JP6486950B2 - 新規の官能性1,3−ベンゼンジオール及び肝性脳症を治療するためのそれらの使用方法 - Google Patents
新規の官能性1,3−ベンゼンジオール及び肝性脳症を治療するためのそれらの使用方法 Download PDFInfo
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- JP6486950B2 JP6486950B2 JP2016547058A JP2016547058A JP6486950B2 JP 6486950 B2 JP6486950 B2 JP 6486950B2 JP 2016547058 A JP2016547058 A JP 2016547058A JP 2016547058 A JP2016547058 A JP 2016547058A JP 6486950 B2 JP6486950 B2 JP 6486950B2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 42
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- 235000002639 sodium chloride Nutrition 0.000 description 41
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- 239000000243 solution Substances 0.000 description 37
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 28
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- 230000015572 biosynthetic process Effects 0.000 description 25
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- 239000011734 sodium Substances 0.000 description 25
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 24
- 239000002609 medium Substances 0.000 description 23
- 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 description 22
- 125000003118 aryl group Chemical group 0.000 description 22
- 150000004677 hydrates Chemical class 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
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- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 20
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 15
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 15
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- 239000012312 sodium hydride Substances 0.000 description 15
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- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 12
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 12
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- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 description 6
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- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- SUBUUGVBEKEFGW-UHFFFAOYSA-N tetramethylazanium;azide Chemical compound [N-]=[N+]=[N-].C[N+](C)(C)C SUBUUGVBEKEFGW-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect 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
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
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- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/16—Anti-Parkinson drugs
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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Description
本出願は、2014年1月13日出願の米国仮出願第61926869号の利益を主張するものであり、参照によりその全体が本明細書に組み込まれる。
Aが、
zが、0、1、又は2であり、
Aが
Aが
Aが
Aが
R1が
R1が
R1が
R2が
Wが、(CH2)mであり、
mが、1又は2であり、
Yが、(CH2)qであり、
qが、1又は2であり、
nが、0、1、2、又は3であり、
bが、0、1、2、又は3であり、
dが、0、1、2、又は3であり、
R3が、COR5、CO2R6、CONR7aR7b、SO2NR7aR7b 、SO2R8、及び任意に置換されたヘテロアリールよりなる群から選択され、
R4a及びR4bが各々独立して、水素及びC1〜6アルキルよりなる群から選択され、
R4cが、水素及びOHよりなる群から選択され、
R5が、水素、C1〜6アルキル、任意に置換されたヘテロアリール、
−C(R9aR9b)NR7aR7b、及びC(R9aR9b)OR10よりなる群から選択され、
R5も、任意に置換されたC1〜6アルキルから選択され、
R6が、C1〜6アルキルであり、
R6も、任意に置換されたC1〜6アルキルから選択され、
R7a及びR7bが各々独立して、水素及びC1〜6アルキルよりなる群から選択され、
R7a及びR7bも各々独立して、任意に置換されたC1〜6アルキルから選択され、
R8が、水素、C1〜6アルキル、及び任意に置換されたヘテロアリールよりなる群から選択され、
R8も、任意に置換されたC1〜6アルキルから選択され、
R9a及びR9bが各々独立して、よりなる群から選択され、水素、C1〜6アルキル、C3〜7分岐状アルキル、CH2OH、CH(OH)CH3、CH2Ph、CH2(4−OH−Ph)、(CH2)4NH2、(CH2)3NHC(NH2)NH、CH2(3−インドール)、CH2(5−imidazole)、CH2CO2H、CH2CH2CO2H、CH2CONH2、及びCH2CH2CONH2.
R10が、水素及びC1〜6アルキルよりなる群から選択される。
本発明の化合物は、官能性1,3−ベンゼンジオールであり、式:
Aが
zが、0、1、又は2であり、
Aが
Aが
Aが
Aが
R1が
R1が
R1が
R2が
Wが、(CH2)mであり、
mが、1又は2であり、
Yが、(CH2)qであり、
qが、1又は2であり、
nが、0、1、2、又は3であり、
bが、0、1、2、又は3であり、
dが、0、1、2、又は3であり、
R3が、COR5、CO2R6、CONR7aR7b、SO2NR7aR7b 、SO2R8、及び任意に置換されたヘテロアリールよりなる群から選択され、
R4a及びR4bが各々独立して、水素及びC1〜6アルキルよりなる群から選択され、
R4cが、水素及びOHよりなる群から選択され、
R5が、水素、C1〜6アルキル、任意に置換されたヘテロアリール、
−C(R9aR9b)NR7aR7b、及びC(R9aR9b)OR10よりなる群から選択され、
R5も、任意に置換されたC1〜6アルキルから選択され、
R6が、C1〜6アルキルであり、
R6も、任意に置換されたC1〜6アルキルから選択され、
R7a及びR7bが各々独立して、水素及びC1〜6アルキルよりなる群から選択され、
R7a及びR7bも各々独立して、任意に置換されたC1〜6アルキルから選択され、
R8が、水素、C1〜6アルキル、及び任意に置換されたヘテロアリールよりなる群から選択され、
R8も、任意に置換されたC1〜6アルキルから選択され、
R9a及びR9bが各々独立して、よりなる群から選択され、水素、C1〜6アルキル、C3〜7分岐状アルキル、CH2OH、CH(OH)CH3、CH2Ph、CH2(4−OH−Ph)、(CH2)4NH2、(CH2)3NHC(NH2)NH、CH2(3−インドール)、CH2(5−imidazole)、CH2CO2H、CH2CH2CO2H、CH2CONH2、及びCH2CH2CONH2.
R10が、水素及びC1〜6アルキルよりなる群から選択される、化合物。
又はその薬学的に許容される塩形態を有する化合物を含み、式中、R3、Y、W、及びdの非限定的な例は、本明細書で以下の表3に定義される。
本発明はさらに、本発明の1つ以上の賦形剤を製造するためのプロセスに関する。
本発明の化合物の製造で使用される試薬は、商業的に入手され得るか、あるいは文献に記載される標準的な手順によって製造できる。本発明に従って、属する化合物は、以下の反応スキームのうちの1つによって生成できる。
スキームI
スキーム2
スキーム3
スキーム4
スキーム5
スキーム6
スキーム7
スキーム8
スキーム9
スキーム10
スキーム11
スキーム12
スキーム13
スキーム14
スキーム15
スキーム16
スキーム17
スキーム18
スキーム19
スキーム20
スキーム21
スキーム22
スキーム23
スキーム24
スキーム25
スキーム26
スキーム27
スキーム28
スキーム29
スキーム30
スキーム31
スキーム32
スキーム33
スキーム35
スキーム36
スキーム37
スキーム38
スキーム39
スキーム40
スキーム41
スキーム42
スキーム43
次いで、式(134)の化合物は、メタノール、エタノール、テトラヒドロフラン、1,4−ジオキサン、ジクロロメタン、クロロホルム、1,2−ジクロロエタン、N,N−ジメチルホルムアミド等の有機溶媒中で、任意にベンゼン塩化ルテニウム(II)、ビス(2,2′−ビピリジン)−(5−アミノフェナントロリン)ルテニウムビス(ヘキサフルオロホスフェート)、ビス(シクロペンタジエニル)ルテニウム(II)、ビス(シクロペンタジエニルルテニウムジカルボニル)二量体、カルボニルジヒドリドトリス(トリフェニルホスフィン)ルテニウム(II)、塩化クロロペンタアンミンルテニウム(II)、シスージクロロビス(2,2′−ビピリジン)ルテニウム(II)、ジクロロテトラキス(トリフェニルホスフィン)ルテニウム(II)等のルテニウム触媒の存在下で、任意に臭化銅(I)、塩化銅(I)、ヨウ化銅(I)等の銅(I)塩の存在下で、アセチレン(125)と反応して、式(135)の化合物をもたらす。
スキーム44
スキーム45
スキーム46
スキーム47
スキーム48
スキーム49
実施例1〜3は、代表的な式(I)の化合物を製造するための方法を提供する。当業者であれば、本発明の追加の化合物を製造するために、当業者に既知の適切な試薬、出発材料、及び精製方法を置き換える方法を理解するであろう。
テトラヒドロフラン(25mL)中のLiAlH4(0.43g、11.33mmol、1.1当量)の懸濁液に、内温度を30℃未満で維持する速度で、テトラヒドロフラン(20mL)中の(3,5−ジメトキシ−フェニル)−酢酸(2g、10.19mmol、1.0当量)の溶液を滴加し、混合物をさらに30分間撹拌し続けた。薄層クロマトグラフィ分析は、(3,5−ジメトキシ−フェニル)−酢酸の消費を示した。水(1mL)をゆっくりと添加して反応停止処理し、続いて、15%の水性KOH(1mL)及び水(3mL)を添加した。形成された固体を濾過し、濾過されたケーキをテトラヒドロフラン(2×30mL)で洗浄した。合わせた濾液をNa2SO4上で乾燥させ、濃縮して、黄色油として粗2−(3,5−ジメトキシ−フェニル)−エタノールを得て、それをさらなる精製なしで使用した。H−NMR(300MHz、CDCl3)δ 6.41−6.31(m、3H)、3.71(s、6H)、3.59(m、2H)、2.66(t、J=7.2Hz、2H)。
ジクロロメタン(80mL)中のトリフェニルホスフィン(4.56g、17.38mmol、1.5当量)、ヨウ素(4.41g、17.37mmol、1.5当量)及びイミダゾール(1.97g、28.93mmol、2.5当量)の混合物中に、ジクロロメタン(25mL)中の2−(3,5−ジメトキシ−フェニル)−エタノール(2.11g、11.57mmol、1.0当量)の溶液を添加し、結果として得られた混合物を45分間室温で撹拌し続けた。薄層クロマトグラフィ分析は、2−(3,5−ジメトキシ−フェニル)−エタノールの完全な消費を示した。NaHSO3(100mL)の水溶液を添加して反応停止処理した。水相をジエチルエーテル(3×100mL)によって抽出した。合わせた有機相をNa2SO4上で乾燥させ、濾過し、濃縮して、黄色油として粗1−(2−ヨード−エチル)−3,5−ジメトキシ−ベンゼンを得た。原料をカラムクロマトグラフィによって精製して、黄色油として1−(2−ヨード−エチル)−3,5−ジメトキシ−ベンゼンを得た。H−NMR(300 MHz、CDCl3)δ 6.39−6.36(m、3H)、6.36(s、6H)、3.36(t、J=8.1Hz、2H)、3.14(t、J=7.8Hz、2H)。
N,N−ジメチルアセトアミド(72mL)中の2H−1,2,3−トリアゾル(0.28g、4.05mmol、1.0当量)の溶液に、NaH(60%、0.2g、5.0mmol、1.2当量)を添加し、30分間室温で撹拌した。1−(2−ヨード−エチル)−3,5−ジメトキシ−ベンゼン(1.2g、4.1mmol、1.0当量)を添加し、結果として得られた混合物を14時間室温で撹拌した。薄層クロマトグラフィ分析は、反応の完了を示した。水(100mL)を添加して反応停止処理した。水相を酢酸エチル(3×50mL)で抽出した。酢酸エチル相を塩水(3×50mL)で逆洗浄し、乾燥させ、濃縮して、粗生成物を得た。粗生成物を、酢酸エチル/ヘキサンを用いたカラムクロマトグラフィによって精製し、1−[2−(3,5−ジメトキシ−フェニル)−エチル]−1H−[1,2,3]トリアゾルを得た。H−NMR(300MHz、CDCl3)δ 7.64(s、1H)、7.31(s、1H)、4.63(t、J=7.2Hz、2H)、3.75(s、6H)、3.16(t、J=7.2Hz、3H)。
40% HBr/酢酸(1:1)(6mL)中の1−[2−(3,5−ジメトキシ−フェニル)−エチル]−1H−[1,2,3]トリアゾル(0.13g、0.56mmol、1.0当量)の溶液を、窒素の保護下で12時間還流させた。薄層クロマトグラフィ分析は、反応の完了を示した。反応混合物を乾燥するまで濃縮した。残渣を酢酸エチル(10mL)中に溶解し、飽和NaHCO3の溶液で処理して、pHを5〜6に調節した。有機相を分離し、水相を酢酸エチル(2×5mL)によって抽出した。合わせた有機相をNa2SO4上で乾燥させ、濾過し、濃縮して、黄色固体として粗5−(2−[1,2,3]トリアゾル−1−イル−エチル)−ベンゼン−1,3−ジオールを得た。粗5−(2−[1,2,3]トリアゾル−1−イル−エチル)−ベンゼン−1,3−ジオールを、さらなる精製なしで次のステップに直接使用した。H−NMR(300MHz、CD3OD)δ 7.76(s、1H)、7.66(s、1H)、6.09(m、3H)、4.64(t、J=7.0Hz、2H)、3.05(t、J=7.0Hz、2H)。
テトラヒドロフラン/ジクロロメタン(4:1)(10mL)の混合溶媒中の5−(2−[1,2,3]トリアゾル−1−イル−エチル)−ベンゼン−1,3−ジオール(200mg、0.98mmol、1.0当量)及びp−トルエンスルホン酸(74mg、0.43mmol、0.4当量)の混合物に、4−(R)−イソプロペニル−1−(S)−メチル−シクロヘキサ−2−エノール(223mg、1.46mmol、1.5当量)をゆっくり添加した。反応混合物はまた懸濁液であった。次いで、酢酸(2mL)を添加し、反応物を0.5時間室温で撹拌した。反応混合物を酢酸エチル(10mL)で希釈した。飽和NaHCO3溶液の添加によって、pH値を約7に調節した。有機相を分離し、水相を酢酸エチル(2×10mL)によって抽出した。合わせた有機相をNa2SO4上で乾燥させ、濾過し、濃縮して、粗生成物を得た。粗生成物を分取HPLCを通して精製して、5−(2−(1H−1,2,3−トリアゾル−1−イル)エチル)−2−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンゼン−1,3−ジオールを得た。LCMS(ESI):m/z 340(M+1)、m/z 362(M+Na)。H−NMR(300MHz、CD3OD)δ 7.63(s、1H)、7.61(s、1H)、6.04(s、2H)、5.26(s、1H)、4.61(t、J=6.9Hz、2H)、4.45(d、J=3Hz、2H)、4.00−3.92(m、1H)、3.00−2.90(m、3H)、2.30−2.00(m、2H)、1.80−1.70(m、2H)、1.68(s、3H)、1.64(s、3H)。
トルエン(100mL)中の1−ブロモメチル−3,5−ジメトキシ−ベンゼン(12g、51.92mmol、1.0当量)及びトリフェニルホスフィン(15g、57.18mmol、1.1当量)の溶液を4時間還流させた。薄層クロマトグラフィ分析は、出発材料が完全に消費されたことを示した。反応混合物を室温まで冷却し、結果として得られた固体を濾過によって回収した。固体を1時間メタノール/石油エーテル(1:20、220mL)中で超音波分解し、濾過し、濾過ケーキを石油エーテル(3×20mL)によって洗浄して、白色固体として粗生成物(3,5−ジメトキシ−ベンジル)−トリフェニル−ホスホニウムブロミドを得た。粗(3,5−ジメトキシ−ベンジル)−トリフェニル−ホスホニウムブロミドを、さらなる精製なしで次のステップに直接使用した。H−NMR(300 MHz、CDCl3)δ 7.94−7.89(m、3H)、7.79−7.65(m、12H)、6.43(s、1H)、6.12(t、J=2.4Hz、2H)、5.08(s、1H)、5.03(s、1H)、3.50(s、6H)。
N、N−ジメチルホルムアミド(25mL)中の3,5−ジヒドロキシ安息香酸(8.0g、51.9mol、1.0当量)の溶液に、K2CO3(28.6g、0.2076mol)を添加した。混合物を30分間室温で撹拌した。N、N−ジメチルホルムアミド(25mL)中の塩化ベンジル(21.6g、171.3mmol、3.3当量)の溶液が添加され、結果として得られた懸濁液を一晩70℃で撹拌した。反応の進行を薄層クロマトグラフィによって監視した。出発材料が消費された後、水(50mL)を添加して反応停止処理した。反応停止処理した反応混合物を酢酸エチル(3×50mL)で抽出した。合わせた有機相を10%塩水(3×50mL)で洗浄し、Na2SO4上で乾燥させ、濾過し、真空で濃縮して、茶色固体として粗生成物3,5−ビス−ベンジルオキシ−安息香酸ベンジルエステルを得て、それをさらなる精製なしで次のステップに使用した。H−NMR(300MHz、CDCl3)δ 7.50−7.28(m、17H)、6.84(s、1H)、5.37(s、2H)、5.09(s、4H)。
テトラヒドロフラン(100mL)中のLiAlH4(14g、0.368 mol、4当量)の懸濁液に、20分間、テトラヒドロフラン(100mL)中の3,5−ビス−ベンジルオキシ−安息香酸ベンジルエステル(39g、0.092mol、1当量)の溶液を添加し、結果として得られた混合物を1時間室温で撹拌した。薄層クロマトグラフィ分析は、反応の完了を示した。次いで、反応混合物に、水(40mL)、15%KOH水溶液(40mL)、及び水(120mL)を順にゆっくり添加した。結果として得られた固体を濾過した。有機相を分離し、水層を酢酸エチル(100mL)で抽出した。合わせた有機層を乾燥させ、濃縮した。残渣をカラムクロマトグラフィ(酢酸エチル/ヘキサン=1/8)を通して精製し、所望の生成物(3,5−ビス−ベンジルオキシ−フェニル)−メタノールを得た。H−NMR(300MHz、CDCl3)δ 7.50−7.30(m、10H)、6.66−6.50(m、3H)、5.06(s、4H)、4.65(d、J=6.0Hz、2H)。
アセトニトリル(100mL)中の(3,5−ビス−ベンジルオキシ−フェニル)−メタノール(18g、56mmol、1.0当量)の溶液に、0〜5℃で、アセトニトリル(50mL)中の三臭化リン(22.8g、84mmol、1.5当量)の溶液を滴加した。添加後、反応混合物を2時間0〜5℃で撹拌し続けた。薄層クロマトグラフィは、反応の完了を示した。水(50mL)を30分間添加した。形成された固体を濾過した。固体を酢酸エチル(100mL)中に再溶解し、塩水(100mL)によって洗浄し、乾燥させ、濃縮して、粗生成物1,3−ビス−ベンジルオキシ−5−ブロモメチル−ベンゼンを得て、それをさらなる精製なしで使用した。H−NMR(300MHz、CDCl3)δ 7.45−7.33(m、10H)、6.67(s、2H)、6.58(s、1H)、5.05(s、4H)、4.44(s、2H)。
トルエン(100mL)中の1,3−ビス−ベンジルオキシ−5−ブロモメチル−ベンゼン(16g、42mmol、1.0当量)及びトリフェニルホスフィン(12g、46.2mmol、1.1当量)の溶液を、3〜4時間還流させた。薄層クロマトグラフィによって示されるように、出発材料1,3−ビス−ベンジルオキシ−5−ブロモメチル−ベンゼンを完全に消費した。反応混合物を室温まで冷却した。形成された固体を濾過によって回収した。固体を、1時間メタノール/石油エーテル(1:20、220mL)中で超音波分解し、濾過し、濾過ケーキを石油エーテル(3×20mL)によって洗浄して、白色固体として生成物(3,5−ビス−ベンジルオキシ−ベンジル)−トリフェニルホスホニウムブロミドを得て、それをさらなる精製なしで使用した。H−NMR(300MHz、CDCl3)δ 7.89−7.78(m、3H)、7.77−7.68(m、12H)、7.40−7.21(m、10H)、6.62(s、1H)、6.22(s、2H)、5.08(s、1H)、5.03(s、1H)、4.82(s、4H)。
窒素の保護下で、ヘキサン(2.5M、15.1mL、37.75mmol、2当量)中のn−ブチルリチウムを、20分間−5〜0℃で、乾燥テトラヒドロフラン(150mL)中の(3,5−ビス−ベンジルオキシ−ベンジル)−トリフェニルホスホニウムブロミド(8.1g、12.59mmol、1.0当量)の懸濁液に添加した。20分間0℃で撹拌した後、テトラヒドロフラン(100mL)中の3−オキソ−アゼチジン−1−カルボン酸エチルエステル(3.6g、25.17mmol、2当量)の溶液を滴加した。添加後、氷塩冷却槽を除去し、反応物を室温まで温め、さらに1時間撹拌し続けた。薄層クロマトグラフィは、3−オキソ−アゼチジン−1−カルボン酸エチルエステルの消失を示した。水(150mL)を添加して反応停止処理した。混合物を酢酸エチル(3×100mL)によって抽出した。合わせた有機相を塩水(100mL)で洗浄し、乾燥させ、濃縮した。粗生成物をカラムクロマトグラフィ(酢酸エチル/ヘキサン=1/10)によって精製して、所望の生成物3−(3,5−ビス−ベンジルオキシ−ベンジリジン)−アゼチジン−1−カルボン酸エチルエステルを得た。H−NMR(300MHz、CDCl3)δ 7.77−7.37(m、10H)、6.54−6.53(m、1H)、6.33(d、J=1.9 Hz、2H)、6.19(s、1H)、5.05(s、4H)、4.78(s、2H)、4.68(s、2H)、4.21−4.13(q、J=7.1Hz、2H)、1.30(t、J=7.1Hz、3H)。
酢酸エチル(400mL)中の3−(3,5−ビス−ベンジルオキシ−ベンジリジン)−アゼチジン−1−カルボン酸エチルエステル(4.0g、9.3mmol、1当量)及び炭素上の10%のパラジウム(1.0g、0.1当量)の懸濁液を、4時間室温で、水素バルーン下で撹拌した。薄層クロマトグラフィは、反応の完了を示した。炭素触媒上のパラジウムをセライトを通して濾過した。濾液を濃縮して、粗生成物3−(3,5−ジヒドロキシ−ベンジル)−アゼチジン−1−カルボン酸エチルエステルを得て、それをさらなる精製なしで次のステップに直接使用した。LCMS(ESI):m/z 252(M+1)。H−NMR(300MHz、CDCl3)δ 6.24−6.19(m、2H)、5.98(brs、1H)、4.17−4.11(m、2H)、4.06−4.01(m、2H)、3.70−3.67(m、1H)、2.77(brs、2H)、1.30−1.23(m、3H)。
4つの平行バッチを以下の通り実施した。クロロホルム(45mL)中の3−(3,5−ジヒドロキシ−ベンジル)−アゼチジン−1−カルボン酸エチルエステル(0.45g、1.79mmol、1.2当量)の懸濁液に、p−トルエンスルホン酸(68mg、0.39mmol、0.26当量)及び4−(R)−イソプロペニル−1−(S)−メチル−シクロヘキサ−2−エノール(0.23g、1.5mmol、1当量)を添加し、結果として得られた混合物を、10分間室温で撹拌した。薄層クロマトグラフィ分析は、出発材料3−(3,5−ジヒドロキシ−ベンジル)−アゼチジン−1−カルボン酸エチルエステルの約60〜70%の変換を示した。飽和NaHCO3溶液を反応混合物に添加して、pHを9〜10に調節した。有機相を分離し、水相をジクロロメタン(2×50mL)で抽出した。合わせた有機相をNa2SO4上で乾燥させ、濾過し、濃縮して、粗エチル3−(3,5−ジヒドロキシ−4−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンジル)アゼチジン−1−カルボン酸を得た。4つの平行バッチからの粗エチル3−(3,5−ジヒドロキシ−4−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンジル)アゼチジン−1−カルボン酸の4つのバッチを組み合わせて、カラムクロマトグラフィ(酢酸エチル/ヘキサン=1/3)によって精製し、分取HPLCによってさらに精製して、エチル3−(3,5−ジヒドロキシ−4−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンジル)アゼチジン−1−カルボン酸を得た。HPLC:99%。LCMS(ESI):m/z 408(M+Na)。H−NMR(300MHz、CDCl3)δ 6.18−6.03(m、3H)、5.56(s、1H)、5.12(s、1H)、4.64(s、1H)、4.53(s、1H)、4.15−4.04(m、4H)、3.90−3.86(m、1H)、3.70−3.65(m、2H)、2.86−2.74(m、3H)、2.43−2.35(m、1H)、2.24−2.21(m、1H)、2.13−2.08(m、1H)、1.86−1.76(m、5H)、1.66(s、3H)、1.25(t、J=7.1Hz、3H)。
本発明はまた、本発明による官能性1,3−ベンゼンジオールを含む組成物又は製剤に関する。概して、本発明の組成物は、肝性脳症の治療及び予防の提供に有効な、本発明による有効量の1つ以上の官能性1,3−ベンゼンジオール及びその塩ならびに1つ以上の賦形剤を含む。
以下の手順を、エタノール及びアンモニア毒性に対する神経保護薬としての化合物を評価及び選択する際に利用することができる。
全ての化合物を、一次試験システムとして胎生期18日目のラットから得られる解離海馬培養物を用いてスクリーニングした。この製造物を用いて、一次ニューロンを使用して、肝性脳症(HE)に対する非常に関連した実験系において、毒性ならびに神経保護に関して試験した。簡潔に、海馬組織をBrain Bits(Springfield,IL)を通して商業的に得て、培養物をすでに記載されたように製造した(Brewer,1995)。海馬ニューロンを、96ウェル型に低密度で(10,000細胞/ウェル)播種し、B27及びGlutaMAX(Gibco)が補充されたNeurobasal Mediumからなる無血清培地中で維持した。このマトリクス支持体上の海馬ニューロン及びグリアの付着及び生存のため、プレコートポリ−D−リシンでコートされたプレートが使用される。
以前の研究は、カンナビジオールが発作を予防することができることを示している(Consroe and Wolkin,1977)。カンナビジオール関連化合物を評価する別の手段は、それらの抗けいれん効果に対する。
表5:海馬培養物中の神経保護的活性のアッセイにおける本開示の例示的な化合物及びそれらの能力
**NP=海馬培養物中の300μMの酢酸アンモニウム(AmAc)からの神経保護
***NP=海馬培養物中の30mMのエタノール+300μMの酢酸アンモニウムからの神経保護
EC50=最大の観察された保護値の50%を生成するために必要とされる本開示の化合物の濃度(対照レベル)。
本開示の化合物の薬物動態プロファイルは、本開示の化合物の静脈内及び経口用量をCD1マウスに投与することによって、CD1マウスにおいて決定される。血漿試料を0.083、0.25、0.5、1.0、2.0、4.0、8.0、及び24時間に採取して、本開示の化合物の血漿濃度を決定した。脳及びCSF試料を、投与後0.25時間、2時間、及び8時間に回収した。静脈内用量を、0.4mg/mLで、5%ジメチルアセトアミド(DMAC)、5% Solutol HS15、及び90%生理食塩水中の溶液として製造し、経口用量を、1mg/mLで、5%ジメチルアセトアミド(DMAC)、5% Solutol HS15、及び90%生理食塩水中の溶液として製造した。本開示の例示的な化合物に関する実験結果は、表6〜9ならびに図1及び2に記載される。
表6(図1):CD1マウスにおける2mg/kgの静脈内投与後のKLS−13019(実施例2)のPKパラメータ。
表7(図1):CD1マウスにおける10mg/kgの経口投与後のKLS−13019(実施例2)のPKパラメータ。
表8(図2):脳及びCSF透過性を決定するための、CD1マウスにおける10mg/kgの単回経口投与後のKLS−13019(実施例2)のPKパラメータ。
表9(図2):CD1マウスにおける10mg/kgの経口投与後のKLS−13019(実施例2)の個々及び平均の脳及びCSF透過性−時間データ
Claims (18)
- 次式(I):
Aが
nが、0、1、2又は3であり、
R1が
R 1が
R1が
R1が
Wが、(CH2)mであり、
mが、1又は2であり、
Yが、(CH2)qであり、
qが、1又は2であり、
R 3が、COR5、CO2R6、CONR7aR7b、SO2NR7aR7b 、SO2R8、及び任意に置換されたヘテロアリールよりなる群から選択され、
R4a及びR4bが各々独立して、水素及びC1〜6アルキルよりなる群から選択され、
R4cが、水素及びOHよりなる群から選択され、
R5が、水素、任意に置換されたC1〜6アルキル、任意に置換されたヘテロアリール、−C(R9aR9b)NR7aR7b、及びC(R9aR9b)OR10よりなる群から選択され、
R 6が、任意に置換されたC1〜6アルキルであり、
R 7a及びR7bが各々独立して、水素及び任意に置換されたC1〜6アルキルよりなる群から選択され、
R 8が、水素、任意に置換されたC1〜6アルキル、及び任意に置換されたヘテロアリールよりなる群から選択され、
R 9a及びR9bが各々独立して、水素、C1〜6アルキル、C3〜7分岐状アルキル、CH2OH、CH(OH)CH3、CH2Ph、CH2(4−OH−Ph)、(CH2)4NH2、(CH2)3NHC(NH2)NH、CH2(3−インドール)、CH2(5−イミダゾール)、CH2CO2H、CH2CH2CO2H、CH2CONH2、及びCH2CH2CONH2よりなる群から選択され、
R10が、水素及びC1〜6アルキルよりなる群から選択される、前記化合物又はその水和物、溶媒和物、薬学的に許容される塩若しくは鏡像異性体。 - 式(II):
- 式(III):
- 式(IV):
- 式(V):
- 式(VI):
- 5−(2−(1H−1,2,3−トリアゾル−1−イル)エチル)−2−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンゼン−1,3−ジオール、
1−(3−(3,5−ジヒドロキシ−4−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンジル)アゼチジン−1−イル)エタノン、
3−(3,5−ジヒドロキシ−4−((1R,6R)−3−メチル−6−(プロプ−1−エン−2−イル)シクロヘキサ−2−エニル)ベンジル)アゼチジン−1−カルボン酸エチル
である、請求項1に記載の化合物、又はその薬学的に許容される塩。 - 次式(I):
Aが
nが、0、1、2又は3であり、
R 1 が
R 1 が
R 1 が
R 1 が
Wが、(CH 2 ) m であり、
mが、1又は2であり、
Yが、(CH 2 ) q であり、
qが、1又は2であり、
R 3 が、COR 5 、CO 2 R 6 、CONR 7a R 7b 、SO 2 NR 7a R 7b 、 SO 2 R 8 、及び任意に置換されたヘテロアリールよりなる群から選択され、
R 4a 及びR 4b が各々独立して、水素及びC 1〜6 アルキルよりなる群から選択され、
R 4c が、水素及びOHよりなる群から選択され、
R 5 が、水素、任意に置換されたC 1〜6 アルキル、任意に置換されたヘテロアリール、−C(R 9a R 9b )NR 7a R 7b 、及びC(R 9a R 9b )OR 10 よりなる群から選択され、
R 6 が、任意に置換されたC 1〜6 アルキルであり、
R 7a 及びR 7b が各々独立して、水素及び任意に置換されたC 1〜6 アルキルよりなる群から選択され、
R 8 が、水素、任意に置換されたC 1〜6 アルキル、及び任意に置換されたヘテロアリールよりなる群から選択され、
R 9a 及びR 9b が各々独立して、水素、C 1〜6 アルキル、C 3〜7 分岐状アルキル、CH 2 OH、CH(OH)CH 3 、CH 2 Ph、CH 2 (4−OH−Ph)、(CH 2 ) 4 NH 2 、(CH 2 ) 3 NHC(NH 2 )NH、CH 2 (3−インドール)、CH 2 (5−イミダゾール)、CH 2 CO 2 H、CH 2 CH 2 CO 2 H、CH 2 CONH 2 、及びCH 2 CH 2 CONH 2 よりなる群から選択され、
R 10 が、水素及びC 1〜6 アルキルよりなる群から選択され、
前記化合物が1〜10個の重水素原子で同位体標識された化合物。 - 有効量の請求項1に記載の少なくとも1つの化合物を含む、組成物。
- 少なくとも1つの賦形剤をさらに含む、請求項9に記載の組成物。
- 肝性脳症を治療又は予防するための医薬組成物であって、前記医薬組成物が肝性脳症を治療又は予防するのに有効な量の請求項1に記載の少なくとも1つの化合物を含む、医薬組成物。
- 前記医薬組成物が、少なくとも1つの賦形剤をさらに含む、請求項11に記載の医薬組成物。
- 肝性脳症に関連する疾患又は状態を治療又は予防するための医薬組成物であって、前記疾患又は状態を治療又は予防するのに有効な量の請求項1に記載の少なくとも1つの化合物を含む、医薬組成物。
- 前記医薬組成物が、少なくとも1つの賦形剤をさらに含む、請求項13に記載の医薬組成物。
- 病因としてフリーラジカル媒介ストレス及び酸化ストレスを伴う疾患を治療又は予防するための医薬組成物であって、前記医薬組成物が前記疾患を治療又は予防するのに有効な量の請求項1に記載の少なくとも1つの化合物を含み、前記疾患が任意に、てんかん、神経障害性疼痛、外傷性頭部損傷、脳卒中、慢性外傷性脳症(CTE)、心停止後低酸素性虚血性脳症、てんかん性脳症、パーキンソン病、アルツハイマー病、ハンチントン病、及び筋萎縮性側索硬化症(ALS)よりなる群から選択される、医薬組成物。
- 前記医薬組成物が、少なくとも1つの賦形剤をさらに含む、請求項15に記載の医薬組成物。
- 病因としてフリーラジカル媒介ストレス及び酸化ストレスに関連する疾患を治療又は予防するか、又は前記疾患に関連する状態を治療又は予防するための医薬組成物であって、前記医薬組成物が前記疾患又は状態を治療又は予防するのに有効な量の請求項1に記載の少なくとも1つの化合物を含み、前記疾患又は状態が任意に、てんかん、神経障害性疼痛、外傷性頭部損傷、脳卒中、慢性外傷性脳症(CTE)、心停止後低酸素性虚血性脳症、てんかん性脳症、及び神経変性疾患、例えば、パーキンソン病、アルツハイマー病、ハンチントン病、及び筋萎縮性側索硬化症(ALS)よりなる群から選択される、医薬組成物
- 前記医薬組成物が、少なくとも1つの賦形剤をさらに含む、請求項17に記載の医薬組成物。
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