WO2009019506A1 - Heterocyclyc sulfonamides having edg-1 antagonistic activity - Google Patents

Heterocyclyc sulfonamides having edg-1 antagonistic activity Download PDF

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Publication number
WO2009019506A1
WO2009019506A1 PCT/GB2008/050650 GB2008050650W WO2009019506A1 WO 2009019506 A1 WO2009019506 A1 WO 2009019506A1 GB 2008050650 W GB2008050650 W GB 2008050650W WO 2009019506 A1 WO2009019506 A1 WO 2009019506A1
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Prior art keywords
6alkyl
formula
compound
pharmaceutically acceptable
methyl
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PCT/GB2008/050650
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French (fr)
Inventor
Edward Hennessy
Danyang Li
Vibha Oza
Gurmit Grewal
Jamal Carlos Saeh
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009019506A1 publication Critical patent/WO2009019506A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Edg endothelial differentiation gene receptors belong to a family of closely related, lipid activated G-protein coupled receptors.
  • Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 are identified as receptors specific for sphingosine-1 -phosphate (SIP).
  • Edg-2, Edg-4, and Edg-7 are receptors specific for lysophosphatidic (LPA).
  • Edg-1, Edg-3 and Edg-5 are widely expressed in various tissues, whereas the expression of Edg-6 is confined largely to lymphoid tissues and platelets, and that of Edg- 8 to the central nervous system.
  • Edg receptors are responsible for signal transduction and are thought to play an important role in cell processes involving cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. Certain Edg receptors are associated with diseases mediated by the de novo or deregulated formation of vessels — for example, for diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis; and haemangioblastomas such as "strawberry- marks”.
  • retinopathies diabetic retinopathy, age-related macular degeneration
  • psoriasis psoriasis
  • haemangioblastomas such as "strawberry- marks”.
  • Edg receptors are also associated with various inflammatory diseases, such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases or by lymphocyte interactions, for example, in transplantation rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer.
  • An alteration in Edg receptor activity contributes to the pathology and/or symptomology of these diseases.
  • molecules that themselves alter the activity of Edg receptors are useful as therapeutic agents in the treatment of such diseases. Accordingly, the present invention provides a compound of formula (I):
  • Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 4 ;
  • R 1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ aUcyl, C 2 - 6 alkenyl, C 2-6 alkynyl, Ci_ 6 alkoxy, hydrazinyl, ureido, N, N-di(Ci. 3 alkyl)ureido, ⁇ /-(Ci.
  • R 2 is selected from Ci_6alkyl or carbocyclyl; wherein R 2 may be optionally substituted on carbon by one or more R 7 ;
  • Ring D is fused to the imidazole of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 10 ;
  • R 3 is a substituent on carbon and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, ⁇ /-(Ci-6alkyl)amino, N,N-(C 1-6 alkyl) 2 amino, Ci-6alkanoylamino, ⁇ /-(Ci-6alkyl)carbamoyl, ⁇ /, ⁇ /-(Ci.6alkyl)2carbamoyl, Ci.6alkylS(O) a wherein a is 0 to 2, Ci_6alkoxycarbonyl, heterocyclylcarbonyl, N-(C i -6 alkyl)sulphamoyl, N 1 N-(C i -6 alkyl) 2 s
  • R 3 6 alkylsulphonylamino, carbocyclyl or heterocyclyl, or two R 3 may together with the carbon atoms of ring D to which they are attached form a 5 to 8-membered carbocyclyl or heterocyclyl ring; wherein R 3 may be optionally substituted on carbon by one or more R 11 ; and wherein if said heterocyclyl or heterocyclyl ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 12 ; m is 0-5; wherein the values of R 3 may be the same or different;
  • R 5 and R 11 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, Ci_6alkoxy, Ci_6alkanoyl, Ci_6alkanoyloxy, ⁇ /-(Ci-6alkyl)amino, ⁇ /, ⁇ /-(Ci-6alkyl) 2 amino,
  • R 4 , R 6 , R 9 , R 10 , R 12 and R 14 are independently selected from Ci -6 alkyl, Ci -6 alkanoyl, C i _6alkylsulphonyl, C i -6 alkoxycarbonyl, carbamoyl, TV-(C i -6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
  • R 7 is selected from halo, nitro, hydroxy, amino, carboxy, mercapto, sulphamoyl, C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, ⁇ -(d-ealky ⁇ amino, TVTV-(Ci -6 alkyl) 2 carbamoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, Ci -6 alkoxycarbonyl,
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. For example, “C h alky! and include methyl, ethyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. A similar convention applies to other radicals. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
  • a “heterocyclyl” is a saturated, partially saturated or fully unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a Ci_ 6 alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the TV-oxide and or the S-oxides.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, ⁇ /-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine- ⁇ /-oxide and quinoline-7V-oxide.
  • a “heterocyclyl” is a saturated, partially saturated or fully unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “carbocyclyl” is a saturated, partially saturated or fully unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • C3_6carbocyclic ring is a saturated monocyclic carbon ring that contains 3-6 carbon atoms wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Suitable values for "C 3- 6 carbocyclic ring” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Ring D is fused to the imidazole of formula (I), formula (Ia) or formula (Ib) and is a 5-7 membered ring" said ring includes the carbon-carbon double bond of the imidazole and, apart from said double bond, comprises 3-5 additional ring atoms selected from C, N, O or S joined by single or double bonds.
  • Ring D fused to the imidazole of formula (I) include lH-benzimidazolyl, lH-imidazo[4,5- ⁇ ]pyridinyl, l//-imidazo[4,5- c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, 3H-imidazo[4,5- ⁇ ]pyridinyl, 5H-imidazo[4,5- c]pyridazinyl and 7H-purinyl.
  • Two R 3 may, together with the carbons of ring D to which they are attached, form a 5 to 8-membered carbocyclyl or heterocyclyl ring.
  • Examples of such rings include a dioxanyl or dioxolanyl ring.
  • Ci_6alkanoyloxy is acetoxy.
  • Examples of “Ci- ⁇ alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of “Ci_6alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of “Ci-6alkanoylamino” include formamido, acetamido and propionylamino. Examples of "Ci .
  • 6 alkylS(O) a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Examples of "Ci-6alkanoyl” include propionyl and acetyl.
  • Examples of 'W-(Ci-6alkyl)amino” include methylamino and ethylamino.
  • Examples of 'W,A/-(Ci-6alkyl)2amino” include di-N-methylamino, di-(7V-ethyl)amino and 7V-ethyl-7V-methylamino.
  • Examples of "C2-6alkenyl” are vinyl, allyl and 1-propenyl.
  • Examples of "C 2 - 6 alkynyl” are ethynyl, 1-propynyl and 2-prop
  • 'W-(Ci. 6 alkyl)sulphamoyl are 7V-(methyl)sulphamoyl and 7V-(ethyl)sulphamoyl.
  • Examples of 'W,A/-(Ci-6alkyl)2Sulphamoyl are 7V,7V-(dimethyl)sulphamoyl and 7V-(methyl)-7V-(ethyl)sulphamoyl.
  • Examples of 'W-(Ci -6alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl.
  • Examples of 'W,A/-(Ci-6alkyl)2carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of
  • Ci. 6 alkylsulphonylamino include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.
  • Examples of “Ci. 6 alkylsulphonyl” include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
  • Some compounds of formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess Edg-1 antagonistic activity.
  • the invention is further understood to encompass any and all tautomeric forms of the compounds of formula (I) that possess Edg-1 antagonistic activity.
  • Ring A is carbocyclyl. Ring A is heterocyclyl wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 4 .
  • Ring A is heteroaryl
  • Ring A is pyridinyl
  • Ring A is aryl. Ring A is phenyl.
  • Ring A is phenyl or pyridinyl.
  • R 1 is halo, cyano or carbamoyl.
  • R 1 is chloro, fiuoro, cyano or carbamoyl. n is 1. Ring A is phenyl, R 1 is selected from halo, cyano or carbamoyl and n is 1 or 2.
  • R 2 is Ci-ealkyl.
  • R 2 is Ci- 6 alkyl wherein R 2 may be independently optionally substituted on carbon by one or more R 7 .
  • R 2 is ethyl wherein R 2 may be independently optionally substituted on carbon by one or more R 7 .
  • R 2 is ethyl
  • Ring D fused to the imidazole of formula (I), formula (Ia) or formula (Ib) forms 1-H- benzimidazole.
  • R 3 is selected from Ci_ 6 alkyl wherein R 5 may be optionally substituted on carbon by one or more R 11 .
  • R 3 is selected from Ci_ 6 alkyl wherein R 5 may be optionally substituted on carbon by one or more halo.
  • R 3 is Ci -6 alkyl.
  • R 3 is trifluoromethyl. m is 0 or 1. m is 0. m is 1.
  • Ring A is carbocyclyl or heterocyclyl
  • R 1 is halo, cyano or carbamoyl; n is 1 ;
  • R 2 is selected from Ci_ 6 alkyl wherein R 2 may be optionally substituted on carbon by one or more R 7 ;
  • R 3 is wherein is optionally substituted on carbon with halo; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.
  • R 1 is halo, cyano or carbamoyl; n is 1;
  • R 2 is selected from Ci_ 6 alkyl wherein R 2 may be optionally substituted on carbon by one or more R 7 ; Ring D fused to the imidazole of formula (I) forms 1-H-benzimidazole;
  • R 3 is wherein is optionally substituted on carbon with halo; m is 1; or a pharmaceutically acceptable salt thereof.
  • Ring A is heterocyclyl
  • R 1 is halo, cyano or carbamoyl; n is 1;
  • R 2 is selected from Ci_ 6 alkyl wherein R 2 may be optionally substituted on carbon by one or more R 7 ;
  • R 3 is Ci_ 6 alkyl wherein Ci_ 6 alkyl is optionally substituted on carbon with halo; and m is 1; or a pharmaceutically acceptable salt thereof.
  • Ring A is phenyl or pyridyl
  • R 1 is chloro, fluoro, cyano, or carbamoyl; n is 1;
  • R 2 is ethyl
  • R 3 is trifluoromethyl; and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydro lysable ester thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reaction of a compound of formula (II):
  • L is a displaceable group, suitable values for L are for example, a halo for example a chloro or bromo.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
  • An effective amount of a compound of the present invention for use in therapy of infection is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of infection, to slow the progression of infection, or to reduce in patients with symptoms of infection the risk of getting worse.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulf
  • Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen- containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
  • composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
  • this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical compositions can be in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
  • the compounds defined in the present invention are effective anti-cancer agents which property is believed to arise from their Edg-1 antagonistic properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Edg-1, i.e. the compounds may be used to produce an Edg-1 antagonistic effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention provide a method for treating cancer characterized by the antagonistic effect of Edg-1, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the antagonistic effect of Edg-1.
  • the compounds of the present invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example tumor-related angiogenesis.
  • the compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg- 1.
  • Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumours such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumours and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumours.
  • non-solid tumours such as leukemia, multiple myeloma, hematologic
  • Excessive vascular growth also contributes to numerous non-neoplastic disorders for which the compounds of the invention may be useful in treating.
  • These non-neoplastic angiogenesis-related diseases include: atherosclerosis, haemangioma, haemangio endothelioma, angiofibroma, vascular malformations (e.g.
  • HHT Hereditary Hemorrhagic Teleangiectasia
  • warts warts, pyogenic granulomas, excessive hair growth, Kaposis' sarcoma, scar keloids, allergic oedema, psoriasis, dysfunctional uterine bleeding, follicular cysts, ovarian hyperstimulation, endometriosis, respiratory distress, ascites, peritoneal sclerosis in dialysis patients, adhesion formation result from abdominal surgery, obesity, rheumatoid arthritis, synovitis, osteomyelitis, pannus growth, osteophyte, hemophilic joints, inflammatory and infectious processes (e.g.
  • hepatitis hepatitis, pneumonia, glomerulonephritis
  • asthma nasal polyps
  • liver regeneration pulmonary hypertension
  • retinopathy of prematurity diabetic retinopathy
  • age-related macular degeneration leukomalacia
  • neovascular glaucoma corneal graft neovascularization
  • trachoma thyroiditis
  • thyroid enlargement and lymphoproliferative disorders.
  • a method for producing a Edg-1 antagonistic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
  • a method of treating pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxo
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; 3. agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluor
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin); 6.
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and 9.
  • immunotherapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP.
  • the assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and presently owned by Molecular Devices.
  • a human osteogenic sarcoma (U2OS) cell line overexpressing the Edg-1 /SlPl) receptor as well as a beta-arrestin/green fluorescent protein (GFP) construct hereafter termed Edg-1 Transfluor U2OS WT Clone #37 was employed.
  • Edg-1 Transfluor U2OS WT Clone #37 cells were plated at a density of 6250 cells in 40 ⁇ L medium per well in 384 well plastic bottomed microtiter plates (BD Falcon) and incubated overnight at 37°C/5% CO 2 . Prior to screening, compounds were dissolved in 100% dimethyl sulfoxide (DMSO) to a final stock concentration of 10 mM. Compounds were then serially diluted at 3OX final concentration in Edg-1 Transfluor cell growth medium containing 30% DMSO using the Tecan Genesis instrument.
  • DMSO dimethyl sulfoxide
  • 3OX plates were then diluted to 6X final concentration with Edg-1 Transfluor growth medium just prior to dosing.
  • Cells were then dosed with 10 ⁇ L per well of 6X compound dilutions or 6% DMSO and pre-incubated for 15 minutes at room temperature.
  • Cell plates were dosed with 10 ⁇ L per well 6X SlP Edg-1 Transfluor growth medium, then incubated for 45 minutes at 37°C/5% CO 2 .
  • Final concentration in the well of DMSO was 1%, compound was IX (3-fold, 9 point IC50 dilutions starting at 100 ⁇ M final concentration), and either 375 nM or 750 nM SlP ligand.
  • In Vitro Cell Based Receptor Activation Assay-Transfluor Assay This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP.
  • the assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and presently owned by Molecular Devices (MDS Analytical Technologies).
  • Cells were then dosed with 6 ⁇ L per well of 1OX compound dilutions or 6% DMSO and pre-incubated for 15 minutes at room temperature. Cell plates were dosed with 10 ⁇ L per well 6X SlP Edg-1 Transfiuor growth medium, then incubated for 45 minutes at 37°C/5% CO 2 . Final concentration in the well of DMSO was 1%, compound was IX (3-fold, 9 point IC50 dilutions starting at 3 ⁇ M final concentration), and 750 nM SlP ligand.
  • compounds of the invention are generally expected to exhibit EC 50 values ⁇ 100 ⁇ M.
  • the compounds of the invention specifically exemplified below were found to have the following EC50S when tested in one or the other of the above two described assays:
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
  • organic solutions were dried over either anhydrous sodium sulphate or magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60 0 C;
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide (DMSO-d ⁇ ) as solvent unless otherwise indicated;
  • reaction mixture was concentrated to a viscous oil. This was treated with HOAc (5 mL), and the mixture was placed in an 80 0 C oil bath. After 90 minutes, LC-MS indicated complete conversion to the desired product. The mixture was allowed to cool, and the HOAc was evaporated under reduced pressure. The residue was used directly without further purification.

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Abstract

The invention relates to chemical compounds of formula (I) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal, such as man.

Description

HETEROCYCLYC SULFONAMIDES HAVING EDG-1 ANTAGONISTIC ACTIVITY
Edg (endothelial differentiation gene) receptors belong to a family of closely related, lipid activated G-protein coupled receptors. Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 (also known as SlPl, S1P3, S1P2, S1P4, and S1P5) are identified as receptors specific for sphingosine-1 -phosphate (SIP). Edg-2, Edg-4, and Edg-7 (known also as LPAl, LP A2, and LPA3, respectively) are receptors specific for lysophosphatidic (LPA). Among the SIP receptor isotypes, Edg-1, Edg-3 and Edg-5 are widely expressed in various tissues, whereas the expression of Edg-6 is confined largely to lymphoid tissues and platelets, and that of Edg- 8 to the central nervous system.
Edg receptors are responsible for signal transduction and are thought to play an important role in cell processes involving cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. Certain Edg receptors are associated with diseases mediated by the de novo or deregulated formation of vessels — for example, for diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis; and haemangioblastomas such as "strawberry- marks". Edg receptors are also associated with various inflammatory diseases, such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases or by lymphocyte interactions, for example, in transplantation rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer. An alteration in Edg receptor activity contributes to the pathology and/or symptomology of these diseases. Accordingly, molecules that themselves alter the activity of Edg receptors are useful as therapeutic agents in the treatment of such diseases. Accordingly, the present invention provides a compound of formula (I):
Figure imgf000002_0001
(I)
Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R4; R1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^aUcyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, hydrazinyl, ureido, N, N-di(Ci.3alkyl)ureido,
Figure imgf000003_0001
Λ/-(Ci.6alkyl)amino, Λ/,Λ/-(Ci-6alkyl)2amino, Ci.6alkanoylamino, Λ/-(Ci.6alkyl)carbamoyl, Λ/,Λ/-(Ci-6alkyl)2carbamoyl, Ci.6alkylS(0)a wherein a is 0 to 2, Ci_6alkoxycarbonyl,
N-(Ci-6alkyl)sulphamoyl, Λ/,Λ/-(Ci-6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl, heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R5; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6; n is 0-5; wherein the values of R1 may be the same or different;
R2 is selected from Ci_6alkyl or carbocyclyl; wherein R2 may be optionally substituted on carbon by one or more R7;
Ring D is fused to the imidazole of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R10;
R3 is a substituent on carbon and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl,
Figure imgf000003_0002
Ci_6alkanoyl, Ci_6alkanoyloxy, Λ/-(Ci-6alkyl)amino, N,N-(C1-6alkyl)2amino, Ci-6alkanoylamino, Λ/-(Ci-6alkyl)carbamoyl, Λ/,Λ/-(Ci.6alkyl)2carbamoyl, Ci.6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, heterocyclylcarbonyl, N-(C i -6alkyl)sulphamoyl, N1N-(C i -6alkyl)2sulphamoyl, Ci.6alkylsulphonylamino, carbocyclyl or heterocyclyl, or two R3 may together with the carbon atoms of ring D to which they are attached form a 5 to 8-membered carbocyclyl or heterocyclyl ring; wherein R3 may be optionally substituted on carbon by one or more R11; and wherein if said heterocyclyl or heterocyclyl ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R12; m is 0-5; wherein the values of R3 may be the same or different;
R5 and R11 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, Ci_6alkanoyl, Ci_6alkanoyloxy, Λ/-(Ci-6alkyl)amino, Λ/,Λ/-(Ci-6alkyl)2amino,
Ci-6alkanoylamino, Λ/-(Ci-6alkyl)carbamoyl,
Figure imgf000003_0003
Ci.6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, TV-(C i.6alkyl)sulphamoyl, Λ/,Λ/-(Ci.6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 and R11 may be independently optionally substituted on carbon by one or more R13; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R14;
R4, R6, R9, R10, R12 and R14 are independently selected from Ci-6alkyl, Ci-6alkanoyl, C i _6alkylsulphonyl, C i -6alkoxycarbonyl, carbamoyl, TV-(C i -6alkyl)carbamoyl,
Figure imgf000004_0001
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
R7 is selected from halo, nitro, hydroxy, amino, carboxy, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, ^-(d-ealky^amino,
Figure imgf000004_0002
TVTV-(Ci-6alkyl)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl,
TV-(C i-6alkyl)sulphamoyl, TVTV-(Ci-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R7 may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9; R8 and R13 are selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, TV-methyl-TV-ethylamino, acetylamino, TV-methylcarbamoyl, TV-ethylcarbamoyl, TVTV-dimethylcarbamoyl, TVTV-diethylcarbamoyl, TV-methyl-TV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, TV-methylsulphamoyl, TV-ethylsulphamoyl, TVTV-dimethylsulphamoyl, TVTV-diethylsulphamoyl or TV-methyl-TV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof; provided the compound is not TV- [(I -ethyl- 1 H- benzimidazol-2-yl)methyl]-2-oxoindoline-5 -sulfonamide or 4-methyl-TV- [(I -propyl- IH- benzimidazol-2-yl)methyl]benzenesulfonamide.
In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. For example, "Chalky!" and
Figure imgf000004_0003
include methyl, ethyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. A similar convention applies to other radicals. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
A "heterocyclyl" is a saturated, partially saturated or fully unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a Ci_6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the TV-oxide and or the S-oxides. Examples and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, Λ/-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-Λ/-oxide and quinoline-7V-oxide. In one aspect of the invention a "heterocyclyl" is a saturated, partially saturated or fully unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH2- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides. A "carbocyclyl" is a saturated, partially saturated or fully unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH2- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
"C3_6carbocyclic ring" is a saturated monocyclic carbon ring that contains 3-6 carbon atoms wherein a -CH2- group can optionally be replaced by a -C(O)-. Suitable values for "C3- 6carbocyclic ring" include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
"Ring D is fused to the imidazole of formula (I), formula (Ia) or formula (Ib) and is a 5-7 membered ring" said ring includes the carbon-carbon double bond of the imidazole and, apart from said double bond, comprises 3-5 additional ring atoms selected from C, N, O or S joined by single or double bonds. Suitable examples of Ring D fused to the imidazole of formula (I) include lH-benzimidazolyl, lH-imidazo[4,5-ό]pyridinyl, l//-imidazo[4,5- c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, 3H-imidazo[4,5-ό]pyridinyl, 5H-imidazo[4,5- c]pyridazinyl and 7H-purinyl.
Two R3 (m=2) may, together with the carbons of ring D to which they are attached, form a 5 to 8-membered carbocyclyl or heterocyclyl ring. Examples of such rings include a dioxanyl or dioxolanyl ring.
An example of "Ci_6alkanoyloxy" is acetoxy. Examples of "Ci-όalkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Ci_6alkoxy" include methoxy, ethoxy and propoxy. Examples of "Ci-6alkanoylamino" include formamido, acetamido and propionylamino. Examples of "Ci .6alkylS(O)a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "Ci-6alkanoyl" include propionyl and acetyl. Examples of 'W-(Ci-6alkyl)amino" include methylamino and ethylamino. Examples of 'W,A/-(Ci-6alkyl)2amino" include di-N-methylamino, di-(7V-ethyl)amino and 7V-ethyl-7V-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of
'W-(Ci.6alkyl)sulphamoyl" are 7V-(methyl)sulphamoyl and 7V-(ethyl)sulphamoyl. Examples of 'W,A/-(Ci-6alkyl)2Sulphamoyl" are 7V,7V-(dimethyl)sulphamoyl and 7V-(methyl)-7V-(ethyl)sulphamoyl. Examples of 'W-(Ci -6alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of 'W,A/-(Ci-6alkyl)2carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of
"Ci.6alkylsulphonylamino" include methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino. Examples of "Ci.6alkylsulphonyl" include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
Some compounds of formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess Edg-1 antagonistic activity.
The invention is further understood to encompass any and all tautomeric forms of the compounds of formula (I) that possess Edg-1 antagonistic activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Edg-1 antagonistic activity. Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Ring A is carbocyclyl. Ring A is heterocyclyl wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R4.
Ring A is heteroaryl.
Ring A is pyridinyl.
Ring A is aryl. Ring A is phenyl.
Ring A is phenyl or pyridinyl.
R1 is halo, cyano or carbamoyl.
R1 is chloro, fiuoro, cyano or carbamoyl. n is 1. Ring A is phenyl, R1 is selected from halo, cyano or carbamoyl and n is 1 or 2.
R2 is Ci-ealkyl.
R2 is Ci-6alkyl wherein R2 may be independently optionally substituted on carbon by one or more R7.
R2 is ethyl wherein R2 may be independently optionally substituted on carbon by one or more R7.
R2 is ethyl.
Ring D fused to the imidazole of formula (I), formula (Ia) or formula (Ib) forms 1-H- benzimidazole.
R3 is selected from Ci_6alkyl wherein R5 may be optionally substituted on carbon by one or more R11.
R3 is selected from Ci_6alkyl wherein R5 may be optionally substituted on carbon by one or more halo.
R3 is Ci-6alkyl.
R3 is trifluoromethyl. m is 0 or 1. m is 0. m is 1. In a further aspect of the invention there is provided a compound of formula (I) wherein:
Ring A is carbocyclyl or heterocyclyl;
R1 is halo, cyano or carbamoyl; n is 1 ;
R2 is selected from Ci_6alkyl wherein R2 may be optionally substituted on carbon by one or more R7;
Ring D fused to the imidazole of formula (I) forms 1-H-benzimidazole;
R3 is
Figure imgf000008_0001
wherein
Figure imgf000008_0002
is optionally substituted on carbon with halo; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.
In a still further aspect of the invention there is provided a compound of formula (I) wherein: Ring A is carbocyclyl;
R1 is halo, cyano or carbamoyl; n is 1;
R2 is selected from Ci_6alkyl wherein R2 may be optionally substituted on carbon by one or more R7; Ring D fused to the imidazole of formula (I) forms 1-H-benzimidazole;
R3 is
Figure imgf000008_0003
wherein
Figure imgf000008_0004
is optionally substituted on carbon with halo; m is 1; or a pharmaceutically acceptable salt thereof.
In a still further aspect of the invention there is provided a compound of formula (I), formula (Ia) or formula (Ib) (as depicted above) wherein:
Ring A is heterocyclyl;
R1 is halo, cyano or carbamoyl; n is 1;
R2 is selected from Ci_6alkyl wherein R2 may be optionally substituted on carbon by one or more R7;
Ring D fused to the imidazole of formula (I) forms 1-H-benzimidazolyl;
R3 is Ci_6alkyl wherein Ci_6alkyl is optionally substituted on carbon with halo; and m is 1; or a pharmaceutically acceptable salt thereof.
Therefore in a further aspect of the invention there is provided a compound of formula (I) wherein:
Ring A is phenyl or pyridyl;
R1 is chloro, fluoro, cyano, or carbamoyl; n is 1;
R2 is ethyl;
Ring D fused to the imidazole of formula (I) forms 1-H-benzimidazole;
R3 is trifluoromethyl; and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In another aspect of the invention, preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydro lysable ester thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reaction of a compound of formula (II):
Figure imgf000009_0001
(H) with an amine of formula (III):
Figure imgf000009_0002
(HI) and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt. L is a displaceable group, suitable values for L are for example, a halo for example a chloro or bromo.
Specific reaction conditions for the above reactions are as follows.
Process a) Compounds of formula (II) and (III) can be reacted together in the presence of a suitable solvent such as DCM and a base such as trie thy lamine. The reaction may require thermal conditions.
Compounds of formula (II) are commercially available, or they are known in the literature or they may be prepared by processes known in the art.
Compounds of formula (III) may be prepared according to Scheme 1:
Figure imgf000010_0001
Compounds of formula (III) may also be prepared according to Scheme 2:
Figure imgf000010_0002
l " Acid e"g" Ac0H then stron§ H+ 2. Lawesson's Reagent then acid ** (111)
3. Strong H+
Figure imgf000010_0003
Scheme 2 Compounds of formula (2b) may also be prepared according to Scheme 2a:
Figure imgf000011_0001
Scheme 2a
Compounds of formula (III) may also be prepared according to Scheme 3:
Figure imgf000011_0002
Figure imgf000011_0003
Scheme 3
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
An effective amount of a compound of the present invention for use in therapy of infection is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of infection, to slow the progression of infection, or to reduce in patients with symptoms of infection the risk of getting worse.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen- containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product. The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin. In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein. The term composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anti-cancer agents which property is believed to arise from their Edg-1 antagonistic properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Edg-1, i.e. the compounds may be used to produce an Edg-1 antagonistic effect in a warm-blooded animal in need of such treatment.
Thus the compounds of the present invention provide a method for treating cancer characterized by the antagonistic effect of Edg-1, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the antagonistic effect of Edg-1.
Thus the compounds of the present invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example tumor-related angiogenesis. The compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg- 1.
Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumours such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumours and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumours. Excessive vascular growth also contributes to numerous non-neoplastic disorders for which the compounds of the invention may be useful in treating. These non-neoplastic angiogenesis-related diseases include: atherosclerosis, haemangioma, haemangio endothelioma, angiofibroma, vascular malformations (e.g. Hereditary Hemorrhagic Teleangiectasia (HHT), or Osier- Weber syndrome), warts, pyogenic granulomas, excessive hair growth, Kaposis' sarcoma, scar keloids, allergic oedema, psoriasis, dysfunctional uterine bleeding, follicular cysts, ovarian hyperstimulation, endometriosis, respiratory distress, ascites, peritoneal sclerosis in dialysis patients, adhesion formation result from abdominal surgery, obesity, rheumatoid arthritis, synovitis, osteomyelitis, pannus growth, osteophyte, hemophilic joints, inflammatory and infectious processes (e.g. hepatitis, pneumonia, glomerulonephritis), asthma, nasal polyps, liver regeneration, pulmonary hypertension, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration., leukomalacia, neovascular glaucoma, corneal graft neovascularization, trachoma, thyroiditis, thyroid enlargement, and lymphoproliferative disorders. Thus according to this aspect of the invention there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament.
According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
According to this aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
According to a further feature of the invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in the manufacture of a medicament for use in the treatment of pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for producing a Edg-1 antagonistic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above. According to an additional feature of this aspect of the invention there is provided a method of treating pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:
1. antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
2. cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; 3. agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
4. inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
5. antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); 6. vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
7. antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; 8. gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and 9. immunotherapy approaches, including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. Biological Activity
The following assays can be used to measure the effects of the compounds of the present invention as SlPl/Edgl inhibitors. I. In Vitro Cell Based Receptor Activation Assay-Transfluor Assay
This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP. The assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and presently owned by Molecular Devices. A human osteogenic sarcoma (U2OS) cell line overexpressing the Edg-1 /SlPl) receptor as well as a beta-arrestin/green fluorescent protein (GFP) construct hereafter termed Edg-1 Transfluor U2OS WT Clone #37 was employed.
Using a high content screening approach (Cellomics Arrayscan), receptor activity was measured by assessment of the relocalization of beta-arrestin GFP in response to stimulation of Edg-1 by SlP. Specifically, Edg-1 Transfluor U2OS WT Clone #37 cells were plated at a density of 6250 cells in 40 μL medium per well in 384 well plastic bottomed microtiter plates (BD Falcon) and incubated overnight at 37°C/5% CO2. Prior to screening, compounds were dissolved in 100% dimethyl sulfoxide (DMSO) to a final stock concentration of 10 mM. Compounds were then serially diluted at 3OX final concentration in Edg-1 Transfluor cell growth medium containing 30% DMSO using the Tecan Genesis instrument. These 3OX plates were then diluted to 6X final concentration with Edg-1 Transfluor growth medium just prior to dosing. Cells were then dosed with 10 μL per well of 6X compound dilutions or 6% DMSO and pre-incubated for 15 minutes at room temperature. Cell plates were dosed with 10 μL per well 6X SlP Edg-1 Transfluor growth medium, then incubated for 45 minutes at 37°C/5% CO2. Final concentration in the well of DMSO was 1%, compound was IX (3-fold, 9 point IC50 dilutions starting at 100 μM final concentration), and either 375 nM or 750 nM SlP ligand. Cell plates were then fixed by adding 50 μL per well of 5% formaldehyde in IX Dulbecco's phosphate buffered saline (DPBS) directly and incubating for 30 minutes at room temperature in darkness. Fixative was removed and replaced with 50 μL per well of IX DPBS, after which cells were stained with 10 μg/mL final concentration of Hoechst 33342 (Molecular Probes) for 15 minutes at room temperature in darkness. Stain was then removed from the plates and replaced with 50 μL per well of IX DPBS using the BioTek ExL405 plate washer. Plates were then sealed and analysed on the Cellomics Arrayscan using the GPCR signalling algorithm. EC50 values were then calculated using IDBS ActivityBase software. II. In Vitro Cell Based Receptor Activation Assay-Transfluor Assay This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP. The assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and presently owned by Molecular Devices (MDS Analytical Technologies). A human osteogenic sarcoma (U2OS) cell line overexpressing the Edg-1 /SlPl) receptor as well as a beta- arrestin/green fluorescent protein (GFP) construct hereafter termed Edg-1 Transfiuor U2OS Clone #3 was employed.
Using a high content screening approach (Molecular Devices Image Express), receptor activity was measured by assessment of the relocalization of beta-arrestin GFP in response to stimulation of Edg-1 by SlP. Specifically, Edg-1 Transfiuor U2OS Clone #3 cells were plated at a density of 6250 cells in 44 μL medium per well in 384 well plastic bottomed microtiter plates (BD Falcon) and incubated overnight at 37°C/5% CO2. Prior to screening, compounds were dissolved in 100% dimethyl sulfoxide (DMSO) to a final stock concentration of 10 mM. Compounds were then serially diluted at 1OX final concentration in Edg-1 Transfiuor cell growth medium containing 6% DMSO using the BioMek instrument. Cells were then dosed with 6 μL per well of 1OX compound dilutions or 6% DMSO and pre-incubated for 15 minutes at room temperature. Cell plates were dosed with 10 μL per well 6X SlP Edg-1 Transfiuor growth medium, then incubated for 45 minutes at 37°C/5% CO2. Final concentration in the well of DMSO was 1%, compound was IX (3-fold, 9 point IC50 dilutions starting at 3 μM final concentration), and 750 nM SlP ligand. Cell plates were then fixed by adding 50 μL per well of 5% formaldehyde in IX Dulbecco's phosphate buffered saline (DPBS) directly and incubating for 30 minutes at room temperature in darkness. Fixative was removed and replaced with 50 μL per well of IX DPBS, after which cells were stained with 10 μg/mL final concentration of Hoechst 33342 (Molecular Probes) for 15 minutes at room temperature in darkness. Stain was then removed from the plates and replaced with 50 μL per well of IX DPBS using the BioTek ExL405 plate washer. Plates were then sealed and analysed on the Molecular Devices ImageXpress using the GPCR signalling algorithm. EC50 values were then calculated using IDBS ActivityBase software.
In the above-described assays, compounds of the invention are generally expected to exhibit EC50 values <100 μM. The compounds of the invention specifically exemplified below were found to have the following EC50S when tested in one or the other of the above two described assays:
Example ECsoJuM)
1 0.058
2 0.039
3 0.106
4 0.144
5 0.798
6 5.690
On retesting in the same assay, the compounds were found to have the following
EC50S: :
Example ECsoJuM)
1 0.054
2 0.062
3 0.133
4 0.294
5 0.769
6 0.127
Examples
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (0C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over either anhydrous sodium sulphate or magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60 0C; (iii) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide (DMSO-dβ) as solvent unless otherwise indicated;
(vii) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) solvent ratios are given in volume:volume (v/v) terms; and
(ix) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (M/Z);
(x) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example; and
(xi) the following abbreviations have been used:
THF tetrahydrofuran;
BOC tert-butyloxycarbonyl;
DMF 7V,7V-dimethylformamide;
EtOAc ethyl acetate;
DMSO dimethylsulphoxide;
AcOH Acetic acid;
PyBOP Benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate;
NMM N-methyl morpholine; and
MgSO4 Magnesium sulfate. Example 1
4-Chloro-N-((l-ethyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)methyl)benzenesulfonamide:
Figure imgf000024_0001
A 50 mL round bottom flask containing crude tert-butyl (l-ethyl-6-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)methylcarbamate (INT 1, 435.6 mg, 1.27 mmol) was treated with 4 N HCl/dioxane (5 mL). The resulting mixture was allowed to stir at room temperature. After 90 minutes, the dioxane and excess HCl were evaporated under reduced pressure. The residue was dissolved in CH2CI2 (5 mL) and triethylamine (1.50 mL, 10.8 mmol). A-
Chlorobenzenesulfonyl chloride (330 mg, 1.56 mmol) was added, and the mixture was allowed to stir at room temperature. After 2 hours, the mixture was partitioned between CH2CI2 and H2O. The aqueous layer was extracted with CH2CI2, and the combined organics were washed with saturated NaHCOβ, brine, and dried. The crude material was purified by silica gel chromatography (gradient elution; Rf in 40:60 hexanes: EtOAc = 0.41) to give a colorless solid (265 mg, 50% over 3 steps). M/Z = 417.
1U NMR δ ppm 1.30 (t, J=7.07 Hz, 3 H) 4.30 - 4.39 (m, 4 H) 7.48 (m, 1 H) 7.55 (m, 2 H) 7.72 (m, 1 H) 7.77 (m, 2 H) 7.98 (m, 1 H) 8.58 (m, 1 H). tert-Butyl (l-ethyl-6-(trifluoromethyl)-lH-benzo [d] imidazol-2-yl)methylcarbamate (INT 1):
Figure imgf000024_0002
A 50 mL roundbottom flask was charged with BOC-GIy-OH (Boc protected glycine) (223 mg, 1.27 mmol), PyBOP (671 mg, 1.29 mmol), and CH2Cl2 (3.0 mL). Triethylamine (200 μL, 1.43 mmol) was added, and the solution was allowed to stir at room temperature for 20 minutes. N'-Ethyl-S-^rifluoromethy^benzene-l^-diamine (SM 1, 260 mg, 1.27 mmol) was added, and additional CH2Cl2 (3 x 1 mL) was used to rinse in the remaining diamine. The resulting solution was allowed to stir at room temperature overnight. The reaction mixture was concentrated to a viscous oil. This was treated with HOAc (5 mL), and the mixture was placed in an 80 0C oil bath. After 90 minutes, LC-MS indicated complete conversion to the desired product. The mixture was allowed to cool, and the HOAc was evaporated under reduced pressure. The residue was used directly without further purification.
N^Ethyl-S-^rifluoromethyObenzene-l^-diamine (SM 1)
Step I:
N-Ethyl-4-nitrobenzotrifluoride
Figure imgf000025_0001
3-Chloro-4-nitrobenzotrifiuoride (Ig, 4.43 mmols) and ethylamine (2M in THF, 12 mL) were taken in a microwave tube equipped with a stir bar. The contents were stirred, sealed and heated in a microwave at 100 0C for 2 hours. The reaction mixture was then transferred into a round bottom flask and concentrated to obtain a bright orange solid. The solid was partitioned between ethyl acetate (300 mL) and water (50 mL). The organic layer was washed with brine, dried with sodium sulfate (anhydrous), filtered and dried in vacuo to obtain 1.45 g (94.66%) of desired product. Step II: N-Ethyl-4-aminobenzotrifluoride
Figure imgf000025_0002
N-Ethyl-4-nitrobenzotrifluoride (1.94 g, 8.29 mmols), ethanol (25 mL), 10% Pd/C (3 g) and cyclohexane (20 mL) were taken in a round bottom flask equipped with a stir bar and a reflux condenser. The resultant mixture was heated to 800C for 3 h when the reaction was judged to have reached completion based on LC-MS monitoring. The reaction mixture was cooled to room temperature and was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to obtain an off- white solid, which was used for the next reaction after LC-MS characterization. M/Z = 204. The compounds of examples 2- 4, shown in Table 1, were prepared by a procedure analogous to that of Example 1, using the appropriate sulfonyl chloride (all of which are commercially available).
TABLE 1
Figure imgf000026_0001
Example 5
5-(N-((l-Ethyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)methyl)sulfamoyl)picolinamide
Figure imgf000027_0001
A 50 mL Erlenmeyer flask was charged with 6-cyano-N-((l-ethyl-6-(trifluoromethyl)-lH- benzo[d]imidazol-2-yl)methyl)pyridine-3 -sulfonamide (Example 4) (100 mg, 0.24 mmol) and was treated with concentrated H2SO4 (2 mL). The resulting mixture was allowed to stir at room temperature for 4 hours, and was then treated with crushed ice (-25 mL). The mixture was carefully neutralized with solid NaHCOβ in portions, and was extracted with EtOAc (3x).
The combined organics were washed with saturated NaHCOβ, dried (MgSC^), filtered, and concentrated to a solid residue. This was purified by silica gel chromatography (gradient elution; Rf in 100% EtOAc = 0.28) to give a colorless solid (30 mg, 29%). M/Z = 427. 1H NMR (400 MHz, DMSO-D6) d ppm 1.30 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.07 Hz, 2 H) 4.47 (m, 2 H) 7.46 (m, 1 H) 7.65 (m, 1 H) 7.83 (broad s, 1 H) 7.99 (m, 1 H) 8.10 (m, IH) 8.20 (broad s, 1 H) 8.30 (m, 1 H) 8.87 (m, 1 H) 8.93 (m, 1 H).
Example 6 4-Chloro-ΛL[(l-ethyl-lH-benzimidazol-2-yl)methyl]benzenesulfonamide
Figure imgf000027_0002
A 25 ml round bottom flask was charged with tert-butyl (lH-benzimidazol-2- ylmethyl)carbamate ( INT 2, 0.1072 g, 0.36 mmol) and TΗF (5 mL). The solution was treated with cesium carbonate (0.52 g, 1.58mmol) and ethyl iodide (32uL, 3.96mmol) and allowed to stir at room temperature overnight before the volatile components were evaporated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Ηexane 40:60) to afford 165 mg of desired product. This was subsequently dissolved in 4N HCl/dioxane (1.5 mL) and the solution was allowed to stir for 1.5 hours. At this point, the reaction was concentrated under reduced pressure, and the residue was treated with triethylamine (307ul, 2.20 mmol), CH2Cl2 (5 mL), and 4-chlorobenzenesulfonyl chloride (170 mg, 0.80 mmol). After the reaction had stirred for 1 h, the reaction was partitioned between CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2, and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; EtOAc: Hexane 40%). This was lyophilized (MeCN/H2O) to give colorless solid (118.2 mg, 40%). M/Z = 349. 1R NMR (300 MHz, CDCl3) δ 1.50 (t, 3 H), 4.37 (q, 2 H), 4.62 (s, 2 H), 5.23 (s, 1 H) 7.25 (d, 2 H) 7.45 (m, 2 H) 7.65-7.68 (m, 2 H) 7.73 (d, 2 H).
tert-Bntyl (lH-benzimidazol-2-ylmethyl)carbamate (INT 2)
Figure imgf000028_0001
A solution of BOC-Gly-OΗ (1.56g, 8.24mmol) and 4-methylmorpholine (NMM, 0.91ml, 8.24 mmol) in 7V,7V-dimethylformamide (DMF, 15ml) was treated at -20 0C with isobutyl chloroformate (1.08ml, 8.24mmol). After 10 min at -20 0C, o-phenylendiamine (0.89g, 8.24 mmol) was added. The reaction mixture was allowed to stir while slowly warming to room temperature (Ih) and was then stirred for 3h. The solvent was evaporated, and the residue was partitioned between ethyl acetate and H2O. The EtOAc layer was washed with 5% NaHCO3 and brine and dried over Na2SO4. The solution was filtered, the solvent was evaporated, and the residue solid was dissolved in glacial AcOH (15ml). The solution was heated at 65 0C for Ih. After the solvent was evaporated, the residue was purified by silica gel chromatography (EtOAc/Hexane 50:50) to afford pale white solid. 1U NMR (300 MHz, CDCl3) δ 1.43 (s, 9 H), 1.56 (t, 3 H), 4.58 (m, 2 H), 4.88 (d, 2 H), 6.45 (b m, IH) 7.46 (d, 2 H) 7.59 (m, 1 H) 7.81 (m, 1 H). M/Z=275

Claims

Claim
1. A compound of formula (I):
Figure imgf000029_0001
(I) Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R4;
R1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^aUcyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, hydrazinyl, ureido, N, N-di(Ci_3alkyl)ureido, Ci_6alkanoyl, Ci_6alkanoyloxy, Λ/-(Ci-6alkyl)amino, Λ/,Λ/-(Ci-6alkyl)2amino, Ci-6alkanoylamino, TV-(C i.6alkyl)carbamoyl,
Λ/,Λ/-(Ci-6alkyl)2carbamoyl, Ci.6alkylS(O)a wherein a is 0 to 2, Ci.6alkoxycarbonyl, N-(Ci.6alkyl)sulphamoyl, Λ/,Λ/-(Ci-6alkyl)2sulphamoyl, Ci.6alkylsulphonylamino, carbocyclyl, heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R5; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6; n is 0-5; wherein the values of R1 may be the same or different; R2 is selected from
Figure imgf000029_0002
or carbocyclyl; wherein R2 may be optionally substituted on carbon by one or more R7;
Ring D is fused to the imidazole of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R10;
R3 is a substituent on carbon and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl,
Figure imgf000029_0003
Ci_6alkanoyl, Ci_6alkanoyloxy, Λ/-(Ci-6alkyl)amino, Λ/,Λ/-(Ci-6alkyl)2amino, Ci.6alkanoylamino, Λ/-(Ci.6alkyl)carbamoyl,
Λ/,Λ/-(Ci-6alkyl)2carbamoyl, Ci.6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, heterocyclylcarbonyl, N-(C i -6alkyl)sulphamoyl, N1N-(C i .6alkyl)2 sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl, or two R3 may together with the carbon atoms of ring D to which they are attached form a 5 to 8-membered carbocyclyl or heterocyclyl ring; wherein R3 may be optionally substituted on carbon by one or more R11; and wherein if said heterocyclyl or heterocyclyl ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R12; m is 0-5; wherein the values of R3 may be the same or different; R5 and R11 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy,
Ci_6alkanoyl, Ci_6alkanoyloxy, Λ/-(Ci-6alkyl)amino, Λ/,Λ/-(Ci-6alkyl)2amino,
Ci-6alkanoylamino, Λ/-(Ci-6alkyl)carbamoyl,
Figure imgf000030_0001
Ci.6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, TV-(C i.6alkyl)sulphamoyl,
Λ/,Λ/-(Ci-6alkyl)2sulphamoyl, Ci.6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 and R11 may be independently optionally substituted on carbon by one or more R13; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R14;
R4, R6, R9, R10, R12 and R14 are independently selected from Ci-6alkyl, Ci-6alkanoyl,
Ci-6alkylsulphonyl, Ci_6alkoxycarbonyl, carbamoyl, N-(Ci -6alkyl)carbamoyl, N,N-(Ci.6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
R7 is selected from halo, nitro, hydroxy, amino, carboxy, mercapto, sulphamoyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, N-(Ci-6alkyl)amino,
N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(Ci-6alkyl)carbamoyl,
N,N-(Ci-6alkyl)2carbamoyl, Ci.6alkylS(O)a wherein a is 0 to 2, Ci_6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl, N,N-(Ci-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R7 may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9;
R8 and R13 are selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl,
N.N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N.N-dimethylsulphamoyl,
N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof; provided the compound is not N- [(I -ethyl- IH- benzimidazol-2-yl)methyl]-2-oxoindoline-5-sulfonamide or 4-methyl-N- [(I -propyl- IH- benzimidazol-2-yl)methyl]benzenesulfonamide.
2. A compound according to claim 1 selected from
4-Chloro-N-((l-ethyl-6-(trifluoromethyl)-lΗ-benzo[d]imidazol-2- yl)methyl)benzenesulfonamide;
N-((l-Ethyl-6-(trifluoro-methyl)-lH-benzo[d]imidazol-2-yl)methyl)-4- fluorobenzenesulfonamide; 4-Cyano-N-((l -ethyl-6-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)methyl)benzenesulfonamide;
6-Cyano-N-((l-ethyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl)methyl)pyridine-3- sulfonamide;
5-(N-((l-Ethyl-6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl)methyl)sulfamoyl)picolinamide; 4-Chloro-7V-[(l -ethyl- lH-benzimidazol-2-yl)methyl]benzenesulfonamide; and pharmaceutically acceptable salts thereof.
3. A pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2 in association with a pharmaceutically-acceptable carrier, diluent or excipient.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2 for use as a medicament.
5. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2 in the manufacture of a medicament for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
6. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2 in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
7. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2 in the manufacture of a medicament for use in the treatment of angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.
8. A method for producing an Edg-1 antagonistic effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2.
9. A method for producing an anti-cancer effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 2.
10. A method of treating of angiogenesis-related diseases including non-solid tumors, solid tumors and their metastases, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors, in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in 1- 2.
11. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1- 2, in association with a pharmaceutically-accep table carrier, diluent or excipient for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
12. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 2, in association with a pharmaceutically-acceptable carrier, diluent or excipient for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
13. A Process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the variables are, unless otherwise specified, as defined in claim 1 , which process comprises Process a) reacting a compound of formula (II):
Figure imgf000033_0001
(H) wherein L is a displaceable group with an amine of formula (III):
Figure imgf000033_0002
(HI) and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
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