CN87106553A - 含乙炔苯基的视黄酸衍生物的生产 - Google Patents
含乙炔苯基的视黄酸衍生物的生产 Download PDFInfo
- Publication number
- CN87106553A CN87106553A CN87106553.3A CN87106553A CN87106553A CN 87106553 A CN87106553 A CN 87106553A CN 87106553 A CN87106553 A CN 87106553A CN 87106553 A CN87106553 A CN 87106553A
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- formula
- compound
- acid
- alkynyl
- alkene
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- 238000004519 manufacturing process Methods 0.000 title claims 4
- SHGAZHPCJJPHSC-YCNIQYBTSA-N retinoic acid group Chemical class C\C(=C/C(=O)O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 150000001408 amides Chemical class 0.000 claims abstract description 14
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- 241001597008 Nomeidae Species 0.000 claims description 5
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- 238000007163 homologation reaction Methods 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- DULCUDSUACXJJC-UHFFFAOYSA-N Ethyl phenylacetate Chemical compound CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- CRTGSPPMTACQBL-UHFFFAOYSA-N 2,3-dihydroxycyclopent-2-en-1-one Chemical compound OC1=C(O)C(=O)CC1 CRTGSPPMTACQBL-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000000243 solution Substances 0.000 description 34
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- 239000000203 mixture Substances 0.000 description 22
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- -1 ethynyl phenyl functional group Chemical group 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
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- 238000002360 preparation method Methods 0.000 description 9
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- 229910052786 argon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
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- 229920006395 saturated elastomer Polymers 0.000 description 5
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
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- 229910052740 iodine Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- PSQYTAPXSHCGMF-BQYQJAHWSA-N β-ionone Chemical compound CC(=O)\C=C\C1=C(C)CCCC1(C)C PSQYTAPXSHCGMF-BQYQJAHWSA-N 0.000 description 4
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 3
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- 229960003424 phenylacetic acid Drugs 0.000 description 3
- 239000003279 phenylacetic acid Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 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 3
- 239000007787 solid Substances 0.000 description 3
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- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- SFEOKXHPFMOVRM-UHFFFAOYSA-N (+)-(S)-gamma-ionone Natural products CC(=O)C=CC1C(=C)CCCC1(C)C SFEOKXHPFMOVRM-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000006218 Arndt-Eistert homologation reaction Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
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- 125000003118 aryl group Chemical group 0.000 description 2
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- 150000001983 dialkylethers Chemical class 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
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- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 2
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- KVBWBCRPWVKFQT-UHFFFAOYSA-N 3-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC(I)=C1 KVBWBCRPWVKFQT-UHFFFAOYSA-N 0.000 description 1
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 description 1
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- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- BNSOYWDFFBDEFB-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O BNSOYWDFFBDEFB-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
- C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
如下式化合物具有类视黄质活性式中n为0—5而A为H,低级烷基,或-COOH或其酯或酰胺;-CH2OH或其醚或酯;或-CHO或缩醛衍生物;
或药物可接受的盐。
Description
本发明涉及具有类视黄质活性的新颖化合物,更具体地说,本发明涉及其中在视黄酸的含酸部份的三个烯烃单位都被乙炔基苯基官能基所取代的化合物。已经发现对视黄酸结构作此种修正可保有类视黄质的活性。
日本专利56-123903所揭示的杀线虫化合物,具有结构式2-(2-(((1,1-二甲基)-二甲基甲硅烷基)氧基)乙基-α-(4-(2,6,6-三甲基-1-环己烯-1-基)-3-丁烯-1-炔基)-1-环戊烯-1-甲醇,系采用本文所揭示的化合物的1-(2′,6′,6′-三甲基-环己-1′-烯基)-丁-1-烯-3-炔部分。然而,该部分是日本专利化合物与本文所揭示化合物之唯一类似点,此种化合物并未包括本发明。
本发明包括式Ⅰ化合物
式中n为0-5而A为H,低级烷基,或-COOH或药物可接受的盐,或其酯或酰胺;-CH OH或其醚或酯;或-CHO或缩醛衍生物。
本发明的第二特点系有关式Ⅰ化合物用于治疗皮肤病,例如痤疮,毛囊角化病,牛皮癣,鱼鳞癣,湿疹,异位性皮肤炎小上皮癌的用法。这些化合物也可用于治疗关节疾病及其他免疫疾患(例如,红斑性狼疮),用于促进创伤愈合及治疗干眼病候群。
本发明也关于包含式Ⅰ化合物与药用可接受的赋形剂混合之药物配方。
另一特点,本发明系关于其中A为酸或酯官能的式Ⅰ化合物的制法,该方法包含使式Ⅱ化合物与式Ⅲ化合物在Pd(PQ3)4(Q为苯基)或类似之复合物存在下反应
式中n为0-5而A为H,低级烷基,COOR其中R为本文所定义的酯基,-CH2OH的醚或酯或-CHO的缩醛衍生物,而当n=0时X为Br或I,较好为I,或当n为1-5时为I;或同系化如下式化合物
式中n为0-4,而A为COOH,或
将式Ⅰ之酸转化成盐;或
将式Ⅰ之酸转化成酯;或
将式Ⅰ之酸转化成酰胺;或
将式Ⅰ之酸还原成醇或醛;或
将式Ⅰ之醇转化醚或酯;或
将式Ⅰ之醇氧化成醛;或
将式Ⅰ之醛转化成缩醛。
实施例
本文所用的“酯”一词代表且包括所有有机化学传统使用之名词定义范围内之任一种化合物,包括有机酯及无机酯。当A为-COOH时,本词包括使用醇或硫醇处理此官能基所衍生的产物。当从A为-CH2OH的化合物衍生得到酯时,本词包括从可形成酯的有机酸例如磷基及硫基酸衍生得到的化合物,或式-CH2OCOR化合物,式中R为任何经取代或未经取代的脂肪族,芳香族,杂芳香族或脂肪族-芳香族基。
较佳酯系从10或10以下的碳原子的饱和脂肪族醇或酸衍生而得,或从5至10碳原子的环状或饱和脂肪族环形醇或酸衍生而得。特佳的脂肪族酯为从低级烷基酸或醇衍生而得。在此,及在出现的他处,低级烷基代表具有1-6碳原子。也属较佳者为苯基或低级烷基苯基酯。
酰胺具有有机化学界传统使用的该名词定义。此种情况下包括未取代酰胺及所有脂肪族及芳香族一-及二-取代酰胺。较佳酰胺为从10或10以下碳原子的饱和脂肪族基或5至10碳原子的环形或饱和脂肪族-环形基衍生而得的一-及二-取代酰胺。特佳酰胺为从饱和及不饱和低级烷基胺类衍生而得。也属较佳者为从取代及未取代之苯基或低级烷基苯基胺类衍生而得之一-及二-取代酰胺,未取代的酰胺也属较佳。
缩醛包括式-CK基团,式中K为(-OR)2。在此,R为低级烷基。同时,K可为OR1O-,式中R1为2-5碳原子的低级链烯烃,直链或支链。
对本发明具有可形成盐类官能基,例如酸或胺官能基的任何化合物皆可制成药物可接受盐。药物可接受盐为任何保有亲代化合物活性而对用药个体以及投药方式未赋予任何有害或非所需效应的任一种盐。
药物可接受盐可从有机或无机酸或碱衍生而得。盐可为一价或多价离子。特别感兴趣者为无机离子,钠,钾,钙,及镁。有机盐可使用胺,尤其铵盐例如一-,二-及三烷基胺或乙醇胺制得。盐也可使用咖啡因,托美沙明及类似分子而生成。
本发明的较佳化合物为式Ⅰ化合物中的取代基与苯环上的乙炔基链呈对位者;n为0,1或2;而A为-COOH,碱金属盐或有机胺盐,或低级烷基酯,或-CH2OH及其低级烷基酯。最佳化合物为:
4-〔4′-(2″,6″,6″-三甲基-环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯;及
4-〔4′-(2″.6″,6″-三甲环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸。
本发明化合物可经全身性或局部性投药,依据例如有待处理的病情,对于部位特异性疗法的需要,有待投药的药量,及无数其他考虑点而定。
在皮肤病的治疗中,通常较好局部用药,唯某些病例中例如治疗严重囊性痤疮或牛皮癣时,也可使用口服投药。任何常用局部配方例如溶液,悬浮液,胶浆,软膏,或油膏等皆可使用,此种局部用配方的制备在药物配方领域已有详细叙述,例如,叙述于雷明顿药物科学,17版,宾州,伊斯顿市,麦克出版公司。供局部用药,此等化合物也可呈粉剂或喷洒剂,尤其呈气溶胶形式投药。
若化合物系经全身性投药,则可调配成粉剂,丸剂,片剂等,或呈糖浆或酏剂适用于口服投药。供静脉或腹内投药,则化合物可制成可经注射投药的溶液剂或悬浮液剂。某些情况下,可将此等化合物调配成栓剂剂型或呈延长释放配方以供经皮肤或肌肉注射而沉积。
其他药物可加入此种局部配方中以供例如治疗皮肤干燥等第二目的;提供防晒保护;其他治疗皮肤病药物;预防感染,减少刺激,发炎等的药物。
可经由投与治疗有效剂量的一种或多种本发明化合物而治疗皮肤病或任何其他已知或已发现对类视黄酸化合物的治疗具有敏感性的任何其他适应病。治疗浓度为可减少特定病情或延迟其扩展的该种浓度。某些病例中,本化合物可以预防方式用以防止特定病情的出现。
有用的治疗浓度随著各病情而异,某些情况下可能随有待治疗的病情严重度及病人对治疗的敏感度而异。因此,不必一致地使用单一浓度,而须依据有待治疗之疾病特定情况加以修饰。此种浓度可经由例行实验而获知。然而,预期用于治疗,例如,痤疮,或类似之皮肤病,含有0.01至1.0mg/ml之配方可构成局部用药之治疗有效浓度,若经全身性投药,则预期0.01至5mg/kg/日体重之数量可用于治疗许多可使用此等化合物之疾病而获得疗效。
此等化合物的类视黄酸活性可经由传统测定视黄酸活性而加以验证,系测定视黄酸对鸟氨酸脱羧酶之功效。对于视黄酸与细胞增生降低间之关系最初系由Verma及Boutwell进行研究,癌症研究,1977,37,2196-2201。该参考文献揭示,在聚胺生物合成之前有鸟氨酸脱羧酶(ODC)的活性增高。其他研究者已经确定聚胺合成的增加可能与细胞增生有关;因此,若可抑制ODC活性,则可调节细胞过度增生之问题。虽然ODC活性增高之因素仍未知,但已知12-0-十四烷基佛伯-13-乙酸酯(TPA)可诱出ODC活性,而视黄酸可抑制由TPA诱出ODC活性。大体遵照癌症研究:1662-1670,1975,所述之程序进行检定可验证本发明化合物,也可抑制TPA诱出ODC。
特定具体实施例
预期本发明化合物可由多种不同化学合成路径而制造。为说明本发明,在此列出一系列步骤,当在步骤与精神上遵照此种合成时,已证实可提供式Ⅰ化合物。合成化学家将可了解在此所列的条件乃特定具体实施例,而此等实施例可应用至任何或所有由式Ⅰ所代表的化合物。式Ⅰ化合物的制备如下:
前述反应式中,当式2中的n为0时,X为Br或I,唯较好为I;而当n为1-5时,X为I。此反应式中,R′为低级烷基。
式2化合物系从其对应酸制备而得。此等酸(式1)皆可由化学品制造商获得或可用已公开的方法而制备。酯化作用系将酸在亚硫酰氯存在下在适当醇溶液内回流而进行,回流2-5小时可得所需酯。酯由常规方式回收及纯化。
欲获得其中n为1-5的式ⅠA化合物时,其中R为氢的式Ⅰ化合物在Arndt-Eistert条件下,经由连续处理而进行同系化作用。此例中之X为I。然后可将酸用前段所述的一般程序而转成式2的酯。
式3化合物由Aldrich化学品公司以Beta-Ionone之名出售。乙炔官能基系利用锂二异丙酰胺或类似之碱于减温下,于惰性气氛下引进其中。反应系在醚-型溶剂例如二烷基醚或环形醚,如四氢呋喃,吡喃等内进行。
更确切地说,锂二异丙酰胺系经由将二异丙胺在干溶剂例如四氢呋喃内混合,然后在惰性气氛下冷却至-70至-50℃间之温度而原地生成。然后在减温下加入等摩尔量之烷基锂化合物例如n-丁基锂于合宜溶剂且混合经适当时间而使锂二异丙酰胺(LDA)生成。式3之酮(至少10%摩尔过量)溶解于反应溶剂内,溶液冷却至LDA混合物之温度,且加入该溶液内,经短暂混合后,将溶液用氯磷酸二烷酯,较好氯磷酸二乙酯以约20%摩尔过量处理。然后将反应溶液逐渐升回室温,接着将此溶液加入第二锂二异丙酰胺溶液(约2当量)内,后一溶液系使用干溶剂及在惰性气氛,较好氩之下于减温(如-78℃)下原地制备,随后,将反应混合物再度温热至室温,搅拌历长时间,较好10至20小时,最好约15小时。接着将溶液酸化且由常规手段回收式4产物。
式5化合物在排除水及氧的条件下制备。可使用干燥,醚-型溶剂例如二烷基醚或环形醚如呋喃或吡喃,较好为四氢呋喃,作溶剂。首先在惰性气氛如氩或氮之下制得式4之溶液,然后加入强碱如N-丁基锂(以约10%摩尔过量)。此反应始于-10℃至+10℃的减温下,较好约为0℃。反应混合物搅拌短时间,约30分钟至2小时,然后使用约10%摩尔过量之熔融氯化锌溶解于反应溶剂内处理。此混合物于约开始温度下又搅拌1-3小时,然后将温度升高至约室温10-40分钟。
欲进行式6之生成,将囟苯甲酸烷酯溶解于干燥反应溶剂内。酯之用量约等于化合物4开始数量之摩尔量。此溶液引进四-三苯膦钯(约5至10%摩尔量,以反应物之量为准)于反应溶剂的悬浮液内,此悬浮液之温度约为-10℃至+10℃间。短暂搅拌此混合物,历约15分钟。然后于此新制之混合物内加入预先一制备的式5溶液,此添加可于约室温下进行。此溶液于室温下搅拌长时间,约15至25小时。然后使用酸淬熄反应,产物用常规手段分离及纯化而得式6化合物。
制造其中n为1-5之化合物的另一手段,系将其中n为0的式6化合物使用前述Arndt-Eistert方法进行同系化以便经由同系化作用将式Ⅰ化合物转成式2。
由式7所代表的酸,药用可接受盐及酰胺溶液由式6的酯而得。使用碱金属碱进行碱性皂化作用可得酸。例如,式6的酯可溶解于极性溶剂如烷醇内,较好系在惰性气氛下于室温下使用约3摩尔过量之碱,例如氢氧化钾,而溶解。溶液搅拌长时间,15至20小时,冷却,酸化且用常规手段回收水解产物。
酰胺可用本领域已知的任何合宜酰胺化手段而生成。一种此化合物之制备手段系首先制成酰基氯。然后使用氢氧化铵或合宜胺处理该化合物。例如,使用醇性溶液碱例如乙醇性KOH(以约10%摩尔过量)处理该酸且于室温下约反应1/2小时;去除溶剂,残渣溶解于有机溶剂例如醚内,使用二烷基甲酰胺处理,然后使用10倍过量的草酰氯处理,全部皆系于约-10℃至+10℃间之减温下进行。然后,后述溶液于减温下搅拌1-4小时,较好2小时。去除溶剂可得残渣,溶解于惰性无机溶剂如苯内,冷却至约0℃,使用浓氢氧化铵处理。所得混合物于减温下搅拌1-4小时。用常规手段回收产物。
醇的制法,可将对应的酸使用亚硫酰氯转成酰基氯(J.March,“先进有机化学”,第2版,麦克罗-希耳出版公司),然后使用硼氢化钠还原酰基氯(March之同文,1124页),可得对应之醇;使用合宜之烷基卤化物在威廉森氏反应条件(March同文,357页)下烷基化此等醇而得对应的醚。
醛可使用温和氧化剂,例如重铬酸吡啶于亚甲基氯化物,从对应之一级醇制备而得(Corey,E.J.schmidt,G.Tet,Lett.,399,1979)。
缩醛可用March同文,810页所述的方法,从对应之醛制备而得。
其中A为氢或低级烷基的化合物可从对应之碘苯基部分制备而得。此种碘苯基化合物如反应图Ⅰ且更特定地于实施例3中所述与乙炔基氯化锌化合物反应。其中A为氢或低级烷基之碘苯基化合物可由市面购得或可用文献中的方法制备。
列举如下实施例以说明本发明,而非限制其范围。
实施例1
4-碘苯甲酸乙酯
10g(40.32mmol)4-碘苯甲酸(Alfa产品公司Thiokol/Ventron分公司)于100ml绝对乙醇之悬浮液内,加入2ml亚硫酰氯。然后将此混合物回流加热3小时。真空去除溶剂,残渣溶解于100ml醚内。醚溶液使用饱和NaHCO3及饱和NaCl溶液洗涤且干燥(MgSO4);然后真空去除溶剂,残渣在硅藻土装置(100℃;0.55mm)上蒸馏而得9g标题化合物,呈无色油。
PMR
(CDCl3)δ1.42(3H,t,J~7Hz),4.4(2H,q,J~7Hz),7.8(4H,s).
以类似的方式进行,唯取代2-碘苯甲酸及3-碘苯甲酸,可制得如下酯:
3-碘苯甲酸乙酯-PMR(CDCl3)δ1.4(3H,t,J~7Hz),4.37(2H,q,J~7Hz),7.12(1H,t,J~8Hz),7.95(2H,m),8.37(1H,s);and 2-碘苯甲酸乙酯-PMR(CDCl3)δ1.4(3H,t,J~8Hz),4.35(2H,q,J~8Hz),7.25(2H,m),7.65(2H,m).
此方法可用于制造制备如本文权利要求所提出的化合物所需的任何酯。
实施例2
1-(2′,6′,6′-三甲基环己-1′-烯基)-丁-1-烯-3-炔
12.17g(120.27mmol)二异丙胺于200ml干四氢呋喃的溶液于氩下冷却至-78℃且经注射筒使用75ml 1.6M(120摩尔)n-丁基锂于己烷逐滴处理。此混合物于-78℃搅拌1小时,然后经由导管使用21.99g(114.35mmol)β-ionone(Aldrich化学品公司)于20ml干四氢呋喃的冷(-78℃)溶液处理。此混合物于-78℃搅拌1小时,使用21.73g(125.93mmol)氯磷酸二乙酯逐滴处理且经2小时温热至室温;然后用导管将此混合物移入LDA溶液内,LDA溶液系在氩下,于-78℃搅拌26.57g(262.57mmol)二异丙胺于150ml干四氢呋喃及164ml 1.6M(262.4mmol)n-丁基锂于己烷之溶液经0.5小时而制得。令混合物温热至室温,搅拌15小时,以250ml 3N HCl酸化且使用戊烷萃取。有机萃液以1N HCl水,饱和NaHCO3及饱和NaCl洗涤及干燥(MgSO4)。产物于硅藻土装置(50℃;0.1mm Hg)上浓缩及蒸馏而得标题化合物,呈无色油。
PMR(CDCl3)δ1.0(2CH3,s),1.45(2H,m),1.65(CH3,s),1.92(2H,m)2.85(1H,d,J~3Hz),5.35(1H,dd,J~16Hz,J~3Hz),6.6(1H,d,J~16Hz).
实施例3
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯
本程序所用的反应容器在真空下经火焰干燥且全体操作系在无氧氩或氮气氛下进行。实施例2所制的970mg(5.5656mmol)乙炔基化合物(式4)于5ml干四氢呋喃于0℃之溶液内加入3.6ml 1.6M(5.76mmol)n-丁基锂于己烷。此混合物于0℃搅拌1.25小时。然后经导管使用790mg(5.7968mmol)熔融氯化锌于4ml干四氢呋喃的溶液处理且于0℃搅拌2小时,随后于室温搅拌20分钟。1.53g(5.542mmol)4-碘苯甲酸乙酯于4ml干四氢呋喃的溶液用导管移入450mg(0.3894mmol)四-三苯膦钯于4ml干四氢呋喃于0℃之悬浮液内。此混合物于0℃搅拌15分钟,然后经由导管使用新制炔基氯化锌化合物溶液处理,所形成的混合物于室温搅拌20小时。混合物用添加30ml 2N HCl而淬熄且使用100ml混合的己烷及100ml醚萃取。合并有机萃液以饱和NaHCO3及NaCl溶液洗涤,干燥(MgSO4)及浓缩而得褐色油。此油用中压液相层析(Waters 500;2×硅胶预先充填物;20%CH2Cl2于己烷)纯化而得标题化合物,呈灰黄色油。
PMR(CDCl3):δ1.05(2CH3,s),1.35(3H,t,J~7Hz),1.5(2H,m),1.75(CH3,s),2.0(2H,M),4.55(2H,q,J~7Hz),5.65(1H,d,J~16.5Hz),6.70(1H,d,J~16.5Hz),7.4(2H,d,J~8Hz),7.9(2H,d,J~8Hz).
以类似方式进行,唯使用实施例1制备的2-碘及3-碘同系物取代4-碘苯甲酸乙酯,可制得对应之邻及间位化合物,其PMR资料为:
3-〔4′(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯
-PMR(CDCl3):δ1.05(2CH3,s),1.37(3H,t,J~7Hz),1.50(2H,m),1.75(CH3,s),2.0(2H,m),4.33(2H,q,J~7Hz),5.65(1H,d,J~16Hz),6.66(1H,d,J~16Hz),7.32(1H,t,J~8Hz),7.55(1H,dt,J~8,1.6Hz),7.9(1H,dt,J~8,1.6Hz),8.07(1H,t,J 1.6Hz);和.
2-[4′-(2″,6″,6″-三甲基環己-1″-烯基)-丁-3′-烯-1′-炔基苯甲酸乙酯-PMR(CDCl3):δ1.05(2CH3,s),1.42(3H,t,J~7Hz),1.47(1H,m),1.60(1H,m),1.78(CH3,s),2.02(2H,m),4.4(2H,q,J~7Hz),5.76(1H,d,J~16Hz),6.73(1H,d,J~16Hz),7.32(1H,td,J~7,1.5Hz),7.44(1H,td,J~7,1.5Hz),7.56(1H,dd,J~7,1.5Hz),7.94(1H,dd,J~7,1.5Hz);
以类似方式进行,可制得如下各化合物:
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸乙酯;
3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸乙酯。
2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基乙酸乙酯。
3-(4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)丙酸乙酯。
3-(3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基)丙酯乙酯。
3-(2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)丙酸乙酯。
4-(4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)丁酸乙酯。
4-(3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)丁酸乙酯。
4-(2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)丁酸乙酯。
5-(4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)戊酸乙酯。
5-(3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)戊酸乙酯。
5-(2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1-炔基〕苯基)戊酸乙酯。
实施例4
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸
292mg(0.9056mmol)4-〔4′-(2″,6″,6″-三甲基-环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯于1ml乙醇之溶液内在氩之下逐滴加入180mg(3.2mmol)KOH于2ml乙醇及0.5ml水的溶液。此混合物于室温搅拌18小时,冷却且以3N HCl酸化。所形成之沉淀溶解于醚内,醚溶液以饱和NaCl洗涤及浓缩而得固体,从甲醇/水中再结晶而得标题化合物,呈灰黄色固体。
PMR(CDCl3):δ1.05(2CH3,S),1.47(1H,m),1.62(1H,m),1.78(CH3,S),2.05(2H,m),5.78(1H,d,J~16Hz),6.78(1H,d,J~16Hz),7.58(2H,d,J~8Hz),8.02(2H,d,J~8Hz).
以相同方式进行,唯以实施例3所制备的化合物取代上述苯甲酸酯,可制得如下各化合物:
3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基-丁-3′-烯-1′-炔基〕苯甲酸;
2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸;
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸;
3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸;
2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸;
3-〔4-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕丙酸;
3-〔3-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕丙酸;
3-〔2-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕丙酸;
4-〔4-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕丁酸;
4-(3-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基)丁酸;
4-〔2-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕丁酸;
5-〔4-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕戊酸;
5-〔3-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕戊酸;
5-〔2-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕戊酸;
6-〔4-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕己酸;
6-〔3-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)己酸;和
6-〔2-(4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基)苯基〕己酸。
实施例5
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酰胺
48.8mg(0.1658mmol)实施例4及1.3ml 0.14M(0.182mmol)乙醇性KOH的混合物于室温搅拌0.5小时,真空去除溶剂,残渣溶解于2ml醚内,用1滴二甲基甲酰胺处理,冷却至0℃,然后使用143mg(1.1mmol)草酰氯处理。于0℃搅拌2小时后,混合物经过滤,残渣以醚洗涤且将合并的有机溶液浓缩。残渣溶解于苯内,冷却至0℃且使用1ml浓NH4OH逐滴处理。混合物于0℃搅拌2小时,以25ml水稀释及以醚萃取。醚萃液以饱和NaCl洗涤,干燥(MgSO4)及真空浓缩而得标题化合物,呈白色固体。
PMR(CDCl3):δ1.05(2CH3,s),1.46(1H,m),1.6(1H,m),1.76(CH3,s),2.05(2H,m),5.7(1H,d,J~16Hz),6.27(2H,寛 s),6.72(1H,d,J~16Hz),7.5(2H,d,J~8Hz),7.76(2H,d,J~8Hz).
以类似方式进行,依实施例4所制备的化合物可转成其对应之酰胺。
Claims (8)
2、根据权利要求1的方法,其中A为COOR而n为0-3。
3、根据权利要求2的方法,其中化合物为:
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯;3-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯;
2-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸乙酯;
4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯基乙酸乙酯;或
3-(4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基-丁-3′-烯-1′-炔基〕苯基)丙酸乙酯。
4、一种制造式Ⅰ化合物的方法
式中n为0-5而A为-COOH或其药物上可接受的盐,-CH2OH,或-CHO,其方法包括水解式Ⅰ的化合物。
式中A为COOR而R为低级烷基,-CH2OH的醚或酯,或-CHO的缩醛衍生物。
5、根据权利要求4的方法,其中n为0-3而A为-COOH或其药物上可接受的盐。
6、根据权利要求5的方法,其中化合物为:4-〔4′-(2″,6″,6″-三甲基环己-1″-烯基)-丁-3′-烯-1′-炔基〕苯甲酸。
7、根据权利要求5及6的方法,其中水解剂为碱。
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US5149705A (en) * | 1987-03-13 | 1992-09-22 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a tetralin group and having retinoid like activity |
US5264578A (en) * | 1987-03-20 | 1993-11-23 | Allergan, Inc. | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity |
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US5068252A (en) * | 1989-07-26 | 1991-11-26 | Allergan, Inc. | Methods of using phenylethenyl compounds having retinoid-like activity |
US5162546A (en) * | 1989-09-19 | 1992-11-10 | Allergan, Inc. | Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
US5399561A (en) * | 1989-09-19 | 1995-03-21 | Allergan, Inc. | Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-oxochromanyl, 2-oxothiochromanyl or 2-oxo-1,2,3,4-tetrahydro-quinolinyl group having retinoid-like biological activity |
US5248777A (en) * | 1989-09-19 | 1993-09-28 | Allergan, Inc. | Process and intermediates for preparing compounds having a disubstituted acetylene moiety and retinoic acid-like biological activity |
US5053523A (en) * | 1989-09-19 | 1991-10-01 | Allergan, Inc. | Ethynyl-chroman compounds |
US5023341A (en) * | 1989-09-19 | 1991-06-11 | Allergan, Inc. | Compounds having a disubstituted acetylene moiety and retinoic acid-like biological activity |
US5183827A (en) * | 1989-09-19 | 1993-02-02 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
US5272156A (en) * | 1989-09-19 | 1993-12-21 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
US4980369A (en) * | 1989-09-19 | 1990-12-25 | Allergan, Inc. | Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl or thiochromanyl group having retinoid-like activity |
US5013744B1 (en) * | 1989-12-29 | 1994-09-20 | Allegran Inc | Acetylenes disubstituted with a pyridinyl group and a substituted phenyl group having retinoid like activity |
US5175185A (en) * | 1989-12-29 | 1992-12-29 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity |
US5264456A (en) * | 1989-12-29 | 1993-11-23 | Allergan, Inc. | Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity |
US5006550A (en) * | 1989-12-29 | 1991-04-09 | Allergan, Inc. | Chroman esters of phenols and benzoic acids having retinoid-like activity |
US5202471A (en) * | 1990-02-06 | 1993-04-13 | Allergan, Inc. | Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity |
JP3062248B2 (ja) * | 1991-02-13 | 2000-07-10 | アラーガン、インコーポレイテッド | レチノイド様生物学的活性を有する7位にフェニルエチニル置換基を有するクロマンおよびチオクロマン |
WO1992017471A1 (en) * | 1991-03-26 | 1992-10-15 | Allergan, Inc. | Chromans and thiochromans with heteroarylethynyl substituents at the 7-position having retinoid-like biological activity |
US5134159A (en) * | 1991-03-26 | 1992-07-28 | Allergan, Inc. | 7-chromanyl esters of phenols and benzoic acids having retinoid-like activity |
WO1993016067A1 (en) * | 1992-02-11 | 1993-08-19 | Allergan, Inc. | Heteroaryl substituted phenylethenyl compounds having retinoid-like biological activity |
US5326898A (en) * | 1992-02-11 | 1994-07-05 | Allergan, Inc. | Substituted phenylethenyl compounds having retinoid-like biological activity |
US5324840A (en) * | 1992-06-11 | 1994-06-28 | Allergan, Inc. | Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects |
US6172115B1 (en) | 1993-02-11 | 2001-01-09 | Allergan Sales, Inc. | Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid |
US5455265A (en) | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
US5399586A (en) * | 1993-03-11 | 1995-03-21 | Allergan, Inc. | Treatment of mammals afflicted with tumors with compounds having RXR retinoid receptor agonist activity |
US5344959A (en) * | 1993-05-18 | 1994-09-06 | Allergan, Inc. | Tetrahydronaphthyl and cyclopropyl substituted 1,3-butadienes having retinoid-like activity |
US5475022A (en) * | 1993-10-18 | 1995-12-12 | Allergan, Inc. | Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity |
US5470999A (en) * | 1993-12-30 | 1995-11-28 | Allergan, Inc. | Cyclohexene and bicyclic aromatic substituted ethyne compounds having retinoid-like biological activity |
US5426118A (en) * | 1993-12-30 | 1995-06-20 | Allergan, Inc. | [4-(1,2-epoxycyclohexanyl)but-3-en-1-ynyl]aromatic and heteroaromatic acids and derivatives having retinoid-like biological activity |
US5451605A (en) * | 1993-12-30 | 1995-09-19 | Allergan, Inc. | 1,2-epoxycyclohexanyl and bicyclic aromatic substituted ethyne compounds having retinoid-like biological activity |
US5420295A (en) * | 1994-01-19 | 1995-05-30 | Allergan, Inc. | Process for preparing 4,4-dialkyl-6-halo-chromans or thiochromans useful as pharmaceutical intermediates |
US5498755A (en) * | 1994-08-23 | 1996-03-12 | Chandraratna; Roshantha A. | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
US5489584A (en) * | 1994-12-29 | 1996-02-06 | Allergan, Inc. | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5648514A (en) * | 1994-12-29 | 1997-07-15 | Allergan | Substituted acetylenes having retinoid-like biological activity |
US5618943A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5534641A (en) * | 1994-12-29 | 1996-07-09 | Allergan | Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups having retinoid-like biological activity |
US5543534A (en) * | 1994-12-29 | 1996-08-06 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity |
US5599967A (en) * | 1994-12-29 | 1997-02-04 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity |
US5514825A (en) * | 1994-12-29 | 1996-05-07 | Allergan, Inc. | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5556996A (en) * | 1994-12-29 | 1996-09-17 | Allergan | Oxiranyls disubstituted with a phenyl group and a substituted chromanyl or tetrahydroquinolinyl group having retinoid like activity |
US5618931A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
CA2215731A1 (en) * | 1995-03-20 | 1996-09-26 | Allergan | Use of retinoids for the manufacture of a medicament for the treatment of restenosis |
US6025388A (en) | 1995-04-26 | 2000-02-15 | Allergan Sales, Inc. | Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids |
US5616712A (en) * | 1995-05-16 | 1997-04-01 | Allergan | Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-thio-1,2,3,4-tetrahdroquinolinyl, 2-alkylthio-3,4-dihydroquinolinyl or 2-alkoxy-3,4-dihydroquinolinyl group having retinoid-like biological activity |
US5917082A (en) * | 1995-06-06 | 1999-06-29 | Allergan Sales, Inc. | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
US5675033A (en) * | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
US6218128B1 (en) | 1997-09-12 | 2001-04-17 | Allergan Sales, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
US5952345A (en) * | 1995-09-01 | 1999-09-14 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5958954A (en) * | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6008204A (en) | 1995-09-01 | 1999-12-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US6942980B1 (en) | 1995-09-01 | 2005-09-13 | Allergan, Inc. | Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities |
DE19539814C2 (de) * | 1995-10-26 | 1999-08-12 | Mannesmann Sachs Ag | Hydrodynamischer Drehmomentwandler mit Stabilisierungsring an den Schaufelrädern |
AU7598596A (en) * | 1995-11-01 | 1997-05-22 | Allergan, Inc. | Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity |
US5675024A (en) | 1995-11-22 | 1997-10-07 | Allergan | Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity |
US5663357A (en) | 1995-11-22 | 1997-09-02 | Allergan | Substituted heteroarylamides having retinoid-like biological activity |
US5688957A (en) * | 1995-12-29 | 1997-11-18 | Allergan | (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!aryl and (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!heteroaryl carboxylic acids and esters having retinoid-like biological activity |
US5965606A (en) | 1995-12-29 | 1999-10-12 | Allergan Sales, Inc. | Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity |
US20030219832A1 (en) * | 1996-03-11 | 2003-11-27 | Klein Elliott S. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5763635A (en) * | 1996-06-21 | 1998-06-09 | Allergan | Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity |
US5741896A (en) * | 1996-06-21 | 1998-04-21 | Allergan | O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5723666A (en) * | 1996-06-21 | 1998-03-03 | Allergan | Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5773594A (en) | 1996-06-21 | 1998-06-30 | Allergan | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US6555690B2 (en) | 1996-06-21 | 2003-04-29 | Allergan, Inc. | Alkyl or aryl substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5747542A (en) * | 1996-06-21 | 1998-05-05 | Allergan | Oxo-substituted tetrahydronaphthalene derivatives having retinold and/or retinoid antagonist-like biological activity |
US5808124A (en) * | 1996-06-21 | 1998-09-15 | Allergan | O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5739338A (en) * | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
US5728846A (en) | 1996-12-12 | 1998-03-17 | Allergan | Benzo 1,2-g!-chrom-3-ene and benzo 1,2-g!-thiochrom-3-ene derivatives |
US5760276A (en) * | 1997-03-06 | 1998-06-02 | Allergan | Aryl-and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity |
US6037488A (en) * | 1997-04-19 | 2000-03-14 | Allergan Sales, Inc. | Trisubstituted phenyl derivatives having retinoid agonist, antagonist or inverse agonist type biological activity |
US5919970A (en) | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
US6166244A (en) | 1999-05-07 | 2000-12-26 | Allergan Sales, Inc. | Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity |
US6177588B1 (en) | 1999-05-07 | 2001-01-23 | Allergan Sales, Inc. | 1-alkoxy and 1-acyloxy substituted cyclohex-1-ene compounds and sulfur and 1-alkoxycarbonyl analogs having retinoid-like biological activity |
US6313107B1 (en) * | 2000-08-29 | 2001-11-06 | Allergan Sales, Inc. | Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI |
CA2974196C (en) | 2015-01-20 | 2023-12-12 | TetraDerm Group LLC | Versatile topical drug delivery vehicle and multifactorial tissue moisturizer that provides mucosal and skin barrier restoration |
Family Cites Families (1)
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US4532343A (en) * | 1982-11-19 | 1985-07-30 | Sri International | Aromatic retinoic acid analogues |
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1986
- 1986-09-22 US US06/910,096 patent/US4739098A/en not_active Expired - Lifetime
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1987
- 1987-08-24 CA CA000545206A patent/CA1329620C/en not_active Expired - Fee Related
- 1987-08-25 ZA ZA876306A patent/ZA876306B/xx unknown
- 1987-08-28 NZ NZ221614A patent/NZ221614A/xx unknown
- 1987-08-31 PH PH35748A patent/PH24108A/en unknown
- 1987-09-08 DK DK468587A patent/DK468587A/da not_active Application Discontinuation
- 1987-09-16 IL IL83915A patent/IL83915A/xx unknown
- 1987-09-16 DE DE8787308166T patent/DE3767277D1/de not_active Expired - Fee Related
- 1987-09-16 AT AT87308166T patent/ATE59843T1/de not_active IP Right Cessation
- 1987-09-16 EP EP87308166A patent/EP0265069B1/en not_active Expired - Lifetime
- 1987-09-16 ES ES198787308166T patent/ES2037724T3/es not_active Expired - Lifetime
- 1987-09-21 KR KR870010435A patent/KR880003893A/ko not_active Application Discontinuation
- 1987-09-21 IE IE253587A patent/IE60614B1/en not_active IP Right Cessation
- 1987-09-21 NO NO873939A patent/NO167086C/no unknown
- 1987-09-21 EG EG534/87A patent/EG18207A/xx active
- 1987-09-21 FI FI874115A patent/FI87558C/fi not_active IP Right Cessation
- 1987-09-22 JP JP62238600A patent/JPS63101360A/ja active Pending
- 1987-09-22 HU HU874269A patent/HU200316B/hu not_active IP Right Cessation
- 1987-09-22 AU AU78861/87A patent/AU602919B2/en not_active Ceased
- 1987-09-22 CN CN87106553A patent/CN1021325C/zh not_active Expired - Fee Related
- 1987-09-22 PT PT85771A patent/PT85771B/pt not_active IP Right Cessation
- 1987-09-30 MY MYPI87002691A patent/MY103029A/en unknown
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1991
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Publication number | Publication date |
---|---|
IL83915A (en) | 1992-02-16 |
EP0265069A1 (en) | 1988-04-27 |
AU602919B2 (en) | 1990-11-01 |
JPS63101360A (ja) | 1988-05-06 |
DE3767277D1 (de) | 1991-02-14 |
EG18207A (en) | 1992-09-30 |
HUT45470A (en) | 1988-07-28 |
AU7886187A (en) | 1988-03-24 |
FI874115A (fi) | 1988-03-23 |
ATE59843T1 (de) | 1991-01-15 |
NZ221614A (en) | 1990-02-26 |
ZA876306B (en) | 1988-08-31 |
KR880003893A (ko) | 1988-05-31 |
FI87558B (fi) | 1992-10-15 |
PT85771A (en) | 1987-10-01 |
NO873939D0 (no) | 1987-09-21 |
IL83915A0 (en) | 1988-02-29 |
CN1021325C (zh) | 1993-06-23 |
PT85771B (pt) | 1990-07-31 |
MY103029A (en) | 1993-04-30 |
US4739098A (en) | 1988-04-19 |
PH24108A (en) | 1990-03-05 |
EP0265069B1 (en) | 1991-01-09 |
IE872535L (en) | 1988-03-22 |
DK468587D0 (da) | 1987-09-08 |
HU200316B (en) | 1990-05-28 |
CA1329620C (en) | 1994-05-17 |
ES2037724T3 (es) | 1993-07-01 |
NO167086C (no) | 1991-10-02 |
NO167086B (no) | 1991-06-24 |
FI874115A0 (fi) | 1987-09-21 |
NO873939L (no) | 1988-03-23 |
GR3001373T3 (en) | 1992-09-11 |
FI87558C (fi) | 1993-01-25 |
IE60614B1 (en) | 1994-07-27 |
DK468587A (da) | 1988-03-23 |
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