JP2013529602A - ホスホジエステラーゼ阻害剤としてのベンゾジオキソールまたはベンゾジオキセピンヘテロ環化合物 - Google Patents
ホスホジエステラーゼ阻害剤としてのベンゾジオキソールまたはベンゾジオキセピンヘテロ環化合物 Download PDFInfo
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- JP2013529602A JP2013529602A JP2013515698A JP2013515698A JP2013529602A JP 2013529602 A JP2013529602 A JP 2013529602A JP 2013515698 A JP2013515698 A JP 2013515698A JP 2013515698 A JP2013515698 A JP 2013515698A JP 2013529602 A JP2013529602 A JP 2013529602A
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- Prior art keywords
- compound
- spiro
- difluoromethoxy
- ethanone
- tetrahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 benzodioxepin heterocyclic compounds Chemical class 0.000 title claims abstract description 38
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 title 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 30
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims abstract description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 239000011593 sulfur Substances 0.000 claims abstract description 4
- 241000534944 Thia Species 0.000 claims abstract description 3
- 125000004429 atom Chemical group 0.000 claims abstract description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 68
- 238000000034 method Methods 0.000 claims description 26
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 24
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- 206010040799 Skin atrophy Diseases 0.000 claims description 8
- AOYVMYGVYYGONA-UHFFFAOYSA-N 2-(3,5-dichloropyridin-4-yl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-thiane]-4-yl]ethanone Chemical compound C1=2OC3(CCSCC3)OC=2C(OC(F)F)=CC=C1C(=O)CC1=C(Cl)C=NC=C1Cl AOYVMYGVYYGONA-UHFFFAOYSA-N 0.000 claims description 7
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- 230000002757 inflammatory effect Effects 0.000 claims description 6
- LXHMXTSEVTVMHJ-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-thiane]-4-carboxamide Chemical compound C1=2OC3(CCSCC3)OC=2C(OC(F)F)=CC=C1C(=O)NC1=C(Cl)C=NC=C1Cl LXHMXTSEVTVMHJ-UHFFFAOYSA-N 0.000 claims description 6
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 6
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- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 5
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 4
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 claims description 4
- GAGUHQWNDGBDCG-UHFFFAOYSA-N 1,3-dithiane 1,3-dioxide Chemical compound O=S1CCCS(=O)C1 GAGUHQWNDGBDCG-UHFFFAOYSA-N 0.000 claims description 4
- 201000004384 Alopecia Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 208000003251 Pruritus Diseases 0.000 claims description 4
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 claims description 4
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 4
- 208000024780 Urticaria Diseases 0.000 claims description 4
- 231100000360 alopecia Toxicity 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
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- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 4
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 claims description 4
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 claims description 4
- GINSRDSEEGBTJO-UHFFFAOYSA-N thietane 1-oxide Chemical compound O=S1CCC1 GINSRDSEEGBTJO-UHFFFAOYSA-N 0.000 claims description 4
- SKJBPWNKKILJEX-UHFFFAOYSA-N 2-(3,5-dichloropyridin-4-yl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4'-oxane]-4-yl]ethanone Chemical compound C1=2OC3(CCOCC3)OC=2C(OC(F)F)=CC=C1C(=O)CC1=C(Cl)C=NC=C1Cl SKJBPWNKKILJEX-UHFFFAOYSA-N 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 3
- 208000031091 Amnestic disease Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 3
- 206010012289 Dementia Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010022491 Insulin resistant diabetes Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 206010052428 Wound Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 230000006986 amnesia Effects 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 201000008383 nephritis Diseases 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 208000023516 stroke disease Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- FCFMKFHUNDYKEG-UHFFFAOYSA-N thietane 1,1-dioxide Chemical compound O=S1(=O)CCC1 FCFMKFHUNDYKEG-UHFFFAOYSA-N 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims 2
- 230000008816 organ damage Effects 0.000 claims 2
- 230000001568 sexual effect Effects 0.000 claims 1
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 abstract description 12
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 150000004677 hydrates Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 238000009472 formulation Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- UKHWJBVVWVYFEY-UHFFFAOYSA-M silver;hydroxide Chemical compound [OH-].[Ag+] UKHWJBVVWVYFEY-UHFFFAOYSA-M 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- SDKPSXWGRWWLKR-UHFFFAOYSA-M sodium;9,10-dioxoanthracene-1-sulfonate Chemical compound [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)[O-] SDKPSXWGRWWLKR-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical class CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229950006828 timegadine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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Abstract
[式中、
mおよびnは、それぞれ独立して、0または1であり;
R1およびR2は、それらが結合している炭素原子と一体となって、酸素、硫黄、−S(O)−および−S(O)2−から選択される1個または2個のヘテロ原子を含むヘテロ環式環を形成し;
R3は、−CHF2、−CF3、−OCHF2、−OCF3、−SCHF2または−SCF3であり;
Xは、結合、−CH2−または−NH−であり;
Aは、アリール、シクロアルキル、シクロアルケニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルまたはヘテロシクロアルケニルであり、これらは、所望によりR4から選択される1個以上の同一または異なる置換基で置換されており;
R4は、水素、アミノ、チオキソ、アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシ、ハロアルコキシ、ハロゲン、オキソ、チアまたはヒドロキシである。]
の化合物またはその薬学的に許容される塩、水和物または溶媒和物が、PDE4阻害活性を示し、炎症性疾患および障害の処置に有用であり得ることが見出された。
Description
本発明は、ホスホジエステラーゼ阻害活性を有する新規化合物、および、炎症性疾患および状態の処置における治療薬としてのその使用に関する。
ホスホジエステラーゼは、細胞中のサイクリックAMPおよび/またはサイクリックGMPを、それぞれ5−AMPおよび5−GMPに加水分解するのを触媒する酵素であり、それ自身、cAMPまたはcGMPレベルの細胞制御に重要である。現在までに同定された11個のホスホジエステラーゼのうち、ホスホジエステラーゼ(PDE)4、PDE7およびPDE8は、cAMPに選択的である。PDE4は、免疫細胞および炎症細胞、例えば好中球、マクロファージおよびT−リンパ球中で発現されるcAMPの最も重要なモジュレーターである(Z. Huang and J.A. Mancini, Current Med. Chem. 13, 2006, pp. 3253-3262)。cAMPは、炎症応答の制御における重要な第2メッセンジャーであるため、PDE4は、炎症性サイトカイン、例えばTNFα、IL−2、IFN−γ、GM−CSFおよびLTB4を制御することによって、炎症細胞の炎症応答を制御することが見出された。従って、PDE4の阻害は、炎症性疾患、例えば喘息、慢性閉塞性肺疾患(COPD)、関節リウマチ、アトピー性皮膚炎、クローン病などの魅力的な治療標的となっている(M.D. Houslay et al., Drug Discovery Today 10 (22), 2005, pp. 1503-1519)。アトピー性皮膚炎(AD)患者はPDE活性が増大しているため、PDE4阻害はまた、ADの実行可能な処置であると考えられる(Journal of Investigative Dermatology (1986), 87(3), 372-6)。
本発明者らは、驚くべき事に、本発明の化合物が、経口投与した際にPDE4阻害活性を示し、炎症性アレルギー性疾患、例えば気管支喘息、COPD、アレルギー性鼻炎および腎炎;自己免疫疾患、例えば関節リウマチ、多発性硬化症、クローン病および全身性エリテマトーデス;中枢神経系の疾患、例えば鬱病、健忘症および認知症;心不全、卒中および脳血管疾患などによって引き起こされる虚血性逆流と関連した臓器障害;インスリン抵抗性糖尿病;創傷;ならびに炎症が疾患の病因または進行に役割を果たす他の疾患の全身性処置における治療薬として有用であることを見出した。
mおよびnは、それぞれ独立して、0または1であり;
R1およびR2は、それらが結合している炭素原子と一体となって、酸素、硫黄、−S(O)−および−S(O)2−から選択される1個または2個のヘテロ原子を含むヘテロ環式環を形成し;
R3は、−CHF2、−CF3、−OCHF2、−OCF3、−SCHF2または−SCF3であり;
Xは、結合、−CH2−または−NH−であり;
Aは、アリール、シクロアルキル、シクロアルケニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルまたはヘテロシクロアルケニルであり、これらは、所望によりR4から選択される1個以上の同一または異なる置換基で置換されており;
R4は、水素、アミノ、チオキソ、アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシ、ハロアルコキシ、ハロゲン、オキソ、チアまたはヒドロキシである。]
の化合物またはその薬学的に許容される塩、水和物または溶媒和物に関する。
定義
用語“炭化水素基”は、水素原子および炭素原子のみを含む基を示すことが意図され、1個以上の二重および/または三重炭素−炭素結合を含んでよく、分枝鎖または直鎖部分と組み合わせて、環状部分を含んでよい。当該炭化水素は、1〜20個の炭素原子、好ましくは1〜12個、例えば1〜6個、例えば1〜4個、例えば1〜3個、例えば1〜2個の炭素原子を含む。該用語は、アルキル、アルケニル、シクロアルキル、シクロアルケニル、アルキニルおよびアリール、アリールアルキルを含む。
用語“ヘテロアリールアルキル”は、アルキル基に共有結合している、上で定義したヘテロアリール基を示すことが意図される。
用語“ハロアルキル”は、上で定義したハロゲン原子で1個以上置換されている、上で定義したアルキル基、例えばジフルオロメチルを示すことが意図される。
現在好ましい態様において、本発明は、Xが−CH2−または−NH−である一般式Iの化合物に関する。
一つの態様において、R3は、−OCHF2または−OCF3であり、例えば−OCHF2である。
他の態様において、R3は、−SCHF2または−SCF3である。
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物101)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物102)
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物103)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物104)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物105)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物106)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−イル)エタノン(化合物107)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物108)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物109)
N−(3,5−ジクロロ−4−ピリジル)−7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−カルボアミド(化合物110)
N−(3,5−ジクロロ−1−オキソ−4−ピリジル)−7−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[1,3−ベンゾジオキソール−2,4'−チアン]−4−カルボキサミド(化合物111)
である。
単位投与形において、本化合物は、常に患者の状態に応じて、いずれにしても、医療従事者によって為される処方に従って、適切な時間間隔で1日1回以上投与され得る。好都合には、製剤の単位投与形は、0.1mgから1000mgの間の、好ましくは1mgから100mg、例えば5〜50mgの式Iの化合物を含む。
本発明の化合物を、合成分野の技術者に周知の幾つかの方法で製造することができる。式Iの化合物は、例えば、合成有機化学の分野で既知の方法または該分野の技術者に認められているその変形と共に、下で概説する反応および方法を用いて製造され得る。好ましい方法は、下に記載されるものを含むが、これらに限定されない。反応は、変換が行われるのに用いられる適当な反応材および物質に適切な溶媒中で行われる。また、下に記載される合成方法において、溶媒の選択、反応雰囲気、反応温度、実験時間および後処理方法を含む全ての提案された反応条件は、反応について標準の条件であるよう選択され、それは当業者に容易に認識されるべきであることが理解されるべきである。示されるクラスに分類される全ての化合物が、記載される幾つかの方法で要求される幾つかの反応条件に適合性であるわけではない。反応条件に適合性である置換基についてのこのような制限は、当業者に容易に明らかであり、代替方法を用いることができる。
1H 核磁気共鳴(NMR)スペクトルを、300MHzで測定し、13C NMRスペクトルを、75.6MHzで測定した。化学シフト値(δ, ppm)を、特定の溶媒中、内部テトラメチルシラン(δ=0.00)またはクロロホルム(δ=7.25)またはジューテリオクロロホルム(13C NMRについてδ=76.81)標準に対する値で述べる。定義される(二重項(d)、三重項(t)、四重項(q))か、または定義されない(m)多重項の値は、範囲が述べられないときは、ほぼ中央点で示される。(bs)は、ブロードな一重項を示す。用いられる有機溶媒は、通常無水である。クロマトグラフィーは、Merck シリカゲル 60 (0.040〜0.063mm)で行った。示される溶媒比は、断りのないかぎりv:vで述べる。
分取HPLC/MSを、2つのShimadzu PP150 分取ポンプおよびThermo MSQ Plus 質量分析計を有するDionex APS-systemで行った。カラム:Waters XTerra C-18, 150mm×19mm, 5μm;溶媒系:A=水(0.1%蟻酸)およびB=アセトニトリル(0.1%蟻酸);流速=18mL/分;方法(10分):10% B〜100% B, 6分の直線的濃度勾配法を行い、100% B, さらに2分とどめる。フラクションを、関連するイオンの痕跡およびPDAシグナル(240〜400nm)に基づいて集めた。
方法A:分析的HPLC/MSを、P680A 分析ポンプおよびThermo MSQ Plus 質量分析計を有するDionex APS-systemで行った。カラム:Waters XTerra C-18, 150mm×4.6mm, 5μm;溶媒系:A=水(0.1%蟻酸)およびB=アセトニトリル(0.1%蟻酸);流速=1.0mL/分;方法(10分):10% B〜100% B, 6.6分の直線的濃度勾配法を行い、100% Bでさらに1.5分とどめる。
本発明の化合物を、例えば下記の通り製造することができる。n、m、R1、R2が上で定義した通りであり、R3=OCF2Hである一般式IIaおよびIIbの化合物を、下記の通り製造することができる。
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ヒドロキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物401)
1H NMR (300 MHz, DMSO) δ 8.65 (s, 2H), 7.36 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.64 (s, 2H), 4.54 (s, 2H), 4.53-4.42 (m, 4H), 4.33 (s, 2H).
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物101)
1H NMR (300 MHz, CDCl3) δ 8.51 (s, 2H), 7.46 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.64 (t, J = 74 Hz, 1H), 4.68 - 4.56 (m, 8H), 4.56 - 4.46 (bs, 2H).
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物102)
1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H), 7.47 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.63 (t, J=74Hz, 1H), 4.70 - 4.59 (m, 6H), 4.56 (bs, 2H), 4.52 (bs, 2H).
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ヒドロキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物402)
1H NMR (300 MHz, CDCl3) δ 8.49 (s, 2H), 7.51 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.30 (s, 1H), 4.60 (s, 2H), 4.27 (s, 2H), 4.21 (s, 2H), 3.91 - 3.55 (m, 4H), 1.76 (t, J = 5.5 Hz, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物103)
1H NMR (300 MHz, CDCl3) δ 8.50 (s, 2H), 7.44 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.63 (t, J= 74Hz, 1H), 4.62 (s, 2H), 4.27 (s, 2H), 4.22 (s, 2H), 3.87 - 3.58 (m, 4H), 1.85 - 1.62 (m, 4H).
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物104)
1H NMR (600 MHz, CDCl3) δ 8.21 (s, 2H), 7.45 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.64 (t, J=74Hz, 1H), 4.55 (s, 2H), 4.28 (s, 2H), 4.24 (s, 2H), 3.86 - 3.61 (m, 4H), 1.89 - 1.64 (m, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ヒドロキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物403)
1H NMR (300 MHz, DMSO) δ 8.65 (s, 2H), 7.95 (s, 1H), 7.25 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 8.9 Hz, 1H), 4.59 (s, 2H), 3.92 - 3.67 (m, 4H), 2.21 - 1.94 (m, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物105)
1H NMR (300 MHz, CDCl3) δ 8.52 (s, 2H), 7.46 (d, J = 9.1 Hz, 1H), 6.81 (d, J=9.0, 1H), 6.74 (t, J=73Hz, 1H), 4.60 (s, 2H), 4.05 - 3.83 (m, 4H), 2.21 (t, J = 5.5 Hz, 4H).
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物106)
1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H), 7.46 (d, J = 9.1 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 6.74 (t, J= 73Hz, 1H), 4.53 (s, 2H), 4.08 - 3.88 (m, 4H) 2.21 (t, J = 5.5 Hz, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ヒドロキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−イル)エタノン(化合物404)
1H NMR (300 MHz, CDCl3) δ 8.52 (s, 2H), 7.38 (d, J = 9.0Hz, 1H), 6.54 (d, J = 9.0 Hz, 1H), 4.60 (s, 2H), 2.94 - 2.77 (m, 4H), 2.46 - 2.15 (m, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2, 4'−(4H)−チオピラン]−4−イル)エタノン(化合物107)
1H NMR (400 MHz, DMSO) δ 8.67 (s, 2H), 7.61 - 7.09 (m, 2H), 6.93 (d, J = 9.0 Hz, 1H), 4.67 (s, 2H), 3.05 - 2.74 (m, 4H), 2.42 - 2.16 (m, 4H).
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物108)
1H NMR (300 MHz, CDCl3) δ 8.23 (s, 2H), 7.52 (d, J = 9.1 Hz, 1H), 6.89 (d, J= 9.1Hz, 1H), 6.70 (t, J=72Hz ,1H), 4.48 (s, 2H), 3.50 - 3.18 (m, 4H), 2.83 - 2.55 (m, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ヒドロキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物405)
1H NMR (300 MHz, DMSO) δ 8.65 (s, 2H), 7.95 (s, 1H), 7.28 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 8.9 Hz, 1H), 4.64 (s, 2H), 3.6-3.3 (m, 4H), 2.65 - 2.50 (m, 4H).
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物109)
1H NMR (300 MHz, CDCl3) δ 8.53 (s, 2H), 7.52 (d, J = 9.1 Hz, 1H), 6.89 (d, J~9Hz, 1H), 6.69 (t, J= 72Hz, 1H), 4.56 (s, 2H), 3.56 - 3.15 (m, 4H), 2.91 - 2.50 (m, 4H).
7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−カルボン酸
4−ニトロフェニル 7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−カルボキシレート
N−(3,5−ジクロロ−4−ピリジル)−7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−カルボアミド
1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.57 (s, 2H), 7.63 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 9.1 Hz, 1H), 6.73 (t, J = 72Hz, 1H), 3.03 - 2.81 (m, 4H), 2.49 - 2.29 (m, 4H).
N−(3,5−ジクロロ−1−オキソ−4−ピリジル)−7−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[1,3−ベンゾジオキソール−2,4'−チアン]−4−カルボキサミド
1H NMR (300 MHz, DMSO) δ 9.46 (s, 1H), 8.76 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.39 (t, J = 73,5 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 3.76 - 3.56 (m, 2H), 3.34 (m, 2H), 2.75 - 2.53 (m, 4H).
X=−NH−である下記の化合物は、例えば、国際公開第2008/104175号に記載された通りに、および、本明細書の実施例10および実施例11に記載された通りに製造され得る。
N−(3,5−ジクロロ−4−ピリジル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−オキセタン]−9−カルボキサミド
N−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−オキセタン]−9−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,4'−テトラヒドロピラン]−9−カルボキサミド
N−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,4'−テトラヒドロピラン]−9−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−7−(ジフルオロメトキシ)スピロ[1,3−ベンゾジオキソール−2,4'−テトラヒドロピラン]−4−カルボキサミド
N−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−7−(ジフルオロメトキシ)スピロ[1,3−ベンゾジオキソール−2,4'−テトラヒドロピラン]−4−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−7−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[1,3−ベンゾジオキソール−2,4'−チアン]−4−カルボキサミド
N−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−6−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−6−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−カルボキサミド
N−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−カルボキサミド
N−(3,5−ジクロロ−4−ピリジル)−6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−カルボキサミド。
下記の化合物は、本明細書の一般的な手順に記載された通りに合成され得る。
2−(3,5−ジクロロ−4−ピリジル)−1−[6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−イル]エタノン
2−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−1−[6−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−イル]エタノン
2−(3,5−ジクロロ−4−ピリジル)−1−[6−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−イル]エタノン
2−(3,5−ジクロロ−1−オキシド−ピリジン−1−イウム−4−イル)−1−[6−(ジフルオロメトキシ)スピロ[2,4−ジヒドロ−1,5−ベンゾジオキセピン−3,3'−チエタン]−9−イル]エタノン。
PDE4アッセイ
ヒト組み換えPDE4(Genbank受付番号NM_006203)を、10μMまでの濃度の試験化合物、cAMP(1×10−5M)および低量(0.021MBq)の放射活性標識cAMPと共に、1時間インキュベートした。インキュベーションの終了時に、放射活性トレーサーに結合したとき化学発光を生じるSPAビーズへのAMP生成物の結合によって、基質の分解を評価した。AMP生成物は、放射活性トレーサーのビーズへの結合を阻害し、発光シグナルを低下させた。
コントロールサンプルと比較して基質分解の50%阻害を起こしたモル濃度として結果を計算し、IC50(M)として表す。
インビボ薬物動態分析
1匹のラットに経口投与し(5mg/kg, DMSO/H2O/プロピレングリコール[1:5:4]に溶解)、血液サンプルを、舌下静脈叢から30分、1時間、2時間、4時間および6時間で採取する。
血液サンプルをBD Vacutainer SST血清分離管に採取し、血清を遠心分離によって単離し、微小管に移し、続いて分析する。
国際公開第2008/104175号からの化合物101の経口投与:親化合物の血清Cmaxは<3ng/mlであるが、代謝物(R3=OH)の血清Cmaxは約2000ng/mlである。代謝物(化合物403)のPDE4活性は5000nMであり、すなわち、親化合物(PDE4=20nM)に比べて不活性である。
化合物105の経口投与, 5mg/kg:親化合物の血清Cmaxは<3ng/mlであるが、活性代謝物である化合物106の血清Cmaxは93ng/mlである。
化合物106の経口投与, 5mg/kg:血清Cmaxは133ng/mlであり、バイオアベイラビリティーは22%である。
Claims (21)
- 一般式I:
mおよびnは、それぞれ独立して、0または1であり;
R1およびR2は、それらが結合している炭素原子と一体となって、酸素、硫黄、−S(O)−および−S(O)2−から選択される1個または2個のヘテロ原子を含むヘテロ環式環を形成し;
R3は、−CHF2、−CF3、−OCHF2、−OCF3、−SCHF2または−SCF3であり;
Xは、結合、−CH2−または−NH−であり;
Aは、アリール、シクロアルキル、シクロアルケニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヘテロシクロアルキルまたはヘテロシクロアルケニルであり、これらは、所望によりR4から選択される1個以上の同一または異なる置換基で置換されており;
R4は、水素、アミノ、チオキソ、アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシ、ハロアルコキシ、ハロゲン、オキソ、チアまたはヒドロキシである。]
の化合物またはその薬学的に許容される塩、水和物または溶媒和物。 - Xが−CH2−または−NH−である、請求項1記載の化合物。
- mおよびnが共に0である、請求項1、2または3に記載の化合物。
- mおよびnが共に1である、請求項1、2または3に記載の化合物。
- R3が−OCHF2または−OCF3である、請求項1〜5の何れか1項に記載の化合物。
- R3が−OCHF2である、請求項6記載の化合物。
- R3が−SCHF2または−SCF3である、請求項1〜5の何れか1項に記載の化合物。
- R1およびR2が、それらが結合している炭素原子と一体となって、4員、5員または6員ヘテロ環式環を形成する、請求項1〜8の何れか1項に記載の化合物。
- ヘテロ環式環が、テトラヒドロピラン、オキセタン、[1,3]ジオキソラン、[1,3]ジオキサン、テトラヒドロチオピラン、テトラヒドロチオピラン−1,1−ジオキシド、テトラヒドロチオピラン−1−オキシド、テトラヒドロチオフェン、[1,3]−ジチアン、チエタン、[1,3]−ジチアン−1,3−ジオキシド、チエタン−1−オキシド、または、チエタン−1,1−ジオキシドである、請求項9記載の化合物。
- ヘテロ環式環が1個のヘテロ原子を含む、請求項9記載の化合物。
- ヘテロ原子が酸素または−S(O)2−である、請求項11記載の化合物。
- 2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物101)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),3'−オキセタン]−6−イル}エタノン(化合物102)
2−(3,5−ジクロロピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物103)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−{9−ジフルオロメトキシ−スピロ[2H−1,5−ベンゾジオキセピン−3(4H),4'−テトラヒドロピラン]−6−イル}エタノン(化合物104)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物105)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−ピラン]−4−イル)エタノン(化合物106)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−イル)エタノン(化合物107)
2−(3,5−ジクロロ−1−オキシド−ピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物108)
2−(3,5−ジクロロピリジン−4−イル)−1−(7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン−1',1'−ジオキシド]−4−イル)エタノン(化合物109)
N−(3,5−ジクロロ−4−ピリジル)−7−ジフルオロメトキシ−2',3',5',6'−テトラヒドロ−スピロ[1,3−ベンゾジオキソール−2,4'−(4H)−チオピラン]−4−カルボアミド(化合物110)
N−(3,5−ジクロロ−1−オキソ−4−ピリジル)−7−(ジフルオロメトキシ)−1',1'−ジオキソ−スピロ[1,3−ベンゾジオキソール−2,4'−チアン]−4−カルボキサミド(化合物111)
からなる群から選択される、請求項1、2または3に記載の化合物。 - 治療に使用するための、請求項1〜13の何れか1項に記載の化合物。
- 炎症性疾患、例えば気管支喘息、COPD、アレルギー性鼻炎および腎炎;自己免疫疾患、例えば関節リウマチ、多発性硬化症、クローン病および全身性エリテマトーデス;中枢神経系の疾患、例えば鬱病、健忘症および認知症;心不全、卒中、および脳血管疾患などによって引き起こされる虚血性逆流と関連した臓器障害;インスリン抵抗性糖尿病;創傷;癌;増殖性および炎症性皮膚障害、例えば乾癬、表皮の炎症、挫瘡、皮膚炎、アトピー性皮膚炎、脂漏性皮膚炎、接触皮膚炎、蕁麻疹、掻痒症および湿疹;ならびに、他の皮膚状態、例えば脱毛症、皮膚萎縮症、ステロイド誘発皮膚萎縮症、皮膚老化および光線性皮膚老化の処置に使用するための、請求項1〜13の何れか1項に記載の化合物。
- 治療有効成分として請求項1〜13の何れか1項に記載の化合物、および、薬学的に許容される担体またはビークルを含む医薬組成物。
- 薬学的に許容される担体またはビークルが、経口投与に適当なものである、請求項16記載の組成物。
- 1種以上のさらなる治療有効成分をさらに含む、請求項16または17に記載の組成物。
- 炎症性疾患または状態を予防、処置または寛解する方法であって、それを必要とする患者に、治療有効量の請求項1〜13の何れか1項に記載の化合物を投与することを含む方法。
- 疾患または状態が、炎症性疾患、例えば気管支喘息、COPD、アレルギー性鼻炎および腎炎;自己免疫疾患、例えば関節リウマチ、多発性硬化症、クローン病および全身性エリテマトーデス;中枢神経系の疾患、例えば鬱病、健忘症および認知症;心不全、卒中、および脳血管疾患などによって引き起こされる虚血性逆流と関連した臓器障害;インスリン抵抗性糖尿病;創傷;癌;増殖性および炎症性皮膚障害、例えば乾癬、表皮の炎症、挫瘡、皮膚炎、アトピー性皮膚炎、脂漏性皮膚炎、接触皮膚炎、蕁麻疹、掻痒症および湿疹;ならびに他の皮膚状態、例えば脱毛症、皮膚萎縮症、ステロイド誘発皮膚萎縮症、皮膚老化および光線性皮膚老化からなる群から選択される、請求項19記載の方法。
- 化合物が経口経路によって投与される、請求項19または20に記載の方法。
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JP2020524131A (ja) * | 2017-06-20 | 2020-08-13 | レオ ファーマ アクティーゼルスカブ | 1,3−ベンゾジオキソール複素環式化合物の調製方法 |
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WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
FI3724196T3 (fi) | 2017-12-15 | 2023-01-31 | Substituoituja atsetidiinidihydrotienopyridiinejä ja niiden käyttö fosfodiesteraasin estäjinä | |
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JP2018537510A (ja) * | 2015-12-18 | 2018-12-20 | レオ ファーマ アクティーゼルスカブ | 1,3−ベンゾジオキソール複素環化合物の製造方法 |
JP2020524131A (ja) * | 2017-06-20 | 2020-08-13 | レオ ファーマ アクティーゼルスカブ | 1,3−ベンゾジオキソール複素環式化合物の調製方法 |
JP2023029877A (ja) * | 2017-06-20 | 2023-03-07 | ユニオン・セラピューティクス・アクティエセルスカブ | 1,3-ベンゾジオキソール複素環式化合物の調製方法 |
JP7549635B2 (ja) | 2017-06-20 | 2024-09-11 | ユニオン・セラピューティクス・アクティエセルスカブ | 1,3-ベンゾジオキソール複素環式化合物の調製方法 |
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