WO2006083711A1

WO2006083711A1 - Tachykinin receptor antagonists

Info

Publication number: WO2006083711A1
Application number: PCT/US2006/002929
Authority: WO
Inventors: Palaniappan Kulanthaivel
Original assignee: Eli Lilly And Company
Priority date: 2005-02-01
Filing date: 2006-01-27
Publication date: 2006-08-10

Abstract

The present invention provides novel compounds of Formula (I) compositions thereof, and methods for using the compounds in the treatment of disorders associated with an excess of tachykinins.

Description

TACHYKININ RECEPTOR ANTAGONISTS

The present invention provides compounds of Formula (T), compositions thereof, and a method of antagonizing the NK-I subtype of tachykinin receptor that comprises administering to a patient in need thereof an effective amount of a compound of Formula (T). In addition, the present invention relates to processes for preparing the compounds of Formula (T).

BACKGROUND OF THE INVENTION

Tachykinins are a family of peptides that are widely distributed in both the central and peripheral nervous systems. These peptides exert a number of biological effects through actions at tachykinin receptors. To date, three such receptors have been characterized, including the NK-I, NK-2, and NK-3 subtypes of tachykinin receptor.

The role of the NK-I receptor subtype in numerous disorders of the central nervous system and the periphery has been thoroughly demonstrated in the art. For instance, NK-I receptors are believed to play a role in depression, anxiety, and central regulation of various autonomic, as well as cardiovascular and respiratory functions. NK- 1 receptors in the spinal cord are believed to play a role in pain transmission, especially the pain associated with migraine and arthritis. In the periphery, NK-I receptor activation has been implicated in numerous disorders, including various inflammatory disorders, asthma, and disorders of the gastrointestinal and genitourinary tract. There is an increasingly wide recognition that selective NK-I receptor antagonists would prove useful in the treatment of many diseases of the central nervous system and the periphery. While many of these disorders are being treated by new medicines, there are still many shortcomings associated with existing treatments. For example, benzodiazepines, often prescribed for the treatment of anxiety, are associated with drug dependence, irritability, drowiness, decreased mental sharpness, and nausea. Tricyclic antidepressants, which are often used for the treatment of depression and anxiety, may cause blurred vision, tachycardia, and cognitive impairment, among other side effects. Newer classes of anti-depressants, such as selective serotonin reuptake inhibitors (SSRIs), are increasingly prescribed for the treatment of depression; however, SSRIs have numerous side effects, including nausea, insomnia, anxiety, and sexual dysfunction. These side effects could significantly affect patient compliance rate. The development of NK-I receptor antagonists will therefore greatly enhance the ability to treat such disorders more effectively. Thus, the present invention provides novel, potent, non-peptide NK-I receptor antagonists, compositions comprising these compounds, and methods of using the compounds.

In vivo, many amine-containing drugs are oxidized to their N-oxides as a part of metabolism and excretion. It is well known that the physical and chemical properties of the N-oxide will differ from its parent amine. However, the biological and pharmacological effect of N-oxide formation is highly unpredictable. Often, the N-oxides are pharmacologically less active or inactive, compared to the parent compound. For example, N-oxidation of the Vinca alkaloids leads to biological inactivity {see, Barnett et al, J. Med. Chem. (1978) 21(1): 78-96). The present invention provides N-oxides that are surprisingly useful as compared to previously characterized NK-I receptor antagonists.

BRIEF SUMMARY OF THE INVENTION

The invention provides compounds of Formula (I):

⁽D wherein X is -CH(OH)- or -C(O)-, or a pharmaceutically acceptable salt thereof.

The compounds of Formula (I) are antagonists of tachykinin receptors. Specifically, the compounds of Formula (I) are antagonists of the NK-I subtype of tachykinin receptor. Because these compounds inhibit the physiological effects associated with an excess of tachykinins, the compounds are useful in the treatment of numerous disorders related to tachykinin receptor activation. These disorders include: anxiety, . depression, psychosis, and schizophrenia and other psychotic disorders; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome; seizure disorders, such as epilepsy; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders, such as peripheral neuropathy, diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculoskeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; atherosclerosis; fibrosin and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders associated with blood pressure, such as hypertension; or disorders of blood flow caused by vasodilation and vasospastic diseases, such as angina, migraine, and Reynaud's disease; emesis, including chemotherapy-induced nausea and emesis; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions.

In one embodiment, this invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

In another embodiment, the present invention provides a method of selectively antagonizing an NK-I receptor by contacting the receptor with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, this invention provides methods of treating a condition associated with an excess of tachykinins, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. That is, the present invention provides for the use of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a disorder associated with an excess of tachykinins.

In another aspect, the present invention provides for the use of a compound of Formula (T), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for antagonizing the NK-I receptor. Thus, the present invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with an excess of tachykinins by means of the method described above.

Of the disorders listed above, depression, anxiety, schizophrenia and other psychotic disorders, emesis, pain, asthma, inflammatory bowel disease, irritable bowel syndrome, and dermatitis are of importance. Of these disorders, depression and anxiety are of particular importance.

Thus, in a preferred embodiment, the present invention provides a method for treating major depressive disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating generalized anxiety disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating panic disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating obsessive-compulsive disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another preferred embodiment, the present invention provides a method for treating social phobia, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (T), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating irritable bowel syndrome, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating inflammatory bowel disease, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a method for treating emesis (chemotherapy-induced nausea and acute or delayed emesis), comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The terms and abbreviations used in the preparations and examples have their normal meanings unless otherwise designated. For example "⁰C" refers to degrees Celsius; "mol" refers to mole or moles; "h" refers to hour(s); "g" refers to gram or grams;

"L" refers to liter or liters; "M" refers to molar or molarity; "ES" refers to electrospray; "MS" refers to mass spectrometry; "NMR" refers to nuclear magnetic resonance spectroscopy; "DMSO" refers to dimethylsulf oxide; "MeOH" refers to methanol; "EtOH" refers to ethanol.

The term "Pg" refers to an alcohol, carboxyl, or amino protecting group. Typical protecting groups include tetrahydropyranyl (THP), silanes such as trimethylsilane (TMS), tert-butyldimethylsilane (TBDMS), and tert-butyldiphenylsilane (TBDPS), methoxymethyl (MOM), benzyl (Bn), p-methoxybenzyl, formyl, acetyl (Ac), and tert- butoxycarbonyl (t-BOC). Typical carboxyl protecting groups may include methyl, ethyl, and tot-butyl. The selection and use of protecting groups is well known and appreciated in the art. See for example, Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience); Protecting Groups, Philip J. Kocienski, Thieme Medical Publishers, inc: New York 1994, chapters 2,4,6.

The compounds of the present invention may exist as stereoisomers. The Cahn- Prelog-Ingold designations of (R)- and (S)- and the designations of L- and D- for stereochemistry relative to the isomers of glyceraldehyde are used herein to refer to specific isomers. The specific stereoisomers can be prepared by stereospecific synthesis or can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described in E.L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, (Wiley-Interscience 1994), and J. Jacques, A. Collet, and S. H. Wilen, Enantiomers, Racemates, and Resolutions, Wiley-Interscience 1981). It is understood that the present invention contemplates all enantiomers and mixtures of enantiomers, including racemates.

The skilled artisan will recognize that compounds of the present invention may exist as tautomers. It is understood that tautomeric forms of the compounds of Formula

(I) are also encompassed in the present invention.

This invention includes the pharmaceutically acceptable salts of the compounds of Formula (J). A compound of this invention can possess a sufficiently basic functional group, which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically-acceptable salt" as used herein, refers to a salt of a compound of the above Formula (J). It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

The compounds of Formula (I) and the intermediates described herein form pharmaceutically-acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically-acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. A pharmaceutically- acceptable acid addition salt is formed from a pharmaceutically-acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2-19 (1977), which are known to the skilled artisan. See also, The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (ED.s), Verlag, Zurich (Switzerland) 2002.

Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2- benzoate, bromide, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4- dicarboxylate, hexyne-l,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, naphthalene- 1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. As used herein, the term "patient" refers to a mammal that is afflicted with one or more disorders associated with excess tachykinins. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of mammals within the scope of the meaning of the term. It will be understood that the most preferred patient is a human. It is also understood that this invention relates specifically to the inhibition of mammalian NK-I receptors.

It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of Formula (T). Thus, the terms "treatment" and "treating" are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, and is intended to include prophylactic treatment of such disorders, but does not necessarily indicate a total elimination of all disorder symptoms.

As used herein, the term "effective amount" of a compound of Formula (T) refers to an amount that is effective in treating the disorders described herein.

The compounds of Formula (T) are prepared by selective oxidation of the 4-pyridyl at the 5-ρosition of the triazole compounds of Formula (TT), as depicted below:

(π) wherein X is -CH(OH)- or -C(O)-. Compounds of Formula (TT) are prepared by the procedures described in PCT published application, WO03/091226. Processes for preparing a compound of Formula (TT) in which X is -C(O)- are further described in international application no. PCT/US04/030914.

Below are examples of the preparation of the compounds of Formula (T). The skilled artisan will recognize that the Examples below teach one method for preparing the compounds of the present invention. Other methods are well known in the art. For example, the compounds can be prepared through enzymatic biotransformation using microorganisms. See, e.g., R. Azerad, Advances in Biochemical Engineering/Biotechnology (1999) 63 (Biotransformations): 169-218.

EXAMPLES

Example 1

{2-[l-(3,5-Bis-trifluoromethyl-benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]- pyridin-3-yl } -(2-chloro-phenyl)-methanone

Dissolve {2-[l-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol- 4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (100 mg, 0.17 mmol) in dichloromethane (1.7 mL) and cool the resulting mixture to 0 °C. Add m- chloroperoxybenzoic acid (29.3 mg, 0.17 mmol) and allow the mixture to slowly warm to room temperature. After 18 h, load the crude reaction mixture directly onto a silica gel column and elute using a chloroform/methanol gradient (30:1 to 3:1) to provide, after concentration of the fractions, 70 mg (68%) of the title compound as a white solid. R_f = 0.45 (10:1 CHCl₃ZMeOH); MS [ES] 604.3 [(M+l)⁺]; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (m, IH), 8.23 (m, 2H), 7.96 (m, IH), 7.89 (s, IH), 7.66 (m, IH), 7.58 (s, 2H), 7.42 (m, IH), 7.25 (m, 5H), 5.54 (s, 2H).

Example 2

{ 2-[ 1 -(3 ,5-Bis-trifluoromethyl-benzyl)-5-( 1 -oxy-pyridin-4-yl)- IH-[1 ,2,3]triazol-4-yl]- pyridin-3-yl } -(2-chloro-phenyl)-methanol

Dissolve {2-[l-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol- 4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanol (100 mg, 0.17 mmol) in a mixture of dichloromethane (1.7 mL) and DMSO (0.2 mL) and cool the resulting solution to 0 °C. Add m-chloroperoxybenzoic acid (29.3 mg, 0.17 mmol) and allow the mixture to slowly warm to room temperature. After 24 h, load the crude reaction mixture directly onto a silica gel column and elute using a chloroform/methanol gradient (30:1 to 1:1) to provide, after concentration of the fractions, 60 mg (58%) of the title compound as a white solid. R_f = 0.38 (10:1 CHCl₃MeOH); MS [ES] 605.9 [(M+l)⁺], 587.8 [(M-OH)⁺].

The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition, that is, combined with pharmaceutically acceptable carriers, or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice. The compounds of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts, for purposes of stability, convenience of crystallization, increased solubility, and the like.

Thus, the present invention provides pharmaceutical compositions comprising a compound of Formula (T), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

The compounds of Formula (I) can be administered by a variety of routes. In effecting treatment of a patient afflicted with disorders described herein, a compound of Formula (I) can be administered in any form or mode that makes the compound bioavailable in an effective amount, including oral and parenteral routes. For example, compounds of Formula (I) can be administered orally, by inhalation, or by the subcutaneous, intramuscular, intravenous, transdermal, intranasal, rectal, occular, topical, sublingual, buccal, or other routes. Oral administration is generally preferred for treatment of the neurological and psychiatric disorders described herein.

One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).

The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like. The compounds of the present invention may be administered orally, for example, with an inert diluent or capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention may be determined by a person skilled in the art. The tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as povidone, hydroxypropyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as dicalcium phosphate, starch, or lactose; disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as talc, magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents, such as sucrose, aspartame, or saccharin, or a flavoring agent, such as peppermint, methyl salicylate or orange flavoring, may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials that modify the physical form of the dosage unit, for example, coatings. Thus, tablets or pills may be coated with sugar, shellac, or other coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the compounds of the present invention may be incorporated into a solution or suspension. These preparations typically contain at least 0.001% of a compound of the invention, but may be varied to be between 0.001 and about 90% of the weight thereof. The amount of the compound of Formula (T) present in such compositions is such that a suitable dosage will be obtained. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylene diaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administered topically, and when done so, the carrier may suitably comprise a solution, ointment, or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bees wax, mineral oil, diluents such as water and alcohol, and emulsifiers, and stabilizers. Topical formulations may contain a concentration of a compound of Formula (I) or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).

The compounds of Formula (I) are antagonists of NK-I receptors. Furthermore, the compounds of Formula (I) selectively antagonize NK-I receptors relative to other tachykinin receptors. The antagonist activity of NK-I receptor antagonists may be determined by the methods below.

NK-I Receptor Binding Assay The EvI-9 cell line is a well-characterized and readily available human cell line.

See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London). 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71:84-88 (1974). These cells are routinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamicin sulfate and 10% fetal calf serum.

The IM-9 cells are homogenized from cell pellets for crude membranes. The membranes are isolated by homogenizing tissue samples in 30 ml w/v with 50 mM Tris buffer (pH 7.4). After an initial spin at 900 x g, the supernatant is transferred to a clean centrifuge tube and the membranes isolated by centrifugation at 38,000 x g.

Approximately 25 μg of membranes are incubated with 0.2nM [¹²⁵IJ-substance P (NEN, Boston, MA) in a receptor binding assay. The assay buffer contains 50 mM Tris, 3 mM MnCl₂, 0.02% bovine serum albumin, 40 μg/ml bacitracin, 2 μg/ml chymostatin, 4 μg/ml leupeptin and 40 μg/ml thiorphan (pH 7.4). Binding studies are conducted in a final volume of 200 μl containing various concentrations of test compounds. Nonspecific binding is determined by incubating some tubes in the presence of 1 μM substance P (Peninsula, Belmont, CA).

Binding is terminated 1 hour later by rapid filtration using a TOMTEC 96-well cell harvester (TOMTEC, Orange, CT) through GF/A filters that have been presoaked with 0.3% polyethyleneimine (Sigma, St Louis) for 1 hour. The filters are washed with 5 ml of ice-cold 50 mM Tris buffer (pH 7.4) and placed in a drying oven at 6O⁰C. The dried filters are treated with MeltiLex A melt-on scintillator sheets (Wallac, Gaithersburg, MD), and the radioactivity retained on the filters counted using the Wallac 1205 Betaplate scintillation counter. The results are analyzed using a Log-Logit plot from a Microsoft Excel™ workbook and converted to Ki values with the Cheng-Prusoff equation. Protein concentrations are measured using Coomassie® protein assay reagent (Pierce, Rockford, IL), with BSA for standards (Bradford, 1976).

Binding studies are carried out to evaluate the ability of compounds of the present invention to inhibit NK-I receptor activation. Such studies provide in vitro data regarding the efficacy of the compounds of the present invention.

When tested in binding assays, such as that described above, the compounds of Formula (I) demonstrate binding affinities (Ki values) of < 100 nM.

Several preclinical laboratory animal models have been described for a number of the disorders associated with an excess of tachykinins. One such in vivo assay, described below, can be used to determine whether NK-I receptor antagonists are CNS-penetrant. Gerbil Foot-Tapping

The gerbil foot-tapping assay is well recognized in the art. For example, see Rupniak et al, EMr. J. Phaπnacol. (1997) 326: 201-209.

Male Gerbils (Mongolian), weighing between 20-40 gm (Harlan Labs, Indianapolis, Indiana) are used for the experiments. Animals are allowed to acclimate prior to any testing.

An NK-I receptor agonist, such as GR73632 (δ-Aminovaleryl [Pro⁹, N-Me- Leu^lo]-Substance P(7-ll)) (Peninsula Labs), is dissolved in acidified saline (ImI acetic acid in 1 liter of 0.09% saline) to make a 1 mg/ml solution (corrected for peptide content). The stock solution is further diluted to 10 μg/ml in saline (0.9% normal saline), aliquoted and kept frozen until use. The stock solution is further diluted to 3 pmol/5 μl in saline for i.c.v. injections.

Test compounds are formulated in appropriate vehicle to a concentration of 1 ml/100 gm body weight. Compounds are dosed by oral gavage (p.o.) or subcutaneously (s.c.) or intraperitoneally (i.p.) at pre-determined times prior to intracerebroventricular

(i.c.v.) challenge of agonist. For i.c.v. administration, test compound is co-injected with agonist.

Free hand i.c.v. injection is performed by direct vertical insertion of a cuffed 27- gauge needle with a Hamilton 50 μl syringe, to a depth of 4.5 mm below bregma. Light anesthesia with isoflurane may be needed prior to the injection, but is not used routinely.

Following i.c.v. injection of agonist, animals are placed in a plexiglas observation box, and hind foot tapping events are counted for 5 minutes. Data collection is computerized.

Data are analyzed by ANOVA followed by Dunnett's test using JMP statistical program (IBM platform). Data are expressed as number of events/5 minutes.

The results of NK-I receptor binding studies demonstrate the ability of compounds of the present invention to act as antagonists of NK-I receptors. Thus, the compounds of the present invention are expected to be useful in the treatment of various disorders associated with excess tachykinins, as described to be treated herein, and other disorders that can be treated by such antagonists, as are appreciated by those skilled in the art. In one embodiment, the present invention provides methods of treating disorders selected from the group consisting of anxiety, depression, psychosis, schizophrenia and other psychotic disorders, neurodegenerative disorders (including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome), seizure disorders (including generalized and partial seizures), demyelinating diseases (including multiple sclerosis and amyotrophic lateral sclerosis), neuropathological disorders (including peripheral neuropathy, diabetic and chemotherapy- induced neuropathy, and post-herpetic and other neuralgias), acute and chronic obstructive airway diseases (including adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma), inflammatory diseases (including inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis), disorders of the musculo-skeletal system (such as osteoporosis), allergies (including eczema and rhinitis), hypersensitivity disorders (such as poison ivy), ophthalmic diseases (such as conjunctivitis, vernal conjunctivitis, and the like), cutaneous diseases (including contact dermatitis), atopic dermatitis, urticaria, other eczematoid dermatites, addiction disorders (including alcoholism), stress-related somatic disorders, reflex sympathetic dystrophy (such as shoulder/hand syndrome), dysthymic disorders, adverse immunological reactions (such as rejection of transplanted tissues), disorders related to immune enhancement or suppression (such as systemic lupus erythematosis), gastrointestinal disorders, diseases associated with the neuronal control of viscera (such as ulcerative colitis, Crohn's disease and irritable bowel syndrome); disorders of bladder function (such as bladder detrusor hyper-reflexia and incontinence), atherosclerosis, fibrosis and collagen diseases (such as scleroderma and eosinophilic fascioliasis), irritative symptoms of benign prostatic hypertrophy, disorders associated with blood pressure (such as hypertension), disorders of blood flow caused by vasodilation or vasospastic diseases (such as angina, migraine, and Reynaud's disease), emesis (including chemotherapy-induced nausea and acute or delayed emesis), and pain or nociception (including that attributable to or associated with any of the foregoing conditions), comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. That is, the present invention provides methods of treating disorders associated with an excess of tachykinins, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention contemplates the various disorders described to be treated herein and others that can be treated by such antagonists, as appreciated by those skilled in the art.

The disorders associated with an excess of tachykinins are treated by administering an effective amount of a compound or pharmaceutical composition comprising a compound of Formula (I). An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining an effective amount, the dose of a compound of Formula (I), a number of factors are considered by the attending diagnostician, including, but not limited to: the compound of Formula (T) to be administered; the species of mammal - its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.

An effective amount of a compound of Formula (I) is expected to vary from about 0.001 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts may be readily determined by one skilled in the art.

Of the disorders associated with an excess of tachykinins that are treated according to the present invention, the treatment of depression, anxiety, inflammatory bowel disease, irritable bowel syndrome, and emesis (chemotherapy-induced nausea and acute or delayed emesis) are particularly preferred. Thus, in a preferred embodiment, the present invention provides a method for treating a depressive disorder, including major depressive disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof.

In another preferred embodiment, the present invention provides a method for treating anxiety, including generalized anxiety disorder, panic disorder, social anxiety disorder, and obsessive-compulsive disorder, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (T) or a pharmaceutical composition thereof.

Disorders of the central nervous system, including depressive and anxiety disorders, have been characterized in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, D.C.). The DSM-IV™ provides clear descriptions of diagnostic categories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for these disorders, and that these systems may evolve with medical scientific progress. For instance, the ICHPPC-2 (International Classification of Health Problems in Primary Care) (3^rd edition, 1983, Oxford University Press, Oxford) provides an alternative classification system. Thus, the terms "depression," "depressive disorders," "anxiety," and "anxiety disorders" are intended to include like disorders that are described in other diagnostic sources.

According to the fourth edition of the DSM-IV™, major depressive disorders are characterized by one or more major depressive episodes, which consist of a period of at least two weeks of depressed mood or loss of pleasure, in addition to other symptoms. Thus, the skilled artisan will recognize that the present invention is useful for the treatment of either a single episode or recurrent episodes of major depressive disorder. The skilled artisan will appreciate that other depressive disorders may also be treated by administering an effective amount of a compound of Formula (I). Such other depressive disorders include dysthymic disorder, and depressive disorders not otherwise specified (for example, premenstrual dysphoric disorder, minor depressive disorder, recurrent brief depressive disorder, or postpsychotic depressive disorder of schizophrenia). In addition, the treatment of depression by the compounds of Formula (I) may also include the treatment of mood disorders due to a general medical condition and substance-induced mood disorders.

The DSM-IV™ also provides a diagnostic tool for anxiety and related disorders. These disorders include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia or social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein, the term "anxiety" includes treatment of those anxiety disorders and related disorders described in the DSM-IV.

Claims

WHAT IS CLAIMED IS:

1. A method for the treatment of a condition associated with an excess of tachykinins, comprising: administering to a patient in need thereof an effective amount of a compound of Formula (T)

(I) wherein

X is -CH(OH)- or -C(O)-, or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1 wherein the compound of Formula (T) is {2-[l-

(3 ,5-Bis-trifluoromethyl-benzyl)-5-( 1 -oxy-pyridin-4-yl)- IH- [ 1 ,2,3]triazol-4-yl]-pyridin-3- yl } -(2-chloro-phenyl)-methanone.

3. The method of Claim 1 wherein the compound of Formula (T) is {2-[l- (3,5-Bis-trifluoromethyl-benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]-pyridin-3- yl } -(2-chloro-phenyl)-methanol.

4. The method of any one of Claims 1-3 wherein the condition associated with an excess of tachykinins is selected from the group consisting of major depressive disorder, generalized anxiety disorder, social anxiety disorder, irritable bowel syndrome, and emesis.

5. The method of Claim 4 wherein the condition associated with an excess of tachykinins is major depressive disorder.

6. The method of Claim 4 wherein the condition associated with an excess of tachykinins is generalized anxiety disorder.

7. Use of a compound of Formula (I)

(T) wherein

X is -CH(OH)- or -C(O)-, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition associated with an excess of tachykinins.

8. The use according to Claim 7 wherein the compound of Formula (I) is {2-

[l-(3,5-Bis-trifluoromethyl-benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]- pyridin-3-yl } -(2-chloro-phenyl)-methanone.

9. The use according to Claim 7 wherein the compound of Formula (I) is {2- [l-(3,5-Bis-trifluoromethyl-benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]- pyridin-3-yl } -(2-chloro-phenyl)-methanol.

10. The use according to any one of Claims 7-9 wherein the condition associated with an excess of tachykinins is selected from the group consisting of major depressive disorder, generalized anxiety disorder, social anxiety disorder, irritable bowel syndrome, and emesis.

11. The use according to Claim 10 wherein the condition associated with an excess of tachykinins is major depressive disorder.

12. The use according to Claim 10 wherein the condition associated with an excess of tachykinins is generalized anxiety disorder.

13. A compound of Formula (T):

(I) wherein

X is -CH(OH)- or -C(O)-, or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 13 which is {2-[l-(3,5-Bis-trifluoromethyl- benzyl)-5-( l-oxy-pyridin-4-yl)- IH-[1 ,2,3]triazol-4-yl]-pyridin-3-yl } -(2-chloro-phenyl)- methanone.

15. The compound of Claim 13 which is {2-[l-(3,5-Bis-trifluoromethyl- benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)- methanol.

16. A pharmaceutical composition comprising a compound of Formula (T)

(D wherein X is -CH(OH)- or -C(O)-, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents.

17. The composition of Claim 16 wherein the compound of Formula (T) is {2- [l-(3,5-Bis-trifluoromethyl-benzyl)-5-(l-oxy-pyridin-4-yl)-lH-[l,2,3]triazol-4-yl]- pyridin-3-yl } -(2-chloro-phenyl)-rhethanone.

18. The composition of Claim 16 wherein the compound of Formula (T) is {2- [l-CS.S-Bis-trifluoromethyl-benzy^-S-Cl-oxy-pyridin^-y^-lH-tl^^ltriazoM-yl]- pyridin-3-yl } -(2-chloro-phenyl)-methanol.