Substituted piperazines and diazepanes

Abstract

A novel class of substituted piperazines and diazepanes, pharmaceutical compositions comprising them and use thereof in the treatment of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.

1 . A compound of the general formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
    designates a single bond or a double bond, 
 R 1  is 
 (a) C 3 -C 9 -alkyl, C 3 -C 9 -alkenyl, C 3 -C 9 -alkynyl,
 which may optionally be substituted with one or more substituents selected from the group consisting of halogen and hydroxy, 
 
 (b) C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, di(C 3-8 -cycloalkyl)-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-4 -cycloalkyl-C 2-6 -alkynyl, C 5-8 -cycloalkenyl-C 1-6 -alkyl, C 5-8 -cycloalkenyl-C 2-4 -alkenyl, C 5-8 -cycloalkenyl-C 2-6 -alkynyl, 4-pyridyl or tetrahydropyranyl,
 wherein the cyclic moieties may optionally be substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, 2,2,2-trifluoroethyl and C 3-8 -cycloalkyl, 
 
 X is —(CH 2 ) m -(Z) n -(CR 2 R 3 ) o —(CH 2 ) p —(V) q —, 
 m and p independently are 0, 1, 2, 3 or 4, 
 n, o and q independently are 0 or 1, 
 Z and V independently are —O—, —NH—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —CH═CH— or —C≡C—, 
 R 2  and R 3  independently are hydrogen, C 1-6 -alkyl or hydroxy, 
 Y is 
 (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, oxo, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, —C(═O)O—C 1-6 -alkyl, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 4 R 5  and —O(C═O)NR 4 R 5 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 4  and R 5  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 4  and R 5  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, and 
 
 aryl, aryl-C 1-6 -alkyl, aryloxy and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 6 R 7  and —O(C═O)NR 6 R 7 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 6  and R 7  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 6  and R 7  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
 
 
 
 (b) C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl, which may optionally be substituted with one or more substituents selected from the group consisting of
 C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen, and 
 aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 8 R 9  and —O(C═O)NR 8 R 9 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 8  and R 9  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 8  and R 9  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
 
 
 
 
       with the proviso that when Y is selected from the group (a), the sum of m, n, o, p and q must be at least 1, 
       and with the proviso that when
 R 1  is cyclohexyl and X is —(CH 2 ) 3 —O—, Y must not be 1,2,3,4-tetrahydro-2-oxo-6-quinolinyl, 1,2-dihydro-2-oxo-6-quinolinyl or 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-5-yl, 
 R 1  is cycloheptyl and X is —(CH 2 ) 3 —O—, Y must not be 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]-quinolin-7-yl, 
 R 1  is cycloheptyl and X is —(CH 2 ) 4 —O—, Y must not be 2,3-dihydro-2-oxo-1H-pyrrolo[2,3-b]quinolin-6-yl, 
 Y must not be unsubstituted or substituted indolyl, 
 R 1  is cycloheptyl and X is —CH 2 —, Y must not be (3-benzyl)phenyl, 
 R 1  is cyclohexyl and X is —O—CH 2 —, Y must not be phenyl, 
 R 1  is cyclohexyl and X is —CH═CH—, Y must not be benzofuran-2-yl, 
 R 1  is cyclohexyl and X is —NH—, Y must not be cyclohexyl, 
 R 1  is 2-propen-1-yl and X is —NH—, Y must not be phenyl, 
 R 1  is n-propyl and X is —C≡C—, Y must not be phenyl, 
 R 1  is cyclopentyl and X is —CH 2 —O—, Y must not be 4-phenyl-1,2,3-thiadiazol-5-yl, 
 R 1  is isopropyl and X is —CH 2 —, Y must not be 4-oxothiazolidin-3-yl, 
 R 1  is isopropyl and X is —CH 2 —, Y must not be 2-oxopyrrolidin-1-yl, 
 R 1  is isopropyl and X is —O—, Y must not be 6-(5-chloropyridin-2-yl)-2,3,6,7-tetrahydro-7-oxo-5H-1,4-dithiino[2,3-c]pyrrol-5-yl, 
 R 1  is isopropyl and X is —CH═CH—, Y must not be 5-nitrofuran-2-yl, 
 R 1  is isopropyl and X is —O—, Y must not be 3-oxo-2-pyridin-2-yl-2,3-dihydro-1H-isoindol-1-yl, 
 
       as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to  claim 1  of the general formula (I 1 ): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , X and Y are as defined in  claim 1 . 
     
     
         3 . A compound according to  claim 1  of the general formula (I 2 ): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , X and Y are as defined in  claim 1 . 
     
     
         4 . A compound according to  claim 1 , wherein R 1  is C 3-8 -cycloalkyl, which may optionally be substituted with one or two substituents selected from the group consisting of C 1-6 -alkyl and C 3-8 -cycloalkyl. 
     
     
         5 . A compound according to  claim 4 , wherein R 1  is 1-ethylcyclopropyl, 1-methylcyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         6 . A compound according to  claim 5 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 1  is C 3-8 -cycloalkyl-C 1-6 -alkyl. 
     
     
         8 . A compound according to  claim 7 , wherein R 1  is cyclopropylmethyl or 1-cyclopropyl-1-methylethyl. 
     
     
         9 . A compound according to  claim 8 , wherein R 1  is 1-cyclopropyl-1-methylethyl. 
     
     
         10 . A compound according to  claim 1 , wherein R 1  is 4-pyridyl. 
     
     
         11 . A compound according to  claim 1 , wherein R 1  is tetrahydropyranyl. 
     
     
         12 . A compound according to  claim 1 , wherein R 1  is C 3-9 -alkenyl, which may optionally be substituted with one or two halogen substituents. 
     
     
         13 . A compound according to  claim 12 , wherein R 1  is allyl. 
     
     
         14 . A compound according to  claim 1 , wherein R 1  is C 3-9 -alkyl, which may optionally be substituted with one or more hydroxy substituents. 
     
     
         15 . A compound according to  claim 14 , wherein R 1  is 1-ethylpropyl, isopropyl, n-propyl or n-butyl. 
     
     
         16 . A compound according to  claim 1 , wherein R 1  is C 5-8 -cycloalkenyl. 
     
     
         17 . A compound according to  claim 1 , wherein X is —(CH 2 ) 0-4 —, —(CH 2 ) 0-4 —CH═CH—(CH 2 ) 0-4 —, —(CH 2 ) 0-4 —O(CH 2 ) 0-4 —, —(CH 2 ) 0-4 —S—(CH 2 ) 0-4 —, —(CH 2 ) 0-4 —C(═O)—(CH 2 ) 0-4 —, —(CH 2 ) 0-4 —CH(OH)—, —CH(OH)—(CH 2 ) 0-4 —, —CH(OH)—(CH 2 ) 0-4 —C(═O)—, —CH═CH—CH(OH)—, —(CH 2 ) 0-4 —O—(CH 2 ) 1-4 —O— or —(CH 2 ) 0-4 —CH═CH—(CH 2 ) 0-4 —C(═O)—. 
     
     
         18 . A compound according to  claim 17 , wherein X is —(CH 2 ) 1-4 —, —CH═CH—, —CH═CH—CH 2 —, —O—, —(CH 2 ) 1-4 —O—, —O—(CH 2 ) 1-4 —, —(CH 2 ) 1-4 —S—(CH 2 ) 1-4 —, —(CH 2 ) 1-4 —S—, —(CH 2 ) 1-4 —C(═O)—, —O—(CH 2 ) 2-3 —O—, —CH═CH—C(═O)—, —CH═CH—CH(OH)—, —CH(OH)—CH 2 —C(═O)— or —CH(OH)—CH 2 —CH 2 —. 
     
     
         19 . A compound according to  claim 18 , wherein X is —(CH 2 ) 1-4 —, —CH═CH—, —(CH 2 ) 1-4 —O, —O—(CH 2 ) 1-4 —, —(CH 2 ) 1-4 —S—(CH 2 ) 1-4 —, —(CH 2 ) 1-4 —S—, —(CH 2 ) 1-4 —C(═O)—, —O—(CH 2 ) 2-3 —O— or —CH═CH—C(═O)—. 
     
     
         20 . A compound according to  claim 19 , wherein X is —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH═CH—, —CH 2 —O—, —(CH 2 ) 3 —O—, —O—(CH 2 ) 2 —, —CH 2 —S—CH 2 —, —CH 2 —S—, —(CH 2 ) 2 —C(═O)— or —(CH 2 ) 3 —C(═O)—. 
     
     
         21 . A compound according to  claim 20 , wherein X is —CH 2 —, —(CH 2 ) 3 —, —CH═CH—, —O—(CH 2 ) 2 — or —(CH 2 ) 2 —C(═O)—. 
     
     
         22 . A compound according to  claim 21 , wherein X is —(CH 2 ) 3 —. 
     
     
         23 . A compound according to  claim 21 , wherein X is —(CH 2 ) 2 —C(═O)—. 
     
     
         24 . A compound according to  claim 21 , wherein X is —CH 2 —. 
     
     
         25 . A compound according to  claim 1 , wherein Y is phenyl, pyridyl, naphthyl, benzoxazolyl, indanyl, benzothienyl, benzthiazolyl, pyrazolyl or benzofuryl, which may optionally be substituted as defined in  claim 1 . 
     
     
         26 . A compound according to  claim 25 , wherein Y is phenyl or naphthyl, which may optionally be substituted as defined in  claim 1 . 
     
     
         27 . A compound according to  claim 26 , wherein Y is phenyl, which may optionally be substituted as defined in  claim 1 . 
     
     
         28 . A compound according to  claim 1 , wherein Y is C 3-8 -cycloalkyl, which may optionally be substituted as defined in  claim 1 . 
     
     
         29 . A compound according to  claim 28 , wherein Y is cyclohexyl, which may optionally be substituted as defined in  claim 1 . 
     
     
         30 . A compound according to  claim 25 , wherein Y is unsubstituted or substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, —C(═O)O—C 1-6 -alkyl, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 4 R 5  and —O(C═O)NR 4 R 5 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 4  and R 5  independently are hydrogen, C 1-6 -alkyl, C 3-4 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 4  and R 5  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
   phenyl, phenoxy and phenyl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 6 R 7  and —O(C═O)NR 6 R 7 , or wherein two substituents in adjacent position form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 6  and R 7  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 6  and R 7  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring. 
 
   
     
     
         31 . A compound according to  claim 30 , wherein Y is unsubstituted or substituted with one or more substituents selected from the group consisting of
 halogen, nitro, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-4 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 4 R 5  and —O(C═O)NR 4 R 5 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 4  and R 5  are C 1-6 -alkyl, or R 4  and R 5  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
   phenyl and phenyl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from halogen and C 1-6 -alkyl.   
     
     
         32 . A compound according to  claim 31 , wherein Y is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1-6 -alkoxy, —CF 3 , halogen, —N(C 1-6 -alkyl) 2 , phenyl and 4-fluorophenyl, or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—. 
     
     
         33 . A compound according to  claim 32 , wherein Y is substituted with one halogen substituent. 
     
     
         34 . A compound according to  claim 32 , wherein Y is substituted with one —N(C 1-6 -alkyl) 2  substituent. 
     
     
         35 . A compound according to  claim 28 , wherein Y is unsubstituted or substituted with one or two substituents selected from the group consisting of
 aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 8 R 9  and —O(C═O)NR 8 R 9 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 8  and R 9  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or a carbon atom of R 8  and R 9  together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated or unsaturated ring. 
 
   
     
     
         36 . A compound according to  claim 35 , wherein Y is unsubstituted or substituted with one or two substituents selected from the group consisting of
 phenyl and phenoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 8 R 9  and —O(C═O)NR 8 R 9 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 8  and R 9  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or a carbon atom of R 8  and R 9  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring. 
 
   
     
     
         37 . A compound according to  claim 36 , wherein Y is unsubstituted or substituted with phenyl, which is unsubstituted or substituted with halogen. 
     
     
         38 . A pharmaceutical composition comprising, as an active ingredient, at least one compound according to  claim 1  together with one or more pharmaceutically acceptable carriers or excipients. 
     
     
         39 . A pharmaceutical composition according to  claim 38  in unit dosage form, comprising said compound in an amount between about 0.05 mg and about 1000 mg. 
     
     
         40 . A pharmaceutical composition according to  claim 39 , wherein said amount is between about 0.5 mg and about 200 mg. 
     
     
         41 . A method for the treatment of treatment of a disorder or disease related to the H3 histamine receptor, said method comprising administering to a patient in need of such treatment an effective amount for treating said disorder or disease of a compound having the formula (I′) 
       
         
           
           
               
               
           
         
       
       wherein
    designates a single bond or a double bond, 
 R 1  is 
 (a) C 3 -C 9 -alkyl, C 3 -C 9 -alkenyl, C 3 -C 9 -alkynyl,
 which may optionally be substituted with one or more substituents selected from the group consisting of halogen and hydroxy, 
 
 (b) C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, di(C 3-8 -cycloalkyl)-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 5-8 -cycloalkenyl-C 1-6 -alkyl, C 5-8 -cycloalkenyl-C 2-6 -alkenyl, C 5-8 -cycloalkenyl-C 2-6 -alkynyl, 4-pyridyl or tetrahydropyranyl,
 wherein the cyclic moieties may optionally be substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl, halogen, trifluoromethyl, 2,2,2-trifluoroethyl and C 3-8 -cycloalkyl, 
 
 X is —(CH 2 ) m -(Z) n -(CR 2 R 3 ) o —(CH 2 ) p —(V) q —, 
 m and p independently are 0, 1, 2, 3 or 4, 
 n, o and q independently are 0 or 1, 
 Z and V independently are —O—, —NH—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —CH═CH— or —C≡C—, 
 R 2  and R 3  independently are hydrogen, C 1-6 -alkyl or hydroxy, 
 Y is 
 (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, oxo, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, —C(═O)O—C 1-6 -alkyl, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 4 R 5  and —O(C═O)NR 4 R 5 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 4  and R 5  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or a carbon atom of R 4  and R 5  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
 
 aryl, aryl-C 1-6 -alkyl, aryloxy and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 6 R 7  and —O(C═O)NR 6 R 7 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 6  and R 7  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or a carbon atom R 6  and R 7  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
 
 
 
 (b) C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl, which may optionally be substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,
 aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from the group consisting of
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 8 R 9  and —O(C═O)NR 8 R 9 , or wherein two substituents in adjacent positions together form a radical —O—(CH 2 ) 1-3 —O—,
 wherein R 8  and R 9  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or a carbon atom of R 8  and R 9  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, 
 
 
 
 
       with the proviso that when Y is selected from the group (a), the sum of m, n, o, p and q must be at least 1, 
       as well as any diastereomer or enantiomer or tautomeric form thereof, mixtures of these or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method according to  claim 41 , wherein said compound exhibits histamine H3 antagonistic activity or histamine H3 inverse agonistic activity. 
     
     
         43 . The method according to  claim 41 , wherein said disorder or disease is selected from the group consisting of: overweight, obesity, appetite disorders, bulimia, IGT, progression from IGT to Type 2 diabetes, and progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes. 
     
     
         44 . The method according to  claim 41 , wherein said compound exhibits histamine H3 agonistic activity. 
     
     
         45 . The method according to  claim 41 , wherein said disorder or disease is selected from the group consisting of allergic rhinitis, ulcer, anorexia, Alzheimer's disease, narcolepsy, and attention deficit disorder. 
     
     
         46 . The method according to  claim 41  wherein the effective amount is between about 0.05 mg and about 2000 mg per day. 
     
     
         47 . The method according to  claim 46 , wherein the effective amount is between about 0.1 mg and about 1000 mg per day. 
     
     
         48 . The method according to  claim 47 , wherein the effective amount is between about 0.5 mg to about 500 mg per day.