JP2008525524A - Arylsulfonamide modulator - Google Patents

Abstract

A compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Ar 1 and X are as described herein, pharmaceutically acceptable salts thereof, methods for their preparation, As well as their use in therapy, particularly for treating conditions associated with reduced nicotine transmission.
[Chemical 1]

Description

  The present invention relates to compounds or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The present invention particularly relates to positive modulators of nicotinic acetylcholine receptors, such positive modulators having the ability to increase the effectiveness of nicotinic receptor agonists.

  Cholinergic receptors usually bind to the endogenous neurotransmitter, acetylcholine (ACh), thereby causing ion channel opening. Mammalian central nervous system ACh receptors can be classified into muscarinic (mAChR) and nicotinic (nAChR) subtypes, respectively, based on muscarinic and nicotine agonist activity. The nicotinic acetylcholine receptor is a ligand-gated ion channel that contains five subunits. Members of the gene family of nAChR subunits are classified into two groups based on their amino acid sequences, the first group includes so-called β subunits and the second group includes α subunits. . Three of the α subunits, α7, α8, and α9, have been shown to form functional receptors when expressed alone and are therefore presumed to form homo-oligomeric pentameric receptors. Yes.

  An allosteric transition state model of nAChR has been developed that includes at least the quiescent state, the activated state, and the “desensitized” closed channel state, a process by which receptors become insensitive to agonists. . Different nAChR ligands can stabilize the conformational state of the receptor to which they preferentially bind. For example, the agonists ACh and (−)-nicotine stabilize the activated and desensitized states, respectively.

  Altered activity of nicotine receptors has been linked to many diseases. Some of these, such as myasthenia gravis and ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy), are associated with decreased nicotine transmission activity, either due to decreased receptor number or increased desensitization. . It has been hypothesized that nicotine receptor loss also results in cognitive deficits found in diseases such as Alzheimer's disease and schizophrenia.

  Because the effects of tobacco-derived nicotine are also mediated by the nicotine receptor, and the effect of nicotine stabilizes the receptor in a desensitized state, increased activity of the nicotine receptor can reduce smoking desire .

  Compounds that bind to nACHr have decreased cholinergic function, such as Alzheimer's disease, cognitive or attention disorder, attention deficit hyperactivity disorder, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, It has been suggested to treat a range of disorders including Tourette syndrome and Parkinson's disease.

  However, treatment with nicotinic receptor agonists that act at the same site as ACh is problematic. This is because ACh not only activates but also blocks receptor activity through processes including desensitization and uncompetitive blockade. Furthermore, sustained activation seems to induce persistent inactivation. Therefore, ACh agonists can be expected to enhance this activity simultaneously with a decrease in activity.

  In general, at nicotine receptors, and notably at the α7-nicotine receptor, desensitization limits the duration of action of the applied agonist.

式中、
Ａｒ¹は、アリール又はヘテロアリールから選択され、ここでアリールは、フェニル又はナフチルから選択され、そしてヘテロアリールは、フリル、チエニル、イミダゾリル、オキサゾリル、チアゾリル、ピロリル、ピリジル、ピラジニル、ピリミジニル又はキノリニルから選択され；
Ｒ³、Ｒ⁴及びＲ⁵は、それぞれ水素、Ｃ_1-4アルキル及びＣ_1-4アルコキシから独立して選択され；
Ｘは、次の式ＩＩ、ＩＩＩ、ＩＶ、Ｖ、ＶＩ又はＶＩＩの部分から選択され、

Ｒ¹及びＲ²は、それぞれ水素、ハロゲン、−Ｃ_1-6アルキル、−Ｃ_1-6アルコキシ、−Ｃ_2-6アルケニル、−Ｃ_2-6アルキニル、Ｃ_3-8シクロアルキル、−ＣＮ、−ＮＯ₂、−ＣＦ₃、−ＣＯＮＲ³Ｒ⁴、−Ｓ（Ｏ）_nＲ³（式中、ｎは０、１若しくは２である）、−ＮＲ³Ｒ⁴、−ＣＨ₂ＮＲ³Ｒ⁴、−ＯＲ³、−ＣＨ₂ＯＲ³又は−ＣＯ₂Ｒ³から独立して選択され、式中Ｒ³及びＲ⁴は、それぞれ水素又はＣ_1-4アルキルから独立して選択される。 The inventors have found that certain compounds can increase the effectiveness of agonists at the nicotinic acetylcholine receptor (nAChR). Compounds having this type of action are the following compounds of formula I:

Where
Ar ¹ is selected from aryl or heteroaryl, where aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl or quinolinyl Is;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy;
X is selected from the following moieties of formula II, III, IV, V, VI or VII;

R ¹ and R ² are each hydrogen, halogen, —C _1-6 alkyl, —C _1-6 alkoxy, —C _2-6 alkenyl, —C _2-6 alkynyl, C _3-8 cycloalkyl, —CN, ^{_{-NO 2, -CF 3, -CONR 3}} R 4, -S (O) n R 3 ( wherein, n is 0, 1 or ^{2), - NR 3 R 4} , -CH 2 NR 3 R 4 , —OR ³ , —CH ₂ OR ³ or —CO ₂ R ³ , wherein R ³ and R ⁴ are each independently selected from hydrogen or C _1-4 alkyl.

  The present invention also includes stereoisomers, enantiomers, in vivo hydrolysable precursors and pharmaceutically acceptable salts of the compounds of formula I, pharmaceutical compositions and formulations containing them, diseases and conditions alone or Methods of using them to treat in combination with other therapeutically effective compounds or substances, methods and intermediates used to make them, their use as drugs, these in the manufacture of drugs Includes use, and their use for diagnostic and analytical purposes.

  The compounds of the present invention are positive modulators that appear to be particularly useful in the treatment of conditions associated with reduced nicotine transmission. In the therapeutic context, such compounds can restore normal interneuron transmission without affecting the transient activation profile. In addition, positive modulators are not expected to cause long-term inactivation of the receptors, unlike when agonists are applied continuously.

式中、
Ａｒ¹は、アリール又はヘテロアリールから選択され、ここでアリールは、フェニル又はナフチルから選択され、そしてヘテロアリールは、フリル、チエニル、イミダゾリル、オキサゾリル、チアゾリル、ピロリル、ピリジル、ピラジニル、ピリミジニル又はキノリニルから選択され；
Ｒ³、Ｒ⁴及びＲ⁵は、それぞれ水素、Ｃ_1-4アルキル及びＣ_1-4アルコキシから独立して選択され；
Ｘは、次の式ＩＩ、ＩＩＩ、ＩＶ、Ｖ、ＶＩ又はＶＩＩの部分から選択され、

Ｒ¹及びＲ²は、それぞれ水素、ハロゲン、−Ｃ_1-6アルキル、−Ｃ_1-6アルコキシ、−Ｃ_2-6アルケニル、−Ｃ_2-6アルキニル、Ｃ_3-8シクロアルキル、−ＣＮ、−ＮＯ₂、−ＣＦ₃、−ＣＯＮＲ³Ｒ⁴、−Ｓ（Ｏ）_nＲ³（式中、ｎは０、１若しくは２である）、−ＮＲ³Ｒ⁴、−ＣＨ₂ＮＲ³Ｒ⁴、−ＯＲ³、−ＣＨ₂ＯＲ³又は−ＣＯ₂Ｒ³から独立して選択され、式中Ｒ³及びＲ⁴は、それぞれ水素又はＣ_1-4アルキルから独立して選択される。 In one aspect, the present invention includes the following compounds of formula I, as well as stereoisomers, enantiomers, in vivo hydrolysable precursors and pharmaceutically acceptable salts thereof.

Where
Ar ¹ is selected from aryl or heteroaryl, where aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl or quinolinyl Is;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy;
X is selected from the following moieties of formula II, III, IV, V, VI or VII;

R ¹ and R ² are each hydrogen, halogen, —C _1-6 alkyl, —C _1-6 alkoxy, —C _2-6 alkenyl, —C _2-6 alkynyl, C _3-8 cycloalkyl, —CN, ^{_{-NO 2, -CF 3, -CONR 3}} R 4, -S (O) n R 3 ( wherein, n is 0, 1 or ^{2), - NR 3 R 4} , -CH 2 NR 3 R 4 , —OR ³ , —CH ₂ OR ³ or —CO ₂ R ³ , wherein R ³ and R ⁴ are each independently selected from hydrogen or C _1-4 alkyl.

Ｒ¹及びＲ²は、それぞれ水素又はハロゲンから独立して選択される。 Particular embodiments of this aspect of the invention include the following compounds of formula I, and stereoisomers, enantiomers, in vivo hydrolysable precursors and pharmaceutically acceptable salts thereof, wherein
Ar ¹ is phenyl or pyridyl;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy;
X is selected from the following moieties of formula II, III, IV, V, VI or VII;

R ¹ and R ² are each independently selected from hydrogen or halogen.

  The most unique compounds of the present invention are the compounds described herein.

  In another aspect, the present invention is a method of treating or preventing a psychotic disorder, intellectual deficit disorder or a disease or condition in which modulation of α7 nicotine receptor is beneficial, said method comprising a therapeutically effective amount of the above Administration of a positive modulator of formula I or a diastereoisomer, enantiomer or pharmaceutically acceptable salt thereof.

  Particular aspects of the method of the invention include Alzheimer's disease, learning deficits, cognitive deficits, attention deficits, memory loss, Lewy body dementia, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania, manic depression, Parkinson It is a method for treating Alzheimer's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders with cholinergic synaptic deficiency, jet lag, nicotine addiction, pain, ulcerative colitis or irritable bowel syndrome.

  The treatment method of the present invention administers a positive modulator as the only active substance, thus modulating the activity of an endogenous nicotinic receptor agonist, such as acetylcholine or choline, or in combination with a nicotine receptor agonist Including any administration.

  In a particular form of this aspect of the invention, the method of treatment comprises treatment with an α7-nicotinic receptor modulator and an α7-nicotinic receptor agonist described herein. Examples of suitable α7-nicotinic receptor agonists are (−)-spiro [1-azabicyclo [2.2.2. ] Octane-3,5'-oxazolidine] -2'-one. Other α7-nicotinic receptor agonists useful for treatment in combination with the positive modulators of the present invention are described in International Publications WO 96/06098, WO 97/30998 and WO 99/03859.

  Another aspect of the present invention includes a process for preparing a compound of formula I.

  The positive modulators of the present invention are less toxic, more effective, longer acting, have a broader activity, more potent, have fewer side effects, are more easily absorbed, or other It has the advantage of having useful pharmacological properties.

  Acid addition salts are also within the scope of the present invention. Such salts include mineral salts such as hydrochloride and hydrobromide, and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate and fumaric acid. Salt. Acid addition salts of compounds of Formula I can be formed by reacting the free base, or salt, enantiomer, or protected derivative with one equivalent or more of a suitable acid. This reaction can be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which can be carried out in vacuo or by lyophilization. Can be removed. This reaction can be a metathesis step or can be performed on an ion exchange resin.

  The compounds of formula I may exist in tautomeric or enantiomeric forms, all of which are included within the scope of the invention. The various optical isomers can be isolated by separating the racemic mixture of the compounds using conventional techniques such as fractional crystallization or chiral HPLC. Alternatively, individual enantiomers can be generated by reacting the appropriate optically active starting material under reaction conditions that do not cause racemization.

  A further aspect of the invention provides a pharmaceutical composition for treating or preventing a condition or disorder described herein resulting from a dysfunction of neurotransmission of a nicotinic acetylcholine receptor in a mammal, preferably a human. Including. Such pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula I, an enantiomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt, effective to treat or prevent such disorders or conditions. Including possible carriers.

  Another aspect of the present invention provides a compound of formula I as described herein or a diastereoisomer, enantiomer or pharmaceutically acceptable salt thereof at least one pharmaceutically acceptable dilution. A pharmaceutical composition comprising an agent or carrier.

  In particular, this aspect of the invention provides a pharmaceutical composition, preferably mixed with a pharmaceutically acceptable diluent or carrier, preferably containing less than 80% and more preferably less than 50% by weight of a compound of the invention. To do.

Examples of diluents and carriers are as follows.
Tablets and dragees: lactose, starch, talc, stearic acid Capsules: tartaric acid or lactose Injectable solutions: water, alcohol, glycerin, vegetable oils Suppositories: natural or hardened oil or wax.

  Yet another pharmaceutical composition of the invention further comprises a nicotinic receptor agonist.

  Another aspect of the present invention provides a method for preparing a pharmaceutical composition, the method comprising including the ingredients in the composition by conventional methods.

  A still further aspect of the invention is the use of a compound of formula I, an enantiomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

  Certain aspects of the invention include psychotic disorders, intellectual deficit disorders, human diseases or conditions that benefit from modulation of α7 nicotinic receptors (Alzheimer's disease, learning deficits, cognitive deficits, attention deficits, memory loss, Lewy bodies Dementia, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania, manic depression, Parkinson's disease, Huntington's disease, Tourette syndrome, neurodegenerative disorder with cholinergic synaptic deficiency, jet lag, nicotine addiction, pain, Compounds of formula I as described herein or diastereoisomers, enantiomers or pharmaceutically acceptable thereof in the manufacture of a medicament for treating or preventing (including ulcerative colitis or irritable bowel syndrome) Use of salt.

  In certain forms, this aspect of the invention relates to a condition associated with a decrease in nicotine receptor transmission or a decrease in nicotine receptor density, which can be one of the diseases or conditions referred to herein. The use of a compound of the present invention in the manufacture of a medicament for treating or preventing a related condition, the treatment comprising administering to the patient this medicament comprising a therapeutically effective amount of the compound of the present invention.

  The manufacture of a medicament that either contains a positive modulator as the only active substance that results in modulation of the activity of the endogenous nicotinic receptor agonist, or contains a positive modulator in combination with a nicotine receptor agonist It is understood that This use thus provides for the manufacture of a medicament comprising a positive modulator and further comprising a nicotinic receptor agonist.

  In a particular form of this aspect of the invention, the agent or pharmaceutical composition comprises an α7-nicotine receptor modulator and an α7-nicotine receptor agonist as described herein. Examples of suitable α7-nicotinic receptor agonists are (−)-spiro [1-azabicyclo [2.2.2. ] Octane-3,5'-oxazolidine] -2'-one. Other α7-nicotinic receptor agonists useful for drugs in combination with the positive modulators of the invention are described in International Publications WO 96/06098, WO 97/30998 and WO 99/03859.

  A still further aspect of the present invention is a method of treating or preventing the mammals and particularly human conditions or disorders referred to herein resulting from dysfunction of nicotinic acetylcholine receptor neurotransmission.

  Certain forms of this aspect of the invention provide a method of treating a condition associated with reduced nicotine transmission, which involves receiving a medically effective amount of nicotine in a patient in need of such treatment. This is done by administering a positive modulator of a body agonist, which positive modulator has the ability to increase the effectiveness of the nicotinic receptor agonist.

  In the compositions, uses and methods described above, the amount of compound of formula I used will, of course, vary depending on the compound used, the mode of administration and the desired treatment. In general, however, good results have been obtained when the compounds of the invention are administered to give a daily dose of about 0.1 mg / kg to about 20 mg / kg of the animal's body weight, which dose is given 1-4 times per day. In divided doses or in sustained release form. For humans, the total daily dosage is in the range of 5 mg to 1,400 mg, more preferably in the range of 10 mg to 100 mg, and unit dosage forms suitable for oral administration include solid or liquid pharmaceutical carriers or diluents Mix to contain 2 mg to 1,400 mg of this compound.

  In the compositions, uses and methods of the present invention, a compound of formula I, an enantiomer thereof or a pharmaceutically acceptable salt thereof is used as such in the form of a pharmaceutical formulation suitable for enteral or parenteral administration. Or can be used in compositions containing other pharmacologically active agents. For example, a composition comprising other pharmacologically active factors may comprise a positive modulator compound of formula I with a nicotine receptor agonist.

  Accordingly, the present invention comprises a positive modulator as the only active substance, and thus a composition that modulates the activity of an endogenous nicotine receptor agonist, such as acetylcholine or choline, and a composition that comprises a positive modulator in combination with a nicotine receptor agonist including. Thus, this pharmaceutical composition comprising a positive modulator of a nicotine receptor agonist can further comprise a nicotine receptor agonist.

  Examples of diseases or conditions for which aspects of the invention are useful include schizophrenia, mania and manic depression, anxiety, Alzheimer's disease, learning deficits, cognitive deficits, attention deficits, memory loss, Lewy body dementia, excessive attention deficits. Active disorders, Parkinson's disease, Huntington's disease, Tourette syndrome, jet lag, and nicotine addiction (including those resulting from exposure to nicotine-containing products).

  The positive modulators of the present invention can be administered for either the purpose of modulating the action of an endogenous nicotinic receptor agonist, such as acetylcholine or choline, or for modulating the action of an exogenous nicotinic receptor agonist. Is understood.

Experimental Methods The activity of the compounds of the invention can be measured in the tests shown below:
(A) Current recording of Xenopus oocytes Xenopus oocytes provided an effective means of assessing the function of proteins thought to be subunits of ligand-gated ion channels. Injection of RNA transcribed from a cDNA clone encoding the appropriate receptor subunit, or injection of cDNA with the coding sequence located downstream of the promoter will result in a functional ligand-gated ion on the surface of the oocyte. This results in the appearance of channels (see, for example, Boulter et al. (1987) Proc. Natl. Acad. Sci. USA 84, 7763-7767).

  As a result, one convenient technique for assessing enhanced nicotine efficacy is a two-electrode voltage clamp technique that records from Xenopus oocytes that express the cRNA-derived α7-nicotine receptor.

Xenopus laevis frogs (Xenopus I, Kalamazoo, MI) could be anesthetized with 0.15% tricaine. Oocytes were removed into OR2 solution (82 mM NaCl, 2.5 mM KCl, 5 mM HEPES, 1.5 mM NaH ₂ PO ₄ , 1 mM MgCl ₂ , 0.1 mM EDTA; pH 7.4). The oocytes were follicularly removed by two incubations for 60 minutes on a platform oscillating at 1 Hz in 25 mL of OR2 containing 0.2% collagenase 1A (Sigma), and Leibovitz L-15 medium (50 μg / could be stored in ml gentamicin, 10 units / ml penicillin and 10 μg / ml streptomycin. Approximately 50 ng of cRNA was injected into each oocyte the next day.

Oocytes were placed in an external recording solution consisting of 90 mM NaCl, 1 mM KCl, 1 mM MgCl ₂ , 1 mM BaCl ₂ , 5 mM HEPES, pH 7.4. Two-electrode voltage-clamp recording could be performed using an Ocycle Clamp amplifier (eg, OC 725C; Warner Instrument, Hamden, CT). Oocytes were fixed with two electrodes with a chip resistance of 1-2 MΩ filled with 3 M KCl. Recording began when the membrane potential became stable at negative to -20 mV (resting membrane potential became more negative when Ba ⁺⁺ in the immersion solution replaced Ca ⁺⁺ ). The membrane potential was fixed at -80 mV. Oocytes were continuously perfused at 5 mL / min with a recording solution with or without acetylcholine.

Current amplitude was measured from baseline to peak. EC ₅₀ values and Hill slope, which are maximum effects, could be estimated by fitting the data to a logical expression using, for example, GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.).

The increase in agonist efficacy elicited by positive modulators could be calculated in two ways:
(1) As a percent enhancement of current amplitude defined as 100 (Im-Ic) / Ic, where Im is current amplitude in the presence of modulator and Ic is in the absence of modulator Current).
(2) As a percent enhancement of the “area under the curve” of the agonist trace, which is the integration of the net current over a period of time. The area under the curve is a general representation of the total ion flux through the channel.

(B) Ca ⁺⁺ flux imaging Imaging of Ca ⁺⁺ flux through the expressed nAChR [alpha] 7 receptors transiently in cell line is another means of assaying modulator activity.

  Cells expressing the α7 receptor (eg, HEK-293 cells or cell-cultured neurons) were grown to confluence in 96 well plates and supplied with a fluorescent calcium indicator, fluo-3 . To screen for α7 modulator activity, 96-well plates were placed in a fluorescence imaging plate reader (FLIPR) and test compounds along with α7 agonist were given to all wells simultaneously. Receptor activation was measured by calcium influx into the cells, which was quantified by the increase in fluorescence intensity of each well recorded simultaneously by the FLIPR. The modulator effect was shown by an increase in fluorescence over that induced by agonist alone. Similarly, to test nAChR α7 agonist activity, test compounds along with α7 modulators were given to all wells simultaneously. Receptor activation was measured by calcium influx into the cells, which was quantified by an increase in fluorescence intensity in each well. Agonist effects were determined by fluorescence increase over that induced by modulator alone.

Cell cultured neurons could be prepared as follows. An 18-day-old Sprague-Dawley rat fetus (E-18) is aseptically removed from a pregnant female rat, sacrificed, the frontal cortex of the brain removed, the meninges detached, and the cleaned cortex Placed in cold HBSS. If hippocampal tissue was desired, the hippocampus was excised from the cortex and then placed in cold HBSS. The tissue was mechanically dispersed and washed once in HBSS (4 ° C., 200 g for 30 minutes), glutamine, antibiotics, potassium chloride, insulin, transferrin, selenium and 5% heat-inactivated fetal calf serum (FBS Resuspended in Sato medium supplemented with (without endotoxin) and placed in each of 24-well plates (coated with poly-L-lysine). The wells could contain glass cover slips that were also coated with PLL. The plate was incubated at 37 ° C. in a CO ₂ incubator. After 24 hours, the medium was removed, fresh medium was added, and the cells were allowed to grow for at least an additional 11 days, feeding if necessary.

The compounds of the present invention cause a 2-fold increase in baseline current (100% potentiation) when measured from baseline to peak at low concentrations of acetylcholine (30 μM), which is useful therapeutic activity. It is expected to have The compounds of the present invention also increased Ca ⁺⁺ flux when applied to the Ca 2+ flux-imaging assay. Any increase in Ca ⁺⁺ flux caused by the compounds of the present invention (measured in fluorescence intensity units) compared to Ca ⁺⁺ flux caused by agonist alone indicates that it is expected to have useful therapeutic activity. It was.

  The compounds of the present invention may be less toxic, may be more effective, may work longer, may have broader activity, may be more potent, may produce fewer side effects, more easily Have the advantage of being absorbed or having other useful pharmacological properties.

General Experimental Methods The present invention is illustrated by, but is not limited to, the examples described herein, in which the following terms, abbreviations and abbreviations apply, unless applicable, and unless otherwise indicated: The condition is used:
Commercial reagents were used without further purification.

  The following abbreviations are used herein: aq. Atm, atmospheric pressure; BOC, 1,1-dimethylethoxycarbonyl; DCM, dichloromethane; DMF, N, N-dimethylformamide; DMSO, dimethyl sulfoxide; EtOH, ethanol; Et20, diethyl ether; EtOAc, ethyl acetate; HPLC, high pressure liquid chromatography; HOBT, 1-hydroxybenzotriazole; MeOH, methanol; min, minutes; MS, mass spectrum; NMR, nuclear magnetic resonance; psi, pounds per square inch; RT, room temperature; , Saturated; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran.

  Temperatures are given in degrees Celsius (° C); unless otherwise stated, operations were performed at room temperature or ambient temperature (18-25 ° C).

  The organic solution was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate; solvent evaporation was carried out using a rotary evaporator under reduced pressure (4.5-30 mmHg) at a bath temperature up to 60 ° C.

  Chromatography means flash column chromatography on silica gel unless otherwise stated; the composition of the solvent mixture was given as a volume percentage or volume ratio.

  When given, the NMR data is in the form of proton δ values (given in parts per million (ppm) relative to tetramethylsilane as an internal standard) that are useful for major diagnostics measured at 300 MHz.

  Melting points are uncorrected.

  Mass spectra were recorded using either a Hewlett Packard 5988A or MicroMass Quattro-1 mass spectrometer and reported as m / z relative to the parent molecular ion. Room temperature refers to 20-25 ° C.

  The reactions described herein were usually carried out at a pressure of about 1 to about 3 atmospheres, preferably ambient pressure (about 1 atmosphere) unless otherwise stated.

  Unless otherwise stated, the reaction was carried out under an inert atmosphere, preferably a nitrogen atmosphere.

  Compounds of the invention and intermediates could be isolated from these reaction mixtures by standard techniques.

As used herein, unless otherwise stated, “C _1-6 alkyl” includes methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl. , S-butyl and the like, and the C _3-8 alkyl moiety may be linear, branched or cyclic, for example cyclopropyl or cyclobutyl.

As used herein, unless otherwise stated, “C _2-4 alkenyl” includes 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl. It is not limited to these.

As used herein, unless otherwise stated, “C _2-4 alkynyl” includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. However, it is not limited to these.

  As used herein, “halogen” means fluoride, chloride, bromide or iodide.

Examples The compounds of the present invention may generally be produced by the methods described in Examples 1-5. In all the methods described herein, if necessary, hydroxy, amino or other reactive groups can be protected with protecting groups as will be understood by those skilled in the art.

クロロホルム中のメシトニトリル−Ｎ−オキシド１ａ（０.２００ｇ、１.２３ｍｍｏｌ）及び４−ビニル−ベンゼンスルホンアミド１ｂの撹拌溶液を、１８時間加熱して還流させた。この残留物を濃縮し、そしてクロマトグラフィー（ＳｉＯ₂、ＣＨＣｌ₃／ＭｅＯＨ、勾配はＭｅＯＨ中０〜１０％）を用いて精製して、固体として表題化合物を得た（０.０３０、７％）：¹Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃，３００Ｋ）δ２.１８（ｓ，６Ｈ）、２.３３（ｓ，３Ｈ）、３.０３−３.１１（ｂｒ ｍ，１Ｈ）、３.６３−３.７２（ｂｒ ｍ，１Ｈ）、４.８６（ｂｒ ｓ，２Ｈ）、５.８０−５.８５（ｂｒ ｍｓ，１Ｈ）、６.８８（ｓ，２Ｈ）、７.５７（ｄ，２Ｈ，Ｊ＝７.２Ｈｚ）、７.９５（ｄ，２Ｈ，Ｊ＝７.２Ｈｚ。ＡＰＣＩ（ｍ＋１）、ｍ／ｚ＝３４５。ＬＣ／ＭＳ＝２.３８。 Example 1
4- [3- (2,4,6-Trimethyl-phenyl) -4,5-dihydro-isoxazol-5-yl] -benzenesulfonamide

A stirred solution of methitonitrile-N-oxide 1a (0.200 g, 1.23 mmol) and 4-vinyl-benzenesulfonamide 1b in chloroform was heated to reflux for 18 hours. The residue was concentrated and chromatographed _{(SiO 2, CHCl 3 / MeOH} , gradient 0 to 10% in MeOH) as eluant to give the title compound as a solid (0.030,7%) : ¹ H NMR (300 MHz, CDCl ₃ , 300 K) δ 2.18 (s, 6H), 2.33 (s, 3H), 3.03-3.11 (br m, 1H), 3.63-3. 72 (br m, 1H), 4.86 (br s, 2H), 5.80-5.85 (br ms, 1H), 6.88 (s, 2H), 7.57 (d, 2H, J = 7.2 Hz), 7.95 (d, 2H, J = 7.2 Hz, APCI (m + 1), m / z = 345. LC / MS = 2.38.

クロロホルム中のメシトニトリル−Ｎ−オキシド１ａ（０.０７３ｇ、０.３３ｍｍｏｌ）及び２−クロロ−４−エチニル−ベンゼンスルホンアミド２ｂ（０.０３４ｇ、０.３３ｍｍｏｌ）の撹拌溶液を、１８時間加熱して還流させた。この残留物を濃縮し、そしてクロマトグラフィー（ＳｉＯ₂、ＥｔＯＡｃ／Ｈｅｘ、勾配はＥｔＯＡｃ中０〜２０％）を用いて精製して、固体として表題化合物を得た（０.０３７、２８％）：¹Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃，３００Ｋ）δ２.１８（ｓ，６Ｈ）、２.３３（ｓ，３Ｈ）、５.１８（ｂｒ ｓ，２Ｈ）、６.６２（ｓ，１Ｈ）、６.９７（ｓ，２Ｈ）、７.８５（ｄ，１Ｈ，Ｊ＝８.０Ｈｚ）、８.０２（ｓ，１Ｈ）、８.２３（ｄ，１Ｈ，Ｊ＝８.０Ｈｚ）。ＡＰＣＩ（ｍ＋１）、ｍ／ｚ＝３７７。ＬＣ／ＭＳ＝２.７１。 Example 2
2-Chloro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide

A stirred solution of methitonitrile-N-oxide 1a (0.073 g, 0.33 mmol) and 2-chloro-4-ethynyl-benzenesulfonamide 2b (0.034 g, 0.33 mmol) in chloroform was heated for 18 hours. Refluxed. The residue was concentrated and chromatographed (SiO _2, EtOAc / Hex, gradient from 0 to 20% in EtOAc) as eluant to as a solid to give the title compound (0.037,28%): ¹ H NMR (300 MHz, CDCl ₃ , 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 5.18 (brs, 2H), 6.62 (s, 1H), 6. 97 (s, 2H), 7.85 (d, 1H, J = 8.0 Hz), 8.02 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz). APCI (m + 1), m / z = 377. LC / MS = 2.71.

トリエチルアミン（２４ｍＬ）中の２−クロロ−４−ブロモ−ベンゼンスルホンアミド２ｄ（１.０２ｇ、３.７７ｍｍｏｌ）及びトリメチルシリルアセチレン（ｔｒｉｍｅｔｈｌｙｓｉｌｙｌａｃｅｔｙｌｅｎｅ）（０.５５ｇ、５.６６ｍｍｏｌ）の撹拌溶液に、ヨウ化銅（Ｉ）（０.０２８ｇ、０.１４ｍｍｏｌ）及びテトラキストリフェニルホスフィノパラジウム（０）（０.０６３ｇ、０.０５ｍｍｏｌ）を添加した。この混合物を、１８時間８０℃に加熱した。この混合物を濃縮し、そしてジエチルエーテルを残留物に添加した。得られる固体を濾別した。この固体に、ＭｅＯＨ（１００ｍＬ）及びＫ₂ＣＯ₃（８.６６ｍｍｏｌ）を添加し、そしてこの反応物を１８時間撹拌した。この反応物を濃縮し、そしてＣＨＣｌ₃とＨ₂Ｏとの間で分配した。沈殿した淡褐色の固体を濾過によって回収し、そしてさらに精製せずに用いた。 Preparation of 2-chloro-4-ethynyl-benzenesulfonamide 2b

To a stirred solution of 2-chloro-4-bromo-benzenesulfonamide 2d (1.02 g, 3.77 mmol) and trimethylsilylacetylene (0.55 g, 5.66 mmol) in triethylamine (24 mL) was added copper iodide. (I) (0.028 g, 0.14 mmol) and tetrakistriphenylphosphinopalladium (0) (0.063 g, 0.05 mmol) were added. The mixture was heated to 80 ° C. for 18 hours. The mixture was concentrated and diethyl ether was added to the residue. The resulting solid was filtered off. To this solid was added MeOH (100 mL) and K ₂ CO ₃ (8.66 mmol) and the reaction was stirred for 18 hours. The reaction was concentrated and partitioned between CHCl ₃ and H ₂ O. The precipitated light brown solid was collected by filtration and used without further purification.

実施例３を、３−クロロ−４−エチニル−ベンゼンスルホンアミド３ｂを用いて実施例２と類似の方法で調製した。物質を、クロマトグラフィー（ＣＨ₂Ｃｌ₂、ＳｉＯ₂）を用いて単離し、次いで予備的ＨＰＬＣ（アセトニトリル／Ｈ₂Ｏ勾配）上で再び精製して、白色固体として表題化合物を得た（０.０１２ｇ、６％）：¹Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃，３００Ｋ）δ２.１８（ｓ，６Ｈ）、２.３３（ｓ，３Ｈ）、５.００（ｂｒ ｓ，２Ｈ）、６.７８（ｄ，Ｊ＝４.２Ｈｚ）、１Ｈ）、６.９６（ｓ，１Ｈ）、７.７７（ｄ，１Ｈ，Ｊ＝１１.０Ｈｚ）、７.８５（ｓ，Ｊ＝８.４Ｈｚ，１Ｈ）、８.１９−８.２４（ｍ，１Ｈ）。ＡＰＣＩ（ｍ＋１）、ｍ／ｚ＝３６１。ＬＣ／ＭＳ＝２.４２。 Example 3:
3-Fluoro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide

Example 3 was prepared in an analogous manner to Example 2 using 3-chloro-4-ethynyl-benzenesulfonamide 3b. The material was isolated using chromatography (CH ₂ Cl ₂ , SiO ₂ ) and then purified again on preparative HPLC (acetonitrile / H ₂ O gradient) to give the title compound as a white solid (0. 012 g, 6%): ¹ H NMR (300 MHz, CDCl ₃ , 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 5.00 (br s, 2H), 6.78 (d , J = 4.2 Hz), 1H), 6.96 (s, 1H), 7.77 (d, 1H, J = 11.0 Hz), 7.85 (s, J = 8.4 Hz, 1H), 8.19-8.24 (m, 1H). APCI (m + 1), m / z = 361. LC / MS = 2.42.

実施例４を、４−エチニル−ベンゼンスルホンアミド４ｂを用いて実施例２と類似の方法で調製した。物質を、クロマトグラフィー（ＥｔＯＡｃ／ヘキサン ２０／８０、ＳｉＯ₂）を用いて単離して、白色固体として表題化合物を得た（０.０１１ｇ、８％）：¹Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ₃，３００Ｋ）δ２.１８（ｓ，６Ｈ）、２.３３（ｓ，３Ｈ）、４.８６（ｂｒ ｓ，２Ｈ）、６.５９（ｓ，１Ｈ）、６.９６（ｓ，２Ｈ）、７.９５（ｄ，Ｊ＝８.４Ｈｚ，２Ｈ）、８.０６（ｄ，Ｊ＝８.４Ｈｚ，２Ｈ）。ＡＰＣＩ（ｍ＋１）、ｍ／ｚ＝３４３。ＬＣ／ＭＳ＝２.６０。 Example 4:
4- [3- (2,4,6-Trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide

Example 4 was prepared in an analogous manner to Example 2 using 4-ethynyl-benzenesulfonamide 4b. The material was isolated using chromatography (EtOAc / hexane 20/80, SiO ₂ ) to give the title compound as a white solid (0.011 g, 8%): ¹ H NMR (300 MHz, CDCl ₃ , 300K). ) Δ 2.18 (s, 6H), 2.33 (s, 3H), 4.86 (br s, 2H), 6.59 (s, 1H), 6.96 (s, 2H), 7.95 (D, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H). APCI (m + 1), m / z = 343. LC / MS = 2.60.

実施例５を、４−エチニル−ベンゼンスルホンアミド５ｂを用いて実施例２と類似の方法で調製した。物質を、クロマトグラフィー（ＥｔＯＡｃ／ヘキサン ２０／８０、ＳｉＯ₂）を用いて単離して、白色固体として表題化合物を得た（０.０９１ｇ、３０％）：¹Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃，３００Ｋ）δ２.１８（ｓ，６Ｈ）、２.３３（ｓ，３Ｈ）、５.１０（ｂｒ ｓ，２Ｈ）、６.６０（ｓ，１Ｈ）、６.９６（ｓ，２Ｈ）、７.６８−７.７３（ｂｒ ｍ，２Ｈ）、８.０３（ａｐｐ ｔ，Ｊ＝７.５Ｈｚ，１Ｈ）。ＡＰＣＩ（ｍ＋１）、ｍ／ｚ＝３６１。ＬＣ／ＭＳ＝２.６５。 Example 5:
2-Fluoro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide

Example 5 was prepared in an analogous manner to Example 2 using 4-ethynyl-benzenesulfonamide 5b. The material was isolated using chromatography (EtOAc / hexane 20/80, SiO ₂ ) to give the title compound as a white solid (0.091 g, 30%): ¹ H NMR (300 MHz, CDCl ₃ , 300K). ) Δ 2.18 (s, 6H), 2.33 (s, 3H), 5.10 (br s, 2H), 6.60 (s, 1H), 6.96 (s, 2H), 7.68 -7.73 (brm, 2H), 8.03 (appt, J = 7.5 Hz, 1H). APCI (m + 1), m / z = 361. LC / MS = 2.65.

  The compounds of Examples 6 and 7 could be prepared using methods substantially similar to those described in the above examples.

Example 6:
4- [3- (2,4,6-Trimethyl-phenyl)-[1,2,4] oxadiazol-5-yl] -benzenesulfonamide

Example 7:
4- [3- (4-Methoxy-2,3-dimethyl-phenyl) -4,5-dihydro-isoxazol-5-yl] -benzenesulfonamide

Claims (16)

Formula I:

And the stereoisomers, enantiomers, in vivo hydrolysable precursors and pharmaceutically acceptable salts thereof.
Where
Ar ¹ is selected from aryl or heteroaryl, where aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl or quinolinyl Is;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy;
X represents the following formula II, III, IV, V, VI or VII:

Selected from
R ¹ and R ² are each hydrogen, halogen, —C _1-6 alkyl, —C _1-6 alkoxy, —C _2-6 alkenyl, —C _2-6 alkynyl, C _3-8 cycloalkyl, —CN, ^{_{-NO 2, -CF 3, -CONR 3}} R 4, -S (O) n R 3 ( wherein, n is 0, 1 or ^{2), - NR 3 R 4} , -CH 2 NR 3 R 4 , —OR ³ , —CH ₂ OR ³ or —CO ₂ R ³ , wherein R ³ and R ⁴ are each independently selected from hydrogen or C _1-4 alkyl. Ar ¹ is phenyl or pyridyl;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy;
X represents the following formula II, III, IV, V, VI or VII:

Selected from
R ¹ and R ² are each independently selected from hydrogen or halogen,
2. The compound of claim 1, and stereoisomers, enantiomers, in vivo hydrolysable precursors and pharmaceutically acceptable salts thereof. Less than:
4- [3- (2,4,6-trimethyl-phenyl) -4,5-dihydro-isoxazol-5-yl] -benzenesulfonamide;
2-chloro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide;
3-fluoro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide;
4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide;
2-Fluoro-4- [3- (2,4,6-trimethyl-phenyl) -isoxazol-5-yl] -benzenesulfonamide;
4- [3- (2,4,6-trimethyl-phenyl)-[1,2,4] oxadiazol-5-yl] -benzenesulfonamide, and 4- [3- (4-methoxy-2, 2. A compound according to claim 1 selected from 3-dimethyl-phenyl) -4,5-dihydro-isoxazol-5-yl] -benzenesulfonamide.   A method of treating or preventing a disease or condition comprising administering a therapeutically effective amount of the compound of claim 1 to a patient suffering from a disease or condition in which modulation of α7 nicotine receptor is beneficial.   5. The method of claim 4, wherein the disease or condition is anxiety, schizophrenia, mania or manic depression.   A method of treating or preventing a nervous system disorder, psychotic disorder or intellectual deficit disorder comprising administering a therapeutically effective amount of the compound of claim 1.   Disability is Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's disease, Tourette syndrome, neurodegenerative disorder with deficiency of cholinergic synapse, jet lag, nicotine 7. The method of claim 6, wherein the method is addiction, desire, pain or ulcerative colitis.   A method of inducing smoking cessation comprising administering an effective amount of a compound of claim 1.   A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent, lubricant or carrier.   A method of treating or preventing a disease or condition comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a patient suffering from a disease or condition in which activation of α7 nicotinic receptor is beneficial. .   11. The method of claim 10, wherein the disease or condition is anxiety, schizophrenia, mania or manic depression.   A method of treating or preventing a nervous system disorder, psychotic disorder or intellectual deficit disorder comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9.   Disability is Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's disease, Tourette syndrome, neurodegenerative disorder with deficiency of cholinergic synapse, jet lag, nicotine 13. The method of claim 12, wherein the method is addiction, desire, pain or ulcerative colitis.   A method of inducing smoking cessation comprising administering an effective amount of the pharmaceutical composition of claim 9.   Nervous system disorder, psychotic disorder, intellectual deficit disorder, Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, In the manufacture of a medicament for treating or preventing a human disease or condition beneficial to activation of an α7 nicotinic receptor selected from a neurodegenerative disorder having a deficiency of Huntington's disease, Tourette's syndrome or cholinergic synapses Use of the described compounds, their enantiomers or pharmaceutically acceptable salts thereof.   Claims in the manufacture of a medicament for treating or preventing jet lag, pain or ulcerative colitis, or a medicament that facilitates cessation of smoking, or a remedy for desire including those resulting from exposure to nicotine addiction or nicotine-containing products Use of the compound according to Item 1.