MXPA99005895A - Crf antagonistic quino- and quinazolines - Google Patents

Abstract

This invention concerns compounds of formula (I), including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R1 is C1-6alkyl, NR6R7, OR6 or SR7;R2 is hydrogen, C1-6alkyl, C1-6alkyloxy or C1-6alkylthio;R3 is Ar1 or Het1;R4 and R5 are each independently selected from hydrogen, halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano, nitro, amino, and mono- or di(C1-6alkyl)amino;R6 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio;R7 is hydrogen, C1-8alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxy-C1-6alkyl or C1-6alkyloxyC1-6alkyl;R6 is C1-8alkyl, mono- or di(C3-6cycloalkyl)-methyl, Ar2CH2, C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, C3-6alkenyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl;or R6 and R7 taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C1-6alkyl or C1-6alkyloxyC1-6alkyl;and Ar1 and Ar2 are each optionally substituted phenyl;and Het1 is optionally substituted pyridinyl;having CRF receptor antagonistic properties;pharmaceutical compositions containing such compounds as active ingredients;methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

Description

I QUINO- AND QUINAZOLINAS ANTAGONISTS OF CRF BACKGROUND OF THE INVENTION This invention relates to quino- and quinazolines possessing CRF receptor antagonistic properties, to pharmaceutical compositions containing these compounds as active ingredients, and to the use thereof in the treatment of endocrine, psychiatric and neuro-logical diseases and conditions, including disorders. general related to ef stress. The corticotropin releasing factor (CRF) that was first isolated was that of ovine hypothalamus and was identified as a peptide of 41 amino acids (Vale et al, Science 213: 1394-1397, 1981). Subsequently, the human and rat CRF sequences were isolated and determined to be identical, but different from ovine CRF in 7 of the 41 amino acid residues (Rivier et al, Proc. Ntl. Acá. Sci. USA 80: 4851 , 1983; Shibahara et al, EMBO J.2: 775, 1983). It has been found that CRF produces profound alterations in endocrine, nervous and immune system function. It is believed that CRF is the main physiological regulator of basal and stress-releasing adrenocorticotropic hormone ("ACTH"), β-endorphin, and other pro-opiomelanocortin ("POMC") peptides from the anterior pituitary (Vale et al, Science 213,: 1394: 1397, 1981) In summary, it is believed that CRF initiates its biological effects by adhering to a membrane receptor of plasma that has been found to be distributed throughout the brain (De Souza et al, Science 221: 1449-1451, 1984), pituitary (De Souza et al, Methods Enzymol, 124: 560, 1986; Wynn et al. al, Biochem Biophys, Res. Comm. 110: 602-608, 1983), adrenal (Udelsman et al, Nature 319: 147-150, 1986) and spleen (Webster, EL and EB De Souza, Endocrinology 122: 609-617 , 1988). The CRF receptor is coupled to a GTP binding protein (Perrin et al Endocrinology, 118: 1171-1179, 1986) which is an intermediate in an estimated increase by CRF in the intraceiular production of cAMP (Bilezikjian, LM, and WW Vale, Endocrinology 113-657-662, 1983). In addition to its role in stimulating the production of ACTH and POMC, it is also believed that the CRP coordinates many of the responses to stress, autonomous endocrine and behavioral and that it may be involved in the pathophysiology of affective disorders. In addition, it is believed that CRF is a key intermediary that is in communication with the immune, central nervous, endocrine and cardiovascular systems (Crofford et al, J. Clin. Invest. 90: 2555-2564, 1992; Sapolsky et al., Science 238-522-524, 1987; Tilders et al., Regul. Peptides 5: 77-84, 1982). In general, CRF appears to be one of the central neurotransmitters of the central nervous system, and plays a crucial role in the integration of the body's general responses to stress. The administration of CRF directly to the brain produces physiological, endocrine and behavioral responses identical to those observed for an animal that is exposed to a causative environment. stress. For example, intracerebroventricular injection of CRF results in an activation of functioning (Sutton et al, Nature 297: 331, 1982), the persistent activation of the electroencephalogram (Ehlers et ai, Brain Res. 2/8332, 1983), stimulation of sympathetic-medullary pathways (Brown et al, Endocrinology, 110: 928, 1982), an increase in heart beats and blood pressure (Fisher et al, Endocrinology 110-2222 , 1982), an increase in oxygen consumption (Brown et al, Life Sciences : 207, 1982), alteration of gastrointestinal activity (Williams et al, Am. J.

Physiol. 253: G582, 1987) suppression of food consumption (Levine et al, Neuropharmacology, 22: 337, 1983), modification of sexual functioning (Slrinathsinghyji et al, Nature 305: 232, 1983), and commitment of the immupitary function (Irwin et al, Am. J. Physiol. 255: R744, 1988). In addition, clinical data suggest that CRF can be hypersecreted in the brain in depressions, anxiety-related disorders, and anorexia nervosa. (De Souza, Ann, Reports in Med. Chem. 25-215-223, 1990). Therefore, clinical data suggest that CRF receptor antagonists may represent new antidepressant and / or anxiolytic drugs that may be useful in the treatment of neuropsychiatric disorders that manifest hypersecretion of CRF. Due to the physiological significance of CRF, the development of other biologically active small molecules that have significant CRF binding activity and that are capable of antagonizing the CRF receptor remain a desirable goal. These CRF receptor antagonists would be useful ep treatment of conditions or endocrine, psychiatric and neurological diseases, including disorders in general related to stress. CRF receptor antagonists have been described for example in WO-94/13676, WO-94/13677, WO-95/33750 and WO 96/35689 which describe pyrroiopyrimidines, pyrazolo [3,4-d] pyrimidines and substituted purines as CRF receptor antagonists. The aminoquinoline derivatives have been described by Michel W.F. et al J. Med. Chem. 38: 2748-2762, 1995, as intermediates for 1,4-dihydroquinolines-4-substituted. German Patent DE-2,909,871 discloses substituted quinoiins as intermediates useful in the synthesis of nitriles. Other structurally related quinoxy derivatives have been described by Schroeder E. et al. in Eur. J. Med. Chem - Chim. Ther. 14: 499-506, 1979, as non-steroidal anti-inflammatory agents and by Wommack J.B. et al, in J. Med. Chem., 14: 1218-1220, 1971, as antimalarial agents. Ollis W.D. et ai J.C.S. Perkin Trans, 1, 953-956, 1989, describes 2,4-dimethyl-8-2-nitrophenyl) -quinoline as intermediates in the synthesis of heterocycline betaines. 2,4-Diamonoquinazolines are known from WO-94/18980 for their insecticidal activity. The compounds of the present invention differ from the prior art compounds structurally, by the nature of the substituents in the quinoline or quinazoline moiety, and pharmacologically by the fact that it was unexpectedly found that these compounds have CRF antagonistic properties.

Description of the invention This invention relates to CFR antagonist compounds having the formula (I) including stereoisomers and pharmaceutically acceptable acid addition salt forms thereof, wherein X is N or CH; R1 is C ^ -Q alkyl, NR6R7, OR7 or SR7; in the case where X is N, R2 represents hydrogen, alkyl C - ^ - g, alkyloxy C- | -? or C-j-g alkyiitium, in the case where X is CH, R 2 represents C ^ -g-alkyl, C-j-g alkyloxy or C-j-6 alkylthio, R 3 is Ar 1 or Het 1; R 4 and R 5 are each independently selected from hydrogen, halo, C 1 -Q alkyne, C 1 -g alkyloxy, trifluoromethyl, cyano, nitro, amino and mono- or di (C 1 -g alkyl) amino; R6 is hydrogen, Cjs alkyl, mono or di (C3-g) cycloalkyl methyl, cycloalkyl 3-, C3- alkenyl, hydroxy C- | g alkyl, C- | g alkylcarbonyloxy, Cjg alkyl or C- ^ - g alkyloxy Cjg alkyl, R7 is Cjg alkyl, mono- or di- (C3-cycloalkyl) methyl, Ar CH2, C- ^ - alkyloxy (Cjg alkyl, Cjg hydroxyalkyl, C3g alkenyl, thienylmethio, furaniimetifo, Cth alkylthio, Cjg akyc, mono - or di- (alkyl Cjg) aminoalkyl Cjg, or R6 and R7 taken together with the nitrogen atom to which they are attached can form a pyrrolidinyl, piperidinyl, homopyperidinium or morpholinium group, optionally substituted by C-α-alkyl or Cjg alkyloxy alkylC-jg, and Ar1 is phenylene, substituted with 1, 2 or 3 substituents each independently selected from halo, Cjg alkyl, trifiuormethyl, hydroxy, cyano, Cjg alkyloxy, benzyloxy, Cth, alkyl, nitro, amino and mono- or di- (Cjg alkyl) amino; Het1 is pyridinyl, pyridinyl substituted with 1, 2 or 3 substituents each independently selected from halo, Cjg alkyl, trifluoromethyl, hydroxy, cyano, Cjg alkyloxy, benzyloxy, alkylthio C._d nitro , amino, and mono or di (alkyl C-j-g) amino; and Ar2 is phenyl; Fepyl substituted with 1, 2 or 3 substituents each independently selected from halo, C-j-g alkyl, C-j-g alkyloxy, di (C-j-g alkyl) amino C- | g alkyl, trifluoromethyl. In another of its aspects, the invention relates to novel compounds of formula (I) as defined above with the proviso that 2,4-dimetii-8- (2-nitrofepil) -quinino is not included.

This condition has the purpose of excluding said quinoline compound which has been described by Ollis W.D. et al, in J.C.S. Perkin Trans. I, (5), 953-956 (1989). As used in the preceding definitions and below, halo is generic for fluorine, chlorine, bromine and iodine: alkanediyl Cjg defines divalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example , methylene, 1,2-ethanediyl, 1,3-propapodiiio, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C-j-2 alkyl defines straight chain saturated hydrocarbon radicals having from 1 to 2 carbon atoms, such as methyl and ethyl; C2-4 alkyl defines saturated branched chain hydrocarbon radicals having from 2 to 4 carbon atoms, such as ethyl, propyl, butyl, 1-methyleryl and the like; Cjg alkyl includes alkyl radicals Cj-2 and alkyl 03-4 as defined above and higher homologs thereof having from 5 to 6 carbon atoms such as pentyl, pentyl, hexyl isomers and hexyl isomers; C-j-β alkyl includes C-j-g alkyl and higher homologs thereof having from 7 to 8 carbon atoms such as, for example, heptyl, octyl and the like; C3-g alkenyl defines straight and branched chain hydrocarbon radicals containing a double bond and having from 3 to 6 carbon atoms, such as for example 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3- methyl-2-butenyl, and the like; and wherein said C3-g alkenyl is attached to a nitrogen or oxygen atom, the carbon atom constituting the bond being, preferably saturated. Cycloalkyl C3 ~ g comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Hydroxy alkyl (C-j-g) refers to C-j-g alkyl substituted with a hydroxy group. The pharmaceutically acceptable acid addition salts mentioned above, comprise the non-toxic therapeutically active acid addition salt forms which the compounds of formula (I) are capable of forming. Compounds of formula (!) Having basic properties can be converted to their pharmaceutically acceptable acid addition salts by treatment of said base form with an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and similar acids; or organic acids such as for example acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic, malonic, succinic (ie butanedioic acid), maleic, fumaric, melic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-amino-salicylic, pamoic and the like. The term "acid addition salts" also includes hydrates and solvent addition forms which are capable of forming the compounds of formula (I). Examples of such forms are for example hydrates, alcoholates and the like. The expression "stereochemically isomeric forms of the compounds of the formula (I)," as used in the foregoing, defines all possible compounds constituted by the same atoms joined by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, that the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all stereoisomerically possible isomeric forms which said compound may possess. Said mixture can contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (i) both in pure form and in admixture with each other, will be encompassed within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric forms. Said forms, although not explicitly indicated in the preceding formula, will be included within the scope of the present invention. For example, the compounds of formula (I) in which Het1 is pyridinyl substituted with hydroxy, can exist in their corresponding tautomeric form. Whenever used in the following, the term "compounds of formula (I)" will also include pharmaceutically acceptable acid addition salts and all stereoisomeric forms. The numbering of the bicyclic ring system present in the compounds of formula (I) is shown below.

Particular groups of compounds within the invention are those compounds of formula (I) in which one or more of the radicals have the following meaning: a) R1 is NR6R7 where R6 is hydrogen or Cjg alkyl, in particular C2- alkyl, and R7 is the Cj-8 alkyl or C3-g cycloalkymethyl, in particular C2-4 alkyl or cyclopropylmethyl; b) R1 is OR7 or SR7 where R7 is C-j-g alkyl, in particular C-j -4 alkyl, c) R2 is C-j -g alkyl, in particular C-j-; alkyl; d) R3 is phenyl substituted with 1, 2 or 3 substituents each independently selected from C-j-g alkyl, C-j-g alkyloxy or halo; wherein the phenyl portion is preferably substituted at the positions, 3-, 4-, 6-. 2,4- or 2,4,6-; or R3 is a pyridinyl substituted with 1, 2 or 3 substituents each independently selected from halo, amino, nitro, trifluoromethyl, mono- or di (C? -g) amino alkyl, or C? -g alkyl, where the portion pyridinyl is preferably connected through the 2- or 3- position with the rest of the molecule; and e) R4 and R5 are each independently selected from hydrogen or C-j-g alkyl. Preferred compounds are those compounds of formula (I) in which R1 is NRdR7 where R is C3-4 alkyl, preferably propy; R7 is C3-4 alkyl or cyclopropylmeryl; preferably propyl; R2 is methyl; R3 is a phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, methyl or methoxy; or Rβ is pyridinyl substituted with 1, 2 or 3 substituents each independently selected from halo, methyl, or dimethylamino; and R4 and R5 are hydrogen. More preferably R is phenyl substituted in the 2- and 4-position with C-j-2-alkyl or halo; in particular R is 2,4-dichlorophenyl. The most preferred compounds of formula (I) are: 2-methyl-4-dipropylamino-8- (2 ', 4'-dichlorophenol) -quinoline, and 2-methyl-4- (N-propyiN-cyclopropanomethyl); l) amino-8- (2,4'-dichlorophenyl) -quinoline; the stereoisomeric forms and the pharmaceutically acceptable acid addition salts thereof. The compounds of the present invention can be prepared generally by the reaction of an intermediate of formula (IV), wherein Z is bromine or iodine, with an intermediate of formula (V) under Suzuki coupling conditions. Suzuki coupling conditions are for example, stirring a solution of an intermediate (IV) and a catalyst of tetrakis (triphenylphosphine) palladium, in a solvent inert to the reaction, for example toluene, in the presence of an appropriate base, for example sodium carbonate, while adding the intermediate (V) dissolved in a alcohol, for example Yanol (IV) (V) The aforementioned Suzuki reaction is to say the reaction of Palladium-catalyzed cross-linking of a phenylboronic acid derivative with a haloarene in the presence of a base has been extensively described in Suzuki A. et al. Synthetic Communications, 1 1: 513-519, 1981 and Suzuki A. Puree and Applied Chemistry , 66, 213-222 (1994). The compounds of formula (I-a), defined as compounds of formula (I) in which R1 'has the meaning of R1 other than alkyl C-j-g, can be prepared by the reaction of an intermediate of formula (II) with a formula intermediate (III). In the intermediate (II), W is an appropriate leaving group such as halo, for example chlorine, bromine or a group sulfonyloxy, for example a mesyloxy group or a tosyloxy group.

Said reaction can be carried out in a solvent inert to the reaction such as for example acetonitrile, N.N-dimethylformamide, methyl isobutyl ketone, tetrahydrofuran or dichloromethane; and in the presence of an appropriate base, such as, for example, sodium carbonate, sodium hydrogen carbonate or triethiamine. When the intermediates of formula (III) are volatile amines, said reaction can also be carried out in a closed reaction vessel. Agitation can improve the reaction regime. The reaction can be carried out conveniently at a temperature between room temperature and reflux temperature. The compounds of formula (I) in which R1 is OR, which are represented by formula (Ib), can be prepared by O-alkylation of an intermediate of formula (VI) with an intermediate of formula (VII) in which W1 is a leaving group appropriate tai as halo, for example chloro, bromo or a sulfonyloxy group, for example a mesiioxy or tosyloxy group.

Said reaction for preparing the compounds of formula (I-b) can be carried out in a solvent inert to the reaction such as for example N, N-dimethylformamide, and in the presence of an appropriate base, such as, for example, sodium hydride, preferably at a temperature between room temperature and reflux temperature. The compounds of formula (I) in which R 1 is -NHR 7 represented by the formula (1-c), can be prepared by N-alkylation of an intermediate of formula (HIV) with an intermediate of formula R-W, in which W is as previously defined. The compounds of formula (I-c) can be further N-alkylated with an intermediate of formula R ^ -W, where W is as previously defined, obtaining the compounds of formula (! -d). These N-alkylations are carried out in a solvent inert to the reaction such as for example an ether, for example tetrahydrofuran and preferably in the presence of a strong base, for example NaH. (vm) (I-c) (I-d) Compounds of formula (Ie), wherein X is CH and R1"and R2" are Cj-Cg alkyl, can be prepared by reaction of an intermediate of formula (IX) with an intermediate of formula (XIII) and subsequently heating in sulfuric acid concentrated.

In addition, the compounds of formula (I) can also be converted to one another, following methods of transformation of functional groups known in the art. The intermediates of formula (II) in which X is CH, and which are represented by the formula (I I-a), can be prepared as outlined below in Scheme I.

Scheme In Scheme I, the intermediates of formula (IX) are reacted with the intermediates of formula (X) and subsequently heated, thereby obtaining intermediates of formula (Vl-a), in The hydroxy group is converted to the leaving group W, for example by treatment of said intermediates (V1-a) with methanesulfonyloxy chloride or with a halogenating reagent such as, for example, SOCI2 or POCI3, thereby obtaining intermediates of the formula (Ha ), said intermediates of formula (VII-a) are intermediates of formula (VI) in which X is CH. The intermediates of formula (IX) can be prepared by treatment of the intermediates of formula (XI) in which Z is as previously described, with a formula (V) intermediate under Suzuki stocking conditions.

The intermediates of formula (IX) can also be prepared by reaction of an intermediate of the Intermediate (XI) in which the amino group is replaced by a nitro group, with the intermediate (V) under the conditions of Suzuki coupling, and the subsequent conversion of the nitro group to an amino group, for example by hydrogenation using hydrogen gas and an appropriate catalyst such as palladium on carb.

Likewise, the intermediates of formula (IX) can also be prepared by reaction of an analogue of! intermediate (XI) in which the amino group is replaced with a carboxy group, with the intermediate (V) under Suzuki coupling conditions, and the subsequent conversion of the carboxy group to an amino group. The intermediates of formula (IV) can be prepared in general! by reacting an intermediate of formula (XII) wherein Z is as previously described, with an intermediate of formula (lil). Said reaction can be carried out as previously described for the synthesis of the compounds of the formula (I).

The intermediates of the formula (VIII) are prepared by treating the intermediates of formula (II) with ammonia. The compounds of formula (I) and some of the intermediates may have one or more stereogenic centers in their structure, present in the R or S configuration.

The compounds of formula (i) prepared in the processes described above can be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated one from the other following procedures known in the art. The racemic compounds of the formula (I) can be converted to the corresponding diastereomeric salt forms by reaction with a chiral acid! appropriate. Said diaesteromeric sai forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom with alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of the appropriate starting materials, with the proviso that the reaction occurs stereospecifically. These methods will advantageously employ enantiomerically pure starting materials. The effectiveness of a compound as a CRF receptor antagonist can be determined by various test methods. Suitable CRF antagonists of this invention are capable of inhibiting the specific adhesion of CRF to its receptor and antagonizing activities that are associated with CRF. A compound of structure (I) can be controlled to determine activity as a CRF agonist by one or more of the assays generally accepted for this purpose, including (but not limited to) the assays described by DeSouza et al (J. Neuroscience 7:88, 1987) and Battagiia et al (Synapse 1: 572, 1987). As mentioned above, suitable CRF antagonists include compounds that demonstrate the receptor affinity of CRF. The receptor affinity of CRF can be determined by adhesion studies that measure the ability of a compound to inhibit a radiolabeled CRF (eg [-j25¡] trosros CFR) to the receptor (eg, receptors prepared from rat cerebral cortex membranes). The radioligand adhesion assay described by DeSouza et al. (supra, 1987) provides an assay to determine the affinity of a compound with the CRF receptor. Said activity is typically calculated from the IC 50 as concentration of a compound necessary to displace 50% of radio-labeled ligand from the receptor, and is indicated as the "Ki" value calculated by the following equation: Cl '50 Ki = 1 + L / Kr where L = radioligand and KD = affinity of the radioligand with the receptor (Cheng and Prusoff, Biochem Pharmacol 22: 3099, 1973). In addition to inhibiting the adhesion of the CRF receptor, the activity of the CRF receptor antagonist to the compound can be established, by the ability of compounds to antagonize an activity that is associated with CRF. For example, it is known that CRF stimulates various biochemical procedures, including adenylate cyciase activity. Therefore, the compounds can be evaluated as CRF antagonists for their ability to antagonize the activity of adenylate cyclase stimulated by CRF, for example by measuring the levels of cAMP. The activity of adenylate cyclase stimulated by CRF described by Battagiia et al (supra 1987) provides an assay to determine the ability of the compound to antagonize CRF activity. Accordingly, the antagonist activity of the CRF receptor can be determined by assay techniques that generally include an initial adhesion assay (such as that described by De Souza (supra, 1987) followed by a cAMP tracking protocol (as described by Battagiia (supra 1987) With reference to the affinities of adhesion to the CRF receptor, the CRF receptor antagonists of this invention have a Kj of less than 10 uM In a preferred embodiment of this invention, a CRF receptor antagonist has a K i of less of 1 μM, and more preferably less than 0.25 μM (ie, 250 nM) The CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site, and can be used as therapeutic agents for extensive treatment range of disorders or diseases that include endocrine, psychiatric and neurobiological diseases or disorders, more specifically, receptor antagonists of CRF of the p invention can be useful in the treatment of physiological conditions or disorders that arise from hypersecretion of CRF. Because CRF is considered a critical neurotransmitter that activates and coordinates responses to endocrine, behavioral, and automatic stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric disorders. Neuropsychiatric disorders that may be treatable by the CRF receptor antagonists of this invention include affective disorders such as depression; disorders related to anxiety such as generalized anxiety disorders, panic disorders, obsessive-compulsive disorders, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and eating disorders such as anorexia nervosa, buiimia, and irritable bowel syndrome. CRF antagonists may also be useful in the treatment of suppression of stress-induced immunity that is associated with various disease states, as well as stroke. Other uses of the CRF antagonists of this invention include the treatment of inflammatory conditions (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease, and GI motility) Cushing's disease, infantile spasms, epilepsy, and other attacks in both children and adults. adults, and various abuses and substance abstinence (including alcoholism). In another embodiment of the invention, pharmaceutical compositions containing one or more CRF receptor antagonists are disclosed.

For the purposes of administration, the compounds of the present invention can be formulated in the form of pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a CRF receptor antagonist of the present invention (ie a compound of structure (I)) and a pharmaceutically acceptable carrier and / or diluent. The CRF receptor antagonist is present in the composition in an amount that is effective to treat a particular disorder, ie, in an amount that is sufficient to achieve CRF receptor antagonistic activity, and preferably with acceptable toxicity to the patient. Preferably, the pharmaceutical compositions of the present invention can include a CRF receptor antagonist in an amount of from 0 to 250 mg per dose depending on the route of administration, and m. { preferably from 1 mg to 60 mg. The appropriate concentrations and dosages can be quickly determined by a person skilled in the art. The pharmaceutically acceptable carrier and / or diluent is known to those skilled in the art. For compositions formulated in the form of liquid solutions, acceptable carriers and / or diluents include sterilized and saline water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pellets, capsules, granules or tablets containing, in addition to a CRF receptor antagonist, diluents, dispersing agents and surfactants, binders, and lubricants.

An expert in this field may also formulate the CRF receptor antagonist in an appropriate form, and in accordance with accepted practices. In another embodiment, the present invention provides a method for treating a variety of disorders or disorders, including diseases or endocrine, psychiatric and neurological disorders. Such methods include administering a compound of the present invention to a caudate blood animal in an amount that is sufficient to treat the disorder or disease. Such methods include the systemic administration of a receptor antagonist of this invention preferably in the form of a pharmaceutical composition. Ta! As used herein, systemic administration includes oral methods and parenteral administration. For oral administration, the appropriate pharmaceutical compositions of the CRF receptor antagonists include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavors, preservatives, suespension agents, thickeners and emulsifiers, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention can be prepared in aqueous injectable solutions which may contain, in addition to the CRF receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions. As mentioned above, the administration of a compound of the present invention can be used to treat a broad variety of disorders or diseases. In particular, the compounds of the present invention can be administered to a warm-blooded animal for the treatment of depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, abnormal aggressions, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, suppression of stress-induced immunity, stroke, inflammation, Cushing's disease, infantile spasms, epilepsy, and abstinence from addictive substances. Therefore this invention provides e! use of compounds of formula (I) for the manufacture of a medicament for treating physiological conditions or disorders arising from the hypersecretion of corticotropin-releasing factor (CRF) and in particular for treating the disorders or diseases mentioned above; and in another embodiment the use of new compounds of formula (I) is provided. The following examples are provided for illustrative purposes, and not for limitation.

Experimental Part "THF" then means tetrahydrofuran and "DCM" means dichloromethane.

A. Preparation of the intermediates Example A.1 a) To a stirred solution of 2-bromoaniline (4.0 g) in 120 ml of toluene was added tetrakis (triphenylphosphine) palladium (0) (2.7 g, 2.33 mmofes, 10% moles) and a 2.0 M aqueous sodium carbonate solution (35 ml, 70 mmol). In a separate bottle, dichlorobenzeneboronic acid (5.0) was dissolved in ethyl alcohol (35 ml). A mixture of 2-bomoaniline was added to the boronic acid solution. The resulting mixture was heated to reflux overnight. The reaction mixture was cooled, diluted with ethyl acetate, and washed with a saturated solution of ammonium chloride. The organic layer was dried, filtered, and concentrated. The residue was purified by evaporative chromatography on silica gel to obtain 2-amino- (2,4'-dichloro) biphenium (intermediate) (7)), (4.8 g). 300 MHz 1 H NMR (CDC 3) d 3.54 (br s, 2 H), 6.78 (d, 1 H), 6.84 (d, 1 H), 7.01 (d, 1 H), 7.19-7.35 (m, 3 H), 7.53 ( d, 1 H). b) A solution of intermediate (7) (4.71 g) of ethyl acetate (2.58 g) and 20 mg of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 30 minutes. The reaction mixture was cooled, concentrated and purified by evaporative chromatography on silica gel obtaining intermediate (8) (4.5 g). 300 MHz 1 H NMR (CDCl 3): d 1.21 (t, 3 H), 1.86 (s, 3 H), 4.04 (q, 2 H), 4.57 (s, 1 H), 7.18 (s, 1 H), 7.25- 7.43 (m, 5H), 7.47 (d, 1 H), 9.89 (s, 1 H). c) A solution of! intermediate (8), (2.34 g) in 5 ml of diphenylic ether was added to 10 ml of diphenyl ether at a temperature of 240 ° C and said solution was then heated to reflux for 5 minutes. The reaction mixture was cooled and the solid was collected by filtration and rinsed with diethyl ether to obtain intermediate 2-methyl-4-hydroxy-8- (2 ', 4'-dichlorophenyl) quinoline 9) as a crystalline solid. white (1.33 g). 300 MHz 1 H NMR (CDCl 3): d 2.56 (s 3 H), 7.34 (s, 2 H), 7.39 (s, 1 H), 7.53 (s, 1 H), 7.63-7.65 (m, 2 H). 8.26 (dd, 1 H). d) A mixture of intermediate (9) (1.32 g) and phosphorus oxychloride (5 ml) was refluxed for 2 hours, cooled, poured onto ice and neutralized with 1 N NaOH. The aqueous layer was extracted with ethyl acetate. ethyl. The organic layer was washed with brine, dried, concentrated to give 2-methyl-4-chloro-8- (2 ', 4'-dichlorophenyl) quinoline (intermediate 1) (1.31 mg, 300 MHz 1 H NMR (CDCb)). : d 2.58 (s, 3H), 7.34 (s, 2H), 7.39 (s, 1 H), 7.53 (s, 1H), 7.63-7.65 (m, 2H), 8.26 (dd, 1 H).

Example A.2 a) A mixture of 2-amino-3-bromo-methyl benzoic acid (1 g) and formamide (0.6 ml) was placed in a flask under a pressure of 1 ml and heated to 145 ° C. After heating for 1 hour, the bottle was cooled to room temperature, and 50 ml of water was added. The white solid mass was then separated by filtration and recrystallized from methanol, obtaining intermediate (10) (1.01 g). b) A mixture of! intermediate (10) (1 g) was refluxed in 4 ml of POCI3 for 2 hours. After reflux, the reaction was cooled and poured into 50 ml of ice. The aqueous solution was basified with sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined, dried and concentrated, obtaining an intermediate (11) which was used in the next step without purification. c) The intermediate (11) was refluxed in preemption of 5 ml of dipropyl amine for 2 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was combined, dried and concentrated, obtaining a residue which was dissolved in ethyl acetate and passed through a plug of silica. Evaporation provided the intermediate (6) (0.4g).

Example A.3 a) A mixture of 4'-chloro-6-methoxy-2-biphenyl carboxylic acid (1.2 g), prepared according to the procedure of Meyers to A. I. et al in J. Org. Chem. 43: 1372-1379 (1978) h, triethylamine (1.1 ml) diphenylphosphoryl azide (1.2 ml) and tert-butyl alcohol (80 ml) was placed in a 250 ml flask under a nitrogen atmosphere. The solution was stirred and refluxed for 5 hours. After refluxing, the reaction mixture was cooled and concentrated, obtaining a residue which was suspended in diethyl ether. The solid by-product was separated by filtration and the mother liquor was concentrated, obtaining 2.4 g of the intermediate (12). b) The intermediate (12) was dissociated in THF (60 ml), water (12 ml) and concentrated HCl (12 ml) were added and refluxed for 2 hours. The solution was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried and concentrated, obtaining the intermediate (13). c) The intermediate (13) was suspended in benzene (100 m!) in the presence of ethyl acetoacetate (2 ml) and refluxed using a Dean Stark trap for 3 hours. The reaction mixture was concentrated and the residue was added to a solution that was hot (200 ° C) of diphenyl ether (20 ml). This reaction mixture was left under stirring for 25 minutes, cooled and triturated slowly with diethyl ether (200 ml), obtaining intermediate (14). d) The intermediate (14) (400 mg) was suspended in phosphorus oxychloride (2 ml) and heated to reflux for 2 hours. The reaction mixture was cooled and poured onto 200 ml of ice. The mixture was partitioned between ethyl acetate (200 ml and an aqueous sodium bicarbonate solution.) The organic layer was separated, dried and concentrated, yielding the intermediate 4-chloro-7-methoxy-2-methyl-8- ( 4'-chlorophenii) quinoline (5).

TABLE i-1 TABLE 1-2 Preparation of the final compounds Example B.1 A mixture of intermediate (1) (0.1 g) and p-toluenesulfonic acid monohydrate (160 mg) in 0.4 ml of dipropylamine in 3 ml reaction vessels was refluxed at 180 ° C. for 48 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated, purified on a preparative TLC plate (hexane / EtOAc, 10: 1). It was isolated e! compound (1) in the form of a pale yellow oil (80 mg.).

Example B.2 A solution of intermediate (1) (20 mg) in 0.5 ml of dimethyl sulfoxide in 1 ml reaction vessels was refluxed at 180 ° C for 12 hours. The reaction mixture was cooled, partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated, purified on preparative TLC plate (hexane / EtOAc, 10: 1). The compound (20) was isolated in the form of a colorless oil.

Example B.3 Intermediate (5) (0.4 g) and palladium tetraphenylphosphine were dissolved (40 mg) in 10 ml of toluene and added to a solution of 2,4-dichlorophenyl boronic acid (490 mg) in ethanoi (3 ml). To this was added a 2M solution of sodium carbonate (3 ml) and the resulting mixture refluxed under nitrogen for 25 hours. After reflux, the solution was cooled and extracted with diethyl ether (100 ml). The ether layer was dried, concentrated and purified on silica (1; 9 ethephexanes) to obtain compound (19).

EXAMPLE B.4 a) A mixture of intermediate (7) (1.08 g), 2,4-pentanedione (908 mg) and calcium sulfate (2 g) was heated at 100 ° C overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated. The crude product was purified by evaporative chromatography on silica gel to provide 1.2 g (83%) of the intermediate (15). b) A solution of intermediate (15) (0.5 g) in concentrated sulfuric acid (5 ml) was heated overnight at 100 ° C. The reaction mixture was cooled and basified by 6N NaOH addition and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, washed with brine, dried, filtered and evaporated. The residue was purified by evaporative chromatography on silica gel, obtaining 0.4 g (85%) of 2,4-dimethyl-8- (2,, 4'-dichlorophenyl) quinoline (compound 22). Tables F-1 through F-2 list the intermediaries that were prepared according to one of the preceding examples and Table F-3 lists the analytical data for these compounds.

TABLE F-1 B.1 7-CH30 n-propyium n-propyium 4-cyclophenium 11 B.1 7-CH3 n-propyium n-propyl 2-chlorophenium12 B.1 H n-propiio n-propiio 4-metiiphenyl I 13 B.1 7-CH3 2-methoxy-2,4-dichioro-ethyl? feniio 14 B.1 7-CH3 n-propyl 2-methoxy-2,4-dichloroethyl phenyl B.1 7-CH3 n-propyl cyclopro-2,4-dichloro-piimethiium fenium 16 B.1 H n-prop io n-propyl 2,4,6-trimethyl-I phenyl 7 B.1 H n-propyium cyclopro-2,4,6-trimethyl-phenylmethyl phenyl 18 B.1 H 2-methoxy-n-propyium 2,4,6-trimethyl-phenyl 23 B.1 H ethyl 2-methoxy-2,4,6-trimethyl-1 ethyl and phenyl 24 B.1 H n-propyl n-butyl 2,4,6-trimethyl-I phenyl I 25 B.1 H n-propyl phenylmethyl-2,4,6-trimethiol fenium 26 B.1 n-propyl n-butyl 4-trifluorom- H! tilphenyl I TABLE F-2 Cone. Ex.No. X R1 R2 R4 R 19 B.3 N N (CH2CH2CH3) 2l H 7-CH3 2,4-dichiorophenyl B.2 CN -S-CH3; CH3 H 2,4-dichiorophenyl 21 B.2 CH -OCH3 CH3 H 2,4-dichlorophenyl 22 B.4 CH-CH3 CH3 H 2,4-dichlorophenyl TABLE F-3: Analytical Data.

C. Pharmacological examples EXAMPLE C.1 CRF receptor adhesion activity The compounds were evaluated to determine the adhesion activity to the CRF receptor by a conventional assay to calculate the adhesion of radioligands in the manner described in general form. by DeSouza et al. (J. Neurosci., 7: 88-100, 1987). Through the use of several labeled CRF radio ligands, the assay can be used to evaluate the adhesion activity of the compounds of the present invention with any sub-type of CRF receptor. In summary, the adhesion assay involves the displacement of a radiolabeled CRF ligand from the CRF receptor. More specifically, the adhesion assay was carried out in 1.5 ml Eppendorf tubes using approximately 1 x 106 cells per tube stably transfected with human CRF receptors. Each of the tubes received approximately 0.1 ml of assay buffer (for example, Dulbecco's phosphate buffered saline solution, 10 mM magnesium chloride, 20 μM bacitracin) with or without unlabeled sauvagine, urotensin I or CRF (concentration final, 1 μM) in order to determine non-specific adhesion, 0.1 ml of [125 |] tyrosine-ovine CFR (final concentration approximately 200 pM or approximately the KD determined by analysis Scatchard) and 0.1 ml of a suspension of membrane cells containing the CRF receptor. The mixture was incubated for 2 hours at 22 ° C followed by separation of the adhered and free radioligand by centrifugation. Next, two washes of the granules were made, the tubes were cut just above the granulate and controlled in a gamma counter to determine the radioactivity with an efficiency of approximately 80%. All the radioiigand adhesion data were analyzed using a minimum square root-square non-linear curve fitting program. The adhesion activity corresponds to the concentration (nM) of the compound necessary to displace 50% of the radiolabelled ligand from the receptor. It was found that compounds 1, 2,4,6-11, 20 and 21 had a K < 250 nM.

Claims (16)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula including stereoisomers and pharmaceutically acceptable acid addition salt forms thereof, wherein X is N or CH; R1 is alkyl C-j.g, NR6R7, OR7 or SR7; in the case where X is N, R 2 represents hydrogen, C 1 - 4 alkyl, C 1 γ alkyloxy or C 1 ω alkylthio; in the case where X is CH, R2 represents alkyl C-j.g, alkyloxy C-j.g or alkytio C-j.g; R3 is Ar1 or Het1; R 4 and R 4 are each independently selected from hydrogen, halo, C 1 -g alkyl, C 1 -g alkyloxy, trifluoromethyl, cyano, nitro, amino and mono- or di (C 1 -alkyl) amino; R ^ is hydrogen, C- | _8 alkyl, mono or di (C3_g) alkyl, methyl, C3_g cycloalkyl, C3_g alkenyl, hydroxyCJ alkyl. g, C 1 -C 7 alkycarbonyloxy, C 1 -g alkyl or C 1-6 alkyloxy C 1 -g alkyl; R7 is alkyl C, g, mono- or di- (C3_g cycloalkyl) methyl, Ar2CH2, aikyloxy, C, g alkyl, hydroxyalkyl, g, C3_g alkenyl, thienylmethyl, furaniimethyl, alkylthio C, g, alkyl, C, g. , mono- or di- (C? _g) alkyl amino C -] _ g alkyl, or R ^ y R7 taken together with the nitrogen atom to which they are attached can form a pyrrolidinyl, piperidinium, homopiperidinyl or morpholinyl group, optionally substituted with C- | g alkyl or C 1-6 alkyloxy C-j g alkyl; and Ar1 is phenyl; substituted phenyl with 1, 2 or 3 substituents each independently selected from haio, Cj.g, alkyl trifluoromethyl, hydroxy, cyano, C 1-6 alkyloxy, benzyloxy, alkylthio C, g, nitro, amino and mono-di - (a.kine Cj.g) amino; Het1 is pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents each independently selected from haio, C-j_g alkyl, trifiuoromethyl, hydroxy, cyano, alkoxy C, g, benzyloxy, alkylthio C, g, nitro, amino, and mono or di ( alkyl C-j_g) amino; and Ar2 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from haio, alkyl C-j.g, aikyloxy C-j.g, di (C-j_g alkyl) amino aiquiio C-j.g, trifluoromethyl; with the proviso that 2,4-dimethyl-8- (2-nitrophenyl) -quinoline is not included.

2. A compound according to claim 1, wherein R1 is OR7 or SR7 and R7 is alkyl C-j.g; or R1 is NR6R7 and R6 is hydrogen or C-j_g alkyl; or R7 is alkyl C-j_g; or C3_g cycloalkimimethyl; R2 is alkyl C-j_g; Rβ is a phenyl substituted with 1, 2 or 3 substituents each of which is independently selected from alkyl C-j.g; alkyloxy C-j_g or halo, or Rβ is a pyridinyl substituted with 1, 2 or 3 substituents each of which is independently selected from alkyl C-j.g; or di (C-j_g) alkyl amino; and R4 or R5 are each independently selected from hydrogen or C-j.g alkyl.

3. - A compound according to any of claims 1 to 2, wherein R1 is NR6R7 wherein R6 is C2-4 alkyl; R7 is C2-4 alkyl; or cyclopropylmethyl; R2 is alkyl C-j_2; R3 is phenyl substituted with 1, 2 or 3 substituents each of which is independently selected from hydrogen, halo or alkyl C-j.g.

4. A compound according to any of claims 1 to 2, wherein R1 is NR ^ R7 where R ^ is C3.4 alkyio and R7 is C3.4 alkyl or cyclopropylmethyl; R2 is methyl; β is 3-pyridinyl substituted in the 4- and / or 6- position with methyl or dimethylamino.

5. A compound according to claim 1, in e! that the compound is 2-methyl-4-dipropyamino-8- (2 ', 4'-dichlorophenyl) -quinoline; or 2-methyl-4- (N-propii-N-cyclopropanomethyl) amino-8- (2 ', 4'-dichiorophenyl) -quininoin; a stereoisomeric form or a pharmaceutically acceptable acid addition salt thereof.

6. A composition comprising a pharmaceutically acceptable carrier, and as an active ingredient a therapeutically effective amount of a compound according to any of claims 1 to 5.

7. A process for preparing a composition according to claim 6, wherein a therapeutically effective amount of a compound according to any of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.

8. - A compound according to any of claims 1 to 5 which is used as a medicine.

9. A compound of formula (I I-a) in which the radicals X, R2, R3, R4 and R5 are as defined in claim 1 and W is halo, mesyloxy or tosyloxy; a stereoisomeric form or an acid addition salt form of! same.

10. - The use of compounds of formula including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein X, R 1"R 2, R 3, R 4 and R 5 are as defined in claim 1, including the compound 2,4- dimethyl-8- (2-nitrophenyl) -quinoline, for the manufacture of a medicament for treating physiological conditions or diers arising from the hypersecretion of corticotropin-releasing factor (CRF).

11. - A process for preparing a compound of formula (I) according to claim 1 in which a) intermediates of formula (IV) are reacted with formula intermediates (V) under Suzuki coupling conditions; (IV) (V) b) an intermediate of formula (ü) is reacted with an intermediate of formula (III), wherein R1 'has the meaning of R1 other than aikido Cj.g, whereby compounds are obtained of formuia (ia); c) an intermediate of formula (VI) is O-alkylated with an intermediate of formula (VII) in a solvent inert to the reaction and in the presence of an appropriate base, obtaining compounds of formula (lb), defined as compounds of formula (I) in which R1 is OR7, where in the preceding reaction schemes, the radicals R1, R2, R3, R6, R7 and X are as defined in claim 1, Z is bromine or iodine and W and W1 are the appropriate leaving groups; or if desired, the compounds of formula (I) are converted to one another following transformation reactions known in the art; and further, if desired, the compounds of formula (I) are converted to the addition salt by treatment with an acid, or conversely, the acid addition salt forms are converted to the free base by alkali treatment.; and, if desired, the stereochemically isomeric forms thereof are prepared.

12. A process for preparing a compound of formula (ll-a) according to claim 9 wherein a) an intermediate of formula (IX) is treated with methyloxy-ioxy chloride, benzenesuifonyloxy-chloride or a hagiogenating reagent as, for example SOC2 or POCI3; where in the foregoing reaction scheme, the radicals X, R2, R3, R4 and R are as defined in claim 1 and W is halo, mesyloxy or tosyloxy; or, if desired, the compounds of the formula (ll-a) are converted to one another following transformation reactions known in the art; Y moreover, if desired, the compounds of formula (ia) are converted to the acid addition site by treatment with an acid, or conversely, the acid addition forms are converted to the free base. by treatment with alkali; and if desired, the stereochemically isomeric forms thereof are prepared.

13. The use of a compound of any of claims 1 or 5 for the manufacture of a medicament for aniagonizing a CRF receptor in a warm-blooded animal.

14. The use of a compound of any of claims 1 or 5 for the manufacture of a medicament for treating a dier that manifests hypersecretion of CRF in an animal. of warm blood.

15. The use according to claim 14, wherein the dier is selected from depression, a dier related to anxiety, an augmentation dier, suppression of stress-induced immunity, stroke, Cushing's disease, infantile spasms, epilepsy. , access to a disease or inflammatory conditions.

16. The use of claim 15, wherein the eating dier is anorexia nervosa, bulimia or irritable bowel syndrome. SUMMARY OF THE INVENTION This invention relates to the compounds of formula including the stereoisomers and pharmaceutically acceptable acid addition forms thereof, wherein R1 is alkyl C-j_g, NR6R7, OR6, or SR7; R 2 is hydrogen, C 1 -g alkyl, C 1 -g alkyloxy or C 1 7 alkylthio; R3 is Ar1 or Het1; R4 and R5 are each independently selected from hydrogen, halo, C-j.g alkyl, C-j.g alkyloxy, trifluoromethyl, cyano, nitro, ammonium, and mono- or di (C-jg alkyl) amino; R6 is hydrogen, alkyl C-j.g, alkylsulfonyl C-j.g, aicylsulfoxy C-j.g or alkylthio C-j.g; R7 is hydrogen, C-j .3 alkyl, mono- or di (C3_g cycloalkyl) methyl, C3_g cycloalkyl, C3_g alkenyl, hydroxyC12 alkyl; alkylcarbonyloxy C-j.g-alkyio C- | _g or alkyloxyC-j.alkyl C-j.g; R6 is alkyl C-j_8, mono or di (C3_g cycloalkyl) -methio, Ar2CH2, alkyloxyC ^ g alkyl Cj.g, hydroxyalkyl Cj.g, C3_g alkenyl, thienylmethyl, furanylmethyl, alkyllith Cj.g, mono or di ( alkyl C-j_g) aminoalkyl C-j_g, dl (alkylC-j_g) amino, alkylcarbonyl Cj.g, alkyl C- | g; or R6 and R7 taken together with the nitrogen atom to which they are bound can form a pyrrolidinyl, piperidinyl, homopiperidinyl or morphounyl group, optionally substituted with alkyl C-j.g or alkyloxy C-j.g C-j.g alkyl; and Ar1 and Ar2 are each optionally substituted phenium; and Het "is optionally substituted pyridinium, which has CRF receptor antagonist properties, pharmaceutical compositions containing said compounds as active ingredients, methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, abuse of addictive substances, Administration of an effective amount of a compound of formula (I). JANSSEN / ald * mmr * P99 / 735F