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WO1994027947A1 - COMPOSES DE PHENYLCYCLOPROPANE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE cAMP ET DE TNF - Google Patents

COMPOSES DE PHENYLCYCLOPROPANE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE cAMP ET DE TNF Download PDF

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Publication number
WO1994027947A1
WO1994027947A1 PCT/GB1994/001189 GB9401189W WO9427947A1 WO 1994027947 A1 WO1994027947 A1 WO 1994027947A1 GB 9401189 W GB9401189 W GB 9401189W WO 9427947 A1 WO9427947 A1 WO 9427947A1
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Prior art keywords
group
trans
compound
cyclopentyloxy
alkyl
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PCT/GB1994/001189
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English (en)
Inventor
Garry Fenton
Jonathan Stephen Mason
Malcom Norman Palfreyman
Andrew James Ratcliffe
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Rhone-Poulenc Rorer Ltd.
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Priority to AU68035/94A priority Critical patent/AU6803594A/en
Publication of WO1994027947A1 publication Critical patent/WO1994027947A1/fr

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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C45/67—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
    • C07C45/68—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
    • 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
    • C07C45/71—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 being hydroxy groups
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Definitions

  • This invention relates to therapeutically useful cyclopropane derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to methods for their use in the treatment of disease states, for example disease states associated with proteins that mediate cellular activity.
  • This invention is directed to substituted cyclopropane compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
  • TNF is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
  • TNF The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and acute respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of general inflammation. TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators.
  • TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatpry cytokines such ILi , lU, i and GM-CSF, which in some case mediate the end effects of TNF.
  • cytokines such as ILi , lU, i and GM-CSF.
  • the ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages.
  • HIV Human Immunodeficiency Virus
  • endotoxic shock such as fever, metabolic acidosis, hypotension and intravascuiar coagulation are thought to be mediated through the actions of TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells.
  • the cachexia associated with certain disease states is mediated through indirect effects on protein catabolism.
  • TNF also promotes bone resorption and acute phase protein synthesis.
  • TNF disease states associated with TNF
  • disease states associated with other cytokines such as but not limited to IL-1 , or IL-6, that are modulated by associated with TNF.
  • IL-1 IL-1 associated disease state
  • IL-6 IL-6 associated disease state
  • a IL-1 associated disease state where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF.
  • TNF-alpha and TNF-beta are also herein referred to collectively as TNF' unless specifically delineated otherwise, since theRE is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biologic responses and bind to the same cellular receptor.
  • cyclic AMP phosphodiesterase is an important enzyme which regulates cyclic AMP levels and in turn thereby regulates other important biological reactions.
  • inhibitors of type IV cyclic. AMP phosphodiesterase have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
  • Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
  • WO Patent Application Publication No. 93/18024 discloses that 1- alkoxy-2-(alkoxy- or cycloalkyloxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-)- benzene compounds are inhibitors of cyclic AMP phosphodiesterase and TNF, but does not disclose or suggest that the compound may be substituted by a 4- cyclopropyl moiety.
  • This invention is directed to the pharmaceutical use of a compound of formula I below to inhibit the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF), where formula I is as follows:
  • R is an alkyl, substituted alkyl, acyl, arylacyl, heterocyclylacyi, carboxy, alkoxycarbonyl, arylalkoxycarbonyl, heterocyclylalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl or cyano group, or a group of formula -NR 3 R 4 , -CONR 5 R 6 , -NR 9 COCOR 10 or
  • R is a lower alkyl or halo substituted lower alkyl group
  • R is an alkyl, alkenyl, halo substituted alkyl, halo substituted alkenyl, hydrocarbyl, substituted hydrocarbyl, heterohydrocarbyl or substituted heterohydrocarbyl group;
  • R is a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, aryl or heterocyclyl group;
  • R is a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, acyl, arylacyl, heterocyclylacyi, alkoxycarbonyl, arylalkoxycarbonyl, heterocyclylalkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkylsulphonyl, arylalkylsulphonyl, heterocyclylalkylsulphonyl, arylsulphonyl or
  • R is a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, aryl or heterocyclyl group;
  • R is a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, aryl, heterocyclyl or alkoxy group
  • R and R are independently a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, aryl or heterocyclyl group; g
  • R is a hydrogen atom or an alkyl, arylalkyl, heterocyclylalkyl, aryl or heterocyclyl group;
  • R 10 is an amino, hydroxyamino, alkoxy, hydroxy, aikylamino or dialkylamino group;
  • R 1 1 is a hydrogen atom or an alkyl, arylalkyl,- heterocyclylalkyl, aryl or heteroaryl group;
  • R is an amino, aikylamino, dialkylamino, hydroxyamino or ethoxy group
  • R , R , R and R are independently a hydrogen atom or an alkyl group
  • X and Y are independently an oxygen or sulphur atom
  • Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase.
  • the present invention is therefore directed to their pharmacological use, pharmacological compositions comprising the compounds and methods for their preparation.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain; preferably about 1 to about 12 carbon atoms in the chain; and more preferably about 1 to about 4 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • Lower alkyl means about 1 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkyl groups include methyl, ethyl, propyl, ⁇ -butyl, t- butyl, n-pentyl, heptyl, octyl or decyl.
  • Substituted alkyl means an alkyl group as described above substituted by one or more substituents selected from hydroxy, acyloxy, arylacyloxy, Heterocyclylacyloxy, hydroxyimino, alkoxy, arylalkoxy, heterocyclylalkoxy, aryloxy, heterocyclyloxy, halo, alkylthio, arylalkylthio, heterocyciylalkylthio, arylthio, heterocyclylthio, alkylsulphinyl, arylalkylsulphinyl, heterocyclylalkylsulphinyl, arylsulphinyl, heterocyclylsulphinyl, alkylsulphonyl, arylalkylsulphonyl, heterocyclylalkylsulphonyl, arylsulphonyl, heterocyclylsulphonyl, alkylcarbamoyloxy, ary
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heterocyclylalkyl means an heterocyclyl-alkyl- group wherein the heterocyclyl and alkyl are as described herein.
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n- butenyl, Abutenyl, 3-methyibut-2-enyl, ⁇ -pentenyl, heptenyl, octenyl and decenyl.
  • Substituted alkenyl means an alkenyl group as described above substituted by one or more halo atoms; more preferably a fluoro atom.
  • Hydrocarbyl means a saturated or unsaturated mono cyclic or multi cyclic ring system of about 3 to about 10 carbon ring atoms.
  • exemplary hydrocarbyl groups include cycloalkyl and cycloalkenyl groups as described below. The hydrocarbyl is attached to Y by a direct bond or lower alkyl group.
  • Substituted hydrocarbyl means a hydrocarbyl group as described above substituted by one or more halo atoms; more preferably a fluoro atom.
  • Heterohydrocarbyl means a saturated or unsaturated mono cyclic or multi cyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is oxygen or sulphur and the other ring atoms are carbon.
  • exemplary heterohydrocarbyl groups include oxacycloalkyl, oxacycloalkenyl, cyclothioalkyl and cyclothioalkenyl groups as described below.
  • the heterohydrocarbyl is attached to Y by a direct bond or lower alkyl group.
  • Substituted heterohydrocarbyl means a heterohydrocarbyl group as described above substituted by one or more halo atoms; more preferably a fluoro atom.
  • Cycloalkyl means a non-aromatic mono cyclic or multi cyclic ring system of about 3 to about 10 carbon atoms.
  • the cyclic alkyl may be optionally partially unsaturated.
  • Preferred cyclic cycloalkyl rings include a cyclopentyl, cyclohexyl, cyclohexenyl and cycloheptyl groups; more preferred is a cyclopentyl group.
  • Preferred multicyclic cycloalkyl rings include a 1-decalin, adamant-(1- or 2-)yl and norbomanyl groups.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Preferred monocyclic cycloalkenyl rings include cyciopentenyl, cyclohexenyl and cycloheptenyl groups; more preferred is a cyciopentenyl group.
  • a preferred multicyclic cycloalkenyl ring is a norbomylenyl group.
  • the cycloalkenyl group is optionally substituted by one or more halo.
  • Oxacycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is oxygen and the other ring atoms are carbon. Preferred rings include about 5 to about 8 ring atoms.
  • the oxacycloalkenyl group may be substituted by one or more halo, groups; preferred is a fluoro group.
  • Exemplary monocyclic rings include tetrahydrofuranyl, fluorotetrahydrofuranyl and tetrahydropyranyl groups. Preferred is a tetrahydrofuranyl group.
  • Exemplary multicyclic cycloalkyl rings include 7-oxabicyclo[2.2.1]heptanyl and oxatricyclanyl groups.
  • Oxacycloalkenyl means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is oxygen and the other ring atoms are carbon and the ring system contains a carbon-carbon double bond.
  • Preferred rings include about 5 to about 8 ring atoms. Preferred rings have one ring atom which is oxygen.
  • the oxacycloalkenyl group may be substituted by one or more halo; preferred is a fluoro group.
  • Exemplary mono oxacycloalkenyl rings include dihydrofuranyl, fluorodihydrofuranyl and dihydropyranyl groups. Preferred is a dihydrofuranyl group.
  • An exemplary multicyclic oxacycloalkenyl ring is a 7-oxabicyclo[2.2.1]- heptenyl group.
  • Cyclothioalkyl means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon. Preferred rings include about 5 to about 6 ring atoms. Preferred rings have one ring atom which is sulfur.
  • the cyclothioalkyl may be optionally substituted by one or more halo. Exemplary cyclothioalkyl groups include tetrahydrothiophenyl and pentamethylensulfidyl groups.
  • the thio moiety of the cyclothioalkyl ring may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide.
  • "Cyclothioalkenyl” means a non-aromatic monocyclic or multicyclic ring system having about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon and the ring system contains a carbon-carbon double bond.
  • Preferred rings include about 5 to about 6 ring atoms and wherein one of the ring atoms is sulfur.
  • the cyclothioalkenyl may be optionally substituted by one or more halo.
  • Preferred monocyclic cyclothioalkyl rings include dihydrothiophenyl and dihydrothiopyranyl; more preferred is dihydrothiophenyl.
  • the thio moiety of the cyclothioalkyl may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide
  • Aromatic means aryl or heterocyclyl as defined below. Preferred aromatic groups include phenyl, halo substituted phenyl and azaheteroaryl.
  • Aryl means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms.
  • exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent” includes hydrogen, alkyl, alkoxy and halo.
  • Heterocyclyl means an about 5 to about 1Q member monocyclic or multicyclic ring system, which is aromatic or non-aromatic, wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulfur atoms.
  • Preferred heterocyclyl contain from about 5 to about 7 ring atoms.
  • the heterocyclyl is optionally substituted by one or more aryl group substituents.
  • Heteroaryl means the subclass of heterocyclyl groups that are aromatic.
  • heterocyclyl groups include quinuclidine, pyrrolidinyl, piperidinyl, cyclothioalkyl, cyclothioalkenyl, oxacycloalkyl and oxacycloalkenyl groups.
  • Heteroaryl means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • the heteroaryl may also be substituted by one or more aryl group substituents.
  • “Azaheteroaryl” means a subclass of heteroaryl wherein one or more of the atoms in the ring system is/are replaced by nitrogen.
  • heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, pyridazinyl, 1 ,2,4-triazinyl, quinolinyl, and isoquinolinyl.
  • Preferred heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl and isothiazolyl groups.
  • Preferred azaheteroaryl groups include (2-, 3- or 4-)pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and 1,2,4-triazinyl groups.
  • acyl means an H-CO-, alkyl-CO- group wherein the alkyl group is as previously described, aryi-CO- group wherein the aryl group is phenyl or naphthyl or heterocyclyl-CO- wherein the heterocyclyl is as previously described.
  • Preferred acyl have an alkyl containing 1 to about 3 carbon atoms in the alkyl group.
  • Exemplary groups include formyl, acetyl, propanoyl, 2- methylpropanoyl, butanoyl, benzoyl and 1- and 2-naphthoyl groups.
  • Arylacyr means an aryl-alkyl-CO- group wherein the aryl and alkyl groups are as previously described.
  • Heterocyclylacyi means an heterocyclyl-alkyl-CO- group wherein the heterocyclyl and alkyl groups are as previously described.
  • Alkoxy means an alkyl-O- group wherein the alkyl group is as previously described.
  • Lower alkoxy means a lower alkyl-O- group wherein the lower alkyl group is as previously described.
  • Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, Apropoxy, ⁇ -butoxy, heptoxy and decoxy groups.
  • Aryloxy means an aryl-O- group wherein the aryl group is as previously described.
  • Heterocyclyioxy means a heterocyclyl-O- group wherein the heterocyclyl group is as previously described.
  • Arylalkoxy means an aryl-alkyl-O- group wherein the aryl and alkyl groups are as previously described.
  • Heterocyclylalkoxy means an heterocyclyl-alkyl-O- group wherein the heterocyclyl and alkyl groups are as previously described.
  • Alkoxycarbonyl means an alkoxy-CO- group wherein the alkoxy group is as previously described.
  • Arylalkoxycarbonyl means an arylalkoxy-CO- group wherein the aryialkoxy group is as previously described.
  • Heterocyclylalkoxycarbonyl means an heterocyclylalkoxy-CO- group wherein the heterocyclylalkoxy group is as previously described.
  • Aryloxycarbonyl means an aryloxy-CO- group wherein the aryloxy group is as previously described.
  • Heterocyclyloxycarbonyl means a heterocyclyloxy-CO- group wherein the heterocyclyloxy group is as previously described.
  • Alkylthio means an alkyl-S- group wherein the alkyl group is as previously described.
  • Arylalkylthio means an arylalkyl-S- group wherein the arylalkyl group is as previously described.
  • Heterocyclylalkylthio means a heterocyclylalkyl-S- group wherein the heterocyclylalkyl group is as previously described.
  • Arylthio means an aryl-S- group wherein the aryl group is as previously described.
  • Heterocyclylthio means a heterocyclyl-S- group wherein the heterocyclyl group is as previously described.
  • Alkylsulphinyl means an alkyl-SO- group wherein the alkyl group is as previously described.
  • Arylalkylsulphinyl means an arylalkyl-SO- group wherein the arylalkyl group is as previously described.
  • Heterocyclylalkylsulphinyl means a heterocyclylalkyl-SO- group wherein the heterocyclylalkyl group is as previously described.
  • Arylsulphinyl means an aryl-SO- group wherein the aryl group is as previously described.
  • Heterocyclylsulphinyl means a heterocyclyl-SO- group wherein the heterocyclyl group is as previously described.
  • Alkylsulphonyl means an alkyl-S02- group wherein the alkyl group is as previously described.
  • Arylalkylsulphonyl means an arylalkyl-S02- group wherein the arylalkyl group is as previously described.
  • Heterocyclylalkylsulphonyl means a heterocyclyl-S02- group wherein the heterocyclylalkyl group is as previously described.
  • Arylsulphonyl means an aryl-S02- group wherein the aryl group is as previously described.
  • Heterocyclylsulphonyl means a heterocyclyl-S02- group wherein the heterocyclyl group is as previously described.
  • acyloxy means an acyl-O- group wherein the acyl group is as previously described.
  • Arylacyloxy means an arylacyl-O- group wherein the arylacyl group is as previously described.
  • Heterocyclylacyloxy means an heterocyclylacyl-O- group wherein the heterocyclylacyi group is as previously described.
  • Alkylcarbamoyloxy means an alkyl-NH-CO-O- group wherein the alkyl group is as previously described.
  • Arylalkylcarbamoyloxy means an arylalkyi-NH-CO-0- group wherein the arylalkyl group is as previously described.
  • Heterocyclylalkylcarbamoyloxy means a heterocyclylalkyl-NH-CO-O- group wherein the heterocyclylalkyl group is as previously described.
  • Arylcarbamoyloxy means an aryl-NH-CO-O- group wherein the aryl group is as previously described.
  • Heterocyclylcarbamoyloxy means a heterocyclyl-NH-CO-O- group wherein the heterocyclyl group is as previously described.
  • Halo means fluoro, chloro, bromo and iodo groups.
  • R is a substituted alkyl, acyl or carboxy group, or a group of formula
  • R is a hydrocarbyl group or substituted hydrocarbyl
  • R is a hydrogen atom
  • R is a hydrogen atom or an alkyl group
  • R is a hydrogen atom or an alkyl or alkoxy group
  • R and R are hydrogen atoms
  • R is a hydrogen atom
  • R is an amino or ethoxy group
  • R 13 , R 14 , R 5 and R 16 are hydrogen atoms
  • X and Y are oxygen atoms.
  • R is a hydroxy substituted alkyl group
  • R1 s a halo substituted lower alkyl group
  • R1 s a fluoro substituted lower alkyl group
  • R1 s a fluoro substituted methyl group
  • R1 s a methyl group
  • R2 s a cyclopentyl or cyclothiopentyl group
  • R2 s a cyclopentyl group
  • X is an oxygen atom
  • Y is an oxygen atom.
  • Preferred compounds for use according to the invention are selected from the following:
  • R, R 1 , R 2 , R 13 , R 14 , R 15 and R 16 are as described above.
  • a sulphoxonium salt e.g. trimethylsulphoxonium iodide
  • a base e.g. sodium hydride
  • a dry solvent e.g. dimethyl sulphoxide
  • compounds of general formula I are prepared by interconversion of other compounds of genera! formula I.
  • R is a straight- or branched-chain alkyl group containing up to about 10 carbon atoms, optionally substituted by an aryl or heterocyclyl group, or an aryl or heterocyclyl group, R is a subclass of R wherein the
  • R 12a 12 alkyl portion thereof contains up to 5 carbon atoms
  • R is a subclass of R , i.e., R 12a is amino, aikylamino, dialkylamino or hydroxyamino
  • m is 1 or 2.
  • the preparation of lb from la preferably takes place by means of reaction with a base, for example an alkali metal alkoxide, e.g. potassium t-butoxide, preferably in the presence of water and a suitable solvent, e.g. diethyl ether, from about room temperature to about 100°C.
  • a base for example an alkali metal alkoxide, e.g. potassium t-butoxide, preferably in the presence of water and a suitable solvent, e.g. diethyl ether, from about room temperature to about 100°C.
  • the preparation of lc from la preferably takes place by means of reduction by a metal hydride, e.g. diisobutylaluminium hydride, preferably in a solvent such as tetrahydrofuran, from about -78°C to room temperature, e.g. from about -40°C to about 0°C
  • a metal hydride e.g. diisobutylaluminium hydride
  • a solvent such as tetrahydrofuran
  • the preparation of lb from lc preferably takes place by means of oxidation, for example by reaction with sodium chlorite, preferably buffered to about pH4 (for example using sodium dihydrogen phosphate buffer), preferably at temperatures from about 0°C to room temperature.
  • This reaction preferably employs lc wherein X and Y are oxygen atoms, and R is an alkyl, alkenyl, halo substituted alkyl or halo substituted alkenyl, hydrocarbyl, substituted hydrocarbyl, oxygen or nitrogen containing heterohydrocarbyl or oxygen or nitrogen containing substituted heterohydrocarbyl.
  • the preparation of Id from la preferably takes place by reaction with a compound of formula R Li or R MgBr, wherein R is described above, in an ethereal solvent such as diethyl ether or tetrahydrofuran, from about -50°C to about room temperature, e.g. from about 0°C to about 10°C.
  • an ethereal solvent such as diethyl ether or tetrahydrofuran
  • the preparation of If from lb preferably takes place by reaction with chlorosulphonyl isocyanate, preferably in a solvent such as dimethylformamide, preferably at temperatures from about 0°C to about room temperature.
  • the preparation of lg from lc preferably takes place by the application or adaptation of known methods for preparing oximes from aldehydes, for example by reaction with hydroxylamine hydrochloride in a solvent such as ethanol, in the presence of a base such as pyridine, from about room temperature to about 100°C, e.g. from about the reflux temperature.
  • the preparation of Ih from lc preferably takes place by means of reduction by a metal hydride, e.g. sodium borohydride, preferably in a solvent such as ethanol, from about 0°C to about 80°C, e.g. at about room temperature.
  • a metal hydride e.g. sodium borohydride
  • solvent such as ethanol
  • the preparation of II from Ih preferably takes place by means of esterification, for example by reaction with an acid anhydride of formula (R 17 CO)2 ⁇ , preferably in the presence of a base such as
  • 4-dimethylaminopyridine preferably in a solvent such as ethyl acetate, at temperatures from about 0°C to about 80°C, e.g. at about room temperature.
  • the preparation of Iq from Ih preferably takes place by means of reaction with compounds of formula R -NCO, with the aid of a base, for example an alkali metal alkoxide, e.g. potassium t-butoxide, preferably in a solvent such as tetrahydrofuran, from about 0°C to about room temperature.
  • a base for example an alkali metal alkoxide, e.g. potassium t-butoxide, preferably in a solvent such as tetrahydrofuran, from about 0°C to about room temperature.
  • the preparation of lo from Id preferably takes place by reaction with a compound of formula R Li or R MgBr in an ethereal solvent such as dieth ether or tetrahydrofuran, from about -50°C to about room temperature.
  • the preparation of Iba from lc preferably takes place by conversion of lc to a compound of the .
  • general formula ACH CH2, wherein A is as hereinbefore defined, preferably by reaction with a methyltriarylphosphonium halide, preferably a bromide, e.g.
  • methyltriphenylphosphonium bromide in the presence of a base such as butyllithium, preferably in a solvent such as tetrahydrofuran, preferably below about 5°C, followed by conversion to Iba, preferably by reaction with borane, preferably in a solvent such as tetrahydrofuran, followed by reaction with an oxidizing agent such as hydrogen peroxide in the presence of a base such as sodium bicarbonate, preferably in a solvent system such as aqueous ethanol.
  • a base such as butyllithium
  • a solvent such as tetrahydrofuran
  • an oxidizing agent such as hydrogen peroxide
  • X and Y are oxygen atoms
  • R is an alkyl, halo substituted alkyl, saturated hydrocarbyl, substituted saturated hydrocarbyl, saturated oxygen or nitrogen containing heterohydrocarbyl or substituted saturated oxygen or nitrogen containing heterohydrocarbyl group.
  • methyltriphenylphosphonium chloride in the presence of a base such as phenyllithium, preferably in a solvent such as tetrahydrofuran, preferably below about 5°C, followed by conversion to ACH2COH by treating with aqueous acid, such as hydrochloric acid, in an inert solvent, and then converting to Iba, by reducing by a metal hydride, e.g. sodium borohydride, preferably in a solvent such as ethanol, from about 0°C to about 80°C, e.g. at about room temperature.
  • a base such as phenyllithium
  • solvent such as tetrahydrofuran
  • the preparation of ly from lb preferably takes place by reaction with ammonia with the aid of an acid activating agent, e.g. oxalyl chloride, from about 0°C to about room temperature.
  • the preparation of lu from lb preferably takes place by reaction with an acid activating agent, e.g. oxalyl chloride, followed by sodium azide, followed by a compound of formula R 17 OH, from about 50°C to about 120°C, e.g., at about 90°C.
  • the preparation of Ir from lb preferably takes place by reaction with an acid activating agent, e.g. oxalyl chloride, followed by sodium azide, followed by ammonia, from about 50°C from about 120°C, e.g., at about 90°C.
  • an acid activating agent e.g. oxalyl chloride, followed by sodium azide, followed by ammonia
  • the preparation of It from laa preferably takes place by reaction with compounds of formula R 17 S ⁇ 2CI in the presence of a base such as triethylamine, preferably in a solvent such as dichloromethane, from about 0°C to about 80°C.
  • a base such as triethylamine
  • a solvent such as dichloromethane
  • the preparation of Iw from laa preferably takes place by reaction with the appropriate 3,4-diethoxycyclobut-3-ene-1,2-dione, preferably in a solvent such as ethanol, from about 0°C to about 80°C, e.g. at about room temperature.
  • a solvent such as ethanol
  • the preparation of Is from laa preferably takes place by means of reaction with an acid anhydride of formula (R 17 CO)2 ⁇ , preferably in the presence of a base such as 4-dimethylamino-pyridine, in a solvent such as ethyl acetate, at about 0"C to about 100°C, e.g. room temperature.
  • a base such as 4-dimethylamino-pyridine
  • the preparation of Ii from Id preferably takes place by the application or adaptation of known methods for preparing oximes from ketones, for example by reaction with hydroxylamine hydrochloride in a solvent, in the presence of a base such as pyridine, at room temperature to about 100°C.
  • the preparation of le from lb preferably takes place by means of esterif iiccaattiioonn bbyy ccoommppoouunnddss ooff ffoorrmmuullaa RR OOHH pprreeffeerraatbly in the presence of an acid, e.g. concentrated hydrochloric acid, e.g. at reflux.
  • an acid e.g. concentrated hydrochloric acid, e.g. at reflux.
  • the preparation of Ij from lc preferably takes place by reaction with compounds of formula R 17 NH2, with the aid of a reducing agent such as sodium cyanoborohydride, at or near pH5.
  • a reducing agent such as sodium cyanoborohydride
  • the preparation of Im from Ij preferably takes place by reaction with an acid anhydride of formula (R 17 CO)2 ⁇ , preferably in the presence of a base.
  • the preparation of In from Ik preferably takes place by oxidation.
  • m is 2
  • the desired product is a sulphone
  • the oxidation preferably takes place by reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
  • a peroxyacid e.g. 3-chloroperbenzoic acid
  • an inert solvent e.g. dichloromethane
  • the oxidation preferably takes place by reaction with sodium periodate, preferably in a solvent system such as aqueous methanol, preferably from about 0°C to about room temperature.
  • a solvent system such as aqueous methanol, preferably from about 0°C to about room temperature.
  • These reactions preferably employs Ik wherein X and Y are oxygen atoms, and R is an alkyl, halo substituted alkyl, saturated hydrocarbyl, substituted saturated hydrocarbyl, saturated oxygen or nitrogen containing heterohydrocarbyl or substituted saturated oxygen or nitrogen containing heterohydrocarbyl group.
  • the oxidation is carried out by reaction with a peroxomonosulphate, e.g. potassium peroxomonosulphate, conveniently in a solvent such as methanol, buffered to about pH5, from about 0°C to about room temperature and the progress of the reaction may be monitored so as to arrange for the production of sulphone or sulphoxide, as desired.
  • a peroxomonosulphate e.g. potassium peroxomonosulphate
  • This reaction preferably employs Ik wherein X and Y are oxygen atoms, and R is an alkyl, halo substituted alkyl, hydrocarbyl, substituted hydrocarbyl, oxygen or nitrogen containing heterohydrocarbyl or substituted oxygen or nitrogen containing heterohydrocarbyl group.
  • the preparation of lae from lb preferably takes place by reaction with compounds of formula R 17 NH2, with the aid of an acid activating agent and a base, from about 0°C to about room temperature.
  • the preparation of laf from lb preferably takes place by reaction with compounds of formula (R 17 )2NH with the aid of an acid activating agent and a base, from about 0°C to about room temperature.
  • lac from lb preferably takes place by means of compounds of formula R 17 NH2, an acid activating agent and sodium azide, from about 50 * C to about 120°C.
  • the preparation of lad from lb preferably takes place by means of compounds of formula (R 17 )2NH, an acid activating agent and sodium azide, from about 50 * C to about 120°C.
  • the preparation of lab from laa preferably takes place by means of a formylating agent, for example an aryl formate, e.g. phenyl formate, preferably in a solvent such as diethyl ether, from about 0°C to about room temperature.
  • a formylating agent for example an aryl formate, e.g. phenyl formate, preferably in a solvent such as diethyl ether, from about 0°C to about room temperature.
  • the preparation of Iz from laa preferably takes place by means of an acid activating agent, oxalic acid and a base, from about 0°C to about room temperature, and by means of an acid activating agent, a compound of formula R H, and a base, from about 0°C to about room temperature.
  • R 17 in laq represents a straight- or branched-chain alkyl group containing up to about 10 carbon atoms, optionally substituted by an aryl or heterocyclyl group, preferably takes place by means of a reducing agent, such as lithium aluminium hydride, preferably in a solvent such as tetrahydrofuran, preferably from about -78'C to about room temperature.
  • a reducing agent such as lithium aluminium hydride
  • solvent such as tetrahydrofuran
  • R 17 represents an aryl or heterocyclyl group
  • a compound R 17 -Hal wherein Hal represents a halo, preferably fluoro, atom, preferably In the presence of a base, such as an alkali metal carbonate, e.g. potassium carbonate, preferably in a solvent such as dimethylformamide, preferably from about 0°C to about 100°C.
  • a base such as an alkali metal carbonate, e.g. potassium carbonate
  • a solvent such as dimethylformamide
  • the preparation of Ian from lag preferably takes place by means of compounds of formula R OCOCI in the presence of a base.
  • the preparation of lap from lag preferably takes place by means of compounds of formula R NCO in the presence of a base.
  • the preparation of lah from lag preferably takes place by means of compounds of formula (R 17 CO)2 ⁇ in the presence of a base.
  • the preparation of lai from lag preferably takes place by means of compounds of formula R 17 S ⁇ 2CI in the presence of a base.
  • the preparation of lam from lag preferably takes place by means of a formylating agent, for example an aryl formate, e.g. phenyl formate, preferably in a solvent such as diethyl ether, from about 0°C to about room temperature.
  • a formylating agent for example an aryl formate, e.g. phenyl formate, preferably in a solvent such as diethyl ether, from about 0°C to about room temperature.
  • the preparation of lal from lag preferably takes place by means of an acid activating agent, oxalic acid and a base, from about 0°C to about room temperature, followed by an acid activating agent, a compound of formula R H, and a base, from about 0°C to about room temperature.
  • the preparation of laj from lag preferably takes place by reaction with 3,4-diethoxycyclobut-3-ene-1 ,2-dione, preferably in a solvent such as ethanol, from about 0°C to about 80°C, e.g. at about room temperature.
  • the preparation of lak from laj preferably takes place by reaction with
  • R H a compounds of formula R H, where R 12 is other than ethoxy, preferably in a
  • SUBSTITUTE SHEET RULE 26 solvent such as ethanol and/or tetrahydrofuran, from about 0°C to about 80°C, e.g. at about room temperature.
  • the preparation of lao from lag preferably takes place by reaction with urea from about 100°C to about 175°C.
  • compounds of general formula I are prepared by other interconversions of other compounds of general formula I.
  • the compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention. Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free base are not vitiated by side effects ascribable to the anions.
  • pha ⁇ naceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and suifamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid.
  • the corresponding acid addition salts comprise the following: hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • hydrohalides e.g. hydrochloride and hydrobromide
  • acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non- toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free acid are not vitiated by side effects ascribable to the cations.
  • salts including for example alkali and alkaline earth metal salts, especially sodium salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
  • Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound.
  • the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
  • Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound.
  • Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
  • the base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • some of the compounds of this invention do not form stable salts, for example compounds containing an acid-labile group, such as those wherein the moiety R contains a carbon-carbon double bond , e.g. a cyclopent-2-enyl group.
  • Acid addition salts are most likely to be formed by compounds of this invention wherein a nitrogen-containing heterocyclyl group and/or an amino group is present.
  • Preferable acid addition salts of the compounds of the invention are those wherein R 2 is other than an acid labile group.
  • salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • Geometrical isomers include the cis and trans forms of compounds of the invention.
  • Compounds of the present invention may contain asymmetric centers.
  • Optical isomers, i.e., compounds having asymmetric centers, may independently be in either the R or S configuration.
  • Within the scope of the present invention are the individual geometrical isomers and stereoisomers and mixtures thereof. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
  • compounds of formula III can be prepared from compounds of general formula V,
  • reaction mixture is then treated with dilute hydrochloric acid (50mL; 2 N), followed by water (300 mL), and ethyl acetate (200 mL).
  • the layers are thoroughly stirred, and then separated, and the aqueous phase is extracted with further quantities of ethyl acetate (2x200 mL).
  • the combined organic layers are dried over sodium sulphate and solvent is removed under reduced pressure.
  • This oil is subjected to flash chromatography on silica gel, using a mixture of toluene and ethyl acetate (3:1v/v) as eluent, to give ( ⁇ )-trans-2-(3-cyclopentyloxy-4- methoxyphenyl)cyclopropanecarbaldehyde oxime (0.5 g), in the form of a cream solid, m.p. 105-107°C. [Elemental analysis:- C,69.7;H,7.7;N,4.76%; calculated:- C,69.79;H,7.69;N,5.09%].
  • a solution of methyltriphenylphosphonium bromide (7.8 g) in dry tetrahydrofuran at 0°C under nitrogen is treated dropwise with a solution of butyllithium in hexanes (2.5 M; 8.8 mL), maintaining the temperature at below 5°C.
  • the resulting mixture is stirred at this temperature for 30 minutes, and then it is allowed to warm to room temperature, and stirred for a further 30 minutes. It is then treated with a solution of ( ⁇ )-trans-2-(3-cyclopentyloxy-4- methoxy-phenyl)cyclopropanecarbaldehyde (5.2 g) in dry tetrahydrofuran (75 mL), dropwise, and the resulting mixture is stirred overnight.
  • the mixture is then treated with glacial acetic acid (0.5 mL) in dry tetrahydrofuran (5 mL), and partitioned between a mixture of cyclohexane and diethyl ether (1:1v/v; 150 mL) and saturated aqueous sodium bicarbonate solution (75 mL).
  • the layers are thoroughly shaken and separated and the aqueous phase is extracted further with a mixture of cyclohexane and diethyl ether (1:1v/v; 100 mL).
  • reaction mixture is allowed to warm to room o temperature and stirred for 17 hours, and then it is stirred at 50 C for 2 hours.
  • the solution is then cooled to room temperature, diluted with diethyl ether (1000 mL), and washed with aqueous sodium hydroxide solution (1 M;
  • N.O-dimethylhydroxylamine hydrochloride (6.50 g) and pyridine (10.8 mL) in dry chloroform and the resulting mixture is left to stand under nitrogen overnight.
  • the resulting orange solution is treated with a further quantity of chloroform (100 mL). It is then washed with saturated aqueous cupric sulphate solution (2x100 mL) and dried over sodium sulphate, and the solvent is removed under reduced pressure.
  • a solution of 3-hydroxy-4-methoxybenzaldehyde (100 g) arid cyclopentyl bromide (81 mL) in dimethyl fqrmamide (610 mL) is treated with potassium carbonate (139.73 g), and the mixture is stirred at 55-65°C for 21 hours. After cooling, the bulk of the dimethylformamide is evaporated in vacuo, and the residue is treated with aqueous sodium hydroxide solution (1000 mL; 7.5%w/v).
  • the compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors.
  • the present invention provides compounds of formula I, and compositions containing compounds of formula I, which are of use in a method for the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase.
  • compounds within the present invention are useful as bronchodilators and asthma-prophylactic agents and agents for the inhibition of eosinophil accumulation and of the function of eosinophils, e.g.
  • inflammatory airways disease especially reversible airway obstruction or asthma
  • other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
  • inflammatory diseases such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatic arthritis, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome and diabetes insipidus
  • proliferative skin diseases such as keratosis and various types of dermatitis
  • conditions associated with cerebral metabolic inhibition such as cerebral senility, multi- infarct dementia, senile dementia (Alzheimer's disease), and memory impairment associated with Parkinson's disease
  • neuroprotectant activity such as cardiac arrest, stroke, and intermittent claudication.
  • the compounds are also inhibitors of tumor necrosis factor, especially
  • the present invention provides compounds of formula I, and compositions containing compounds of formula I, which are of use in a method for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of TNF-alpha.
  • compounds of the present invention are useful in joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis.
  • the compounds are useful in treatment of sepsis, septic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, asthma and other chronic pulmonary diseases, bone resorption diseases, reperfusion injury, graft vs. host reaction and allograft rejection.
  • the compounds are useful in the treatment of infections such as viral infections and parasitic infections, for example malaria such as cerebral malaria, fever and myalgias due to infection, HIV, AIDS, cachexia such as cachexia secondary to AIDS or to cancer.
  • infections such as viral infections and parasitic infections
  • malaria such as cerebral malaria, fever and myalgias due to infection, HIV, AIDS, cachexia such as cachexia secondary to AIDS or to cancer.
  • Other disease states that may be treated with the compounds of the present invention include Crohn's disease, ulcerative colitis, pyresis, systemic lupus erythematosus, multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease and leukemia.
  • a special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase or of TNF, especially TNF-alpha, for example conditions as hereinbefore described which comprises the administration to the patient of an effective amount of compound of formula I or a composition containing a compound of formula I.
  • Effective amount is meant to describe an amount of compound of the present invention effective in inhibiting cyclic AMP phosphodiesterase and/or TNF and thus producing the desired therapeutic effect.
  • the present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I in association with a pharmaceutically acceptable carrier or coating.
  • compounds of the present invention may generally be administered parenterally, rectally or orally, but they are preferably administered by inhalation.
  • compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine.
  • compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • the choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the product, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • emulsions, suspensions or solutions of the products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • aqueous-organic solutions such as water and propylene glycol
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration.
  • compositions containing the compounds of the invention may be prepared by conventional means.
  • compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
  • the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
  • several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient.
  • the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration.
  • the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • the products according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • aortas of freshly slaughtered pigs are placed in Hepes buffered krebs solution, extraneous tissue on the outside of the aorta is trimmed off and the endothelial layer on the intimal surface is removed by rubbing with a cotton swab. Smooth muscle strips are plucked from the aorta and 25 g are homogenized using a Waring Blender in homogenization buffer (20 mM Tris/HCI, pH 7.5, 2 mM MgCl2, 1 mM dithiothreitol, 5 mM EDTA and 1mg/ml aprotinin).
  • the homogenate is further homogenized with an Ultra- Turrax and then centrifuged (3000 g, 5 minutes). The supernatant is removed, and the pellet is sonicated in a small volume (25-50 mL) of homogenization buffer. The sonicate is centrifuged (3000 g, 5 minutes), the pellet discarded and the supernatant is pooled with that from the first centrifugation step.
  • the pooled supernatants are centrifuged (100,000 g, 1 hour), the resulting high ⁇ speed supernatant is filtered (0.45 ⁇ m) and then applied to a DEAE-trisacryl (IBF) column (50 x 2.44 cm) preequilibrated in column buffer (20 mM Tris/HCI, pH 7.5, 2 mM MgCl2, 1 mM dithiothreitol, 20 ⁇ M TLCK).
  • the column is washed with 500-700 mL of column buffer and PDE activities are eluted with 2 successive linear gradients of NaCl (0-200 mM, 400 mL and 200-300 mM, 200 mL) in column buffer.
  • the fractions in the separated peaks of activity corresponding to the different PDE isozymes are pooled and stored at -20°C in 30% (v/v) ethylene glycol.
  • PDE activity is determined by the two-step radioisotopic method of Thompson et al., Adv. Cyclic Nucl. Res.. 10. 69-92 (1979).
  • the reaction mixture contains 20 mM Tris/HCI (pH 8.0), 10 mM MgCl2, 4 mM 2- mercaptoethanol, 0.2 mM EGTA and 0.05 mg of BSA/mL
  • the concentration of substrate is 1 ⁇ M.
  • the IC50 values for the compounds examined are determined from concentration-response curves in which concentrations range from 0.1 nM to 40 ⁇ M. 1.3 Results.
  • PDE IV porcine aortic cyclic AMP-specific phosphodiesterase
  • concentrations from about 10" 9 M up to about 10" 5 M, preferably from about 10 *9 up to about 10" 8 M.
  • the compounds of the invention are from about 10,000-fold to about 50-fold more selective for cyclic AMP phosphodiesterase IV than cyclic nucleotide phosphodiesterase types I, III or V.
  • Superoxide anion generation is determined as the superoxide dismutase inhibitable reduction of p-iodonitrotetrazolium violet (INTV) (Souness et al, Biochem. Pharmacol. 42. 937-945, 1991). Briefly, cells are incubated in 96 well microtitre plates in 0.25 mL of Hanks buffered salt solution (HBSS) containing INTV (0.5mg/mL) plus other additions for 45 minutes at 37°C. The cells are then centrifuged at 500 g for 5 minutes and the supernatant is aspirated. The pellet is solubilized by incubation overnight at room temperature in DMSO containing 0.6 M HCI and the absorbance of the reduced dye is measured at 492 nm. The results are expressed in absorbance units.
  • HBSS Hanks buffered salt solution
  • INTV 0.5mg/mL
  • Compounds within the scope of the invention produce up to about 50% inhibition of superoxide generation from eosinophiis harvested from the peritoneal cavities of guinea-pigs at concentrations from about 10 ⁇ 8 M to about 10 -5 M, preferably from about 10 "8 M up to about 10 "7 M. 3. Effects of compounds on tracheal smooth muscle contractility.
  • tracheas are removed from male, Dunkin-Hartley guinea-pigs (400-500 g) are placed in Krebs Ringer Bicarbonate (KRB) solution and fat and connective tissue are dissected away. Epithelium is removed by mechanical abrasion and the tracheal strips are suspended under an applied load, such that they are at their optimal length, derived from preliminary experiments, and equilibrated for 90 minutes, washing at 15 minute intervals.
  • KRB Krebs Ringer Bicarbonate
  • Cumulative concentration-response curves to spasmogens are constructed and the concentration producing 30% of maximum contraction (EC30) is determined by computerized linear regression analysis.
  • tissue are contracted with spasmogens (such as methacholine, histamine, leukotriene D4) (EC30) and when the response plateaus, PDE inhibitors (10 nM-100 ⁇ M) or vehicle control (DMSO) are added cumulatively.
  • the concentration of relaxant producing 50% inhibition (IC50) of the agonist response is calculated by linear regression.
  • PDE inhibitors, as above may be added to tissues under basal tone and the concentration producing 50% relaxation (EC50) calculated as above.
  • Compounds within the scope of the invention produce about 50% relaxation of guinea-pig tracheal strips (under basal tone or which had been contracted by treatment with spasmogens) at concentrations from about 5x10 '9 M to about 10 "5 M, preferably from about 5x10 "9 M to about 10 -7 M.
  • Bronchorelaxant activity is measured in in vivo tests in the anaesthetized guinea-pig or rat according to the method described in Underwood et al., Pulm. Pharmacol. 5. 203-212, (1992) in which the effects on bronchospasm induced by histamine (or other spasmogens such as methacholine or leukotriene D4) is determined.
  • Nebulized aerosols generated from aqueous solutions of compounds of the invention are each administered for one minute to the anaesthetized animals.
  • dry powder formulations made up from compounds of the invention and lactose are blown into the airways of the anaesthetized guinea-pigs or rats by the method described in Underwood et al., J. Pharm. Methods. 26. 203-210, 1991.
  • Compounds within the scope of the invention produce from about 30% up to about 90% decrease in bronchospasm when administered at effective doses of about 4 to about 1000 ⁇ g/kg, preferably about 4 to about 50 ⁇ g/kg, without any significant effect on blood pressure.
  • PBMs peripheral blood monocytes
  • Blood is drawn from normal donors, mixed with dextran, and the erythrocytes allowed to sediment for 35 minutes at 37°C.
  • Leukocytes are fractionated by centrifugation through a discontinuous (18, 20 and 22%) metrizamide gradient.
  • the mononuclear cell fraction comprising 30-40% PBMs is suspended in HBSS and stored at 4°C until use.
  • Cells from the PBM-rich metrizamide fraction are spun down (200 g for 10 minutes at 20°C), resuspended at 10 6 PBMs/mL of medium; R ' PMI 1640 containing 1%v/v FCS, 50 U/mL penicillin and 50 mg/mL streptomycin (Gibco, U.K.), then plated out in 96 well plates at 2x10 5 cells/well.
  • the medium (200 ⁇ L) is changed to remove any non-adherent cells and the remaining, adherent PBMs left in the incubator overnight (18 hours). One hour prior to challenge, the medium is changed to that containing compound for test or drug vehicle. Control treatments and compounds for test are assayed in quadruplicate wells.
  • TNFalpha levels in cell supernatants are quantified using a standard sandwich ELISA technique.
  • ELISA plates (Costar, U.K.) are coated overnight at 4°C with 3 mg/mL polyclonal goat anti-human TNFalpha antibody (British Biotechnology, U.K.) in pH 9.9 bicarbonate buffer.
  • Rabbit polyclonal anti- human TNFalpha antiserum (Janssen Biochimicha, Belgium) at 1/500 dilution is used as the second antibody and polyclonal goat anti-rabbit IgG horseradish peroxidase (Caibiochem, U.S.A.) at 1/8000 dilution is used as the detection antibody.
  • Color development is measured by absorbance at 450 nm using a Titertek plate reader.
  • TNFalpha levels are calculated by interpolation from a standard curve using recombinant human TNFalpha (British Biotechnology U.K.)(0.125-8 ng/mL). Data (log-cone. vs. log-resp) are fitted by linear regression (p > 0.99) using a Multicalc (Wallac Pharmacia, U.K.) software program. Basal TNFalpha levels are less than 100 pg/mL whilst LPS stimulation of the PBMs increases TNFalpha levels to 3-10 ng/mL.
  • Compounds within the scope of the invention produce 50% inhibition of LPS-induced TNFalpha release from human PBMs at concentrations within the range of about 10 -9 M to about 10 "6 M., preferably about 10 -9 M to about 10 _8 M. 6.
  • Sensitized guinea-pigs are anaesthetised and dry powder formulations of PDE inhibitors or lactose are administered (i.t.) into the airways. In some cases PDE inhibitors are administered orally. 23 hours later the procedure is repeated and 60 minutes later the guinea-pigs are challenged with nebulised saline or ovalbumin (1% in saline) for 15 seconds. 24 hours after challenge the guinea-pigs are killed and the lungs are lavaged with warm saline. Total and differential cell counts are made.
  • Compounds within the scope of the invention administered one hour before challenge, inhibit by at least 50% ovalbumin-induced eosinophilia in guinea-pigs which is measured 24 hours after challenge, at oral doses of about 1 to about 50 mg/kg, preferably about 1 to 10 mg/kg and inhaled doses of about 4 to 1000 ⁇ g/kg, preferably.4 to 50 ⁇ g/kg.
  • SRaw Specific airways resistance
  • Test compounds or vehicle (lactose carrier) are instilled into the airways as dry powders through a metal gavage needle. 30 minutes later, the animals are injected with mepyramine (30 mg/kg i.p.) to prevent anaphylactic collapse and placed into the plethysmography chambers where SRaw is determined at 1 minute intervals. Resting SRaw is then determined. Animals are challenged with an aerosol of ovalbumin and SRaw is determined every 5 minutes for 15 minutes.
  • Compounds within the scope of the invention inhibit antigen-induced bronchoconstriction by up to 80% at doses of between about 1 to about 1000 ⁇ g kg (i.t.), preferably about 1 to about 20 ⁇ g/kg (i.t.).
  • mice Female Balb/c mice (age 6-8 weeks, weight 20-22 g from Charles River, U.K.) in groups of five or more animals are dosed p.o. with compounds suspended in 1.5% (w/v) carboxymethyl cellulose then challenged after a minimum period of 30 min with 30 mg of LPS i.p. After 90 min the animals are killed by CO2 asphyxiation and bled by cardiac puncture. Blood is allowed to clot at 4°C, centrifuged (12,000 g for 5 minutes) and serum taken for TNFalpha analysis.
  • TNFalpha levels are measured using a commercially available murine
  • TNFalpha ELISA kit purchased from Genzyme (Cat. no. 1509.00 ), as recommended by the manufacturer. Values for TNFalpha are calculated from a recombinant murine TNFalpha standard curve.
  • Compounds within the scope of the invention inhibit LPS-induced serum TNFalpha at doses between about 10 and about 10,000 mg/kg, preferably about 10 to about 250 ⁇ g/kg.
  • the following Composition Examples illustrate pharmaceutical compositions according to the present invention.
  • No. 2 size gelatin capsules each containing:

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Abstract

L'invention concerne des dérivés substitués de phénylcyclopropane portant différents substituants sur le noyau de cyclopropane, des procédés servant à leur préparation, des compositions pharmaceutiques les contenant, ainsi que des procédés d'utilisation desdits dérivés dans le traitement d'états pathologiques, par exemple, des maladies associées à des protéines médiatrices de l'activité cellulaire, par exemple, par inhibition du facteur de nécrose tumorale et/ou de la phosphodiestérase cyclique de AMP.
PCT/GB1994/001189 1993-06-01 1994-06-01 COMPOSES DE PHENYLCYCLOPROPANE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE cAMP ET DE TNF WO1994027947A1 (fr)

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