Non-imidazole alkylamines as histamine h3-receptor ligands and their therapeutic applications

Abstract

Use of a compound of formula (A), wherein: W is a residue which imparts antagonistic and/or agonistic activity at histamine H 3 -receptors when attached to an imidazole ring in 4(5) position; R 1 and R 2 may be identical or different and represent each independently a lower alkyl or cycloalkyl, or taken together with the nitrogen atom to which they are attached, a saturated nitrogen-containing ring (i) as defined, a non-aromatic unsaturated nitrogen-containing ring (ii) as defined, a morpholino group, or a N-substituted piperazino group as defined for preparing medicaments acting as antagonists and/or agonists at the H 3 -receptors of histamine.

1 . A compound of formula (IIb): 
       
         
           
           
               
               
           
         
         in which:
 R 1  and R 2  may be identical or different and represent each independently 
 
         a lower alkyl or cycloalkyl, or taken together with the nitrogen atom to which they are attached, 
         a saturated nitrogen-containing ring 
       
       
         
           
           
               
               
           
         
       
       with m ranging from 2 to 8, or
 a non-aromatic unsaturated nitrogen-containing ring 
 
       
         
           
           
               
               
           
         
       
       with p and q being from 0 to 3 independently and r being from 0 to 4, provided that p and q are not simultaneously 0 and 2≦p+q+r≦8, 
       R a-d  being independently a hydrogen atom or a lower alkyl, cycloalkyl, or carboalkoxy group, or
 a morpholino group, or 
 a N-substituted piperazino group: 
 
       
         
           
           
               
               
           
         
         
           with R being a lower alkyl, cycloalkyl, carboalkoxy, aryl, arylalkyl, an alkanoyl or aroyl group, 
           the chain A″ represents an unbranched, branched or unsaturated alkyl group —(CH 2 ) nII — where n II  is an integer which can vary between 1 and 8 and preferably between 1 and 4; an unbranched or branched alkene group comprising from 1 to 8 carbon atoms and preferably 1 to 4 carbon atoms; an unbranched or branched alkyne group comprising from 1 to 4 carbon atoms; 
           the group X II  represents —OCONH—; —OCON(alkyl)-; —OCON(alkene)-; —OCO—; —OCSNH—; —CH 2 —; —O—; —OCH 2 CO—; —S—; —CO—; —CS—; amine; saturated or unsaturated alkyl; 
           the group Y II  represents a phenyl group, unsubstituted or mono- or polysubstituted with one or more identical or different substituents selected from halogen atoms, OCF 3 , CHO, CF 3 , SO 2 N(alkyl) 2  such as SO 2 N(CH 3 ) 2 , NO 2 , S(alkyl), S(aryl), SCH 2 (phenyl), an unbranched or branched alkene, an unbranched or branched alkyne optionally substituted with a trialkylsilyl radical, —O(alkyl), —O(aryl), —CH 2 CN, a ketone, an aldehyde, a sulphone, an acetal, an alcohol, a lower alkyl, —CH═CH—CHO, —C(alkyl)=N—OH, —C(alkyl)=N—O(alkyl) and other keto derivatives, —CH═NOH, —CH═NO(alkyl), and other aldehyde derivatives, —C(alkyl)=NH—NH—CONH 2 , an O-phenyl or —OCH 2 (phenyl) group, —C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl), an optionally substituted heterocycle; a heterocycle comprising a sulphur hetero atom; a cycloalkyl; a bicyclic group and preferably a norbornyl group; a phenyl ring fused to a heterocycle comprising a nitrogen hetero atom or to a carbocycle or a heterocycle bearing a keto function; an unbranched or branched lower alkyl comprising from 1 to 8 carbon atoms; an unbranched or branched alkyne comprising from 1 to 8 carbon atoms and preferably 1 to 5 carbon atoms; a linear or branched alkyl mono- or polysubstituted with phenyl groups which are either unsubstituted or mono- or polysubstituted; a phenyl alkyl ketone in which the alkyl group is branched or unbranched or cyclic; a substituted or unsubstituted benzophenone; a substituted or unsubstituted, unbranched or branched or cyclic phenyl alcohol; an unbranched or branched alkene; a piperidyl group; a phenylcycloalkyl group; a polycyclic group, in particular a fluorenyl group, a naphthyl or polyhydronaphthyl group or an indanyl group; a phenol group; a ketone or keto derivative; a diphenyl group; a phenoxyphenyl group; a benzyloxyphenyl group, 
         
       
       as well as their pharmaceutically acceptable salts 
     
     
         2 . The compound according to  claim 1 , characterized in that X II  is selected from —O—, —NH—, —CH 2 —, —OCONH—, —NHCO—, —NHCONH— and represents more preferably an oxygen atom. 
     
     
         3 . The compound according to  claim 1  characterized in that Y II  is selected from a linear or branched alkyl group; a cycloalkyl group, in particular cyclopentyl or cyclohexyl group; a phenyl group unsubstituted or mono-substituted, preferred substituent being halogen atom, in particular chlorine; a heterocyclic radical, in particular pyridyl N-oxide or pyrazinyl radicals; a bicyclic radical such as a benzothiazolyl radical, Y II  being more preferably a phenyl group unsubstituted or mono-substituted as above-defined. 
     
     
         4 . The compound according to  claim 1  characterized in that Y II  represents a phenyl group at least mono-substituted with a keto-substituent, in particular a linear or branched chain aliphatic ketone comprising from 1 to 8 carbon atoms and optionally bearing a hydroxyl group, a cycloalkylketone, an aryl alkyl ketone or arylalkenylketone in which the aryl group is optionally substituted, or a heteroaryl ketone, preferably a cycloalkylketone; an oxime-substituent or an halogen atom. 
     
     
         5 . The compound according to  claim 1  characterized in that Y II  is a phenyl group at least mono-substituted with —CHO, a ketone, an aldehyde, —CH═CH—CHO, —C(alkyl)=N—OH, —C(alkyl)=N—O(alkyl) and other keto derivatives, —CH═N—OH, —CH═NO(alkyl) and other aldehyde derivatives, —C(cycloalkyl)=NOH, —C(cycloalkyl)=N—O(alkyl). 
     
     
         6 . The compound according to  claim 1  characterized in that chain A II  is a chain —(CH 2 ) nII — with n varying from 1 to 6, preferably from 1 to 4, the chain A II  representing especially —(CH 2 ) 3 —. 
     
     
         7 . The compound according to  claim 1  characterized in that X is an oxygen atom, the chain A represents —(CH 2 ) 3 — and, for compounds of formula (IIa), the chain B represents —(CH 2 ) 3 — also. 
     
     
         8 . A compound of  claim 1  of general formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         C n H 2 n is a linear or branched hydrocarbon chain with n ranging from 2 to 8; 
         X is an oxygen or sulfur atom; 
         R 1  and R 2  are as defined in  claim 1 ; 
         n 3  is an integer from 0 to 5; and 
         R 3  represents each independently
 a halogen atom, 
 a lower alkyl or cycloalkyl, a trifluoromethyl, aryl, alkoxy, α-alkyloxyalkyl, aryloxy, nitro, formyl, alkanoyl, aroyl, arylalkanoyl, amino, carboxamido, cyano, alkyloximino, aryloximino, alkylalkoximino, □-hydroxyalkyl, alkenyl, alkynyl, sulphamido, sulfamoyl, sulphonamido, carboxamide, carbonylcycloalkyl, alkylcarbonylalkyl, carboalkoxy, arylalkyl or oxime group, 
 or taken together with the carbon atoms of the phenyl ring to which it is fused, a 5- or 6-membered saturated or unsaturated ring or a benzene ring. 
 
       
     
     
         9 . The compound according to  claim 8  characterized in that n 3  is zero. 
     
     
         10 . The compound according to  claim 8 , characterized in that n 3  is 1 with R 3  being as defined in  claim 9  and preferably in para-position. 
     
     
         11 . The compound according to  claim 8 , characterized in that R 3  is a lower alkyl, preferably a C 1 -C 4  alkyl. 
     
     
         12 . The compound according to  claim 8 , characterized in that R 3  is a halogen atom, a cyano, nitro, alkanoyl, alkyloximino or hydroxyalkyl, preferably CN, NO 2 , COCH 3 , COC 2 H 5 , H 3 C—C═N—OH or H 3 C—CHOH or cycloalkyl-CO. 
     
     
         13 . The compound according to  claim 8 , characterized in that R 3  taken together with the carbon atoms of the phenyl group to which it is fused, form a 5- or 6-membered saturated or unsaturated ring, in particular a 5,6,7,8-tetrahydronaphthyl group. 
     
     
         14 . The compound according to  claim 8 , characterized in that R 3  taken together with the phenyl group to which it is fused, form a naphthyl group. 
     
     
         15 . The compound according to  claim 8  characterized in that —C n H 2n — is a linear hydrocarbon chain —(CH 2 ) n —, n being as defined in  claim 16 . 
     
     
         16 . The compound according to  claim 8 , characterized in that X is an oxygen atom. 
     
     
         17 . The compound according to  claim 8 , characterized in that X is a sulfur atom. 
     
     
         18 . The compound according to  claim 8 , characterized in that n is varying from 3 to 5 and is preferably 3. 
     
     
         19 . The compound according to  claim 1  characterized in that it is one of the following compounds:
 1-(5-phenoxypentyl)-piperidine 
 1-(5-phenoxypentyl)-pyrrolidine 
 N-methyl-N-(5-phenoxypentyl)-ethylamine 
 1-(5-phenoxypentyl)-morpholine 
 N-(5-phenoxypentyl)-hexamethyleneimine 
 N-ethyl-N-(5-phenoxypentyl)-propylamine 
 1-(5-phenoxypentyl)-2-methyl-piperidine 
 1-[3-(4-cyclopropanecarbonylphenoxy) propyl]-piperidine 
 1-[3-(4-acetylphenoxy)-2-R-methylpropyl]piperidine 
 1-[3-(4-cyanophenoxy)propyl]-4-methylpiperidine 
 1-[3-(4-cyanophenoxy)propyl]-3-methylpiperidine 
 1-[3-(4-acetylphenoxy)-2-S-methylpropyl]piperidine 
 1-{3-[4-(3-oxobutyl)phenoxy]propyl}piperidine 
 1-[3-(4-cyano-3-fluorophenoxy)propyl]piperidine 
 1-[3-(4-nitrophenoxy)propyl]-3-methylpiperidine 
 1-[3-(4-cyanophenoxy)propyl]-2-methylpiperidine 
 1-[3-(4-nitrophenoxy)propyl]-2-methylpiperidine 
 1-[3-(4-nitrophenoxy)propyl]-4-methylpiperidine 
 1-[3-(4-cyanophenoxy)propyl]-2,6-dimethylpiperidine 
 1-[3-(4-propionylphenoxy)propyl]-3-methylpiperidine 
 1-[3-(4-cyclobutanecarbonylphenoxy)propyl]piperidine 
 1-[3-(4-cyclopentanecarbonylphenoxy) propyl]piperidine 
 1-[3-(4-cyanophenoxy)propyl]-cis-2-methyl-5-ethylpiperidine 
 1-[3-(4-cyanophenoxy)propyl]-trans-2-methyl-5-ethylpiperidine 
 1-[3-(4-cyanophenoxy)propyl]-cis-3,5-dimethylpiperidine 
 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine 
 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine 
 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl}-3-methylpiperidine 
 1-{3-[4-(1-hydroxypropyl)phenoxy]propyl}-4-methylpiperidine 
 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine 
 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine methoxime 
 1-[3-(4-cyanophenoxy)propyl]-trans-3,5-dimethylpiperidine 
 1-[3-(4-cyclopropyl carbonyl phenoxy)propyl]-trans-3,5-dimethylpiperidine 
 1-[3-(4-cyclopropyl carbonyl phenoxy)propyl]-cis-3,5-dimethylpiperidine 
 1-[3-(4-carbomethoxyphenoxy)propyl]piperidine 
 1-[3-(4-propenylphenoxy)propyl]-2-methyl piperidine 
 1-[3-(4-propionylphenoxy)propyl]-2-methylpiperidine 
 1-{3-[4-(1-ethoxypropyl)phenoxy]propyl}-2-methyl piperidine 
 1-[3-(4-propionylphenoxy)propyl]-4-methylpiperidine 
 1-[3-(4-bromophenoxy)propyl]piperidine 
 1-[3-(4-nitrophenoxy)propyl]piperidine 
 1-[3-(4-N,N-dimethylsulfonamidophenoxy)propyl]piperidine 
 1-[3-(4-isopropylphenoxy)propyl]piperidine 
 1-[3-(4-sec-butylphenoxy)propyl]piperidine 
 1-[3-(4-propylphenoxy)propyl]piperidine 
 1-[3-(4-ethylphenoxy)propyl]piperidine 
 1-(5-phenoxypentyl)-4-propyl-piperidine 
 1-(5-phenoxypentyl)-4-methyl-piperidine 
 1-(5-phenoxypentyl)-3-methyl-piperidine 
 1-acetyl-4-(5-phenoxypentyl)-piperazine 
 1-(5-phenoxypentyl)-3,5-trans-dimethyl-piperidine 
 1-(5-phenoxypentyl)-3,5-cis-dimethyl-piperidine 
 1-(5-phenoxypentyl)-2,6-cis-dimethyl-piperidine 
 4-carboethoxy-1-(5-phenoxypentyl)-piperidine 
 3-carboethoxy-1-(5-phenoxypentyl)-piperidine 
 1-(5-phenoxypentyl)-1,2,3,6-tetrahydropyridine 
 1-[5-(4-nitrophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-chlorophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-methoxyphenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-methylphenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-cyanophenoxy)-pentyl]-pyrrolidine 
 1-[5-(2-naphthyloxy)-pentyl]-pyrrolidine 
 1-[5-(1-naphthyloxy)-pentyl]-pyrrolidine 
 1-[5-(3-chlorophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-phenylphenoxy)-pentyl]-pyrrolidine 
 1-{5-[2-(5,6,7,8-tetrahydronaphthyl)-oxy]-pentyl}-pyrrolidine 
 1-[5-(3-phenylphenoxy)-pentyl]-pyrrolidine 
 1-(5-phenoxypentyl)-2,5-dihydropyrrole 
 1-{5-[1-(5,6,7,8-tetrahydronaphthyl)-oxy]-pentyl}-pyrrolidine 
 1-(4-phenoxybutyl)-pyrrolidine 
 1-(6-phenoxyhexyl)-pyrrolidine 
 1-(5-phenylthiopentyl)-pyrrolidine 
 1-(4-phenylthiobutyl)-pyrrolidine 
 1-(3-phenoxypropyl)-pyrrolidine 
 1-[5-(3-nitrophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-fluorophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-nitrophenoxy)-pentyl]-3-methyl-piperidine 
 1-[5-(4-acetylphenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-aminophenoxy)-pentyl]-pyrrolidine 
 1-[5-(3-cyanophenoxy)-pentyl]-pyrrolidine 
 N-[3-(4-nitrophenoxy)-propyl]-diethylamine 
 N-[3-(4-cyanophenoxy)-propyl]-diethylamine 
 1-[5-(4-benzoylphenoxy)-pentyl]-pyrrolidine 
 1-{5-[4-(phenylacetyl)-phenoxy]-pentyl}-pyrrolidine 
 N-[3-(4-acetylphenoxy)-propyl]-diethylamine 
 1-[5-(4-acetamidophenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-phenoxyphenoxy)-pentyl]-pyrrolidine 
 1-[5-(4-N-benzamidophenoxy)-pentyl]-pyrrolidine 
 1-{5-[4-(1-hydroxyethyl)-phenoxy]-pentyl}-pyrrolidine 
 1-[5-(4-cyanophenoxy)-pentyl]-diethylamine 
 1-[5-(4-cyanophenoxy)-pentyl]-piperidine 
 N-[5-(4-cyanophenoxy)-pentyl]-dimethylamine 
 N-[2-(4-cyanophenoxy)-ethyl]-diethylamine 
 N-[3-(4-cyanophenoxy)-propyl]-dimethylamine 
 N-[4-(4-cyanophenoxy)-butyl]-diethylamine 
 N-[5-(4-cyanophenoxy)-pentyl]-dipropylamine 
 1-[3-(4-cyanophenoxy)-propyl]-pyrrolidine 
 1-[3-(4-cyanophenoxy)-propyl]-piperidine 
 N-[3-(4-cyanophenoxy)-propyl]-hexamethyleneimine 
 N-[6-(4-cyanophenoxy)-hexyl]-diethylamine 
 N-[3-(4-cyanophenoxy)-propyl]-dipropylamine 
 N-3-[4-(1-hydroxyethyl)-phenoxy]-propyl-diethylamine 
 4-(3-diethylaminopropoxy)-acetophenone-oxime 
 1-[3-(4-acetylphenoxy)-propyl]-piperidine 
 1-[3-(4-acetylphenoxy)-propyl]-3-methyl-piperidine 
 1-[3-(4-acetylphenoxy)-propyl]-3,5-trans-dimethyl-piperidine 
 1-[3-(4-acetylphenoxy)-propyl]-4-methyl-piperidine 
 1-[3-(4-propionylphenoxy)-propyl]-piperidine 
 1-[3-(4-acetylphenoxy)-propyl]-3,5-cis-dimethyl-piperidine 
 1-[3-(4-formylphenoxy)-propyl]-piperidine 
 1-[3-(4-isobutyrylphenoxy)-propyl]-piperidine 
 N-[3-(4-propionylphenoxy)-propyl]-diethylamine 
 1-[3-(4-butyrylphenoxy)-propyl]-piperidine 
 1-[3-(4-acetylphenoxy)-propyl]-1,2,3,6-tetrahydropyridine 
 3,3-Dimethylbutyl 3-piperidinopropyl ether 
 2-Benzothiazolyl 3-piperidinopropyl ether 
 N-Phenyl-3-piperidinopropyl carbamate 
 N-Pentyl-3-piperidinopropyl carbamate 
 (S)-(+)-N-[2-(3,3-Dimethyl)butyl]-3-piperidinopropyl carbamate 
 2-((2-Piperidinoethyl)amino)benzothiazole 
 5-Piperidinopentylamine 
 N-(6-Phenylhexyl)piperidine 
 
     
     
         20 . Pharmaceutical composition characterized in that it comprises as active ingredient, a therapeutically effective amount of a compound according to  claim 1  in combination with a pharmaceutically acceptable vehicle or excipient. 
     
     
         21 . Method for the treatment of central nervous system disorders, in particular Alzheimer disease, mood and attention alterations, cognitive deficits in psychiatric pathologies, obesity, vertigo and motion sickness comprising administering a compound of  claim 1 . 
     
     
         22 . A method for promoting wakefulness, attention, memory and improving mood, and other cognitive disorders in aged persons, depressive or asthenic states, comprising administering a compound of  claim 1 . 
     
     
         23 . A method for stimulating attention and memorization capacity, comprising administering a compound of  claim 1 . 
     
     
         24 . A method for the treatment of CNS disorders, in particular of aged persons comprising administering a compound of  claim 1 . 
     
     
         25 . A method for exerting sedative, tranquilizing, anti-stress, analgesic and antimigraine activity, and for treating psychosomatic disorders, respiratory, allergic and rheumatic conditions of inflammatory conditions of the eye, urogenital system, digestive tract, skin, respiratory system and bronchi, comprising administering a compound of  claim 1 . 
     
     
         26 . A method for the treatment of asthma, bronchitis, rhinitis, tracheitis, myocardial dysfunctions and infarctions, gastric or duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel syndrome, cystitis, metritis, urinary and faecal incontinence, urticaria, itching, arthritis, conjunctivitis and premenstrual syndrome, comprising administering a compound of  claim 1 .