ES2348918T3 - CONDENSED N-HETEROCYCLIC COMPOUND AND USE OF THE SAME AS AN ANTEGONIST OF THE CRF RECEIVER. - Google Patents

Abstract

1- {1- [1- (4-Methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1 H -pyrrolo [2,3-b] pyridin-4-yl] -1 H -pyrazol-3 -il} -imidazolidin-2-one (compound 1-1), including its pharmaceutically acceptable salts or solvates.

Description

The present invention relates to bicyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The first corticotropin release factor (CRF) was isolated from sheep hypothalamus and identified as a 41 amino acid peptide (Vale et al., Science 213: 1394-1397, 1981).

It has been discovered that CRF produces profound alterations in the function of the endocrine, nervous and immune system. CRF is believed to be the main physiological regulator of baseline and stress release of the adrenocorticotropic hormone ("ACTH"), B-endorphin and other peptides derived from propiomelanocortins ("POMC") of the anterior pituitary gland (Vale et al. , Science 213: 1394-1397, 1981).

In addition to its role in stimulating the production of ACTH and POMC, CRF appears to be one of the main neurotransmitters of the central nervous system and plays a crucial role in integrating the overall body's stress response.

The administration of CRF directly to the brain induces behavioral, physiological and endocrine responses identical to those observed for an animal exposed to a stressful environment. 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 CRF hypersecretion.

The first CRF receptor antagonists were peptides (see, for example, Rivier et al., U.S. Patent No. 4,605,642; Rivier et al., Science,

224: 889, 1984). Although these peptides left consolidated that CRF receptor antagonists can attenuate the pharmacological responses to CRF, CRF receptor peptide antagonists suffer the usual disadvantages of peptide therapeutic agents including the absence of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been presented.

WO 95/10506 describes, among others, compounds of general formula (A) with general CRF antagonistic activity

image 1

in which Y can be CR29; V may be nitrogen, Z may be carbon or nitrogen, R3 may correspond to an amine derivative, and R4 may be considered together with R29 to form a 5-membered ring and is -CH (R28) when R29 is -CH (R30 ).

WO 95/33750 also describes compounds of the general formula

(B) that have CRF antagonistic activity,

image 1

wherein A and Y can be nitrogen and carbon, and B can correspond to an amine derivative.

Recently, a patent application has been published as WO 02/08895, in which the following compounds, CRF antagonists, are the subject of the patent application:

image 1

In particular, R2 and R3 with N may form a saturated or unsaturated heterocycle, which may be substituted with a 5-6 membered heterocycle, which may be substituted with 1 to 3 groups selected from: C1-C6 alkyl, C1C2 halogenoalkyl , C1-C6 alkoxy, halogen, nitro or cyano

Another recent patent application has been published as WO 03/008412, in which the following compounds, CRF antagonists, are subject to the patent application:

image 1

In particular, R2 and R3 with N can form a 5-14 membered heterocycle, which can be substituted with a 5-6 membered heterocycle, which can be saturated or can contain 1 to 3 double bonds, and which can be replaced with 1

or more groups such as C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 halogenoalkoxy, hydroxy, halogen, nitro, cyano or C ( O) NR6R7.

None of the above references describe compounds that are within the scope of the present invention.

Due to the physiological importance of CRF, the development of biologically active small molecules that have significant CRF receptor binding activity and are capable of antagonizing the CRF receptor remains a desirable objective. These CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurological conditions or diseases, including stress-related disorders in general.

Although significant steps have been taken to achieve CRF regulation through the administration of CRF receptor antagonists, there is still a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing said CRF receptor antagonists, as well as methods related to their use to treat, for example, stress-related disorders. The present invention satisfies these needs and provides other related advantages.

In particular, the invention relates to novel compounds that are potent and specific antagonists of corticotropin-releasing factor (CRF) receptors.

The present invention provides compounds of formula (I) corresponding to 1- {1- [1- (4-methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1H-pyrrolo [2,3b] pyridin-4-yl] -1H-pyrazol-3-yl} imidazolidin-2-one, including its pharmaceutically acceptable salts or solvates.

image 1

The compounds of the present invention may be in the form of a pharmaceutically acceptable salt and / or may be administered as a pharmaceutically acceptable salt. For review of suitable salts, see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.

Typically, a pharmaceutically acceptable salt can be easily prepared using a desired acid or base as appropriate. The salt can precipitate in the solution and be collected by filtration or it can be recovered by evaporation of the solvent.

Suitable addition salts are formed from acids that form non-toxic salts, and examples are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate salts. , formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, sucrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and isethionate.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and salts with organic bases, including primary, secondary and tertiary amine salts, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine and N-methyl-Dglucamine.

Those skilled in organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or in which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as "hydrate." Solvates of the compound of the invention are within the scope of the invention.

In addition, prodrugs are also included within the context of this invention.

As used herein, the term "prodrug" means a compound that is converted within the body, for example, through hydrolysis in the blood, in its active form that has medical effects. Pharmaceutically acceptable prodrugs are described by T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, vol. A.C.S. 14 Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramón and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ", Advanced Drug Delivery Reviews (1996), 19 (2), 115-130, each of which is incorporated herein by reference.

Prodrugs are any covalently bound vehicle that releases a compound of structure (I) in vivo when said prodrug is administered to a patient. Prodrugs are generally prepared by modification of functional groups so that the modification is cleaved, by conventional manipulation

or in vivo, producing the compound of origin. Prodrugs include, for example, compounds of this invention in which the hydroxy, amine or sulfhydryl groups are attached to any group that, when administered to a patient, is cleaved to form the hydroxy, amine or sulfhydryl groups. Therefore, representative examples of prodrugs include (but not limited to) derivatives of acetate, formate and benzoate of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). In addition, in the case of a carboxylic acid (-COOH), esters, such as methyl esters, ethyl esters and the like can be used. The esters can be active by themselves and / or can be hydrolyzed under conditions in vivo in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily degrade in the human body to leave the acid of origin or its salt.

Those skilled in organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or in which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as "hydrate." Solvates of the compounds of the invention are within the scope of the invention.

In addition, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.

In general, the compounds of structure (I) can be prepared according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.

The compounds of formula (I) and salts and solvates thereof can be prepared by the general methods indicated hereinafter.

memory.

The compounds of formula (I), which correspond to the compounds of formula

(II) in which D and G are -CH2; R is 4-methoxy-2-methyl-phenyl; R1 is methyl; Y is CH-; Z-W is:

image 1

they can be conveniently prepared, from the compounds of formula (VII), according to the following Scheme 1:

image 1

in which

Step a represents the conversion of the leaving group L, selected from the group consisting of: halogen or sulfonic acid reactive moiety (e.g., mesylate, tosylate), preferably chloride, in the compounds (VII), by reaction with the derivative ZW suitable;

Step b represents the reduction of the ester group (E) with a suitable reducing agent (such as DIBAl-H) to the hydroxy group of the compounds (IX);

Step c represents adequate protection of an NH group optionally present in group W, with a group P, such as a pmethoxybenzyl group;

Step d represents the oxidation of the hydroxy group with a suitable oxidizing agent (such as Dess-Martin's periodic) to the aldehyde group of the compounds (XI);

Stage e + f represents the formation of the aldehyde group of the compounds (XIII) by Wittig reaction under the usual conditions, through the formation of the enol ether followed by acid hydrolysis (step f);

Step g represents the optional alkylation of the position � of the aldehyde by deprotonation with a suitable base (such as LiN (SiMe3) 2), followed by the addition of a suitable alkylating agent (such as MeI) to form the alkylated aldehyde of the compounds (XIV), (XV);

Step h represents the conversion of the aldehyde group with a Grignard reagent (such as MeMgBr) into an alcohol group of compounds (XVI) and (XVIII);

Step i represents the oxidation of the hydroxy group with a suitable oxidizing agent (such as Dess-Martin's periodic) to the ketone group of the compounds (XVII);

Step j represents the conversion of the hydroxy group into the appropriate protecting group of the compounds (XIX) (such as TBS: tert-butyldimethylsilyl);

Step k represents a Buchwald coupling reaction with the RNH2 amine suitable to give the compounds of formula (XX);

Step 1 represents the deprotection reaction to give the hydroxy group of the compounds (XXI);

Step m represents the intramolecular cyclization after the conversion of the hydroxy group of the compounds (XXI) into a suitable leaving group (such as bromide, by a reaction with CBr4 and PPh3) to give the cycled compounds (XXII);

Step n represents the deprotection reaction of the protected NH group optionally present in group W, to give the final compounds (II);

Stage or represent oxidation by a suitable oxidizing agent (such as DDQ) in order to form the double bond of the compounds (II), when D is CHR8 and G is CHR10.

The compounds of formula (VII) are known compounds or can be

prepare according to methods known in the literature.

Alternatively, the compounds of formula (I) corresponding to a

compound of formula (IIr) in which

R is 4-methoxy-2-methyl-phenyl;

R1 is methyl;

X1 is oxygen or -NH;

Y is CH-;

Lg is triflate and

Z-W is:

image 1

they can be conveniently prepared, from the compounds of formula (XXIII), according to the following Scheme 2:

image 1

in which:

Stage a 'represents the formation of the pyrrolidinone moiety of the compounds (XXIV), which will form the cycle B present in the final compounds (IIr), reacting the compounds (XXIII) with a reactive derivative of butyric acid, such as 4-chloride -chlorobutyryl; followed by a cyclization reaction under basic conditions (for example KOtBu);

Stage b 'represents the formation of amidine by reacting the compounds

(XXIV) with a 3-aminocrotonate derivative and POCl3 when X1 is oxygen; or represents the alkylation of the amidine formation by reacting the compound (XXIV) with a butinoate derivative, when X1 is NH;

Step c 'represents the cyclization of the compounds (XXV) or (XXVa) under basic conditions (eg, tBuOK) to give the hydroxy-pyridine precursor of cycle A in the final compounds (IIr);

Step d 'represents the formation of a reactive derivative (i.e., a leaving group, Lg) of the hydroxypyridine (for example, selected from a group consisting of triflate, halogen and mesylate) of the compounds (XXVI) by a reaction, for example, with triflic anhydride;

Step e 'represents the nucleophilic displacement of the leaving group of the compounds (XXVII) to give the halogenated compounds (XXVIII), preferably iodinated or brominated compounds;

Step f 'represents the arylation reaction with the suitable -Z-W derivative by a metal catalyzed coupling reaction procedure (eg, a Buchwald reaction or a Suzuki coupling) to give the final compounds (IIr); said derivative -Z-W can be adequately protected with a group P, as defined in Scheme 1,

Step g 'represents the activation of carbon 3 by the addition of an electron attractor group (eg, acylation to give an ester group, such as acylation with diethyl carbonate to give the ethyl ester derivative, E);

Stage h 'corresponds to stage b)' when X1 is oxygen.

Step i 'represents a metal-halogen exchange reaction (with a suitable base, such as n-BuLi) followed by a transmetalation reaction with a suitable metallation agent (such as trialkyl borate or trialkylstannyl chloride);

Step j 'represents the cyclisation of the �-amidoester of formula (XXIVb) with a salt (e.g., hydrochloride) of a substituted amidine (such as acetamidine hydrochloride) in order to form the pyrimidine A cycle, when Y is N;

Step m 'represents the conversion of the hydroxy group into a halogen by the halogenation reaction carried out using, for example, treatment with PO (Hal) 3, in which Hal is preferably chlorine.

In general, the starting compounds of formula (XXIII) are known compounds or can be prepared according to methods known in the literature. The process of scheme 2 is particularly convenient for preparing the compounds of the present invention. 5 The compounds of the general formula (XXIV), (XXIVb), (XXVI), (XXVII), (XXVIII),

(XXIX) are novel intermediates useful for the preparation of the CFR antagonists object of the present invention or other CFR antagonists, which can be conveniently prepared using said intermediates. Representative CRF antagonists that can be prepared using the

The above intermediate products include, but are not limited to, those described in the patent applications cited above: WO 95/10506, WO 95/33750, WO 02/08895 and WO 03/008412.

In particular, the compounds of formula (XXVIA), which correspond to the compounds of formula (XXVI) when Y corresponds to a carbon atom, may exist in the tautomeric form (XXVIB).

image 1

Scheme for the synthesis of a derivative suitable for preparing the compounds of formula (II) in which Z and W are as defined above, for example 1- (1 H -pyrazol-3-yl) imidazolidin-2-one (product intermediate 8):

image2

wherein Step a "represents the reaction of 3-aminopyrazole with chloroethyl isocyanate in DMF at 0 ° C;

Stage b "'represents the cyclization reaction with KOt-Bu in THF at t.a .;

Step c "'represents the deprotection reaction by LiOH in MeOH / H2O at 80 ° C. Those skilled in the art will appreciate that in the preparation of the compound of the invention or one of its solvates it may be necessary and / or desirable to protect one or more 5 Sensitive groups in the molecule to prevent undesirable side reactions The protective groups suitable for use according to the present invention are well known to those skilled in the art and can be used in a conventional manner See, for example, "Protective groups in organic synthesis, "by TW Greene and PGM Wuts (John Wiley & sons, 1991), or" Protecting Groups, "by PJ 10 Kocienski (Georg Thieme Verlag, 1994). Examples of suitable amino protecting groups include acyl-like protecting groups (by for example, formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (for example, benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane type protecting groups (e.g. emplo, 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (eg, benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include, for example, alkylsilyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers, such as tetrahydropyranyl or tert-butyl; or esters, such as acetate. Pharmaceutically 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) can be easily isolated associated with solvent molecules by crystallization or evaporation of a suitable solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) is required, it can be obtained, for example, by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Therefore, the required enantiomer can be obtained from the racemic compound of formula (I) by the use of a chiral HPLC method.

The present invention also includes compounds labeled with isotopes, which are identical to those indicated in formula (I) and following, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass Atomic or mass number that is normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I and

125I.

The compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H, 14C are incorporated, are useful in tissue distribution assays of drugs and / or substrates. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detection. The 11C and 18F isotopes are particularly

125I

useful in PET (positron emission tomography), and isotopes of are particularly useful in SPECT (single photon emission computed tomography), all useful in brain imaging. In addition, substitution with heavier isotopes, such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, a greater half-life in vivo or lower dosage requirements and, therefore, may be preferred in Some circumstances The isotope-labeled compounds of formula I and following of this invention can be prepared, in general, by performing the procedures described in the schemes and / or in the examples shown below, substituting an unlabeled reagent with isotopes for a reagent. easily acquired isotope labeling.

The CRF receptor antagonists of the present invention demonstrate activity at the CRF receptor site and can be used in the treatment of conditions mediated by CRF or CRF receptors.

The efficacy of a compound as a CRF receptor antagonist can be determined by various assay procedures. 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) can be evaluated with respect to activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the trials described by DeSouza et al. (J. Neuroscience 7: 88, 1987) and Battaglia et al. (Synapse, 1: 572, 1987).

The CRF receptor binding assay was performed using the homogeneous proximity scintillation technique (SPA). The ligand binds to a recombinant membrane preparation that expresses the CRF receptors that, in turn, bind to SPA beads coated with wheat germ agglutinin. Details of the experiments will be described in the Experimental Part.

With reference to the CRF receptor binding affinities, the CRF receptor antagonists of this invention have a Ki of less than 10 μM.

The compounds of the invention are useful in the treatment of disorders of the central nervous system in which CRF receptors are involved. In particular, in the treatment or prevention of major depressive disorders that include bipolar depression, unipolar depression, single or recurrent major depressive disorders with or without psychotic characteristics, catatonic characteristics, melancholic characteristics, atypical or onset characteristics after delivery, treatment of anxiety and the treatment of panic disorders. Other mood disorders included within the term major depression disorders include dysthymic disorder of early or late onset and with or without atypical manifestations, neurotic depression, posttraumatic stress disorders, postoperative stress and social phobia; Alzheimer's dementia, 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 depressive disorder; and adjustment disorder with depressed mood. Major depressive disorders may also be due to a general medical condition that includes, but is not limited to, myocardial infarction, diabetes, abortion.

spontaneous or abortion, etc.

The compounds of the invention are also useful in the treatment or prevention of schizophrenic disorders including paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia and residual schizophrenia.

The compounds of the invention are useful as analgesics. In particular, they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as the brachial plexus; chronic pain such as arthritic pain such as that it appears in osteoarthritis, rheumatoid arthritis or psoriatic arthritis; neuropathic pain such as postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-induced neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, dystrophy, sympathetic pain of ghost member; various forms of headaches such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; visceral pain; gastrointestinal pain; trapped nerve pain; sports injury pain; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain, for example spinal stenosis; prolapsed disk; sciatica; angina; ankylosing spondylitis; gout; Burns; pain of the scars; itching and thalamic pain such as thalamic pain after a stroke.

The compounds of the invention are also useful for the treatment of appetite dysfunctions and food intake and in circumstances such as anorexia, anorexia nervosa and bulimia.

The compounds of the invention are also useful in the treatment of sleep disorders that include dysomnia, insomnia, sleep apnea, narcolepsy and circadian rhythm disorders.

The compounds of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive disorders include dementia, amnesic disorders and cognitive disorders not otherwise specified.

In addition, the compounds of the invention are also useful as memory and / or cognitive enhancers in healthy humans with non-cognitive and / or memory deficits.

The compounds of the invention are also useful in the treatment of tolerance to numerous substances and their dependence. For example, they are useful in the treatment of nicotine, alcohol, caffeine, phencyclidine dependence (phencyclidine-type compounds), or in the treatment of tolerance and dependence on opiates (e.g., cannabis, heroin, morphine) or benzodiazepines ; in the treatment of cocaine addiction, sedative hypnotics, amphetamines or amphetamine-related drugs (for example, dextroamphetamine and methylamphetamine) or a combination thereof.

The compounds of the invention are also useful as anti-inflammatory agents. In particular, 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, postoperative gastric ileus (POI), inflammatory bowel disease (IBD) and lesions induced by non-steroidal anti-inflammatory drugs; inflammatory skin diseases such as herpes and eczema; inflammatory bladder diseases such as cystitis and urge incontinence; and ocular and dental inflammation.

The compounds of the invention are also useful in the treatment of allergic disorders, in particular allergic skin disorders such as hives, and allergic respiratory disorders such as rhinitis.

The compounds of the invention are also useful in the treatment of 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, even if induced. For example, emesis can be induced by drugs such as chemotherapeutic agents for cancer such as alkylating agents, for example cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, for example dactinomycin, doxorubicin, mitomycin-C and bleomycin; antimetabolites, for example cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, for example etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiotherapy, eg irradiation of the chest or abdomen, such as in the treatment of cancer; poisons toxins such as toxins produced by metabolic disorders or by infection, for example gastritis, or those released during a bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders such as motion sickness, vertigo, fainting and Meniere's disease; postoperative disease; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, for example myocardial infarction or peritonitis; migraine; increased intracranial pressure; reduction of intracranial pressure (for example, altitude sickness); opioid analgesics such as morphine; and gastroesophageal reflux disease, acid indigestion, food or beverage overindulgence, heartburn, sour stomach, epigastric burning / regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn and food-induced heartburn and dyspepsia.

The compounds of the invention are of particular utility in the treatment of gastrointestinal disorders such as irritable bowel syndrome (SCI); skin disorders such as psoriasis, pruritus and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischemia such as cerebral vasospasm after a subarachnoid hemorrhage; fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune potentiation or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; And cough.

The compounds of the invention are useful for the treatment of neurotoxic lesions that appear after a cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, hypoxia, anoxia, perinatal axphysia and cardiac arrest.

Therefore, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.

Also provided, as a further aspect of the invention, is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions mediated by CRF.

In an alternative or additional aspect, a method is provided for the treatment of a mammal, including the human being, in particular in the treatment of a condition mediated by CRF, which comprises the administration of an effective amount of a compound of formula (I ) or a pharmaceutically acceptable salt or solvate thereof.

Although it is possible that, for use in therapy, a compound of the invention can be administered as a crude chemical agent, it is preferable to present the active ingredient as a pharmaceutical formulation, for example, when the agent is mixed with a pharmaceutical excipient, diluent or carrier. suitable selected according to the desired route of administration and conventional pharmaceutical practice.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of the invention or its pharmaceutically acceptable derivative in association with a pharmaceutically acceptable carrier and / or excipient. The vehicle and / or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not being detrimental to the recipient thereof.

Accordingly, the present invention also provides a pharmaceutical formulation comprising at least one compound of the invention or its pharmaceutically acceptable derivative, in association with a pharmaceutically acceptable carrier and / or excipient. The vehicle and / or the excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient receiving them.

In addition, the present invention provides a process for preparing a pharmaceutical composition, said process comprising mixing at least one compound of the invention or its pharmaceutically acceptable derivative, together with a pharmaceutically acceptable carrier and / or excipient.

The pharmaceutical compositions may be for human or animal use in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier or excipient. Vehicles or diluents acceptable for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of the pharmaceutical vehicle, excipient or diluent can be selected based on the desired route of administration and conventional pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, vehicle, excipient or diluent any or any suitable binders, lubricants, suspending agents, coating agents and solubilizing agents.

Preservative, stabilizing, coloring and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used.

There may be different composition / formulation requirements depending on the different administration systems. By way of example, the pharmaceutical composition of the present invention can be formulated to be administered using a minipump or through the mucosa, for example, as a nasal spray or inhalation spray or a solution that can be ingested, or parenterally. , wherein the composition is formulated in an injectable form, for administration, for example, intravenously, intramuscularly or subcutaneously. Alternatively, the formulation can be designed to be administered by both routes.

When the agent is to be administered mucosally, through the gastrointestinal mucosa, it must be able to remain stable during transit through the gastrointestinal tract; for example, it must be resistant to proteolytic degradation, stable at acidic pH and resistant to the detergent effects of bile.

When appropriate, pharmaceutical compositions may be administered by inhalation, in the form of a vaginal suppository or suppository, topically in the form of a lotion, solution, cream, ointment or fine powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients, or in the form of elixirs, solutions or suspensions containing flavoring agents

or dyes, or they can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions can best be used in the form of a sterile aqueous solution that may contain other substances, for example, sufficient salts or monosaccharides to make the solution isotonic with blood. For oral or sublingual administration, the compositions can be administered in the form of tablets or dragees that can be formulated in a conventional manner.

For some embodiments, the agents of the present invention can also be used in conjunction with a cyclodextrin. It is known that cyclodextrins form inclusion complexes and other complexes with drug molecules. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and / or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to the direct formation of complexes with the drug, cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are the most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

In a preferred embodiment, the agents of the present invention are administered systemically (such as orally, orally or sublingually), more preferably orally.

In fact, the agent is preferably in a form that is suitable for oral administration.

It should be understood that not all compounds need to be administered by the same route. Similarly, if the composition comprises more than one active component, those components can be administered by different routes.

The compounds of the invention can be crushed using known crushing methods, such as wet crushing to obtain an appropriate particle size for tablet formation and for other types of formulation. Finely divided preparations (in the form of nanoparticles) of the compounds of the invention can be prepared by processes known in the art, for example, see International Patent Application No. WO 02/00196 (SmithKline Beecham).

For oral administration, 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 (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulfate). The tablets may be coated by methods well known in the art. 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 to be reconstituted with water or other suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, colorants and sweeteners, as appropriate.

Preparations for oral administration can be adequately formulated.

to give a controlled release of the active compound.

For oral administration, the composition may take the form of tablets or be formulated in the conventional manner.

The compounds of the invention can be formulated for parenteral administration by embolate injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. ex. sterile pyrogen-free water, before use.

The compounds of the invention can be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (eg, eye, ear or nose drops). Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Ointments for administration in the eye can be manufactured in a sterile manner using sterilized components.

Lotions can be formulated with an aqueous or oily base and, in general, will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. The drops may be formulated with an aqueous or non-aqueous base which also comprises one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They can also contain a preservative.

The compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention can also be formulated as depot preparations. These long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as moderately soluble derivatives, for example, as a salt moderately soluble

For intranasal administration, the compounds of the invention can be formulated as solutions for administration through a suitable unit dosage device or measure or, alternatively, as a powder mixture with a vehicle suitable for administration using a suitable release device.

A proposed dose of the compounds of the invention is from 1 to about 1000 mg per day. It will be appreciated that it may be necessary to make routine variations of the dosage depending on the age and condition of the patient, and the precise dosage will finally be at the discretion of the doctor or veterinarian in charge of the case. 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 in the range of 1 to 300 mg, for example, 1 to 100 mg.

EXAMPLES

In intermediate products and examples, unless otherwise indicated:

All temperatures are indicated in ºC. The infrared spectra were measured on an FT-IR instrument. The compounds were analyzed by direct infusion of the sample dissolved in acetonitrile into mass spectra operated in positive electrospray ionization (ES +) mode. Proton Magnetic Resonance (1H NMR) spectra were recorded at 400 MHz, chemical shifts are given in ppm at low field (d) from Me4Si, used as internal standard, and are assigned as singles (s), wide singles ( s width), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiples (m). A strategy has been implemented that includes the NOE correlation (nuclear Overhauser effect) and / or measurements of long-range scalar correlations of 1H, 15N, in order to allow the elucidation of the structure of the possible regioisomers of the compounds of the present invention. The proposed structures were verified by measuring the proximity in the space of key hydrogens, therefore the Overhauser 1 D nuclear difference spectra were used to measure the dipole-dipole correlations 1H, 1H.

In cases where NOE measurements were inconclusive, long-range scalar correlations of 1H, 15N were measured by 1H, 15N-HMBC experiments. For an optimal result, a delay corresponding to an average long-range scalar coupling of 2.3J (1H, 15N) of 6Hz was established. Column chromatography was performed on silica gel (Merck AG Darmstaadt, Germany). In the text, the following abbreviations are used: EtOAc = ethyl acetate, cHex = cyclohexane, CH2Cl2 = dichloromethane, Et2O = diethyl ether, DMF = N, N'dimethylformamide, DIPEA = N, N-diisopropylethylamine, DME = dimethyl ether ethylene glycol, MeOH = methanol, Et3N = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, DIBAI-H = diisobutylaluminum hydride, DMAP = dimethylaminopyridine, LHMDS = lithium hexamethyldisilazane, KOt-methoxy-potassium-C-methyl-potassium = N-methyl-potassium pyrrolidinone, MTBE = tert-butyl and methyl ether, IPA = isopropanol, DAST = (diethylamino) sulfur trifluoride, TMSBr = trimethylsilyl bromide, DDQ = 2,3-dichloro5,6-dicyano-1,4-benzoquinone, SCX = strong cation exchanger, Tlc refers to thin layer chromatography on silica gel plates, and drying refers to a dried solution over anhydrous sodium sulfate, ta (TA) refers to room temperature.

Intermediate Product 1 1- (4-Methoxy-2-methylphenyl) pyrrolidin-2-one

To a solution of Et3N (156 ml, 1 eq) and 4-methoxy-2-methylaniline (150 g, 1.09 mol) in anhydrous THF (2.4 liters), in a 10-liter reaction flask, at 0 ° C , under N2 atmosphere, a solution of 4-chlorobutyryl chloride (126 ml, 1 eq) in anhydrous THF (480 ml) was added dropwise. The internal temperature was maintained at about 10 ° C and the reaction mixture was stirred for 1.5 h. It was cooled to 0 ° C and 1M KOt-Bu / THF (2.64 liters, 2.4 eq) was added dropwise over a period of 1.5 h, keeping the internal temperature at <10 ° C. The reaction mixture was stirred at this temperature for 30 min. Water (1.5 liters) was added slowly and the phases separated. The organic layer was treated with conc. HCl. (250 ml) and water (1.26 liters) and the phases were separated. The combined aqueous layers were extracted with EtOAc (2.6 liters) and the combined organic layers were washed with brine (2 liters). The solvent was evaporated and the residue was purified by flash chromatography (Biotage 150, EtOAc / cHex 8: 2) to give the title compound as a pale brown solid (206 g, 92%).

NMR (1H, CDCl3): � 7.05 (d, 1H), 6.79-6.72 (m, 2H), 3.75 (s, 3H), 3.64 (t, 2H), 2, 18 (s, 6H).

MS (m / z): 206 [MH] +.

Intermediate Product 2 Ethyl 3 - {[1- (4-Methoxy-2-methylphenyl) pyrrolidin-2-ylidene] amino} but-2-enoate

To a solution of intermediate 1 (8.3 g, 40.49 mmol) in anhydrous 1,2-dichloroethane (100 ml), at rt, under N2 atmosphere, POCl3 (7.5 ml, 2 eq) was added dropwise ) followed by ethyl 3-aminocrotonate (5.17 ml, 1 eq). The reaction mixture was heated at 60 ° C for 3.5 h. Then, it cooled to t.a. and neutralized to pH 7 by the careful addition of saturated aqueous NaHCO3 solution. The neutralized solution was extracted with CH2Cl2 (3 x 50 ml). The combined organic extracts were washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The solids were filtered and the solvent was evaporated. The crude product was used as it was in the next stage (17.8 g).

Alternatively, to a solution of intermediate 10 (3 g, 14.7 mmol) in anhydrous THF (18 ml), at rt, under N2 atmosphere, ethyl 2-butynate (2.23 ml, 1.3) was added eq). The reaction mixture was heated at reflux for 14 h and then cooled to t.a. The reaction mixture was evaporated to dryness. The crude product was used as it was in the next stage (5.05 g).

MS (m / z): 317 [MH] +.

Intermediate Product 3

1- (4-Methoxy-2-methylphenyl) -6-methyl-1,2,3,7-tetrahydro-4H-pyrrolo [2,3-b] pyridin4-one

A solution of intermediate 2 (17.8 g, 55 mmol) in anhydrous DMF (50 ml) was added dropwise to a suspension of 60% NaH in oil (4.5 g, 2 eq) in anhydrous DMF. The reaction mixture was heated at 100 ° C for 8 h. More 60% NaH in oil (2.25 g, 1 eq) was added and the reaction mixture was heated for an additional 4 h. It cooled to t.a. and carefully poured into a saturated aqueous solution of NH4Cl. The aqueous solution was extracted with CH2Cl2 (5 x 50 ml) and the combined organic extracts were dried over anhydrous Na2SO4. The solids were filtered and the solvent was evaporated. The crude compound was purified by flash chromatography (Biotage 75, CH2Cl2MeOH 95: 5 � 80:20). The title compound was obtained as a brown oil (952 mg, 9%, 2 steps)

Alternatively, to a solution of intermediate 2 (2.46 g, 7.77 mmol) in anhydrous THF (10 ml), at t, under N2 atmosphere, 1M t-BuOK / THF (15.6 ml) was added , 2 eq). The reaction mixture was heated to reflux and stirred for 6 h. The solution was allowed to cool to t.a., evaporated to about 10 ml and diluted with MTBE (10 ml). The organic layer was extracted with water (10 ml), the organic phase was discarded while the aqueous one was diluted with saturated aqueous NH4Cl solution (10 ml). The aqueous layer was extracted with CH2Cl2 (10 ml). The combined organic extracts were evaporated to dryness and the crude product thus obtained was used as it was in the next step (1.32 g).

NMR (1H, DMSO-d6): � 9.8 (width, 1H), 7.08 (d, 1H), 6.80 (d, 1H), 6.75 (dd, 1H), 5.92 ( s, 1H), 3.72 (s, 3H), 3.68 (t, 2H), 2.89 (t, 2H), 2.12 (s, 3H), 2.02 (s, 3H).

MS (m / z): 271 [MH +].

Intermediate Product 4

1- (4-Methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1-pyrrolo [2,3-b] pyridin-4-yl trifluoromethanesulfonate

To a solution of intermediate 3 (9.0 g, 33.3 mmol) in anhydrous CH2Cl2 (64 ml), at t.a., under N2 atmosphere, pyridine (5.08 ml, 1.8 eq) was added. The solution was cooled to -20 ° C and triflic anhydride (5.9 ml, 1.1 eq) was added dropwise over 50 min. The temperature never exceeded -10 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. Saturated aqueous NaHCO3 solution (31.2 ml) was added and the phases were separated. The organic layer was washed further with water (31.2 ml) and concentrated to an oil, which was passed through a pad of silica gel (12.7 g, EtOAc / cHex 1/9). The crude product thus obtained was diluted with MTBE (38.1 ml) and washed with 10% HCl (63.5 ml). The combined aqueous layers were treated with conc. NH4OH. (38.1 ml) and extracted with CH2Cl2 (25.4 ml). The organic layer was washed further with 10% NaCl (12.7 ml) and evaporated to an oil. The oil was dissolved in IPA (38.1 ml) and seeded with authentic intermediate 4 (0.02 g). The suspension was stirred for 30 min. Water (38 ml) was added over 30 min and the mixture was allowed to stand for 1.5 h. The suspension was filtered, the filter cake was washed with a 1: 1 IPA / water mixture (12.7 ml), collected and dried in the oven at 40 ° C under high vacuum for 14 h. The title compound was obtained as a pale yellow solid (3.8 g, 42%).

NMR (1H, DMSO-d6): � 7.17 (d, 1H), 6.85 (d, 1H), 6.77 (dd, 1H), 6.40 (s, 1H), 3.89 ( t, 2H), 3.73 (s, 3H), 3.16 (t, 2H), 2.17-2.11 (2s, 6H)

MS (m / z): 403 [MH] +

Intermediate Product 5

4-Iodo-6-methyl-1- [2-methyl-4- (methyloxy) phenyl] -2,3-dihydro-1H-pyrrolo [2,3b] pyridine

To a solution of intermediate 4 (913 mg, 2.27 mmol) in anhydrous NMP (7 ml) was added KI (1.13 g, 3 eq) and the reaction mixture was stirred at 150 ° C for 18 h. Then it cooled to t.a. and diluted in water / saturated aqueous NaCl solution. The aqueous phase was extracted with EtOAc (3 x 30 ml) and the combined organic extracts were dried over anhydrous Na2SO4. The solids were filtered and the solvent was evaporated. The crude product was purified by flash chromatography (silica gel, cHex / EtOAc 9: 1) to give the title compound as a clear oil, which solidified on standing (681 mg, 79%).

NMR (1H, CDCl3): � 7.14 (d, 1H), 6.81-6.74 (m, 2H), 6.70 (s, 1H), 3.84 (t, 2H), 3, 81 (s, 3H), 3.03 (t, 2H), 2.22 (s, 6H).

MS (m / z): 381 [MH] +.

Intermediate Product 6

N- (2-Chloroethyl) -3 - ({[(2-chloroethyl) amino] carbonyl} amino) -1 H -pyrazol-1-carboxamide

To a solution of 3-aminopyrazole (500 mg, 6 mmol) in anhydrous DMF (3 ml), at 0 ° C, under N2 atmosphere, 3-chloroethyl isocyanate (1.53 ml, 3 eq) was added and the mixture of reaction was stirred at rt for 2 h, after which the solvent was evaporated. The crude product was purified by flash chromatography (silica gel, cHex / EtOAc 1: 1) to give the title compound (1,593 g, 89%).

NMR (1H, DMSO): � 9.20 (s, 1H), 8.26 (m, 1H), 8.10 (d, 1H), 7.25 (bs, 1H), 6.37 (d, 1H), 3.74 (m, 2H), 3.66 (m, 2H), 3.58 (m, 2H), 3.46 (m, 2H).

MS (m / z): 296 [MH] +.

Intermediate 7 N- (2-Chloroethyl) -3- (2-oxoimidazolidin-1-yl) -1 H -pyrazol-1-carboxamide

To a solution of intermediate 6 (100 mg, 0.34 mmol) in anhydrous THF (4 ml), at rt, under N2 atmosphere, KOt-Bu (42 mg, 1.1 eq) was added and the mixture of reaction was stirred for 2 h. Water (0.5 ml) was added and the solvent was evaporated. The aqueous phase was diluted with H2O and extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solids were filtered and the solvent was evaporated. The crude product was purified by flash chromatography (silica gel, EtOAc / cHex 8: 2, then 9: 1) to give the title compound (39 mg, 44%) as a white solid.

NMR (1H, DMSO): � 8.18 (wide t, 1H), 8.11 (d, 1H), 7.14 (wide s, 1H), 6.75 (d, 1H), 3.89 ( m, 2H), 3.73 (m, 2H), 3.56 (m, 2H), 3.40 (m, 2H).

MS (m / z): 258 [MH].

Intermediate 8 1- (1H-Pirazol-3-yl) limidazolidin-2-one

To a solution of intermediate 7 (190 mg, 0.74 mmol) in a mixture of MeOH / H2O 2: 1 (15 ml), at rt, under N2 atmosphere, LiOH (177 mg, 10 eq) was added and The reaction mixture was heated at 80 ° C for 3 h. Then it cooled to t.a. and neutralized to pH 7 with 2M HCl. Then, silica gel was added and the solvents were evaporated. The adsorbed crude product was purified by flash chromatography (silica gel, EtOAc / MeOH 9: 1) to give the title compound (80 mg, 71%) as a white solid.

NMR (1H, DMSO): � 12.10 (wide s, 1H), 7.6 (s, 1H), 6.7 (s, 1H), 6.4 (s, 1H), 3.8 (t , 2H), 3.4 (t, 2H).

MS (m / z): 152 [MH +].

Intermediate Product 9 4 - {[2-Methyl-4- (methyloxy) phenyl] amino} butanonitrile

A solution of DIPEA (39 ml, 1 eq) and 4-methoxy-2-methylaniline (30 g, 0.22 mol) in anhydrous DMF (90 ml), under N2 atmosphere, was heated to 100 ° C. 4-Bromobutanonitrile (21 ml, 1 eq) was added dropwise. The internal temperature was raised to 110 ° C and the reaction mixture was stirred for 2 h. The mixture was cooled to t.a. and diluted with MTBE (240 ml). Water (270 ml) was added and the phases were separated. The organic layer was washed more with water (150 ml) and evaporated to 150 ml. Newly added MTBE (150 ml) was added and the mixture was evaporated again to 150 ml. The mixture was treated with cHex (540 ml) over 20 min and the resulting suspension was left at room temperature for 1.5 h. The suspension was filtered and the filter cake was washed with a mixture of MTBE (30 ml) / cHex (90 ml). The title compound was collected as a violet solid (23.8 g, 53%).

NMR (1H, DMSO-d6): � 6.65 (d, 1H), 6.63 (dd, 1H), 6.47 (d, 1H), 4.49 (wide t, 1H), 3.64 (s, 3H), 3.10 (q, 2H), 2.59 (t, 2H), 2.09 (s, 3H), 1.86 (m, 2H).

MS (m / z): 205 [MH] +.

Intermediate 10 1- [2-Methyl-4- (methyloxy) phenyl] -2-pyrrolidinimine

To a suspension of intermediate 9 (35.0 g, 0.173 mol) in anhydrous IPA (280 ml), at rt, under N2 atmosphere, 6 N HCl / IPA (51.45 ml, 1.5 eq) was added . The mixture was heated at reflux for 4 h, allowed to cool to t.a. and evaporated to 140 ml. Water (350 ml) was added, the clear solution was re-evaporated to 140 ml and treated with 10% NaOH (140 ml). The mixture was extracted with CH2Cl2 (350 ml) and the organic layer was washed again with 10% NaCl (140 ml). The organic layer was evaporated to dryness. The crude product was used as it was in the next stage (36.4 g, 100%).

- 28 - NMR (1H, DMSO-d6): � 7.09 (d, 1H), 6.87 (d, 1H), 6.80 (dd, 1H), 5.8-5.4 (width, 1H), 3.75 (s, 1H), 3.54 (t, 2H), 2.51 (t, 2H), 2.11 (s, 3H), 2.01 (m, 2H). MS (m / z): 205 [MH] +.

Intermediate Product 11

4-Bromo-6-methyl-1- [2-methyl-4- (methyloxy) phenyl] -2,3-dihydro-1H-pyrrolo [2,3b] pyridine

To a solution of intermediate 4 (50.0 g, 0.15 mol) in anhydrous DMF (175 ml), at rt, under N2 atmosphere, CH3SO3H (58.1 ml, 1.2 eq) was added followed by NaBr (19.18 g, 1.5 eq) and the resulting mixture was heated at 85 ° C for 2 h. It was then diluted with MTBE (250 ml) and washed with 1 N NaOH (250 ml). The aqueous phase was extracted with MTBE (150 ml) and the combined organic extracts were washed twice with water (250 ml), and then dried over anhydrous Na2SO4. The solids were filtered and the solvent was evaporated to give the title compound (38 g, 76%) as a yellow solid.

EXAMPLE 1

Synthesis of the compounds of general formula (II), (I)

Example 1-1

1- {1- [1- (4-Methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1 H -pyrrolo [2,3-b] pyridin-4-yl] -1 H -pyrazol-3-yl } imidazolidin-2-one

In a closed vial, at rt, under N2 atmosphere, intermediate 5 (60 mg, 0.158 mmol), Cul (6 mg, 0.2 eq) and K2CO3 (4.5 mg, 2.5) are mixed together eq). A solution of dodecane (14.3 µl, 0.4 eq), trans-cyclohexanediamine (14 µl, 0.6 eq) and intermediate 8 (48 mg, 2 eq) in anhydrous NMP (5 ml) were added and The reaction mixture was stirred at 130 ° C for 3.5 h. Then, it cooled to t.a. and poured into EtOAc / H2O. The phases were separated and the aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered and the solvent was evaporated. The crude product was chromatographed by flash chromatography (EtOAc / cHex 6: 4, then 1: 1, then 3: 7) followed by a SCX cartridge (100% MeOH, then 2M NH3 / MeOH) to give the title compound in the form of a white solid (34 mg, 53%).

Alternatively, to a suspension of Cul (8 mg, 0.02 eq) in anhydrous DMF (1.8 ml), at rt, under N2 atmosphere, (1R, 2R) -N, N'-dimethyl-1 was added , 2-cyclohexanediamine (90 mg, 0.3 eq) and the blue solution obtained was stirred at rt for 1.5 h. Intermediate 8 (0.80 g, 2.5 eq) and K2CO3 (0.87 g, 3.0 eq) were added followed by intermediate 11 (0.7 g, 21 mmol) in anhydrous DMF (1, 8 ml) The resulting mixture was heated at 125 ° C for 30 h. The mixture was cooled to 60 ° C and water (10 ml) was added dropwise. The suspension was stirred at room temperature for 1 h and the white precipitate was filtered and washed once with a DMF / water 1: 2 mixture (10 ml), and then twice with water (10 ml). The collected solid was dried at 80 ° C for 24 h. The crude solid thus obtained was dissolved at t.a. in a mixture of CH2Cl2 / MeOH 9: 1 (10 ml). The solution was filtered through a carbon pad and the filter cake was washed with the same solvent (10 ml). Heptane (20 ml) was added dropwise at t.a., the resulting suspension was allowed to stand for 2 h, filtered and washed with MeOH. The collected solid was dried at 80 ° C for 24 h to obtain the title compound (410 mg, 48%) as a white solid.

EXAMPLE 2 CRF binding activity

In vitro CRF binding affinity was determined by the ability of compounds to displace 125I-oCRF and 125I-sauvagina for SPA CRF1 and CRF2, respectively, of recombinant human CRF receptors expressed in Chinese hamster ovary cell membranes (CHO) For membrane preparation, CHO cells from confluent T flasks were collected in SPA buffer (50 mM HEPES / KOH, 2 mM EDTA, 10 mM MgCl2, pH 7.4), in 50 ml centrifuge tubes, homogenized in a Polytron and centrifuged (50,000g for 5 min at 4 ° C: Beckman centrifuge with JA20 rotor). The sediment was resuspended, homogenized and centrifuged as indicated above.

The SPA experiment was performed on an Optiplate by adding 100 µl of the reagent mixture to 1 µl of the compound dilution (100% DMSO solution) per well. The test mixture was prepared by mixing SPA buffer, WGA SPA beads (2.5 mg / ml), BSA (1 mg / ml) and membranes (50 and 5 µg protein / ml for CRF1 and CRF2 respectively) and a concentration 50 pM radioligand.

The plate was incubated overnight (> 18 hours) at room temperature and read with the Packard Topcount counter with a WGA-SPA 125I counting protocol.

EXAMPLE 3 CRF functional test

The compounds of the invention were characterized in a functional assay for the determination of their inhibitory effect. Human CRF-CHO cells were stimulated with CRF and receptor activation was assessed by measuring the accumulation of cAMP.

The CHO cells were resuspended from a confluent T flask with culture medium without G418 and distributed in a 96-well plate, 25,000 c / well, 100 µl / well and incubated overnight. After incubation, the medium was replaced with 100 µl of IBMX cAMP buffer heated to 37 ° C (5 mM KCI,

5 5 mM NaHCO3, 154 mM NaCl, 5 mM HEPES, 2.3 mM CaCl2, 1 mM MgCl2, pH 7.4 supplemented with 1 mg / ml BSA and 1 mM IBMX) and 1 µl dilution of the antagonist in pure DMSO. After an additional 10 minutes of incubation at 37 ° C in a plateless incubator without CO2, 1 µl of agonist dilution in pure DMSO was added. As before, the plate was incubated for 10 minutes and then the content was measured

10 cAMP cell using the Amersham RPA 538 kit.

Claims (7)

1. 1- {1- [1- (4-Methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-4-yl] 1H-pyrazole- 3-yl} imidazolidin-2-one (compound 1-1), image 1 5 including its pharmaceutically acceptable salts or solvates. 2. Method for preparing the compound of claim 1, which corresponds to a compound of formula (IIr) in which: R 10 is 4-methoxy-2-methyl-phenyl; R1 is methyl; X1 is oxygen; Y is CH-, -NH; Lg is triflate and 15 Z-W is: image 1 that part of the corresponding compound of formula (XXIII), which comprises the following steps as in scheme 2, image2 in which: Stage a 'represents the formation of the pyrrolidinone moiety of the compounds (XXIV), which will form the cycle B present in the final compounds (IIr), reacting the compounds (XXIII) with a reactive derivative of butyric acid, such as 4-chloride -chlorobutyryl; followed by a cyclization reaction under basic conditions (for example KOtBu); Stage b 'represents the formation of amidine by reacting the compounds (XXIV) with a 3-aminocrotonate derivative and POCl3 when X1 is oxygen; or represents the alkylation of the amidine formation by reacting the compound (XXIV) with a butinoate derivative, when X1 is NH; Step c 'represents the cyclization of the compounds (XXV) or (XXVa) under basic conditions (eg, tBuOK) to give the hydroxy-pyridine precursor of cycle A in the final compounds (IIr); Step d 'represents the formation of a reactive derivative (i.e., a leaving group, Lg) of the hydroxypyridine (for example, selected from the group consisting of triflate, halogen and mesylate) of the compounds (XXVI) by a reaction, by example, with triflic anhydride; Stage e 'represents the nucleophilic displacement of the leaving group of the compounds (XXVII) to give the halogenated compounds (XXVIII); Step f 'represents the arylation reaction with the suitable -Z-W derivative by a metal catalyzed coupling reaction procedure (eg, a Buchwald reaction or a Suzuki coupling) to give the final compounds (IIr); said derivative -Z-W can be adequately protected with a group P, as defined in Scheme 1, Step g 'represents the activation of carbon 3 by the addition of an electron attractor group (eg, acylation to give an ester group, such as acylation with diethyl carbonate to give the ethyl ester derivative, E); Stage h 'corresponds to stage b)' when X1 is oxygen. Step i 'represents a metal-halogen exchange reaction (with a suitable base, such as n-BuLi) followed by a transmetalation reaction with a suitable metallation agent (such as a trialkyl borate or a trialkylmethanyl chloride); Step j 'represents the cyclisation of the �-amidoester of formula (XXIVb) with a salt (e.g., hydrochloride) of a substituted amidine (such as acetamidine hydrochloride) in order to form the pyrimidine A cycle, when Y is N; Step m 'represents the conversion of the hydroxy group into a halogen by the halogenation reaction, carried out using, for example, treatment with PO (Hal) 3. 3. 1- {1- [1- (4-Methoxy-2-methylphenyl) -6-methyl-2,3-dihydro-1 H -pyrrolo [2,3-b] pyridin-4-yl] 1H-pyrazol-3-yl} imidazolidin-2-one for use as a medicine. 4. The use of a compound according to claim 1, in the preparation of a medicament for use in the treatment of mediated conditions - 3. 4 - by CRF (corticotropin release factor). 5. The use of a compound according to claim 4, in the Preparation of a medication for use in the treatment of depression and anxiety. 6. A compound according to claim 1, for the treatment of conditions mediated by CRF (corticotropin release factor). A compound according to claim 6, for the treatment of depression and anxiety. 8. A pharmaceutical composition comprising a compound according with claim 1, mixed with one or more physiologically acceptable carriers or excipients.