JP5877553B2 - オリゴマー−抗コリン剤複合体 - Google Patents
オリゴマー−抗コリン剤複合体 Download PDFInfo
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- JP5877553B2 JP5877553B2 JP2009553621A JP2009553621A JP5877553B2 JP 5877553 B2 JP5877553 B2 JP 5877553B2 JP 2009553621 A JP2009553621 A JP 2009553621A JP 2009553621 A JP2009553621 A JP 2009553621A JP 5877553 B2 JP5877553 B2 JP 5877553B2
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- water
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- small molecule
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- 238000001361 intraarterial administration Methods 0.000 description 1
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- 238000007913 intrathecal administration Methods 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
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- 239000005017 polysaccharide Substances 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
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- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
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- 229960000697 propantheline Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
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- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 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
- 238000004885 tandem mass spectrometry Methods 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
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 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
- 150000003555 thioacetals Chemical class 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 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
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
- C07C69/736—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本出願は、合衆国法典35巻第119(e)の下、2007年3月12日に出願された米国仮出願番号第60/906,329号の優先権の利益を主張するものであり、参照することにより本願明細書に組み込まれる。
本発明は、(とりわけ)化学修飾を欠く小分子抗コリン剤と比較して、特定の利点を有する、化学的に修飾された小分子抗コリン剤を提供する。本願明細書に記載されている化学的に修飾された小分子抗コリン剤は、(とりわけ)創薬、薬物療法、生理学、有機化学、および高分子化学の分野に関連する、および/またはその分野における用途を有する。
R1は、H、OH、および有機基部から成る群より選択され、好ましくはR1は、‐H、‐OH、‐CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択され、
(i)R2は、‐H、‐OH、および有機基部から成る群より選択され[好ましくは、R2は、‐H、‐OH、‐CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択される]、かつR3は、H、OH、および有機基部から成る群より選択される[好ましくは、R3は、‐H、‐OH、‐CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択される]か、または(ii)R2およびR3は、組み合わされてシクロヘキシル等の環を形成するかのいずれかであり、
但し、R1およびR3のうちの少なくとも1つは、芳香族含有有機基部(フェニル等)であることを条件とし、
L1は、‐O‐、‐C(O)O‐、‐OC(O)‐、‐C(O)‐であり、
L2は、C2−4含有炭化水素リンカー、(化学式IのNを組み込む)ヘテロシクロ、(化学式IのNを組み込む)ビヘテロシクロであり、
R4は、有機基部、好ましくは‐CH3または‐CH2CH3であり、
R5は、有機基部、好ましくはCH3またはCH2CH3であり、さらに、化学式Iのアミンは、任意選択で荷電される(例えば、CH3基がアミンに結合される結果としての第4級窒素)。
(項目1)
安定したまたは分解性結合を介して水溶性非ペプチドオリゴマーに共有結合した抗コリン剤の残基を含む、化合物。
(項目2)
以下の構造を有し、
R 1 は、H、OH、および有機基部から成る群より選択され、
(i)R 2 は、H、OH、および有機基部から成る群より選択され、かつR 3 は、H、OH、および有機基部から成る群より選択されるか、または(ii)R 2 およびR 3 は、組み合わされて環を形成するかのいずれかであり、
但し、R 1 およびR 3 のうちの少なくとも1つは、芳香族含有有機基部であることを条件とし、
L 2 は、C 2−4 含有炭化水素リンカー、ヘテロシクロリンカー、およびビヘテロシクロリンカーから成る群より選択され、
R 5 は、有機基部であり、
Xは、スペーサ部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物、
ならびに前記化合物の荷電種。
(項目3)
R 5 は、‐CH 3 および‐CH 2 CH 3 から成る群より選択される、項目2に記載の化合物。
(項目4)
R 1 は、シクロヘキシルであり、R 2 は、‐OHであり、R 3 は、フェニルである、項目2に記載の化合物。
(項目5)
L 2 は、‐CH 2 ‐C≡C‐CH 2 ‐である、項目2に記載の化合物。
(項目6)
以下の構造を有し、
R 1 は、H、OH、および有機基部から成る群より選択され、
R 3 は、H、OH、および有機基部から成る群より選択され、
但し、R 1 およびR 3 のうちの少なくとも1つは、芳香族含有有機基部であることを条件とし、
L 2 は、C 2−4 含有炭化水素リンカー、ヘテロシクロリンカー、およびビヘテロシクロリンカーから成る群より選択され、
R 4 は、有機基部であり、
R 5 は、有機基部であり、
Xは、スペーサ部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物、
ならびに前記化合物の荷電種。
(項目7)
R 4 は、‐CH 3 および‐CH 2 CH 3 から成る群より選択され、R 5 は、‐CH 3 および‐CH 2 CH 3 から成る群より選択される、項目6に記載の化合物。
(項目8)
R 1 は、シクロヘキシルであり、R 3 は、フェニルである、項目6に記載の化合物。
(項目9)
L 2 は、‐CH 2 ‐C≡C‐CH 2 ‐である、項目6に記載の化合物。
(項目10)
前記抗コリン剤は、以下の化学式を有し、
R 1 は、H、OH、および有機基部から成る群より選択され、
(i)R 2 は、H、OH、および有機基部から成る群より選択され、かつR 3 は、H、OH、および有機基部から成る群より選択されるか、または(ii)R 2 およびR 3 は、組み合わされて環を形成するかのいずれかであり、
但し、R 1 およびR 3 のうちの少なくとも1つは、芳香族含有有機基部であることを条件とし、
L 1 は、‐O‐、‐C(O)O‐、‐OC(O)‐、‐C(O)‐であり、
L 2 は、C 2−4 含有炭化水素リンカー、ヘテロシクロリンカー、およびビヘテロシクロリンカーから成る群より選択され、
R 4 は、有機基部であり、
R 5 は、有機基部であり、
Xは、スペーサ部分であり、
POLYは、水溶性非ペプチドオリゴマーである、項目1に記載の化合物、
ならびに前記化合物の荷電種。
(項目11)
前記抗コリン剤は、オキシブチニン、ジサイクロミン、オキシフェンサイクリミン、フラボキサート、クリンジウム(clindium)、シクロペントラート、オイカトロピン、グリコピロレート、メペンゾラート、メタンテリン、スコポラミン、アトロピン、およびプロパンテリンから成る群より選択される、項目1に記載の化合物。
(項目12)
前記抗コリン剤は、オキシブチニンである、項目1に記載の化合物。
(項目13)
前記水溶性非ペプチドオリゴマーは、ポリ(アルキレンオキシド)である、項目1、2、および6のうちのいずれか1項に記載の化合物。
(項目14)
前記ポリ(アルキレンオキシド)は、ポリ(エチレンオキシド)である、項目13に記載の化合物。
(項目15)
前記スペーサ部分は、共有結合である、項目2に記載の化合物。
(項目16)
前記スペーサ部分は、‐O‐である、項目6に記載の化合物。
(項目17)
前記水溶性非ペプチドオリゴマーは、1〜30個のモノマーを有する、項目1に記載の化合物。
(項目18)
前記水溶性非ペプチドオリゴマーは、1〜10個のモノマーを有する、項目17に記載の化合物。
(項目19)
前記ポリ(アルキレンオキシド)は、アルコキシまたはヒドロキシの末端封止部分を含む、項目13に記載の化合物。
(項目20)
前記抗コリン剤の前記残基は、安定した結合を介して共有結合される、項目1に記載の化合物。
(項目21)
前記結合は、エーテル結合である、項目1に記載の化合物。
(項目22)
前記結合は、エステル結合である、項目1に記載の化合物。
(項目23)
前記結合は、アミン結合である、項目1に記載の化合物。
(項目24)
安定したまたは分解性結合を介して水溶性非ペプチドオリゴマーに共有結合した、抗コリン剤の残基を含む化合物と、任意選択で薬剤として許容される賦形剤と、を含む、組成物。
(項目25)
安定したまたは分解性結合を介して水溶性非ペプチドオリゴマーに共有結合した、抗コリン剤の残基を含む化合物を含む組成物であって、前記化合物が投薬形態で存在する、組成物。
(項目26)
水溶性非ペプチドオリゴマーを、抗コリン剤に共有結合させるステップを含む、方法。
(項目27)
安定したまたは分解性結合を介して水溶性非ペプチドオリゴマーに共有結合した、抗コリン剤の残基を含む化合物を投与するステップを含む、方法。
本発明の、これら、および他の目的、態様、実施形態、および特徴は、以下の発明を実施するための形態と共に読み取ることでさらに明らかになるであろう。
R1は、H、OH、および有機基部から成る群より選択され、好ましくはR1は、‐H、‐OH、−CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択され、
(i)R2は、‐H、‐OH、および有機基部から成る群より選択され[好ましくは、R2は、‐H、‐OH、‐CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択される]、かつR3は、H、OH、および有機基部から成る群より選択される[好ましくは、R3は、‐H、‐OH、‐CH2OH、‐CH3、シクロペンチル、1‐ヒドロキシルシクロペンチル、シクロヘキシル、および芳香族含有有機基部(フェニル等)から成る群より選択される]か、または(ii)R2およびR3は、組み合わされてシクロヘキシル等の環を形成するかのいずれかであり、
但し、R1およびR3のうちの少なくとも1つは、芳香族含有有機基部(フェニル等)であることを条件とし、
L1は、‐O‐、‐C(O)O‐、‐OC(O)‐、‐C(O)‐であり、
L2は、C2−4含有炭化水素リンカー、(化学式IのNを組み込む)ヘテロシクロ、(化学式IのNを組み込む)ビヘテロシクロであり、
R4は、有機基部、好ましくは‐CH3または‐CH2CH3であり、
R5は、有機基部、好ましくはCH3またはCH2CH3であり、さらに、化学式Iのアミンは、任意選択で荷電される(例えば、CH3基がアミンに結合される結果としての第4級窒素)。
本発明は、ある種の好適な特定の実施形態に関して記載されているが、上述の説明およびそれに続く実施例は、例示することを意図したものであり、本発明の範囲を制限するものではないことを理解されたい。本発明の範囲内の他の態様、利点、および修正物が、本発明に関係する当業者には明らかとなるであろう。
PEG−オキシブチニンを調製した。概略的に、本実施例に適用された手法を以下に示す。
ジクロロメタン(30mL)中の3,4−ジヒドロ−2H−ピロン(18.3mL、0.196mol)を、0℃のDCM(250mL)中の2−ブチン−1,4−ジ−オール(16.832g、0.194mol)およびp−TsOH(2.236g、11.58mmol)の撹拌溶液に30分かけて滴下した。添加後、室温で4時間混合物を撹拌した。重炭酸ナトリウム(858mg)を添加した。さらに1時間混合物を撹拌した。水(10mL)を添加し、その後、飽和水性炭酸カリウム(150mL)を添加した。有機相を分離し、食塩水(200mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、減圧下で濃縮した(温度25℃未満)。5〜25%のEtOAc/ヘキサンを使用して、シリカゲルのフラッシュカラムクロマトグラフィーにより残渣を分離し、12.05gの二保護化副生成物と共に、12.88gの生成物(収率:39%)を得た。1H−NMR(CDCl3):δ4.78(t,J=3.0−3.3Hz、1H)、4.37−4.21(m,4H)、3.86−3.78(m,1H)、3.55−3.50(m,1H)、1.83−1.64(m,6H)。
無水DMF(7.0mL)中の2−シクロヘキシル−2−フェニルグリコール酸12(240mg、1.0mmol)および2−ブチン−1,4−ジオール(87mg、1.0mmol)の撹拌溶液に、HOBt(135.7mg、1.0mmol)を添加し、0℃に冷却した。N−メチルモルフィノン(0.25mL、2.26mmol)を添加した。結果として生じた混合物を、0℃で30分間撹拌した。DCC(216.5mg、1.05mmol)を添加した。結果として生じた混合物を0℃で30分間、次いで室温で21.5時間撹拌した。EtOAc(20mL)を添加し、白色沈殿物を濾過により除去した。有機溶液を分離し、水溶液をEtOAc(2×25mL)で抽出した。合わせた有機溶液を食塩水で洗浄し、Na2SO4上で乾燥させ、濃縮した。0〜20%のEtOAc/ヘキサンを使用して、シリカゲルのフラッシュカラムクロマトグラフィーによって残渣を分離し、シクロヘキシルフェニル酢酸4−(2−シクロヘキシル−2−ヒドロキシ−2−フェニルアセトキシ)−ブト−2−イニルエステル(26)(99mg、37%の収率)(以下の構造に示すように)と共に、生成物(20)(50mg、17%収率)を得た。
2−シクロヘキシル−2−フェニルグリコール酸(12)(579mg、2.47mmol)および1,1’−カルボニルジイミダゾール(462mg、2.85mmol)の溶液を、50℃で5時間撹拌し、室温に冷却した。該溶液を、−70℃(イソプロパノール/ドライアイス)の無水DMF(15mL)中の2−ブチン−1,4−ジオール(1)(1.0085g、11.60mmol)およびトリエチルアミン(2.0mL、14.28mmol)の撹拌溶液に、5分かけて添加した。結果として生じた混合物を、−70℃で1時間撹拌した。冷却浴を除去し、反応混合物を放置して室温まで温め、室温で18時間継続して撹拌した。水を添加して反応を停止させた。混合物を、酢酸エチル(3×25mL)で抽出した。合わせた有機溶液を食塩水(2×50mL)で洗浄し、無水硫酸ナトリウム上で乾燥させ、濃縮した。ジクロロメタン中0〜5%のメタノールを使用して、シリカゲルのフラッシュカラムクロマトグラフィーにより残渣を分離し、副生成物、シクロヘキシルフェニル酢酸4−(2−シクロヘキシル−2−ヒドロキシ−2−フェニルアセトキシ)−ブト−2−イニルエステル(26)(129mg、20%の収率)と共に、生成物(20)(509mg)を68%の収率で得た。
Claims (5)
- 以下の構造:
を有し、式中、nは1〜30である、化合物。 - nは1〜10である、請求項1に記載の化合物。
- 請求項1に記載の化合物と、任意選択で薬剤として許容される賦形剤と、を含む、組成物。
- 請求項1に記載の化合物を含む組成物であって、前記化合物が投薬形態で存在する、組成物。
- 以下の構造:
を有する、請求項1に記載の化合物。
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