WO2004092176A1 - Composes de pyrrolo[1,2-b]pyridazine et leurs utilisations - Google Patents

Composes de pyrrolo[1,2-b]pyridazine et leurs utilisations Download PDF

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WO2004092176A1
WO2004092176A1 PCT/IB2004/001250 IB2004001250W WO2004092176A1 WO 2004092176 A1 WO2004092176 A1 WO 2004092176A1 IB 2004001250 W IB2004001250 W IB 2004001250W WO 2004092176 A1 WO2004092176 A1 WO 2004092176A1
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compound
formula
crf
disorder
compounds named
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PCT/IB2004/001250
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Jian-Min Fu
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Pharmacia & Upjohn Company Llc
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Priority to JP2006506519A priority Critical patent/JP2006523675A/ja
Priority to CA002520805A priority patent/CA2520805A1/fr
Priority to EP04725761A priority patent/EP1615929A1/fr
Priority to MXPA05010833A priority patent/MXPA05010833A/es
Priority to BRPI0409444-1A priority patent/BRPI0409444A/pt
Publication of WO2004092176A1 publication Critical patent/WO2004092176A1/fr

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Definitions

  • the present invention relates generally to compounds that bind to CRF receptors, and particularly to substituted pyrrolo[1 ,2-b]pyridazine derivatives as CRF-i receptor antagonists and use thereof as a treatment for disorders that are associated with CRF or CRFi receptors.
  • Corticotropin releasing factor is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Natl. Acad. Sci (USA) 80:4851 (1983); W. Vale et a!., Science 213:1394 (1981 )].
  • POMC proopiomelanocortin
  • CRF In addition to its endocrine role at the pituitary gland, CRF is known to have a broad extrahypothalmic distribution in the CNS, contributing therein to a wide spectrum of autonomic behavioral and physiological effects consistent with a neurotransmitter or neuromodulator role in the brain jW. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5:3189 (1985)].
  • CRF cerebral spastic syndrome
  • psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders, and in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuciear palsy and amyotrophic lateral sclerosis, as they relate to the dysfunction of CRF neurons in the central nervous system [J.E. Blalock, Physiological Reviews 69:1 (1989); J.E. Morley, Life Sci. 41 :527 (1987); E.B. De Souze, Hosp. Practice 23:59 (1988)].
  • CRF has been implicated in the etiology of mood disorder, also known as affective disorder. It was shown that in individuals afflicted with affective disorder, or major depression, the concentration of CRF in the cerebral spinal fluid (CSF) is significantly increased.
  • CSF cerebral spinal fluid
  • CRF has also been implicated in the etiology of anxiety-related disorders.
  • Anxiety disorders are a group of diseases, recognized in the art, that includes phobic disorders, anxiety states, post-traumatic stress disorder and atypical anxiety disorders [The Merck Manual of Diagnosis and Therapy, 16 th edition (1992)]. Emotional stress is often a precipitating factor in anxiety disorders, and such disorders generally respond to medications that lower response to stress. Excessive levels of CRF are known to produce anxiogenic effects in animal models [see, e.g., Britton et al., 1982; Berridge and Dunn, 1986 and 1987].
  • CRFi antagonists are useful for treating arthritis and inflammation disorders [E.L. Webster et al., J Rheumatol 29(6):1252 (2002); E.P. Murphy et al., Arthritis Rheum 44(4):782 (2001)]; stress-related gastrointestinal disorders [K.E. Gabry et al., Molecular Psychiatry 7(5): 474 (2002),]; and skin disorders [C.C. Zouboulis et al., Proc. A/at/. Acad. Sci. 99: 7148 (2002)]. It was disclosed recently that, in an animal model, stress-induced exacerbation of chronic contact dermatitis is blocked by a selective CRF !
  • EP1085021 discloses pyrrolo[1 ,2-b]pyridazine compounds as sPLA2 inhibitors.
  • the following publications each describes CRFi antogonist compounds; however, none disclose the specific compounds provided herein: WO 98/08847 (International Publication Date 5
  • the present invention provides a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, which is potent antagonist of CRFi receptor.
  • the present invention provides a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, which is useful for the treatment of a disorder in a warm-blooded animal, which disorder manifests hypersecretion of CRF, or the treatment of which disorder can be effected or facilitated by antagonizing CRF ! receptors.
  • disorders include anxiety-related disorders such as anxiety states, generalized anxiety disorder, phobic disorders, social anxiety disorder, anxiety with co- morbid depressive illness, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and atypical anxiety disorders; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; and cyclothymia; supranuciear palsy; immune suppression; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; fertility problems including infertility; pain; asthma; allergies; sleep disorders induced by stress; pain perception such as fibromyalgia; fatigue syndrome; stress- induced headache; cancer; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post
  • the present invention provides for the use of a compound of formula (I), and stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, for treatment of a disorder disclosed herein above.
  • the present invention provides for a composition
  • a composition comprising a compound of formula (I), and stereoisomers, pharmaceutically acceptable salts, and prodrugs thereof, useful for treatment of a disorder disclosed herein above.
  • the present invention provides for the use of a compound of the invention in a binding assay, wherein one or more of the compounds may be joined to a label, where the label can directly or indirectly provide a detectable signal.
  • Various labels include radioisotopes, fluorescers, chemiluminescers, specific binding molecules, particles, e.g. magnetic particles, and the like.
  • the present invention relates to the use of the compounds of the invention (particularly labeled compounds of this invention) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds.
  • Labeled compounds of the invention may be used for in vitro studies such as autoradiography of tissue sections or for in vivo methods, e.g. PET or SPECT scanning. Particularly, compounds of the invention are useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF ! receptor.
  • R 1 and R 2 are independently selected from H, Me or OMe.
  • Compounds provided herein can have one or more asymmetric centers or planes, and all chiral (enantiomeric and diastereomeric) and racemic forms of the compound are included in the present invention.
  • Compounds of the invention are isolated in either the racemic form, or in the optically pure form, for example, by resolution of the racemic form by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column, or synthesized by an asymmetric synthesis route enabling the preparation of enantiomerically enriched material.
  • the present invention encompasses all possible tautomers of the compounds represented by formula (I).
  • Compounds of the invention can generally be prepared using the synthetic routes illustrated in Scheme 1 indicated below. Starting materials are either commercially available or can be prepared by procedures known in the art. Scheme 1
  • 1-Bromo-2,4-dichlorobenzene (1) can be treated with a strong base such as n- butyllithium or t-butyllithium and react with ⁇ -methyl- ⁇ -butyrolactone (2) to form ketone 3.
  • Oxidation of alcohol 3 to aldehyde 4 can be accomplished by a method such as Swern oxidation.
  • the generated dicarbonyl compound 4 can react with ⁇ /-aminophthalimide to provide the substituted pyrrole compound 5.
  • the hydroxyl group in compound 7 can be converted into its triflate group by reacting with trifluoromethanesufonic anhydride or ⁇ -phenyltrifluoromethanesulfonimide in the presence of a base such as triethylamine or sodium hydride in a solvent such as dichloromethane or DMF, or a bromo group by reacting with phosphorus tribromide in refluxing bromobenzene.
  • the generated triflate or bromo compound 8 can undergo palladium (e.g. Pd(OAc) 2 , Pd 2 (dba) 3 , etc) catalyzed amination reaction (see, Ahman, J. and Buchwald, S. L. Teirahydron Lett.
  • the present invention also encompasses pharmaceutically acceptable salts of the compounds of formula (I).
  • Pharmaceutically acceptable salts of the invention can be prepared from suitable inorganic acids or organic acids. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically-acceptable salts of compounds of formula (I) may be prepared from inorganic acid or from organic aci d. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbon c, sulfuric and phosphoric acid.
  • organic acids include aliphatic, cycloaliphati ;c, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
  • organic acids include aliphatic, cycloaliphati ;c, aromatic, araliphatic, heterocyclic, carb
  • salts of the compounds of the invention can be prepared by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of the compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the present invention provides a prodrug of a compound of formula (I).
  • the prodrug is prepared with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • improved chemical stability improved patient acceptance and compliance
  • improved bioavailability prolonged duration of action
  • improved organ selectivity e.g., increased hydrosolubility
  • side effects e.g., toxicity
  • Prodrugs of the invention can be readily prepared from the compounds of formula (I) using methods known in the art.
  • prodrugs of the compounds of formula (I) can be prepared by modifying amine group on the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • forms of the prodrugs prepared in such a way include biohydrolyzable amides, biohydrolyzable carbamates, and thiocarbamates.
  • the invention provides isotopically-labeled compounds, which are identical to the compounds of formula (1), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine, such as 3 H, 11 C, and 14 C.
  • Compounds of formula (I) that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 1 C, isotopes are particularly useful in PET (positron emission tomography). Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, maybe preferred in some circumstances. Isotopically labeled compounds of formula (I) of this invention can generally be prepared by carrying out the synthetic procedures by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of formula (I) are antagonists at the CRFi receptor, capable of inhibiting the specific binding of CRF to CRFi receptor and antagonizing activities associated with CRF.
  • the effectiveness of a compound as a CRF receptor antagonist may be determined by various assay methods.
  • a compound of formula (I) may be assessed for activity as a CRF receptor antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the assays disclosed by DeSouza et al. ⁇ J. Neuroscience 7:88, 1987) and Battaglia et al. ⁇ Synapse 1:572, 1987).
  • CRF receptor affinity may be determined by binding studies that measure the ability of a compound to inhibit the binding of a radiolabeled CRF (e.g., [ 125 l]tyrosine-CFR) to its receptor (e.g., receptors prepared from rat cerebral cortex membranes).
  • a radiolabeled CRF e.g., [ 125 l]tyrosine-CFR
  • receptor e.g., receptors prepared from rat cerebral cortex membranes.
  • the radioligand binding assay described by DeSouza et al. ⁇ supra 1987 provides an assay for determining a compound's affinity for the CRF receptor.
  • Such activity is typically calculated from the IC 50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the receptor, and is reported as a "Ki " value calculated by the following equation: 1 ⁇ 50
  • a compound's CRF receptor antagonist activity may be established by the ability of the compound to antagonize an activity associated with CRF.
  • CRF is known to stimulate various biochemical processes, including adenylate cyclase activity. Therefore, compounds may be evaluated as CRF receptor antagonists by their ability to antagonize CRF-stimuIated adenylate cyclase activity by, for example, measuring cAMP levels.
  • the CRF-stimulated adenylate cyclase activity assay described by Battaglia et al. ⁇ supra 1987) provides an assay for determining a compound's ability to antagonize CRF receptor activity.
  • CRF receptor antagonist activity may be determined by assay techniques which generally include an initial binding assay (such as disclosed by DeSouza ⁇ supra 1987)) followed by a cAMP screening protocol (such as disclosed by Battaglia ⁇ supra 1987)).
  • an initial binding assay such as disclosed by DeSouza ⁇ supra 1987
  • a cAMP screening protocol such as disclosed by Battaglia ⁇ supra 1987
  • An example of the CRF-stimulated adenylate cyclase activity assay is provided in Example C below.
  • the present invention provides a method of antagonizing CRFi receptors in a warm-blooded animal, comprising administering to the animal a compound of the invention at amount effective to antagonize CRFi receptors.
  • the warmblooded animal is preferably a mammal, and more preferably a human.
  • the present invention provides a method for screening for ligands for CRFi receptors, which method comprises: a) carrying out a competitive binding assay with CRF ! receptors, a compound of formula (I) which is labeled with a detectable label, and a candidate ligand; and b) determining the ability of said candidate ligand to displace said labeled compound.
  • the present invention provides a method for detecting CRF receptors in tissue comprising: a) contacting a compound of formula (I), which is labeled with a detectable label, with a tissue, under conditions that permit binding of the compound to the tissue; and b) detecting the labeled compound bound to the tissue.
  • Assay procedure for detecting receptors in tissues is well known in the art.
  • the present invention provides a method of inhibiting the binding of
  • CRF to CRFi receptors comprising contacting a compound of the invention with a solution comprising cells expressing the CRFi receptor, wherein the compound is present in the solution at a concentration sufficient to inhibit the binding of CRF to the CRF-i receptor.
  • a cell line that expresses the CRFi receptor and can be used in the in vitro assay is IMR32 cells known in the art.
  • Compounds of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof, are useful for the treatment of a disorder in a warm-blooded animal, which disorder manifests hypersecretion of CRF, or the treatment of which disorder can be effected or facilitated by antagonizing CRFi receptors. Examples of such disorders are described herein above.
  • the present invention provides a method of treating a disorder described herein above, comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of the invention.
  • the warm-blooded animal is preferably a mammal, particularly a human.
  • anxiety-related disorders such as anxiety states, generalized anxiety disorder, phobic disorders, social anxiety disorder, anxiety with co-morbid depressive illness, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and atypical anxiety disorders
  • mood disorders such as dysthemia, bipolar disorders, cyclothymia, and depression including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression
  • chemical dependencies and addictions such as dependences on alcohol, cocaine, heroin, benzodiazepines, or other drugs
  • inflammatory disorders such as rheumatoid arthritis and osteoarthritis
  • gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress
  • skin disorders such as acne, psoriasis, chronic contact dermatitis, and stress- exacerbated skin disorders.
  • disorders that can be treated by the method of the invention more preferably include anxiety-related disorders such as anxiety states, generalized anxiety disorder, phobic disorders, social anxiety disorder, anxiety with co-morbid depressive illness, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and atypical anxiety disorders and mood disorders such as dysthemia, bipolar disorders, cyclothymia, and depression including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression.
  • anxiety-related disorders such as anxiety states, generalized anxiety disorder, phobic disorders, social anxiety disorder, anxiety with co-morbid depressive illness, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and atypical anxiety disorders and mood disorders such as dysthemia, bipolar disorders, cyclothymia, and depression including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression.
  • the therapeutically effective amounts of the compounds of the invention for treating the diseases or disorders described above in a warm-blooded animal can be determined in a variety of ways known to those of ordinary skill in the art, e.g., by administering various amounts of a particular agent to an animal afflicted with a particular condition and then determining the effect on the animal.
  • therapeutically effective amounts of a compound of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.
  • a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.
  • the specific dose levels for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most CNS disorders, a dosage regimen of four-times daily or less is preferred. For the treatment of stress and depression, a dosage regimen of one or two-times daily is particularly preferred.
  • a compound of this invention can be administered to treat the above disorders by means that produce contact of the active agent with the agent's site of action in the body of a mammal, such as by oral, topical, dermal, parenteral, or rectal administration, or by inhalation or spray using appropriate dosage forms.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound can be administered alone, but will generally be administered with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutically acceptable salt of the prodrug thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient therefore.
  • a "pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of biologically active agents to warm-blooded animals, including humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for.
  • compositions include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.
  • suitable pharmaceutically acceptable carriers, and factors involved in their selection are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, the contents of which are incorporated herein by reference.
  • compositions intended for oral use may be in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, and can be prepared according to methods known to the art.
  • Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and a delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexital such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl p-hydroxybenzoate, one or more coloring agents, one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n- propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • Additional excipients for example sweetening, flavoring and coloring agents, may also be present.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • Suppositories for rectal administration of a compound of the invenition can be prepared by mixing the compound with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Examples of such materials are cocoa butter and polyethylene giycols.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable solution or suspension may be formulated in a non- toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanedioI.
  • the acceptable vehicles and solvents that may be employed are water, Ringers's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Dosage forms suitable for administration generally contain from about 1 mg to about 100 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
  • Examples of dosage forms for administration of the compounds of this invention includes the following: (1) Capsules. A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate; (2) Soft Gelatin Capsules.
  • a mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules were washed and dried; (3) Tablets.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose.
  • Appropriate coatings may be applied to increase palatability or delayed adsorption.
  • the present invention provides an article of manufacture comprising: a) a packaging material; b) a pharmaceutical agent comprising a compound of the invention contained within said packaging material; and c) a label or package insert which indicates that said pharmaceutical agent can be used for treating a disorder described below.
  • a packaging material comprising: a) a packaging material; b) a pharmaceutical agent comprising a compound of the invention contained within said packaging material; and c) a label or package insert which indicates that said pharmaceutical agent can be used for treating a disorder described below.
  • a compound according to formula I which is (+)-7-(2,4-dichlorophenyl)- 2,6-dimethyl-N-[(1S)-1-methylpropyl]pyrrolo[1,2-b]pyridazin-4-amine.
  • a compound according to formula I which is (-)-7-(2,4-dichlorophenyl)-2,6-dimethyl-N-[(1R)-1- methylpropyl]pyrrolo[1 ,2-b]pyridazin-4-amine.
  • a pharmaceutical composition comprising a compound of any of the compounds of formula I.
  • a pharmaceutical composition according to formula I further comprising a pharmaceutically acceptable carrier.
  • a method of antagonizing a CRF receptor in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula I.
  • a method of treating a disorder manifesting hypersecretion of CRF in a warm-blooded animal comprising administering to the animal a therapeutically effective amount of a compound formula I.
  • a method for the treatment of a disorder in a mammal, the treatment of which disorder can be effected or facilitated by antagonizing CRF comprising administering to the mammal a therapeutically effective amount of a compound of formula I.
  • a method for screening for ligands for CRF receptors comprises: a) carrying out a competitive binding assay with a CRF receptor, a compound of formula I, which is labeled with a detectable label, and a candidate ligand; and b) determining the ability of said candidate ligand to displace said labeled compound.
  • a method for detecting CRF receptors in tissue comprising: a) contacting a compound of formula I, which is labeled with a detectable label, with a tissue, under conditions that permit binding of the compound to the tissue; and b) detecting the labeled compound bound to the tissue.
  • a method of inhibiting the binding of CRF to a CRFi receptor comprising contacting a compound of formula I, with cells expressing the CRFi receptor, wherein the compound is present in the solution at a concentration sufficient to inhibit the binding of CRF to the CRFi receptor.
  • the method above, wherein the cells are IMR32 cells.
  • a method of treating a disorder in a mammal comprising administering to the mammal in need thereof an effective amount of a compound according to formula I, wherein the disorder is selected from anxiety-related disorders; mood disorders; supranuciear palsy; immune suppression; rheumatoid arthritis; osteoarthritis; infertility; pain; asthma; allergies; sleep disorders induced by stress; fibromyalgia; fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus infections; Alzheimer's disease; Parkinson's disease; Huntington's disease; gastrointestinal ulcers; irritable bowel syndrome; Crohn's disease; spastic colon; diarrhea; post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; anorexia; bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone ; obesity; head traumas; spinal cord trauma; cerebral hippocampal ischemia
  • a method of treatment where the disorder is selected from anxiety-related disorder and mood disorder.
  • Treatment where the anxiety-related disorder is generalized anxiety disorder and the mood disorder is major depression.
  • a method of promoting hair growth in a human comprising administering to the human in need thereof an effective amount of a compound according to the compounds of formula I.
  • An article of manufacture comprising: a) a packaging material; b) a pharmaceutical agent comprising a compound of formula I, and c) a label or package insert contained within said packaging material indicating an intended use of the pharmaceutical agent or compound.
  • a method of promoting smoking cessation in a human comprising administering to the human in need thereof an effective amount of a compound of formula I.
  • pharmaceutically acceptable refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of or animals including humans without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers".
  • racemate or “racemic mixture” refers to a mixture of equal parts of enantiomers.
  • prodrug means a compound, other than a compound of formula (I), which is transformed in vivo to yield a compound of formula (I). The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • terapéuticaally effective amount is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disease or condition.
  • a compound of the invention is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disease or condition.
  • treatment refers to compounds of formula (I), or stereoisomers thereof, pharmaceutically acceptable salts thereof, or prodrugs thereof, or pharmaceutically acceptable salts of a prodrug of compounds of formula (I).
  • treatment are meant to include both slowing or reversing the progression of a disorder, as well as curing the disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if progression of the disorder or condition is not itself slowed or reversed.
  • treatment and like terms also include preventive (e.g., prophylactic) and palliative treatment. Prevention of the disease is manifested by a prolonging or delaying of the onset of the symptoms of the disease.
  • Step 1 Preparation of 4-(2.4-dichlorophenyl)-3-methyl-4-oxobutanal To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added a solution of 2,4-dichlorobromobenzene (65.5 g, 290.7 mmol) in 1.1 L of THF under nitrogen. The solution is cooled to -95 °C with a MeOH/liquid nitrogen bath.
  • Step 4 Preparation of 7-(2.4-dichlorophenyl)-2,6-dimethylpyrrolo[1.2-blpyridazin-4-ol
  • 2-(2,4-dichlorophenyl)-3-methyl-1H-pyrrol-1-amine (2.34 g, 9.69 mmol)
  • ethyl trans-3-ethoxycrotonate (1.58 g, 10.0 mmol)
  • p-toluenesulfonic acid 0.095 g, 0.50 mmol
  • CHCI 3 100 mL
  • Step 5 Preparation of 4-bromo-7-(2,4-dichlorophenyl)-2.6-dimethylpyrrolo[1 ,2- blpyridazine
  • a solution of 7-(2,4-dichlorophenyl)-2,6-dimethyIpyrrolo[1 ,2-b]pyridazin-4-ol (34.2 g,
  • Step 6 Preparation of 7-(2.4-dichlorophenyl)- ⁇ /-(1-ethylpropyl)-2,6- dimethylpyrrolori ,2-b]pyridazin-4-amine
  • the binding assay utilizes brain membranes, commonly from rats.
  • rat frontal cortex is homogenized in 10 mL of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCI 2 , 2 mM EGTA, 1 ⁇ glml aprotinin, 1 ⁇ glm leupeptin and 1 g/mL pepstatin).
  • the homogenate is centrifuged at 48,000 x g for 10 min. and the resulting pellet rehomogenized in 10 mL of tissue buffer.
  • Binding assays are performed in 96 well plates at a final volume of 300 juL. The assays are initiated by the addition of 150 juL membrane suspension to 150 JLL of assay buffer containing 125 l-ovine-CRF (final concentration 150 pM) and various concentrations of inhibitors.
  • the assay buffer is the same as described above for membrane preparation with the addition of 0.1 % ovalbumin and 0.15 mM bacitracin.
  • Radioligand binding is terminated after 2 hours at room temperature by filtration through Packard GF/C unifilter plates (presoaked with 0.3% polyethyleneimine) using a Packard cell harvester. Filters are washed three limes with ice cold phosphate buffered saline pH 7.0 containing 0.01% Triton X-100. Filters are assessed for radioactivity in a Packard TopCount.
  • tissues and cells that naturally express CRF receptors such as IMR-32 human neuroblastoma cells (ATCC; Hogg et al., 1996), can be employed in binding assays analogous to those described above.
  • a compound is considered to be active if it has a Ki value of less than about 10 ⁇ M for the inhibition of CRF.
  • Compounds of Formula (I) have a Ki value of less than 5 nanomolar.
  • Ex vivo CRFi Receptor Binding Assay for the Evaluation of Biological Activity
  • rats Two hours after drug administration, rats were sacrificed by decapitation, frontal cortices were quickly dissected and placed on dry ice, then frozen at -80 °C until assayed; trunk blood was collected in heparinized tubes, plasma separated by centrifugation (2500 RPM's for 20 minutes), and frozen at -20 °C.
  • CRF-stimulated adenylate cyclase activity can be performed as previously described [G. Battaglia el al., Synapse 1 :572 (1987)]. Briefly, assays are carried out at 37 °C for 10 min in 200 mL of buffer containing 100 mM Tris-HCI (pH 7.4 at 37 °C), 10 mM MgCi 2 , 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/mL phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM o-CRF, antagonist peptides (various concentrations) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein).
  • Reactions are initiated by the addition of 1 mM ATP/[ 32 P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 mL of 50 mM Tris-HCI, 45 mM ATP and 2% sodium dodecyl sulfate.
  • 1 mL of [ 3 H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation.
  • the separation of [ 32 P]cAMP from [ 3 P]ATP is performed by sequential elution over Dowex and alumina columns.
  • adenylate cyclase activity can be assessed in a 96-well format utilizing the Adenylyl Cyclase Activation FlashPlate Assay from NEN Life Sciences according to the protocols provided. Briefly, a fixed amount of radiolabeled cAMP is added to 96-well plates that are precoated with anti-cyclic AMP antibody. Cells or tissues are added and stimulated in the presence or absence of inhibitors. Unlabeled cAMP produced by the cells will displace the radiolabeled cAMP from the antibody. The bound radiolabeled cAMP produces a light signal that can be detected using a microplate scintillation counter such as the Packard TopCount.
  • a microplate scintillation counter such as the Packard TopCount.
  • EXAMPLE D in vivo Biological Assay
  • the in vivo activity of a compound of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C.W. Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990). A compound may be tested in any species of rodent or small mammal.

Abstract

L'invention concerne de nouveaux inhibiteurs des récepteurs de la corticolibérine et leur utilisation pour traiter une grande variété de troubles, notamment des troubles se manifestant par une hypersécrétion de la corticolibérine ou bien associés à la corticolibérine ou à des récepteurs de la corticolibérine, comme par exemple l'anxiété et la dépression. Ces inhibiteurs des récepteurs de la corticolibérine présentent la structure répondant à la formule (I) dans laquelle R1 et R2 sont choisis indépendamment parmi H, Me ou OMe. L'invention concerne également leurs stéréoisomères ou un mélange de ceux-ci, leurs promédicaments pharmaceutiquement acceptables, ou bien leurs sels pharmaceutiquement acceptables.
PCT/IB2004/001250 2003-04-15 2004-04-05 Composes de pyrrolo[1,2-b]pyridazine et leurs utilisations WO2004092176A1 (fr)

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CA002520805A CA2520805A1 (fr) 2003-04-15 2004-04-05 Composes de pyrrolo[1,2-b]pyridazine et leurs utilisations
EP04725761A EP1615929A1 (fr) 2003-04-15 2004-04-05 Composes de pyrrolo [1,2-b]pyridazine et leurs utilisations
MXPA05010833A MXPA05010833A (es) 2003-04-15 2004-04-05 Compuestos de pirrolo[1,2-b]piridazina y sus usos.
BRPI0409444-1A BRPI0409444A (pt) 2003-04-15 2004-04-05 compostos de pirrolo[1,2-b]piridazina e suas utilizações

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WO2004099213A2 (fr) * 2003-05-07 2004-11-18 Pharmacia & Upjohn Company Llc Composes pyrrolo[1,2-b]pyridaziniques

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EP1085021A1 (fr) * 1998-05-21 2001-03-21 Shionogi & Co., Ltd. DERIVES DE LA PYRROLO 1,2-B] PYRIDAZINE, A EFFET INHIBITEUR SUR LE sPLA 2?
US20010007867A1 (en) * 1999-12-13 2001-07-12 Yuhpyng L. Chen Substituted 6,5-hetero-bicyclic derivatives
WO2002072202A1 (fr) * 2001-03-13 2002-09-19 Bristol-Myers Squibb Pharma Company 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) pyrazolo-[1,5-a]-1,3,5-triazine, ses enantiomeres et sels pharmaceutiquement acceptables en tant que ligands du recepteur de la corticoliberine
WO2002072101A1 (fr) * 2001-03-13 2002-09-19 Bristol-Myers Squibb Pharma Company Ligand du recepteur de la corticoliberine, son enantiomere et ses sels pharmaceutiquement acceptables

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WO1998008847A1 (fr) * 1996-08-28 1998-03-05 Pfizer Inc. Derives 6,5-hetero-bicycliques substitues
US20020151713A1 (en) * 1996-08-28 2002-10-17 Pfizer Inc. Substituted 6,5-hetero-bicyclic derivatives
EP1085021A1 (fr) * 1998-05-21 2001-03-21 Shionogi & Co., Ltd. DERIVES DE LA PYRROLO 1,2-B] PYRIDAZINE, A EFFET INHIBITEUR SUR LE sPLA 2?
US20010007867A1 (en) * 1999-12-13 2001-07-12 Yuhpyng L. Chen Substituted 6,5-hetero-bicyclic derivatives
WO2002072202A1 (fr) * 2001-03-13 2002-09-19 Bristol-Myers Squibb Pharma Company 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) pyrazolo-[1,5-a]-1,3,5-triazine, ses enantiomeres et sels pharmaceutiquement acceptables en tant que ligands du recepteur de la corticoliberine
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WO2004099213A2 (fr) * 2003-05-07 2004-11-18 Pharmacia & Upjohn Company Llc Composes pyrrolo[1,2-b]pyridaziniques
WO2004099213A3 (fr) * 2003-05-07 2005-04-28 Pharmacia & Upjohn Co Llc Composes pyrrolo[1,2-b]pyridaziniques

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CA2520805A1 (fr) 2004-10-28

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