JP2000507253A - Azaspiro derivative - Google Patents

Abstract

(57) Abstract: Formula (I) having 5HT _1B receptor antagonist activity, wherein B is oxygen or sulfur, D is nitrogen or CH, E is oxygen, CR ₂₀ R ₂₁ or NR ₂₂ ).

Description

DETAILED DESCRIPTION OF THE INVENTION                             Azaspiro derivative   The present invention relates to novel piperidine derivatives, methods for their preparation, and containing them To a pharmaceutical composition.   EPA 0533266/7/8 is 5HT_1DReceptor antagonist activity A series of benzanilide derivatives that are claimed to have are disclosed. PCT / EP / 9 5/04889 further discloses 5HT having a spiropiperidine structure._1DReceptor An antagonist is disclosed. These compounds are useful for treating various CNS disorders It is supposed to be. Currently 5HT_1DBThe receptor is 5HT_1BAs a receptor (P.R Hartig et al Trends in Pharmacological Science, 1 996, 17, 103-105).   Now, structurally different classes of compounds have been found and 5HT_1BReceptor It has been shown to exhibit antagonistic activity. Therefore, in the first aspect, the invention Akira is of the formula (I): 中   R¹Is hydrogen, halogen, C_1-6Alkyl, C_3-6Cycloalkyl, COC_1-6A Luquil, C_1-6Alkoxy, hydroxy, hydroxy C_1-6Alkyl, hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkoxy, acyl, nitro, trif Ruoromethyl, cyano, SR¹¹, SOR¹¹, SO_TwoR¹¹, SO_TwoNR¹²R¹³, CO_TwoR¹², NR¹²SO_TwoR¹³, CONR¹²R¹³, CO_TwoNR¹²R¹³, CONR¹²(CH_Two)_pCO_TwoR¹³, (CH_Two)_pNR¹²R¹³, (CH_Two)_pCONR¹²R¹³, (CH_Two)_pNR¹²COR¹³, (CH_Two)_pCO_TwoC_1-6Archi Le, CO_Two(CH_Two)_pOR¹², CONHNR¹²R¹³, NR¹²R¹³, N = CNR¹¹NR¹²R¹³, NR¹²CO_TwoR¹³, NR¹²CO (CH_Two)_pN'R¹²R¹³ , NR¹²CONR¹²R¹³, CR¹²= NOR¹³, CNR¹²= NOR¹³Or NR¹⁴COR¹⁵[Where R¹¹, R¹²And R¹³Is independently hydrogen or C_{1- 6} Alkyl, p is 1-4, and R¹⁴Is hydrogen, C_1-6Is alkyl Or bonded to the phenyl ring (CH_Two)_k(Where k is 2, 3 or 4) To form R¹⁵Is hydrogen, C_1-6Alkyl or optionally substituted Is an optionally aryl]; or R¹Are oxygen and nitrogen respectively Or an optionally substituted one to four heteroatoms selected from sulfur An optionally substituted bicyclic heterocycle or 5- to 7-membered monocyclic heterocycle;   R^TwoAnd R^ThreeIs independently hydrogen, halogen, C_1-6Alkyl, C_3-6Cycloa Luquil, C_3-6Cycloalkenyl, C_1-6Alkoxy, hydroxy C_1-6Alkyl , C_1-6Alkyl OC_1-6Alkyl, acyl, aryl, acyloxy, hydroxy Si, nitro, trifluoromethyl, cyano, CO_TwoR¹², CONR¹²R¹³, NR¹²R¹³(Where R¹²And R¹³Is independently hydrogen or C_1-6With alkyl Is) or R^TwoAnd R^ThreeTogether − (CH_Two)_r-R¹⁶− (CH_Two)_sGroup (where R¹⁶Is O, S, CH_TwoOr NR¹⁷And R¹⁷Is hydrogen or C_1-6Alkyl and r and s are independent 0, 1 or 2) to form   B is oxygen or sulfur;   D is a nitrogen or CH group;   R⁶Is hydrogen or C_1-6Alkyl, R⁷Is hydrogen, C_1-6Alkyl, C_{1- 6} Alkoxy or halogen, or R⁶Is R⁷Together with -A- Group [where A is (CR¹⁸R¹⁹)_t(t is 2, 3, or 4; R¹⁸and R¹⁹Is independently hydrogen or C_1-6Alkyl) or A is (CR¹⁸R¹⁹)_u-J (u is 0, 1, 2 or 3; J is oxygen, Sulfur, CR¹⁸= CR¹⁹, CR¹⁸= N, = CR¹⁸O, = CR¹⁸S or = CR¹⁸-NR¹⁹Is));   R⁸Is hydrogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_2-6Alkenyl or C_1-6Alkyl C_3-6Cycloalkyl;   R⁹And R^TenIs independently hydrogen or C_1-6Alkyl;   E is oxygen, CR²⁰R^{twenty one}Or NR^{twenty two}(Where R²⁰, R^{twenty one}And R^{twenty two}Is German Standing, hydrogen or C_1-6Or E is S (O)_v(This Wherein v is 0, 1 or 2);   G is C = O or CR^{twenty three}R^{twenty four}(Where R^{twenty three}And R^{twenty four}Is, independently, hydrogen Or C_1-6Alkyl));   X and Y are independently CR⁹R^Ten(Where R⁹And R^TenAgree with the above Is righteous); and   m is 1, 2 or 3; Or a salt or N-oxide thereof.   C_1-6An alkyl group, whether alone or as part of another group, is straight or branched May be. The term aryl as used herein includes phenyl and naphthyl Is included. Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidi And pyrazinyl groups. The desired aryl and heteroaryl groups The substituent is R^Two/ R^ThreeThe groups listed above for are included.   Suitably, R¹Is hydrogen, halogen, C_1-6Alkyl, C_3-6Cycloalkyl, COC_1-6Alkyl, C_1-6Alkoxy, hydroxy, hydroxy C_1-6Alkyl , Hydroxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkoxy, acyl, d Toro, trifluoromethyl, cyano, SR¹¹, SOR¹¹, SO_TwoR¹¹, SO_TwoNR¹²R¹³, CO_TwoR¹², NR¹²SO_TwoR¹³, CONR¹²R¹³, CO_TwoNR¹²R¹³, CONR¹²(CH_Two)_pCO_TwoR¹³, (CH_Two)_pNR¹²R¹³, (CH_Two)_pCONR¹²R¹³, (CH_Two)_pNR¹²COR¹³, (CH2)_pCO_TwoC_1-6Al Kill, CO_Two(CH_Two)_pOR¹², CONHNR¹²R¹³, NR¹²R¹³, N = CNR¹¹NR¹²R¹³, NR¹²CO_TwoR¹³, NR¹²CO (CH_Two)_pNR¹²R¹³, NR¹²CONR¹²R¹³, CR¹²= NOR¹³, CNR¹²= NOR¹³Or NR¹⁴COR¹⁵[Where R¹¹, R¹²And R¹³Is independently hydrogen or C_1-6Alkyl, p is 1-4, and R¹⁴Is hydrogen, C_1-6With alkyl Or is attached to the phenyl ring (CH_Two)_kGroup (where k is a few or Is 4) and R¹⁵Is hydrogen, C_1-6Is alkyl or optionally Optionally substituted aryl]; or R¹Are Optionally containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur A more optionally substituted bicyclic heterocycle or 5- to 7-membered monocyclic heterocycle. You.   R¹Is one to four heteroatoms, each selected from oxygen, nitrogen or sulfur. Optionally substituted bicyclic heterocycles containing 5 atoms or 5 to When a 7-membered monocyclic heterocycle, such groups are saturated, partially saturated or aromatic. be able to. R¹The group is via a carbon atom or, if present, a nitrogen atom Can bind to other parts of the molecule. Suitable aromatic groups include thienyl, furyl, pyrrolyl , Thiazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazoly , Isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl Is included. Suitable saturated and partially saturated groups include lactams and thiocyanates. Those having an oxo or thioxo group such as lactam are included. Of this type Suitable groups are of formula (a): (Where a is 1, 2 or 3) Is a lactam. Preferably, a is 1 or 2, and has a 5- or 6-membered ring Formed, most preferably, a is 1. Other preferred lactam groups include those of formula (b) :Wherein a is 1 or 2, preferably a is 1. And a bicyclic ring.   Preferably, R₁Is an optionally substituted oxadiazolyl or 2-oxo A sopyrrolidin-1-yl ring, more preferably R₁Is C_1-6Alkyl Oxadiazolyl, most preferably 5-methyl-1,2,4- Oxadiazol-3-yl group.   Suitably, R^TwoAnd R^ThreeIs independently hydrogen, halogen, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkenyl, C_1-6Alkoxy, hydroxy C_1-6Alkyl, C_1-6Alkyl OC_1-6Alkyl, acyl, aryl, acylo Xy, hydroxy, nitro, trifluoromethyl, cyano, CO_TwoR¹¹, CONR¹²R¹³, NR¹²R¹³(Where R¹¹, R¹²And R¹³The water independently Elementary or C_1-6Alkyl) or R^TwoAnd R^ThreeTogether − (CH_Two)_r-R¹⁴− (CH_Two)_s-Group (where R¹⁴Is O, S, CH_TwoOr NR¹⁵And R¹⁵Is hydrogen or C_1-6Alkyl and r and s are independent 0, 1 or 2). Preferably, R^TwoIs C_1-6Alkyl It is. Preferably, R^TwoThe groups are ortho to the biphenyl linking group. Have And preferably R^TwoIs methyl. Preferably, R^ThreeIs hydrogen.   Suitably, B is oxygen or sulfur. Preferably, B is oxygen.   Suitably, D is a nitrogen or CH group. Preferably, D is nitrogen.   Suitably, R⁶Is hydrogen or C_1-6Alkyl, R⁷Is hydrogen, C_1-6Al Kill, C_1-6Alkoxy or halogen, or R⁶And R⁷Are together A -A- group [where A is (CR¹⁸R¹⁹)_t(Where t is 2, 3 or 4 R¹⁸And R¹⁹Is independently hydrogen or C_1-6Alkyl) Or, A is (CR¹⁸R¹⁹)_u-J (where u is 0, 1, 2, or 3 And J is oxygen, sulfur, CR¹⁸= CR¹⁹, CR¹⁸= N, = CR¹⁸O, = CR¹⁸S or = CR¹⁸-NR¹⁹) Is formed. Preferably, R⁶And R⁷Are both hydrogen.   Suitably, R⁸Is hydrogen, C_1-6Alkyl or C_3-6Cycloalkyl. Preferably, R⁸Is C_1-6Alkyl, most preferably R⁸Is It is. Preferably, m is 2 to form a spiropiperidine ring.   Suitably, B is oxygen or sulfur, preferably B is oxygen.   Suitably, R⁹And R^TenIs independently hydrogen or C_1-6Alkyl. Good Preferably, R⁹And R^TenAre both hydrogen.   Suitably, E is oxygen, CR²⁰R^{twenty one}Or NR^{twenty two}(Where R²⁰, R^{twenty one}and R^{twenty two}Is independently hydrogen or C_1-6Or E is alkyl) or E is , S (O)_v(Where v is 0, 1 or 2). Preferably, E is , Oxygen.   Suitably, G is C = O or CR^{twenty three}R^{twenty four}(Where R^{twenty three}And R^{twenty four}Is independent And hydrogen or C_1-6Alkyl). Preferably, G is CH_TwoIn You.   Suitably, X and Y are independently CR⁹R^Ten(Where R⁹And R^TenIs Is the same as the above). Preferably, X and Y are both CH_TwoIs .   Particularly preferred compounds of the invention include:   N- [2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole- 3-yl) biphenyl-4-yl] -2,3-dihydro-1'-methylspiro [ Benzofuran-3,4'-piperidine] -5-carboxamide;   N- [2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl- 4-yl] -2,3-dihydro-1'-methylspiro [benzofuran-3,4 ' -Piperidine] -5-carboxamide Or their pharmaceutically acceptable salts are included.   Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include Hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate , Citrate, oxalate, methanesulfonate and p-toluenesulfonate And the like.   Certain compounds of formula (I) can exist in stereoisomeric forms. The present invention relates to a compound of the formula (I) All geometric and optical isomers of the product and their mixtures, including racemates It will be understood that it encompasses compounds. Also tautomers and mixtures thereof Further, one embodiment of the present invention is formed.   In a further aspect, the present invention is a process for preparing a compound of formula (I), wherein:   D is nitrogen, B is oxygen, R₆Is hydrogen or C_1-6Formulas that are alkyl ( In the case of compounds of I), formula (II): [Wherein, R¹, R^Two, R^ThreeIs a group having the same meaning as described in formula (I), or , Their protected derivatives, R₆Is hydrogen or C_1-6Alkyl] And a compound of formula (III): [Wherein, R⁷, R⁸, R⁹, R^Ten, E, G, X, Y, m and n are represented by the formula (I) Or a protected derivative thereof.] And then, if desired, in any order. But: .Remove protective groups Converting a compound of formula (I) into another compound of formula (I) ・ Form a pharmaceutically acceptable salt A method comprising:   Suitable activated carboxylic acid derivatives of the formula (III) include acyl halides and And acid anhydrides. The activated compound of formula (III) may also Rubonic acid and carbonyldiimidazole, dicyclohexylcarbodiimide or Can be prepared by reacting with a binder such as diphenylphosphoryl azide.   Compounds of formulas (II) and (III) are typically treated with DMF, THF or dichloromethane. Alkali metal water in an inert organic solvent such as React together in the presence of a base such as an oxide, triethylamine or pyridine. Let   Alternatively, the compound of formula (II) can be treated with an organoaluminum such as trimethylaluminum. Reaction with a compound of formula (III) wherein L is an ester forming group in the presence of be able to. Typically, such reactions are carried out in the presence of an inert solvent such as toluene. Do.   Intermediate compounds of formulas (II) and (III) can be prepared by standard techniques known in the art. Can be prepared using various methods. Certain intermediate compounds of formulas (II) and (III) are new And form a further aspect of the invention.   One skilled in the art will recognize that certain reactive substituents may be protected during some of the above methods. It will be clear that there is a need to do so. GreeneT.W.'Protective groups in orga nic synthesis' Standard protection and protection as described in New York, Wiley (1981). And deprotection methods can be used. For example, a primary amine is phthalimide, It can be protected as a benzyl, benzyloxycarbonyl or trityl derivative. These groups can be removed by conventional methods well known in the art.   Carboxylic acid groups can be protected as ester groups. Aldehyde or ketone groups , Can be protected as acetal, ketal, thioacetal or thioketal . Deprotection can be performed using standard conditions.   5HT_1BReceptor antagonists, and especially the compounds of the present invention, can be used for depression, Mood disorders including seasonal effects and dysthymia; generalized anxiety, panic disorder, widespread Anxiety disorders, including phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder; dementia Memory disorders, including amnesia, amnesia and age-related memory disorders; anorexia nervosa, bulimia nervosa It is useful in the treatment of CNS diseases such as eating behavioral disorders, including: Other CNS diseases Patients include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, Relaxant-induced Parkinsonism and tardive dyskinesia, and other neurologists Includes clinical disorders.   5HT_1BThe receptor antagonists, and in particular the compounds of the invention, are highly prolacty For the treatment of endocrine disorders such as hypertension, vasospasm (especially cerebral vasculature) and hypertension Treatment and treatment of disorders in the gastrointestinal tract where alterations in movement and secretion are associated It is also useful in They are also useful in treating sexual dysfunction and hypothermia Can be useful.   Therefore, the present invention provides a compound of general formula (I) or a compound thereof for use in therapy. These physiologically acceptable salts or solvates are provided.   The invention also provides a compound of general formula (I) for use in the treatment of the aforementioned diseases. Or their physiologically acceptable salts or solvates.   In other embodiments, the present invention provides compounds of general formula (I) or their pharmaceutically acceptable Use of the salts or solvates used in the manufacture of a medicament for the treatment of the above diseases. provide.   In a further aspect, the present invention relates to a method for the treatment of a disease as defined above, comprising the treatment A compound of general formula (I) or a pharmaceutically acceptable salt thereof Or administering an effective amount of a solvate.   In particular, the present invention provides a compound of general formula (I) or the like for use in the treatment or prevention of depression. Or a physiologically acceptable salt or solvate thereof.   The compounds of the present invention may advantageously include one or more other therapeutic agents, for example, different therapeutic agents. It will be appreciated by those skilled in the art that it may be used in combination with an antidepressant.   The invention also relates to compounds of formula (I) or their pharmaceutically acceptable salts and medicaments A pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided.   Suitably, the composition of the present invention prepared by mixing at ambient temperature and atmospheric pressure is Usually applied by oral, parenteral or rectal administration, tablets, capsules, oral liquid Agent, powder, granule, lozenge, reconstitutable powder, injectable or injectable liquid or It is formulated into suspensions or suppositories. Orally administrable compositions are generally preferred.   Tablets or capsules for oral administration can be formulated into unit doses, binders, fillers Can contain conventional excipients such as tablet lubricants, disintegrants and acceptable wetting agents. You. Tablets may be coated according to methods well known in normal pharmaceutical practice. .   Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups Or elixirs, or water or other suitable vehicle. Can be used as a dry preparation for reconstitution before use. Such a liquid Formulations include suspending agents, emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and If desired, it may contain conventional additives such as conventional flavoring or coloring agents.   For parenteral administration, a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle are required. To form a liquid unit dosage form. Depends on vehicle and concentration used Alternatively, the compound can be suspended or dissolved in the vehicle. When producing a solution, Compounds can be dissolved for injection and filled into suitable vials or ampoules and sealed Can be sterile filtered before. Advantageously, auxiliary agents such as a local anaesthetic, preservatives and buffering agents can be added to the solution. Dissolve in the vesicle. To increase the stability, fill the vial with the composition Freeze and remove water under vacuum. Parenteral suspensions dissolve the compound in the vehicle Except that instead of being suspended, sterilization cannot be performed by filtration. And can be manufactured in substantially the same manner. Before suspending the compound in the sterile vehicle, add It can be sterilized by exposure to lenoxide. Advantageously, a uniform distribution of the compound Surfactants or wetting agents are included in the composition to facilitate it.   The composition may contain from 0.1% to 99% by weight of active substance, depending on the method of administration, Preferably, it contains 10% to 60% by weight.   The dose of the compound used in the treatment of the aforementioned diseases may vary depending on the severity of the disease, the weight of the patient, and other factors. Depending on various factors, it can vary within the usual range. However, as a general guideline, A suitable unit dose is between 0.05 and 1000 mg, more suitably no more than 1.0 200 mg, and such a unit dose may be administered more than once a day, for example It may be administered two or three times. Such treatment takes weeks or months You may pass.   The following examples illustrate the preparation of the compounds of the present invention. Description example 1 Ethyl 3-bromo-4- (1-methyl-1,2,5,6-tetrahydropyrido- 4-yl) methoxybenzoate   Ethyl 3-bromo-4-hydroxybenzoate (5.0 g, 0.020 mo le), 1-methyl-1,2,5,6-tetrahydropyrid-4-ylmethano (2.67 g) 0.021 mole; Med. Chem. 1988, 31, 545) and Liphenylphosphine (5.5 g, 0.021 mole) in dry THF (150 stirred solution in argon at room temperature under argon. 3 ml, 0.021 mole) in THF (15 ml) dropwise over 10 minutes And processed. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under vacuum. Remaining The residue was treated with ethyl acetate (150 ml) and 2M HCl (150 ml). Shake to separate the acidic layer,_TwoCO_ThreeTo basify, then acetic acid Extracted with ethyl. The extract is dried (Na_TwoSO_Four), Concentrate under vacuum and remove the residue Dissolve in 0-20% methanol / ethyl acetate by chromatography on Rica gel Discharge and purification afforded the title compound as a beige solid (3.34 g, 47%).¹ HNMR (250 MHz, CDCl_Three) δ (ppm): 8.22 (d, 1H), 7.9 5 (dd, 1H), 6.90 (d, 1H), 5.84 (brs, 1H), 4.45 (s, 2H), 4.35 (q, 2H), 3.00 (brs, 2H), 2.59 (t, 2H), 2 . 37 (s, 3H), 2.40-2.25 (m, 2H), 1.38 (t, 3H). Description example 2 Ethyl 2,3-dihydro-1'-methylspiro [benzofuran [3,4 '] pipe Lysine] -5-carboxylate   Ethyl 3-bromo-4- (1-methyl-1,2,5,6-tetrahydropyrido -4-yl) methoxybenzoate (Description Example 1, 3.32 g, 0.0094 mo) le) in toluene (180 ml) was stirred at 80 ° C. under argon Libutyltin (3.76 ml, 0.014 mole) and AIBN (250 m The solution of g) in toluene (60 ml) was allowed to react dropwise over 40 minutes. Anti The reaction mixture was heated to 80 ° C. for a further 1.5 hours, then cooled and concentrated in vacuo . The residue was treated with 1M HCl (100 ml) and ethyl acetate (100 ml). , Shake well, separate the acidic layer,_TwoCO_ThreeBasified with and extracted with ethyl acetate . The extract is dried (Na_TwoSO_Four), Concentrate under vacuum to give the title compound a beige solid (2.08 g, 81%).¹ HNMR (200 MHz, CDCl_Three) δ (ppm): 7.90 (dd, 1H); 84 (d, 1H), 6.80 (d, 1H), 4.45 (s, 2H), 4.33 (q, 2 H), 2.95-2.80 (m, 2H), 2.33 (s, 3H), 2.10-1.9 0 (m, 4H), 1.85-1.65 (m, 2H), 1.37 (t, 3H). Description example 3 2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Bifeninole-4-amine   2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole-3-i B) biphenyl-4-carboxylic acid (EP0533268A1) (5.0 g, 0.0 17 moles) with thionyl chloride (60 ml) and stirred at room temperature for 3 hours, It was then concentrated in vacuo to give the acid chloride as a pale yellow solid. This substance is Dissolved in methanol (150 ml), cooled to 0 ° C., Monium bromide (50 mg) and sodium azide (1.45 g, 0.0 22mol) in water (25ml) and then at 0 ° C for 1.75 hours Stir vigorously for a while. The mixture was diluted with water (100 ml) and the dichloromethane layer was separated. Release, dry (Na_TwoSO_Four), Trifluoroacetic acid (2.03 ml, 0.026 and heated under reflux with stirring for 20 hours. True reaction mixture Concentration under air left trifluoroacetamide as an orange solid. This is 2% NaOH solution (200 ml), methanol (200 ml) and dichloromethane (2 00 ml) and the resulting solution was stirred and heated under reflux for 12 hours. mixture Was concentrated in vacuo to remove the organic solvent and the aqueous residue was extracted with dichloromethane. Extraction Dry the material (Na_TwoSO_Four), Concentrate under vacuum and concentrate the residue on silica gel And eluted with 50-100% ether / 60.80 petrol. The compound was obtained as a white solid (2.26, 50%).¹ HNMR (200 MHz, CDCl_Three) δ (ppm): 7.96 (s, 1H), 7.9 0 (dd, 1H), 7.32 (d, 1H), 7.17 (d, 2H), 6.75 (d, 2H) ), 3.75 (brs, 2H), 2.67 (s, 3H), 2.37 (s, 3H). Description example 4 Propyl 2,3-dihydro-1'-methylspiro [benzofuran-3,4'-pi Peridine] -5-carboxylate   In a manner analogous to the corresponding ethyl ester (Examples 1 and 2), The title compound was prepared from propyl 3-bromo-4-hydroxybenzoate.¹ HNMR (250 MHz, CDCl_Three) δ (ppm): 7.92 (dd, 1H), 7. 85 (d, 1H), 6.80 (d, 1H), 4.45 (s, 2H), 4.22 (t, 2H) ), 2.95-2.85 (m, 2H), 2.34 (s, 3H), 2.10-1.96 ( m, 4H), 1.85-1.70 (m, 4H), 1.13 (t, 3H). Description example 5 1- (4-bromo-3-methylphenyl) pyrrolidin-2-one   4-bromo-3-methylaniline (50.3 g, 0.27 mole) and Liethylamine (41.1 ml, 0.30 mole) in THF (250 ml) The stirred solution was added to 4-chlorobutyryl chloride (33.4m) at 0 ° C under argon. 1, 0.30 mole) was added dropwise. Stir the mixture at 0-5 ° C for 1 hour Then, while maintaining the temperature at 25 ° C. or lower, potassium 1-butoxide (82. 5 g, 0.74 mole) was added dropwise over 20 minutes. Keep the reaction mixture at 25 ° C. And then stirred for 2.5 hours, then water (100 ml), 2.5 hours later, 10% Na_TwoCO_ThreeThe solution was treated and then extracted with ethyl acetate. Extract the extract with water, diluted hydrochloric acid, It is then washed with brine, dried (Na_TwoSO_Four) And concentrate under vacuum to give the title compound pale yellow Obtained as a color solid (61.6 g, 89%).¹ HNMR (250 MHz, CDCl_Three) δ (ppm): 7.54 (d, 1H), 7.48 (d, 1H), 7.30 (dd, 1H), 3.82 (t, 2H), 2.58 (t, 2H) , 2.40 (s, 3H), 2.16 (quintet, 2H). Description example 6 2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4-ca Rubonic acid   1- (4-bromo-3-methylphenyl) pyrrolidin-2-one (Description Example 5, 50 g, 0.20 mole) and 4-bromobenzoic acid (32 g, 0.20 mol) le) in DME (500 ml) was stirred with sodium carbonate (94 g, 0.8 g). 8mol) in water (500ml) and then 0.25h argon Was bubbled and degassed. Tetrakis (triphenylphosphine) palladium ( O) (5 g) is added and the mixture is heated at reflux for 22 hours, then cooled and cooled to about 50 Concentrated under vacuum to% volume. Dilute the aqueous residue to about 1000 ml with water and add Washed with chill, then acidified with concentrated hydrochloric acid. The precipitate is filtered off, washed with water and dried And recrystallized from ethanol to give the title compound as a cream solid (30 . 3g, 52%)¹ HNMR (250 MHz, d⁶DMSO) δ (ppm): 8.01 (d, 2H), 7. 67-7.58 (m, 2H), 7.49 (d, 2H), 7.25 (d, 1H), 3.8 6 (t, 2H), 2.52 (t, 2H), 2.25 (s, 3H), 2.09 (quin tet, 2H). Description example 7 2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4-amido In   2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4- From the carboxylic acid (Description Example 6), sodium hydroxide was used in the final hydrolysis step. Instead of using sodium carbonate, the same procedure as described in Example 3 was repeated to give the title compound. Was prepared.¹ HNMR (250 MHz, CDCl_Three) δ (ppm): 7.49 (s, 1H), 7.4 1 (dd, 1H), 7.22 (d, 1H), 7.10 (d, 2H), 6.73 (d, 2) H), 3.89 (t, 2H), 3.7 (br, 2H), 2.62 (t, 2H). 2.3 0 (s, 3H). 3.7 (br, 2H), 2.26-2.08 (m, 2H). Example 1 N- [2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole-3 -Yl) biphenyl-4-yl] -2,3-dihydro-1'-methylspiro [be Nzofuran-3,4'-piperidine] -5-carboxamide   2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole-3-i Ru) Biphenyl-4-amine (Example 3, 390 mg, 1.4 mmol) The stirred solution in ene (30 ml) was triturated with 2M toluene at room temperature under argon. Treated with aluminum (0.87 ml, 1.7 mmol). 15 minutes later, solution With ethyl 2,3-dihydro-1'-methylspiro [benzofuran [3,4 '] pi Peridine] -5-carboxylate (Description example 2, 400 mg, 1.4 mmol) In toluene (15 ml) and heated at reflux for 1.5 hours. Reaction mixing The mass was cooled, then stirred in silica gel (15 g) in dichloromethane (30 ml) Poured into the slurry. When foaming stops, the slurry is packed into a chromatography column. Eluted with 10% methanol / chloroform to give the title compound as a pale yellow oil (136 mg, 20%). This is converted to its hydrochloride, which is converted from acetone to white Crystallized as a color solid.¹ HNMR (free base) (250 MHz, CDCl_Three) δ (ppm): 7.98 (s, 1H), 7.93 (d, 1H), 7.85 (s, 1H), 7.75-7.65 (m, 4 H), 7.40-7.30 (m, 3H), 6.88 (d, 1H), 4.48 (s, 2 H), 2.95-2.80 (m, 2H), 2.68 (s, 3H), 2.35 (s, 3H) ), 2.33 (s, 3H), 2.15-1.95 (m, 4H), 1.85-1.70 ( m, 2H). Example 2 N- [2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4 -Yl] -2,3-dihydro-1'-methylspiro [benzofuran-3,4'- Piperidine] -5-carboxamide   2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4-a Mine (Description Example 7, 276 mg, 1.05 mmol) was added to propyl 2,3-dihydro- 1'-methylspiro [benzofuran-3,4'-piperidine] -5-carboxy Rate (described example 4, 300 mg, 1.04 mmol) and the same as described in Example 1. Reacted in a similar manner to give the title compound as a dark beige solid (22%) . This was converted to the hydrochloride salt and crystallized from acetone as a beige solid.¹ HNMR (free base) (250 MHz, CDCl_Three) δ (ppm): 7.90 (s, 1 H), 7.74 (s, 1H), 7.70 (d, 1H), 7.66 (d, 2H), 7.5 3 (d, 1H), 7.45 (dd, 1H), 7.36-7.15 (m, 3H), 6.8 6 (d, 1H), 4.47 (s, 2H), 3.90 (t, 2H), 2.99-2.80 (m, 2H), 2.63 (t, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.27-1.94 (m, 6H), 1.90-1.66 (m, 2H).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/22 A61K 31/00 626K 25/28 626N 25/16 626F 43/00 643G A61K 31/438 31 / 435 607 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), JP, US

Claims (1)

[Claims] 1. Formula (I): Wherein R ¹ is hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, COC _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy C _1-6 alkyl, hydroxy C _{1- 6} alkoxy, C _1-6 alkoxy C _1-6 alkoxy, acyl, nitro, trifluoromethyl, cyano, SR ¹¹ , SOR ¹¹ , SO ₂ R ¹¹ , SO ₂ NR ¹² R ¹³ , CO ₂ R ¹² , NR ¹² SO _{^{2 R 13, CONR 12 R 13}} , CO 2 NR 12 R 13, CONR 12 (CH 2) p CO 2 R 13, (CH 2) p NR 12 R 13, (CH 2) p CONR 12 R 13, (CH ₂ ) pNR ¹² COR ¹³ , (CH ₂ ) _p CO ₂ C _1-6 alkyl, CO ₂ (CH ₂ ) _p OR ¹² , CONHNR ¹² R ¹³ , NR ¹² R ¹³ , N = CNR ¹¹ NR ¹² R ¹³ , NR ¹² CO ₂ R ¹³ , NR ¹² CO (CH ₂ ) _p NR ¹² R ¹³ , NR ¹² CONR ¹² R ¹³ , C R ¹² = NOR ¹³ , CNR ¹² = NOR ¹³ or NR ¹⁴ COR ¹⁵ wherein R ¹¹ , R ¹² and R ¹³ are independently hydrogen or C _1-6 alkyl, and p is 1 to 4. R ¹⁴ is hydrogen, C _1-6 alkyl, or is bonded to a phenyl ring to form a (CH ₂ ) _k group where k is 2, 3 or 4; ¹⁵ is hydrogen, C _1-6 alkyl or aryl which may be substituted]]; or R ¹ is 1 to 4 carbon atoms selected from oxygen, nitrogen or sulfur, An optionally substituted bicyclic heterocycle or 5- to 7-membered monocyclic heterocycle containing a heteroatom; R ² and R ³ are independently hydrogen, halogen, C _1-6 alkyl , C _3-6 cycloalkyl, C _3-6 cycloalkenyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, _6alkyl OC _1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, _{^{cyano, CO 2 R 12, CONR 12}} R 13, NR 12 R 13 ( here, R ¹² and R ¹³ are Or, independently, hydrogen or C _1-6 alkyl), or R ² and R ^{3 taken} together are a — (CH ₂ ) _r —R ¹⁶ — (CH ₂ ) _s — group (wherein Wherein R ¹⁶ is O, S, CH ₂ or NR ¹⁷ , R ¹⁷ is hydrogen or C _1-6 alkyl, and r and s are independently 0, 1 or 2) B is oxygen or sulfur; D is nitrogen or a CH group; R ⁶ is hydrogen or C _1-6 alkyl; R ⁷ is hydrogen, C _1-6 alkyl, C _{1- 6} or alkoxy or halogen, or, R ⁶ is taken together with R ⁷ - A- group [herein, a is, (CR ^{18 19)} _t (t is 2, 3 or a 4,, R ¹⁸ and R ¹⁹ are independently hydrogen or C _1-6 alkyl), or, A is, (CR ¹⁸ R ¹⁹ ) _u -J (u is 0, 1, 2 or 3; J is oxygen, sulfur, CR ¹⁸ = CR ¹⁹ , CR ¹⁸ = N, = CR ¹⁸ O, = CR ¹⁸ S or = CR ¹⁸ to form a -NR ¹⁹ a is) a]; R ⁸ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, in C _2-6 alkenyl or C _1-6 alkyl C _3-6 cycloalkyl R ⁹ and R ¹⁰ are independently hydrogen or C _1-6 alkyl; E is oxygen, CR ²⁰ R ²¹ or NR ²² (where R ²⁰ , R ²¹ and R ²² are independently G is C or C _1-6 alkyl), or E is S (O) _v (where v is 0, 1 or 2); O or CR ^{23 24} (here, R ²³ and R ²⁴ are independently hydrogen or C _1-6 alkyl) be a; X and Y are independently CR ⁹ R ¹⁰ (wherein, R ⁹ and R ^And m is 1, 2 or 3; or a salt or N-oxide thereof. 2. The compound according to claim 1, wherein R ¹ is an optionally substituted oxadiazolyl or 2-oxopyrrolidin-1-yl. 3. ^3. The compound according to claim 1, wherein R ² is C _1-6 alkyl and R ³ is hydrogen. 4. The compound according to any one of claims 1 to 3, wherein m is 2. 5. The compound according to any one of claims 1 to 4, wherein R ⁸ is C _1-6 alkyl. 6. Claims 1 X and Y are both CH ₂ A compound according to any one of the 5. 7. N- [2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] -2,3-dihydro-1'-methylspiro [benzofuran- 3,4'-piperidine] -5-carboxamide, N- [2'-methyl-4 '-(2-oxopyrrolidin-1-yl) biphenyl-4-yl] -2,3-dihydro-1'- The compound according to claim 1, which is methylspiro [benzofuran-3,4'-piperidine] -5-carboxamide, or a pharmaceutically acceptable salt or N-oxide thereof. 8. A process for the preparation of a compound of formula (I), wherein (a) for a compound of formula (I) wherein D is nitrogen, B is oxygen and R ⁶ is hydrogen or C _1-6 alkyl, (II): Wherein R ¹ , R ² , R ³ are as defined in formula (I) or are protected derivatives thereof, and R ⁶ is hydrogen or C _1-6 alkyl. With a compound of formula (III): [Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , E, G, X, Y, m and n are the same as described in the formula (I), or a protected derivative thereof. And then, if desired, in any order: removing the protecting group, converting the compound of formula (I) to another compound of formula (I), A method comprising forming an acceptable salt. 9. A compound according to any one of claims 1 to 7 for use in therapy. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 in combination with a pharmaceutically acceptable carrier or excipient.