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(12) Patent Application Publication (10) Pub. No.: US 2005/0267096 A1 Allerton Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0267096 A1 Allerton Et Al US 2005O267096A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0267096 A1 Allerton et al. (43) Pub. Date: Dec. 1, 2005 (54) NEW INDAZOLE AND INDOLONE (52) U.S. Cl. ................ 514/210.21; 514/232.5; 514/321; DERVATIVES AND THEIR USE 514/406; 514/418; 544/140; PHARMACEUTICALS 546/199; 546/201: 548/465; 548/361.1 (75) Inventors: Charlotte Moira Norfor Allerton, Sandwich (GB); David Hepworth, (57) ABSTRACT Sandwich (GB); Duncan Charles The present invention provides for compounds of formula Miller, Sandwich (GB) (I), Correspondence Address: PFIZER INC. (I) PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD GROTON, CT 06340 (US) (73) Assignee: Pfizer Inc (21) Appl. No.: 11/138,706 (22) Filed: May 26, 2005 which are a class of dopamine agonists, more particularly a class of agonists that are selective for D3 over D2. These Related U.S. Application Data compounds are useful for the treatment and/or prevention of Sexual dysfunction, for example female Sexual dysfunction (60) Provisional application No. 60/598,716, filed on Aug. (FSD), in particular female sexual arousal disorder (FSAD), 3, 2004. hypoactive sexual desire disorder (HSDD; lack of interest in (30) Foreign Application Priority Data sex), female orgasmic disorder (FOD; inability to achieve orgasm); and male Sexual dysfunction, in particular male May 26, 2004 (GB). 0411810.5 erectile dysfunction (MED). Male sexual dysfunction as Jul. 9, 2004 referred to herein is meant to include ejaculatory disorders (GB)......................................... O415455.5 Such as premature ejaculation, anorgasmia (inability to Publication Classification achieve orgasm) or desire disorders Such as hypoactive sexual desire disorder (HSDD; lack of interest in sex). These (51) Int. Cl." .................. A61K 31/5377; A61K 31/454; compounds are also useful in treating neuropSychiatric dis A61K 31/416; A61K 31/404 orders and neurodegenerative disorders. US 2005/0267096 A1 Dec. 1, 2005 NEW NDAZOLE AND INDOLONE DERVATIVES 0010) R' represents H or (C-C)alkyl; wherein said AND THEIR USE PHARMACEUTICALS (C-C)alkyl may be optionally Substituted by (C- C.)alkyl, OR, phenyl, or heteroaryl; 0001. The present invention relates to a class of dopam ine agonists, more particularly a class of agonists that are 0011) R' represents H or (C-C)alkyl; wherein said selective for D3 over D2. These compounds are useful for (C-C)alkyl may be optionally substituted by OR; the treatment and/or prevention of Sexual dysfunction, for example female Sexual dysfunction (FSD), in particular 0012) R' represents H or (C-C)alkyl; female Sexual arousal disorder (FSAD), hypoactive Sexual 0013 R represents H, methyl, ethyl, methoxy, or desire disorder (HSDD; lack of interest in sex), female ethoxy, orgasmic disorder (FOD; inability to achieve orgasm); and male Sexual dysfunction, in particular male erectile dysfunc 0014) R' represents (C-C)alkyl; tion (MED). Male sexual dysfunction as referred to herein is 0.015 R7 represents H or (C-C)alkyl; wherein said meant to include ejaculatory disorderS Such as premature (C-C)alkyl may be optionally substituted with 1 or ejaculation, anorgasmia (inability to achieve orgasm) or 2 Substituents each independently Selected from desire disorderS Such as hypoactive Sexual desire disorder OR, phenyl or substituted phenyl; (HSDD; lack of interest in sex). These compounds are also useful in treating neuropsychiatric disorders and neurode (oys spresents H., (C-C)alkyl, phenyl, or generative disorders. 2)phenyl, 0002 The present invention provides for compounds of 0017 wherein heteroaryl means a 5 to 7 membered formula (1), aromatic ring, containing from 1 to 4 heteroatoms, Said heteroatoms each independently selected from O, S and N: (I) said heteroaryl may be optionally substituted with 1 or more substituents selected from (C-C)alkyl, halo and OR, each Substituent may be the same or different; and 0018 wherein substituted phenyl means phenyl substi tuted with 1 or more substituents selected from (C- C.)alkyl, halo and OR, each substituent may be the same or different; 0.019 and pharmaceutically acceptable salts, Solvates, 0003 wherein: polymorphs and prodrugs thereof, with the provisoS that: 0004) A is selected from N or C=O 0020 Z is 0 when A is C=O; and 0005 X is selected from H, methyl, ethyl, OH, OCH, 0021 when A is C=O, X is H and R' is (IV), then R OCHCH, halo, SCH, CN or CF cannot be H. 0022 Unless otherwise indicated, (C-C)alkyl may be Straight chain or branched. 0023 Suitable heteroaryl groups include pyridinyl, pyri 0006) (the dashed bond in formula (I)) represents a midinyl, pyridaZinyl and pyrazinyl. single bond when A is N, and is absent when A is C=O 0024. Unless otherwise indicated, the term halo means 0007) R' is selected from: fluoro, chloro, bromo or iodo. (II) 0025. Unless otherwise indicated, the term substituted R", means Substituted by one or more defined groups. In the case where groupS may be Selected from a number of alternatives groups, the Selected groups may be the same or different. 0026. The pharmaceutically acceptable salts of the com pounds of the formula (I) include the acid addition salts thereof. (III) 0027) A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing and together Solutions of a compound of the formula (I) and the desired acid. The Salt may precipitate from Solution and be N collected by filtration or may be recovered by evaporation of R2 the solvent. (IV) 0028 Suitable acid addition salts are formed from acids R5 R7 which form non-toxic Salts. Examples include the acetate, adipate, aspartate, benzoate, beSylate, bicarbonate/carbon -N- n ate, bisulphate/Sulphate, borate, camsylate, citrate, cycla mate, edisylate, eSylate, formate, fumarate, gluceptate, glu conate, glucuronate, hexafluorophosphate, hibenzate, 0008 wherein: hydrochloride/chloride, hydrobromide/bromide, hydroio dide/iodide, isethionate, lactate, malate, maleate, malonate, 0009 Z represents O or CH; meSylate, methylsulphate, naphthylate, 2-napSylate, nicoti US 2005/0267096 A1 Dec. 1, 2005 nate, nitrate, orotate, Oxalate, palmitate, pamoate, phos where they are next to other water molecules. In metal-ion phate/hydrogen phosphate/dihydrogen phosphate, pyro coordinated hydrates, the water molecules are bonded to the glutamate, Saccharate, Stearate, Succinate, tannate, tartrate, metal ion. tosylate, trifluoroacetate and Xinofoate Salts. 0040. When the solvent or water is tightly bound, the 0029 Hemisalts of acids and bases may also be formed, complex will have a well-defined Stoichiometry independent for example, hemisulphate and hemicalcium Salts. of humidity. When, however, the solvent or water is weakly bound, as in channel Solvates and hygroscopic compounds, 0.030. For a review on suitable salts, see Handbook of the water/solvent content will be dependent on humidity and Pharmaceutical Salts. Properties, Selection, and Use by drying conditions. In Such cases, non-Stoichiometry will be Stahl and Wermuth (Wiley-VCH, 2002). the norm. 0.031) Pharmaceutically acceptable salts of compounds of 0041. Hereinafter all references to compounds of formula formula I may be prepared by one or more of three methods: I include references to the Salts and Solvates thereof. 0032 (i) by reacting the compound of formula I with 0042. The compounds of the invention include com the desired acid; pounds of formula I as hereinbefore defined, including all 0033 (ii) by removing an acid- or base-labile protect polymorphs and crystal habits thereof, prodrugs and isomers ing group from a Suitable precursor of the compound of thereof (including optical, geometric and tautomeric iso formula I or by ring-opening a Suitable cyclic precur mers) as hereinafter defined and isotopically-labeled com Sor, for example, a lactone or lactam, using the desired pounds of formula I. acid; or 0043 Included within the scope of the present invention are all Stereoisomers, geometric isomers and tautomeric 0034 (iii) by converting one salt of the compound of forms of the compounds of formula I, including compounds formula I to another by reaction with an appropriate exhibiting more than one type of isomerism, and mixtures of acid or by means of a Suitable ion exchange column. one or more thereof. Also included are acid addition or base 0.035 All three reactions are typically carried out in Salts wherein the counterion is optically active, for example, Solution. The resulting Salt may precipitate out and be d-lactate or l-lysine, or racemic, for example, dl-tartrate or collected by filtration or may be recovered by evaporation of dl-arginine. the Solvent. The degree of ionisation in the resulting Salt may 0044) A compound of the formula (I) contains one or vary from completely ionised to almost non-ionised. more asymmetric carbon atoms and therefore exists in two 0.036 The compounds of the invention may exist in a or more Stereoisomeric forms. Furthermore, the skilled continuum of Solid States ranging from fully amorphous to person will understand that moiety (II) encompasses all fully crystalline. The term “amorphous’ refers to a state in Stereoisomeric and distereoisomeric forms, in particular: which the material lackS long range order at the molecular level and, depending upon temperature, may exhibit the (IIa) physical properties of a Solid or a liquid. Typically Such Z. R4 materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a Solid, are more formally described as a liquid. Upon heating, a change from Solid to liquid properties occurs which is characterised by a O. change of State, typically Second order (glass transition). The term “crystalline refers to a solid phase in which the R2 material has a regular ordered internal Structure at the (IIb) molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated s Z. D R4 sufficiently will also exhibit the properties of a liquid, but the change from Solid to liquid is characterised by a phase N "/R3 change, typically first order (melting point).
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