JP2021528387A - ベンゼンスルホンアミド化合物および治療剤としてのその使用 - Google Patents
ベンゼンスルホンアミド化合物および治療剤としてのその使用 Download PDFInfo
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- JP2021528387A JP2021528387A JP2020568796A JP2020568796A JP2021528387A JP 2021528387 A JP2021528387 A JP 2021528387A JP 2020568796 A JP2020568796 A JP 2020568796A JP 2020568796 A JP2020568796 A JP 2020568796A JP 2021528387 A JP2021528387 A JP 2021528387A
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- Prior art keywords
- methyl
- amino
- compound
- azabicyclo
- heptane
- 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.)
- Granted
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- 229940124597 therapeutic agent Drugs 0.000 title description 11
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- -1 benzenesulfonamide compound Chemical class 0.000 claims abstract description 225
- 239000000203 mixture Substances 0.000 claims abstract description 128
- 206010015037 epilepsy Diseases 0.000 claims abstract description 75
- 108010052164 Sodium Channels Proteins 0.000 claims abstract description 65
- 102000018674 Sodium Channels Human genes 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 55
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 49
- 239000000651 prodrug Substances 0.000 claims abstract description 46
- 229940002612 prodrug Drugs 0.000 claims abstract description 46
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 30
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- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 22
- CHKFOGJYAICJSR-UHFFFAOYSA-N benzenesulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NS(=O)(=O)C1=CC=CC=C1 CHKFOGJYAICJSR-UHFFFAOYSA-N 0.000 claims description 22
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 125000000623 heterocyclic group Chemical group 0.000 description 33
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- 229910052757 nitrogen Inorganic materials 0.000 description 25
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- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 1
- 229960003855 solifenacin Drugs 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008221 sterile excipient Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 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
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- BBQYPDIOKSGVGG-UHFFFAOYSA-N tert-butyl N-(1,2-thiazol-4-yl)carbamate Chemical compound C(C)(C)(C)OC(=O)NC=1C=NSC=1 BBQYPDIOKSGVGG-UHFFFAOYSA-N 0.000 description 1
- IBHBABFDCMKSOA-UHFFFAOYSA-N tert-butyl n-(1,2-oxazol-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC=1C=CON=1 IBHBABFDCMKSOA-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- FVECELJHCSPHKY-JLSHOZRYSA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-JLSHOZRYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
- C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
本出願は、米国特許法第119条(e)項の下、2018年6月13日出願の米国特許仮出願第62/684,436号(その全体が本明細書中で参考として援用される)の利益を主張する。
本発明は、ベンゼンスルホンアミド化合物、この化合物を含む薬学的組成物、ならびに、ナトリウムチャネルで媒介される疾患または状態(例えばてんかんおよび/またはてんかん発作障害など)ならびにナトリウムチャネルの媒介に伴う他の疾患および状態の処置において、この化合物およびこの薬学的組成物を使用する方法に関する。
電位開口型ナトリウムチャネル(NaV)は、筋肉および神経における細胞の興奮性の重要な決定因子である(Hille,B,Ion Channels of Excitable Membranes(2001),Sunderland,MA,Sinauer Associates,Inc.)。特に、4つのアイソフォームNaV1.1、NaV1.2、NaV1.3、およびNaV1.6は、中枢神経系のニューロンにおけるナトリウム電流の大部分を担う。NaV1.3は主として、胚で発現される。新生児期を過ぎると、NaV1.1、NaV1.2、およびNaV1.6が、脳におけるニューロンシグナル伝達を調節する重要なアイソフォームである(Catterall,W.A.,Annual Review of Pharmacology and Toxicology (2014年),第54巻,317−338頁)。
したがって、てんかんおよび他のNaV1.6関連病理状態を効果的に、かつ他のナトリウムチャネル(例えば、NaV1.1および/またはNaV1.5)の遮断に起因する有害な副作用なしに、処置するという、満たされていない医学的要求が存在する。本発明は、これらの重大な要求を満たす方法を提供する。
本発明は、ベンゼンスルホンアミド化合物、およびこれらの化合物を含む薬学的組成物、ならびに電位開口型ナトリウムチャネル活性(特に、NaV1.6活性)によって媒介される疾患または状態(例えばてんかんおよび/またはてんかん発作障害など)を処置するために本発明の化合物および薬学的組成物を使用する方法に関する。
式(I)において:
qは、1または2であり;
rは、1または2であり;
R1は、水素またはアルキルであり;
R2は、チアゾリル、イソチアゾリル、またはイソオキサゾリルであり;
R3aおよびR3bは各々独立して、水素またはアルキルであり;
各R4は独立して、ハロまたはアルキルであり;
R5はハロであり;
各R6は独立して、ハロまたはアルコキシであり;
R7はアザビシクロ[2.2.1]ヘプタニルアルキルであるか、またはrが2であり、少なくとも1つのR6がアルコキシである場合、R7は((メチル)(プロパ−2−イル)アミノ)アルキルである。
定義
本明細書中で名前の挙げられる特定の化学基には、その示された化学基中に見出されることになる炭素原子の総数を示す省略表現が先行することもある。例えば、C7〜C12アルキルは、以下に定義されている通り、合計7から12個の炭素原子を有するアルキル基について述べており、C4〜C12シクロアルキルアルキルは、以下に定義されている通り、合計4から12個の炭素原子を有するシクロアルキルアルキル基について述べている。省略表現における炭素の総数は、記載された基の置換基に存在し得る炭素は含まない。
(a)哺乳動物において疾患または状態が生じることを予防すること、特に、そのような哺乳動物がその状態にかかりやすくなっているが、これに罹っているとの診断が依然として出されていない場合、
(b)疾患または状態を阻害する、すなわち、その発生を阻むこと、
(c)疾患または状態を緩和する(もしくは軽減する)、すなわち、その疾患もしくは状態の退行を起こすこと、または
(d)疾患または状態から生じる症状を緩和する(もしくは軽減する)、例えば、基礎疾患もしくは状態を阻むことなく、てんかんを緩和させること。
本発明の1つの局面は、発明の要旨に記載されるような式(I)の化合物の、個々の立体異性体、エナンチオマーもしくは互変異性体、またはその混合物としての化合物;あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグである。
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミド;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される。
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−3−クロロ−2−フルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−3−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される。
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
(S)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;および
(R)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド
から選択される。
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミド;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される式(I)の化合物である。
2,6−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
2,6−ジフルオロ−4−((6−フルオロ−3−イソプロポキシ−2−((イソプロピル(メチル)アミノ)メチル)ベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
2,3−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
5−クロロ−2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;および
2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−5−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される。
本発明の化合物は、哺乳動物、特にヒトにおける電位依存性ナトリウムチャネル(好ましくはNaV1.6)を介したイオン流動を、調節、好ましくは阻害する。任意のそのような調節を、それがイオン流動の部分的または完全な阻害または予防であるかに関わらず、本明細書中では「遮断する」と呼び、対応する化合物を「遮断剤」または「阻害剤」と呼ぶことがある。一般的に、本発明の化合物は、ナトリウムチャネルの電位依存性の活性を阻害することにより、下向きに電位開口型ナトリウムチャネルの活性を調節し、そして/またはイオン流動などのナトリウムチャネル活性を防止することにより、細胞膜を横断するナトリウムイオンの流動を減少または防止する。
本発明はまた、本明細書中に開示されている本発明の化合物を含有する薬学的組成物に関する。一実施形態では、本発明は、例えば、動物、好ましくは哺乳動物、最も好ましくはヒト患者に投与された場合、ナトリウムチャネルによって媒介される疾患(例えば、てんかんおよび/またはてんかん発作障害)を治療するために、薬学的に受容可能なキャリア、添加剤または賦形剤中に、電位依存性ナトリウムチャネルを介したイオン流動を調節、好ましくは阻害するのに有効な量で、本発明の化合物を含む組成物に関する。
本発明の化合物は、電位開口型ナトリウムチャネル活性に関連する疾患および状態の治療において、1つもしくは複数の他の本発明の化合物または1つもしくは複数の他の治療薬あるいはこれらの任意の組み合わせを有用に組み合わせることができる。例えば、本発明の化合物は、これらだけに限らないが、以下を含めた他の治療薬と組み合わせて、同時、持続的または別々に投与することができる:
・オピエート鎮痛剤、例えばモルヒネ、ヘロイン、コカイン、オキシモルヒネ、レボルファノール、レバロルファン、オキシコドン、コデイン、ジヒドロコデイン、プロポキシフェン、ナルメフェン、フェンタニル、ヒドロコドン、ヒドロモルフォン、メリピジン、メタドン、ナロルフィン、ナロキソン、ナルトレキソン、ブプレノルフィン、ブトルファノール、ナルブフィンおよびペンタゾシンなど、
・非オピエート鎮痛剤、例えばアセトアミノフェン、サリチレート(例えばアスピリン)など、
・非ステロイド性抗炎症剤(NSAID)、例えばイブプロフェン、ナプロキセン、フェノプロフェン、ケトプロフェン、セレコキシブ、ジクロフェナク、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンおよびゾメピラックなど、
・抗痙攣剤、例えばカルバマゼピン、オキシカルバゼピン、ラモトリジン、バルプロエート、トピラメート、ガバペンチンおよびプレガバリンなど、
・抗うつ剤、例えば三環系抗うつ薬、例えばアミトリプチリン、クロミプラミン、デスプラミン、イミプラミンおよびノルトリプチリンなど、
・COX−2選択的阻害剤、例えばセレコキシブ、ロフェコキシブ、パレコキシブ、バルデコキシブ、デラコキシブ、エトリコキシブ、およびルミラコキシブなど、
・α−アドレナリン作動性剤、例えばドキサゾシン、タムスロシン、クロニジン、グァンファシン、デキシメタトミジン、モダフィニル、および4−アミノ−6,7−ジメトキシ−2−(5−メタンスルホンアミド−1,2,3,4−テトラヒドロイソキノール−2−イル)−5−(2−ピリジル)キナゾリンなど、
・バルビツレート鎮静剤、例えばアモバルビタール、アプロバルビタール、ブタバルビタール、ブタビタール、メフォバルビタール、メタルビタール、メトヘキシタール、ペントバルビタール、フェノバルチタール、セコバルビタール、タルブタール、テアミラールおよびチオペンタールなど、
・タキキニン(NK)アンタゴニスト、特に、NK−3アンタゴニスト、NK−2アンタゴニストまたはNK−1アンタゴニスト、例えば(αR、9R)−7−[3,5−ビス(トリフルオロメチル)ベンジル)]−8,9,10,11−テトラヒドロ−9−メチル−5−(4−メチルフェニル)−7H−[1,4]ジアゾシノ[2,1−g][1,7]−ナフチリジン−6−13−ジオン(TAK−637)、5−[[2R,3S)−2−[(1R)−1−[3,5−ビス(トリフルオロメチルフェニル]エトキシ−3−(4−フルオロフェニル)−4−モルホリニル]−メチル]−1,2−ジヒドロ−3H−1,2,4−トリアゾール−3−オン(MK−869)、アプレピタント、ラネピタント、ダピタントまたは3−[[2−メトキシ5−(トリフルオロメトキシ)フェニル]−メチルアミノ]−2−フェニルピペリジン(2S,3S)など、
・コールタール鎮痛剤、特にパラセタモール、
・セロトニン再取り込み阻害剤、例えばパロキセチン、セルトラリン、ノルフルオキセチン(フルオキセチンデスメチルメタボライト)、メタボライトデメチルセルトラリン、’3フルボキサミン、パロキセチン、シタロプラム、シタロプラムメタボライトデスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン、シアノドチエピン、リトキセチン、ダポキセチン、ネファゾドン、セリクラミン、トラゾドンおよびフルオキセチンなど、
・ノルアドレナリン(ノルエピネフリン)再取り込み阻害剤、例えばマプロチリン、ロフェプラミン、ミルタゼピン、オキサプロチリン、フェゾラミン、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオンメタボライトヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジン(Vivalan(登録商標))、特に選択性ノルアドレナリン再取り込み阻害剤、例えばレボキセチン、特に(S,S)−レボキセチン、およびベンラファキシンデュロキセチン神経弛緩剤、鎮静/抗不安剤、
・デュアルセロトニン−ノルアドレナリン再取り込み阻害剤、例えばベンラファキシン、ベンラファキシンメタボライトO−デスメチルベンラファキシン、クロミプラミン、クロミプラミンメタボライトデスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミンなど、
・アセチルコリンエステラーゼ阻害剤、例えばドネペジルなど、
・5−HT3アンタゴニスト、例えばオンダンセトロンなど、
・代謝調節型グルタミン酸受容体(mGluR)アンタゴニスト、
・局所麻酔剤、例えばメキシレチンおよびリドカインなど、
・副腎皮質ステロイド剤、例えばデキサメタゾンなど、
・抗不整脈剤、例えばメキシレチンおよびフェニトインなど、
・ムスカリンアンタゴニスト、例えば、トルテロジン、プロピベリン、トロプシウムクロリド、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウムなど、
・カンナビノイド、
・バニロイド受容体アゴニスト(例えばレジンフェラトキシンなど)またはアンタゴニスト(例えばカプサゼピンなど)、
・鎮静剤、例えばグルテチミド、メプロバメート、メタカロン、およびジクロラルフェナゾンなど、
・抗不安剤、例えばベンゾジアゼピンなど、
・抗うつ剤、例えばミルタザピンなど、
・局所用薬剤(例えばリドカイン、カプサイシン(capsacin)およびレシニフェラトキシン(resiniferotoxin)、
・筋弛緩剤、例えばベンゾジアゼピン、バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メトカルバモールおよびオルフレナジンなど、
・抗ヒスタミン剤またはH1アンタゴニスト、
・NMDA酸受容体アンタゴニスト、
・5−HT受容体アゴニスト/アンタゴニスト、
・PDEV阻害剤、
・トラマドール(登録商標)、
・コリン作動性(ニコチン性)鎮痛剤、
・α−2−デルタリガンド、
・プロスタグランジンE2サブタイプアンタゴニスト、
・ロイコトリエンB4アンタゴニスト、
・5−リポキシゲナーゼ阻害剤、および
・5−HT3アンタゴニスト。
本発明はまた、1種またはそれより多くの本発明の化合物を含む薬学的組成物を含有するキットを提供する。キットにはまた、電位開口型イオンチャネル(好ましくはNaV1.6)の活性を阻害するための薬学的組成物の使用のため、てんかんの治療のため、ならびに本明細書中に開示されている他の利用のための使用説明書も含まれている。好ましくは、市販のパッケージは、薬学的組成物の1またはそれより多くの単位用量を含有する。例えば、そのような単位用量は、静脈内用注射剤の調製に十分な量であってよい。軽い、および/または空気に敏感な化合物が、特別なパッケージングおよび/または製剤を必要とする可能性があることは、当業者であれば明らかであろう。例えば、光を通さず、および/また周囲の空気との接触から密閉され、および/または適切なコーティングもしくは添加剤と共に調合されているパッケージングを、使用してもよい。
以下の反応スキームは、式(I)の化合物を、本発明の概要において上記したように、その個々の立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物として、あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグとして、作製する方法を図示する。
式(Ia)の化合物は、qが1であり、R3aおよびR3bがそれぞれ水素であり、R7がアザビシクロ[2.2.1]ヘプタニルメチルであり、r、R1、R2、R5、およびR6が、それぞれ、発明の概要において定義されたとおりである、発明の概要において上に記載されたような式(I)の化合物であり、下で反応スキーム1に開示される方法によって調製することができ、ここで、nは1〜6であり、各Xは独立して、フルオロ、クロロ、またはブロモであり、R4aはブロモであり、R4bはフルオロであり、R8はアルキルであり、DPPAはジフェニルホスホリルアジドである:
反応スキーム1
反応スキーム2
反応スキーム3
反応スキーム4
反応スキーム5
反応スキーム6
反応スキーム7
反応スキーム8
反応スキーム9
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミドの合成
2,6−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミドの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−3−クロロ−2−フルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−3−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
2,6−ジフルオロ−4−((6−フルオロ−3−イソプロポキシ−2−((イソプロピル(メチル)アミノ)メチル)ベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
(S)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミドおよび(R)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
2,3−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミドの合成
5−クロロ−2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−5−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテートの合成
本発明の化合物の活性を試験するため、または公知の薬学的に受容可能な添加剤中でのその溶解度を求めるため、様々な技法が当技術分野で公知である。本明細書中に記述されている本発明をより完全に理解するため、以下の生物学的アッセイを記載する。これらの実施例は、単に例示を目的とするもので、いかなる方法によっても、本発明を制限すると解釈されてはならないことを理解されたい。
電気生理学的アッセイ(インビトロアッセイ)
パッチ電圧クランプ電気生理学は、電位開口型ナトリウムチャネル(NaV)の遮断の直接的な測定および定量を可能にし、そして遮断の時間依存および電圧依存の決定を可能にする。これは、ナトリウムチャネルの休止状態、開口状態、および不活性化状態への差示的な結合と解釈されている(Hille,B.,Journal of General Physiology(1977),69:497−515)。
ナトリウム流入アッセイ(インビトロアッセイ)
このナトリウム流入アッセイは、ナトリウムチャネル調節因子の使用によって開いた状態に維持されるナトリウムチャネルを通したナトリウムイオンの流入を定量するために、細胞透過性のナトリウム感受性色素ANG2の使用を採用する。このハイスループットナトリウム流入アッセイは、ナトリウムチャネル遮断剤の迅速なプロファイリングと特徴付けとを可能にする。
電気刺激発作アッセイ
抗痙攣活性を持つ、すなわち、発作の閾値を引き起こす、化合物を同定するために、多くの電気刺激発作試験が使用されている。当該分野で頻繁に使用される電気刺激発作アッセイの2つの例は、6Hz精神運動発作アッセイ(6Hz)と最大電気ショック発作(MES)アッセイである。6Hzアッセイは、ヒトで観察される部分発作のモデルと考えられる(Loescher,W.およびSchmidt,D.,Epilepsy Res.(1988年),第2巻,145−81頁;Barton,M.E.ら,Epilepsy Res.(2001年),第47巻,217−27頁)。MESアッセイは、ヒトにおける全般強直間代発作のモデルであり、脳内の全神経回路が最も活発なときに発作の拡がりを防止する化合物の能力の指標を提供する。これらの発作は、再現性が高く、ヒトの発作と電気生理学的に一致している(Tomanら,1946;Pireddaら,1984;Whiteら,1995)。実験は、健康な動物、または、遺伝性てんかん症候群をモデル化するように遺伝子改変された発作傾向のある動物を用いて実施され得る(Piredda,S.G.ら,J.Pharmacol.Exp.Ther.(1985年),第232巻,741−5頁;Toman,J.E.ら,J.Neurophysiol.(1946年),第9巻,231−9頁;およびWhite,H.S.ら,Ital.J.Neurol.Sci.(1995年),第16(1−2)巻,73−7頁)。
予備処置後、各マウスを、いくつかの強度(12〜44mA)にて角膜電極を通じて送達される低周波数(6Hz,0.3msのパルス幅)の刺激で3秒間チャレンジする。動物は手で押さえ、刺激後直ちに解放し、発作活性の存在または非存在について観察する。典型的に、6Hzの刺激は、最小の間代期と、それに続く、典型的な自動性の挙動(触毛の攣縮および挙尾を含む)によって、または、全般強直間代発作によって特徴づけられる発作を生じる。電流適用後の発作の存在、種類および潜伏期間(秒で)をモニターする。間代発作または全般強直間代発作を示さない動物は、「保護された」と考えられる。アッセイの終了時にはすべての動物を安楽死させる。血漿および脳のサンプルを回収する。
予備処置後、各マウスを、強度(44〜55mA)にて角膜電極を通じて送達される交流(60Hz,0.4〜0.6msのパルス幅)で0.2〜0.5秒間チャレンジする。
Claims (23)
- 式(I):
あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグであって;
式(I)において:
qは、1または2であり;
rは、1または2であり;
R1は、水素またはアルキルであり;
R2は、チアゾリル、イソチアゾリル、またはイソオキサゾリルであり;
R3aおよびR3bは各々独立して、水素またはアルキルであり;
各R4は独立して、ハロまたはアルキルであり;
R5はハロであり;
各R6は独立して、ハロまたはアルコキシであり;
R7はアザビシクロ[2.2.1]ヘプタニルアルキルであるか、またはrが2であり、少なくとも1つのR6がアルコキシである場合、R7は((メチル)(プロパ−2−イル)アミノ)アルキルである、
その個々の立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物としての、化合物;
あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグ。 - R7がアザビシクロ[2.2.1]ヘプタニルアルキルである、請求項1に記載の化合物。
- R2がイソチアゾリルである、請求項2に記載の化合物。
- 4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミド;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(イソチアゾール−3−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される、請求項3に記載の化合物。 - R2がチアゾリルである、請求項2に記載の化合物。
- rが1である、請求項5に記載の化合物。
- 4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−3−クロロ−2−フルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−3−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される、請求項6に記載の化合物。 - rが2である、請求項5に記載の化合物。
- 4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロ−3−メトキシベンジル)アミノ)−2,3−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
54−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;
(S)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド;および
(R)−4−((2−(1−(7−アザビシクロ[2.2.1]ヘプタン−7−イル)エチル)−3,6−ジフルオロベンジル)アミノ)−2,6−ジフルオロ−N−(チアゾール−4−イル)ベンゼンスルホンアミド
から選択される、請求項8に記載の化合物。 - R2がイソオキサゾリルである、請求項2に記載の化合物。
- 4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2,6−ジフルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミド;および
4−((2−((7−アザビシクロ[2.2.1]ヘプタン−7−イル)メチル)−6−フルオロベンジル)アミノ)−2−フルオロ−N−(イソオキサゾール−3−イル)−3−メチルベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される、請求項10に記載の化合物。 - R7が((メチル)(プロパ−2−イル)アミノ)アルキルであり、ただし、rは2であり、少なくとも1つのR6はアルコキシである、請求項1に記載の化合物。
- R2がイソチアゾリルである、請求項12に記載の化合物。
- R2がチアゾリルである、請求項12に記載の化合物。
- 2,6−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
2,6−ジフルオロ−4−((6−フルオロ−3−イソプロポキシ−2−((イソプロピル(メチル)アミノ)メチル)ベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
2,3−ジフルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド;
5−クロロ−2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート;および
2−フルオロ−4−((6−フルオロ−2−((イソプロピル(メチル)アミノ)メチル)−3−メトキシベンジル)アミノ)−5−メチル−N−(チアゾール−4−イル)ベンゼンスルホンアミド2,2,2−トリフルオロアセテート
から選択される、請求項14に記載の化合物。 - R2がイソオキサゾリルである、請求項12に記載の化合物。
- 薬学的に受容可能な賦形剤、および請求項1〜16のいずれか1項に記載の、その立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物としての、化合物、あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグを含有する、薬学的組成物。
- 哺乳動物において、NaV1.6活性に関連する疾患または状態を処置する方法であって、該疾患または状態は、てんかんおよび/またはてんかん発作障害であり、そして該方法は、該処置の必要がある哺乳動物に、治療有効量の、請求項1〜16のいずれか1項に記載の、その立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物としての、化合物、あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグを投与する工程を包含する、方法。
- 哺乳動物細胞において、NaV1.6を通るイオン流動を減少させる方法であって、該方法は、該細胞を、請求項1〜16のいずれか1項に記載の、その立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物としての、化合物、あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグと接触させる工程を包含する、方法。
- 哺乳動物において、第二の電位開口型ナトリウムチャネルに優先して第一の電位開口型ナトリウムチャネルを選択的に阻害する方法であって、該方法は、該哺乳動物に、調節量の、請求項1〜16のいずれか1項に記載の、その立体異性体、エナンチオマーもしくは互変異性体、またはこれらの混合物としての、化合物、あるいはその薬学的に受容可能な塩、溶媒和物またはプロドラッグを投与する工程を包含する、方法。
- 前記第一の電位開口型ナトリウムチャネルはNaV1.6である、請求項18に記載の方法。
- 前記第二の電位開口型ナトリウムチャネルはNaV1.5である、請求項18に記載の方法。
- 前記第二の電位開口型ナトリウムチャネルはNaV1.1である、請求項16に記載の方法。
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US10745392B2 (en) | 2020-08-18 |
PE20211389A1 (es) | 2021-07-27 |
MA52888A (fr) | 2021-04-21 |
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NI202000098A (es) | 2021-05-28 |
KR20210019507A (ko) | 2021-02-22 |
SG11202011862PA (en) | 2020-12-30 |
US20200361927A1 (en) | 2020-11-19 |
CN112262142B (zh) | 2023-11-14 |
US11325902B2 (en) | 2022-05-10 |
BR112020024729A2 (pt) | 2021-03-23 |
CL2020003197A1 (es) | 2021-04-30 |
IL278949A (en) | 2021-01-31 |
PH12020552111A1 (en) | 2021-08-02 |
US20190382398A1 (en) | 2019-12-19 |
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UA127024C2 (uk) | 2023-03-15 |
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