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WO1993007111A1 - Cyclopentane et derives de cyclopentane presentant une activite antiallergique, anti-inflammatoire et inhibant le facteur necrotique tumoral - Google Patents

Cyclopentane et derives de cyclopentane presentant une activite antiallergique, anti-inflammatoire et inhibant le facteur necrotique tumoral Download PDF

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Publication number
WO1993007111A1
WO1993007111A1 PCT/US1992/008609 US9208609W WO9307111A1 WO 1993007111 A1 WO1993007111 A1 WO 1993007111A1 US 9208609 W US9208609 W US 9208609W WO 9307111 A1 WO9307111 A1 WO 9307111A1
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Prior art keywords
methoxyphenyl
cyclopentyloxy
substituted
cyclopentane
alkyl
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PCT/US1992/008609
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English (en)
Inventor
Siegfried Benjamin Christensen, Iv
Mark Alan Levy
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Smithkline Beecham Corporation
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Priority to JP50720193A priority Critical patent/JP3333510B2/ja
Priority to EP92921752A priority patent/EP0642489A1/fr
Publication of WO1993007111A1 publication Critical patent/WO1993007111A1/fr

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    • 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
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    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
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Definitions

  • the present invention relates to novel cyclopentane and cyclopentene derivatives, pharmaceutical compositions containing these compounds and their use in treating allergic and inflammatory diseases, and for inhibiting the production of Tumor Necrosis Factor (TNF).
  • TNF Tumor Necrosis Factor
  • Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
  • methylxanthines, disodium cromoglycate are inadequate to control the disease; none of them modify all three phases of asthma and nearly all are saddled with limiting side effects. Most importantly, none of the agents, with the possible exception of steroids, alter the course of progression of chronic asthma.
  • Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs (Robison et al., Cyclic AMP Academic Press, New York, pgs. 17-47, 1971; Krebs
  • inhibit PDE should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
  • PDEs cyclic nucleotide phosphodiesterases
  • PDE cyclic nucleotide phosphodiesterase
  • Torphy "Phosphodiesterase Isozymes: Potential Targets for Novel Anti- asthmatic Agents” in New Drugs for Asthma. Barnes, ed. IBC Technical Services Ltd. (1989).
  • PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
  • PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
  • Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
  • the compounds of this invention also inhibit production of Tumor Necrosis
  • TNF Tumorinogen activator factor
  • TNF has been implicated in various roles with the human acquired immune
  • AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • monokines, specifically TNF are implicated in the infection of T lymphocytes with HIV by playing a role in maintaining T lymphocyte activation.
  • monokines, specifically TNF are implicated in activated T cellmediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation.
  • Monokines such as TNF have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
  • monokine activity such as by inhibition of TNF production
  • an HIV-infected individual aids in enhancing the quality of life of HIV-infected patients by reducing the severity of monokine-mediated disease associated problems such as cachexia and muscle degeneration.
  • 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, Vol. 58, No. 9, p. 2750-54 (1990); and Jafari et al.. Journal of Infectious Diseases, Vol. 164, p. 389-95 (1991). See also Wasan et al., Antimicrobial Agents and Chemotherapy, Vol. 35, No. 10, p. 2046-48 (1991) and Luke et al., Journal of Infectious Diseases, Vol. 162, p. 211-214 (1990)].
  • R 1 is C 1-12 alkyl unsubstituted or substituted by 1 or more halogens; C 3-6 cyclic alkyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; C 4-6 cycloalkyl containing one or two unsaturated bonds; C 7-11 polycycloalkyl, - (CR 14 R 14 ) n C(O)-O-(CR 14 R 14 ) m -R 10 , -(CR 14 R 14 ) n C(O)-O-(CR 14 R 14 ) r -R 11 , - (CR 14 R 14 ) x OH, -(CR 14 R 14 ) s O(CR 14 R 14 ) m -R 10 , -(CR 14 R 14 ) s O(CR 14 R 14 ) r -Rll, -(CR 14 R 14 ) r ⁇ -(C(O)NR 14 )-(CR 14 R 14 )
  • X 2 is O orNR 14 ;
  • X 3 is hydrogen or X
  • R2 is -CH 3 or -CH 2 CH 3 , each may be unsubstituted or substituted by 1 to 5 fluorines;
  • A is:
  • R 3 is hydrogen, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, cyclopropyl unsubstituted or substituted by R 9 , OR 5 , -CH 2 OR 5 , -NR 5 R 16 ,
  • R 3' is hydrogen, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, cyclopropyl unsubstituted or substituted by R 9 , -CN, -CH 2 OR 5 , -CH 2 NR 8 R 16 , -C(O)OR 5 , -C(O)NR 8 R 16 or -C(Z)H;
  • Z is O, NR 8' , NOR 8 , NCN, NNR 8 R 16 , C(-CN) 2 , CR 5 NO 2 , CR 5 C(O)OR 5 , CR 5 C(O)NR 8 R 16 , C(-CN)NO 2 , C(-CN)C(O)OR 12 or C(-CN)C(O)NR 8 R 16 ;
  • Z is O, NR 12 , NOR 5 , NCN, C(-CN) 2 , CR 5 NO 2 , CR 5 C(O)OR 5 ,
  • R 4 is E or Q
  • E is OR 8 , OC(O)R 8 , OC(O)NR 5 R 8 , OS(O)2NR 5 R 8, OS(O) 2 R 8', SR 8, S(O) m 'R 8', S(O) 2 NR 8 R 16, NR 8 R 16, NR 8 C(O)R 5, NR 16 C(Y')R 8,
  • Q is C(Y')R 8 , C(O)OR 8 , C(Y')NR 8 R 16, C(CR 5 NO 2 )NR 8 R 16,
  • Y' is O or S
  • R 5 is independently hydrogen or C 1-4 alkyl, unsubstituted or substituted by one to three fluorines;
  • R 6 is R 5, -C(O)R 5 , -C(O)C(O)R 7 , -C(O)NR 5 R 16, -S(O) m R 12,
  • R 7 is OR 5 , -NR 5 R 16 or R 12 ;
  • R 8 is hydrogen or R 8';
  • R 8 is -(CR 14 R 14 ) m -D;
  • D is C 1-6 alkyl , phenyl, (2-, 3- or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1-, 2-, 4- or 5-imidazolyl), (2- or 3-thienyl), (2- or 5-pyrimidyl) or (4- or 5-thiazolyl), triazolyl, quinolinyl or naphthyl all of which may be unsubstituted or substituted by one or more: Br, F, Cl, NR 5 R 16 , NR 6 R 16, NO 2 , -COR 7 , -S(O) m R 12 , CN, OR 5 , -OC(O)NR 5 R 16, (1- or 1-(R 5 )-2-imidazolyl), -C(NR 16 )NR 5 R 16, -C(NR 5 )-SR 12, -OC(O)R 5 , -C(NCN)NR 5 R 16, -C(S)NR 5 R 16, -NR 16 -C
  • R 9 is hydrogen, F or R 12;
  • R 10 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC 1- 3alkyl, halo substituted aryloxyC 1-3 alkyl, indanyl, indenyl, C 7-11 polycycloalkyl, furanyl, pyranyl, thienyl, thiopyranyl, (3- or 4-tetrahydrothiopyranyl),
  • R 11 is 2-tetrahydropyranyl or 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;
  • R 12 is C 1-4 alkyl unsubstituted or substituted by one to three fluorines
  • R 14 is independently hydrogen or a C 1-2 alkyl unsubstituted or substituted by fluorine;
  • R 15 is -C(O) C 1-4 alkyl , unsubstituted or substituted by one or more halogens, oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl or pyrrolyl, and each of the heterocyclics may be unsubstituted or substituted by one or two C 1-2 alkyl groups;
  • R 16 is OR 5 or R 5, or when R 8 and R 16 are as NR 8 R 16 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from 0, N or S;
  • R 17 is R 5 orQ
  • R 18 is Q, S(O) 2 R 8', OR 8', OC(O)NR 8 R 16 or NR 8 R 16;
  • n is an integer from 0 to 2;
  • n is an integer from 1 to 4.
  • q is an integer from 0 to 1;
  • r is an integer from 1 to 2;
  • s is an integer from 2 to 4.
  • x is an interger from 2 to 6;
  • y is an integer from 1 to 6;
  • z is an integer from 0 to 6; provided that
  • R 17 is hydrogen, both of the q terms are zero and R 4 is OH, OC 1-4 alkyl or SC 1-4 alkyl in radical (c) of term A, then R 3 is other than hydrogen;
  • the invention further provides for the novel compositions of the compounds of Formula I.
  • the compounds of Formula Ia, a subgroup of Formula I have activity as PDE IV inhibitors. Therefore, this invention provides a method of inhibiting PDE IV which comprises administering to a subject in need thereof a compound of the Formula (la):
  • R 1 is phenyl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines; C 4-6 cycloalkyl, CH 2 -cyclopentyl, CH 2 -cyclopropyl, C 7-11 polycycloalkyl, 3-tetrahydrofuranyl, cyclopentenyl, -(CH 2 ) n C(O)-O-(CH 2 ) m -CH 3 , -(CH 2 ) 2-4 OH, -(CH 2 ) s O(CH 2 ) m -CH 3 , -(CH 2 ) n -(C(O)NR 14 )-(CH 2 ) m -CH 3 , all of which may be substituted by 1 to 3 methyl groups or one ethyl group;
  • X 3 is hydrogen or X
  • X is YR 2 , halogen, nitro, NR 14 R 14 or formamide
  • Y is O or S(O)m
  • R 2 is -CH 3 or -CH 2 CH 3 , each may be unsubstituted or substituted by 1 to 5 fluorines;
  • R 3 is hydrogen,F, CH 3 , CF 3 , CF 2 H, CH 2 F, -CN, -CH 2 OR 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -G ⁇ CR 9 or -C(O)H;
  • R 3' is hydrogen, C 1-3 alkyl, CF 3 , CF 2 H, CH 2 F, -CN, -CH 2 OR 5 ,
  • Z' is O. NR 12 orNOR 5 ;
  • R 4 is E or Q
  • E is OR 8 , NR 8 R 16, NR 16 C(O)R 8 , NR 16 C(O)OR 8' , NR 16 C(O)NR 8 R 16, NR 16 S(O)2NR 8 R 16 , NR 16 C(NCN)NR 8 R 16, NR 16 C(CR 5 NO 2 )NR 8 R 16 ,
  • R 5 is independently hydrogen or C 1-2 alkyl, unsubstituted or substituted by one to three fluorines;
  • R 6 is R 5 , -C(p)R 5 , -C(O)C(O)R 7 , -C(O)NR 5 R 16,
  • R 7 is OHor-NR 5 R 16 ;
  • R 8 is hydrogen or R 8' ;
  • R 8 is -(CH 2 ) m -D;
  • D is phenyl, (2-, 3- or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1- or 2-imidazolyl), (4- or 5-thiazolyl) or (2- or 3-thienyl), all of which may be unsubstituted or substituted by one or more: Br, F, Cl, NR 5 R 16 , NR 6 R 16 , NO 2 , -COR 7 , -S(O) m R 12 , CN, OR 5 , -OC(O)NR 5 R 16, 1 or2-imidazolyl, -C(NR 16 )NR 5 R 16, -C(NR 5 )-SR 12 , -OC(O)R 5 , -C(NCN)NR 5 R 16 , -C(S)NR 5 R 16 , -NR 16 -C(O)-R 15 , oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazoly
  • NR 5 R 16 they may together with the nitrogen form a 5 to 7 membered ring optionally contaijiing at least one additional heteroatom selected from O, N or S;
  • R 9 is R 5 .
  • R 12 is C 1-4 alkyl unsubstituted or substituted by one to three fluorines
  • R 14 is hydrogen or a C 1-2 alkyl unsubstituted or substituted by fluorine;
  • R 15 is -C(O)C 1-4 alkyl, unsubstituted or substituted by one or more halogens, oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and each of the heterocyclics may be unsubstituted or substituted by one or two C 1-2 alkyl groups;
  • R 15 is OR 5 or R 5 , or when R 8 and R 16 are as NR 8 R 16 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S;
  • R 17 is R 5 or Q
  • R 18 is Q, OR 8' orNR 8 R 16 ;
  • R 19 is independently hydrogen, F, C 1-3 alkyl, CF 3 , CF 2 H, CH 2 F, -CN, -CH 2 OR 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -C1 ⁇ 4CR 9 or -C(O)H;
  • n is an integer from 0 to 2;
  • n is an integer from 1 to 4.
  • q is an integer from 0 to 1;
  • r is an integer from 1 to 2;
  • s is an integer from 2 to 4.
  • x is an interger from 2 to 6;
  • y is an integer from 1 to 6;
  • z is an integer from 0 to 6;
  • Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticardia, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophillic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus, (Kidney Int. 37:362, 1990; Kidney Int. 35:494, 1989) and central nervous system disorders such as depression and multi-infarct dementia.
  • HAV human immunodeficiency virus
  • ARC AIDS Related Complex
  • any other disease state associated with an HIV infection comprises administering to such a human an effective TNF inhibiting amount of a compound of Formula (I).
  • the present invention also provides a method of preventing a TNF mediated disease state in an animal in need thereof, including humans, by prophylactically administering an effective amount of a compound of Formula I.
  • the compounds of the present invention are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • the viruses contemplated for treatment herein are 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, Herpes Zoster and Herpes Simplex.
  • the compounds of Formula (I) are also useful in the treatment of 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 the Formula (I) may be administered in conjunction with other drugs of choice, either simultaneously or in a consecutive manner, for systemic yeast and fungal infections.
  • Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidaozles, such as
  • the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.
  • the preferred organism for treatment is the Candida organism.
  • compounds of the Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents.
  • the compounds of the Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by
  • a compound of the Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
  • TNF mediated diseases exist in animals, including commercially important livestock and pets populations, particularly as regards viral infections.
  • viruses include feline immunodeficiency virus (FIV) and other retroviruses such as equine infectious anemia visus, caprine arthritis virus, visna virus, maedi virus, and other lentiviruses.
  • this invention relates to a composition
  • a composition comprising a compound of formula I in admixture with a carrier.
  • a composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
  • All defined alkyl groups can be straight or branched.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.
  • halogen is used to mean chloro, fluoro, bromo or iodo.
  • cycloalkyl as used herein includes groups of 3-6 carbon atoms such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.
  • aryl or “aralkyl”, unless specified otherwise, as used herein is meant an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl.
  • aryl is monocyclic, i.e., phenyl.
  • C 7-11 polycycloalkyl examples are bicyclo[2.2.1]heptyl
  • rings when R 5 and R 16 in the moiety -NR 5 R 16 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/ and S include, but are not limited to 1-imidazolyl, 1 -pyrazolyl, 1-triazoly, 2-triazolyl, tetrazolyl, 2-tetrazoyl,
  • Preferred compounds are those wherein R 1 is cyclopentyl, CHF 2 ,
  • R 2 is CHF 2 or CH 3 ;
  • A is (a), (b), (c), (d) or (e);
  • R 3 is H, -CN, or C ⁇ CH;
  • R 3' and R 19 are independently -CN, C 1-3 alkyl, -C(O)OR 5 or -C(O)NR 8 R 16 ;
  • Z is O, CR 5 C(O)OR 5 , NOR 8 or NNR 8 R 16 ;
  • Z' is O;
  • E is OR 5 , NHC(O)R 5 , NHC(O)NH 2 , NHC(NCN)NH 2 , NHC(O)C(O)NH 2 , or NR 5 C(O)NR 16 S(O) 2 (4-methylphenyl);
  • Q is COOR 5 , CONR 5 R 5 , tetrazol-5-yl or CN; q is 0 or 1;
  • R 18 is Q or OR 8
  • the present invention provides compounds of the formula (I) which are prepared by a process comprising reacting a compound of the formula (II):
  • OR x is a leaving group to provide a compound of the formula (IV):
  • a suitable source of a counterion M + is an alkyl metal compound, such as a butyl lithium, optionally modified by the addition of other metal ions, such as zinc(2 + ) and palladium (0).
  • This source of counter-ion is in turn reacted with the appropriate aryl halide, such as a bromide, to provide the compounds of formula (II).
  • Generating and reacting compounds of the formula (II) are typically conducted in an inert solvent, such as tetrahydrofuran, at temperatures below ambient and under an inert atmosphere.
  • Suitable leaving groups OR x in compounds of the formula (HI) are, e.g., ethoxy or isopropyloxy when M + is lithium, and trifluoromethylsulfonyl when zinc(2 + ) and palladium (0) are also present.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, parenterally, sublingually, transdermally, rectally, via inhalation or via buccal administration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lerithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lerithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoro-methane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to herself a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 mg to 100 mg/Kg, and preferably from 1 mg to 30 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.01 mg to 100 mg, of a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I) or (Ia).
  • Each dosage unit for rectal administration contains suitably 0.01 mg to 100 mg of a compound of Formula (I) or (Ia).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for parenteral is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 1200 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit antiinflammatory activity, or if used as a TNF inhibitor, the active ingredient is administered in an amount sufficient to inhibit TNF production such that normal or subnormal levels are achieved which are sufficient to ameliorate or prevent the disease state.
  • Phosphodiesterase inhibitory activity and selectivity of compounds is determined using a battery of five distinct PDE isozymes.
  • the characteristics of these PDEs appear in Table 1.
  • the tissues used as sources of the different isozymes are as follows: 1) PDE Ia, canine trachealis; 2) PDE Ib, porcine aorta; 3) PDE Ic, guinea-pig heart; 4) PDE III, guinea-pig heart; and 5) PDE IV, human monocyte.
  • PDEs Ia, Ib, Ic and III are partially purified using standard chromatographic techniques (Torphy and Cieslinski, Mol. Pharmacol.37:206-214, 1990).
  • PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography (White et al., FASEB J.4:A1987, 1990).
  • Phosphodiesterase activity is assayed as described in Torphy and Cieslinski,
  • the reaction is conducted in 0.1 ml of standard mixture containing (final concentrations): 50 mM Tris-HCl buffer (pH 7.5), 5 mM MgGL2, 50 mM [14C]-5'AMP (approximately 400 dpm/nmole) as a carrier and for determining recovery of product, 1 mM [3H]-cAMP (approximately 2000 dpm/pmole), enzyme, and vehicle or various concentrations of test compounds.
  • the reaction is initiated with either enzyme or substrate and conducted at 30°C.
  • the reaction is termninated by placing reaction vessels in a 100°C heating block for 1 min.
  • a polyacrylamide-boronate gel column 0.5 g of Biorad Affi-gel® 601 in a 0.7 ⁇ 10 cm Biorad® econo-column
  • the unreacted cyclic nucleotides are eluted with 8 ml of equilibration buffer.
  • the 5-monophosphate products are eluted with 10 ml of 0.25 M acetic acid into a scintillation vial containing 10 ml of scintillation cocktail.
  • Recovery of [3H]5-AMP, as determined with the [14C]5'-AMP carrier, is 80- 90%. All assays are conducted in the linear range of the reaction where less than 20% of the initial substrate is hydrolyzed. Cyclic GMP hydrolysis is assayed using a protocol identical to the one described above, with [3H]cGMP as the substrate.
  • [3H]cGMP is used as the substrate for PDEs Ia, Ib and Ic.
  • [3H]cAMP is used as the substrate for PDEs HI and IV.
  • IC50s for compounds of this invention range from 0.05 mM to 40 mM.
  • PDE IV inhibitors The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV.
  • Approximately 2 x 106 cells in a volume of 100 ml are incubated at 37°C in a Krebs-Ringer buffer (pH 7.5) containing (mM); CaCl 2 , 1; Hepes, 5; glucose, 1.1; Nacl, 118; KCl, 4.6; NaHCO 3 , 24.9; KH 2 PO 4 > 1; BSA, 0.2 mg/ml.
  • Cells are treated with various concentrations of test compounds (PDE inhibitors) for 1 min before the addition of a threshold concentration of PGE2 (0.1 mM).
  • EC 50 s for compounds of this invention range from 0.3 mM to >10 mM.
  • Human peripheral blood monocytes were isolated and purified from either blood bank buffy coats or platletpheresis residues, according to the procedure of Colotta, R. et al., J. Iolmmunol, 132(2):936 (1984).
  • the monocytes were plated at a density of 1 ⁇ 106 cells/ml medium/well in 24-well multi-dishes. The cells were allowed to adhere for 1 hour after which time the supernatant was aspirated and 1 ml fresh medium (RPMI-1640 Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum and penicillin and streptomycin at 10 units/ml was added.
  • the cells were incubated for 45 minutes in the presence or absence of test compounds at 1 nM-10 um dose ranges (compounds were solubilized in Dimethylsulfoxide/Ethanol such that the final solvent concentration in the culture medium was 0.5% Dimethyl sulfoxide/0.5% Ethanol).
  • Bacterial lipopolysaccharide E. coli 055:B5[LPS] from Sigma Chemicals Co.
  • PBS Phosphate Buffered Saline
  • culture supernatants were removed from the cells, centrifuged at 3000 revolutions per minute (rpm) to remove cell debris and .05 ml of the supernatant assayed for the TNF activity using the radioimmunoassay described below.
  • the assay buffer consisted of 0.01 M NaPO 4 , 0.15M NaCl, 0.025M EDTA and 0.1% sodium azide at pH 7.4.
  • Human recombinant TNF (rhTNF) obtained using the procedure of Chen et al., Nature. 330:581-583 (1987) was iodinated by a modified Chloramine-T method described in Section III below.
  • samples 50 ml culture supernatants
  • rhTNF standards a 1/9000 dilution of polyclonal rabbit anti-rhTNF (Genzyme, Boston, MA) and 8000 cpm of 125I-TNF was added in a final volume of 400 ml buffer and incubated overnight (18 hours) at 4°C.
  • Normal rabbit serum and goat anti-rabbit IgG (Calbiochem) were titered against each other for maximum precipitation of the anti-rhTNF.
  • the appropriate dilutions of carrier normal rabbit serum (1/200), goat anti-rabbit IgG (1/4) and 25 Units heparin (Calbiochem) were allowed to precipitate about 200 ⁇ l of this complex was added per assay tube and incubated overnight at 4°C. Tubes were centrifuged for 30 minutes at 2000 rpm, supernatants were carefully aspirated, and radioactivity associated with the pellets measured in a Beckman Gamma 5500 counter. The logit-log linear transformation curve was used for the calculations. The concentrations of TNF in the samples were read off a standard curve of rhTNF that was linear in the 157 to 20,000 pg/ml range.
  • rhTNF Iodination of rhTNF was performed using a modified chloramine-T method of Frolik et al., J. Biol, Chem., 259: 10995-11000 (1984). Briefly, 5 mg of rhTNF in 5 ml of 20 mM Tris pH 7.5, was diluted with 15 ml of 0.5M KPO4 and 10 ml of carrier free 125I(100mCi/ml; ICN). To initiate the reaction, a 5 ml aliquot of a 200 mg/ml
  • TNF TNF-binding protein
  • the ELISA employed a murine monoclonal anti-human TNF antibody, described below, as the capture antibody and a polyclonal rabbit anti-human TNF, described below, as the second antibody.
  • TNF levels in samples were calculated from a standard curve generated with recombinant human TNF produced in E. coli (obtained from SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA).
  • Section V Production of anti-human TNF antibodies
  • Monoclonal antibodies to human TNF were prepared from spleens of BALB/c mice immunized with recombinant human TNF using a modification of the method of Kohler and Millstein, Nature 256:495 (1975), the entire disclosure of which is hereby incorporated by reference.
  • Polyclonal rabbit anti-human TNF antibodies were prepared by repeated immunization of New Zealand White (NZW) rabbits with recombinant human TNF emulsified in complete Freund's adjuvant (DIFCO, IL., USA).
  • TNF Activity Plasma levels of TNF were measured using a modification of the basic sandwich ELISA method described in Winston et al., Current Protocols in Molecular Biology. Pg. 11.2.1, Ausubel et al., Ed. (1987) John Wiley and Sons, New York, USA.
  • the ELISA employed a hampster monoclonal anti-mouse TNF (Genzyme, Boston, MA, USA) as the detecting antibody.
  • TNF levels in mouse samples were calculated from a standard curve generated with recombinant murine TNF (Genzyme, Boston, MA, USA).
  • TNF levels determined by ELISA correlated with levels detected by the L929 bioassay of Ruff et al., J. Immunol. 125:1671-1677 (1980), with 1 Unit of activity in the bioassay corresponding to 70 picograms (pg) of TNF in the ELISA.
  • the ELISA detected levels of TNF down to 25 pg/ml.
  • the mixture was filtered through celite, combined with the product from a similar reaction conducted on a 55 mg scale, and the filtrate was partitioned between methylene chloride and saturated aqueous sodium carbonate. After three extractions, the organic layers were dried (potassium carbonate) and evaporated to a colorless oil.
  • Methyl 2-[3-(3-cyclopentyloxy-4-methoxyphenyl)cyclopentane]acetate A mixture of methyl [3-(3-cyclopentyloxy-4-methoxyphenyl)cyclopentan-1-ylidine]acetate ((0.14 g, 0.42 mmol) and 10% palladium on carbon (50 mg) in methanol (5 mL) was hydrogenated at 60 psi for 4h. The mixture was diluted with methylene chloride, filtered and evaporated. Purification by flash chromatography, eluting with
  • the resulting mixture was stirred at room temperature for 18 h.
  • the reaction mixture was partitioned between methylene chloride and acidic water.
  • the organic extract was washed with acidic water (3x) and dried (magnesium sulfate).
  • the solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 40% ethyl acetate/ cyclohexane to provide the dialkylated product as a solid: m.p. 145 - 161°C.

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Abstract

Composés illustrés par la formule générale (I), utiles comme inhibiteurs de PDE IV et de la production du facteur nécrotique tumoral (TNF). Dans la formule, R1 représente alkyle C1-12 non substitué par un ou plusieurs halogènes; alkyle cyclique C3-6 non substitué ou substitué par 1 à 3 groupes méthyle ou un groupe éthyle; cycloalkyle C4-6 contenant une ou deux liaisons insaturées; polycycloalkyle C7-11, (CR14R14)nC(O)-O-(CR14R14)m-R10, -(CR14R14)nC(O)-O-(CR14R14)r-R11, -(CR14R14)xOH, -(CR14R14)sO(CR14R14)m-R10, -(CR14R14)sO(CR14R14)r-R11, -(CR14R14)n-C(O)NR14)-(CR14R14)m-R10, -(CR14R14)n-(C(O)NR14)- (CR14R14)r-R11, -(CR14R14)y-R11 ou -(CR14R14)z-R10; X2 représente O ou NR14; X3 représente hydrogène ou X; X représente YR2, halogène, nitro, NR14R14 ou formamide; Y représente O ou S(O)m; R2 représente -CH3 ou -CH2CH3, chacun pouvant être non substitué ou substitué par 1 à 5 atomes de fluor; A représente (a), (b), (c), (d) ou (e); B est >C=Z ou C=S.
PCT/US1992/008609 1991-10-02 1992-10-01 Cyclopentane et derives de cyclopentane presentant une activite antiallergique, anti-inflammatoire et inhibant le facteur necrotique tumoral WO1993007111A1 (fr)

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EP92921752A EP0642489A1 (fr) 1991-10-02 1992-10-01 Cyclopentane et derives de cyclopentane presentant une activite antiallergique, anti-inflammatoire et inhibant le facteur necrotique tumoral

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US6255326B1 (en) 1991-01-28 2001-07-03 Aventis Pharma Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
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US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
US5602157A (en) * 1992-04-02 1997-02-11 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
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US5643946A (en) * 1992-04-02 1997-07-01 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
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US5840724A (en) * 1993-06-01 1998-11-24 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or
US7045660B2 (en) 1993-07-28 2006-05-16 Aventis Pharma Limited Compounds as PDE IV and TNF-inhibitors
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EP0642489A1 (fr) 1995-03-15
AU2807192A (en) 1993-05-03
CA2120351A1 (fr) 1993-04-15
MX9205680A (es) 1993-05-01
JP3333510B2 (ja) 2002-10-15
ZA927591B (en) 1993-04-13
NZ244605A (en) 1995-05-26
PT100928A (pt) 1993-10-29
JPH07500108A (ja) 1995-01-05

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