USRE31467E - Triaryl or diarylpyridyl methanes - Google Patents
Triaryl or diarylpyridyl methanes Download PDFInfo
- Publication number
- USRE31467E USRE31467E US06/127,135 US12713580A USRE31467E US RE31467 E USRE31467 E US RE31467E US 12713580 A US12713580 A US 12713580A US RE31467 E USRE31467 E US RE31467E
- Authority
- US
- United States
- Prior art keywords
- radical
- formula
- hydrogen
- acid
- compound
- 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.)
- Expired - Lifetime
Links
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 239000002253 acid Substances 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 62
- -1 C1-6 alkyl radical Chemical class 0.000 claims description 51
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 150000003254 radicals Chemical class 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 17
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 16
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical group C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 36
- 239000004480 active ingredient Substances 0.000 abstract description 24
- 239000002674 ointment Substances 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- 230000004968 inflammatory condition Effects 0.000 abstract description 2
- 208000027866 inflammatory disease Diseases 0.000 abstract description 2
- 238000011200 topical administration Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 16
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 206010015150 Erythema Diseases 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- 230000003110 anti-inflammatory effect Effects 0.000 description 10
- 231100000321 erythema Toxicity 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003701 inert diluent Substances 0.000 description 9
- 239000001117 sulphuric acid Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 235000011149 sulphuric acid Nutrition 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012024 dehydrating agents Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 229960004592 isopropanol Drugs 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- WPWHSFAFEBZWBB-UHFFFAOYSA-N 1-butyl radical Chemical compound [CH2]CCC WPWHSFAFEBZWBB-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000012345 acetylating agent Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 229940096529 carboxypolymethylene Drugs 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- GEAXLHPORCRESC-UHFFFAOYSA-N chlorocyclohexatriene Chemical compound ClC1=CC=C=C[CH]1 GEAXLHPORCRESC-UHFFFAOYSA-N 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000001587 sorbitan monostearate Substances 0.000 description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 description 2
- 229940035048 sorbitan monostearate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical compound O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 description 1
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 description 1
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- XWMRMJOORZIBKJ-UHFFFAOYSA-N 2-hydroxy-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1O.CC1=CC=CC(C(O)=O)=C1O XWMRMJOORZIBKJ-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- 241000335053 Beta vulgaris Species 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 240000001307 Myosotis scorpioides Species 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 101150111584 RHOA gene Proteins 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 241001290864 Schoenoplectus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- FDMBBCOBEAVDAO-UHFFFAOYSA-N Stovaine Chemical compound CN(C)CC(C)(CC)OC(=O)C1=CC=CC=C1 FDMBBCOBEAVDAO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960000806 amylocaine Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 229960004311 betamethasone valerate Drugs 0.000 description 1
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
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- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- REHHBTUVMSHZNT-UHFFFAOYSA-N bromocyclohexatriene Chemical compound BrC1=CC=C=C[CH]1 REHHBTUVMSHZNT-UHFFFAOYSA-N 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
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- 125000000068 chlorophenyl group Chemical group 0.000 description 1
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- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229940117173 croton oil Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
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- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
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- JWRMHDSINXPDHB-OJAGFMMFSA-N flumethasone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(=O)C(C)(C)C)(O)[C@@]2(C)C[C@@H]1O JWRMHDSINXPDHB-OJAGFMMFSA-N 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960004905 gramicidin Drugs 0.000 description 1
- ZWCXYZRRTRDGQE-SORVKSEFSA-N gramicidina Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](NC=O)C(C)C)CC(C)C)C(=O)NCCO)=CNC2=C1 ZWCXYZRRTRDGQE-SORVKSEFSA-N 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008177 pharmaceutical agent 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
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C205/60—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms in ortho-position to the carboxyl group, e.g. nitro-salicylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/61—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/30—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing —CHO groups
Definitions
- This invention relates to new pharmaceutical compositions which have anti-inflammatory activity and, in particular, which have anti-inflammatory activity when applied topically to an area of inflammation.
- a pharmaceutical composition which comprises as active ingredient a compound of the formula: ##STR1## wherein either X is hydrogen and Y is a radical of the formula: ##STR2## or X and Y together are a radical of the formula: ##STR3## and wherein R 1 is hydrogen or an acetyl radical; R 2 is hydrogen or a phenyl radical optionally substituted by a halogen atom; R 3 is hydrogen, a C 1-6 -alkyl radical or a halogen atom; and B is a 4-pyridyl radical, or a phenyl which may optionally bear from 1 to 3 substituents selected from halogen atoms, nitro, cyano, carbamoyl, carboxy, formyl and N-hydroxyazomethylidene (HO--N ⁇ CH--) radicals; or a pharmaceutically acceptable salt of a compound of formula I wherein R 2 is hydrogen; together with a pharmaceutically-acceptable diluent or
- a particularly suitable value for R 2 when it is a phenyl radical optionally substituted by a halogen atom is, for example, a chloro- or bromo-phenyl radical, for example a 4-chloro- or 4-bromo-phenyl radical.
- a particularly suitable value for R 3 when it is a C 1-6 -alkyl radical is for example a methyl, ethyl, propyl or butyl radical, and when it is a halogen atom is, for example, a fluorine, chlorine or bromine atom.
- a particularly suitable value for a halogen atom when present as a substituent when B is an optionally substituted phenyl radical is, for example, a fluorine, chlorine or bromine atom.
- a particularly suitable value for B when it is an optionally substituted phenyl radical is, for example, a phenyl or a 3-nitro-, 4-nitro, 4-fluoro-, 2-chloro, 4-chloro, 4-bromo-, 4-cyano-, 4-carboxy-, 4-carbamoyl-, 2,6-difluoro-, 2,4-dichloro-, 2,6-dichloro-, 2,4,6-trichloro-, 2-fluoro-6-chloro-, 2-chloro-4-cyano, 2-chloro-4-nitro-, 2-chloro-5-nitro-, 2-bromo-6-chloro-, 4-formyl- or 4-(N-hydroxyazomethylidene)-phenyl radical.
- Presently preferred active ingredients of the composition of the invention are, for example, 4"-cyano-, 4"-nitro-, and 2"-chloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- a particularly suitable salt of active ingredient of formula I wherein R 2 is hydrogen is, for example an alkali metal salt, for example a sodium salt, an alkaline earth metal salt, for example a calcium salt, an ammonium or an aluminium salt, or the salt of an organic base affording a pharmaceutically-acceptable cation, for example a triethanolamine salt.
- the pharmaceutical composition of the invention may be obtained by conventional means and using conventional diluents and carriers, and is in a form suitable for topical application to an area of inflammation, for example, on the skin.
- a particularly suitable form of a composition of the invention is therefore, for example, an ointment, gel, emulsion, solution or suspension.
- a composition of the invention may in general contain 0.5% to 10% w/w of an active ingredient of formula I as defined above.
- a particularly suitable ointment formulation is prepared by dispersing an active ingredient as defined above in a pharmaceutically acceptable organic diluent, for example soft paraffin, optionally in the presence of an emulsifying and/or thickening agent, for example sorbitan monostearate.
- a pharmaceutically acceptable organic diluent for example soft paraffin
- an emulsifying and/or thickening agent for example sorbitan monostearate.
- a further particularly suitable ointment formulation is prepared by dissolving an active ingredient as defined above in a pharmaceutically-acceptable organic solvent, for example diethyleneglycol monoethyl ether, and then dispersing the solution in a pharmaceutically-acceptable organic diluent, for example soft paraffin, optionally in the presence of a stabiliser, for example lanolin.
- a pharmaceutically-acceptable organic solvent for example diethyleneglycol monoethyl ether
- a pharmaceutically-acceptable organic diluent for example soft paraffin
- a stabiliser for example lanolin
- a particularly suitable gel formulation is prepared by adding a gelling agent, for example carboxy polymethylene, to a solution of an active ingredient as defined above, in a pharmaceutically-acceptable organic solvent, for example isopropyl alcohol.
- a gelling agent for example carboxy polymethylene
- a particularly suitable emulsion formulation for example a cream or a lotion, is prepared by mixing an active ingredient as defined above with a suitable conventional emulsifying system and water.
- a particularly suitable solution formulation for example a tincture, is prepared by dissolving an active ingredient as defined above in a pharmaceutically-acceptable organic solvent, for example isopropylalcohol or actone.
- a pharmaceutically-acceptable organic solvent for example isopropylalcohol or actone.
- a particularly suitable suspension formulation is, for example, an aqueous suspension, and may contain an active ingredient as defined above, in admixture with one or more suitable excipients selected from, for example, suspending, dispersing and wetting agents.
- a further particularly suspension formulation is, for example, a suspension in a form suitable for aerosol dispensation, and is prepared from an active ingredient as defined above in very finely divided form, together with one or more conventional aerosol propellents, for example a halogenated hydrocarbon, such as 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane or 1,2-dichloro-1,1,2,2-tetrafluoroethane.
- a halogenated hydrocarbon such as 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane or 1,2-dichloro-1,1,2,2-tetrafluoroethane.
- composition of the invention may contain in addition to an active ingredient or formula I, one or more known pharmaceutical agents selected from corticosteroids, for example fluocinolone acetonide, prednisolone, flumethasone pivalate, betamethasone valerate, hydrocortisone or dexamethasone, and antibacterial agents, for example oxytetracycline, gentamicin, neomycin, gramicidin, chlorhexidine or cetyltrimethylammonium bromide, and anti-fungal agents, for example griseofulvin or nystatin, and antihistamines, for example diphenhydramine or chlorphenamine, and local anaesthetics, for example amylocaine, benzocaine or procaine.
- the compositions may also contain conventional excipients such as colours, chelating agents or preservatives as desired.
- novel compounds of formula I comprise those compounds wherein X is hydrogen and Y is a radical of formula II and:
- R 2 is a phenyl radical optionally substituted by a halogen atom
- R 3 is a halogen atom or a C 2-6 -alkyl radical
- B is a phenyl radical bearing a fluorine or bromine atom, or a carbamoyl, carboxy, formyl, N-hydroxyazomethylidene (HO--N ⁇ CH--) or cyano radical, or a mono-nitro radical;
- R 3 is a methyl radical
- B is a phenyl radical bearing a 3-, 5- or 6-chloro-radical; or a 2,3-,2,4- or 3,5-dichloro radical, or a 2,3,4-, 2,4,6- or 2,5,6-trichloro radical, or a dinitro radical;
- R 3 is hydrogen and B is a phenyl radical bearing a chloro, dichloro, or trichloro radical, or a 2,3- 2,5-, 3,5- or 2,6-dinitro radical;
- R 1 , R 2 , R 3 and B have the general meanings stated herein above unless specified otherwise; together with, for those compounds wherein R 2 is hydrogen, the pharmaceutically acceptable salts thereof.
- novel compounds of formula I comprise those compounds wherein X and Y together are a radical of formula III, and wherein R 2 , R 3 and B have the specific meanings ascribed immediately above in groups (a) to (g), or, where no meaning is so ascribed, the general meanings stated hereinabove; together with, for those compounds wherein R 2 is hydrogen, the pharmaceutically acceptable salts thereof.
- a particularly suitable value for R 3 when it is a C 2-6 -alkyl radical is, for example, an ethyl, propyl or butyl radical; and a particularly preferred value for R 3 , is hydrogen or a methyl, n-propyl or chloro radical.
- a preferred group of novel compounds of formula I comprises those compounds of formula I wherein X is hydrogen, Y is a radical of formula II, R 1 and R 2 are hydrogen, and R 1 is hydrogen or a methyl radical; and the pharmaceutically acceptable salts thereof.
- a further preferred group of novel compounds of formula I comprises those compounds of formula I wherein X is hydrogen, Y is a radical of formula II R 3 is hydrogen or a methyl radical and B is a 4-nitro- or 4-cyano-phenyl radical; and the pharmaceutically-acceptable salts thereof.
- Especially preferred novel compounds of the invention are 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid and 4"-nitro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- novel compounds of formula I may be obtained by any process applicable to the manufacture of analogous chemical compounds. Such processes are provided as a further feature of the invention and are exemplified by the following in which X,Y,R 1 , R 2 , R 3 and B have the general meanings stated above unless specifically stated otherwise:
- a particularly suitable strong inorganic acid is, for example, concentrated sulphuric, hydrochloric or hydrofluoric acid, and a particularly suitable strong organic acid is trifluoroacetic acid.
- the process is conveniently carried out at, for example, 0° to 50° C., and preferably at 10° to 30° C. The duration of the process is from 30 minutes to 4 days, depending upon the reactivity of the reactants.
- the strong inorganic or organic acid is conveniently used in excess, but a conventional inert diluent may also be included.
- the salicylic acid of formula IV is conveniently employed in excess, for example in an excess of 1 molecular equivalent, over the aldehyde of formula V.
- the oxidation may be carried out with an inorganic or organic oxidising agent, conveniently at 10°-30° C. and optionally in the presence of an inert solvent or diluent, for example formic or acetic acid.
- an inert solvent or diluent for example formic or acetic acid.
- Particularly suitable inorganic oxidising agents are, for example, nitrous acid, sodium or potassium periodate or hydrogen peroxide, all conveniently used in the presence of an acid, for example formic, acetic or sulphuric acid.
- nitrous acid When nitrous acid is employed it may conveniently be generated in situ using a suitable nitrite, for example an alkali metal nitrite, such as sodium nitrite.
- a particularly suitable organic oxidising agent is, for example, lead tetra-acetate, which is conveniently used in the presence of acetic acid.
- the oxidation is in general exothermic and is preferably maintained at 10° to 30° C., and more particularly at 15°-25° C., by suitable cooling.
- a particularly suitable acetylating agent is, for example, an acetyl halide, for example acetyl chloride or acetyl bromide, or acetic anhydride.
- the process may optionally be carried out in an inert solvent or diluent, for example acetone, acetonitrile or tetrahydrofuran and is preferably catalysed by addition of a mineral acid, for example sulphuric acid.
- the process is conveniently carried out at, for example 0°-100° C. and more particularly at 20°-60° C.
- an acid of formula I wherein R 2 is hydrogen may be converted into an acid halide, for example an acid chloride, using a halogenating agent, for example phosphorus oxychloride or thionyl chloride, optionally in an inert solvent or diluent, for example toluene.
- a halogenating agent for example phosphorus oxychloride or thionyl chloride
- This reaction is conveniently carried out at 50° to 100° C., for example at reflux temperature.
- the acid halide thus obtained may then be reacted with the appropriate phenol of the formula R 4 .OH, wherein R 4 has the meaning stated above, optionally in the presence of a base, for example pyridine, conveniently in an inert diluent or solvent, for example tetrahydrofuran, and at a temperature of, for example, from 0°-100° C.
- a base for example pyridine
- an inert diluent or solvent for example tetrahydrofuran
- the acid halide may be prepared in the presence of the above phenol, in which case the need for a separate reaction is eliminated.
- the above acid of formula I may be reacted with the above phenol in the presence of a condensing agent, for example dicyclohexylcarbodiimide, in an inert diluent or solvent, for example, tetrahydrofuran or acetonitrile and conveniently at a temperature of, for example, from 10°-100° C.
- a condensing agent for example dicyclohexylcarbodiimide
- an inert diluent or solvent for example, tetrahydrofuran or acetonitrile
- the dehydration is conveniently carried out in the presence of a dehydrating agent.
- a particularly suitable dehydrating agent when Z is an N-hydroxyazomethylidene (HO--N ⁇ CH--) radical is, for example, thionyl chloride, a mixture of N,N-dimethylformamide and sodium formate, a mixture of sodium acetate and acetic acid, or acetic anhydride.
- thionyl chloride a mixture of N,N-dimethylformamide and sodium formate
- acetic anhydride is used as dehydrating agent on a starting material of formula VIII wherein R 1 is hydrogen
- the first product isolated is a compound of formula I wherein R 1 is an acetyl radical, but this may be readily hydrolysed in accordance with process (f) described herein below.
- a particularly suitable dehydrating agent when Z is a carbamoyl radical is for example phosphorus pentoxide, phosphorus oxychloride or thionyl chloride.
- phosphorus oxychloride or thionyl chloride is used as dehydrating agent on a starting material of formula VII wherein R 2 is hydrogen, the carboxylic acid chloride may conveniently be isolated, or this may be hydrolysed to give the required compound of formula I wherein R 2 is hydrogen.
- the dehydration is conveniently carried out at elevated temperature, for example at 50°-200° C., and more particularly at 100°-150° C., and an inert solvent or diluent, for example 1,1,2,2-tetrachloroethane, may optionally be present.
- elevated temperature for example at 50°-200° C., and more particularly at 100°-150° C.
- an inert solvent or diluent for example 1,1,2,2-tetrachloroethane, may optionally be present.
- the starting materials of formula VII may be prepared as described hereinabove in parts (a)-(d), from known starting benzaldehyde and salicylic acid derivatives.
- Z is an N-hydroxyazomethylidene radical
- they may be prepared by reacting a formyl compound of the formula: ##STR11## wherein R 1 , R 2 , R 3 , X and Y have the general meanings stated above, with hydroxylamine using conventional conditions for the formation of oximes of aldehydes.
- the hydrolysis is conveniently carried out either in the presence of aqueous acid, for example sulphuric or hydrochloric acid, or in the presence of aqueous base, for example sodium or potassium hydroxide; and at a temperature of, for example, 20°-100° C.
- aqueous acid for example sulphuric or hydrochloric acid
- aqueous base for example sodium or potassium hydroxide
- An inert solvent or diluent for example acetic acid or ethanol, may also optionally be used.
- the starting materials of formula IX may either be obtained by the processes described specifically hereinabove or by direct analogy to them.
- the reduction may be conveniently carried out using any reducing agent generally known to be capable of reducing the quinonemethide radical in analogous compounds, for example, hydrogen in the presence of a metal catalyst for example palladium or platinum, a reducing metal for example zinc or iron preferably in the presence of acid, sodium borohydride or sodium dithionite.
- a metal catalyst for example palladium or platinum
- a reducing metal for example zinc or iron preferably in the presence of acid, sodium borohydride or sodium dithionite.
- the reduction is preferably carried out at, for example, 20° to 100° C. and in water or an inert solvent or diluent, for example, acetic acid, methanol or ethanol, or in an aqueous mixture containing such a solvent or diluent.
- an inert solvent or diluent for example, acetic acid, methanol or ethanol, or in an aqueous mixture containing such a solvent or diluent.
- a compound of formula I wherein R 2 is hydrogen is reacted with a base affording a pharmaceutically acceptable cation, for example sodium hydroxide, calcium hydroxide, ammonia or triethanolamine.
- the compounds of formula I possess anti-inflammatory properties when applied topically to an area of inflammation and are particularly useful in treating inflammatory diseases or inflammatory conditions of the skin, in warm-blooded animals.
- certain of the compounds of formula I possess anti-bacterial properties. These antibacterial properties are to be understood to be only a useful addition to the anti-inflammatory properties and are insufficient in themselves to justify using a compound possessing them solely as an anti-bacterial agent.
- a particular group of active ingredients of formula I having both anti-inflammatory and anti-bacterial properties comprises 2",4"-dichloro-4,4'-dihydroxy-3,3'-triphenylmethane-dicarboxylic acid, 4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenyl-methanedicarboxylic acid, 4"-chloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid and 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- a particular group of novel compounds of formula I having both anti-inflammatory and anti-bacterial properties comprises 2",4"-dichloro-4,4"-dihydroxy-3,3'-triphenyl-methanedicarboxylic acid and 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- the anti-inflammatory properties of a compound of formula I may be demonstrated in a standard test involving the inhibition of croton oil induced inflammation on the mouse ear.
- the activity of an individual compound in this test depends upon its particular chemical structure, but specific compounds of formula I as described in the specification produced a significant inhibition of the inflammation at a topically applied dose in the range 100 ⁇ g. to 2000 ⁇ g. per ear. No overt toxic effects were detected at the active dose in this test.
- the anti-bacterial properties of an active ingredient may be demonstrated in a standard test involving the inhibition of growth of Gram positive bacteria, for example Strep. faecalis and Staph. aureus, cultured in a known manner.
- the anti-bacterial activity of an individual compound depends on its particular chemical structure but in general the specific compounds of formula I as described in the specification were active at a concentration in the range from 10 to 1,000 parts per million.
- an active ingredient of the composition When an active ingredient of the composition is used for the topical treatment of an area of inflammation affecting the skin of a warm-blooded animal, for example man, it is expected that the active ingredient will be administered topically so that a daily dose of up to 300 mg. per man is received.
- the active ingredient is conveniently administered at intervals, for example three times daily, and at a rate of, for example, l mg. of active ingredient per square centimeter of skin, or at a lower rate.
- the substituted benzaldehyde (0.15 mole) was added in portions to stirred cooled (10° C.) concentrated sulphuric acid (93% w/v, 153 ml.).
- the salicylic acid derivative (0.335 mole) was then added rapidly and the mixture was stirred at 10°-25° C. for 40 minutes to 4 days depending upon the particular reactants involved.
- the reaction mixture was then poured into ice-water, and the precipitated solid was filtered off and washed thoroughly with water. The solid was then crystallised using the solvent(s) indicated.
- Terephthalaldehyde (25 g.) was added in portions to a stirred mixture of concentrated sulphuric acid (98% w/w, 300 ml.) and water (23 ml.), cooled to 20°-25° C.
- o-Cresotic acid (2-hydroxy-3-methylbenzoic acid) (58 g.) was then added rapidly and the mixture was then further stirred at 20°-25° C. for 16 hours.
- reaction mixture was then poured into ice-water (1.5 l.), and the precipitated solid was separated by filtration, washed with water, and recrystallised from 50% v/v aqueous acetone to give 4"-formyl-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid, m.p. 274°-277° C. (decomposition).
- Hydroxylamine hydrochloride (16.0 g.) was added at 20°-25° C. to a solution of 4"-formyl-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid, (42.0 g.) in a mixture of water (300 ml.) and aqueous ammonia solution (density 0.88) (25 ml.). The mixture was stirred at the same temperature for 1 hour and then adjusted to pH 4 by addition of glacial acetic acid (approximately 20 ml.).
- the precipitated solid was separated by filtration, washed with water and reprecipitated with acetic acid from solution in a mixture of aqueous ammonia and acetone to give the oxime of 4"-formyl-4,4'-dijhydroxy-5,5'-dimethyl-3,3'-triphenylmethane-dicarboxylic acid, m.p. 275°-277° C. (decomposition).
- Acetic anhydride (2.1 ml.) was added to a suspension of the oxime of 4"-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (4.35 g.), and the mixture heated under reflux for 24 hours. After it had been cooled to 20°-25° C. the mixture was stirred vigorously with 2N aqueous sodium hydroxide solution (approximately 40 ml.) so that the mixture was maintained near pH 11. The aqueous phase was then separated and acidified to pH 3 with hydrochloric acid.
- a mixture of cetostearyl alcohol (9 parts by weight), liquid paraffin (7 parts by weight), sorbitan monostearate (2 parts by weight), polysorbate 60 (2 parts by weight) and finely divided 4 ⁇ -cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (1 part by weight) was fused by heating at 65°-70° C. Water (79 parts by weight) was added with stirring to the melt thus obtained. The mixture was then stirred rapidly with slow cooling to 20°-25° C. until a homogeneous cream, suitable for human use, was obtained.
- the lanolin which is present to help stabilise the physical condition of the ointment, may if desired be omitted.
- Example 9 The procedure described in Example 9 was repeated except that a compound of formula I wherein R 1 and R 2 are hydrogen, R 3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R 1 , R 2 and R 3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- Example 10 The precedure described in Example 10 was repeated except that a compound of formula I wherein R 1 and R 2 are hydrogen, R 3 is a methyl radical, and B is a phenyl,2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5 dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R 1 , R 2 and R 3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- Example 11 The procedure described in Example 11 was repeated except that a compound of formula I wherein R 1 and R 2 are hydrogen, R 3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R 1 , R 2 and R 3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4---cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- Example 13 The procedure described in Example 13 was repeated except that a compounds of formula I wherein R 1 and R 2 are hydrogen, R 3 is a methyl radical, and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R 1 , R 2 and R 3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
- the anti-inflammatory activity of an active ingredient of formula I and, in particular, the anti-inflammatory activity of an active ingredient of formula I when applied topically to an area of inflammation, has been demonstrated in man in the following manner involving the reduction of erythema in the skin, induced after exposure to U.V. light:
- the appropriate control that is the solvent (10 ⁇ per square) or no treatment, being applied to the corresponding square on the contralateral arm.
- each of the squares on each forearms was exposed to the pre-determined dose of U.V. light.
- the rest of the arm was protected during this exposure by a shield having holes cut in it corresponding to the three squares.
- the degree of erythema was then assessed for each square at intervals of 2,4,7,24,31 and 48 hours after the exposure to U.V. light, using the following verbal scoring system:
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Abstract
Pharmaceutical compositions, containing a 4,4'-dihydroxy-3,3'-triphenylmethanedicarboxylic acid (or an oxidized derivative) as active ingredient, are described and are prepared conventionally in a form suitable for topical administration e.g. ointment. The compositions are useful for the treatment of inflammatory diseases and inflammatory conditions of the skin. Many of the active ingredients are novel compounds. A representative novel active ingredient is 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
Description
This is a division of application Ser. No. 747,995 filed Dec. 6, 1976, now U.S. Pat. No. 4,113,879.
This invention relates to new pharmaceutical compositions which have anti-inflammatory activity and, in particular, which have anti-inflammatory activity when applied topically to an area of inflammation.
According to the invention there is provided a pharmaceutical composition which comprises as active ingredient a compound of the formula: ##STR1## wherein either X is hydrogen and Y is a radical of the formula: ##STR2## or X and Y together are a radical of the formula: ##STR3## and wherein R1 is hydrogen or an acetyl radical; R2 is hydrogen or a phenyl radical optionally substituted by a halogen atom; R3 is hydrogen, a C1-6 -alkyl radical or a halogen atom; and B is a 4-pyridyl radical, or a phenyl which may optionally bear from 1 to 3 substituents selected from halogen atoms, nitro, cyano, carbamoyl, carboxy, formyl and N-hydroxyazomethylidene (HO--N═CH--) radicals; or a pharmaceutically acceptable salt of a compound of formula I wherein R2 is hydrogen; together with a pharmaceutically-acceptable diluent or carrier.
The nomenclature used in this specification is based on the following system, the formula IV being given by way of example only: ##STR4##
A particularly suitable value for R2 when it is a phenyl radical optionally substituted by a halogen atom is, for example, a chloro- or bromo-phenyl radical, for example a 4-chloro- or 4-bromo-phenyl radical.
A particularly suitable value for R3 when it is a C1-6 -alkyl radical is for example a methyl, ethyl, propyl or butyl radical, and when it is a halogen atom is, for example, a fluorine, chlorine or bromine atom.
A particularly suitable value for a halogen atom when present as a substituent when B is an optionally substituted phenyl radical is, for example, a fluorine, chlorine or bromine atom.
A particularly suitable value for B when it is an optionally substituted phenyl radical is, for example, a phenyl or a 3-nitro-, 4-nitro, 4-fluoro-, 2-chloro, 4-chloro, 4-bromo-, 4-cyano-, 4-carboxy-, 4-carbamoyl-, 2,6-difluoro-, 2,4-dichloro-, 2,6-dichloro-, 2,4,6-trichloro-, 2-fluoro-6-chloro-, 2-chloro-4-cyano, 2-chloro-4-nitro-, 2-chloro-5-nitro-, 2-bromo-6-chloro-, 4-formyl- or 4-(N-hydroxyazomethylidene)-phenyl radical.
Presently preferred active ingredients of the composition of the invention are, for example, 4"-cyano-, 4"-nitro-, and 2"-chloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
A particularly suitable salt of active ingredient of formula I wherein R2 is hydrogen is, for example an alkali metal salt, for example a sodium salt, an alkaline earth metal salt, for example a calcium salt, an ammonium or an aluminium salt, or the salt of an organic base affording a pharmaceutically-acceptable cation, for example a triethanolamine salt.
The pharmaceutical composition of the invention may be obtained by conventional means and using conventional diluents and carriers, and is in a form suitable for topical application to an area of inflammation, for example, on the skin. A particularly suitable form of a composition of the invention is therefore, for example, an ointment, gel, emulsion, solution or suspension. A composition of the invention may in general contain 0.5% to 10% w/w of an active ingredient of formula I as defined above.
A particularly suitable ointment formulation is prepared by dispersing an active ingredient as defined above in a pharmaceutically acceptable organic diluent, for example soft paraffin, optionally in the presence of an emulsifying and/or thickening agent, for example sorbitan monostearate.
A further particularly suitable ointment formulation is prepared by dissolving an active ingredient as defined above in a pharmaceutically-acceptable organic solvent, for example diethyleneglycol monoethyl ether, and then dispersing the solution in a pharmaceutically-acceptable organic diluent, for example soft paraffin, optionally in the presence of a stabiliser, for example lanolin.
A particularly suitable gel formulation is prepared by adding a gelling agent, for example carboxy polymethylene, to a solution of an active ingredient as defined above, in a pharmaceutically-acceptable organic solvent, for example isopropyl alcohol.
A particularly suitable emulsion formulation, for example a cream or a lotion, is prepared by mixing an active ingredient as defined above with a suitable conventional emulsifying system and water.
A particularly suitable solution formulation, for example a tincture, is prepared by dissolving an active ingredient as defined above in a pharmaceutically-acceptable organic solvent, for example isopropylalcohol or actone.
A particularly suitable suspension formulation is, for example, an aqueous suspension, and may contain an active ingredient as defined above, in admixture with one or more suitable excipients selected from, for example, suspending, dispersing and wetting agents.
A further particularly suspension formulation, is, for example, a suspension in a form suitable for aerosol dispensation, and is prepared from an active ingredient as defined above in very finely divided form, together with one or more conventional aerosol propellents, for example a halogenated hydrocarbon, such as 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane or 1,2-dichloro-1,1,2,2-tetrafluoroethane.
The composition of the invention may contain in addition to an active ingredient or formula I, one or more known pharmaceutical agents selected from corticosteroids, for example fluocinolone acetonide, prednisolone, flumethasone pivalate, betamethasone valerate, hydrocortisone or dexamethasone, and antibacterial agents, for example oxytetracycline, gentamicin, neomycin, gramicidin, chlorhexidine or cetyltrimethylammonium bromide, and anti-fungal agents, for example griseofulvin or nystatin, and antihistamines, for example diphenhydramine or chlorphenamine, and local anaesthetics, for example amylocaine, benzocaine or procaine. In addition the compositions may also contain conventional excipients such as colours, chelating agents or preservatives as desired.
The majority of the compounds of formula I are novel compounds. However a specific group of compounds of formula I which are known comprises those compounds of formula I wherein R1 and R2 are hydrogen, R3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, and those compounds wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical.
According to a further feature of the invention there is provided a novel 3,3'-triarylmethanedicarboxylic acid derivative of the formula: ##STR5## wherein either X is hydrogen and Y is a radical of the formula: ##STR6## or X and Y together are a radical of the formula: ##STR7## and wherein R1 is hydrogen or an acetyl radical; R2 is hydrogen or a phenyl radical optionally substituted by a halogen atom; R3 is hydrogen, a C1-6 -alkyl radical or a halogen atom; and B is a 4-pyridyl radical, or a phenyl radical which may optionally bear from 1 to 3 substituents selected from halogen atoms, nitro, cyano, carbamoyl, carboxy, formyl and N-hydroxyazomethylidine (HO--N═CH--) radicals; or a pharmaceutically-acceptable salt of a compound of formula I wherein R2 is hydrogen; but excluding those compound of formula I as defined above wherein R1 and R2 are hydrogen, R3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical; and those compounds wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical.
Particular groups of novel compounds of formula I comprise those compounds wherein X is hydrogen and Y is a radical of formula II and:
(a) wherein R1 is an acetyl radical;
(b) wherein R2 is a phenyl radical optionally substituted by a halogen atom;
(c) wherein R3 is a halogen atom or a C2-6 -alkyl radical;
(d) wherein B is a 4-pyridyl radical;
(e) wherein B is a phenyl radical bearing a fluorine or bromine atom, or a carbamoyl, carboxy, formyl, N-hydroxyazomethylidene (HO--N═CH--) or cyano radical, or a mono-nitro radical;
(f) wherein R3 is a methyl radical, and B is a phenyl radical bearing a 3-, 5- or 6-chloro-radical; or a 2,3-,2,4- or 3,5-dichloro radical, or a 2,3,4-, 2,4,6- or 2,5,6-trichloro radical, or a dinitro radical;
(g) wherein R3 is hydrogen and B is a phenyl radical bearing a chloro, dichloro, or trichloro radical, or a 2,3- 2,5-, 3,5- or 2,6-dinitro radical;
and wherein in each of parts (a) to (g) R1, R2, R3 and B have the general meanings stated herein above unless specified otherwise; together with, for those compounds wherein R2 is hydrogen, the pharmaceutically acceptable salts thereof.
Yet further particular groups of novel compounds of formula I comprise those compounds wherein X and Y together are a radical of formula III, and wherein R2, R3 and B have the specific meanings ascribed immediately above in groups (a) to (g), or, where no meaning is so ascribed, the general meanings stated hereinabove; together with, for those compounds wherein R2 is hydrogen, the pharmaceutically acceptable salts thereof.
A particularly suitable value for R3 when it is a C2-6 -alkyl radical is, for example, an ethyl, propyl or butyl radical; and a particularly preferred value for R3, is hydrogen or a methyl, n-propyl or chloro radical.
A preferred group of novel compounds of formula I comprises those compounds of formula I wherein X is hydrogen, Y is a radical of formula II, R1 and R2 are hydrogen, and R1 is hydrogen or a methyl radical; and the pharmaceutically acceptable salts thereof.
A further preferred group of novel compounds of formula I comprises those compounds of formula I wherein X is hydrogen, Y is a radical of formula II R3 is hydrogen or a methyl radical and B is a 4-nitro- or 4-cyano-phenyl radical; and the pharmaceutically-acceptable salts thereof.
Especially preferred novel compounds of the invention are 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid and 4"-nitro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The novel compounds of formula I may be obtained by any process applicable to the manufacture of analogous chemical compounds. Such processes are provided as a further feature of the invention and are exemplified by the following in which X,Y,R1, R2, R3 and B have the general meanings stated above unless specifically stated otherwise:
(a) For a compound of formula I wherein X is hydrogen, Y is a radical of formula II, and RR1 and R2 are both hydrogen, reacting a salicylic acid of the formula: ##STR8## with an aldehyde of the formula:
B --CHO V
in the presence of a strong inorganic or organic acid.
A particularly suitable strong inorganic acid is, for example, concentrated sulphuric, hydrochloric or hydrofluoric acid, and a particularly suitable strong organic acid is trifluoroacetic acid. The process is conveniently carried out at, for example, 0° to 50° C., and preferably at 10° to 30° C. The duration of the process is from 30 minutes to 4 days, depending upon the reactivity of the reactants. The strong inorganic or organic acid is conveniently used in excess, but a conventional inert diluent may also be included. The salicylic acid of formula IV is conveniently employed in excess, for example in an excess of 1 molecular equivalent, over the aldehyde of formula V.
(b) For a compound of formula I wherein X and Y together are a radical of formula III and R1 is hydrogen, oxidising a compound of the formula: ##STR9##
The oxidation may be carried out with an inorganic or organic oxidising agent, conveniently at 10°-30° C. and optionally in the presence of an inert solvent or diluent, for example formic or acetic acid.
Particularly suitable inorganic oxidising agents are, for example, nitrous acid, sodium or potassium periodate or hydrogen peroxide, all conveniently used in the presence of an acid, for example formic, acetic or sulphuric acid. When nitrous acid is employed it may conveniently be generated in situ using a suitable nitrite, for example an alkali metal nitrite, such as sodium nitrite.
A particularly suitable organic oxidising agent is, for example, lead tetra-acetate, which is conveniently used in the presence of acetic acid.
The oxidation is in general exothermic and is preferably maintained at 10° to 30° C., and more particularly at 15°-25° C., by suitable cooling.
(c) For a compound of formula I wherein R1 is an acetyl radical, reacting the corresponding phenol of formula I wherein R1 is hydrogen with an acetylating agent.
A particularly suitable acetylating agent is, for example, an acetyl halide, for example acetyl chloride or acetyl bromide, or acetic anhydride. The process may optionally be carried out in an inert solvent or diluent, for example acetone, acetonitrile or tetrahydrofuran and is preferably catalysed by addition of a mineral acid, for example sulphuric acid. The process is conveniently carried out at, for example 0°-100° C. and more particularly at 20°-60° C.
(d) For a compound of formula I wherein R2 is a phenyl radical optionally substituted by a halogen atom, esterifying an acid of formula I wherein R2 is hydrogen, by reaction with a phenol of the formula R4.OH, wherein R4 is a phenyl radical optionally substituted by a halogen atom, for example, with phenol or 4-chlorophenol.
The process may be carried out by any procedure conventionally used for the esterification of acids. Thus, for example, an acid of formula I wherein R2 is hydrogen may be converted into an acid halide, for example an acid chloride, using a halogenating agent, for example phosphorus oxychloride or thionyl chloride, optionally in an inert solvent or diluent, for example toluene. This reaction is conveniently carried out at 50° to 100° C., for example at reflux temperature.
The acid halide thus obtained may then be reacted with the appropriate phenol of the formula R4.OH, wherein R4 has the meaning stated above, optionally in the presence of a base, for example pyridine, conveniently in an inert diluent or solvent, for example tetrahydrofuran, and at a temperature of, for example, from 0°-100° C.
Alternatively, and conveniently, the acid halide may be prepared in the presence of the above phenol, in which case the need for a separate reaction is eliminated.
Alternatively the above acid of formula I may be reacted with the above phenol in the presence of a condensing agent, for example dicyclohexylcarbodiimide, in an inert diluent or solvent, for example, tetrahydrofuran or acetonitrile and conveniently at a temperature of, for example, from 10°-100° C.
(e) For a compound of formula I wherein B is a phenyl radical bearing a cyano radical, dehydrating a compound of the formula: ##STR10## wherein Z is a carbamoyl or N-hydroxyazomethylidene (HO--N═CH--) radical.
The dehydration is conveniently carried out in the presence of a dehydrating agent.
A particularly suitable dehydrating agent when Z is an N-hydroxyazomethylidene (HO--N═CH--) radical is, for example, thionyl chloride, a mixture of N,N-dimethylformamide and sodium formate, a mixture of sodium acetate and acetic acid, or acetic anhydride. When acetic anhydride is used as dehydrating agent on a starting material of formula VIII wherein R1 is hydrogen, the first product isolated is a compound of formula I wherein R1 is an acetyl radical, but this may be readily hydrolysed in accordance with process (f) described herein below.
A particularly suitable dehydrating agent when Z is a carbamoyl radical is for example phosphorus pentoxide, phosphorus oxychloride or thionyl chloride. When phosphorus oxychloride or thionyl chloride is used as dehydrating agent on a starting material of formula VII wherein R2 is hydrogen, the carboxylic acid chloride may conveniently be isolated, or this may be hydrolysed to give the required compound of formula I wherein R2 is hydrogen.
The dehydration is conveniently carried out at elevated temperature, for example at 50°-200° C., and more particularly at 100°-150° C., and an inert solvent or diluent, for example 1,1,2,2-tetrachloroethane, may optionally be present.
The starting materials of formula VII may be prepared as described hereinabove in parts (a)-(d), from known starting benzaldehyde and salicylic acid derivatives. Alternatively, for those starting materials of formula VII wherein Z is an N-hydroxyazomethylidene radical, they may be prepared by reacting a formyl compound of the formula: ##STR11## wherein R1, R2, R3, X and Y have the general meanings stated above, with hydroxylamine using conventional conditions for the formation of oximes of aldehydes.
The starting materials of formula VIII may themselves be prepared as described hereinabove in parts (a)-(d).
(f) For a compound of formula I wherein R1 and R2 are hydrogen hydrolysing a compound of the formula: ##STR12## wherein P is hydrogen or a C1-6 acyl radical, for example an acetyl radical; and Q is a hydrogen, a C1-6 alkyl radical, for example a methyl or ethyl radical, or a phenyl radical optionally substituted by a halogen atom, for example a phenyl or 4-chlorophenyl radical; provided that at least one of P and Q is other than hydrogen.
The hydrolysis is conveniently carried out either in the presence of aqueous acid, for example sulphuric or hydrochloric acid, or in the presence of aqueous base, for example sodium or potassium hydroxide; and at a temperature of, for example, 20°-100° C. An inert solvent or diluent, for example acetic acid or ethanol, may also optionally be used.
The starting materials of formula IX may either be obtained by the processes described specifically hereinabove or by direct analogy to them.
(g) For a compound of formula I wherein X is hydrogen and Y is a radical of formula II, reducing a compound of formula I wherein X and Y together are a radical of formula III.
The reduction may be conveniently carried out using any reducing agent generally known to be capable of reducing the quinonemethide radical in analogous compounds, for example, hydrogen in the presence of a metal catalyst for example palladium or platinum, a reducing metal for example zinc or iron preferably in the presence of acid, sodium borohydride or sodium dithionite.
The reduction is preferably carried out at, for example, 20° to 100° C. and in water or an inert solvent or diluent, for example, acetic acid, methanol or ethanol, or in an aqueous mixture containing such a solvent or diluent. It is to be understood that the particular reducing agent employed is conditioned by the substituents present in the required compound of formula I. Thus for example when either or both of R1 and R2 are other than hydrogen, catalytic hydrogenation is preferred, and when ring B bears a nitro radical the reduction must be stopped before reduction of the nitro radical occurs.
When a pharmaceutically acceptable salt is required, a compound of formula I wherein R2 is hydrogen is reacted with a base affording a pharmaceutically acceptable cation, for example sodium hydroxide, calcium hydroxide, ammonia or triethanolamine.
The compounds of formula I possess anti-inflammatory properties when applied topically to an area of inflammation and are particularly useful in treating inflammatory diseases or inflammatory conditions of the skin, in warm-blooded animals.
In addition to anti-inflammatory properties, certain of the compounds of formula I possess anti-bacterial properties. These antibacterial properties are to be understood to be only a useful addition to the anti-inflammatory properties and are insufficient in themselves to justify using a compound possessing them solely as an anti-bacterial agent.
A particular group of active ingredients of formula I having both anti-inflammatory and anti-bacterial properties comprises 2",4"-dichloro-4,4'-dihydroxy-3,3'-triphenylmethane-dicarboxylic acid, 4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenyl-methanedicarboxylic acid, 4"-chloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid and 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
A particular group of novel compounds of formula I having both anti-inflammatory and anti-bacterial properties comprises 2",4"-dichloro-4,4"-dihydroxy-3,3'-triphenyl-methanedicarboxylic acid and 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The anti-inflammatory properties of a compound of formula I may be demonstrated in a standard test involving the inhibition of croton oil induced inflammation on the mouse ear. The activity of an individual compound in this test depends upon its particular chemical structure, but specific compounds of formula I as described in the specification produced a significant inhibition of the inflammation at a topically applied dose in the range 100 μg. to 2000 μg. per ear. No overt toxic effects were detected at the active dose in this test.
The anti-bacterial properties of an active ingredient may be demonstrated in a standard test involving the inhibition of growth of Gram positive bacteria, for example Strep. faecalis and Staph. aureus, cultured in a known manner. The anti-bacterial activity of an individual compound depends on its particular chemical structure but in general the specific compounds of formula I as described in the specification were active at a concentration in the range from 10 to 1,000 parts per million.
When an active ingredient of the composition is used for the topical treatment of an area of inflammation affecting the skin of a warm-blooded animal, for example man, it is expected that the active ingredient will be administered topically so that a daily dose of up to 300 mg. per man is received. The active ingredient is conveniently administered at intervals, for example three times daily, and at a rate of, for example, l mg. of active ingredient per square centimeter of skin, or at a lower rate.
The invention is illustrated, but is not limited, by the following Examples:
The compounds listed below were all obtained in the following general manner:
The substituted benzaldehyde (0.15 mole) was added in portions to stirred cooled (10° C.) concentrated sulphuric acid (93% w/v, 153 ml.). The salicylic acid derivative (0.335 mole) was then added rapidly and the mixture was stirred at 10°-25° C. for 40 minutes to 4 days depending upon the particular reactants involved. The reaction mixture was then poured into ice-water, and the precipitated solid was filtered off and washed thoroughly with water. The solid was then crystallised using the solvent(s) indicated.
__________________________________________________________________________ ##STR13## Com- Duration of pound stirring at Crystallisation No. R.sup.3 B 10-25° C. solvent m.p. (°C.) __________________________________________________________________________ 1 H 4-NO.sub.2 Ph 18 hours precipitated from 164-166 (dec.) aqueous ethanol 2 H 2,6-Cl.sub.2 Ph 18 hours precipitated from 197-198 (dec.) aqueous acetic acid 3 H 2,4-Cl.sub.2 Ph 18 hours aqueous acetic 263-268 acid 4 CH.sub.3 4-FPh 16 hours aqueous ethanol 285-288 (dec.) 5 " 4-NO.sub.2 Ph 18 hours aqueous ethanol 275-278 (dec.) 6 " 2-Cl5-NO.sub.2 Ph 3 hours aqueous acetic acid 291-293 (dec.) 7 Cl 2,4-Cl.sub.2 Ph 3 days methanol and 303 (dec.) acetonitrile 8 CH.sub.3 3-NO.sub.2 Ph 18 hours aqueous ethanol 248-240 (dec.) 9 " 4-(HO.sub.2 C)Ph 5 hours aqueous acetic 311-312 acid 10 " 4-pyridyl 3 days aqueous acetic 230-232 (dec.) acid 11 " 4-(H.sub.2 NCO)Ph 18 hours aqueous ethanol 294-295 (dec.) 12 " 4-CNPh 40 mins. aqueous ethanol 287-289 (dec.) 13 " 2-Cl4-NO.sub.2 Ph 18 hours aqueous ethanol 148-150 (dec.) 14 " 4-BrPh 18 hours aqueous ethanol 280-281 (dec.) 15 " 2-F6-ClPh 18 hours aqueous acetic 255-258 acid 16 " 2-Br6-ClPh 24 hours precipitated from 288-290 aqueous acetic acid 17 " 2,6-F.sub.2 Ph 18 hours aqueous acetic 297-299 acid 18 " 2-Cl4CNPh 4 hours aqueous acetic 282-284 acid 19 " 2,4-Cl.sub.2 Ph 3 hours aqueous acetic 282-283 acid 20 H 2,6-F.sub.2 Ph 18 hours .sup.b aqueous acetic 280-285 acid 21 CH.sub.3 2,4,6-Cl.sub.3 Ph 18 hours aqueous acetic 305-308 acid 22 n-C.sub.3 H.sub.7 4-NO.sub.2 Ph 18 hours aqueous ethanol 274-280 (dec.) __________________________________________________________________________
The compounds listed below were all obtained in the following general manner:
The substituted benzaldehyde (0.15 mole) was added in portions to stirred, cooled (10° C.) sulphuric acid (93% w/v. 153 ml.). The substituted salicylic acid (0.335 mole) was then added rapidly and the mixture stirred at 10°-25° C. for 40 minutes to 3 days depending on the particular reactants involved. Concentrated sulphuric acid (40.5 ml.) and sodium nitrite (0.168 mole) was then added, the temperature being maintained at 20° C. by cooling during the addition. The cooling bath was removed and the reaction mixture stirred for a further 11/2 hours, during which time the temperature rose to 30° C. The reaction mixture was poured with stirring into ice-water (3 l.) and filtered. The solid residue was washed with water until the washings were neutral to Congo red, and the solid was then dried at 37° C. in a vacuum oven. In this way the following compounds were obtained:
__________________________________________________________________________ ##STR14## Com- Duration of pound stirring at NMRτ values No. B 10-25° C. (in CDCl.sub.3 unless otherwise stated) __________________________________________________________________________ 1 Ph 3 days 1.71 (2H, doublet J = 3 c.p.s., ArHa 2.2-2.8 (7H, complex, ArH + ArH.sub.b) and 7.75 (6H, singlet, CH.sub.3) 2 4-NO.sub.2 Ph 3 hours 1.80 (4H, A.sub.2 B.sub.2, J = 8 c.p.s.), 1.65 (2H, doublet J = 3 c.p.s., ArH.sub.a) 2.26 (2H, broad, ArH.sub.b) and 7.57 (6H, singlet, ArCH.sub.3) 3 4-FPh 40 hours *1.68 (2H, doublet, J = 3 c.p.s., ArH.sub.a,) 2.1-2.6 (6H, complex, ArH + ArH.sub.b) and 7.51 (6H, singlet ArCH.sub.3) 4 2,4-Cl.sub.2 Ph 21/2 hours 1.95 (2H, doublet, J = 3 c.p.s. ArH.sub.a) 2.4-3.2 (5H, complex ArH) and 7.78 (6H, singlet, ArCH.sub.3) 5 2-Cl5- 3 hours *1.33 (1H, quartet, J = 9, c.p.s. and NO.sub.2 Ph 2.4 c.p.s., ArHo-NO.sub.2), 1.61 (2H, doublet J = c.p.s., ArH.sub.a) 1.70 (1H, doublet J = 2.4 c.p.s., ArHo-NO.sub.2), 2.01 (1H, doublet, J = 9, c.p.s. ArH.sub.b) and 7.58 (6H, singlet, ArCH.sub.3) __________________________________________________________________________ *Spectral data recorded for trifluoroacetic acid solutions.
4,4'-Dihydroxy-5,5'-dimethyl-4"-nitro-3,3'-triphenylmethanedicarboxylic acid (1.59 g.), acetic anhydride (6 ml.) and concentrated sulphuric acid (0.05 ml.) were stirred together at 50°-60° C. for 11/2 hours. The reaction mixture was poured into ice-water (100 ml.) and the solid which precipitated was filtered off. The solid was crystallised from ethanol and there was thus obtained 4,4'-diacetoxy-5,5'-dimethyl-4"-nitro-3,3'-triphenylmethane-dicarboxylic acid, m.p. 235°-237° C.
In a similar manner, using the corresponding 2",4"-dichlorophenyl derivative as starting material, there was obtained 4,4'-diacetoxy-5,5'-dimethyl-2",4"-dichloro-3,3'-triphenylmethanedicarboxylic acid, m.p. 163°-165° C. (crystallised from toluene).
A mixture of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (2.08 g.), 4-chlorophenol (1.3 g.), phosphorus oxychloride (0.5 ml.) and toluene (10 ml.) was heated on a steam bath for 18 hours. The reaction mixture was poured into 10% w/v sodium carbonate solution (25 ml.) and extracted with ethyl acetate (3×50 ml.). The combined extracts were washed successively with water (50 ml.) and brine (50 ml.), and then dried (MgSO4) and evaporated. The residue was crystallised from ethanol, and there was thus obtained di-4-chlorophenyl 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylate, m.p. 120° C. (decomposition),(after recrystallisation from ethanol).
In a similar manner there was obtained from 2",4"-dichloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid and phenol, diphenyl 2",4"-dichloro-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylate, m.p. 215°-220° C. (after recrystallisation from acetone-ethanol).
Terephthalaldehyde (25 g.) was added in portions to a stirred mixture of concentrated sulphuric acid (98% w/w, 300 ml.) and water (23 ml.), cooled to 20°-25° C. o-Cresotic acid (2-hydroxy-3-methylbenzoic acid) (58 g.) was then added rapidly and the mixture was then further stirred at 20°-25° C. for 16 hours. The reaction mixture was then poured into ice-water (1.5 l.), and the precipitated solid was separated by filtration, washed with water, and recrystallised from 50% v/v aqueous acetone to give 4"-formyl-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid, m.p. 274°-277° C. (decomposition).
Hydroxylamine hydrochloride (16.0 g.) was added at 20°-25° C. to a solution of 4"-formyl-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid, (42.0 g.) in a mixture of water (300 ml.) and aqueous ammonia solution (density 0.88) (25 ml.). The mixture was stirred at the same temperature for 1 hour and then adjusted to pH 4 by addition of glacial acetic acid (approximately 20 ml.). The precipitated solid was separated by filtration, washed with water and reprecipitated with acetic acid from solution in a mixture of aqueous ammonia and acetone to give the oxime of 4"-formyl-4,4'-dijhydroxy-5,5'-dimethyl-3,3'-triphenylmethane-dicarboxylic acid, m.p. 275°-277° C. (decomposition).
Acetic anhydride (2.1 ml.) was added to a suspension of the oxime of 4"-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (4.35 g.), and the mixture heated under reflux for 24 hours. After it had been cooled to 20°-25° C. the mixture was stirred vigorously with 2N aqueous sodium hydroxide solution (approximately 40 ml.) so that the mixture was maintained near pH 11. The aqueous phase was then separated and acidified to pH 3 with hydrochloric acid. The precipitated solid ws separated by filtration, washed with water and recrystallised from a mixture of methanol and acetonitrile to give 4"-cyano-4,4'l-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid, m.p. 287°-289° C. (decomposition)
A mixture of 4,4'-diacetoxy-5,5'-dimethyl-4"-nitro-3,3'-triphenylmethanedicarboxylic acid (2.0 g.), 50% v/v aqueous acetic acid (20 ml.) and 2N hydrochloric acid (5 ml.) was heated at 95°-100° C. for 2 hours. The solid was then filtered off, washed with water and recrystallised from aqueous ethanol to give 4,4'-dihydroxy-5,5'-dimethyl-4"-nitro-3,3'-triphenylmethanedicarboxylic acid. m.p. 275°-278° C.
A mixture of finely powdered 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (5 parts by weight) in liquid paraffin (10 parts by weight) was added to molten, white soft paraffin (85 parts by weight). The resulting mixture was allowed to cool to 20°-25° C. with fast stirring, until a uniform ointment, suitable for human use, was formed.
In a similar manner, an ointment containing a compound as described in any one of Examples 1-4 or in a numbered part thereof, was obtained by substituting such a compound for 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid in the above process.
A solution of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (1 part by weight) in isopropyl alcohol (80 parts by weight) prepared at 40°-50° C. is cooled to 20°-25° C. Water (16 parts by weight) was added and the mixture was stirred rapidly during the further addition of "Carbopol" 940* (3 parts by weight) until a fully dispersed gel, suitable for human use, was formed. *"Carbopol" 940 is a grade of carboxypolymethylene gelling agent available from B. F. Goodrich Chem. Co., Cleveland, U.S.A., "Carbopol" is a trade mark.
In a similar manner, a gel containing a compound as described in any one of Examples 1-4, or in a numbered part thereof, was obtained by substituting such a compound for 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid in the above process.
A mixture of cetostearyl alcohol (9 parts by weight), liquid paraffin (7 parts by weight), sorbitan monostearate (2 parts by weight), polysorbate 60 (2 parts by weight) and finely divided 4Δ-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid (1 part by weight) was fused by heating at 65°-70° C. Water (79 parts by weight) was added with stirring to the melt thus obtained. The mixture was then stirred rapidly with slow cooling to 20°-25° C. until a homogeneous cream, suitable for human use, was obtained.
In a similar manner, a cream containing a compound as described in any one of Examples 1-4, or in a numbered part thereof, was obtained by substituting such a compound for 4"-cyano-4,4'-dihydrosy-5,5'-dimetyl-3,3'-triphenylmethanedicarboxylic acid in the above process.
The procedure described in any one of Examples 9-11 was repeated except that a novel compound of formula I as described in any one of Examples 5-8 was incorporated as active ingredient instead of 4"-cyano-4,4"-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid. There was thus obtained an ointment, gel or cream formulation, suitable for human use.
A solution of finely powdered 4"-cyano-4,4'-dihydroxy-5,5'-dimetjhyl-3,3'-triphenylmethanedicarboxylic acid (2 parts by weight) in diethyleneglycol monoethyl ether (10 parts by weight) was stirred into molten white soft paraffin (88 parts by weight), itself containing lanolin (5-10 parts by weight. The resulting mixture was then cooled with sufficient stirring to obtain a fine dispersion of solution globules in the paraffin base. There was thus obtained an ointment suitable for human use.
The lanolin, which is present to help stabilise the physical condition of the ointment, may if desired be omitted.
In a similar manner an ointment containing a compound described in any one of Examples 1-8 or in a numbered part thereof, was obtained by substituting such a compound for 4"-cyano-4,4'-dihydro-5,5'-dimethyl-3,3'-triphenylmethane-dicarboxyxlic acid in the above process.
The procedure described in Example 9 was repeated except that a compound of formula I wherein R1 and R2 are hydrogen, R3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The precedure described in Example 10 was repeated except that a compound of formula I wherein R1 and R2 are hydrogen, R3 is a methyl radical, and B is a phenyl,2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5 dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The procedure described in Example 11 was repeated except that a compound of formula I wherein R1 and R2 are hydrogen, R3 is a methyl radical and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4---cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The procedure described in Example 13 was repeated except that a compounds of formula I wherein R1 and R2 are hydrogen, R3 is a methyl radical, and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical, or wherein R1, R2 and R3 are hydrogen and B is a 2,4-dinitrophenyl radical, was used instead of 4"-cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid.
The anti-inflammatory activity of an active ingredient of formula I and, in particular, the anti-inflammatory activity of an active ingredient of formula I when applied topically to an area of inflammation, has been demonstrated in man in the following manner involving the reduction of erythema in the skin, induced after exposure to U.V. light:
Seven healthy male volunteers were involved in the study. During the week before the study began, each volunteer had administered to his skin test doses of U.V. light to determine the appropriate dose for induction of erythema.
Three 1.0 cm. squares, spaced apart by 2 cm. edge to edge, were defined on the volar aspects of both forearms of each volunteer. Solutions of the test compound in a suitable solvent, such as acetone, were then prepared at concentrations of 1% w/v and 9% w/v. The solutions were then applied (10 μl. per square) to separate squares in the following sequence:
______________________________________ Square 1 Square 2 Square 3 ______________________________________ 1st arm 9% w/v solution solvent no treatment 2nd arm solvent 1% w/v solution no treatment ______________________________________
the appropriate control, that is the solvent (10μ per square) or no treatment, being applied to the corresponding square on the contralateral arm.
One hour after the applications indicated above, each of the squares on each forearms was exposed to the pre-determined dose of U.V. light. The rest of the arm was protected during this exposure by a shield having holes cut in it corresponding to the three squares. The degree of erythema was then assessed for each square at intervals of 2,4,7,24,31 and 48 hours after the exposure to U.V. light, using the following verbal scoring system:
0--No erythema
1--Very slight erythema (barely perceptible)
2--Well defined erythema
3--Moderate to severe erythema
4--Severe erythema (beet redness) with slight sloughing of the skin.
A cumulative score was then obtained for the assessments during the 48 hours following exposure to U.V. light.
Using this procedure the following results were obtained with 1% w/v and 9% w/v solutions of 4"-cyano-5,5'-dimethyl-4,4'-dihydroxy-3,3'-triphenylmethanedicarboxylic acid (referred to as "A" below) in acetone:
______________________________________ Erythema scores (cumulative over 48 hours) Volunteer 9% acetone 1% acetone No. "A" control "A" control ______________________________________ 1 0 5 5 7 2 1 7 6 8 3 1 8 6 8 4 0 8 4 5 5 0 8 6 8 6 3 8 8 8 7 3 8 5 8 Total 8 52 40 52 ______________________________________
From these results it can be seen that both 9% and 1% w/v solutions of "A" in acetone gave statistically significant (p<0.02 and p<0.05 respectively) protection from the erythema induced by U.V. light.
Claims (4)
1. A compound of the formula: ##STR15## wherein .[.either.]. X is hydrogen and Y is a radical of the formula: ##STR16## wherein R1 is hydrogen or an acetyl radical; R2 is hydrogen or a phenyl radical optionally substituted by a halogen atom; R3 is hydrogen, a C1-6 alkyl radical or a halogen atom; B is a 4-pyridyl radical, or a phenyl radical which may optionally bear from 1 to 3 substituents selected from halogen atoms, nitro, cyano, carbamoyl, carboxy, formyl and N-hydroxyazomethylidene (HO--N═CH--) radicals; or a pharmaceutically acceptable salt of a compound of formula I wherein R2 is hydrogen; but excluding those compounds of formula I as defined above wherein R1 and R2 are hydrogen, R3 is a methyl radical, and B is a phenyl, 2-chlorophenyl, 4-chlorophenyl, .Iadd.2-nitrophenyl, 4-nitrophenyl, .Iaddend.2,6-dichlorophenyl, 2,5-dichlorophenyl or a 2,3,6-trichlorophenyl radical; or wherein R1, R2 and R3 are hydrogen and B is a 2,4dinitrophenyl radical.
2. A compound of formula I wherein X is hydrogen, Y is a radical of formula II, R1 and R2 are hydrogen, and R3 is hydrogen or a methyl radical, and wherein B has the meanings set out in claim 1; or a pharmaceutically acceptable salt thereof.
3. A compound of formula I wherein X is hydrogen Y is a radical of formula II, R3 is hydrogen or a methyl radical, B is a .Badd..[.4-nitro- or.]. .Baddend.4-cyano-phenyl radical, and wherein R1 and R2 have the meanings set out in claim 1; or a pharmaceutically acceptable salt thereof.
4. 4"-Cyano-4,4'-dihydroxy-5,5'-dimethyl-3,3'-triphenylmethanedicarboxylic acid .[., or 4'-nitro-4, 4"-dihydroxy-5,5'-dimethyl-3,3'- triphenylmethanedicarboxylic acid.]..
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MX (1) | MX4655E (en) |
NL (1) | NL7614015A (en) |
NO (1) | NO146138C (en) |
NZ (1) | NZ182807A (en) |
PH (1) | PH13545A (en) |
PL (1) | PL104291B1 (en) |
SE (1) | SE428468B (en) |
ZA (1) | ZA767215B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US5434185A (en) * | 1993-05-17 | 1995-07-18 | The University Of Kentucky Research Foundation | Method for inhibiting angiogenesis with aurintricarboxylic acid, its analogues or salts |
US5312988A (en) * | 1993-05-28 | 1994-05-17 | Hoechst Celanese Corporation | Amines derived from THPE |
US5756781A (en) * | 1995-09-29 | 1998-05-26 | General Electric Company | Method for making tris(hydroxyphenyl) compounds using ion exchange |
US9751824B2 (en) | 2013-11-18 | 2017-09-05 | Aurin Biotech Inc. | Acetyl salicyclic acid dimers, synthesis thereof, and uses thereof to prevent and treat complement-mediated disorders |
Citations (8)
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US998139A (en) * | 1911-04-11 | 1911-07-18 | Farbenfab Vorm Bayer F & Co | Greenish-blue triphenylmethane dye. |
US1004609A (en) * | 1911-02-07 | 1911-10-03 | Farbenfab Vorm Bayer F & Co | Triphenylmethane dye. |
US1034173A (en) * | 1911-09-07 | 1912-07-30 | Farbenfab Vorm Bayer F & Co | Red-violet triphenylmethane dye. |
US2506486A (en) * | 1948-04-21 | 1950-05-02 | Union Carbide & Carbon Corp | Thermosetting resin from a diphenol and a diglycidyl ether of a diphenol |
US2764590A (en) * | 1952-03-17 | 1956-09-25 | Thomae Gmbh Dr K | Certain 4, 4'-disubstituted-diphenylpyridyl methanes and process |
US3549656A (en) * | 1967-12-28 | 1970-12-22 | Kefalas As | Antidepressant 1 - aminoalkyl - thiophthalanes and acid addition salts thereof |
US3558641A (en) * | 1967-10-06 | 1971-01-26 | Merck & Co Inc | Certain pyridyl salicylic acid derivatives |
US3714226A (en) * | 1970-06-09 | 1973-01-30 | Merck & Co Inc | Phenyl benzoic acid compounds |
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US3579542A (en) * | 1968-06-26 | 1971-05-18 | Hoechst Co American | 4,4',4''-trihydroxytriphenylmethyl-methane |
US3794642A (en) * | 1973-01-15 | 1974-02-26 | Lilly Co Eli | Oxidation of substituted methanes to the corresponding substituted methanols |
-
1975
- 1975-12-29 GB GB52999/75A patent/GB1560880A/en not_active Expired
-
1976
- 1976-11-29 CY CY1147A patent/CY1147A/en unknown
- 1976-12-01 IE IE2633/76A patent/IE43994B1/en not_active IP Right Cessation
- 1976-12-03 ZA ZA767215A patent/ZA767215B/en unknown
- 1976-12-04 IN IN2159/CAL/76A patent/IN145508B/en unknown
- 1976-12-06 CA CA267,212A patent/CA1086743A/en not_active Expired
- 1976-12-06 NZ NZ182807A patent/NZ182807A/en unknown
- 1976-12-06 US US05/747,995 patent/US4113879A/en not_active Expired - Lifetime
- 1976-12-07 IL IL51065A patent/IL51065A/en unknown
- 1976-12-10 MX MX765211U patent/MX4655E/en unknown
- 1976-12-14 PH PH19243A patent/PH13545A/en unknown
- 1976-12-16 AU AU20605/76A patent/AU512090B2/en not_active Expired
- 1976-12-17 NL NL7614015A patent/NL7614015A/en not_active Application Discontinuation
- 1976-12-20 SE SE7614304A patent/SE428468B/en not_active IP Right Cessation
- 1976-12-20 HU HU76IE770A patent/HU176679B/en unknown
- 1976-12-21 PL PL1976194591A patent/PL104291B1/en unknown
- 1976-12-23 FR FR7638911A patent/FR2336921A1/en active Granted
- 1976-12-24 DE DE19762658840 patent/DE2658840A1/en not_active Ceased
- 1976-12-24 BE BE173648A patent/BE849872A/en not_active IP Right Cessation
- 1976-12-28 NO NO764371A patent/NO146138C/en unknown
- 1976-12-28 LU LU76483A patent/LU76483A1/xx unknown
- 1976-12-28 JP JP16078376A patent/JPS5283356A/en active Granted
- 1976-12-28 DD DD7600196658A patent/DD128671A5/en unknown
- 1976-12-29 CH CH1643576A patent/CH624378A5/de not_active IP Right Cessation
- 1976-12-29 ES ES454657A patent/ES454657A1/en not_active Expired
- 1976-12-29 CS CS768759A patent/CS191326B2/en unknown
- 1976-12-29 FI FI763735A patent/FI763735A/fi not_active Application Discontinuation
- 1976-12-29 DK DK586576A patent/DK147105C/en not_active IP Right Cessation
-
1980
- 1980-03-04 US US06/127,135 patent/USRE31467E/en not_active Expired - Lifetime
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1981
- 1981-01-22 CH CH44281A patent/CH627156A5/de not_active IP Right Cessation
- 1981-10-19 KE KE3169A patent/KE3169A/en unknown
- 1981-12-10 HK HK618/81A patent/HK61881A/en unknown
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US1004609A (en) * | 1911-02-07 | 1911-10-03 | Farbenfab Vorm Bayer F & Co | Triphenylmethane dye. |
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US2506486A (en) * | 1948-04-21 | 1950-05-02 | Union Carbide & Carbon Corp | Thermosetting resin from a diphenol and a diglycidyl ether of a diphenol |
US2764590A (en) * | 1952-03-17 | 1956-09-25 | Thomae Gmbh Dr K | Certain 4, 4'-disubstituted-diphenylpyridyl methanes and process |
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US3549656A (en) * | 1967-12-28 | 1970-12-22 | Kefalas As | Antidepressant 1 - aminoalkyl - thiophthalanes and acid addition salts thereof |
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Title |
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