3,4-di-substituted cyclobutene-1,2-diones as CXC chemokine receptor antagonists

专利摘要:
The present invention provides compounds of formula (I), useful for the treatment of chemokine mediated diseases (e.g., acute and chronic inflammatory diseases and cancers), wherein various A and B are aryl or hetero as described in the claims. Aryl groups}, prodrugs thereof, pharmaceutically acceptable salts, solvates or isomers of said compounds or prodrugs thereof. Formula I
公开号:KR20030090629A
申请号:KR10-2003-7009958
申请日:2002-02-01
公开日:2003-11-28
发明作者:타베라스아써지.；아키신씨아제이.；본드리챠드더블유.；챠오지안핑；드와이어마이클；페레이라조안에이.；패치터조나던；볼드윈죤제이.；카이저베른드；라이게；메릿제이.로버트；넬슨킹슬리에이치.주니어.；로코스즈라우라엘.
申请人:쉐링 코포레이션；파마코페이아, 인크.；
IPC主号:

专利说明:

3,4-di-substituted cyclobutene-1,2-diones as CXC chemokine receptor antagonists} as CBC chemokine receptor antagonists
[2] Chemokines are chemotactic cytokines released from a wide variety of cells that attract macrophages, T cells, eosinophils, basophils, neutrophils and endothelial cells to inflammation and tumor growth areas. (chemotactic cytokine). There are two main types of chemokines: CXC-chemokine and CC-chemokine. The classification is determined by whether the first two cysteines are separated by a single amino acid (CXC-chemokine) or adjacent (CC-chemokine). CXC-chemokines include interleukin-8 (IL-8), neutrophil-activated protein-1 (NAP-1), neutrophil-activated protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78, IP- 10, MIG and PF4. CC chemokines include RANTES, MIP-1α, MIP-2β, monosite chemotactic protein-1 (MCP-1), MCP-2, MCP-3, GCP-2 and eotaxin. Each individual chemokine belonging to the above chemokine class is known to be bound by at least one chemokine receptor (CXC chemokines are generally bound by receptors belonging to the CXCR receptor class and CC chemokines are receptors belonging to the CCR receptor class). Commonly bound by). For example, IL-8 is bound by CXCR-1 and CXCR-2 receptors.
[3] CXC-chemokines have been suggested to be involved in a variety of acute and chronic inflammatory diseases, including psoriasis and rheumatoid arthritis, because they promote the accumulation and activation of neutrophils. See Baggiolini et al., FEBS Lett . 307 , 97 (1992). ); Miller et al., Crit . Rev. Immunol . 12, 17 (1992); Oppenheim et al., Annu . Fev . Immunol . 9 , 617 (1991); Seitz et al., J. Clin . Invest . 87 , 463 (1991); Miller et al., Am . Rev. Respir . Dis . 146 , 427 (1992); Donnely et al., Lancet 341 , 643 (1993)}.
[4] In addition, ELRCXC chemokines, including IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78, have been suggested to be involved in the induction of tumor angiogenesis (neovascular growth) {Strieter et al., 1995. , JBC 270 p. 27348-57}. All of the above chemokines exhibit activity by binding to receptor CXCR2 (also known as IL-8RB) bound to the 7 transmembrane G-protein, whereas IL-8 binds to CXCR1 (also known as IL-8RA). . Therefore, their angiogenesis activity is achieved by binding to and activating CXCR2 (CXCR1 in the case of IL-8) expressed on the surface of vascular endothelial cells (EC) in the surrounding blood vessels.
[5] A variety of other tumors are known to produce ELRCXC chemokines, the production of which is more aggressive phenotype {Inoue et al., 2000, Clin. Cancer Res. 6, p.2104-2119} and bad prognosis {Yoneda et al. , 1998, J. Nat. Cancer Inst. 90, p. 447-454. Chemokines are potent chemotactic factors, and ELRCXC chemokines have been known to induce EC chemotaxis. Thus, these chemokines seem to induce endothelial cells chemotactic to their production sites in tumors. This may be a key step in inducing angiogenesis by tumors. Inhibitors of CXCR2, or inhibitors of both CXCR2 and CXCR1, inhibit the angiogenesis activity of ELRCXC chemokines to block tumor growth. Such anti-tumor activity is described by antibodies to IL-8 (Arenberg et al., 1996, J. Clin. Invest. 97, p. 2792-2802}, antibodies against ENA-78 {Arenberg et al., 1998, J. Clin. Invest. 102, p. 465-72} and antibodies against GROα (Haghnegahdar et al., J. Leukoc. Biology 2000, 67, p.53-62).
[6] It has also been found that many tumor cells express CXCR2, which can promote their growth when tumor cells release ELRCXC chemokines. Thus, inhibitors of CXCR2 may directly inhibit tumor cell growth, as well as a reduction in angiogenesis.
[7] Thus, the CXC-chemokine receptor is a promising target for the development of new anti-inflammatory and anti-tumor agents.
[8] There is a need for compounds that can modulate activity at the CXC-chemokine receptor. For example, symptoms associated with increased IL-8 production (involved in chemotaxis to tumor sites and tumor growth of neutrophils and T cell subsets) can be ameliorated by inhibitor compounds of IL-8 receptor binding.
[9] Summary of the Invention
[10] The present invention provides novel compounds of formula (I) below, prodrugs thereof, pharmaceutically acceptable salts, solvates or isomers of said compounds or prodrugs:
[11]
[12] Where
[13] A is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;
[14]
[15] R ² is hydrogen, OH, C (O) OH, SH, SO ₂ NR ⁷ R ⁸ , NHC (O) R ⁷ , NHSO ₂ NR ⁷ R ⁸ , NHSO ₂ R ⁷ , C (O) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , OR ¹³ or substituted or unsubstituted heterocyclic acid functional group;
[16] R ³ and R ⁴ are the same or different; Independently hydrogen, halogen, alkoxy, OH, CF ₃ , OCF ₃ , NO ₂ , C (O) R ⁷ , C (O) OR ⁷ , C (O) NR ⁷ R ⁸ , SO _(t) NR ⁷ R ⁸ , SO _(t) R ⁷ , C (O) NR ⁷ OR ⁸ , , Cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
[17] R ⁵ and R ⁶ are the same or different; Independently hydrogen, halogen, alkyl, alkoxy, CF ₃ , OCF ₃ , NO ₂ , C (O) R ⁷ , C (O) OR ⁷ , C (O) NR ⁷ R ⁸ , SO _(t) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , cyano, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;
[18] R ⁷ and R ⁸ are the same or different; Independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, carboxyalkyl, aminoalkyl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heteroalkylaryl;
[19] R ⁷ , R ⁸ , and N of NR ⁷ R ⁸ and NR ⁷ OR ⁸ may form a 3 to 7 membered ring with each other, the ring having 1 to 3 additional heteroatoms as ring atoms on the ring; It may further include, wherein the ring may be substituted or unsubstituted with one or more residues, each residue is the same or different, hydroxy, cyano, carboxy, hydroxyalkyl, alkoxy, COR ⁷ R ⁸ or amino Independently selected from alkyl;
[20] R ⁹ and R ¹⁰ are the same or different; Independently hydrogen, halogen, CF ₃ , OCF ₃ , NR ⁷ R ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , OH, C (O) OR ⁷ , SH, SO _(t) NR ⁷ R ⁸ , SO ₂ R ⁷ , NHC (O) R ⁷ , NHSO ₂ NR ⁷ R ⁸ , NHSO ₂ R ⁷ , C (O) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , OR ¹³ , or substituted or unsubstituted hetero Cyclic acid functional groups;
[21] R ¹³ is COR ⁷ ;
[22] R ¹⁵ is hydrogen, OR ¹³ , substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted alkyl group;
[23] t is 1 or 2.
[24] Another aspect of the invention relates to a pharmaceutical composition comprising the compound of formula (I) together with a pharmaceutically acceptable carrier or diluent.
[25] Another aspect of the invention is an α-chemokine mediated activity in a mammal comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or solvate thereof. It relates to a method for treating a disease.
[26] Another aspect of the invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula (I); And (b) antibodies or interferons to microtubule affecting agents or anti-neoplastic agents or anti-angiogenesis agents or VEGF receptor kinase inhibitors or VEGF receptors; And / or (c) administering the radiation simultaneously or sequentially to the patient.
[27] In a preferred embodiment, the compound of formula (I) is combined with one of the following anti-tumorigenic agents: gemcitabine, paclitaxel ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan) ), Temozolomide, taxotere or vincristine.
[28] In another preferred embodiment of the invention, cancer is administered, comprising simultaneously or sequentially administering (a) an effective amount of a compound of formula (I) and (b) an agent that affects the microtubules (eg, paclitaxel) Provide a method of treatment.
[1] The present invention relates to novel substituted cyclobutenedione compounds, pharmaceutical compositions containing such compounds, and the use of such compounds and compositions for use in the treatment of CXC chemokine-mediated diseases.
[29] Unless stated otherwise, the following definitions apply throughout this application and claims. In addition, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following definitions apply regardless of whether the term is used alone or in combination with other terms. Thus, the definition of the term "alkyl" applies not only to "alkyl" but also to "alkyl" such as "alkoxy".
[30] If any variable (eg aryl, R ² ) is used more than once in any component, the definition is independent in each case. In addition, such combinations are permitted only if a stable compound is prepared by the combination of substituents and / or variables.
[31] "Substituted" in "substituted or unsubstituted" means optionally substituted with one or more residues that are the same or different; Each moiety independently of one another is halogen, hydroxy, cyano, nitro, alkyl, alkoxy, aryl, cycloalkyl, COOalkyl, COOaryl, carboxamide, sulfhydryl, arylalkyl, alkylaryl, amino, alkylamino, Dialkylamino, alkylsulfonyl, arylsulfonyl, arylsulfonamido, alkylsulfonamido, heteroaryl, carboxyl, carboxyalkyl, heteroarylalkyl, heteroalkylaryl and aryloxy. The term "substituted" also refers to the substitution of a methylenedioxy group on two adjacent ring carbons on an aromatic ring or to fusion of a carbocyclic or heterocyclic ring on two adjacent carbons of an aromatic ring.
[32] "Alkyl" refers to a straight or branched chain saturated hydrocarbon chain having the specified number of carbon atoms. When the number of carbon atoms is not specified, it means 1 to 6 carbon atoms. Examples of representative alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, iso-butyl, t-butyl and the like.
[33] The term "cycloalkyl" means a non-aromatic mono or multicyclic ring system containing 3 to 10 carbon atoms (preferably 5 to 10). Cycloalkyls may be substituted on the ring by replacing possible hydrogen atoms on the ring with one or more substituents, the same or different. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, and the like. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
[34] The term "halogen" or "halo" means that fluorine, chlorine, bromine or iodine are included.
[35] "Aryl" is a mono or bicyclic ring having one or two aromatic rings, including but not limited to phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl, and the like Refers to the system.
[36] The term “heterocycle” or “heterocyclic ring” means any non-aromatic, heterocyclic ring having 3 to 7 atoms containing 1 to 3 heteroatoms selected from N, O and S For example, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine , Hydantoin, valerolactam, pyrrolidinone, and the like.
[37] "Heteroaryl" refers to a 5- or 10-membered single or benzofused aromatic ring consisting of 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S and -N =, wherein the ring is adjacent It does not carry oxygen and / or sulfur atoms. The heteroaryl group described above is independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, sulfhydryl, amino, alkylamino and dialkylamino It may or may not be substituted with 1, 2 or 3 substituents.
[38] The term “heterocyclic acidic functional group” is meant to include pyrrole, imidazole, triazole, tetrazole and the like. These groups are lower alkyl, alkyl, cycloalkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carbamoylalkyl, COOH, COOalkyl, COOaryl, carboxamide, sulfhigh 1, 2 or 3 independently selected from drill, amino, alkylamino, aminoalkyl, alkylaminoalkyl, aminoalkoxy, dialkylamino, sulfonyl, sulfonamido, aryl, heterocyclylalkyl and heteroaryl It may or may not be substituted with a substituent.
[39] "N-oxide" can be formed on the tertiary nitrogen present on the R substituent or on the = N- on heteroaryl ring substituents and is included in the compound of formula (I) above.
[40] The term "composition" herein is meant to include all products that are prepared directly or indirectly by combining certain components in specific amounts, as well as products comprising certain components in specific amounts.
[41] The term “prodrug” refers to a compound that is rapidly converted in vivo to a parent compound of the formula, for example, through hydrolysis in the blood. An in-depth discussion on this can be found in T.Higuchi and V.Stella, "Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward B. Roche et al., Incorporated herein by reference. "Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987".
[42] For compounds of the invention having at least one non-symmetric carbon atom, all isomers (including diastereomers, enantiomers and rotamers) are included as part of the compounds of the invention. In the present invention, the d and l isomers in their pure form, and mixtures thereof (including racemic mixtures). Isomers can be prepared using conventional techniques or by separating the isomers of compounds of formula (I).
[43] The compounds of formula (I) may exist as solvated and non-solvated forms, including hydrated forms. In general, the solvated forms with pharmaceutically acceptable solvents (eg, water, ethanol, etc.) are equivalent to the non-solvated forms for the purposes of the present invention.
[44] Compounds of formula (I) can form pharmaceutically acceptable salts with organic and inorganic acids or bases. Examples of preferred acids for salt formation include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid, other minerals, Carboxylic acid. The salt is produced in a conventional manner by contacting a free base form with a sufficient amount of a suitable acid. The freebase form is an aqueous solution of diluted base suitable for the salt (e.g. diluted aqueous sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, ammonia or sodium bicarbonate) Can be reproduced by processing. The neutral form differs from the corresponding salt form in certain physical properties (eg, solubility in polar solvents). However, unless stated otherwise, the salts are equivalent to the corresponding neutral forms for the purposes of the present invention.
[45] Among the preferred groups of compounds of formula (I), A is selected from the following groups:
[46]
[47]
[48] Where
[49] R ¹¹ and R ¹² are the same or different; Independently of each other H, OH, halogen, cyano, CF ₃ , CF ₃ O, NR ⁷ R ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CO ₂ R ⁷ , OR ⁷ , SO _(t) NR ⁷ R ⁸ , NR ⁷ SO _(t) R ⁸ , COR ⁷ , substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl Alkyl, substituted or unsubstituted heteroaryl, aryloxy, heteroarylalkyl, heteroarylalkoxy, heterocyclylalkyl, hydroxyalkyl, alkylaminoCOOalkyl, aminoalkoxy, alkoxyaminoalkyl and aminoalkyl.
[50] In a preferred group of compounds of formula (I), B is
[51]
[52] Where
[53] R ² is selected from the group consisting of OH, NHC (O) R ⁷ and NHSO ₂ R ⁷ ;
[54] R ³ is selected from the group consisting of SO ₂ NR ⁷ R ⁸ , NO ₂ , CN, C (O) NR ⁷ R ⁸ and SO ₂ R ⁷ ;
[55] R ⁴ is selected from the group consisting of H, NO ₂ , CN and CF ₃ ;
[56] R ⁵ is selected from the group consisting of H, CF ₃ , halogen and CN;
[57] R ⁶ is selected from the group consisting of H and CF ₃ .
[58] Compounds of formula (I) may be prepared through processes known to those skilled in the art described in the following schemes, preparations and examples.
[59]
[60]
[61] The general process used for the preparation of compounds of formula (I) is as follows:
[62] Scheme 1
[63] The amine is condensed with nitrosalicylic acid under standard coupling conditions (step A) and the nitrobenzamide obtained is reduced in the presence of a suitable catalyst and in a hydrogen environment (step B). The remaining reactants required to synthesize the final desired product are prepared by condensation of aryl amines with diethylsquarate, which is commercially available, to yield the aniline ethoxysquarate product. Condensation of the aminobenzamide with the intermediate prepared above yields the desired chemokine antagonist (Scheme 1).
[64] Scheme 2
[65] Alternatively, the aminobenzamide of Scheme 1 is condensed with diethylsquarate, which is commercially available, to provide alternative monoethoxy intermediates. The intermediate is condensed with aryl or heteroaryl amine to give the desired chemokine antagonist.
[66]
[67]
[68] Scheme 3
[69] Benztriazole compounds of formula (I) are prepared by stirring nitrophenylenediamine with sodium nitrate in acetic acid at 60 ° C. to obtain nitrobenzotriazole intermediate (Scheme 3). The nitro group is reduced in the presence of a palladium catalyst and in a hydrogen atmosphere to give an amine compound. Then, the condensation reaction of the previously prepared anilinoethoxysquarate (Scheme 1) with the intermediate yields the desired chemokine antagonist.
[70] Scheme 4
[71] Condensation reaction of anhydride or activated acid with nitrophenylenediamine under reflux (Scheme 4) to obtain benzimidazole intermediate, reduction reaction using hydrogen gas and palladium catalyst, and prepared anilinoethoxysquarate (Scheme 1) Condensation reaction with a benzimidazole chemokine antagonist.
[72]
[73]
[74] Scheme 5
[75] The indazole structure of formula (I) is prepared according to Scheme 5, after reduction of nitroindazole (A) to obtain aminoindazole (B) (see J. Am. Chem Soc. 1943, 65, 1804-1805}, can be prepared by condensation reaction with an anilinoethoxysquarate (Scheme 1) already prepared.
[76] Scheme 6
[77] The indole structure of formula (I) is prepared according to Scheme 6 to obtain nitroindole (A) to obtain aminoindole (B), followed by J.Med. Chem. 1995, 38, 1942-1954}, can be prepared by condensation reaction with an anilinoethoxysquarate (Scheme 1) already prepared.
[78] Biological Example
[79] The compounds of the present invention can be used for the treatment of CXC-chemokine mediated symptoms and diseases. This utility of the compounds of the invention is manifested in the ability of the compounds of the invention to inhibit IL-8 and GRO-α chemokines, as shown in the in vitro assays below.
[80] Receptor binding assays:
[81] CXCR1 SPA Black
[82] In each well of a 96-well plate, a reaction mixture of 200 μg / well of WGA-SPA beads (Amersham) and 10 μg of hCXCR1-CHO overexpressing membrane (100 μM) in 100 μl of CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 125 mM NaCl, 0.1% BSA; Sigma). 0.4 nM stocks of ligand [ ¹²⁵ I] -IL-8 (NEN) were prepared in the CXCR1 assay buffer. 20X stock solutions of test compounds were prepared in DMSO (Sigma). 6X stock solutions of IL-8 (R & D) were prepared in CXCR2 assay buffer. The above solutions were added to the following 96-well assay plates (PerkinElmer): 10 μl test compound or DMSO, 40 μl CXCR1 assay buffer or IL-8 stock, 100 μl reaction mixture, 50 μl ligand stock (Final [ligand] = 0.1 nM). The assay plate was shaken for 5 minutes on a plate shaker, then incubated for 8 hours, and cpm / well was measured on a Microbeta Trilux counter (PerkinElmer). Total binding-% inhibition of NSB (250 nM IL-8) was determined to determine IC ₅₀ levels.
[83] CXCR2 SPA Black
[84] In each well of a 96-well plate, a reaction mixture of 200 μg / well of WGA-SPA beads (Amersham) and 4 μg of hCXCR2-CHO overexpressing membrane (Biosignal) in 100 μl was added to the CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl). ₂ , 1 mM MgCl ₂ ). 0.4 nM stocks of ligand [ ¹²⁵ I] -IL-8 (NEN) were prepared in the CXCR2 assay buffer. 20X stock solutions of test compounds were prepared in DMSO (Sigma). 6X stock solutions of GRO-α (R & D) were prepared in CXCR2 assay buffer. The above solutions were added to the following 96-well assay plates (PerkinElmer): 10 μl of test compound or DMSO, 40 μl of CXCR2 assay buffer or GRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock. (Final [ligand] = 0.1 nM). When a 40 × stock solution of test compound in DMSO was prepared, the above protocol was used, except using 5 μl of test compound or DMSO, 45 μl of CXCR2 assay buffer. The assay plate was shaken on a plate shaker for 5 minutes, then incubated for 2-8 hours and cpm / well was measured on a Microbeta Trilux counter (PerkinElmer). IC ₅₀ values were calculated by determining the percent inhibition of total binding—non-specific binding (250 nM GRO-α or 50 μM antagonist).
[85] Calcium Fluorescence Assay (FLIPR)
[86] HEK 293 cells stably transfected with hCXCR2 and G _{α1 / q} were placed 10,000 cells per well in a poly-D-lysine Black / Clear plate (Becton Dickinson), and 48 hours at 37 ° C. and 5% CO ₂ for 48 hours. Incubate. The cultures were then incubated with dye loading buffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), Probenicid (Sigma)) 4 mM Fluor-4, AM (Molecular Probes) for 1 hour. The culture was washed three times with wash buffer (HBSS w Ca & Mg, 20 mM HEPES, Probenicid (2.5 mM)), and then 100 μl / well of wash buffer was added.
[87] During incubation, compounds were prepared as 4X stock in 0.4% DMSO (Sigma) and wash buffer and then added to the corresponding wells in the first additional plate. IL-8 or GRO-α (R & D Systems) concentrates were prepared at 4 × in wash buffer + 0.1% BSA and then added to the corresponding wells in the second additional plate.
[88] The culture plate and the two additional plates were then placed in the FLIPR imaging system to determine the change in calcium fluorescence upon compound addition and subsequent ligand addition. Briefly, 50 μl of compound solution or DMSO solution was added to each well and the change in calcium fluorescence was measured by FLIPR for 1 minute. After incubation for 3 minutes in the device, the change in calcium fluorescence was measured by FLIPR for 1 minute after the addition of 50 μl of ligand. Measure the area under each stimulation curve and use this number to determine% stimulation by the compound (agonist) and% inhibition of total calcium response to the ligand (0.3nM IL-8 or GRO-α). By measuring, the IC ₅₀ value of the test compound was obtained.
[89] Chemotaxis Assay for 293-CXCR2
[90] A chemotaxis assay was set up with Fluorblok inserts (Falcon) on 293-CXCR2 cells (HEK-293 overexpressing human CXCR2). The standard protocol used herein is as follows:
[91] 1. Coat inserts with collagen IV (2 μg / ml) at 37 ° C. for 2 hours.
[92] 2. Remove the collagen and allow the insert to air dry overnight.
[93] 3. Label cells with 10 μM calcein AM (Molecular Probes) for 2 hours. Labeling is performed in complete medium with 2% FBS.
[94] 4. Dilution of the compound is carried out in minimal medium (0.1% BSA) and placed inside the insert located inside the well of a 24-well plate. Place IL-8 in the well at a concentration in minimal media 0.025 nM. Cells are washed and resuspended in minimal medium and placed in the insert at a concentration of 50,000 cells per insert.
[95] 5. Incubate the plate for 2 hours, remove the insert and place it in a new 24 well. Fluorescence is measured at excitation (485 nM) and emission (530 nM).
[96] Cytotoxicity assay
[97] Cytotoxicity assays of CXCR2 compounds are performed on 293-CXCR2 cells. To determine whether it can be used for further binding assays and cell-based assays, toxicity testing of compound concentrates is performed at high concentrations. The protocol is as follows:
[98] 1. Leave 293-CXCR2 cells overnight at a concentration of 5000 cells / well in complete medium.
[99] 2. Prepare compound dilutions in minimal medium w / 0.1% BSA. After the complete medium has been poured, the compound dilutions described above are added. Plates are incubated for 4 hours, 24 hours and 48 hours. Cell viability was measured by labeling cells with 10 μM calcein AM for 15 minutes. The detection method is as above.
[100] Soft baby black
[101] 10,000 SKMEL-5 cells / well are placed in a mixture of complete medium with 1.2% agar and various compound dilutions. The final concentration of agar is 0.6%. Survival cell colonies after 21 days are stained with MTT solution (1 mg / ml in PBS). The plate is then scanned to determine colony number and size. Total area vs. By comparing the compound concentrations, IC ₅₀ is determined.
[102] For the compounds of the present invention, CXCR2 receptor binding activity was observed in the range of about 1 nM to about 10,000 nM. The binding activity of the compound of the present invention is preferably about 1 nM to 1000 nM, more preferably about 1 to 500 nM, and most preferably about 1 nM to 100 nM.
[103] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use (e.g., tablets, troches, lozenges, aqueous or oil suspensions, dispersed powders or granules, emulsions, hard or soft capsules, syrups or elixirs) Can be. Oral compositions can be prepared using any method known in the art for preparing pharmaceutical compositions, and in order to provide a pharmaceutically attractive and delicious preparation, such compositions comprise a group consisting of sweetening, flavoring, coloring and preservatives. It may contain one or more agents selected from. Tablets contain the active ingredient together with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (eg calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granules and disintegrants (eg corn starch or alginic acid), binders (eg , Starch, gelatin or acacia), lubricants (eg magnesium stearate, stearic acid or talc). Tablets may be uncoated or coated with known techniques to delay disintegration and absorption in the gastrointestinal tract, allowing them to have long lasting activity. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. The tablets may also be coated using the techniques described in US Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.
[104] In addition, oral formulations may be used for the preparation of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or the active ingredient in a water or oil vehicle (e.g. peanut oil, aqueous Paraffin or olive oil) as a soft gelatin capsule.
[105] Aqueous suspending agents may contain the active ingredient with suitable excipients. Such excipients may be suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia), dispersants or wetting agents ( Natural phosphatides such as lecithin; condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; polyoxyethylene sorbitol mono Condensation products of fatty acids with hexitol derived partial esters and ethylene oxide; condensation products of fatty acids with hexitol anhydride such as polyethylene sorbitan monooleate and ethylene oxide) . Aqueous suspending agents may also include one or more preservatives (eg, ethyl or n-propyl, p-hydroxybenzoate), one or more colorants, one or more flavoring agents, or one or more sweetening agents (eg, sucrose, Saccharin or aspartame).
[106] Oily suspending agents can be formulated by suspending the active ingredient in vegetable oils (eg arachis oil, olive oil, sesame oil or coconut oil) or mineral oils (eg liquid paraffin). Oily suspending agents may include thickening agents (eg beeswax, hard paraffin or cetyl alcohol). The sweetening and flavoring agents described above may be added to provide a delicious oral formulation. Antioxidants (eg, ascorbic acid) may be added to preserve the composition.
[107] Dispersible powders and granules suitable for aqueous suspension formulations by adding water provide the active ingredient in admixture with the dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have already been exemplified above. Additional excipients may also be included such as sweetening, flavoring and coloring agents.
[108] In addition, the pharmaceutical compositions of the present invention may have the form of an oil-in-water emulsion in water. The oil phase may be vegetable oil (eg olive oil or arachis oil) or mineral oil (eg liquid paraffin) or mixtures thereof. Suitable emulsifying agents include, but are not limited to, partial esters or esters (eg, sorbitan monooleate) derived from natural phosphatides (eg soybean, lecithin), fatty acids and hexitol anhydrides, ethylene oxide and the aforementioned portions. Condensation products of esters (eg polyoxyethylene sorbitan monooleate). Emulsions may also include sweetening and flavoring agents.
[109] Syrups and elixirs can be formulated with sweetening agents (eg, glycerol, propylene glycol, sorbitol or sucrose). Such formulations may also include demulcents, preservatives, flavors and colorants.
[110] The pharmaceutical composition may be in the form of sterile injectable aqueous or oily suspensions. Suspensions can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Injectable sterile formulations may be injectable sterile solutions or suspensions (eg, solutions in 1,3-butane diol) in nontoxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used are water, Ringer's solution and sodium chloride isotonic solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blended nonvolatile oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
[111] In addition, the compounds of the present invention may be administered in the form of suppositories for rectal administration. The composition may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[112] For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the invention are used (for these uses topical use includes mouthwashes and gargles).
[113] The compounds of the invention can be administered via the transdermal route using transdermal patch forms well known to those skilled in the art, or in intranasal forms via topical use of suitable intranasal vehicles. For administration in the form of a transdermal delivery system, administration is continuous rather than discontinuous. The compounds of the invention may also be delivered as suppositories containing bases, such as, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
[114] Dosage regimens with the compounds of the present invention may include the type, species, weight, sex and medical condition of the patient; The severity of the condition to be treated; Route of administration; Kidney and liver function of the patient; It is chosen according to various factors including the specific compound used. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of the drug required to prevent, antagonize, block or reverse the progression of the condition. In order to achieve optimal accuracy in determining drug concentrations within the range of efficacy without toxicity, management based on pharmacokinetics in which the drug can move to the target site is required. In such management, dispensing, equilibrium and elimination of drugs are considered. Preferably, the dosage of a compound of the invention useful in the methods of the invention is 0.01 to 1000 mg (most preferably 0.1 to 500 mg / day) per adult. Preferably, in the case of oral administration, the composition adjusts the dosage depending on the patient to be treated, depending on the symptoms, so that the active ingredient 0.01 to 1000 mg (especially 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0) , 25.0, 50.0, 100 and 500 mg). An effective amount of the drug is usually in the range of about 0.0002 mg / kg to about 50 mg / kg (in particular about 0.001 to 1 mg / kg) per day.
[115] The active agents of the present invention may be administered in a single dosage form per day, and the total daily dose may be administered in two, three or four divided doses.
[116] The amount of active ingredient that can be combined with the carrier material for a single dosage form will vary depending upon the subject treated and the dosage form.
[117] However, the specific dosage level of a particular patient depends on various factors, including age, weight, general health, sex, diet, frequency of administration, route of administration, rate of release, drug combination, and the severity of the disease to be treated.
[118] Another aspect of the invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula (I); And (b) administering a therapeutically effective amount of an anticancer agent to the patient simultaneously or sequentially, such as a microtubule affecting agent or an anti-neoplastic agent or an angiogenesis agent. It relates to a method of treating cancer, including. In addition, the compounds of the present invention may be administered in conjunction with radiation therapy.
[119] Compound types that can be used as anticancer chemotherapeutic agents (anti-tumor preparations) include alkylating agents, anti-metabolic agents, natural products and derivatives thereof, hormones, anti-hormones, anti-angiogenesis agents, steroids (synthetic analogs) ), And synthetic agents. Examples of compounds belonging to this class are as follows.
[120] Alkylating agents (including nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustards, chlormethine, cyclophosphamide (Cytoxan) ), Phosphamide, melphalan, chlorambucil, fibrobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine and temozolomide.
[121] Anti-metabolic agents (including folate antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate, 5-fluorouracil, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine , Fludarabine phosphate, pentostatin and gemcitabine.
[122] Natural products and derivatives thereof (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epi Rubicin, idarubicin, paclitaxel (Commercially Taxol , Which is described in more detail in the section "Microtubule Affecting Agents" below, Mithramycin, Deoxyco-Formamycin, Mitomycin-C, L-asparaginase , Interferon (particularly IFN-α), etoposide and teniposide.
[123] Hormones and steroids (including synthetic analogues): 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone, propionate, testosterone, megestrolacetate, Tamoxifen, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutetimide, esturamustine, methoxyprogesterone acetate, leuprolide, flutamide, toremifene, zoladex.
[124] Synthetic formulations (including inorganic complexes such as platinum combination complexes): cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotan, mitoxantrone, levamisol, hexamethylmelamine.
[125] Anti-Angiogenesis preparations include marimastat, AG3340, Col-3, neovastat, BMS-275291, thalidomide, squalane, endostatin, SU-5416, SU-6668, interferon-alpha, anti-VEGF Antibodies, EMD121974, CAI, Interleukin-12, IM862, Platelet Factor-4, Nontaxin, Angiostatin, Suramin, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566, CGS27023A, Taxotere and Taxol .
[126] Safe and effective methods of administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, the administration method is described in the standard document. For example, methods of administering many chemotherapeutic agents are described in the literature, which is incorporated herein by reference ("Physicians' Desk Reference" (PDR), eg, 1996 Edition (Medical Economics Company, Montvale, NJ 07645-). 1742, USA.
[127] Microtubule affecting agents are compounds that interfere with mitosis of cells by affecting the formation and / or activity of microtubules. Such agents can be, for example, microtubule stabilizing agents or agents which interfere with the formation of microtubules.
[128] Microtubule affecting agents useful in the present invention are well known in the art and include allocol kitchen (NSC 406042), halicone B (NSC 609395), colchicine (NSC 757), kohl Kitchen derivatives (eg, NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), lysine (NSC 332598), paclitaxel (Taxol , NSC 125973), Taxol Derivatives (e.g., NSC 608832), thiocolkitchin (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, Discothemolde (Service (1996) Science , 274: 2009), estradiol, nocodazole, MAP4 and the like. In addition, such exemplary agents are described in the scientific and patent literature (see, eg, Bulinski (1997) J. Cell Sci. 110: 3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94: 10560-10564; Muhlradt (1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) Nature 387: 268-272; Vasquez (1997) Mol. Biol. Cell. 8: 973-985; Panda (1996) J. Biol. Chem. 271: 29807-29812}.
[129] Particularly preferred agents are compounds having paclitaxel-like activity. Such compounds include, but are not limited to, paclitaxel, derivatives thereof (paclitaxel-like compounds), analogs. Paclitaxel and its derivatives are commercially available. In addition, methods for preparing paclitaxel, derivatives and analogs thereof are well known to those skilled in the art. {See, eg, US Pat. Nos. 5,569,729, 5,565,478,5,530,020, 5,527,924, 5,508,447, 5,489,589, 5,488,116, 5,484,809, 5,478,854, 5,478,736, 5,475,120, 5,468,769, 5,461,169, 5,440,057, 5,422,364, 5,411,984, 5,405,972, and 506,5,296.
[130] In particular, the term “paclitaxel” herein refers to Taxol (NSC No. 125973). Taxol Inhibits eukaryotic replication by enhancing the polymerization of tubulin into stabilized microtubules that cannot be rearranged into a structure suitable for mitosis. Of the many chemotherapeutic drugs available, paclitaxel is of interest by showing efficacy in clinical trials for drug-resistant tumors (including ovarian and mammary tumors). Hawkins (1992) Oncology 6: 17-23 ; Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146; Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247-1259}.
[131] Agents that affect additional microtubules include several assays known in the art (eg, semi-automated assays that measure tubulin-polymerization activity of paclitaxel analogs and the ability of such compounds to block cells during mitosis). Combinations of assays to determine whether there is one) can be assayed using Lopes (1997) Cancer Chemother. Pharmacol. 41: 37-47.
[132] In general, the activity of a test compound is determined by measuring whether the cell cycle is disturbed (especially through inhibition of mitosis) after contacting a given cell with the test compound. Such inhibition may be mediated by obstruction of mitotic tissue (eg, disruption of normal spindle formation). Cells that interfere with mitosis are characterized by modified forms (eg, microtubule compaction, increase in chromosome number, etc.).
[133] In a preferred embodiment, compounds capable of tubulin polymerization activity are screened in vitro. In a preferred embodiment, the compounds were screened against cultured WR21 cells for inhibition of proliferation and / or for modified cell morphology (especially microtubule compression). Then, using nude mice with WR21 tumor cells, compounds with positive (+)-test results were screened in vivo. Specific protocols for this screening method are described in Porter (1995) Lab. Anim. Sci. 45 (2): 145-150.
[134] Other methods of screening for compounds with the desired activity are also well known to those skilled in the art. Typically, such assay methods include assays for inhibition of microtubule aggregation and / or degradation. Assays for microtubule assembly are described, for example, in Gaskin et al. (1974) J. Molec. Biol. 89: 737-758. In addition, US Pat. No. 5,569,720 provides methods for in vitro and in vivo assays for compounds having paclitaxel-like activity.
[135] Safe and effective methods of administration of agents affecting the microtubules described above are known to those skilled in the art. In addition, these methods of administration are described in the standard literature. For example, methods of administering many chemotherapeutic agents are described in the literature, which is incorporated herein by reference ("Physicians' Desk Reference" (PDR), eg, 1996 Edition (Medical Economics Company, Montvale, NJ 07645-). 1742, USA.
[136] The dosage and frequency of administration of the compound of formula (I), chemotherapeutic agent and / or radiation therapy may be adjusted according to the judgment of the clinician (medical physician) in consideration of the age, condition and size of the patient as well as the severity of the disease to be treated. will be. The method of administering the compound of formula (I) to block tumor growth is 2 to 4 times (preferably 10 to 2000 mg / day (preferably 10 to 1000 mg / day, more preferably 50 to 600 mg / day) Can be administered orally. In addition, intermittent therapies (eg, one out of three weeks, or three out of four weeks) can also be used.
[137] Chemotherapeutic agents and / or radiation therapy can be administered according to therapeutic protocols known in the art. It is apparent to those skilled in the art that the chemotherapeutic and / or radiation therapy depends on the disease to be treated and the known effects of the chemotherapy and / or radiation therapy on the disease to be treated. In addition, treatment protocols (e.g., dosage and frequency of administration) may, depending on the clinician's knowledge, determine the effects of treatments observed after administration (i.e., anti-tumorigenic agents or radiation) on patients and those observed after administration. It may vary based on the response of the disease to the therapeutic agent.
[138] In the methods of the invention, the compound of formula (I) is administered simultaneously or sequentially with the chemotherapeutic agent and / or radiation. Thus, for example, the chemotherapeutic agent and the compound of formula (I), or the radiation and the compound of formula (I), need not be administered simultaneously or essentially simultaneously. It is up to the clinician to decide whether co-administration or essentially co-administration is better.
[139] Also, in general, the compounds of formula (I) and chemotherapeutic agents need not be included and administered in the same pharmaceutical composition, and may need to be administered via different routes due to different physical and chemical properties. For example, compounds of formula (I) may be administered orally to produce and maintain their blood levels, while chemotherapeutic agents may be administered intravenously. It is within the judgment of the clinician to determine the route of administration and, where possible, to administer it in the same composition. Initial administration can be performed according to established protocols known in the art, after which the clinician can adjust the dosage, route of administration and frequency of administration depending on the effects observed.
[140] The specific choice of compounds of formula (I) and chemotherapeutic and / or radiotherapy will depend on the diagnosis of clinical physicians, judgment of patient condition and suitable treatment protocols.
[141] If the compound of formula (I) and chemotherapeutic agent and / or radiation are not administered simultaneously or essentially simultaneously, the order of initial administration of the compound of formula (I) and chemotherapeutic agent and / or radiation may not be important. Thus, the chemotherapeutic agent and / or radiation may be administered after the compound of formula (I); The compound of formula (I) may also be administered after administering a chemotherapeutic agent and / or radiation. This alternate method of administration can be repeated during a single administration protocol. Determination of the order of administration and the number of repeats of administration of each therapeutic agent during a treatment protocol is a question that the clinician will determine by examining the condition to be treated and the condition of the patient. For example, in the case of cytotoxic agents, for example, the treatment protocol may be administered by first administering a chemotherapeutic agent and / or radiation, followed by administering a compound of formula (I) where the administration of the chemotherapeutic agent and / or radiation has an advantage. Treatment may continue until completion.
[142] Thus, based on experience and knowledge, the clinician can modify the protocol of administering a therapeutic ingredient (therapeutic agent, ie a compound of formula (I), a chemotherapeutic agent or radiation), as the treatment progresses, as the individual patient needs .
[143] In determining whether the treatment is effective at the amount currently administered, the clinician
[144] More obvious signs (eg, alleviation of disease-related symptoms, inhibition of tumor growth, substantial reduction of tumor or inhibition of metastasis), as well as the overall comfort of the patient will be considered. Tumor size can be measured by standard methods (e.g., radio-logical studies such as CAT or MRI scans) and subsequently measured to determine if tumor growth is slowing or reversing. . Alleviation of disease-related symptoms such as pain and improvement of the overall condition can be used to determine the effectiveness of treatment.
[145] The following examples illustrate the preparation of certain compounds of the invention and are not intended to limit the invention herein. Alternative mechanical routes and analogs will be apparent to those skilled in the art.
[146] Preparation Example 1
[147]
[148] Step A
[149] 3-nitrosalicylic acid (500 mg, 2.7 mmol), 1,3-dicyclohexylcarbodiimide (DCC) (563 mg) and ethyl acetate (10 ml) were combined and then stirred for 10 minutes. (R)-(-)-2-pyrrolidinemethanol (0.27 ml) was added and the resulting suspension was stirred at rt overnight. The solid was filtered off and the filtrate was concentrated and purified directly or washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The organic phase obtained was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative plate chromatography (silica gel, CH ₂ Cl ₂ saturated with 5% MeOH / AcOH) to afford the desired compound (338 mg, 46%, MH ⁺ = 267).
[150] Step B
[151] The product of Step A was stirred overnight under hydrogen gas atmosphere with 10% Pd / C. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo, and the resulting residue was purified by column chromatography (silica gel, CH ₂ Cl ₂ saturated with 4% MeOH / NH ₄ OH), Product (129 mg, 43%, MH ⁺ = 237) was obtained.
[152] Preparation Example 2
[153]
[154] Step A
[155] Bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) (1.30 g, 2.68 mmol, 1.0 equiv), diisopropylethylamine (DIEA) (1.4 ml) in anhydrous dichloromethane (25 ml) at room temperature under a nitrogen atmosphere. , 8.03 mmol, 3.0 equiv) and 3-hydroxy-4-nitrobenzoic acid (500 mg, 2.68 mmol, 1.0 equiv) were added 1 part of cyclohexylmethanamine (0.7 ml, 5.35 mmol, 2.0 equiv). The mixture was stirred at rt for 12 h and then diluted with 1.0 M aqueous NaOH solution (50 ml). The mixture was extracted with dichloromethane (4 × 25 ml) and the organic extracts were discarded. The aqueous phase was adjusted to ˜pH 2 using 6.0 M HCl aqueous solution and extracted with ethyl acetate (4 × 25 ml). The combined organic extracts were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under house-vacuum at 30 ° C. Without further purification, the obtained solid (588 mg, 2.11 mmol, 79%, MH ⁺ = 279) was used directly.
[156]
[157] Step B
[158] Under a hydrogen gas atmosphere, the acidic aqueous solution of step A was stirred overnight with 10% Pd / C. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo, and the residue obtained was purified by column chromatography (silica gel, CH ₂ Cl ₂ saturated with 4% MeOH / NH ₄ OH) (319 mg, 62%, MH ⁺ = 249).
[159] Except for using the carboxylic acids, amines, coupling agents (DCC (Preparation Example 1) or PyBrop (Preparation Example 2)) described in Table 1 below, using the process of Preparation Examples 1 and 2, The amide product described was obtained and used without further purification.
[160] TABLE 1
[161]
[162]
[163]
[164] Preparation Example 20
[165]
[166] Step A
[167] 3-nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate (10 ml) were combined and then stirred for 10 minutes. N, N-dimethyl-1,3-propanediamine (0.34 ml) was added and the resulting suspension was stirred at rt overnight. The solid was filtered off and washed with 1N NaOH. After filtering the mixture, the aqueous filtrate was used directly in the subsequent reaction.
[168] Step B
[169] The acidic aqueous solution of step A was stirred overnight with 10% Pd / C under hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo, and the resulting residue was purified by column chromatography (silica gel, CH ₂ Cl ₂ saturated with 4% MeOH / NH ₄ OH), The desired product (183 mg, 29%, MH ⁺ = 238) was obtained.
[170] Following the two step process described in Preparation Example 20, except using the carboxylic acids and amines described in Table 2 below, the products of Table 2 were obtained.
[171] TABLE 2
[172]
[173] Preparation Example 25
[174]
[175] Step A
[176] According to the process described in Preparation Example 2, Step A, 2,2-diethoxy-ethylamine (4.2 ml) and 3-hydroxy-4-nitrobenzoic acid (5 g) were reacted (yield 40%, MH ⁺ =). 299).
[177]
[178] Step B
[179] The product of step A (806 mg) and P ₄ S ₁₀ (1.5 g) were heated to 130 ° C. and then immediately cooled to room temperature. Water was added and the resulting mixture was filtered. The filtrate was extracted with ethyl acetate and the organic phase was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative plate chromatography (silica gel, 2% MeOH / CH ₂ Cl ₂ ) to give the product (90 mg, 15%).
[180] Preparation Example 26
[181]
[182] Coupling the carboxylic acid described in Khimiya Geterotsiklicheskikh Soedinenii 1986, 328-330 to Chemistry of Heterocyclic Compounds 1986, 22, 265-267 with dimethylamine and reducing the nitro substituent according to the process described in Preparation Example 2 To give the pyrazole product shown.
[183] Preparation Example 27
[184]
[185] According to processes known in the art, BOC aminothiophene compounds (prepared according to the methods described in J. Org. Chem. 1985, 50, 2730-2736) are prepared in HCl in dioxane or trifluoro in dichloromethane. Treatment with acetic acid (TFA) yielded the thiophene product shown.
[186] Preparation Example 28
[187]
[188] Step A
[189] In accordance with processes established in the art, lithium hydroxide in a suitable solvent was treated with the title compound of Preparation Example 27 to obtain the lithium carboxylate intermediate shown.
[190] Step B
[191] According to the process outlined in Preparation Example 2, the lithium carboxylate prepared in step A was coupled with dimethylamine to obtain the thiophene product shown.
[192] Preparation Example 29
[193]
[194] Step A
[195] Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 ml of acetone. Potassium carbonate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 ml, 233.0 mmol). The mixture was heated to reflux and lasted for 6 hours. After cooling to room temperature, the mixture was filtered and the solid material was washed with acetone (˜200 ml). The filtration and washings were concentrated to a solid under reduced pressure and further dried under high vacuum to afford methyl-3-methoxy-4-bromo-2-thiophencarboxylate (13.7 g, 100%, MH ⁺ = 251.0). Obtained.
[196] Step B
[197] Methyl-3-methoxy-4-bromo-2-thiophencarboxylate (13.7 g) obtained in step A was dissolved in 75 ml of THF and 1.0 M aqueous sodium hydroxide solution (65 ml, 65.0 mmol) was added. . The mixture was stirred at rt for 24 h. 1.0M aqueous hydrogen chloride solution was added dropwise to the mixture until the pH was about 2. The acidic mixture was extracted with CH ₂ Cl ₂ (100 ml × 2,50 ml). The combined organic extracts were washed with brine (40 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 10.0 g of 3-methoxy-4-bromo-2-thiophencarboxylic acid as a solid (in step 2). Over 100%, MH ⁺ = 237.0).
[198] Step C
[199] To a stirred solution of 3-methoxy-4-bromo-2-thiophencarboxylic acid (6.5 g, 27.4 mmol) in 140 ml of CH ₂ Cl ₂ , bromotripyrrolidinophosphonium hexafluoro Phosphate (PyBrop, 12.8 g, 27.5 mmol), 2.0 M solution of dimethyl amine in THF (34.5 ml, 69.0 mmol), diisopropylethyl amine (12.0 ml, 68.7 mmol) were added. After 3 days, the mixture was diluted with 100 ml of CH ₂ Cl ₂ and washed with 1.0 M aqueous sodium hydroxide solution (30 ml × 3) and brine (30 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to an oil. The crude oil product was purified by flash column chromatography [eluted with CH ₂ Cl ₂ -hexanes (1: 1, v / v)]. Solvent was removed to give a solid which was further dried under high vacuum to give N, N'-dimethyl-3-methoxy-4-bromo-2-thiophencarboxamide (6.76 g, 93%, MH ⁺ = 265.0). , M + 2 = 266.1).
[200] Step D
[201] An oven-dried three necked round bottom flask was fitted with a reflux condenser, palladium acetate (95 mg, 0.42 mmol), (R) -2,2'-bis (diphenylphosphino) -1,1'-by Naphthyl (BINAP) (353 mg, 0.57 mmol), cesium carbonate (9.2 g, 28.33 mmol), and N, N'-dimethyl-3-methoxy-4-bromo-2-thiophencarboxamide (3.74 g , 14.2 mmol, obtained in step C) were charged in that order. The solid mixture was flushed with nitrogen (“gas up / nitrogen via house vacuum”, 3 cycles). Toluene (95 ml) was added to the solid mixture, followed by benzophenone imine (3.6 ml, 21.5 mmol). The mixture was heated to reflux and lasted for 10 hours. A second batch of (R) -BINAP (353 mg, 0.57 mmol) and palladium acetate (95 mg, 0.42 mmol) in 5 ml of toluene was added. Reflux was continued for 14 hours. A third batch of (R) -BINAP (88 mg, 0.14 mmol) and palladium acetate (30 mg, 0.13 mmol) was added and reacted at 110 ° C. for 24 hours. The mixture was cooled to room temperature, diluted with ether (50 ml), filtered through celite bed and washed with ether. The filtration and washings were concentrated to an oil under reduced pressure and purified by two flash column chromatography using CH ₂ Cl ₂ and CH ₂ Cl ₂ -MeOH (200: 1) as eluent. The solvent was removed to give 4.1 g (79%, MH ⁺ = 365.1) of amido-thiophene diphenylimine product as a solid.
[202] Step E
[203] At -78 ℃, 140ml CH ₂ Cl ₂ was added dropwise a 1.0M solution of boron tribromide in CH ₂ Cl ₂ To a stirred solution of tetrahydrofuran (obtained in step D) thiophene-imine (5.09g, 13.97mmol). While the mixture was stirred for 3 hours, the temperature of the cold bath was slowly increased from -78 ° C to -15 ° C. 100 ml of H ₂ O was added, and the mixture was stirred at room temperature for 30 minutes, and then the two layers were separated. The organic layer (A) was extracted with H ₂ O (30 ml × 2). The aqueous layer and the aqueous extract were combined, washed with 30 ml of CH ₂ Cl ₂ , and then adjusted to pH ˜8 with saturated aqueous NaHCO ₃ . The neutralized aqueous solution was extracted with CH ₂ Cl ₂ (100 ml × 3), the extract was washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and solid N, N′-dimethyl-3-hydroxy 1.49 g of 4-amino-2-thiophencarboxamide (first obtained) were obtained. The already separated organic layer A and the organic wash were combined, and then stirred with 30 ml of 1.0M HCl aqueous solution for 1 hour. The two layers were separated, the aqueous layer was washed with 30 ml of CH ₂ Cl ₂ , adjusted to pH ˜8 with saturated aqueous NaHCO ₃ and the separated organic and organic washes were combined as organic layer B. The neutralized aqueous solution was extracted with CH ₂ Cl ₂ (30 ml × 4), the extract was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 0.48 g of the second obtained solid of the title compound. Got it. The organic layer B was washed with brine, concentrated to an oil and then separated by preparative TLC (CH ₂ Cl ₂ -MeOH = 50: 1) to give 0.45 g of the third obtained solid of the title compound. The overall yield of product N, N'-dimethyl-3-hydroxy-4-amino-2-thiophencarboxamide is 2.32 g (89%) (MH ⁺ = 187.0).
[204] Preparation Example 30
[205]
[206] At 0 ° C., aniline (12 ml) in anhydrous EtOH (150 ml) was added dropwise to a stirred ethanol solution (150 ml) of diethylsquarate over 6 hours. After stirring at room temperature overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The obtained residue was washed with cold EtOH and ether to give the above product (23.5 g, 92%, MH ⁺ = 218).
[207] Preparation Example 31
[208]
[209] The compound of Preparation Example 19 (14.6 g) dissolved in anhydrous EtOH (100 ml) was added dropwise over 4 hours to a solution of diethylsquarate (19 ml, 128 mmol) in stirred ethanol (100 ml). After 5 days, the reaction mixture was concentrated in vacuo and the residue obtained was purified by column chromatography (silica gel, 0-5% MeOH / CH ₂ Cl ₂ ) to give the product (65%, MH ⁺ = 305, mp = 178.6 ° C). ) Was obtained.
[210] Preparation Example 32
[211] Step A
[212]
[213] 3-nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethyl acetate (20 ml). After addition of 1,3-dicyclohexylcarbodiimide (0.568 g, 2.8 mmol), the mixture was stirred for about 10 minutes and then cooled to 0 ° C. In the meantime, a precipitate formed. Azetidine (0.39 ml, 5.8 mmol) is added and the mixture is stirred overnight and allowed to come to room temperature. After this time the reaction was cooled to 0 ° C. and filtered. The collected solid was washed with cold ethyl acetate. The filtrate was concentrated and purified by column chromatography (80% EtOAc / Hex) to give the product (476 mg, 39.0%).
[214] ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.40 (m, 2H), 4.38 (m, 4H), 6.97 (m, 1H), 7.62 (d, 1H), 8.12 (d, 1H), 12.88 (m, 1H) ppm.
[215] Step B
[216]
[217] The nitro compound of Preparation Example 32, step A (0.48 g, 2.1 mmol) was dissolved in methanol (25 ml) and stirred with 10% Pd / C overnight under hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the product (344 mg, 90%).
[218] ¹ H NMR (300 MHz, CDCl ₃ ) δ2.52 (m, 2H), 4.57 (bs, 4H), 6.75 (m, 1H), 6.90 (m, 2H), 12.71 (bs, 1H) ppm.
[219] Preparation Example 33
[220]
[221] The products of Table 3 were obtained using the two step process of Preparation Example 32, except using the carboxylic acids and amines described in Table 3 below.
[222] TABLE 3
[223]
[224]
[225]
[226] Preparation Example 48
[227] Step A
[228]
[229] 3-nitrobenzoic acid (1.004 g, 6.0 mmol) was combined with N, N'-diisopropylethylamine (6.25 ml, 36.0 mmol) in dichloromethane (60 ml). Bromo-tris-pyrrolodino-phosphonium hexafluorophosphate (PyBrOP) (2.80 g, 6.0 mmol) was added to the solution and the mixture was stirred for 10 minutes. Methyl picolinate hydrochloride (1.08 g, 6.0 mmol) was added to the mixture before the reaction was stirred overnight. After this time the reaction was concentrated and the product was separated by column chromatography (1: 9 EtOAc / DCM). The product as a yellow solid (1.66 g, 95%) was isolated and used without further purification.
[230] ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46 (m, 2H), 1.65 (m, 1H), 1.90 (m, 2H), 2.39 (m, 1), 3.32 (m, 1H), 3.53 (m, 1H), 3.81 (s, 3H), 5.50 (m, 1H), 7.62 (m, 1H), 7.78 (m, 1H), 8.31 (m, 2H) ppm.
[231] Step B
[232]
[233] Methyl ester (1.79 g, 6.1 mmol) was dissolved in dioxane / water (20 ml / 15 ml) at room temperature. Lithium hydroxide (0.258 g, 6.2 mmol) was added to the solution. After a few hours, additional lithium hydroxide (0.128 g, 3.0 mmol) was added and the reaction was further stirred for 1 hour. The reaction was then concentrated and recovered in water. The solution was extracted twice with ether. The aqueous phase was then acidified and extracted three times with ethyl acetate. The organic fractions were then dried over sodium sulphate, filtered and concentrated. It was separated by column chromatography (95% EtOAc / Hex, 0.05% HOAc) to give product (1.66 g, 98%).
[234] ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.49 (m, 2H), 1.68 (m, 1H), 1.82 (m, 2H), 2.44 (m, 1H), 3.32 (m, 1H), 3.58 (m, 1H), 5.57 (m, 1H), 7.65 (m, 1H), 7.80 (m, 1H), 8.32 (m, 2H), 10.04 (bs, 1Hppm).
[235] Step C
[236]
[237] The nitro compound was dissolved in excess methanol (20 ml) and surrounded by argon. 5% palladium / C (catalyst) was added and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated three times in total. The reaction was then stirred overnight under hydrogen. The hydrogen balloon was then removed, the solution was filtered through celite and washed several times with methanol. The filtrate was concentrated and dried on a vacuum line to give the desired aniline product (1.33 g, 90%).
[238] ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40 (m, 2H), 1.50 (m, 1H), 1.68 (m, 2H), 2.33 (m, 1H), 3.18 (m, 1H), 3.62 (m, 1H), 5.39 (m, 1H), 6.12 (bs, 2H), 6.75 (m, 2H), 7.12 (m, 1H) ppm. Mass spectrum-calculated: 248, measured: 249.1 (M + 1) ⁺
[239] Preparation Example 49-51
[240]
[241] Using the three step process described in Preparation Example 48, except using the carboxylic acids and amines described in Table 4, the products of Table 4 were obtained.
[242] TABLE 4
[243]
[244] Preparation Example 52
[245]
[246] Step A
[247] 3-nitrobenzoic acid (2.00 g, 10.9 mmol) was combined with 1,3-diisopropylcarbodiimide (1.71 ml, 10.9 mmol) and 4- (dimethylamino) pyridine (catalyst) in dichloromethane (150 ml). And stirred for a few minutes. 2,4,6-trimethoxybenzylamine hydrochloride (0.664 g, 2.8 mmol) was added with N, N-diisopropylethylamine (1.88 ml, 10.8 mmol). The reaction was stirred overnight. The reaction was then concentrated and purified by column chromatography (1/1 hexanes / EtOAc) to use the product (1.62 g, 41%).
[248] ¹ H NMR (300 MHz, CDCl ₃ ) δ3.83 (m, 9H), 4.72 (d, 2H), 6.17 (s, 2H), 7.01 (m, 1H), 7.88 (m, 1H), 8.18 (dd, 1H), 8.25 (dd, 1H) ppm
[249] Mass spectrum-found: 362.11, found: 362.9 (M + 1) ⁺
[250] Step B
[251] 3-nitrosalicylic-2,4,6-trimethoxybenzylamide (0.146 g, 0.4 mmol) in Step A was combined with a solution of true fluoroacetic acid / dichloromethane (1: 1, 5 ml). The reaction was stirred for 45 minutes. TLC (30% E / H) then indicated that no starting material was present. The reaction was concentrated and dried over a vacuum line. The material was purified by column chromatography (5% MeOH / CH ₂ Cl ₂ ) to afford the product (0.06 g, 80%).
[252] ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.16 (m, 1H), 8.28 (m, 1H), 8.49 (m, 1H), 12.26 (s, 1H) ppm.
[253] Step C
[254] The nitro compound of step B (0.32 g, 1.6 mmol) was dissolved in excess methanol (40 ml) and surrounded by argon. 5% palladium / C (catalyst) was added and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated three times in total. The reaction was then stirred overnight under hydrogen. The hydrogen balloon was then removed, the solution was filtered through celite and washed several times with methanol. The filtrate was concentrated and dried on a vacuum line to give the desired aniline product (0.17 g, 70%).
[255] ¹ H NMR (300 MHz, d4-MeOH) δ 6.63 (m, 1H), 6.88 (m, 1H), 7.07 (d, 1H) ppm.
[256] Preparation Example 53
[257]
[258] Step A
[259] 3-nitrosalicylic acid (2.00 g, 10.9 mmol) was combined with 4- (dimethylamino) pyridine (catalyst) and 1,3-diisopropylcarbodiimide (1.71 ml, 10.9 mmol) in dichloromethane (150 ml). After the addition of methanol, the reaction was stirred for 2 hours. The reaction was then concentrated and purified by column chromatography (3/1 H / E) to afford methyl ester (0.32 g, 15%).
[260] ¹ H NMR (300 MHz, d ₆ -DMSO) δ3.92 (s, 3H), 7.11 (dd, 1H), 8.05 (d, 1H), 8.19 (d, 1H), 11.46 (s, 1H) ppm.
[261] Step B
[262] The nitro compound (0.32 g, 1.6 mmol) was dissolved in excess methanol (40 ml) and surrounded by argon. 5% palladium / C (catalyst) was added and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated three times in total. The reaction was then stirred overnight under hydrogen. The hydrogen balloon was then removed, the solution was filtered through celite and washed several times with methanol. The filtrate was concentrated and dried on a vacuum line to give the desired aniline product (0.18 g, 68%).
[263] ¹ H NMR (300 MHz, d ₆ -DMSO) δ3.92 (bs, 3H), 6.70 (dd, 1H), 6.89 (dd, 1H), 7.22 (d, 1H), 10.85 (bs, 1H) ppm.
[264] Mass spectrum-found: 167, found: 168.0 (M + 1) ⁺
[265] Preparation Example 54
[266]
[267] Phenylenediamine (2.20 g, 20 mmol) was dissolved in pyridine (20 ml) and cooled to 0 ° C. Acetic anhydride (1.89 ml, 20 mmol) and dichloromethane (10 ml) were mixed and then added to the solution over 15 minutes. The reaction was stirred at 0 ° C. for 1 h and then brought to ambient temperature. After 2 hours, the solvent was evaporated. An azeotropic mixture with toluene was allowed to dry and dried under vacuum to afford the above compound (2.8 g, 93%) as a solid.
[268] ¹ H NMR (300 MHz, d ₆ -DMSO) δ 2.15 (s, 3H), 4.80-5.05 (bs, 2H), 6.62 (m, 1H), 6.80 (d, 1H), 7.00 (t, 1H), 7.23 (d, 1 H), 9.20 (s, 1 H) ppm.
[269] Preparation Example 55
[270]
[271] Phenylenediamine (5.0 g, 46 mmol) was dissolved in dichloromethane (50 ml). A solution of methanesulfonyl chloride (3.6 ml, 46 mmol) in dichloromethane (50 ml) was added slowly with stirring. After 16 hours, the precipitate was filtered off and discarded. The residual solution was evaporated to afford the above compound (5.5 g, 65%) as a solid.
[272] Mass spectrum-calculated: 186.0, measured: 186.9 (M + 1) ⁺
[273] Preparation Example 56
[274]
[275] Step A
[276] 2-nitrobenzyl bromide (5.0 g, 0.0231 mol), THF (50 ml) and morpholine (6.05 g, 0.0694 mol) were added to the sealed tube. The reaction mixture was heated to reflux overnight. After the solvent was removed, water (400 ml) was added and extracted with DCM (3 × 80 ml). The combined organic phases were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (25% EtOAc / HEX) to afford the compound (5.07 g, 99%).
[277] ¹ H NMR (300 MHz, d-CHCl ₃ ) δ2.5 (m, 4H), 3.8 (m, 4H), 3.9 (s, 2H), 7.5 (t 1H), 7.7 (m, 2H), 7.9 (d , 1H) ppm.
[278] Step B
[279] The nitro compound of step A (4.57 g, 0.0206 mol) was dissolved in methanol (100 ml) and stirred with 10% Pd / C overnight under hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated and purified by column chromatography (EtOAc / HEX / Et ₃ N 20/60/1) to afford the compound (3.14 g, 79%).
[280] ¹ H NMR (300 MHz, d-DMSO) δ 2.5 (m, 4H), 3.5 (s, 2H), 3.7 (m, 4H), 5.4 (s, 2H), 6.6 (t 1H), 6.7 (d, 1H), 7.1 (m, 2H) ppm.
[281] Preparation Example 57
[282]
[283] Step A
[284] 2-nitrobenzyl bromide (5.0 g, 0.0231 mol), THF (50 ml) and imidazole (4.72 g, 0.0694 mol) were added to the sealed tube. The reaction mixture was heated to reflux overnight. The solvent was evaporated to yield a residue, then recovered in water (400 ml) and extracted with EtOAc (3 × 80 ml). The combined organic phases were dried over Na ₂ SO ₄ , concentrated and then concentrated in vacuo to afford the desired compound (4.07 g, 87%).
[285] ¹ H NMR (300MHz, d-DMSO) δ5.7 (s, 2H), 6.9 (d, 1H), 7.1 (d, 1H), 7.3 (s, 1H), 7.7 (t, 1H), 7.8 (m , 2H), 8.2 (d, 1H) ppm.
[286] Step B
[287] The nitro compound of step A (2.23 g, 0.0110 mol) was dissolved in methanol (50 ml) and stirred with 10% Pd / C overnight under hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated and purified by column chromatography (DCM / MeOH / Et ₃ N 20/2/1) to afford the compound (1.77 g, 93%).
[288] ¹ H NMR (300 MHz, d-DMSO) δ5.2 (s, 2H), 5.3 (s, 2H), 6.6 (t, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.0 (s , 1H), 7.1 (t, 1H), 7.2 (s, 1H), 7.8 (s, 1H) ppm.
[289] Preparation Example 58
[290]
[291] Step A
[292] 2-nitrophenol (4.32 g, 30 mmol) was dissolved in EtOH (40 ml) and KOH (3.5 g, 63.0 mmol) and 2- (dimethylamino) ethyl chloride hydrochloride (5.56) in BuOH (50 ml) and DMF (10 ml). g, 34 mmol)). The reaction mixture was heated to reflux overnight. After cooling to room temperature, most of the solvent was evaporated under reduced pressure. The residue was taken up in water (400 ml) and then extracted with EtOAc (3 × 100 ml). The combined organic phases were then washed with 5% NaOH (3 × 100 ml) and dried over sodium sulphate. The solution was concentrated and purified by column chromatography (10% MeOH / DCM) to give the product (1.35 g, 21%).
[293] H NMR (300 MHz, CDCl ₃ ) δ 2.48 (s, 6H), 2.93 (2, 2H), 4.36 (t, 2H), 7.16 (dd, 1H), 7.20 (d, 1H), 7.63 (dd, 1H ), 7.97 (d, 1 H) ppm.
[294] Step B
[295] The nitro compound of step A (1.35 g, 6.43 mmol) was dissolved in MeOH (50 ml) and shaken with 10% Pd / C for 3 hours under a 10 psi hydrogen gas atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the compound (980 mg, 85%) via column chromatography (DCM / MeOH / NH ₄ OH = 20/1 / 0.1).
[296] H NMR (300 MHz, CDCl ₃ ) δ 2.46 (s, 6H), 2.95 (t, 2H), 3.60 (bs, 2H), 4.21 (t, 2H), 6.81 (m, 2H), 6.95 (m, 2H ppm.
[297] Preparation Example 59
[298]
[299] Step A
[300] 2-nitrobenzyl bromide (2.0 g, 9.3 mmol) was dissolved in DCM (50 ml). Dimethylamine (2.0 N in THF, 9.3 ml, 18.6 mmol) was added and then the reaction mixture was stirred overnight. The mixture was then poured into water (200 ml) and extracted with DCM (3 × 100 ml). The combined organic phases were dried over sodium sulphate. The solution was concentrated in vacuo and the pure compound (540 mg, 32%) was obtained via column chromatography (DCM / MeOH / NH ₄ OH = 20/1 / 0.1).
[301] H NMR (300 MHz, CDCl ₃ ) δ 2.36 (s, 6H), 3.73 (s, 2H), 7.21 (t, 1H), 7.37 (d, 1H), 7.43 (t, 1H), 7.52 (d, 1H ppm.
[302] Step B
[303] The nitro compound of step B (500 mg, 2.78 mmol) was dissolved in MeOH (500 ml) and stirred with 10% Pd / C overnight under hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and the compound (400 mg, ˜80%) was obtained via column chromatography (DCM / MeOH / NH ₄ OH = 20/1 / 0.1).
[304] H NMR (300 MHz, CDCl ₃ ) δ2.32 (s, 6H), 3.62 (s, 2H), 4.11 (bs, 2H), 6.42 (m, 2H), 6.85 (m, 2H) ppm.
[305] Preparation Example 60
[306]
[307] Step A
[308] 2-nitrophenol (5.0 g, 36.0 mmol) was added to water (20 ml). After addition of NaOH (1.44 g, 36.0 mmol) and dibromoethylene (27.0 g, 144.0 mmol), the reaction mixture was refluxed for 40 hours. After cooling to rt, the mixture was poured into water (400 ml) and extracted with EtOAc (3 × 100 ml). The combined organic phases were then washed with 5% NaOH (3 × 100 ml) and dried over sodium sulphate. The solution was concentrated and purified by column chromatography (75% EtOAc / pentane) to give the product (3.4 g, 38%).
[309] H NMR (300 MHz, CDCl ₃ ) δ 3.79 (t, 2H), 4.57 (t, 2H), 7.20 (m, 2H), 7.65 (dd, 1H), 7.97 (d, 1H) ppm.
[310] Step B
[311] Nitrobromide (1.7 g, 6.9 mmol) was dissolved in THF (20 ml). After addition of morpholine (1.81 ml, 20.7 mmol), the reaction mixture was refluxed overnight. After cooling to rt, the reaction mixture was poured into water (300 ml) and extracted with DCM (3 × 100 ml). The combined organic phases were dried over sodium sulphate. The solution was concentrated and purified by column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH = 20/1 / 0.1) to give the product (1.73 g, 99%).
[312] H NMR (300 MHz, CDCl ₃ ) δ2.74 (t, 4H), 3.00 (t, 2H), 3.84 (t, 4H), 4.39 (t, 2H), 7.18 (dd, 1H), 7.20 (d, 1H ), 7.63 (dd, 1 H), 7.93 (d, 1 H) ppm.
[313] Step C
[314] The nitro compound of step B (1.71 g, 6.78 mmol) was dissolved in MeOH (50 mL) and stirred with 10% Pd / C overnight under hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and the target compound (1.43 g, 95%) was obtained via column chromatography (DCM / MeOH / NH ₄ OH = 20/1 / 0.1).
[315] H NMR (300 MHz, CDCl ₃ ) δ2.71 (t, 4H), 2.92 (t, 2H), 3.84 (t, 4H), 4.00 (bs, 2H), 4.28 (t, 2H), 6.82 (m, 2H ), 6.94 (m, 2H) ppm.
[316] Preparation Example 61
[317]
[318] Step A
[319] The reaction follows Step A of Preparation Example 60.
[320] H NMR (300 MHz, CDCl ₃ ) δ 3.79 (t, 2H), 4.57 (t, 2H), 7.20 (m, 2H), 7.65 (dd, 1H), 7.97 (d, 1H) ppm.
[321] Step B
[322] Nitrobromide (1.7 g, 6.9 mmol) of step A was dissolved in THF (20 ml). After addition of imidazole (1.41 ml, 20.7 mmol), the reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was poured into water (300 ml) and extracted with CH ₂ Cl ₂ (3 × 100 ml). The combined organic phases were dried over sodium sulphate. The solution was concentrated and purified by column chromatography (CH ₂ Cl ₂ / MeOH / NH ₄ OH = 10/1 / 0.1) to give the product (1.25 g, 78%).
[323] H NMR (300 MHz, CDCl ₃ ) δ4.41 (t, 2H), 4.56 (t, 2H), 7.06 (d, 1H), 7.18 (s + dd, 2H), 7.26 (s, 1H), 7.63 (dd , 1H), 7.74 (s, 1H), 7.99 (d, 1H) ppm.
[324] Step C
[325] The nitro compound of step B (1.23 g, 5.28 mmol) was dissolved in MeOH (50 mL) and stirred with 10% Pd / C for 3 h under a hydrogen gas atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo and the compound (1.01 g, 94%) was obtained via column chromatography (DCM / MeOH / NH ₄ OH = 10/1 / 0.1).
[326] H NMR (300 MHz, CDCl ₃ ) δ 3.41 (bs, 2H), 4.38 (t, 2H), 4.48 (t, 2H), 6.82 (m, 3H), 6.95 (m, 1H), 7.17 (s, 1H ), 7.21 (s, 1 H), 7.62 (d, 1 H) ppm.
[327] Preparation Example 62
[328]
[329] Step A
[330] 2,6-dinitroaniline (10.0 g, 55.0 mmol) and tin (II) chloride dihydrate (111.0 g, 492.0 mmol) were dissolved in concentrated HCl (170 ml). The reaction mixture was refluxed for 5 hours and then cooled to room temperature. After standing overnight, the precipitate was filtered off and dissolved in 10% NaOH (50 ml). After evaporation of the solvent under reduced pressure, the residue was extracted with EtOAc (10 x 80 ml). The solvent of the combined extracts was removed and the residue obtained (2.5 g crude) was used in step B without further purification.
[331] Step B
[332] The crude material of step A was dissolved in 96% formic acid (10 ml). After refluxing for 1 hour, the solution was evaporated to dryness. After addition of water (10 ml), the pH of the acidic solution was adjusted to 7 using ammonium hydroxide solution. The precipitate thus obtained was collected, dried and used in the next step without further purification.
[333] Step C
[334] The form amide crude of step B was dissolved in 10% HCl (25 ml) and refluxed for 30 minutes. After removing the solvent, 10% NaOH (6 ml) was added. After evaporation of the solvent, the obtained residue was extracted with EtOH (4 x 50 ml). The solution was concentrated and column chromatography (DCM / MeOH / NH ₄ OH = 5/1 / 0.1) gave the final compound (1.23 g, 18% over 3 steps).
[335] H NMR (300 MHz, d ₆ -DMSO) δ 5.38 (bs, 2H), 6.44 (d, 1H), 7.82 (d, 1H), 6.99 (t, 1H), 8.11 (s, 1H), 12.30 (bs , 1H) ppm.
[336] Preparation Example 63
[337]
[338] Step A
[339] 2,3-dihydroxybenzoic acid (15.0 g, 97.3 mmol) was suspended in water (30 ml). A solution of KOH (16.4 g, 292 mmol) in water (70 ml) was added followed by diiodomethane (8.1 ml, 100.2 mmol). The reaction mixture was heated to 100 ° C. for 5 days or until almost all of the diiodo compound disappeared. The remainder of the dihalogen starting material was co-evaporated with some water. The solution was acidified with concentrated HCl to give a precipitate. Acetal crude was collected and recrystallized once from EtOH to give crystals (7.0 g, 43%).
[340] H NMR (300 MHz, d ₆ -DMSO) δ 6.21 (s, 2H), 6.99 (dd, 1H), 7.22 (d, 1H), 7.39 (d, 1H), 13.07 (bs, 1H) ppm.
[341] Step B
[342] The material recrystallized in step A (2.0 g, 12.0 mmol) was refluxed in a mixture of dioxane (35 ml) and tert-butyl alcohol (10 min) for 10 minutes. After allowing the mixture to come to room temperature, diphenylphosphoryl azide (2.6 ml, 12.0 mmol) and DIEA (1.81 ml, 13.0 mmol) were added in one batch. The reaction mixture was refluxed for 8 hours and dioxane was removed under reduced pressure. The reaction mixture was poured into water (200 ml) and extracted with CH ₂ Cl ₂ (3 × 100 ml). The combined organic phases were dried over sodium sulphate. The solution was concentrated and purified by column chromatography to give the product (2.28 g, 80%).
[343] H NMR (300 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 6.21 (s, 2H), 6.56 (m, 2H), 6.81 (t, 1H), 7.23 (s, 1H) ppm.
[344] Step C
[345] Carbamate (2.28 g, 9.6 mmol) of step B was suspended in EtOH (50 ml). To the suspension was added 5N HCl (50 ml). Stir overnight, a clear solution was obtained. The solvent was removed under reduced pressure and the residue was dissolved in water (200 ml). The solution was neutralized with KOH and extracted with EtOAc (3 × 100 ml). The combined organic phases were dried over sodium sulphate and concentrated before column chromatography (DCM / MeOH / NH ₄ OH = 20/1 / 0.2) to afford the desired compound (1.05 g, 80%).
[346] H NMR (300 MHz, CDCl ₃ ) δ 3.48 (bs, 2H), 6.03 (s, 2H), 6.43 (d, 1H), 6.46 (d, 1H), 6.79 (t, 1H) ppm.
[347] Preparation Example 64
[348]
[349] 2-aminobenzyl amine (5.0 g, 41.0 mmol) was dissolved in a mixture of dioxane / water (30 ml each). Boc-anhydride (8.94 g, 41.0 mmol) and potassium carbonate (8.5 g, 61.5 mmol) were added and then the mixture was stirred overnight. The solution was poured into water (300 ml) and extracted with EtOAc (3 × 100 ml). The combined organic phases were dried over sodium sulphate, concentrated and then subjected to column chromatography (25% EtOAc / pentane) to afford the desired compound (7.28 g, 80%).
[350] Mass spectrum-found: 222.1, found: 223.0 (M + 1) ⁺
[351] Preparation Example 65
[352]
[353] Step A
[354] 2,3-diaminonitrophenol (4.0 g, 26.1 mmol) was dissolved in AcOH (200 ml). After adding sodium nitrile (2.25 g, 32.7 mmol), the reaction mixture was heated to 60 ° C. for 3 hours. The solvent was removed under reduced pressure, the residue was taken in water and extracted with EtOAc (3 × 100 ml). The combined organic phases were dried over sodium sulphate, concentrated and then subjected to column chromatography (50% EtOAc / pentane) to afford the desired compound (3.42 g, 80%).
[355] H NMR (300 MHz, d ₆ -DMSO) δ 7.78 (dd, 1H), 8.60 (d, 1H), 8.73 (d, 1H) ppm.
[356] Step B
[357] The nitro triazole (3.4 g, 20.9 mmol) of step A was dissolved in MeOH (50 ml) and stirred with 10% Pd / C overnight under hydrogen gas atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the desired compound (2.38 g, 85%).
[358] H NMR (300 MHz, d ₆ -DMSO) δ 5.99 (bs, 2H), 6.51 (d, 1H), 6.93 (d, 1H), 7.22 (dd, 1H) ppm.
[359] Preparation Example 66
[360]
[361] 3,4-Dimethoxy-3-cyclobutene-1,2-dione (1.30 g, 9.2 mmol) was dissolved in methanol. Aniline (0.84 ml, 9.2 mmol) was added dropwise to the solution. The reaction was stirred at rt for 16 h. Thereafter, a solid was formed that would be the desired compound. This solid was collected by filtration and dried in vacuo (1.8 g, 96%).
[362] ¹ H NMR (300 MHz, d ₆ -DMSO) δ 4.39 (s, 3H), 7.12 (m, 1H), 7.35 (m, 4H), 10.75 (bs, 1H) ppm.
[363] Preparation Examples 67-83
[364]
[365] Following the procedure described in Preparation Example 66, except for using the alkoxysquarate and amine or aniline (R ₂ -NH ₂ ) described in Table 5 below, the following products were obtained.
[366] TABLE 5
[367]
[368]
[369]
[370] Preparation Example 84
[371]
[372] 1,2-phenylenediamine (5.0 g, 0.0462 mol) was dissolved in methylene chloride (125 ml). Benzenesulfonyl chloride (5.6 ml, 0.0439 mol) was added dropwise and the reaction stirred for 72 hours. TLC (5% MeOH / DCM) then indicated the reaction was complete. The reaction was filtered to remove all solid material and the solute was washed with methylene chloride. The filtrate was concentrated and purified by column chromatography (3% MeOH / DCM). The desired product (2.28 g, 0.0092 mol, 20%) was obtained as a solid.
[373] ¹ H NMR (300 MHz, CD ₃ OD) δ6.40 (m, 2H), 6.73 (d, 1H), 6.94 (m, 1H), 7.46 (m, 2H), 7.58 (m, 1H), 7.68 (m , 2H) ppm.
[374] MS-APCI-Found: 248.06, Found: 248.9 (M + 1) ⁺
[375] Preparation Example 85
[376]
[377] Step A
[378] 2-nitrobenzyl bromide (5.18 g, 0.024 mol) was dissolved in EtOH (25 ml). NaOMe (11.0 ml, 25 wt.% In MeOH, 0.048 mol) was added dropwise under argon atmosphere. After stirring for 1 hour at room temperature, saturated sodium hydrogen carbonate solution (200 ml) was added. The mixture was extracted with chloroform (3 x 80 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (80 ml), water (80 ml), brine (80 ml) and dried over sodium sulphate. Concentration and purification by column chromatography (20% EtOAc / HEX) gave the desired compound (3.70 g, 92%).
[379] ¹ H NMR (300 MHz, d-CHCl ₃ ) δ 3.60 (s, 3H), 4.95 (s, 2H), 7.55 (t, 1H), 7.78 (t, 1H), 7.90 (d, 1H), 8.20 ( d, 1H) ppm.
[380] Step B
[381] Under an argon atmosphere, an ethanol suspension of Raney-Ni was added to a stirred solution of nitro compound of step A (3.00 g, 0.018 mol) in EtOAc / EtOH (10 ml / 10 ml). The mixture was stirred overnight and filtered through celite. The filtrate was concentrated and purified by column chromatography (25% EtOAc / HEX) to afford the desired compound (1.65 g, 67%).
[382] ¹ H NMR (300 MHz, d-CHCl ₃ ) δ 3.45 (s, 3H), 4.38 (bs, 2H), 4.60 (s, 2H), 6.82 (t, 2H), 7.22 (m, 2H) ppm.
[383] MS (MH ⁺ ): 137.08, found 137.9
[384] Preparation Example 86
[385]
[386] 2-aminophenol (1.26 g, 0.012 mol), sodium hydroxide (1.84 g, 0.046 mol) and tetrabutylammonium bromide (0.19 g, 0.58 mmol) were mixed at room temperature and then stirred for 10 minutes. 1-chlorobutane (1.2 ml, 0.012 mol) was added and the mixture was heated to 60 ° C. for 8 hours. The mixture was purified directly by column chromatography (25% EtOAc / HEX) to afford the desired compound (0.95 g, 50%).
[387] ¹ H NMR (300 MHz, d-CHCl ₃ ) δ1.08 (t, 3H), 1.62 (m, 2H), 1.90 (m, 2H), 4.05 (t, 2H), 4.23 (bs, 2H), 6.85 ( m, 4H) ppm.
[388] MS (MH ⁺ ): 165.12, found 166.1
[389] Preparation Example 87
[390]
[391] 2-aminophenol (5.0 g, 0.046 mol), sodium hydroxide (7.33 g, 0.183 mol) and tetrabutylammonium bromide (0.74 g, 2.29 mmol) were mixed at room temperature and then stirred for 10 minutes. 1-chloropropane (4.2 ml, 0.046 mol) was added and the mixture was heated to 60 ° C. for 8 h. The mixture was purified directly by column chromatography (25% EtOAc / HEX) to afford the desired compound (0.92 g, 13%).
[392] ¹ H NMR (300 MHz, d-CHCl ₃ ) δ 1.45 (d, 6H), 4.03 (bs, 2H), 4.60 (m, 1H), 6.93 (m, 4H) ppm.
[393] MS (MH ⁺ ): 151.10. Found 152.1
[394] Preparation Example 89
[395]
[396] Step A
[397] 2-nitrobenzaldehyde (2.0 g, 0.0132 mol), 1,2-dichloroethane (100 ml) and 3- (dimethylamino) propylamine (1.83 ml, 0.0145 mol) were stirred for 1 hour. Sodium triacetoxyborohydride (4.20 g, 0.0198 mol) was added and the reaction mixture was stirred overnight. 1N NaOH (100 ml) was added followed by extraction with EtOAc (3 × 100 ml) and dried over sodium sulphate. After the solution was concentrated, the target compound (1.62 g, 52%) was obtained by column chromatography (DCM / MeOH / Et ₃ N 40/4/1).
[398] ¹ H NMR (300 MHz, d-DMSO) δ 1.58 (m, 2H), 2.20 (s, 6H), 2.28 (t, 2H), 2.58 (m, 2H), 3.15 (s, 1H), 4.00 (s , 2H), 7.58 (t, 1H), 7.78 (m, 2H), 8.00 (d, 1H) ppm.
[399] MS (MH ⁺ ): 237.15, found 238.2
[400] Step B
[401] The nitro compound of step A (1.62 g, 0.0068 mol) was dissolved in THF (50 ml) and water (50 ml). Di-tert butyl dicarbonate (1.49 g, 0.0068 mol) and sodium carbonate (1.44 g, 0.0136 mol) were added and the reaction mixture was stirred overnight. Water (100 ml) was added and extracted with EtOAc (3 × 50 ml). The combined organic phases were dried over sodium sulphate and concentrated before column chromatography (DCM / MeOH / NH ₄ OH 40/4/1) to afford the desired compound (1.38 g, 60%).
[402] ¹ H NMR (300 MHz, d-DMSO) δ 1.40 (d, 9H), 1.68 (m, 2H), 2.18 (s, 6H), 2.23 (t, 2H), 3.32 (d, 2H), 4.78 (s , 2H), 7.42 (d, 1H), 7.26 (t, 1H), 7.83 (t, 1H), 8.15 (d, 1H)
[403] MS (MH ⁺ ): 337.20, found 338.1
[404] Step C
[405] The nitro compound of step B was dissolved in MeOH (25 ml) and stirred with a catalytic amount of 5% Pd / C overnight under hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated and then the desired compound (1.16 g, 92%) was obtained via column chromatography (4% Et ₃ N / EtOAc).
[406] ¹ H NMR (300MHz, d-DMSO) δ1.53 (s, 9H), 1.62 (m, 2H), 2.08 (s, 6H), 2.20 (t, 2H), 3.15 (t, 2H), 4.33 (s , 2H), 5.20 (s, 2H), 6.58 (t, 1H), 6.72 (d, 1H), 7.03 (m, 2H) ppm.
[407] MS (MH ⁺ ): 307.23, found 308.1
[408] Preparation Example 90
[409]
[410] Step A
[411] Squaaric acid (1.14 g, 10 mmol) suspended in thionyl chloride (8 ml) and N, N-dimethylformamide (0.050 ml) was refluxed under argon for 2 hours. The solvent was evaporated and the residue dissolved in diethyl ether and washed with cold water. The ether phase was dried over sodium sulfate and evaporated to give an oil. The oil was stored under vacuum for 1 hour.
[412] Step B
[413] The dichloride of step A was dissolved in 1,2-dichlorobenzene (5 ml) and mixed with 2-amino-5-nitrophenol (1.54 g, 10 mmol). After 10 minutes a precipitate formed. The solution was further stirred for 2 hours. The solid was collected by filtration and washed with 1,2-dichlorobenzene.
[414] ¹ H NMR (300 MHz, CD ₃ OD) δ 7.29 (d, 1H), 7.87 (m, 2H) ppm.
[415] MS-: calculated 268.0, measured 267.0 (M-1) ^-
[416] Preparation Example 91
[417]
[418] Dichloride (1.13 g, 7.5 mmol) of Preparation Example 90, Step A, was dissolved in tetrahydrofuran (5 ml) and cooled to 0 ° C. Aniline (0.697 ml, 7.5 mmol) was dissolved in tetrahydrofuran (5 ml), cooled to 0 ° C. and added dropwise to the dichloride solution over 10 minutes. The mixture was allowed to come to ambient temperature with stirring for 1 hour. The solvent was evaporated to give a solid. The solid was recovered in acetonitrile and washed with additional acetonitrile. Powder (0.91 g, 59% yield) was obtained.
[419] MS: calculated 207.0, found 209.2 (M + 2) ⁺
[420] Example 1
[421]
[422] The product of Preparation Example 22 (93 mg), the ethoxysquarate compound of Preparation Example 30 (75 mg), triethylamine (0.12 ml) and anhydrous ethanol (5 ml) were heated under reflux overnight. The reaction mixture was concentrated in vacuo and the residue was purified by preparative plate chromatography (silica gel, CH ₂ Cl ₂ saturated with 8% MeOH / NH ₄ OH) to give the product (51 mg, 34%, MH ⁺ = 437). It was.
[423] Examples 2 to 27
[424]
[425] According to the process of Example 1, using the indicated amines of the preparation example (or, instead, commercially available aniline) and the ethoxy squarate of preparation example 30, the products described in Table 6 below were obtained.
[426] TABLE 6
[427]
[428]
[429]
[430]
[431] Example 28
[432]
[433] Compound (100 mg), 3-amino benzonitrile (78 mg), triethylamine (0.23 ml) and anhydrous ethanol (10 ml) of Preparation Example 31 were heated to 80 ° C. overnight. The reaction mixture was concentrated in vacuo, diluted with 1N NaOH (aq.) And washed with dichloromethane. The aqueous phase was acidified (1M HCl), extracted with EtOAc, the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH ₂ Cl ₂ saturated with 5% MeOH / NH ₄ OH) to give the product (35 mg, 28%, MH ⁺ = 377, mp = 135-140 ° C.). .
[434] Examples 29-37
[435]
[436] According to the process of Example 28, the products of Table 7 were prepared using the following aromatic amines in place of 3-aminobenzonitrile. In certain instances, the product precipitated out of this solution and was separable without further purification.
[437] TABLE 7
[438]
[439] Example 38
[440]
[441] According to a known process {Farmaco 1993, 48, 857-869}, 2-aminopyridine is oxidized to give pyridyl N-oxide, and according to the process described in Example 28, a couple with the compound of Preparation Example 31 Ring to give the desired compound.
[442] Example 39
[443]
[444] According to a known process {Chem. Lett. 1998, 8, 829-830}, 3-aminopyridine was oxidized to give pyridyl N-oxide, and according to the process described in Example 28, Coupling with the compound affords the desired compound.
[445] Example 40
[446]
[447] Step A
[448] Commercially available 3-aminopyrazine instead of aniline is used and the ethoxy intermediate is obtained following the process of Preparation Example 30.
[449] Step B
[450] According to the process described in Preparation Example 1, the ethoxy intermediate of Step A was condensed with the compound of Preparation Example 19 to obtain the title compound.
[451] Examples 41 to 43
[452]
[453] Using the aromatic amines below, instead of 3-aminopyrazine, the products of Table 8 can be obtained following the process described in Example 40.
[454] TABLE 8
[455]
[456] Example 44
[457]
[458] N, N-dimethylamide (0.74 g, 4.1 mmol) of Production Example 33 and the methyl squaring derivative (0.84 g, 4.1 mmol) of Production Example 66 were combined in methanol and heated to reflux. The mixture was stirred for 96 hours. LCMS then showed the presence of the target compound. The reaction was concentrated and the product (102.6 mg, 7.31%) was isolated via HPLC purification.
[459] ¹ H NMR (300 MHz, d ₆ -DMSO) δ 2.95 (s, 6H), 6.94 (m, 2H), 7.09 (m, 1H), 7.39 (m, 2H), 7.51 (d, 2H), 7.74 ( dd, 1 H) ppm.
[460] LCMS: calculated 351.12, found 352.0 (M + 1) ⁺
[461] Examples 45-82
[462] Using the aniline of the indicated preparation example (or illustrated commercially available aniline) and the alkoxy squaring of the indicated preparation example, following the process of Example 44, the products of Table 9 were prepared. According to the aniline measured in TLC, the reaction was completed within 16 to 96 hours.
[463] TABLE 9
[464]
[465]
[466]
[467]
[468]
[469]
[470] Example 83
[471]
[472] Aniline 314 (52 mg, 0.25 mmol) of Preparation Example 46 and the ethoxy squary derivative (50 mg, 0.25 mmol) of Preparation Example 67 were combined with diisopropylethylamine (0.10 ml) in ethanol (2 ml), Heated to reflux for 16 hours. The reaction was concentrated and the product (7.2 mg, 7.4%) was isolated via HPLC purification.
[473] ¹ H NMR (300MHz, d ₆ -DMSO) δ3.04 (s, 6H), 7.02 (d, 1H), 7.20 (t, 1H), 7.48 (t, 2H), 7.59 (m, 2H), 8.03 ( d, 1H), 9.70 (s, 1H), 10.34 (s, 1H), 10.60 (s, 1H) ppm.
[474] LCMS: calculated 385.1, measured 386.0 (M + 1) ⁺
[475] Examples 84-93
[476] Using the amines of the indicated preparation example (or the illustrated commercially available aniline) and the ethoxy squaring of the indicated preparation example, the products of Table 10 were prepared according to the process of Example 83.
[477] TABLE 10
[478]
[479]
[480] Example 94
[481]
[482] The compound of Preparation Example 90 (50 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 ml). Aniline (0.017 ml, 0.19 mmol) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was recovered in acetonitrile. Filtration recovered the desired product of insoluble powder (30 mg, yield 49%).
[483] ¹ H NMR (300 MHz, d ₆ -DMSO) δ7.18 (m, 1H), 7.35 (m, 1H), 7.48 (m, 2H), 7.54 (m, 1H), 7.83 (m, 2H), 8.13 ( d, 1H), 9.95 (s, 1H), 10.86 (s, 1H), 11.50 (s, 1H) ppm.
[484] LCMS: calculated 325.0, found 326.1 (M + 1) ⁺
[485] Examples 95-105
[486] Using the aniline of the indicated preparation example (or illustrated commercially available aniline) and the chloride of the indicated preparation example, following the process of Example 94, the products of Table 11 were prepared.
[487] TABLE 11
[488]
[489]
[490]
[491] Example 107
[492]
[493] The Boc-protected compound of Example 101 (14.5 mg, 0.027 mol) was stirred in TFA / DCM (5 ml / 5 ml) for 2 hours. Simple concentration afforded the product (11.2 mg, 95%).
[494] ¹ H NMR (300 MHz, d ₆ -DMSO) δ2.08 (t, 2H), 2.82 (s, 6H), 3.18 (m, 4H), 4.40 (s, 2H), 7.43 (m, 2H), 7.58 ( d, 1H), 7.65 (d, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.18 (d, 1H), 9.18 (1H), 9.80 (m, 1H), 10.43 (s, 1H) ), 11.62 (s, 1H) ppm.
[495] LCMS: calculated 439.19, found 439.8
[496] Example 108
[497]
[498] General Process of Resin Manufacturing
[499] Resin Double-Loading
[500] Arogel (NH 2) resin (10 g, 160 μ, 0.4 mmol / g) was suspended in dichloromethane (100 ml) in a large peptide container. Bis- (Fmoc) -lysine (7.09 g, 12 mmol) and 1-hydroxybenzotriazole hydrate (1.62 g, 12 mmol) are dissolved in dichloromethane (100 ml) together with N, N-dimethylformamide (12 ml), It was added to the vessel. The vessel was shaken for 10 minutes. 1,3-Diisopropylcarbodiimide (3.76 ml, 24 mmol) was added to the vessel with frequent ventilation during the first 15 minutes of shaking. The mixture was shaken for 16 hours. The resin was filtered off and washed three times with dichloromethane, methanol and dichloromethane each. The resin was dried under vacuum.
[501] Acid-Cleavable Linker Attachment
[502] The double-loaded resin (0.9 g) was placed in a small peptide container with a 20% piperidine solution in DMF. The mixture was shaken for 2 hours and then filtered. The resin was filtered off and washed three times with N, N-dimethylformamide, methanol and dichloromethane, respectively. The resin was added with 1-hydroxybenzotriazole hydrate (0.262 g, 2 mmol) and 4- (4'-formyl-3'-methoxy) -phenoxybutyric acid (0.463 g, 2 mmol) in dichloromethane (10 ml). Suspended in a solution. The mixture was shaken for 10 minutes and then 1,3-diisopropylcarbodiimide was added with frequent ventilation for the first 15 minutes. The mixture was shaken for 16 hours. The resin was filtered off and washed three times with dichloromethane, methanol and dichloromethane each. The resin was dried under vacuum.
[503] Step A
[504] The prepared resin (1 g) was suspended with dichloroethane (10 ml) and sodium triacetoxyborohydride (1.1 g, 5 mmol) in a small peptide container. o-anisidine (0.564 ml, 5 mmol) was added and the mixture was shaken for 16 h. The resin was filtered off and washed sequentially with methanol, dichloromethane, methanol and dichloromethane twice each.
[505] Step B
[506] Squaryl chloride (0.690 g, 4.6 mmol) was dissolved in tetrahydrofuran (10 ml) and added to the resin of step A. The mixture was shaken overnight and washed sequentially with dichloromethane, acetonitrile and dichloromethane twice each.
[507] Step C
[508] The resin of step B was suspended with N, N-diisopropylethylamine (0.35 ml, 2 mmol) and 2-amino-5-nitrophenol (0.308 g, 2 mmol) in tetrahydrofuran (4 ml). The mixture was shaken for 16 hours. The resin was filtered off and washed three times with dichloromethane, methanol and dichloromethane each. For cleavage, the resin was suspended in 90% trifluoroacetic acid / dichloromethane with stirring for 6 hours. The resin was filtered off, treated with acetonitrile and then discarded. The filtrate and washings were concentrated to give the desired pure product (11.6 mg, yield 26%).
[509] ¹ H NMR (300MHz, d ₆ -DMSO) δ4.01 (s, 3H), 7.08 (m, 1H), 7.22 (m, 2H), 7.62 (d, 1H), 7.81 (s, 1H), 7.88 ( dd, 1H), 8.09 (d, 1H), 10.33 (s, 1H), 10.42 (s, 1H), 11.38 (s, 1H) ppm.
[510] Mass spectrum-found: 355.1, measured: 356.0 (M + 1) ⁺
[511] Preparation Examples 109-120
[512] In accordance with the process of Example 108, the products of Table 12 below were prepared using the commercially available aniline or amine of the indicated preparation example or the amine or the aniline of step C (or illustrated commercially available aniline) Here, the yield (<50 mg resin) in small scale manufacture is not accurate, and is described as "NA" in the following table}.
[513] TABLE 12
[514]
[515]
[516]
[517] Example 123
[518]
[519] According to the process described in Example 1, the compound of Preparation Example 26 was reacted with the compound of Preparation Example 30 to obtain the above product.
[520] Example 124
[521]
[522] According to the process described in Example 1, the compound of Preparation Example 27 was reacted with the compound of Preparation Example 30 to obtain the above product.
[523] Example 125
[524]
[525] According to the process described in Example 1, the compound of Preparation Example 28, Step B or the Compound of Preparation Example 29, Step E is reacted with the compound of Preparation Example 30 to obtain the above product.

权利要求:
Claims (38)
[1" claim-type="Currently amended] A compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:
Formula I

Where
A is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;

R ² is hydrogen, OH, C (O) OH, SH, SO ₂ NR ⁷ R ⁸ , NHC (O) R ⁷ , NHSO ₂ NR ⁷ R ⁸ , NHSO ₂ R ⁷ , C (O) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , OR ¹³ or substituted or unsubstituted heterocyclic acid functional group;
R ³ and R ⁴ are the same or different; Independently of each other hydrogen, halogen, alkoxy, OH, CF ₃ , OCF ₃ , NO ₂ , C (O) R ⁷ , C (O) OR ⁷ , C (O) NR ⁷ R ⁸ , SO _(t) NR ⁷ R ⁸ , SO _(t) R ⁷ , C (O) NR ⁷ OR ⁸ , , Cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R ⁵ and R ⁶ are the same or different; Independently of each other hydrogen, halogen, alkyl, alkoxy, CF ₃ , OCF ₃ , NO ₂ , C (O) R ⁷ , C (O) OR ⁷ , C (O) NR ⁷ R ⁸ , SO _(t) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , cyano, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group;
R ⁷ and R ⁸ are the same or different; Independently from each other hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, carboalkylalkyl, aminoalkyl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heteroalkylaryl;
R ⁷ , R ⁸ , and N of NR ⁷ R ⁸ and NR ⁷ OR ⁸ may form a 3 to 7 membered ring with each other, the ring having 1 to 3 additional heteroatoms as ring atoms on the ring; It may further include, wherein the ring may be substituted or unsubstituted with one or more residues, each residue is the same or different, hydroxy, cyano, carboxy, hydroxyalkyl, alkoxy, COR ⁷ R ⁸ or amino Independently selected from alkyl;
R ⁹ and R ¹⁰ are the same or different; Independently of each other hydrogen, halogen, CF ₃ , OCF ₃ , NR ⁷ R ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , OH, C (O) OR ⁷ , SH, SO _(t) NR ⁷ R ⁸ , SO ₂ R ⁷ , NHC (O) R ⁷ , NHSO ₂ NR ⁷ R ⁸ , NHSO ₂ R ⁷ , C (O) NR ⁷ R ⁸ , C (O) NR ⁷ OR ⁸ , OR ¹³ , or substituted or unsubstituted Heterocyclic acid functional groups;
R ¹³ is COR ⁷ ;
R ¹⁵ is hydrogen, OR ¹³ , substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted arylalkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted alkyl group;
t is 1 or 2.
[2" claim-type="Currently amended] The method of claim 1,


R ¹¹ and R ¹² are the same or different; Independently of each other H, OH, halogen, cyano, CF ₃ , CF ₃ O, NR ⁷ R ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , CO ₂ R ⁷ , OR ⁷ , SO _(t) NR ⁷ R ⁸ , NR ⁷ SO _(t) R ⁸ , COR ⁷ , substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, alkylaminoCOOalkyl , Aminoalkoxy, alkoxyaminoalkyl and substituted or unsubstituted aminoalkyl, compounds, prodrugs thereof, pharmaceutically acceptable salts, solvates or isomers of said compounds or prodrugs.
[3" claim-type="Currently amended] The method of claim 1,
R ² is hydrogen, OH, NHC (O) R ⁷ or NHSO ₂ R ⁷ ;
R ³ is SO ₂ NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , SO ₂ R ⁷ , NO ₂ or cyano;
R ⁴ is H, NO ₂ , CF ₃ or cyano;
R ⁵ is H, halogen, NO ₂ , cyano or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[4" claim-type="Currently amended] The method of claim 2,

A compound, prodrug thereof, pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug.
[5" claim-type="Currently amended] The method of claim 2,
R ² is hydrogen, OH, NHC (O) R ⁷ or NHSO ₂ R ⁷ ;
R ³ is SO ₂ NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , SO ₂ R ⁷ , NO ₂ or cyano;
R ⁴ is H, NO ₂ , CF ₃ or cyano;
R ⁵ is H, halogen, NO ₂ , cyano or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[6" claim-type="Currently amended] The method of claim 4, wherein
R ² is hydrogen, OH, NHC (O) R ⁷ or NHSO ₂ R ⁷ ;
R ³ is SO ₂ NR ⁷ R ⁸ , C (O) NR ⁷ R ⁸ , SO ₂ R ⁷ , NO ₂ or cyano;
R ⁴ is H, NO ₂ , CF ₃ or cyano;
R ⁵ is H, halogen or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[7" claim-type="Currently amended] The method of claim 3,
R ² is OH or NHSO ₂ R ⁷ ;
R ³ is C (O) NR ⁷ R ⁸ , NO ₂ or cyano;
R ⁴ is H, NO ₂ or cyano;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[8" claim-type="Currently amended] The method of claim 7, wherein
R ² is OH;
R ³ is C (O) NR ⁷ R ⁸ ;
R ⁴ is H;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H, a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[9" claim-type="Currently amended] The method of claim 5,
R ² is OH or NHSO ₂ R ⁷ ;
R ³ is C (O) NR ⁷ R ⁸ , NO ₂ or cyano;
R ⁴ is H, NO ₂ or cyano;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[10" claim-type="Currently amended] The method of claim 6,
R ² is OH or NHSO ₂ R ⁷ ;
R ³ is C (O) NR ⁷ R ⁸ , NO ₂ or cyano;
R ⁴ is H, NO ₂ or cyano;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H or CF ₃ , a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[11" claim-type="Currently amended] The method of claim 9,
R ² is OH;
R ³ is C (O) NR ⁷ R ⁸ ;
R ⁴ is H;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H, a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[12" claim-type="Currently amended] The method of claim 10,
R ² is OH;
R ³ is C (O) NR ⁷ R ⁸ ;
R ⁴ is H;
R ⁵ is H, Cl or CF ₃ ;
R ⁶ is H, a compound, a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of the compound or prodrug.
[13" claim-type="Currently amended] The method of claim 1,
A and B are compounds, prodrugs thereof, pharmaceutically acceptable salts, solvates or isomers of the compounds or prodrugs, as described in the table below:



[14" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[15" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[16" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[17" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[18" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[19" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[20" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[21" claim-type="Currently amended] The compound according to claim 13, wherein the compound of formula: a prodrug thereof, a pharmaceutically acceptable salt, solvate or isomer of said compound or prodrug:

[22" claim-type="Currently amended] A compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of a compound of claim 1 or a prodrug thereof; And a pharmaceutically acceptable carrier.
[23" claim-type="Currently amended] CXCR2 of a mammal, wherein the chemokine comprises administering to a patient a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of the compound of claim 1 or a prodrug thereof, and And / or a method of treating chemokine mediated disease that binds to the CXCR1 receptor.
[24" claim-type="Currently amended] The CXC receptor of a mammalian chemokine comprising administering to a patient a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of the compound of claim 1 or a prodrug thereof. A method of treating chemokine mediated disease that binds to.
[25" claim-type="Currently amended] The method of claim 23, wherein the chemokine mediated disease is psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pulmonary shock, endotoxin shock, Gram-negative pulmonary sepsis, toxic shock syndrome, seizures, heart and kidney reperfusion injury, glomerulonephritis or thrombosis, Alzheimer's disease, graft-to-host response, allograft rejection, malaria, acute respiratory distress syndrome, delayed hypersensitivity reactions, atherosclerosis, and Brain and cardiac ischemia.
[26" claim-type="Currently amended] A method of treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of the compound of claim 1 or a prodrug thereof.
[27" claim-type="Currently amended] 27. The method of claim 26, further comprising administering at least one anticancer agent and / or radiation.
[28" claim-type="Currently amended] The method of claim 27, wherein the anticancer agent is selected from the group consisting of alkylating agents, anti-metabolic agents, natural products and derivatives thereof, hormones, anti-hormones, anti-angiogenesis agents, steroids and synthetics.
[29" claim-type="Currently amended] An eye comprising administering to a patient an amount of a compound that exhibits an anti-angiogenetic effect, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of the compound of claim 1 or a prodrug thereof. How to suppress geogenesis.
[30" claim-type="Currently amended] The method of claim 29, further comprising administering at least one known anti-angiogenesis agent to the patient.
[31" claim-type="Currently amended] 31. The method of claim 30, wherein the known anti-angiogenesis formulations are marimastat, AG3340, Col-3, neovastat, BMS-275291, thalidomide, squalane, endostatin, SU-5416, SU-6668, Interferon-alpha, anti-VEGF antibody, EMD121974, CAI, interleukin-12, IM862, platelet factor-4, bitaxin, angiostatin, suramine, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566 , CGS27023A, VEGF receptor kinase inhibitor, taxotere and taxol.
[32" claim-type="Currently amended] Gingivitis, respiratory virus, herpes, comprising administering to a patient a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate or isomer of the compound of claim 1 or a prodrug thereof A method of treating a disease selected from the group consisting of virus, hepatitis virus, HIV, Kaposi's sarcoma-associated virus and atherosclerosis.
[33" claim-type="Currently amended] 24. The method of claim 23, wherein the chemokine mediated disease is angiogenesis eye disease.
[34" claim-type="Currently amended] 34. The method of claim 33, wherein the angiogenic eye disease is selected from the group consisting of ocular inflammation, prematurity retinopathy, diabetic retinopathy, macular (preferably wet) degeneration and corneal neovascularization.
[35" claim-type="Currently amended] The method of claim 26, wherein the cancer tumor type is melanoma, gastrointestinal cancer, or non-small cell lung cancer.
[36" claim-type="Currently amended] 36. The method of claim 35, further comprising administering at least one anticancer agent and / or radiation.
[37" claim-type="Currently amended] The method of claim 36, wherein the anticancer agent is selected from the group consisting of alkylating agents, anti-metabolic agents, natural products and derivatives thereof, hormones, anti-hormones, anti-angiogenesis agents, steroids and synthetics.
[38" claim-type="Currently amended] 38. The anti-angiogenic agent of claim 37, wherein the anti-angiogenesis agent is marimastat, AG3340, Col-3, neovastat, BMS-275291, thalidomide, squalane, endostatin, SU-5416, SU-6668, interferon- Alpha, anti-VEGF antibody, EMD121974, CAI, interleukin-12, IM862, platelet factor-4, nontaxin, angiostatin, suramin, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566, CGS27023A , VEGF receptor kinase inhibitor, taxotere and taxol.

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同族专利:

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公开号 | 公开日

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NO20033424L|2003-09-30|

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RU2003126913A|2005-03-10|

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ZA200305881B|2005-01-26|

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JP2004529911A|2004-09-30|

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NO20033424D0|2003-07-31|

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EP1355875A1|2003-10-29|

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SK9782003A3|2004-01-08|

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MXPA03006950A|2003-11-18|

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HU0304047A2|2004-04-28|

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CA2436351A1|2002-10-03|

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US20030097004A1|2003-05-22|

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BR0206968A|2004-03-09|

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ECSP034712A|2003-09-24|

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IL156793D0|2004-02-08|

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NZ527947A|2005-10-28|

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WO2002076926A1|2002-10-03|

---

CZ20032098A3|2004-01-14|

---

AU2002303084B2|2006-05-25|

---

CN1575273A|2005-02-02|

---

PL367534A1|2005-02-21|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-02-02|Priority to US26595101P

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2001-02-02|Priority to US60/265,951

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2002-02-01|Application filed by 쉐링 코포레이션, 파마코페이아, 인크.

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2002-02-01|Priority to PCT/US2002/002888

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2003-11-28|Publication of KR20030090629A

优先权:

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申请号 | 申请日 | 专利标题

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US26595101P| true| 2001-02-02|2001-02-02|

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US60/265,951|2001-02-02|

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PCT/US2002/002888|WO2002076926A1|2001-02-02|2002-02-01|3,4-di-substituted cyclobutene-1, 2-diones as cxc chemokine receptor antagonists|