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WO2005020985A1 - Derives d'indolamide possedant une activite inhibitrice de la glycogene phosphorylase - Google Patents

Derives d'indolamide possedant une activite inhibitrice de la glycogene phosphorylase Download PDF

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Publication number
WO2005020985A1
WO2005020985A1 PCT/GB2004/003620 GB2004003620W WO2005020985A1 WO 2005020985 A1 WO2005020985 A1 WO 2005020985A1 GB 2004003620 W GB2004003620 W GB 2004003620W WO 2005020985 A1 WO2005020985 A1 WO 2005020985A1
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Prior art keywords
alkyl
formula
compound
pharmaceutically acceptable
hydroxy
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Inventor
Stuart Norman Lile Bennett
Iain Simpson
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Priority claimed from GB0320242A external-priority patent/GB0320242D0/en
Priority claimed from GB0401800A external-priority patent/GB0401800D0/en
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Publication of WO2005020985A1 publication Critical patent/WO2005020985A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to heterocyclic amide derivatives, pharmaceutically acceptable salts and in-vivo hydrolysable esters thereof. These heterocyclic amides possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity and thus are potentially useful in methods of treatment of a warm-blooded animal such as man.
  • the invention also relates to processes for the manufacture of said heterocyclic amide derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit glycogen phosphorylase activity in a warm-blooded animal such as man.
  • the liver is the major organ regulating glycaemia in the post-absorptive state.
  • HGO hepatic glucose output
  • EPG fasting plasma glucose
  • Glycogen phosphorylase is a key enzyme in the generation by glycogenolysis of glucose- 1 -phosphate, and hence glucose in liver and also in other tissues such as muscle and neuronal tissue. Liver glycogen phosphorylase a activity is elevated in diabetic animal models including the db/db mouse and the fa/fa rat (Aiston S et al (2000). Diabetalogia 43, 589-597).
  • heterocyclic amides of the present invention possess glycogen phosphorylase inhibitory activity and accordingly are expected to be of use in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia and obesity, particularly type 2 diabetes.
  • Our patent application WO 02/20530 discloses a spectrum of active glycogen phosphorylase inhibitors, amongst which are a very limited number of amino-indan containing compounds.
  • A is phenylene or heteroarylene; n is 0, 1 or 2; m is 0, 1 or 2;
  • R 1 is independently selected from halo, nitro, cyano, hydroxy, carboxy, carbamoyl,
  • N-(l-4C)alkylcarbamoyl N,N-((l-4C)alkyl) 2 carbamoyl, sulphamoyl, N-(l-
  • R 2 and R 3 together with the nitrogen to which they are attached form a 4- to 7-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S (provided that there are no O-O, O-S or S-S bonds), wherein any N, S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,
  • R 4 is independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl,
  • substituents independently selected from halo, nitro, cyano, hydroxy, fluoro
  • the invention relates to compounds of formula (1) as hereinabove defined or to a pharmaceutically acceptable salt.
  • the invention relates to compounds of formula (1) as hereinabove defined or to a pro-drug thereof.
  • pro-drugs of compounds of formula (1) are in- vivo hydrolysable esters of compounds of formula (1). Therefore in another aspect, the invention relates to compounds of formula (1) as hereinabove defined or to an in- vivo hydrolysable ester thereof.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses glycogen phosphorylase inhibition activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • a compound of the formula (1) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which has glycogen phosphorylase inhibition activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
  • the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
  • certain compounds of the formula (1) and salts thereof 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 have glycogen phosphorylase inhibition activity. It is also to be understood that certain compounds of the formula (1) may exhibit polymorphism, and that the invention encompasses all such forms which possess glycogen phosphorylase inhibition activity.
  • the present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently basic to form such salts.
  • Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid.
  • Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates.
  • pharmaceutically acceptable salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
  • Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention.
  • a prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug.
  • pro-drags examples include in- vivo hydrolysable esters of a compound of the invention or a pharmaceutically-acceptable salt thereof.
  • Various forms of prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
  • H. Bundgaard Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).
  • An in-vivo hydrolysable ester of a compound of formula (1) containing carboxy or hydroxy group is, for example a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include alkyl esters, (l-6C)alkoxymethyl esters for example methoxymethyl, (l-6C)alkanoyloxymethyl esters for example pi valoyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and (l-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group
  • Suitable pharmaceutically-acceptable esters for hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include (l-lOC)alkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, (l-lOC)alkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-((l-4C))alkylcarbamoyl andN-(di-((l-4C))alkylaminoethyl)-N- ((l-4C))alkylcarbamoyl (to give carbamates); di-((l-4C))alkylaminoacetyl and carboxyacetyl.
  • (l-lOC)alkanoyl for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, (l-lOC)alkoxycarbon
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, ((1- 4C))alkylaminomethyl and di-(((l-4C))alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
  • Other interesting in-vivo hyrolysable esters include, for example, R A C(O)O((l- 6C))alkyl-CO-, wherein R A is for example, benzyloxy-((l-4C))alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-((l-4C))piperazino-((l- 4C))alkyl, piperazino-((l-4C))alkyl and morpholino(l-4C)alkyl.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
  • “(l-4C)alkyI” includes methyl, ethyl, propyl, isopropyl and t-butyl
  • examples of "(1- 6C)alkyl” include the examples of "(l-4C)alkyl”and additionally pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl.
  • (2-4C)alkenyl includes vinyl, allyl and 1-propenyl and examples of “(2- 6C)alkenyl” include the examples of "(2-4C)alkenyl” and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-l-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • Examples of “(2-4C)alkynyl” includes ethynyl, 1-propynyl and 2-propynyl and examples of “C 2- 6alkynyl”include the examples of “(2-4C)alkynyl” and additionally 3-butynyl, 2-pentynyl and l-methylpent-2-ynyl.
  • the term "hydroxy(l-4C)alkyl” includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and hydroxybutyl.
  • hydroxy(l-4C)alkyl also includes hydroxycyclopropyl and hydroxycyclobutyl.
  • hydroxyethyl includes 1- hydroxyethyl and 2-hydroxyethyl.
  • hydroxypropyl includes 1 -hydroxypropyl, 2- hydroxypropyl and 3 -hydroxypropyl and an analogous convention applies to terms such as hydroxybutyl.
  • dihydroxy(2-4C)alkyl includes dihydroxyethyl, dihydroxypropyl, dihydroxyisopropyl and dihydroxybutyl.
  • dihydroxypropyl includes 2,3- dihydroxypropyl and 1,3-dihydroxypropyl. An analogous convention applies to terms such as dihydroxyisopropyl and dihydroxybutyl.
  • dihydroxy(2-4C)alkyl is not intended to include structures which are geminally disubstituted and thereby unstable.
  • halo refers to fluoro, chloro, bromo and iodo.
  • dihalo(l- 4C)alkyl includes difluoromethyl and dichloromethyl.
  • trihalo(l-4C)alkyl includes trifluoromethyl. Examples of "(l-4C)alkoxy” include methoxy, ethoxy, propoxy and isopropoxy.
  • Examples of "(l-6C)alkoxy” include the examples of “(1-4C) alkoxy” and additionally butyloxy, t-butyloxy, pentoxy and l,2-(methyl) 2 propoxy.
  • Examples of "(l-4C)alkanoyl” include formyl, acetyl and propionyl.
  • Examples of "(l-6C)alkanoyl” include the example of “(l-4C)alkanoyl” and additionally butanoyl, pentanoyl, hexanoyl and l,2-(methyl) propionyl.
  • Examples of "(l-4C)alkanoyloxy” are formyloxy, acetoxy and propionoxy.
  • Examples of "(1- 6C)alkanoyloxy” include the examples of “(l-4C)alkanoyloxy” and additionally butanoyloxy, pentanoyloxy, hexanoyloxy and l,2-(methyl) 2 propionyloxy.
  • Examples of "N-((l- 4C)alkyl)amino” include methylamino and ethylamino.
  • Examples of “N-((l-6C)alkyl)amino” include the examples of "N-((l-4C)alkyl)amino" and additionally pentylamino, hexylamino and 3-mefhylbutylamino.
  • N,N-((l-4C)alkyl) 2 amino examples include N-N- (methyl) 2 amino, N-N-(ethyl) 2 amino and N-ethyl-N-methylamino.
  • Examples of "N,N-((1- 6C)alkyl) 2 amino” include the example of "N,N-((l-4C)alkyl) 2 amino” and additionally N- methyl-N-pentylamino and N,N-(penty ⁇ ) 2 amino.
  • Examples of "iV-((l-4C)alkyl)carbamoy ' are methylcarbamoyl and ethylcarbamoyl.
  • N-((l-6C)alkyl)carbamoyl examples of “N-((l-4C)alkyl)carbamoyl”and additionally pentylcarbamoyl, hexylcarbamoyl and l,2-(methyl)2pro ⁇ ylcarbamoyl.
  • Examples of "NN-((l-4C)alkyl)2carbamoyl” areNN- (methyl) 2 carbamoyl, N,N-(ethyl) 2 carbamoyl and N-methyl-N-ethylcarbamoyl.
  • N,N-((l-6C)alkyl) 2 carbamoyl are the examples of “N,N-((l-4C)alkyl) 2 carbamoyl” and additionally N,N-(pentyl) 2 carbamoyl, N-methyl-N-pentylcarbamoyl and N-ethyl-N- hexylcarbamoyl.
  • N-((l-4C)alkyl)sulphamoyl are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • N-((l-6C)alkyl)sulphamoyl examples of “N-((l- 4C)alkyl)sulphamoyl” and additionally N-pentylsulphamoyl, N-hexylsulphamoyl and 1,2- (methyl)2propylsulphamoyl.
  • N,N-((l-4C)alkyl) 2 Sulphamoyl are N,N-(methyl) 2 Sulphamoyl, N,N-(ethyl) 2 Sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.
  • N,N-((l-6C)alkyl) 2 sulphamoyl are the examples of “N,N-((1- 4C)alkyl) 2 Sul ⁇ hamoyl” and additionally NN-(pentyl) 2 Sulphamoyl, N-methyl-N- pentylsulphamoyl and N-ethyl-N-hexylsulphamoyl.
  • Examples of “- ⁇ HSO 2 (l-4C)alkyl” include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino and tert-butylsulfonylamino.
  • Examples of “cyano((l-4C))alkyl” are cyanomethyl, cyanoethyl and cyanopropyl.
  • Examples of “(5-7C)cycloalkyl” are cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of "(3-8C)cycloalkyl” and “(3-7C)cycloalkyl” include “(5-7C)cycloalkyl", cyclopropyl, cyclobutyl and cyclooctyl.
  • Examples of “(3-6C)cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Examples of “(3-6C)cycloalkyl(l-4C)alkyl” include cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • amino(l-4C)alkyl includes aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and aminobutyl.
  • aminoethyl includes 1-aminoethyl and 2- aminoethyl.
  • aminopropyl includes 1 -aminopropyl, 2-aminopropyl and 3- aminopropyl and an analogous convention applies to terms such as aminoethyl and aminobutyl.
  • Examples of "(l-4C)alkoxy(l-4C)alkyl” include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and propoxymethyl.
  • Examples of "-S(O) b (l-4C)alkyl (wherein b is 0,1 or 2)" include methylthio, ethylthio, propylthio, methylsulphinyl, ethylsulphinyl, propanesulphinyl, mesyl, ethylsulphonyl, propylsulphonyl and isopropylsulphonyl.
  • Examples of "-(l-4C)alkylS(O) b (l-4C)alkyl (wherein b is 1 or 2)" include methylthiomethyl, ethylthiomethyl, propylthioethyl, methylsulphinylmethyl, ethylsulphinylmethyl, propylsulphinylmethyl, mesylmethyl, ethylsulphonylmethyl, propylsulphonylmethyl and isopropylsulphonylmethyl.
  • Examples of "(l-6C)alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • composite terms are used to describe groups comprising more that one functionality such as -(l-4C)alkylSO 2 (l-4C)alkyl. Such terms are to be interpreted in accordance with the meaning which is understood by a person skilled in the art for each component part.
  • -(l-4C)alkylSO 2 (l-4C)alkyl includes -rnethylsulphonylmethyl, -methylsulphonylethyl, -ethylsulphonylmethyl, and -propylsulphonylbutyl.
  • Heteroarylene is a diradical of a heteroaryl group.
  • a heteroaryl group is an aryl, monocyclic ring containing 5 to 7 atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen.
  • heteroarylene examples include oxazolylene, oxadiazolylene, pyridylene, pyrimidinylene, imidazolylene, triazolylene, tetrazolylene, pyrazinylene, pyridazinylene, pyrrolylene, thienylene and furylene.
  • Suitable optional substituents for heteroaryl groups are 1, 2 or 3 substituents independently selected from halo, cyano, nitro, amino, hydroxy, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylS(O) b (wherein b is 0, 1 or 2), N-((l-4C)alkyl)amino and N,N-((1- 4C)alkyl) 2 amino.
  • heteroaryl groups are 1, 2 or 3 substituents independently selected from fluoro, chloro, cyano, nitro, amino, methylamino, di ethylamino, hydroxy, methyl, ethyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl.
  • A, R 1 to R 4 , m and n are as follows. Such values may be used where appropriate with any of the definitions, claims, aspects or embodiments defined hereinbefore or hereinafter.
  • compounds of formula (1) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (1), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (1).
  • pro-drags of compounds of formula (1) are provided in a still further alternative embodiment are provided pharmaceutically-acceptable salts of pro-drugs of compounds of formula (1).
  • A is phenylene. In another aspect of the invention A is heteroarylene. Suitable values for A are phenylene, pyridylene, pyrimidinylene, pyrrolylene, imidazolylene, triazolylene, tetrazolylene, oxazolylene, oxadiazolylene, thienylene and furylene. Further suitable values for A are phenylene, pyridylene, pyrimidinylene, pyrrolylene and imidazolylene. Further suitable values for A are phenylene, pyridylene and pyrimidinylene. Further suitable values for A are phenylene and pyridylene.
  • A when A is heteroarylene, there is a nitrogen in a bridgehead position. In another embodiment, when A is heteroarylene, the heteroatoms are not in bridgehead positions. It will be appreciated that the preferred (more stable) bridgehead position is as shown below:
  • m is 1 or 2. In another aspect of the invention m is 1. In another aspect of the invention, m is 0. In one aspect of the present invention R 4 is selected from halo, cyano, hydroxy, fluoromethyl, difluoromethyl and trifluoromethyl. In one aspect of the present invention R 4 is selected from halo and methyl. In another aspect of the invention R 4 is halo. In another aspect of the invention R 4 is selected from chloro and bromo. In another aspect of the invention R 4 is selected from methyl, chloro and fluoro. In another aspect of the invention R 4 is selected from chloro and fluoro. More preferably R 4 is chloro. In one aspect of the invention n is 0 or 1.
  • n is 1. In another aspect, preferably n is 0.
  • n is 2, and the two R 1 groups, together with the carbon atoms of A to which they are attached, form a 4 to 7 membered saturated ring, optionally containing 1 or 2 heteroatoms independently selected from O, S and N, conveniently such a ring is a 5 or 6 membered ring.
  • such a 5 or 6 membered ring contains two O atoms (ie a cyclic acetal).
  • the two R 1 groups together form such a cyclic acetal, preferably it is not substituted.
  • the two R 1 groups together are the group -O-CH 2 -O-.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl and (l-4C)alkoxy.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b (l-4C)alkyl (wherein b is 0, 1 or 2), -OS(O) 2 (l-4C)alkyl, (l-4C)alkyl and (l-4C)alkoxy.
  • R 1 is selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -S(O) b Me (wherein b is 0, 1 or 2), -OS(O) 2 Me, methyl and methoxy.
  • R 1 is (l-4C)alkyl.
  • R 1 is selected from halo and (l-4C)alkoxy.
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-.
  • R 2 and R 3 together with the nitrogen to which they are attached form a 5- or 6-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S (provided that there are no O-O, O-S or S-S bonds), wherein any N, S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (l-4C)alkanoyl, hydroxy(l-4C)alkyl, dihydroxy(2-4C)alkyl, amino(l-4C)alkyl, (l
  • R 2 and R 3 together with the nitrogen to which they are attached form a 5- or 6-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S (provided that there are no O-O, O-S or S-S bonds), wherein any N, S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (1- 4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (l-4C)alkanoyl, -(l-4C)alkylS(O) b (l- 4C)aIkyl (wherein b is
  • R 2 and R 3 together with the nitrogen to which they are attached form a 4-membered ring as defined hereinbefore or hereinafter. In another aspect of the invention R 2 and R 3 together with the nitrogen to which they are attached form a 5 -membered ring as defined hereinbefore or hereinafter. In another aspect of the invention R 2 and R 3 together with the nitrogen to which they are attached form a 6-membered ring as defined hereinbefore or hereinafter. In another aspect of the invention R 2 and R 3 together with the nitrogen to which they are attached form a 7-membered ring as defined hereinbefore or hereinafter. In one aspect of the invention R 2 and R 3 together with the nitrogen to which they are attached form a saturated ring.
  • R 2 and R 3 together with the nitrogen to which they are attached form a partially unsaturated ring. In one aspect of the invention R 2 and R 3 together with the nitrogen to which they are attached form a unsaturated ring. In one aspect of the invention, invention R 2 and R 3 together with the nitrogen to which they are attached form a ring containing a carbonyl group. In another aspect of the invention, the ring formed by R 2 and R 3 together with the nitrogen to which they are attached does not contain any further heteroatoms. An example of such a ring is 2-pyrrolidonyl. In another aspect of the invention, the ring formed by R 2 and R 3 together with the nitrogen to which they are attached contains one further heteroatom selected from O, N and S.
  • a 4-7 -membered ring comprising R 2 -N-R 3
  • Suitable values for a 4-7 -membered ring comprising R 2 -N-R 3 are morpholino, pyrrolyl, piperazinyl, triazolyl, tetrazolyl, imidazolyl, 3-oxazolidinonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-2-yl, pyrazolyl, pyrazolinyl, 4-oxopyridyl, 2-oxo ⁇ yrrolidyl, 2-oxoazetidinyl, 1-oxidoisothiazolidinyl, 1 -oxido- 1 ,2-thiazinanyl, 1 , 1 -dioxidoisothiazolidinyl , 1,1 -dioxido- 1 ,2-thiazin
  • Suitable values for a 5- or 6-membered ring comprising R 2 -N-R 3 are morpholino, pyrrolyl, piperazinyl, triazolyl, tetrazolyl, imidazolyl, 3-oxazolidinonyl, thiomorpholino, pyrrolinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-2-yl, pyrazolyl, pyrazolinyl, 4-oxopyridyl, 2-oxopyrrolidyl, 1-oxidoisothiazolidinyl, 1 -oxido- 1,2-thiazinanyl,
  • ring comprising R -N-R are morpholino, piperazinyl, 3-oxazolidinonyl, 3,5-dioxidopiperidinyl, 3-oxopyrazolin-2-yl, 4-oxopyridyl, 2- oxopyrrolidyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl and 2- oxohexahydropyrimidinyl.
  • Suitable values for the ring comprising R 2 -N-R 3 are thiomorpholino, 1 -oxidoisothiazolidinyl, 1 -oxido- 1 ,2-thiazinanyl, 1 , 1 -dioxidoisothiazolidinyl, 1 , 1 -dioxido- 1 ,2-thiazinanyl, 2-oxido- 1 ,2,3-oxathiazolidinyl, 2,2-dioxido-l, 2,3-oxathiazolidinyl, 2-oxido-l, 2,3-oxathiazinanyl, 2,2-dioxido-l ,2,3-oxathiazinanyl, 1-oxido-l ,2,5-thiadiazolidinyl,
  • ring comprising R 2 -N-R 3
  • morpholino piperazinyl, 3-oxazolidinonyl, thiomorpholino, 3,5-dioxidopiperidinyl, 2-oxopyrrolidyl, 1-oxidoisothiazolidinyl, 1,1 -dioxidoisothiazolidinyl, 2-oxopiperidinyl, 2-oxohexahydropyrimidinyl, 2-oxido-l ,2,3-oxathiazolidinyl, 2,2-dioxido-l, 2,3-oxathiazolidinyl, 2-oxido-l,2,3-oxathiazinanyl, 2,2-dioxido-l, 2,3-oxathiazolidinyl, 2-oxido-l,2,3-oxathiazinanyl, 2,2-dioxido-l, 2,3-oxathiazolidinyl, 2-oxido-l,2,3-oxathiazinany
  • Suitable values for the ring comprising R -N-R are 2-oxo-l,3-oxazolidin-3- yl (3-oxazolidinonyl) and 2-oxopyrrolidinyl.
  • Suitable values for the optional substituents for the ring comprising R -N-R are 1 or 2 substituents independently selected from halo, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, (1- 4C)alkyl, (l-4C)alkoxy, hydroxy(l-4C)alkyl, and dihydroxy(2-4C)alkyl.
  • substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from halo, carboxy, (l-4C)alkyl, (l-4C)alkoxy, hydroxy(l-4C)alkyl, and dihydroxy(2-4C)alkyl.
  • substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from hydroxy, hydroxy(l-4C)alkyl, amino(l- 4C)alkyl, imidazolyl, -(l-4C)alkylS(O) (l-4C)alkyl (wherein b is 1 or 2), halo, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, (l-4C)alkyl, (1- 4C)alkoxy, and dihydroxy(2-4C)alkyl.
  • substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from halo, carboxy, (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino(l-4C)alkyl, imidazolyl, -(1- 4C)alkylS(O) b (l-4C)alkyl (wherein b is 1 or 2), hydroxy(l-4C)alkyl, and dihydroxy(2- 4C)alkyl.
  • suitable values for the optional substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from hydroxy, hydroxy(l-4C)alkyl, amino(l- 4C)alkyl, imidazolyl, and -(l-4C)alkylS(O) b (l-4C)alkyl (wherein b is 1 or 2).
  • Further suitable values for the optional substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from hydroxy, hydroxymethyl, aminomethyl, imidazolyl, methylsulfonylmethyl and methylsulfinylmethyl.
  • suitable values for the optional substituents for the ring comprising R 2 -N-R 3 are 1 or 2 substituents independently selected from hydroxy and hydroxymethyl.
  • the ring comprising R 2 -N-R 3 is substituted with one substituent selected from any of the suitable values for such substituents mentioned hereinbefore.
  • the ring comprising R -N-R is unsubstituted.
  • A is phenylene; n is 0, 1 or 2; m is 0, 1 or 2;
  • R 4 is halo
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a 5- or 6-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S (provided that there are no O-O,
  • any N, S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (l-4C)alkanoyl, hydroxy(l-4C)alkyl, dihydroxy(2-4C)alkyl, amino(l-4C)alkyl, (1-
  • A is phenylene; n is 0, 1 or 2; m is 1 or 2;
  • R 4 is chloro, fluoro or methyl
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-C ⁇ 2-O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a 5- or 6-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, ⁇ and S (provided that there are no O-O,
  • any ⁇ , S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (1-
  • A is heteroarylene; n is 0, 1 or 2; m is 0, 1 or 2;
  • R 4 is halo
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a 5- or 6-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, ⁇ and S (provided that there are no O-O,
  • any ⁇ , S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (1-
  • R 4 is chloro, fluoro or methyl
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-C ⁇ 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a 4- to 7-membered, saturated, partially unsaturated or unsaturated heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, ⁇ and S (provided that there are no O-O,
  • any ⁇ , S or C atom may optionally be oxidised, and wherein said heterocyclic ring is optionally substituted with 1 or 2 substituents independently selected from halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, (l-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkoxy, (1-
  • A is phenylene; n is 0, 1 or 2; m is 0, 1 or 2;
  • R 4 is halo
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-C ⁇ 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a ring selected from morpholino, pyrrolyl, piperazinyl, triazolyl, tetrazolyl, imidazolyl, 3-oxazolidinonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-2-yl, pyrazolyl, pyrazolinyl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl, 1-oxidoisothiazolidinyl, 1-oxido- 1,2-thiazinanyl, 1,1 -dioxidoisothiazolidinyl,
  • R 4 is chloro, fluoro or methyl
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a ring selected from morpholino, pyrrolyl, piperazinyl, triazolyl, tetrazolyl, imidazolyl, 3-oxazolidinonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-2-yl, pyrazolyl, pyrazolinyl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl, 1-oxidoisothiazolidinyl, 1-oxido- 1,2-thiazinanyl, 1,1-dioxidoisothiazolidinyl, l,l-dioxido-l,2-thiazinanyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoimidazolidinyl, 2-ox
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a ring selected from morpholino, pyrrolyl, piperazinyl, triazolyl, tetrazolyl, imidazolyl, 3-oxazolidinonyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, 3-oxopyrazolin-2-yl, pyrazolyl, pyrazolinyl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl, 1-oxidoisothiazolidinyl, l-oxido-l,2-thiazinanyl, 1,1-dioxidoisothiazolidinyl, l,l-dioxido-l,2-
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-; R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl,
  • A is phenylene; n is 0, 1 or 2; m is 1 or 2; R 4 is chloro, fluoro or methyl;
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl,
  • 2,2-dioxido-l, 2,3-oxathiazinanyl 1 -oxido- 1,2,5-thiadiazolidinyl, l,l-dioxido-l,2,5-thiadiazolidinyl, 1-oxido- 1,2,6-thiadiazinanyl and l,l-dioxido-l,2,6-thiadiazinanyl; which ring is optionally substituted by 1 or 2 substituents independently selected from halo, carboxy, (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino(l-
  • A is phenylene; n is 0, 1 or 2; m is 0, 1 or 2; R 4 is chloro;
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl, 3,5-dioxidopiperidinyl, 3-oxopyrazolin-2-yl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl,
  • A is phenylene; n is 0, 1 or 2; m is 1 or 2;
  • R 4 is chloro, fluoro or methyl
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl, 3,5-dioxidopiperidinyl, 3-oxopyrazoIin-2-yl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl,
  • 1,1 -dioxido- 1,2,5-thiadiazolidinyl 1,1 -dioxido- 1,2,5-thiadiazolidinyl, 1-oxido- 1,2,6-thiadiazinanyl and l,l-dioxido-l,2,6-thiadiazinanyl; which ring is optionally substituted by 1 or 2 substituents independently selected from hydroxy, hydroxy(l-4C)alkyl, amino(l-4C)alkyl, imidazolyl, and
  • A is phenylene; n is 0, 1 or 2; m is 1 or 2;
  • R 4 is chloro
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH 2 -O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl,
  • 1,1 -dioxido- 1,2,6-thiadiazinanyl which ring is optionally substituted by 1 or 2 substituents independently selected from halo, carboxy, (l-4C)alkyl, (l-4C)alkoxy, hydroxy(l-4C)alkyl, and dihydroxy(2-4C)alkyl; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
  • substituents independently selected from halo, carboxy, (l-4C)alkyl, (l-4C)alkoxy, hydroxy(l-4C)alkyl, and dihydroxy(2-4C)alkyl; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
  • A is phenylene; n is 0, 1 or 2; m is l;
  • R 4 is chloro, fluoro or methyl
  • R 1 is selected from fluoro, chloro, methyl, ethyl, methoxy and -O-CH2-O-;
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl, 3,5-dioxidopiperidinyl, 3-oxopyrazolin-2-yl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl,
  • A is phenylene; n is O; m is O or 1;
  • R 4 is chloro; R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl,
  • A is phenylene; n is 0; m is 1;
  • R 4 is chloro, fluoro or methyl
  • R 2 and R 3 together with the nitrogen to which they are attached form a morpholino, piperazinyl, 3-oxazolidinonyl, thiomorpholino, homopiperazinyl, 3,5-dioxidopiperidinyl, 3-oxopyrazolin-2-yl, 4-oxopyridyl, 2-oxopyrrolidyl, 2-oxoazetidinyl,
  • R 4 is chloro, fluoro or methyl
  • R 2 and R 3 together with the nitrogen to which they are attached form a 3-oxazolidinonyl or 2-oxopyrrolidinyl ring which ring is optionally substituted by 1 substituent selected from hydroxy, hydroxymethyl, aminomethyl, imidazolyl, methylsulfonylmethyl and methylsulfinylmethyl; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.
  • Preferred compounds of the invention are of the formula (1 A), wherein R to R and n are as defined in any aspect or embodiment described hereinbefore or hereinafter.
  • Particular compounds of the invention are each of the Examples or a pharmaceutically acceptable salt or pro-drug thereof, each of which provides a further independent aspect of the invention.
  • Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt or an in-vivo hydrolysable ester thereof which process (wherein A, R 1 to R 4 , m and n are, unless otherwise specified, as defined in formula (1)) comprises of: a) reacting an acid of the formula (2):
  • Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) and dicyclohexyl-carbodii ide (DCCI), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or
  • 2,6-di- fcyZ-pyridines such as 2,6-lutidme or 2,6-di-tert-butylpyridine.
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
  • the coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
  • Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters.
  • the reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above.
  • the reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
  • the acids of formula (2) are commercially available or they are known compounds or they are prepared by processes known in the art.
  • Compounds of formula (3) may be prepared according to Scheme 3: (wherein P is a protecting group such as tert-butyloxycarbonyl (Boc), p-toluenesulfonate (tosylate) or methanesulfonate (mesylate) group).
  • compound of formula (3) may be prepared by the cyclisation of a group
  • R ,2a -Y (wherein Y is a nucleophile such as OH, NH 2 or SH, and R 2a : is a group such as (1- 3C)alkylsulfonyl, (l-3C)alkylcarbonyl or (l-3C)alkyl, optionally substituted by any of the optional substituents for the ring defined by R 2 -N-R 3 or by a carbonyl or sulfonyl group) with a group R 3a -X (wherein X is a leaving group such as F, CI, Br, mesylate or tosylate, and R 3a is a group such as (l-3C)alkylsulfonyl, (l-3C)alkylcarbonyl or (l-3C)alkyl, optionally substituted by any of the optional substituents for the ring defined by R 2 -N-R 3 or by a carbonyl or sulfonyl group), as shown in Scheme
  • Steps 1, 2, 3, 4, 5 and 6 are known in the literature or they are standard transformation known in the art.
  • the regiosomeric azaindanones (22a, 22b, 22c) are known in the literature or they are prepared by processes known in the art. It will be appreciated that starting from these alternative azaindanones will give rise to the regioisomeric pyridyl products.
  • 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.
  • 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.
  • 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).
  • a suitable protecting group for an amino or alkyla ino 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 trifluoroacetic 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.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • thermodynamic solubility data for the compounds of the invention as given above may be measured by agitating the compound in 0.1 M phosphate at pH7.4 for 24hours, then analysis of the supernatant (for example by LCUV/MS) using a solution (for example in DMSO) of known concentration as the calibrant.
  • Plasma Protein binding may be measured using an equilibrium dialysis technique, whereby compound is added to 10% plasma giving a concentration of 20 ⁇ M and dialysed with isotonic buffer for 18 hours at 37°C. The plasma and buffer solutions are analysed using LCUNMS and the first apparent binding constant for the compound derived. The binding constant is then used to determine the % free in 100% plasma.
  • the binding constant derived from the dialysis experiment is based upon a model of 1:1 binding between compound and albumin.
  • the compounds defined in the present invention possesses glycogen phosphorylase inhibitory activity. This property may be assessed, for example, using the procedure set out below.
  • Assay The activity of the compounds is determined by measuring the inhibitory effect of the compounds on glycogen degradation, the production of glucose-1-phosphate from glycogen is monitored by the multienzyme coupled assay, as described in EP 0 846464 A2, general method of Pesce et al ( Pesce, M A, Bodourian, S H, Harris, R C, and Nicholson, J F (1977) Clinical Chemistry 23, 1171 - 1717).
  • the reactions were in 384well microplate format in a volume of 50 ⁇ l.
  • the change in fluorescence due to the conversion of the co-factor NAD to NADH is measured at 340nM excitation, 465nm emission in a Tecan Ultra Multifunctional Microplate Reader.
  • the reaction is in 50mM HEPES, 3.5mM KH 2 PO 4, 2.5mM MgCl 2 , 2.5mM ethylene glycol-bis(b-aminoethyl ether) N,N,N',N'-tetraacetic acid, lOOmM KC1, 8mM D-(+)-glucose pH7.2, containing 0.5mM dithiothreitol, the assay buffer solution.
  • Human recombinant liver glycogen phosphorylase a (hrl GPa) 20nM is pre-incubated in assay buffer solution with 6.25mM NAD, 1.25mg type HI glycogen at 1.25 mg ml "1 the reagent buffer, for 30 minutes.
  • the coupling enzymes, phosphoglucomutase and glucose-6-phosphate dehydrogenase ( Sigma) are prepared in reagent buffer, final concentration 0.25Units per well. 20 ⁇ l of the hrl GPa solution is added to lO ⁇ l compound solution and the reaction started with the addition of 20ul coupling enzyme solution.
  • % inhibition (1 - (compound RFUs - fully inhibited RFUs)/ (non-inhibited rate RFUs - fully inhibited RFUs)) * 100.
  • Typical IC 50 values for compounds of the invention when tested in the above assay are in the range lOO ⁇ M to InM.
  • Compounds of the Examples typically have IC 5 0 values of less than lO ⁇ M.
  • Example 2 gave an IC 50 value of 0.47 ⁇ M.
  • the inhibitory activity of compounds was further tested in rat primary hepatocytes. Rat hepatocytes were isolated by the collagenase perfusion technique, general method of Seglen (P.O. Seglen, Methods Cell Biology (1976) 13 29-83).
  • DMEM Dulbeco's Modified Eagle's Medium
  • NEAA non essential amino acids
  • Glutamine penicillin /streptomycin ((100units/100ug)/ml)
  • the hepatocytes were then cultured in the DMEM solution without foetal calf serum and with lOnM insulin and lOnM dexamethasone.
  • Experiments were initiated after 18-20 hours culture by washing the cells and adding Krebs-Henseleit bicarbonate buffer containing 2.5mM CaCl 2 and 1% gelatin.
  • a pharmaceutical composition which comprises a compound of the formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the compositions of the invention are in a form suitable for oral dosage.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the compound of formula (1) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the inhibition of glycogen phosphorylase activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • Simultaneous treatment may be in a single tablet or in separate tablets.
  • the compounds of the present invention or their pharmaceutically acceptable salts may be administered in combination with one or more of the following agent(s): 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide) and glucokinase activators 3) Agents that improve incretin action (for example dipeptidyl peptidase IN inhibitors, GLP-1 agonists) 4) Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone); and agents with combined PPARalpha and gamma activity 5) Agents that modulate hepatic glucose balance (for example metformin, fructose 1, 6 bisphosphat
  • nifedipine Angiotensin receptor antagonists (eg candesartan), antagonists and diuretic agents (eg. furosemide, benzthiazide); 12)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; 13) Agents which antagonise the actions of glucagon; and 14) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
  • non-steroidal anti-inflammatory drugs eg. aspirin
  • steroidal anti-inflammatory agents eg. cortisone
  • a compound of the formula (1) for use as a medicament in the treatment of type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity in a warm-blooded animal such as man.
  • a compound of the formula (1), or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof as defined hereinbefore in the manufacture of a medicament or use in the treatment of type 2 diabetes in a warm-blooded animal such as man.
  • a method of producing a glycogen phosphorylase inhibitory 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 (1).
  • a method of treating type 2 diabetes, insulin resistance, syndrome X, hyperinsulinaemia, hyperglucagonaemia, cardiac ischaemia or obesity 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 (1).
  • a method of treating type 2 diabetes 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 (1).
  • a dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
  • the compounds of formula (1) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the alternative and preferred embodiments of the compounds of the invention described herein also apply.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon;
  • chromatography means flash chromatography on silica gel; thin layer chromatography
  • 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 300 MHz using perdeuterio dimethyl sulphoxide (DMSO- ⁇ 6 ) as solvent unless otherwise indicated, other solvents (where indicated in the text) include deuterated chloroform
  • reduced pressures are given as absolute pressures in Pascals (Pa); elevated pressures are given as gauge pressures in bars;
  • SM starting material EtOAc ethyl acetate; MeOH methanol; EtOH ethanol; DCM dichloromethane; HOBt 1-hydroxybenzotriazole; D ⁇ PEA di-isopropylethylamine ; EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et 2 O diethyl ether; THF tetrahydrofuran; DMF N, N-dimethylformamide; HATU 6>-(7-Azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate EDAC 1 -(3 -dimethylaminopropyl)-3 -ethyl-c arbodiimide hydrochloride TFA Trifluoroacetic acid DMTMM 4-(4,6-Dimethoxy-l
  • Example 3 5-Fluoro-N-l(lR.2R)-l-[(35)-3-hvdroxy-2-oxopyrrolidin-l-vn-2.3-dihvdro- lff-inden-2-vI #-indole-2-carboxamide
  • Example 4 5-Methyl-N- ⁇ (lR,2R)-l-r(35)-3-hvdroxy-2-oxopyrrolidin-l-yl1-2 -dihvdro- l - r -inden-2-yl -li?-indole-2-carboxamide
  • reaction mixture was diluted with ethyl acetate (25 mL) washed with water (10 mL), brine (10 mL), dried (MgSO ), filtered and the volatiles were removed by evaporation under reduced pressure.
  • the crade residues were purified by silica chromatography (2:1, iso-hexane:ethyl acetate) to give the title compound (250 mg, 39%) as a pale brown foam.
  • the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (75 mL) washed with water (6x30 mL), brine (30 mL) and dried (MgSO 4 ), filtered and the volatiles were removed by evaporation under reduced pressure.
  • the crude residues were purified by silica chromatography (ethyl acetate) to give the title compound (900 mg, 26%) as a brown foam.
  • the crade material was re-dissolved in EtOH:water (60 mL, 5:1) and mesopourous carbonate resin (5 g) added and the suspension stirred at ambient temperature for 1 h. The suspension was filtered and the volatiles removed under reduced pressure to afford the title compound (1.5 g, 70%).

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Abstract

La présente invention se rapporte à un composé représenté par la formule (1) ou à un sel pharmaceutiquement acceptable, ou promédicament, de ce composé; dans la formule (1), A est phénylène ou hétéroarylène; n est égal à 0, 1 ou 2; m est égal à 0, 1 ou 2; R1 est par exemple sélectionné parmi halo, nitro, cyano, hydroxy, carboxy, carbamoyle, N-(1-4C)alkylcarbamoyle, N-(1-4C)alkylsulphamoyle, (1-4C)alkyle, (1-4C)alcoxy, (1-4C)alcanoyle, (1-4C)alcanoyloxy, hydroxy(1-4C)alkyle, fluorométhyle, et -NHSO2(1-4C)alkyle; ou, lorsque n est égal à 2, les deux groupes R1 conjointement aux atomes de carbone de A auxquels ils sont fixés, peuvent former un noyau saturé comportant 4 à 7 éléments, contenant éventuellement 1 ou 2 hétéroatomes indépendamment sélectionnés parmi 0, S et N; R2 et R3 forment, conjointement à l'azote auquel ils sont fixés, un noyau hétérocyclique éventuellement substitué comportant 4 à 7 éléments; et R4 est par exemple halo ou (1-4C)alkyle. Le composé de la présente invention présente une activité inhibitrice de la glycogène phosphorylase et s'avère par conséquent utile pour le traitement des états pathologiques associés à une activité accrue de la glycogène phosphorylase. L'invention se rapporte également à des procédés de fabrication des composés et des compositions pharmaceutiques contenant ce composé.
PCT/GB2004/003620 2003-08-29 2004-08-25 Derives d'indolamide possedant une activite inhibitrice de la glycogene phosphorylase Ceased WO2005020985A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
US7307174B2 (en) 2002-10-03 2007-12-11 Astrazeneca Ab Process and intermediates for the preparation of thienopyrrole derivatives
US7411074B2 (en) 2002-10-03 2008-08-12 Astrazeneca Ab Process and intermediates for the preparation of the thienopyrrole derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1136071A2 (fr) * 2000-03-22 2001-09-26 Pfizer Products Inc. Utilisation d'inhibiteurs de la glycogène phosphorylase
WO2002020530A1 (fr) * 2000-09-06 2002-03-14 Astrazeneca Ab Amides de pyrrolyle bicycliques servant d'inhibiteurs de glycogene phosphorylase
WO2003074484A1 (fr) * 2002-03-06 2003-09-12 Astrazeneca Ab Derives d'indolamide presentant une activite inhibitrice de la glycogene phosphorylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1136071A2 (fr) * 2000-03-22 2001-09-26 Pfizer Products Inc. Utilisation d'inhibiteurs de la glycogène phosphorylase
WO2002020530A1 (fr) * 2000-09-06 2002-03-14 Astrazeneca Ab Amides de pyrrolyle bicycliques servant d'inhibiteurs de glycogene phosphorylase
WO2003074484A1 (fr) * 2002-03-06 2003-09-12 Astrazeneca Ab Derives d'indolamide presentant une activite inhibitrice de la glycogene phosphorylase

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7332515B2 (en) 2002-03-06 2008-02-19 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7307174B2 (en) 2002-10-03 2007-12-11 Astrazeneca Ab Process and intermediates for the preparation of thienopyrrole derivatives
US7411074B2 (en) 2002-10-03 2008-08-12 Astrazeneca Ab Process and intermediates for the preparation of the thienopyrrole derivatives
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv

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