WO2011138265A2 - Indole and indazole derivatives as orexin receptor antagonists - Google Patents
Indole and indazole derivatives as orexin receptor antagonists Download PDFInfo
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- WO2011138265A2 WO2011138265A2 PCT/EP2011/056938 EP2011056938W WO2011138265A2 WO 2011138265 A2 WO2011138265 A2 WO 2011138265A2 EP 2011056938 W EP2011056938 W EP 2011056938W WO 2011138265 A2 WO2011138265 A2 WO 2011138265A2
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- methyl
- acetamide
- sulfonyl
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- phenylmethyl
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- GVPFGXZXYKZOGJ-UHFFFAOYSA-N CN(Cc1cccc(Cl)c1)C(C[n](c1cc(F)ccc11)nc1S(Cc1ccccc1)(=O)=O)=O Chemical compound CN(Cc1cccc(Cl)c1)C(C[n](c1cc(F)ccc11)nc1S(Cc1ccccc1)(=O)=O)=O GVPFGXZXYKZOGJ-UHFFFAOYSA-N 0.000 description 1
- DLNVQPWSOFIKGL-UHFFFAOYSA-N O=C(C[n]1c2ccccc2c(S(Cc(cc2)ccc2F)(=O)=O)c1)NCc(cc1)ccc1F Chemical compound O=C(C[n]1c2ccccc2c(S(Cc(cc2)ccc2F)(=O)=O)c1)NCc(cc1)ccc1F DLNVQPWSOFIKGL-UHFFFAOYSA-N 0.000 description 1
- SRNYTHNOXOMWQJ-UHFFFAOYSA-N O=S(Cc(cc1)ccc1F)(c1c[nH]c2c1cccc2)=O Chemical compound O=S(Cc(cc1)ccc1F)(c1c[nH]c2c1cccc2)=O SRNYTHNOXOMWQJ-UHFFFAOYSA-N 0.000 description 1
- LYFRUBQVZGVXPR-UHFFFAOYSA-N Sc1c[nH]c2c1cccc2 Chemical compound Sc1c[nH]c2c1cccc2 LYFRUBQVZGVXPR-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Definitions
- the present invention relates to Orexin Receptor antagonists, especially Orexin 2 Receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.
- orexins are neuropeptides discovered in 1998 by two research groups; orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide which are derived from a common pre-propeptide (Sakurai et al, Cell, 1998, 92, 573- 585; De Lecea L. et al, PNAS, 1998, 95, 322-27).
- Orexins are produced in the lateral hypothalamus and bind to two eponymous G-protein-coupled receptors (0X1 and 0X2). The 0X1 receptor is selective for OX-A, whereas the 0X2 receptor binds both OX-A and OX-B.
- Orexin Receptors are associated with diseases and disorders including eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, and Type II Diabetes.
- Orexin Receptor antagonists are described in the art. However, most of these compounds are non-selective and used as dual, 0X1 and 0X2 receptor, antagonists.
- cinnamide compounds as antagonists are described in WO-A 00/47576.
- Phenylurea compounds are described in WO-A 00/47577.
- Tetrahydroisoquinoline derivatives are decribed in, e.g., WO-A 01/68609.
- Piperidines are described in WO-A 01/96302.
- N-Aroyl cyclic amine derivatives are described in, e.g., WO-A 02/089800.
- the present invention provides compounds or a pharmaceutically acceptable salt thereof of formula (I)
- A is CH; N; or C(CH 3 );
- R 1 is hydrogen; halogen; or Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different;
- R 2 is hydrogen; or halogen;
- R 3 is hydrogen; or Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different; R 4 , R 5 are independently selected from the group consisting of hydrogen; halogen; and CN;
- R 6 is hydrogen; Ci_ 4 alkyl; or cyclopropyl, wherein Ci_ 4 alkyl and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
- R 7 is hydrogen; or methyl;
- R ⁇ s T 1 are joined together with the carbon atom to which they are attached to form a ring T 2 ;
- T 1 is cyclohexyl; or phenyl, wherein T 1 is optionally substituted with one or more R 9 , which are the same or different;
- T 2 is a 7 to 1 1 membered carbobicycle, wherein T 2 is optionally substituted with one or more R 10 , which are the same or different; R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 1 1 ; OR 1 1 ;
- Ci_ 6 alkyl wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different;
- R 1 1 , R l la , R l lb are independently selected from the group consisting of H; and Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different, provided that the following compounds are excluded:
- A is CH; N; or C(CH 3 );
- R is hydrogen; halogen; or Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different;
- R 2 is hydrogen; or halogen;
- R 3 is hydrogen; or Ci_ 4 alkyl, wherein Ci_ 4 alkyl is optionally substituted with one or more halogen, which are the same or different;
- R 4 , R 5 are independently selected from the group consisting of hydrogen; halogen; and CN;
- R 6 is hydrogen; Ci_ 4 alkyl; or cyclopropyl, wherein Ci_ 4 alkyl and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
- R 7 is hydrogen; or methyl
- R 7 and R 8 are joined together with the carbon atom to which they are attached to form a ring T 2 ;
- T 1 is cyclohexyl; or phenyl, wherein T 1 is optionally substituted with one or more R 9 , which are the same or different;
- T 2 is a 7 to 1 1 membered carbobicycle, wherein T 2 is optionally substituted with one or more R 10 , which are the same or different;
- variable or substituent defined herein can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
- the terms are used as follows:
- Alkyl means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified herein.
- Ci_4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g.
- Ci_ 4 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
- Each hydrogen of a Ci_ 4 alkyl carbon may be replaced by a substituent as further specified herein.
- Ci_6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g.
- Ci_6 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
- Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified herein.
- Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
- C 3 _ 7 cycloalkyl or “C3_ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein.
- 7 to 11 membered carbobicyclyl or “7 to 11 membered carbobicycle” means a carbocyclic system of two rings, like C 3 _ 7 cycloalkyl or phenyl rings, with 7 to 11 carbon ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated).
- An example is indan.
- Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given above, with all combinations of preferred substituent definitions being a subject of the present invention.
- the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
- A is CH; or C(CH 3 ), more preferred is CH.
- R 1 is H; F; CI; CH 3 ; or CF 3 . More preferably, R 1 is H; F; CH 3 . Even more preferably, R 1 is H.
- R 2 is H; F; or CI. More preferably, R 2 is H; or F. Even more preferably, R 2 is H.
- R 3 is H; or CH 3 . More preferably, R 3 is H.
- R 4 is H; or F and/or R 5 is H; F; or CN. More preferably, R 4 , R 5 are H.
- R 6 is H; CH 3 ; CH 2 CH 3 ; or cyclopropyl.
- T 1 is unsubstituted or substituted with 1, 2 or 3 R 9 , which are the same or different.
- R 9 is F; CI; CH 3 ; CF 3 ; CN; N(CH 3 ) 2 ; CH 3 0; or CHF 2 0.
- T 2 is indanyl and wherein T 2 is unsubstituted or substituted with one or more (preferably 1, 2 or 3) R 10 , which are the same or different.
- R 10 is F; CI; CH 3 ; CF 3 ; CN; N(CH 3 ) 2 ; CH 3 0; or CHF 2 0.
- the substituents A, R 1 to R 8 of formula (I) independently have the abovementioned meaning. Hence, one or more of the substituents A, R 1 to R 8 can have the preferred meanings given above. Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred meanings are also an object of the present invention.
- Preferred compounds are selected from the group consisting of 3-(benzylsulfonyl)-N-benzyl, N-methyl- indole- 1 -acetamide;
- tautomerism like e.g. keto-enol tautomerism, of compounds of formula (I) may occur
- the individual forms e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
- stereoisomers e.g. enantiomers, cis/trans isomers, conformers and the like.
- Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.
- the isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
- the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
- the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
- Compounds of the formula (I) which contain one or more basic groups i.e.
- acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
- suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
- the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
- the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art , for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
- the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
- the present invention provides compounds of general formula (I) as Orexin Receptor antagonists, preferably as selective 0X2 receptor antagonists.
- orexins are neuropeptides discovered in 1998 by two research groups; orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide which are derived from a common pre-propeptide (Sakurai et al, Cell, 1998, 92, 573-585; De Lecea L. et al, PNAS, 1998, 95, 322-27). Orexins are produced in the lateral hypothalamus and bind to two eponymous G-protein-coupled receptors (0X1 and 0X2).
- the 0X1 receptor is selective for OX-A, whereas the 0X2 receptor binds both OX-A and OX-B.
- the orexins stimulate food consumption in rats, suggesting a physiological role for these peptides as mediators of feeding behaviour (Sakurai T. et al, Cell, 1998, 92, 573-585; Ishii Y. et al, Behav.Brain.Res., 2005, vol. 157, 331-341; Thorpe A.J. et al, Brain Res., 2005, vol. 1050, 156-162).
- the orexins regulate sleep-wake behaviour, indicating a potential therapeutic approach to narcolepsy, insomnia and other sleep disorders (Chemelli R.M.
- indole and indazole derivatives of formula (I) are antagonists of Orexin receptors, preferably selectively of the 0X2 receptor.
- the present invention relates to the use of indole and indazole derivatives of formula (I) and pharmaceutically acceptable salts and solvates thereof in the treatment of disorders in which blockade of Orexin receptors is reasonably expected to be of therapeutic benefit e.g. eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity and Type II Diabetes.
- the compounds of formula (I) may be used for the preparation of a medicament, and are suitable, for the prevention or treatment of diseases selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes.
- Compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes.
- Another aspect of the present invention is a method for the treatment or prophylaxis of diseases, which are related to the Orexin receptors such as eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes comprising the administration to a patient a therapeutically effective amount of a compound of formula (I).
- one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of formula (I) for use as a medicament.
- Those compounds can be used in a pharmaceutical composition comprising at least one of said compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
- Other bioactive compounds may be further compounds of the present invention, i.e. a mixture of two or more of these compounds.
- Further bioactive compounds are further Orexin 2 Receptor antagonists and the like.
- Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the Orexin 2 Receptor.
- Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method for the treatment or prophylaxis of diseases and disorders associated with the Orexin 2 Receptor.
- Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes. More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
- Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method for the treatment or prophylaxis of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes. More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
- Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the Orexin 2 Receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
- Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, and Type II Diabetes, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
- “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- the active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions).
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
- the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
- any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
- oral liquid preparations such as, for example, suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
- tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
- the active compounds can also be administered intranasally, for example, as liquid drops or spray.
- the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
- a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
- a liquid carrier such as a fatty oil.
- Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
- a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
- oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
- Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
- compounds of formula (I) are administered orally.
- the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
- a further aspect of the present invention is a method for the preparation of a compound of formula (I) as defined in above comprising the step of reacting a compound of formula (IV)
- R 1 to R 5 have the meaning as indicated above with a compound of formula HN(R 6 )CH(R 7 R 8 ), wherein R 6 to R 8 have the meaning as indicated above to yield a compound of formula (I).
- CHO-Kl cell line stably expressing human Orexin-1 receptor (hOXIR, coding sequence of AF041243) was obtained from Euroscreen/PerkinElmer (CHO-hOXIR, ES-330-C).
- a plasmid containing the human Orexin-2 receptor (hOX2R) cDNA was purchased from RZPD (RZPDo834A1045-pT-REx-DEST30).
- the human Orexin-2 receptor coding region was amplified in a gradient PCR reaction using hOX2Rfor (5' ccaggatccgc caccatgtccggcaccaaattggaggactcc) and hOX2Rrev (5' ccgcggccgctaccagttttgaagtggtcctgc) primers containing restriction sites for the restriction enzymes BamHI and Notl.
- the PCR reaction was performed with the LightCycler system from Roche Applied Science.
- the amplified DNA fragment was digested with restriction enzymes BamHI and Notl (Fermentas) and subsequently cloned into the BamHI/NotI sites of the pFB-Neo vector (Stratagene) thereby generating plasmid pFB-Neo-hOX2R.
- CHO-hOX2R cell line For a stably expressing CHO-hOX2R cell line viral transduction of CHO-Kl cells were performed by using the pFB-Neo-hOX2R plasmid and the pVPack vector system from Stratagene according to the manufacturer's manual. Cells expressing the hOX2 receptor were selected using G418 at a final concentration of 50( ⁇ g/ml and single cell clones were produced by limited dilution cloning.
- CHO-hOXIR cells were grown in HAM F12 Nutrient Mixture (Sigma, N6658), 10%Fetal Bovine Serum (Sigma, F9665), 1% Penstrep (Sigma, p4333) and 400mg/ml G418 (Sigma, A1720).
- CHO-hOX2R cells were grown in DMEM F12 medium (Sigma, D8437) supplemented with 10%Fetal Bovine Serum (Sigma, F9665), 1% Penstrep (Sigma, p4333) and 500mg/ml G418 (Sigma, A1720). Cells were maintained under 5% C0 2 atmosphere at 37°C. Cells were passaged every 2-3 days.
- CHO-hOXIR and CHO-hOX2R cells were seeded at a density of 7500 cells per well into black, 384 well Costar Cellbind plates and cultured overnight in the appropriate cell culture medium as described above without G418 selection. The next day the medium was removed and the cells were incubated for 1.5hrs at 37°C in fluo-4, AM dye solution [2 ⁇ fluo-4,AM (Molecular Probes; F- 14202, Lot#28Cl-12) in 5mM probenecid (Sigma, P-8761, Lot# 121K1662), 0.1% Bovine Serum Albumin (BSA, MERCK, 1.12018.0100), lxHBSS (Invitrogen, 14025-050), 20mM HEPES (Invitrogen,.
- AM dye solution [2 ⁇ fluo-4,AM (Molecular Probes; F- 14202, Lot#28Cl-12) in 5mM probenecid (Sigma, P-8761, Lot# 121K1662), 0.1% Bovine Serum Albumin (
- agonist solution (5nM Orexin-A, TOCRIS, 1455) in 5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES was added during incubation of the plate at 37°C in the fluorescence plate reader (FlexStation, Molecular Devices). Fluorescence was measured for 0-60 seconds per well at an excitation of 485nm and emission o f 538nm.
- Orexin-A For EC50 determination of Orexin-A the cells were incubated as described above for 20min at 37°C in probenecid buffer (5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES, P/oDMSO) without compound solution. Agonist injection occurred in the fluorescence plate reader (FlexStation, Molecular Devices) at different concentrations ranging from 0-lOOnM in 5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES. Detection of fluorescence was as described above.
- NMR Spectroscopy was determined using either a Bruker DPX 250 MHz NMR or a Bruker DRX 500 MHz NMR. Values are reported as shifts (in ppm), with zero corresponding to tetramethylsilane as an internal standard. Chemical shifts are reported in ppm ([delta]). Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90 C.
- Solvent A 0.1% Formic acid / water
- Solvent B 0.1% Formic acid / acetonitrile
- UV Detection wavelength 215nm
- Eluent 0 mins to 5 mins, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5 mins to 5.4 mins, 100% solvent B; 5.4 mins to 5.42 mins, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 5.42 mins to 7.00 mins, 95% solvent A + 5% solvent B
- UV Detection wavelength 215nm
- Solvent B 0.1% Formic acid / acetonitrile
- UV Detection wavelength 215nm
- Solvent A 0.1% TFA / water
- Flash silica gel chromatography was carried out on silica gel 230-400 mesh or on pre-packed silica cartridges.
- 3-Benzylsulfonyl- N-methyl, N-(4-trifluoromethylbenzyl)-indole-l-acetamide was prepared from 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and N- methyl-4-trifluoromethylbenzylamine (18 mg, 0.1 mmol) according to the method described for Example 5.
- the title compound (9.4 mg, 31%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution.
- 3-Benzylsulfonyl-N-methyl, N-(3-trifluoromethylbenzyl)-indole-l-acetamide was prepared from 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and N- methyl-3-trifluoromethylbenzylamine (18 mg, 0.1 mmol) according to the method described for Example 5.
- the title compound (12.8 mg, 42%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 :1 gradient) elution.
- 3-(4-Fluorobenzylsulfonyl)-N-(4-fluorobenzyl)-indole-l -acetamide was prepared from 3-(4- fluorobenzylsulfonyl)indol-l-yl acetic acid (Intermediate 13, 128 mg, 0.36 mmol) and 4- fluorobenzylamine (0.049 ml, 0.43 mmol) according to the method described for Example 5.
- the title compound was prepared from (3-benzylsulfonyl-6-fluoroindazol-lyl)-acetic acid (Intermediate 29, 100 mg, 0.29 mmol) and 4-fluoro-N-cyclopropylbenzylamine (Intermediate 32, 71 mg, 0.43 mmol), according to the method described above for Example 22, with the following modifications: the crude product was purified by column chromatography with heptane: EtOAc (1 : 1 - 0: 10 gradient) elution and subsequent recrystallisation from EtOAC / heptane (58.1 mg, 40%).
- Example 28 N-(4-Fluorobenzyl), N-cyclopropyl-3-(3-fluorobenzylsulfonyl)-6- fluoroindazo le- 1 -acetamide
- 3-(4-Methylbenzylsulfonyl)indole was prepared from 3-(4-methylbenzylthio)indole (Intermediate 3, 0.31 g, 1.2 mmol) and Oxone (1.88 g, 3.0 mmol), according to the method described above for Intermediate 5.
- the title compound (0.30g, 86%>) was isolated after purification by column chromatography with heptane:ethyl acetate (1 :0 - 3:2 gradient) elution.
- 3-(4-Fluorobenzylsulfonyl)indole was prepared from 3-(4-fluorobenzylthio)indole (Intermediate 4, 2.1 g, 5.2 mmol) and Oxone (6.2 g, 16.1 mmol), according to the method described above for Intermediate 5.
- the title compound (0.93 g, 40%) was isolated after purification by column chromatography with heptane: ethyl acetate (9: 1 - 2: 1 gradient) elution.
- Ethyl 3-(4-methylbenzylsulfonyl)indol-l-yl acetate was prepared from 3-(4- methylbenzylsulfonyl)indole (Intermediate 6, 0.30 g, 1.05 mmol) and ethyl bromoacetate (0.14 ml, 1.26 mmol) according to the method described above for Intermediate 8.
- the title compound (0.32g, 82%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 2: 1 gradient) elution.
- Ethyl 3-(4-fluorobenzylsulfonyl)indol-l-yl acetate was prepared from 3-(4- fluorobenzylsulfonyl)indole (Intermediate 7, 0.93 g, 3.2 mmol) and ethyl bromoacetate (0.27 ml, 3.6 mmol) according to the method described above for Intermediate 8, with the following modification.
- the title compound (0.40g, 33%) was used without further purification.
- Ethyl 3-benzylsulfonylindol-l-yl acetate (Intermediate 8, 0.8 g, -2.2 mmol) was dissolved in water / methanol (5 ml / 5 ml) and aqueous sodium hydroxide solution (2M, 2.5 ml) was added. The mixture was stirred at room temperature for 2 h then diluted with water (10 ml). The mixture was extracted with diethyl ether (10 ml). The aqueous phase was acidified with dilute hydrochloric acid and extracted with ethyl acetate (x2).
- 3-(4-Methylbenzylsulfonyl)indol-l-yl acetic acid was prepared from ethyl 3-(4- methylbenzylsulfonyl)indol-l-yl acetate (Intermediate 9, 0.31 g, 0.83 mmol) and aqueous sodium hydroxide solution (2M, 2 ml) according to the method described above for Intermediate 1 1.
- the title compound (0.23g, 81%) was obtained after purification column chromatography with heptane: ethyl acetate (1 :0 - 2: 1 gradient) elution.
- Oxone (2.5 eq, 4.15 g, 13.5 mmol) was added portionwise to a solution of 3- benzylthioindazole (Intermediate 15, 1.3 g, 5.4 mmol) and sodium hydrogencarbonate (5 eq, 2.27 g, 27.0 mmol) in acetone (13 ml) and aqueous sodium hydrogencarbonate solution (0.2M, 13 ml) at 0 C (ice bath). The mixture was warmed to room temperature and stirred for 2 h. Aqueous sodium thiosulfate solution (1 M, 50 ml) was added and the mixture was stirred for 30 min.
- Powdered potassium hydroxide (3.75 eq, 3.93 g, 69 mmol) was added to a solution of 6- fluoroindazole (2.5 g, 18.4 mmol) and iodine (2 eq, 9.35 g, 36.8 mmol) in DMF (45 ml) and the mixture was stirred overnight.
- the reaction mixture was poured into aqueous sodium thiosulfate solution (10%, 400 ml) and extracted with toluene (x 2).
- the combined organic phases were washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid (4.57 g, 95%).
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Abstract
The invention relates to compounds of formula (I) wherein A, R1 to R8 have the meaning as cited in the description and the claims. Said compounds are useful as Orexin Receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.
Description
Indole and Indazole Derivatives as Orexin Receptor Antagonists
The present invention relates to Orexin Receptor antagonists, especially Orexin 2 Receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.
The orexins (orexin A or OX-A and orexin B or OX-B) are neuropeptides discovered in 1998 by two research groups; orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide which are derived from a common pre-propeptide (Sakurai et al, Cell, 1998, 92, 573- 585; De Lecea L. et al, PNAS, 1998, 95, 322-27). Orexins are produced in the lateral hypothalamus and bind to two eponymous G-protein-coupled receptors (0X1 and 0X2). The 0X1 receptor is selective for OX-A, whereas the 0X2 receptor binds both OX-A and OX-B.
It is believed that Orexin Receptors are associated with diseases and disorders including eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, and Type II Diabetes. Orexin Receptor antagonists are described in the art. However, most of these compounds are non-selective and used as dual, 0X1 and 0X2 receptor, antagonists.
For example, cinnamide compounds as antagonists are described in WO-A 00/47576. Phenylurea compounds are described in WO-A 00/47577. Tetrahydroisoquinoline derivatives are decribed in, e.g., WO-A 01/68609. Piperidines are described in WO-A 01/96302. N-Aroyl cyclic amine derivatives are described in, e.g., WO-A 02/089800. 7,8,9, 10-T etrahydro-6H- azepino-, 6,7,8,9-tetrahydro-pyrido- and 2,3-dihydro-2H-pyrrolo[2,l-b]-quinazolinone derivatives are described in WO-A 2004/004733. Azetidine compounds are described in WO- A 2008/020405. Benzofuran derivatives as Orexin Receptor antagonists are described in EP- A 2 161 266.
Accordingly, the present invention provides compounds or a pharmaceutically acceptable salt thereof of formula (I)
wherein A is CH; N; or C(CH3);
R1 is hydrogen; halogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different; R2 is hydrogen; or halogen;
R3 is hydrogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different; R4, R5 are independently selected from the group consisting of hydrogen; halogen; and CN;
R6 is hydrogen; Ci_4 alkyl; or cyclopropyl, wherein Ci_4 alkyl and cyclopropyl are optionally substituted with one or more halogen, which are the same or different; R7 is hydrogen; or methyl;
R^s T1;
Optionally R7 and R8 are joined together with the carbon atom to which they are attached to form a ring T2;
T1 is cyclohexyl; or phenyl, wherein T1 is optionally substituted with one or more R9, which are the same or different;
T2 is a 7 to 1 1 membered carbobicycle, wherein T2 is optionally substituted with one or more R10, which are the same or different; R9, R10 are independently selected from the group consisting of halogen; CN; COOR1 1; OR1 1 ;
C(0)Rn; C(0)N(RnRl la); S(0)2N(RnRl la); S(0)N(RnRl la); S(0)2Rn; S(0)Rn;
N(Rn)S(0)2N(Rl laRl lb); SR1 1; N(RnRl la); N02; OC(0)Rn; N(Rn)C(0)Rl la;
N(Rn)S(0)2Rl la; N(Rn)S(0)Rl la; N(Rn)C(0)ORl la; N(Rn)C(0)N(Rl laRl lb);
OC(0)N(RnRl la); oxo (=0), where the ring is at least partially saturated; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R1 1, Rl la, Rl lb are independently selected from the group consisting of H; and Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different, provided that the following compounds are excluded:
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N-methyl-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N-ethyl-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N-butyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N-ethyl-3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-chlorophenyl)methyl]sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N-butyl-3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl]sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(3-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; N-( 1 -methylethyl)-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; N- [(2-chlorophenyl)methyl] -3 - [ [(3-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; N- [(4-chlorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide; N- [(2-chlorophenyl)methyl] -3 - [ [(4-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; N-ethyl-3 - [ [(3 -fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N-butyl-3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] - N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-methylphenyl)methyl] sulfonyl] - N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-( 1 -phenylmethyl)- 1 H-indo le- 1 -acetamide;
N-butyl-3 - [ [(2-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N-butyl-3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(3-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N-( 1 -methylethyl)-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N-( 1 -methylethyl)-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; N-ethyl-3 - [ [(3 -methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N- [(2-chlorophenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(3 -methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(3-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [(phenylmethyl)sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(4-fluorophenyl)methyl] - 1 H-indo le- 1 -acetamide;
N-methyl-3 - [ [(3 -methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N-butyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N-ethyl-3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide; N- [(4-fluorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(3 -fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(4-methoxyphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide; N- [(4-methoxyphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(4-methoxyphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(4-fluorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3-[[(4-fluorophenyl)methyl]sulfonyl]-N-methyl-N-(phenylmethyl)- lH-indole- 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(3-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide; N- [(2-chlorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 -acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N-ethyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 -acetamide;
N-methyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N- [(4-methylphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N-ethyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N-methyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; and
N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide.
The compounds excluded from the scope of compounds of the present invention as such are commercially available compounds but not known for use as a medicament.
Thus another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of formula (I)
R
wherein
A is CH; N; or C(CH3); R is hydrogen; halogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is hydrogen; or halogen;
R3 is hydrogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R4, R5 are independently selected from the group consisting of hydrogen; halogen; and CN;
R6 is hydrogen; Ci_4 alkyl; or cyclopropyl, wherein Ci_4 alkyl and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
R7 is hydrogen; or methyl;
R^s T1;
Optionally R7 and R8 are joined together with the carbon atom to which they are attached to form a ring T2;
T1 is cyclohexyl; or phenyl, wherein T1 is optionally substituted with one or more R9, which are the same or different;
T2 is a 7 to 1 1 membered carbobicycle, wherein T2 is optionally substituted with one or more R10, which are the same or different;
R9, R10 are independently selected from the group consisting of halogen; CN; COOR1 1 ; OR1 1 ; C(0)Rn; C(0)N(RnRl la); S(0)2N(RnRl la); S(0)N(RnRl la); S(0)2Rn; S(0)Rn; N(Rn)S(0)2N(Rl laRl lb); SR1 1; N(RnRl la); N02; OC(0)Rn; N(Rn)C(0)Rl la; N(Rn)S(0)2Rl la; N(Rn)S(0)Rl la; N(Rn)C(0)ORl la; N(Rn)C(0)N(Rl laRl lb); OC(0)N(RnRl la); oxo (=0), where the ring is at least partially saturated; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different; R1 1, Rl la, Rl lb are independently selected from the group consisting of H; and Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different;
for use as a medicament.
In case a variable or substituent defined herein can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different. Within the meaning of the present invention the terms are used as follows:
"Alkyl" means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified herein. "Ci_4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. - CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, -C(CH3)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent as further specified herein.
"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or e.g. -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(C2H5)-, - C(CI¾)2-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified herein.
"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro. "C3_7 cycloalkyl" or "C3_7 cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein.
"7 to 11 membered carbobicyclyl" or "7 to 11 membered carbobicycle" means a carbocyclic system of two rings, like C3_7 cycloalkyl or phenyl rings, with 7 to 11 carbon ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated). An example is indan.
Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given above, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and
stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.
Preferably, A is CH; or C(CH3), more preferred is CH. Alternatively preferred is A nitrogen (N).
Preferably, R1 is H; F; CI; CH3; or CF3. More preferably, R1 is H; F; CH3. Even more preferably, R1 is H. Preferably, R2 is H; F; or CI. More preferably, R2 is H; or F. Even more preferably, R2 is H. Preferably, R3 is H; or CH3. More preferably, R3 is H.
Preferably, R4 is H; or F and/or R5 is H; F; or CN. More preferably, R4, R5 are H.
Preferably, R6 is H; CH3; CH2CH3; or cyclopropyl.
Preferably, T1 is unsubstituted or substituted with 1, 2 or 3 R9, which are the same or different.
Preferably, R9 is F; CI; CH3; CF3; CN; N(CH3)2; CH30; or CHF20.
Preferably, T2 is indanyl and wherein T2 is unsubstituted or substituted with one or more (preferably 1, 2 or 3) R10, which are the same or different. Preferably, R10 is F; CI; CH3; CF3; CN; N(CH3)2; CH30; or CHF20.
In preferred embodiments of the present invention, the substituents A, R1 to R8 of formula (I) independently have the abovementioned meaning. Hence, one or more of the substituents A, R1 to R8 can have the preferred meanings given above. Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred meanings are also an object of the present invention.
Preferred compounds are selected from the group consisting of
3-(benzylsulfonyl)-N-benzyl, N-methyl- indole- 1 -acetamide;
3-(benzylsulfonyl)-N-benzyl, N-ethyl- indole- 1 -acetamide;
3-(4-methylbenzylsulfonyl)-N-benzyl, N-methyl- indole- 1 -acetamide;
3-(4-methylbenzylsulfonyl)-N-benzyl, N-ethyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-chlorobenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-methylbenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-methoxybenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl- N-methyl, N-(4-trifluoromethylbenzyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-methyl, N-(3-trifluoromethylbenzyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-chlorobenzyl), N-methyl-indole- 1 -acetamide;
3 -benzylsulfonyl-N-benzyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-methylbenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-fluorobenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-fluorobenzyl), N-methyl-indole- 1 -acetamide;
3 -benzylsulfonyl-N-(3 -methoxybenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl-N-(cyclohexylmethyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-(2,6-difluorobenzyl)-indole- 1 -acetamide;
(RS) 3-benzylsulfonyl-N-(indan- 1 -yl)-indole- 1 -acetamide;
3-(4-fiuorobenzylsulfonyl)-N-(4-fluorobenzyl), N-methyl-indole- 1 -acetamide;
3-(4-fiuorobenzylsulfonyl)-N-(4-fluorobenzyl)-indole- 1 -acetamide;
3-(benzylsulfonyl)-N-benzyl, N-methyl- indazole- 1 -acetamide;
N-benzyl, N-methyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(3-chlorobenzyl), N-methyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(4-fiuorobenzyl), N-cyclopropyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(3-chlorobenzyl), N-methyl-3-(4-fluorobenzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(4-fiuorobenzyl), N-cyclopropyl-3-(4-fluorobenzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(3-chlorobenzyl), N-methyl-3-(3-fluorobenzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(4-fiuorobenzyl), N-cyclopropyl-3-(3-fluorobenzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
3-(benzylsulfonyl)-N-(3-chlorobenzyl), N-methyl- indazole- 1 -acetamide;
3 -(benzylsulfonyl)-N-(3 -cyanobenzyl)-indazo le- 1 -acetamide; and
(RS) 3-(l -phenyl- 1 -ethylsulfonyl)-N-benzyl, N-methyl-6-fluoroindazole- 1 -acetamide.
Where tautomerism, like e.g. keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, e.g. the keto and enol form, are comprised separately and together as
mixtures in any ratio. Same applies for stereoisomers, e.g. enantiomers, cis/trans isomers, conformers and the like.
Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.
If desired, the isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be
obtained by customary methods which are known to the person skilled in the art , for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
The present invention provides compounds of general formula (I) as Orexin Receptor antagonists, preferably as selective 0X2 receptor antagonists.
As described before, the orexins (orexin A or OX-A and orexin B or OX-B) are neuropeptides discovered in 1998 by two research groups; orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide which are derived from a common pre-propeptide (Sakurai et al, Cell, 1998, 92, 573-585; De Lecea L. et al, PNAS, 1998, 95, 322-27). Orexins are produced in the lateral hypothalamus and bind to two eponymous G-protein-coupled receptors (0X1 and 0X2). The 0X1 receptor is selective for OX-A, whereas the 0X2 receptor binds both OX-A and OX-B. The orexins stimulate food consumption in rats, suggesting a physiological role for these peptides as mediators of feeding behaviour (Sakurai T. et al, Cell, 1998, 92, 573-585; Ishii Y. et al, Behav.Brain.Res., 2005, vol. 157, 331-341; Thorpe A.J. et al, Brain Res., 2005, vol. 1050, 156-162). The orexins regulate sleep-wake behaviour, indicating a potential therapeutic approach to narcolepsy, insomnia and other sleep disorders (Chemelli R.M. et al, Cell, 1999, 98, 437-451; Smith M.I. et al, Neurosci. Letters, 2003, 256-258; Midea M. et al, PNAS, 2004, vol. 101 (13), 4649-4654; Adamantidis A.R. et al, Nature, 2007, 420-425). A post-mortem study of human narcolepsy patients failed to detect orexin peptides in the cortex and pons; there was an 80-100% reduction in the number of neurons containing detectable prepro-orexin mRNA or orexin-like immunoreactivity in the hypothalamus. Orexin A was undetectable in the cerebrospinal fluid of narcolepsy patients. The vast majority of patients with narcolepsy show decreased orexin A levels in the cerebrospinal fluid. A low
cerebrospinal fluid concentration of orexin A is now one of the diagnostic criteria for narcolepsy-cataplexy (Sakurai T., Nature Reviews Neuroscience, 2007, 8, 171-181). Thus, blockade of Orexin receptors is expected to be of potential use in the treatment of insomnia. Unexpectedly, it has been found that indole and indazole derivatives of formula (I) are antagonists of Orexin receptors, preferably selectively of the 0X2 receptor. The present invention relates to the use of indole and indazole derivatives of formula (I) and pharmaceutically acceptable salts and solvates thereof in the treatment of disorders in which blockade of Orexin receptors is reasonably expected to be of therapeutic benefit e.g. eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity and Type II Diabetes.
The compounds of formula (I) may be used for the preparation of a medicament, and are suitable, for the prevention or treatment of diseases selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes.
Compounds of formula (I) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes. Another aspect of the present invention is a method for the treatment or prophylaxis of diseases, which are related to the Orexin receptors such as eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes comprising the administration to a patient a therapeutically effective amount of a compound of formula (I).
Accordingly, one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of formula (I) for use as a medicament. Those compounds can be used in a pharmaceutical composition comprising at least one of said compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions. Other bioactive compounds may be further compounds of the present invention, i.e. a mixture of two or more of these compounds. Further bioactive compounds are further Orexin 2 Receptor antagonists and the like.
Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the Orexin 2 Receptor. Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method for the treatment or prophylaxis of diseases and disorders associated with the Orexin 2 Receptor.
Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes. More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method for the treatment or prophylaxis of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, or Type II Diabetes. More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the Orexin 2 Receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of eating disorders, sleep disorders, cognitive dysfunctions in psychiatric and neurological disorders, drug dependence, obesity, and Type II Diabetes, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
More specific diseases and disorders are mentioned above, which are also preferred for this aspect of the present invention.
"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral
solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture
and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
Starting materials for the synthesis of preferred embodiments of the invention as well as compounds of the present invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR or can be synthesized using known methods by one skilled in the art.
In general, several methods are applicable to prepare compounds of the present invention. In some cases various strategies can be combined. Sequential or convergent routes may be used.
Compounds of formula (I) may be conveniently prepared according to Scheme 1 below. Sulfone (II) reacts with a reagent such as ethyl bromoacetate in the presence of a suitable base e.g. sodium hydride in a solvent such as DMF to provide ester (III), which is hydrolysed to give acid (IV) using for example aqueous sodium hydroxide. Coupling of acid (IV) with amine (V) using a suitable coupling reagent e.g. carbonyldiimidazaole or HBTU / HOBt provides a compound of formula (I). Compounds of formula (I) where R3 is methyl can be formed from compounds of formula (I) where R3 is H by reaction with a strong base such as sodium hydride, followed by treatment with an alkylating agent for example iodomethane.
Scheme 1: Preparation of a compound of formula (I)
Compounds of formula (II) where A = CH may be prepared according to Scheme 2 below. Indole (VI) is treated sequentially with iodine and thiourea to form an intermediate, which is reacted with a reagent such as aqueous sodium hydroxide solution to produce indole-thiol (VI). Reaction of indole-thiol (VI) with benzylating agent (VII), where LG is a leaving group, in the presence of a suitable base e.g. sodium hydride produces thioether (VIII), which can be oxidised to sulfone (II) using a suitable reagent, for example Oxone.
Scheme 2: Preparation of a compound of formula (II) where A
Compounds of formula (II) where A = N may be prepared according to Scheme 3 below. Indazole (IX) is treated with iodine and a base such as potassium hydroxide to produce iodide (X). Reaction of iodide (X) with benzyl mercaptan (XI) in the presence of a suitable catalyst e.g. copper iodide produces thioether (XII), which can be oxidised to sulfone (II) using a suitable reagent, for example Oxone.
Scheme 3: Preparation of a compound of formula (II) where A
Thus a further aspect of the present invention is a method for the preparation of a compound of formula (I) as defined in above comprising the step of reacting a compound of formula (IV)
Examples
Biological Assays
Cell Lines
A CHO-Kl cell line stably expressing human Orexin-1 receptor (hOXIR, coding sequence of AF041243) was obtained from Euroscreen/PerkinElmer (CHO-hOXIR, ES-330-C).
A plasmid containing the human Orexin-2 receptor (hOX2R) cDNA was purchased from RZPD (RZPDo834A1045-pT-REx-DEST30). The human Orexin-2 receptor coding region was amplified in a gradient PCR reaction using hOX2Rfor (5' ccaggatccgc caccatgtccggcaccaaattggaggactcc) and hOX2Rrev (5' ccgcggccgcctaccagttttgaagtggtcctgc) primers containing restriction sites for the restriction enzymes BamHI and Notl. The PCR reaction was performed with the LightCycler system from Roche Applied Science. The amplified DNA fragment was digested with restriction enzymes BamHI and Notl (Fermentas) and subsequently cloned into the BamHI/NotI sites of the pFB-Neo vector (Stratagene) thereby generating plasmid pFB-Neo-hOX2R.
For a stably expressing CHO-hOX2R cell line viral transduction of CHO-Kl cells were performed by using the pFB-Neo-hOX2R plasmid and the pVPack vector system from Stratagene according to the manufacturer's manual. Cells expressing the hOX2 receptor were selected using G418 at a final concentration of 50(^g/ml and single cell clones were produced by limited dilution cloning.
Cell Culture CHO-hOXIR cells were grown in HAM F12 Nutrient Mixture (Sigma, N6658), 10%Fetal Bovine Serum (Sigma, F9665), 1% Penstrep (Sigma, p4333) and 400mg/ml G418 (Sigma, A1720). CHO-hOX2R cells were grown in DMEM F12 medium (Sigma, D8437) supplemented with 10%Fetal Bovine Serum (Sigma, F9665), 1% Penstrep (Sigma, p4333) and 500mg/ml G418 (Sigma, A1720). Cells were maintained under 5% C02 atmosphere at 37°C. Cells were passaged every 2-3 days.
Ca2+-flux Assay for EC50/IC50 Determination
CHO-hOXIR and CHO-hOX2R cells were seeded at a density of 7500 cells per well into black, 384 well Costar Cellbind plates and cultured overnight in the appropriate cell culture medium as described above without G418 selection. The next day the medium was removed and the cells were incubated for 1.5hrs at 37°C in fluo-4, AM dye solution [2μΜ fluo-4,AM (Molecular Probes; F- 14202, Lot#28Cl-12) in 5mM probenecid (Sigma, P-8761, Lot# 121K1662), 0.1% Bovine Serum Albumin (BSA, MERCK, 1.12018.0100), lxHBSS
(Invitrogen, 14025-050), 20mM HEPES (Invitrogen,. 15630-056)]. For IC50 determination of compounds the dye supernatant was removed and cells were incubated for 20min at 37°C in probenecid buffer [5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES, l%DMSO (Merck, 1.02931.1000)] containing compounds at concentrations ranging from 1.28nM to 20μΜ (7 dilution steps at 1 :5, last compound concentration is OnM). All compound concentrations were measured in triplicates. Subsequently, agonist solution (5nM Orexin-A, TOCRIS, 1455) in 5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES was added during incubation of the plate at 37°C in the fluorescence plate reader (FlexStation, Molecular Devices). Fluorescence was measured for 0-60 seconds per well at an excitation of 485nm and emission o f 538nm.
For EC50 determination of Orexin-A the cells were incubated as described above for 20min at 37°C in probenecid buffer (5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES, P/oDMSO) without compound solution. Agonist injection occurred in the fluorescence plate reader (FlexStation, Molecular Devices) at different concentrations ranging from 0-lOOnM in 5mM probenecid, 0.1% BSA, IxHBSS, 20mM HEPES. Detection of fluorescence was as described above.
The activities of compounds of formula (I) are listed in Table 1 below:
OXl OX2
Example
IC5o / nM IC5o / nM
1 3455 35
2 3704 50
3 2942 257
4 1494 319
5 8459 50
6 9402 74
7 9033 59
8 7429 265
9 1282 18
10 855 13
11 >10 uM 220
12 1533 61
13 1221 59
14 1176 23
15 8010 75
16 4682 120
17 >10 uM 194
18 3775 456
19 4364 5
20 9191 96
21 998 14
22 3271 27
23 672 5
24 798 13
25 1058 4
26 1283 5
27 1263 6
28 1263 35
29 1578 6
30 20000 123
31 1710 15
Table 1: 0X1 and 0X2 antagonism of compounds of formula (I)
NMR Methods
NMR Spectroscopy was determined using either a Bruker DPX 250 MHz NMR or a Bruker DRX 500 MHz NMR. Values are reported as shifts (in ppm), with zero corresponding to tetramethylsilane as an internal standard. Chemical shifts are reported in ppm ([delta]). Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90 C.
Analytical HPLC-MS
Method A
Column: Waters Atlantis dC18 (2.1 xlOOmm, 3um column)
Flow rate: 0.6 ml/min
Solvent A: 0.1% Formic acid / water
Solvent B: 0.1% Formic acid / acetonitrile
Injection Volume: 3 μΐ
Column temperature: 40°C
UV Detection wavelength: 215nm
Eluent: 0 mins to 5 mins, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5 mins to 5.4 mins, 100% solvent B; 5.4 mins to 5.42 mins, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 5.42 mins to 7.00 mins, 95% solvent A + 5% solvent B
Method B
Column: Waters Atlantis dC 18 (2.1 x 50mm, 3um) Solvent A = Formic acid (aq) 0.1% Solvent B = Formic acid (acetonitrile) 0.1% Flow rate 1 ml/min Injection volume 3ul
UV Detection wavelength: 215nm
Eluent: 0 to 2.5 minutes, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 2.5 minutes to 2.7 minutes, 100% solvent B; 2.71 to 3.0 minutes, 95% solvent A + 5% solvent B.
Method C
Column: Waters Atlantis dC 18 (2.1 x 30mm, 3um column) Flow rate: 1 ml/min Solvent A: 0.1% Formic acid / water
Solvent B: 0.1% Formic acid / acetonitrile
Injection volume: 3ul
UV Detection wavelength: 215nm
Eluent: 0 mins to 1.5 mins, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 1.5 mins to 1.6 mins, 100% solvent B; 1.60 min to 1.61 mins, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 1.61 mins to 2.00 min, 95% solvent A + 5% solvent B.
MS detection using Waters LCT or LCT Premier, or ZQ or ZMD
UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV
Preparative HPLC-MS
Column: Waters SunFire Prep C18 OBD (5um 19 x 100mm)
Flow rate: 26ml/min
Solvent A: 0.1% TFA / water
Solvent B: 0.1% TFA / acetonitrile
Injection Volume: ΙΟΟΟμΙ
Column Temperature: room temperature
Detection: Mass directed
Eluent: 0 mins to 1 minute, 90% solvent A + 10% solvent B; 1 minute to 7.5 mins, constant gradient from 90% solvent A + 10% solvent B to 100% solvent B; 7.5 mins to 9 mins, 100% solvent B; 9 mins to 9.1 mins, constant gradient from 100% solvent B to 90% solvent A + 10% solvent B; 9.1 mins to 10 mins, 90% solvent A + 10% solvent B.
Waters Micromass Platform LCZ single quadrupole mass spectrometer
Waters 600 solvent delivery module
Waters 515 ancillary pumps
Waters 2487 UV detector
Gilson 215 autosampler and fraction collector
Compound Naming
All compounds are named either using ACD Labs 10.0 naming software (which conforms to IUPAC naming protocols) or by analogy to conventional nomenclature familiar to a skilled practitioner. Some compounds are isolated as TFA salts, which is not reflected by the chemical name. Within the meaning of the present invention the chemical name represents the
compound in neutral form as well as its TFA salt or any other salt, especially pharmaceutically acceptable salt, if applicable.
Flash silica gel chromatography was carried out on silica gel 230-400 mesh or on pre-packed silica cartridges.
Abbreviations
aq. aqueous
br broad
C degrees Celcius
CDC13 deuteriochloroform
CDI carbonyl di- imidazole
cone. concentrated
DABCO 1 ,4-diazabicyclo[2.2.2]octane
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF Ν,Ν-dimethyl formamide
DMSO dimethylsulfoxide
EDCI 1 -ethyl-3-(3-dimethylaminopropyy carbodiimide
EtOH ethanol
FCC flash column chromatography
h hours
HBTU 0-( 1 H-benzotriazo 1- 1 -yl)-N,N,N ' ,N ' -tetramethyluronium
hexafluorophosphate
HC1 hydrochloric acid
HOBt 1 -hydroxybenzotriazo le
HPLC-MS high performance liquid chromatography and mass spectrometry m multiplet
MeOH methanol
mg milligrams
min minutes
mmol millimoles
mL milliliters
MHz megahertz
NMR nuclear magnetic resonance
rt room temperature
s singlet
t triplet
THF tetrahydrofuran
All N-Methyl and N-Ethyl amides were seen as a mixture of rotamers by 1H-NMR.
Example 1: 3-(Benzylsulfonyl)-N-benz l, N-methyl- indole-1 -acetamide
To a stirred solution of 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 100 mg, 0.3 mmol) in DMF (2 ml) were added HOBt (49 mg, 0.36 mmol) and HBTU (138 mg, 0.36
mmol) and the mixture was stirred at room temperature for 10 min. N-methylbenzylamine (0.047 ml, 0.36 mmol) was added and the mixture was stirred at room temperature for 72 h. The mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate (x2). The combined organic phases were washed with water and brine and concentrated in vacuo. The crude product was purified by column chromatography with heptane:ethyl acetate (1 :0- 1 : 1 gradient) elution to give the title compound (89.5 mg, 68%). HPLC-MS (Method A): MH+ requires m/z=433; Found m/z=433 Rt 4.44 min (99%). 1H NMR (500 MHz, CDC13) δ ppm 2.92 & 3.13 (s rotamers, 3 H), 4.40 & 4.53 (s rotamers, 2 H), 4.54 & 4.78 (s rotamers, 2H), 5.08 & 5.30 (s rotamers, 2 H), 7.02 - 7.40 (m, 11 H), 7.40 - 7.49 (m, 2 H) and 7.49 - 7.66 (m, 2 H).
Example 2: 3-(Benzylsulfonyl)-N-benz l, N-ethyl-indole-l-acetamide
3-(Benzylsulfonyl)-N-benzyl, N-ethyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 100 mg, 0.35 mmol) and N- ethylbenzylamine (0.054 ml, 0.36 mmol) according to the method described above for Example 1. The title compound (55.7 mg, 41%) was isolated after purification by column chromatography with heptane:ethyl acetate (1 :0 - 2: 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=447; Found m/z=447, Rt 4.59 min (98%). 1H NMR (500 MHz, CDC13) δ ppm 1.04 - 1.30 (m, 3 H), 3.47 (d, J=7.17 Hz, 2 H), 4.46 & 4.49 (s rotamers, 2H), 4.57 & 4.81 (s rotamers, 2 H), 5.02 & 5.32 (s rotamers, 2 H), 7.03 - 7.42 (m, 12 H) and 7.42 - 7.63 (m, 3 H).
Example 3: 3-(4-Methylbenzylsulfonyl)-N-benzyl, N-methyl-indole-l-acetamide
3-(4-Methylbenzylsulfonyl)-N-benzyl, N-methyl-indole-l-acetamide was prepared from 3-(4- methylbenzylsulfonyl)indol-l-yl acetic acid (Intermediate 12, 50 mg, 0.15 mmol) and N- methylbenzylamine (0.023 ml, 0.18 mmol) according to the method described for Example 1. The title compound (14.8 mg, 22%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 3:2 gradient) elution and further purification by preparative HPLC. HPLC-MS (Method A): MH+ requires m/z=447; Found m/z=447, Rt 4.58 min (84%). 1H NMR (500 MHz, CDC13) δ ppm 2.23 - 2.36 (m, 3 H), 2.93 & 3.17 (s rotamers, 3 H), 4.31 & 4.45 (s rotamers, 2 H), 4.59 & 4.69 (s rotamers, 2 H), 4.81 & 4.97 (s rotamers, 2 H), 6.93 - 7.14 (m, 4 H), 7.14 - 7.51 (m, 10 H) and 7.57 - 7.75 (m, 1H).
Example 4: 3-(4-Methylbenzylsulfon l)-N-benzyl, N-ethyl-indole-l-acetamide
3-(4-Methylbenzylsulfonyl)-N-benzyl, N-ethyl-indole-l-acetamide was prepared from 3-(4- methylbenzylsulfonyl)indol-l-yl acetic acid (Intermediate 12, 50 mg, 0.15 mmol) and N- ethylbenzylamine (0.026 ml, 0.18 mmol) according to the method described above for Example 1. The title compound (6.3 mg, 9%) was isolated after purification by column
chromatography with heptane:ethyl acetate (1 :0 - 3:2 gradient) elution and further purification by preparative HPLC. HPLC-MS (Method A): MH+ requires m/z=461; Found m/z 461, Rt = 4.73 min (68%). 1H NMR (500 MHz, CDC13) δ ppm 1.14 (dd, J=10.6, 7.1 Hz, 3 H), 2.22 (s, 3 H), 3.19 - 3.55 (m, 2 H), 4.28 & 4.31 (s rotamers, 2 H), 4.55 - 4.56 (m, 2 H), 4.66 & 4.97 (s rotamers, 2 H), 6.82 - 7.04 (m, 4 H), 7.05- 7.46 (m, 9 H) and 7.49 - 7.65 (m, 1 H).
Example 5: 3-Benzylsulfonyl-N-(4-chlorobenzyl), N-methyl-indole-l-acetamide
To a stirred suspension of 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) in DCM (1 ml) was added CDI (95 mg, 0.073 mmol) and the mixture was stirred at room temperature for 30 min. 4-Chlorobenzyl-N-methylamine (15 mg, 0.1 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was washed with dilute hydrochloric acid (0.5 ml); the organic phase was purified by column chromatography with heptane:ethyl acetate (1 :0- 1 : 1 gradient) elution to give the title compound (18.2 mg, 64%). HPLC-MS (Method A): MH+ requires m/z=467; Found m/z=467, Rt 4.58 min (100%). 1H NMR (500 MHz, MeOD) δ ppm 2.97 & 3.10 (s rotamers, 3 H), 4.43 & 4.54 (s rotamers, 2 H), 4.54 & 4.79 (s rotamers, 2 H), 5.13 & 5.37 (s rotamers, 2 H), 7.07 - 7.23 (m, 5 H), 7.23 - 7.41 (m, 6 H), 7.44 (m, 1 H) and 7.50 - 7.65 (m, 2 H).
Example 6: 3-Benzylsulfonyl-N-(4-methylbenzyl), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(4-methylbenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and N-methyl-4- methylbenzylamine (13 mg, 0.1 mmol) according to the method described for Example 5. The title compound (10.1 mg, 37%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=447; Found m/z 447, Rt = 4.55 min (99%). 1H NMR (500 MHz, MeOD) δ ppm 2.34 - 2.39 (s rotamers, 3 H), 3.00 - 3.08 (s rotamers, 3 H), 4.48 - 4.50 (s rotamers, 2 H), 4.57 - 4.71 (s rotamers, 2 H), 5.22 - 5.28 (s rotamers, 2 H), 7.06 - 7.35 (m, 11 H) and 7.40 - 7.68 (m, 3 H).
Example 7: 3-Benzylsulfonyl-N-(4-methox benzyl), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(4-methoxybenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 4- methoxybenzyl-N-methylamine (15 mg, 0.1 mmol) according to the method described for Example 5. The title compound (10.8 mg, 38%) was obtained after purification by column
chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=463; Found m/z=463, Rt 4.35 min (100%). 1H NMR (500 MHz, MeOD) δ ppm 2.99 - 3.08 (s rotamers, 3 H), 3.80 - 3.84 (s rotamers, 3 H), 4.48 & 4.51 (s rotamers, 2 H), 4.55 & 4.70 (s rotamers, 2 H), 5.24 & 5.26 (s rotamers, 2 H), 6.85 - 7.07 (m, 2 H), 7.08 - 7.37 (m, 9 H), 7.39 - 7.49 (m, 1 H) and 7.50 - 7.62 (m, 2 H).
Example 8: 3-Benzylsulfonyl- N-meth l, N-(4-trifluoromethylbenzyl)-indole-l-acetamide
3-Benzylsulfonyl- N-methyl, N-(4-trifluoromethylbenzyl)-indole-l-acetamide was prepared from 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and N- methyl-4-trifluoromethylbenzylamine (18 mg, 0.1 mmol) according to the method described for Example 5. The title compound (9.4 mg, 31%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=501; Found m/z=501, Rt 4.70 min (81%). 1H NMR (500 MHz, CDC13) δ ppm 2.92 & 3.98 (s rotamers, 3 H), 4.30 - 4.33 (s rotamers, 2 H), 4.56 & 4.58 (s rotamers, 2H), 4.72 - 4.81 (s rotamers, 2 H), 7.02- 7.04 (m, 2 H), 7.10 - 7.34 (m, 9 H) and 7.43 - 7.69 (m, 3 H).
Example 9: 3-Benzylsulfonyl-N-methyl, N-(3-trifluoromethylbenzyl)-indole-l-acetamide
3-Benzylsulfonyl-N-methyl, N-(3-trifluoromethylbenzyl)-indole-l-acetamide was prepared from 3-benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and N- methyl-3-trifluoromethylbenzylamine (18 mg, 0.1 mmol) according to the method described for Example 5. The title compound (12.8 mg, 42%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 :1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=501; Found m/z=501 , Rt = 4.68 min (100%). 1H NMR (500 MHz, CDC13) δ ppm 2.92 & 2.97 (s rotamers, 3 H), 4.30 & 4.32 (s rotamers, 2 H), 4.56 - 4.58 (s rotamers, 2 H), 4.71 & 4.80 (s rotamers, 2 H), 7.02- 7.04 (m, 3 H), 7.10 - 7.28 (m, 6 H), 7.28 - 7.44 (m, 3 H) and 7.44 - 7.66 (m, 2 H).
Example 10: 3-Benzylsulfonyl-N-(3-chlorobenz l), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(3-chlorobenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 3- chlorobenzyl-N-methylamine (15 mg, 0.1 mmol) according to the method described for Example 5. The title compound (14.2 mg, 50%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=467; Found m/z=467, Rt 4.62 min (95%). 1H NMR (500 MHz,
CDC13) δ ppm 2.90 & 2.98 (s rotamers, 3 H), 4.30 & 4.32 (s rotamers, 2 H), 4.48 & 4.51 (s rotamers, 2 H), 4.71 & 4.79 (s rotamers, 2 H), 6.91 - 7.09 (m, 4 H), 7.09 - 7.35 (m, 9 H) and 7.44 - 7.64 (m, 1H).
Example 11: 3-Benzylsulfonyl-N-benz l-indole-l-acetamide
3-Benzylsulfonyl-N-benzyl-indole-l-acetamide was prepared from 3-benzylsulfonylindol-l- yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and benzylamine (0.011 ml, 0.1 mmol) according to the method described for Example 5. The title compound (9.9 mg, 39%) was obtained after purification by column chromatography with heptane: ethyl acetate (1 :0 - 1 :1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=419; Found m/z=419, Rt 4.23 min (79%). 1H NMR (500 MHz, CDC13) δ ppm 4.22 - 4.36 (m, 4 H), 4.66 (s, 2 H), 5.72 (m, 1 H), 6.88 - 7.08 (m, 5 H), 7.08 - 7.36 (m, 9 H) and 7.57-7.59 (m, 1H).
Example 12: 3-Benzylsulfonyl-N- 3-methylbenzyl), N-methyl- indole- 1-acetamide
3-Benzylsulfonyl-N-(3-methylbenzyl), N-methyl- indole- 1-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 3-methyl-N-
methylbenzylamme (0.015 ml, 0.1 mmol) according to the method described for Example 5. The title compound (11.6 mg, 43%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=447; Found m/z 447, Rt = 4.58 min (86%). 1H NMR (500 MHz, CDC13) δ ppm 2.26 & 2.32 (s rotamers, 3 H), 2.88 & 3.00 (s rotamers, 3 H), 4.30 & 4.32 (s rotamers, 2 H), 4.48 & 4.50 (s rotamers, 2 H), 4.76 & 4.80 (s rotamers, 2 H), 6.84 - 7.00 (m, 2 H), 7.09 (s, 3 H), 7.09 - 7.35 (m, 8H) and 7.42 - 7.67 (m, 1 H).
Example 13: 3-Benzylsulfonyl-N-(4-fluorobenz l), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(4-fluorobenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 4-fluoro-N- methylbenzylamine (0.013 ml, 0.1 mmol) according to the method described for Example 5.
The title compound (15.0 mg, 55 >) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 2:3 gradient) elution. HPLC-MS (Method
A): MH+ requires m/z=451; Found m/z=451, Rt 4.46 min (90%). 1H NMR (500 MHz,
CDC13) δ ppm 2.88 & 2.95 (s rotamers, 3 H), 4.30 & 4.32 (s rotamers, 2 H), 4.47 & 4.49 (s rotamers, 2 H), 4.73 - 4.77 (s rotamers, 2 H), 6.87 - 7.00 (m, 2 H), 6.99 - 7.30 (m, 1 1 H) and
7.40 - 7.62 (m, 1 H).
Example 14: 3-Benzylsulfonyl-N-(3-fluorobenzyl), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(3-fluorobenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 3-fluoro-N- methylbenzylamine (0.013 ml, 0.1 mmol) according to the method described for Example 5. The title compound (9.8 mg, 36%) was obtained after purification by column chromatography with heptane: ethyl acetate (1 :0 - 2:3 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=451; Found m/z=451, Rt 4.46 min (83%). 1H NMR (500 MHz, CDC13) δ ppm 2.91 & 2.99 (s rotamers, 3 H), 4.30 & 4.32 (s rotamers, 2 H), 4.50 & 4.529 (s rotamers, 2 H), 4.72 & 4.80 (s rotamers, 2 H), 6.73 - 7.08 (m, 6 H), 7.09 - 7.40 (m, 8 H) and 7.42 - 7.65 (m, 1 H).
Example 15: 3-Benzylsulfonyl-N- 3-methoxybenzyl), N-methyl-indole-l-acetamide
3-Benzylsulfonyl-N-(3-methoxybenzyl), N-methyl-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (Intermediate 11, 20 mg, 0.061 mmol) and 3-methoxy-N- methylbenzylamine (0.015 ml, 0.1 mmol) according to the method described for Example 5. The title compound (9.6 mg, 34%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 2:3 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=463; Found m/z=463, Rt 4.43 min (82%). 1H NMR (500 MHz, CDC13) δ ppm 2.90 & 3.01 (s rotamers, 3 H), 3.70 & 3.75 (s rotamers, 3 H), 4.31 & 4.33 (s rotamers, 2 H), 4.50 &
4.51 (s rotamers, 2 H), 4.79 & 4.81 (s rotamers, 2 H), 6.60 - 6.90 (m, 3 H), 6.95 - 7.09 (m, 3 H) 7.09 - 7.36 (m, 7 H) and 7.44 - 7.65 (m, 1 H).
Example 16: 3-Benzylsulfonyl-N-(cyclohexylmethyl)-indole- 1 -acetamide
3 -Benzylsulfonyl-N-(cyclohexylmethyl)-indole-l -acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (prepared in an analogous manner to Intermediate 1 1, 66 mg, 0.2 mmol) and cyclohexylmethylamine (0.039 ml, 0.3 mmol) according to the method described for Example 5. The title compound (59.1 mg, 70%) was obtained after purification by column chromatography with heptane:ethyl acetate (4: 1 - 1 : 1 gradient) elution. HPLC-MS (Method A): MH+ requires m/z=425; Found m/z=425, Rt 4.54 min (100%). 1H NMR (500 MHz, CDC13) δ ppm 0.60 - 0.77 (m, 2 H), 0.90 - 1.12 (m, 3 H), 1.23 - 1.27 (m, 2 H), 1.38- 1.41 (m, 2 H), 1.46 - 1.78 (m, 4 H), 2.92 (t, J=6.48 Hz, 2 H), 4.34 (s, 2 H), 4.65 (s, 6 H), 5.45 (t, J=5.80 Hz, 3 H), 7.02 (d, J=7.32 Hz, 2 H), 7.06 - 7.38 (m, 7 H) and 7.57 (d, J=8.09 Hz, 1H).
Example 17: 3-Benzylsulfonyl-N-(2,6-difluorobenzyl)-indole- 1 -acetamide
Example 18: (RS) 3-Benzylsulfon l-N-(indan-l-yl)-indole-l-acetamide
(RS) 3-Benzylsulfonyl-N-(indan-l-yl)-indole-l-acetamide was prepared from 3- benzylsulfonylindol-l-yl acetic acid (prepared in an analogous manner to Intermediate 11, 100 mg, 0.3 mmol) and 1-aminoindane (0.057 ml, 0.45 mmol) according to the method described for Example 5. The title compound (70.5 mg, 53%) was obtained after purification by preparative HPLC. HPLC-MS (Method A): MH+ requires m/z=445; Found m/z=445, Rt 4.39 min (99%). 1H NMR (500 MHz, CDC13) δ ppm 1.63 (dd, J=12.9, 8.0 Hz, 1 H), 2.42 - 2.62 (m, 1 H), 2.73- 2.99 (m, 2 H), 4.33 (s, 2 H), 4.64 - 4.84 (m, 2 H), 5.45 (q, J=7.9 Hz, 1 H), 5.90 (d, J=8.4 Hz, 1 H), 6.90 -7.09 (m, 5 H), 7.09 - 7.15 (m, 1 H), 7.15 - 7.22 (m, 3 H), 7.22 - 7.31 (m, 1 H), 7.31 - 7.46 (m, 3 H) and 7.61 (d, J=8.1 Hz, 1 H).
Example 19: 3-(4-Fluorobenzylsulfonyl)-N-(4-fluorobenzyl), N-methyl-indole-l-acetamide
3-(4-Fluorobenzylsulfonyl)-N-(4-fluorobenzyl), N-methyl-indole-l-acetamide was prepared from 3-(4-fluorobenzylsulfonyl)indol-l-yl acetic acid (Intermediate 13, 128 mg, 0.36 mmol) and 4-fluoro-N-methylbenzylamine (0.057 ml, 0.43 mmol) according to the method described for Example 5. The title compound (77.7 mg, 46%) was obtained after purification by preparative HPLC. HPLC-MS (Method A): MH+ requires m/z=469; Found m/z=469, Rt 4.43 min (100%). 1H NMR (500 MHz, CDC13) δ ppm 3.01 & 3.05 (s rotamers, 3 H), 4.35 & 4.37 (s rotamers, 2 H), 4.56 & 4.61 (s rotamers, 2H), 4.82 & 4.86 (s rotamers, 2 H), 6.83 - 6.99 (m, 2H), 6.99 - 7.12 (m, 4 H), 7.12 - 7.37 (m, 6 H) and 7.54 - 7.74 (m, 1H).
Example 20: 3-(4-Fluorobenzylsulfonyl)-N-(4-fluorobenzyl)-indole- 1 -acetamide
3-(4-Fluorobenzylsulfonyl)-N-(4-fluorobenzyl)-indole-l -acetamide was prepared from 3-(4- fluorobenzylsulfonyl)indol-l-yl acetic acid (Intermediate 13, 128 mg, 0.36 mmol) and 4- fluorobenzylamine (0.049 ml, 0.43 mmol) according to the method described for Example 5. The title compound (44.5 mg, 27%) was obtained after purification by column
chromatography using heptane: ethyl acetate (4: 1 - 1 : 1 gradient) elution followed by recrystallisation from ethyl acetate / heptane. HPLC-MS (Method A): MH+ requires m/z=455; Found m/z=455, Rt 4.27 min (84%). 1H NMR (500 MHz, CDC13) δ ppm 4.29 - 4.44 (m, 4 H), 4.83 (s, 2 H), 5.48 - 5.71 (m, 1 H), 6.88 (t, J=8.6 Hz, 2 H), 6.92 - 7.17 (m, 6 H), 7.22 - 7.30 (m, 5 H), 7.30 - 7.46 (m, 3 H) and 7.70 (d, J=7.8 Hz, 1H).
Example 21: 3-(Benzylsulfonyl)-N-benzyl, N-methyl-indazole-l-acetamide
To a solution of 3-(benzylsulfonyl)indazol-l-yl acetic acid (Intermediate 18, 0.2 g, 0.61 mmol) in THF (2 ml) was added CDI (3 eq, 0.21 g, 1.29 mmol) and the mixture was stirred at room temperature for 1 h. N-Methylbenzylamine (2 eq, 0.16 ml, 1.21 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue diluted with ethyl acetate. The mixture was washed with aqueous potassium hydrogensulfate solution (1M, 2.5 ml) and aqueous potassium carbonate solution (2M, 2.5 ml). The organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by column chromatography with heptane:EtOAc (9: 1- 3:2 gradient) elution to give the title compound as a white foamy solid (153 mg, 47%). HPLC- MS (Method A): MH+ requires m/z=434; Found m/z=434, Rt 4.51 min (99%). 1H NMR (500 MHz, acetone-d6) δ ppm 2.99 and 3.22 (rotamers, s, 3H), 4.6-4.9 (2 x rotamers, 4 H), 5.69 - 5.75 (rotamers, s, 2H), 7.15-7.25 (6H, m), 7.26-7.40 (4H, m), 7.40-7.52 (2H, m) and 7.58- 7.73 (2H, m).
Example 22: N-Benzyl, N-methyl-3-(benzylsulfonyl)-6-fluoroindazole-l-acetamide
To a stirred solution of (3-benzylsulfonyl-6-fluoroindazol-lyl)-acetic acid (Intermediate 29, 0.15 g, 0.43 mmol) in THF (3 ml) was added CDI (3 eq, 0.21 g, 1.29 mmol) and the mixture was stirred at room temperature for 1 h. N-Benzyl, N-methylamine (2 eq, 0.86 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue diluted with ethyl acetate. The mixture was washed with aqueous potassium hydrogensulfate solution (1M, 2.5 ml) and aqueous potassium carbonate solution (2M, 2.5 ml). The organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (0.16 g, 80%). HPLC-MS (Method A): MH+ requires m/z=452; Found m/z=452, Rt 4.46 min (100%). 1H NMR (500 MHz, CDC13) δ 3.04 & 3.06 (s rotamers, 3 H), 4.48 & 4.52 (s rotamers, 2 H), 4.61 & 4.68 (s rotamers, 2H), 5.31 & 5.33 (s rotamers, 2H), 6.81 - 7.03 (m, 2 H), 7.08 - 7.10 (m, 1 H), 7.12 - 7.29 (m, 6 H), 7.29 -7.40 (m, 2 H) and 7.40 - 7.57 (m, 2H).
Example 23: N-(3-Chlorobenzyl), N-methyl-3-(benzylsulfonyl)-6-fluoroindazole-l- acetamide
The title compound was prepared from (3-benzylsulfonyl-6-fluoroindazol-lyl)-acetic acid (Intermediate 29, 100 mg, 0.29 mmol) and 3-chloro-N-methylbenzylamine (0.062 ml, 0.43 mmol) according to the method described above for Example 22, with the following modifications: the crude product was purified by column chromatography with heptane: EtOAc (10:0 - 1 : 1 gradient) elution and subsequent recrystallisation from EtOAC / heptane (17.8 mg, 13%). HPLC-MS (Method A): MH+ requires m/z=486; Found m/z=486, Rt 4.76 min (100%). 1H NMR (500 MHz, CDC13) δ 3.08 (s, 3 H), 4.50 & 4.55 (s rotamers, 2 H), 4.61 & 4.66 (s rotamers, 2 H), 5.33 & 5.35 (s rotamers, 2 H), 6.89 - 7.00 (m, 1 H), 7.03 - 7.14 (m, 1 H), 7.16 (m., 7 H), 7.29 - 7.41 (m, 2 H) and 7.51 - 7.63 (m, 1 H).
Example 24: N-(4-Fluorobenzyl), N-cyclopropyl-3-(benzylsulfonyl)-6-fluoroindazole-l- acetamide
Example 25: N-(3-Chlorobenzyl), N-methyl-3-(4-fluorobenzylsulfonyl)-6-fluoroindazole-l- acetamide
The title compound was prepared from [3-(4-fluorobenzylsulfonyl)-6-fluoroindazol-lyl]- acetic acid (Intermediate 30, 98 mg, 0.27 mmol) and 3-chloro-N-methylbenzylamine (83 mg, 0.53 mmol), according to the method described above for Example 22, with the following modifications: the crude product was purified by recrystallisation from EtOAC / heptane (63.6 mg, 47%). HPLC-MS (Method A): MH+ requires m/z=504; Found m/z=504, Rt 4.67 min (100%). 1H NMR (500 MHz, CDC13) δ 3.09 (s, 3H), 4.46 & 4.52 (s rotamers, 2H), 4.61 & 4.69 (s rotamers, 2H), 5.29 & 5.34 (s rotamers, 2H), 6.81-6.96 (m, 2H), 7.00 - 7.04 (m, 1H), 7.09-7.21 (m, 4H), 7.26 (s, 1H), 7.32-7.46 (m, 2H) and 7.56-7.73 (m, 1H).
Example 26: N-(4-Fluorobenzyl), N-cyclopropyl-3-(4-fluorobenzylsulfonyl)-6- fluoroindazo le- 1 -acetamide
The title compound was prepared from [3-(4-fluorobenzylsulfonyl)-6-fluoroindazol-lyl]- acetic acid (Intermediate 30, 98 mg, 0.27 mmol) and 4-fluoro-N-cyclopropylbenzylamine (Intermediate 32, 88 mg, 0.53 mmol) according to the method described above for Example 22, with the following modifications: the crude product was purified by recrystallisation from EtOAC / heptane (91.7 mg, 67%). HPLC-MS (Method A): MH+ requires m/z=514; Found m/z=514, Rt 4.75 min (100%). 1H NMR (500 MHz, CDC13) δ 1.00 ( br.s, 2H), 1.07 (d, J = 5.8 Hz, 2H), 2.61-2.76 (m, 1H), 4.50 (s, 2H), 4.62 (s, 2H), 5.49 (s, 2H), 6.90 (t, J = 8.6 Hz, 2H), 6.95-7.09 (m, 4H), 7.12 (dd, J= 8.4 Hz, 2H) and 7.56-7.72 (m, 1H).
Example 27: N-(3-Chlorobenzyl), N-methyl-3-(3-fluorobenzylsulfonyl)-6-fluoroindazole-l- acetamide
The title compound was prepared from [3-(4-fluorobenzylsulfonyl)-6-fluoroindazol-lyl]- acetic acid (Intermediate 31, 83 mg, 0.23 mmol) and 3-chloro-N-methylbenzylamine (71 mg, 0.45 mmol) according to the method described above for Example 22, with the following modifications: the crude product was purified by recrystallisation from ethyl acetate / heptane
(86.8 mg, 76%). HPLC-MS (Method A): MH+ requires m/z=504; Found m/z=504, Rt 4.69 min (100%). 1H NMR (500 MHz, CDC13) δ 3.08 & 3.09 (s rotamers, 3H), 4.48 & 4.54 (s rotamers, 2H), 4.61 & 4.70 (s rotamers, 2H), 5.29 & 5.35 (s rotamers, 2H), 6.94 - 6.98 (m, 4H), 7.16 - 7.18 (m, 3H), 7.22-7.29 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.46 (m, 1H) and 7.59- 7.77 (m, 1H).
Example 28: N-(4-Fluorobenzyl), N-cyclopropyl-3-(3-fluorobenzylsulfonyl)-6- fluoroindazo le- 1 -acetamide
The title compound was prepared from [3-(4-fluorobenzylsulfonyl)-6-fluoroindazol-lyl]- acetic acid (Intermediate 31, 83 mg, 0.23 mmol) and 4-fluoro-N-cyclopropylbenzylamine (Intermediate 32, 75 mg, 0.45 mmol), according to the method described above for Example 22, with the following modifications: the crude product was purified by recrystallisation from ethyl acetate / heptane (63 mg, 54%). HPLC-MS (Method A): MH+ requires m/z=514; Found m/z=514, Rt 4.74 min (96%). 1H NMR (500 MHz, CDC13) δ 0.92-1.16 (m, 4H), 2.70 (br.s, 1H), 4.52 (s, 2H), 4.61 (s, 2H), 5.50 (s, 2H), 6.85-7.10 (m, 8H), 7.16 - 7.30 (m, 2H) and 7.67 (dd, J= 9.2, 4.9 Hz, 1H).
Example 29: 3-(Benzylsulfonyl)-N-(3-chlorobenzyl), N-methyl-indazole-1 -acetamide
To a stirred solution of 3-(benzylsulfonyl)indazol-l-yl acetic acid (Intermediate 18, 0.15 g, 0.46 mmol) in DCM / DMF (2 ml) was added EDCI (1.5 eq, 0.13 g, 0.65 mmol) and the mixture was stirred at room temperature for 10 min. 3-Chloro-N-methylbenzylamine (1.5 eq, 0.09 ml, 0.65 mmol) was added and the mixture was stirred at room temperature overnight. A further 1.5 eq of both EDCI and 3-chloro-N-methylbenzylamine were added and stirring was continued for 5 h. The mixture was dissolved in ethyl acetate and washed with water. The organic phase was dried (sodium sulfate) and concentrated in vacuo. The crude product was purified twice by preparative HPLC to give the title compound (17.4 mg, 8%). HPLC-MS (Method A) MH+ requires m/z=468; Found m/z=468, Rt 4.54 min (100%). 1H NMR (500 MHz, CDC13) δ 2.96 (s, 3H), 4.39 & 4.46 (s rotamers, 2H), 4.51 & 4.60 (s rotamers, 2H), 5.26 & 5.31 (s rotamers, 2H), 6.95-7.30 (m, 10H), 7.30-7.42 (m, 2H) and 7.50-7.59 (m, 1H).
Example 30: 3-(Benzylsulfonyl)-N- 3-cyanobenzyl)-indazole- 1 -acetamide
3-(Benzylsulfonyl)-N-(3-cyanobenzyl)-indazole-l-acetamide was prepared from 3- (benzylsulfonyl)indazol-l-yl acetic acid (Intermediate 18, 83 mg, 0.25 mmol) and 3- cyanobenzylamine (50.2 mg, 0.38 mmol) according to the method described for Example 22. The title compound (6.6 mg, 6%) was isolated after purification by preparative HPLC-MS:
HPLC-MS (Method A) MH+ requires m/z=445; Found m/z=445, Rt 4.09 min (96%). 1H NMR (500 MHz, Methanol-d4) δ 4.38 (s, 2H), 4.54 (s, 2H), 5.25 (s, 2H), 6.98-7.08 (m, 4H), 7.08-7.17 (m, 2H), 7.29-7.46 (m, 2H), 7.46-7.66 (m, 5H) and 8.80 (br.s, 1H). Example 31: (RS) 3 -(1 -Phenyl- l-ethylsulfonyl)-N-benzyl, N-methyl-6-fluoroindazole-l- acetamide
To a stirred solution of 3-(benzylsulfonyl)-6-fluoroindazol-l-yl N-benzyl, N-methyl- acetamide (Example 22, 156 mg, 0.35 mmol) in DMF (2 ml) at 0 C (ice bath) was added sodium hydride (60%> suspension in oil; 21 mg, 0.52 mmol), and the mixture was stirred at room temperature for 2 h. Iodomethane (0.032 ml, 0.52 mmol) was added and stirring continued for 24 h (2 further portions of sodium hydride (21 mg) and iodomethane (0.032 ml) were added during this time). Water was added and the mixture was extracted with DCM (x 2). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane / ethyl acetate gradient elution (10:0 - 1 : 1) and recrystallisation from EtOAc / heptane to yield the target compound (19.7 mg, 12%). HPLC-MS (Method A): MH+ requires m/z=466; Found m/z=466, Rt 4.79 min (79%). 1H NMR (500 MHz, CDC13) δ 1.77- 1.90 (m, 3H), 3.06 & 3.10 (s rotamers, 3H), 4.43- 4.54 (m, 1H), 4.64 & 4.71 (s rotamers, 2H), 5.29 & 5.33 (s rotamers, 2H), 6.82- 7.01 (m, 2H), 7.08- 7.10 (m, 1H), 7.17- 7.31 (m, 5H), 7.31- 7.43 (m, 3H) and 7.43- 7.53 (m, 2H).
Intermediate 1: 3-Thioindole
Intermediate 2: 3-(Benzylthio)indole
To a stirred solution of indole-3 -thiol (Intermediate 1, 0.7 g, 4.7 mmol) in dry dioxane (10 ml) was added sodium hydride (60%> suspension in mineral oil, 61 mg, 1.6 mmol) and the mixture was stirred for 10 min. Benzyl bromide (0.55 g, 4.7 mmol) was added and the mixture was stirred at room temperature for 10 min. A further portion of sodium hydride (125 mg, 3.2 mmol) was added and the mixture was stirred for a further 90 min. The mixture was partitioned between water and ethyl acetate (x2). The combined organic phases were washed with water and concentrated in vacuo. The crude residue was purified by column chromatography with heptane: ethyl acetate (1 :0 - 10: 1) as the eluent to give the title compound (0.62 g, 55%). HPLC-MS (Method C): MH+ requires m/z=240; Found: m/z=240, Rt 1.52 min (91%). 1H NMR (250 MHz, CDC13) δ ppm 3.87 (s, 2 H), 6.91 - 7.15 (m, 3 H), 7.15 - 7.33 (m, 5 H), 7.33 - 7.45 (m, 1 H), 7.62 - 7.84 (m, 1 H) and 7.96 - 8.34 (m, 1 H).
Intermediate 3: 3-(4-Methylbenzylthio)indole
3-(4-Methylbenzylthio)indole was prepared from indole-3 -thiol (prepared in an analogous method to Intermediate 1, 0.55 g, 3.7 mmol) and 4-methylbenzylbromide (0.68 g, 3.7 mmol) according to the method described above for Intermediate 2. The title compound (0.32 g, 34%) was isolated after purification by column chromatography with heptane:ethyl acetate (1 :0 -20: 1 - 10: 1 gradient) elution. HPLC-MS (Method C): MH+ requires m/z=254; Found m/z=254 Rt 1.65 min (91%). 1H NMR (250 MHz, CDC13) δ ppm 2.32 (s, 3H), 3.85 (s, 2 H), 6.90 - 7.12 (m, 5 H), 7.12 - 7.31 (m, 2 H), 7.31 - 7.50 (m, 1 H), 7.74 (dd, J=7.99, 1.14 Hz, 1 H) and 7.99 - 8.33 (m, 1 H).
Intermediate 4: 3-(4-Fluorobenzylthio)indole
3-(4-Fluorobenzylthio)indole was prepared from indole-3 -thiol (prepared in an analogous method to Intermediate 1, 3.0 g, 20.0 mmol) and 4-fluorobenzylbromide (1.25 ml, 10.0 mmol) according to the method described above for Intermediate 2 with the following modification: the title compound (2.1 g, 41%>) was used without further purification. HPLC-MS (Method B): MH+ requires m/z=258; Found m/z=258 Rt 2.27 min (53%). 1H NMR (250 MHz, DMSO-<¾) δ ppm 3.85 (s, 2 H), 6.79 - 7.62 (m, 9 H) and 11.16 - 11.42 (m, 1 H).
Intermediate 5: 3-(Benzylsulfonyl)indole
To a stirred solution of 3-benzylthioindole (Intermediate 2, 0.6 g, 2.5 mmol) in aqueous sodium hydrogencarbonate solution (0.2 M, 5 ml) and acetone (5 ml) was added Oxone (3.85 g, 6.25 mmol) portionwise and the mixture was stirred for 18 h. The mixture was partitioned between water and ethyl acetate (x2) and the combined organic phases were washed with water (x2) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane: ethyl acetate (1 :0 - 1 : 1 gradient) elution to give the title compound (0.59 g, 87%). HPLC-MS (Method C): MH+ requires m/z=272; Found m/z 272,
Rt 1.26 min (90%). 1H NMR (500 MHz, CDC13) δ ppm 4.43 (s, 2 H), 7.08 (d, J=7.32 Hz, 2 H), 7.14 - 7.35 (m, 6H), 7.45 (d, J=8.24 Hz, 1 H), 7.72 (d, J=7.93 Hz, 1 H) and 8.97 (br. s., 1 H).
Intermediate 6: 3-(4-Methylbenzylsulfonyl)indole
3-(4-Methylbenzylsulfonyl)indole was prepared from 3-(4-methylbenzylthio)indole (Intermediate 3, 0.31 g, 1.2 mmol) and Oxone (1.88 g, 3.0 mmol), according to the method described above for Intermediate 5. The title compound (0.30g, 86%>) was isolated after purification by column chromatography with heptane:ethyl acetate (1 :0 - 3:2 gradient) elution. HPLC-MS (Method C): MH+ requires m/z=286; Found m/z=286, Rt 1.31 min (94%).
1H NMR (500 MHz, CDC13) δ ppm 2.31 (s, 3H), 4.39 (s, 2 H), 6.89 - 7.00 (m, 2 H), 7.00 - 7.09 (m, 2 H), 7.34 (t, J=7.63 Hz, 1 H), 7.40 - 7.51 (m, 2 H), 7.77 (d, J=8.09 Hz, 1 H) and 8.58 - 8.78 (m, 1H).
Intermediate 7: 3-(4-Fluorobenzylsulfonyl)indole
3-(4-Fluorobenzylsulfonyl)indole was prepared from 3-(4-fluorobenzylthio)indole (Intermediate 4, 2.1 g, 5.2 mmol) and Oxone (6.2 g, 16.1 mmol), according to the method described above for Intermediate 5. The title compound (0.93 g, 40%) was isolated after purification by column chromatography with heptane: ethyl acetate (9: 1 - 2: 1 gradient) elution. 1H NMR (500 MHz, DMSO-<¾) δ ppm 4.56 (s, 2 H), 6.89 - 7.20 (m, 5 H), 7.20 - 7.39 (m, 1 H), 7.39 - 7.64 (m, 2 H), 7.68 - 7.87 (m, 1 H) and 12.00 - 12.30 (m, 1 H).
Intermediate 8: Ethyl 3-benzylsulfon lindol-l-yl acetate
A solution of 3-(benzylsulfonyl)indole (Intermediate 5, 0.55 g, 2.0 mmol) in DMF (2 ml) was added to a suspension of sodium hydride (60%> suspension in mineral oil, 89 mg, 2.2 mmol) in DMF (2 ml) and the mixture was stirred for 10 min. Ethyl bromoacetate (0.25 ml, 2.2 mmol) was added and stirring continued for a further 5 h. The mixture was partitioned between water and ethyl acetate (x2). The combined organic phases were washed with water (x2) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane: ethyl acetate (1 :0 - 2:1 gradient) elution to yield the title compound (0.84 g, 10:1 mixture of product: starting material). HPLC-MS (Method C): MH+ requires m/z=358; Found m/z=358, Rt 1.37 min (57%). 1H NMR (500 MHz, CDC13) δ ppm 1.15 - 1.42 (m, 3
H), 4.26 (q, J=7.12 Hz, 2 H), 4.42 (s, 2H), 4.82 (s, 2 H), 7.10 (d, J=7.48 Hz, 2 H), 7.18 - 7.33 (m, 5 H), 7.33 - 7.42 (m, 2 H) and 7.70 (d, J=7.93 Hz, 1H).
Intermediate 9: Ethyl 3-(4-methylbenzylsulfonyl)indol-l-yl acetate
Ethyl 3-(4-methylbenzylsulfonyl)indol-l-yl acetate was prepared from 3-(4- methylbenzylsulfonyl)indole (Intermediate 6, 0.30 g, 1.05 mmol) and ethyl bromoacetate (0.14 ml, 1.26 mmol) according to the method described above for Intermediate 8. The title compound (0.32g, 82%) was obtained after purification by column chromatography with heptane:ethyl acetate (1 :0 - 2: 1 gradient) elution. HPLC-MS (Method C): MH+ requires m/z=372; Found m/z=372, Rt 1.42 min (76%). 1H NMR (250 MHz, CDC13) δ ppm 1.00 - 1.28 (m, 3 H), 2.15 (s, 3H), 4.09 (q, J=7.16 Hz, 2 H), 4.22 (s, 2H), 4.68 (s, 2 H), 6.71 - 6.96 (m, 4 H), 7.02 - 7.23 (m, 4 H) and 7.48 - 7.65 (m, 1 H).
Intermediate 10: Ethyl 3-(4-fluorobenzylsulfonyl)indol-l-yl acetate
Intermediate 11: 3-Benzylsulfonylindol-l-yl acetic acid
Ethyl 3-benzylsulfonylindol-l-yl acetate (Intermediate 8, 0.8 g, -2.2 mmol) was dissolved in water / methanol (5 ml / 5 ml) and aqueous sodium hydroxide solution (2M, 2.5 ml) was added. The mixture was stirred at room temperature for 2 h then diluted with water (10 ml). The mixture was extracted with diethyl ether (10 ml). The aqueous phase was acidified with dilute hydrochloric acid and extracted with ethyl acetate (x2). The combined ethyl acetate phases were washed with water and concentrated in vacuo to give the title compound as a yellow solid (0.6 g, 90% for 2 steps). HPLC-MS (Method C): MH+ requires m/z=330; Found m/z=330, Rt = 1.22 min (93%). 1H NMR (500 MHz, MeOD) δ ppm 4.50 (s, 2 H), 5.06 (s, 2 H), 7.08 (d, J=7.32 Hz, 2 H), 7.20 (t, J=7.55 Hz, 3 H), 7.23 - 7.30 (m, 1 H), 7.30 - 7.37 (m, 1 H), 7.45 (s, 1 H), 7.58 (s, 1 H) and 7.63 (s, 1 H).
Intermediate 12: 3-(4-Methylbenzylsulfonyl)indol-l-yl acetic acid
3-(4-Methylbenzylsulfonyl)indol-l-yl acetic acid was prepared from ethyl 3-(4- methylbenzylsulfonyl)indol-l-yl acetate (Intermediate 9, 0.31 g, 0.83 mmol) and aqueous sodium hydroxide solution (2M, 2 ml) according to the method described above for Intermediate 1 1. The title compound (0.23g, 81%) was obtained after purification column chromatography with heptane: ethyl acetate (1 :0 - 2: 1 gradient) elution. HPLC-MS (Method C): MH+ requires m/z=344; Found m/z=344, Rt 1.28 min (85%). 1H NMR (500 MHz, MeOD) δ ppm 2.25 (s, 3H), 4.42 (s, 2 H), 5.04 (s, 2 H), 6.78 - 7.05 (m, 4 H), 7.10 - 7.25 (m, 1 H), 7.31 (td, J=7.69, 1.22 Hz, 1 H), 7.36 - 7.50 (m, 1 H) and 7.50 - 7.65 (m, 2 H).
Intermediate 13: 3-(4-Fluorobenzylsulfonyl)indol-l-yl acetic acid
3-(4-Fluorobenzylsulfonyl)indol-l-yl acetic acid was prepared from ethyl 3-(4- fluorobenzylsulfonyl)indol-l-yl acetate (Intermediate 10, 0.26 g, 0.7 mmol) and aqueous sodium hydroxide solution (2M, 6.5 ml) according to the method described above for Intermediate 1 1 (0.26g, quantitative). HPLC-MS (Method B): M-H requires m/z =346); Found m/z=346, Rt = 1.77 min (93%). 1H NMR (500 MHz, MeOD) δ ppm 4.37 (s, 2 H), 4.96
(s, 2 H), 6.69 - 6.88 (m, 2 H), 6.88 - 7.03 (m, 2 H), 7.04 - 7.16 (m, 1 H), 7.16 - 7.29 (m, 1 H), 7.31 - 7.40 (m, 1 H), 7.42 - 7.51 (m, 1 H) and 7.54 (s, 1 H).
Intermediate 14: 3-Iodoindazole
Powdered potassium hydroxide (3.75 eq, 1.78 g, 31.7 mmol) was added to a solution of indazole (1.0 g, 8.46 mmol) and iodine (4.29 g, 16.9 mmol) in DMF (17 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into aqueous sodium thiosulfate solution (10%, 200 ml) and extracted with toluene (2 x 75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid (2.0 g, 96%). 1H NMR (250 MHz, CDC13) δ 6.98 - 7.27 (m, 2 H) and 7.32 - 7.59 (m, 2 H).
Intermediate 15: 3-Benzylthioindazole
A mixture of 3-iodoindazole (Intermediate 14, 2.0 g, 8.2 mmol), copper iodide (0.13 eq, 0.2 g, 1.05 mmol), ethylene glycol (2 eq, 0.91 ml, 16.4 mmol), benzyl mercaptan (2 eq, 1.93 ml, 16.4 mmol) and potassium carbonate (2 eq, 2.27 g, 16.4 mmol) in isopropanol (10 ml) was heated to 90 C in a sealed tube and stirred for 18 hr. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of celite; the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography with heptane: EtOAc (9: 1 - 4: 1 gradient) elution to yield the title compound as a yellow oil (1.3 g, 66%>). HPLC-MS (Method B): MH+ requires m/z=241; Found m/z=241, Rt 2.11 min (95%). 1H NMR (500 MHz, CDC13) δ 4.31 (s, 2 H), 7.04 - 7.36 (m, 6 H), 7.37 - 7.47 (m, 1 H), 7.51 (d, J=8.35 Hz, 1 H) and 7.64 (d, J=8.20 Hz, 1 H).
Intermediate 16: 3-Benzylsulfonylindazole
Oxone (2.5 eq, 4.15 g, 13.5 mmol) was added portionwise to a solution of 3- benzylthioindazole (Intermediate 15, 1.3 g, 5.4 mmol) and sodium hydrogencarbonate (5 eq, 2.27 g, 27.0 mmol) in acetone (13 ml) and aqueous sodium hydrogencarbonate solution (0.2M, 13 ml) at 0 C (ice bath). The mixture was warmed to room temperature and stirred for 2 h. Aqueous sodium thiosulfate solution (1 M, 50 ml) was added and the mixture was stirred for 30 min. The mixture was filtered through Celite and washed with water (10 ml) and ethyl acetate (20 ml). The filtrate was extracted with ethyl acetate (3 x 40 ml) and the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo to give the title compound as a light brown solid (1.32 g, 90%). HPLC-MS (Method B): MH+ requires m/z=273; Found m/z=273, Rt 1.81 (92%). 1H NMR (500 MHz, CDC13) δ ppm 4.57 (s, 2 H), 6.99 - 7.19 (m, 4 H), 7.19 - 7.34 (m, 2H), 7.48 (t, J=7.7 Hz, 1 H), 7.71 (dd, J=14.7, 8.51 Hz, 2 H) and 11.76 (br. s., 1 H).
Intermediate 17: Ethyl 3-(benzylsulfon l)indazol-l-yl acetate
Potassium carbonate (1.1 eq, 0.83 g, 5.8 mmol) was added to a stirred solution of 3- benzylsulfonylindazole (Intermediate 16, 1.32 g, 4.84 mmol) in DMF (13 ml) followed by ethyl bromoacetate (1 eq, 0.6 ml, 5.32 mmol) and the mixture was heated at 60 C overnight. After cooling, the mixture was poured into water (150 ml) and extracted with toluene (2 x 50 ml). The combined organic phases were washed with water (100 ml), dried (magnesium
sulfate) and concentrated in vacuo. The residue was purified by column chromatography with heptane: ethyl acetate (9: 1 - 1 : 1 gradient) elution to yield the title compound as a pale yellow solid (1.62 g, 93%). HPLC-MS (Method B): MH+ requires m/z=359; Found m/z=359 Rt 2.04 min (95%). 1H NMR (500 MHz, CDC13) δ ppm 1.17 - 1.39 (m, 3 H), 4.29 (q, J=7.1 Hz, 2 H), 4.57 (s, 2H), 5.27 (s, 2 H), 7.07 - 7.27 (m, 5 H), 7.38 (d, J=8.5 Hz, 1 H), 7.41 - 7.53 (m, 1 H) and 7.65 (d, J=8.2 Hz, 1H).
Intermediate 18: 3-(Benzylsulfonyl)indazol-l-yl acetic acid
Ethyl 3-(benzylsulfonyl)indazol-l-yl acetate (Intermediate 17, 1.62 g, 4.52 mmol) was dissolved in THF / MeOH (10 ml / 10 ml), aqueous sodium hydroxide solution (2M, 6 ml) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water (80 ml) and extracted with diethyl ether (2 x 50 ml). The aqueous phase was acidified with hydrochloric acid (1M, 18 ml) and extracted with diethyl ether (2 x 50 ml). The acidic organic extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to give the title compound as a yellow solid (1.42 g, 95%>). HPLC-MS (Method B): MH+ requires m/z=331; Found m/z=331, Rt 1.95 min (92%). 1H NMR (500 MHz, acetone- d6) δ 4.67 (s, 2 H), 5.53 (s, 2 H), 7.09 - 7.33 (m, 6 H), 7.51 (t, J=7.7 Hz, 1H) and 7.63 - 7.86 (m, 2 H).
Intermediate 19: 6-Fluoro-3-iodoindazole
Powdered potassium hydroxide (3.75 eq, 3.93 g, 69 mmol) was added to a solution of 6- fluoroindazole (2.5 g, 18.4 mmol) and iodine (2 eq, 9.35 g, 36.8 mmol) in DMF (45 ml) and
the mixture was stirred overnight. The reaction mixture was poured into aqueous sodium thiosulfate solution (10%, 400 ml) and extracted with toluene (x 2). The combined organic phases were washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo to give the title compound as an off-white solid (4.57 g, 95%). HPLC-MS (Method B): MH+ requires m/z=263; Found m/z=263, Rt 1.89 min (99%). 1H NMR (500 MHz, CDC13) δ 6.95 (td, J= 8.9, 2.1 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H) and 7.41 (dd, J= 8.9, 5.0 Hz, 1 H).
Intermediate 20: 3-Benzylthio-6-fluoroindazole
A mixture of 6-fluoro-3-iodoindazole (Intermediate 19, 1.88 g, 7.18 mmol), copper(I)iodide (0.13 eq, 0.18 g, 0.93 mmol), ethylene glycol (2 eq, 0.80 ml, 14.4 mmol), benzyl mercaptan (2 eq, 1.70 ml, 14.4 mmol), potassium carbonate (2 eq, 1.99 g, 14.4 mmol) and isopropanol (10 ml) was heated to 90 C in a sealed tube and stirred for 18 hr. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was concentrated in vacuo to give the title compound, which was used without further purification (4.2 g, »100%). HPLC-MS (Method B): MH+ requires m/z=259; Found m/z=259, Rt 2.13 min (40%).
Intermediate 21: 3-(4-Fluorobenzylthio)-6-fluoroindazole
The title compound was prepared from 6-fluoro-3-iodoindazole (Intermediate 19, 2.28 g, 8.7 mmol) and 4-fluorobenzylmercaptan (2.14 ml, 17.4 mmol) according to the method described
for Intermediate 20 (5.6 g, >100%). HPLC-MS (Method B): MH+ requires m/z=277; Found m/z=277, Rt 2.21 min (51%)). 1H NMR (500 MHz, CDC13) δ 3.60 (s, 2 H), 6.82 - 6.97 (m, 2 H), 6.99 - 7.10 (m, 2 H), 7.17 - 7.26 (m, 2 H) and 7.52 (dd, J=8.8, 5.1 Hz, 1 H).
Intermediate 22: 3-(3-Fluorobenzylthio)-6-fluoroindazole
The title compound was prepared from 6-fluoro-3-iodoindazole (prepared in an analogous manner to Intermediate 19, 2.28 g, 8.7 mmol) and 3-fluorobenzylmercaptan (2.47 g, 17.4 mmol) according to the method described for Intermediate 20 (5.18 g, >100%). HPLC-MS (Method B): MH+ requires m/z=277; Found m/z=277, Rt 2.21 min (48%). 1H NMR (500 MHz, CDC13) δ 3.60 (s, 2 H), 6.83 - 7.07 (m, 5 H), 7.09 - 7.24 (m, 1 H) and 7.23 - 7.38 (m, 1 H).
Intermediate 23: 3-Benzylsulfonyl-6-fluoroindazole
To a stirred mixture of 3-benzylthio-6-fluoroindazole (Intermediate 20, 4.2 g, 16.3 mmol) and sodium hydrogencarbonate (5 eq, 6.83 g, 81.3 mmol) in acetone (42 ml) and 0.2 M sodium hydrogen carbonate (42 ml) at 0 C (ice-bath) was added portionwise Oxone (2.5 eq, 12.48 g, 40.6 mmol). The mixture was stirred for 2 h at room temperature. Aqueous sodium thiosulfate solution (1M, 50 ml) was added, and the mixture was stirred for 30 min then filtered through Celite, washing with water (10 ml) and ethyl acetate (20 ml). The filtrate was extracted with ethyl acetate (3 x 40 ml) and the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo to give the title compound (1.3 g, ~30%>)
which was used without further purification. HPLC-MS (Method B)
m/z=290; Found m/z=290, Rt 1.83 min (53%).
Intermediate 24: 3-(4-Fluorobenzylsulfonyl)-6-fluoroindazole
The title compound was prepared from 3-(4-fluorobenzylthio)-6-fluoroindazole (Intermediate 21, 5.6 g, 20.3 mmol) and Oxone (26.64 g, 86.7 mmol) according to the method described for Intermediate 23, with the following modification: the crude compound was purified by column chromatography with heptane: EtOAc (10:0 - 1 : 1) to give the title compound (0.85 g, 32%). HPLC-MS (Method B): MH+ requires m/z=308; Found m/z=308, Rt 1.92 min (70%). 1H NMR (500 MHz, CDC13) δ 4.46 - 4.63 (m, 2 H), 6.78 - 7.10 (m, 4 H), 7.10 - 7.24 (m, 2 H), 7.33 (dd, J=8.5, 1.8 Hz, 1H), 7.65 (dd, J=9.0, 5.0 Hz, 1 H) and 11.42 - 11.79 (m, 1 H).
Intermediate 25: 3-(3-Fluorobenzylsulfonyl)-6-fluoroindazole
The title compound was prepared from 3-(3-fluorobenzylthio)-6-fluoroindazole (Intermediate 22, 5.18 g, 18.7 mmol) and Oxone (26.64 g, 86.7 mmol) according to the method described for Intermediate 23, with the following modification: the crude product was purified by column chromatography with heptane: EtOAc (10:0 - 1 : 1) to give the title compound (0.42 g, 16%). HPLC-MS (Method B): MH+ requires m/z=308); Found m/z=308, Rt 1.92 min (70%).
Intermediate 26: Ethyl (3-benzylsulfonyl-6-fluoroindazol-lyl)-acetate
To a stirred solution of 3-benzylsulfonyl-6-fluoroindazole (Intermediate 23, 1.3 g, 4.48 mmol) in DMF (13 ml) were added potassium carbonate (1.1 eq, 0.68 g, 4.93 mmol) and ethyl bromoacetate (1 eq, 0.5 ml, 4.48 mmol) and the mixture was heated at 60 C overnight. After cooling, the mixture was poured into water (150 ml) and was extracted with toluene (2 x 50 ml). The combined organic phases were washed with water (100 ml), dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane / ethyl acetate gradient elution (9: 1 - 1 : 1) to yield the title compound (0.51 g, 30%). 1H NMR (500 MHz, DMSO-d6) δ 1.24 (t, J=7.1 Hz, 3 H), 4.21 (d, J=7.1 Hz, 2 H), 4.79 (s, 2 H), 5.58 (s, 2 H), 7.14 (s, 3 H), 7.20 (s, 2 H), 7.23 - 7.32 (m, 1 H), 7.48 - 7.65 (m, 1 H) and 7.75 - 7.87 (m, 1 H).
Intermediate 27: Ethyl [(3-(4-fluorobenzyl)sulfonyl-6-fluoroindazol-lyl]-acetate
The title compound was prepared from 3-(4-fluorobenzylsulfonyl)-6-fluoroindazole (Intermediate 24, 0.79 g, 2.56 mmol) and ethyl bromoacetate (0.28 ml, 2.56 mmol), according to the method described for Intermediate 26, with the following modification: purification by
column chromatography with heptane: EtOAc (10:0 - 7:3) (0.55 g, 54%). HPLC-MS (Method B): MH+ requires m/z=395; Found m/z=395, Rt 2.17 min (91%). 1H NMR (500 MHz, CDC13) δ 1.34 (t, J=7 Hz, 3 H), 4.31 (d, J=7 Hz, 2 H), 4.53 (s,2 H), 5.21 (s, 2 H), 6.89 (t, J=8.5 Hz, 2 H) 7.01 (d, J=9.0 Hz, 2 H), 7.13 (dd, J=8.4, 5.3 Hz, 2 H) and 7.57 -7.72 (m, 1 H).
Intermediate 28: Ethyl [(3-(3-fluorobenzyl)sulfonyl-6-fluoroindazol-lyl]-acetate
The title compound was prepared from 3-(4-fluorobenzylsulfonyl)-6-fluoroindazole (Intermediate 25, 0.42 g, 1.35 mmol) and ethyl bromoacetate (0.15 ml, 1.35 mmol), according to the method described for Intermediate 26, with the following modification: purification by column chromatography with heptane: EtOAc (10:0 - 7:3) (0.38 g, 71%). HPLC-MS (Method B): MH+ requires m/z=395; Found m/z=395, Rt 2.15 min (88%). 1H NMR (500 MHz, CDC13) δ 1.29 - 1.38 (m, 3 H), 4.31 (q, J=7.1 Hz, 2H), 4.55 (s, 2H), 5.16 - 5.28 (m, 2 H), 6.81 - 7.09 (m, 5 H), 7.11 - 7.22 (m, 1 H) and 7.66 (dd, J=9.0, 5.0 Hz, 1 H).
Intermediate 29: (3-Benzylsulfonyl-6-fluoroindazol-lyl)-acetic acid
To a stirred solution of ethyl (3-benzylsulfonyl-6-fluoroindazol-lyl)-acetate (Intermediate 26, 0.51 g, 1.35 mmol) in THF / MeOH (2 ml / 2 ml) was added aqueous sodium hydroxide
solution (2M, 4 ml) and the mixture was stirred at room temperature overnight. The reaction was diluted with water (30 ml) and the mixture was extracted with diethyl ether (2 x 30 ml). The aqueous phase was acidified with hydrochloric acid (1M, 6 ml) and extracted with diethyl ether (2 x 30 ml). The combined acidic organic phases were dried (magnesium sulfate) and concentrated in vacuo to give the target compound as a white solid (0.35 g, 75%). HPLC-MS (Method B): MH+ requires m/z=349; Found m/z=349, Rt 1.78 min (94%). 1H NMR (500 MHz, DMSO-d6) δ 4.78 (s, 2 H), 5.46 (s, 2 H), 7.08 - 7.17 (m, 3 H), 7.20 (s, 2 H), 7.23 -7.31 (m, 1 H), 7.50 - 7.63 (m, 1 H) and 7.75 - 7.87 (m, 1 H).
Intermediate 30: [3-(4-Fluorobenzylsulfonyl)-6-fluoroindazol-lyl]-acetic acid
The title compound was prepared from ethyl [(3-(4-fluorobenzyl)sulfonyl-6-fluoroindazol- lyl]-acetate (Intermediate 27, 0.53 g, 1.35 mmol) and aqueous sodium hydroxide solution (1M, 4 ml) according to the method described for Intermediate 29 (0.55 g, 100%). HPLC-MS (Method B): MH+ requires m/z=366; Found m/z=366, Rt 1.92 min (84%). 1H NMR (500 MHz, DMSO-d6) δ 4.79 (s, 2 H), 5.44 (s, 2 H), 7.01 (s, 2 H), 7.09 - 7.28 (m, 3 H), 7.50 -7.68 (m, 1 H) and 7.72 - 7.88 (m, 1 H).
Intermediate 31: [3-(3-Fluorobenzylsulfonyl)-6-fluoroindazol-lyl]-acetic acid
The title compound was prepared from ethyl [(3-(3-fluorobenzyl)sulfonyl-6-fluoroindazol- lyl]-acetate (Intermediate 28, 0.35 g, 0.91 mmol) and aqueous sodium hydroxide solution (1M, 2.7 ml), according to the method described for Intermediate 29 (0.33 g, 100%). HPLC- MS (Method B): MH+ requires m/z=367; Found m/z=367, Rt 1.91 min (91%). 1H NMR (500 MHz, DMSO-d6) δ 4.72 - 4.94 (m, 2 H), 5.45 (s, 2 H), 6.89 - 7.04 (m, 2 H), 7.04 - 7.34 (m, 3 H), 7.50 - 7.66 (m, 1 H) and 7.71 - 7.89 (m, 1 H).
Intermediate 32: 4-Fluoro-N-cyclopropylbenzylamine
A mixture of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol), cyclopropylamine (1.34 ml, 19.3 mmol) and acetic acid (0.92 ml, 19.1 mmol) in 1 ,2-dichloroethane (50 ml) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (5.12 g, 24.2 mmol) was added and stirring continued overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The combined organic phases were dried (magnesium sulfate) and concentrated in vacuo to yield the title compound (2.40 g, 90%). HPLC-MS (Method B): MH+ requires m/z=166; Found m/z=166, Rt 0.64 min (72%). 1H NMR (500 MHz, MeOD) δ 0.05- 0.19 (m, 2H), 0.19- 0.30 (m, 2H), 1.87 (dt, J = 7.1, 3.3 Hz, 1H), 3.53 (s, 2H), 6.71- 6.89 (m, 2H) and 7.12 (dd, J= 8.5, 5.6 Hz, 2H).
Claims
Patent claims
A compound or a pharmaceutically acceptable salt thereof of formula (I)
wherein
A is CH; N; or C(CH3);
R1 is hydrogen; halogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is hydrogen; or halogen;
R3 is hydrogen; or Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R4, R5 are independently selected from the group consisting of hydrogen; halogen; and CN;
R6 is hydrogen; Ci_4 alkyl; or cyclopropyl, wherein Ci_4 alkyl and cyclopropyl are optionally substituted with one or more halogen, which are the same or different;
R7 is hydrogen; or methyl;
R^s T1;
Optionally R7 and R8 are joined together with the carbon atom to which they are attached to form a ring T2;
T1 is cyclohexyl; or phenyl, wherein T1 is optionally substituted with one or more R9, which are the same or different;
T2 is a 7 to 1 1 membered carbobicycle, wherein T2 is optionally substituted with one or more R10, which are the same or different;
R9, R10 are independently selected from the group consisting of halogen; CN; COOR1 1; OR1 1; C(0)Rn; C(0)N(RnRl la); S(0)2N(RnRl la); S(0)N(RnRl la); S(0)2Rn; S(0)Rn; N(Rn)S(0)2N(Rl laRl lb); SR1 1; N(RnRl la); N02; OC(0)Rn ; N(Rn)C(0)Rl la; N(Rn)S(0)2Rl la; N(Rn)S(0)Rl la; N(Rn)C(0)ORl la; N(Rn)C(0)N(Rl laRl lb); OC(0)N(RnRl la); oxo (=0), where the ring is at least partially saturated; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R1 1, Rl la, Rl lb are independently selected from the group consisting of H; and Ci_4 alkyl, wherein Ci_4 alkyl is optionally substituted with one or more halogen, which are the same or different; for use as a medicament.
A compound for use as a medicament of claim 1 , wherein A is CH; or C(CH3).
A compound for use as a medicament of claim 1 , wherein A is N.
A compound for use as a medicament of any of claims 1 to 3, wherein R1 is H; F; CI; CH3; or CF3.
5. A compound for use as a medicament of any of claims 1 to 4, wherein R2 is H; F; or CI.
6. A compound for use as a medicament of any of claims 1 to 5, wherein R3 is H; or CH3.
7. A compound for use as a medicament of any of claims 1 to 6, wherein R4 is H; or F and/or R5 is H; F; or CN.
8. A compound for use as a medicament of any of claims 1 to 7, wherein R6 is H; CH3;
CH2CH3; or cyclopropyl.
9. A compound for use as a medicament of any of claims 1 to 8, wherein T1 is unsubstituted or substituted with 1 , 2 or 3 R9, which are the same or different.
10. A compound for use as a medicament of any of claims 1 to 9, wherein R9 is F; CI;
CH3; CF3; CN; N(CH3)2; CH30; or CHF20.
11. A compound for use as a medicament of any of claims 1 to 8, wherein T2 is indanyl and wherein T2 is unsubstituted or substituted with one or more R10, which are the same or different.
12. A compound for use as a medicament of claim 1 selected from the group consisting of
3-(benzylsulfonyl)-N-benzyl, N-methyl- indole- 1 -acetamide;
3-(benzylsulfonyl)-N-benzyl, N-ethyl- indole- 1 -acetamide;
3-(4-methylbenzylsulfonyl)-N-benzyl, N-methyl- indole- 1 -acetamide;
3-(4-methylbenzylsulfonyl)-N-benzyl, N-ethyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-chlorobenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-methylbenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-methoxybenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl- N-methyl, N-(4-trifluoromethylbenzyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-methyl, N-(3-trifluoromethylbenzyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-chlorobenzyl), N-methyl-indole- 1 -acetamide;
3 -benzylsulfonyl-N-benzyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-methylbenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(4-fluorobenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-fluorobenzyl), N-methyl- indole- 1 -acetamide;
3-benzylsulfonyl-N-(3-methoxybenzyl), N-methyl-indole- 1 -acetamide;
3-benzylsulfonyl-N-(cyclohexylmethyl)-indole- 1 -acetamide;
3-benzylsulfonyl-N-(2,6-difluorobenzyl)-indole- 1 -acetamide;
(RS) 3-benzylsulfonyl-N-(indan- 1 -yl)-indole- 1 -acetamide;
3-(4-fluorobenzylsulfonyl)-N-(4-fluorobenzyl), N-methyl-indole- 1 -acetamide;
3-(4-fluorobenzylsulfonyl)-N-(4-fluorobenzyl)-indole-l -acetamide;
3-(benzylsulfonyl)-N-benzyl, N-methyl- indazole- 1 -acetamide;
N-benzyl, N-methyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide;
N-(3-chlorobenzyl), N-methyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide; N-(4-fluorobenzyl), N-cyclopropyl-3-(benzylsulfonyl)-6-fluoroindazole- 1 -acetamide; N-(3-chlorobenzyl), N-methyl-3-(4-fluorobenzylsulfonyl)-6-fluoroindazole- 1 - acetamide;
N-(4-fluorobenzyl), N-cyclopropyl-3-(4-fluorobenzylsulfonyl)-6-fluoroindazole- 1 - acetamide;
N-(3-chlorobenzyl), N-methyl-3-(3-fluorobenzylsulfonyl)-6-fluoroindazole- 1 - acetamide;
N-(4-fluorobenzyl), N-cyclopropyl-3-(3-fluorobenzylsulfonyl)-6-fluoroindazole- 1 - acetamide;
3-(benzylsulfonyl)-N-(3-chlorobenzyl), N-methyl- indazole- 1 -acetamide;
3 -(benzylsulfonyl)-N-(3 -cyanobenzyl)-indazo le- 1 -acetamide; and
(RS) 3-(l -phenyl- 1 -ethylsulfonyl)-N-benzyl, N-methyl-6-fluoroindazole- 1 -acetamide.
A compound as defined in any of claims 1 to 11, provided that the following compounds are excluded:
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N-methyl-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N-ethyl-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N-butyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide; N- [(4-chlorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N-ethyl-3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N-butyl-3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H- indole- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(3-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-( 1 -methylethyl)-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(3-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(4-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-ethyl-3 - [ [(3 -fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H- indole- 1 -acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N- [(4-fluorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-butyl-3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] - N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-methylphenyl)methyl] sulfonyl] - N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-( 1 -phenylmethyl)- 1 H-indo le- 1 -acetamide; N-butyl-3 - [ [(2-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N-butyl-3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-methylphenyl)methyl] sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide; N- [(2-chlorophenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N-( 1 -methylethyl)-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H- indole- 1 -acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le 1 -acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N-( 1 -methylethyl)-3 - [ [(2-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H- indole- 1 -acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H- indole- 1 -acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-ethyl-3 - [ [(3 -methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(2-chloro-6-fluorophenyl)methyl] sulfonyl] -N- [(2-chlorophenyl)methyl] - 1 H- indole- 1 -acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(3 -methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(3-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [(phenylmethyl)sulfonyl] -N-( 1 -phenylethyl)- 1 H-indo le- 1 -acetamide;
3 - [ [(4-chlorophenyl)methyl] sulfonyl] -N- [(4-fluorophenyl)methyl] - 1 H-indo le- 1 - acetamide;
N-methyl-3 - [ [(3 -methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-butyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N-ethyl-3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2,5 -dimethylphenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(4-chlorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl]sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-( 1 -methylethyl)-N-(phenylmethyl)- 1 H-indo le 1 -acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 acetamide;
3 - [ [(3-fluorophenyl)methyl]sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(3 -fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N- [(2-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-fluorophenyl)methyl]sulfonyl] -N- [(4-methoxyphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-fluorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(4-methoxyphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(4-methoxyphenyl)methyl] -3 - [ [(2-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N- [(2-methoxyphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; N- [(4-methoxyphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; N- [(4-fluorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; 3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-ethyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(3-chlorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-methyl-N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(3-chlorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(2-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(2-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(4-fluorophenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
3 - [ [(4-fluorophenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; 3 - [ [(2-chlorophenyl)methyl] sulfonyl] -N- [(4-methylphenyl)methyl] - 1 H-indo le- 1 - acetamide;
N- [(4-methylphenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-ethyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
N- [(2-chlorophenyl)methyl] -3 - [ [(4-methylphenyl)methyl] sulfonyl] - 1 H-indo le- 1 - acetamide;
N-methyl-3 - [ [(4-methylphenyl)methyl]sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 - acetamide;
3 - [ [(4-methylphenyl)methyl] sulfonyl] -N-(phenylmethyl)- 1 H-indo le- 1 -acetamide; N- [(4-methylphenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; N-ethyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide;
N- [(2-chlorophenyl)methyl] -3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; N-methyl-N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide; and N-(phenylmethyl)-3 - [(phenylmethyl)sulfonyl] - 1 H-indo le- 1 -acetamide.
14. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 12 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.
15. A compound or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 12 for use in a method of treating or preventing diseases and disorders associated with the Orexin Receptors.
16. A method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the Orexin 2 Receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound as defined in any of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
17. A method for the preparation of a compound of formula (I) as defined in any of claims 1 to 12 comprising the step of
reacting a compound of formula (IV)
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| EP10161735.5 | 2010-05-03 | ||
| EP10161735 | 2010-05-03 |
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| WO2011138265A2 true WO2011138265A2 (en) | 2011-11-10 |
| WO2011138265A3 WO2011138265A3 (en) | 2015-06-25 |
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| US9440982B2 (en) | 2012-02-07 | 2016-09-13 | Eolas Therapeutics, Inc. | Substituted prolines/piperidines as orexin receptor antagonists |
| US9499517B2 (en) | 2012-02-07 | 2016-11-22 | Eolas Therapeutics, Inc. | Substituted prolines / piperidines as orexin receptor antagonists |
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| US10221170B2 (en) | 2014-08-13 | 2019-03-05 | Eolas Therapeutics, Inc. | Difluoropyrrolidines as orexin receptor modulators |
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| US12084437B2 (en) | 2016-02-12 | 2024-09-10 | Astrazeneca Ab | Halo-substituted piperidines as orexin receptor modulators |
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| WO2024209363A1 (en) | 2023-04-06 | 2024-10-10 | Pfizer Inc. | Substituted indazole propionic acid derivative compounds and uses thereof as ampk activators |
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