A mixture of (+) - 3- (2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3-ene-1 2-dione (150 mg, 0.46 mmol, prepared from enantiomer B, (+) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole) and (R) -1-pyridin-2- Yl-propylamine hydrochloride (96 mg, 0.55 mmol) in methanol (4 mL) and in the presence of triethylamine (77 μL, 0.55 mmol) is heated at 50 ° C for 14 hours and then at 55 ° C for 2 days. The solvent is evaporated and the residue is chromatographed on silica gel with solid deposition (puriFlash IR-50SI / 12G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (-) - 3-12-Hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylaminecyclobut-3-en) 1,2-dione (158 mg, 81%) is obtained; MS (ES +) m / z 415 (MH +); t = 0.92 min; [414] Wb = -5.2 ° (c = 10.1 mg / ml). 1 H NMR (400 MHz, DMSO): δ (ppm) 0.85-0.89 (t, J = 7.3 Hz, 3H), 1.83-1.99 (m, 2H), 2.83 (s, 3H), 3.45 (s, 3H), 5.24-5.30 (q, J = 7.3 Hz, 1H), 6.88-6.92 (t, J = 8.1 Hz, 1H), 7.34-7.39 (m, 1H), 7.41-7.43 (t, J = 6.2 Hz, 1H) , 7.81-7.86 (td, J = 7.7-1.6 Hz, 1H), 8.0-8.02 (d, J = 8.8 Hz, 1H), 8.63-8.64 (d, J = 4.2 Hz, 1H), 9.0-9.02 (d , J = 9.2 Hz, 1H).
[0033] EXAMPLE 16 (+) - 3-12-Hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylaminol) cyclobut-3-ene-1,2-dione A mixture of (-) - 3- (2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino) -4-ethoxy-cyclobut-3- ene-1,2-dione (586 mg, 1.81 mmol, prepared from enantiomer A, (-) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole) and (R) -1- ( 5-methyl-furan-2-yl) propylan hydrochloride (381 mg, 2.17 mmol) in methanol (10 ml) and in the presence of triethylamine (301 μl, 2.17 mmol) is heated at 50 ° C for 15 hours. The solvent is evaporated and the residue is chromatographed on HP silica gel (puriFlash PF15HP / 40G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (+) - 3-12- Hydroxy-3-methane- [(N-methyl) sulfoximin] phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) propylaminecyclobut) -3-ene-1,2-dione (751 mg, 98%) is obtained; MS (ES +) m / z 418 (MH +); t = 5.97 min; 99.19%; [ ] D = + 22.0 ° (c = 10.2 mg / ml). 1H NMR (400 MHz, DMSO): δ (ppm) 0.90-0.94 (t, J = 7.3 Hz, 3H), 1.80-1.89 (m, 1H), 1.91-1.99 (m, 1H), 2.27 (s, 3H); ), 2.82 (s, 3H), 3.45 (s, 3H), 5.10-5.16 (q, J = 7.7 Hz, 1H), 6.05 (dd, J = 1.0 Hz, 1H), 6.26 (d, J = 3.0 Hz) , 6.88-6.92 (t, J = 8.0 Hz, 1H), 7.39-7.41 (d, J = 8.1 Hz, 1H), 8.03-8.05 (d, J = 7.8 Hz, 1H), 8.70-8.72 (d, J = 7.8 Hz, 1H), d, J = 9.0 Hz, 1H), 9.36 (s, 1H). MS (ES +) m / z 418 (MH +) EXAMPLE 17 (+) - 3-12-Hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (5) -methylfuran-2-yl) -propylaminol-cyclobut-3-ene-1,2-dione A mixture of (+) - 3- (2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino 4-ethoxy-cyclobut-3-ene-1,2-dione (150 mg, 0.46 mmol, prepared from B, (+) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole enantiomer ) and (R) -1- (5-methyl-furan-2-yl) -propylan hydrochloride (97 mg, 0.55 mmol) in methanol (4 ml) and in the presence of triethylamine (77 μl, 0.55 mmol) is heated at 50 ° C for 12 hours. The solvent is evaporated and the residue is chromatographed on silica gel with solid deposition (puriFlash IR-50S1 / 12G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (+) - 3-12- Hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propyl] aminecyclobut-3-ene-1,2-dione (158 mg, 81%) is obtained; MS (ES +) m / z 418 (MH +); t = 5.98 min; 99.66%; [ct] p = + 94.1 ° (c = 10.1 mg / ml) 1H NMR (400 MHz, DMSO): δ (ppm) 0.90-0.94 (t, J = 7.3 Hz, 3H), 1.80-1.89 (m.p. , 1H), 1.91-1.99 (m, 1H), 2.27 (s, 3H), 2.82 (s, 3H), 3.45 (s, 3H), 5.10-5.16 (q, J = 7.7 Hz, 1H), 6.05 ( dd, J = 1.0 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 6.88-6.92 (t, J = 8.0 Hz, 1H), 7.38-7.41 (dd, J = 8.21.4 Hz, 1H). ), 8.03-8.05 (d, J = 7.8 Hz, 1H), 8.70-8.73 (d, J = 9.0 Hz, 1H), 9.35 (s, 1H). EXAMPLE 18 (-) - 3- (2-Hydroxy) 3-methane-RN-methyl) -sulfoxim-1-phenylamino- [4- (1-ethylpropylaminol-cyclobut-3-ene-1,2-dione) A mixture of (-) - 3- (2-hydroxy-3) -methane-RN-methyl) -sulfoximin-phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (586 mg, 1.81 mmol), prepared from enantiomer A, (-) - 2-tert -butyl-6-chloro-7-methanesulfoximin-benzooxazole), and 1-ethyl-propylamine (0.25 ml, 2.17 mmol) in methanol (10 ml) is heated at 50 ° C for 15 hours. The solvent is evaporated and the residue is chromatographed on HP silica gel (puriFlash PF-15HP / 40G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (-) - 3- (2-Hydroxy-3-methane- [(N-methyl) sulfoxim] -phenylamino- [4- (1-ethyl-propylaminol-cyclobut-3-ene-1,2-dione (584 mg; 88%) is obtained as a pale yellow solid, MS (ES-) m / z 364 (MH-), t = 5.20 min, 99.57%, [a] D = -45.8 ° (c = 10.0). mg / ml) 1H NMR (400 MHz, DMSO): δ (ppm) 0.86-0.90 (t, J = 7.4 Hz, 3H), 0.88-0.92 (t, J = 7.3 Hz, 3H), 1.42-1.53 ( m, 2H), 1.58-1.68 (m, 2H), 2.83 (s, 3H), 3.46 (s, 3H), 3.85-3.94 (m, 1H), 6.88-6.92 (t, J = 8.0 Hz, 1H). , 7.37-7.40 (dd, J = 8.7 Hz, 1H), 8.07-8.09 (d, J = 8.1-1.0 Hz, 1H), 8.06-8.08 (d, J = 7.2 Hz, 1H), 8.23-8.25 (d , J = 9.0 Hz, 1H), 9.30 (s, 1H) EXAMPLE 19 0 (+) - 3- (2-Hydroxy-3-methane-RN-methyl) -sulfoxim-1-phenylaminot 4- (1-ethylpropylaminol-cyclobut) -3-ene-1,2-dione A mixture of (+) - 3- (2-hydroxy-3-methane-RN-methyl) -sulfoximin-phenylamino) -4-ethoxy-cyclobut-3-ene-1, 2-dione (150 mg, 0.46 mmol), prepared from enantiomer B, (+) - 2-tert-butyl-6-chloro-7-methanesulfoximin-benzooxazole and 1-ethyl-propylamine (65 μl; 5 mmol) in methanol (4 ml) is heated at 50 ° C for 12 hours. The solvent is evaporated and the residue is chromatographed on silica gel with solid deposition (puriFlash IR-50SI / 12G column, CombiFlash) eluted with dichloromethane / methanol (98/2 to 95/5). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (+) - 3- (2-Hydroxy-3-methane- [(N-methyl) sulfoxim] -phenylamino- [4- (1-ethyl-propylaminol-cyclobut-3-ene-1,2-dione (156 g) mg, 91%) is obtained, MS (ES +) m / z 366 (MH +), t = 5.22 min, 99.26%, [and] p = + 40.8 ° (c = 10.2 mg / ml). 400 MHz, DMSO): δ (ppm) 0.86-0.90 (t, J = 7.4 Hz, 3H), 0.88-0.92 (t, J = 7.3 Hz, 3H), 1.42-1.53 (m, 2H), 1.58-1.68 (m, 2H), 2.83 (s, 3H), 3.46 (s, 3H), 3.85-3.94 (m, 1H), 6.88-6.92 (t, J = 8.0 Hz, 1H), 7.37-7.40 (dd, J). = 8.1-1.2 Hz, 1H), 8.07-8.09 (d, J = 8.1-1.0 Hz, 1H), 8.06-8.08 (d, J = 7.2 Hz, 1H), 8.23-8.25 (d, J = 9.0 Hz, 1H), 9.30 (s, 1H) EXAMPLE 20 (+) - 3-14-Chloro-2-hydroxy-3-methane-RN-methyl) -sulfoximin-1-phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylaminol-cyclobut-3-ene-1,2-dione A mixture of (-) - 3- (4-chloro-2-hydroxy-3-methan- [(N -methyl) -sulfoximin [-phenylamino) -4-ethoxy-cyclobut-3-ene-1,2-dione (270 mg, 0.75 mmol), prepared from enantiomer A, (-) - 2-tert-butyl; 6-chloro-7-methanesulfoximin-benzooxazole), and (R) -1- (5-methy) 1-furan-2-yl) -propylan hydrochloride (158.6 mg; 0.90 mmol) in methanol (5 ml) and in the presence of triethylamine (125 μl, 0.90 mmol) is heated at 50 ° C for 38 hours. The solvent is evaporated and the residue is chromatographed on HP silica gel (puriFlash PF-15HP / 25g column, CombiFlash) eluted with dichloromethane / ethyl acetate (95/5 to 90/10). The solid is taken up with a little heptane / ethyl acetate, filtered and dried under vacuum at 45 ° C. (-) - 3-14-Chloro-2-hydroxy-3-methane- [(N-methyl) sulfoximin] -phenylamino} -4 - [(R) -1 - (5-methyl-furan-2-yl) propylaminecyclobut-3-ene-1,2-dione (228 mg, 65%) is obtained as a pale yellow solid; t = 17.1 min; 99.6%; Pah = + 30.8 ° (c = 2.5 mg / mi). 1 H NMR (400 MHz, DMSO): δ (ppm) 0.90-0.94 (t, J = 7.3 Hz, 3H), 1.82-1.99 (m, 2H), 2.27 (s, 3H), 2.90 (s, 3H), 3.69 (s, 3H), 5.10-5.16 (q, J = 7.7 Hz, 1H), 6.06 (dd, J = 1.0 Hz, 1H), 6.26 (d, J = 3.0 Hz, 1H), 6.97-6.99 (d, J); , J = 8.7 Hz, 1H), 8.03-8.05 (d, J = 8.7 Hz, 1H), 8.758.77 (d, J = 9.0 Hz, 1H), 9.35 (s, 1H). BIOLOGICAL TESTS EXAMPLE 21: In Vitro Affinity The In Vitro affinity of the compounds of the present invention for the CXCR1 and CXCR2 receptors is determined on a functional test of the P-arrestin recruitment type after activation of the receptor. CXCL8 activation of the CXCR2 receptor in cells of the PathHunter line HEK293-CXCR2 or CXCR1 receptor in cells of the U2OS h CXCR1 P-arrestin line has been shown to lead to recruitment of 13-arrestin (Richardson, RM, RJ Marjoram, LS Barak, R. Snyderman, 2003. Role of the cytoplasmic tails of CXCR1 and CXCR2 in mediating leukocyte migration, activation, and regulation, J. Immunol 170: 2904-2911.) To evaluate interaction CXCR2 or CXCR1 receptor directly with 13-arrestin 2, a 13-arrestin 2 recruitment test for CXCR2 or CXCR1 based on the complementation of the β-galactosidase enzyme (Olson KR, Eglen RM, Beta galactosidase complementation: Based on Assay Drug Dey Technol 2007 Feb; 5 (1); 137-44), as established by DiscoveRx Corporation was used. Stimulation of these two cell lines with CXCL8 (10 nM) induces the recruitment of 13-arrestin 2 as indicated by a significant increase in induction factor. All CXCR2 antagonists are assayed in a dose-dependent manner and the concentration corresponding to 50% inhibition of the response is determined (IC 50 = half inhibition concentration).
[0034] 13-arrestin Recruitment Test: "PathHunter HEK293-CXCR2" or "U2OS hCXCR1 13-arrestin" cells (DiscoveRx Corporation) were seeded overnight at 10,000 cells / well (384 well format) in 20 μl of medium. Opti MEM I. Preincubation with the antagonist or 30 min vehicle at 37 ° C and 5% CO2 was followed by 60 minutes of stimulation with CXCL8 at 37 ° C and 5% CO2. The cells were then placed at room temperature for 30 minutes. The PathHunter Detection Reagent (DiscoveRx Corporation) has been added. After a 60 min incubation at room temperature, 13-arrestin-CXCR2-induced 13-galactosidase was measured for 0.3 sec in an Envision 2102 Multilabel Reader (PerkinElmer Life and Analytical Sciences). The data is analyzed by a nonlinear curve procedure using XLFit4 operating software (IDBS) and IC50s are determined. Table 3 Example # CXCR2 IC50 (nM) CXCR1 IC50 (nM) 1 AC 2 AC 3 BD 4 BD 5 BC 6 BD 7 BD 8 BC 9 BD 10 BD 11 BD 12 AC 13 BD 14 BCBD 16 AC 17 BD 18 BD 19 BDACA: IC50 <20nM, B: IC50> or = 20nM C: IC50 <200nM; D: IC50> or = 200nM EXAMPLE 22: Neutrophil Migration Purification and Culture of Human Neutrophils Peripheral blood preparations (18-24 hours) are collected in clinically registered clinics or clinical laboratories from healthy volunteers who have consented the reuse of their blood for scientific research (Supplier: Biopredic International). Neutrophils are separated from whole blood by positive selection (Whole Blood CD15 MicroBeads: MiltenyiBiotech, Reference: 130-091-058). The cells are resuspended at a rate of 4x106 cells per ml in the RPMI 1640 culture medium (Invitrogen) supplemented with 5% fetal calf serum (FCS) filtered and inactivated by heat (Invitrogen) Chemotaxis Assay The experiments were carried out in filter plates "HTS Transwell 96 Well Permeable Supports 31.1m pore size" (Corning, Reference: 3386). Response doses of CXCRS antagonists are applied in the lower compartments of the plates in the presence of 10 nM IL-8 (1-72 aa, R & D Systems, Cat No. IL-208). Neutrophils are then seeded in the upper compartment (2x105 cells / well). After lh incubation at 37 ° C and 5% CO2, the number of viable cells having crossed the membrane and found in the lower compartment is determined by a colorimetric method (CellTiter 96® AO-One Solution Cell Proliferation Assay - PROMEGA Cat # G3581). Each treatment condition is evaluated in duplicate. The IC50 are calculated with the XLFit4 Software Table 4 No. example Human neutrophil migration IC50 (nM) 1 E 2 E 3 ND 4 ND 5 E 6 ND 7 ND 8 F 9 ND 10 ND 11 ND 12 E 13 ND 14 F 15 ND 16 F 17 ND 18 F 19 ND 20 E ND: not determined; E: IC50 <300nM; F: IC50> or = 300nM

权利要求:
Claims (9)
[0001]
REVENDICATIONS1. A compound of the following general formula (I), or a salt thereof or an enantiomer thereof: ABN "NHH (I) wherein A is 0 OR (Al) (A2) B is R1 ', OR (B1) (B2) with R1 'and R2', which may be identical or different, are hydrogen, halogen, C1 to C5 alkyl unsubstituted or substituted by one or more fluorine atoms, C1 to C5 alkoxy, OCF3, OH, CN, NR11R12, R1 and R2, which may be identical or different, represent: - a hydrogen, - a C1 to C5 alkyl, unsubstituted or substituted with one or more groups selected from F, OH, OCH3 and NR11R12; R11 and R12 having the significance given below, it being understood that when the alkyl radical of Cl to C5 is substituted only by one or more fluorine atoms, it is a fluorinated alkyl radical or a perfluorinated alkyl radical of Cl to C5 a C1 to C5 alkyl in which a carbon atom is replaced by an oxygen atom or a sulfur atom, said alkyl of C 1 to C5 being unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the meaning given hereinafter, - a C3 to C8 cycloalkyl - an C2 to C5 alkyne, unsubstituted or substituted with one or more groups chosen from F, OH, phenyl, NR11R12, R11 and R12 having the meaning given below, - a cycloalkyl corresponding to one of the formulas (1), (2), (3), ( 4), (5) or (6) in which R5 ', X and X' have the meanings given below: R5 'i ---.) <R5' / R5 'j1 X R5' X R5 'j I (1) (2) (3) (4) (5) (6) - an aromatic or heteroaromatic ring selected from the group consisting of rings of the following formulas (a) to (o) wherein R7, R7a, Y and Z have the following meanings: R7 / ei R7 z (C) (d) (e) R7 R7 R7 R7 R7 R7 R7 R7 (h) / (i) R7 4 -R7 N1 1 (I) ) (N% (m) (f) (g) R7N / / 1 NN (k) R7 R7 R7 R7 (n) (o) R7 may be present several times over one cycle, and maximally m, as many times as there are substitutable atoms. The meanings of each substituent R7 may be the same or different. R3 represents a hydrogen, a halogen, a C1 to C5 alkyl, a C1 to C5 alkoxy, CF3, -OCF3, -OH, -NO2, -CN R4 and R5, which may be identical or different, represent: a hydrogen, a C1 to C8 alkyl, unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the meaning given below, a C1 to C8 alkyl in which a carbon atom is replaced by a nitrogen atom, an oxygen atom or a sulfur atom, said C1 to C8 alkyl being unsubstituted or substituted by one or more groups selected from F, OH, NR11R12, R11 and R12 having the meaning given below, - a C3 to C8 cycloalkyl, - a C3 to C8 cycloalkyl of which one of the carbon atoms is replaced by an oxygen atom or by a nitrogen atom substituted by an R7a radical, - a heterocycloalkyl of 5 to 7 ring atoms, - a cycloalkylalkyl, the cycloalkyl being C3 to C8 and the alkyl of C1 to C8, - a phenyl e, - a phenyl substituted by an R7 radical, - a heteroaryl, - an arylalkyl, the alkyl being Cl-05, - a heteroarylalkyl, the alkyl being Cl-05, or else R4 and R5 represent a chain - (CH2) ', - forming a ring containing from 5 to 8 atoms with the sulfur and nitrogen atoms to which they are respectively attached, one of the carbons of the ring being optionally replaced by an oxygen atom, sulfur or by a nitrogen atom substituted with an R8 radical; m and R8 having the meanings given below, R5 'represents a hydrogen atom, a fluorine, an alkyl radical having 1 to 5 carbon atoms inclusive or a fluorinated or perfluorinated alkyl radical containing from 1 to 5 carbon atoms R6 represents a hydrogen atom, a -COOtBu radical or a -COOBn radical, R7 represents a hydrogen, a C1 to C3 alkyl, a halogen, -CF3, -COR9, -OR9, -NR9R10, -NO2, - CN, -SO2R9, -S (O) R9, -S (= O) (= NR9) R10 ', -SO2NR9R10, -NR9SO2R10, -NR9COR10, -NR9CO2R10, -CONR9R10, or -OO2R9, R7a represents a hydrogen or a C1 to C5 alkyl, R8 is hydrogen, -OH, -SO2R9, -COR9, -O2R9, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R9 and R10 are the same or different and are independently selected from the group consisting of hydrogen, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl e, or alternativelyR9 and R10 may be linked to one another when they are borne by the same nitrogen atom so as to form a heterocycle having between 3 and 7 members and containing one or two heteroatoms chosen from oxygen, sulfur and nitrogen in addition to the nitrogen atom to which they are attached. R10 'represents aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, cycloalkyl or cycloalkylalkyl, R11 and R12, which may be identical or different, represent hydrogen, C1 to C5 alkyl, C3 to C6 cycloalkyl, a chain - (CH 2) p - forming a ring containing from 4 to 6 atoms with the nitrogen atom to which they are attached, X and X ', identical or different, represent an oxygen atom, a sulfur atom, or a nitrogen atom substituted with a radical R6, Y represents an oxygen atom, a sulfur atom, or a nitrogen atom substituted by an R8 radical, Z represents a carbon atom or a nitrogen atom, m = 3, 4, 5, or 6 and p = 3.4, or 5.
[0002]
2. Compound according to claim 1, characterized in that in formula (I) above: A represents (Al) B represents (B1) R1 represents a hydrogen, a C1 to C5 alkyl, a C3 to C8 cycloalkyl, a cycloalkyl corresponding to the following formula (1 ') in which X has the meaning given below: R2 represents: - a C1 to C5 alkyl, unsubstituted or substituted with one or more groups selected from F, it being understood that when the alkyl radical of Cl to C5 is substituted only by one or more fluorine atoms, it is a fluorinated alkyl radical or a perfluorinated alkyl radical of Cl to C5, an alkyl of Cl to C5 wherein a carbon atom is replaced by an oxygen atom, a C2-C5 alkyne, unsubstituted or substituted by one or more groups selected from fluorine and phenyl, an aromatic or heteroaromatic ring selected from the group constituted by the cycles corresponding to formulas (a), (b 1) and (dl) su R7 and Z have the meanings given below: R7 0 R7 0 / R7 z 0- / (a) (b1) (d1) R7 may be present several times in one cycle, and at most as many times that there are substitutable atoms. The meanings of each substituent R7 may be the same or different, R3 represents a hydrogen or a chlorine, R4 and R5, which may be identical or different, represent a hydrogen, a C1 to C3 alkyl or a C1 to C8 alkyl in which an atom of carbon is replaced by oxygen, R7 is hydrogen, C1 to C3 alkyl or fluorine, X is sulfur, and Z is carbon or nitrogen.
[0003]
3. Compound according to claim 1 or 2, characterized in that in formula (I) above: A represents (Al) B represents (B1) R1 represents a C1 to C5 alkyl, R2 represents: - an alkyl of Ci to C5, an alkyne C2 to C5, substituted with one or more groups selected from fluorine and phenyl, an aromatic or heteroaromatic ring selected from the group consisting of the rings corresponding to formulas (a), (b 1) and (dl) wherein R7 and Z have the meanings given below: R7 0/0 / R7 R7 0 - / z (a) (b1) (di) R7 may be present several times on a ring, and at most, as many times as there are substitutable atoms. The meanings of each substituent R7 may be the same or different, R3 represents hydrogen or chlorine, R4 and R5, which may be identical or different, represent a hydrogen or an alkyl of C1 to C3, R7 represents a hydrogen or a C1 to C3 alkyl or a fluorine, and Z represents a carbon atom or a nitrogen atom.
[0004]
4. A compound according to claim 1, selected from: Compound 1: 3- (4-Chloro-2-hydroxy-3-methanesulfoxymin-phenylamino) -4 - [(R) -1- (5-methylfuran-2-yl) -propylamino] -cyclobut -3-ene-1,2-dione Compound 2: 3-14-Chloro-2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4- [(R) 1- (5-Methyl-furan-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 3: 3-14-Chloro-2-hydroxy-3-methane - [(N pyridin-4-yl) -sulfoximin] phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 4: 3 -14-Chloro-2-hydroxy-3-methane- [(N-pyridin-4-yl) sulfoximin] -phenylamino} -4- (1-ethyl-propylamino) -cyclobut-3-ene-1 2-dione Compound 5: 3 -14-Chloro-2-hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4-1 [(S) - (5-methyl-furan-2) -y1) - (R) -tetrahydro-thiophen-2-yl-methyl] -amino} -cyclobut-3-ene-1,2-dione Compound 6: 1- (2-chloro-3-fluoro-phenyl) 3- (4-Chloro-2-hydroxy-3-methanesulfoximinephenyl) -urea Compound 7: 1- (2-Chloro-3-fluoro-phenyl) -3-14-chloro-2-hydrox γ-3-methanes - [(N-methyl) -sulfoximin] -phenyl} -urea Compound 8: 3 -12-hydroxy-3-methane- [(N-methyl) sulfoximin] -phenylamino} -4- [( R) -1- (5-methyl-furan-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 9: 3- [4-chloro-3- [N- (2-dimethylaminoethyl) ) -S-Methylsulfonimidoyl] -2-hydroxy-anilino] -4-ethoxy-cyclobut-3-ene-1,2-dione Compound 10: 3- [4-chloro-3- [N- (2-dimethylaminoethyl) ) -S-methylsulfonimidoyl] -2-hydroxyanilino] -4- (1-ethylpropylamino) cyclobut-3-ene-1,2-dione Compound 11: 3- [4-chloro-2-hydroxy-3-N] (2-methoxyethyl) -S-methyl-sulfonimidoyl] anilino] -4 - [[(1R) -1- (5-methyl-2-furyl) propyl] amino] cyclobut-3-ene-1,2-dione Compound 12: (-) - 3-14-Chloro-2-hydroxy-3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 13: (+) - 3-14-Chloro-2-hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} - 4 - [(R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dioneCompound 14: (-) - 3-12-Hydroxy-3-methan- [(N- methyl) - sulfoximin] -phenylamino} -4- [(R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 15: (-) - 3-12-Hydroxy 3-methane- [(N-methyl) -sulfoximin] -phenylamino} -4 - [(R) -1- (pyridin-2-yl) -propylamino] -cyclobut-3-ene-1,2-dione Compound 16: (+) - 3-12-Hydroxy-3-methane - [(N-methyl) sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino} -cyclobut-3-ene-1,2-dione Compound 17: (+) - 3-12-Hydroxy-3-methane - [(N-methyl) -sulfoximin] -phenylamino} -4- [(R) ) -1- (5-methyl-furan-2-yl) -propylamino} -cyclobut-3-ene-1,2-dione Compound 18: (-) - 3- (2-Hydroxy-3-methane - [( N-methyl) -sulfoxim] -phenylamino- [4- (1-ethyl-propylamino) -cyclobut-3-ene-1,2-dione Compound 19: (+) - 3- (2-Hydroxy-3-methane) [(N-methyl) -sulfoxim] -phenylamino- [4- (1-ethylpropylamino) cyclobut-3-ene-1,2-dione Compound 20: (+) - 3-14-Chloro-2-hydroxy-3 -methane- [(N-methyl) sulfoximin] -phenylamino} -4 - [(R) -1- (5-methyl-furan-2-yl) -propylamino} -cyclobut-3-ene-1,2- dione.
[0005]
A pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 in association with a pharmaceutically acceptable solvent or carrier.
[0006]
6. Compound according to one of claims 1-4 or pharmaceutical composition according to claim 5 for use as a medicament.
[0007]
A compound according to any of claims 1-4 or a pharmaceutical composition according to claim 5 for use in the treatment of chemokine-mediated diseases.
[0008]
A compound or pharmaceutical composition according to claim 7 for use in the treatment of diseases of the group comprising neutrophilic dermatoses, including psoriasis, atopic dermatitis, acne, rosacea, asthma, chronic obstructive pulmonary diseases. , adult respiratory diseases, arthritis, inflammatory bowel diseases, Crohn's disease, transplant rejection, cystic fibrosis and skin cancers.
[0009]
9. A compound or pharmaceutical composition according to claim 7 for use in the treatment of dermatological diseases such as neutrophilic dermatoses, including psoriasis, atopic dermatitis, acne and rosacea.

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FR1463209A|FR3030515B1|2014-12-23|2014-12-23|NOVEL ANTAGONIST COMPOUNDS FOR CHEMOKINE CXCR1 AND CXCR2 RECEPTORS AND THEIR USE IN THE TREATMENT OF CHEMOKINE MEDIATED PATHOLOGIES|FR1463209A| FR3030515B1|2014-12-23|2014-12-23|NOVEL ANTAGONIST COMPOUNDS FOR CHEMOKINE CXCR1 AND CXCR2 RECEPTORS AND THEIR USE IN THE TREATMENT OF CHEMOKINE MEDIATED PATHOLOGIES|

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EP15828354.9A| EP3237384B1|2014-12-23|2015-12-22|Novel chemokine cxcr1 and cxcr2 receptor antagonist compounds, and use thereof in the treatment of chemokine-mediated pathologies|

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US15/539,590| US10287278B2|2014-12-23|2015-12-22|Chemokine CXCR1 and CXCR2 receptor antagonist compounds, and use thereof in the treatment of chemokine-mediated pathologies|

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PCT/FR2015/053703| WO2016102877A1|2014-12-23|2015-12-22|Novel chemokine cxcr1 and cxcr2 receptor antagonist compounds, and use thereof in the treatment of chemokine-mediated pathologies|

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