THETWO TONTTI TUNUS 20170313706A1 MAHTUMAN MITTELHAN ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0313706 A1 YAMAMOTO et al. (43 ) Pub . Date : Nov . 2 , 2017 ( 54 ) PURINONE DERIVATIVE (30 ) Foreign Application Priority Data HYDROCHLORIDE Nov . 29 , 2011 ( JP ) ...... 2011 - 259662 (71 ) Applicant: ONO PHARMACEUTICAL CO ., LTD . , Osaka ( JP ) Publication Classification (51 ) Int . CI. ( 72 ) Inventors : Shingo YAMAMOTO , Osaka ( JP ) ; C07D 473 /34 ( 2006 .01 ) Toshio YOSHIZAWA , Osaka (JP ) A61K 31/ 522 (2006 . 01 ) C07D 473 /00 ( 2006 .01 ) (73 ) Assignee : ONO PHARMACEUTICAL CO ., ( 52) U . S . CI. LTD . , Osaka ( JP ) CPC ...... C07D 473 /34 (2013 .01 ); C07D 473 /00 (21 ) Appl. No. : 15 /653 ,614 ( 2013. 01 ) ; A61K 31/ 522 (2013 .01 ) ; COZB 2200 /13 ( 2013 .01 ) ( 22 ) Filed : Jul. 19 , 2017 (57 ) ABSTRACT Related U . S . Application Data The purinone derivative 6 -amino - 9 - [ ( 3R ) - 1 - ( 2 - butynoyl) - 3 (60 ) Division of application No . 15 / 158 ,993 , filed on May pyrrolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro -8H - purin 19, 2016 , which is a continuation of application No. 8 -one hydrochloride has Btk - selective inhibitory activity 14 / 737 ,595 , filed on Jun . 12 , 2015 , now Pat. No . and , in addition to having excellent metabolic stability , it is 9 ,371 , 325 , which is a continuation of application No . a compound that exhibits a high level of solubility and 14 / 360 , 725 , filed on May 27 , 2014 , now Pat. No . absorption with respect to the free base and can be crystal 9 ,199 ,997 , filed as application No . PCT /JP2012 / lized , hence it can serve as a therapeutic agent for diseases 080769 on Nov . 28 , 2012 . involving B cells and mast cells . PatentPatent Application Publication Nov. 2 , 2017 Sheet 1 of 3 US 2017 / 0313706 A1
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PURINONE DERIVATIVE ( in the formula , L4 represents CH , O , NH , or S ; Art HYDROCHLORIDE represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; Y4 represents any substituent TECHNICAL FIELD selected from alkyl, heteroalkyl, cycloalkyl , heterocy [0001 ] The present invention relates to 6 - amino - 9 -[ ( 3R ) cloalkyl , aryl, and heteroaryl ; Z4 represents CO , OCO , 1 - ( 2 - butynoyl) - 3 - pyrrolidinyl] - 7 - ( 4 - phenoxyphenyl ) - 7 , 9 NHCO , or CS ; R7- 4 and R8- 4 each independently represent dihydro - 8H -purin - 8 - one hydrochloride (hereinafter , referred H , unsubstituted C , -C4 alkyl, substituted C , -C4 alkyl , to as the compound of the present invention ), which has Btk unsubstituted C1 -C4 heteroalkyl, substituted C1- C4 het inhibitory activity and is useful as a therapeutic agent for eroalkyl, unsubstituted Cz -Co cycloalkyl, substituted Cz- Co autoimmune diseases , cancer , and the like ; crystals thereof ; cycloalkyl, unsubstituted C2 -C6 heterocycloalkyl, and sub and a pharmaceutical composition containing the same. stituted C2- C6 heterocycloalkyl; or R7- 4 and R8- 4 together form a bond ; and R6- 4 represents H , substituted or unsub BACKGROUND ART stituted C , -C4 alkyl, substituted or unsubstituted C , -C4 [0002 ] Bruton ' s tyrosine kinase ( abbreviated below as heteroalkyl, C , - C alkoxyalkyl, C / - Cg alkylaminoalkyl, sub “ Btk ” ) belongs to the Tec family of kinases , which are stituted or unsubstituted Cz - Co cycloalkyl, or substituted or non - receptor tyrosine kinases , and is selectively expressed unsubstituted aryl (the definitions of these groups have been in the B cell and myelocyte lines . Btk plays an important role excerpted )) (refer to Patent Documents 1 , 2, and 3 ). in signal transduction in B cells and is a factor that contrib [ 0005 ] On the other hand , for example , compounds rep utes to the survival, differentiation , proliferation , and acti resented by general formula ( B ) vation of B cells . Signaling in B cells via the B cell antigen receptor (BCR ) induces a broad range of biological responses , and abnormal signal transduction here causes [C 2] abnormal B cell activation and the formation of pathogenic (B ) autoantibodies . Btk is believed to form a link in the BCR R4B mediated signal transduction pathways into B cells . Thus, (CR2BR3BvB X - linked agammaglobulinemia (XLA ) is known to be caused by a defect in the human Btk gene that results in the induction of abnormal B cell differentiation and a drastic decline in immunoglobulin production ( refer to Non - patent Document 1 ) . The symptoms of this disease include a substantial decline in B cells in the peripheral blood and an RIB RSB increased susceptibility to bacterial infections. Btk is also known to participate in mast cell activation and in the physiological functions of platelets . Due to this , compounds (in the formula , QlB and Q2B are independently selected that have a Btk inhibitory activity are effective for the from CX1B , CX2B, and nitrogen ; Q3B represents N or CH ; treatment of diseases in which B cells or mast cells partici X1B and X2B are independently selected from the group pate , for example , allergic diseases , autoimmune diseases , consisting of hydrogen , ( C , -Co ) alkyl, cyano , halogen , and inflammatory diseases, thromboembolic diseases, and can so forth ; RIB is selected from the group consisting of cers (refer to Non - patent Document 2 ) . hydrogen and (C .- C . ) alkyl; y? represents 0 or an integer [ 0003] The following compounds are known as prior art from 1 to 3 ; R2B and R3B are independently selected from for the compounds of the present invention . hydrogen and (C , -C .) alkyl ; R4B is selected from the group [0004 ) Compounds represented by general formula ( A ) consisting of alkyl, heterocyclyl, aryl, heteroaryl, and so are known as compounds that have a Btk inhibitory activity forth ; and RSB is selected from the group consisting of alkyl, heterocyclyl, and substituted heterocyclyl ( the definitions of these groups have been excerpted ) ) ( refer to Patent Docu [C1 ] ment 4 ) are known as compounds that have a purinone ( A ) skeleton . AM [ 0006 ] Compounds represented by general formula ( C ) are L. 4 also known
[C3 ] NH2 04C bec VO SO10 R6- 4 R2CR2CN
R8- 4 R7- 4 US 2017 /0313706 A1 Nov . 2 , 2017
( in the formula , Xº is selected from the group consisting of 16 .64 , 18 .06 , 19 .74 , 20 .42 , 21. 05 , 22 . 57 , 23 . 21, 23 . 85 , nitrogen and CR8C ; R & C is selected from the group consist and 24 .70 degrees in a powder X - ray diffraction spectrum ; ing of hydrogen , halogen , substituted or unsubstituted alkyl, [0023 ] [ 4 ] The crystal as in [ 2 ] or [ 3 ] above having peaks and so forth ; Q1C is selected from the group consisting of O , at angle 20 of approximately 8 .11 , 8 .43 , 14 .20 , 14 .67 , S , and so forth ; Zº is selected from the group consisting of 14 .91 and 23. 21 degrees in a powder X - ray diffraction oxygen , sulfur, and NYSC ; YSC is selected from the group spectrum ; consisting of hydrogen , substituted or unsubstituted alkyl, [0024 ] [ 5 ] The crystal as in any of [ 2 ] to [ 4 ] above having and so forth ; Q2C , Q3C , and Q4C are independently selected peaks at angle 20 selected from approximately 8 . 11 , 8 . 43 , from the group consisting of hydrogen , substituted or unsub 11 .57 , 12 .73 , 13 .85 , 14 . 20 , 14 .67 , 14 .91 , 15 .94 , 16 .64 , stituted alkyl, substituted or unsubstituted aryl, and so forth ; 18 . 06 , 19 .74 , 20 . 42 , 21 . 05 , 22 . 57 , 23 . 21 , 23 . 85 , and 24 . 70 R2C is selected from the group consisting of hydrogen and degrees in a powder X - ray diffraction spectrum ; substituted or unsubstituted alkyl; and nC represents 0 , 1 , 2 , ( 0025 ] [ 6 ] The crystal as in any of [ 2 ] to [ 5 ] above which 3, or 4 ( the definitions of these groups have been excerpted )) is characterized by the powder X - ray diffraction spectral ( refer to Patent Document 5 ) . chart in FIG . 3 ; [0007 ] In addition , Patent Document 6 discloses a com [0026 ] [ 7 ] The crystal as in any of [ 2 ] to [6 ] above having pound having a purinone backbone as Formula 20 ( see an endothermic peak at a peak temperature of 216° C . in paragraph [0028 ] ). differential scanning calorimetry ; [ 0008 ] The present invention relates to 6 -amino - 9 -[ (3R )- [0027 ] [ 8 ] The crystal as in any of [2 ] to [7 ] above which 1 - ( 2 - butynoyl) - 3 -pyrrolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 is characterized by the differential scanning calorimetry dihydro - 8H -purin - 8 - one hydrochloride, which has Btk - se chart in FIG . 4 ; lective inhibitory activity , and in addition to excellent [0028 ] [ 9 ] A pharmaceutical composition comprising metabolic stability , has greater solubility and absorption 6 -amino - 9 - [ ( 3R ) - 1 - ( 2 -butynoyl ) - 3 - pyrrolidinyl ] - 7 - ( 4 than the free base ; such matters are neither described nor phenoxyphenyl) - 7, 9 - dihydro - 8H -purin -8 -one hydrochlo suggested by the prior art documents . ride; 10009 ) Patent Document 1 : Japanese Translation of PCT [0029 ] [ 10 ] The pharmaceutical composition as in [ 9 ] Application No. 2010 -504324 above that is a Btk inhibitor ; [ 0010 ] Patent Document 2 : WO 2008 / 121742 [0030 ] [ 11 ] The pharmaceutical composition as in [ 10 ] 10011 ] Patent Document 3 : WO 2010 /009342 above that is an agent for the prevention and /or treatment [ 0012 ] Patent Document 4 : WO 2008 /060301 of a Btk -related disease ; 10013 ] Patent Document 5 : WO 2007 / 142755 [0031 ] [ 12 ] The pharmaceutical composition as in [ 11 ] [0014 ] Patent Document 6 : Japanese Translation of PCT above wherein the Btk - related disease is an allergic dis Application No . 2003 -509427 ease , autoimmune disease , inflammatory disease , throm [0015 ] Non - Patent Document 1 : Nature, Vol. 361 , pages boembolic disease , bone - related disease , or cancer ; and 226 - 233 , 1993 [0032 ] [ 13 ] The pharmaceutical composition as in [12 ] [ 0016 Non - Patent Document 2 : Anticancer Agents in above wherein the cancer is non -Hodgkin ' s lymphoma , Medicinal Chemistry , Vol. 7 , No . 6 , pages 624 -632 , 2007 etc . [0033 ] The compound of the present invention has Btk DISCLOSURE OF THE INVENTION selective inhibitory activity , and in addition to having excel [0017 ]. The problem to be solved by the present invention lent metabolic stability , is a compound with greater solubil is the development of a compound that has Btk - selective ity and absorption than the free base; therefore , it is useful inhibitory activity, and in addition to excellent metabolic as an outstandingly safe therapeutic agent for a disease stability , has greater solubility and absorption than the free involving B cells and mast cells such as non -Hodgkin ' s base in order to provide a very stable agent for the treatment lymphoma. of a disease involving B cells and mast cells. In addition , a compound that has excellent stability as the active ingredient BRIEF DESCRIPTION OF THE DRAWINGS of a pharmaceutical product and that can be crystalized to [ 0034 ] FIG . 1 shows a powder x -ray diffraction spectral enable long - term storage is preferred . chart of a crystal of 6 - amino - 9 -[ ( 3R )- 1 - ( 2 - butynoyl) - 3 - pyr [ 0018 ] As the result of their diligent and incisive research rolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro - 8H -purin - 8 to solve the aforementioned problem , the inventors discov one ( in FIG . 1 , the vertical axis represents intensity ( counts ) , ered that the compound of the present invention has Btk and the horizontal axis represents 20 ( degrees )) ; selective inhibitory activity, and in addition to excellent [0035 ] FIG . 2 shows a differential scanning calorimetry metabolic stability , has greater solubility and absorption (DSC ) chart of a crystal of 6 - amino - 9 - [ (3R ) - 1 - ( 2 -butynoyl ) than the free base , and can be crystallized , thereby complet 3 -pyrrolidinyl ]- 7 -( 4 -phenoxyphenyl ) - 7 ,9 - dihydro -8H -pu ing the present invention . rin - 8 -one ; [0019 ] More specifically , the present invention relates to : [ 0036 ] FIG . 3 shows a powder x -ray diffraction spectral [ 0020 ] [ 1 ] 6 - amino - 9 - [ ( 3R ) - 1 - ( 2 -butynoyl ) - 3 -pyrrolidi chart of a crystal of 6 - amino - 9 - [ (3R ) - 1 - ( 2 -butynoyl ) - 3 - pyr nyl] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro - 8H -purin - 8 - one rolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro -8H -purin - 8 hydrochloride; one hydrochloride ( in FIG . 3 , the vertical axis represents [0021 ] [ 2 ] A crystal of 6 -amino - 9 - [ (3R ) - 1 - ( 2 -butynoyl ) - 3 intensity ( counts ) , and the horizontal axis represents 20 pyrrolidinyl] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro - 8H -pu ( degrees ) ) ; and rin - 8 - one hydrochloride ; [0037 ] FIG . 4 shows a differential scanning calorimetry [0022 ] [3 ] The crystal as in [ 2 ] above having at least 2 or (DSC ) chart of a crystal of 6 - amino - 9 - [ ( 3R ) - 1 - ( 2 - butynoyl) more peaks at angle 20 selected from approximately 8 . 11 , 3 -pyrrolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 -dihydro - 8H - pu 8 .43 , 11. 57 , 12. 73 , 13 . 85, 14 . 20 , 14 .67 , 14 .91 , 15 . 94 , rin - 8 -one hydrochloride . US 2017 /0313706 A1 Nov . 2 , 2017
BEST MODE FOR CARRYING OUT THE [0043 ] [ 1 ] Powder X - ray Diffraction Spectrum INVENTION 0044 ] < Measurement Conditions > [ 0045 ] Device : BRUKER D8 DISCOVER with GADDS [0038 ] The present invention is described in greater detail manufactured by Bruker AXS below . [0046 ] Target: Cu [0039 ] The term “ Btk -selective inhibitory activity ” means 10047 ) Filter : None Btk - selective inhibitory activity with regard to tyrosine [0048 ] Voltage: 40 kV kinases other than Btk , particularly Lck , Fyn , and LynA . [0049 ] Current: 40 mA Due to this property , unexpected adverse reactions caused by [0050 ] Exposure time: 3 min inhibiting other tyrosine kinases can be avoided . [ 0051 ] [ 2 ] Differential Scanning calorimetry (DSC ) [0040 ] In the present invention 6 -amino - 9- [( 3R )- 1 -( 2 -bu 10052 ]
TABLE 2 -continued Example 9 is shown in FIG . 3 , and the differential scanning calorimetry (DSC ) chart is shown in FIG . 4 . Moreover, Acidic counter- ion Step ( 1) Step (2 ) Table 3 below shows the diffraction angle 20 and the relative Succinic acid Oil Crystals intensity in the powder X - ray diffraction spectrum . Among Methanesulfonic acid Amorphous Oil these , the 20 angles showed characteristic peaks at 8 . 11 , p - toluenesulfonic acid Amorphous Oil 8 .43 , 14 . 20 , 14. 67 , 14 .91 , and 23. 21 degrees. Benzenesulfonic acid Amorphous Oil ( - ) - camphorsulfonic acid Amorphous Oil ( + ) -camphorsulfonic acid Amorphous Oil TABLE 3 2 -naphthalenesulfonic acid Oil Oil 1 - hydroxy - 2 - naphthoic acid Oil Crystals Diffraction angle 20 (degrees ) Relative intensity (% ) Benzoic acid Oil Crystals Nicotinic acid Nicotinic acid Crystals 8 . 11 21. 8 crystals 8 . 43 20 . 6 11 . 57 52 12 . 73 19 . 1 13 . 85 30 . 4 [ 0061] As a result, any crystals did not form a precipitate 14 . 20 45 . 3 in step ( 1 ) , meanwhile although crystals were obtained from 14 .67 33 . 4 10 species of acidic counter- ions (acetic acid , citric acid , 14 . 91 49 . 8 15 . 94 35 . 1 ( + ) - tartaric acid , phosphoric acid , fumaric acid , lactic acid , 16 .64 14 succinic acid , 1 -hydroxy - 2 - naphthoic acid , benzoic acid , 18 . 06 15 and nicotinic acid ) in step ( 2 ) , these crystals all matched the 19 . 74 38 . 7 powder X -ray diffraction spectral chart of the crystal of 20 .42 100 21. 05 32 . 6 Compound A , so it was clear that no salts were formed 22 . 57 32 . 4 thereby . On the other hand , a crystalline powder was not 23 .21 46 . 7 obtained from the remaining 8 species of acidic counter - ions 23 .85 48 . 6 (hydrochloric acid , sulfuric acid , methanesulfonic acid , 24 .70 29 . 3 p - toluenesulfoinic acid , benzenesulfonic acid , ( - ) -camphor sulfonic acid , ( + ) - camphorsulfonic acid and 2 - naphthalene [0065 ] Moreover , as shown in FIG . 4 , the crystals of the sulfonic acid ), but because crystals of Compound A did not compound prepared in Example 9 showed endothermic precipitate , it appeared that salts had been formed . As a peaks corresponding to melting represented by an onset result, the following crystallization study was carried out on temperature of approximately 201° C . and a peak tempera these 8 species of acidic counter -ions . ture of approximately 216° C . [0062 ] [Crystallization Study of Salts of Compound A ] [0066 ] [ Isomers ] [0063 ] A crystallization study of the salts of Compound A [ 0067 ] The compound of the present invention can be was carried out with an automatic crystallization device either a 100 % pure optical isomer , or it can contain less than ( Core Module X manufactured by Freeslate , Inc . ) using 50 % of other optical isomers . sulfuric acid , methanesulfonic acid , benzenesulfonic acid , [0068 ] It is apparent to persons skilled in the art that , and p -toluenesulfonic acid as the acidic counter - ions , and unless otherwise stated , in the present invention the symbol methanol, 2 - propanol, acetone , toluene , ethyl acetate , acetonitrile , MTBE , and n - pentane as the solvents . For the crystallization methods, four conditions were established , [Chemical Formula 6 ] i. e . the slurry method (50° C ., natural cooling to room temperature ), the chilling method (50° C . to 10° C ., decrease of - 10° C ./ hour ) , precipitation method ( dissolution at 50° C . followed by precipitation at room temperature ) , and the evaporation enrichment method (dissolution at 50° C . fol represents bonding in the direction of the viewer of the page lowed by evaporation at room temperature ) , and by com ( i . e . the B position ) , and bining the solvent and crystallization methods a total of 72 crystallization conditions were established for each salt . As a result , however, a crystalline powder could not be obtained Chemical Formula 71 from any of the salts. [0064 ] On the other hand , when a similar crystallization study was carried out using hydrochloric acid as the acidic counter - ion , if 1 , 2 - dimethoxy ethane (DME ) was used as the represents the a position, ß position , or a mixture thereof in solvent a crystalline powder was obtained . When a powder any ratio . X -ray diffraction measurement of the said crystalline powder [0069 ] The compound of the present invention can be was performed under the aforementioned conditions , the converted to a solvate . The solvate preferably has low peak shape was different from that of the crystals of Com toxicity and is water soluble . For example , a solvate of water pound A , and the results of ' H - NMR and elemental analysis or an alcohol system ( e . g . ethanol, etc . ) can be noted as a revealed these crystals were the hydrochloride of Compound suitable solvate . A . Moreover , it was learned that because the powder X - ray [0070 ] Moreover , the term “ prodrug” of the compound of diffraction spectral patterns match , crystals of the hydro - the present invention refers to a compound that is converted chloride of Compound A can be obtained even with the to the compound of the present invention in vivo by reacting method of Example 9 below . The powder X - ray diffraction with an enzyme, gastric acid , and the like . For example , if spectrum of the crystals of the compound prepared in the compound of the present invention has an amino group , US 2017 /0313706 A1 Nov . 2 , 2017 a prodrug thereof can include a compound wherein the carditis , myositis , nephritis , oophoritis , orchitis , osteitis , amino group is acylated , alkylated , phosphorylated , and so pancreatitis , parotitis , pericarditis , peritonitis , pharyngitis , on ( e . g . a compound wherein the amino group of the pleuritis , phlebitis , pneumonia , proctitis , prostatitis , pyelo compound of the present invention is eicosanoylated , ala nephritis , rhinitis , salpingitis , sinusitis , stomatitis , synovitis , nylated , pentylaminocarbonylated , (5 -methyl - 2 -oxo - 1, 3 -di tendinitis , tonsillitis , uveitis , vaginitis , vasculitis , vulvitis , oxolen - 4 - yl) , methoxy carbonylated , tetrahydrofuranylated , and the like . pyrrolidinylmethylated , pivaloyloxymethylated , acetoxym [0078 ] Examples of a thromboembolic disease in the pres ethylated , tert - butylated , etc . ) These compounds can be ent invention include myocardial infarction , angina pectoris , produced by publicly known methods. Moreover , a prodrug reocclusion after angioplasty , restenosis after angioplasty , of the present invention can be either a hydrate or a reocclusion after aortocoronary bypass , restenosis after aor non -hydrate . In addition , a prodrug of the invention of the tocoronary bypass, cerebral infarction , transient ischemia , present invention can be one that converts into the com peripheral vascular occlusive disease , pulmonary embolism , pound of the present invention under physiological condi deep vein thrombosis , and the like . tions as described in “ Iyakuhin no Kaihatsu ” Dai 7 kan , 100791. Examples of a bone -related disease in the present “ Bunshi Sekkei, ” pages 163- 198 , Hirokawa Shoten 1990 invention include osteoporosis , periodontitis , metastasis of [ Drug Development” Vol. 7 , “ Molecular Design ,” pages cancer to bone , osteoarthritis, hypercalcemia , bone frac 163- 198 , Hirokawa Shoten , 1990 ) . Furthermore , the com tures , Behcet' s disease , and the like . pound of the present invention can be labeled with an [ 0080 ] Examples of cancer in the present invention isotope (e . g . 2H , 3H , 110 , 13C , 14C , 13N , 15N , 150 , 170 , 180 , include non - Hodgkin ' s lymphomas, and among those B cell 355, 18F, 36C1, 1231, 1251, etc . ) non -Hodgkin ' s lymphoma is most applicable , for example , [ 0071] [ Toxicity ] Burkitt 's lymphoma, AIDS- related lymphoma, marginal [0072 ] The toxicity of the compound of the present inven zone B - cell lymphoma (nodal marginal zone B cell lym tion is low enough that it can be used safely as a pharma phoma, extranodalmarginal zone B -cell lymphoma, splenic ceutical product. marginal zone B -cell lymphoma) , diffuse large B -cell lym [ 0073 ] [Application in a Pharmaceutical Product ] phoma, primary effusion lymphoma, lymphoma- like granu [0074 ] Because the compound of the present invention lomatous disease, follicular lymphoma, B - cell chronic lym selectively inhibits Btk , it is useful as an agent for the phocytic leukemia , B cell prolymphocytic leukemia , prevention and/ or treatment of diseases that involve Btk , i . e . lymphoplasmacytic leukemia /Waldenstrom ’ s macroglobu diseases that involve B cells and mast cells , for example , linemia , plasmacytoma, mantle cell lymphoma, mediastinal allergic diseases , autoimmune diseases, inflammatory dis large B - cell lymphoma, intravascular large B - cell lym eases , thromboembolic diseases , bone - related diseases , can phoma, and hairy cell leukemia . Moreover, examples of cer, graft - versus- host disease, and the like. Moreover , cancer in the present invention include cancers other than because the compound of the present invention has the effect non -Hodgkin ' s lymphoma such as pancreatic endocrine of selectively inhibiting B cell activation , it is useful as a B tumors and multiple myeloma. Examples of pancreatic cell activation inhibitor. endocrine tumors include insulinoma , gastrinoma , gluca [0075 ] Examples of an allergic disease in the present gonoma, somatostatinoma, VIP -producing tumor (VIPoma ) , invention include allergy , anaphylaxis , allergic conjunctivi PP - producing tumor (PPoma ) , GRF - producing tumor, and tis , allergic rhinitis , atopic dermatitis and the like . the like . 10076 ) Examples of an autoimmune disease in the present [0081 ] The compound of the present invention can be invention include inflammatory bowel disease , arthritis , administered together with another drug as a concomitant lupus , rheumatoid arthritis , psoriatic arthritis , osteoarthritis , medication to : Still ' s disease , juvenile arthritis , type I diabetes , myasthenia gravis , Hashimoto ' s thyroiditis , Ord 's thyroiditis , Base [0082 ] ( 1 ) supplement and / or enhance the preventive and / dow ' s disease , Sjogren ' s syndrome, multiple sclerosis , Guil or therapeutic effect of the said compound ; lain -Barre syndrome, acute disseminated encephalomyelitis , [ 0083 ] ( 2 ) improve the kinetics/ absorption , or reduce the Addison disease , opsoclonus -myoclonus syndrome, ankylo dose of the said compound ; and /or sing spondylitis , antiphospholipid antibody syndrome, [ 0084 ] ( 3 ) mitigate the side effects of the said compound . aplastic anemia , autoimmune hepatitis , celiac disease , [ 0085 ] The concomitant medication that contains the other Goodpasture ' s syndrome, idiopathic thrombocytopenic pur drug , and the compound of the present invention can be pura , optic neuritis , scleroderma, primary biliary cirrhosis , administered as a formulation that combines both compo Reiter 's disease, Takayasu arteritis , temporal arteritis , warm nents therein or as a separate drug product. Administration autoimmune hemolytic anemia , Wegener granuloma, pso thereof as a separate drug product includes both adminis riasis , alopecia universalis , Burchett disease , chronic fatigue tration at the same time or administration at a different time. syndrome, dysautonomia , endometriosis , interstitial cystitis , For administration at a different time, the compound of the myotonia , vulvodynia , systemic lupus erythematosus, and present invention can be administered first followed by the the like. other drug , or the other drug can be administered first [0077 ] Examples of an inflammatory disease in the present followed by the compound of the present invention . The invention include asthma, appendicitis , blepharitis , bronchi mode of administration of each can be the same or different . olitis , bronchitis , bursitis , cervicitis , cholangitis , cholecys [0086 ] The disease for which the protective and / or thera titis , colitis , conjunctivitis , cystitis , dacryoadenitis , derma peutic effect is to be provided is not particularly limited titis , dermatomyositis , encephalitis , endocarditis , herein as long as it is a disease wherein the protective and / or endometritis , enteritis , epicondylitis , epididymitis , fasciitis , therapeutic effect of the compound of the present invention fibrositis , gastritis , gastroenteritis, hepatitis , hidradenitis is supplemented and / or enhanced by the above concomitant suppurativa , laryngitis , mastitis , meningitis , myelitis ,myo medication . US 2017 /0313706 A1 Nov . 2 , 2017
[0087 ) Other drugs that supplement and / or enhance the ride , dl- chlorpheniramine maleate , clemastine fumarate , protective and / or therapeutic effect of the compound of the ketotifen fumarate , cimetidine , dimenhyrinate , diphenhy present invention against allergic diseases include , for dramine hydrochloride , cyproheptadine hydrochloride , ceti example , antihistamines, leukotriene antagonists , anti -al rizine hydrochloride, desloratadine , terfenadine , famotidine , lergy drugs, thromboxane A2 receptor antagonist, throm fexofenadine hydrochloride, bepotastine , bepotastine besi boxane synthetase inhibitors , steroids and the like . late , mizolastine , mequitazine , mometasone furoate , raniti [ 0088 ] Other drugs that supplement and /or enhance the dine, ranitidine hydrochloride , loratadine, promethazine protective and / or therapeutic efficacy of the compound of hydrochloride , homochlorcyclizine hydrochloride , etc . the present invention against autoimmune diseases include , 100941 Examples of leukotriene antagonists include pran for example , immunosuppressants , steroids , disease -modi lukast hydrate , montelukast sodium , zafirlukast , ablukast , fying antirheumatic drugs , elastase inhibitors , cannabinoid - 2 pobilukast , sulukast , iralukast sodium , verlukast, ritolukast , receptor agonists , prostaglandins, prostaglandin synthetase cinalukast , pirodomast , tomelukast , doqualast , and the like . inhibitors , phosphodiesterase inhibitors , metalloproteinase [0095 ] Examples of anti - allergy drugs include amlexanox , inhibitors, adhesion molecule inhibitors , anti - cytokine pro azelastine hydrochloride, israpafant, ibudilast , imitrodast tein preparations such as anti- TNF -a preparations, anti - IL - 1 sodium , ebastine , epinastine hydrochloride, emedastine preparations, and anti - IL - 6 preparations, and cytokine fumarate , oxatomide , Ozagrel hydrochloride , olopatadine inhibitors , non - steroidal anti -inflammatory drugs, anti hydrochloride , cromoglicic acid , sodium cromoglicate , CD20 antibodies , and the like. ketotifen fumarate , seratrodast , cetirizine hydrochloride , [0089 ] Other drugs that supplement and / or enhance the suplatast tosilate , tazanolast, terfenadine, domitroban cal protective and /or therapeutic efficacy of the compound of cium hydrate , tranilast , nedocromil, fexofenadine, fexofena the present invention against inflammatory diseases include , dine hydrochloride , pemirolast potassium , mequitazine , for example, steroids, elastase inhibitors , cannabinoid - 2 receptor agonists , prostaglandins, prostaglandin synthetase ramatroban , repirinast, loratadine, and the like . inhibitors , phosphodiesterase inhibitors , metalloproteinase [0096 ] Examples of thromboxane A2 receptor antagonists inhibitors , adhesion molecule inhibitors, anti - leukotriene include seratrodast , domitroban calcium hydrate , and rama agents , anticholinergic agents , thromboxane A2 receptor troban . antagonists , thromboxane synthase inhibitors , xanthine [0097 ] The thromboxane synthase inhibitors can be exem derivatives, expectorants , antibacterial agents , antihista plified by imitrodast sodium and ozagrel hydrochloride . mines , anti -cytokine protein preparations, cytokine inhibi [0098 ] Examples of steroids include amcinonide, hydro tors , forskolin preparations , mediator release inhibitors , non cortisone sodium succinate , prednisolone sodium succinate , steroidal anti -inflammatory drugs , and the like . methylprednisolone sodium succinate , ciclesonide , diflu [0090 ] Other drugs that supplement and / or enhance the prednate , betamethasone propionate , dexamethasone , defla protective and / or therapeutic efficacy of the compound of zacort , triamcinolone , triamcinolone acetonide , halcinonide , the present invention against thromboembolic diseases dexamethasone palmitate , hydrocortisone , flumetasone include , for example , thrombolytic agents , heparin , hepari pivalate , prednisolone butylacetate , budesonide , prasterone noids, low molecular weight heparin , warfarin , thrombin sulfate, mometasonem furoate , fluocinonide , fluocinolone inhibitors , factor Xa inhibitors, ADP receptor antagonists , acetonide , fludroxycortide, flunisolide, prednisolone , alclo cyclooxygenase inhibitors , and the like . metasone propionate , clobetasol propionate , dexamethasone [0091 ] Other drugs that supplement and /or enhance the propionate , deprodone propionate , fluticasone propionate , protective and/ or therapeutic efficacy of the compound of beclometasone propionate , betamethasone, methylpredniso the present invention against bone -related diseases include , lone , methylprednisolone suleptanate , methylprednisolone for example , bisphosphonates, prostaglandins , vitamin D sodium succinate , dexamethasone sodium phosphate , hydro preparations, calcium preparations, estrogen preparations , cortisone sodium phosphate , prednisolone sodium phos calcitonin preparations, ipriflavone preparations, protein phate , diflucortolone valerate , dexamethasone valerate , anabolic steroids , vitamin K preparations, cathepsin K betamethasone valerate , prednisolone valerate acetate , cor inhibitors , parathyroid hormones , growth factors , caspase - 1 tisone acetate , diflorasone acetate , dexamethasone acetate , inhibitors , PTHrP derivatives , metalloproteinase inhibitors , triamcinolone acetate , paramethasone acetate , halopredone farnesoid X receptor agonists, anti -androgen agents , selec acetate , fludrocortisone acetate , prednisolone acetate , meth tive estrogen receptor modulators (SERMs ) , progesterone ylprednisolone acetate , clobetasone butyrate , hydrocorti agonists , calcium receptor antagonists ( calcylitics) , stron sone butyrate , hydrocortisone butyrate propionate , betame tium preparations , a -calcitonin gene -related peptide prepa thasone butyrate propionate , and the like . rations , osteogenetic protein preparations, anti -RANKL [0099 ] Examples of immunosuppressants include azathio antibodies , anti - TNF - a antibodies, anti - IL - 6 antibodies , and prine , ascomycin , everolimus, salazosulfapyridine , the like . cyclosporine , cyclophosphamide, sirolimus, tacrolimus, [0092 ] Other drugs that supplement and / or enhance the bucillamine , methotrexate , leflunomide, and the like . protective and / or therapeutic efficacy of the compound of [0100 ] Examples of disease -modifying anti- rheumatic the present invention against non -Hodgkin ' s lymphoma drugs include D -penicillamine , actarit , auranofin , salazosul include , for example , alkylating agents , antimetabolites , fapyridine , hydroxychloroquine , bucillamine , methotrexate , antitumor antibiotics, plant alkaloids, hormone drugs, plati leflunomide , lobenzarit sodium , aurothioglucose , sodium num compounds, anti - CD20 antibody, other anti- cancer aurothiomalate , and the like. agents and the like . [0101 ] Examples of elastase inhibitors include ONO 10093 ) Examples of antihistamines include azelastine 5046 , ONO -6818 , MR - 889 , PBI- 1101 , EPI- HNE - 4 , R - 665 , hydrochloride , ebastine , epinastine hydrochloride, emedas ZD - 0892 , ZD - 8321 , GW - 311616 , DMP -777 , L -659286 , tine fumarate , auranofin , oxatomide , olopatadine hydrochlo L -680833 , L -683845 , AE -3763 , and the like. US 2017 /0313706 A1 Nov . 2 , 2017
[0102 ] Examples of prostaglandins ( hereinafter , abbrevi - [ 0118 ] Examples of thrombin inhibitors include arga ated as PG ) include PGE1 drugs ( e . g . alprostadil alfadex , troban , ximelagatran , melagatran , dabigatran , bivalirudin , alprostadil , etc . ), PGI2 drugs ( e . g . beraprost sodium , etc . ) , lepirudin , hirudin , desirudin , and the like. PG receptor agonists , PG receptor antagonists , and the like . [0119 ] Examples of ADP receptor antagonists include Examples of PG receptors include PGE receptors (EP1 , EP2 , ticlopidine hydrochloride, clopidogrel sulfate , and the like . EP3 , EP4 ), PGD receptors (DP , CRTH2) , PGF receptors 10120 ] Examples of cyclooxygenase inhibitors include ( FP ), PGI2 receptors ( IP ) , TX receptors ( TP ) , and the like . aspirin and the like . [0103 ] Examples of prostaglandin synthetase inhibitors [0121 ] Examples of bisphosphonate preparations include include salazosulfapyridine, mesalazine , olsalazine , 4 - amin alendronate sodium hydrate , ibandronic acid , incadronate osalicylic acid , JTE -522 , auranofin , carprofen , diphenpyra disodium , etidronate disodium , olpadronate , clodronate mide , flunoxaprofen , flurbiprofen , indometacin , ketoprofen , sodium hydrate, zoledronic acid , tiludronate disodium , lornoxicam , loxoprofen , meloxicam , oxaprozin , parsalmide , neridronate , pamidronate disodium , piridronate , minodronic piproxen , piroxicam , piroxicam cinnamate , zaltoprofen , pra acid hydrate , sodium risedronate hydrate, YM 175 and the noprofen , and the like . like . [ 0104 ] Examples of phosphodiesterase inhibitors include [0122 ] Examples of vitamin D preparations include alfa rolipram , cilomilast, Bay19 - 8004, NIK -616 , roflumilast calcidol, falecalcitriol , calcitriol, la , 25 - dihydroxy chole (BY - 217 ) , cipamfylline (BRL -61063 ) , atizoram (CP calciferol, dihydrotachysterol, ST- 630 , KDR , ED - 71 , rocal 80633 ) , ONO -6126 , SCH - 351591, YM - 976 , V - 11294A , trol, tacalciol, maxacalcitol and the like . PD - 168787 , D -4396 , IC - 485 and the like . [0123 ] Examples of calcium preparations include calcium [0105 ] Examples of adhesion molecule inhibitors include chloride , calcium gluconate , calcium glycerophosphate , cal alpha4 integrin antagonists and the like . cium lactate , calcium L -aspartate , calcium hydrogen phos [0106 ] Examples of anti - TNF -a preparations include anti phate and the like. TNF - a antibodies, soluble TNF - a receptors , anti- TNF - a [0124 ] Examples of estrogen preparations include estra receptor antibodies, soluble TNF - a binding proteins, and the diol, estradiol benzoate , estradiol cypionate , estradiol dipro like, and particularly infliximab and etanercept. pionate , estradiol enanthate , estradiol hexahydrobenzoate , [0107 ] Examples of anti - IL - 1 preparations include anti estradiol phenylpropionate , estradiol undecanoate , estradiol IL - 1 antibodies, soluble IL - 1 receptors , anti - IL - 1Ra anti valerate , estrone, ethynyl estradiol, mestranol and the like. bodies and / or anti- IL - 1 receptor antibodies , and the like , [0125 ] Examples of calcitonin preparations include calci particularly anakinra . tonin , salmon calcitonin , chicken calcitonin , secalciferol, [0108 ] Examples of anti - IL - 6 preparations include anti elcatonin , TJN - 135 and the like . IL - 6 antibodies, soluble IL - 6 receptors, anti - IL -6 receptor [0126 ] Examples of ipriflavone preparations include ipri flavone and the like . antibodies , and the like , particularly tocilizumab . [0127 ] Examples of protein anabolic steroids include [0109 ] Examples of cytokine inhibitors include suplatast oxymetholone , stanozolol, nandrolone decanoate , nan tosylate , T -614 , SR -31747 , sonatimod , and the like . drolone phenylpropionate, nandrolone cyclohexylpropi [0110 ] Examples of anticholinergic agents include tri onate , metenolone acetate , mestanolone, ethylestrenol, hexyphenidyl, trihexyphenidyl hydrochloride , biperiden , calusterone and the like . biperiden hydrochloride , and the like . [0128 ] Examples of vitamin K preparations include mena [0111 ] Examples of xanthine derivatives include amino tetrenone , phytonadione and the like . phylline , theophylline , doxofylline, sipamphylline , diproph [0129 ] Examples of cathepsin K inhibitors include ONO ylline , and the like . 5334 , AAE 581 , SB 462795 , and odanacatib , and the like . [0112 ] Examples of expectorants include foeniculated [0130 ] Examples of parathyroid hormone ( PTH ) include ammonia spirit , sodium bicarbonate , bromhexine hydro dried thyroid , levothyroxine sodium , liothyronine sodium , chloride, carbocysteine , ambroxol hydrochloride, methyl propylthiouracil, thiamazole , teriparatide acetate and the cysteine hydrochloride , acetylcysteine , L - cysteine ethyl like . ester hydrochloride , tyloxapol , and the like . [0131 ] Examples of growth factors include fibroblast [0113 ] Examples of antibacterials include sodium cefu growth factor ( FGF ) , vascular endothelial growth factor roxime, meropenem trihydrate , netilmicin sulfate , sisomicin (VEGF ) , hepatocyte growth factor (HGF ) , insulin - like sulfate , ceftibuten , PA - 1806 , IB - 367 , tobramycin , PA - 1420 , growth factor ( IGF) and the like . doxorubicin , astromicin sulfate , cefetamet pivoxil hydro [0132 ] Examples of caspase - 1 inhibitors include nitroflu chloride, and the like . biprofen , pralnacasan and the like. [ 0114 ] Examples of mediator release agents include tra [0133 ] Examples of PTHrP derivatives include hPTHrP , nilast , sodium cromoglicate , amlexanox , repirinast, ibudi RS -66271 and the like. last , dazanolast , pemirolast potassium , and the like . [0134 Examples of the farnesoid X receptor agonists [0115 ] Examples of thrombolytic agents include alteplase , include SR - 45023A and the like . urokinase , tisokinase, nasaruplase, nateplase , t -PA , [0135 ] Examples of anti - androgen agents include osateron pamiteplase , monteplase , prourokinase , streptokinase, and acetate and the like . the like. [0136 ] Examples of selective estrogen receptor modula [0116 ] An example of a heparinoid is fondaparinux . tors (SERMs ) include TSE - 424 , WJ- 713 /MPA , lasofoxifene [0117 ] Examples of low molecular weight heparins tartrate , raloxifene hydrochloride , tamoxifen citrate and the include danaparoid sodium , enoxaparin (sodium ), like . nadroparin calcium , bemiparin ( sodium ) , reviparin ( so [0137 ] Examples of progesterone agonist include trimege dium ), tinzaparin ( sodium ), and the like. stone and the like . US 2017 /0313706 A1 Nov . 2 , 2017
[ 0138 ] Examples of calcium receptor antagonists (calci - drop suspensions , etc .) ) , topical formulations (e . g. ointments lytics ) include NPS - 423557 and the like. ( such as ophthalmic ointments , etc .) ) , ear drops ), and the [0139 ] Examples of strontium preparations include stron like . These preparations can be controlled release formula tium ranelate and the like . tions such as rapid release formulations, sustained release [0140 ] Examples of anti -RANKL antibodies include formulations, and the like. These preparations can be pro denosumab (AMG 162) and the like. duced by publicly known methods such as the methods [ 0141] Examples of osteogenetic protein preparations described in The Japanese Pharmacopoeia . include YM 484 and the like . [0152 ] As agents for oral administration , the liquid prepa [ 0142 ] Examples of alkylating agents include nitrogen rations for oral administration can be produced , for example , mustard N -oxide hydrochloride, cyclophosphamide , ifosf by dissolving, suspending, or emulsifying the compound of amide , melphalan , thiotepa , carboquone, busulfan , the present invention in a commonly used diluent ( e . g . nimustine hydrochloride, dacarbazine, ranimustine , and the purified water, ethanol, or a mixture thereof, etc. ) . These like. liquid preparations may also contain a wetting agent, sus [0143 ] Examples of antimetabolites include methotrexate , pending agent, emulsifier, sweetener, flavoring , fragrance , mercaptopurine, 6 -mercaptopurine riboside, fluorouracil, preservative , buffer, and the like . tegafur, tegafur uracil, carmofur, doxifluridine , cytarabine , 10153 ]. As a solid for oral administration , the solid oral enocitabine , tegafur gimestat otastat potassium , gemcitabine preparations can be prepared by mixing the compound of the hydrochloride , cytarabine ocfosfate , procarbazine hydro present invention with , an excipient ( e . g . lactose , mannitol, chloride , hydroxycarbamide , and the like . glucose, microcrystalline cellulose , starch , etc . ) , a binder [0144 ] Examples of anticancer antibiotics include actino ( e . g . hydroxypropyl cellulose , polyvinyl pyrrolidone , mag mycin D , mitomycin C , daunorubicin hydrochloride, doxo nesium metasilicate aluminate , etc .) , a disintegrant (e . g . rubicin hydrochloride , aclarubicin hydrochloride , neocar cellulose calcium glycolate , etc . ) , a lubricant ( e . g . magne zinostatin , pirarubicin hydrochloride , epirubicin sium stearate , etc . ) , a stabilizer, a solubilizer ( e . g . glutamic (hydrochloride ) , idarubicin hydrochloride , chromomycin acid , aspartic acid , etc . ) , and the like, and formulating A3 , bleomycin (hydrochloride ), peplomycin sulfate , thera according to conventionalmethods . As needed , coating can rubicin , zinostatin stimalamer , and the like . be carried out with a coating agent ( e . g . sugar, gelatin , [0145 ] Examples of plant preparations include vinblastine hydroxypropyl cellulose , hydroxypropyl methylcellulose sulfate , vincristine sulfate , vindesine sulfate , irinotecan phthalate , etc .) and two or more layers can be applied . hydrochloride , etoposide, flutamide, vinorelbine tartrate , [0154 ] As parenteral preparations , topical preparations docetaxel hydrate , paclitaxel, and the like . can be produced using a publicly known method and a [014 ] Examples of hormones include estramustine phos commonly used formulation . For example, an ointment can phate sodium , mepitiostane , epitiostanol, goserelin acetate , be prepared by incorporating or dissolving the compound of fosfestrol ( diethylstilbestrol phosphate ) , tamoxifen citrate , the present invention into a base . The ointment base can be toremifene citrate , fadrozole hydrochloride hydrate , selected from publicly known ointment bases or a com medroxyprogesterone acetate , bicalutamide, leuprorelin monly used ointment base . For example , one item alone or acetate , anastrozole , exemestane , and the like. a mixture of two or more items selected from the following [ 0147 Examples of platinum compounds include carbo can be used : higher fatty acids and higher fatty acid esters platin , cisplatin , nedaplatin , and the like . ( e . g . adipic acid , myristic acid , palmitic acid , stearic acid , [0148 ] Examples of anti -CD20 antibodies include ritux oleic acid , adipate esters , myristate esters , palmitate esters , imab , ibritumomab , ocrelizumab , and the like . stearate esters, oleate esters , etc . ) , waxes ( e . g . beeswax , [ 0149 Examples of other anticancer agents include L -as spermaceti , ceresin , etc . ) , surfactants ( e . g . polyoxyethylene paraginase , octreotide acetate , porfimer sodium , mitoxan alkyl ether phosphate esters , etc . ), higher alcohols (e . g . trone acetate , and the like . cetanol, stearyl alcohol, cetostearyl alcohol, etc . ), silicone [0150 ] The concomitantmedication used together with the oils ( e . g . dimethyl polysiloxane, etc . ) , hydrocarbons ( e . g . compound of the present invention can include not only hydrophilic petrolatum , white petrolatum , purified lanolin , drugs that have been discovered to date, but also drugs that liquid paraffin , etc . ), glycols ( e . g . ethylene glycol, diethylene may be discovered in the future . glycol, propylene glycol, polyethylene glycol, macrogol, [0151 ] The compound of the present invention is generally etc . ), plant oils (e .g . castor oil, olive oil, sesame oil , turpen administered systemically or locally , and as an oral or tine oil , etc .) , animal oils ( e . g , mink oil, egg yolk oil , parenteral form . Examples of oral formulations include squalane , squalene, etc. ) , water, absorption promoters, and liquids for oral administration ( e . g . elixirs, syrups , pharma anti- irritants . A humectant, preservative, stabilizer, antioxi ceutically acceptable water -based formulations , suspen dant, fragrance, and the like may also be included therein . sions, and emulsions ) and solids for oral administration ( e . g . [0155 ] As parenteral preparations , injectables include tablets ( including sublingual tablets and orally disintegrating solutions, suspensions, and emulsions as well as injectables tablets ), pills , capsules ( including hard capsules, soft cap in solid form to be used after dissolution or suspension in a sules , gelatin capsules , and microcapsules ) , powders, gran solvent at the time of use . For example , an injectable can be ules, and lozenges ) , and the like . Examples of parenteral used by dissolving , suspending , or emulsifying the com formulations include solutions ( e . g . injectables ( such as pound of the present invention in a solvent. Examples of the subcutaneous injectables , intravenous injectables , intramus solvent include distilled water for injection , physiological cular injectables, intraperitoneal injectables, and drip for saline solution , vegetable oil, propylene glycol, polyethyl mulations ) , eye drops ( e . g . aqueous eye drops ( such as ene glycol, an alcohol such as ethanol, or a combination aqueous eye drops , aqueous eye drop suspensions , viscous thereof . The injectable can also contain a stabilizer, a solu eye drops, solubilized eye drops , etc .) and nonaqueous eye bilizer ( e . g . glutamic acid , aspartic acid , Polysorbate 80® , drops (such as nonaqueous eye drops and nonaqueous eye etc . ), a suspending agent, an emulsifier, a soothing agent , a US 2017 /0313706 A1 Nov . 2 , 2017 buffer, a preservative , and the like . The injectable can be was added , and the mixture was stirred for 5 hours at 50° C . sterilized in the final process or can be manufactured using The reaction mixture was returned to room temperature , the aseptic processing methods . The injectable can also be solvent was distilled off , water was added , and extraction manufactured as a sterile solid form , for example , a freeze was performed with ethyl acetate . The organic layer was dried product, and can be used after dissolution in distilled washed with saturated aqueous sodium chloride solution , water for injection or another solvent that is either sterile or then dried over anhydrous sodium sulfate , and the solvent sterilized prior to use . was distilled off . The residue was purified by silica gel 10156 ] The dose of the compound of the present invention column chromatography to obtain the title compound ( 27 . 0 can be selected appropriately depending on the condition , g ) with the physical property value shown below . age , type of formulation , and the like , and in the case of an [0166 ] TLC : Rf 0 . 29 (hexane : ethyl acetate = 4 : 1 ) oral preparation preferably 1 to 100 mg, or more preferably 5 to 30 mg can be administered 1 to several times a day ( e . g . Example 3 1 to 3 times ) . Moreover, the compound of the present invention can be administered parenterally 1 to several times tert -butyl (3R )- 3 - { [ 5 - amino -6 - (dibenzylamino )py a day in a range of 50 ug to 500 mg per dose , or can be rimidin -4 - yl] amino } pyrrolidine - 1 -carboxylate continuously administered intravenously in a range from 1 [0167 ] An ethyl acetate ( 360 mL ) solution of the com to 24 hours per day . pound prepared in Example 2 ( 17 . 5 g ) was dripped into a [0157 ] Of course , as noted above , the dose will depend mixture of zinc ( 23 . 3 g ) and a 3 . 0 M aqueous ammonium upon various conditions and , as a result , cases will occur chloride solution ( 11. 4 g ) on an ice bath , and the temperature wherein an amount less than the above dosage will be was immediately raised to room temperature . After stirring sufficient or cases will occur wherein those ranges must be for 2 hours , the reaction mixture was filtered through exceeded . CeliteTM and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the EXAMPLES title compound (12 .4 g ) with the physical property value 10158 ] The present invention is described in detail below shown below . through examples, but is by no means limited thereto . [0168 ] TLC : Rf 0 .69 (hexane : ethyl acetate = 1 : 1) [ 0159 ] The solvents in parentheses shown in the sections Example 4 on chromatographic separation and TLC indicate the elution solvent or development solvent that was used , and the ratio tert - butyl ( 3R )- 3 - [6 - ( dibenzylamino ) - 8 -oxo - 7 , 8 represents the ratio by volume. dihydro - 9H -purin - 9 - yl] pyrrolidin - 1 -carboxylate 0160 ] Unless otherwise stated , the NMR data is ' H -NMR [0169 ] The compound prepared in Example 3 ( 8 . 4 g ) and data . 1 , 1 ' -carbonyl diimidazole ( 5 . 9 g ) were dissolved in tetrahy [0161 ] The items in parentheses shown in the NMR sec drofuran ( 120 mL ) and the solution was stirred for 15 hours tions represent the solvents used in measurement. at 60° C . The solvent was distilled off from the reaction [ 0162] The compound names used in this Description are mixture , water was added , and extraction with ethyl acetate generally names generated based on IUPAC nomenclature was performed . The organic layer was washed with satu or generated using ACD /Name® , a computer program from rated aqueous sodium chloride solution , then dried over Advanced Chemistry Development, Inc ., that performs nam anhydrous sodium sulfate , and the solvent was distilled off . ing based on IUPAC rules . The residue was purified by silica gel column chromatog raphy to obtain the title compound ( 7 . 8 g ) with the physical Example 1 property value shown below . N ,N -dibenzyl - 6 - chloro -5 -nitropyrimidine -4 - amine [0170 ] TLC : Rf 0 . 28 (hexane : ethyl acetate = 2 : 1 ) [0163 ] A solution of dibenzylamine (10 . 2 g ) in dichlo Example 5 romethane ( 30 mL ) was dripped into a solution of 4 ,6 tert -butyl (3R )- 3 -( 6 - amino - 8 -oxo -7 , 8 -dihydro -9H dichloro - 5 -nitropyrimidine (10 g ) in dichloromethane (70 purin - 9 -yl ) pyrrolidine - 1 - carboxylate mL ) on an ice bath . Then triethylamine (14 . 4 mL ) was added , and the mixture was stirred for 1 hour. Water was [0171 ] The compound prepared in Example 4 ( 7 . 8 g ) was added to the reaction mixture , the organic layer was washed dissolved in methanol (240 mL ) and ethyl acetate (50 mL ), with a saturated aqueous sodium chloride solution and dried 20 % Pearlman ' s catalyst (Pd (OH ) 2 / C ) ( 8 . 0 g , 100 wt % ) was over anhydrous sodium sulfate , and the solvent was con added , hydrogen gas replacement was carried out, and centrated under reduced pressure to obtain the title com stirring was performed for 7 .5 hours at 60° C . The reaction pound ( 19. 2 g ) with the physical property value shown mixture was filtered through CeliteTM and the solvent was below . distilled off to obtain the title compound ( 5 . 0 g ) with the physical property value indicated below . [0164 ] TLC : Rf 0 . 50 (hexane : ethyl acetate = 7 : 1 ) . [0172 ] TLC : Rf 0 .50 ( ethyl acetate ) Example 2 Example 6 tert- butyl ( 3R )- 3 - {[ 6 -( dibenzylamino )- 5 -nitropy tert - butyl (3R ) - 3 - [ 6 - amino - 8 - oxo - 7 - ( 4 -phenoxyphe rimidin - 4 - yl) amino }pyrrolidine - 1 - carboxylate nyl) - 7 ,8 -dihydro - 9H - purin - 9 - yl] pyrrolidine - 1 -car [0165 ] The compound prepared in Example 1 ( 19 g ) and boxylate tert- butyl ( 3R ) - 3 - aminopyrrolidine - 1 - carboxylate ( 10 . 5 g ) [0173 ] At room temperature p -phenoxy phenyl boronic were dissolved in dioxane (58 mL ). Triethylamine (8 . 1 mL ) acid (2 .1 g ), copper (II ) acetate (1 . 48 g ) ,molecular sieve 4A US 2017 /0313706 A1 Nov . 2 , 2017
( 2 . 5 g ) , and pyridine ( 0 . 82 mL ) were added to a dichlo 28 % ammonia water = 90 : 10 : 1 ) to obtain the title compound romethane suspension (200 mL ) of the compound prepared (75 mg) with the physical property values shown below . in Example 5 ( 2 . 5 g ) , followed by stirring for 21 hours . The [0180 ] TLC : Rf 0 .68 ( ethyl acetate : methanol = 9 : 1 ) ; reaction mixture was filtered through CeliteTM and the 1H - NMR (CDC13 ) : 8 1 . 94 - 2 . 03 , 2 . 23 - 2 . 39 , 2 . 80 - 3 .01 , residue was purified by silica gel column chromatography to 3 . 50 - 3 .63 , 3 .67 - 3 . 80 , 3 . 86 - 4 . 02 , 4 .03 - 4 . 18 , 4 .23 - 4 .33 , obtain the title compound ( 1 . 3 g ) with the physical property 4 .42 - 4 .51 , 5 . 11 - 5 . 25 , 7 .04 - 7 . 23 , 7 . 34 - 7 . 45, 8 . 20 - 8 . 23 value shown below . [0174 ] TLC : Rf 0 . 18 (hexane : ethyl acetate = 1 : 1 ) Example 9 Example 7 6 - amino - 9 - [ (3R ) - 1 - ( 2 -butynoyl ) - 3 -pyrrolidinyl ] - 7 ( 4 - phenoxyphenyl) - 7 , 9 - dihydro - 8H - purin - 8 - one (3R )- 6 -amino - 9 -pyrrolidin - 3 -yl - 7 -( 4 -phenoxyphe hydrochloride nyl) - 7 , 9 - dihydro -8H - purin - 8 - one dihydrochloride [0181 ] [0175 ] At room temperature 4 N HC1/ dioxane ( 13 mL ) was added to a methanol ( 13 mL ) suspension of the com pound prepared in Example 6 ( 1 . 3 g 2 .76 mmol, 1 . 0 equiva Chemical Formula 91 lent ), and the mixture was stirrred for 1 hour. The solvent was then distilled off to obtain the title compound ( 1 . 5 g ) with the physical property value shown below . [0176 ] TLC : Rf 0 .50 (dichloromethane : methanol: 28 % ammonia water = 9 : 1 : 0 . 1 )
Example 8 NH . HCI 6 - amino - 9 - [ ( 3R ) - 1 - ( 2 -butynoyl ) - 3 -pyrrolidinyl ] - 7 ( 4- phenoxyphenyl) - 7, 9 -dihydro -8H -purin - 8 -one (Compound A ) [0177 ]
[ Chemical Formula 8 ]
[0182 ] The compound prepared in Example 8 ( 3 . 0 g ) was placed in a 300 mL 3 - neck pear- shaped flask , ethyl acetate (30 mL ) and 1 -propanol ( 4 . 5 mL ) were added , and the NH , external temperature was set at 70° C . ( internal temperature 61° C .) . After it was confirmed that the compound prepared in Example 8 had dissolved completely , 10 % HCl/ methanol ( 3 . 5 mL ) was added , and after precipitation of crystals was confirmed , the crystals were ripened by the following sequence : external temperature 70° C . for 30 min , external temperature 60° C . for 30 min , external temperature 50 C for 60 min , external temperature 40 C for 30 min , room tem perature for 30 min , and on an ice bath for 30 min . The resulting crystals were filtered , washed with ethyl acetate ( 6 mL ), and dried under vacuum at 50° C . to obtain white crystals of the title compound ( 2 . 76 g ) with the physical property values shown below . [ 0178 ] After 2 -butylnoic acid (34 mg) , 1- ethyl- 3 -( 3 - dim 0183 ] TLC : Rf 0 .55 (dichloromethane : methanol = 9 : 1 ) ; ethylaminopropyl) carbodiimide hydrochloride ( EDC ) (78 1H -NMR (CD , OD ): d 1 . 97 - 2 . 07 , 2 .38 - 2 .52 , 2 .63 - 2 .80 , mg) , 1- hydroxybenzotriazole (HOBt ) (62 mg ), and triethyl 3 . 51 -3 .63 , 3 .77 -3 . 94 , 4 .00 - 4 . 19 , 4 .27 - 4 .35 , 5 .26 -5 .38 , amine ( 114 uL ) were added to a solution of the compound prepared in Example 7 ( 100 mg ) in dimethyl formamide ( 3 7 . 08 - 7 . 23 , 7 .38 - 7 .52 , 8 .44 - 8 .47 mL ), the mixture was stirred at room temperature for 3 Pharmacological Test Examples hours . Water was added to the reaction mixture and extrac tion with ethyl acetate was performed . Biological Example 1 [0179 ] The organic layer was washed with saturated sodium carbonate solution and saturated aqueous sodium Measurement of Btk inhibitory activity and chloride solution , then dried over anhydrous sodium sulfate , selectivity toward Btk ( in vitro ) and the solvent was distilled off . The residue was purified by [0184 ] The measurement of Btk enzyme inhibitory activ thin layer chromatography ( dichloromethane: methanol: ity was performed using the following reagents : Z - LYTETM US 2017 /0313706 A1 Nov . 2 , 2017
Kinase Assay Kit- Tyr 1 ( containing Tyr 1 peptide, Thy 1 Biological Example 2 phospho -peptide , 5x kinase buffer , ATP, development reagent B , development buffer , and stop reagent) , Tyr 1 peptide ( InvitrogenTM ), and Btk ( InvitrogenTM ) according to Blood Kinetics in Dogs the instructions accompanying the kit . [0195 ] The kinetic profiles of compound A and the salt [0185 ] First 5 uL /well of either a solution prepared by thereof ( the compound prepared in Example 9 ) in blood diluting the test compound in dimethyl sulfoxide (DMSO ) or were evaluated in male beagle dogs under fasting condi DMSO alone was added to the wells of a 96 -well assay plate tions. Intravenous administration , as well as both oral liquid together with 10 uL /well of substrate / enzyme mixture and and oral suspension administrations were carried out for allowed to react for 20 minutes at 30° C . The substrate ! Compound A prepared in Example 8 , and oral administra enzyme mixture solutions were prepared by dilution in tion by capsule was carried out for the compound prepared kinase buffer (DL - dithiothreitol (DTT ; 2 . 7mM ) and 1 . 33x in Example 9 . For the intravenous and oral solution admin kinase buffer ) so that the final concentration of Tyr - 1 peptide istrations, a solubilized solution of Compound A dissolved would be 4 uM , and the final concentration of Btk would be in WellSolve ( Celeste Inc .) heated to 60° C . was used . Using 5 nM . Next 5 uL /well of adenosine triphosphate was added the solubilized solutions, doses of 1 mg/ 1 mL/ kg were (ATP ; final concentration 36 uM ) and reacted for 1 hour at rapidly administered intravenously with a syringe via a 30° C . After the reaction was completed , 10 uL of devel forelimb cephalic vein , and doses of 1 mg/ 5 ml /kg were opment solution prepared by diluting development reagent B administered by gavage using a catheter. Approximately 300 in development buffer 128 - fold was added and reacted for an uL blood samples were drawn from the jugular vein as additional 1 hour at 30° C . Then the enzyme reaction was follows: for intravenous administration - before administra stopped by adding 10 uL of stop solution . The fluorescence tion , 2 , 5 , 15 , and 30 minutes after administration , and 1 , 2 , intensity in each well was measured using a fluorescence 4 , 6 , 8 , and 24 hours after administration ; for oral admin plate reader (Fusion Universal Microplate Analyzer, Perki istration — before administration , 5, 15 , and 30 minutes after nElmer, Inc . ) at 520 nm and 445 nm . In accordance with the administration , and 1 , 2 , 4 , 6 , 8 , and 24 hours after admin instructions accompanying the kit , the phosphorylation rate istration . The blood samples were cooled on ice , separated was determined by the ratio of the emission at 445 nm by centrifuge at 12 , 000 rpm for 3 min , and the plasma was ( coumalin emission ) in relation to emission at 520 nm collected . The concentration of Compound A in the plasma ( fluorescein emission ) . was measured by LC /MS / MS (UPLC /Xevo , Waters ). The [0186 ] The inhibition ( % ) was calculated from the follow area under the curve ( AUC , ng - h /mL ), maximum concen ing formula . tration (Cmor , ug /mL ) and clearance (CL , mL /hr / kg ) were calculated from the plasma concentration . The bioavailabil Phosphorylation inhibition rate ( % ) = 1 - { (AC - Ax )/ ity (BA ) of Compound A was calculated from the AUC of (Ac - Ab) } x100 [Mathematical Formula 1 ] the oral dose and the AUC of the intravenous dose . It was [ 0187 ] Ay: Phosphorylation rate when test compound was found that the BA of Compound A using the solubilized added solution was 114 . 6 % . [0188 ] Ag: Phosphorylation rate without ATP (blank ) [0196 ] Moreover, for the oral suspension administration a [0189 ] Ac: Phosphorylation rate with DMSO alone ( con liquid was prepared by finely pulverizing Compound A and trol) suspending the particles in an aqueous solution of 0 . 5 % methylcellulose , and then administering doses of 3 and 10 [ 0190 ] The 50 % inhibition rate of the test compound ( IC50 mg/ kg in the same manner as the forced oral administration value ) was calculated from an inhibition curve based on the by gavage described above . The compound from Example 9 rate of inhibition at each concentration of the test compound . was mixed at a 1 : 1 ratio with D -mannitol to make a dose of [0191 ] Measurements of the inhibitory activity on other 3 mg/ kg and placed in a No . 4 capsule (Qualicaps Co ., Ltd . ) . kinases were made in the same manner as described above The capsule was administered orally by placing 3 mg/ cap using various kinases such as Lck , Fyn , LynA ( Invitrogen sule doses deep in the throat to avoid chewing , holding the Corporation ) in place of Btk . mouth closed , and inserting 50 mL of water for injection [0192 ] Results revealed that the IC50 value of the com between the teeth to force swallowing. The timing of plasma pound prepared in Example 9 was 0 . 0021 uM . sampling and measurement of the plasma concentration of [0193 ] In addition , Btk - selective inhibitory activity rates Compound A for each administration method were per of the compound prepared in Example 9 toward other formed in the same manner as in the oral administration of kinases, particularly Lck , Fyn , and LynA , were calculated on Compound A using the solubilized solution that was the basis of the IC50 values for each kinase , and these are described above . The BA values for each administration shown in Table 4 below . method and at each concentration were calculated as relative BA by assigning the BA of Compound A in the solubilized TABLE 4 solution a value of 100 % . The results are shown in Table 5 below . Lck [ IC50 ] Fyn [IC50 ] LynA [ IC50 ] Btk [ IC50 ] Btk [ IC50 ] Btk [IC50 ] TABLE 5 Example 9 375 1057 1662 375 1057 1662 Dose Relative ( mg/ kg ) BA ( % ) [0194 ] Results show that the compound of the present Solubilized solution of Compound A 100 invention not only has Btk inhibitory activity , but also has Suspension of pulverized Compound A ?? 42 Btk -selective inhibitory activity toward other kinases. US 2017 /0313706 A1 Nov . 2 , 2017
TABLE 5 -continued [0210 ] From the above it is clear that the compound of the present invention has greater solubility in all of the solvents Dose Relative than Compound A . ( mg/ kg ) BA ( % ) Suspension of pulverized Compound A 10 Biological Example 4 Capsule of compound prepared in Example 9 ON Evaluation of Stability in Rat and Human Liver [0197 ] The results show that the relative BA of the liquid Microsomes suspension of pulverized Compound A decreased as the dose [0211 ] ( 1 ) Preparation of test compound solution increased . Conversely , the relative BA of the compound [0212 ] A 0 . 25 mmol/ L solution was prepared by diluting prepared in Example 9 was higher than the liquid suspension the test compound ( 5 uL of 10 mmol/ L DMSO solution ) in of pulverized Compound A at the same dose . Therefore , it 50 % acetonitrile /water solution ( 195 uL ) . was found that the absorption of the compound of the [0213 ] ( 2 ) Preparation of 0 Min -Reaction Sample present invention surpasses that of Compound A . 10214 ]. First 245 uL of 0 . 1 mol/ L phosphate buffer (pH 7 . 4 ) containing 0 . 5 mg/mL of rat and human liver microsomes Biological Example 3 (Xenotech ) and NADPH - Co - factor (BD Biosciences ) was placed in a reaction vessel that had been pre -heated to 37° Measurement of Solubility C . and pre - incubated for 5 min . Then the test compound [0198 ] First 0 . 5 mg to 2 . 5 mg of Compound A (pulverized solution (5 uL ) was added to start the reaction . Immediately by a JetMill ) and the compound prepared in Example 9 were after the reaction was started , a 20 uL sample was taken , 180 placed in 2 . 5 mL of various solvents (Japanese Pharmaco uL of acetonitrile containing the internal reference substance poeia dissolution test I liquid , Japanese Pharmacopoeia (warfarin ) was added , and the reaction was stopped . After dissolution test II liquid , diluted Mcllvaine buffer (pH 4 . 0 , the 20 uL of solution was stirred together with 180 uL of pH 7 . 4 ) , purified water, and artificial intestinal fluids ( FaS 50 % acetonitrile /water solution on a plate equipped with a SIF , FeSSIF ). With stirring at 700 rpm with a magnetic protein extraction filter , the liquid was suction - filtered and stirrer , approximately 1 mL samples were taken from the test used as the standard sample . suspension at 30 min and 24 h after the start of the test, and [0215 ] ( 3 ) Preparation of 15 Min - Reaction Sample after filtering with a 0 . 2 um filter, the solubility of Com [0216 ] After it was incubated for 15 min at 37° C . , 20 uL pound A was measured by HPLC under the conditions of the above reaction solution was added to 180 uL of cold shown below . Table 6 below compares the solubility of acetonitrile ( containing internal reference substance warfa Compound A and the compound prepared in Example 9 . rin ) , and the reaction was stopped . After the 20 uL of solution was stirred together with 180 uL of 50 % acetoni [0199 ]
pyrrolidinyl ] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro -8H - purin 6 -amino - 9 - [ (3R ) - 1 - ( 2 -butynoyl ) - 3 -pyrrolidinyl ] - 7 - ( 4 200 g 8 -one , adding HC1, and allowing precipitation of a crystal. phenoxyphenyl) - 7 , 9 - dihydro -8H - purin - 8 -one hydrochloride 16 . The method according to claim 15 , wherein the crystal Mannitol 20 g has at least 2 or more peaks at angle 20 selected from Distilled water 50 L approximately 8 . 11 , 8 .43 , 11 . 57 , 12 .73 , 13 . 85 , 14 . 20 , 14 .67 , 14 . 91 , 15 . 94 , 16 .64 , 18 .06 , 19 .74 , 20 .42 , 21. 05 , 22 .57 , 23. 21, 23 . 85 , and 24 . 70 degrees in a powder X -ray diffrac INDUSTRIAL APPLICABILITY tion spectrum . 17 . The method according to claim 15 , wherein the crystal [ 0221 ] In addition to having Btk - selective inhibitory activ has peaks at angle 20 of approximately 8 . 11 , 8 .43 , 14 . 20 , ity , the compound of the present invention has excellent 14. 67 , 14 .91 and 23. 21 degrees in a powder X -ray diffraction metabolic stability , is a compound with greater solubility spectrum . and absorption than the free base , and can be crystallized ; 18 . The method according to claim 15 , wherein the crystal therefore , it is useful as a therapeutic agent for a disease has peaks at angle 20 selected from approximately 8 . 11 , involving B cells and mast cells such as non -Hodgkin ' s 8 .43 , 11. 57 , 12 . 73 , 13 . 85 , 14 . 20 , 14 .67 , 14 .91 , 15 . 94 , 16 .64 , lymphoma. 18 . 06 , 19 .74 , 20 .42 , 21. 05 , 22. 57 , 23 .21 , 23 . 85 , and 24 . 70 1 - 13 . ( canceled ) degrees in a powder x -ray diffraction spectrum . 14 . A method of preparing 6 - amino - 9 - [ (3R ) - 1 - ( 2 -bu 19 . The method according to claim 15 , wherein the crystal tynoyl) - 3 - pyrrolidinyl] - 7 - ( 4 - phenoxyphenyl) - 7 , 9 - dihydro is characterized by the powder X -ray diffraction spectral 8H -purin -8 -one hydrochloride, said method comprising dis chart in FIG . 3 . solving 6 -amino - 9 -[ ( 3R )- 1 -( 2 -butynoyl ) - 3 -pyrrolidinyl ] - 7 20 . The method according to claim 15 , wherein the crystal (4 -phenoxyphenyl )- 7 , 9 -dihydro -8H -purin -8 -one and adding has an endothermic peak at a peak temperature of 216° C . in HC1. differential scanning calorimetry . 15 . A method of preparing a crystal of 6 - amino - 9 - [ ( 3R ) 21 . The method according to claim 15 , wherein the crystal 1 -( 2 -butynoyl )- 3 -pyrrolidinyl ] - 7 -( 4 -phenoxyphenyl ) - 7 ,9 is characterized by the differential scanning calorimetry dihydro - 8H -purin - 8 -one hydrochloride , said method com chart in FIG . 4 . prising dissolving 6 -amino - 9 - [ ( 3R ) - 1 - ( 2 - butynoyl) - 3 * * * * *