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WO1996036596A1 - 3,4-phenylsulfamides disubstitues et leur utilisation therapeutique - Google Patents

3,4-phenylsulfamides disubstitues et leur utilisation therapeutique Download PDF

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Publication number
WO1996036596A1
WO1996036596A1 PCT/GB1996/001205 GB9601205W WO9636596A1 WO 1996036596 A1 WO1996036596 A1 WO 1996036596A1 GB 9601205 W GB9601205 W GB 9601205W WO 9636596 A1 WO9636596 A1 WO 9636596A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
dimethoxybenzenesulphonamide
optionally substituted
alkoxy
aryl
Prior art date
Application number
PCT/GB1996/001205
Other languages
English (en)
Inventor
Hazel Joan Dyke
John Montana
Original Assignee
Chiroscience Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9510163.0A external-priority patent/GB9510163D0/en
Priority claimed from GBGB9523677.4A external-priority patent/GB9523677D0/en
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU57723/96A priority Critical patent/AU5772396A/en
Publication of WO1996036596A1 publication Critical patent/WO1996036596A1/fr

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    • 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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to novel sulphonamide compounds and pharmaceutically acceptable salts thereof, processes for their production and their formulation and use as pharmaceuticals.
  • R is al yl, alkenyl, cycloalkyl, cycloalkenyl, cyclothioalkyl, or cyclothioalkenyl ;
  • R 2 is lower alkyl;
  • R 3 is aryl or heteroaryl;
  • Z and Z are independently oxygen or sulphur.
  • the only sulphonamide exemplified is N-(2- c h l o r o p h e n y l ) - 3 - c y c l o p e n t y l o x y - 4 - methoxybenzenesulphonamide.
  • European Patent Application 306 846 discloses sulphonamides of formula:-
  • R 3 may be sulphonamide, as catechol-O-methyl transferase inhibitors.
  • Phosphodiesterases regulate cyclic AMP concentrations.
  • Phosphodiesterase IV has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. [See Torphy and Creslinski, Molecular Pharmacology 37, 206, (1990) ; Dent et al British Journal of Pharmacology, 90 I63p (1990)].
  • Inhibitors of phosphodiesterase IV have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and the function of eosinophils.
  • Inhibitors of phosphodiesterase IV are also implicated in treating inflammatory diseases, proliferative skin disease and conditions associated with cerebral metabolic inhibition.
  • Tumour Necrosis Factor a serum glycoprotein
  • TNF Tumour Necrosis Factor
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS) , AIDS, ARC, (AIDS related complex) , keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • AIDS human acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis or pyresis
  • pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
  • HIV Human Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
  • Cytokines are implicated in activated T- cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells, such as Kupffer and glial cells have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV) , influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus herpes virus
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9) :2750-54, (1990); and Jafari et al., Journal of Infectious Diseases, 164:389-95, (1991) . See also Wasan et al., Antimicrobial Agents and Chemotherapy,' 35, (10):2046- 48, (1991); and Luke et al., Journal of Infectious Diseases, 162:211-214, (1990)].
  • novel compounds of formula (i) have ability to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV.
  • the novel compounds are of formula (i) :
  • R 1 represents C.. 6 alkyl (optionally substituted with one or more substituents chosen from amongst halogen, C 1 . 6 alkoxy, aryloxy, arylalkyloxy, C 1 . 6 alkylamino, arylalkylamino or arylamino) or cycloalkyl (optionally substituted with one or more substituents chosen from amongst halogen, C ⁇ alkoxy, aryloxy, arylalkyloxy, C 6 alkylamino, arylalkylamino or arylamino) ;
  • R 2 represents Cl-3 alkyl optionally substituted with halogen;
  • R 3 represents H, arylalkyl, heteroarylalkyl, heterocycloalkyl, COR 7 , S(0) m R 7 or C ⁇ alkyl optionally substituted with one or more substituents chosen from amongst hydroxy, C ⁇ alkoxy, -C0 2 H, C0 2 R 8 , SO 2 NR 9 R 10 , CONR c ⁇ R ⁇ , NR g R ⁇ -CN, carbonyl oxygen, COR- or S(0) n R 7 ;
  • R 3 represents arylalkyl, heteroarylalkyl or heterocycloalkyl
  • the alkyl portion may be optionally substituted with one or more substituents chosen from amongst C0 2 H, C0 2 R 8 , SO ⁇ R p R ⁇ , CONR ⁇ Q , hydroxy, C 1 . 6 alkoxy, NR j R ⁇ COR 7 , S(0) n R 7 , -CN or carbonyl oxygen and/or the aryl/heteroaryl/heterocyclo portion may be optionally substituted with one or more substituents C0-6 alkyl-R ⁇ ;
  • R 4 represents a 5 or 6 membered saturated or unsaturated carbocyclic or heterocyclic ring to which ring is fused an aryl, heteroaryl, carbocyclic or heterocyclic ring, in which either or both rings may optionally be substituted by one or more substituents chosen from aryl, heterocyclo, heteroaryl, C ⁇ alkyl ( optionally substituted with aryl, heteroaryl, heterocyclo, carbonyl oxygen, hydroxy, NR g R g , C,_ 6 alkoxy, -CN, C0 2 H, C0 2 R 8 or CONR 9 R 10 ) , carbonyl oxygen, hydroxy, C . 6 alkoxy, -CN, C0 2 H, C0 2 R 8 , SO ⁇ R ⁇ Q , CONR ⁇ R ⁇ , halogen, C,. 6 alkoxy, hydroxy or -NR ⁇ ;
  • R j and R 6 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C,_ 6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, C, ⁇ alkylcarbonyl, C,_ 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl heteroarylcarbonyl, heterocyclocarbonyl or C ⁇ alkylsulphonyl, provided that when R g is C 1 . 6 alkylcarbonyl, C ⁇ .
  • R 6 is not C.. ⁇ alkylcarbonyl, C ⁇ alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C,. 6 alkylsulphonyl, R 6 is not C.. ⁇ alkylcarbonyl, C ⁇ alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C ⁇ 6 alkylsulphonyl ;
  • R 7 represents aryl, heteroaryl, heterocyclo or C 1 . 6 alkyl, any of which may be optionally substituted with one or more substituents chosen from amongst halogen, aryl, heteroaryl, heterocyclo, C ⁇ alkoxy, hydroxy, C0 2 H, C0 2 R 8 , SO 2 NR 9 R 10 , CONR ⁇ Q , NR g R 6 or carbonyl oxygen;
  • R 8 represents C ⁇ alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl
  • R, and R 10 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C._ 6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl;
  • R ⁇ represents H, aryl, heteroaryl, heterocyclo, hydroxy, C 6 alkoxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, -C0 2 H, C0 2 R g , SO 2 NR 9 R 10 , CONR p R ⁇ , halogen, -CN, -NR ⁇ , COR 7 , S(0) n R 7 , -CN or carbonyl oxygen;
  • n 0-2;
  • Preferred compounds of the invention include those in which, independently or in any combination:
  • R 1 is C 1 . 6 alkyl (optionally substituted with aryloxy) or cycloalkyl;
  • R 2 is methyl optionally substituted with halogen;
  • R 3 is H, arylalkyl, heteroarylalkyl, S0 2 R 7 or C, ⁇ alkyl (optionally substituted with one or more subdtituents chosen from hydroxy, CONR y R ⁇ , SO 2 NR-R 10 , NRgR ⁇ carbonyl oxygen, COR 7 , S0 2 R 7 , CN, C0 2 H or C0 2 R 8 ) ;
  • R 4 is a 5 or 6 membered saturated ring ( optionally substituted with C 6 alkyl, carbonyl oxygen, hydroxy, CN, C0 2 H, C0 2 R 8 ) to which ring is fused an aryl or heteroaryl ring, optionally substituted with one or more substituents chosen from C 1 . 6 alkyl, aryl, heteroaryl, hydroxy, C 1 . 6 alkoxy, C0 2 H, C0 2 R 8 , CN, CONR 9 R 10 , halogen or NR g R ⁇
  • R j and R 6 which may be the same or different, are H, C 1 . 6 alkyl, arylalkyl, aryl, heteroarylalkyl, heteroaryl, C 1 . 6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulphonyl, heteroarylsulphonyl or C 1 . 6 alkylsulphonyl;
  • R 7 is C 1 . 6 alkyl (optionally substituted with CN, C0 2 H, C0 2 R a , CONR g R ⁇ , SO 2 NR-R 10 , carbonyl oxygen or NR j R 6 ) , aryl or heteroaryl;
  • R 8 is C,. 6 alkyl
  • R, and R 1fJ which may be the same or different, are H, C 1 . 6 alkyl, arylalkyl or heteroarylalkyl.
  • Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine. Certain of the compounds of formula (i) which contain an amino group form acid addition salts.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobro ide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, ⁇ -ketoglutarate, ⁇ -glycerophosphate and glucose-l-phosphate.
  • the pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
  • the compounds of formula (i) may exist in more than one tautomeric form. This invention extends to all tautomeric forms. It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers, and diastereoisomers and mixtures including race ic mixtures thereof.
  • alkyl when used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms.
  • Alkyl-R ⁇ means that the substituent R classroom may be attached at any position of the alkyl group.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • Aryloxy means an aryl-O- group in which the aryl group is as defined below.
  • Arylalkyloxy means an aryl-alkyl-O- group.
  • Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl- N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below) .
  • Cycloalkyl includes a non- aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated.
  • Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms.
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heteroarylalkyl means a heteroaryl-alkyl group and heterocycloalkyl means a heterocyclo-alkyl group.
  • Alkyl amide includes both monoalkyl and dialkyl amides, in which the alkyl groups (previously descirbed) may be the same or different.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described.
  • Arylsulphonyl means an aryl-S0 2 - group in which the aryl group is as previously described.
  • Heteroarylcarbonyl means a heteroaryl-CO- group and heterocyclocabonyl means a heterocyclo-CO- group.
  • Heteroarylsulphonyl means a heteroaryl-S0 2 - group and heterocyclosulphonyl means a heterocyclo-S0 2 - group.
  • Alkoxycarbonyl means an alkyloxy-CO- group in wich the alkoxy group is as previously desribed.
  • Alkylsulphonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
  • Carbonyl oxygen means a -CO- group. It will be appreciated that a carbonyl oxygen can not be a substituent on an aryl or heteroaryl ring.
  • Carbocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system which may saturated or partially unsaturated.
  • Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms.
  • Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF-j ⁇ also known as ly photoxin
  • TNF- ⁇ also known as cachectin
  • This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including: asthma, chronic bronchitis
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease) , memory impairment associated with Parkinson's disease, depression and multi- infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i) .
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV) , influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV) , which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of formula (i) are preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • the invention further provides a process for the preparation of a compound of formula (i) , in which R ⁇ R ⁇ and m-n are as defined above.
  • functional groups such as a ino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene.
  • the process for preparing compounds of formula (i) in which R 3 contains a -C0 2 H comprises deprotecting (for example by hydrolysis) a compound of formula (1) in which R 3 contains an appropriate -C0 2 R group wherein R represents a suitable protecting group (eg methyl) .
  • a process for the preparation of a compound of formula (ia) comprises reaction of an appropriate sulphonyl chloride of formula (ii) with a suitable amine of formula (iii)
  • R 1a represents R 1 as defined in relation to formula (i) or a group convertable to R 1 and R 2a -R 4a similarly represent R 2 -R 4 or groups convertable to R 2 -R 4 respectively; and thereafter, if required, converting any group R 1a to R 1 and/or R 2a to R 2 and/or R 3a to R 3 and/or R 4a to R 4 .
  • the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Sulphonyl chlorides of formula (ii) are either commercially available or are prepared using standard procedures known to those skilled in the art.
  • a sulphonyl chloride of formula (ii) is conveniently prepared from the appropriate sulphonic acid (iv) by treatment with a suitable agent such as thionyl chloride or oxalyl chloride.
  • An appropriate sulphonic acid may be prepared from a compound of formula (v) by sulphonylation using an appropriate sulphonylating agent, for example chlorosulphonic acid.
  • a sulphonyl chloride of formula (ii) may be prepared directly from a compound of formula (v) by using excess chlorosulphonic acid.
  • Compounds of formula (v) are either commercially available or may be prepared by standard procedures known to those skilled in the art.
  • a sulphonyl chloride of formula (ii) may be prepared directly from a compound of formula (v) by using excess chlorosulphonic acid.
  • Compounds of formula (v) are either commercially available or may be prepared by standard procedures known to those skilled in the art.
  • Amines of formula (iii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. Some of the amines of formula (iii) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable amine. This amination may be carried out under any suitable standard conditions known to those skilled in the art.
  • a compound of formula (ia) may also be prepared by reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) to provide a compound of formula (ia) in which R 3a is H, followed by reaction with an appropriate agent of formula (xi) .
  • R 1a -R 4a are as defined earlier and X represents a suitable leaving group such as a halogen.
  • the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Amines of formula (x) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • agent of formula (xi) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide.
  • Agents of formula (xi) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • Agent (xi) can be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl chloride or a sulphonylating agent such as methanesulphonyl chloride.
  • a compound of formula (i) may also be prepared by interconversion of other compounds of formula (i) .
  • a compound in which R 4 contains an alkoxy group may be prepared by appropriate alkylation of a compound in which R 4 contains a hydroxy group.
  • a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example macrocrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or macrocrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example macrocrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stea
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i) may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10mg, for example 0.5, 1, 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for a
  • Acetyl chloride (3ml) was carefully added to methanol (60ml) at room temperature.
  • the solution was treated with ( ⁇ )-3-oxo-l- indane carboxylic acid (lOg) and the mixture heated at 60°C for two hours.
  • the reaction was cooled and the solvent removed in vacuo.
  • the residue was dissolved in ethyl acetate (100ml) and washed with saturated aqueous sodium hydrogen carbonate (50ml) , water (50ml) and saturated aqueous sodium chloride (50ml) .
  • the organic layer was then dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to yield a colourless solid Yield lOg.
  • the aqueous phase was reextracted with ethyl acetate (50ml) , then basified with solid potassium hydroxide pellets to pH12. The aqueous phase was then extracted into ethyl acetate (3 x 75ml) with the addition of sodium chloride. The combined organic phases were dried (magnesium sulphate) , filtered and evaporated to afford crude 7-aminopyrindane as a brown oil.
  • a solution of the crude amine and triethylamine (330ml) in dichloromethane was cooled to 0°C-and a solution of 3 , 4-dimethoxybenzenesulphonamide (511mg) in dichloromethane (3ml) was added dropwise over 15 minutes.
  • reaction mixture was stirred at 0°C for 15 minutes, then at room temperature for 25h.
  • the reaction mixture was diluted with dichloromethane (25ml) , washed with dilute aqueous sodium hydrogen carbonate solution (25ml) , dried (magnesium sulphate) , filtered and evaporated in vacuo. Purification by flash chromatography (silica, 70g, eluting with ethyl acetate) furnished the title compound (95mg) as a pale pink foam.
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (i) are standard assay procedures as disclosed by Schilling et al Anal. Biochem. 216 154 (1994) , Thompson and Strada Adv. Cycl. Nucl. Res. 8 119 (1979) and Gristwood and Owen Br. J. Pharmacol. 87 91P (1986).

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Abstract

3,4-benzènesulfamides disubstitués représentés par la formule générale (i) dans laquelle R4 représente un noyau hétérocyclique ou carbocyclique insaturé ou saturé à 5 ou 6 éléments, auquel est fusionné un noyau aryle, hétéroaryle, hétérocyclique ou carbocyclique, où un ou les deux noyaux peuvent éventuellement être substitués, les autres substituants étant tels qu'ils sont définis dans la revendication 1, et présentant une utilité thérapeutique étant donné qu'ils inhibent la phosphodiestérase IV.
PCT/GB1996/001205 1995-05-19 1996-05-20 3,4-phenylsulfamides disubstitues et leur utilisation therapeutique WO1996036596A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57723/96A AU5772396A (en) 1995-05-19 1996-05-20 3,4-disubstituted-phenylsulphonamides and their therapeutic use

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GBGB9510163.0A GB9510163D0 (en) 1995-05-19 1995-05-19 Novel compounds
GB9510163.0 1995-05-19
GBGB9523677.4A GB9523677D0 (en) 1995-11-20 1995-11-20 Novel compounds
GB9523677.4 1995-11-20

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004521A1 (fr) * 1996-07-26 1998-02-05 Icagen, Inc. Inhibiteurs du canal de potassium
WO1999026616A1 (fr) * 1997-11-25 1999-06-03 Warner-Lambert Company Inhibiteurs benzenesulfamides de la phosphodiesterase iv et utilisation therapeutique de ces derniers
US5925636A (en) * 1996-05-20 1999-07-20 Darwin Discovery Limited Benzofuran carboxamides and their therapeutic use
US6069151A (en) * 1996-11-06 2000-05-30 Darwin Discovery, Ltd. Quinolines and their therapeutic use
JP2001026506A (ja) * 1999-04-28 2001-01-30 Takeda Chem Ind Ltd スルホンアミド誘導体
US6197798B1 (en) 1998-07-21 2001-03-06 Novartis Ag Amino-benzocycloalkane derivatives
WO2001046155A1 (fr) * 1999-12-21 2001-06-28 Icagen, Inc. Inhibiteurs des canaux potassiques
US6333337B1 (en) 1998-01-27 2001-12-25 Icagen, Inc. Potassium channel inhibitors
WO2002060874A1 (fr) * 2000-12-21 2002-08-08 Icagen Incorporated Inhibiteurs du canal potassique
EP1174028A4 (fr) * 1999-04-28 2002-11-06 Takeda Chemical Industries Ltd Derives de sulfamide
US6566380B2 (en) 2000-07-25 2003-05-20 Icagen, Inc. Potassium channel inhibitors
US6620849B2 (en) 2000-07-26 2003-09-16 Icafen, Inc. Potassium channel inhibitors
US6878707B2 (en) 2000-01-18 2005-04-12 Novartis Ag Carboxamides useful as inhibitors of microsomal triglyceride transfer protein and of apolipoprotein b secretion
JP2005523289A (ja) * 2002-02-27 2005-08-04 テバ ファーマシューティカル インダストリーズ リミティド 脳選択性ｍａｏ阻害剤としてのプロパルギルアミノインダン誘導体及びプロパルギルアミノテトラリン誘導体
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
JP2007231000A (ja) * 2006-02-01 2007-09-13 Fujifilm Corp オキシム化合物及びそれを含む感光性組成物
US7276608B2 (en) 2003-07-11 2007-10-02 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
WO2008090640A1 (fr) * 2007-01-23 2008-07-31 Fujifilm Corporation Composé d'oxime, composition photosensible, filtre coloré, procédé de fabrication du filtre coloré, et élément d'affichage à cristaux liquides
JP2008249857A (ja) * 2007-03-29 2008-10-16 Fujifilm Corp 感光性樹脂組成物、カラーフィルタ及びその製造方法、並びに液晶表示素子
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
EP2223920A2 (fr) 1996-06-19 2010-09-01 Aventis Pharma Limited Composes azabicycliques substitues
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
CN105111095A (zh) * 2015-08-26 2015-12-02 吴玲 一种制备s-5,6-二甲氧基-1-氨基茚满的方法
CN105175272A (zh) * 2015-08-31 2015-12-23 吴玲 制备r-5-溴-1-氨基茚满的方法

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EP0306846A2 (fr) * 1987-09-11 1989-03-15 Dr. Karl Thomae GmbH Combinaison synergique comprenant un inhibiteur de phosphodiestérase et un antagoniste de thromboxane-A2 et leur application resp. préparation
EP0497564A1 (fr) * 1991-01-28 1992-08-05 Rhone Poulenc Rorer Limited Benzamides
WO1994002465A1 (fr) * 1992-07-28 1994-02-03 Rhone-Poulenc Rorer Limited Inhibiteurs de phosphodiesterase d'amp cyclique et du facteur de necrose tumorale

Patent Citations (3)

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EP0306846A2 (fr) * 1987-09-11 1989-03-15 Dr. Karl Thomae GmbH Combinaison synergique comprenant un inhibiteur de phosphodiestérase et un antagoniste de thromboxane-A2 et leur application resp. préparation
EP0497564A1 (fr) * 1991-01-28 1992-08-05 Rhone Poulenc Rorer Limited Benzamides
WO1994002465A1 (fr) * 1992-07-28 1994-02-03 Rhone-Poulenc Rorer Limited Inhibiteurs de phosphodiesterase d'amp cyclique et du facteur de necrose tumorale

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US5925636A (en) * 1996-05-20 1999-07-20 Darwin Discovery Limited Benzofuran carboxamides and their therapeutic use
US5972936A (en) * 1996-05-20 1999-10-26 Darwin Discover Limited Benzofuran carboxamides and their therapeutic use
EP2223920A2 (fr) 1996-06-19 2010-09-01 Aventis Pharma Limited Composes azabicycliques substitues
US6083986A (en) * 1996-07-26 2000-07-04 Icagen, Inc. Potassium channel inhibitors
WO1998004521A1 (fr) * 1996-07-26 1998-02-05 Icagen, Inc. Inhibiteurs du canal de potassium
US6069151A (en) * 1996-11-06 2000-05-30 Darwin Discovery, Ltd. Quinolines and their therapeutic use
WO1999026616A1 (fr) * 1997-11-25 1999-06-03 Warner-Lambert Company Inhibiteurs benzenesulfamides de la phosphodiesterase iv et utilisation therapeutique de ces derniers
US6162830A (en) * 1997-11-25 2000-12-19 Warner-Lambert Company Benzenesulfonamide inhibitors of PDE-IV and their therapeutic use
US6333337B1 (en) 1998-01-27 2001-12-25 Icagen, Inc. Potassium channel inhibitors
US6197798B1 (en) 1998-07-21 2001-03-06 Novartis Ag Amino-benzocycloalkane derivatives
JP2001026506A (ja) * 1999-04-28 2001-01-30 Takeda Chem Ind Ltd スルホンアミド誘導体
US6586617B1 (en) 1999-04-28 2003-07-01 Sumitomo Chemical Takeda Agro Company, Limited Sulfonamide derivatives
EP1174028A4 (fr) * 1999-04-28 2002-11-06 Takeda Chemical Industries Ltd Derives de sulfamide
EP2193808A1 (fr) 1999-08-21 2010-06-09 Nycomed GmbH Combinaision synergique
US6858610B2 (en) 1999-12-21 2005-02-22 Icagen, Inc. Potassium channel inhibitors
US6458794B2 (en) 1999-12-21 2002-10-01 Icagen, Inc. Potassium channel inhibitors
WO2001046155A1 (fr) * 1999-12-21 2001-06-28 Icagen, Inc. Inhibiteurs des canaux potassiques
US6878707B2 (en) 2000-01-18 2005-04-12 Novartis Ag Carboxamides useful as inhibitors of microsomal triglyceride transfer protein and of apolipoprotein b secretion
US6566380B2 (en) 2000-07-25 2003-05-20 Icagen, Inc. Potassium channel inhibitors
US6858611B2 (en) 2000-07-25 2005-02-22 Icagen, Inc. Potassium channel inhibitors
US6620849B2 (en) 2000-07-26 2003-09-16 Icafen, Inc. Potassium channel inhibitors
US6849634B2 (en) 2000-12-21 2005-02-01 Icagen Potassium channel inhibitors
WO2002060874A1 (fr) * 2000-12-21 2002-08-08 Icagen Incorporated Inhibiteurs du canal potassique
EP1490324A4 (fr) * 2002-02-27 2007-10-10 Teva Pharma Derives de propargylaminoindane et derives de propargylaminotetraline utilises comme inhibiteurs de la mao cerebro-selectifs
JP2005523289A (ja) * 2002-02-27 2005-08-04 テバ ファーマシューティカル インダストリーズ リミティド 脳選択性ｍａｏ阻害剤としてのプロパルギルアミノインダン誘導体及びプロパルギルアミノテトラリン誘導体
US7057046B2 (en) 2002-05-20 2006-06-06 Bristol-Myers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US7425550B2 (en) 2002-05-20 2008-09-16 Bristol-Meyers Squibb Company Lactam glycogen phosphorylase inhibitors and method of use
US7098235B2 (en) 2002-11-14 2006-08-29 Bristol-Myers Squibb Co. Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
US7153824B2 (en) 2003-04-01 2006-12-26 Applied Research Systems Ars Holding N.V. Inhibitors of phosphodiesterases in infertility
US7276608B2 (en) 2003-07-11 2007-10-02 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US8119808B2 (en) 2003-07-11 2012-02-21 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US7884113B2 (en) 2003-07-11 2011-02-08 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
JP2007231000A (ja) * 2006-02-01 2007-09-13 Fujifilm Corp オキシム化合物及びそれを含む感光性組成物
WO2008090640A1 (fr) * 2007-01-23 2008-07-31 Fujifilm Corporation Composé d'oxime, composition photosensible, filtre coloré, procédé de fabrication du filtre coloré, et élément d'affichage à cristaux liquides
JP2008249857A (ja) * 2007-03-29 2008-10-16 Fujifilm Corp 感光性樹脂組成物、カラーフィルタ及びその製造方法、並びに液晶表示素子
US8252829B2 (en) 2009-06-05 2012-08-28 Link Medicine Corporation Aminopyrrolidinone derivatives and uses thereof
CN105111095A (zh) * 2015-08-26 2015-12-02 吴玲 一种制备s-5,6-二甲氧基-1-氨基茚满的方法
CN105175272A (zh) * 2015-08-31 2015-12-23 吴玲 制备r-5-溴-1-氨基茚满的方法

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