WO2001032622A1 - Positive modulators of nicotinic receptor agonists - Google Patents

Abstract

A compound of Formula (I), wherein R1 represents hydrogen, C¿1?-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or (CH2)nAr; W represents C(O), C(O)O, C(O)NR?6¿, or a bond; R2 represents hydrogen, Ar, or (CH¿2?)pCH[(CH2)qR?7](CH¿2)tR8; or together R?2 and R6¿ represent (CH¿2?)jY(CH2)k; R?3 and R5¿ independently represent hydrogen, halogen, or C¿1?-C4 alkyl; X represents oxygen, or NH; R?4¿ represents hydrogen, C¿1?-C4 alkyl(CH2)uAr, R?9¿CO, or R9SO2; R6 represents hydrogen, C¿1?-C4 alkyl, aryl or heteroaryl, or together R?2 and R6¿ represent (CH¿2?)jY(CH2)k; R?7 and R8¿ independently represent hydrogen, halogen, CN, -C CH, N¿3?, CF3, NO2, Ar, OR?10, NR10R11¿, C(O)OR10, OC(O)R10, C(O)NR?10R11, NR10C(O)R11, SO¿2NR?10R11, or NR10SO¿2R11; R9 represents C¿1?-C4 alkyl, or Ar; Ar represents phenyl, naphthyl, or a 5- or 6-membered heterocyclic ring containing 0-3 nitrogens, 0-1 sulfurs and 0-1 oxygens; Ar is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (CH2)naryl, CN, NO2, CF3, OR?12, NR12R13¿ and COOR?12; R10, R11, R12 and R13¿ independently represent hydrogen, C¿1?-C4 alkyl, aryl, or heteroaryl; or together R?10 and R11¿ and/or R?12 and R13¿ independently represent (CH¿2?)jY(CH2)k; Y represents oxygen, sulfur, NR?14¿, or a bond; j is 2-4; k, m, n, p, q, t and u are independently 0-2; R14 represents hydrogen, C¿1?-C4 alkyl, aryl or heteroaryl; or an enantiomer thereof,and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially for treatment of conditions associated with reductions in nicotinic transmission. The compounds of the invention enhance the efficacy of agonists at nicotinic receptors.

Description

POSΠTVE MODULATORS OF NICOTINIC RECEPTOR AGONISTS

The present invention relates to novel compounds or pharmaceutically acceptable salts thereof, processes for prepaπng them, pharmaceutical compositions containing them and their use in therapy. The novel compounds referred to are positive modulators of nicotmic receptor agonists, said positive modulator having the capability to increase the efficacy of the said nicotmic receptor agonists. Background Art

Cho nergic receptors normally bind the endogenous neurotransmitter acetylcho ne (ACh), thereby tπggeπng the opening of ion channels. ACh receptors in the mammalian central nervous system can be divided into muscaπnic (mAChR) and nicotmic (nAChR) subtypes based on the agonist activities of muscaπne and nicotine, respectively. The nicotmic acetylchohne receptors are hgand-gated ion-channels containing five subumts (for reviews, see Colquhon et al (1997) Advances in Pharmacology 39, 191-220; Williams et al. (1994) Drug News & Perspectives 7, 205-223; Doherty et al. (1995) Annual reports in Medicinal

Chemistry 30, 41-50). Members of the nAChR gene family have been divided into two groups based on their sequences; members of one group are considered β subumts, while a second group are classified as a subumts (for reviews, see Karhn & Akabas (1995) Neuron 15, 1231- 1244; Sargent (1993) Annu. Rev. Neurosci. 16, 403-443). Three of the α subumts, al, α8 and α9, form functional receptors when expressed alone and thus presumably form homo- ohgomeπc receptors.

An allosteπc transition state model of the nAChR involves at least a resting state, an activated state and a "desensitized" closed channel state (Williams et al., supra; Karhn & Akabas, supra). Different nAChR hgands can thus differentially stabilize the conformational state to which they preferentially bind. For example, the agonists ACh and (-)-nιcotme stabilize the active and desensitized states.

Changes of the activity of nicotmic receptors has been implicated in a number of diseases. Some of these, e.g myasthenia gravis and ADNFLE (autosomal dominant nocturnal front lobe epilepsy) (Kuryatov et al. (1997) J. Neurosci. 17(23):9035-47), are associated with reductions in the activity of nicotinic transmission either through a decrease m receptor number or increased desensitization. a process by which receptors become insensitive to the agonist. Reductions in nicot ic receptors have also been hypothesized to mediate cognitive deficits seen in diseases such as Alzheimer's disease and schizophrenia (Williams et al . supra) The effects of nicotine from tobacco are also mediated by nicotinic receptors Increased activity of nicotmic receptors may reduce the desire to smoke

The use of compounds which bind nicotmic acetylchohne receptors in the treatment of a range of disorders involving reduced cholmergic function such as Alzheimer's disease, cognitive or attention disorders, attention deficit hyperactivity disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia. Tourette's syndrome, and Parkinson's disease has been discussed m McDonald et al. (1995) "Nicotmic Acetylchohne Receptors: Molecular Biology, Chemistry and Pharmacology", Chapter 5 in Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc , San Diego, CA: and m Williams et al., supra.

However, treatment with nicotmic receptor agonists which act at the same site as ACh is problematic because ACh not only activates, but also blocks receptor activity through processes which include desensitization (for a review, see Ochoa et al. (1989) Cellular and Molecular Neurobiology 9, 141-178) and uncompetitive blockade (open-channel block).

Forman & Miller (1988) Biophysical Journal 54(1): 149-58. Furthermore, prolonged activation appears to induce a long-lasting mactivation. Therefore agonists of ACh can be expected to reduce activity as well as enhance it At nicotmic receptors in general, and, of particular note, at the cc7-nιcotιmc receptor, desensitization limits the duration of current duπng agonist application.

Disclosure of the Invention

It has surprisingly been found that certain compounds can enhance the efficacy of agonists at nicotmic receptors. It is believed that compounds having this type of action (hereinafter referred to as "positive modulators") will be particularly useful for treatment of conditions associated with reductions nicotmic transmission. In a therapeutic setting such compounds could restore normal intemeuronal communication without affecting the temporal profile of activation. In addition, they would not produce long-term mactivation as prolonged application of agonist may

According to the invention it has been found that compounds of Formula I:

wherein:

R¹ represents hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C -C₄ alkynyl, or (CH₂)_nAr; W represents C(O), C(O)O, C(O)NR⁶, or a bond; R² represents hydrogen, Ar, or (CH₂) _pCH[(CH₂) _qR⁷](CH₂) _tR⁸; or together R² and R⁶ represent (CH₂)_jY(CH₂) ;

R^J and R³ independently represent hydrogen, halogen, or C₁-C₄ alkyl;

X represents oxygen, or NH;

R⁴ represents hydrogen, C C₄ alkyl, (CH₂) _uAr, R⁹CO, or R⁹SO₂; R represents hydrogen, C₁-C4 alkyl, aryl, or heteroaryl; or together R" and R represent (CH₂)jY(CH₂) k;

R⁷ and R⁸ independently represent hydrogen, halogen, CN, -C≡CH, N₃, CF , NO₂, Ar, OR¹⁰, NR¹⁰R^U, C(0)OR¹⁰, OC(O)R¹⁰, C(O)NR¹⁰R^π, NR¹⁰C(O)Rⁿ, SO₂NR^I0Rⁿ , or NR^,0SO₂Rⁿ; R⁹ represents C₁-C₄ alkyl, or Ar;

Ar represents phenyl, naphthyl, or a 5- or 6-membered heterocyclic ring containing 0-3 nitrogens, 0-1 sulfurs and 0-1 oxygens;

Ar is optionally substituted with one or more substituents independently selected from: hydrogen, halogen. C₁-C4 alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, (CH₂)„aryl, CN, NO₂, CF_3l OR¹², NR¹²R¹³ and COOR¹²;

R¹⁰, R¹¹, R^1" and R¹³ independently represent hydrogen, -C₄ alkyl, aryl, or heteroaryl; or together R¹⁰ and R¹¹ and/or R¹² and R^lj independently represent (CH₂)_jY(CH₂) ki

Y represents oxygen, sulfur, NR¹⁴, or a bond; j is 2-4; k, m, n, p, q, t, and u are independently 0-2;

R¹⁴ represents hydrogen, C1-C4 alkyl, aryl or heteroaryl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof, enhance the efficacy of agonists at nicotinic receptors.

Preferred compounds of the invention are compounds of Formula I, wherein;

R⁴ represents hydrogen, methyl, or benzyl; R¹ represents hydrogen, or methyl;

R^J and R⁵ independently represent hydrogen;

W represents a bond;

X represents oxygen;

R² represents hydrogen, methyl; (4-benzyl)oxazolin-2-yl, or A; A represents COOR¹⁵, or CONR¹⁶R¹⁷;

R¹³ represents hydrogen, or CH₂CH₃;

R¹⁶ represents hydrogen, or Cι-C alkyl;

R¹⁷ represents C,-C₄ alkyl, (CH₂) _n-Phenyl-Y, or CHR^{I 8}CHR¹⁹-Z;

R¹⁸ represents hydrogen, phenyl, or benzyl; R¹⁹ represents hydrogen, or benzyl;

R²⁰ represents benzyl;

Y represents hydrogen, Cl, N(CH₃) ₂, or phenyl;

Z represents Cl, OH, F, N₃, or NH₂; n is 0-4; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include the following:

Ethyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxylate ;

4-Ηydroxy-l -methyl- lH-indole-2-carboxylic acid;

N-Phenethyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide; N-Methyl-N-Phenethyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide;

N-(4-Dimethylaminobenzyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide;

N-(4-Chlorobenzyl) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide;

N-Benzyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide;

N-(4-Phenylbuty 1) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide; N-(3-Phenylpropyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide;

N-Phenyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide;

N-(4-Chlorophenyl) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide; N-(3-Bιphenyl) 4-hydroxy- l-methyl-lH-ιndole-2-carboxamιde,

N-Ethyl 4-hydroxy-l-methyl-lH-ιndole-2-carboxaιrude;

4-Ηydroxy- 1 -methyl-2-(pyrrohdm- 1 -ylcarbony 1)- lH-mdole;

N-(l-Fluoromethyl-2-phenylethyl) 4-hydroxy-l-methyl-lH-ιndole-2-carboxamιde. (R)-N-(2-Ηydroxy-l-phenylethyl) 4-hydroxy-l-methyl-lH-ιndole-2-carboxamιde;

(S)-N-(2-Azιdo-l-benzylethyl)-4-hydroxy-l-methyl-lH-ιndole-2-carboxamιde;

N-(2-Fluoroethyl)-4-hydroxy-l-methyl-lH-ιndole-2-carboxamιde;

(R)-N-(2-Fluoro-3-phenylpropyl)- 4-hydroxy- 1 -methyl- lH-ιndole-2-carboxamιde; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Unless otherwise indicated, the -C₄ alkyl groups referred to herein, e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, may be straight-chained or branched, and the C3-C₄ alkyl groups may also be cyclic, e.g., cyclopropyl, cyclobutyl.

Unless otherwise indicated, the C2-C₄ alkenyl groups referred to herein may contain one or two double bonds, e.g., ethenyl, l-propenyl, n-butenyl, 1-butenyl, allyl, 1.3-butadιenyl. Unless otherwise indicated, the C₂-C₄ alkynyl groups referred to herein contain one tπple bond, e.g., ethynyl, propynyl, 1- or 2-butynyl.

Halogen referred to herein is fluoride, chloride, bromide, or iodide.

Aryl referred to herein is phenyl or naphthyl.

Heteroaryl referred to herein is a 5- or 6-membered heterocyclic πng containing 0-3 nitrogens, 0-1 sulfurs and 0-1 oxygens.

The compounds of the invention have the advantage that they may be less toxic, be more efficacious, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties. Methods of Preparation In the reaction schemes and text that follow R¹, R², R³, R⁴, R⁵, W, and X, unless otherwise indicated, are as defined above for formula I. The compounds of formula I may be prepared according to the methods outlined in Schemes I, II and III

Scheme I outlines general methods for the preparation of compounds of formula I wherein XR⁴ represents OH and W represents COΝR⁶ (formula Ila), COO (formula IXa) or CO (formula Xlla) from a common intermediate of formula Va wherein XR⁴ represents OBn (Bn referring to benzyl), W represents COO, and R^" represents hydrogen. The other substituents. R¹, R¹ and R⁵, are as defined for formula I.

Scheme I.

Compounds of formula Ila may be prepared from compounds of formula Ilia, representing compounds of formula I wherein XR⁴ represents OBn and W represents CONR⁶, by catalytic hydrogenation with a suitable hydrogen source in a suitable solvent. Suitable catalysts include palladium black and palladium on charcoal. Suitable hydrogen sources include hydrogen gas and 1,4-cyclohexadiene. Suitable solvents include ethanol (EtOH), ethyl acetate (EtOAc), water, and tetrahydrofuran (THF). The reaction is preferably performed at a temperature of 20-50 °C, a pressure of 1-4 atmospheres and most preferably at ambient temperature and pressure with 1,4-cyclohexadiene or at ambient temperature and a pressure of 3 atmospheres with hydrogen gas.

Compounds of formula Ilia may be prepared from compounds of formula Va, representing compounds of formula I wherein XR represents OBn, W represents COO, and R^" represents hydrogen, by reaction with a compound of formula IV, wherein R" and R are as defined for formula I, in the presence of an amide bond forming agent in a suitable solvent. Suitable amide bond forming agents include (a) carbodiimides such as dicyclohexylcarbodiimide and diisopropylcarbodiimide, (b) carbodiimides with additives such as 1-hydroxybenzotriazole (HOBt) and N-hydroxy succinimide (HOSu), and (c) phosphonium and uranium salts such as BOP, PyBOP, HBTU, and TBTU (benzotriazole-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1- y loxytrispyrrolidinophosphonium hexafluorophosphate, 2-( 1 H-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3- tetrametyluronium hexafluorophosphate, and 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetrametyluronium tetrafluoroborate; respectively) in the presence of a suitable tertiary amine base such as N,N-diisopropylethylamine (DIEA) or triethylamine (TEA). Suitable solvents include N,N-dimethylformamide (DMF), N-methylpyrrolidone (ΝMP), trifluoroethanol (TEE), acetonitrile (ACΝ), THF, dichloromethane (DCM), chloroform and EtOAc. The reaction is preferably performed at a temperature of 0-50 °C and most preferably at ambient temperature. Alternatively, compounds of formula Ilia may be prepared from compounds of formula Va by reaction with an acid chloride forming agent such as thionyl chloride (SOCl ) followed by reaction with a compound of formula IV in the presence of a suitable base and solvent. Compounds of formula IV are either commercially available or may be prepared by methods known to one skilled in the art.

Alternatively, compounds of formula Ila may be prepared sequentially from compounds of formula Va by (1) reductive cleavage of the benzyl group by the method described two paragraphs above, (2) carboxyl activation over 5-30 min with amide bond forming agents a or b as described in the paragraph above; and (3) amidation with compounds of formula IV. The reaction conditions are in accordance with those described in the preceding two paragraphs. Compounds of formula Va may be prepared from compounds of formula Via, representing compounds of formula I wherein XR represents OBn, W represents COO, and R represents R which is methyl or ethyl, by hydrolysis with a suitable base in a suitable solvent. Suitable bases include sodium hydroxide (ΝaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH) and cesium hydroxide (CsOH). Suitable solvents include aqueous MeOH, aqueous EtOH and aqueous THF. The reaction is preferably performed at a temperature of 0-50 °C and most preferably at ambient temperature.

Compounds of formula Via may be prepared from compounds of formula Villa, representing compounds of formula I wherein R represents hydrogen, XR⁴ represents OBn, W represents COO, and R" represents R which is methyl or ethyl, by reaction in a suitable solvent with a suitable base followed by treatment with a compound of formula VII, wherein R¹ is defined as in formula I and L is a suitable leavmg group Suitable bases include sodium hydride (NaH), potassium hydride (KH), potassium tert-butoxide (KOtBu), lithium dnsopropylamide (LDA), lithium hexamethyldisilazide (LHMDA) and sodium amide

(NaNH₂) Suitable leaving groups include halogen, tπflate (TfO), methanesulfonate (MsO) andp-toluenesulfonate (pTsO) Suitable solvents for the reaction include DMF, NMP, ACN, and THF The reaction is preferably performed at a temperature of 0-50 °C and most preferably at ambient temperature Compounds of formula VII and Villa are either commercially available or may be prepared by methods known to one skilled in the art Compounds of formula IXa may be prepared from compounds of formula Xa, representing compounds of formula I wherein XR⁴ represents OBn and W represents COO, according to an analogous procedure descπbed for the preparation of compounds of formula Ila Compounds of formula Xa may be prepared from compounds of formula Va, representing compounds of formula I wherein XR represents OBn, W represents COO, and R² represents hydrogen, by reaction with an acid chloπde forming agent such as SOCI2 followed by reaction with an alcohol of formula XI, wherein R" is as defined for formula I, in the presence of a suitable base and solvent Suitable bases mclude DIEA. TEA, pyπdme, sodium bicarbonate (NaHC0₃) and sodium carbonate (Na₂CO₃) Suitable solvents include THF, DCM, chloroform, benzene, toluene and EtOAc The reaction is preferably performed at a temperature of 0-100 °C and most preferably at ambient temperature while the pπor acid chloπde forming step is preferably performed in a refluxmg solvent such as benzene, chloroform or neat SOCl₂ Alcohols of formula XI are either commercially available or may be prepared by methods known to one skilled in the art

Compounds of formula Xlla may be prepared from compounds of formula Xllla, representing compounds of formula I wherein XR represents OBn and W represents CO, according to an analogous procedure descπbed for the preparation of compounds of formula Ila Compounds of formula Xllla may be prepared from compounds of formula Va, representing compounds of formula I wherein XR represents OBn, W represents COO, and R" represents hydrogen, by reaction in a suitable solvent with an organometallic compound of formula XIV, wherein R" is as defined for formula I and M represents a metal such as magnesium or preferably lithium. Suitable solvents include ether, 1,2-dimethoxyethane. THF and 1,4-dioxane. The reaction is preferably performed at a temperature of 0-100 °C and most preferably at a temperature of 25-60 °C. Organometallic compounds of formula XIV are either commercially available or may be prepared by methods known to one skilled in the art.

Scheme II outlines general methods for the preparation of compounds of formula I wherein XR⁴ represents NH₂ and W represents CONR⁶ (formula lib), COO (formula IXb) or CO (formula Xllb) from a common intermediate of formula Vb wherein XR⁴ represents NO2, W represents COO, and R² represents hydrogen. The other substituents, R¹, R^J and R⁵, are as defined for formula I.

Scheme II.

Compounds of formula lib may be prepared from compounds of formula Illb, representing compounds of formula I wherein XR represents NO₂ and W represents CONR⁶, by reaction with a suitable reducing agent in a suitable solvent. Suitable reducing agents include hydrogen gas with palladium on charcoal, zinc dust with acetic acid (HOAc) or hydrochloric acid (HC1), or iron powder with HOAc. Suitable solvents and co-solvents include EtOH, HOAc and water. The reaction is preferably performed at a temperature of 25-

120 °C.

Compounds of formula Illb may be prepared from compounds of formula Vb, representing compounds of formula I wherein XR⁴ represents NO₂, W represents COO, and R² represents hydrogen, by reaction with a compound of formula IV, wherein R² and R are as defined for formula I, according to an analogous procedure described for the preparation of compounds of formula Ilia.

Compounds of formula Vb may be prepared from compounds of formula VIb, representing compounds of formula I wherein XR⁴ represents NO₂, W represents COO, and R" represents R which is methyl or ethyl, according to an analogous procedure described for the preparation of compounds of formula Va.

Compounds of formula VIb may be prepared from compounds of formula VHIb, representing compounds of formula I wherein R represents hydrogen, XR represents N0₂.

W represents COO, and R" represents R which is methyl or ethyl, by reaction in a suitable solvent with a suitable base followed by treatment with a compound of formula VII, wherein

R¹ is defined as in formula I and L is a suitable leaving group, according to an analogous procedure described for the preparation of compounds of formula Via. Compounds of formula VHIb are either commercially available or may be prepared by methods known to one skilled in the art. Compounds of formula IXb may be prepared from compounds of formula Xb, representing compounds of formula I wherein XR represents NO₂ and W represents COO, according to an analogous procedure described for the preparation of compounds of formula πb.

Compounds of formula Xb may be prepared from compounds of formula Vb, representing compounds of formula I wherein XR represents NO₂, W represents COO, and

R" represents hydrogen, by reaction with an acid chloride forming agent such as SOCI2 followed by reaction with an alcohol of formula XI, wherein R² is as defined for formula I, according to an analogous procedure described for the preparation of compounds of formula

Xa. Compounds of formula Xllb may be prepared from compounds of formula XHIb, representing compounds of formula I wherein XR represents NO₂ and W represents CO, according to an analogous procedure described for the preparation of compounds of formula lib. Compounds of formula XHIb may be prepared from compounds of formula Vb, representing compounds of formula I wherein XR represents NO₂, W represents COO, and R² represents hydrogen, by reaction in a suitable solvent with an organometallic compound of formula XIV, wherein R^" is as defined for formula I and M represents a metal such as magnesium or preferably lithium, according to an analogous procedure described for the preparation of compounds of formula Xllla.

Scheme III.

Scheme III outlines general methods for the preparation of compounds of formula I wherein X represents NH and R⁴ represents R⁹SO₂ (formula XVII), R⁹CO (formula XIX), or R⁴ (formula XXI) from a common intermediate of formula XV wherein XR⁴ represents NH . The other substituents, R¹, W, R², R³ and R⁵, are as defined for formula I. Compounds of formula XV may be prepared by methods outlined in Scheme II.

Compounds of formula XVII may be prepared from compounds of formula XV, representing compounds of formula I wherein XR represents NH₂, by reaction with a sulfonyl chloride of formula XVI, wherein R⁹ is as defined for formula I, in the presence of a suitable base and solvent. Suitable bases include DIEA, TEA, pyridine, NaHCO₃ and Na₂CO₃. Suitable solvents include THF, DCM, chloroform, benzene, toluene and EtOAc. The reaction is preferably performed at a temperature of 0-100 °C and most preferably at a temperature of 25-50 °C. Compounds of formula XVI are either commercially available or may be prepared by methods known to one skilled in the art.

Compounds of formula XIX may be prepared from compounds of formula XV, representing compounds of formula I wherein XR represents NH₂, by reaction with an acid chloride of formula XVIII, wherein R⁹ is as defined for formula I, in the presence of a suitable base and solvent. Suitable bases include DIEA, TEA, pyridine, NaHCO₃ and Na₂CO . Suitable solvents include THF, DCM, chloroform, benzene, toluene and EtOAc. The reaction is preferably performed at a temperature of 0-100 °C and most preferably at ambient temperature. Compounds of formula XVIII are either commercially available or may be prepared by methods known to one skilled in the art.

Compounds of formula XXI may be prepared from compounds of formula XV, representing compounds of formula I wherein XR represents NH₂, by reaction with an aldehyde of formula XX, wherein R represents Cι-C₃ alkyl, Ar, or CHiAr, in the presence of a suitable reducing agent and solvent. Suitable reducing agents include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc and HCl, and hydrogen and a suitable catalyst. Suitable catalyst include platinum oxide or Raney nickel. Suitable solvents include EtOH, aqueous EtOH, water and THF. The reaction is preferably performed at a temperature of 20-100 °C and most preferably at ambient temperature. Compounds of formula XX are either commercially available or may be prepared by methods known to one skilled in the art.

Where necessary, hydroxy, a ino or other reactive groups may be protected using a protecting group as described in the standard text, 'Protecting Groups in Organic Synthesis', 3^rd Edition, T. W. Greene and P. G. M. Wuts, 1999, J Wiley & Sons. Inc.

The above described reactions, unless otherwise noted, are usually conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).

Unless otherwise stated, the above described reactions are conducted under an inert atmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated from their reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentioned include salts of mineral acids, for example the hydrochloride and hydrobromide salts; and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate, and fumarate salts. Acid addition salts of compounds of formula I may be formed by reacting the free base or a salt, enantiomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be caπied out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e g , water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuum or by freeze drying The reaction may be a metathetical process or it may be earned out on an ion exchange resin

The compounds of formula I exist in tautomeπc or enantiomeπc forms, all of which are included withm the scope of the invention. The vaπous optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, e.g., fractional crystallization, or chiral HPLC. Alternatively the individual enantiomers may be made by reaction of the appropπate optically active starting mateπals under reaction conditions which will not cause racemization.

The compounds of formula I, or an enantiomer thereof, and pharmaceutically acceptable salts thereof, may be used on their own or in the form of appropπate medicinal preparations for enteral or parenteral administration. According to a further aspect of the invention, there is provided a pharmaceutical composition including preferably less than 80% and more preferably less than 50% by weight of a compound of the invention m admixture with an inert pharmaceutically acceptable diluent or earner Examples of diluents and earners are

- for tablets and dragees: lactose, starch, talc, steanc acid; for capsules- tartaπc acid or lactose;

- for mjectable solutions: water, alcohols, glyceπn, vegetable oils; for suppositories' natural or hardened oils or waxes. There is also provided a process for the preparation of such a pharmaceutical composition, which compπses mixing the ingredients

It will be understood that a pharmaceutical composition compπsing a positive modulator of a nicotinic receptor agonist together with a pharmaceutically acceptable carrier said positive modulator having the capability to increase the efficacy of the said receptor agonist. For the purposes of the present invention, the term "positive modulator" or "positive modulator of a nicotinic receptor agonist" shall be understood as a compound having the capability to increase the maximum efficacy of a nicotinic receptor agonist It will be understood that the invention includes compositions compπsing either a positive modulator as the only active substance, thus modulating the activity of endogenous nicotinic receptor agonists, such as acetylchohne, or chohne, or a positive modulator combination with a nicotinic receptor agonist. Thus, the said pharmaceutical compositions containing a positive modulator of a nicot ic receptor agonist may, m addition compπse a nicotmic receptor agonist.

In a prefeπed form of the invention, the said nicotmic receptor agonist is an α7- mcotinic receptor agonist. Example of an cc7-nιcotmιc receptor agonist is (-)-Spιro[l- Azabιcyclo[2.2.2 ]Octane-3,5*-Oxazohdme]-2^1:-One. Several α7-nιcotmιc receptor agonists are known in the an, e.g. from WO 96/06098, WO 97/30998 and WO 99/03859.

A further aspect of the invention provides a method for the treatment of a condition associated with reduced nicotine transmission, by administeπng to a patient in need of such treatment, a medically effective amount of a positive modulator of a nicotinic receptor agonist, said positive modulator having the capability to increase the efficacy of the said nicotinic receptor agonist.

It will be understood that the methods of treatment of this invention includes either a positive modulator as the only active substance, thus modulating the activity of endogenous nicotmic receptor agonists, such as acetylchohne or chohne, or a positive modulator administered together with a nicotinic receptor agonist In another prefeπed form of the invention, the said method of treatment includes a nicotinic receptor agonist, which is an α7-nιcotιnιc receptor agonist. Example of an 7- mcotinic receptor agonist is (-)-Spιro[l-Azabιcyclo[2.2.2.]Octane-3,5*-Oxazohdιne]-2*-One. Several c7-nιcotιmc receptor agonists are known m the art, e.g. from WO 96/06098, WO 97/30998 and WO 99/03859 Utility

A further aspect of the invention is the use of compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of a condition associated with reduced nicotinic receptor transmission or a condition associated with reduced nicotmic density which could be one of the below mentioned diseases or conditions which compπses administeπng a therapeuucally effective amount of compounds according to the invention to a patient It will be understood that the use includes compositions compπsing either a positive modulator as the only active substance, thus modulating the activity of endogenous nicotmic receptor agonists, or a positive modulator in combination with a nicotmic receptor agonist Thus, the said use of pharmaceutical compositions containing a positive modulator of a nicotinic receptor agonist may, in addition comprise a nicotmic receptor agonist

In a prefeπed form of the invention, the use of the said nicotmic receptor agonist is represented by an 7-nιcotmιc receptor agonist Example of an α7-nιcotιnιc receptor agonist is (-)-spιro[l-azabιcyclo[2 2 2 ]octane-3,5 ^;-oxazolιdme]-2*-one Several α7-nιcotmιc receptor agonists are known in the art, e g from WO 96/06098, WO 97/30998 and WO 99/03859

Examples of diseases or conditions include schizophrenia, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, jetlag, and nicotine addiction (including that resulting from exposure to products containing nicotine)

It will be understood that the said positive modulator can be administered either with the purpose of acting on endogenous nicotine receptor agonists, or in combination with an exogenous nicotmic receptor agonist

A further aspect of the invention relates to a compound for treating or preventing a condition or disorder as exemplified above aπsmg from dysfunction of nicot ic acetylchohne receptor neurotransmission in a mammal, preferably a human, compositions compπsing either a positive modulator as the only active substance, thus modulating the activity of endogenous nicotinic receptor agonists, or a positive modulator in combination with a nicotmic receptor agonist Thus, the said use of pharmaceutical compositions containing a positive modulator of a nicotinic receptor agonist may, in addition compπse a nicotinic receptor agonist, effective in treating or preventing such disorder or condition and an inert pharmaceutically acceptable earner Experimental Methods

The activity of the compounds of the invention may be measured m the tests set out below (a) Xenopus oocyte cuπent recording

The Xenopus oocyte has provided a powerful means of assessing the function of proteins thought to be subumts of hgand-gated ion-channels. Injection of RNA transcπbed from cDNA clones encoding the appropriate receptor subumts, or injection of cDNA in which the coding sequence is placed downstream of a promoter, results in the appearance of functional hgand-gated ion-channels on the surface of the oocyte (see e.g. Boulter et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 7763-7767).

Consequently, one convenient technique to assess the enhancement of nicot ic efficacy is two-electrode voltage-clamp recording from Xenopus oocytes expressing α7- nicotmic receptors from cRNA

Xenopus laevis frogs (Xenopus I, Kalamazoo, MI) were anesthetized using 0.15% tπcaine. Oocytes were removed to OR2 solution (82 mM NaCl, 2.5 mM KC1, 5 mM HEPES, 1.5 mM NaH₂P0₄. 1 mM MgCl₂, 0.1 mM EDTA; pH 7.4). The oocytes were defolhculated by incubation 25 mL OR2 containing 0.2% collagenase 1A (Sigma) two times for 60 mm on a platform vibrating at 1 Hz and stored in Leibovitz's L-15 medium (50 μg/mL gentomycin, 10 Umts/mL penicillin, and 10 μg/mL streptomycin). Approximately 50 ng of cRNA was injected in each oocyte the following day. cRNA was synthesized from cDNA using Message Machine (purchased from Abion).

The external recording solution consisted of 90 mM NaCl, 1 mM KC1, 1 mM MgCl₂, 1 mM BaCl₂, 5 mM HEPES; pH 7.4 Two-electrode voltage-clamp recording was earned out using an Oocyte Clamp amplifier (OC 725C, Warner Instrument, Hamden, CT). Oocytes were impaled with two electrodes of 1-2 MΩ tip resistance when filled with 3M KC1. Recordings were begun when membrane potential became stable at potentials negative to -20mV (resting membrane potentials are less negative when Ba⁺⁺ replaces Ca⁺⁺ in bathing solutions). Membrane potential was clamped at -80 mV. ACh was purchased from Sigma. Oocytes were continuously perfused (5 mL/min) with recording solution with or without ACh.

Cuπent amplitude was measured from baseline to peak. EC₅₀ values, maximal effect, and Hill slopes were estimated by fitting the data to the logistic equation using GraphPad Pπsm (GraphPad Software, Inc., San Diego, CA).

Increases in agonist efficacy elicited by a positive modulator can be calculated in two ways' (1) As percent potentiation of cuπent amplitude which is defined as 100(I_m— I_c)/I_c where I_m is cuπent amplitude in the presence of modulator and I_c is cuπent in the absence of modulator

(2) As percent potentiation of "area under curve" of an agonist trace, which is the integration of net cuπent over time Area under the curve is a common representation of the total ion flux through the channel

(b) Ca²⁺ flux imaging

Imaging of Ca-⁺ flux through nAChR α7 receptors transiently expressed in a cell line is another means of assaying modulator activity

Cells expressing α7 receptors (for example HEK-293 cells or cell cultured neurons) are grown to confluence in 96 well plates and loaded with fluo-3, a fluorescent calcium indicator To screen for α7 modulatory activity, the 96 well plate is placed m a fluorescence imaging plate reader (FLIPR) and test compounds along with an al agonist are applied simultaneously to all wells Receptor activation is measured by calcium influx into cells, which is quantified by the increase in fluorescence intensity of each well, recorded simultaneously by the FLIPR A modulatory effect is determined by the increase in fluorescence over that of agonist alone Similarly, to test for nAChR al agonist activity, test compounds along with an α7 modulator are applied simultaneously to all wells Receptor activation is measured by calcium influx into cells which is quantified by the increase in fluorescence intensity of each well, recorded simultaneously by the FLIPR An agonist effect is determined by the increase in fluorescence over that of modulator alone

Cell-cultured neurons are prepared according to the following method Eighteen day old Sprague-Dawley rat fetuses (E-18) were aseptically removed from the pregnant male, sacπficed, the frontal cortices of the brains removed, the meninges stnpped, and the cleaned cortex placed into cold HBSS If hippocampus was desired, the hippocampus was dissected away from the cortex and then placed into cold HBSS The tissues were mechanically dispersed, washed once in HBSS (200 g for 30 minutes in 4 °C) resuspended m a modification of Sato's medium supplemented with glutam e, antibiotics, potassium chloπde, insulin, transferπn, selenium, and 5% heat-inactivated fetal bovine serum (FBS, endotoxin free) and plated into each of a 24-well plate (coated with poly-L-lysine) The wells could contain glass covershps which were also coated with PLL The plates were incubated at 37 °C in a CO₂ incubator. After 24 hours the medium was removed, fresh medium added, and the cells allowed to grow for at least another 11 days, feeding when necessary.

The compounds of the invention are compounds, which causes a 100% potentiation (2-fold increase) of baseline cuπent (as described above), as measured baseline to peak at low concentration of Acetylchohne (30 μM), indicating that they are expected to have useful therapeutic activity. The compounds of the invention are also compounds, which increase the flux of Ca²⁺ when applied in the Ca ⁺ flux-imaging assay, as described above. Any increase of Ca²⁺ flux, caused by a compound of the invention, compared to the Ca ⁺ flux casued by an agonist alone (as measured in Fluorescence Intensity Units) indicates that they are expected to have useful therapeutic activity.

The use of compounds of the invention have the advantage that they may be less toxic, be more efficacious, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties. General Experimental Procedures

Commercial reagents were used without further purification. Mass spectra were recorded following either chemical ionization (MS Cl) or electrospray (MS ES) ionization methods and are reported as m/z for the protonated cationic parent molecular ion (M⁺+H) or the deprotonated anionic parent molecular ion (M^"-H). Room temperature refers to 20-25°C. Examples

The following examples are preferred non-limiting examples embodying prefeπed aspects of the invention. Intermediate examples Example 1 Ethyl 4-benzyloxy-l-methyl-lH-indole-2-carboxylate

To a stiπed suspension of sodium hydride (0.27 g, 60% dispersion in mineral oil) in DMF (50 mL) under nitrogen at room temperature was added ethyl 4-benzyloxyindole-2- carboxylate (1.59 g). Methyl iodide (0.5 mL) was added 10 min later. After 2 h excess sodium hydride was quenched with acetic acid (0.4 mL) and the solvent evaporated under reduced pressure. The residue was taken into EtOAc, washed with water and brine, dried over MgSO , and evaporated to dryness to give an oil which was triturated with hexane to precipitate 1.45 g of the title compound. M.P. 89-90.5 °C. Example 2

4-Benzyloxy-l-methyl-lH-indole-2-carboxylic acid

To a stiπed solution of ethyl 4-benzyloxy-l-methyl-lH-indole-2-carboxylate (3.09 g) in TΗF (200 mL) was added LiOΗ-Η₂O (1.26 g) in water (200 mL) and the resulting two phase solution was heated at 45 °C under nitrogen overnight. The cooled reaction mixture was evaporated to remove THF and the remaining aqueous solution was acidified with NaHSO₄ to precipitate the title compound, which was collected, washed with water, and dried to give 2.87 g of the title compound. M.P. 216.6-216.8 °C. Example 3 4-Benzyloxy-l-methvi-lH-indole-2-carbonyl chloride

To a stiπed suspension of 4-benzyloxy-l -methyl- lH-indole-2-carboxylic acid (0.75 g) in benzene (5 mL) was added thionyl chloride (2.8 mL) in benzene (5 mL) followed by heated at 80 °C for 45 min to give a clear orange solution. Evaporation to dryness gave 0.80 g of the title compound as an orange solid, which was used without further purification. Example 4 l-Fluoromethyl-2-phenylethyl methanesulfonate

To a stiπed solution of l-fluoromethyl-2-phenylethanol (1.0 g, prepared as described by Bergmann, et al.. J. Chem. Soc, 1961, 3448-3452) in DCM (30 mL) at 0 °C under nitrogen was added triethylamine (1.36 mL) followed by dropwise addition of methanesulfonyl chloride (0.6 mL). The mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 1.3 g of the title compound. MS Cl, (M⁺+Η) = 233, (M⁺+H - CH₃SO₃H) = 138. Example 5 (2-Azido-3-fluoro-propyl)benzene

To a stiπed solution of l-fluoromethyl-2-phenylethyl methanesulfonate (1.1 g) in anhydrous DMF (15 mL) under nitrogen was added sodium azide (0.53 g) followed by heating at 80 °C overnight. The cooled reaction mixture was diluted with equal parts of water and brine and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2S0₄, and concentrated to an oil which was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.70g of the title compound. MS ES (M⁺+H - N₂) 151. Example 6 l-Fluoromethyl-2-phenylethylamme

To a solution of (2-azιdo-3-fluoro-propyl)benzene (0.6 g) in MeOH (50 mL) was added 10% Pd/C catalyst and the suspension was hydrogenated for 2 h at 3 atmospheres pressure The filtered reaction mixture and MeOH washings were concentrated to an oil which was chromatographed over silica gel with an ammoniated mixture of MeOH/ether (1:9) to give 0.38 g of the title compound. MS ES (M⁺+H) = 154.

Example 7

,_ )-N-(2-Fluoro-3-phenylpropyI)-4-methylbenzenesulfonamιde To a stiπed solution of hydrogen fluoπde-pyndine (13 mL) at 0 °C under nitrogen was added (5)-(+)-2-benzyl-l-( -tolylsulfonyl)azιπdme (2 g) m one portion. The cooling bath was removed bπefly until reaction became exothermic and then returned. After an additional 5 mm the reaction mixture was poured onto 100 mL of cracked ice. The product was extracted into ether, washed carefully with saturated ΝaHCO₃ and bπne, dned over Na₂SO₄, and evaporated to a white solid. The solid was tπturated with hexane, collected and washed with ether/hexane to give 1.7 g of the title compound. M.P. 130-133 °C; MS ES (M⁺+H) = 308.

Example 8

(R)-2-Fluoro-3-phenylpropylamιne

To a two necked flask equipped with a dry ice condenser was added ( ?)-N-(2-Fluoro- 3-phenylpropyl)-4-methylbenzenesulfonamιde (1.0 g) and ammonia gas to condense about 25 mL of liquid Small pieces of sodium were added to the stiπed solution until a dark orange color persisted for 5 mm. Methanol was added to quench the reaction. After evaporation of the ammonia the product was dissolved in MeOH, filtered, and concentrated. The residue was extracted into chloroform and chromatographed over silica gel with an ammoniated mixture of MeOH ether (1.19) to give 0.14 g of the title compound as an oil. MS ES (M⁺+H - ΝH₃) =

136.

Compound examples

Example 9

Ethyl 4-hvdroxy-l -methyl- lH-mdole-2-carboxylate To 10% Pd/C (0.13g) in EtOΗ (250 mL) was added ethyl 4-benzyloxy-l -methyl- 1H- ιndole-2-carboxylate (1.33 g) and the suspension was shaken overnight under a hydrogen pressure of 3 atmospheres at room temperature The residue left on evaporation of the filtered reaction mixture was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.43 g of the title compound MS ES (M^"*"+H) = 220.

Example 10

4-Hydroxy-l-methyl-lH-ιndole-2-carboxyhc acid To a solution of ethyl 4-hydroxy-l-methyl-lH-ιndole-2-carboxylate (0.20 g) in TΗF

(20 mL) was added LιOΗ-Η_.0 (0.1 g) in water (20 mL) and the resulting two phase solution was stirred at room temperature under nitrogen for 4 h. The reaction mixture was acidified with KHSO4 and the product was extracted into EtOAc, washed with bπne, dπed over

MgSO4, and concentrated The residue was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.12 g of the title compound MS ES (M⁺+H) = 192.

Example 11

N-Phenethyl 4-hvdroxy-l-methyl-lH-ιndole-2-carboxamιde

To a solution of 4-benzyloxy-l -methyl- lH-mdole-2-carboxylιc acid (0.20 g) in DMF

(10 mL) was added TBTU (0.23 g), ΗOBt (0.11 g) and DIEA (0.27 mL). After 5 mm., phenethylamme (0.11 mL) was added and stirπng was continued overnight under nitrogen at room temperature The residue remaining after DMF evaporation was dissolved in EtOAc; washed with dilute ΗC1, saturated ΝaΗCO₃, and bπne; dπed over MgSO ; and concentrated at reduced pressure to give the intermediate product N-phenethyl 4-benzyloxy-l-methyl-lH- ιndole-2-carboxyamιde (0.18 g) which was used without further purification. Ηydrogenation of this product by a method analogous to that descnbed in Example 9 give 0.14 g of the title compound. MS Cl (M⁺+Η) = 295

Example 12

N-Methyl-N-Phenethyl 4-hvdroxy-l -methyl- lH-mdole-2-carboxamιde From 4-benzyloxy-l -methyl- lH-mdole-2-carboxyhc acid and N- methylphenethylamine the title compound was prepared by a method analogous to that descπbed in Example 11. MS ES (M⁺+Η) = 309

Example 13

N-(4-Dιmethylamιnobenzyl) 4-hvdroxy-l-rnethyl-lH-ιndole-2-carboxamιde

To a solution of 4-hydroxy- 1 -methyl- lH-ιndole-2-carboxyhc acid (Example 10, 0.12 g) in DMF (10 mL) was added TBTU (0.20 g), ΗOBt (0 10 g) and DIEA (0.35 mL)

After 5 mm. 4-(dιmethylamιno)benzylamme dihydrochloπde (0.14 g) was added and stirπng was continued overnight under nitrogen at room temperature. The residue remaining after DMF evaporation was punfied by reversed phased chromatography on s silica with a tnfluoroacetic acid (0.025%) acidified acetomtπle water gradient to give 0.14 g of the title compound. MS ES (M⁺+H) = 324. Example 14 N-(4-Chlorobenzyl) 4-hvdroxy-l-methyl-lH-mdole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-mdole-2-carboxyhc acid and 4-chlorobenzylamιne the title compound was prepared by a method analogous to that descnbed in Example 11. MS ES (M⁺+Η) = 315 and 317. Example 15 N-Benzyl 4-hydroxy-l-methyl-lH-mdoIe-2-carboxamιde

From 4-benzyloxy-l-methyl-lH-mdole-2-carboxyhc acid and benzylamme the title compound was prepared by a method analogous to that described in Example 11. MS ES (M⁺+Η) = 281 Example 16 N-(4-Phenylbutyl) 4-hydroxy-l-meth\l-lH-ιndole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-ιndole-2-carboxylιc acid and 4-phenylbutylamme the title compound was prepared by a method analogous to that descπbed in Example 11. MS ES (M⁺+Η) = 323. Example 17 N-(3-Phenylpropyl) 4-hvdroxy- 1 -methyl- lH-mdole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-mdole-2-carboxyhc acid and 3-phenylpropylamme the title compound was prepared by a method analogous to that descπbed in Example 11. MS ES (M⁺+Η) = 309 Example 18 N-Phenyl 4-hvdroxy- 1 -methyl- lH-ιndole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-mdole-2-carboxyhc acid and aniline the title compound was prepared by a method analogous to that descnbed in Example 11. MS ES (M⁺+Η) = 267. Example 19 N-(4-Chlorophenyl) 4-hydroxy-l -methyl- lH-mdole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-ιndole-2-carboxyhc acid and 4-chloroanιlιne the title compound was prepared by a method analogous to that described m Example 11 MS ES (M⁺+Η) = 301 and 303 Example 20

N-(3-Bιphenyl) 4-hvdroxy- l-methyl-lH-mdole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-ιndole-2-carboxylιc acid and 3-ammobιphenyl the title compound was prepared by a method analogous to that descπbed in Example 11 MS ES (M⁺+Η) = 343. Example 21 N-Ethyl 4-hvdroxy- 1 -methyl- lH-mdole-2-carboxamιde

From 4-benzyloxy-l -methyl- lH-ιndole-2-carboxylιc acid and ethyl amine the title compound was prepared by a method analogous to that descπbed in Example 11. MS ES (M⁺+Η) = 219. Example 22

From 4-benzyloxy-l -methyl- lH-mdole-2-carboxyhc acid and pyπohdine the title compound was prepared by a method analogous to that descπbed m Example 11 MS ES (M⁺+Η) = 245 Example 23 N-(l-Fluoromethyl-2-phenylethyl) 4-hydroxy-l-methyl-lH-ιndole-2-carboxamιde

To a solution of l-fluoromethyl-2-phenylethylamιne (0.38 g) in DCM (5 mL) at 0 °C under nitrogen was add 4 benzyloxy-l-methyl-lH-ιndole-2-carbonyl chloπde (0.37 g) in DCM (5 mL) followed by slow warming to room temperature over 2 h. Reaction mixture concentrated to half volume and partitioned between EtOAc and water The organic layer was washed with water and bπne, dned over Νa₂SO , and concentrated to a residue which was tπturated with ether to give 0.32 g of the intermediate compound N-(l-fluoromethyl-2- phenylethyl) 4-benzyloxy-l-methyl-lH-mdole-2-carboxamide: M.P. 172-173 °C; MS ES (M^+Η) = 417. Hydrogenation of this intermediate (0.26 g) by a method analogous to that descπbed in Example 9 gave 0 12 g of the title compound. M.P. 163.5-165.5 °C; MS ES (M⁺+H) = 327. Example 24

(R)-N-(2-Hvdroxy-l-phenylethyl) 4-hvdroxy- 1 -methyl- lH-mdole-2-carboxamιde From (R)-2-hydroxy-l-phenylethylamιne and 4 benzyloxy-l-methyl-lH-ιndole-2- carbonyl chlonde the title compound was prepared by a method analogous to that descπbed in Example 23. MS ES (M⁺+Η) = 311 Exa ple 25

(S -N-(2-Azido-l-benzylethyl)-4-hvdroxy-l-methyl-lH-indole-2-carboxamide

From (5)-2-azido-l-benzylethylamine (prepared as described by Ηorwell. et al., J.

Med. Chem., 1991, 404-414) and 4 hydroxy-l-methyl-lH-indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 23. MS ES

(M⁺+Η) = 350.

Example 26

N-(2-Fluoroethyl⁾-4-hvdroxy-l-methyl-lH-indole-2-carboxamide

From 2-fluoroethylamine and 4 benzyloxy-1 -methyl- lH-indole-2-carbonyl chloride the title compound was prepared by a method analogous to that described in Example 23. MS ES

(M^"-Η) = 235.

Example 27

(R)-N-(2-Fluoro-3-phenylpropyl)- 4-hvdroxy- l-methyl-lH-indole-2-carboxamide

From (R)-2-fluoro-3-phenylpropylamine and 4 benzyloxy-l-methyl-lH-indole-2- carbonyl chloride the title compound was prepared by a method analogous to that described in

Example 23. MS ES (M⁺+Η) = 327.

Example 28

Resolution of Example 23

(-)-Ν-(l-Fluoromethyl-2-phenylethyl) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide Chiral chromatography of Example 23 (40 mg) on a Chiralpak® AD column (Chiral

Technologies, Inc.. 5x50 cm, 20 μ) in isopropyl alcohol/hexanes/diethylamine (40:59:1) at 40 mL/min with UV (238 nM) monitoring gave two peaks. The faster eluting peak was isolated to give 12 mg of the title compound as a white solid. MS ES (M⁺+H) = 327; M.P. 161-162

°C; [α]_D = -158.6° (MeOH, C=l; 99.6% ee by chiral HPLC). Example 29

Resolution of Example 23

(+)-N-(l-Fluoromethyl-2-phenylethyl) 4-hydroxy- l-methyl-lH-indole-2-carboxamide

The slower eluting peak from Example 28 was isolated to give 12 mg of material which was chromatographed on silica gel with EtOAc/hexanes (1:4) to give 8.8 mg of the title compound. MS ES (M⁺+H) = 327; M.P. 157-158 °C; [α]_D = +141° (MeOH, C=l; 96.2% ee by chiral HPLC). Example 30

(R)-N-(2-Azido-l-benzylethyl -4-hvdroxy-l -methyl- lH-indole-2-carboxamide

From (R)-2-azido-l-benzylethylamine (prepared as described by Horwell, et al., J.

Med. Chem., 1991, 404-414) and 4 hydroxy-1 -methyl- lH-indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES

(M⁺+H) = 350; [α]_D = +94.8° (MeOH, C=l).

Example 31

(S)-N-(2-Cvano-l-benzylethyl)-4-hvdroxy-l-methyl-lH-indole-2-carboxamide

From (S)-2-cyano-l-benzylethylamine (prepared by an adaptation of a method described by Caputo, et al., Tetrahedron, 1995, 12337-12350) and 4 hydroxy-1-methyl-lH- indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES (M⁺+H) = 334; [α]_D = -110.8° (MeOH, C=l).

Example 32

Methyl (S)-2-{ (4-hvdroxy-l-methyl-lH-indol-2-yl)carbonyllamino)-3-phenylpropano-ate From L-phenylalanine methyl ester hydrochloride and 4 hydroxy-1-methyl-lH-indole-

2-carboxylic acid the title compound was prepared by a method analogous to that described in

Example 13. MS ES (M⁺+H) = 353.

Example 33

N-(l-phenyl-3-bυtvnyl)-4-hydroxy-l-methyl-lH-indole-2-carboxamide From l-phenyl-3-butyn-l-amine (Leboutet, et al., J Organomet Chem, 1991, 155-161) and 4 hydroxy-l-methyl-lH-indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES (M⁺+H) = 319.

Example 34

(S)-N-[2-Azido-l-(4-methoxybenzyl)ethyl1-4-hydroxy-l-methyl-lH-indole-2-carbox-amide From (S)-l-azido-3-(4-methoxyphenyl)-2-propanamine [prepared by an adaptation of a method described by Horwell, et al., J. Med. Chem., 1991, 404-414 from (S)-2-amino-3-(4- methoxyphenyl)-l-propanol (prepared from O-methyl-L-tyrosine by an adaptation of a method described by Sutherland, et al., J Org Chem, 1998, 7764-7769] and 4 hydroxy-1 -methyl- 1H- indole-2-carboxylic acid the title compound was prepared by a method analogous to that described in Example 13. MS ES (M⁺+H) = 380. Example 35

(S)-N-, l-benzyl-2-hvdroxyethyll-4-hydroxy-l-methyl-lH-indole-2-carboxamide

From (5)-2-amino-3-phenylpropan-l-ol and 4-benzyloxy-l-methyl-lH-indole-2- carbonyl chloride the intermediate compound (S)-N-[l-benzyl-2-hydroxyethyl]-4-(benzyloxy)- l-methyl-lH-indole-2-carboxamide was prepared by a method analogous to that described in

Example 23. MS ES (M⁺+Η) = 415. Hydrogenation of this intermediate by a method analogous to that described in Example 9 gave the title compound. MS ES (M⁺+H) = 325.

Example 36

2-, (4S)-4-benzyl-4.5-dihvdro-1.3-oxazol-2-yl1-l-methyl-lH-indol-4-ol To an ice chilled solution of (5)-N-[l-benzyl-2-hydroxyethyl]-4-(benzyloxy)-l-methyl- lH-indole-2-carboxamide (0.6 g) in benzene (25 mL) was added slowly a solution of thionyl chloride (1 mL) in benzene (5 mL). The ice bath was removed and the reaction mixture allowed to warm to room temperature over 2 h. Concentration of the reaction mixture, in vacuo, gave a solid which was washed with cold benzene and dried yielding 0.35 g of the intermediate 2-[(4S)-4-benzyl-4,5-dihydro-l,3-oxazol-2-yl]-4-(benzyloxy)-l-methyl-lH- indole hydrochloride. MS ES (M⁺+Η) = 397. The free base of this intermediate was hydrogenated by a method analogous to that described in Example 9 to give 0.25 g of the title compound. MS ES (M⁺+H) = 307.

Example 37 2-. (4fl)-4-benzyl-4.5-dihydro-1.3-oxazol-2-yl1-l-methyl-lH-indol-4-ol

From (R)-N-[l-benzyl-2-hydroxyethyl]-4-(benzyloxy)-l-methyl-lH-indole-2- carboxamide the title compound was prepared by a method analogous to that described in

Example 36. MS ES (M⁺+Η) = 307.

Claims

1. A compound of Formula I:

wherein:

R¹ represents hydrogen, C[-C₄ alkyl, C?-C alkenyl, C₂-C₄ alkynyl, or (CH₂) _nAr; W represents C(O), C(O)O, C(O)NR⁶, or a bond;

R² represents hydrogen, Ar, or (CH₂) _PCH[(CH₂) _qR⁷](CH₂) _R^S; or together R² and R⁶ represent (CH₂) j Y(CH₂) _k;

R^J and R⁵ independently represent hydrogen, halogen, or C₁-C₄ alkyl; X represents oxygen, or NH;

R⁴ represents hydrogen, C,-C₄ alkyl, (CH₂) _uAr, R⁹CO, or R⁹SO₂; R⁶ represents hydrogen, C₁-C₄ alkyl, aryl, or heteroaryl; or together R² and R⁶ represent (CH₂) j Y(CH₂) _k;

R⁷ and R⁸ independently represent hydrogen, halogen, CN, -C≡CH, N₃, CF₃, NO₂, Ar, OR¹⁰, NR¹⁰Rⁿ, C(O)OR¹⁰, OC(O)R¹⁰, C(O)NR¹⁰R^π, NR¹⁰C(O)Rⁿ, SO₂NR¹⁰R^U , or NR¹⁰SO₂R^U;

R⁹ represents C₁-C₄ alkyl, or Ar; Ar represents phenyl, naphthyl, or a 5- or 6-membered heterocyclic ring containing 0-3 nitrogens, 0-1 sulfurs and 0-1 oxygens;

Ar is optionally substituted with one or more substituents independently selected from: hydrogen, halogen, C1-C4 alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, (CH₂)_naryl, CN, NO₂, CF₃, OR¹², NR^,2R¹³ and COOR¹²; R¹⁰, R^u, R¹² and R¹³ independently represent hydrogen, C₁-C₄ alkyl, aryl, or heteroaryl; or together R and R , 1 1 and/or R . 12 and R independently represent (CH₂) _jY(CH₂) , Y represents oxygen, sulfur, NR¹⁴, or a bond: j is 2-4; k, m, n, p. q, t, and u are independently 0-2; R¹⁴ represents hydrogen, C₁-C₄ alkyl, aryl or heteroaryl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein: R⁴ represents hydrogen, methyl, or benzyl; R¹ represents hydrogen, or methyl;

R³ and R^D independently represent hydrogen; W represents a bond;

X represents oxygen;

R² represents hydrogen, methyl; (4- benzyl)oxazolin-2-yl, or A;

A represents COOR¹⁵, or CONR¹⁶R¹⁷;

R¹⁵ represents hydrogen, or CH_CH₃; R¹⁶ represents hydrogen, or C₁-C₄ alkyl;

R¹⁷ represents d-C₄ alkyl, (CH₂) _n-Phenyl-Y, or CHR¹⁸CHR¹⁹-Z;

R¹⁸ represents hydrogen, phenyl, or benzyl;

R¹⁹ represents hydrogen, or benzyl;

R²⁰ represents benzyl; Y represents hydrogen, Cl, N(CH₃) ₂, or phenyl;

Z represents Cl, OH, F, N₃, or NH₂; n is 0-4; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

3. A compound according to claim 1, said compound being: Ethyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxylate;

4-Ηydroxy-l-methyl-lH-indole-2-carboxylic acid; N-Phenethyl 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-Methyl-N-Phenethyl 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide; N-(4-Dimethylaminobenzyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-(4-Chlorobenzyl) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide;

N-Benzyl 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-(4-Phenylbutyl) 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide; N-(3-Phenylpropyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-Pheny 1 4-hydroxy- 1 -methyl- lH-indole-2-carboxamide ; N-(4-Chlorophenyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-(3-Biphenyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; N-Ethyl 4-hydroxy-l-methyl-lH-indole-2-carboxamide;

4-Ηydroxy- 1 -methyl-2-(pyπolidin- 1 -ylcarbonyl)- lH-indole; N-(l-Fluoromethyl-2-phenylethyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; (R)-N-(2-Ηydroxy-l-phenylethyl) 4-hydroxy-l-methyl-lH-indole-2-carboxamide; (S)-N-(2-Azido-l-benzylethyl)-4-hydroxy-l -methyl- lH-indole-2-carboxamide; N-(2-Fluoroethyl)-4-hydroxy-l -methyl- lH-indole-2-carboxamide;

(R)-N-(2-Fluoro-3-phenylpropyl)- 4-hydroxy-l-methyl-lH-indole-2-carboxamide; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

4. A compound according to any one of claims 1 to 3 for use in therapy.

5. A pharmaceutical composition including a compound as defined in any one of claims 1 to 3, in admixture with an inert pharmaceutically acceptable diluent or carrier.

6. The pharmaceutical composition according to claim 5, in addition comprising a nicotinic receptor agonist.

7. The pharmaceutical composition according to claim 5 or claim 6, for the use in the treatment or prophylaxis of human diseases or conditions in which the compound is having the capability to increase the efficacy of a nicotinic receptor agonist.

8. The pharmaceutical composition according to claim 5 or claim 6, for use in the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders.

9. The pharmaceutical composition according to claim 5 or claim 6. for use in the treatment or prophylaxis of human diseases or conditions in which activation of the al nicotinic receptor is beneficial.

10. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Ηyperactivity Disorder, Lewy Body Dementia, anxiety, schizophrenia, or mania or manic depression, Parkinson's disease, Ηuntington's disease, Tourette's syndrome, neurodegeneradve disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain, or ulcerative colitis.

11. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, Lewy Body Dementia, memory loss or Attention Deficit Hyperactivity Disorder.

12. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of anxiety, schizophrenia, or mania or manic depression.

13. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of Parkinson's disease, Huntmgton's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses.

14. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of jetlag, nicotine addiction including that resulting from exposure to products containing nicotine, pain, or ulcerative colitis.

15. The pharmaceutical composition according to claim 8, for use in the treatment or prophylaxis of Alzheimer's disease.

16. Use of a compound as defined in any one of claims 1 to 3, in the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders or intellectual impairment disorders.

17. The use of a compound as defined in any one of claims 1 to 3, in the manufacture of a medicament for the treatment or prophylaxis of human diseases or conditions in which activation of the al nicotmic receptor is beneficial. 18. The use of a compound as defined m any one of claims 1 to 3, in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Lewy Body Dementia, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntmgton's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain, or ulcerative colitis. 19. The use according to claim 18, wherein the condition or disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, or Attention Deficit Hyperactivity Disorder. 20. The use according to claim 18, wherein the disorder is anxiety, schizophrenia, mania or manic depression. 21 The use according to claim 18, wherein the disorder is Parkinson^'s disease, Huntmgton's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses

22 The use according to claim 18, wherein the condition or disorder is Alzheimer's disease

23 The use according to claim 18, wherein the condition or disorder is jetlag, nicotine addiction including that resulting from exposure to products containing nicotine, pa , and for ulcerative colitis

24 A method for the treatment of a condition associated with reduced nicotine transmission, by administeπng to a patient in need of such treatment, a medically effective amount of a compound according to any one of claims 1 to 3, said compound having the capability to increase the efficacy of a nicotmic receptor agonist

25 The method according to claim 24, wherein the said compound is administered together with a nicotinic receptor agonist 26 The method according to claim 24 or claim 25, wherein the said agonist is an cc7- nicotimc receptor agonist

27 A method of treatment or prophylaxis of psychotic disorders or intellectual impairment disorders, which compπses admmisteπng a therapeutically effective amount of a compound as defined in any one of claims 1 to 3 28 A method of treatment or prophylaxis of human diseases or conditions in which activation of the al nicotinic receptor is beneficial which compπses admmistenng a therapeutically effective amount of a compound as defined in any one of claims 1 to 3 29 The method according to any one of claims 24 to 28, wherein the disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Lewy Body Dementia, anxiety, schizophrenia, mama or manic depression, Parkinson's disease, Huntmgton's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain, or ulcerative colitis 30 The method according to claim 29, wherein the disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, or Attention Deficit Hyperactivity Disorder

31. The method according to claim 29, wherein the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synapses.

32. The method according to claim 28, wherein the disorder is anxiety, schizophrenia, mania or manic depression.

33. The method according to claim 29, wherein the disorder is jetlag, nicotine addiction, pain, and for ulcerative colitis.

34. The method according to claim 29, wherein the disorder is Alzheimer's disease.