US2010197720A1PendingUtilityA1

Heteroaryl-substituted diazatricycloalkanes and methods of use thereof

Assignee: TARGACEPT INCPriority: Aug 22, 2005Filed: Apr 7, 2010Published: Aug 5, 2010

Est. expiryAug 22, 2025(expired)· nominal 20-yr term from priority

Inventors:Anatoly Mazurov Lan Miao Jozef Klucik

A61P 9/00A61P 25/28C07D 471/18A61P 35/00A61P 25/00A61P 25/14A61P 25/04C07D 471/14A61P 31/04A61P 25/18A61P 25/24A61P 29/00A61P 25/22A61P 25/16A61K 31/439

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References

Claims

Abstract

The present invention relates to amide and urea derivatives of heteroaryl-substituted diazatricycloalkanes, pharmaceutical compositions including the compounds, methods of preparing the compounds, and methods of treatment using the compounds. More specifically, the methods of treatment involve modulating the activity of the α7 nAChR subtype by administering one or more of the compounds to treat or prevent disorders mediated by the α7 nAChR subtype. The diazatricycloalkanes typically consist of a 1-azabicyclooctane fused to pyrrolidine ring. The substituent heteroaryl groups are 5- or 6-membered ring heteroaromatics, such as 3-pyridinyl and 5-pyrimidinyl moieties, which are attached directly to the diazatricycloalkane. The secondary nitrogen of the pyrrolidine moiety is substituted with an arylcarbonyl (amide type derivative) or an arylaminocarbonyl (N-arylcarbamoyl) (urea type derivative) group. The compounds are beneficial in therapeutic applications requiring a selective interaction at certain nAChR subtypes. That is, the compounds modulate the activity of certain nAChR subtypes, particularly the α7 nAChR subtype, and do not have appreciable activity toward muscarinic receptors. Radiolabeled versions of the compounds can be used in diagnostic methods.

Claims

exact text as granted — not AI-modified

1 . A compound having a structure of the formula: 
     
       
         
         
             
             
         
       
       wherein: 
       Y is either oxygen or sulfur, 
       Z is either NR′ or a covalent bond, 
       A is either absent or a linker species selected from the group consisting of —CR′R″—, —CR′R″—CR′R″—, —CR′═CR′—, and —C≡C—, and wherein R′ and R″ are as hereinafter defined, 
       Ar is a phenyl or a napthyl; and 
       Cy is a pyridine, 
       wherein, individually, Ar, Cy, and the various open valencies positions on the depicted 1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane ring, can be unsubstituted or can be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C≡CR′—, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)—R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —O(CR′R″) r C(═O)R′, —O(CR′R″) r NR″C(═O)R′, —O(CR′R″) r NR″SO 2 R′, —OC(═O)NR′R″, —NR′C(═O)O—R″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where each R′ and R″ are individually hydrogen, alkyl C 1 -C 8  alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and r is an integer from 1 to 6, or R′ and R″ combine to form a cyclic functionality, 
       or a radiolabeled version thereof, 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The compound of  claim 1  wherein Cy is 3-pyridinyl. 
   
   
       3 . The compound of  claim 1 , wherein Y is O, and Z is NR′. 
   
   
       4 . The compound of  claim 1 , wherein Y is O and Z is a covalent bond. 
   
   
       5 . A compound selected from the group consisting of:
 5-benzoyl-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(4-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3,4-dichlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2,4-dimethoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(3,4,5-trimethoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(naphth-1-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane, and   5-(naphth-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   or a pharmaceutically acceptable salt thereof.   
   
   
       6 . A compound selected from the group consisting of:
 5-(phenylacetyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(diphenylacetyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(2-phenylpropanoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane, and   5-(3-phenylprop-2-enoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   or a pharmaceutically acceptable salt thereof.   
   
   
       7 . A compound selected from the group consisting of
 5-N-phenylcarbamoyl-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3,4-dichlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(2,4-dimethoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(3,4,5-trimethoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(1-naphthyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane, and   5-(N-(2-naphthyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   or a pharmaceutically acceptable salt thereof.   
   
   
       8 . A compound selected from the group consisting of
 5-(N-benzylcarbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-bromobenzyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(4-methoxybenzyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   5-(N-(1-phenylethyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane, and   5-(N-(diphenylmethyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0&lt;2,6&gt;]undecane,   or a pharmaceutically acceptable salt thereof.   
   
   
       9 . The compound of  claim 1 , wherein A is absent. 
   
   
       10 . A pharmaceutical composition comprising a pharmaceutical carrier and a compound of  claim 1 . 
   
   
       11 . The compound of  claim 1 , wherein the compound is radiolabeled. 
   
   
       12 . The compound of  claim 11 , wherein the compound comprises  11 C,  18 F,  76 Br,  123 I, or  125 I.

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