Non-imidazole heterocyclic compounds

Abstract

Certain non-imidazole heterocyclic compounds are histamine H 3 modulators useful in the treatment of histamine H 3 receptor mediated diseases.

1 . A compound having histamine H 3  receptor modulating activity of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1 , optionally mono- or di-substituted with R s , is selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, and —C 3-7 cycloalkyl;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R m )R n  (wherein R m  and R n  are independently H or C 1-4 alkyl), —(C═O)N(R m )R n , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 
 n is 1 or 2; 
 X is O or S; 
 the A-containing ring is thiophene; 
 L is —C 1-4 alkylene-; 
 R 2 , optionally mono- or di-substituted with R q , is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 3 , optionally mono- or di-substituted with R q  is independently selected from the group consisting of —C 1-17 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; 
 R q  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-14 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with halo or —C 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 or, alternatively 
 R 2  and R 3  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NR 11 , having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R p ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NR pp , having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R p ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-14 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with halo or —C 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 R pp  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, benzyl, pyrimidinyl, pyrrolyl, —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —COOC 1-4 alkyl, and —COOC 1-4 -benzyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
 
   
   
       2 . The compound of  claim 1  wherein R 1  is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, propenyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyethyl, methoxyethyl, and diethylaminoethyl. 
   
   
       3 . The compound of  claim 1  wherein R 1  is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl. 
   
   
       4 . The compound of  claim 1  wherein R 1  is isopropyl. 
   
   
       5 . The compound of  claim 1  wherein n is 1. 
   
   
       6 . The compound of  claim 1  wherein X is O. 
   
   
       7 - 13 . (canceled) 
   
   
       14 . The compound of  claim 1  wherein L is methylene. 
   
   
       15 . The compound of  claim 1  wherein R 2  is independently selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl, pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl. 
   
   
       16 . The compound of  claim 1  wherein R 2  is independently selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl, pyridylethyl, and diethylaminoethyl. 
   
   
       17 . The compound of  claim 1  wherein R 2  is independently selected from the group consisting of —H, methyl, and methoxyethyl. 
   
   
       18 . The compound of  claim 1  wherein R 3  is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl, pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl. 
   
   
       19 . The compound of  claim 1  wherein R 3  is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl, pyridylethyl, and diethylaminoethyl. 
   
   
       20 . The compound of  claim 1  wherein R 3  is independently selected from the group consisting of methyl and methoxyethyl. 
   
   
       21 . The compound of  claim 1  wherein R 2  and R 3  may be taken together with the nitrogen of attachment to form a ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, and pyrrolidine. 
   
   
       22 . The compound of  claim 1  wherein R 2  and R 3  may be taken together with the nitrogen of attachment to form a ring selected from the group consisting of piperidine, morpholine, and piperazine. 
   
   
       23 . The compound of  claim 1  wherein R 2  and R 3  may be taken together with the nitrogen of attachment to form 4-fluoropiperidine. 
   
   
       24 . The compound of  claim 1  wherein R 2  and R 3  may be taken together with the nitrogen of attachment to form a ring selected from the group consisting of piperidine and morpholine. 
   
   
       25 . The compound of  claim 1  wherein R pp  is —C 1-6 alkyl. 
   
   
       26 . A compound selected from the group consisting of: 
     (4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone; 
   
   
       27 . A compound selected from the group consisting of: 
     (4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-2-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-2-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-{5-[(2-methoxy-ethylamino)-methyl]-thiophen-2-yl}-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-thiophen-3-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-thiophen-3-yl)-methanone; and. 
   
   
       28 . The compound of  claim 1  wherein said pharmaceutically acceptable salt is an effective amino addition salt. 
   
   
       29 . The compound of  claim 1  wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. 
   
   
       30 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compound having histamine H 3  receptor modulator activity of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 R 1 , optionally mono- or di-substituted with R s , is selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, and —C 3-7 cycloalkyl;
 R s  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R m )R n  (wherein R m  and R n  are independently H or C 1-4 alkyl), —(C═O)N(R m )R n , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 
 n is 1 or 2; 
 X is O or S; 
 the A-containing ring is thiophene; 
 L is —C 1-4 alkylene-; 
 R 2 , optionally mono- or di-substituted with R q  is independently selected from the group consisting of —H, —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds; and 
 R 3 , optionally mono- or di-substituted with R q , is independently selected from the group consisting of —C 1-7 alkyl, —C 2-7 alkenyl, —C 2-7 alkynyl, —C 3-7 cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, having 0, 1, or 2 double bonds;
 R q  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-4 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with halo or —C 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , and —COOC 1-4 alkyl, and —COOH; 
 
 or, alternatively 
 R 2  and R 3  may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of:
 i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NR 11 , having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R p ; and 
 ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NR pp , having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R p ; 
 R p  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, -Ophenyl, -Obenzyl, —SH, —SC 1-6 alkyl, —SC 3-6 cycloalkyl, -Sphenyl, -Sbenzyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H and C 1-14 alkyl; or R y  and R z  may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC 1-4 alkyl, said ring optionally substituted with halo or —C 1-4 alkyl), —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —SCF 3 , —OCF 3 , —CF 3 , —COOC 1-4 alkyl, and —COOH; 
 R pp  is independently selected from the group consisting of —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, phenyl, pyridyl, benzyl, pyrimidinyl, pyrrolyl, —(C═O)N(R y )R z , —(C═O)C 1-4 alkyl, —COOC 1-4 alkyl, and —COOC 1-4 benzyl; 
 
 and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
 
   
   
       31 - 32 . (canceled) 
   
   
       33 . A compound of  claim 1  isotopically-labelled to be detectable by PET or SPECT. 
   
   
       34 . A method for studying histamine-mediated disorders comprising the step of using an  18 F-labeled or  11 C-labelled compound of  claim 1  as a positron emission tomography (PET) molecular probe. 
   
   
       35 - 37 . (canceled)