JP2015522622A - 5,5−ヘテロ芳香族抗感染症化合物 - Google Patents
5,5−ヘテロ芳香族抗感染症化合物 Download PDFInfo
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- JP2015522622A JP2015522622A JP2015523260A JP2015523260A JP2015522622A JP 2015522622 A JP2015522622 A JP 2015522622A JP 2015523260 A JP2015523260 A JP 2015523260A JP 2015523260 A JP2015523260 A JP 2015523260A JP 2015522622 A JP2015522622 A JP 2015522622A
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- Prior art keywords
- compound
- alkyl
- compound according
- heterocycle
- alkoxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 163
- 230000002924 anti-infective effect Effects 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 44
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 230000002147 killing effect Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
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- 150000001412 amines Chemical class 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 26
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical class C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 22
- WBRDQYDKCJPDHJ-UHFFFAOYSA-N n-[[4-(4-chlorophenoxy)phenyl]methyl]-2,6-dimethylimidazo[2,1-b][1,3]thiazole-5-carboxamide Chemical compound CC=1N=C2SC(C)=CN2C=1C(=O)NCC(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 WBRDQYDKCJPDHJ-UHFFFAOYSA-N 0.000 claims description 18
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 17
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
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- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
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- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical class O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 2
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 2
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- 230000001665 lethal effect Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 26
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- 230000015572 biosynthetic process Effects 0.000 abstract description 21
- 241000186367 Mycobacterium avium Species 0.000 abstract description 9
- 208000022155 mycobacterium avium complex disease Diseases 0.000 abstract description 3
- GGNIKGLUPSHSBV-UHFFFAOYSA-N thiazole-5-carboxamide Chemical compound NC(=O)C1=CN=CS1 GGNIKGLUPSHSBV-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
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- 238000002360 preparation method Methods 0.000 description 14
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 13
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- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- 238000010998 test method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 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
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
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Abstract
Description
本出願は、米国特許仮出願61/672,968(2012年7月18日出願)(参照により本明細書中で援用される)に対して、35U.S.C.§119(e)下での優先権を主張する。
本発明は、国立衛生研究所により授与される補助金R01 AI 054193下での政府支援でなされた。
X2は、S、スルフィニル(S(=O))、スルホニル(S(=O)2)、CH2、CHR1 、O、NHまたはNR4であり;
Zは、−C(=O)NH−、−C(=O)O−、−C(=O)C(=O)−、−CH2C(=O)−、−C(=O)CH2−または−NH−C(=O)NH−であり;そして
nは、0〜4である)
の化合物を提供する。
R1は、アルキル、シクロアルキル、複素環、アルコキシ、アリール、ヘテロアリール、ハロまたはアミンであり;
R2は、H、アルキル、シクロアルキル、複素環、アルコキシ、アリール、ヘテロアリール、ハロまたはアミンであり;
R3は、H、アルキル、アルコキシ、アミノ、シクロアルキル、複素環、アリール、アリールオキシまたはヘテロアリールであり;そして
R4は、各々独立して、H、アルキル、シクロアルキル、複素環、アリールまたはヘテロアリールであって;
この場合、R1、R2、R3またはR4のアルキル、シクロアルキル、複素環、アリール、アリールオキシ、ヘテロアリール、アルコキシまたはアミンは、1またはそれ以上の置換基、例えば約1〜約5つの置換基で任意に置換される。上記のまたは本明細書中に記載されるR基の値のいずれかは、さらにまた、特許請求される発明の特定のR基定義または式から排除され得る。
(a)OR4またはNHR4;
(b)
(c)
(d)
(e)
(f)
(g)
(h)
であり得る。
定義
本明細書中で用いる場合、引用される用語は、以下の意味を有する。本明細書中で用いられるその他の用語および語句はすべて、当業者が理解するようなそれらの通常の意味を有する。このような通常の意味は、技術用語辞典、例えばHawley’s Condensed Chemical Dictionary 14th Edition, by R.J.Lewis,John Wiley & Sons,New York,N.Y.,2001を参照することにより得られる。
本発明は、種々の5,5−ヘテロ芳香族化合物およびその製造方法に関する。化合物は、ラセミ的に、またはエナンチオマー形態で調製され得る。それらの調製および修飾のためのある個々の合成変換は、当該技術分野で周知である。これらの既知の技法の多くは、Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6;ならびに標準有機参照テキスト、例えばMarch's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed.,by M.B. Smith and J. March (John Wiley & Sons, New York, 2001); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor−in−Chief (Pergamon Press, New York, 1993 printing); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); Protecting Groups in Organic Synthesis, Second Edition, Greene, T.W.,and Wutz, P.G.M.,John Wiley & Sons, New York;およびComprehensive Organic Transformations, Larock, R.C.,2nd Ed., John Wiley & Sons, New York (1999)で詳述されている。
本明細書中に記載される化合物は、例えば、当該化合物を製薬上許容可能な希釈剤、賦形剤または担体と組み合わせることにより、治療用薬学的組成物を調製するために用いられ得る。化合物は、塩または溶媒和物の形態で、担体に付加され得る。例えば、化合物が安定非毒性酸または塩基塩を生成するのに十分に塩基性または酸性である場合、塩としての化合物の投与が適切である。製薬上許容可能な塩の例は、生理学的に許容可能な陰イオンを生成する酸を用いて生成される有機酸付加塩、例えばトシル酸塩、メタンスルホン酸塩、酢酸塩、クエン酸塩、マロン酸塩、酒石酸塩、コハク酸塩、安息香酸塩、アスコルビン酸塩、α−ケトグルタル酸塩およびβ−グリセロリン酸塩である。適切な無機塩、例えば、塩酸塩、ハロゲン化物、硫酸塩、硝酸塩、重炭酸塩および炭酸塩も生成され得る。
実施例
本明細書中に記載される化合物は、以下の一般手順に従って合成され得る。例えばND−010081は、容易に入手可能な安価な試薬から、2〜3の合成ステップで製造され得る。マルチグラム規模でのこの化合物の製造の潜在的利用可能性および手頃性を評価するために、以下の手順を用いてキログラム規模で、ND−010081を調製した(下記のスキーム1)。
種々の5,5−複素環式誘導体(イミダゾ[2,1−b]チアゾール−5−カルボキサミドに関しては「ITA」、イミダゾ[2,1−b]オキサゾール−5−カルボキサミドに関しては「IOA」、イミダゾ[2,1−b][1,3,4]チアゾール−5−カルボキサミドに関しては「ITDA」、イミダゾ[2,1−b][1,3,4]オキサジアゾール−5−カルボキサミドに関しては「IODA」、ピロロ[1,2−a]イミダゾール−3−カルボキサミドに関しては「PIA」、イミダゾ[1,2−b]ピラゾール−3−カルボキサミドに関しては「IPYA」)を調製するために用いられる一般合成手順は、以下の通りである:
本明細書中に記載される5,5−ヘテロ芳香族物質を基礎にした最初の「ヒット」であるND−010081、すなわちN−(4−(4−クロロフェノキシ)ベンジル)−2,6−ジメチルイミダゾ[2,1−b]チアゾール−5−カルボキサミドは、一般臨床候補に匹敵するH37Rv TBに対するin vitro活性を、そしてin vivo処置のための十分な治療ウィンドウを有する。
A=<2mM
B=<2mM−10mM
C=<10mM−20mM
D=<20mM−32mM
E=<32mM
Mtb H37Rv(ATCC# 27294)に対する試験化合物MICsを、リファムピンおよび陽性対照としてのPA−824を用いて、MABAを査定した。128mMの濃度でDMS中で化合物ストック溶液を調製し、最終試験濃度は128μM〜0.5μMの範囲であった。GAS検定のために96ウェルマイクロプレート(BD Optilux(商標)、96−ウェルマイクロプレート、黒色/透明平底)中で100μLの容積でのグリセロール−アラニン−塩培地中に、GAST検定に付加される20%トゥイーン80を有する鉄欠乏グリセロール−アラニン塩培地中に、ならびに7H12検定のために96ウェルマイクロプレート(BD Optilux(商標)、96−ウェルマイクロプレート、黒色/透明平底)中で100μLの容積でのMiddlebrook 7H12培地(0.1%w/vカシトン、5.6μg/mLパルミチン酸、5mg/mLウシ血清アルブミン、4mg/mLカタラーゼを含有する7H9ブロス)中に、化合物の2倍溶液を調製した。TB培養(2×105cfu/mLの100μL接種物)を培地に付加し、最終試験容積を200μLとした。プレートを、37℃でインキュベートした。インキュベーションの7日目に、12.5μLの20%トゥイーン80および20μLのAlamar Blue(Invitrogen BioSource(商標))を試験プレートのウェルに付加した。37℃で16〜24時間インキュベーション後、530nm(励起)および590nm(発光)でウェルの蛍光を測定した。MICsは、複製細菌のみの対照の平均に比して、≧90%の蛍光の低減を実行する最低濃度として定義される。
1. Collins,L.;Franzblau,S.G.Microplate alamar blue assay versus BACTEC 460 system for high−throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob.Agents Chemother.1997,41,1004−1009.
2. De Voss,J.J.;Rutter,K.;Schroeder,B.G.;Su,H.;Zhu,Y.;Barry,C.E. The salicylate−derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages.Proc.Nat.Acad.Sci.U.S.A. 2000,97,1252−1257.
以下の処方物は、本明細書中に記載される式の化合物、本明細書中で具体的に開示される化合物、あるいはその製薬上許容可能な塩または溶媒和物(本明細書中では以後、「化合物X」として言及される)の治療的または予防的投与のために用いられ得る代表的薬学的剤形を示す:
(i)錠剤1 mg/錠剤
「化合物X」 100.0
ラクトース 77.5
ポビドン 15.0
クロスカルメロースナトリウム 12.0
微晶質セルロース 92.5
ステアリン酸マグネシウム 3.0
300.0
(ii)錠剤2 mg/錠剤
「化合物X」 20.0
微晶質セルロース 410.0
デンプン 50.0
デンプングリコール酸ナトリウム 15.0
ステアリン酸マグネシウム 5.0
500.0
(iii)カプセル mg/カプセル
「化合物X」 10.0
コロイド二酸化ケイ素 1.5
ラクトース 465.5
アルファデンプン 120.0
ステアリン酸マグネシウム 3.0
600.0
(iv)注射液1(1mg/mL) mg/mL
「化合物X」(遊離酸形態) 1.0
二塩基性リン酸ナトリウム 12.0
一塩基性リン酸ナトリウム 0.7
塩化ナトリウム 4.5
1.0N水酸化ナトリウム溶液 十分量(pHを7.0〜7.5に調節)
注射液用の水 全量を1mLとするのに十分な量
(v)注射液2(10mg/mL) mg/mL
「化合物X」(遊離酸形態) 10.0
一塩基性リン酸ナトリウム 0.3
二塩基性リン酸ナトリウム 1.1
ポリエチレングリコール 400 200.0
0.1N水酸化ナトリウム溶液 十分量(pHを7.0〜7.5に調節)
注射液用の水 全量を1mLとするのに十分な量
(vi)エーロゾル mg/缶
「化合物X」 20
オレイン酸 10
トリクロロモノフルオロメタン 5,000
ジクロロジフルオロメタン 10,000
ジクロロテトラフルオロエタン 5,000
(vii)局所ゲル1 重量%
「化合物X」 5%
カルボマー 934 1.25%
トリエタノールアミン 十分量(pHを5〜7に調節)
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
(viii)局所ゲル2 重量%
「化合物X」 5%
メチルセルロース 2%
メチルパラベン 0.2%
プロピルパラベン 0.02%
精製水 全量を100gとするのに十分な量
(ix)局所軟膏 wt.%
「化合物X」 5%
プロピレングリコール 1%
無水軟膏基剤 40%
ポリソルベート80 2%
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
(x)局所クリーム1 wt.%
「化合物X」 5%
白色蜜蝋 10%
液体パラフィン 30%
ベンジルアルコール 5%
精製水 全量を100gとするのに十分な量
(xi)局所クリーム2 wt.%
「化合物X」 5%
ステアリン酸 10%
グリセリルモノステアレート 3%
ポリオキシエチレンステアリルエーテル 3%
ソルビトール 5%
イソプロピルパルミテート 2%
メチルパラベン 0.2%
精製水 全量を100gとするのに十分な量
Claims (26)
- 式(A):
X2は、S、S(=O)、S(=O)2、CH2、CHR1 、O、NHまたはNR4であり;
Zは、−C(=O)NH−、−C(=O)O−、−C(=O)C(=O)−、−CH2C(=O)−、−C(=O)CH2−または−NH−C(=O)NH−であり;
nは、0〜4であり;
R1は、アルキル、シクロアルキル、複素環、アルコキシ、アリール、ヘテロアリール、ハロまたはアミンであり;
R2は、H、アルキル、シクロアルキル、複素環、アルコキシ、アリール、ヘテロアリール、ハロまたはアミンであり;
R3は、アルキル、アルコキシ、アミノ、シクロアルキル、複素環、アリール、アリールオキシまたはヘテロアリールであり;そして
R4は、各々独立して、アルキル、シクロアルキル、複素環、アリールまたはヘテロアリールであって;
R1、R2、R3またはR4の任意のアルキル、シクロアルキル、複素環、アリール、アリールオキシ、ヘテロアリール、アルコキシまたはアミンは、1〜5つの置換基で任意に置換される)
の化合物、またはその製薬上許容可能な塩。 - R1、R2、R3またはR4のアルキル、シクロアルキル、複素環、アリール、アリールオキシ、ヘテロアリール、アルコキシまたはアミンが1〜5つの(C1−C6)アルキル、(C1−C6)アルケン、(C1−C6)アルキン、エポキシド、オキソ、アルキルカルボキシレート、アルコキシ、カルバルデヒド、ハロ、OH、CN、NO2またはSH基で置換される請求項1記載の化合物。
- nが1であり、そしてR3がフェニル、ピリジル、インドリル、ジヒドロベンゾフラニルまたはベンゾ[d]オキサゾリルである請求項2記載の化合物。
- nが1であり、そしてR3がフェニルまたはピリジル(1、2または3つのアルキル、アルコキシ、ハロ、トリフルオロメチル、トリフルオロメトキシ、メチルアミノ、ジメチルアミノ、フェニル、フェニルオキシ、モルホリノ、チオモルホリノ、ピペラジニル、ピペリジニル、イミダゾリル、ジアジニル、トリアジニルまたはピロリジニル基で置換される)である請求項2記載の化合物。
- R1が(C1−C6)アルキル、ハロまたはトリフルオロメチルである請求項1〜4のいずれか一項に記載の化合物。
- R2が(C1−C6)アルキルまたはトリフルオロメチルである請求項1〜4のいずれか一項に記載の化合物。
- X1がCHであり、X2がSであり、Zが−C(=O)NH−または−C(=O)O−であり、そしてnが1である請求項1〜4のいずれか一項に記載の化合物。
- Zが−C(=O)NH−であり、そしてnが1〜4である請求項1記載の化合物。
- Zが−C(=O)O−であり、そしてnが1〜4である請求項1記載の化合物。
- Zが−C(=O)C(=O)−であり、そしてnが1〜4である請求項1記載の化合物。
- Zが−CH2C(=O)−、−C(=O)CH2−または−NH−C(=O)NH−であり;そしてnが1〜4である請求項1記載の化合物。
- R1がメチル、トリフルオロメチル、クロロまたはフルオロである請求項1記載の化合物。
- R2がメチル、トリフルオロメチルまたはエチルである請求項1または12記載の化合物。
- Zが−C(=O)NH−であり、nが1〜4であり、R1がメチル、トリフルオロメチル、クロロまたはフルオロであり、そしてR2がメチル、トリフルオロメチルまたはエチルである請求項1記載の化合物。
- R3が、以下の:
(a)OR4またはNHR4;
(b)
(c)
(d)
(e)
(f)
(g)
(h)
である請求項8〜13のいずれか一項に記載の化合物。 - R2がアルキルまたはアルコキシである請求項16〜19のいずれか一項に記載の化合物。
- R2が−Me、−Etまたは−CF3である請求項16〜19のいずれか一項に記載の化合物。
- N−(4−(4−クロロフェノキシ)ベンジル)−2,6−ジメチルイミダゾ[2,1−b]チアゾール−5−カルボキサミド(ND−010081)である請求項1記載の化合物。
- 表1で例示される化合物、またはその製薬上許容可能な塩である請求項1記載の化合物。
- 請求項1〜23のいずれか一項に記載の化合物を製薬上許容可能な希釈剤または担体と組合せて含む組成物。
- 細菌を死滅させるかまたは細菌の増殖を抑制する方法であって、細菌を、有効致死または抑制量の請求項1、19、22または23記載の化合物と接触させることを包含する方法。
- 細菌を死滅させるかまたは細菌の増殖を抑制するための、あるいは細菌感染を処置するための請求項1、19、22または23記載の化合物の使用。
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KR20150088990A (ko) | 2015-08-04 |
US20150210715A1 (en) | 2015-07-30 |
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CN104718213B (zh) | 2018-02-27 |
JP6483610B2 (ja) | 2019-03-13 |
CA2879460C (en) | 2021-10-19 |
BR112015001201B1 (pt) | 2022-02-22 |
AU2018200569A1 (en) | 2018-02-15 |
WO2014015167A3 (en) | 2014-03-13 |
AU2019250199A1 (en) | 2019-11-07 |
CA2879460A1 (en) | 2014-01-23 |
RU2696278C2 (ru) | 2019-08-01 |
EP2875029A2 (en) | 2015-05-27 |
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US9605002B2 (en) | 2017-03-28 |
EP2875029A4 (en) | 2016-03-02 |
EP2875029B8 (en) | 2021-12-15 |
KR102178590B1 (ko) | 2020-11-13 |
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AU2013292529A1 (en) | 2015-02-12 |
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