MXPA97004299A - Bencimida derivatives - Google Patents

Abstract

Benzimidazole derivatives of the formula (See Formula) wherein B, Y, R 1, R 2, R 3 and R 4 are as defined in the specification. These compounds and their pharmaceutically acceptable salts are useful in the treatment of CNS and related disorders.

Description

BENCIMIDRZOL DERIVATIVES BACKGROUND OF THE INVENTION This invention relates to novel benzyldazole derivatives, to pharmaceutical compositions containing them and to methods of using same for treating certain central nervous system (CNS) disorders and other disorders. The compounds of this invention are corticotropin releasing factor (CRF) receptor antagonists. CRF antagonists are cited in U.S. Patent Nos. 4,605,642 and 5,063,245, which pertain, respectively, to peptides and pyrazolonates, and which were granted respectively, on August 12, 1986 and on August 5, 1986. November 1991. These are also cited in the following documents: PCT Patent Application POT / TB95 / 00419, which designates the United States and was filed on June 6, 1995; PCT patent application PCT / IB95 / 00373, which designates the United States and the IB of May 1995 was filed; United States patent application 08 / 448,539, which was filed with the PCT on November 12, 1993 and filed in the United States national phase on June 14, 1995; U.S. Patent Application 08 / 481,413, which was filed on PCT on November 26, 1993 and filed in the United States National Phase on July 24, 1995; and U.S. Patent Application 08 / 254,820, which was filed on April 19, 1995. The above patents and patent applications are all incorporated herein by reference in their entirety. The importance of CRF antagonists is described in the literature, for example, as described in U.S. Patent 5,063,245, which is incorporated in the patent as a whole. In M. 3. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), incorporated herein by reference, is a recent description of the different activities possessed by CRF antagonists. Based on the investigations described in these and other references, CRF antagonists are effective in the treatment of a wide range of stress-related diseases, such as depression, anxiety, headache, irritable bowel syndrome, inflammatory diseases, immune suppression. , Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hernorragic estros, alcohol and drug withdrawal symptoms, drug addiction, sterility, head injury, cerebrovascular accident and stress-induced infections in humans and animals.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula wherein B is hydrogen or linear Ci-Cio alkyl or rarnit i cado; And it is hydrogen or methyl; R1 is hydrogen, -S ~ (Ci-Cio alkyl) or Ci-Cio straight or branched alkyl, wherein said alkyl may be optionally substituted by one or more substituents selected from halogen, -S- (Ci-C * alkyl), ammo, NH- (C?-C4 alkyl) and -NT (C?-C «alkyl) 2j V R2, RJ and R« are selected from Independent form, etre hydrogen, fluoro, chloroalkyl Ci-Cj and alkoxy Ci-Cj; or, of R2, RJ and R *, two are hydrogen and the other selects between Idroxy, iodo, bromo forrnyl, cyano, nitro, t ri fluo romet i lo, animo, (Ci-Cß alkyl) -0 ~ (C? -C6 alkyl), -NHCH3, -N (CH3) 2, - COOH , -COOalkyl C? -C "), -CO-C-C-alkylcarbonyl), -S02 ~ NH (C -Calkyl), -S02-NHC (C? -C4alkyl) 32, -S02NH2 , ~ NHS02- (Ci-Ct alkyl,), -S (Ci-C6 alkyl) and -S02- (C? -C alkyl), and that the C? -C4 alkyl and Ci alkyl radicals -Cß of groups R2, R3 and R < above may be optionally substituted by one or two fluoro groups or by a substituent selected from hydroxy, mood, methylamino, di eti lami and acetiio; and the pharmaceutically acceptable salts of said compounds. Preferred embodiments of this invention include compounds of formula T, wherein R2, RJ and R * are methyl, R >; it is methyl, ethyl or chlorine, and B is diet and irnetium. Other more specific embodiments of this invention include the following: (a) compounds of formula I wherein Y is hydro ene; (b) compounds of formula I wherein R2, R * and R * are selected from hydrogen, fluoro, chloro and C1-C3 alkyl; (c) compounds of formula I wherein B is hydrogen; (d) compounds of formula I in which Y is hydrogen and R 1 is hydrogen, halogen, - ^ - (Ci-Cg alkyl) or straight or branched Ci-Cβ alkyl; and (e) compounds of formula T in B is C 1 -alkyl or branched alkyl. the compounds of formula T have asymmetric centers and therefore in different enantiores forms. This invention relates to all optical isomers (e.g., enantiomers and diastereoisomers) and to all stereoisomers of the compounds of formula I, as well as to racemic mixtures and other types of mixtures thereof.

Formula I above includes compounds identical to those represented, except for the fact that one or more hydrogen or carbon atoms are replaced by their isotopes. Such compounds are useful as tools of investigation and diagnosis in far acocmeticos studies of the metabolism and in union tests. The present invention also relates to the pharmaceutically acceptable acid addition salts and bases of the compounds of formula I. The acids that can be used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds of this invention are those which form addition salts and non-toxic acids, ie, salts containing pharmacologically acceptable amones, such as hydrochloride, hydrazide, hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, Jactate, citrate, citrate salts acid, tartrate, bi tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulphonate, benzenesulphonate, p-toluenesulfonate and pamoate. Tes say, 1,1'-rnetilen-bis- (2-hydrox) ? -3-naphthoate). The term "halogen," as used herein, unless otherwise indicated, includes chlorine, fluorine, bromine, and iodine. The term "alkyl", as used in the preamble, unless otherwise indicated, includes monovalent hydrocarbon radicals having straight, branched or cyclic radicals or combinations thereof. The term "one or more other ingredients", as used herein, includes from one to the maximum number of substitutes possible based on the number of available binding sites. The invention also relates to a pharmaceutical composition for the treatment of (a) a disorder whose treatment can be accomplished or facilitated by antagonizing CRF at its receptor sites, including, but not limited to, disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteartritis, gun pain, psoriasis and allergies; osteoporosis; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain such as Lbrthia gia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, premenstrual dysphoric disorder, mood disorders associated with premenstrual syndrome, postpartum depression and dysternia; bipolar disorders; ciclot mia; fatigue syndrome; stress induced headache; psychosocial dwarfism; Cancer; irritable bowel syndrome; Crohn's disease; ulcer; diarrhea; spastic colon; infections of human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease, Parson's disease and Huntington's disease; gastrointestinal diseases; Eating disorders such as anorexia and bulirnia nervosa; hemorrhagic stress; dependencies and chemical addictions (for example, dependence on alcohol, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal; psychotic episodes induced by stress; euthyroid disease syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; head trauma; trauma of the spinal cord; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident, mnnunitap dysfunctions including stress-induced mnnunitapa dysfunctions (for example, porcine stress syndrome, septicemia, orralgia of cattle, equine paroxysmal fibration and chicken-induced malfunctioning, stress to open spaces in sheep, or stress due to man-animal interaction in dogs); stress-induced fever, muscle spasms; urinary incontinence; cardiovascular and cardiac disorders such as hypertension, tachycardia and congestive heart failure; senile dementia of the Alzheimer type; dementia ultunfarto; lateral sclerosis arniotrófi ca; and hi poglucernia in a mammal, including a human, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of said disorder, and a pharmaceutically acceptable carrier abl. The invention also relates to a method for the treatment of (a) a disorder whose treatment can be performed or facilitated by antagonizing CRF at its receptor sites, including, but not limited to, disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as reurnatoid arthritis and osteoartptis, pain, asthma, psoriasis and allergies; oeteoporoeis; generalized anxiety disorder; panic; obias; obsessive-compulsive disorder; Post-rheumatism stress disorder, stress-induced sleep disorders; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, premenstrual dyspepsia disorder, mood disorders associated with premenstrual syndrome, postpartum depression and dystemia; bipolar disorders; cyclothirnia; fatigue syndrome; stress induced headache; psychosocial dwarfism; Cancer; irritable bowel syndrome; Crohn's disease; ulcer; diarrhea; spastic colon; Porvirus infections of human immunodeficiency (HIV); neurodegenerative diseases such as Alzheirner's disease, Parkinson's disease and Huntington's disease, gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; Hernorragic stress; psychotic episodes induced by stress; euthyroid disease syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; cranial ism trauma; spinal cord trauma; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident Inmumula dysfunctions including immune-induced malfunctioning dysfunctions (eg, porcine stress syndrome, herriorgic septicemia of cattle, equine paroxysmal fibration and confinement induced dysfunction in chickens, stress in sheep vacuum or stress induced by male interaction -animal in dogs); stress-induced fever, muscle spasms; urinary incontinence; cardiovascular and cardiac disorders such as hypertension, tachycardia and congestive heart failure; senile dementia of the Alzheirnei type; dementia rnult i i nfarto; arniotrofica lateral sclerosis; dependencies and chemical addictions (for example, dependence on alcohol, cocaine, heroin, henzodiacephaem or other drugs); withdrawal symptoms of drugs and alcohol; and hypoglycemia in a mammal, including a human, which comprises administering to a subject in need of such treatment, an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, that is effective in the treatment of said disorder. This invention also relates to a pharmaceutical composition for preventing premature birth in a mammal, including a human, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective in preventing premature birth , and a pharmaceutically acceptable vehicle. This invention also relates to a method for preventing premature birth in a mammal, including a human, which comprises administering to said mammal an amount of a compound d formula I, or a pharmaceutically acceptable salt thereof, which is effective for avoid premature birth. The term "avoid premature birth," as used herein, refers both to preventing premature birth, and to delaying the time of premature birth.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared as described in the following reaction and description schemes. Unless indicated otherwise, in the reaction schemes and in the following description, R1, R2, R3, R * and B are defined above.

SCHEME I SCHEME I (Continued) SCHEME 2 Figure 1 illustrates a process for preparing compounds of formula 1 in which Y is hydrogen. With reference to Scheme 1, is 2-brorno-5 ~ n methyl ester reacted? trobenzoic (II) with a corn p ue st o of f o r -rn u 1 a. in the presence of a tetrakis catalyst (tnfen? lphosphine) palladium (O) and cesium fluoride to form a compound of formula Til. The preferred solvent for this reaction is di ethoxy ethane (DME), although other inert reaction solvents such as ethyl ether ("ter-") and tet rahydrofuran (THF) can also be used. Preferably, the reaction is started at about room temperature and then the reaction mixture is heated to reflux. Next, the compound of formula III is hydrolyzed, using conventional procedures well known in the art, to form the corresponding acid of formula TV. For example, the compound of formula Til can be reacted with sodium hydroxide in a methanol / water solvent and heated to reflux. The acid of formula TV can be converted into the protected form of formula V by reacting it with di-pheni Ifosptoplazide in an inert solvent such as anhydrous benzene or anhydrous toluene, in the presence of a tertiary amine base such as toluene and, after leaving the reaction mixture at reflux for about one hour, stirring mixture and adding t-butanol. This reaction is generally carried out at a temperature of about 50 ° C at approximately the reflux temperature of the reaction mixture. In T. Greene, Protective Groups m Organic Synthesi, John Uiley and Sons, New York, 1991, alternative nitrgene protective groups and procedures for adding and replacing them can be found. Reduction of the resulting compound of formula V formed in the previous step, using conventional procedures well known in the art, provides the corresponding compound of formula VI. This reduction can be carried out, for example, by using hydrogen in the presence of a catalyst such as Raney nickel or palladium on carbon in an inert reaction solvent, such as methanol, ethanol or ethyl acetate, at an initial pressure of about one to about three atmospheres and at a temperature of about OQC to about 60QC. Typically, the reaction is carried out with methanol as the solvent and at approximately three atmospheres of hydrogen gas pressure at room temperature and for about 0.5 to 1.0 hours. Reaction of the compound of formula VI with the appropriate aldehyde or ketone to add substituent B to the nitrogen of the free arnmo group, in the presence of a reducing agent and a dehydrating agent, provides the corresponding compound of formula VII. The aldehyde or ketone is chosen such that the carbonyl carbon atom is the binding point of group B to free arnino nitrogen. This reaction is carried out under anhydrous conditions using a dehydration agent such as sodium sulfate or magnesium sulfate. Suitable reducing agents include sodium txethoxyborohydride and sodium cyanoborohydride. Sodium t-natoxyborohydride is preferred. Suitable solvents include acetic acid, acetonitrile and rnetanol. The preferred solvent is acetic acid. The reaction temperature may vary from about 0 C to about 60 ° C and preferably is 21 ° C. The corresponding compound of formula VIII can be formed by removing the t-butoxy carbonyl protecting group. This can be carried out using conventional procedures well known in the art., for example, using trifluoroacetic acid in ethylene chloride, or hydrochloric acid in water. The desired compound of formula I can be formed by the reaction of the corresponding compound of formula VIII with an ortho-acid derivative of formula (CHaCHiGhCRi.) This reaction is generally carried out in the presence of a tai acid catalyst such as concentrated hydrochloric acid, hydrochloric acid or nitric acid, preferably concentrated hydrochloric acid, at a temperature of about 5QC to about 60QC, preferably about 23QC .. Scheme 2 illustrates a process for preparing compounds of formula I wherein Y is methyl With reference to Scheme 2, a compound of formula V is reacted with dimethyl disulfide and N-chlorosuccmarnide to form the corresponding compound of formula IX This reaction is generally carried out in an aprotic solvent such as netienene chloride, chloroform or dichloroethanes, preferably sodium chloride. methylene, at a temperature of approximately OSC at approximately 50 C, preferred The deprotection step, which provides the corresponding compound of formula X and the animo substitution step, which provides the corresponding compound of formula XI, can be carried out using procedures analogous to those illustrated in Scheme 1 and described above. The compounds of formula I in which Y is CH 3 can be formed by reduction of the corresponding compounds of formula XII. This reduction can be carried out using hydrogen in the presence of a catalyst - such as Raney nickel or palladium on carbon, in an inert reaction solvent such as methanol, ethanol or ethyl acetate, at an initial pressure of about one to about four atmospheres and at a temperature of from about OQC to about 60SC. Typically, the reaction is carried out with methanol as the solvent and with about three atmospheres of gaseous hydrogen pressure at room temperature for about 0.5 to 1.0 hours. The preparation of the remaining compounds of formula I not specifically described in the above experimental section can be carried out using combinations of the reactions described above which will be apparent to those skilled in the art. Unless indicated otherwise, in each of the reactions described or illustrated in Schemes 1 and 2 above, the pressure is not critical. In general, pressures from about 0.5 atmospheres to about 5 atmospheres are acceptable and, for convenience reasons, the ambient pressure is preferred, ie, 1 atmosphere. The novel compounds of formula I and the pharmaceutically acceptable salts thereof are useful as CRF antagonists at their receptor sites in mammals and, therefore, they can act as therapeutic agents in the treatment of the disorders and diseases mentioned above in an affected mammal The compounds of formula I that are basic can form a wide range of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, a reaction mixture such as a pharmaceutically unacceptable salt is often desired in practice and then the former is converted to the free base compound by treatment with an alkaline reagent and thereafter converting it. above free base in a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treatment of a basic compound with a substantially equivalent amount of the chosen mineral or organic acid in a solvent medium or in a suitable organic solvent, such as methanol or ethanol . By carefully evaporating the solvent, the desired solid salt is easily obtained. It is preferred to employ rich amounts of the reagents in order to ensure the completion of the reaction and the maximum yields of the desired final product. The compounds of formula I and their pharmaceutically acceptable salts ("the active compounds of this invention") can be administered alone or in combination with pharmaceutically acceptable carriers., in single or divided doses. Suitable pharmaceutical carriers include solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of formula I and their pharmaceutically acceptable carriers can be easily administered in a series of dosage forms such as tablets, powders, tablets, syrups, injectable solutions and the like. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavorants, binders, excipients and the like. In this way, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used, together with various excipients.such as starch, rilethylcellulose, algic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, for the purpose of tablet preparation, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful. Solid compositions of a similar type as car-gas can also be employed in hard and soft filled gelatin capsules. The preterm materials for this include lactose or milk sugar and high molecular polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient of the rnisrna may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycepine and combinations of the same. For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof may be employed in sesame or peanut oil, aqueous propylene glycol or sterile aqueous solution. Such aqueous solutions will be adequately damped if necessary and the liquid diluent will be made isotomal with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intrapeptoneal administration. The sterile aqueous media used is readily available by conventional techniques known to those skilled in the art. The effective doses for the compounds of formula I and pharmaceutically acceptable salts will depend on the desired route of administration and on factors such as the age and weight of the patient, as is generally known to a physician. The doses will also depend on the particular-treated disease. For example, the target dose for stress-induced diseases, inflammatory disorders, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hernorrhagic stress and alcohol and drug withdrawal symptoms will normally vary from approximately 0.1 to approximately 50 mg / kg. kg of body weight of the patient in question. The procedures that can be used to determine the CRF antagonist activity of the active compounds of this invention and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1659 (1985) and Pep ides, , 179-188 (1985). The binding activities of the compounds of formula I, II and III, expressed as or Clsβ values, range generally from about 0.5 nanomolar to about 10 micromolar. The present invention is illustrated by the following examples. However, it will be understood that the invention is not limited to the specific details of these examples. The melting points are uncorrected. Proton nuclear magnetic resonance (1 H NMR) and 13 C nuclear magnetic resonance spectra (13 C NMR) spectra were measured for solutions in deuterchloroform (CDCl 3) and the peak positions are expressed in parts per million (ppm) downstream of tetrarnethylsilane (TMS). The shape of the peaks is represented as follows: s, singlet; d, doublet; t, tri piéte; q, quartet; rn, rnul ti piete; b, width. In the Examples, the following abbreviations are used: Ph = phenol; 1 Pr =? I sopped it; HRMS-high resolution mass spectrum.

EXAMPLE 1 2 ', 4', 6'-Trimethyl-3-nitro-biphenyl-2-carboxylic acid methyl ester 1.44 g (5.54 mmol) of methyl 2-bruno-5-nitrobenzoate, 1.68 (ll.l mmol) of cesium fluoride and 192 rng of tet rachis (tp fem Ifoef ina) palladium (0) under an atmosphere were combined. of nitrogen in 20 ml of dimethoxyethane (DME) anhydrous.

The reaction was stirred for 5 minutes, at which time 1.00 g (6.09 mmol) of mesit iboronic acid was added. The solution was refluxed for 20 hours, and then cooled and separated on silica gel using hexane: ethyl acetate (EtOAc) 6: 1 providing, after concentration in vacuo and re-separating using toluene, 5.65 g (54 %) of the title compound. 1 H NMR (CDC13) 1.93 (s, 6H), 2.30 (s, 3H), 3.57 (s, 3H), 6.88 (s, 2H), 7.47 (d, 1H), 7.62 (dd, 1H), 8.17 ( d, IH).

EXAMPLE 2 Acid 2 ',' jB'-trimethyl-S-nitro-biphenyl-S-carboxylic acid 600 mg (2 mmol) of the title compound of Example 1 were combined with 5 ml of THF, 3 ml of methanol and 5 ml of water under a nitrogen atmosphere. To this solution 320 rng (8 mmol) of sodium hydroxide were added and the resulting solution was heated to reflux for 96 hours. The reaction was cooled and concentrated in vacuo, diluted with water to a volume of 40 nmol and extracted with ethyl acetate (1 x 25 mL). The aqueous layer was acidified to pH = 1.5 with 6N hydrochloric acid (HCl) and The aqueous layer was extracted with ethyl acetate (2 x 25 ml). The organic extracts were washed with water (2 x 5 ml) and then with brine (1 x 5 rnl) and then dried over magnesium sulfate, filtered and concentrated in vacuo to give 526 mg (92%) of the desired acid ( composed of the title). 1 H NMR (1.92 (s, 6H), 2.31 (s, 3H), 6.89 (s, 2H), 7.47 (d, 1H), 7.63 (dd, 1H), 8.18 (d, 1H).

EXAMPLE 3 Tertiary butyl ester of (2 ', k', 6'-trimethyl-3-nitro-biphenyl-2-yl) -carbamic acid 526 g (1.85 mmol) of the title compound of Example 2 and 0.25 ml of t-phenylalanine (TEA) were combined under a nitrogen atmosphere in 20 ml of anhydrous benzene. To this suspension was added 398 μl (1.85 mmol) of di-phenyl-phosphoryl azide and the resulting solution was heated at reflux for 1 hour. The reaction mixture was cooled, 353 μl (3.70 inmol) of t-butanol was added and the solution was heated to reflux for 16 hours. The crude reaction mixture was concentrated in vacuo and separated on silica gel using hexane: EtOAc 5: 1, providing, after vacuum concentration, some pure product. Additional product was obtained in triturations in hexane of fractions containing product providing 430 mg (65%) of the title compound. 1 H NMR (CDCl 3) 1.37 (s, 9 H), 1.93 (s, 6 H), 2.32 (s, 3H), 6.08 (bs, 1H), 6.96 (s, 2H), 7.31 (m, 2H), 7.89 (m, lH).

EXAMPLE 4 (3-amino-2, K ', 6-trimethyl-biphenyl-2-yl) -carbamic acid tert-butyl ester % palladium on carbon (50 ng) was added to a methanol solution (35 ml) containing 430 g (1.20 mmol) of the title compound of Example 3 and the solution was hydrogenated at 3.44 x lOs Pa. After 30 minutes, the reaction was stopped and the resulting solution was filtered to remove the catalyst- and concentrated in vacuo to provide 385 mg (98%) of the title compound as a white solid. 1 H NMR (CDC13) 1-38 (s, 9H), 1.93 (s, 6H), 2.31 (s, 3H), 4.10 (bs,? H), 5.57 (bs, 1H), 6.50 (d, 1H) , 6.77 (d, 1H), 6.92 (s, 2H), 7.10 (dd, 1H).

EXAMPLE 5 [S-d-ethyl-propylamm] ^ ', k', 6'-trimethyl-biphen-l-2-yl) -carbamic acid tert-butyl ester ml of acetic acid, 205 mg (0.62 mmol) of the title compound of Example 4 and 126 μl (1.25 mmol) of 3-pentanone were combined under a nitrogen atmosphere, followed by 090 ing (6.29 mmol) of sodium sulfate. in powder (Na2S0 ,?). The solution was left stirring for 20 minutes, at which time 158 m (0.75 mmol) of sodium triacetoxyborohydride (NaBH (OAch) was added.) The solution was left stirring for 45 minutes and then quenched with aqueous bicarbonate (75 nl). ) and extracted with ethyl acetate (2 x 30 ml) The organic extract was washed with water (1 x 25 rnl) and then brine (1 x 25 rnl), then dried over a2S0t, filtered and concentrated in vacuo. , yielding 232 mg of crude product, which was chromatographed on silica gel using hexane: ethyl acetate 9: 1, yielding 186 mg (74.7%) of the title compound.1H-NMR (CDCl3) 0.98 (FIG. t, 6H), 1.33 (s, 9H), 1.57 (rn, 4H), 1.98 (s, 6H), 2.32 (s, 3H), 3.30 (m, 1H), 4.18 (bs, 1H) 5.30 (bs , 1H), 6.39 (d, 1H), 6.68 (d, 1H), 6.92 (s, 25 2H), 7.20 (dd, 1H), NMR of »c (CDCI3) 10.13, 20.25, 21.05, 26..61 , 28.03, 55.29, 80.03, 110.77, 117.19, 127.69, 128.11, 120.80, 135.79, 136.09, 136.57, 144.30, 153.60.

EXAMPLE 6 N-3 (l-ethyl-propyl) -2 *, 4 ', 6'-trimethyl-biphenyl-2,3-diamine 124 rng (3 mol) of the title compound of Example 5 were dissolved in 1 ml of dichloromethane under a nitrogen atmosphere and the resulting solution was cooled to OOC. T-rhipouoroacetic acid co (10 rnl) was added and the solution was allowed to warm at room temperature. After one hour, the reaction was concentrated in vacuo, the residue was dissolved in dichloroethane (40 ml) and the organic solution was washed with 1N sodium hydroxide (NaOH) (25 ml), dried over NajSO *, filtered and concentrated in vacuo to provide 94.3 (100%) of the crude title compound. 1 H NMR (CDCl 3) 0.93 (t, 6H), 1.60 (m, 4H), 1.98 (s, s, 6H), 2.30 (s, 3H), 3.08 (, 3H), 3.22 (, 1H), 6.39 ( d, 1H), 6.61 (d, 1H), 6.82 (dd, 1H), 6.95 (s, 2H).

EXAMPLE 7 2-Ethyl-1- (1-ethyl-propyl) -4- (2,4-J6-trimethyl-phenyl) -lH-benzimidazole 47 rng (0.15 nmol) of the title compound of Example 6 were combined in 2 ml of triethyl orthopropionate ba or a nitrogen atmosphere. This solution was added to a drop of concentrated HCl. The solution was allowed to stir for 18 hours and then concentrated in vacuo. The crude product was dissolved in 5 mL of EtOAc, followed by 3 mL of ethyl ether (Et0), saturated with HCl. The solution was concentrated in vacuo and triturated with ether. The resulting solids were filtered and washed with ether, yielding the title compound as its hydrochloride salt. NMR of «H (CDCl3) 0.83 (t, 6H), 1.33 (t, 3H), 1.98 (s, 6H), 2.00 (rn, 4H), 2.20 (m, 2H), 2.32 (s, 3H), 2.88 (q, 2H), 4.08 (m, 1H), 6.93 (rn, 3H), 7.18 (dd, 1H), 7.42 (d, 1H).

Claims (10)

1. NOVELTY OF THE INVENTION CLAIMS A compound of formula wherein B is hydrogen or straight or branched Ci-Cio alkyl; And it's hydrogen or methyl; R1 is hydrogen or straight or branched C1-Cio alkyl, wherein said alkyl may optionally be substituted by one or more substituents selected from halogen, (eg, chloro, fluoro, bromo, or iodo), -S- ( alkyl C? -C <), amino, -NH- (Ci-Ct alkyl), and -NC (Ci-Ct alkyl; R2, RJ, and R * are independently selected from hydrogen , fluoro, chloro, Ci-Cj alkyl and Ci-Cj alkoxy, or R2, RJ and R *, two are hydrogen and the other is selected from hydroxy, iodo, bromo, formyl, cyano, nitro, nf luorometlo, a mo, (Ci-Cj alkyl) -0- (CI-Cι alkyl), -NHCH 3, - (CH 3) 2, -COCH, -COO (alkyl? C? ~ C <), -CO (alk ? l? Ci-Ct), -SOjNH (alkyl C? ~ C <), S? 2 ~ NC (alkyl Ct-Cí, -SO2NH2, -NHS02 - (alkyl C? ~ 0 *), -Salky Ci-Cí) and -SO 2 - (Ci-Cj alkyl), and wherein the C C-C < and C 1 -C 4 alkyl radicals of the above R2, RJ, and R * groups may be optionally substituted by one or two fluoro or by a sust 1 listener selected from hydroxy, animo, metílamíno, dirnetilammo and acetilo; or an acceptable pharmaceutical salt of said compound.
2. 2. A compound according to claim 1, wherein B is linear or branched C? -C6 alkyl.
3. A compound according to claim 1, wherein Y is hydrogen.
4. 4. A compound according to claim 1, wherein R2, RJ and R * are methyl, R1 is methyl, ethyl or chloro and B is diethiirneti lo.
5. 5. A compound according to claim 1, wherein R1 is methyl, ethyl or chloro.
6. 6. A compound according to claim 1, wherein Y is hydrogen and R1 is hydrogen, halogen, -S- (alkyl or Ci-Cj) or straight or branched CI-C2 alkyl.
7. 7. A pharmaceutical composition for the treatment of (a) a disorder whose treatment can be made or facilitated by antagonizing CRF, including, but not limited to, disorders induced or facilitated by CRF, or (b) a disorder selected from among disorders inflammatory diseases such as reurnatoid arthritis and osteoarthritis, pain, asrna, psoriasis and allergies; osteoporosis; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain such as fibromyalgia; mood disorder, such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, premenstrual dysphoric disorder, mood disorders associated with premenstrual syndrome, postpartum depression and dystemia; bipolar disorders; cyclothymia; fatigue syndrome; stress induced headache; psycho-social dwarfism; Cancer; irritable bowel syndrome; Crohn's disease; ulcer; diarrhea; spastic colon; infections by human immunodeficiency virus; neurodegenerative diseases such as Alzheimer's diseases, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; dependencies and chemical addictions; symptoms of drug and alcohol withdrawal; psychotic episodes induced by stress; euthyroid disease syndrome; inadequate antidiarrheal hormone syndrome; obesity; sterility; head trauma; spinal cord trauma; Ischemic neuronal injury; excitotoxic neuronal injury; epilepsy; cerebrovascular accident immune dysfunctions including immune dysfunctions induced by stress; stress-induced fever; spasms rnuscularee; urinary incontinence; cardiovascular and cardiac disorders such as hypertension, tachycardia and congestive heart failure; senile dementia of the Alzheirner type; multi-infarct dementia; arniotrophic lateral sclerosis; and hypoglycernia in a mammal, comprising an amount of a compound according to claim 1, which is effective in the treatment of said disorder, and a pharmaceutically acceptable carrier.
8. 8. Use of a compound of claim 1, in the preparation of compositions for the treatment of (a)? N disorder whose treatment can be performed or facilitated by an <; agonizing on CRF, including, but not limited to, disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as reurnatoid arthritis and osteoarthritis, asthma pain, psoriasis and allergies; osteoporosis; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorder caused by stress; perception of tai pain as a fibula ialgia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, premenstrual dyspnopian disorder, mood disorders associated with premenstrual syndr poparthort depression and dysternia; bipolar disorders; cyclothymia; fatigue syndr stress induced headache; psi cosocial dwarfism; Cancer; irritable bowel syndr Crohn's disease; ulcer; diarrhea; spastic colon; infections by virus of a human deficiency; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntmgton's disease; gastrointestinal diseases; Eating disorders such as anorexia and bulirnia nervosa; hernorragic stress; psychotic episodes induced by stress; euthyroid disease syndr antidiarrheal hormone syndr inadequate obesity; sterility; head trauma; spinal cord trauma; Ischemic neuronal injury; neuronal excitotoxic injury; epilepsy; cerebrovascular accident mmunitapun dysfunctions including immune-induced stress dysfunctions; stress-induced fever, muscle spasms; urinary incontinence; cardiovascular and cardiac disorders such as hypertension, tachycardia and congestive heart failure; senile dementia of the Alzheimer type; dementia rn? lt n infarct; Amyotrophic Lateral Sclerosis; dependencies and chemical addictions; withdrawal symptoms of drugs and alcohol; and hypoglycemia in a mammal, comprising administering to a subject in need of such treatment, an amount of a compound according to claim 1. that is effective in the treatment of said disorder.
9. 9. A pharmaceutical composition for preventing premature birth in a mammal, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective to prevent premature birth, and a pharmaceutically acceptable carrier.
10. 10. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the preparation of compositions for preventing premature birth in a mammal.