CN88101424A - 具有类视网膜活性和含有杂芳香族和杂二环基团的取代乙炔及制备方法 - Google Patents
具有类视网膜活性和含有杂芳香族和杂二环基团的取代乙炔及制备方法 Download PDFInfo
- Publication number
- CN88101424A CN88101424A CN88101424.9A CN88101424A CN88101424A CN 88101424 A CN88101424 A CN 88101424A CN 88101424 A CN88101424 A CN 88101424A CN 88101424 A CN88101424 A CN 88101424A
- Authority
- CN
- China
- Prior art keywords
- ethynyl
- acid
- dimethyl
- compound
- thiochroman
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 58
- 125000002534 ethynyl group Chemical class [H]C#C* 0.000 title claims description 69
- 238000002360 preparation method Methods 0.000 title claims description 15
- 230000000694 effects Effects 0.000 title abstract description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title 1
- 125000001072 heteroaryl group Chemical group 0.000 title 1
- 150000004492 retinoid derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000002541 furyl group Chemical group 0.000 claims abstract description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 68
- 239000002253 acid Substances 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 150000002576 ketones Chemical class 0.000 claims description 18
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 17
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229960003512 nicotinic acid Drugs 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 64
- 150000002148 esters Chemical class 0.000 abstract description 20
- 150000001408 amides Chemical class 0.000 abstract description 14
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract description 10
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
- 239000000243 solution Substances 0.000 description 75
- -1 chromanyl compound Chemical class 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000002585 base Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- KHTFVXZBUYUMCT-UHFFFAOYSA-N 5,5-dimethyl-2-phenylcyclohexa-1,3-diene Chemical group C1=CC(C)(C)CC=C1C1=CC=CC=C1 KHTFVXZBUYUMCT-UHFFFAOYSA-N 0.000 description 16
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 230000000171 quenching effect Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000001467 acupuncture Methods 0.000 description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 238000005194 fractionation Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 210000004761 scalp Anatomy 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 6
- 239000012346 acetyl chloride Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 229930002330 retinoic acid Natural products 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 5
- 150000001412 amines Chemical group 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- HXBZCHYDLURWIZ-UHFFFAOYSA-N diphenyl hydrogen phosphate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 HXBZCHYDLURWIZ-UHFFFAOYSA-N 0.000 description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 2
- UKTQYFIDMREWNQ-UHFFFAOYSA-N 4,4-dimethyl-2,3-dihydrothiochromene Chemical compound C1=CC=C2C(C)(C)CCSC2=C1 UKTQYFIDMREWNQ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- NTRBNFOLBJWRAO-INIZCTEOSA-N N(2),N(5)-dibenzoyl-L-ornithine Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C=CC=CC=1)CCNC(=O)C1=CC=CC=C1 NTRBNFOLBJWRAO-INIZCTEOSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- 239000001533 (4R,6S)-2,4,6-trimethyl-1,3,5-dithiazinane Substances 0.000 description 1
- LCCDINSFSOALJK-UHFFFAOYSA-N 1,3,4-trimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2(C)N=CN=C21 LCCDINSFSOALJK-UHFFFAOYSA-N 0.000 description 1
- RAHDGDHJQHAKRI-UHFFFAOYSA-N 1-(4,4,7-trimethyl-2,3-dihydrochromen-6-yl)ethanone Chemical compound C1=C(C)C(C(=O)C)=CC2=C1OCCC2(C)C RAHDGDHJQHAKRI-UHFFFAOYSA-N 0.000 description 1
- APBGIHIRYOFIJA-UHFFFAOYSA-N 1-(4,4-dimethyl-2,3-dihydrochromen-6-yl)ethanone Chemical compound O1CCC(C)(C)C2=CC(C(=O)C)=CC=C21 APBGIHIRYOFIJA-UHFFFAOYSA-N 0.000 description 1
- DHIVJYNSSSHXRG-UHFFFAOYSA-N 1-(4,4-dimethyl-2,3-dihydrothiochromen-6-yl)ethanone Chemical compound S1CCC(C)(C)C2=CC(C(=O)C)=CC=C21 DHIVJYNSSSHXRG-UHFFFAOYSA-N 0.000 description 1
- FUKHNXJKIWRQEM-UHFFFAOYSA-N 1-(7-butyl-4,4-dimethyl-2,3-dihydrochromen-6-yl)ethanone Chemical compound O1CCC(C)(C)C2=C1C=C(CCCC)C(C(C)=O)=C2 FUKHNXJKIWRQEM-UHFFFAOYSA-N 0.000 description 1
- RCIGWKFLWDZDPT-UHFFFAOYSA-N 1-(7-ethyl-4,4-dimethyl-2,3-dihydrochromen-6-yl)ethanone Chemical compound O1CCC(C)(C)C2=C1C=C(CC)C(C(C)=O)=C2 RCIGWKFLWDZDPT-UHFFFAOYSA-N 0.000 description 1
- VPXVSORHYJZEPF-UHFFFAOYSA-N 1-(7-hexyl-4,4-dimethyl-2,3-dihydrochromen-6-yl)ethanone Chemical compound O1CCC(C)(C)C2=C1C=C(CCCCCC)C(C(C)=O)=C2 VPXVSORHYJZEPF-UHFFFAOYSA-N 0.000 description 1
- FIGGGNADMGYZFG-UHFFFAOYSA-N 1-pyridin-3-ylpropan-1-ol Chemical compound CCC(O)C1=CC=CN=C1 FIGGGNADMGYZFG-UHFFFAOYSA-N 0.000 description 1
- GRAQJNIKCLUNMF-UHFFFAOYSA-N 2-ethynyl-3,4-dihydro-2h-thiochromene Chemical compound C1=CC=C2SC(C#C)CCC2=C1 GRAQJNIKCLUNMF-UHFFFAOYSA-N 0.000 description 1
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 1
- KVHNVHGCQWNGLG-UHFFFAOYSA-N 6-ethynyl-4,4-dimethyl-2,3-dihydrothiochromene Chemical compound C1=C(C#C)C=C2C(C)(C)CCSC2=C1 KVHNVHGCQWNGLG-UHFFFAOYSA-N 0.000 description 1
- SKPFWXCSFDSGKJ-UHFFFAOYSA-N 7-butyl-4,4-dimethyl-2,3-dihydrochromene Chemical compound O1CCC(C)(C)C=2C1=CC(CCCC)=CC=2 SKPFWXCSFDSGKJ-UHFFFAOYSA-N 0.000 description 1
- QBMPDWFSKLFCPL-UHFFFAOYSA-N 7-butyl-4,4-dimethyl-2,3-dihydrothiochromene Chemical compound S1CCC(C)(C)C=2C1=CC(CCCC)=CC=2 QBMPDWFSKLFCPL-UHFFFAOYSA-N 0.000 description 1
- DBHKVCYGAHJHGI-UHFFFAOYSA-N 7-ethyl-4,4-dimethyl-2,3-dihydrochromene Chemical compound O1CCC(C)(C)C=2C1=CC(CC)=CC=2 DBHKVCYGAHJHGI-UHFFFAOYSA-N 0.000 description 1
- NOOXTOHCSRQUQK-UHFFFAOYSA-N 7-ethyl-4,4-dimethyl-2,3-dihydrothiochromene Chemical compound S1CCC(C)(C)C=2C1=CC(CC)=CC=2 NOOXTOHCSRQUQK-UHFFFAOYSA-N 0.000 description 1
- WUGWIUMHAGOVJS-UHFFFAOYSA-N 7-hexyl-4,4-dimethyl-2,3-dihydrochromene Chemical compound O1CCC(C)(C)C=2C1=CC(CCCCCC)=CC=2 WUGWIUMHAGOVJS-UHFFFAOYSA-N 0.000 description 1
- JDEHNHXNPALDNE-UHFFFAOYSA-N 7-hexyl-4,4-dimethyl-2,3-dihydrothiochromene Chemical compound S1CCC(C)(C)C=2C1=CC(CCCCCC)=CC=2 JDEHNHXNPALDNE-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000002506 Darier Disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010023369 Keratosis follicular Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 241000315040 Omura Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FBMVFHKKLDGLJA-UHFFFAOYSA-N Thialdine Chemical compound CC1NC(C)SC(C)S1 FBMVFHKKLDGLJA-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 206010048222 Xerosis Diseases 0.000 description 1
- WPGUUPJOAVPZBQ-UHFFFAOYSA-N [Cl].OP(O)(O)=O Chemical compound [Cl].OP(O)(O)=O WPGUUPJOAVPZBQ-UHFFFAOYSA-N 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- NKRNGKIEDAVMHL-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1 NKRNGKIEDAVMHL-UHFFFAOYSA-L 0.000 description 1
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical compound CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- YSCZJXUXOSCESY-UHFFFAOYSA-N ethyl 5-(5-iodofuran-2-yl)pentanoate Chemical compound CCOC(=O)CCCCC1=CC=C(I)O1 YSCZJXUXOSCESY-UHFFFAOYSA-N 0.000 description 1
- FPLVRROPVSUKJH-UHFFFAOYSA-N ethyl 5-(5-iodothiophen-2-yl)pentanoate Chemical compound CCOC(=O)CCCCC1=CC=C(I)S1 FPLVRROPVSUKJH-UHFFFAOYSA-N 0.000 description 1
- XLLOFJRVQWCJQZ-UHFFFAOYSA-N ethyl 5-(6-chloropyridin-3-yl)pentanoate Chemical compound CCOC(=O)CCCCC1=CC=C(Cl)N=C1 XLLOFJRVQWCJQZ-UHFFFAOYSA-N 0.000 description 1
- ILDJJTQWIZLGPO-UHFFFAOYSA-N ethyl 6-chloropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=C(Cl)N=C1 ILDJJTQWIZLGPO-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
- 150000002830 nitrogen compounds Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000000088 plastic resin Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000008833 sun damage Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- IQIBKLWBVJPOQO-UHFFFAOYSA-N tazarotenic acid Chemical compound C1=C2C(C)(C)CCSC2=CC=C1C#CC1=CC=C(C(O)=O)C=N1 IQIBKLWBVJPOQO-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N trimethylxanthine Natural products CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
本发明是关于下式的具有类视网膜活性的化合物或其药物上可接受的盐,及其制法,
式中X是S,O或NR1其中R1是氢或低级烷基;R是氢或低级烷基;A是吡啶基,噻吩基,呋喃基,哒嗪基,嘧啶基或吡嗪基;n是0-5;B是H,-COOH或其药物上可接受的盐,酯或酰胺,-CH2OH或醚或酯衍生物,或-CHO或缩醛衍生物,或-COR1或缩酮衍生物基中R1是-(CH2)mCH3(m为0-4)。
Description
本发明涉及具有类视网膜活性的新化合物。更具体是涉及含有一个乙炔基杂芳香酸部分和第二个为四氢喹啉基,二氢苯并噻喃基,苯并二氢吡喃基部分的化合物。酸官能团还可被转换成醇,醛,酮或其衍生物,或被还原成-CH3。可以预料到这些化合物的氧化产物,特别是二氢苯并噻喃基化合物的二氧化物,也具有类似于母体化合物的活性。
1985年1月9日公开的欧洲专利申请0133795中,揭示了通式4-(2-(4,4-二甲基-6-X)-2-甲基乙炔基)苯甲酸的羧酸衍生物具有抑制软骨变形作用,通式中X未示四氢喹啉基,苯并二氢吡喃基或二氢苯并噻喃基。M.I.Dawson等人在医学化学杂志,第27卷,1516页的文章中揭示了类似于本发明的化合物,他的用炔属基团代替甲基取代的反式双键(Dawson中所显示的)。并且在Dawson中,芳香基部分不是本文所述的杂芳香基团,而是苯基。在1986年4月2日公开的欧洲专利申请176034A中,也提示了含有乙炔基苯甲酸的四氢萘化合物。
本发明是关于下面式Ⅰ化合物
式中X是S,O或NR1其中R1是氢或低级烷基;R是氢或低级烷基;A是吡啶基,噻吩基,呋喃基,哒嗪基,噻啶基或吡嗪基;n是0-5;并且B是H,-COOH或其药物上可接受的盐,酯或酰胺,-CH2OH或醚或酯的衍生物,或-CHO或缩醛衍生物,或-COR1或缩酮衍生物其中R1是-(CH2)mCH3(m是0-4)。
本发明第二方面是关于使用式Ⅰ化合物治疗皮肤病,例如痤疮,达里埃氏病,牛皮癣,鳞癣,湿疹,特应性皮炎和上皮癌。这些化合物还可以用于治疗关节炎病症和其它免疫性疾病(例如红斑狼疮),促进伤口愈合,干眼综合症以及消除阳光损伤皮肤。
本发明还涉及一种药物配方,该配方包括式Ⅰ化合物和用于组合的药物上可接受的赋形剂。
本发明的另一方面是关于制备式Ⅰ化合物的方法,其包括在有Pd(PQ3)4(Q是苯基)或类似配合物存在下,式Ⅱ化合物同式Ⅲ化合物反应得到相应的式Ⅰ化合物,
式中X1是卤素,较好为I;n和A定义同上;B是H,或一个保护的酸,醇,醛或酮;
或去除式Ⅰ的保护的酸,醇,醛或酮或把下式化合物(n是0-4)进行反应得到式Ⅰ的酸;
或把式Ⅰ的酸转化成盐;
或形成酸加成盐;
把式Ⅰ的酸转化成酯;
或把式Ⅰ的酸转化成酰胺;
或Ⅰ的酸还原成醇或醛;
或把式Ⅰ的醇转化成醚或酯;
或把式Ⅰ的醇氧化成醛;
或把式Ⅰ的醛转化成缩醛;
或把式Ⅰ的酮转化成缩酮。
本文所用述语“酯”是指和包括属于有机化学经典使用述语定义内的任何化合物。当A为-COOH时,该述语包括处理有醇官能团所衍生得到的产物。如酯是由A为-CH2OH的化合物衍生得到的,那么这个述语包括式-CH2OOCR化合物,其中R是任何取代的或未取代的脂肪族,芳香族或脂肪一芳香族基团。
较理想的酯是由10或10多个碳原子的饱和脂肪醇或酸,或5到10个碳原子的环状或饱和脂肪环醇和酸衍生得到的酯。最佳的脂肪酯是低级烷基酸和醇衍生得到的化合物,在本文,无论何处凡使用的低级烷基均指1-6个碳原子,但苯基或低级烷基苯基酯也是较理想的。
酰胺具有有机化学经典的定义。在本文情况里,酰胺包括未取代酰胺和全部脂肪和芳香族单和二取代酰胺。较好的酰胺是由10或十多个碳原子的饱和脂肪基或环基或5至10个碳原子的饱和脂肪环基衍生得到的单和二取代酰胺。那些由低级烷基胺得到的酰胺最好。由苯基或低级烷基苯基胺衍生得到的单和二取代酰胺也是理想的,这对未取代酰胺也是如此。
缩醛和缩酮包括式-CK的基团,其中K是(-OR)2,这里R为低级烷基。K也可为-OR1O-,其中R1是2-5个碳原子的直链或支链的亚烷基。
凡具有能形成例如酸或胺官能度等盐的本发明化合物,都能制成其药物上可接受的盐。药物上可接受的盐是指保留母体化合物活性并且对给药者或给药后的用者都不引起有害或不利影响的任何盐类。
这样的盐可以由任何有机或无机酸或硷制得。盐可以是单或多价离子。所涉及的特别有意义的酸的官能是无机离子,钠,钾,钙和镁。有机胺盐可由胺,尤其是铵盐如单,二和三烷胺或醇胺制得胺盐。盐类也可由咖啡碱,三甲胺和类似分子来形成。如存在有足够硷性能形成酸加成盐的氮原子时,其可以由任何无机或有机酸或烷化剂如甲基碘来形成。较理想的盐是由例如盐酸,硫酸或磷酸的无机酸所形成的盐。也可以使用众多的任何无机酸,如单,二或三酸。
本发明较好的化合物为这些一类化合物,其中乙炔基和B基团是分别连接在吡啶环(按吡啶命名法中的2/5位相当于按烟酸命名法中的6和3位置)的2和5位置,或者分别连接在噻吩基的5和2位置上;n是0,1或2;B是-COOH,硷金属盐或有机胺盐,或低级烷基酯,或-CHOH和低级烷基酯以及它的醚类。最理想的化合物为:
6-〔2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸;
6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸;和
6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯。
根据参考需治疗的症状,治疗的具体部位,给药量以及类似情况,本发明化合物可以采用全身或局部给药。
在治疗皮肤病中,虽然在某些情况下,如治疗严重的囊性痤疮也可使用口服给药,但通常都采用局部给药。可以常用的局部配方例如是溶液、悬浮液、凝胶、软膏、油膏。这种局部给药的配制在药物配制的技术中已有具体描述,如Mack出版公司,Easton,Pennsylvania,第17版,Remington′s Pharmacentical Science。对于局部使用,这些化合物还可以以粉剂或喷雾形式,尤其以气溶胶形式给药。
如果是采用全身给药时,可以制成粉剂,丸剂,片剂等,或制成糖浆或剂用于口服。而用于静脉内或腹膜内给药时,本化合物可制成溶液或悬浮液进行注射给药。在某些情况下,也可配制成栓剂的形式或在用于植入皮内的或肌肉内注射时可制成持续释放的配方形式。
在这种局部配方中加入另外的药剂,可起到治疗如皮肤干燥,防止光照等第二个目的,同样可加入其它的药剂,用于治疗皮肤病,防此感染,减缓疼痛,炎症等。
对于皮肤病的治疗或用类视网膜酸化合物可治疗的其它已表明或发现的病症,使用本发明的一个或多个化合物的治疗有效量给药也将有作用。治疗浓度是能有效减缓具体病情或阻缓病情发展的浓度。在一些情况中,能以预防形式使用本药物,用于预防具体病情的发起。根据具体不同的病情所给的治疗浓度是不同的,在某些情况下,根据治疗情况的严重程度和病者对治疗的反应来决定药物浓度。因此,最好是在用的时候和地方,通过常规实验测定所用治疗浓度。然而,可以预计到在治疗如痤疮,或其它皮肤病时,通常有效治疗浓度的配方是含0.001至5重量百分比。较好是约0.01至1%。如果是全身给药,那每天用量为0.01至100mg/kg体重,但在大多数情况下,0.1至10mg/kg的治疗结果较好。
这些化合物的类视网膜酸活性已经用常规测定视网膜酸活性的方法加以证明,这包括在鸟尿酸脱酸酶上的视网膜酸的作用。最初的工作是有verma & Boutwell,(癌研究,37卷,2196-2201页,1977年)研究视网膜酸与减少细胞增生之间的关系。这篇文献揭示了在聚胺生物合成前,鸟尿酸脱酸酶(ODC)活性已增加了。另外还确立了这样的理论,即聚胺合成的增加同细胞增生有关或者有联系。因此,如果能抑制ODC活性的话,也就能调节细胞高增生。虽然还不知道引起ODC活性增加的全部因素,但12-邻十四酰佛波醇-13-乙酸盐(TPA)诱发ODC活性是已知的。视网膜酸能抑制由TPA引起ODC活性的诱发。本发明化合物也具有抑制TPA诱发ODC的功用,这可基本上按《癌研究》,1662-1670,1975的方法测定。
本发明化合物能用不同的化学合成方法进行制备。为了描述本发明,本文概述了一系列合成步骤,实际按照它们或按其原则就能合成式Ⅰ化合物。对化学合成工作者来说,这里所列的条件显然是具体的例子,其可以推广到式Ⅰ表示的任何一个化合物。
其中X是-S-的式Ⅰ化合物按照反应路线Ⅰ制备
反应路线Ⅰ
式中,R是氢或低级烷基,A定义同上,n是0-5,B是H,或保护的酸,醇,醛或酮。X1较好是卤素,较好是Ⅰ。
X为氧的式Ⅰ化合物按反应路线Ⅱ制备。
反应路线Ⅱ
R,n,A,B和X1定义如同路线Ⅰ。
X为氮的化合物例子,由反应路线Ⅲ概括的步骤次序得到
反应路线Ⅲ
R,n,A,B和X1定义如同路线Ⅰ,R2是氢或-COCH3。
下将对制备上面反应路线列举的各个化合物进行全面地说明。
在反应路线Ⅰ中,可使用下列通用的反应条件。首先式Ⅰ的苯硫酚在丙酮中用约等摩尔量的强硷如硷金属氢氧化物回流处理,回流时间为1至4小时,较好为2.5小时,然后溶液用等摩尔量式2的1-溴-3-甲基-2-丁烯(Aldrich)于丙酮中处理。再继续回流2天后,在室温下搅拌24小时,生成式3,用常规方法加以分离。
在隋性气氛和有磷酸存在下,用五氧化二磷处理上面所得硫化物(式3)进行闭环得式4的二氢苯并噻喃。具体操作是,硫化物首先溶于隋性溶剂如苯,甲苯等,然后用略为述量的五氧化二磷及浓磷酸处理。所得溶液于是在隋性气体如氩气或氮气中,搅拌回流24。然后按常规操作回收和纯化产物。
在有氯化铝存在下,二氢苯并噻喃经乙酰氯处理得到式5的酮。在隋性气氛和低温(-10至10℃)下。制备氯化铝于极性隋性溶剂中的悬浮液。所说隋性气氛可以是氩气或氯气,较好为氩气。本步骤反应通常是在如二氯甲烷的溶剂中进行。用滴液漏斗或类似装置把氯化铝悬浮液加到二氢苯并噻喃和乙酰氯中。使用相对于二氢苯并噻喃物料的5%摩尔过量的乙酰氯和10%摩尔过量的氯化铝。本反应是在10-50℃的温度下搅拌0.5-4小时。最好是在室就下搅拌约2小时。然后用水和/或冰骤冷反应物,萃取产物并分馏或一些其它合适的方法纯化产物。
在隋性气氛和低温下,用二异丙基酰胺锂或类似的硷引进式6的乙炔基官能度。该反应是在醚类溶剂如二烷基醚或环醚中进行,例如四氢呋喃,吡喃等。
具体地说,二异丙基酰胺锂是在现场制备的,通过二异丙基酰胺在无水溶剂如四氢呋喃中混合,然后于隋性气氛下冷却至-70℃和-50℃间。在低温下,在适当溶剂中的等摩尔烷基锂化合物被加入,混合适当的时间至生成二异丙基酰胺锂(LDA)。把式5的酮(至少10%摩尔过量)溶于反应溶剂中并冷却至LDA混合物的温度,然后加入到LDA混合物中。经简单混合后,用20%摩尔过量的氯磷酸二烷酯,最好是氯磷酸二乙酯处理溶液。然后反应液渐渐热至室温,并加入到第二部份的二异丙基酰胺锂溶液中,该二异丙基酰胺锂也是在现场,于隋性气氛(较好氩气)和低温(例如-78℃)下使用无水溶剂制得的。从而再将所得反应混合物温热至室温,并搅拌维持一段时间,较好是10至20小时,最好约15小时。然后酸化溶液,用常规方法回收产物。
式7化合物的制备是在无水隔氧的条件下进行的。可以使用无水的醚类溶剂如二烷基醚或环醚如呋喃或吡喃,尤其是四氢呋喃作为溶剂。
式6溶液的制备首先是在隋性气氛如氩气或氮气下,然后加入强硷如正丁基锂(约10%摩尔过量)。该反应是介于-10℃至10℃的低温,较好在0℃下进行。反应混合物短期搅拌30分钟至2小时,接着用溶于反应溶剂的10%摩尔过量的熔融氯化锌进行处理。在起始温度下再搅拌混合物1-3小时,然后升温至约环境温度10-40分钟。
把保护的杂芳香化合物同式7化合物偶合可以由其相应的酸,醇,酮或醛来制备。这些起始物质,保护的酸,醇,醛或酮都是化工厂有售的或者可用公知的方法加以制备的。在亚硫酰二氯存在下,酸在适当的醇溶液中回流酯化,经回流2-5小时后得到所需的酯。另外,在二环己基碳二亚胺和二甲氨基吡啶存在下,酸能够同相应的醇缩合。用常规方法回收和纯化所得酯。缩醛和缩酮可按“高等有机化学”,第二版,McGraw-Hill Book Company,p810,所描述的方法容易制得。醇,醛和酮都可以用已知的方法各自通过形成醚和酯,缩醛或缩酮来进行保护,如Mcomie,Plenum Publishing Press,1973和《保护基团》,Ed.Greene,John Willey & Sons,1981所描述的方法。
为了在进行偶合反应前,增加n数值,并且B为-COOH的杂芳香基不是商业有售时,该杂芳香基需在阿恩特-艾斯特条件下经连续地处理。然后用前文所述的通常方法酯化这些酸。
为了有效地用式Ⅲ化合物偶合二氢苯并噻喃部分,需把卤取代的杂芳香基化合物溶于无水反应溶剂中。使用的杂芳香基化合物摩尔浓度与式7化合物的相接近。把上述溶液放到温度为-10℃到10℃的,于反应溶剂中的四-三苯基磷钯的悬浮液(约过量于反应物摩尔量的5至10%)中。将该混合物短暂搅拌约15分钟,在所制得的混合物中加入式7的预制溶液,加料温度是在室温进行。在室温下,搅拌该溶液约15至25小时。然后用酸骤冷反应物,用常规操作分离和纯化产物得式Ⅰ化合物。
制备n为1-5的化合物的另外方法是对B为酸官能度的式Ⅰ化合物进行由上面提到的阿恩特-艾斯特反应。
式Ⅰ化合物衍生的酸和盐可容易的由相应的酯得到。通过硷金硷的硷性皂化可得到酸。例如,最好是在室温和惰性气氛下把式Ⅰ的酯同约三摩尔过量的硷如氢氧化硷溶介于一个极性溶剂如醇中,搅拌该溶液15至20小时,冷却,酸化,并用常规方法回收水解产物。
可使用已有技术中的任何相应的酰胺化方法制得酰胺。其中之一的制备这些化合物方法是,把酸转化成酰基氯,然后用氢氧化铵或适当的胺处理。例如,在室温下用硫硷如乙醇/KOH(约10%摩尔过量)处理酸约30分钟。除去溶剂,剩余物用有机溶剂如乙醚提取,二烷基甲酰胺处理,然后用10倍过量的草酰氯处理。这操作都是在介于约-10℃至10℃的适当低温下进行的。然后把所得的溶液于低温下搅拌1-4小时,较好是2小时。除去溶剂,剩余物溶介于隋性有机溶剂如苯;冷却至约0℃,浓氢氧化铵处理。在低温下搅拌所得混合物1-4小时。常规方法回收产物。
醇类可以通过亚硫酰二氧或其包方法先由相应的酸转化成酰基氯,(J.March,“高等有机化学”,第2版,McGraw-Hill Book Company),然后用氢硼化钠还原酰基氯(March,Ibid,Pg.1124)得到相应醇类。另外,酯类也可以在低温下用氢化锂铝还原。在威廉逊制醚反应条件下(March,Ibid,Pg.347),用适当的烷基囟烷基化醇类得到相应的醚。在有酸催化剂或二环己基碳二亚胺和二甲氨基吡啶存在下,这些醇类同适当的酸反应可转化成相应的酯。
使用温和氧化剂如二铬酸吡啶鎓/二氯甲烷(Corey,E.J.,Schmidt,G.,Tet.Lelt.,399,1979),或二甲亚砜/草酰氯的二氯甲烷(Omura,K.Swern,D.Tetrahedron,1978,34,1651),由相应的伯醇制得醛。
使用烷基格利雅试剂或其它类似试剂,处理经氧化所得的醛制得相应的酮。
缩醛或缩酮可按March,Ibid,P810描述的方法,由相应的醛或酮制备。
B为H的化合物由相应的卤代杂环物制得,其中卤元素较好为Ⅰ。按照反应路线Ⅰ和更具体见实施例6的描述,卤代杂环化合物与乙炔基氯化锌反应。B为H的卤取代杂环化合物是商业有售的或可按文献方法制备。
反应路线Ⅱ概括了制备X为氧的化合物的步骤。由相应的氯磷酸二苯酯和3-甲基-3-丁烯-1-醇(Aldrich提供或由已有方法制得)制得式10磷酸酯。制备式10较好方法为,在惰性气氢下,把在约10%过量的吡啶中式9的醇溶介于冷却至约-10-10℃的一种极性惰性溶剂中,然后于惰性气氛下,所得溶液滴加到冷却的等量反应试剂的氯磷酸二苯酯中。其中使用约过量于醇2-5%摩尔的氯磷酸二苯酯,所说惰性气氛可以是氩、氮或其它惰性气体。加热回流反应混合物1至5小时,较好约3小时。然后用常规方法回收产物。
然后将上面所得的二苯基磷酸酯(式10)与苯酚或3-甲基苯酚反应得到式11化合物。例如,将有四氯化锡的烧瓶冷却至-10-10℃,加入苯酚。在低温下,搅拌这些混合物约15分钟至1小时至完全混合,在低温下加入磷酸。上面两步都是在惰性气氛下进行操作,如氢气或氮气。磷酸加毕后,于约室温下搅拌混合物至24小时。然后用硷金属硷水溶液或类似的稀释溶液骤冷反应物。用萃取或其它常替方法回收产物。
乙酰化式11转化得乙炔,然后按反应路线Ⅰ概括的步骤,转化成炔基氯化锌盐,接着和适当的杂环进行偶合。
四氢喹啉部分(其X为氮)的制备可部分按1985年9月1公开的欧洲专利申请0130795号的方法制备。首先,将3-甲基丁烯酰氯同苯胺反应得到相应酰胺。在溶剂中,用氯化铝环化酰胺。然后由氢化铝锂或其它相似类型的可接受的还原剂还原2-氧代-1,2,3,4-四氢喹啉,这最好在惰性溶剂如乙醚中进行。然后在极性溶剂如吡啶中,用乙酰氯酰化胺。接着有氯化铝存在下,酰化已保护的胺。通过硷性水解除去氮上的乙酰基官能团。再按反应路线Ⅰ的方法把乙酰化的化合物转化成乙炔和氯化锌盐。所得盐同前面提到的适当的式Ⅲ化合物偶合给出式Ⅰ化合物。
下列实施例用于说明本发明,而非限制本发明的范围。
实施例1
苯基-3-甲基丁-2-炔基硫化物
加热14.91g(135.324mmol)苯硫酚和5.5g(137.5mmol)NaOH的100ml丙酮混合物2.5小时,然后滴加20g(134.19mmol)1-溴-3-甲基-2-丁烯的20ml丙酮溶液进行处理。将溶液回流40小时,并室温搅拌24小时。然后真空除去溶剂,剩余物溶于水中,乙醚萃取3×50ml。合并乙醚萃取液,先后用3×30ml 5%NaOH溶液,水,饱和的NaCl溶液洗涤和干燥(MgSO4)。再真空除去溶剂,剩余物经Kugelrohr分馏(80℃,0.75mm)纯化得浅黄油状的本标题化合物。PMR(CDCl3):δ1.57(3H,s),1.69(3H,s),3.52(2H,d,J~7.7Hz),5.29(1H,t,J~7.7Hz),7.14(1H,t,J~7.0Hz),7.24(2H,t,J~7.0Hz),7.32(2H,d,J~7.0Hz).
实施例2
4,4-二甲基二氢苯并噻喃
在15.48g(86.824mmol)苯基-3-甲基-丁-2-炔基硫化物的160ml苯溶液中依次加入12.6g(88.767mmol),五氧代磷和11ml85%磷酸。在氩气氛和剧烈搅拌下,回流所得溶液20小时,然后冷至室温。滤出上层澄清有机液;余下的浆料用乙醚萃取3×50ml。合并有机液部分并分别用水,饱和的NaHCO3和饱和的NaCl溶液洗涤,然后干燥(MgSO4)。真空除去溶剂,剩余物经Kugelrohr分馏(80℃,0.5mm)纯化得浅黄油状的标题化合物。
PMR(CDCl3):δ1.30(6H,s),1.90-1.95(2H,m),2.95-3.00(2H,m),6.96-7.00(2H,m),7.04-7.07(1H,m),7.30-7.33(1H,m).
该方法能用于制备6-位烷基类似物,如下列化合物:
4,4,7-三甲基二氢苯并噻喃;
4,4-二甲基-7-乙基二氢苯并噻喃;
4,4-二甲基-7-丙基二氢苯并噻喃;
4,4-二甲基-7-丁基二氢苯并噻喃;
4,4-二甲基-7-己基二氢苯并噻喃。
实施例3
4,4-二甲基-6-乙酰二氢苯并噻喃
14.3g(80.21mmol)4,4-二甲基二氢苯并噻喃(从例2所得)和6.76g(86.12mmol)乙酰氯的65ml苯溶液用冰浴冷却和滴加26.712g(102.54mmol)氯化锡来处理。室温搅拌混合物12小时,然后用65ml水和33ml浓盐酸分别处理,并加热回流0.5小时。经冷却至室温后,分离出有机层,水层用苯萃取5×50ml。合并回收的有机层并依次用5%碳酸钠溶液,水,饱和的NaCl溶液洗涤,然后干燥(MgSO4)。真空除去溶剂,剩余物经闪色谱(硅胶;5%乙酸乙酯的己烷)纯化,接着经kugelrohr分馏(150℃,0.7mm)得浅黄油状标题化合物。
PMR(CDCl3):δ1.35(6H,s),1.92-1.98(2H,m)2.54(3H,s),3.02-3.08(2H,m),7.13(1H,d,J~8.6Hz),7.58(1H,dd,J~8.6Hz,2Hz),7.99(1H,d,J~2Hz).
这个方法可用于由实施例2所制得化合物来制备6-乙酰化合物。
实施例4
4,4-二甲基-6-乙炔基二氢苯并噻喃
1.441g(14.2405mmol)二异丙胺的30ml无水四氢呋喃溶液在-78℃的氩气下,滴加入9ml 1.6M(14.4mmol)正丁基锂/己烷。-78℃下搅拌该溶液1小时,并通过滴加2.95g(13.389mmol)4,4-二甲基-6-乙酰二氢苯并噻喃的5ml无水四氢呋喃溶液处理溶液。经-78℃再搅拌1小时后,溶液用2.507g(14.53mmol)氯磷酸二乙酯处理,然后升至室温,并搅拌3.75小时。在-78℃下,用一种双头针(double ended needle)将溶液转移到二异丙基酰胺锂〔同前面一样制备,2.882g(28.481mmol)二异丙胺和18ml 1.6M(28.8mmol)正丁基锂的己烷〕的60ml无水四氢呋喃溶液中。移开冷凝浴并室温搅拌溶液15小时,然后用水骤冷和3N氯化氢酸化到pH1。室温搅拌混合物12小时,用65ml水和33ml浓氯化氢处理,然后加热回流0.5小时。经冷却至室温后,分离出有机层,水层用苯萃取5×50ml。合并有机相部分,并依次用5%碳酸钠溶液,水,饱和的NaCl溶液洗涤,以及干燥(MgSO4)。真空除去溶剂,剩余物经闪色谱(硅胶,5%乙酸乙酯的己烷)纯化,接着Kugelrohr分馏(150℃,0.7mm)得浅黄色油状的标题化合物。
PMR(CDCl3):δ1.35(6H,s),1.92-1.98(2H,m)2.54(3H,s),3.02-3.08(2H,m),7.13(1H,d,J~8.6Hz),7.58(1H,dd,J~8.6Hz,2Hz),7.99(1H,d,J~2Hz).
用相同方法,可把实施例3制得的全部含乙酰化合物转化成其相应的乙炔基类似物。
实施例5
6-氯代烟酸乙酯
15.75g(0.1mol)6-氯代烟酸,6.9g(0.15mol)乙醇,22.7g(0.11mol)二环己基碳二亚胺和3.7g二甲氨基吡啶的200ml二氯甲烷混合物被加热回流2小时。冷却混合物并真空除去溶剂,剩余物经闪色谱法得低熔点的白色本标题化合物。PMR
PMR
(CDCl3):δ1.44(3H,t,J~6.2Hz)4.44(2H,q,J~4.4Hz),7.44(1H,d,J~8.1Hz),8.27(1H,dd,J~8.1Hz,3Hz),9.02(1H,d,J3Hz).
本方法可用于酯化用于下列化合物制的任何其它卤代酸:
2-(2-氯吡啶-5-基)乙酸乙酯;
5-(2-氯吡啶-5-基)戊酸乙酯;
2-(2-碘呋喃-5-基)乙酸乙酯;
5-(2-碘呋喃-5-基)戊酸乙酯;
2-(2-碘噻吩-5-基)乙酸乙酯;
5-(2-碘噻吩-5-基)戊酸乙酯;
2-(3-氯哒嗪-6-基)乙酸乙酯;
5-(3-氯哒嗪-6-基)戊酸乙酯和这些酯的氯,或其它卤代嘧啶基或哌嗪基相应类似物。
实施例6
6-〔2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯
本操作使用的反应容器需经真空火焰干燥并且整个操作都需在无氧条件如氩气氮气下进行。在0℃的465.7mg(2.3019mmol)4,4-二甲基-6-乙炔基二氢苯并噻喃的4ml无水四氢呋喃溶液中滴加入1.5ml 1.6M(2.4mmol)正丁基的己烷。在0℃和室温分别搅拌溶液10分钟,再冷却至0℃并通过一个二头针,用330mg(2.4215mmol)熔融ZnCl2的4ml无水四氢呋喃处理溶液。接着,溶液在0℃搅拌30分钟,以及室温搅拌10分钟。使用2头针把426.3mg(2.2967mmol)6-氯烟酸乙酯(由实施例5得)的4ml无水四氢呋喃溶液转移到430mg(0.37mmol)四苯基磷钯的4ml无水四氢呋喃悬浮液中,并室温搅拌10分钟,然后通过二头针和上面制得的炔锌溶液反应。所得混合物在室温搅拌18小时,然后用100ml水骤冷。用乙醚3×75ml萃取回收产物,合并乙醚部分,用饱和的NaCl溶液洗涤和干燥(MgSO4)。真空除去溶剂,剩余物经闪色谱法(硅胶;5%乙酸乙酯的己烷)和HPLC(Whatman Paryisil M-9 10/50;4%乙酸乙酯的己烷)纯化得白色固体的标题化合物。
PMR(CDCl3):δ1.36(6H,s),1.45(3H,t,J~7Hz),1.96-2.00(2H,m),3.05-3.09b7894G(2H,m),4.45(2H,q,J~7Hz),7.11(1H,d,J~8.4Hz),7.29(1H,dd,J~8.4Hz,2.2Hz),7.59(1H,d,J~7.8Hz),7.66(1H,d,J~2.2Hz),8.30(1H,dd,J~7.8Hz,2.3Hz),9.22(1H,d,J~2.3Hz).
使用本方法,只是替代实施例4的适当的乙炔基二氢苯并噻喃和实施例5的适当的卤取代杂芳香酯,可制得下列化合物:
6-〔2-(4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)烟酸乙酯;
6-〔2-(4,4-二甲基-7-丙基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯;
〔2-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
3-〔2-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
5-〔2-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基)乙酸乙酯;
〔5-(4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基)乙酸乙酯;
5-〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
〔6-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
5-〔6-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
5-〔6-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
5-〔6-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-〕戊酸乙酯;
5-〔6-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
〔5-((4,4-二甲二氢苯并噻喃-6-基)乙炔基)噻啶-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;和
5-〔5-((4,4-二甲基-7-己基二氢苯并噻喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯。
实施例7
二苯基-3-甲基-3-丁烯-1-基磷酸盐
在氩气氛下,向冰冷却的12.2g(141.65mmol)3-甲基-3-丁烯-1-醇(Aldrich)和11.9g(150.44mmol)吡啶的100ml四氢呋喃溶液中,滴加入38.5g(143.21mmol)氯磷酸二苯酯93的100ml四氢呋喃溶液。加热回流混合物3小时,然后冷却并过滤。滤液真空浓缩,剩余物溶于400ml的乙醚和己烷(1∶1)中,然后用水2×200ml,75ml饱和的NaCl溶液洗涤和干燥(MgSO4)。真空除去溶剂得浅黄色油状的标题化合物。
实施例8
4,4-二甲基苯并二氢吡喃
在氯气氛下向盛有34.95g(0.134mol)氯化锡的干燥的冰冷却烧瓶中快速加入63.0g(0.669mol)苯酚。0℃搅拌混合物0.5小时并用43.0g(0.135mol)二苯基-3-甲基-3-丁烯-1-基磷酸处理,接着经二氧化硫树脂处理。室温搅拌混合物21小时,然后注入到700g冰和1升1.5N NaOH中骤冷。混合物用乙醚1×600ml和2×300ml萃取。合并乙醚部分,用2N NaOH,饱和的NaCl洗涤和经干燥(MgSO4)。真空除去溶剂,剩余物经闪色谱(硅胶;2%乙醚的己烷液)纯化得无色油状的本标题化合物。
PMR(CDCl3)δ:1.34(6H, ),1.80-1.85(2H,m),4.15-4.20(2H,m),6.80(1H,dd,J~8.1Hz,1.5Hz),6.87(1H,td,J~8.1Hz,1.5Hz),7.07(1H,td,J~8.1Hz,1.5Hz),7.26(1H,dd,J~8.1Hz,1.5Hz).
由适当的3-烷基苯酚为起始物,按本文方法制得相应的7-烷基苯并二氢吡喃化合物:
4,4,7-三甲基苯并二氢吡喃;
4,4-二甲基-7-乙基苯并二氢吡喃;
4,4-二甲基-7-丙基苯并二氢吡喃;
4,4-二甲基-7-丁基苯并二氢吡喃;
4,4-二甲封-7-戊基苯并二氢吡喃;
4,4-二甲基-7-己基苯并二氢吡喃。
实施例9
4,4-二甲基-6-乙酰苯并二氢吡喃
于氩气氛下,在搅拌的7.94g(48.9425mmol)4,4-二甲基苯并二氢吡喃的70ml硝基甲烷溶液中先后加入4.0g(50.96mmol)乙酰氯和6.8g(51mmol)氯化铝,在室温搅拌5.5小时,然后用冰浴冷却和慢慢加入70ml 6N氯化氢进行处理。室温搅拌所得混合物10分钟,接着用100ml乙醚处理并分离出有机层。有机层依次用水,饱和的NaHCO3和饱和的NaCl溶液洗涤,用MgSO4干燥。真空除去溶剂,剩余物经闪色谱法(硅胶;10%乙酸乙酯的己烷液)纯化,再用Kugelrohr分馏(95-100℃;0.15mm)得无色油状的本标题化合物。
PMR(CDCl3):δ1.40(6H, ),1.95-2.00(2H,m),2.58(3H, ),4.25-4.30(2H,m),6.83(1H,d,J~8.0Hz),7.62(1H,dd,J~8.0Hz,1.5Hz),8.00(1H,d,J~1.5Hz).
按本方法,由实施例8的化合物可制得下列化合物:
4,4-二甲基-6-乙酰-7-甲基苯并二氢吡喃;
4,4-二甲基-6-乙酰-7-乙基苯并二氢吡喃;
4,4-二甲基-6-乙酰-7-丙基苯并二氢吡喃;
4,4-二甲基-6-乙酰-7-丁基苯并二氢吡喃;
4,4-二甲基-6-乙酰-7-戊基苯并二氢吡喃;
4,4-二甲基-6-乙酰-7-己基苯并二氢吡喃。
实施例10
4,4-二甲基-6-乙炔基苯并二氢吡喃
于氩气氛和-78℃下向2.47g(24.41mmol)二异丙胺的40ml无水四氢呋喃溶液中滴加入15.2ml 1.6M(24.32mmol)正丁基锂的己烷液。-78℃下搅拌混合物1小时并滴加入4.98g(24.38mmol)4,4-二甲基-6-乙酰苯并二氢吡喃的4ml无水四氢呋喃溶液进行处理。经-78℃搅拌1小时后,溶液用4.2g(24.36mmol)氯磷酸二乙酯处理。然后移去冷却浴,室温搅拌混合物2.75小时。于-78℃下用二头针把有溶液转移到二异丙基酰胺锂〔如同实施例4制备:用4.95g(48.92mmol)二异丙胺和30.50ml 1.6M(48.8mmol)正丁基锂的己烷液〕的80ml无水四氢呋喃溶液。移去冷却浴,混合物室温搅拌18小时,然后用50ml水和25ml 3N氯化氢骤冷。混合物用戊烷2×100ml和3×50ml洗涤,合并的有机层依次用3N氯化氢,水,饱和的NaHCO3和饱和的NaCl溶液洗涤并MgSO4干燥。真空除去溶剂,剩余物经闪色谱(硅胶;10%乙酸乙酯的己烷液)和Kugelrohr分馏(70%,0.35mm)纯化得无色晶体的标题化合物。
PMR(CDCl3):δ1.33(6H,s),1.81-1.86(2H,m),3.00(1H,s),4.19-4.24(2H,m),6.75(1H,d,J~8.5Hz),7.22(1H,dd,J~8.5Hz,2.3Hz),7.44(1H,d,J~2.3Hz).
本方法可用于把实施例9的制得的6-乙酰化合物全部转化成其相应的6-乙炔基类似物。
实施例11
6-〔2-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯
本操作所用反应容器需经真空火焰干燥,全部操作都在无氧的氩气或氮气氛下进行。509.4mg(2.74mmol)4,4-二甲基-6-乙炔基苯并二氢吡喃的4ml 1.6M无水四氢呋喃的0℃溶液中,滴加入1.72ml 1.6M(2.74mmol)正丁基锂的己烷液,分别在0℃和室温搅拌30分钟和15分钟。然后把溶液再冷至0℃,通过一种二头针用380mg(2.79mmol)熔融氯化锌的5ml无水四氢呋喃溶液处理。所得溶液分别在0℃和室温搅拌1小时和15分钟。通过二头针把628.6mg(2.74mmol)6-氯烟酸乙酯的4ml无水四氢呋喃转移到380mg(0.33mmol)四苯基磷钯的5ml无水四氢呋喃溶液中,混合物室温搅拌15分钟,然后通过二头针用上面已制得的炔基锌溶液处理。所得混合物在室温搅拌20小时并用冰和30ml 3N氯化骤冷。然后用乙醚3×75ml萃取混合物,合并醚萃取液,依次用饱和的NaHCO3和饱和的NaCl洗涤,MgSO4干燥。真空除去溶剂,剩余物经闪色谱(硅胶;10%乙酸乙酯的己烷液)进一步纯化得黄色固体的本标题化合物。
PMR(CDCl3):δ1.36(6H,s),1.44(3H,t,J~7.1Hz),1.83-1.87(2H,m),4.22-4.26(2H,m),4.44(2H,q,J~7.1Hz),6.80(1H,d,J~7.6Hz),7.35(1H,d,J~8.9Hz),7.58(1H,d,J~7.6Hz),7.60(1H, ),8.28(1H,d,J~8.9Hz),9.21(1H,s).
使用适当的前体,用本方法可制得下列化合物:
6-〔2-(4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基-7-丙基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯;
6-〔2-(4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯;
〔2-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
〔2-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕乙酸乙酯;
3-〔2-((4,4-二甲基苯并二氢吡喃-2-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
3-〔2-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕丙酸乙酯;
5-〔2-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
5-〔2-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)吡啶-5-基〕戊酸乙酯;
〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基)乙酸乙酯;
〔5-(4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基)乙酸乙酯;
5-〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)呋喃-2-基〕戊酸乙酯;
〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)噻吩-2-基〕戊酸乙酯;
〔6-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
〔6-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕乙酸乙酯;
5-〔6-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
5-〔6-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
5-〔6-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-〕戊酸乙酯;
5-〔6-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)哒嗪-3-基〕戊酸乙酯;
〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)噻啶-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)嘧啶-2-基〕戊酸乙酯;
〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕乙酸乙酯;
5-〔5-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;
5-〔5-((4,4,7-三甲基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;
5-〔5-((4,4-二甲基-7-乙基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯;和
5-〔5-((4,4-二甲基-7-己基苯并二氢吡喃-6-基)乙炔基)吡嗪-2-基〕戊酸乙酯。
实施例12
6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸
本实验所用的无水酒精是通过真空和同时进行氮气鼓泡脱气的。101.1mg(0.30mmol)6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯的2ml乙醇溶液在氩气下,用0.7ml,1.81M(1.27mmol)的氢氧化钾的乙醇和水溶液处理。室温搅拌混合物60小时,然后真空除去溶剂,剩余物溶于25ml水中,用25ml乙醚萃取。水层用冰醋酸酸化,接着4×50ml乙醚萃取。合并醚萃取液分别用水,饱和的NaCl洗涤和MgSO4干燥。真空蒸除溶剂得本标题化合物。
PMR((CD3)2CO):δ1.40(6H,s)1.88-1.92(2H,m),4.26-4.30(2H,m),6.82(1H,d,J~8.7Hz),7.37(1H,dd,J~7.6Hz,2.2Hz),7.62(1H, ),7.63(1H,d,J~8.7Hz),8.37(1H,dd,J~7.6Hz,2.2Hz),9.27(1H,d,J~2.2Hz).
按相同方法由6-〔2-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯制得6-〔2-((4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸。
PMR[CDCl3(CD3)2CO]:δ1.37(6H, ),1.99(2H,m),3.09(2H,m),7.10(1H,d,J~8.1Hz),7.28(1H,dd,J~8.1Hz),2.1Hz),7.64(1H,dd,J~7.8Hz),1.8Hz),7.65(1H,d,J~7.8Hz,1.5Hz),9.24(1H,m).
按相同方法,可把实施例6和11制得的酯转化成相应的酸。
实施例13
2-〔2-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕-5-羟甲基吡啶
在装有搅拌器,滴液漏斗,氨气入口管和温度计的250ml三颈瓶中加入379.5mg(10mmol)氢化锂铝的30ml无水乙醚的溶液,氮气下冷却溶液至-65℃。控制温度不超过-65℃情况下,滴加入3.2343g(10mmol)6-〔2-((4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯的15ml无水醚溶液。混合物在-30℃下搅拌1小时,加入300mg(3.4mmol)乙酸乙酯除去溶液中的过量氢化物。然后加入3ml饱和氯化铵溶液水解反应混合物,并让溶液温度升至室温。过滤混合物,醚洗涤剩余物,醚层用饱和的氯化钠溶液洗涤,MgSO4干燥,然后真空浓缩。剩余物色谱纯化和重结晶,给出标题化合物。
采用相同方法可把本发明的酸或酯转化成其相应的伯醇。
实施例14
2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕-5-乙酸基甲基吡啶
在室温下,将2.81g(10mol)4,4-二甲基-6-〔2-(5-羟甲基吡啶-2-基)乙炔基〕苯并二氢吡喃,600mg(10mmol)冰醋酸,2.06g(10mmol)二环己基碳二亚胺和460mg(3.765mmol)4-二甲氨基吡啶的150ml二氯甲烷溶液搅拌48小时。然后过滤反应混合物,剩余物用50ml二氯甲烷洗涤。滤液在真空下浓缩,剩余物经色谱纯化和重结晶得标题化合物。
按本方法的操作可酯化本发明的醇。
实施例15
2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕吡啶-5-羰醛
在装有搅拌器,温度计以及配有干燥管的二个恒压滴漏斗的4颈瓶中加入1.396g(11mmol)新鲜蒸馏的草酰氯的25ml二氯甲烷溶液。把溶液冷却至-60℃,然后于五分钟内滴加1.875g(24mmol)二甲亚砜(经氯化钙蒸馏得到)的5ml二氯甲烷溶液进行处理。再在-60℃下搅拌反应混合物10分钟。在反应混合中,5分钟滴加入2.81g(10mmol)4,4-二甲基-6-〔2-(5-羟甲基吡啶-2-基)乙炔基〕苯并二氢吡喃的10ml二氯甲烷溶液。再搅拌反应混合物15分钟,接着用5.06g(50mmol)三乙胺处理。然后移去冷却浴,让混合物温热至室温。向混合中加入30ml水并搅拌10分。分离出有机层,水层用20ml二氯甲烷萃取。合并有机层并依次用稀HCl,水和稀Na2CO3溶液洗涤,并MgSO4干燥。过滤溶液和真空浓缩,剩余物经色谱纯化和重结晶得本标题化合物。
用本方法也可把本发明的伯醇氧化成其相应的醛。
实施例16
2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕-5-(1-羟丙基)吡啶
在装有机械搅拌器,及配有干燥管的回流冷凝管和恒压滴液漏斗的三颈烧瓶中加入4ml 3M(12mmol)的溴化乙基镁的乙醚溶液。在冰浴冷却和剧烈搅拌下,慢慢滴入2.8g(10mmol)2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕吡啶-5-羰醛的10ml干醚溶液。移去冰浴,混合物加热回流3小时,然后再冰盐浴冷却并加入5ml饱和的氯化铵溶液。再搅拌混合物1小时,过滤,剩余物用醚每次10ml洗涤2次。分离出醚溶液,用MgSO4干燥,真空移去醚。剩余物经色谱纯化和重结晶得标题化合物。
本发明的任何其它的醛都能用该方法转化成仲醇。
按实施例15的操作,这些仲醇可转化成其相应的酮。
实施例17
2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕-5-二甲氧甲基吡啶
在装有迪安-斯达克装置的圆底烧瓶(其配有干燥管的回流冷凝管)中,加入3.35g(12mmol)2-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕吡啶-5-羰醛,4.80mg(15mmol)无水甲醇,2mg对甲苯磺酸单水合物和10ml无水苯的混合物。氢气下加热回流混合物至迪安-斯达克榻分水器收集到理论量的水。把混合物冷却至室温,依次用5ml 10%氢氧化钠溶液和每次为5ml水洗涤二次,MgSO4干燥。然后过滤溶液,并真空除去溶剂。剩余物色谱纯化和重结晶得标题化合物。
本发明的醛或酮可采用本方法转化成缩醛和缩酮。
实施例18
这些化合物较好以各种配方经局部给药。配方可为如下:
组份 百分重量
溶液
类视网膜 0.1
BHT 0.1
醇USP 58.0
聚乙二醇400NF 41.8
凝胶
类视网膜 0.1
BHT 0.1
醇USP 97.8
羟丙基纤维素 2.0
Claims (11)
2、根据权利要求1的方法,其中R是氢或甲基,n是0,1或2,A是吡啶基。
3、根据权利要求2的方法,其中B是一个保护的酸。
4、根据权利要求3的方法,其中所得的化合物是6-〔2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸乙酯。
5、根据权利要求3的方法,其中所得的化合物是6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸乙酯。
6、根据权利要求1的方法,其中X是S或O,A是噻吩基,B是保护的酸。
7、根据权利要求1的方法,其中X是S或O,A是呋喃基,B是保护的酸。
8、根据权利要求1的方法,其中X是S或O,A是达嗪基,嘧啶基或吡嗪基,B是保护的酸。
9、一种制备下式Ⅰ化合物的方法
式中X是S,O或NR1,其中R1是氢或低级烷基;R是氢或低级烷基;A是吡啶基,噻吩基,哒嗪基,嘧啶基或吡嗪基;n是0-5;B是-COOH或一个药物上可接受的盐,醇,醛或酮,本方法包括脱除保护的酸,醇,醛或酮。
10、根据权利要求9的方法,其中得到6-〔2-(4,4-二甲基二氢苯并噻喃-6-基)乙炔基〕烟酸,6-〔2-(4,4-二甲基苯并二氢吡喃-6-基)乙炔基〕烟酸或其药物上可接受的盐。
11、一种制备含有权利要求1至10任何一个化合物的药物组合物的方法,该方法包括把所说化合物同药物上可接受的载体相结合。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2827987A | 1987-03-20 | 1987-03-20 | |
US028,279 | 1987-03-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN88101424A true CN88101424A (zh) | 1988-10-05 |
CN1026789C CN1026789C (zh) | 1994-11-30 |
Family
ID=21842553
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN88101424A Expired - Lifetime CN1026789C (zh) | 1987-03-20 | 1988-03-19 | 具有类视网膜活性的含有杂芳香族和杂二环基团的二取代乙炔的制备方法 |
Country Status (23)
Country | Link |
---|---|
EP (1) | EP0284288B1 (zh) |
JP (2) | JPH085874B2 (zh) |
KR (1) | KR960014357B1 (zh) |
CN (1) | CN1026789C (zh) |
AT (1) | ATE76641T1 (zh) |
AU (1) | AU613346B2 (zh) |
CA (1) | CA1305480C (zh) |
DE (2) | DE3871414D1 (zh) |
DK (1) | DK175081B1 (zh) |
ES (1) | ES2034196T3 (zh) |
FI (1) | FI92398C (zh) |
GR (1) | GR3005243T3 (zh) |
HK (1) | HK5794A (zh) |
HU (1) | HU204818B (zh) |
IE (1) | IE60566B1 (zh) |
IL (1) | IL85787A (zh) |
LU (1) | LU90227I2 (zh) |
MY (1) | MY103237A (zh) |
NO (1) | NO169489C (zh) |
NZ (1) | NZ223948A (zh) |
PH (1) | PH27119A (zh) |
PT (1) | PT86975B (zh) |
ZA (1) | ZA881515B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749210A (zh) * | 2016-11-22 | 2017-05-31 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂类化合物及其制备方法与应用 |
CN106749211A (zh) * | 2016-11-22 | 2017-05-31 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂及其制备方法与应用 |
CN106854204A (zh) * | 2016-11-22 | 2017-06-16 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂化合物及其制备方法与应用 |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
US5234926A (en) * | 1987-03-20 | 1993-08-10 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
US5602130A (en) * | 1987-03-20 | 1997-02-11 | Allergan | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
CA1305480C (en) * | 1987-03-20 | 1992-07-21 | Roshantha A.S. Chandraratna | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups 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 |
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 |
US5045551A (en) * | 1989-09-19 | 1991-09-03 | 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 |
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 |
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 |
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 |
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 |
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 |
US5202471A (en) * | 1990-02-06 | 1993-04-13 | Allergan, Inc. | Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity |
CA2091763A1 (en) * | 1990-10-09 | 1992-04-10 | Roshantha A. S. Chandraratna | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydroquinolinyl group having retinoid-like activity |
AU648158B2 (en) * | 1991-02-13 | 1994-04-14 | Allergan, Inc. | Chroman and thiochromans with phenylethynyl 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 |
CA2105379A1 (en) * | 1991-03-26 | 1992-09-27 | Roshantha A. S. Chandraratna | Chromans and thiochromans with heteroarylethynyl substituents at the 7-position having retinoid-like biological activity |
CA2129831A1 (en) * | 1992-02-11 | 1993-08-19 | Roshantha A. S. Chandraratna | Heteroaryl substituted phenylethenyl compounds having retinoid-like biological activity |
US7655699B1 (en) | 1992-04-22 | 2010-02-02 | Eisai Inc. | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
US5962731A (en) * | 1992-04-22 | 1999-10-05 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
US5780676A (en) * | 1992-04-22 | 1998-07-14 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors |
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 |
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 |
US5470999A (en) * | 1993-12-30 | 1995-11-28 | Allergan, Inc. | Cyclohexene and bicyclic aromatic substituted ethyne compounds 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 |
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 |
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 |
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 |
WO1996020930A1 (en) * | 1994-12-29 | 1996-07-11 | Allergan | Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl 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 |
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 |
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 |
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 |
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 |
US5952345A (en) | 1995-09-01 | 1999-09-14 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
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 |
US5723666A (en) * | 1996-06-21 | 1998-03-03 | Allergan | Oxime substituted tetrahydronaphthalene derivatives 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 |
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 |
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 |
US5808124A (en) * | 1996-06-21 | 1998-09-15 | Allergan | O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
JPH10158192A (ja) * | 1996-10-03 | 1998-06-16 | Eisai Co Ltd | 移植片対宿主疾患(gvhd)の治療および臓器移植時の移植片拒絶反応抑制のための医薬組成物 |
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 |
WO1999020309A1 (fr) * | 1997-10-22 | 1999-04-29 | Eisai Co., Ltd. | Agonistes de l'acide retinoique, agents preventifs et therapeutiques des nephrites |
ITMI20050357A1 (it) | 2005-03-08 | 2006-09-09 | Solmag S P A | Procedimento di preparazione del tazarotene |
EP2089023A2 (en) * | 2006-11-02 | 2009-08-19 | Aestus Therapeutics, Inc. | Methods of treating neuropathic pain with agonists of ppar-gamma |
CN107176945B (zh) * | 2016-03-11 | 2021-06-08 | 中国科学院上海有机化学研究所 | 一种视黄酸类化合物、其制备方法、中间体及应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE793865A (fr) * | 1972-09-25 | 1973-07-10 | Syntex Corp | Composes d'acides xanthone-carboxyliques substitues par des groupes alcenyles et alcynyles |
DE3434946A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
CA1305480C (en) * | 1987-03-20 | 1992-07-21 | Roshantha A.S. Chandraratna | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
US5015661A (en) * | 1988-08-09 | 1991-05-14 | Hoffmann-La Roche Inc. | Chromanes and their pharmaceutical compositions and methods |
-
1988
- 1988-03-01 CA CA000560189A patent/CA1305480C/en not_active Expired - Lifetime
- 1988-03-03 ZA ZA881515A patent/ZA881515B/xx unknown
- 1988-03-03 PH PH36586A patent/PH27119A/en unknown
- 1988-03-14 PT PT86975A patent/PT86975B/pt not_active IP Right Cessation
- 1988-03-16 DK DK198801439A patent/DK175081B1/da not_active IP Right Cessation
- 1988-03-17 ES ES198888302318T patent/ES2034196T3/es not_active Expired - Lifetime
- 1988-03-17 EP EP88302318A patent/EP0284288B1/en not_active Expired - Lifetime
- 1988-03-17 AT AT88302318T patent/ATE76641T1/de active
- 1988-03-17 DE DE8888302318T patent/DE3871414D1/de not_active Expired - Lifetime
- 1988-03-17 DE DE1997175022 patent/DE19775022I2/de active Active
- 1988-03-18 IE IE80288A patent/IE60566B1/en not_active IP Right Cessation
- 1988-03-18 AU AU13268/88A patent/AU613346B2/en not_active Expired
- 1988-03-18 MY MYPI88000282A patent/MY103237A/en unknown
- 1988-03-18 NZ NZ223948A patent/NZ223948A/xx unknown
- 1988-03-18 IL IL85787A patent/IL85787A/xx not_active IP Right Cessation
- 1988-03-18 HU HU881363A patent/HU204818B/hu unknown
- 1988-03-18 KR KR88002880A patent/KR960014357B1/ko not_active IP Right Cessation
- 1988-03-18 FI FI881315A patent/FI92398C/fi not_active IP Right Cessation
- 1988-03-18 NO NO881200A patent/NO169489C/no not_active IP Right Cessation
- 1988-03-19 CN CN88101424A patent/CN1026789C/zh not_active Expired - Lifetime
- 1988-03-22 JP JP63070855A patent/JPH085874B2/ja not_active Expired - Lifetime
-
1992
- 1992-07-21 GR GR920401577T patent/GR3005243T3/el unknown
-
1994
- 1994-01-20 HK HK57/94A patent/HK5794A/xx not_active IP Right Cessation
-
1995
- 1995-02-17 JP JP7029226A patent/JP2859551B2/ja not_active Expired - Lifetime
-
1998
- 1998-03-13 LU LU90227C patent/LU90227I2/fr unknown
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749210A (zh) * | 2016-11-22 | 2017-05-31 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂类化合物及其制备方法与应用 |
CN106749211A (zh) * | 2016-11-22 | 2017-05-31 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂及其制备方法与应用 |
CN106854204A (zh) * | 2016-11-22 | 2017-06-16 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂化合物及其制备方法与应用 |
CN106749211B (zh) * | 2016-11-22 | 2019-08-09 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸酯及其制备方法与应用 |
CN106854204B (zh) * | 2016-11-22 | 2019-10-08 | 斯芬克司药物研发(天津)股份有限公司 | 一种烟酸脂化合物及其制备方法与应用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1026789C (zh) | 具有类视网膜活性的含有杂芳香族和杂二环基团的二取代乙炔的制备方法 | |
CN1032204C (zh) | 具有类视网膜活性的苯基和杂二环基取代的乙炔的制备方法 | |
CN1028174C (zh) | 制备具有类视黄酸生物活性的带有二取代的乙炔部分的化合物的方法 | |
CN1036920C (zh) | 含杂环碳酸衍生物 | |
CN1031266C (zh) | 含氮的六元或十元杂环的制法 | |
CN1038839C (zh) | 一类环胺化合物的制备方法 | |
CN1023404C (zh) | 苯并吡喃衍生物的制备方法 | |
CN1032203C (zh) | 制备取代2-吡啶酮和吡啶-2-硫酮的方法 | |
CN1045435C (zh) | 萘衍生物、其制备方法及其合成中间体 | |
CN1226888A (zh) | 含氟-1,4-二取代哌啶衍生物 | |
CN1153771C (zh) | 苯并呋喃并[3,4-f]喹啉衍生物、含有其的药物组合物及其应用 | |
CN1906180A (zh) | 新的长效β-2-激动剂及其作为药物的用途 | |
CN86103398A (zh) | 生产抗坏血酸衍生物的方法 | |
CN101052633A (zh) | 制备吲唑化合物的方法 | |
CN1471515A (zh) | 作为β2-肾上腺素受体激动剂及PDE-4抑制剂的有效的化合物 | |
CN1289483C (zh) | 甘氨酰胺的杂环衍生物及其医药用途 | |
CN1060467A (zh) | 1,3-苯并嗪衍生物、其生产方法和用途 | |
CN86107826A (zh) | 新的福斯克林衍生物 | |
CN1244578C (zh) | 取代的苯并呋喃-2-甲酰胺衍生物 | |
CN1059903A (zh) | 环上取代的2-氨基-1,2,3,4,-四氢化萘,3-氨基二氢苯并吡喃3-氨基二氢苯并噻喃 | |
CN1290265A (zh) | 凝血酶受体拮抗剂 | |
CN1184813A (zh) | 吡啶衍生物、制备吡啶衍生物的方法及其中间体 | |
CN1007153B (zh) | 具有抗过敏活性的新的苯并噻吩类和苯并呋喃类化合物的制备方法 | |
CN1229407A (zh) | 双芳基化合物和含有它们的药物和化妆品组合物 | |
CN1058207A (zh) | 新的哌啶化合物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
C17 | Cessation of patent right |