Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/16—Peri-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/06—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/06—Peri-condensed systems

Definitions

• the present invention relates to tricyclic derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy.
• CRF corticotropin-releasing factor
• CRF In addition to its role in stimulating the production of ACTH and POMC, CRF appears to be one of the pivotal central nervous system neurotransmitters and plays a crucial role in integrating the body's overall response to stress.
• CRF receptor antagonists may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF, and, in particular, may represent novel antidepressant and/or anxiolytic drugs.
• the first CRF receptor antagonists were peptides (see, e. g., Rivier et al., U. S. Patent No. 4,605,642; Rivier et al., Science 224: 889,1984). While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported.
• A, B and C are nitrogen, A, B and C are not all nitrogen and either A-B or B-C is a double bond.
• A, B and C may be nitrogen or carbon.
• CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general. While significant strides have been made toward achieving CRF regulation through administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods relating to the use thereof to treat, for example, stress-related disorders. The present invention fulfills these needs, and provides other related advantages.
• the invention relates to novel compounds which are potent and specific antagonists of corticotropin-releasing factor (CRF) receptors.
• CCF corticotropin-releasing factor
• the present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof
• R is aryl or heteroaryl, wherein each of the above groups R may be substituted by 1 to 4 substituents indendently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, cyano and a group R ⁇
• R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, NH 2 , halogen or cyano;
• R 2 is hydrogen or C(H) n (R 5 ) q (CH 2 ) p ZR 6 ;
• R 3 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or [CH(R 5 )(CH 2 ) p ] m ZR 6 ;
• R is C3-C7 cycloalkyl, which may contain one or more double bonds; aryl; or a 5-6 membered heterocycle; wherein each of the above groups R 4 may be substituted by one or more groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, Cl- C6 mon a or dialkylamino, nitro, and cyano;
• R 5 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl or (CH 2 ) P ZR 6 ;
• Re is C1-C6 alkyl, which may be substituted by one or more groups selected from halogen, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 mono or dialkylamino, nitro, cyano and a group R4;
• Y and X are independently carbon or nitrogen; m and n are independently 0 or 1 ; p is 0 or an integer from 1 to 4; q is 1 or 2; Z is a bond, 0, NH or S.
• Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids.
• Suitable organic acids include maleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
• Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
• the solvates may, for example, be hydrates.
• references hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
• prodrugs are also included within the context of this invention.
• Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
• Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
• Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
• prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I).
• esters may be employed, such as methyl esters, ethyl esters, and the like.
• the compounds of structure (I) may have chiral centers and may occur as recemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
• C1-C6 alkyl refers to a straight or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.
• C3-C7 cycloalkyl group means a non aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; while unsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and the like.
• halogen refers to a fluorine, chlorine, bromine or iodine atom.
• halo C1-C6 alkyl means an alkyl group having one or two carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like.
• C2-C6 alkenyl defines straight or branched chain hydrocarbon radicals containing one or more double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl and the like.
• C1-C6 alkoxy group may be a straight or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
• halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF 2 , or OCF 3 .
• C2-C6 alkynyl defines straight or branched chain hydrocarbon radicals containing one or more triple bond and having from 2 to 6 carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl, 3 -methyl- 1-butynyl and the like.
• C1-C6 mono or dialkylamino represents an amino group independently substituted with one or two C1-C6 alkyl groups, as defined before.
• aryl means an aromatic carbocyclic moiety such as phenyl, biphenyl or naphthyl.
• heteroaryl means an aromatic heterocycle ring of 5 -to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems.
• heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
• heterocycle means a 5 to 7-membered monocyclic, or 7-to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings.
• the heterocycle may be attached via any heteroatom or carbon atom.
• Heterocycles include heteroaryls as defined above.
• heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• 5-6 membered heterocycle means, according to the above definition, a monocyclic heterocyclic ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
• the heterocycle may be attached via any heteroatom or carbon atom.
• the term includes (but is not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Representative compounds of this invention include the following structure (II) and (IH)
• representative compounds of this invention include the followmg structures (Ha), (Hb), X corresponds to a carbon atom
• the representative compounds of this invention include, but are not limited to, the following compounds (Ia-1), (Ib-1), (Ic-1).
• the representative compounds of this invention include, but .
• More specific embodiments of the invention include, but are not limited to, compounds of the formula (I); (IT), (UJ), (Ha), (Hb), (He), (lid); (Ia-1), (Ib-1), (Ic-1); (1-1), (1-2), (1-3), (1-4): wherein:
• Furtehr specific embodiments of the invention include, but are not limited to, compounds of the formula (I); (II), (HI), (Da), (Hb), (He), (IM); (Ia-1), (Ib-1), (Ic-1); (1-1), (1-2), (1-3), (1-4): wherein:
• R is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl.
• Preferred embodiments of the invention include, but are not limited to, compounds of the formula (I); (IT), (UJ), (Ha), (Ub), (He), (Ed); (Ia-1), (Ib-1), (Ic-1); (1-1), (1-2), (1-3), (1-4): wherein:
• R 2 and R 3 are not simultaneously hydrogen; and • Ri is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl;
• More preferred embodiments of the invention include, but are not limited to, compounds of the formula (I); (U), (HI), (Ha), (Hb), (He), ( ⁇ d); (Ia-1), (Ib-1), (Ic-1); (1-1), (1-2), (1-3), (1-4): wherein:
• Ri is C1-C3 alkyl group or halo C1-C3 alkyl group, preferably methyl or trifluoromethyl;
• R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2- chloro-4-trifluoromethyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4- dimethyl-phenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4- trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2- methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4- isopropylphenyl 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4- trifluoromethylphen
• Preferred compounds according to the invention are:
• R 7 is a C1-C4 linear or branched alkyl group and m is 1, equivalent to compounds of formula (VI). Then compounds of formula (VI) may react with the organo-metallic compound GM,
• M is a metal to give compounds of formula (IV), optionally in the presence of a Lewis acid such as borontrifluoride etherate.
• Suitable metals for this reaction include lithium, copper or magnesium.
• Compounds of formula (I) when R 3 is hydrogen are equivalent to compounds of formula (la), may be prepared by reduction of a compound of formula (V) wherein R 7 is hydrogen and equivalent to compounds of formula (Va), in the presence of an organic acid (e.g. trifluoroacetic).
• organic acid e.g. trifluoroacetic
• Convenient reducing agents for this reaction are trialkylsilanes (e.g. triethylsilane).
• the reaction is preferably carried out in an aprotic solvent such as dichloromethane.
• L is a leaving group selected in a group consisted from halogens, preferably chlorine and reactive residue of sulphonic acid (such as mesylate, triflate) and La represents a suitable reactive group able to render OLa a good leaving group (such as mesylate, triflate).
• the reaction takes place by heating using the amine R 2 NH 2 (DC) in excess, preferably as solvent.
• Compounds of formula (VI), may be prepared by oxidation of the allyl group of compounds of formula (VHI) to the corresponding aldehyde followed by in situ cyclisation and conversion of the hydroxy group into the alkoxy group which will be described in details later on.
• the oxidation is carried out with osmium tetroxide in the presence of N-methylmorpholine oxide (NMO), followed by treatment with sodium periodate.
• NMO N-methylmorpholine oxide
• the reaction is conveniently carried out in a water miscible organic solvent such acetone, tetrahydrofuran optionally in the presence of water.
• the conversion of the hydroxy group into C1-C4 alkoxy may be carried out by treatment of the hydroxy group with C1-C4 alcohol in the presence of a suitable inorganic acid, e.g. hydrochloric acid.
• a suitable inorganic acid e.g. hydrochloric acid.
• Compounds of formula (VHI) may be prepared by treatment of a compound of formula (X), with the amine R 2 NH 2 (DC).
• compounds of formula (Ha) may be prepared by reaction of a compound of formula (XI),
• Suitable reducing agents for this reaction include hydride, for example a borane hydride, or a metal hydride complex like lithium aluminum hydride, borohydride, or an organo-metallic complex such as borane methyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride.
• hydride for example a borane hydride, or a metal hydride complex like lithium aluminum hydride, borohydride, or an organo-metallic complex such as borane methyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydride.
• hydride for example a borane hydride, or a metal hydride complex like lithium aluminum hydride, borohydride, or an organo-metallic complex such as borane methyl sulph
• boranes may be produced in situ by reacting Sodium Borohydride in the presence of Iodine, an inorganic acid (e.g. sulphoric acid) or an organic acid such as formic acid, trifluoroacetic, acetic acid or methansulphonic acid.
• Suitable solvents for this reaction are alcohol (e.g. methanol), ether (e.g. tetrahydrofuran), or halohydrocarbon (e.g. dichloromethane) or an amide (e.g. N,N-dimethylformamide) at a temperature within the range of room temperature to the reflux temperature of the reaction mixture.
• X is carbon
• La is a suitable reactive group able to render OLa a good leaving group, (such as mesylate) and Ra corresponds to hydrogen or a suitable nitrogen protecting group, if necessary.
• Compounds of formula (XHa) may be subjected to the following reactions: i) optionally removal of the nitrogen protecting group Ra; and ii) cyclisation in the presence of organic base such as a tertiary amine e.g. triethylamine. These reactions are preferably carried out in an aprotic solvent such as ether (e.g. tetrahydrofuran), halohydrocarbon such as dichloromethane or amide such as N,N- dimethylformamide.
• ether e.g. tetrahydrofuran
• halohydrocarbon such as dichloromethane
• amide such as N,N- dimethylformamide.
• Compounds of formula (XHT) may be obtained by reaction of a compound of formula (XV), wherein Rb is a suitable hydroxy protecting group, with amine (XIV), followed by protection of the nitrogen group (if necessary) and removal of hydroxy protecting group.
• reaction with the amine is suitably carried out in an aprotic solvent such as DMF
• Compounds of formula (XV) may be prepared by reduction of an ester of formula (XVI) to the corresponding hydroxy with a suitable reducing agent, such as diisobuiylaluminumhydride followed by protection of the hydoxy group with a hydroxy suitable protecting group.
• a suitable reducing agent such as diisobuiylaluminumhydride
• Compounds of formula (XVI) may be prepared by reaction of a compound of formula (XVH) with allyl halide (e.g. allyl iodide). The reaction is carried out in the presence of an organic base such as lithiumhexamethyldisilazane at low temperature and in an aprotic solvent (e.g. tetrahydrofuran).
• allyl halide e.g. allyl iodide
• Compounds of formula (XII) wherein n is 1 and X is carbon are equivalent to compounds of formula (Xllb), may be prepared by reduction of a compound of formula (XVHI), with a suitable reducing agent, e.g. sodium borohydride in a solvent such as for example an alcohol (e.g. methanol).
• a suitable reducing agent e.g. sodium borohydride in a solvent such as for example an alcohol (e.g. methanol).
• Compounds of formula (XX) may also be prepared by oxidation of a compound of formula (Xm).
• the oxidation may be carried out using the conventional methods known for converting a hydroxy group into an aldehyde group. Thus, for example, the reaction may be carried out using Swern conditions.
• Compounds of formula (X) when Y is carbon and X is carbon are equivalent to compounds of formula (Xb), may be prepared by halogenation of a compound of formula (XXI),
• the halogenation reaction may be carried out using conventional methods known in the art.
• reaction may be carried out by treatment with PO(Hal) 3 , wherein within the halogens, chlorine is preferred.
• the reaction is carried out in the presence of a C1-C4 alkaline alkoxylate (e.g. sodium methoxylate), in a solvent such as methyl alcohol.
• a C1-C4 alkaline alkoxylate e.g. sodium methoxylate
• organo metallic compound Rg 2 M (XXVH), in which R 9 is an allyl group and M is a metal, optionally in the presence of a Lewis acid such as boron trifluoride etherate.
• Suitable metals for this reaction include lithium, copper and magnesium.
• Compounds of formula (X) when X is nitrogen are equivalent to compound of formula (Xc), may be prepared by reaction of a compound of formula (XXVIH) with allyl halide (e.g. allyl bromide). The reaction is carried out in the presence of an inorganic base such as sodium hydride at low temperature and in aprotic solvent (e.g. tetrahydrofuran or NN- dimethylformamide).
• allyl halide e.g. allyl bromide
• an inorganic base such as sodium hydride at low temperature and in aprotic solvent (e.g. tetrahydrofuran or NN- dimethylformamide).
• Compounds of formula (XXDCa), corresponding to compounds (XXDC) in which q isl and Y is carbon, may be subjected to the following reactions: i) conversion of the hydroxy group into a suitable leaving group such as mesylate, ii) conversion of the nitro group into the amine by reduction in the presence of Na 2 S 2 0 and an inorganic base such as potassium carbonate and in situ cyclisation.
• Compounds of formula (XXDCa) may be prepared by reduction of an ester compound of formula (XXX). The reduction can be conveniently carried out with sodium borohydride in a protic solvent such alcohol (e.g. methanol or ethanol) and preferably heating e.g. 40-100°C.
• Compounds of formula (XXX) may be prepared by reaction of a compound of formula (XXXI), with an ester compound (XXXH).
• the reaction takes place in an aprotic solvent such as DMF and in the presence of an inorganic base (i.e. sodium hydride).
• an aprotic solvent such as DMF
• an inorganic base i.e. sodium hydride
• (XXXIV) Compounds of formula (XXXHI) may be obtained by hydrolysis of enolether of formula (XXXTV). The reaction is preferably carried out in the presence of an inorganic acid such as for example hydrogen chloride. Compounds of formula (XXXIV) may be obtained from (XXXV) by Wittig reaction with the ylide (XDC), in the presence of a suitable organic base like n-BuLi. The reaction is carried out in an aprotic solvent such as acetonitrile or an ether such as tetrahydrofuran. Compounds of formula (XXXV) may be prepared by oxidation of compounds (XXDCa) when Y corresponds to carbon, by using conventional methods known to convert alcohol to aldehyde.
• the oxidation reaction is conveniently carried out in the presence of ozone at low temperature e.g. -78°C in a solvent such as dicholoromethane.
• the oxidation takes place by reaction with with osmium tetraoxide in the presence of N-methyl morpholine oxide (NMO) followed by treatment with sodium periodate.
• NMO N-methyl morpholine oxide
• the reaction is conveniently carried out in a water miscible organic solvent such as acetone or tetrahydrofuran optionally in the presence of water.
• Compounds of formula (XIc) when X and Y are carbon, m is 0 and n is 1 are equivalent to compounds of formula (Xle), may be prepared by treating compounds of formula (XXXVIH) with an inorganic base such as potassium hydroxide in a solvent such as alcohol, followed by reaction with potassium permanganate. The reaction is suitably carried out in water.
• an inorganic base such as potassium hydroxide in a solvent such as alcohol
• Compounds of formula (XXXVHI) may be prepared by halogenation of a compound of formula (XXXDC). The halogenation reaction may be carried as described above.
• Compounds of formula (XXXDC) may be prepared by reaction of a compound of formula (XL) with a salt (e.g hydrochloric acid) of acetamidine (XXII) using condition as described above.
• Compounds of formula (XL) may be prepared by reacting compounds of formula (XXIV), in which R7 is as defined before, with nitromethane.
• Compounds of formula (XLI) may be prepared by subjecting a compound of formula (XLH), wherein La is a suitable leaving group, such as mesylate, Ra and Rb are as defined above, to the following reactions: i) optionally, removal of the nitrogen protecting group, ii) cyclisation and iii) removal of the hydroxy protecting group Rb.
• Compounds of formula (XLH) may be prepared as discussed before by oxidation of a compound of formula (XLHI), followed by reduction to hydroxy group and conversion in a leaving group.
• the oxidation reaction is conveniently carried out in the presence of ozone at low temperature e.g. -78°C in a solvent such as dichloromethane.
• the reduction is carried out using sodium borohydride as reducing agent.
• Compounds of formula (XLHT) may be obtained from a compound of formula (XV) with amine (XIV), followed by protection of the nitrogen group.
• Compounds of formula (XLI) may be converted to compounds of formula (VHa), corresponding to compounds of formula (VII) in which X is carbon, Y is nitrogen m and n arel, according to known methods.
• compounds of formula (VHa) may be converted to compound of formula (I-la), corresponding to compound of formula (1-1) in which R 3 is hydrogen.
• Compounds of formula (Xc) in which X and Y are nitrogen and n is 1 are equivalent to compounds of formula (Xc'), may be prepared by reaction of a compound of formula (XLIV) with dibromoethane, in the presence of an organic or inorganic base.
• the reaction is suitably carried out in an aprotic solvent such as NN-dimethylformamide or acetonitrile.
• Compounds of formula (XLTV) may be prepared by compounds of formula (XLV) by treatment with iron and an inorganic acid e.g. hydrochloric acid.
• Compounds of formula (XLV) may be prepared by reaction of compound (XXXI) and the amine (XIV).
• R 7 is a methyl group
• Hal is chlorine
• Ra is t-butylcarbonyl
• Rb is t-BuPh 2 Si derivative
• OLa is a mesyl group and step a stands for allylation with allyl iodide at 0°C in basic conditions (e.g.
• the starting material may be prepared in similar way to what described in Wayne G. C. et al., J. Prakt. Chem., (2000), 342(5), 504-7;
• step b stands for reduction of the ester group with a suitable reducing agent, e.g. DH3A1-H, in usual conditions (CH 2 C1 2 , 0°C to r.t.);
• step c stands for protection of the hydroxy group, preferably with t-BuPh 2 SiCl, in
• step d stands for reaction with the amine RNH 2 (XIV) as described above
• step e stands for protection of the amino group with a suitale protecting group, for example by treatment with (BOC) 2 0 in presence of DMAP
• step f stands for, i) oxidation with OsO in acetone/water, then ii) treatment with
• step g stands for deprotection of the amino protecting group (e.g. CF 3 C0 2 H in CH 2 C1 2 );
• step h stands for intramolecular cyclisation, for example by mesylation of the hydroxy group in basic conditions (i.e. Et 3 N);
• step i stands for deprotection of the hydroxy protecting group (e.g. Et 3 N - 3HF in
• step j stands for transformation of the hydroxy group in a suitable leaving group
• step k stands for reaction with the amine (DC) as described above.
• step 1 stands for the first two reactions of previous step f
• step m stands for treatment with Et 3 SiH in the presence of BF 3 -Et 2 O.
• step n corresponds to previous step f
• step o corresponds to previous step j
• step p stands for reaction with the amine RNH 2 (XIV) as described above; The synthesis is then completed as described in Scheme 1.
• R 7 is a methyl group
• Hal is chlorine
• Rb is t-BuPh 2 Si derivative
• OLa is a mesyl group
• step a' stands for esterification in usual conditions (R 7 OH, acid catalyst, reflux);
• step b' stands for alkylation with the suitable alkylating agent (e.g. methyl
• step c' stands for intramolecular cyclisation in basic conditions (i.e. MeONa, refluxing toluene);
• step d' stands for phenylselenylation followed by oxidation with H 2 0 2 and subsequent elimination;
• step e' stands for 1,4-carbonyl addition with a suitable silane such as allyltrimethylsilane catalysed by TiCl 4 ;
• step f stands for reaction with the amidine (XXII) as described above;
• step g' stands for halogenation of the hydroxy group (e.g. by treatment with POCl 3 at reflux);
• step h' stands for oxidative cleavage of the double bond by, for example, ozonization;
• step i' stands for reductive amination in the presence of NaBH 3 CN with the amine
• compounds of formula (1-3) in which R3 is hydrogen are equivalent to compounds of formula (1-3 a) may be prepared according to Scheme 4 in which step a stands for protection of the amino group with a suitale protecting group, for example by treatment with (BOC) 2 0 in presence of DMAP; step b" corresponds to previous step i); step c" stands for mesylation of the hydroxy group in basic conditions (i.e. Et 3 N); step d" stands for deprotection of the protective group of the amino, e.g. by treatment with TFA and then subsequent cyclisation in basic conditions, e.g. Et 3 N; step e" corresponds to previous step h') or corresponds to previous step 1); step f" corresponds to previous step i');
• step a corresponds to previous step k
• step b' corresponds to previous step 1
• step c' ' ' stands for reduction, e.g. by treatment with Et 3 SiH, TFA
• step d' ' ' stands for formation of the ether group, e.g. by treatment with methanol in presence of PTSA
• step e" ' stands for reaction with an organo-metallic compound, such as R 3 Cu in presence of BF 3 .Et 2 0.
• organo-metallic compound such as R 3 Cu in presence of BF 3 .Et 2 0.
• step a" corresponds to previous step i
• step b corresponds to previous step j
• step d corresponds to previous steps j
• step k corresponds to previous steps j
• step a" ' stands for reaction with nitromethane in usual conditions
• step b" “ ' stands for reaction with the amidine (XXII) as described above
• step c " " ' corresponds to previous step g' )
• step d" " ' stands for formation of the aldehyde group, e.g. by treatment with KOH in methanol and subsequent oxidation by KMnO 4
• step e" " ' corresponds to previous step i').
• suitable nitrogen protecting group include alkoxycarbonyl, e.g. t- butoxycarbonyl and arylsulphonyl, e.g phenylsulphonyl.
• the nitrogen protecting group may be removed by conventional procedures known for removing such groups (such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)).
• the group may be removed by acid hydrolisis using for example trifluoro acetic acid.
• Suitable hydroxy protecting group include trihydrocarbyl silyl ethers such as the trimethylsilyl or t-butyldimethylsilyl ether.
• hydroxyl protectin groups may be removed by well-known standard procedures (such as those described in Protective Groups in Organic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press, 1973)). For example when Rb is a t-butyldimethylsilyl group, this may be removed by treatment with triethylamine trihydrofluoride.
• Pharmaceutical acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.
• the compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation or evaporation of an appropriate solvent to give the corresponding solvates.
• the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3 H, n C, 14 C, 18 F, 123 I and 125 I.
• Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
• Isotopically - labeled compounds of the present invention are useful in drug and/or substrate tissue distribution assays.
• Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• ⁇ C and 8 F isotopes are particularly useful in PET (positron emission tomography), and 125 I are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
• isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagen.
• the CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site including CRF 1 and CRF 2 receptors and may be used in the treatment of conditions mediated by CRF or CRF receptors.
• Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with CRF.
• a compound of structure (I) may be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7: 88,1987) and Battaglia et al. (Synapse 1: 572,1987).
• the CRF receptors-binding assay was performed by using the homogeneous technique of scintillation proximity (SPA).
• SPA scintillation proximity
• the ligand binds to recombinant membrane preparation expressing the CRF receptors which in turn bind to wheatgerm agglutinin coated SPA beads.
• SPA scintillation proximity
• CRF receptor antagonists of this invention have a Ki less than 10 ⁇ m.
• a CRF receptor antagonist has a Ki of less than 10 ⁇ m.
• the value of Ki is less than 1 ⁇ m and more preferably less than 0.1 ⁇ m.
• the Ki values of representative compounds of this invention were assayed by the methods set forth in Example 5.
• Preferred compounds having a Ki of less than 1 ⁇ m are compound numbers 3-1-3 and 3-1-10. More preferred compounds having a Ki less than 0.1 ⁇ m are compound numbers 1-1-1, 1-1-4, 1-1-5, 1-2-1, 3-1-5, and 3-1-6.
• Compounds of the invention may be useful in the treatment of central nervous system disorders where CRF receptors are involved.
• major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, the treatment of anxiety and the treatment of panic disorders.
• Major depressive disorders include dysthymic disorder with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorders and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
• Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
• Compounds of the invention are useful as analgesics.
• traumatic pain such as postoperative pain
• traumatic avulsion pain such as brachial plexus
• chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis
• neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain
• various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain
• Compounds of the invention are also useful for the treatment of dysfunction of appetite and food intake and in circumstances such as anorexia, anorexia nervosa and bulimia.
• Compounds of the invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy, and circadian ritrnic disorders.
• Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
• compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
• Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds), or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in the treatment of cocaine, sedative ipnotic, amphetamine or amphetamine- related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
• opiates e.g. cannabis, heroin, morphine
• benzodiazepines e.g. cocaine, sedative ipnotic, amphetamine or amphetamine- related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
• Compounds of the invention are also useful as anti-inflammatory agents.
• they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease (ffiD) and non- steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation.
• Compounds of the invention are also useful in the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
• Emesis i.e. nausea, retching and vomiting.
• Emesis includes acute emesis, delayed emesis and anticipatory emesis.
• the compounds of the invention are useful in the treatment of emesis however induced.
• emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
• cytarabine methotrexate and 5- fluorouracil
• vinca alkaloids e.g. etoposide, vinblastine and vincristine
• others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof
• radiation sickness e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g.
• gastritis or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as mo hine; and gastro-oesophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
• vestibular disorders such as motion sickness, vertigo, dizziness and Meniere's disease
• gastrointestinal obstruction reduced gastrointestinal motility
• visceral pain e.g. myocardial infarction or peritonitis
• migraine increased inter
• Compounds of the invention are of particular use in the treatment of gastrointestinal disorders such as irritable bowel syndrome (IBS); skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
• IBS irritable bowel syndrome
• skin disorders such as psoriasis, pruritis and sunburn
• vasospastic diseases such as angina, vascular headache and Reynaud's disease
• cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrh
• Compounds of the invention are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
• the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
• a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
• a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions mediated by CRF.
• a method for the treatment of a mammal including man, in particular in the treatment of condition mediated by CRF, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
• Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
• the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route.
• a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route.
• Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
• compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
• the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvmylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
• binding agents e.g. pregelatinised maize starch, polyvmylpyrrolidone or hydroxypropyl methylcellulose
• fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
• lubricants e.g. magnesium stearate, talc or silica
• disintegrants e.g. potato starch or sodium starch glycollate
• Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
• the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
• Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
• the composition may take the form of tablets or formulated in conventional manner.
• the compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
• the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
• Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
• Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
• Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non- aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
• the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
• the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
• a proposed dose of the compounds of the invention is 1 to about lOOOmg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian.
• the dosage will also depend on the route of administration and the particular compound selected. Thus for parenteral administration a daily dose will typically be in the range of 1 to about 100 mg, preferably 1 to 80 mg per day. For oral administration a daily dose will typically be within the range 1 to 300 mg e.g. 1 to 100 mg.
• EtOAc ethyl acetate
• cHex cyclohexane
• CH 2 C1 2 dichloromethane
• Et 2 0 dietyl ether
• DMF N,N-dimethylformamide
• MeOH methanol
• Et 3 N triethylamine
• TFA frifluoroacetic acid
• THF tetrahydrofuran
• DH3AL-H diisobutylaluminium hydride
• DMAP dimethylaminopyridine
• LHMDS lithium hexamethyldisilazane
• Tic refers to thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate
• r.t. (RT) room temperature.
• reaction mixture was first flushed with oxygen and then with nitrogen for 20 min.
• Methanesulfonic acid 4-(tert-butyl-diphenyl-silanyloxy -3-r4-chloro-6-(2.4-dichlorophenyl- amino -2-methyl-pyrimidin-5-vn-butyl ester
• Phenylselenenylchloride (2.44g) was placed in a two-necked flask under nitrogen and dissolved in anh. CH 2 C1 2 (21mL). The brown solution was cooled to 0°C and anh. pyridine (0.9mL) was added resulting in a yellow solution which was stirred at 0°C for 30 min. A solution of intermediate 22 (1.5g) in anh. CH 2 C1 2 (12mL) was added dropwise at 0°C and the reaction mixture was stirred at r.t. for 4.5 hr. The reaction mixture was then fransfered to a separatory funnel and washed with IM HCl (2xl0mL) and with water (3xl0mL).
• aqueous layer was extracted with CH 2 C1 2 and the organic phase was washed with brine (lxlOmL) and dried over anh. Na 2 S0 .
• the solids were filtered and the solvent evaporated to obtain the allylated compound (676mg) as pale yellow oil and as a mixture of diastereoisomeric enolesters and ketoesters.
• Sodium (140mg, 3eq) was added portionwise to anh. MeOH (6mL) under N 2 . After consumption of metallic sodium, acetamidine hydrochloride (600mg) was added. After 10 min of stirring, the precipitated NaCl was filtered off and washed with anh. MeOH (2mL).
• Isomer 1 ⁇ 8.15 (m, 2H), 7.72 (m, 5H), 7.44 (m, 6H), 6.19 (d, IH), 5.27 (m, IH), 4.41 (t, IH), 4.08 (dd, IH), 3.52 (m, IH), 2.81 (m, IH), 2.35 (m, IH), 2.15 (s, 3H), 1.07 (s, 9 H).
• Methanesulfonic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl)-5,6.7.8- tetrahvdro-pyridor2.3- ⁇ 1pyrimidin-5-ylmethyl ester
• This intermediate was dissolved in an 8:1 mixture of acetone/H 2 0 (18mL) and N-methyl-morpholine-JV-oxide (230mg, 2eq) and Os0 4 (403 ⁇ l, O.leq) were added.
• the reaction mixture was stirred at r.t. for 6 h.
• the solvent was evaporated and a saturated solution of Na 2 S0 3 was added.
• the product was extracted with EtOAc (3x20mL) and the combined organic extracts were dried over anh. Na 2 S0 .
• the solids were filtered and the solvent evaporated.
• the crude product was dissolved into a 9:1 mixture of THF/H 2 0 (15mL) and NaI0 (210mg, 1.5eq) was added.
• reaction mixture was stirred at r.t. for 18 hr, then it was diluted with water and the product was extracted with EtOAc (3x20mL). The combined organic exfracts were washed with brine and dried over anh. Na 2 S0 4 . The solids were filtered and the solvent evaporated to give the title compound (250mg, 0.59mmol, 90%) as a clear oil.
• Step 1 Time-Reserv.
• A-ReservB 95/3.5/1.5 Flow rate [mL/min]: 1.0
• Methanesulfonic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyD-5.6.7.8- tetrahydro-pyrido[2.3-J]pyrimidin-5(S)-ylmethyl ester
• Step 1 Time-Reserv.A-Reserv.B:95/l .5/3.5 v/v
• Methanesulfonic acid 4-chloro-2-methyl-8-(2.4-bis-trifluoromethyl-phenyl ' )-5.6.7.8- tetrahydro-pyrido[2.3-J1pyrimidin-5(R -ylmethyl ester
• CRF binding affinity has been determined in vitro by the compounds' ability to displace 125 I- oCRF and 125 I-Sauvagine for CRFl and CRF2 SPA, respectively, from recombinant human CRF receptors expressed in Chinese Hamster Ovary (CHO) cell membranes.
• CHO cells from confluent T-flasks were collected in SPA buffer (HEPES/KOH 50mM, EDTA 2mM; MgCl 2 lOmM, pH 7.4.) in 50mL centrifuge tubes, homogenized with a Polytron and centrifuged (50'000g for 5min at 4°C: Beckman centrifuge with JA20 rotor).
• the pellet was resuspended, homogenized and centrifuged as before.
• the SPA experiment has been carried out in Optiplate by the addition of 100 ⁇ L the reagent mixture to l ⁇ L of compound dilution (100% DMSO solution) per well.
• the assay mixture was prepared by mixing SPA buffer, WGA SPA beads (2.5mg/mL), BSA (lmg/mL) and membranes (50 and 5 ⁇ g of protein/mL for CRFl and CRF2 respectively) and 50 pM of radioligand.
• the plate was incubated overnight (>18 hr) at room temperature and read with the Packard Topcount with a WGA-SPA 125 I counting protocol.
• Compounds of the invention were characterised in a functional assay for the determination of their inhibitory effect.
• Human CRF-CHO cells were stimulated with CRF and the receptor activation was evaluated by measuring the accumulation of cAMP.
• CHO cells from a confluent T-flask were resuspended with culture medium without G418 and dispensed in a 96-well plate, 25'000c/well, 100 ⁇ L/well and incubated overnight.

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