EP1991528A2 - Modulatoren von alpha7-nicotinischen acetylcholinrezeptoren und therapeutische verwendungen davon - Google Patents

Modulatoren von alpha7-nicotinischen acetylcholinrezeptoren und therapeutische verwendungen davon

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Publication number
EP1991528A2
EP1991528A2 EP07722757A EP07722757A EP1991528A2 EP 1991528 A2 EP1991528 A2 EP 1991528A2 EP 07722757 A EP07722757 A EP 07722757A EP 07722757 A EP07722757 A EP 07722757A EP 1991528 A2 EP1991528 A2 EP 1991528A2
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EP
European Patent Office
Prior art keywords
branched
cyclic
linear
alkyl
mono
Prior art date
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EP07722757A
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English (en)
French (fr)
Inventor
Hendrick Bothmann
Renza Roncarati
Laura Bettinetti
Joanna Quinn
Maurizio Varrone
Michela Valacchi
Arianna Nencini
Iolanda Micco
Chiara Ghiron
Simon Haydar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Siena Biotech SpA
Wyeth Pharmaceuticals Inc
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Siena Biotech SpA
Wyeth Pharmaceuticals Inc
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Publication of EP1991528A2 publication Critical patent/EP1991528A2/de
Withdrawn legal-status Critical Current

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds with o ⁇ nicotinic acetylcholine receptor ( ⁇ f7 nAChR) agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological and psychiatric diseases.
  • ⁇ f7 nAChR nicotinic acetylcholine receptor
  • o ⁇ nicotinic acetylcholine receptor represents a valid molecular target for the development of agonists/positive modulators active as neuroprotective molecules.
  • oil nicotinic receptor agonists have already been identified and evaluated as possible leads for the development of neuroprotective drugs (16-20).
  • Involvement of cCl nicotinic acetylcholine receptor in inflammatory processes has also recently been described (21).
  • novel modulators of this receptor should lead to novel treatments of neurological, psychiatric and inflammatory diseases.
  • Heterocyclic compounds carrying a basic nitrogen and hexibiting various types of biological activity were found to be described: anti herpes virus compounds (US6288091); 2H-phthalazin-l-one derivatives (WO00044726); l,4-dihydro-2(2H)isoquinolines (DE2406490); pyridine compounds (JP06016638); piperidine amides (WOO 198268); 8-amino-aryl- substituted imidazopyrazines as kinase inhibitors (US2005009832);
  • Heterocyclic compounds were also disclosed in Heterocycles (1997), 45(4), 723-734: l-[ ⁇ [(arylamino)carbonyl]alkyl]-4- (benzocycloalkyl)piperazines.
  • the invention provides novel compounds acting as full or partial agonists at the al nicotinic acetylcholine receptor ( ⁇ 7 nAChR), pharmaceutical compositions containing the same compounds and the use thereof for the treatment of diseases that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor such as neurological and psychiatric disorders, in particular Alzheimer's disease and schizophrenia.
  • ⁇ 7 nAChR al nicotinic acetylcholine receptor
  • Kl and K2 which are bound to either the same or a different carbon atom where k>l, represent independently from one another hydrogen; halogen; (C] -C 5 ) alkyl, alkoxy, fluoroalkyl, alkylene, fluoroalkylene; hydroxyalkyl; or Kl and K2 taken together may form an alkylidene or a fluoroalkylidene group; or Kl and K2, taken together with the carbon atom to which they are attached, form a (C 3 -C 6 ) cycloalkyl group; or when k is . ⁇ , two () k carbon atoms may form an unsaturated bond; or when w is 1, 2, or 3, and k is 1, Kl and K2 taken together with the carbon atom to which they are attached may form an oxo group; j is 0, 1 or 2; X is a group of formula
  • p is O, 1, 2 or 3;
  • n is 0, 1 or 2;
  • s is 1 or 2;
  • q and q' are, independently from one another, integers from 1 to 4;
  • T' represent, independently from one another, hydroxy; mercapto; amino; cyano; nitro; linear, branched or cyclic (Ci-C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic
  • U and U' represent, independently from one another, hydrogen; cyano; hydroxy; amino; a mono- or di-, linear, branched, or cyclic (C 1 -C 6 ) alkylamino group; a linear or branched (Ci-C 6 ) alkoxy group; a linear, branched or cyclic
  • Q is a 5 to 10-membered aromatic or heteroaromatic ring;
  • R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (C]-C 6 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic (C]-C 6 ) alkylcarbonylamino, mono- or di- (C 5 -Ci 0 ) aryl- or heteroarylaminocarbonyl; mono- or di, linear, branched, or cyclic (C 1 -C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic
  • this invention provides compounds hereafter referred to as Gl, in which: X is:
  • z is selected from CH 2 , N, O; T' represent, independently from one another when p is greater than 1, hydroxy; amino; cyano; nitro; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; mono- or di-, linear, branched or cyclic (C 1 -C 6 ) alkylamino; linear, branched or cyclic (C 1 -C 6 ) alkoxy-(C J -C 6 ) alkyl, mono- or di- (Cj-C 6 ) alkylamino-(Cj-C 6 ) alkyl, or (Cj-C 6 ) alkylthio-(C J -C 6 ) alkyl; (Cj-C 3 ) al
  • Q is a 6 to 10-membered aromatic or heteroaromatic ring
  • R represents a 5 to 10-membered aromatic or heteroaromatic ring optionally substituted with one or more groups independently selected from: halogen; hydroxy; mercapto; cyano; nitro; amino; linear, branched or cyclic (Ci-C 6 ) alkyl, trihaloalkyl, .
  • alkoxy or alkylcarbonyl linear, branched, or cyclic (C 1 -C 6 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (C 1 -C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphonylamino; linear, branched, or cyclic (C 1 -C 6 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (Ci-C 6 ) alkylsulphamoyl; linear, branched or cyclic
  • (Ci-C 3 ) alkylsulphonylamino linear, branched, or cyclic (C]-C 3 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 3 ) alkoxy-(Ci-C 3 ) alkyl, mono- or di- (C r C 3 ) alkylamino-(C r C 3 ) alkyl, (C r C 3 ) alkylthio-(C r C 3 ) alkyl;
  • a particular embodiment provides compounds in which k is 0; X is a group of formula:
  • R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (C 1 -C 6 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (C]-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl;
  • R' represents halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (Ci-C 3 ) alkyl, alkoxy.
  • Kl and K2 represent, independently from one another hydrogen; halogen; (C 1 -C 3 ) alkyl, alkoxy;
  • X is a group of formula:
  • z is CH 2 , N, O; p is 0 or 1 ;
  • T' represents linear, branched or cyclic (C 1 -C 3 ) alkyl, trihaloalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (C 1 -C 3 ) alkylaminocarbonyl; carbamoyl; R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (Ci-C 3 ) alkyl, trihaloalkyl, alkoxy or alkylcarbonyl; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (Ci-C 3 ) alkylsul
  • G3 a particular embodiment defines a group of compounds hereafter referred to as G3 in which:
  • Kl and K2 represent, independently from one another hydrogen; halogen; (C,-C 3 ) alkyl;
  • X is a group of formula:
  • z is CH 2 , N; q and q' are, independently from one another, integers from 1 to 3 ;
  • T' represents linear, branched or cyclic (Ci-C 3 ) alkyl, alkylcarbonyl;
  • R represents a 5 to 10-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (Ci -C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (C 1 -C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl;
  • G4a a particular embodiment is that in which:
  • Q is a phenyl or pyridyl ring; j is 1 or 2;
  • R represents a phenyl, pyridyl, or pyrazolyl ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (Ci-C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic
  • Kl and K2 represent, independently from one another hydrogen; halogen; (C, -C 3 ) alkyl;
  • X is a group of formula:
  • T' represents linear, branched or cyclic (C 1 -Cs) alkyl, alkylcarbonyl;
  • Q is a phenyl or pyridyl
  • R represents a phenyl, pyridyl or pyrazole ring, optionally substituted with one or more groups independently selected from: halogen; linear, branched or cyclic (C 1 -C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (C 1 -C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic
  • G5a one embodiment provides a group of compounds hereafter referred to as G5a in which: q and q' are, independently from one another, integers from 1 to 3;
  • T' represent, independently from one another when p is greater than 1, hydroxy; cyano; oxo; linear, branched or cyclic (Cj-C 6 ) alkyl, trihaloalkyl, hydroxyalkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (Cj-C 6 ) alkoxy-(Cj-C 6 ) alkyl; (Cj-C 3 ) alkylsulphonylamino; mono- or di- (Cj-C 3 ) alkylaminosulphonyl; sulphamoyl; linear, branched or cyclic (Cj-C 6 ) alkylaminocarbonyl; carbamoyl; linear, branched or cyclic (Cj-C 3 ) alkoxy-(Cj-C 3 ) alkyl; (Cj-C 3 ) alkylsulphonylamino
  • R represents a 5 to 6-membered aromatic or heteroaromatic ring, optionally substituted with one or more groups independently selected from: halogen; hydroxy; cyano; linear, branched or cyclic (C 1 -C 3 ) alkyl, trihaloalkyl, alkoxy; linear, branched, or cyclic (Ci -C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (C 1 -C 3 ) alkylaminocarbonyl; carbamoyl; linear, branched, or cyclic (C 1 -C 3 ) alkylsulphonylamino; linear, branched, or cyclic (C 1 -C 3 ) alkylsulphonyl; mono- or di- linear, branched, or cyclic (Ci-C 3 ) alkylsulphamoyl; linear, branched or cyclic (Ci-C 3 ) 3Ik
  • j 2, halogen; trihalomethyl; trihalomethoxy; linear, branched or cyclic (Ci-C 3 ) alkyl, alkoxy.
  • a particular embodiment is represented by compounds in which k is O; p is 0, or 1 ;
  • T' represents, independently from one another when p is greater than 1, linear, branched or cyclic (C r C 3 ) alkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino; linear, branched or cyclic (Ci-C 3 ) alkylaminocarbonyl; carbamoyl;
  • Q is a phenyl or pyridyl; j is 0 or 1;
  • R represents a phenyl or pyridyl ring optionally substituted with one or more groups independently selected from: halogen; hydroxy; linear, branched or cyclic (C 1 -C 6 ) alkyl, alkoxy; linear, branched, or cyclic (Ci-C 3 ) alkylcarbonylamino; mono- or di, linear, branched, or cyclic (C 1 -C 3 ) alkylaminocarbonyl; carbamoyl;
  • R' represents halogen
  • an organic solvent such as for example dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof
  • a suitably activated ⁇ -haloalkylphthalimide is reacted with an amine X in an organic solvent such as for example but not limited to 2-butanone or dimethylformamide in the presence of a base such as for example triethylamine or potassium carbonate.
  • an organic solvent such as for example but not limited to 2-butanone or dimethylformamide
  • a base such as for example triethylamine or potassium carbonate.
  • a mixture of amine (or its hydrochloride salt) and ⁇ -haloalkylphthalimide are refluxed in methylethyl ketone in the presence of alkaline carbonate until the reaction is complete, then the reaction mixture is cooled, the insoluble materials removed by filtration, the filtrate washed with chloroform or dichloromethane, and the filtrate and washings concentrated to dryness.
  • the ⁇ -aminoalkylphthalimide is converted into a ⁇ -diamine, for example by refluxing a mixture of the ⁇ -aminoalkylphthalimide and hydrazine hydrate in ethanol.
  • the ⁇ -diamine is reacted with an activated species such as for example an isocyanate or a carbamoyl chloride in an organic solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof, to give compounds of formula Ia
  • an activated species such as for example an isocyanate or a carbamoyl chloride in an organic solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof
  • Ia can be further processed - for example via a cross-coupling reaction, for example under the conditions of the Suzuki coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I.
  • Scheme 4 Scheme 4
  • the aldehyde precursor thus obtained is then converted to the aldehyde, for example oxidised under standard conditions (for example Swern oxidation) in the case of an alcohol, and the aldehyde is then reacted with a suitably substituted amine X under standard reductive alkylation conditions - for example with sodium triacetoxyborohydride - to afford compounds Ia.
  • R being a halogen, a boronic acid or a boronic acid ester
  • Ia can be further processed - for example via a cross- coupling reaction, for example under the conditions of the Suzuki coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I.
  • Ia can be further processed - for example via a cross-coupling reaction, for example under the conditions of the Suzuki coupling, with a boronic acid or an aryl or heteroaryl halide - to yield compounds of formula I. f) Scheme 6
  • an ⁇ -aminoalkanoic acid is suitably activated using an agent such for example but not limited to as 1,1 '-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford subject matter compounds of formula I.
  • an agent such for example but not limited to as 1,1 '-carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable heterocyclic amine to afford subject matter compounds of formula I.
  • an ⁇ -aminoalkanoic acid is suitably activated using an agent such for example but not limited to as 1,1 ' -carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable bromoaryl or heteroaryl amine to afford bromoaryl or heteroaryl amides, which are then reacted further under cross-coupling conditions, for example Suzuki conditions, to afford subject matter compounds of formula I.
  • an agent such for example but not limited to as 1,1 ' -carbonyldiimidazole in a solvent such as for example dichloromethane, dimethylformamide or mixtures thereof and reacted with a suitable bromoaryl or heteroaryl amine to afford bromoaryl or heteroaryl amides, which are then reacted further under cross-coupling conditions, for example Suzuki conditions, to afford subject matter compounds of formula I.
  • Scheme 8 shows one possible route towards the synthesis of chain- substituted acids, precursors to compounds of Formula I 1 D) bbaassee HBr 48%, 12O 0 C
  • an alkyl-substituted malonic acid diester it treated with base, such as for example but not limited to sodium hydride in a solvent such as tetrahydrofurane or dimethylformamide and reacted with an ⁇ , ⁇ -dihaloalkane.
  • the disubstituted malonic acid diester thus obtained is hydrolysed and mono-decarboxylated by treatement with a strong acid, such as for example hydrobromic acid. Esterification is then carried out, for example by treatement with methanol and a catalytic amount of acid.
  • Substitution of the ⁇ -halogen may be accomplished by the use of a suitable amine heating in a solvent like toluene, but not limited to this solvent.
  • hydrolysis of the ester function with an aqueous base affords intermediates which can be activated as described to afford compounds of Formula I.
  • the compounds in this invention can in general be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • the amides can be prepared through a base-catalysed nucleophilic addition between the appropriate carboxylic acid with an appropriately selected amine or via a nucleophilic substitution reaction wherein the appropriate amine reacts with either the selected acyl halide, anhydride or ester to yield the required amine.
  • the acid halide is added to the appropriately selected amine to yield the amide using art-known reaction procedures such as the Schotten- Baumann method.
  • the carboxylic acids and the amines are readily available, or may be prepared using methods that are well known in the art. Many compounds are commercially available, for example, from Aldrich Chemicals, or when the compounds are not commercially available, they may be readily prepared from available precursors using straightforward transformations that are well known in the art.
  • the carboxylic acids can be prepared by hydrolysis of nitriles, carbonation of organometallic compounds or oxidation of primary alcoholds or aldehydes.
  • branched alkyl nitriles are prepared from the corresponding alkyl acetonitriles by conversion to the dialkyl or spiroalkyl derivative using e.g. sodium hexamethyldisilazane and methyl iodide or dibromobutane, followed by hydrolysis under acidic or basic conditions to the desired carboxylic acid.
  • acids and bases in the hydrolysis are for example H2SO4 and KOH.
  • the hydrolysis reaction can be conveniently performed using microwave heating.
  • the compounds of formula I, their optical isomers or diastereomers can be purified or separated according to well-known procedures, including but not limited to chromatography with a chiral matrix and fractional crystallisation.
  • the invention is therefore directed to a method of treating neurological and psychiatric disorders, which comprises administering to a subject, preferably a human subject in need thereof, an effective amount of a compound of formula I.
  • Neurological and psychiatric disorders that may benefit from the treatment with the invention compounds include but are not limited to senile dementia, attention deficit disorders, Alzheimer's disease and schizophrenia.
  • the compounds of formula I can be used for treating any disease condition, disorder or dysfunction that may benefit from the activation of the alpha 7 nicotinic acetylcholine receptor, including but not limited to Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, memory or learning deficit, panic disorders, cognitive disorders, depression, sepsis and arthritis.
  • the dosage of the compounds for use in therapy may vary depending upon, for example, the administration route, the nature and severity of the disease. In general, an acceptable pharmacological effect in humans may be obtained with daily dosages ranging from 0.01 to 200 mg/kg.
  • the invention refers to a pharmaceutical composition containing one or more compounds of formula I, in association with pharmaceutically acceptable carriers and excipients.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid preparations, preferably in form of solutions, suspensions, powders, granules, tablets, capsules, syrups, suppositories, aerosols or controlled delivery systems.
  • the compositions can be administered by a variety of routes, including oral, transdermal, subcutaneous, intravenous, intramuscular, rectal and intranasal, and are preferably formulated in unit dosage form, each dosage containing from about 1 to about 1000 mg, preferably from 1 to 600 mg of the active ingredient.
  • the compounds of the invention can be in the form of free bases or as acid addition salts, preferably salts with pharmaceutically acceptable acids.
  • the invention also includes separated isomers and diastereomers of compounds I, or mixtures thereof (e.g. racemic mixtures).
  • the principles and methods for the preparation of pharmaceutical compositions are described for example in Remington's Pharmaceutical Science, Mack Publishing Company, Easton (PA). Experimental Procedures - Synthesis of compounds
  • Preparative HLPC was run using a Waters 2767 system with a binary Gradient Module Waters 2525 pump and coupled to a Waters Micromass ZQ (ES) or Waters 2487 DAD, using a Supelco Discovery HS C 18 5.0 ⁇ m 10 x 21.2 mm column.
  • the reaction was then cooled and acidified with 5 mL of 37% HCl and 2,3-dihydro-phthalazine-l,4-dione was removed by filtration.
  • the solution was concentrated under vacuum, 10 mL of IN HCl were added and the mixture was filtered again to remove the residual 2,3-dihydro-phthalazine-l ,4- dione.
  • the aqueous solution was evaporated under vacuum and 3.O g (yield 48%) of pure product were recovered.
  • triethylamine (1 eq) was added to a solution of aryl or heteroaryl amine (1 eq) in a volume of DCE such as to obtain a 1.2 M solution of amine; 5-bromovaleryl chloride (0.95 eq) was then added dropwise as a solution in 1.2 M solution in DCE and the reaction was stirred at room temperature for 1 hour 30 minutes.
  • a 1.8 M solution of amine R1R2NH (3 eq) and triethylamine (1 eq) in DCE were then added and the reaction mixture strirred at 55°C for a time between 4 and 16 h, until LCMS monitoring showed reaction completion.
  • the acetonitrile phase was separated and the desired products purified over a SCX or silica column. Fractions containing the desired product were combined and dried under reduced pressure.
  • the solution was irradiated in a microwave oven using the following parameters: power: 200 watt; ramp time: 1 min; hold time: 20:00 min; temperature: 9O C; pressure: 200 psi.
  • the acetonitrile phase was separated, the solvent was removed under reduced pressure and the crude material purified using SCX column (eluting with a gradient of DCM/MeOH, MeOH, NH 3 /MeOH). The fractions containing product were combined and dried under reduced pressure.
  • reaction mixture was filtered to remove all solids and the amine (6 mmol, 3 eq) was added, followed by NaBH(OAc) 3 (4 mmol, 2 eq).
  • the reaction was stirred at room temperature for 24 hrs.
  • reaction completion (as monitored by LC-MS), the solvent was removed under reduced pressure and the resulting residue was purified by
  • 3,3-Difluoro-succinamic acid (0.18 g, 1.2 mmol) was dissolved in 10 mL of acetonitrile and the mixture was cooled at 0 0 C under N 2 atmosphere.
  • N,N-dicyclohexylcarbodiimide (0.266 g, 1.3 mmol) was added and the mixture was stirred again at 0 0 C for further 10 minutes.
  • 1-Hydroxybenzotriazole hydrate (0.308 g, ca. 2 mmol) was then added and the ice bath removed.
  • the reaction was then allowed to cool down to room temperature and the solid formed was filtered and then dissolved in water.
  • the solution was then acidified with 2N HCl solution and at pH between 2-6 (depending on the ring substitution on the aryl/heteroaryl system) the product precipitated and was filtered off. If no precipitation occurred, the product was extracted with DCM.
  • Yields were generally between 65 and 90%.
  • the product was prepared according to the general procedure for aminopyrazole synthesis (route Al).
  • the product was prepared according to general procedure for aminopyrazole synthesis (route A2).
  • the crude product was purified with SiO2 column (5 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95:5.
  • the title product (371 mg, 68% yield) was obtained.
  • the product was prepared according to a modification of general route Al .
  • methyl-3-fluorobenzoate (3 g, 18 mmol) in dry toluene (25 mL) under N 2 .
  • NaH 50-60% dispersion in mineral oil, 1.44 g, 36 mmol
  • the reaction was allowed to cool down to room temperature and the solid formed was filtered, then it was dissolved in water and the solution was acidified with 6N HCl solution to pH 5-6 and the product extracted with DCM. The pH of the aqueous phase was adjusted again to 4-5 and another extraction with DCM afforded more product.
  • the product was prepared according to a modification of route A2. To a solution of 3-oxo-3-pyridin-4-yl-propionitrile (1.86 g, 12.74 mmoL) in absolute EtOH (35 mL) hydrazine monohydrate (0.74 mL, 15.29 mmol) was added and the reaction was heated at reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The crude product obtained was washed with ether to afford the title compound (yield: 39%).
  • POCl 3 (2 eq with respect to the aryl/heteroaryl acetophenone) were added dropwise to 4 molar equivalents of anhydrous DMF cooled down to O 0 C, at such a rate that the temperature did not exceed 10 0 C.
  • the acetophenone (1 eq) was then added dropwise and the reaction was allowed to reach room temperature.
  • the reaction was then stirred for further 30' and then 0.4 mmol of hydroxylamine hydrochloride were added.
  • the reaction was then heated up to 5O 0 C, after which heating was removed and additional 4 eq. of hydroxylamine hydrochloride were added portionwise (at such a rate that the temperature never exceeded 120 0 C).
  • the reaction was then stirred until the temperature of the mixture spontaneously decreased to 25°C.
  • Water (100 mL) were then added and the mixture was extracted with diethyl ether. The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was used for the next step without further purification.
  • the reaction mixture was generally heated at 60 0 C for 24-48 hours.
  • the solvent was removed under reduced pressure.
  • the residue was taken up in DCM (2 mL) and washed with Na 2 CO 3 saturated water solution.
  • the organic phase was concentrated under reduced pressure and the crude products were either recrystallised from CH 3 CN, or purified by SiO 2 column (gradient from 100%DCM to DCM-NH3MeOH 2N solution 8:2) or by preparative HPLC (standard acidic conditions).
  • N,N'-carbonyldiimidazole (1.2 g, 7.4 mmol) was added and the mixture was stirred at room temperature for 2 hours (when all the aminoacid was activated complete dissolution of the suspension was generally observed).
  • the 3-amino-5-aryl/heteroarylpyrazole (5.29 mmol) was then added and the reaction was stirred for further 10 hours.
  • Example 3 l-(2, 2 '-Dimethoxy-biphenyl-4-yl)-3-(4-piperidin-l-yl-butyl)-urea l-(4-Bromo-3-methoxy-phenyl)-3-(4-piperidin-l-yl-butyl)-urea (prepared according to the general procedure for urea synthesis, reaction with isocyanate) was weighed into a microwave vessel (100 mg, 0.26 mmol) and dissolved in acetonitrile (1 mL).
  • 5-Imidazol-l-yl-pentanoic acid (3 '-acetylamino-biphenyl-4-yl)-amide
  • 5-Bromopentanoic acid-(4-bromophenyl)-amide 4-Bromo-aniline (6 g, 0.035 mol) and 0.035 mol of NEt 3 (4.87 mL) were dissolved in 120 mL of dichloromethane and cooled at 0 0 C.
  • Example 5 l-(2,2'-Difluoro-biphenyl-4-yl)-3-(4-piperidin-l-yl-butyl)-urea a) l-(4-Bromo-3-fluoro-phenyl)-3-(4-piperidin-l-yl-butyl)-urea Prepared via the general procedure for urea synthesis (triphosgene activation of aniline).
  • Example 11 l-[4-(l-Methyl-lH-pyrazol-4-yl)-phenyl]-3-[4-(3, 3, 3-tri ⁇ uoro- propylamino) -butyl] -urea a) l-(4-Bromo-phenyl)-3-[4-(3, 3, 3-trifluoro-propylamino)-butylJ-urea l-(4-Bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (0.72 g, 2 mmol, 1 eq) was dissolved in dry DCM (10 mL) at room temperature and Montomorrilonite K-5 (0.145 g) is added.
  • the reaction was stirred ar room temperature for 2 hours, when LC-MS shows complete conversion into the aldehyde.
  • the reaction mixture was filtered to remove all solids and trifluopropylamine.HCl (0.9 g, 6 mmol, 3 eq) and diisoproylethylamine (1.05 mL, 6 mmol, 3 eq) were added, followed by NaBH(OAc) 3 (1.2 g, 4 mmol, 2 eq,).
  • the reaction was stirred at rt for 24 hrs.
  • the product was prepared according to the general procedure for aminopyrazole synthesis (route Al).
  • the product was prepared according to the general procedure for aminopyrazole synthesis (route A2)
  • the crude product was purified with SiO2 column (10 g) with gradient elution from 100% DCM to DCM-MeOH 8:2. 1.0 g of pure product were obtained (yield 65%).
  • the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)- amides.
  • the crude product was purified with SiO2 column (2 g) with gradient elution from 100% DCM to DCM-NH3 (2N MeOH solution) 95 :5.
  • Example 16 N-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-4-piperidin-l-yl-butyramide a) 4-Piperidin-l-yl-butyric acid ethyl ester To a solution of piperidine (5.4 g, 65 mmol) in toluene (15 mL) ethyl 4- bromobutyrate (3.8 mL, 26 mmol) was added and the reaction mixture was refluxed for 10 hours. The mixture was allowed to cool down to room temperature and the white solid present (piperidium bromide) was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give the title product which was used in the next step without further purification.
  • piperidine 5.4 g, 65 mmol
  • ethyl 4- bromobutyrate 3.8 mL, 26 mmol
  • the oxopropionitrile was synthesised following the general method for 3-oxopropionitriles (route Al).
  • Example 22 4-(4-Acetyl-[l,4]diazepan-l-yl)-N-[5-(6-methoxy-naphthalen-2-yl)-lH- pyrazol-3-yl] -butyramide a) 6-Methoxy-naphthalene-2-carboxylic acid methyl ester
  • the product was prepared according to the general synthetic method for the one-pot synthesis of ⁇ -amino-alkanoic acid (lH-pyrazol-3-yl-5-aryl)- amides.
  • a solution of 5-bromohexanoyl chloride (0.144 mL, 0.94 mmol) in dry DMA (1 mL) was cooled to -10 0 C (ice/water bath) under N 2 ; 5-(4- methoxy-phenyl)-lH-pyrazol-3-ylamine (178 mg, 0.94 mmol) and diisopropylethylamine (0.324 mL, 1.88 mmol) were added in dry DMA (1 ml).
  • Table 1 shows a selection of the compounds synthesised, which were prepared according to the method indicated in the last column of the table and discussed in detail in the Experimental Procedures with the synthesis of Examples 1-25.
  • the salt was formed by dissolution of the free base in methanol and addition of 1 eq IM HCl in ether followed by evaporation of the solvents.
  • HCOOH formic acid
  • Full length cDNAs encoding the alpha7 nicotinic acetylcholine receptor were cloned from a rat brain cDNA library using standard molecular biology techniques. Rat GH4C1 cells were then transfected with the rat receptor, cloned and analyzed for functional alpha7 nicotinic receptor expression employing a FLIPR assay to measure changes in intracellular calcium concentrations.
  • the FLIPR system allows the measurements of real time Ca 2+ -concentration changes in living cells using a Ca 2+ sensitive fluorescence dye (such as Fluo4). This instrument enables the screening for agonists and antagonists for alpha 7 nAChR channels stably expressed in GH4C1 cells.
  • GH4C1 cells stably transfected with rat- alpha7-nAChR (see above) were used. These cells are poorly adherent and therefore pretreatment of flasks and plates with poly-D-lysine was carried out. Cells are grown in 150 cm 2 T-flasks, filled with 30ml of medium at 37°C and 5% CO 2 .
  • EC 50 and IC 50 values were calculated using the IDBS XLf ⁇ t4.1 software package employing a sigmoidal concentration-response (variable slope) equation:
  • the functional FLIPR assay was validated with the alpha7 nAChR agonists nicotine, cytisine, DMPP, epibatidine, choline and acetylcholine. Concentration-response curves were obtained in the concentration range from 0.001 to 30 microM. The resulting EC 50 values are listed in Table 2 and the obtained rank order of agonists is in agreement with published data (Quik et al.. 1997X22).
  • the assay was further validated with the specific alpha7 nAChR antagonist MLA (methyllycaconitine), which was used in the concentration range between 1 microM to 0.01 nM, together with a competing nicotine concentration of 10 microM.
  • the IC 50 value was calculated as 1.31 ⁇ 0.43 nM in nine independent experiments.
  • the compounds from Examples 1-171 described showed agonist activity in the functional FLIPR primary screening assay employing the stable recombinant GH4C1 cell line expressing the alpha7 nAChR. The most potent hits identified were validated further by generation of concentration-response curves.
  • the potency of compounds from Examples 1-153 as measured in the functional FLIPR screening assay was found to range between 10 nM and 30 microM, with the majority showing a potency ranging between 10 nM and 10 microM.
  • Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons. J.Neurochem. 76, 1395-1403.
  • Nicotine protects against the dexamethasone potentiation of kainic acid- induced neurotoxicity in cultured hippocampal neurons. Brain Res. 735, 335-338.
  • Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res. 779, 359-363.
  • Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease. Behav. Brain Res. 1 13, 121-129.
  • Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann. Neurol. 42, 159-163.
  • Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421 :384-388.

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