AU2003203148A1 - Novel aryl- and heteroarylpiperazines - Google Patents
Novel aryl- and heteroarylpiperazines Download PDFInfo
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- AU2003203148A1 AU2003203148A1 AU2003203148A AU2003203148A AU2003203148A1 AU 2003203148 A1 AU2003203148 A1 AU 2003203148A1 AU 2003203148 A AU2003203148 A AU 2003203148A AU 2003203148 A AU2003203148 A AU 2003203148A AU 2003203148 A1 AU2003203148 A1 AU 2003203148A1
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- C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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Description
WO 03/066604 PCT/DKO3/00071 1 NOVEL ARYL- AND HETEROARYLPIPERAZINES FIELD OF THE INVENTION The present invention relates to novel aryl- and heteroarylpiperazines, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the 5 compounds, and to a method of treatment employing these compounds and compositions. The present compounds show a high and selective binding affinity to the histamine H3 recep tor indicating histamine H3 receptor antagonistic, inverse agonistic or agonistic activity. As a result, the compounds are useful for the treatment of diseases and disorders related to the histamine H3 receptor. 10 BACKGROUND OF THE INVENTION The existence of the histamine H3 receptor has been known for several years and the recep tor is of current interest for the development of new medicaments. Recently, the human his tamine H3 receptor has been cloned. The histamine H3 receptor is a presynaptic autorecep tor located both in the central and the peripheral nervous system, the skin and in organs 15 such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Recent evi dence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (ie it is active in the absence of an agonist. Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A his 20 tamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the re lease of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antago 25 nists could be important mediators of neuronal activity. Accordingly, the histamine H3 recep tor is an important target for new therapeutics. Compounds similar to the compounds of the present invention have previously been dis closed, cf. J. Med. Chem. 1999, 42, 336, J. Med. Chem. 1992, 35, 2369, DE 2804096, J. Org. Chem. 1996, 61, 3849, Bull. Soc. Chim. Fr. 1969, 319, WO 00/66578, WO 99/21845, 30 and J. Med. Chem. 1968, 11(6), 1144-1150. However, these references neither disclose nor suggest that these compounds may have a histamine H3 receptor antagonistic or agonistic activity.
WO 03/066604 PCT/DKO3/00071 2 Several publications disclose the preparation and use of histamine H3 agonists and antago nists. Most of these are imidazole derivatives. However, recently some imidazole-free ligands of the histamine H3 receptor have been described (see e.g. Linney et al., J. Med. Chem. 2000, 43, 2362-2370; US 6,316,475, WO 01/66534 and WO 01/74810). However, these 5 compounds differ structurally from the present compounds. In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antago nists, novel compounds which interact with the histamine H3 receptor would be a highly de sirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of aryl- and heteroarylpiperazines has a high 10 and specific affinity to the histamine H3 receptor. Due to their interaction with the histamine H3 receptor, the present compounds are useful in the treatment of a wide range of conditions and disorders in which an interaction with the his tamine H3 receptor is beneficial. Thus, the compounds may find use eg in the treatment of diseases of the central nervous system, the peripheral nervous system, the cardiovascular 15 system, the pulmonary system, the gastrointestinal system and the endocrinological system. DEFINITIONS In the structural formulae given herein and throughout the present specification, the following terms have the indicated meaning: The term "halogen" means F, CI, Br or I. 20 The term "alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having the indicated number of carbon atoms. Thus, the terms "C 1
.
3 -alkyl", "C 1 .8-alkyl" and "C 1 -o 10 -alkyl" as used herein represent saturated, branched or straight hydrocarbon groups having from 1 to 3 carbon atoms, 1 to 8 carbon atoms and from 1 to 10 carbon at oms, respectively. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 25 isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. The term "alkenyl" as used herein represents a branched or straight hydrocarbon group hav ing the indicated number of carbon atoms and at least one double bond. Thus, the terms
"C
2 -8-alkenyl" and "C 2
-
1 0 -alkenyl" as used herein represents a branched or'straight hydrocar 30 bon group having from 2 to 8 carbon atoms, and from 2 to 10 carbon atoms respectively, and at least one double bond Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1 pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 2 nonenyl, 2-decenyl and the like.
WO 03/066604 PCT/DKO3/00071 3 The term "alkynyl" as used herein represents a branched or straight hydrocarbon group hav ing the indicated number of carbon atoms and at least one triple bond. Thus, the term
"C
2
-
8 -alkynyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. Examples of such groups include, but 5 are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2 pentynyl, 1-hexynyl, 2-hexynyl, 2-heptynyl, 1-octynyl, 2-octynyl and the like. The term "branched C4-6-alkyl" as used herein represents a saturated, branched hydrocarbon group having from 4 to 6 carbon atoms. Typical branched C 4 -8-alkyl groups include, but are not limited to, 1-methylpropyl, tert-butyl, 1-ethylpropyl, 1,1-(dimethyl)propyl, isopentyl 1 10 ethylbutyl, 1,1-(dimethyl)butyl, 1,1-(dimethyl)pentyl, 1-ethylpentyl, 1,1-(dimethyl)hexyl, 1 ethylhexyl and the like. The term "branched C 4
.
6 -alkenyl" as used herein represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one double bond. Typical branched C 4
.
6 -alkenyl groups include, but are not limited to, 1-ethylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1 15 ethylbut-3-enyl, 1,1-(dimethyl)but-2-enyl, 1,1-(dimethyl)pent-3-enyl, 1-ethylpent-2-enyl, 1,1 (dimethyl)pent-3-enyl, 1,1-(dimethyl)hex-3-enyl, 1-ethylhex-4-enyl and the like. The term "branched C4.
6 -alkynyl" as used herein represents a branched hydrocarbon group having from 4 to 6 carbon atoms and at least one triple bond. Typical branched C 4
-
6 -alkynyl groups include, but are not limited to, 1-ethylprop-2-ynyl, 1,1-(dimethyl)prop-2-ynyl, 1 20 ethylbut-3-ynyl, 1,1-(dimethyl)but-2-ynyl, 1,1-(dimethyl)pent-3-ynyl, 1-ethylpent-2-ynyl, 1,1 (dimethyl)pent-3-ynyl, 1,1-(dimethyl)hex-3-ynyl, 1-ethylhex-4-ynyl and the like. The term "Cl.
6 -alkoxy" as used herein refers to the radical -O-C1.6-alkyl, wherein Cl.e-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like. 25 The term "'C 2 1 0 -alkanoyl" as used herein refers to the radical -C(=O)C 1
.
9 -alkyl, wherein C 1 .9 alkyl represents a saturated, branched or straight hydrocarbon groups having from 1 to 9 carbon atoms. Representative examples are acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like. The term "Cl 1 6 -alkylamino" as used herein refers to the radical -NH-Cl.
6 -alkyl, wherein C 1
.-
6 30 alkyl is as defined above. Representative examples are methylamino, ethylamino, isopro pylamino, n-propylamino, butylamino, pentylamino, hexylamino and the like. The term "di-ClB-alkylamino" as used herein refers to the radical -N(Cl.
6 -alkyl) 2 , wherein C 1
._
alkyl is as defined above. It should be understood that the C 1
.
6 -alkyl groups may be the same or different. Representative examples are dimethylamino, methylethylamino, diethylamino, 35 diisopropylamino, di-n-propylamino, dibutylamino, dipentylamino, dihexylamino and the like.
WO 03/066604 PCT/DKO3/00071 4 The term "C 3
.
5 -cycloalkyl" as used herein represents a monocyclic, carbocyclic group having from from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl and the like. In the same way the terms "C 3
.
6 -cycloalkyl" and "C 3
_
8 -cycloalkyl" as used herein represent 5 monocyclic, carbocyclic groups having from 3 to 6 carbon atoms and from 3 to 8 carbon at oms, respectively. The term "C 3
.
7 -cycloalkenyl" as used herein represents a monocyclic, carbocyclic, non aromatic group having from 3 to 7 carbon atoms and at least one double bond. Representa tive examples are cyclopropenyl, cyclobutenyl, cyclopentenyl and the like. 10 In the same way the term "C 3
-
6 -cycloalkenyl"represents a monocyclic, carbocyclic, non aromatic group having from 3 to 6 carbon atoms and at least one double bond. The term "C3.
6 -cycloalkyl-C_ 3 -alkyl" as used herein refers to the radical -C 1
.-
3 -alkyl-C 3
.
6 -cyclo alkyl where C 3
_
6 -cycloalkyl and Cl.
3 -alkyl are as defined above. The term "C 3 -6-cycloalkenyl-C 1 ~
-
3 -alkyl" as used herein refers to the radical -C 1
-
3 -alkyl 15 C3.6-cycloalkenyl where C 3
-
6 -cycloalkenyl and C 1
.
3 -alkyl are as defined above. The term "C 3 8-cycloalkyloxy" as used herein refers to the radical -O-C 3
_
8 -cycloalkyl where
C
3 8 -cycloalkyl is as defined above. Representative examples are cyclopropyloxy, cyclobuty loxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like. The term "C 4
-
9 -cycloalkanoyl" as used herein refers to the radical -C(=O)-C3.8-cycloalkyl 20 where C3.
8 -cycloalkyl is as defined above. Representative examples are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctyl carbonyl and the like. The term "Cl.
6 -alkylsulfonyl" as used herein refers to the radical -S(=O) 2 -C1-6-alkyl, wherein
C
1 _.-alkyl is as defined above. Representative examples are methylsulfonyl, ethylsulfonyl, 25 isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl and the like. The term "Cl.6-alkylsulfanyl" as used herein refers to the radical -S-C,.
6 -alkyl, wherein C1.6 alkyl is as defined above. Representative examples are methylsulfanyl, ethylsulfanyl, isopro pylsulfanyl, n-propylsulfanyl, butylsulfanyl, pentylsulfanyl and the like. The term "C3.
8 -heterocyclyl" as used herein refers to a saturated 3 to 8 membered monocyc 30 lic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tet rahydrofuranyl and the like. The term "C 4
-
9 -heterocycloalkanoyl" as used herein refers to the radical -C(=O)-C38-heterocyclyl where C 3 .8-heterocyclyl is as defined above. Representative exam- WO 03/066604 PCT/DKO3/00071 5 pies are aziridinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl and the like. The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems such 5 as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydro genated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. The term "aryloxy" as used herein refers to the radical -O-aryl, wherein aryl is as defined 10 above. Non-limiting examples are phenoxy, naphthoxy, anthracenyloxy, phenantrenyloxy; fluorenyloxy, indenyloxy and the like. The term "aroyl" as used herein refers to the radical -C(=O)-aryl, wherein aryl is as defined above. Non-limiting examples are benzoyl, naphthoyl, anthracenylcarbonyl, phenantrenyl carbonyl, fluorenylcarbonyl, indenylcarbonyl and the like. 15 The term "arylamino" as used herein refers to the radical -NH-aryl, wherein aryl is as defined above. Non-limiting examples are phenylamino, naphthylamino, anthracenylamino, phe- ' nantrenylamino, fluorenylamino, indenylamino and the like. The term "heteroaryl" as used herein is intended to include heterocyclic aromatic ring sys tems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as 20 furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-tri azinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadi azolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothi 25 azolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl,.isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, di azepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogen ated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, 30 indanyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like. The term "heteroaryloxy" as used herein refers to the radical -O-heteroaryl, wherein het eroaryl is as defined above. The term "heteroaroyl" as used herein refers to the radical -C(=O)-heteroaryl, wherein het eroaryl is as defined above.
WO 03/066604 PCT/DKO3/00071 6 The term "heteroarylamino" as used herein refers to the radical -NH-heteroaryl, wherein het eroaryl is as defined above. Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other. 5 "Aryl-C 1 -6-alkyl", "aryl-C 1
.
6 -alkoxy" etc. mean C 1 _.-alkyl or C 1 .6-alkoxy as defined above, sub stituted by aryl as defined above, for example: IO0, The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups 10 in question are substituted with more than one substituent the substituents may be the same or different. The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of 15 symptoms and complications, and/or the cure or elimination of the disease, disorder or condi tion. The patient to be treated is preferably a mammal, in particular a human being. DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (I):
N
'A R1,N.. (I) 20 wherein (i) R 1 represents 25 * branched C 4 -8-alkyl, branched C 4 -8-alkenyl or branched C 4
-
8 -alkynyl, which may optionally be substituted with one or more halogen substituents, * C, 5 -cycloalkyl, C 3
.-
7 -cycloalkenyl, C 3
.
6 -cycloalkyl-Cl_ 3 -alkyl or C 3 -6-cycloalkenyl
C
4 3-alkyl, WO 03/066604 PCT/DKO3/00071 7 which may optionally be substituted in any position with one or more halogen sub stituents, and A represents ao R 2Y R 2a R R2a Z W W \W X R2b or 2b 5 or (ii) R 1 represents ethyl, n-propyl or isopropyl, and A represents 10 R R 3 R t2a N
R
2 b Z and X independently represent -N=, -CH=, -CF= or -C(CF 3 )=, 15 W represents -N= or -CR 3= , Y represents -N= or -CR 4=,
R
2 , R 2 b, R 3 , and R 4 independently represent 20 *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1
-
10 -alkyl,
C
2 -1 0 -alkenyl, C 3 -8-cycloalkyl, Cl.e-alkoxy, aryl-Cl.e-alkyl, amino, Cl.
6 -alkylamino, di Cl- 6 -alkylamino, C 3 s8-cycloalkyloxy, cyano, nitro, C, 6 -alkylsulfanyl, Cs_ 6 -alkylsulfonyl or
-C(=O)NR
4 aR 4 b, wherein R 4a and R 4 b independently are hydrogen, C 1
.
6 -alkyl or aryl 25 C 1
.
6 -alkyl, * C2.o 10 -alkanoyl, C 4
-
9 -cycloalkanoyl, C 3 -heterocyclyl or C4- 9 -heterocycloalkanoyl, WO 03/066604 PCT/DKO3/00071 8 which may optionally be substituted in any position with one or more substituents se lected from aryl, heteroaryl, C3-8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and Cl.6-alkoxy, 5 aryl, aryl-C 1 6 -alkyl, aryl-CI.
6 -alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy,
C
1
.
6 -alkoxy, Cl 6 -alkyl, amino,
CI-
6 -alkylamino, di-C 1
.
6 -alkylamino, cyano, aryl, heteroaryl and C 3
_
8 -cycloalkyl, 10 * aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from aryl, heteroaryl, C 1
-
10 -alkyl, C 3 _8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, Cl 6 -alkoxy, cyano, amino, C 1 -6-alkylamino, di-Cl.e-alkylamino and hydroxy, 15 * or two of R 2a , R 2 b, R 3 , and R 4 in adjacent positions together form a C 1
.
6 -alkylene bridge, with the proviso that the compound must not be 20 N N CI NH 3 C N NC N HC N
H
3 C N Hz3C H3C WO 03/066604 PCT/DK03/00071 9
O'CH
3 N Cl N HC NHC N
H
3 C
H
3 C N OH N
H
3 C N N
H
3 C N N NH N N N
NH
2 N N O
CF
3
CH
3 N. N NF N
N
WO 03/066604 PCT/DKO3/00071 10 C1 CI NN Nb N or as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 5 In one embodiment, R 1 is branched C4-8-alkyl, C3-5-cycloalkyl or C3-6-cycloalkyl-C1-3-alkyl, which may optionally be substituted with one or more halogen substituents. In another embodiment, R' is branched C4-8-alkyl, C3-5-cycloalkyl or C3-6-cycloalkyl Cl -3-alkyl. 10 In another embodiment, R 1 is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclo propyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl. In another embodiment, R 1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl. 15 In another embodiment, R 1 is branched C4-8-alkyl or C3-5-cycloalkyl, which may optionally be substituted with one or more halogen substituents. In another embodiment, R 1 is branched C4-8-alkyl or C3-5-cycloalkyl. 20 In another embodiment, R 1 is 1-ethylpropyl, cyclopropyl or cyclopentyl. In another embodiment, R' is isopropyl. 25 In another embodiment, A is WO 03/066604 PCT/DK03/00071 11 R2a R2a R2a R2a 2 a R4R
R
2 r R whri R 3 a F~,R n R arRsdeie fofrml R1. F CF 3 3
R
2 or N R 2 b N R 2 b wherein R 2 a, R 2 b, R 3 and R 4 are as defined for formula (I).. 5 In another embodiment, A is
R
2 a R 4 wherein R 2 a, R' and R 4 are as defined for formula (I). 10 In another embodiment, A is
R
4 R wherein R 2 F , R 2 b, R and R are as defined for formula (). wherein R 2a R 3 and W 4 are as defined for formula (1). 15 In another embodiment, A is R' " N - R2b , wherein R a, R b,
W
3 and RW are as defined for formula (1).
WO 03/066604 PCT/DKO3/00071 12 In another embodiment, R 2a , R 2 b, R 3 and R 4 are independently selected from *hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, C2-10-alkanoyl, C4-9 cycloalkanoyl or C4-9-heterocycloalkanoyl, or 5 * aryl-C 1
.
6 -alkyl, aryl-C 1 6 -alkoxy or aroyl, which may optionally be substituted as defined for formula (I). In another embodiment, R 2a , R 2 b, R 3 and R 4 are independently selected from 10 * hydrogen, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, C2-10-alkanoyl, C4-9 cycloalkanoyl or C4-9-heterocycloalkanoyl, * phenyl-C 1
.
6 -alkyl, phenyl-C 1
-
6 -alkoxy or benzoyl, 15 which may optionally be substituted with one or two substituents selected from halo gen and C 1
-
6 -alkoxy. In another embodiment, R 2a , R 2 b and R 4 are hydrogen and R 3 is different from hydrogen. 20 In another embodiment, R 3 is halogen, trifluoromethyl or trifluoromethoxy. In another embodiment, the invention relates to a compound of the general formula (11): N-A
H
3 C
H
3 C wherein A is as defined for formula (I) or in any one of the above embodiments. 25 In another embodiment, the invention relates to a compound of the general formula (12): NA N 2) wherein A is as defined for formula (I) or in any one of the above embodiments. 30 WO 03/066604 PCT/DKO3/00071 13 In another embodiment, the invention relates of the general formula (13): R R 2 a R3 R a N 2 b (13) wherein R' is 5 * branched C4-8-alkyl, branched C 4 -8-alkenyl or branched C 4
-
8 -alkynyl, which may optionally be substituted with one or more halogen substituents, * C3.5-cycloalkyl, C3.
7 -cycloalkenyl, C3.6-cycloalkyl-C.
3 -alkyl or C 3
.
6 -cycloalkenyl 10 C 1
.
3 -alkyl, which may optionally be substituted in any position with one or more halogen sub stituents, *ethyl, n-propyl or isopropyl, 15
R
2a , R 2 b, R 3 and R 4 are as defined for formula (I). In another embodiment the present invention relates to a compound selected from 20 4-(4-cyclopentylpiperazin-1 -yl)phenol, 1-cyclopentyl-4-[4-(4-fluorobenzyloxy)phenyl]piperazine, 1-( 3 -chlorophenyl)-4-cyclopentylpiperazine, 1-[4-(4-cyclopentylpiperazin-1 -yl)phenyl]ethanone, 1-(3,4-dichlorophenyl)-4-(1-ethylpropyl)piperazine, 25 {4-[4-(1 -ethylpropyl)piperazin-I -yl]phenyl}phenylmethanone, 1-(4-benzylphenyl)-4-(1-ethylpropyl)piperazine, cyclopropyl-{4-[4-(1-ethylpropyl)piperazin-1 -yl]phenyl}methanone, (2-chlorophenyl)-{4-[4-(1-ethylpropyl)piperazin-1 -yl]phenyl}methanone, {4-[4-(1 -Ethylpropyl)piperazin-1 -yl]phenyl}-(4-fluorophenyl)methanone, 30 1-cyclopentyl-4-(6-trifluoromethylpyridin-2-yl)piperazine, 1-cyclopentyl-4-(5-trifluoromethylpyridin-2-yl)piperazine, WO 03/066604 PCT/DK03/00071 14 1 -cyclopentyl-4-(3-trifluoromethylpyridin-2-yI)piperazine, 2-[4-(l -ethyl propyl)piperazin-1 -yIlquinoline, 7-chloro-4-[4-(1 -ethylpropyl)piperazin-1 -yi]quinoline, [4-(4-cyclopentylpiperazin-1 -yI)phenylj-(3,4-dimethoxyphenyl)methanone, 5 [4-(4-cyclopentylpiperazin-1 -yI)-3,5-difluorophenyl]phenylmethanone, 2-(4-cyclopentylpiperazin-1 -yI)q ulnoxaline, 2-(4-cyclopropylmethylpiperazin-1 -yI)quinoxaline, [6-(4-cyclopentylpiperazin-1 -yI)pyridin-3-yllpiperidin-1 -ylmethanone, 2-(4-cyciopentylpiperazin-1 -ylquinoline, 10 2-(4-cyclopentylpiperazin-1 -yI)-7-methoxy-3-(4-methoxyphenyl)quinoline, (6-[4-(l1 -cyclopropyl-1 -methylethyi)piperazin-1 -yI]pyridin-3-yI}phenylmethanone,, {4-[4-(l -cyclopropyl-l -methylethyl)piperazin-1 -yI]-3,5-difluorophenyllphenylmethanone, 14-[4-(l -cyclopropyl-1 -methylethyl)piperazin-1 -yi]-3,5-difluorophenyl~phenylmethanol (4-(4-cyclopropylmethylpiperazin-1 -yI)-3,5-difluorophenyl]-(4-fiuorophenyl)methanone, 15 {4-[4-(i -ethylpropyl)piperazin-1 -yI]-3,5-difluorophenyl}-(4-fluorophenyl)methanone, 2-[4-(lI-ethylpropyl)piperazin-1 -yI]-6,7-dimethoxyquinoline, 2-[4-(1 -ethylpropyl)piperazin-1 -yI]-4-trifluoromethylquinoline, 2-(4-cyclopropylmethylpiperazin-1 -yI)-6-methoxy-4-trifluoromethylquinoline, [4-(4-cyclopropylmethylpiperazin-1 -yi)-3,5-difluorophenyl]phenylmethanone, 20 [4-(4-cyclopropylmethylpiperazin-1 -yi)-3, 5-difluorophenyil-(3-fluoro-4-methoxyphenyi) methanone, {6-[4-(1 -ethylpropyl)piperazin-1 -yI]pyridin-3-yl}phenyimethanone, {2-[14-(l -ethyl propyl)piperazin-1 -yI]pyridin-4-yI}phenyl methanone, {4-[4-(l -ethylpropyl)piperazin-1 -yl]phenyl)-(4-hydroxyphenyl)methanone, 25 {6-[4-(l -ethylpropyl)piperazin-1 -yI]pyridin-3-yllpiperidin-1 -yi-methanone, N-benzyl-6-14-(1 -ethyipropyl)piperazin-1 -yI]-N-methylnicotinamide, 2-[4-(l1 -ethylpropyl)piperazin-1 -yI]-6-methoxyquinoline, 6-[4-(1 -ethyl propyl)piperazin-1 -yI]-N-methyl-N-phenylnicotinamide, {6-[4-(l -ethylpropyl)piperaZin-1 -yl]pyridin-3-yI-(4-fluorophenyl)methanone, 30 2-[4-(1 -ethylpropyl)piperazin- I -yI]-4-methylquinoline, 2-[4-(l -ethylpropyl)piperazin-1 -y]-5,6,7,8-tetrahydroquinoline, 2-(4-cyclopropylmethylpiperazin-1 -yi)-6-methoxyquinoline, 2-(4-isopropylpiperazin-I -yi)-6-methoxyquinoline, 2-[4-(lI -ethylpropyl)piperazin-1 -yI]-6-fluoro-4-methylquinoline, 35 2-(4-cyclopropylpiperazin-1-y)-6-trifluoromethylquilolife, WO 03/066604 PCT/DKO3/00071 15 2-(4-cyclopropylpiperazin-1 -yl)-6-propylquinoline, 2-(4-ethylpiperazin-1 -yl)quinoline, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of 5 these or a pharmaceutically acceptable salt thereof. In another aspect the present invention relates to a compound of the general formula (1"): N(1) RN 10 wherein
R
1 represents * branched C 4 -8-alkyl, branched C4--alkenyl or branched C 4
-
8 -alkynyl, 15 which may optionally be substituted with one or more halogen substituents, * C 3 5 -cycloalkyl, C 3
.-
7 -cyloalkenyl, Cm-cycloalkyl-C.
3 -alkyl or C 3
.
6 -cycloalkenyl
C
1
.
3 -alkyl, which may optionally be substituted with one or more halogen substituents, 20 A represents
R
2 -l R or 2 x Z and X independently represent -N=, -CH=, -CF= or -C(CF 3 )=, 25 W represents -N= or -CR 3= , Y represents -N= or -CR 4=, 30 R 2 , R 3 , and R 4 independently represent WO 03/066604 PCT/DKO3/00071 16 * hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1
-
10 -alkyl,
C
2
-
1 0 -alkenyl, C 3
.
8 -cycloalkyl, C 1 6 -alkoxy, aryl-C I 6 -alkyl, amino, CI_0-alkylamino, di
C
1
.
6 -alkylamino, C3.8-cycloalkyloxy or cyano, or 5 * C 2
-
1 0 -alkanoyl or C 4 -9-cycloalkanoyl, which may optionally be substituted with one or more substituents selected from aryl, heteroaryl, C 3 .8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and Cl.o-alkoxy, 10 aryl, aryl-C 1
-
6 -alkyl, aryl-C 1
.
6 -alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1- 6 -alkoxy, C.
6 -alkyl, amino,
C
1
.
6 -alkylamino, di-C 1
.
6 -alkylamino, cyano, aryl, heteroaryl and C3.
8 -cycloalkyl, or 15 *aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from aryl, heteroaryl, C 1
-
10 -alkyl, C 3
-
8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy,
C
1
.
6 -alkoxy, cyano, amino, C l .6-alkylamino, di-Cl.e-alkylamino and hydroxy, 20 with the proviso that the compound must not be NN Cl N H 3 C N Cl NC N
H
3 C N 3 C HC H 3
C
WO 03/066604 PCT/DK03/00071 17 O 'CH 3 N CI N
H
3 C N
H
3 C N
H
3 C NC N
HCH
3 C N N NH NJ
NH
2 NCN N CF I CI N C N _, F F NN5 WO 03/066604 PCT/DKO3/00071 18 CN CI NJN N N N
C
3 c N ),- N N or as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 5 In one embodiment R' is branched C 4 -8-alkyl, C 3
.
5 -cycloalkyl or C 3
.
6 -cycloalkyl-Cl.
3 -alkyl, which may optionally be substituted with one or more halogen substituents. In another embodiment R 1 is branched C 4 -8-alkyl, C 3
-
5 -cycloalkyl or C 3 .6-cycloalkyl-C 1
.
3 -alkyl, such as 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or. 10 cyclopentyl, eg 1-ethylpropyl, cyclopropylmethyl or cyclopentyl. In yet another embodiment R 1 is branched C 4 -8-alkyl or C 3 5 -cycloalkyl, which may optionally be substituted with one or more halogen substituents, such as branched C 4
.-
8 -alkyl or
C
3 .5-cycloalkyl, eg 1-ethylpropyl or cyclopentyl. 15 In a further embodiment A is R R2 R2 R F R R
.R
4 F - R 4 R N F
CF
3 N R 2 IR2 orf R N N wherein R 2 , R 3 and R 4 are as defined for formula (1"). 20 WO 03/066604 PCT/DKO3/00071 19 In another embodiment A is
R
2 X R 3 wherein R 2 , R 3 and R 4 are as defined for formula (I"). 5 In a further embodiment A is
R
2 F R' F wherein R 2 , R 3 and R 4 are as defined for formula (1"). 10 In one embodiment R 2 , R 3 and R 4 are independently selected from * hydrogen, hydroxy, halogen, trifluoromethyl, C2-10-alkanoyl or C4-9-cycloalkanoyl, or 15 * aryl-C 1
-
6 -alkyl, aryl-C 1
.
6 -alkoxy or aroyl, which may optionally be substituted as defined for formula (1"). In another embodiment R 2 , R 3 and R 4 are independently selected from 20 *hydrogen, hydroxy, halogen, trifluoromethyl, C2-10-alkanoyl or C4-9-cycloalkanoyl, * phenyl-Cl.e-alkyl, phenyl-C 1
.
6 -alkoxy or benzoyl, which may optionally be substituted with one or two substituents selected from halo 25 gen and C0 1
.
6 -alkoxy. In still another embodiment R 2 and R 4 are both hydrogen and R 3 is different from hydrogen.
WO 03/066604 PCT/DKO3/00071 20 In yet another embodiment the invention relates to a compound of the general formula (11): N A
H
3 C N ()
H
3 C wherein A is as defined for formula (1") or in any one of the above embodiments. 5 In still another embodiment the invention relates to a compound of the general formula (12): N A N (l2) wherein A is as defined for formula (1") or in any one of the above embodiments. 10 Accordingly, in another aspect the present invention relates to a compound of the general. formula (1)'as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical 15 composition. The invention also relates to pharmaceutical compositions comprising, as an active ingredi ent, at least one compound of the formula (I) or any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. 20 Furthermore, the invention relates to the use of a compound of the general formula (1'): NA R1/N.. J(1') wherein 25 R 1 represents * Cl.
8 -alkyl, C 2 .8-alkenyl or C 2
.
8 -alkynyl, which may optionally be substituted with one or more halogen substituents, WO 03/066604 PCT/DKO3/00071 21 * C 3
.
5 -cycloalkyl, C,_7-cycloalkenyl,
C
3
-
6 -cycloalkyl-C 1
-
3 -alkyl or C 3 -6-cycloalkenyl Cl.
3 -alkyl, which may optionally be substituted with one or more halogen substituents, 5 A represents
R
2a y R 2 a R 2 a Z W W 1 W nX ir or C Z and X independently represent -N=, -CH=, -CF= or -C(CF 3 )=, 10 W represents -N= or -CR 3 =, Y represents -N= or -CR4=, 15 R 2a , R 2 b, R 3 , and R 4 independently represent * hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy,
C
1
_
10 -alkyl,
C
2 o 10 -alkenyl, C 3
.
8 -cycloalkyl, C 1
-
6 -alkoxy, aryl-C.
6 -alkyl, amino, C 1 e-alkylamino, di Cl.e-alkylamino, C3.8-cycloalkyloxy, cyano, nitro, C 1 l 6 -alkylsulfanyl,
C
1
.
6 -alkylsulfonyl, 20 or -C(=O)NR 4 aR 4 b, wherein R4a and R 4 b independently are hydrogen, C 1 6 -alkyl or aryl
C
1
.
6 -alkyl, or * C 2 .- 10-alkanoyl, C4-9-cycloalkanoyl,
C
3
.
8 -heterocyclyl or C4.9-heterocycloalkanoyl, which may optionally be substituted in any position with one or more substituents se 25 lected from aryl, heteroaryl, Ca.
8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy and C 1
-
6 -alkoxy, aryl, aryl-C, 6 E-alkyl, aryl-C 1
-
6 -alkoxy or heteroaryl, which may optionally be substituted with one or more substituents selected from 30 halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Cl 6 -alkoxy, C 1
.
6 -alkyl, amino,
C
1
.
6 -alkylamino, di-Cs_ 6 -alkylamino, cyano, aryl, heteroaryl and Cs38-cycloalkyl, or WO 03/066604 PCT/DKO3/00071 22 aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from aryl, heteroaryl, C 1
.-
10 -alkyl, C 3 .8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy,
C
1
.
6 -alkoxy, cyano, amino, C 1
.
6 -alkylamino, di-Cl- 6 -alkylamino and hydroxy, 5 * or two of R 2a , R 2 b, R 3 , and R 4 in adjacent positions together form a C1- 6 -alkylene bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of 10 these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor. In another aspect the invention provides a compound of the general formula (11): 3 R R-N R2 NA (II) 15 wherein
R
2 is hydrogen or C 1
-
4 -alkyl, (i) R 1 represents * branched C 4 -6-alkyl, branched C 4
-
6 -alkenyl or branched C 4 ~ -alkynyl with the 20 proviso that R' is not isobutyl, * C- 5 -cycloalkyl, C 3
-
7 -cycloalkenyl, C 36 -cycloalkyl-C 1 -3-alkyl or C3-a cycloalkenyl-CI.
3 -alkyl, 25 * R 1 and R 2 together form a C3.6-alkylene bridge, and A represents
R
4 5 7 R or X R ZI WW-" W I I I I Ior R8 "Y X ' W 'R " x
'F
WO 03/066604 PCT/DKO3/00071 23 or (ii) R 1 represents * ethyl, n-propyl or isopropyl, 5 * R 1 and R 2 together form a C 3 6 -alkylene bridge, and A represents Rl
R
4 R io0 R 12 Z R1 o or N o13 N R 10 R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 -o 10 -alkyl, C 2 .- 10-alkenyl,
C
3
-
8 -cycloalkyl, Cl.
6 -alkoxy, aryl, aryl-Cl.
6 -alkyl, amino, Cl.
6 -alkylamino, di-C 6 -alkylamino,
C
3 .8-cycloalkyl, C3- 8 -cycloalkyloxy, cyano, nitro, C 1 -6-alkylsulfanyl, or C 1 .a-alkylsulfonyl, Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or-C(CF 3
)
= , 15 W represents -N= or-C(Ro) = Y represents -N= or-C(R 1
)
=, 20 R 4 , R 5 , R 6 , R 7 , R 8 , R 9
R
1 0 , R 11 , R 1 2 and R 13 independently represent * hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, cyano, nitro, or -C(=O)NR 1 4 R1 5 25 * C 1 -o 10 -alkyl, C 2 -10-alkenyl, C 3
.
8 -cycloalkyl, C 1 6 .- alkoxy, Cs.
38 -cycloalkyl-C l
.
6 -alkoxy,
C
1
.
6 -alkylamino, di-C 1 6 -alkylamino, C 3
.
8 -cycloalkyloxy, C1.6-alkylsulfanyl, C 1
-
alkylsulfonyl, C 2 .o 10 -alkanoyl, C 4
-
9 -cycloalkanoyl, C3.8-heterocyclyl or C 4 -9 heterocycloalkanoyl,
C
4
-
9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R 16 30 WO 03/066604 PCT/DKO3/00071 24 earyl, aryl-C1.
6 -alkyl, aryl-Cl.
6 -alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R", *aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, 5 which may optionally be substituted with one or more substituents selected from R' 8 , * or two of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 in adjacent positions together form a CI.
6 -alkylene bridge or an -O-C_ 6 -alkylene-O- bridge, 10 R 1 4 and R 1 5 are independently hydrogen, C 1
.
6 -alkyl, aryI-Cl.6-alkyl or R 1 4 and R 1 5 may to gether form a C 3
.
6 -alkylene bridge
R
16 is independently selected from aryl, heteroaryl, C 3 8-cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 19
R
2 0 and C 1
:
6 -alkoxy, 15
R
1 7 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C-.6 alkoxy, C 1 6 -alkyl, amino, C 1
-
6 -alkylsulfonyl, Cl.6-alkylamino, di-C,_O-alkylamino, cyano, aryl, ,heteroaryl and C 3 .8-cycloalkyl, 20 R"' is independently selected from aryl, heteroaryl, C 1
.
1 0 -alkyl, Cs_ 8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, Cl 6 -alkoxy, cyano, amino, Cl.
6 -alkylamino, di Cl 6 -alkylamino and hydroxy,
R
19 and R 20 are independently hydrogen or Cl.
6 -alkyl, R 1 9 and R 20 may together form a C 3
.
6 25 alkylene-bridge with the proviso that the compound must not be H3C N H 3 C N
H
3 C
H
3
C
WO 03/066604 PCT/DK03/00071 25 O'CH3 N Cl N HHC N HC N H3C H 3 C OH N
H
3
CN
J NN
H
3 C N H 2 N Nl N O' N NH2 N N C CF 3 NH Cl N N' N NF NN C WO 03/066604 PCT/DK03/00071 26 CIN Cl N N N N N 1 NN N ,, NO CH 2 N H, N N N NH 2 NJN NO HC N H3C N H3C H3C N NH2 H C N H C NO HN N
CH
3
H
3 C H 3
C
WO 03/066604 PCT/DKO3/00071 27 N N CN N HC NJ
CH
3
H
3 C or
CH
3
CH
3
H
3 C N HzC rN
CH
3 as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 5 In another aspect of the invention R 1 is branched C4.
6 -alkyl, C 35 -cycloalkyl or C 3 6-cycloalkyl
C
13 -alkyl with the proviso that R' is not isobutyl. In another aspect of the invention R 1 is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclopropyl methyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl. 10 In another aspect of the invention R 1 is 1-ethylpropyl, cyclopropylmethyl, cyclopropyl or cyclopentyl. In another aspect of the invention R 1 is branched C4- 6 -alkyl or C 3 5 -cycloalkyl with the proviso 15 that R 1 is not isobutyl. In another aspect of the invention R 1 is 1 -ethylpropyl, cyclopropyl or cyclopentyl. In another aspect of the invention Z is -C(H)=, -N=, or -C(F)=. 20 In another aspect of the invention Z is -C(H)= or -N=.
WO 03/066604 PCT/DKO3/00071 28 In another aspect of the invention Z is -C(H)=. In another aspect of the invention Z is -N=. 5 In another aspect of the invention X is -C(H)=, -N=, or -C(F)=. In another aspect of the invention Z is -C(H)= or -N=. In another aspect of the invention Z is -C(H)=. 10 In another aspect of the invention Z is -N=. In another aspect of the invention W is -N=. 15 In another aspect of the invention W is -C(Rio)=. In another aspect of the invention Y is N=. In another aspect of the invention Y is -C(R 1 )=. 20 In another aspect of the invention R 2 is hydrogen. In another aspect of the invention R 2 is C 14 -alkyl. 25 In another aspect of the invention R 2 is methyl or ethyl. In another aspect the invention provides compounds of the general formula (111) H IN A C NSZ 3 (111) R wherein A and R 3 are as defined for compounds of general formula (11) 30 WO 03/066604 PCT/DKO3/00071 29 In another aspect of the invention R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1
-
1 0 -alkyl, Cl.e-alkoxy, aryl, aryl-C 1
.
6 -alkyl, amino, C 3 -8-cycloalkyl,
C._
8 -cycloalkyloxy, cyano or nitro. 5 In another aspect of the invention R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, Cl- 10 -alkyl, C 1
.
6 -alkoxy, cyano or nitro. In another aspect of the invention R 3 is hydrogen, halogen, hydroxy, trifluoromethyl,
C
1
.
6 -alkyl, or cyano. 10 In another aspect of the invention R 3 is hydrogen, halogen, or C 1 .6-alkyl. In another aspect of the invention R 3 is hydrogen or methyl. 15 In another aspect of the invention R 4 , R 5 , R 6 , R, R 8 , and R 9 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, or cyano, 20 * C 1
-
1 0 -alkyl, C3-cycloalkyl, C 1 .6-alkoxy, Co.
8 -cycloalkyloxy, C 2 -1 0 -alkanoyl, C 4 -9 cycloalkanoyl, C 3
-
8 -heterocyclyl or C 4
-
9 -heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R 16 * aryl, aryl-C-.
6 -alkyl, aryl-C l
.
6 -alkoxy or heteroaryl, which may optionally be substi 25 tuted with one or more substituents selected from R, * aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be substituted with one or more substituents selected from R 18 , 30 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1
.
6 -alkylene bridge or an O-Cl.
6 -alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R, R, R 8 , and R 9 independently represent 35 * hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , or cyano, WO 03/066604 PCT/DKO3/00071 30 * C1- 1 0 -alkyl, C 1
.
6 -alkoxy, C 3 8-cycloalkyloxy, which may optionally be substituted with one or more substituents selected from R 1 6 5 *Aryl or aryl-Cl.6-alkyl, which may optionally be substituted with one or more sub stituents selected from R 1 , eAroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R'", 10 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1
.
6 -alkylene bridge or an O-Cl.6-alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent 15 * hydrogen, halogen, or cyano, * C1- 1 0 -alkyl or C 1 .6-alkoxy which may optionally be substituted with one or more sub stituents selected from R 6 ' 20 *Aryl optionally substituted with one or more substituents selected from R", eAroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , 25 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1
.
6 -alkylene bridge or an O-C 1
.
6 -alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R 6 , R, R 8 , and R 9 independently represent * hydrogen, halogen, or cyano, 30 * methyl, ethyl, propyl, isopropyl or C 1 .6-alkoxy which may optionally be substituted with one or more substituents selected from R 16 *Aryl optionally substituted with one or more substituents selected from R 1 7 , 35 WO 03/066604 PCT/DKO3/00071 31 *Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a Cl.6-alkylene bridge or an 5 O-C 1
.
6 -alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent *hydrogen, halogen, or cyano, 10 * C1- 1 0 -alkyl, methoxy, ethoxy or propoxy which may optionally be substituted with one or more substituents selected from R 1 6 *Aryl optionally substituted with one or more substituents selected from R 7 , 15 * Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1
-
6 -alkylene bridge or an O-C 1 .- alkylene-O- bridge. 20 In another aspect of the invention R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent *hydrogen, halogen, or cyano, * C1- 10 -alkyl or methoxy which may optionally be substituted with one or more sub 25 stituents selected from R 1 6 *Aryl optionally substituted with one or more substituents selected from R 17 , *Aroyl or aryloxy, which may optionally be substituted with one or more substituents 30 selected from R 1 8 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C 1 .6-alkylene bridge or an O-C 1 -6-alkylene-O- bridge. 35 In another aspect of the invention R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent WO 03/066604 PCT/DKO3/00071 32 * hydrogen, halogen, or cyano, * C 1
.
1 0 -alkyl or C4.6-alkoxy which may optionally be substituted with one or more sub stituents selected from R 16 5 * phenyl optionally substituted with one or more substituents selected from R 1 7 , *Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , 10 or two of R, R, R, R 8 , R 9 in adjacent positions together form a C_ 6 -alkylene bridge or an O-C 1
.
6 -alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent 15 *hydrogen, halogen, or cyano, * Cl-1-alkyl or C 1 ._-alkoxy which may optionally be substituted with one or more sub stituents selected from R 1 6 20 *Aryl optionally substituted with one or more substituents selected from R 7 , * -C(=O)-;phenyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , 25 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C_ 6 -alkylene bridge or an O-C 1 l.-alkylene-O- bridge. In another aspect of the invention R 4 , R 5 , R , R 7 , R 8 , and R 9 independently represent *hydrogen, halogen, or cyano, 30 * C 1 _10-alkyl or C 1 -6-alkoxy which may optionally be substituted with one or more sub stituents selected from R 16 *Aryl optionally substituted with one or more substituents selected from R 17 , 35 WO 03/066604 PCT/DKO3/00071 33 eAroyl or -O-phenyl, which may optionally be substituted with one or more substitu ents selected from R 1 8 , or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a Cl 6 -alkylene bridge or an 5 O-Cl.6-alkylene-O- bridge. In another aspect of the invention R' is ethyl or isopropyl. In another aspect of the invention R 1 is isopropyl. 10 In another aspect of the invention R 1 is ethyl In another aspect of the invention R 1 and R 2 together form a C 3 4 -alkylene bridge. 15 In another aspect of the invention R 10 , R", R 1 2 and R 1 3 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or
-C(=O)NR
14
R'
5 20 * C 1 10 -alkyl, C 3
.
8 -cycloalkyl, C1- 6 -alkoxy, C2- 1 0 -alkanoyl, C 4
.
9 -cycloalkanoyl, C3-8 heterocyclyl or C 4
-
9 -heterocycloalkanoyl,
C
4
-
9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R 16 * aryl, aryl-C
I
.
6 -alkyl, aryl-Cl.
6 -alkoxy or heteroaryl, which may optionally be substi 25 tuted with one or more substituents selected from R 1 7 , * aroyl optionally substituted with one or more substituents selected from R 8 , or two of R 1 o, R 1 1 , R 12 and R 1 3 in adjacent positions together form a C 16 -alkylene bridge. 30 In another aspect of the invention R 10 , R", R 12 and R 13 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or
-C(=O)NR
14
R
5 s 35 WO 03/066604 PCT/DKO3/00071 34
SC
1
.-
1 0 -alkyl, C3-8-cycloalkyl, C 1 .6-alkoxy, C 2 .1-alkanoyl, C4.
9 -cycloalkanoyl, C 3 -8 heterocyclyl or C 4
-
9 -heterocycloalkanoyl, C 4
-
9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R' 16 5 * aryl, aryl-C 1
.
6 -alkyl, aryl-Cl.
6 -alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R 7 , e aroyl optionally substituted with one or more substituents selected from R 18, 10 or two of R'o, R", R 12 and R 13 in adjacent positions together form a C 1
.
6 -alkylene bridge. In another aspect of the invention R 1 0 , R 1 ", R 1 2 and R 1 3 independently represent *hydrogen, halogen, trifluoromethyl, or-C(=O)NR 1 4
R
5 15 * C 1
-,
1 0 -alkyl, C.a-alkoxy, C 2
-
10 -alkanoyl, C 4 -9-cycloalkanoyl, C 4 -9-heterocycloalkanoyl or
C
4 -9-heterocycloalkoxy, which may optionally be substituted with one or more sub stituents selected from R 16 20 e aryl, aryl-C 1 .- alkyl, or aryl-C 1
.
6 -alkoxy, which may optionally be substituted with one or more substituents selected from R 7 , *aroyl optionally substituted with one or more substituents selected from R 18 , 25 or two of R 10 , R' 1 ", R 1 2 and R 13 in adjacent positions together form a C 1
.
6 -alkylene bridge. In another aspect of the invention R 1 0 , R", R 12 and R' 3 independently represent * hydrogen, halogen, trifluoromethyl, or -C(=O)NR 14
R
15 30 * C 1 -1 0 -alkyl or C 4
-
9 -heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R 16 * aryl optionally substituted with one or more substituents selected from R 17 , 35 WO 03/066604 PCT/DKO3/00071 35 * aroyl optionally substituted with one or more substituents selected from R" , or two of R'o, R 11 , R 12 and R 13 in adjacent positions together form a Cl.
6 -alkylene bridge. 5 In another aspect of the invention R 10 , R 11 , R 12 and R 1 3 independently represent * hydrogen, halogen, trifluoromethyl, or -C(=O)NR 14
R
15 Smethyl, ethyl,, propyl or C 4 -9-heterocycloalkanoyl, which may optionally be substi 10 tuted with one or more substituents selected from R 16 * aryl optionally substituted with one or more substituents selected from R 1 7 , earoyl optionally substituted with one or more substituents selected from R 8 , 15 or two of RIO, R 1 ", R 12 and R 13 in adjacent positions together form a C 1
-
6 -alkylene bridge. In another aspect of the invention R 1 0 , R 11 , R 12 and R 1 3 independently represent 20 * hydrogen, halogen, trifluoromethyl, or -C(=O)NR 14
R
15 * Cl-o-alkyl, piperidin-alkanoyl or pyrrolidin-alkanoyl, which may optionally be substi tuted with one or more substituents selected from R 1 6 25 * aryl optionally substituted with one or more substituents selected from R",7 Saroyl optionally substituted with one or more substituents selected from R 18 , or two of R 1 0 , R 1 ", R 12 and R 1 3 in adjacent positions together form a C 1 6 -alkylene bridge. 30 In another aspect of the invention R 1 0 , R" 1 , R 1 2 and R 1 3 independently represent * hydrogen, halogen, trifluoromethyl, or-C(=O)NR 14
R'
5 WO 03/066604 PCT/DKO3/00071 36 * C 1 1 0 -alkyl or C 4 -9-heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R 16 * Phenyl optionally substituted with one or more substituents selected from R 7 , 5 * aroyl optionally substituted with one or more substituents selected from R 8 , or two of R 1 0 , R 1 1 , R 12 and R 1 3 in adjacent positions together form a C 1
.
6 -alkylene bridge. 10 In another aspect of the invention R 14 and R" are independently methyl, ethyl or benzyl. In another aspect of the invention R 16 is halogen, trifluoromethyl, trifluoromethoxy and C.
6 alkoxy. In another aspect of the invention R 1 7 is halogen, hydroxy, trifluoromethyl, Cl.
8 -alkoxy, 15 C 1
-
6 -alkyl, CI.
6 -alkylsulfonyl, or cyano. In another aspect of the invention R 17 is halogen, trifluoromethyl, C 1
.
6 -alkoxy or C 1
_
6 ,alkylsulfonyl. 20 In another aspect of the invention R"' is C 1
-
10 -alkyl, halogen, trifluoromethyl, C 1 .a-alkoxy, cyano, amino and hydroxy. In another aspect of the invention R 18 is halogen, C 1
.
6 -alkoxy and hydroxy. 25 In another aspect the invention provides the use of a compound according to formula (II) or (111) as a pharmaceutical composition. The pharmaceutical composition may in another as pect of the invention comprise, as an active ingredient, at least one compound according to formula (11) or (111) together with one or more pharmaceutically acceptable carriers or excipi ents. In another aspect the invention provides such a pharmaceutical composition in unit 30 dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the com pound according to formula (II) or (111) In another aspect the invention provides the use of a compound of the general formula (II'): WO 03/066604 PCT/DKO3/00071 37
R
3 R~N R2 ('A ) R A wherein
R
2 is hydrogen or C 1
-
4 -alkyl,
R
1 represents 5 * C 1 .8-alkyl, C 2 -8-alkenyl or C 2
.
8 -alkynyl, which may optionally be substituted with one or more halogen substituents, * Cs.
3 5 -cycloalkyl, C 3
.
7 -cycloalkenyl, C 3 6-cycloalkyl-Cl- 3 -alkyl or C 3
.
6 -cycloalkenyl 10 C 1
_
3 -alkyl, which may optionally be substituted with one or more halogen substituents, * R 1 and R 2 together form a C 3 -6-alkylene bridge A represents
R
4
R
5 7 S[: or I R 15
R
3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1- 1 0 -alkyl, C 2
.-
10 -alkenyl,
C
3
.
8 -cycloalkyl, Cl_-alkoxy, aryl, aryl-C 1
.
6 -alkyl, amino, C 1
.
6 -alkylamino, di-C 1
.
6 -alkylamino, 20 C3.8-cycloalkyl, C 3
_
8 -cycloalkyloxy, cyano, nitro, C 1
.
6 -alkylsulfanyl, or Cl.
6 -alkylsulfonyl, Z and X independently represent -N=, -C(H)=, -C(F)=, -C(C)=, -C(CN)= or -C(CF 3
)
= , W represents -N= or -C(RIo)=, 25 Y represents -N= or-C(R11) =,
R
4 , R 5 , R 6 , R 7 , R 8 , R 9
R
1 o, R" 1 , R 1 2 and R 1 3 independently represent WO 03/066604 PCT/DKO3/00071 38 *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, cyano, nitro, or -C(=O)NR 1 4
R
15 5 * C 1
-
1 0 -alkyl, C 2
-
10 -alkenyl, C3.
8 -cycloalkyl, C 1
-
6 -alkoxy, C3_ 8 -cycloalkyl-C 1
-
6 -alkoxy,
C
1
.
6 -alkylamino, di-C 6 .e-alkylamino, C3.
8 -cycloalkyloxy, Cl.
6 -alkylsulfanyl, C 1
.-
6 alkylsulfonyl, C 2
-
1 0 -alkanoyl, C 4
-
9 -cycloalkanoyl, C 3
_
8 -heterocyclyl or C 4 .9 heterocycloalkanoyl, C 4
-
9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R' 6 10 * aryl, aryl-C
I
.
6 -alkyl, aryl-Cl.6-alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R 7 , * aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, 15 which may optionally be substituted with one or more substituents selected from R
W
"
8 , * or two of R 5 , R 6 , R 7 , R 8 , R 9 , R 1 , R 1 , Rand R 13 in adjacent positions together form a C 1 .E-alkylene bridge or an -O-Cl.
6 -alkylene-O- bridge, 20 R 14 and R 1 5 are independently hydrogen, C 1 -6-alkyl, aryl-Cl.
6 -alkyl or R 1 4 and R 15 may to gether form a C 3
.
6 -alkylene bridge
R
16 is independently selected from aryl, heteroaryl, C 3
.
8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR' 9
R
2 0 and Co.
6 -alkoxy, 25
R
17 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1_6 alkoxy, Cl.
6 -alkyl, amino, C 1 ~ -6-alkylsulfonyl, C 1 .6-alkylamino, di-Cle-alkylamino, cyano, aryl, heteroaryl and C 3 .8-cycloalkyl, 30 R 18 is independently selected from aryl, heteroaryl, Co 10 -alkyl, C 3
.
8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, C 1
.
6 -alkoxy, cyano, amino, Cl 6 -alkylamino, di
C,
6 -alkylamino and hydroxy,
R"
9 and R 2 0 are independently hydrogen or C 1
-
6 -alkyl, R 1 9 and R 20 may together form a 35 C 3 .6-alkylene bridge, WO 03/066604 PCT/DKO3/00071 39 as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of disorders and diseases related to the histamine H3 receptor. 5 In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect. 10 In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity. 15 In another aspect the invention provides the.use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the reduction of weight. In another aspect the invention provides the use of a compound of the general formula (Il') 20 as defined above for the preparation of a pharmaceutical composition for the treatment of overweight or obesity. In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the suppression of 25 appetite or for satiety induction. In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity. 30 In another aspect the invention provides the use of a compound of the general formula (Il') as defined above for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.
WO 03/066604 PCT/DKO3/00071 40 In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of IGT. 5 In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. In another aspect the invention provides the use of a compound of the general formula (II') 10 as defined above for the preparation of a pharmaceutical composition for the delaying or pre vention of the progression from IGT to type 2 diabetes. In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the delaying or pre 15 vention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. In another aspect the invention provides the use of a compound of the general formula (II') as defined above for the preparation of a pharmaceutical composition for the treatment off 20 diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect. In another aspect the invention provides the use of a compound of the general formula (Il') as defined above for the preparation of a pharmaceutical composition having histamine H3 25 agonistic activity. In another aspect the invention provides the use of a compound of the general formula (Il') as defined above for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis, ulcer or anorexia. 30 In another aspect the invention provides the use of a compound of the general formula (11') as defined above for the preparation of a pharmaceutical composition for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.
WO 03/066604 PCT/DKO3/00071 41 In another aspect the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula (11') as defined above or a pharmaceutical composition comprising such a compound. 5 In another aspect the invention provides a method for the treatment of disorders or diseases related to the H3 histamine receptor wherein the effective amount of the compound of the general formula (II') as defined above is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 10 mg to about 500 mg per day. In still another aspect, the invention relates to a method for the treatment of diseases and disorders related to the histamine H3 receptor the method comprising administering to a sub ject in need thereof an effective amount of a compound of the formula (I) or any diastereomer 15 or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. In one aspect the invention relates to compounds with histamine H3 receptor antagonistic activity or inverse agonistic activity which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor blockade is beneficial. 20 In another aspect the invention relates to compounds with histamine H3 receptor agonistic activity and which may accordingly be useful in the treatment of a wide range of conditions and disorders in which histamine H3 receptor activation is beneficial. In a preferred embodiment of the invention the present compounds are used for the prepara tion of a pharmaceutical composition for the reduction of weight. 25 In a preferred embodiment of the invention the present compounds are used for the prepara tion of a pharmaceutical composition for the treatment of overweight or obesity. In another preferred embodiment of the invention the present compounds, are used for the preparation of a pharmaceutical composition for the suppression of appetite or satiety induc tion. 30 In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity such as atherosclerosis, hypertension, IGT (impaired glucose tolerance), diabetes, especially type 2 diabetes (NIDDM (non-insulin de pendent diabetes mellitus)), dyslipidaemia, coronary heart disease, gallbladder disease, os- WO 03/066604 PCT/DKO3/00071 42 teoarthritis and various types of cancer such as endometrial, breast, prostate and colon can cers. In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating 5 disorders such as bulimia and binge eating. In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of IGT. In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment of type 2 diabetes. Such 10 treatment includes inter alia treatment for the purpose of delaying orprevention of the pro gression from IGT to type 2 diabetes as well as delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes. The compounds of the present invention may also be used for the treatment of airway disor ders such as asthma, as anti-diarrhoeals and for the modulation of gastric acid secretion. 15 Furthermore, the compounds of the present invention may be used for the treatment of dis eases associated with the regulation of sleep and wakefulness and for the treatment of nar colepsy and attention deficit disorders. Moreover, the compounds of the invention may be used as CNS stimulants or as sedatives. The present compounds may also be used for the treatment of conditions associated with 20 epilepsy. Additionally, the present compounds may be used for the treatment of motion sick ness and vertigo. Furthermore, they may be useful as regulators of hypothalamo hypophyseal secretion, antidepressants, modulators of cerebral circulation, and in the treat ment of irritable bowel syndrome. Further, the compounds of the present invention may be used for the treatment of dementia 25 and Alzheimer's disease. The compounds of the present invention may also be useful for the treatment of allergic rhini tis, ulcer or anorexia. The compounds of the present invention may furthermore be useful for the treatment of mi graine, see McLeod et al., The Journal of Pharmacology and Experimental Therapeutics 287 30 (1998), 43-50, and for the treatment of myocardial infarction, see Mackins et al., Expert Opin ion on Investigational Drugs 9 (2000), 2537-2542. In a further aspect of the invention treatment of a patient with the present compounds is combined with diet and/or exercise. In a further aspect of the invention the present compounds are administered in combination 35 with one or more further active substances in any suitable ratio(s). Such further active agents WO 03/066604 PCT/DKO3/00071 43 may be selected from antiobesity agents, antidiabetics, antidyslipidemic agents, antihyper tensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or asso ciated with obesity. 5 Thus, in a further aspect of the invention the present compounds are administered in combi nation with one or more antiobesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) 10 agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing fac tor binding protein) antagonists, urocortin agonists, 33 adrenergic agonists such as CL 316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or cita- 15 lopram, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and,noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hor mone, growth factors such as prolactin or placental lactogen, growth hormone releasing , compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase in 20 hibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X re ceptor) modulators, TR 13 agonists, AGRP (Agouti related protein) inhibitors, opioid antago nists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor. In one embodiment of the invention the antiobesity agent is leptin. In another embodiment the antiobesity agent is dexamphetamine or amphetamine. 25 In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine. In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine. In still another embodiment the antiobesity agent is phendimetrazine, diethylpropion, fluoxet 30 ine, bupropion, topiramate or ecopipam. In yet a further aspect the present compounds are administered in combination with one or more antidiabetic agents. Relevant antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 0 792 290 (Novo Nordisk A/S), eg NsB 29 -tetradecanoyl des (B30) human insu 35 lin, EP 0 214 826 and EP 0 705 275 (Novo Nordisk A/S), eg Asp B28 human insulin, US WO 03/066604 PCT/DKO3/00071 44 5,504,188 (Eli Lilly), eg Lys B28 ProB 29 human insulin, EP 0 368 187 (Aventis), eg Lantus®, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents. 5 The orally active hypoglycaemic agents preferably comprise imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, ca glucosidase inhibitors, agents acting on the ATP-dependent potassium channel of the p-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, 10 or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, 15 PTPase (protein tyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator activated receptor) and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 or 20 LG-1069. In one embodiment of the invention the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as Ns 2 9 -tetradecanoyl des (B30) hu man insulin, AspB 28 human insulin, LysB 28 ProB 29 human insulin, Lantus®,.or a mix preparation comprising one or more of these. 25 'In a further embodiment of the invention the present compounds are administered in com bination with a sulfonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide. In another embodiment of the invention the present compounds are administered in com bination with a biguanide eg metformin. 30 In yet another embodiment of the invention the present compounds are administered in com bination with a meglitinide eg repaglinide or nateglinide. In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1 037 or T 174 or the 35 compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 03/066604 PCT/DKO3/00071 45 WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by refer ence. In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer eg such as GI 262570, YM-440, MCC-555, JTT-501, 5 AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX 0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nord 10 isk A/S), which are incorporated herein by reference. In a further embodiment of the invention the present compounds are administered in combi nation with an a-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose. In another embodiment of the invention the present compounds are administered in combi nation with an agent acting on the ATP-dependent potassium channel of the p-cells eg tolbu 15 tamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide. In yet another embodiment of the invention the present compounds may be administered in combination with nateglinide. In still another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, eg cholestyramine, colestipol, clofibrate, 20 gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine. ; In still another embodiment of the invention the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine. In another aspect of the invention, the present compounds are administered in combination 25 with more than one of the above-mentioned compounds eg in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and met formin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and trogli tazone; insulin and lovastatin; etc. 30 Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are P-blockers such as alpre nolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting en zyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni 35 modipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and WO 03/066604 PCT/DKO3/00071 46 terazosin. Further reference can be made to Remington: The Science and Practice of Phar macy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. It should be understood that any suitable combination of the compounds according to the in vention with diet and/or exercise, one or more of the above-mentioned compounds and op 5 tionally one or more other active substances are considered to be within the scope of the. present invention. The compounds of the present invention may be chiral, and it is intended that any enanti omers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. 10 Furthermore, when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule di astereomers may be formed. It is intended that any diastereomers, as separated, pure or, partially purified diastereomers or mixtures thereof are included within the scope of the inven tion. 15 Furthermore, some of the compounds of the present invention may exist in different tauto meric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention. The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharma 20 ceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts.include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, 25 lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable 30 salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Exam Spies of metal salts include lithium, sodium, potassium, magnesium salts and the like. Exam ples of ammonium and alkylated ammonium salts include ammonium, methylammonium, di methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethyl ammonium, butylammonium, tetramethylammonium salts and the like.
WO 03/066604 PCT/DKO3/00071 47 Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds are able to form. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate 5 acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention. 10 The, invention also encompasses prodrugs of the present compounds, which on administra tion undergo chemical conversion by metabolic processes before becoming active pharma cological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives 15 are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The invention also encompasses active metabolites of the present compounds. The compounds of the present invention interact with the histamine H3 receptor and are ac cordingly useful for the treatment of a wide variety of conditions and disorders in which his tamine H3 receptor interactions are beneficial. 20 PHARMACEUTICAL COMPOSITIONS The compounds of the invention may be administered alone or in combination with pharma ceutically acceptable carriers or excipients, in either single or multiple doses. The pharma ceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accor 25 dance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcuta 30 neous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
WO 03/066604 PCT/DKO3/00071 48 Pharmaceutical compositions for oral administration include solid dosage forms such as cap sules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to pro vide controlled release of the active ingredient such as sustained or prolonged release ac 5 cording to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syr ups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous and non aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile pow 10 ders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot in jectable formulations are also contemplated as being within the scope of the present inven tion. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc. 15 A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dos ages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature 20 and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably 25 from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg. For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administra tion, typically doses are in the order of about half the dose employed for oral administration. The compounds of this invention are generally utilized as the free substance or as a pharma ceutically acceptable salt thereof. One example is an acid addition salt of a compound having 30 the utility of a free base. When a compound of the formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in 35 combination with a suitable cation such as sodium or ammonium ion.
WO 03/066604 PCT/DKO3/00071 49 For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first ren dered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suit 5 able for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, 10 cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phosphol ipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositionsformed 15 by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as 20 discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a 25 hard gelatine capsule in powder or pellet form or it can-be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gela tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. 30 A typical tablet, which may be prepared by conventional tabletting techniques, may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg 35 Amberlite® IRP88* 1.0 mg WO 03/066604 PCT/DKO3/00071 50 Magnesii stearas Ph. Eur. q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg 5 Mywacett 9-40 T** approx. 0.9 mg * Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating. 10 If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing. EXAMPLES In the examples the following terms are intended to have the following, general meanings: 15 DIPEA: diisopropylethylamine DMSO: dimethyl sulphoxide THF: tetrahydrofuran HPLC (Method A) NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. HPLC-MS was 20 performed on a Perkin Elmer instrument (API 100). The column used was X-Terra C18, 5 lam, 50 X 3 mm, and elution was done at 1.5 ml/min at room temperature with a gradient of 5% to 90% acetonitrile in water with 0.01% trifluoroacetic acid within 7.5 min. HPLC (Method B) 25 The reverse phase analysis was performed using UV detections at 214 and 254 nm on a 218TP54 4.6 mm x 150 mm C-18 silica column, which was eluted at 1 ml/min at 42 9C. The column was equilibrated with 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid in water and eluted by a linear gradient from 5% acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroacetic acid to 90% acetonitrile and 10% of a solution of 30 0.5% trifluoroacetic acid over 15 min. HPLC (Method C) WO 03/066604 PCT/DKO3/00071 51 The RP-analyses was performed using a Alliance Waters 2695 system fitted with a Waters 2487 dualband detector. UV detections were collected using a Symmetry C18, 3.5 um, 3.0 mm x 100 mm column. The eluation is done with a linear gradient of 5-90% acetonitrile, 90 0% water, and 5% trifluoroacetic acid (1.0%) in water over 8 minutes at a flow-rate of 1.0 5, min/min. General procedure (A) General procedure (A) may be used for the preparation of the compounds of the general formula (la): N A NA 0 21 + NNA 20 r A (la) R " R HN R N--* N., (la) R 10 wherein -CH(R 2 0
R
2 1 ) represents ethyl, isopropyl, branched C 4
-
6 -alkyl, branched C 4
.
6 -alkenyl, branched C4-6-alkynyl, Co- 5 -cycloalkyl, C 3
.
7 -cycloalkenyl, C 3 .0-cycloalkyl-C4.
3 -alkyl or C 3o cycloalkenyl-C 1
.
3 -alkyl, which may optionally be substituted with one or more halogen sub stituents. To a mixture of a monosubstituted piperazine (15.2 mmol) in a suitable solvent such as and 15 THF are added a ketone or an aldehyde (22.6 mmol), water, acetic acid (45.0 mmol), and then NaCNBH 3 (18 mmol). The mixture is stirred at 55 OC for 5.5 hours (ketones) or at room temperature overnight (aldehydes), and then concentrated under reduced pressure. Satu rated aqueous NaHCO 3 solution (100 ml) is added, and the mixture is extracted with a sol vent such as ethyl acetate (3 x 40 ml). The combined extracts are washed with brine, dried 20 over magnesium sulphate, and concentrated under reduced pressure. The residue may be converted into an appropriate salt, such as the hydrochloride salt by co-evaporation with an acid, such as 1 molar aqueous hydrochloric acid, ethanol and toluene, and the residue is then purified by recrystallization. General procedure (B) 25 The compounds of the general formula (I) may be prepared by the general procedure (B): HANH NA (I) HaA RN RiN A mixture of a monosubstituted piperazine (2.00 mmol), DMSO (1.0 ml), a suitable aryl or heteroaryl halide (2.00 mmol), and a base such as DIPEA (0.20 ml) is stirred for one hour at 100 oC and then for 18 hours at 120 oC. Water and potassium carbonate are added and the WO 03/066604 PCT/DKO3/00071 52 mixture is extracted with a solvent such as ethyl acetate (3 x 20 ml). Isolation and purification are done as in General Procedure (A). Non-commercially available substituted 2-chloroquinolines were prepared as described in the literature: F. Effenberger, W. Hartmann, Chemische Berichte 1969, 102, 3260-3267. 5 General procedure (C) The compounds of the general formula (I) may be prepared by the general procedure (C): NH catalyst NA N Br'A + R N R N (i) A compound of formula I may be prepared from a suitable monosubstituted piperazine and a 10 suitable aryl bromide in the presence of a suitable catalyst such as e. g. tris(dibenzylideneacetone)dipalladium in a suitable solvent such as toluene at a suitable temperature between 0 0 C and 150 0 C. Example 1 4-(4-Cyclopentylpiperazin-1-yl)phenol N "OH N 15 To a suspension of 1-(4-hydroxyphenyl)piperazine (2.70 g, 15.2 mmol) in THF (28 ml) were added cyclopentanone (1.90 ml, 22.6 mmol), water (0.15 ml), acetic acid (2.70 ml, 45.0 mmol), and then NaCNBH 3 (18 ml, 1 molar in THF, 18 mmol). The mixture was stirred at 55 oC for 5.5 hours and then concentrated under reduced pressure. Saturated aqueous Na 20 HCO 3 solution (100 ml) and ethyl acetate (40 ml) were added, and the mixture was filtered. The resulting solid was resuspended in methanol (30 ml), heated to reflux, and allowed to stand at room temperature over night. Filtration and drying under reduced pressure yielded the title compound (1.82 g, 49%) as a solid.
WO 03/066604 PCT/DKO3/00071 53 H NMR (DMSO-d 6 ) 61.34 (m, 2H), 1.49 (m, 2H), 1.60 (m, 2H), 1.79 (m, 2H), 2.43 (m, 1H), 2.51 (m, 4H), 2.92 (m, 4H), 6.62 (d, J= 8 Hz, 2H), 6.77 (d, J= 8 Hz, 2H), 8.78 (s, 1H); HPLC MS: mlz 247 (MH ); Rf: 2.70 min. Example 2 5 1-Cyclopentyl-4-[4-(4-fluorobenzyloxy)phenyl]piperazine F N0 N To a suspension of potassium hydroxide (0.165 g, 2.95 mmol) in ethanol (4 ml) was added 4 (4-cyclopentylpiperazin-1-yl)phenol (0.25 g, 1.02 mmol). After 10 min 4-fluorobenzyl chloride (0.18 ml, 0.22 g, 1.51 mmol) was added, and the mixture was stirred at 70 oC for 5 hours. 10 Saturated aqueous NaHCO3 solution (20 ml) was added, and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine, dried over magne sium sulphate, and concentrated. Recrystallization from methanol (4 ml) yielded 0.125 g (35%) of the title compound. 1 H NMR (DMSO-d) 61.34 (m, 2H), 1.50 (m, 2H), 1.62 (m, 2H), 1.81 (m, 2H),2.45 (m, 1H), 15 2.51 (m, 4H), 2.99 (m, 4H), 5.00 (s, 2H), 6.87 (m, 4H), 7.19 (t, J = 8 Hz, 2H), 7.46 (m, 2H); HPLC-MS: m/z 355 (MH'); Rf: 4.73 min. Example 3 1-(3-Chlorophenyl)-4-cyclopentylpiperazine N Cl 20 This compound was prepared as described in Example 1, starting from 1-(3-chlorophenyl) piperazine.
WO 03/066604 PCT/DKO3/00071 54 1 H NMR (DMSO-d 6 ) 81.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45 (m, 1H), 2.51 (m, 4H), 3.14 (m, 4H), 6.78 (d, J= 8 Hz, 1H), 6.88 (m, 2H), 7.19 (t, J= 8 Hz, 1H); HPLC MS: mlz 265 (MH); Rf: 3.88 min. Example 4 5 1-[4-(4-Cyclopentylpiperazin-I -yl)phenyl]ethanone O
CH
3 N aN,, This compound was prepared as described in Example 1, starting from 1-(4-acetylphenyl) piperazine. 1 H NMR (DMSO-d 6 ) 1.30-1.88 (m, 8H), 2.45 (s, 3H), 2.45 (m, 1H), 2.51 (m, 4H), 3.31 (m, 10 4H), 6.95 (d, J= 8 Hz, 2H), 7.79 (d, J= 8Hz, 2H); HPLC-MS: mlz 273 (MH+); Rf: 3.25 min. Example 5 1-(3,4-Dichlorophenyl)-4-(1-ethylpropyl)piperazine CI N Cl N
H
3 C
H
3 C This compound was prepared as described in Example 1, starting from 1-(3,4-dichloro 15 phenyl)piperazine and 3-pentanone. 1 H NMR (DMSO-d 6 ) 80.88 (t, J= 7 Hz, 6H), 1.28 (m, 2H), 1.45 (m, 2H), 2.19 (m, 1H), 2.56 (brs, 4H), 3.12 (brs, 4H), 6.91 (m, 1H), 7.09 (brs, 1H), 7.36 (d, J= 8 Hz, 1H); HPLC-MS: m/z 301 (MH+); Rf: 4.25 min.
WO 03/066604 PCT/DKO3/00071 55 Example 6 {4-[4-(1-Ethylpropyl)piperazin-1 -yl]phenyl}phenylmethanone hydrochloride 0 N N
H
3 C HC A mixture of 1-(3-pentyl)piperazine (0.31 g, 2.00 mmol), DMSO (1.0 ml), 4-fluoro 5 benzophenone (0.40 g, 2.00 mmol), and DIPEA (0.20 ml) was stirred for one hour at 100 oC and then for 18 hours at 120 OC. Water (50 ml) and potassium carbonate (2 g)were added and the mixture was extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine, dried with magnesium sulphate, and concentrated under reduced pres sure. The crude product was redissolved in ethanol (10 ml) and 1 molar aqueous HCI (4 ml), 10 and the solution was concentrated under reduced pressure. After co-evaporation with etha nol and toluene the residue solidified, and was recrystallized from acetonitrile (100 ml). 0.20 g (27%) of the title compound was obtained. 'H NMR (DMSO-d) 60.95 (m, 6H), 1.62 (m, 2H), 1.89 (m, 2H), 3.04-3.27 (m, 3H), 3.48 (m, 4H), 4.05 (m, 2H), 7.08 (m, 2H), 7.51 (m, 2H), 7.65 (m, 5H), 10.75 (brs, 1H); HPLC-MS: m/z 15 337 (MH*); Rf: 4.27 min. Example 7 1-(4-Benzylphenyl)-4-(1 -ethylpropyl)piperazine hydrochloride N HS N
H
3 C A mixture of {4-[4-(1 -ethylpropyl)piperazin-1 -yllphenyl}phenylmethanone hydrochloride (77 20 mg, 0.21 mmol), trifluoroacetic acid (2.0 ml), and triethylsilane (0.5 ml) was stirred at 60 oC for 20 hours. The mixture was concentrated under reduced pressure, and mixed with water WO 03/066604 PCT/DKO3/00071 56 and potassium carbonate. The mixture was extracted with ethyl acetate (3 x 20 ml). The combined extracts were washed with brine, dried with magnesium sulphate, and concen trated under reduced pressure. The crude product was redissolved in ethanol and 1 molar aqueous HCI, and the solution was concentrated under reduced pressure. After co 5 evaporation with ethanol and toluene the residue solidified. 45 mg (61%) of the title com pound was obtained. 1 H NMR (DMSO-d 6 ) 80.98 (t, J = 7 Hz, 6H), 1.64 (m, 2H), 1.89 (m, 2H), 3.04-3.23 (m, 5H), 3.48 (m, 2H), 3.72 (m, 2H), 3.85 (s, 2H), 6.93 (d, J= 8 Hz, 2H), 7.10-7.30 (m, 7H), 10.05 (br s, 1 H); HPLC-MS: mlz 323 (MH'); Rf: 4.93 min. 10 Example 8 Cyclopropyl-{4-[4-(1-ethylpropyl)piperazin-1 -yl]phenyl}methanone hydrochloride O HC
H
3 N This compound was prepared as described in Example 6, starting from 4-fluorophenyl(cyclo propyl)ketone. 15 1 H NMR (DMSO-d 6 ) 60.98 (m, 10OH), 1.64 (m, 2H), 1.89 (m, 2H), 2.82 (brs, 1H), 3.04-3.23 (m, 3H), 3.49 (m, 4H), 4.04 (m, 2H), 7.07 (d, J= 8 Hz, 2H), 7.96 (d, J= 8 Hz, 2H), 10.95 (br s, 1H); HPLC-MS: m/z 301 (MH); Rf: 4.03 min. Example 9 (2-Chlorophenyl)-{4-[4-(1-ethylpropyl)piperazin-1-yl]phenyl}methanone hydrochloride O Cl N H C N HaC 20 WO 03/066604 PCT/DKO3/00071 57 This compound was prepared as described in Example 6, starting from 4-fluorophenyl-(2 chlorophenyl)ketone. 1 H NMR (DMSO-d) 80.98 (t, J= 7 Hz, 6H), 1.64 (m, 2H), 1.88 (m, 2H), 3.08-3.23 (m, 3H), 3.50 (m, 4H), 4.06 (m, 2H), 7.08 (d, J= 8 Hz, 2H), 7.31 (m, 1H), 7.48 (m, 1H), 7.50-7.61 (m, 5 4H), 10.85 (brs, 1H); HPLC-MS: m/z371 (MH*); Rf: 4.43 min. Example 10 {4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}-(4-fluorophenyl)methanone hydrochloride 0 N F H C N
H
3 C This compound was prepared as described in Example 6, starting from 4,4'-difluorobenzo 10 phenone. 1 H NMR (DMSO-de) 80.98 (t, J= 7 Hz, 6H), 1.66 (m, 2H), 1.89 (m, 2H), 3.08-3.25 (m, 3H), 3.41-3.53 (m, 4H), 4.05 (m, 2H), 7.09 (d, J= 8 Hz, 2H), 7.38 (m, 2H), 7.69 (d, J= 8 Hz, 21-H), 7.76 (m, 21-1), 10.80 (br s, 1 H); HPLC-MS: m/z 355 (MH); Rf: 4.37 min. Example 11 15 1-Cyclopentyl-4-(6-trifluoromethylpyridin-2-yl)piperazine F FF N N This compound was prepared as described in Example 1, starting from 1-(6-trifluoromethyl pyridin-2-yl)piperazine.
WO 03/066604 PCT/DKO3/00071 58 1 H NMR (DMSO-d) 61.34 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (mn, 2H), 2.45-2.51 (m, 5H), 3.52 (m, 4H), 7.02 (d, J= 8 Hz, 1H), 7.11 (d, J= 8 Hz, 1H), 7.71 (t, J 8 Hz, 1H); HPLC-MS: m/z 300 (MH+); Rf: 4.10 rmin. Example 12 5 1-Cyclopentyl-4-(5-trifluoromethylpyridin-2-yl)piperazine F F N1 F N N This compound was prepared as described in Example 1, starting from 1-(5-trifluoromethyl pyridin-2-yl)piperazine. 1 H NMR (DMSO-d 6 ) 81.36 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 1.80 (m, 2H), 2.45-2:52 (m, 10 5H), 3.58 (m, 4H), 6.92 (d, J = 8 Hz, 1H), 7.78 (br d, J = 8 Hz, 1H), 8.39 (s, 1 H); HPLC-MS: m/z 300 (MH ); Rf: 3.87 min. Example 13 1-Cyclopentyl-4-(3-trifluoromethylpyridin-2-yl)piperazine N N FFF 15 This compound was prepared as described in Example 1, starting from 1-(3-trifluoromethyl pyridin-2-yl)piperazine. 1 H NMR (DMSO-d 6 ) 31.29-1.65 (m, 6H), 1.80 (m, 2H), 2.45 (m, 1H), 2.52 (m, 4H), 3.18 (m, 4H), 7.16 (m, 1H), 8.02 (m, 1H), 8.49 (m, 1H); HPLC-MS: m/z 300 (MH); Rf: 3.70 min.
WO 03/066604 PCT/DKO3/00071 59 Example 14 2-[4-(1-Ethylpropyl)piperazin-1-yl]quinoline hydrochloride N N
H
3 C
H
3 C This compound was prepared as described in Example 6, starting from 2-chloroquinoline. 5 1H NMR (DMSO-d6) 60.99 (t, J = 7 Hz, 6H), 1.65 (m, 2H), 1.94 (m, 2H), 3.12 (br s, 1H), 3.33 (m, 2H), 3.57 (m, 2H), 3.93 (m, 2H), 4.83 (m, 2H), 7.44-7.58 (m, 2H), 7.76 (m, 1H), 7.92 (m, 1H), 8.25 (br s, 1H), 8.42 (m, 1H), 11.20 (br s, H); HPLC-MS: mlz 284 (MH*); Rf: 3.03 min. Example 15 7-Chloro-4-[4-(1-ethylpropyl)piperazin-1-yl]quinoline hydrochloride
H
3 C CI S H 3 C 10 This compound was prepared as described in Example 6, starting from 4,7-dichloroquinoline. 1 H NMR (DMSO-do) 31.00 (t, J= 7 Hz, 6H), 1.67 (m, 2H), 1.95 (m, 2H), 3.15 (br s, 1H), 3.30 3.70 (m, 4H), 4.05 (m, 2H), 4.20 (m, 2H), 7.32 (m, 1 H), 7.73 (m, 1H), 8.28 (m, 2H), 8.83 (m, 1H), 11.35 (br s, H); HPLC-MS: m/z 318 (MH*); Rf: 3.13 min.
WO 03/066604 PCT/DKO3/00071 60 Example 16 [4-(4-Cyclopentylpiperazin-1-yl)phenyl]-(3,4-dimethoxyphenyl)methanone hydrochloride 0 CH '3 N :O 0CH 3 N This compound was prepared as described in Example 6, starting from 4'-fluoro-3,4 5 dimethoxybenzophenone. 1 H NMR (DMSO-d 6 ) 81.55 (m, 2H), 1.65-1.90 (m, 4H), 2.02 (m, 2H), 3.05-3.40 (m, 4H), 3.55 (m, 3H), 3.81 (s, 3H), 3.88 (s, 3H), 4.08 (m, 2H), 7.10 (m, 3H), 7.29 (m, 2H), 7.69 (d, J= 8 Hz, 2H), 10.78 (br s, 1H); HPLC-MS: mlz 395 (MH*); Rf: 3.03 min. Example 17 10 [4-(4-Cyclopentylpiperazin-1-yl)-3,5-difluorophenyl]phenylmethanone hydrochloride O F N N F This compound was prepared as described in Example 6, starting from 3,4,5-trifluorobenzo phenone. 1 H NMR (DMSO-d 6 ) 81.55 (mn, 21-1), 1.65-1.90 (m, 41-1), 2.02 (m, 2H), 3.15 (m, 2H), 3.50-3.71 15 (m, 7H), 7.42 (m, 2H), 7.58 (m, 2H), 7.68-7.78 (m, 31-H), 10.90 (br s, 1H); HPLC-MS: m/z 371(MH*); Rf: 2.77 min.
WO 03/066604 PCT/DKO3/00071 61 Example 18 2-(4-Cyclopentylpiperazin-1-yl)quinoxaline hydrochloride N N yNj This compound was prepared as Example 6, starting from 2-chloroquinoxaline and using 5 propionitrile as solvent. 1 H NMR (DMSO-d 6 ) 51.55 (m, 2H), 1.64-1.90 (m, 4H), 2.02 (m, 2H), 3.15 (m, 2H), 3.42-3.65 (m, 5H), 4.71 (m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.88 (br d, J = 8 Hz, 1H), 8.91 (s, 1H), 10.92 (br s, 1H); HPLC-MS: m/z 283 (MH); Rf: 1.70 min. Example 19 10 2-(4-Cyclopropylmethylpiperazin-1-yl)quinoxaline hydrochloride N ,N N 1 H NMR (DMSO-d 6 ) 30.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 (m, 4H), 4.71 (m, 2H), 7.48 (m, 1H), 7.66 (m, 2H), 7.88 (d, J= 8 Hz, 1H), 8.90 (s, 15 1H), 11.17 (brs, 1H); HPLC-MS: m/z 269 (MH*); Rf: 1.73 min. Example 20 [6-(4-Cyclopentylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride 0 NN 1 H NMR (DMSO-d 6 ) 81.45-2.08 (m, 14H), 3.06 (m, 2H), 3.38-3.61 (m, 9H), 4.44 (m, 2H), 20 7.02 (d, J= 8Hz, 1H), 7.70 (dd, J= 8 Hz, 1 Hz, IH), 8.19 (d, J = 1 Hz, 1H); HPLC-MS: m/z
(MH).
WO 03/066604 PCT/DKO3/00071 62 This compound was prepared as Example 6 (General Procedure B), using 1-(6-chloro nicotinoyl)piperidine (Thunus, Ann. Pharm. Fr. 1977, 35, 197). Example 21 2-(4-Cyclopentylpiperazin-1-yl)quinoline hydrochloride NnN 5 'H NMR (DMSO-d 6 ) 81.62 (m, 2H), 1.82 (m, 2H), 1.96 (m, 2H), 2.09 (m, 2H), 3.25 (m, 2H), 3.55-3.70 (m, 5H), 4.83 (m, 2H), 7.46-7.60 (m, 2H), 7.80 (m, 1H), 7.94 (m, 1H), 8.13 (m, 1H), 8.42 (m, 1H), 11.52 (br s, 1H); HPLC-MS: m/z 282 (MH); Rf: 0.34 min. This compound was prepared as Example 6, starting from 2-chloroquinoline. 10 Example 22 2-(4-Cyclopentylpiperazin-1-yl)-7-methoxy-3-(4-methoxyphenyl)quinoline hydrochloride 0 H, / / CH3 N N 0 'H NMR (DMSO-do) 61.53 (m, 2H), 1.63-1.86 (m, 4H), 1.98 (m, 2H), 3.05 (m, 2H), 3.33-3.52 (m, 5H), 3.75 (m, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 7.08 (d, J= 8 Hz, 2H), 7.13 (dd, J= 8 Hz, 1 15 Hz, 1H), 7.49 (brs, 1H), 7.61 (d, J= 8 Hz, 2H), 7.83 (d, J= 8 Hz, 1H), 8.15 (s, 1H), 11.29 (br s, 1H); HPLC-MS: m/z418 (MH); Rf: 3.40 min.
WO 03/066604 PCT/DKO3/00071 63 Example 23 {6-[4-(1-Cyclopropyl-1l-methylethyl)piperazin-1-yl]pyridin-3-yl}phenylmethanone hydrochloride 0
H
3 C N N
H
3 C.IN, 1 H NMR (DMSO-d 6 ) 80.48-0.62 (m, 4H), 1.22-1.39 (m, 7H), 3.14 (m, 2H), 3.69 (m, 4H), 4.64 5 (m, 2H), 7.08 (d, J= 8 Hz, 1H), 7.55 (m, 2H), 7.61-7.72 (m, 3H), 8.00 (dd, J= 8 Hz, 1 Hz, IH), 8.52 (d, J= 1 Hz, 1H), 11.27 (brs, 1H); HPLC-MS: m/z350 (MH+); Rf: 3.03 min. This compound was prepared as Example 6, starting from 2-chloro-5-benzoylpyridine (T.D. Penning et al., J. Med. Chem. 2000, 43, 721-735). Example 24 10 {4-[4-(1-Cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyi}phenylmethanone hy drochloride O Fq,
H
3 C N F HCI 1 H NMR (DMSO-d 6 ) 30.48-0.63 (m, 4H), 1.23-1.40 (m, 7H), 3.18 (m, 2H), 3.56 (m, 2H), 3.69 (m, 2H), 3.84 (m, 2H), 7.42 (m, 2H), 7.58 (m, 2H), 7.66-7.76 (m, 3H), 10.90 (br s, 1H); HPLC 15 MS: m/z 385 (MH+); Rf: 3.73 min.
WO 03/066604 PCT/DKO3/00071 64 Example 25 {4-[4-(1-Cyclopropyl-1-methylethyl)piperazin-1-yl]-3,5-difluorophenyl}phenylmethanoI hydro chloride OH F~p N 3 NJ F H3cN 5 'H NMR (DMSO-d) 80.47-0.61 (m, 4H), 1.23-1.34 (m, 7H), 3.12 (m, 2H), 3.29 (m, 2H), 3.65 (m, 4H), 5.66 (m, 1H), 6.08 (m, 1H), 7.06 (m, 2H), 7.19-7.40 (m, 5H), 10.40 (brs, 1H); HPLC MS: mlz 387 (MH+); Rf: 3.40 min., This compound was prepared by reduction with sodium borohydride of Example 24. Example 26 10 [4-(4-Cyclopropylmethylpiperazin-1-yI)-3,5-difluorophenyl]-(4-fluorophenyl)methanone hydro chloride O 0 F rN F NFF 1 H NMR (DMSO-d 6 ) 80.40 (m, 2H), 0.66 (m, 2H), 1.13 (m, 1H), 3.02-3.23 (m, 5H), 3.52-3.68 (m, 5H), 7.40 (m, 4H), 7.82 (m, 2H), 10.55 (brs, 1H); HPLC-MS: m/z 375 (MH); Rf: 2.78 15 min. This compound was prepared as example 6, using 3,4,5,4'-tetrafluorobenzophenone. The latter was prepared by Friedel Crafts acylation of fluorobenzene with 3,4,5-trifluorobenzoyl chloride.
WO 03/066604 PCT/DKO3/00071 65 Example 27 {4-[4-(1-Ethylpropyl)piperazin-1-yl]-3,5-difluorophenyl}-(4-fluorophenyl)methanone hydrochlo ride 0 F SI I
CH
3 N F N F
H
3 C 5 'H NMR (DMSO-d 6 ) 80.97 (t, J= 7 Hz, 6H), 1.68 (m, 2H), 1.88 (m, 2H), 3.06-3.26 (m,3H), 3.52 (m, 4H), 3.75 (m, 2H), 7.41 (m, 4H), 7.82 (m, 2H), 10.31 (br s, 1H); HPLC-MS: mlz 391 (MH'); Rf: 3.00 min. Example 28 2-[4-(1 -Ethylpropyl)piperazin-1-yl]-6,7-dimethoxyquinoline hydrochloride -~0 -~ 0
CH
3
CH
3 r,,,,N .MN 0'.O CH
H
3 C N,,J 10
CH
3 10 1 H NMR (DMSO-d 6 ) 80.99 (t, J= 7 Hz, 6H), 1.66 (m, 2H), 1.91 (m, 2H), 3.11 (m, 1H), 3.29 (m, 2H), 3.56 (m, 4H), 3.88 (s, 3H), 3.92 (s, 3H), 4.72 (m, 2H), 7.31-7.43 (m, 2H), 7.82 (br s, 1H), 8.30 (br s, 1H), 10.95 (br s, 1H); HPLC-MS: m/z 344 (MH+); Rf: 2.00 min. This compound was prepared as example 6 from 2-chloro-6,7-dimethoxyquinoline (Pettit, 15 Can. J. Chem. 1964, 42, 1764).
WO 03/066604 PCT/DKO3/00071 66 Example 29 2-[4-(1-Ethylpropyl)piperazin-1-yi]-4-trifluoromethylquinoline hydrochloride F F F N N
CH
3 H
CH
3 1 H NMR (DMSO-d) J0.99 (t, J= 7 Hz, 6H), 1.65 (m, 2H), 1.91 (m, 2H), 3.08 (m, 1H), 3.19 5 (m, 2H), 3.52 (m, 2H), 3.75 (m, 2H), 4.77 (m, 2H), 7.48 (t, J= 7 Hz, 1H), 7.72 (m, 2H), 7.88 (m, 2H), 11.19 (br s, 1H); HPLC-MS: m/z 352 (MH*); Rf: 3.70 min. This compound was prepared from 2-chloro-4-trifluoromethylquinoline. The latter was pre pared as described in the literature: R.D. Westland et al. J. Med. Chem. 1973, 16, 319-327. Example 30 10 2-(4-Cyclopropylmethylpiperazin-1-yl)-6-methoxy-4-trifluoromethylquinoline hydrochloride. F F F CH 3 O rN N N,, 'H NMR (DMSO-d 6 ) 80.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.01-3.16 (m, 4H), 3.46 (m, 2H), 3.64 (m, 2H), 3.87 (s, 3H), 4.66 (m, 2H), 7.16 (brs, 1H), 7.43 (dd, J= 7 Hz, 1 Hz, 1H), 7.68 (s, 1H), 7.73 (d, J= 7 Hz, 1H), 10.70 (br s, 1H); HPLC-MS: mlz 366 (MH); Rf: 3.63 min. 15 Example 31 [4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]phenylmethanone hydrochloride 0 F N N F WO 03/066604 PCT/DKO3/00071 67 1 H NMR (DMSO-d 6 ) 60.40 (m, 2H), 0.67 (m, 2H), 1.14 (m, 1H), 3.03-3.20 (m, 4H), 3.60 (m, 6H), 7.40 (m, 2H), 7.58 (m, 2H), 7.70 (m, 3H), 10.60 (br s, 1H); HPLC-MS: mlz 357 (MH*); Rf: 3.53 min. Example 32 5 [4-(4-Cyclopropylmethylpiperazin-1-yl)-3,5-difluorophenyl]-(3-fluoro-4-methoxyphenyl) methanone hydrochloride 0 F F N F CH 3 'H NMR (DMSO-d 6 ) 60.41 (m, 2H), 0.65 (m, 2H), 1.15 (m, 1H), 3.06 (m, 2H), 3.18 (m, 2H), 3.50-3.70 (m, 6H), 3.95 (s, 3H), 7.33 (t, J= 8 Hz, 1H), 7.41 (m, 2H), 7.60 (m, 2H), 10.79 (br 10 s, 1H); HPLC-MS: m/z405 (MH+); Rf: 3.67 min. Example 33 {6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}phenylmethanone hydrochloride O CH, N N N
H
3 C 'H NMR (DMSO-d 6 ) 30.97 (t, J= 7 Hz, 6H), 1.65 (m, 2H), 1.90 (m, 2H), 3.02-3.22 (m, 3H), 15 3.49-3.69 (m, 4H), 4.60 (m, 2H), 7.08 (d, J= 8 Hz, 1H), 7.56 (m, 2H), 7.68 (m, 3H), 7.99 (dd, J= 8 Hz, 1 Hz, 1H), 8.50 (d, J= 1 Hz, 1H), 10.90 (br s, 1H); HPLC-MS: mlz 338 (MH*); Rf: 3.00 min.
WO 03/066604 PCT/DKO3/00071 68 Example 34 {2-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-4-yl}phenylmethanone hydrochloride
CH
3 N N 0
H
3 C 'H NMR (DMSO-d 6 ) 30.97 (t, J= 7 Hz, 6H), 1.63 (m, 2H), 1.85 (m, 2H), 3.12 (m, 3H), 3.47 5 (m, 4H), 4.43 (m, 2H), 6.91 (d, J= 6 Hz, 1H), 7.14 (s, 1H), 7.58 (t, J= 8 Hz, 2H), 7.70-7.84 (m, 3H), 8.33 (d, J= 6 Hz, 1H), 10.43 (br s, 1H); HPLC-MS: m/z 338 (MH); Rf: 2.97 min. This compound was prepared from 2-chloro-4-benzoylpyridine, which was prepared by Friedel-Crafts acylation of benzene with 2-chloro-4-chlorocarbonylpyridine. Example 35 10 {4-[4-(1-Ethylpropyl)piperazin-1-yl]phenyl}-(4-hydroxyphenyl)methanone hydrochloride 0 CH r-i N OH N
H
3 C 'H NMR (DMSO-d 6 ) 80.97 (t, J= 7 Hz, 6H), 1.65 (m, 2H), 1.92 (m, 2H), 3.05-3.25 (m, 3H), 3.35-3.55 (m, 4H), 4.02 (m, 2H), 6.89 (d, J= 8Hz, 2H), 7.08 (d, J= 8Hz, 2H), 7.59 (d, J 8 Hz, 2H), 7.63 (d, J= 8 Hz, 2H), 10.36 (s, 1H), 10.60 (br s, 1H); HPLC-MS: mlz 353 (MH*); Rf: 15 2.13 min. Example 36 {6-[4-(1-Ethylpropyl)piperazin-1-yl]pyridin-3-yl}piperidin-1-yl-methanone hydrochloride O \NQ
CH
3 N N HNC
H
3
C
WO 03/066604 PCT/DKO3/00071 69 1 H NMR (DMSO-d 6 ) 80.97 (t, J= 7 Hz, 6H), 1.50 (m, 4H), 1.63 (m, 4H), 1.89 (m, 2H), 3.05 3.20 (m, 3H), 3.50 (m, 8H), 4.46 (m, 2H), 7.04 (m, 1H), 7.70 (m, 1H), 8.18 (brs, 1H), 10.90 (br s, 1H); HPLC-MS: mlz 345 (MH ); Rf: 2.27 min. Example 37 5 N-Benzyl-6-[4-(1-ethylpropyl)piperazin-1-yl]-N-methylnicotinamide hydrochloride 0 HN N N
H
3 C N
H
3 C 1 H NMR (DMSO-d) 80.97 (t, J= 7 Hz, 6H), 1.63 (m, 2H), 1.88 (m, 2H), 2.89 (s, 3H), 3.09 (m, 3H), 3.50 (m, 4H), 4.45 (mn, 2H), 4.62 (brs, 2H), 7.02 (d, J= 8 Hz, 1H), 7.25-7.41 (m, 5H), 7.78 (m, 1H), 8.28 (brs, 1H), 10.78 (brs, 1H); HPLC-MS: m/z381 (MH); Rf: 3.10 min. 10 Example 38 2-[4-(1-Ethylpropyl)piperazin-1-yl]-6-methoxyquinoline hydrochloride 0 'CH 3 N N OC
H
3 C N,
H
3 C "H NMR (DMSO-d 6 ) 80.98 (t, J= 7 Hz, 6H), 1.66 (m, 2H), 1.92 (m, 2H), 3.11 (m, 1H), 3.31 (m, 2H), 3.57 (m, 2H), 3.82 (m, 2H), 3.88 (s, 3H), 4.74 (m, 2H), 7.41 (br s, 2H), 7.53 (m, 1H), 15 8.12 (brs, IH), 8.34 (brs, 1H), 10.95 (brs, 1H); HPLC-MS: m/z 314 (MH ); Rf: 2.17 min.
WO 03/066604 PCT/DKO3/00071 70 Example 39 6-[4-(1-Ethylpropyl)piperazin-1-yl]-N-methyl-N-phenylnicotinamide hydrochloride O N N Hz C N
H
3 C
H
3 C 'H NMR (DMSO-d 6 ) 80.95 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.83 (m, 2H), 3.05 (m, 3H), 3.34 5 (s, 3H), 3.43 (m, 4H), 4.35 (m, 2H), 6.76 (d, J = 8 Hz, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 7.42 (dd, J= 8 Hz, 1 Hz, 1H), 8.01 (d, J= 1 Hz, 1H), 10.54 (brs, 1H); HPLC-MS: m/z 367 (MH); Rf: 2.90 min. Example 40 {6-[4-(1-Ethylpropyl)piperazin-1-ylgpyridin-3-yl}-(4-fluorophenyl)methanone hydrochloride 0
ICY
N N F
H
3C N j 10
H
3 C 'H NMR (DMSO-d 6 ) 80.95 (t, J= 7 Hz, 6H), 1.62 (m, 2H), 1.83 (m, 2H), 3.10 (m, 3H), 3.45 3.65 (m, 4H), 4.55 (m, 2H), 7.05 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 7.78 (dd, J = 8 Hz, 4 Hz, 2H), 7.96 (dd, J= 8 Hz, 1 Hz, 1H), 8.48 (d, J= 1 Hz, 1H), 10.85 (brs, 1H); HPLC-MS: mlz 356 (MH); Rf: 2.40 min. 15 Example 41 2-[4-(1-Ethylpropyl)piperazin-1-yl]-4-methylquinoline hydrochloride
CH
3 I N N
H
3 C N
H
3
C
WO 03/066604 PCT/DKO3/00071 71 1 H NMR (DMSO-d 6 ) 80.98 (t, J= 7 Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.69 (s, 3H), 3.12 (m, 1H), 3.32 (m, 2H), 3.57 (m, 2H), 3.94 (m, 2H), 4.86 (m, 2H), 7.53 (br s, 2H), 7.80 (m, 1H), 8.01 (m, 1H), 8.32 (brs, 1H), 11.20 (brs, 1H); HPLC-MS: m/z298 (MH*); Rf: 1.26 min. Example 42 5 2-[4-(1-Ethylpropyl)piperazin-1 -yl]-5,6,7,8-tetrahydroquinoline hydrochloride rN N
H
3 C N_
H
3 C 1 H NMR (DMSO-d) 50.98 (t, J= 7 Hz, 6H), 1.50-2.03 (m, 8H), 2.63 (m, 2H), 2.90 (m, 2H), 3.00-3.33 (m, 3H), 3.50 (m, 2H), 3.75 (m, 2H), 4.48 (m, 2H), 7.13 (brs, 1H), 7.75 (brs, 1H), 11.10 (br s, 1H); HPLC-MS: m1z288 (MH); Rf: 1.83 min. 10 This compound was prepared from 2-chloro-5,6,7,8-tetrahydroquinoline (S.C. Zimmerman, Z. Zeng, J. Org. Chem. 1990, 55, 4789-5791). Example 43 2-(4-Cyclopropylmethylpiperazin-1-yl)-6-methoxyquinoline hydrochloride -'0
CH
3 N N N 15 H NMR (DMSO-d 6 ) 80.41 (m, 2H), 0.66 (m, 2H), 1.18 (m, 1H), 3.02 (m, 2H), 3.13 (m, 2H), 3.52-3.69 (m, 4H), 3.85 (s, 3H), 4.71 (m, 2H), 7.41 (br s, 2H), 7.53 (m, 1H), 8.12 (brs, 1H), 8.34 (br s, 1 H), 11.38 (br s, 1H); HPLC-MS: mlz 298 (MH'); Rf: 1.87 min. Example 44 2-(4-Isopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride N OCH3
H
3 C N,,
,
) 20
CH
3 WO 03/066604 PCT/DKO3/00071 72 1 H NMR (DMSO-d6) 31.32 (d, J= 7 Hz, 6H), 3.28 (m, 2H), 3.53 (m, 3H), 3.80 (m, 1H), 3.85 (s, 3H), 4.85 (m, 2H), 7.43 (brs, 2H), 7.59 (d, J= 8 Hz, 1H), 8.27 (brs, 1H), 8.34 (br.s, 1H), 8.40 (d, J= 8 Hz, 1H), 11.60 (brs, 1H); HPLC-MS: m/z286 (MH'); Rf: 1.77 min. Example 45 5 2-[4-(1-Ethylpropyl)piperazin-1-yl]-6-fluoro-4-methylquinoline hydrochloride
CH
3 F I rN N
H
3 C N.,)
H
3 C 1 H NMR (DMSO-d) 60.98 (t, J= 7 Hz, 6H), 1.64 (m, 2H), 1.92 (m, 2H), 2.67 (s, 3H), 3.12 (m, 1H), 3.32 (m, 2H), 3.57-4.00 (m, 4H), 4.85 (m, 2H), 7.57 (br s, 2H), 7.68 (m, 1 H), 7.82 (m, 1H), 8.33 (brs, 1H), 11.10 (brs, 1H); HPLC-MS: m/z 316 (MH ); Rf: 1.92 min. 10 This compound was prepared from 2-chloro-6-fluoro-4-methylquinoline, which was prepared by acetoacetylation of 4-fluoroaniline, followed by acid-mediated ring-closure and conversion of the resulting carbostyryl into the chloroquinoline by treatment with phosphorus oxychlo ride. Example 46 15 2-(4-Isopropylpiperazin-1-yl)quinoline hydrochloride N N H3C N
CH
3 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 3.19 (m, 2H), 3.52 (m, 3H), 3.72 (m, 2H), 4.79 (m, 2H), 7.45 (m, 2H), 7.68 (m, 1H), 7.86 (m, 1H), 8.03 (m, 1H), 8.31 (m, 1H), 11.45 (br s, 1H); HPLC-MS: mlz 256 (MH ); Rf: 1.47 min.
WO 03/066604 PCT/DKO3/00071 73 Example 47 2-(4-Cyclopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride 0 0
'CH
3 N~ 'H NMR (DMSO-d 6 ) 60.81 (m, 2H), 1.20 (brs, 2H), 2.86 (br s, IH), 3.25-3.75 (m, 4H), 3.85 5 (s, 3H), 4.09 (m, 2H), 4.73 (m, 2H), 7.41 (m, 2H), 7.55 (m, 1H), 8.14 (m, 1H), 8.37 (m, 1H), 11.51 (br s, 1H); HPLC-MS: m/z 284 (MH'); Rf: 1.80 min. Example 48 2-(4-Isopropyl-piperazin-1-yl)-6-trifluoromethoxyquinoline hydrochloride SN O F HzC N
H
3 C Y N
CH
3 10 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7Hz, 6H), 3.17 (m, 2H), 3.52 (m, 3H), 3.68 (m, 2H), 4.79 (m, 2H), 7.56 (d, J= 8 Hz, IH), 7.68 (brd, J= 7 Hz, 1H), 7.91 (brs, 1H), 8.04 (brs, 1H), 8.35 (brd, J= 7 Hz, 1H), 11.28 (brs, 1H); HPLC-MS: m/z340 (MH ); Rf: 3.04 min. Example 49 6-Chloro-2-(4-cyclopropyl-piperazin-1-yl)-quinoline hydrochloride N c N 15 1 H NMR (DMSO-d 6 ) 30.81 (m, 2H), 1.14 (br s, 2H), 2.88 (br s, 1H), 3.25-3.70 (m, 6H), 4.67 (m, 2H), 7.44 (d, J= 8 Hz, 11-1), 7.61 (d, J= 8 Hz, 1H), 7.72 (m, 1H), 7.91 (brs, 1H), 8.18 (br d, J= 8 Hz, 1H), 10.75 (br s, 1H); HPLC-MS: m/z 288 (MH+); Rf: 1.77 min.
WO 03/066604 PCT/DKO3/00071 74 Example 50 2-(4-Cyclopropyl-piperazin-1-yl)-6-trifluoromethoxyquinoline hydrochloride OF rN N -z F N 1 H NMR (DMSO-d 6 ) 60.81 (m, 2H), 1.15 (br s, 2H), 2.88 (br s, 1H), 3.20-3.70 (m, 6H), 4.68 5 (m, 2H), 7.49 (d, J= 8 Hz, 1H), 7.59 (br d, J = 8 Hz, 1H), 7.82 (m, 2H), 8.27 (d, J 8 Hz, 1H), 10.89 (br s, 1H); HPLC-MS: mlz 338 (MH*); Rf: 2.24 min. Example 51 2-(4-Isopropyl-piperazin-1-yl)-8-trifluoromethylquinoline hydrochloride H3c. N HaY< F F F
CH
3 10 , 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7Hz, 6H), 3.10 (m, 2H), 3.51 (m, 5H), 4.72 (m, 2H), 7.38 (t, J= 8 Hz, 1H), 7.46 (d, J= 8 Hz, 1H), 7.95 (brd, J= 7 Hz, 1H), 8.05 (brd, J= 7 Hz, 1H), 8.26 (d, J= 8 Hz, 1H), 10.66 (brs, 1H); HPLC-MS: mlz 324 (MH*); Rf: 3.08 min. Example 52 2-(4-Isopropyl-piperazin-1-yl)-6-trifluoromethylquinoline ,hydrochloride F F HC N 15
CH
3 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 3.12 (m, 2H), 3.50-3.68 (m, 5H), 4.78 (m, 2H), 7.52 (d, J= 7 Hz, 1H), 7.88 (m, 2H), 8.26 (brs, 1H), 8.36 (d, J= 7 Hz, 1H), 10.95 (brs, 1H); HPLC-MS: m/z 324 (MH*); Rf: 2.11 min.
WO 03/066604 PCT/DKO3/00071 75 Example 53 2-(4-Isopropyl-piperazin-1-yl)-6-propylquinoline hydrochloride N
CH
3 N N H3C YNJ N '' N
CH
3 1 H NMR (DMSO-d 6 ) 30.91 (t, J= 7 Hz, 3H), 1.31 (d, J= 7 Hz, 6H), 1.66 (sext,; J= 7 Hz, 2H), 5 2.70 (t, J = 7 Hz, 2H), 3.23 (m, 2H), 3.48-3.90 (m, 5H), 4.81 (m, 2H), 7.52 (m, 1H), 7.63 (m, 1H), 7.70 (br s, 1H), 8.09 (br s, 1H), 8.34 (br s, 1H), 11.35 (br s, 1H); HPLC-MS: m/z 298 (MH'*); Rf: 1.97 min. Example 54 6,8-Difluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride F H N NF
H
3 C>TNN) F 10
CH
3 'H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 3.09 (m, 2H), 3.51 (m, 5H), 4.66 (m, 2H), 7.45 7.58 (m, 3H), 8.18 (d, J= 7 Hz, 1H), 10.92 (brs, 1H). Example 55 8-Fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride N.
H
3 C. N F 15
CH
3 1 H NMR (DMSO-d 6 ) 61.31 (d, J = 7 Hz, 6H), 3.09 (m, 2H), 3.52 (m, 5H), 4.70 (m, 2H), 7.24 (m, 1H), 7.40 (m, 2H), 7.59 (d, J = 7 Hz, 1H), 8.20 (d, J = 7 Hz, 1 H), 10.84 (br s, I H).
WO 03/066604 PCT/DKO3/00071 76 Example 56 2-(4-Cyclopropylpiperazin-1-yl)-6-trifluoromethylquinoline hydrochloride FF CN Ne VNv 1 H NMR (DMSO-d 6 ) 80.81 (m, 2H), 1.19 (brs, 2H), 2.88 (brs, 1H), 3.20-3.70 (m, 6H), 4.73 5 (m, 2H),7.52(d,J= 8 Hz, 1H),7.86(m, 2H),8.26(brs, 1H),8.33(d,J= 8 Hz, 1H),11.12(br s, 1H); HPLC-MS: mlz 322 (MH'); Rf: 2.41 min. Example 57 2-(4-Cyclopropylpiperazin-1-yl)-6-propylquinoline hydrochloride
CH
3 'N. N N,N 10 ' 1 H NMR (DMSO-d 6 ) 80.82 (m, 2H), 0.91 (t, J= 7Hz, 3H), 1.18 (brs, 2H), 1.66 (sext, J= 7 Hz, 2H), 2.69 (t, J= 7 Hz, 2H), 2.85 (br s, 1H), 3.30-3.75 (m, 6H), 4.72 (m, 2H), 7.51 (m, 1H), 7.62 (m, 1H), 7.69 (brs, 1H), 7.97 (brs, 1H), 8.33 (brs, 1H), 11.20 (brs, 1H); HPLC-MS: mlz 296 (MH ); Rf: 1.97 min. Example 58 15 2-(4-Ethylpiperazin-1-yl)quinoline hydrochloride N H3C,--,N, HCNN Reference can also be made to S. Cacchi et al., SynLett 1997, 1400-1402. 1 H NMR (DMSO-d 6 ) 81.30 (t, J= 7 Hz, 3H), 3.15 (m, 4H), 3.55-3.85 (m, 4H), 4.81 (m, 2H), 7.47 (m, 1H), 7.53 (m, 1H), 7.74 (m, 1H), 7.89 (d, J= 8 Hz, 1H), 8.13 (brs, 1H), 8.40 (brs, 20 1H), 11.34 (br s, 1H); HPLC-MS: m/z242 (MH); Rf: 1.04 min.
WO 03/066604 PCT/DKO3/00071 77 Example 59 (General procedure (B)) 3-(4-Isopropyl-piperazin-1-yl)-6-phenyl-pyridazine, hydrochloride NN This compound was prepared according to General Procedure (B), starting from 1 5 isopropylpiperazine and 3-chloro-6-phenylpyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). 'H NMR (D20): 5 1.46 (d, 6H); 3.28 (m, 2H); 3.48 (m, 2H); 3.64-3.84 (m, 3H); 4.57 (m, 2H); 7.63-7.72 (m, 4H); 7.90 (m, 2H); 8.12 (d, 1 H); HPLC-MS: m/z= 283.2 (M+1); Rt = 1.52 min. Example 60 (General procedure (B)) 10 3-(4-Cyclopentyl-piperazin-1 -yl)-6-(4-methanesulfonyl-phenyl)-pyridazine O N NS N=N - 0 This compound was prepared according to General Procedure (B), starting from 1 cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonyl-phenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). 15 'H NMR (CDCi 3 ): 6 1.38-1.80 (m, 6H), 1.92 (m, 2H); 2.56 (quint, 1H); 2.66 (dd, 4H); 3.10 (s, 3H); 3.97 (dd, 4H); 6.99 (d, 1H); 7.69 (d, 1H); 8.03 (d, 2H); 8.20 (d, 2H); HPLC-MS: m/z =387.0 (M+1); Rt = 2.20 min. Example 61 (General procedure (B)) 20 3-(4-Cyclopropylmethyl-piperazin-1-yl)-6-(4-methanesulfonyl-phenyl)-pyridazine N N / S-CH 3 N- N 0 This compound was prepared according to General Procedure (B), starting from 1 cyclopentylpiperazine and 3-chloro-6-(4-methanesulfonyl-phenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978).
WO 03/066604 PCT/DKO3/00071 78 1 H NMR (CDCI3): 8 0.15 (q, 2H); 0.57,(m, 2H); 0.92 (m, 1H); 2.34 (d, 2H); 2.69 (dd, 4H); 3.10 (s, 3H); 3.80 (dd, 4H); 7.01 (d, 1H); 7.70 (d, 1H); 8.03 (d, 2H); 8.21 (d, 2H); HPLC-MS : m/z= 373.4 (M+1); Rt = 2.04 min. 5 Example 62 (General procedure (B)) 3-(4-Isopropyl-piperazin-1-yl)-6-(4-methanesulfonyl-phenyl)-pyridazine
H~
3 C- 0 -N N -S-OH 3 HC \_I N1=N This compound was prepared according to General Procedure (B), starting from 1 isopropylpiperazine and 3-chloro-6-(4-methanesulfonyl-phenyl)-pyridazine, prepared as de 10 scribed in J. Heterocycl. Chem., 15, 881 (1978). 1 H NMR (DMSO-d 6 ): . 1.01 (d, 6H); 2.57 (m, 4H); 2.71 (m, 1H); 3.26 (s, 3H); 3.67 (m, 4H); 7.39 (d, 1H); 8.02 (d, 2H); 8.06 (d, 1 H); 8.30(d, 2H); HPLC-MS: m/z = 360.8 (M+1); Rt = 1.43 mm. Example 63 (General procedure (B)) 15 3-(4-Chloro-phenyl)-6-(4-isopropyl-piperazin-1-yl)-4-methyl-pyridazine, dihydrochloride Cl N N N This compound was prepared according to General Procedure (B), starting from 1 isopropylpiperazine and 6-chloro-3-(4-chloro-phenyl)-4-methyl-pyridazine, prepared as de scribed in J. Heterocycl. Chem., 15, 881 (1978). 20 1 H NMR (D 2 0): 3 1.08 (d, 6H); 2.10 (s, 1H); 3.01 (m, 2H); 3.23 (m, 2H); 3.28-3.44 (m, 3H); 4.31 (broad d, 2H); 7.27 (d, 2H); 7.34 (d, 2H); 7.58 (s, 1H); HPLC-MS: mlz= 331.1 (M+1); Rt = 3.1 min. C18 H23 N4 CI, 2 HCI WO 03/066604 PCT/DKO3/00071 79 Calc.: C 53.54 H 6.24 N 13.88 Found: C53.34 H 6.31 N 13.70. Example 64 (General procedure (B)) 3-(4-Chloro-phenyl)-6-(4-cyclopentyl-piperazin-1-yl)-4-methyl-pyridazine, hydrochloride CI N N N 5 This compound was prepared according to General Procedure (B), starting from 1 cyclopentylpiperazine and 6-chloro-3-(4-chloro-phenyl)-4-methyl-pyridazine, prepared as de scribed in J. Heterocycl. Chem., 15, 881 (1978). 'H NMR (D 2 0): 8 1.29-1.60 (m, 6H); 1.91 (m, 2H); 2.12 (s, 3H); 3.00 (m, 2H); 3.24 (m, 2H); 10 3.36 (m, 1H); 3.51 (broad d, 2H); 4.29 (broad d, 2H); 7.29 (d, 2H); 7.36 (d, 2H); 7.60 (s, 1H); HPLC-MS: mlz= 357.1 (M+1); Rt = 3.25 min. C20 H25 N4 CI, 2 HCI Calc.: C 55.89 H 6.33 N 13.04 Found: C55.83 H 6.47 N 12.93. 15 Example 65 (General procedure (B)) 3-(4-Chlorophenyl)-6-(4-cyclopentylpiperazin-1 -yl)-pyridazine N /Cl N-N This compound was prepared as described in Example 6, starting from 1 cyclopentylpiperazine and 3-chloro-6-(4-chlorophenyl)-pyridazine, prepared as described in 20 J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 1 H NMR (CDCl 3 ): " 1.39-1.81 (m, 6H), 1.91 (m, 2H), 2.56 (q, 1H), 2.66 (dd, 4H), 3.74 (dd, 4H), 6.96 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 9.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H); HPLC-MS (Method #): m/z = 343 (M+1); Rt = 2.93 min.
WO 03/066604 PCT/DKO3/00071 80 Example 66 (General procedure (B)) 3-(4-Cyclopentylpiperazin-1-yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine, dihydrochloride N N /- 0 N J N-N F This compound was prepared as described in Example 6, starting from 1 5 cyclopentylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). 'H NMR (DMSO-de): 8 1.45-2.15 (m, 8H), 3.17 (m, 2H), 3.40-3.77 (m, 5H), 3.92 (s, 3H), 7.34 (t, J = 8.7 Hz, 1H), 7.80 (d, J = 9.8 Hz, 1H), 7.85-8.05 (m, 2H), 8.29 (d, J = 9.8 Hz, 1H), 11.75 (bs, 1H); HPLC-MS: m/z = 357 (M+1); Rt = 2.47 min. 10 Example 67 (General procedure (B)) 3-(4-Cyclopentylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyridazine N \-/N\ 0 N-NO 0 / This compound was prepared as described in Example 6, starting from 1 15 cyclopentylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)-pyridazine, prepared as de scribed in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 1 H NMR (CDCI 3 ): J 1.40-1.65 (m, 4H), 1.73 (m, 2H), 1.91 (m, 2H), 2.55 (q, 1H), 2.66 (t, 4H), 3.72 (t, 4H), 3.93 (s, 3H), 3.98 (s, 3H), 6.93 (d, 1H), 6.97 (d, 1H), 7.36 (dd, 1H), 7.64 (d, 1H), 20 7.86 (d, 1H); HPLC-MS: mlz = 370 (M+1); Rt = 1.90 min. Example 68 (General procedure (B)) 3-(4-Chlorophenyl)-6-(4-cyclopropylmethylpiperazin-1 -yl)-pyridazine N N__ / _ Cl
N-N
WO 03/066604 PCT/DKO3/00071 81 This compound was prepared as described in Example 6, starting from 1 cyclopropylmethylpiperazine and 3-chloro-6-(4-chlorophenyl)-pyridazine, prepared as de scribed in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 5 1 H NMR (CDC 3 ls): 8 8 0.46 (m, 2H), 0.88 (m, 2H), 1.33 (m, 1H), 2.90 (d, 2H), 3.1-3.5 (m, 4H), 4.1-4.35 (m, 4H), 7.05 (d, 1H), 7.46 (d, 2H), 7.72 (d, 1H), 7.95 (d, 2H); HPLC-MS: mlz= 329 (M+1); Rt = 2.11 min. Example 69 (General procedure (B)) [Name] F F NN ' /\/ F 10 N-N This compound was prepared as described in Example 6, starting from 1 cyclopentylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine, prepared as de scribed in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 15 1 H NMR (CDCl3): 8 1.40-1.65 (m, 4H), 1.65-1.80 (m, 2H), 1.92 (m, 2H), 2.55 (q, 1H), 2.65 (t, 4H), 3.76 (t, 4H), 6.99 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H), 8.12 (d, 2H); HPLC-MS): m/z = 377 (M+1); Rt = 2.68 min. Example 70 (General procedure (B)) 3-(4-Isopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)-pyridazine 20N N F 20 H3 c N=N F This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 1 H NMR (DMSO-d): 8 1.20 (d, 6H), 2.8-4.2 (m, 9H), 7.47 (d, 1H), 7.85 (d, 2H), 8.12 (d, 1H), 25 8.28 (d, 2H); HPLC-MS: mlz= 351 (M+1); Rt = 2.51 min.
WO 03/066604 PCT/DKO3/00071 82 Example 71 (General procedure (B)) 3-(4-Cyclopropylmethylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)-pyridazine 'N N F N=N F This compound was prepared as described in Example 6, starting from 1 5 cyclopropylmethylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 'H NMR (CDC13): 5 0.15 (m, 2H), 0.57 (m, 2H), 0.92 (m, 1H), 2.33 (d, 2H), 2.69 (t, 4H), 3.79 (t, 4H), 7.00 (d, 1H), 7.67 (d, 1H), 7.72 (d, 2H), 8.12 (d, 2H); HPLC-MS: m/z= 363 (M+1); Rt 10 = 2.65 min. Example 72 (General procedure (B)) 3-(4-Chlorophenyl)-6-(4-isopropylpiperazin-1 -yl)-pyridazine H C > N / - N C l HG f\ -D
H
3 G \/ N-N This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine 15 and 3-chloro-6-(4-chlorophenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 'H NMR (CDCl3): 6 1.10 (d, 6H), 2.68 (t, 4H), 2.75 (q, 1H), 3.73 (t, 4H), 6.97 (d, 1H), 7.43 (d, 2H), 7.61 (d, 1H), 7.94 (d, 2H); HPLC-MS: mlz= 317 (M+1); Rt = 2.03 min. Example 73 (General procedure (B)) 20 3-(4-Cyclopropylmethylpiperazin-1 -yl)-6-(3-fluoro-4-methoxyphenyl)-pyridazine - - OH 3 N N / N-N F This compound was prepared as described in Example 6, starting from 1 cyclopropylmethylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, prepared as described in J. Heterocycl. Chem., 15, 881 (1978). The title compound was obtained as 25 the free base.
WO 03/066604 PCT/DKO3/00071 83 1 H NMR (DMSO-d): 3 0.40 (m, 2H), 0.65 (m, 2H), 1.15 (m, 1H), 2.8-3.7 (m, 10H), 3.90 (s, 3H), 7.29 (t, 1H), 7.47 (d, 1H), 7.88 (d, 1H), 7.93 (d, 1H), 8.06 (d, 1H); HPLC-MS: m/z= 343 (M+1); Rt = 1.90 min. Example 74 (General procedure (B)) 5 3
-(
3 -Fluoro-4-methoxyphenyl)-6-(4-isopropylpiperazin-1 -yl)-pyridazine /N N C
H
3 C N-N F This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine, prepared as described in J. Hetero cycl. Chem., 15, 881 (1978). The title compound was obtained as the free base. 10 1 H NMR (CDCl 3 ): 31.11 (d, 6H), 2.70 (m, 4H), 2.80 (q, 1H), 3.74 (m, 4H), 3.94 (s, 3H), 6.96 (d, 1H), 7.04 (t, 1H), 7.57 (d, 1H), 7.72 (d, 1H), 7.78 (m, 1H); HPLC-MS: m/z= 331 (M+1); Rt = 1.57 min. 15 Example 75 (General procedure (B)) 3
-(
3
,
4 -Dimethoxyphenyl)-6-(4-isopropylpiperazin-l1-yl)-pyridazine, dihydrochloride / N N ~ / 0 N-N 0 / This compound was prepared as described in Example 6, starting from 1-isopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)-pyridazine, prepared as described in J. Heterocycl. 20 Chem., 15, 881 (1978). 'H NMR (DMSO-do): 8 1.32 (d, 6H), 3.17 (q, 1H), 3.3-4.1 (m, 6H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (d, 2H), 7.09 (d, 1H), 7.62 (d, 1H), 7.68-7.73 (m, 2H), 8.23 (d, 1H), 11.35 (s, 1H); HPLC MS: m/z = 343 (M+1); Rt = 1.50 min. 25 Example 76 (General procedure (B)) WO 03/066604 - PCT/DKO3/00071 84 (9a-R)-2-(6-Trifluoromethoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride H I O~< OF r- N NK ) N This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-6-trifluoromethoxyquinoline. 5 1 H NMR (DMSO-d 6 ) 1.40-1.55 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25 3.55 (m, 4H), 3.71 (m, 1H), 4.85 (m, 2H), 7.61 (d, J= 8 Hz, 1H), 7.70 (d, J= 8 Hz, 1H), 7.93 (s, 1H), 8.19 (brs, 1H), 8.39 (d, J= 8 Hz, 1H), 11.60 (brs, 1H); HPLC-MS: m/z 352 (MH*); Rt = 2.67 min. 10 Example 77 (General procedure (B)) 7-Fluoro-2-(4-isopropylpiperazin-1-yl)-6-methylquinoline hydrochloride N NCH 3 N N F H3C N
CH
3 15 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline. 1 H NMR (DMSO-d 6 ) 61.32 (d, J= 7 Hz, 6H), 2.36 (s, 3H), 3.26 (m, 2H), 3.54 (m, 3H), 3.83 (m, 2H), 4.88 (br s, 2H), 7.49 (d, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 8.09 (br s, 1H), 8.35 (d, J= 8 Hz, 1H), 11.57 (br s, 1H); HPLC-MS: m/z 287 (MH); Rt = 1.47 min. 20 Example 78 (General procedure (B)) 7-Chloro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride N N CI
H
3 C N
CH
3 WO 03/066604 PCT/DKO3/00071 85 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2,7-dichloroquinoline. 'H NMR (DMSO-d 6 ) 1.31 (d, J= 7 Hz, 6H), 3.23 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.87 (br s, 2H), 7.48 (d, J = 8 Hz, 1 H), 7.54 (d, J = 8 Hz, 1H), 7.92 (d, J = 8 Hz, 1H), 8.26 (br s, 5 1H), 8.38 (d, J = 8 Hz, 1H), 11.50 (br s, 1H); HPLC-MS: m/z 289 (MH*); Rt = 1.61 min. Example 79 (General procedure (B)) 6-Fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride N F HzC N
CH
3 10 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6-fluoroquinoline. 'H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 3.22 (m, 2H), 3.53 (m, 3H), 3.79 (m, 2H), 4.85 (br s, 2H), 7.55-7.70 (m, 2H), 7.45 (d, J = 8 Hz, 1H), 8.26 (br s, 1H), 8.36 (d, J= 8 Hz, 1H), 11.52 (br s, 1H); HPLC-MS: m/z 274 (MH*); Rt = 1.21 min. 15 Example 80 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-7-fluoro-6-methylquinoline hydrochloride N"N
CH
3 rN N F 20 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methylquinoline. 'H NMR (DMSO-d 6 ) 60.82 (m, 2H), 1.20 (m, 2H), 2.36 (s, 3H), 2.87 (m, 1H), 3.25-4.15 (m, 6H), 4.74 (br s, 2H), 7.43 (d, J = 8 Hz, 1H), 7.80 (m, 2H), 8.28 (d, J = 8 Hz, 1H), 11.36 (br s, 1H); HPLC-MS: m/z 287 (MH ); Rt = 1.47 min. 25 WO 03/066604 PCT/DKO3/00071 86 Example 81 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-7-fluoro-6-methoxyquinoline hydrochloride
CH
3 0 N N F 5 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline. 1 H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.18 (m, 2H), 2.88 (m, 1H), 3.25-4.10 (m, 6H), 3.93 (s, 3H), 4.64 (br s, 2H), 7.40 (d, J = 8 Hz, 1 H), 7.55 (d, J = 8 Hz, 1 H), 7.73 (br s, 1H), 8.24 (d, J = 8 Hz, 1H), 11.11 (brs, 1H); HPLC-MS: mlz 301 (MH+); Rt= 1.37 min. 10 Example 82 (General procedure (B)) 7-Fluoro-2-(4-isopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride
CH
3 CN F
CH
3 15 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-7-fluoro-6-methoxyquinoline. 1 H NMR (DMSO-d) 81.31 (d, J= 7 Hz, 6H), 3.16 (m, 2H), 3.45-4.05 (m, 5H), 3.93 (s, 3H), 4.72 (m, 2H), 7.42 (d, J= 8 Hz, 1H), 7.56 (d, J= 8 Hz, 1H), 7.83 (brs, 1H), 8.25 (d, J= 8 Hz, 1H), 11.13 (brs, 1H); HPLC-MS: m/z303 (MH ); Rt = 1.41 min. 20 Example 83 (General procedure (B)) (9a-R)-2-(7-Fluoro-6-methoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride WO 03/066604 PCT/DKO3/00071 87 ca3 HC0 N' F This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methoxyquinoline. 1 H NMR (DMSO-d 6 ) 31.40-1.55 (m, 1H), 1.65-2.08 (m, 5H), 2.93 (m, 1H), 3.20 (m, 1H), 3.25 5 3.55 (m, 4H), 3.73 (m, 1H), 4.81 (m, 2H),7.50 (d, J= 8 Hz, 1H), 7.62 (d, J= 8 Hz, 1H), 8.13 (br s, 1H), 8.34 (d, J= 8 Hz, 1H), 11.59 (br s, 1H); HPLC-MS: m/z 315 (MH+); Rt = 1.41 min. Example 84 (General procedure (B)) 10 (9a-R)-2-(6-Trifluoromethylquinolin-2-yl)octahydropyrido[1,2-]pyrazine hydrochloride F -4 F This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-6-trifluoromethylquinoline. 1 H NMR (DMSO-d) 31.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.92 (m, 1H), 3.20 (m, 1H), 3.30 15 3.55 (m, 4H), 3.70 (m, 1H), 4.88 (m, 2H), 7.61 (d, J= 8 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 8.15 (brs, 1H), 8.31 (s, 1H), 8.43 (d, J= 8 Hz, 1H), 11.60 (brs, 1H); HPLC-MS: m/z335 (MH'); Rt = 2.27 min. Example 85 (General procedure (B)) 20 7-Fluoro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride N N F HaCY N)
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-7-fluoroquinoline.
WO 03/066604 PCT/DKO3/00071 88 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 3.19 (m, 2H), 3.45-4.20 (m, 5H), 4.84 (m, 2H), 7.32 (m, 1H), 7.45 (d, J= 8 Hz, 1H), 7.83 (br s, 1H), 7.95 (m, 1H), 8.35 (m, 1H), 11.35 (br s, 1H); HPLC-MS: m/z 274 (MH ); Rt = 1.31 min. 5 Example 86 (General procedure (B)) 6-Chloro-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride ci H N N
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine 10 - and 236-dichloroquinoline. 1 H NMR (DMSO-ds) 6 1.31 (d, J= 7 Hz, 6H), 3.19 (m, 2H), 3.45-3.80 (m, 5H), 4.82 (m, 2H), 7.55 (d, J = 8 Hz, 1H), 7.72 (d, J= 8 Hz, 1 H), 7.99 (s, 1H), 8.07 (br s, 1H), 8.29 (d, J= 8 Hz, 1H), 11.38 (br s, 1H); HPLC-MS: m/z 290 (MH'); Rt = 1.64 min. 15 Example 87 (General procedure (B)) 6-Isopropyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride H NCH CCH HCyN N
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine 20 and 2-chloro-6-isopropylquinoline. 'H NMR (DMSO-d 6 ) 61.27 (d, J= 7 Hz, 6H), 1.32 (d, J= 7 Hz, 6H), 3.05 (sept, J= 7 Hz, I H), 3.26 (m, 2H), 3.40-3.95 (m, 5H), 4.86 (m, 2H), 7.55 (d, J= 8 Hz, IH), 7.72 (d, J= 8 Hz, IH), 7.77 (s, 1H), 8.21 (br s, 1 H), 8.42 (d, J = 8 Hz, 1 H), 11.55 (br s, 1H); HPLC-MS: m/z 298 (MH); Rt = 1.87 min. 25 WO 03/066604 PCT/DKO3/00071 89 Example 88 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6-isopropylquinoline hydrochloride
CH
3 N CH N' 7-I 5 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-isopropylquinoline. 'H NMR (DMSO-d 6 ) 60.83 (m, 2H), 1.20 (m, 2H), 1.27 (d, J= 7 Hz, 6H), 2.86 (br s, 1H), 3.04 (sept, J= 7 Hz, 1H), 3.25-3.85 (m, 5H), 4.15 (brs, 1H), 4.74 (m, 2H), 7.53 (m, 1H), 7.70 (d, J = 8Hz, 1H), 7.75 (s, 1H), 8.06 (brs, 1H), 8.38 (m, 1H), 11.41 (brs, 1H); HPLC-MS: mlz 10 (MH); Rt = min. Example 89 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)quinoline hydrochloride 15 N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloroquinoline. 'H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.74 (m, 2H), 7.45 (m, 1H), 7.52 (d, J= 8 Hz, 1H), 7.73 (m, 1H), 7.89 (d, J= 8 Hz, 1H), 8.02 (brs, 1H), 20 8.38 (m, 1H), 11.22 (br s, 1H); HPLC-MS: m/z (MH'); Rt = min. Example 90 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6,7-dimethoxyquinoline hydrochloride 25' H 3 25 WO 03/066604 PCT/DKO3/00071 90 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline. 1 H NMR (DMSO-d 6 ) 60.82 (m, 2H), 1.20 (m, 2H), 2.87 (br s, 1H), 3.25-3.75 (m, 6H), 3.86 (s, 3H), 3.90 (s, 3H), 4.66 (m, 2H), 7.25-7.50 (m, 3H), 8.24 (br s, 1H), 11.38 (br s, 1H); HPLC 5 MS: m/z314 (MH+); Rt = 1.27 min. Example 91 (General procedure (B)) 2-(4-lsopropylpiperazin-1-yl)-6,7-dimethoxyquinoline hydrochloride N N 0
.,CH
3
H
3 C N 10
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6,7-dimethoxyquinoline. 1 H NMR (DMSO-d6) 3 1.32 (d, J = 7 Hz, 6H), 3.25 (m, 2H), 3.45-4.00 (m, 5H), 3.87 (s, 3H), 3.91 (s, 3H), 4.80 (m, 2H), 7.39 (m, 2H), 7.96 (br s, 1H), 8.34 (br s, 1H), 11.50 (br s, 1H); 15 HPLC-MS: m/z 316 (MH'); Rt = 1.27 min. Example 92 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-7-fluoroquinoline hydrochloride ^N) F 20 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-7-fluoroquinoline. 1 H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.22 (m, 2H), 2.87 (br s, 1 H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 7.34 (m, I H), 7.47 (d, J = 8 Hz, 1H), 7.85 (br s, 1H), 7.96 (m, 1H), 8.37 (m, 1H), 11.55 25 (br s, 1H); HPLC-MS: m/z 271 (MH+); Rt = 1.24 min.
WO 03/066604 PCT/DKO3/00071 91 Example 93 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)6,8-difluoroquinoline hydrochloride F 5 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6,8-difluoroquinoline. 'H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.19 (m, 2H), 2.87 (br s, 1H), 3.20-3.70 (m, 6H), 4.63 (m, 2H), 7.48 (m, 3H), 8.19 (d, J= 8 Hz, 1H), 11.11 (br s, 1H); HPLC-MS: m/z 290 (MH ); Rt= 2.27 min. 10 Example 94 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6-fluoroquinoline hydrochloride S F N 15 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-fluoroquinoline. 'H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.21 (m, 2H), 2.87 (br s, 1H), 3.30-3.80 (m, 6H), 4.73 (m, 2H), 7.56 (d, J= 8 Hz, 1 H), 7.62 (m, 1 H), 7.71 (d, J= 8 Hz, 1H), 8.09 (br s, 1H), 8.33 (d, J= 8 Hz, 1H), 11.42 (br s, 1 H); HPLC-MS: m/z 272 (MH ); Rt = 1.27 min. 20 Example 95 (General procedure (B)) 7-Chloro-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride N N ci 25 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2,7-dichloroquinoline.
WO 03/066604 PCT/DKO3/00071 92 'H NMR (DMSO-d) 60.82 (m, 2H), 1.20 (m, 2H), 2.87 (br s, 1H), 3.25-3.75 (m, 6H), 4.72 (m, 2H), 7.40 (d, J = 8 Hz, 1H), 7.46 (d, J = 8 Hz, 1H), 7.87 (d, J = 8 Hz, 1H), 7.94 (br s, 1H), 8.29 (d, J= 8 Hz, 1H), 11.29 (brs, 1H); HPLC-MS: m/z288 (MH); Rt = 1.71 min. 5 Example 96 (General procedure (B)) (9a-R)-2-Quinolin-2-yl-octahydropyrido[1,2-a]pyrazine hydrochloride cH NJ N This compound was prepared using the General Procedure (B) from (9a-R) 10 octahydropyrido[1,2-a]pyrazine and 2-chloroquinoline. 1H NMR (DMSO-d 6 ) 61.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.92 (m, 1H), 3.25 (m, 1H), 3.35 3.90 (m, 5H), 4.90 (m, 2H), 7.49 (m, 1H), 7.59 (d, J= 8 Hz, 1H), 7.77 (m, 1H), 7.92 (d, J= 8 Hz, 1H), 8.32 (br s, 1H), 8.46 (m, 1 H), 11.69 (br s, 1H); HPLC-MS: m/z268 (MH*); Rt = 1.07 mm. 15 Example 97 (General procedure (B)) (9a-R)-2-(6-Chloroquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride c i H 20 This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2,6-dichloroquinoline. 1 H NMR (DMSO-d 6 ) 61.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.18 (m, 1H), 3.25 3.55 (m, 4H), 3.68 (m, 1H), 4.90 (m, 2H), 7.56 (d, J = 8 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.98 (s, 1H), 8.07 (br s, 1H), 8.29 (d, J= 8 Hz, 1H), 11.47 (brs, 1H); HPLC-MS: m/z 302 (MH ); Rt 25 = 1.81 min.
WO 03/066604 PCT/DKO3/00071 93 Example 98 (General procedure (B)) (9a-R)-2-(7-Fluoro-6-methylquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride ~ . CH 3 H H :N N M F 5 This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-7-fluoro-6-methylquinoline. 1 H NMR (DMSO-d 6 ) 81.40-1.55 (m, 1H), 1.65-2.10 (m, 5H), 2.36 (s, 3H), 2.92 (m, 1H), 3.23 (m, 1H), 3.30-3.60 (m, 4H), 3.80 (m, 1H), 4.87 (m, 2H), 7.51 (d, J = 8 Hz, 1H), 7.84 (d, J= 8 Hz, 1H), 8.13 (brs, 1H), 8.36 (d, J= 8 Hz, 1H), 11.77 (brs, 1H); HPLC-MS: mz 300 (MH'); 10 Rt = 1.54 min. Example 99 (General procedure (B)) (9a-R)-2-(6-Propylquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride 15 CH This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-6-propylquinoline. 1 H NMR (DMSO-d 6 ) 50.91 (t, J= 7 Hz, 3H), 1.40-1.55 (m, 1H), 1.60-2.10 (m, 7H),.2.70 (t, J= 7 Hz, 2H), 2.92 (m, 1H), 3.24 (m, 1 H), 3.30-3.85 (m, 5H), 4.88 (m, 2H), 7.57 (d, J= 8 Hz, 20 1H), 7.65 (d, J= 8 Hz, 1H), 7.72 (s, 1H), 8.28 (br s, 1H), 8.41 (m, 1H), 11.69 (br s, 1H); HPLC-MS: mlz 309 (MH*); Rt = 2.27 min. Example 100 (General procedure (B)) 25 2-(4-Isopropylpiperazin-1-yl)quinoxaline hydrochloride C N N
CH,
WO 03/066604 PCT/DKO3/00071 94 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloroquinoxaline. 1 H NMR (DMSO-d 6 ) 81.31 (d, J= 7 Hz, 6H), 3.13 (m, 2H), 3.45-3.65 (m, 5H), 4.75 (m, 2H), 7.48 (m, 1H), 7.66 (m, 2H), 7.88 (d, J= 8 Hz, 1H), 8.91 (s, 1H), 11.15 (brs, 1H); HPLC-MS: 5 m/z 257 (MH ); Rt = 1.25 min. Example 101 (General procedure (B)) [4-(4-Cyclopropylpiperazin-1-yl)phenyl]phenylmethanone hydrochloride 0 1 OvO 10 O This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 4-fluorobenzophenone. 1 H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.16 (m, 2H), 2.92 (brs, 1H), 3.30-3.40 (m, 4H), 3.56 (br s, 2H), 4.09 (m, 2H), 7.12 (d, J = 8 Hz, 2H), 7.54 (m, 2H), 7.60-7.75 (m, 5H), 10.82 (br s, 1H); 15 HPLC-MS: m/z 307 (MH ); Rt = 2.00 min. Example 102 (General procedure (B)) [4-(4-Cyclopropylpiperazin-1-yl)-3,5-difluorophenyl]phenylmethanone hydrochloride 0 NF 20 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3,4,5-trifluorobenzophenone. 1 H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.16 (m, 2H), 2.96 (brs, 1H), 3.30-3.75 (m, 8H), 7.43 (d, J= 8 Hz, 2H), 7.58 (t, J= 8 Hz, 2H), 7.65-7.78 (m, 3H), 10.90 (brs, 1H); HPLC-MS: m/z 343 25 (MH ); Rt = 2.29 min.
WO 03/066604 PCT/DKO3/00071 95 Example 103 (General procedure (B)) 2-(4-Isopropylpiperazin-1-yl)-5,6,7-trimethoxyquinoline hydrochloride OMe OMe N N OMe
H
3 C YN,_,
CH
3 5 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-5,6,7-trimethoxyquinoline. 'H NMR (DMSO-d 6 ) 81.31 (d, J= 7 Hz, 6H), 3.21 (m, 2H), 3.45-3.85 (m, 5H), 3.82 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 4.78 (m, 2H), 7.31 (m, 1H), 7.56 (m, 1H), 8.31 (m, 1H), 11.36 (br s, 1 H); HPLC-MS: mlz 346 (MH+); Rt = 1.22 min. 10 Example 104 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-5,6,7-trimethoxyquinoline hydrochloride OMe OMe N N OMe N,_ 15 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-5,6,7-trimethoxyquinoline. 'H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.22 (m, 2H), 2.87 (brs, 1H), 3.30-4.10 (m, 6H), 3.83 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 4.76 (m, 2H), 7.33 (m, 1H), 7.65 (br s, 1H), 8.34 (m, 1H), 11.62 (br s, 1H); HPLC-MS: m/z 344 (MH); Rt = 1.46 min. 20 Example 105 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6-trifluoromethylsulfanylquinoline hydrochloride N SF This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 25 and 2-chloro-6-trifluoromethylsulfanylquinoline.
WO 03/066604 PCT/DKO3/00071 96 1 H NMR (DMSO-d) 60.82 (m, 2H), 1.20 (m, 2H), 2.86 (br s, 1H), 3.20-3.70 (m, 6H), 4.75 (m, 2H), 7.53 (m, 1H), 7.86 (m, 2H), 8.20-8.40 (m, 2H), 11.28 (br s, 1H); HPLC-MS: m/z 354 (MH); Rt = 2.61 min. 5 Example 106 (General procedure (B)) 7-Chloro-2-(4-cyclopropylpiperazin-1-yl)-6-methoxyquinoline hydrochloride I ''
CH
3 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 10 and 2,7-dichloro-6-methoxyquinoline. 'H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.16 (m, 2H), 2.88 (m, 1H), 3.25-3.70 (m, 6H), 3.94 (s, 3H), 4.62 (m, 2H), 7.45 (d, J= 8 Hz, 1H), 7.51 (s, 1H), 7.96 (brs, 1H), 8.23 (d, J= 8 Hz, 1H), 10.98 (brs, 1H); HPLC-MS: m/z318 (MH ); Rt = 1.80 min. 15 Example 107 (General procedure (B)) 5,7-Dichloro-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride cl N CI This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 20 and 2,5,7-trichloroquinoline. 'H NMR (DMSO-d 6 ) 60.82 (m, 2H), 1.19 (m, 2H), 2.86 (m, 1H), 3.20-3.65 (m, 6H), 4.69 (m, 2H), 7.51 (d, J = 8 Hz, 1H), 7.56 (s, 1 H), 7.68 (s, 1H), 8.30 (d, J = 8 Hz, 1H), 11.24 (br s, 1H); HPLC-MS: m/z 322 (MH'); Rt = 2.78 min. 25 Example 108 (General procedure (B)) 1-Cyclopropyl- 4 -[5-( 4 -trifluoromethylphenyl)pyridin-2-yl]piperazine hydrochloride WO 03/066604 PCT/DKO3/00071 97 F /F F N N N The required 2-chloro-5-(4-trifluorophenyl)pyridine was prepared as described by R. Church, R. Trust, J. D. Albright, and D. Powell, J. Org. Chem. 1995, 60, 3750-3758, in the following way: 5 To a solution of Vilsmeier reagent prepared from dimethylformamide (5.98 g, 0.082 mol) and phosphorus oxychloride (22.5 g, 0.146 mol) at 10 oC, 4-(trifluoromethyl)phenyl acetic acid (6.64 g, 0.033 mol) was added. The mixture was stirred at 70 °C for 8 h. After cooling to am bient temperature, the mixture was added slowly to a mixture of ice and water (temperature was < 10 °C) and then the solution of Na 2
CO
3 was added slowly until pH 11 was reached. 10 Toluene (125 ml) was added to the alkaline mixture and the resulting mixture was refluxed for 1.5 h. After cooling to ambient temperature the separated water layer was extracted with toluene (100 ml). The combined organic layers were washed with water, dried (Na 2
SO
4 ), and concentrated under reduced pressure.The resulting solid was recrystallized from a mixture of dichloromethane and heptane to yield 6.98 g (87%) of 3-dimethylamino-2-(4 15 trifluoromethylphenyl)propenal as yellow crystals, mp. 97 *C. 'H NMR spectrum (CDCI 3 ) 69.10 (s, 1H), 7.57 (m, 2H), 7.32 (m, 2H), 6.95 (s, 1H), 2.85 (s, 6H); RF (SiO 2 , chloroform/methanol 95: 5) 0.34. To a solution of sodium methoxide (3.64 g, 0.068 mol) in methanol (68 ml) cyanoacetamide (6.95 g, 0.082 mol) and the previous product (6.98 g, 0.029 mol) were added. The mixture 20 was stirred at ambient temperature for 1.5 h and then refluxed for 8 h. During this time a yel low solid precipitated. The reaction mixture was diluted with water (75 ml), and acidified with 10% aqueous hydrochloric acid. The yellow solid was filtered off, washed with water, ethanol, diethyl ether, and then with hexane. This afforded 2-hydroxy-5-(4 trifluoromethylphenyl)nicotinonitrile (6.66 g, 87%) as a yellow solid, mp. 235-242 oC. 25 'H NMR (DMSO-d 6 ) 88.42 (m, 1H), 7.91 (m, 1H), 7.66 (m, 4H); RF(SiO 2 , chloro form/methanol 95: 5) 0.18. The previous product (6.66 g, 0.025 mol) was added to a mixture of acetic acid (100 ml) and concentrated hydrochloric acid (70 ml). The reaction mixture was refluxed for 18 h, diluted with water (200 ml), and allowed to cool to room temperature while stirring. The solid was WO 03/066604 PCT/DKO3/00071 98 filtered off, washed with water and then with 50% aqueous ethanol, to yield 5.42 g (77%) of 2-hydroxy-5-(4-trifluoromethylphenyl)nicotinic acid as a light-gray solid, mp. 305-315 OC. 1 H NMR (DMSO-d 6 ) 68.71 (d, 1H), 8.43 (d, 1H), 7.96 (m, 2H), 7.81 (m, 2H); RF (SiO 2 , chloro form/methanol 95: 5): 0.13. 5 A mixture of the previous product (5.42 g, 0.019 mol) and freshly distilled quinoline (50 ml) was stirred at 215 OC for 12 h. The reaction mixture was cooled to ambient temperature and heptane (250 ml) was added. The solid was filtered off, washed with heptane, and recrystal lized from a mixture of dichloromethane and heptane to yield 3.92 g (86%) of 2-hydroxy-5-(4 trifluoromethylphenyl)pyridine, mp. 178-182 0C. 10 1 H NMR (CDCl 3 ) 57.79 (dd, 2H), 7.68 (d, 3H), 7.52 (d, 2H), 6.73 (d, 1H); RF (SiO 2 , chloro form/methanol 95 : 5) 0.23. A mixture of phosphorus oxychloride (27.6 g, 0.18 mol) and the previous product (3.92 g, 0.016 mol) was stirred at 105 OC for 10 h. The excess phosphorus oxychloride was evapo rated under reduced pressure, and the residue was stripped once with toluene (75 ml). Water 15 75 (ml) and dichloromethane (75 ml) were added to the residue, the dichloromethane layer was separated and the aqueous phase was extracted with dichloromethane (75 ml). The combined extracts were washed with water, then with solution of sodium hydrogen carbon ate, dried (MgSO 4 ), and concentrated under reduced pressure, to yield 2.95 g (72%) of 2 chloro-5-(4-trifluoromethylphenyl)pyridine as light-brown crystals, mp 98-101 0C. 20 'H NMR (CDC13) 88.62 (dd, 1H), 7.86 (dd, 1H), 7.44 (dd, 1H), 7.66 (m, 2H), 7.75 (m, 2 H); RF (SiO 2 , chloroform/methanol 95 : 5) 0.94. This product was treated with 1-cyclopropylpiperazine as described in General Procedure (B) to yield the title compound. 1 H NMR (DMSO-d 6 ) 60.83 (m, 2H), 1.13 (m, 2H), 2.85 (m, 1H), 3.25-3.75 (m, 6H), 4.51 (m, 25 2H), 7.12 (d, J= 8 Hz, 1H), 7.79 (d, J= 8 Hz, 2H), 7.89 (d, J= 8 Hz, 2H), 8.05 (m, 1H), 8.59 (m, 1H), 10.56 (br s, 1 H); HPLC-MS: m/z 348 (MH*); Rt = 2.77 min. Example 109 (General procedure (B)) 30 3-(4-Cyclopropylpiperazin-1-yl)-6-(4-trifluoromethylphenyl)pyridazine hydrochloride WO 03/066604 PCT/DKO3/00071 99 F - F F N '/..N ,.N'. This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(4-trifluoromethylphenyl)pyridazine. 1 H NMR (DMSO-d 6 ) 30.83 (m, 2H), 1.19 (m, 2H), 2.89 (m, 1H), 3.30-3.70 (m, 6H), 4.61 (m, 5 2H), 7.61 (d, J= 8Hz, 1H), 7.88 (d, J= 8 Hz, 2H), 8.22 (d, J= 8Hz, 1H), 8.29 (d, J= 8Hz, 2H), 11.11 (brs, 1H); HPLC-MS: m/z349 (MH); Rt= 2.40 min. Example 110 (General procedure (B)) 10 6-(4-Cyclopropylpiperazin-1-yl)-[1,3]dioxolo[4,5-g]quinoline hydrochloride N N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 6-chloro[1,3]dioxolo[4,5-g]quinoline. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.15 (m, 2H), 2.88 (m, 1H), 3.20-3.70 (m, 6H), 4.59 (m, 15 2H), 6.17 (s, 2H), 7.29 (m, 3H), 8.13 (m, 1H), 10.80 (brs, 1H); HPLC-MS: m/z298 (MH); Rt = 0.68 min. Example 111 (General procedure (B)) 20 6-Cyclohexyl-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride WO 03/066604 PCT/DKO3/00071 100 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-cyclohexylquinoline. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.10-1.55 (m, 8H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 2.86 (m, 1H), 3.30-3.70 (m, 6H), 4.72 (m, 2H), 7.50 (m, 1H), 7.66 (m, 1H), 7.72 (m, 1H), 7.99 (br s, 5 1H), 8.35 (br s, 1H), 11.29 (br s, 1H); HPLC-MS: m/z 336 (MH ); Rt = 2.55 min. Example 112 (General procedure (B)) 6-Cyclohexyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride NN HC N 10
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6-cyclohexylquinoline. 1 H NMR (DMSO-d 6 ) 81.10-1.55 (m, 8H), 1.31 (d, J= 7 Hz, 6H), 1.70-1.93 (m, 4H), 2.65 (m, 1H), 3.23 (m, 2H), 3.50-3.85 (m, 3H), 4.80 (m, 2H), 7.51 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 15 8.08 (br s, 1H), 8.36 (br s, 1H), 11.31 (br s, 1 H); HPLC-MS: m/z 338 (MH'); Rt = 2.50 min. Example 113 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6,7-dimethoxy-3-methylquinoline hydrochloride I 0 20 The required 2-chloro-6,7-dimethoxy-3-methylquinoline was prepared according to the pro cedure published in Tetrahedron Letters 1979, 4885, in the following way: To a solution of 3,4-dimethoxyaniline (4.70 g, 30.7 mmol) in dichloromethane (50 ml) were added pyridine (8.0 ml, 3 equivalents) and then dropwise propionyl chloride (3.5 ml, 40.5 WO 03/066604 PCT/DK3/00071 101 mmol). After stirring at room temperature for 1 h and 50 min the mixture was poured into a mixture of water (200 ml) and concentrated hydrochloric acid (8 ml). The phases were sepa rated, and the aqueous phase was extracted once with dichloromethane. Washing of the combined organic phases with brine, drying with magnesium sulfate, and concentration 5 yielded 6.89 g of an oil which crystallized after a few minutes. Recrystallization from a mix ture of ethyl acetate and heptane yielded 3.60 g (49%) of N-(3,4 dimethoxyphenyl)propionamide as dark crystals. This anilide (2.1 g, 10.0 mmol) was mixed with DMF (1.1 ml, 15 mmol), and to thismixture
POC
3 (6.5 ml, 70 mmol) was dropwise added at room temperature. When the addition is fin 10 ished the mixture is stirred at 75 oC for 2 h. The mixture was poured into ice-water (100 ml), stirred for 30 min, and filtered. The solid was stripped with toluene and acetonitrile, to yield 1.60 g (67%) of 2-chloro-6,7-dimethoxy-3-methylquinoline as a solid. This product was treated with 1-cyclopropylpiperazine as described in General Procedure (B) to yield the title compound. 15 1 H NMR (DMSO-d) 50.83 (m, 2H), 1.23 (m, 2H), 2.42 (s, 3H), 2.94 (m, 1H), 3.40-4.50 (m, 8H), 3.88 (s, 3H), 3.91 (s, 3H), 7.29 (s, 1H), 7.48 (br s, 1H), 8.12 (br s, 1H), 11.24 (br s, 1H); HPLC-MS: mlz 328 (MH+); Rt = 1.63 min. Example 114 (General procedure (B)) 20 6-(4-Isopropylpiperazin-1-yl)-[1,3]dioxolo[4,5-g]quinoline hydrochloride N N N This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 6-chloro[1,3]dioxolo[4,5-g]quinoline. 25 1 H NMR (DMSO-d) 51.31 (d, J = 7 Hz, 6H), 3.40 (m, 2H), 3.45-4.00 (m, 5H), 4.72 (m, 2H), 6.21 (s, 2H), 7.34 (m, 2H), 7.62 (brs, 1H), 8.21 (m, 1H), 11.12 (brs, 1H); HPLC-MS: m/z 300 (MH*); Rt = 0.65 min.
WO 03/066604 PCT/DK3/00071 102 Example 115 (General procedure (B)) [3,5-Difluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-piperidin-1-yl-methanone hydrochloride 0 N F 5 This compound was prepared using the General Procedure (B) by reaction of 1 isopropylpiperazine with 3,4,5-trifluorobenzoic acid piperidide. This reaction yielded two products, namely the current example and example 121. 1 H NMR (DMSO-d 6 ) 61.31 (d, J = 7 Hz, 6H), 1.40-1.62 (m, 6H), 3.09 (m, 2H), 3.20-3.65 (m, 11H), 7.12 (m, 2H), 10.42 (br s, 1H); HPLC-MS: m/z 352 (MH*); Rt = 3.75 min. 10 Example 116 (General procedure (B)) (9a-R)-2-(6,7-Dimethoxyquinolin-2-yl)octahydropyrido[1,2-a]pyrazine hydrochloride I H O NN 15 This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-6,7-dimethoxyquinoline. 1 H NMR (DMSO-d 6 ) 31.40-1.55 (m, 1H), 1.65-2.05 (m, 5H), 2.93 (m, 1H), 3.22 (m, 1H), 3.25 3.60 (m, 4H), 3.65-4.20 (m, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 4.79 (m, 2H), 7.40 (m, 2H), 8.00 (br s, 1H), 8.33 (br s, 1H), 11.55 (br s, 1H); HPLC-MS: mlz 328 (MH'); Rt = 0.97 min. 20 Example 117 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-5,6,7,8-tetrahydroquinoline hydrochloride WO 03/066604 PCT/DK3/00071 103 This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-5,6,7,8-tetrahydroquinoline. 1 H NMR (DMSO-d 6 ) 80.81 (m, 2H), 1.17 (m, 2H), 1.67-1.82 (m, 4H), 2.62 (m, 2H), 2.75-2.95 5 (m, 3H), 3.20-3.65 (m, 6H), 4.37 (m, 2H), 7.02 (br s, 1H), 7.63 (br s, 1H), 11.10 (br s, 1H); HPLC-MS: m/z 258 (MH'); Rt = 0.62 min. Example 118 (General procedure (B)) 10 [5-Chloro-6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride 0 NN This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 5,6-dichloronicotinic acid piperidide. 1 H NMR (DMSO-de) 80.82 (m, 2H), 1.12 (m, 2H), 1.45-1.65 (m, 6H), 2.96 (m, 1H), 3.30-3.60 15 (m, 10H), 3.96 (m, 2H), 7.89 (s, 1H), 8.27 (s, 1H), 10.68 (br s, 1H); HPLC-MS: m/z 349 (MH'); Rt = 1.50 min. Example 119 (General procedure (B)) 20 (9a-R)-[6-(Octahydropyrido[1,2-a]pyrazin-2-yl)pyridin-3-yl]piperidin-1 -ylmethanone hydro chloride 0 H NNO N N This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 6-chloronicotinic acid piperidide.
WO 03/066604 PCT/DK3/00071 104 'H NMR (DMSO-d 6 ) 81.51 (m, 3H), 1.60 (m, 2H), 1.78-1.98 (m, 3H), 2.90-3.25 (m, 4H), 3.30 3.50 (m, 5H), 3.74 (m, 6H), 4.50 (m, 2H), 7.02 (d, J= 7 Hz, 1H), 7.66 (d, J= 7 Hz, 1H), 8.19 (s, I H), 10.86 (br s, 1H); HPLC-MS: m/z 329 (MH'); Rt = 1.31 min. 5 Example 120 (General procedure (B)) [6-(4-Cyclopropylpiperazin-1-yl)pyridin-3-yl]piperidin-1-ylmethanone hydrochloride 0 N) QN O This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 10 and 6-chloronicotinic acid piperidide. 1 H NMR (DMSO-d 6 ) 80.81 (m, 2H), 1.17 (m, 2H), 1.51 (m, 4H), 1.60 (m, 2H), 2.87 (m, 1H), 3.20-3.60 (m, 10H), 4.47 (m, 2H), 7.01 (d, J= 7 Hz, 1H), 7.67 (d, J= 7 Hz, 1H), 8.21 (s, 1H), 11.04 (brs, 1H); HPLC-MS: m/z315 (MH); Rt = 1.22 min. 15 Example 121 (General procedure (B)) [3,4-Difluoro-5-(4-isopropyl-piperazin-1-yl)-phenyl]-piperidin-1-yl-methanone hydrochloride F rN HC N 0 CH, This compound was prepared using the General Procedure (B) by reaction of 1 20 isopropylpiperazine with 3,4,5-trifluorobenzoic acid piperidide. This reaction yielded two products, namely the current example and example 115 1 H NMR (DMSO-d 6 ) 81.31 (d, J= 7 Hz, 6H), 1.40-1.65 (m, 6H), 3.12-3.62 (m, 13H), 6.89 (d, J = 8 Hz, 1H), 7.09 (m, 1H), 11.09 (br s, 1H); HPLC-MS: m/z 352 (MH'); Rt = 3.95 min. 25 Example 122 (General procedure (B)) WO 03/066604 PCT/DKO3/00071 105 [4-(4-lsopropyl-piperazin-1 -yl)-3-trifluoromethyl-phenyl]-piperidin-1-yl-methanone hydrochlo ride F O 'Ne N_, This compound was prepared using the General Procedure (B) by reaction of 1 5 isopropylpiperazine with 4-fluoro-3-trifluoromethylbenzoic acid piperidide. 'H NMR (DMSO-d 6 ) 51.31 (d, J= 7 Hz, 6H), 1.40-1.65 (m, 6H), 3.05 (m, 1H), 3.15 (m, 1H), 3.28 (m, 8H), 3.52 (m, 3H), 7.57 (br d, J = 8 Hz, 1H), 7.68 (br s, 1H), 7.71 (br d, J = 8 Hz, 1 H), 10.39 (br s, 1H); HPLC-MS: m/z 384 (MH'); Rt = 4.21 min. 10 Example 123 2-(4-Cyclopropyl-3-methyl-piperazin-1-yl)-6,7-dimethoxy-quinoline hydrochloride 9H 3 CH
H
3 C oCH3 T N N 0 ' N,,) This compound was prepared by reductive cyclopropylation of 6,7-dimethoxy-2-(3 15 methylpiperazin-1-yl)quinoline as described by Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; and Hoover, D. J. in Tetrahedron Lett. 1995, 36 (41), 7399-7402. 1 H NMR (DMSO-d 6 ) 80.82 (mi, 1H), 0.99 (mi, 2H), 1.40 (m, 1H), 1.55 (d, J = 7 Hz, 3H), 2.76 (m, 1H), 3.30-3.80 (m, 5H), 3.87 (s, 3H), 3.90 (s, 3H), 4.65-4.83 (m, 2H), 7.38 (br s, 2H), 7.82 (br s, 1H), 8.31 (br s, 1H), 11.30 (br s, 1H); HPLC-MS: m/z 328 (MH); Rt = 3.09 min. 20 Example 124 (General procedure (B)) [6-(4-Cyclopropylpiperazin-1-yl)pyridin-3-yl]pyrrolidin-1-yl-methanone hydrochloride WO 03/066604 PCT/DKO3/00071 106 O N N N N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 6-chloronicotinic acid pyrrolidide. 1 H NMR (DMSO-d 6 ) 80.81 (m, 2H), 1.15 (m, 2H), 1.84 (m, 4H), 2.88 (m, 1H), 3.15-3.60 (m, 5 10 OH), 4.49 (m, 2H), 7.00 (d, J = 7 Hz, 1H), 7.83 (d, J = 7 Hz, 1H), 8.38 (s, 1 H), 10.91 (br s, 1H); HPLC-MS: m/z 301 (MH); Rt = 1.22 min. Example 125 (General procedure (B)) 10 2-(4-lsopropylpiperazin-1-yl)quinoline-6-carbonitrile hydrochloride N N
CH
3 To a mixture of ethyl 3,3-diethoxypropionate (62 g, 326 mmol) and water (100 ml) was added NaOH (16.0 g) while stirring. Stirring at 110 °C (open flask). After 40 min the mixture was 15 homogeneous, heating was interrupted, and the mixture was allowed to cool to room tem perature. The mixture was acidified (approx 35 ml conc. HCI, pH 3-2) and extracted (4 x di chloromethane). The combined extracts were washed with brine (1 x 50 ml), dried (magne sium sulfate), and concentrated. 48 g of an oil was obtained. To the oil was dropwise added thionyl chloride (80 ml). The mixture was stirred at reflux (80 20 oC) for 1 h 30 min. After careful concentration the residue weighted 48 g (theoretical wheight should be 43 g). The acid chloride was kept overnight at -20 oC. This product is mixed with dichloromethane (70 ml) and 5/7 of this solution (approx 230 mmol) was added to a solution of 4-bromoaniline (34.5 g, 201 mmol) and pyridine (50 ml) in dichloromethane (150 ml), and the mixture was shaken at room temperature over night.
WO 03/066604 PCT/DK3/00071 107 The mixture was filtered, and the resulting solid was washed with dichloromethane, and dried, to yield 21 g of N-(4-bromophenyl)-3-ethoxyacrylamide as colorless solid. To the fil trate was added a mixture of water (700 ml) and concentrated hydrochloric acid (50 ml). A solid precipitated upon shaking, and was filtered off, washed with dichloromethane and 5 AcOEt, and dried. Additional 14.4 g of product were obtained. The filtrates were extracted (3 x dichloromethane), washed once with brine, dried, and con centrated. Additional 18 g of product resulted. Total yield: 53.4 g. This product (58.8 g; 218 mmol) was mixed with ice-cold concentrated sulfuric acid (390 ml) and the mixture was stirred first at 0 oC for 15 min (until almost all acrylamide had dissolved) 10 and then at room temperature for 4 h. The mixture was then poured into ice water (3 I) and allowed to stand overnight. The mixture was filtered, and the solid was washed with water. The solid was transferred into a flask with the aid of acetonitrile, ethanol, and dichloro methane, and the suspension was concentrated under reduced pressure. The residue was resuspended in acetonitrile (300 ml), heated to reflux, and allowed to stand at room tempera 15 ture overnight. Filtration and drying of the solid under reduced pressure yielded 31.3 g (64%) of 6-bromo-2-quinolone as a yellow solid. This quinolone (6.28 g, 28.0 mmol) was mixed with copper(l) cyanide (5.02 g, 56.1 mmol) and NMP (15 ml), and the mixture was stirred under reflux (202 oC) for 6 h, and then at room temperature overnight. Water (150 ml) was added, the mixture was filtered, and the solid was 20 washed with water. The solid was resuspended in 1N hydrochloric acid (200 ml) and iron(lll) chloride hexahydrate (17.8 g) was added. The resulting mixture was stirred at room tempera ture for 3 d, filtered, and the solid was washed once with water, stripped with ethanol, and dried under reduced pressure, to yield 4.33 g (91%) of 6-cyano-2-quinolone as a gray solid. Treatment of the product with POC1 3 and then with 1-isopropylpiperazine as described in the 25 General Procedure (B) yielded the title compound. 1 H NMR (DMSO-d 6 ) 1.31 (d, J= 7 Hz, 6H), 3.10 (m, 2H), 3.52 (m, 5H), 4.79 (m, 2H), 7.49 (d, J= 8 Hz, 1H), 7.71 (d, J= 8 Hz, 1H), 7.86 (d, J= 8 Hz, 1H), 8.23 (d, J= 8 Hz, 1H), 8.35 (s, 1H), 10.73 (brs, 1H); HPLC-MS: m/z281 (MH); Rt = 1.62 min. 30 Example 126 (General procedure (B)) 3-(4-Cyclopropylpiperazin-1-yl)-6-phenylpyridazine hydrochloride WO 03/066604 PCT/DK3/00071 108 N,) This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-phenylpyridazine. 'H NMR (DMSO-d 6 ) 80.82 (m, 2H), 1.22 (m, 2H), 2.88 (brs, 1H), 3.37 (m, 2H), 3.59 (m, 4H), 5 4.57 (m, 2H), 7.53 (m, 3H), 7.80 (d, J = 8 Hz, 1H), 8.06 (m, 2H), 8.29 (d, J= 8 Hz, 1H), 11.47 (br s, 1H); HPLC-MS: m/z281 (MH); Rt = 1.43 min. Example 127 (General procedure (B)) 10 3-(4-Cyclopropylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyridazine hydrochloride - O'cH 3 0oCH3 'N N' N,, This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 3-chloro-6-(3,4-dimethoxyphenyl)pyridazine. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.22 (m, 2H), 2.88 (brs, 1H), 3.36 (m, 2H), 3.60 (m, 4H), 15 3.84 (s, 3H), 3.87 (s, 3H), 4.53 (m, 2H), 7.14 (d, J= 8 Hz, 1H), 7.66 (m, 2H), 7.86 (d, J= 8 Hz, 1H), 8.37 (d, J= 8 Hz, 1H), 11.43 (br s, 1H); HPLC-MS: m/z 341 (MH'); Rt = 1.45 min. Example 128 (General procedure (B)) 20 7-(4-Isopropylpiperazin-1 -yl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline N 0 H3C N
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 7-chloro-2,3-dihydro[1,4,]dioxino[2,3-g]quinoline.
WO 03/066604 PCT/DK3/00071 109 1 H NMR (DMSO-do) 51.00 (d, J= 7 Hz, 6H), 2.67 (hept, J= 7 Hz, 1H), 3.33 (s, 4H), 3.56 (m, 4H), 4.29 (m, 4H), 6.95 (s, 1H), 7.02 (d, J= 8 Hz, 1H), 7.13 (s, 1H), 7.84 (d, J= 8 Hz, 1H); HPLC-MS: m/z 314 (MH*); Rt= 1.14 min. 5 Example 129 2-(4-Cyclopropyl-3-methylpiperazin-1-yl)quinoline hydrochloride Hzc'
H
3 o0 N N This compound was prepared by reductive cyclopropylation of 2-(3-methylpiperazin-1 10 yl)quinoline as described by Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; and Hoover, D. J. in Tetrahedron Lett. 1995, 36 (41), 7399-7402. 1 H NMR (DMSO-d 6 ) 80.82 (m, 1H), 1.00 (m, 2H), 1.41 (m, 1H), 1.56 (d, J=7 Hz, 3H), 2.76 (m, 1H), 3.25-3.80 (m, 5H), 4.81 (m, 2H), 7.44 (br s, 1H), 7.55 (m, 1H), 7.72 (m, 1 H), 7.88 (m, 1H), 8.11 (br s, 1H), 8.37 (br s, 1H), 11.40 (br s, 1H); HPLC-MS: m/z 268 (MH'); Rt = 1.18 15 min. Example 130 (General procedure (B)) 6-Cyclopropylmethoxy-2-(4-cyclopropylpiperazin-1-yl)quinoline hydrochloride N N 20 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6-(cyclopropylmethyloxy)quinoline. The required 2-chloro-6 (cyclopropylmethyloxy)quinoline was prepared by treatment of 6-(cyclopropylmethyloxy)-2 quinolone with POCl 3 . 6-(Cyclopropylmethyloxy)-2-quinolone was prepared from the corre 25 sponding 6-hydroxyquinolone by treatment with (bromomethyl)cycylopropane and potassium carbonate in dimethyl formamide in the presence of catalytic amounts of sodium iodide.
WO 03/066604 PCT/DKO3/00071 110 'H NMR (DMSO-d 6 ) 80.35 (m, 2H), 0.60 (m, 2H), 0.82 (m, 2H), 1.20 (m, 2H), 1.28 (m, 1H), 2.87 (br s, 1H), 3.25-4.20 (m, 6H), 3.92 (d, J = 7 Hz, 2H), 4.70 (m, 2H), 7.30-7.60 (m, 3H), 8.08 (br s, 1H), 8.32 (br s, 1H), 11.37 (br s, 1H); HPLC-MS: m/z 324 (MH'); Rt= 1.94 min. 5 Example 131 (General procedure (B)) 2-(4-Isopropylpiperazin-1-yl)-6-pyrazol-1-ylquinoline hydrochloride N N H3G N
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine 10 and 2-chloro-6-(1-pyrazolyl)quinoline. The required 2-chloro-6-(1-pyrazolyl)quinoline was prepared by treatment of 6-(1-pyrazolyl)-2-quinolone with POCl 3 . 6-(1-Pyrazolyl)-2-quinolone was prepared in the following way: A mixture of 6-bromo-2-quinolone (3.58 g, 16.0 mmol), DMF (15 ml), pyrazole (1.66 g, 24.4 mmol), potassium carbonate (3.33 g, 24.1 mmol), and copper(l) iodide (0.76 g, 3.99 mmol) 15 was stirred at 160 oC for 22 h. Water (300 ml) was added, and after thorough trituration the mixture was filtered, and the solid was washed with water. The solid was stripped with EtOH, resuspended in a mixture of acetonitrile and ethanol (100 ml, 1:1), heated to reflux, and kept at room temperature overnight. Filtration, washing with a bit of acetonitrile, and drying under reduced pressure yielded 1.7 g (50%) of 6-(1-pyrazolyl)-2-quinolone as a metallic-green 20 solid. 1 H NMR (DMSO-d 6 ) 81.32 (d, J= 7 Hz, 6H), 3.10-3.70 (m, 7H), 4.81 (m, 2H), 6.60 (m, 1H), 7.56 (d, J= 8 Hz, 1 H), 7.81 (s, 1H), 8.09 (m, 1H), 8.22 (d, J = 8 Hz, 1H), 8.32 (s, 1H), 8.38 (d, J= 8 Hz, 1H), 8.58 (m, 1H), 11.11 (brs, 1H); HPLC-MS: m/z322 (MH); Rt= 1.67 min. 25 Example 132 (General procedure (B)) 2-(4-Isopropylpiperazin-l1-yl)quinolin-6-ol hydrochloride WO 03/066604 PCT/DK3/00071 111 CN.OH r N N - N,, This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6-hydroxyquinoline. 1 H NMR (DMSO-d 6 ) 31.31 (d, J= 7 Hz, 6H), 3.15-3.90 (m, 7H), 4.79 (m, 2H), 7.22 (m, 1H), 5 7.33 (d, J= 8 Hz, 1H), 7.53 (d, J= 8 Hz, 1H), 8.13 (brs, 1H), 8.35 (d, J= 8 Hz, 1H), 10.17 (br s, 1 H), 11.41 (br s, 1H); HPLC-MS: m/z 272 (MH+); Rt = 0.40 min. Example 133 (General procedure (B)) 10 2-(4-Cyclopropylpiperazin-1-yl)quinoline-6-carbonitrile hydrochloride 'N N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-cyanoquinoline. 'H NMR (DMSO-d) 80.83 (m, 2H), 1.15 (m, 2H), 2.87 (br s, IH), 3.20-3.65 (m, 6H), 4.74 (m, 15 2H), 7.49 (d, J= 8 Hz, 1H), 7.72 (d, J= 8 Hz, 1H), 7.86 (d, J= 8 Hz, 1H), 8.24 (d, J= 8 Hz, 1H), 8.35 (s, 1H), 10.88 (br s, 1H); HPLC-MS: mlz 279 (MH'); Rt = 1.43 min. Example 134 (General procedure (B)) 20 (9a-R)-2-(Octahydropyrido[1,2-a]pyrazin-2-yl)quinoline-6-carbonitrile hydrochloride cb H j N This compound was prepared using the General Procedure (B) from (9a-R) octahydropyrido[1,2-a]pyrazine and 2-chloro-6-cyanoquinoline.
WO 03/066604 PCT/DKO3/00071 112 'H NMR (DMSO-d 6 ) 81.40-1.60 (m, 1H), 1.65-2.00 (m, 5H), 2.85-3.65 (m, 7H), 4.80 (m, 2H), 7.53 (d, J = 8 Hz, 1H), 7.79 (d, J= 8 Hz, 1H), 7.89 (d, J= 8 Hz, 1H), 8.26 (d, J= 8 Hz, 1 H), 8.37 (s, 1H), 11.31 (br s, 1 H); HPLC-MS: m/z 293 (MH'); Rt = 1.72 min. 5 Example 135 (General procedure (B)) 4-Chloro-6-(4-isopropylpiperazin-1-yl)-3-phenylpyridazine hydrochloride ci N N
H
3 CY N CHz This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine 10 and 4,6-dichloro-3-phenylpyridazine. 'H NMR (DMSO-d 6 ) 81.31 (d, J= 7 Hz, 6H), 3.13 (m, 2H), 3.40-3.65 (m, 5H), 4.63 (m, 2H), 7.50 (m, 3H), 7.63 (m, 2H), 7.78 (s, 1H), 11.01 (brs, 1H); HPLC-MS: m/z317 (MH*); Rt= 2.11 min. 15 Example 136 (General procedure (B)) 3-(4-Cyclopropylpiperazin-1-yl)-6-(3-trifluoromethylphenyl)pyridazine hydrochloride F NN This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 20 and 3-chloro-6-(3-trifluoromethylphenyl)pyridazine. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.22 (m, 2H), 2.89 (br s, 1H), 3.35 (m, 2H), 3.59 (m, 4H), 4.63,(m, 2H), 7.68 (d, J = 8 Hz, 1 H), 7.77 (m, 1H), 7.84 (m, 1 H), 8.32 (d, J = 8 Hz, 1H), 8.40 (m, 2H), 11.40 (br s, 1H); HPLC-MS: m/z 349 (MH); Rt = 2.43 min.
WO 03/066604 PCT/DKO3/00071 113 Example 137 1-[2-(4-Isopropylpiperazin-1-yl)quinolin-6-yl]ethanone hydrochloride 0 N N N 5 This product was prepared by treatment of 2-(4-isopropylpiperazin-1-yl)quinoline-6 carbonitrile with an excess of methylmagnesium bromide in tetrahydrofuran. 1 H NMR (DMSO-d 6 ) 61.31 (d, J= 7 Hz, 6H), 2.65 (s, 3H), 3.18 (m, 2H), 3.40-3.80 (m, 5H), 4.82 (m, 2H), 7.52 (d, J= 8 Hz, 1H), 7.91 (br s, 1H), 8.15 (d, J= 8 Hz, 1H), 8.40 (d, J= 8 Hz, 10 1H), 8.54 (s, 1H), 11.16 (br s, 1H); HPLC-MS: m/z 298 (MH*); Rt= 1.47 min. Example 138 (General procedure (B)) 3-(4-Isopropylpiperazin-1-yl)-6-phenylpyridazine-4-carbonitrile hydrochloride N i- N N NN N 15 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 3-chloro-6-phenylpyridazine-4-carbonitrile. 'H NMR (DMSO-d 6 ) 81.32 (d, J= 7 Hz, 6H), 3.23 (m, 2H), 3.50-3.75 (m, 5H), 4.46 (m, 2H), 7.55 (m, 3H), 8.13 (d, J= 7 Hz, 2H), 8.72 (s, 1H), 10.67 (brs, 1H); HPLC-MS: m/z 308 20 (MH'); Rt = 2.16 min.
WO 03/066604 PCT/DK3/00071 114 Example 139 (General procedure (B)) 6-Bromo-2-(4-isopropylpiperazin-1 -yl)quinoline Nr - Br NzCN
H
3 C N
CH
3 This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine 5 and 6-bromo-2-chloroquinoline. 1 H NMR (DMSO-d 6 ) 81.00 (d, J= 7 Hz, 6H), 2.52 (m, 4H), 2.69 (sept, J= 7 Hz, 1H), 3.68 (m, 4H), 7.28 (d, J= 8 Hz, 1H), 7.48 (d, J= 8 Hz, 1H), 7.60 (dd, J= 1 Hz, 8 Hz, 1H), 7.93 (d, J 1 Hz, 1H), 8.00 (d, J= 8 Hz, 1H). 10 Example 140 (General procedure (B)) 2-(4-Cyclopropylpiperazin-1-yl)-6-pyrazol-1-ylquinoline hydrochloride N, N N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine 15 and 2-chloro-6-pyrazol-1-ylquinoline. 1 H NMR (DMSO-do) 80.83 (m, 2H), 1.22 (m, 2H), 2.88 (m, 1H), 3.30-3.80 (m, 6H), 4.79 (m, 2H), 6.61 (m, 1H), 7.59 (d, J= 6 Hz, 1H), 7.81 (s, 1H), 8.10-8.30 (m, 2H), 8.34 (s, 1H), 8.41 (d, J= 6 Hz, 1H), 8.59 (s, 1H), 11.47 (br s, 1 H); HPLC-MS: m/z 320 (MH+); Rt = 1.64 min. 20 Example 141 (General procedure (B)) 7-Chloro-2-(4-cyclopropylpiperazin-1-yl)quinolin-6-ol hydrochloride WO 03/066604 PCT/DKO3/00071 115 ~ ~OH N N Cl N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2,7-dichloro-6-hydroxyquinoline. The required 2,7-dichloro-6-hydroxyquinoline was pre pared by demethylation with boron tribromide in dichloromethane of 2,7-dichloro-6 5 methoxyquinoline, which was prepared from 3-chloro-4-methoxyaniline as described by F. Effenberger and W. Hartmann in Chemische Berichte 1969, 102, 3260-3267. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.14 (m, 2H), 2.88 (m, 1H), 3.20-3.80 (m, 6H), 4.61 (m, 2H), 7.32 (s, 1IH), 7.42 (m, 1IH), 7.96 (m, 1H), 8.21 (m, 1IH), 10.65 (brs, 1IH), 10.84 (br s, 1H); HPLC-MS: mlz 304 (MH'); Rt = 1.06 min. 10 Example 142 [2-(4-Cyclopropylpiperazin-1-yl)quinolin-6-yl]-(4-fluorophenyl)methanone hydrochloride 0 N r N F v . 15 This product was prepared by treatment of 2-(4-cyclopropylpiperazin-1-yl)quinoline-6 carbonitrile with an excess of (4-fluorophenyl)magnesium bromide in tetrahydrofuran. 1 H NMR (DMSO-d 6 ) 50.84 (m, 2H), 1.14 (m, 2H), 2.89 (m, 1IH), 3.25-3.90 (m, 6H), 4.77 (m, 2H), 7.44 (m, 3H), 7.76 (m, IH), 7.86 (m, 2H), 7.98 (m, 1H), 8.21 (s, 1H), 8.34 (d, J= 8 Hz, 1H), 10.65 (brs, 1H); HPLC-MS: m/z376 (MH*); Rt = 2.61 min. 20 Example 143 (General procedure (B)) Cyclopropyl-[2-(4-cyclopropylpiperazin-1-yl)quinolin-6-yl]methanone hydrochloride WO 03/066604 PCT/DK03/00071 116 0 ( N This product was prepared by treatment of 2-(4-cyclopropylpiperazin-1-yl)quinoline-6 carbonitrile with an excess of cyclopropylmagnesium bromide in tetrahydrofuran. 1 H NMR (DMSO-d 6 ) 80.83 (m, 2H), 1.07 (m, 4H), 1.18 (m, 2H), 2.88 (m, 1H), 3.00 (quint, J = 5 7Hz, 1H), 3.30-3.70 (m, 6H), 4.76 (m, 2H), 7.50 (d, J 8Hz, 1H), 7.82 (brs, 1H), 8.18 (d, J = 8 Hz, 1H), 8.37 (d, J = 8 Hz, 1H), 8.66 (s, 1H), 11.05 (br s, 1H); HPLC-MS: m/z322 (MH+); Rt = 1.98 min. Example 144 (General procedure (B)) 10 2-(4-Cyclopropylpiperazin-1-yl)-6-(4-fluorobenzyloxy)quinoline hydrochloride O F N N N This compound was prepared using the General Procedure (B) from 1-cyclopropylpiperazine and 2-chloro-6-(4-fluorobenzyloxy)quinoline. 15 1 H NMR (DMSO-d 6 ) 50.83 (m, 2H), 1.20 (m, 2H), 2.87 (m, 1H), 3.30-3.80 (m, 6H), 4.70 (m, 2H), 5.18 (s, 2H), 7.25 (t, J= 8 Hz, 2H), 7.54 (m, 5H), 8.08 (brs, 1H), 8.33 (m, 1H), 11.34 (br s, 1H); HPLC-MS: m/z 378 (MH+); Rt = 2.53 min. Example 145 20 6-Cyclohex-1l-enyl-2-(4-isopropylpiperazin-1-yl)quinoline hydrochloride WO 03/066604 PCT/DKO3/00071 117 N N N This product was prepared by treatment of 6-bromo-2-(4-isopropylpiperazin-1-yl)quinoline with butyllithium and then with cyclohexanone. Upon acidic workup the tertiary alcohol un derwent elimination to yield the title compound. 5 1 H NMR (DMSO-d) 51.31 (d, J = 7 Hz, 6H), 1.60-1.80 (m, 4H), 2.22 (m, 2H), 2.45 (m, 2H), 3.23 (m, 2H), 3.45-4.00 (m, 5H), 4.78 (m, 2H), 6.34 (m, 1H), 7.50 (m, 1H), 7.86 (m, 2H), 7.98 (br s, I H), 8.34 (m, 1H), 11.06 (br s, 1H); HPLC-MS: mlz 336 (MH); Rt = 2.50 min. 10 Example 146 (General procedure (C)) 1-(Biphenyl-3-yl)-4-(cyclopentyl)piperazine N \-/N 15 A mixture of 3-bromobiphenyl (300 mg, 1.28 mmol), 1-cyclopentylpiperazine (238 mg, 1.54 mmol), sodium tert.-butoxide (173 mg, 1.8 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.01 mmol) and racemic 2,2'-bis(diphenylphosphino)-1,1'binaphthyl (24 mg, 0.04 mmol) in toluene (11 ml) was mixted under nitrogen in a closed reaction vessel. The reaction mixture was stirred at 80 0 C for 3 days in a closed reaction vessel. It was cooled to room 20 temperature and washed with water (2 x 10 ml). The combined organic layers were extracted with 1 N hydrochloric acid (2 x 20 ml). The combined aqueous extracts were made basic with an 1 N aqueous sodium hydroxide solution and extracted with tert-butyl methyl ether (3 x 20 ml). The tert-butyl methyl ether layers were dried over magnesium sulphate. The solvent was removed in vacuo to give 220 mg of the title compound.
WO 03/066604 PCT/DKO3/00071 118 1 H-NMR (CDCl3, two sets of signals, broad signals) 5 1.35-1.85 (m, 6 H); 1.95 (m, 2 H); 2.55 (m, 1 H); 2.70 (m, 4 H); 3.30 (m, 4 H); 6.95 (d, 1 H); 7.05 (d, 1 H); 7.15 (s, 1 H); 7.35 (t, 2 H); 7.45 (t, 2 H); 7.60 (d, 2 H). HPLC method B: elution at 10.45 min. The title compound was transferred into its hydrochloride salt, by dissolving it in ethyl acetate 5 (5 ml). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml) was added. The solvent was removed in vacuo. The residue was dissolved in ethanol (50 ml). The solvent was removed in vacuo. Example 147 (General procedure (C)) 10 1-Cyclopentyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]piperazine [>N/-\ N-a N 15 86 mg of the title compound were synthesized as described for 1-(biphenyl-3-yl)-4 (cyclopentyl)piperazine, using 1-(2-(4-bromophenoxy)ethyl)pyrrolidine instead of 3 bromobiphenyl. 1 H-NMR (DMSO-d 6 ) 8 1.55 (m, 2 H); 1.75 (m, 2 H); 1.85 (m, 4 H); 2.00 (m, 4 H); 3.10 (m, 6 H); 3.40-3.70 (m, 9 H); 4.30 (t, 2 H); 7.00 (AB, 4 H); 10.80 (br, 1 H); 11.10 (br, 1 H). HPLC 20 method C: elution at 2.24 min. MS: calc. for [M+H] : 344; found: 344. The title compound was transferred into its hydrochloride salt, by dissolving it in ethyl acetate (5 ml). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml) was added. The solvent was removed in vacuo. The residue was dissolved in ethanol (50 ml). The solvent was removed in vacuo. 25 Example 148 (General procedure (C)) 1-(Biphenyl-4-yl)-4-(cyclopentyl)piperazine WO 03/066604 PCT/DKO3/00071 119 N N 180 mg of the title compound were synthesized as described for 1-(biphenyl-3-yl)-4 (cyclopentyl)piperazine, using 4-bromobiphenyl instead of 3-bromobiphenyl. 5 'H-NMR (CDCl 3 ) 6 1.80-2.00 (m, 8 H); 2.55 (m, 1 H); 2.70 (m, 4 H); 3.20 (m, 4 H); 7.00 (d, 2 H); 7.30 (m, 1 H); 7.40 (t, 2 H); and 7.55 (m, together 4 H). HPLC method C: elution at 4.52 mm. The title compound was transferred into its hydrochloride salt, by dissolving it in ethyl acetate 10 (5 ml). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml) was added. The solvent was removed in vacuo. The residue was dissolved in ethanol (50 ml). The solvent was removed in vacuo. Example 149 (General procedure (C)) 15 [3-(4-(Cyclopentyl)piperazin-1 -yl)phenyl]-(4-fluorophenyl)methanone oF I ; IF N N 0 20 300 mg of the title compound were synthesized as described for 1-(biphenyl-3-yl)-4 (cyclopentyl)piperazine, using 3-bromo-4'-fluorobenzophenone instead of 3-bromobiphenyl. 1 H-NMR (CDCI 3 ) 5 1.45 (m, 2 H); 1.60 (m, 2 H); 1.75 (m, 2 H); 1.90 (m, 2 H); 2.55 (quintet, 1 H); 2.70 (m, 4 H); 3.30 (m, 4 H); 7.15 (m, 4 H); 7.35 (m, 2 H); 7.85 (m, 2 H). HPLC method C: 25 elution at 4.22 min. MS: calc. for [M+H]*: 353; found: 353. The title compound was transferred into its hydrochloride salt, by dissolving it in ethyl acetate (5 ml). A 3.2 M solution of hydrogen chloride in ethyl acetate (5 ml) was added. The solvent WO 03/066604 PCT/DK03/00071 120 was removed in vacuo. The residue was dissolved in ethanol (50 ml). The solvent was re moved in vacuo.
WO 03/066604 PCT/DKO3/00071 121 The following compounds are also within the scope of the present invention: 0 0
NCH
3 NCF3
H
3 C N H 3 C N H:T
H
3 C HC
SCF
3
CF
3 ,N N NI H, J rN NN H c HC N
H
3 CH
H
3 H 0 N F N CH H, NN N H N N FN
H
3 C NH
H
3 C 0 0 H 3 N N .- CH 3 rNa FN0 1, NJN
H
3 C OH 3 0 OH 3 ~ N N 0 ,X N "N IH H, OH 3 NJ H30 OH3 WO 03/066604 PCT/DKO3/00071 122
CH
3 0 CH 3 O F O 0 . N N OCH 3 N OC N N F
H
3 C OH 3
H
3 G CH 3 H0C CH3 N OCH 3 0OH - H 0 N N N. N HsC CH 3 N, N 0
H
3 0 OH 3 PHARMACOLOGICAL METHODS The ability of the compounds to interact with the histamine H3 receptor can be determined by 5 the following in vitro binding assays. Binding assay I Rat cerebral cortex is homogenized in ice cold K-Hepes, 5 mM MgCI 2 pH 7.1 buffer. After two differential centrifugations the last pellet is resuspended in fresh Hepes buffer containing 1 mg/mi bacitracin. Aliquots of the membrane suspension (400 pg/ml) are incubated for 60 min 10 at 250C with 30 pM [ 1 25 1]-iodoproxifan, a known histamine H3 receptor antagonist, and the test compound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GFIB filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding 15 affinity of the tested compound. The results are analyzed by nonlinear regression analysis.
WO 03/066604 PCT/DKO3/00071 123 Binding assay II The H3-receptor agonist ligand R-a-methyl[ 3 H]histamine (RAMHA) is incubated with isolated rat cortex cell-membranes at 25 OC for 1 hour, followed by a filtration of the incubate through Whatman GF/B filters. Radioactivity retained on the filters is measured using a beta counter. 5 Male Wistar rats (150-200 g) are decapitated and cerebral cortex is quickly dissected out and frozen immediately on dry ice. Tissue is kept at -80 oC until membrane preparation. During the membrane preparation the tissue is kept on ice all the time. Rat cerebral cortex is ho mogenized in 10 volumes (wlw) ice-cold Hepes buffer (20 mM Hepes, 5 mM MgCI 2 pH 7.1 (KOH) + 1 mg/ml bacitracin) using an Ultra-Turrax homogenizer for 30 seconds. The ho 10 mogenate is centrifuged at 140 g in 10 min. The supernatant is transferred to a new test tube and centrifuged for 30 min at 23 000 g. Pellet is resuspended in 5-10 ml Hepes buffer, ho mogenized and centrifuged for 10 min at 23 000 g. This short centrifugation step is repeated twice. After the last centrifugation the pellet is resuspended in 2-4 ml Hepes buffer and the protein concentration is determined. The membranes are diluted to a protein concentration of 15 5 mg/ml using Hepes buffer, aliquoted and stored at-80 oC until use. 50 pl test-compound, 100 pLI membrane (200 pg/ml), 300 ll Hepes buffer and 50 [I R-ca methyl[ 3 H]histamine (1 nM) are mixed in a test tube. The compounds to be tested are dis solved in DMSO and further diluted in H 2 0 to the desired concentrations. Radioligand and membranes are diluted in Hepes buffer + 1 mg/mi bacitracin. The mixture is incubated for 60 20 min at 25 'C. Incubation is terminated by adding 5 ml ice-cold 0.9% NaCI, followed by rapid filtration through Whatman GF/B filters pre-treated for hour with 0.5% polyethyleneimine. The filters are washed with 2 x 5 ml ice-cold NaCI. To each filter a 3 ml scintillation cocktail is added and the radioactivity retained is measured with a Packard Tri-Carb beta counter. IC50 values are calculated by non-linear regression analysis of binding curves (6 points mini 25 mum) using the windows program GraphPad Prism, GraphPad software, USA. Binding assay Ill The human H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vec tor. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 30 clones are cultured in DMEM (GIBCO-BRL) with glutamax, 10% foetal calf serum, 1% peni cillin/streptavidin and 1 mg/ml G 418 at 37 oC and 5% CO2. Before harvesting, the confluent cells are rinsed with PBS and incubated with Versene (proteinase, GIBCO-BRL) for approxi mately 5 min. The cells are flushed with PBS and DMEM and the cell suspension collected in a tube and centrifuged for 5-10 min at 1500 rpm in a Heraeus Sepatech Megafuge 1.0. The WO 03/066604 PCT/DKO3/00071 124 pellet is resuspended in 10-20 vol. Hepes buffer (20 mM Hepes, 5 mM MgCl 2 , pH 7.1 (KOH)) and homogenized for 10-20 seconds using an Ultra-Turrax homogenizer. The homogenate is centrifuged for 30 min at 23 000 g. The pellet is resuspended in 5-10 ml Hepes buffer, ho mogenized 5-10 seconds with the Ultra-Turrax and centrifuged for 10 min at 23 000 g. Fol 5 lowing this centrifugation step, the membrane pellet is resuspended in 2-4 ml Hepes buffer, homogenized with a syringe or Teflon homogenizer, and the protein concentration deter mined. The membranes are diluted to a protein concentration of 1-5 mg/ml in Hepes buffer, aliquoted and kept at -80 oC until use. Aliquots of the membrane suspension are incubated for 60 min at 25 °C with 30 pM [1251]_ 10 iodoproxifan, a known compound with high affinity for the H3 receptor, and the test com pound at various concentrations. The incubation is stopped by dilution with ice-cold medium, followed by rapid filtration through Whatman GF/B filters pretreated for 1 hour with 0.5% polyethyleneimine. The radioactivity retained on the filters is counted using a Cobra II auto gamma counter. The radioactivity of the filters is indirectly proportional to the binding affinity 15 of the tested compound. The results are analysed by nonlinear regression analysis. When tested, the present compounds of the formula (I) generally show a high binding affinity to the histamine H3 receptor. Preferably, the compounds according to the invention have an IC50 value as determined by one or more of the assays of less than 10 pM, more preferred of less than 1 l.M, and even 20 more preferred of less than 500 nM, such as of less than 100 nM. Functional assay I The ability of the compounds to interact with the histamine H3 receptor as agonists, inverse agonists and/or antagonists, is determined by an in vitro functional assay utilizing mem branes from HEK 293 cell expressing the human H3 receptors. 25 The H3 receptor is cloned by PCR and subcloned into the pcDNA3 expression vector. Cells stably expressing the H3 receptor are generated by transfecting the H3-expression vectors into HEK 293 cells and using G418 to select for H3 clones. The human H3-HEK 293 clones are cultured in DMEM with glutamax, 10% foetal calf serum, 1% penicillin/streptavidin and 1 mg/ml G 418 at 370C and 5% CO 2 . 30 The H3 receptor expressing cells are washed once with phosphate buffered saline (PBS) and harvested using versene (GIBCO-BRL). PBS is added and the cells are centrifuged for 5 min at 188 g. The cell pellet is resuspended in stimulation buffer to a concentration of 1 x 106 cells/ml. cAMP accumulation is measured using the Flash Plate® cAMP assay (NENTM Life Science Products). The assay is generally performed as described by the manufacturer.
WO 03/066604 PCT/DKO3/00071 125 Briefly, 50 p1 cell suspension is added to each well of the Flashplate which also contained 25 p.l 40 p.M isoprenaline, to stimulate cAMP generation, and 25 pl of test compound (either agonists or inverse agonists alone, or agonist and antagonist in combination). The assay can be run in "agonist-mode" which means that the test compound is added, in increasing con 5 centration, on its own, to the cells, and cAMP is measured. If cAMP goes up, it is an inverse agonist; if cAMP does not change, it is a neutral antagonist, and if cAMP goes down, it is an agonist. The assay can also be run in the "antagonist-mode" which means that a test com pound is added, in increasing concentrations, together with increasing concentrations of a known H3 agonist (eg RAMHA). If the compound is an antagonist, increasing concentrations 10 of it cause a right-ward shift in the H3-agonist's dose-response curves. The final volume in each well is 100 p 1 . Test compounds are dissolved in DMSO and diluted in H 2 0. The mixture is shaken for 5 min, and allowed to stand for 25 min at room temperature. The reaction is stopped with 100 p.l "Detection Mix" per well. The plates are then sealed with plastic, shaken for 30 min, allowed to stand overnight, and finally the radioactivity is counted in the Cobra II 15 auto gamma topcounter. ECo 50 values are calculated by non-linear regression analysis of dose response curves (6 points minimum) using GraphPad Prism. Kb values are calculated by Schild plot analysis. Functional assay II The ability of the compounds to bind and interact with the human H3 receptor as agonists, 20 inverse agonists and/or antagonists, is determined by a functional assay, named [35S] GTPyS assay. The assay measures the activation of G proteins by catalyzing the exchange of guanosine 5'-diphosphate (GDP) by guanosine 5'-triphosphate (GTP) at the a-subunit. The GTP-bounded G proteins dissociate into two subunits, GaGTP and GP 7 , which in turn regulate intracellular enzymes and ion channels. GTP is rapidly hydrolysed by the Ga-sub 25 unit (GTPases) and the G protein is deactivated and ready for a new GTP exchange cycle. To study the function of ligand induced G protein coupled receptor (GPCR) activation by an increase in guanine nucleotide exchange at the G proteins, the binding of [ 35 S]-guanosine-5' O-(3-thio) triphosphate [ 35 S] GTPyS, a non-hydrolysed analogue of GTP, is determined. This process can be monitored in vitro by incubating cell membranes containing the G protein 30 coupled receptor H3 with GDP and [ 35 S] GTPyS. Cell membranes are obtained from CHO cells stably expressing the human H3 receptor. The cells are washed twice in PBS, har vested with PBS+1 mM EDTA, pH 7.4 and centrifuged at 1000 rpm for 5 min. The cell pellet is homogenized in 10 ml ice-cold Hepes buffer (20 mM Hepes, 10 mM EDTA pH 7.4 (NaOH)) WO 03/066604 PCT/DKO3/00071 126 using an Ultra-Turrax homogenizer for 30 seconds and centrifuged for 15 min at 20.000 rpm. Following this centrifugation step, the membrane pellet is resuspended in 10 ml ice-cold Hepes buffer (20 mM Hepes, 0.1 mM EDTA pH 7.4 (NaOH)) and homogenized as describe above. This procedure is repeated twice except for the last homogenization step, the protein 5 concentration is determined and membranes are diluted to a protein concentration at 2 mg/ml, aliquoted and kept at -80 °C until use. In order to study the presence and the potency of an inverse agonist/antagonist the H3 receptor agonist ligand R-a-methyl histamine (RAMHA) is added. The ability of the test com pound to counteract the effect of RAMHA is measured. When studying the effect of an ago 10 nist RAMHA is not added to the assay medium. The test compound is diluted in the assay buffer (20 mM HEPES, 120 mM NaCI, 10 mM MgCl 2 pH 7.4 (NaOH)) at various concentra tions followed by addition of 10 - nM RAMHA (only in the case where an inverse ago nist/antagonist is examined), 3 pM GDP, 2.5 pg membranes, 0.5 mg SPA beads and 0.1 nM [35 S] GTPyS and incubated for 2 hours by slightly shaking at room temperature. The plates 15 are centrifuged at 1500 rpm for 10 min and the radioactivity is measured using a Top counter. The results are analyzed by non linear regression and the IC 5 0 value is determined. RAMHA and other H3 agonists stimulate the binding of [ 35 S] GTP 7 S to membranes express ing the H3 receptor. In the antagonist/inverse agonist test, the ability of increasing amounts of test compound to inhibit the increased [35S] GTPyS binding by 10 - 8 M RAMHA is measured 20 as a decrease in radioactivity signal. The IC 50 value determined for an antagonist is the ability of this compound to inhibit the effect of 1 0 8 -M RAMHA by 50%. In the agonist test, the ability of increasing amounts of test compound is measured as an increase in radioactivity signal. The EC 50 value determined for an agonist, is the ability of this compound to increase the sig nal by 50% of the maximal signal that is obtained by 10 " 5 M RAMHA. 25 Preferably, the antagonists and agonists according to the invention have an IC 50
/EC
50 value as determined by one or more of the assays of less than 10 pM, more preferred of less than 1 pM, and even more preferred of less than 500 nM, such as of less than 100 nM. The open cage Schedule-fed rat model The ability of the present compounds to reduce weight is determined using the in vivo open 30 cage Schedule-fed rat model. Sprague-Dawley (SD) male rats of an age of about 1 to 2 months and a weight of about 200-250 g are purchased from Mollegrd Breeding and Research Centre A/S (Denmark). On arrival they are allowed some days of acclimatisation before being placed in individual open plastic cages. They are habituated to the presence of food (Altromin pelleted rat chow) in WO 03/066604 PCT/DKO3/00071 127 their home cage only during 7 hours in the morning from 07.30 tol4.30 all days a week. Wa ter is present ad libitum. As the consumption of food has stabilised after 7 to 9 days, the ani mals are ready for use. Each animal is used only once to avoid carry-over effects between treatments. During the 5 test sessions, the test compound is administered intraperitoneally or orally 30 min before the start of the sessions. One group of animals is administered the test compound at different doses and a control group of animals is given a vehicle. Food and water intake are monitored at 1, 2 and 3 hours post administration. Any side effects may rapidly be discovered (barrel-rolling, bushy fur etc.) since the ani 10 mals are kept in transparent plastic cages to enable continuous monitoring.
Claims (55)
1. A compound of the general formula (ll): R 3 R~N R N'A R, - N i A wherein 5 R 2 is hydrogen or Cl-4-alkyl, (i) R 1 represents * branched C 4 -6-alkyl, branched C 4 .e-alkenyl or branched C4- 6 -alkynyl with the proviso that R 1 is not isobutyl, 10 * C 3 -5-cycoalkyl, C 3 . 7 -cycloalkenyl, C3. 6 -cycloalkyl-Cl 3 -alkyl or C3- 6 cycloalkenyl-C. 3 -alkyl, * R' and R 2 together form a Cs_ 6 -alkylene bridge, and 15 A represents R 4 5 7 WR 5 I I or . X f R 11 X:FR6 O X 9R or (ii) R 1 represents 20 * ethyl, n-propyl or isopropyl, * R 1 and R 2 together form a C 3 4 .- alkylene bridge, and A represents WO 03/066604 PCT/DKO3/00071 129 Rl R 4 R i o R 1 2 Z R 0 or Al N 13 O R R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 _ 1 o-alkyl, C 2 . 10 -alkenyl, C 3 - 8 -cycloalkyl, C 1 - 6 -alkoxy, aryl, aryl-C l . 6 -alkyl, amino, Cl. 6 -alkylamino, di-Cl.e-alkylamino, 5 C 3 . 8 -cycloalkyl, C 3 . 8 -cycloalkyloxy, cyano, nitro, Cl. 6 -alkylsulfanyl, or C 1 - 6 -alkylsulfonyl, Z and X independently represent -N=, -C(H)=, -C(F)=, -C(C)=, -C(CN)= or -C(CF 3 )=, W represents -N= or-C(R") = , 10 Y represents -N= or-C(R ) = , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 R 1 0 , R 11 , R 12 and R 13 independently represent 15 e hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, cyano, nitro, or -C(=O)NR 14 R 5 * C 1 - 10 -alkyl, C 2 - 10 -alkenyl, C 3 - 8 -cycloalkyl, C 1 . 6 -alkoxy, C 3 - 8 -cycloalkyl-C 1 . 6 -alkoxy, Cl. 6 -alkylamino, di-Cl.6-alkylamino, C 3 . 8 -cycloalkyloxy, C 1 6 -alkylsulfanyl, C 1 -6 20 alkylsulfonyl, C 2 -10-alkanoyl, C 4 - 9 -cycloalkanoyl, C 3 .8-heterocyclyl or C 4 .9 heterocycloalkanoyl, C 4 - 9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R' 1 * aryl, aryl-C 1 - 6 -alkyl, aryl-C 1 . 6 -alkoxy or heteroaryl, which may optionally be substi 25 tuted with one or more substituents selected from R, * aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from R 1 8 , 30 *or two of R 5 , RR, , R', R, Ri 0 , R 1 ", R 1 2 and R 13 in adjacent positions together form a Cl.6-alkylene bridge or an -O-C 1 _. 6 -alkylene-O- bridge, WO 03/066604 PCT/DKO3/00071 130 R 14 and R' 5 are independently hydrogen, Cl6-alkyl, aryl-C 1 . 6 -alkyl or R 1 4 and R" may to gether form a C 3 -6-alkylene bridge 5 R 16 is independently selected from aryl, heteroaryl, C3. 8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, NR 1 9 R 20 and Cs_6-alkoxy, R 1 7 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 . 6 alkoxy, Cl 6 -alkyl, amino, C 1 . 6 -alkylsulfonyl, C 1 - 6 -alkylamino, di-Cl. 6 -alkylamino, cyano, aryl, 10 heteroaryl and C 3
8-cycloalkyl, R 1 8 is independently selected from aryl, heteroaryl, C 1 -1 0 -alkyl, C3. 8 -cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, Cl 6 -alkoxy, cyano, amino, C 1 .6-alkylamino, di CI- 6 -alkylamino and hydroxy, 15 R' 9 and R 2 0 are independently hydrogen or Cl6-alkyl, R 19 and R 20 may together form a C 3 .e6-alkylene bridge with the proviso that the compound must not be 20 N N H3C N H 3 C N H3c H 3 C 0 O'CH 3 N Cl N H 3 C N H3O N H 3 C H 3 C WO 03/066604 PCT/DKO3/00071 131 OH H 3 C N N H 3 C NNN N NHpNH N N N N NN S NH 2 n rN N NN Cl N N NF Nr rNA-NC WO 03/066604 PCT/DKO3/00071 132 C N C NN 2 N N NH N HC HN C N H2 N Hc H..zC N O CHC NN N N N N H3 C N HCH N H 3 C NJ H 3 C TNJ H 3 C H 3 c NH N H 3 C NJ H 3 Crj N CN CH3 CH 3 H 3 WO 03/066604 PCT/DKO3/00071 133 CH 3 CH 3 N CH 3 H 3 C N H 3 C CH 3 as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof. 5 2. A compound according to claim 1, wherein R 1 is branched C 4 - 6 -alkyl, C 3 s- 5 -cycloalkyl or C3 6 -cycloalkyl-C 1 l 3 -alkyl with the proviso that R 1 is not isobutyl. 3. A compound according to claim 2, wherein R' is 1,1-(dimethyl)propyl, 1-ethylpropyl, cyclo propylmethyl, cyclopropyl, cyclobutyl, cyclopentyl or 1-cyclopropyl-1-methylethyl. 10 4. A compound according to claim 3, wherein R 1 is 1-ethylpropyl, cyclopropylmethyl, cyclo propyl or cyclopentyl. 5. A compound according to claim 1, wherein R 1 is branched C 4 - 6 -alkyl or C 3 '-cycloalkyl with 15 the proviso that R 1 is not isobutyl. 6. A compound according to claim 5, wherein R' is 1-ethylpropyl, cyclopropylor cyclopentyl. 7. A compound according to any one of the claims 1 to 6, wherein Z is -C(H)=, -N=, or 20 -C(F)=. 8. A compound according to claim 7 wherein Z is -C(H)= or -N=.
9. A compound according to claim 8 wherein Z is -C(H)=. 25
10. A compound according to claim 8 wherein Z is -N=. WO 03/066604 PCT/DKO3/00071 134
11. A compound according to any one of the claims I to 10 wherein X is -C(H)=, -N=, or -C(F)=.
12. A compound according to claim 11 wherein Z is -C(H)= or -N=. 5
13. A compound according to claim 12 wherein Z is -C(H)=.
14. A compound according to claim 12 wherein Z is -N=. 10 15. A compound according to any one of the claims 1 to 14 wherein W is -N=.
16. A compound according to any one of the claims 1 to 14 wherein W is -C(Rlo)=.
17. A compound according to any one of the claims 1 to 16 wherein Y is -N=. 15
18. A compound according to any one of the claims 1 to 16 wherein Y is -C(R ) = .
19. A compound according to any one of the claims 1 to 18 wherein R 2 is hydrogen. 20 20. A compound according to any one of the claims 1 to 18 wherein R 2 is C 1 4-alkyl.
21. A compound according to claim 20 wherein R 2 is methyl or ethyl.
22. A compound according to claim 1 of the general formula (111) H N Nv (11I) R 3 25 R wherein A and R 3 are as defined in claim 1.
23. A compound according to any one of the claims 1 to 22 wherein R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 1 -alkyl, Cs_ 6 -alkoxy, aryl, aryl-Cl. 6 -alkyl, amino, 30 C 3 . 8 -cycloalkyl, C 3 . 8 -cycloalkyloxy, cyano or nitro. WO 03/066604 PCT/DKO3/00071 135
24. A compound according to claim 23 wherein R 3 is hydrogen, halogen, hydroxy, trifluoro methyl, C1- 1 0 -alkyl, C 1 .6-alkoxy, cyano or nitro.
25. A compound according to claim 24 wherein R 3 is hydrogen, halogen, hydroxy, trifluoro 5 methyl, C 1 .6-alkyl, or cyano.
26. A compound according to claim 25 wherein R 3 is hydrogen, halogen, or C 1 . 6 -alkyl.
27. A compound according to claim 25 wherein R 3 is hydrogen or methyl. 10
28. A compound according to any one of the claims 1 to 27 wherein R 4 , R 5 , R, R, R 8 , and R 9 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, or 15 cyano, * C 1 - 10 -alkyl, C 3 .8-cycloalkyl, C_ 6 -alkoxy, C 3 - 8 -cycloalkyloxy, C 2 .- 1 0 -alkanoyl, C 4 -9 cycloalkanoyl, C 3 8 -heterocyclyl or C 4 - 9 -heterocycloalkanoyl, which may optionally be substituted with one or more substituents selected from R 16 20 earyl, aryl-C l . 6 -alkyl, aryl-C 1 . 6 -alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R 17 , * aroyl, heteroaroyl, aryloxy, heteroaryloxy, which may optionally be substituted with 25 one or more substituents selected from R 18 , or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a Cl. 6 -alkylene bridge or an O-C 1 - 6 -alkyl-O- bridge. 30 29. A compound according to claim 28 wherein R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , or cyano, WO 03/066604 PCT/DKO3/00071 136 * C 1 -lo-alkyl, C 1 - 6 -alkoxy, C 3 .8-cycloalkyloxy, which may optionally be substituted with one or more substituents selected from R 16 * Aryl or aryl-C i .6-alkyl, which may optionally be substituted with one or more sub 5 stituents selected from R", * Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R 18 , 10 or two of R 5 , R", R, R, R 9 in adjacent positions together form a C. 6 -alkylene bridge or an O-C_ 6 -alkyl-O- bridge.
30. A compound according to claim 28 wherein R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently represent 15 * hydrogen, halogen, or cyano, * CI-o 10 -alkyl or Cl. 6 -alkoxy which may optionally be substituted with one or more sub stituents selected from R' 6 20 *Aryl optionally substituted with one or more substituents selected from R 7 , *Aroyl or aryloxy, which may optionally be substituted with one or more substituents selected from R"', 25 or two of R 5 , R 6 , R 7 , R 8 , R 9 in adjacent positions together form a C. 6 -alkylene bridge or an O-C4_ 6 -alkyl-O- bridge.
31. A compound according to claim 30 wherein C 1 _ 1 0 -alkyl represents methyl, ethyl, propyl, or isopropyl. 30
32. A compound according to claim 30 wherein C 1 - 6 -alkoxy represents methoxy, ethoxy or propoxy.
33. A compound according to claim 32 wherein Cl. 6 -alkoxy represents methoxy. 35 WO 03/066604 PCT/DKO3/00071 137
34. A compound according to claim 30 wherein aryl represents phenyl.
35. A compound according to claim 30 wherein aroyl represents -C(=O)-phenyl. 5 36. A compound according to claim 30 wherein aryloxy represents -O-phenyl.
37. A compound according to claim 1, wherein R 1 is ethyl or isopropyl.
38. A compound according to claim 37 wherein R 1 is isopropyl. 10
39. A compound according to claim 37 wherein R 1 is ethyl
40. A compound according to claim 39 wherein R' and R 2 together form a C 3 _ 4 -alkylene bridge. 15
41. A compound according to any one of the claims 37 to 40 wherein R 1 0 , R 1 ", R 12 and R 13 independently represent * hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or 20 -C(=O)NR 14 R 15 * C 1 -o 1 0 -alkyl, C 3 .8-cycloalkyl, C 1 .6-alkoxy, C 2 - 10 -alkanoyl, C 4 - 9 -cycloalkanoyl, C 3 -8 heterocyclyl or C 4 . 9 -heterocycloalkanoyl, C 4 - 9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R 16 25 *aryl, aryl-C I . 6 -alkyl, aryl-Cl_ 6 -alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R 17 , * aroyl optionally substituted with one or more substituents selected from R", 30 or two of R 10 , R", R 12 and R" 3 in adjacent positions together form a C 1 .e-alkylene bridge.
42. A compound according to claim 41 wherein R 1 0 , R" 1 , R 12 and R 13 independently represent WO 03/066604 PCT/DKO3/00071 138 *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or -C(=O)NR 1 4 R 1 ' 5 * C 1 - 10 -alkyl, C 3 . 8 -cycloalkyl, C 16 -alkoxy, C 2 - 1 0 -alkanoyl, C 4 .- 9 -cycloalkanoyl, C3-8 5 heterocyclyl or C 4 9 -heterocycloalkanoyl, C 4 - 9 -heterocycloalkoxy, which may optionally be substituted with one or more substituents selected from R 16 * aryl, aryl-CI. 6 -alkyl, aryl-C 1 6 -alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R", 10 * aroyl optionally substituted with one or more substituents selected from R"', or two of R 10 , R 1 ", R 12 and R 13 in adjacent positions together form a C 1 .6-alkylene bridge. 15 43. A compound according to claim 42 wherein R 1 o, R" 1 , R 12 and R 13 independently represent *hydrogen, halogen, trifluoromethyl, or -C(=O)NR 14 R 15 * C 1 - 10 -alkyl, Co_6-alkoxy, C 2 - 1 0 -alkanoyl, C4- 9 -cycloalkanoyl, C 4 - 9 -heterocycloalkanoyl or 20 C 4 - 9 -heterocycloalkoxy, which may optionally be substituted with one or more sub stituents selected from R 16 * aryl, aryl-C l 6 -alkyl, or aryl-C,. 6 -alkoxy, which may optionally be substituted with one or more substituents selected from R 7 , 25 * aroyl optionally substituted with one or more substituents selected from R"', or two of R 1 o, R" 1 , R 12 and R 13 in adjacent positions together form a Cl. 6 -alkylene bridge. 30 44. A compound according to claim 43 wherein R 10 , R 11 , R 12 and R 1 3 independently represent * hydrogen, halogen, trifluoromethyl, or -C(=O)NR 4 R 5 * C1-1 0 -alkyl or C4 9 -heterocycloalkanoyl, which may optionally be substituted with one 35 or more substituents selected from R m 16 WO 03/066604 PCT/DKO3/00071 139 * aryl optionally substituted with one or more substituents selected from R 1 7 , *aroyl optionally substituted with one or more substituents selected from Re, 5 or two of R 1 o, R 11 , R 1 2 and R 13 in adjacent positions together form a Cl_6-alkylene bridge.
45. A compound according to claim 44 wherein C- 1 0 -alkyl represents methyl, ethyl, or propyl. 10 46. A compound according to claim 44 wherein C 4 . 9 -heterocycloalkanoyl represents piperidin alkanoyl or pyrrolidin-alkanoyl.
47. A compound according to claim 44 wherein aryl represents phenyl 15 48. A compound according to any one of the claims 1 to 47 wherein R 14 and R 1 s are inde pendently methyl, ethyl or benzyl.
49. A compound according to any one of the claims 1 to 48 wherein R 16 is halogen, trifluoro methyl, trifluoromethoxy and C 1 .e-alkoxy. 20 50. A compound according to any one of the claims 1 to 49 wherein R 17 is halogen, hydroxy, trifluoromethyl, C.6-alkoxy, CI-6-alkyl, C 1 - 6 -alkylsulfonyl, or cyano.
51. A compound according to claim 50 wherein R 1 7 is halogen, trifluoromethyl, C 1 . 6 -alkoxy or Cl 6 -alkylsulfonyl. 25
52. A compound according to any one of the claims 1 to 51 wherein R 18 is ClI-alkyl, halo gen, trifluoromethyl, Cs_6-alkoxy, cyano, amino and hydroxy.
53. A compound according to claim 52 wherein R 1 8 is halogen, Cl. 6 -alkoxy and hydroxy. 30
54. Use of a compound according to any one of the preceding claims 1 to 53 as a pharma ceutical composition. WO 03/066604 PCT/DKO3/00071 140
55. A pharmaceutical composition comprising, as an active ingredient, at least one com pound according to any one of the claims 1 to 53 together with one or more pharmaceuti cally acceptable carriers or excipients. 5 56. A pharmaceutical composition according to claim 55 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and espe cially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 53. 10 57. Use of a compound of the general formula (11'): R 3 RN R2 N 'A wherein R 2 is hydrogen or C 1 -4-alkyl, R 1 represents 15 * Cl. 8 -alkyl, C 2 -8-alkenyl or C 2 . 8 -alkynyl, which may optionally be substituted with one or more halogen substituents, * C 3 - 5 -cycloalkyl, C3. 7 -cycloalkenyl, C 3 - 6 -cycloalkyl-Cl_ 3 -alkyl or C 3 -6-cycloalkenyl 20 C0. 3 -alkyl, which may optionally be substituted with one or more halogen substituents, * R 1 and R 2 together form a C 3 . 6 -alkylene bridge, A represents R4 R 5 R; z wWw II W I or R 25 25 WO 03/066604 PCT/DKO3/00071 141 R 3 is hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 _ 10 -alkyl, C 2 -o 10 -alkenyl, C3- 8 -cycloalkyl, C 1 - 6 -alkoxy, aryl, aryl-C 1 . 6 -alkyl, amino, C 1 .- 6 -alkylamino, di-C1. 6 -alkylamino, C 3 8 -cycloalkyl, C 3 -8-cycloalkyloxy, cyano, nitro, Cs6-alkylsulfanyl, or C 1 6 -alkylsulfonyl, 5 Z and X independently represent -N=, -C(H)=, -C(F)=, -C(Cl)=, -C(CN)= or -C(CF 3 )=, W represents -N= or-C(RIo) =, Y represents -N= or-C(Rll) =, 10 R 4 , R 5 , R 6 , R 7 , R 8 , R 9 R 1 0 , R" 1 , R 1 2 and R 13 independently represent *hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, -SCF 3 , amino, cyano, nitro, or -C(=O)NR 14 R 15 15 * C-1 0 -alkyl, C 2 -1 0 -alkenyl, C 3 . 8 -cycloalkyl, C, 6 -alkoxy, C 3 _ 8 -cycloalkyl-C l . 6 -alkoxy, C_ 6 -alkylamino, di-Cl. 6 -alkylamino, C 3 .8-cycloalkyloxy, C.6-alkylsulfanyl, C.6 alkylsulfonyl, C 2 - 0 o-alkanoyl, C 4 - 9 -cycloalkanoyl, C 3 _ 8 -heterocyclyl or C 4 -9 heterocycloalkanoyl, C 4 - 9 -heterocycloalkoxy, which may optionally be substituted with 20 one or more substituents selected from R 16 * aryl, aryl-Cl. 6 -alkyl, aryI-C 1 .6-alkoxy or heteroaryl, which may optionally be substi tuted with one or more substituents selected from R 7 , 25 * aroyl, heteroaroyl, aryloxy, heteroaryloxy, arylamino or heteroarylamino, which may optionally be substituted with one or more substituents selected from R", *or two of R 5 , R 6 , R 7 , R 8 , R 9 , R 1 , R", R 12 and R 13 in adjacent positions together form a C 1 . 6 -alkylene bridge or an -O-CI_6-alkylene-O- bridge, 30 R 14 and R 15 are independently hydrogen, Cl. 6 -alkyl, aryl-C 1 - 6 -alkyl or R 14 and R 15 may to gether form a C 3 6 -alkylene bridge R' 6 is independently selected from aryl, heteroaryl, C 3 .8-cycloalkyl, halogen, trifluoromethyl, 35 trifluoromethoxy, NR' 9 R 20 and C 1 .6-alkoxy, WO 03/066604 PCT/DKO3/00071 142 R 17 is independently selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 - 6 alkoxy, C 1 - 6 -alkyl, amino, Cl.6-alkylsulfonyl, C 1 .6-alkylamino, di-C 1 -6-alkylamino, cyano, aryl, heteroaryl and C 3 _ 8 -cycloalkyl, 5 R'" is independently selected from aryl, heteroaryl, C 110 -alkyl, C 3 -- cycloalkyl, halogen, trifluoromethyl, trifluoromethoxy, Cl. 6 -alkoxy, cyano, amino, C.6-alkylamino, di C 1 . 6 -alkylamino and hydroxy, 10 R 1 9 and R 2 0 are independently hydrogen or C 1 - 6 -alkyl, R 19 and R 20 may together form a C 36 -alkylene bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical 15 composition for the treatment of disorders and diseases related to the histamine H3 receptor.
58. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the treatment of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect. 20
59. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.
60. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com 25 position for the reduction of weight.
61. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the treatment of overweight or obesity. 30 62. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the suppression of appetite or for satiety induction.
63. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the prevention and/or treatment of disorders and diseases related to overweight 35 or obesity. WO 03/066604 PCT/DKO3/00071 143
64. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the prevention and/or treatment of eating disorders such as bulimia and binge eating. 5
65. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the treatment of IGT.
66. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com 10 position for the treatment of type 2 diabetes.
67. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the delaying or prevention of the progression from IGT to type 2 diabetes. 15 68. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the delaying or prevention of the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.
69. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com 20 position for the treatment of diseases and disorders in which a stimulation of the H3 hista mine receptor has a beneficial effect.
70. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position having histamine H3 agonistic activity. 25
71. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com position for the treatment of allergic rhinitis, ulcer or anorexia.
72. Use of a compound as defined in claim 57 for the preparation of a pharmaceutical com 30 position for the treatment of Alzheimer's disease, narcolepsy or attention deficit disorders.
73. A method for the treatment of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 57 or a pharmaceutical composition according to claim 55 or 35 56. WO 03/066604 PCT/DK03/00071 144
74. The method according to claim 73 wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
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| AU2010200135A AU2010200135A1 (en) | 2002-02-05 | 2010-01-13 | Novel aryl-and heteroarylpiperazines |
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| DKPA200200168 | 2002-02-05 | ||
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| DKPA200201142 | 2002-07-26 | ||
| PCT/DK2003/000071 WO2003066604A2 (en) | 2002-02-05 | 2003-02-05 | Novel aryl- and heteroarylpiperazines |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7390813B1 (en) | 2001-12-21 | 2008-06-24 | Xenon Pharmaceuticals Inc. | Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents |
| GB0224084D0 (en) * | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
| WO2004037257A1 (en) | 2002-10-23 | 2004-05-06 | Janssen Pharmaceutica, N.V. | Phenylpiperidines and phenylpyrrolidines as histamine h3 receptor modulators |
| BRPI0413048A (en) * | 2003-07-29 | 2006-10-17 | Novo Nordisk As | compound, pharmaceutical composition, use of a compound, and method for treating histamine h3 receptor-related disorders or diseases |
| ES2375134T3 (en) | 2003-07-30 | 2012-02-27 | Xenon Pharmaceuticals Inc. | DERIVATIVES OF PIPERAZINE AND ITS USE AS THERAPEUTIC AGENTS. |
| US7754711B2 (en) * | 2003-07-30 | 2010-07-13 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives and their use as therapeutic agents |
| EP1651606B1 (en) * | 2003-07-30 | 2012-10-24 | Xenon Pharmaceuticals Inc. | Pyridyl derivatives and their use as therapeutic agents |
| BRPI0412343A (en) | 2003-07-30 | 2006-09-05 | Xenon Pharmaceuticals Inc | pyridazine derivatives and their use as therapeutic agents |
| WO2005035521A1 (en) * | 2003-10-09 | 2005-04-21 | Argenta Discovery Ltd. | Substituted quinolines as mcr modulators |
| GB0324159D0 (en) * | 2003-10-15 | 2003-11-19 | Glaxo Group Ltd | Novel compounds |
| JP4596792B2 (en) * | 2004-02-24 | 2010-12-15 | あすか製薬株式会社 | Drugs having both 5-HT1A agonistic action and 5-HT3 antagonistic action |
| CN1972914A (en) * | 2004-03-31 | 2007-05-30 | 詹森药业有限公司 | Non-imidazole heterocyclic compounds as histamine H3-receptor ligands |
| US20080125403A1 (en) | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
| US20050256309A1 (en) * | 2004-05-12 | 2005-11-17 | Altenbach Robert J | Tri-and bi-cyclic heteroaryl histamine-3 receptor ligands |
| JP2008503560A (en) * | 2004-06-22 | 2008-02-07 | ファイザー・プロダクツ・インク | Diazabicyclo histamine-3 receptor antagonist |
| TW200626138A (en) | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
| WO2006034440A2 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| MX2007003318A (en) | 2004-09-20 | 2007-05-18 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-coa desaturase enzymes. |
| JP5094398B2 (en) | 2004-09-20 | 2012-12-12 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturases |
| WO2006034441A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| CA2580857A1 (en) | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| WO2006034341A2 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase |
| WO2006034312A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coa-desaturase (scd) |
| EP2316457A1 (en) * | 2004-09-20 | 2011-05-04 | Xenon Pharmaceuticals Inc. | Pyridine derivatives for inhibiting human stearoyl-coa-desaturase |
| WO2006050389A2 (en) * | 2004-11-02 | 2006-05-11 | Northwestern University | Pyridazine compounds, compositions and methods |
| CN101166730A (en) | 2005-03-01 | 2008-04-23 | 惠氏公司 | Cinnoline compounds and their use as liver X receptor modilators |
| AU2006343359A1 (en) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| ES2375929T3 (en) * | 2005-07-04 | 2012-03-07 | High Point Pharmaceuticals, Llc | HISTAMINE RECEIVER ANTAGONISTS H3. |
| KR100979582B1 (en) * | 2005-07-05 | 2010-09-01 | 에프. 호프만-라 로슈 아게 | Pyridazine derivatives |
| US8686002B2 (en) | 2005-08-21 | 2014-04-01 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as binding partners for 5-HT5 receptors |
| GB0517184D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
| CA2622760C (en) | 2005-09-16 | 2012-12-04 | Janssen Pharmaceutica N.V. | Cyclopropyl amines as modulators of the histamine h3 receptor |
| JO2769B1 (en) | 2005-10-26 | 2014-03-15 | جانسين فارماسوتيكا ان. في | Fast Dissociting Dopamine 2 Receptor Antagonists |
| NZ570524A (en) * | 2006-03-28 | 2011-08-26 | High Point Pharmaceuticals Llc | Benzothiazoles having histamine H3 receptor activity |
| WO2007127375A2 (en) * | 2006-04-28 | 2007-11-08 | Northwestern University | Formulations containing pyridazine compounds for treating neuroinflammatory diseases |
| EP2038256A1 (en) * | 2006-05-23 | 2009-03-25 | TransTech Pharma, Inc | 6- (4-cyclopropylpiperazin-1-yl) -2 ' -methyl- [3, 4 ']-bipyridine and its use as a medicament |
| ATE538116T1 (en) * | 2006-05-29 | 2012-01-15 | High Point Pharmaceuticals Llc | 3-(1,3-BENYODIOXOL-5-YL)-6-(4-CYCLOPROPYLPIPERAZINE-1-YL)-PYRIDAZINE, ITS SALTS AND SOLVATES AND THEIR USE AS A HISTAMINE H3 RECEPTOR ANTAGONIST |
| CN101495456B (en) | 2006-05-30 | 2014-03-19 | 詹森药业有限公司 | Substituted pyridyl amide compounds as modulators of the histamine H3 receptor |
| US7902184B2 (en) | 2006-05-30 | 2011-03-08 | Hoffmann-La Roche Inc. | Piperazinyl pyrimidine derivatives |
| KR20090024811A (en) | 2006-06-23 | 2009-03-09 | 아보트 러보러터리즈 | Cyclopropyl amine derivatives as histamin h3 receptor modulators |
| US9108948B2 (en) | 2006-06-23 | 2015-08-18 | Abbvie Inc. | Cyclopropyl amine derivatives |
| CA2657702A1 (en) * | 2006-07-03 | 2008-01-10 | Vereniging Voor Christelijk Hoger Onderwijs Wetenschappelijk Onderzoek E N Patieentenzorg | Quinazolines and related heterocyclic comp0unds, and their therapeutic use |
| JO2642B1 (en) | 2006-12-08 | 2012-06-17 | جانسين فارماسوتيكا ان. في | Fast Dissociating Dopamine 2 Receptor Antagonists |
| JO2849B1 (en) | 2007-02-13 | 2015-03-15 | جانسين فارماسوتيكا ان. في | Fast -Dissociating Dopamine 2 Receptor Antagonists |
| CN101663299A (en) | 2007-04-23 | 2010-03-03 | 詹森药业有限公司 | Thiophene (two) azole compounds as fast dissociating dopamine 2 receptor antagonists |
| EP2148873B1 (en) | 2007-04-23 | 2012-08-29 | Janssen Pharmaceutica, N.V. | 4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists |
| JP5603770B2 (en) * | 2007-05-31 | 2014-10-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | CCR2 receptor antagonist and use thereof |
| EP2014656A3 (en) | 2007-06-11 | 2011-08-24 | High Point Pharmaceuticals, LLC | New heteocyclic h3 antagonists |
| WO2009016088A1 (en) * | 2007-08-02 | 2009-02-05 | F. Hoffmann-La Roche Ag | The use of benzamide derivatives for the treatment of cns disorders |
| ATE554081T1 (en) | 2007-09-06 | 2012-05-15 | Glaxo Group Ltd | PIPERAZINE DERIVATIVES WITH AFFINITY FOR HISTAMINE H3 RECEPTOR |
| MY158253A (en) | 2007-11-20 | 2016-09-30 | Janssen Pharmaceutica Nv | Cycloalkyloxy- and heterocycloalkyloxypyridine compounds as modulators of the histamine h3 receptor |
| US20120015957A1 (en) * | 2007-12-17 | 2012-01-19 | Wenying Chai | Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor |
| US20120129870A1 (en) * | 2007-12-17 | 2012-05-24 | Wenying Chai | Piperazinyl derivatives useful as modulators of the neuropeptide y2 receptor |
| WO2010000456A1 (en) | 2008-07-03 | 2010-01-07 | Janssen Pharmaceutica Nv | Substituted 6- (1-piperazinyl) -pyridazines as 5-ht6 receptor antagonists |
| JP5457450B2 (en) | 2008-07-31 | 2014-04-02 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Piperazin-1-yl-trifluoromethyl-substituted-pyridine as a rapidly dissociating dopamine 2 receptor antagonist |
| JP2012512834A (en) | 2008-12-19 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Cyclic pyrimidine-4-carboxamides as CCR2 receptor antagonists for the treatment of inflammation, asthma and COPD |
| US9186353B2 (en) | 2009-04-27 | 2015-11-17 | Abbvie Inc. | Treatment of osteoarthritis pain |
| CN102933579B (en) | 2009-12-17 | 2015-07-15 | 贝林格尔.英格海姆国际有限公司 | New ccr2 receptor antagonists and uses thereof |
| ES2550667T3 (en) | 2010-02-18 | 2015-11-11 | Vtv Therapeutics Llc | Phenylheteroaryl derivatives and methods of use thereof |
| WO2011141477A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
| WO2011141474A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
| EP2571870B1 (en) | 2010-05-17 | 2015-01-21 | Boehringer Ingelheim International GmbH | Ccr2 antagonists and uses thereof |
| JP5636094B2 (en) | 2010-05-25 | 2014-12-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | CCR2 receptor antagonist |
| WO2011151251A1 (en) | 2010-06-01 | 2011-12-08 | Boehringer Ingelheim International Gmbh | New ccr2 antagonists |
| WO2012037258A1 (en) | 2010-09-16 | 2012-03-22 | Abbott Laboratories | Processes for preparing 1,2-substituted cyclopropyl derivatives |
| JP5786258B2 (en) | 2011-07-15 | 2015-09-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Novel and selective CCR2 antagonist |
| WO2013151982A1 (en) | 2012-04-03 | 2013-10-10 | Arena Pharmaceuticals, Inc. | Methods and compounds useful in treating pruritus, and methods for identifying such compounds |
| WO2016020288A1 (en) | 2014-08-04 | 2016-02-11 | Nuevolution A/S | Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases |
| ES2811098T3 (en) | 2015-07-02 | 2021-03-10 | Centrexion Therapeutics Corp | (4 - ((3r, 4r) -3-methoxytetrahydro-pyrano-4-ylamino) piperidin-1-yl) (5-methyl-6 - (((2r, 6s) -6- (p-tolyl) citrate tetrahydro-2hpyrano-2-yl) methylamino) pyrimidin-4-yl) methanone |
| EP4076657A1 (en) | 2019-12-20 | 2022-10-26 | Nuevolution A/S | Compounds active towards nuclear receptors |
| CA3174176A1 (en) | 2020-03-31 | 2021-10-07 | Sanne Schroder Glad | Compounds active towards nuclear receptors |
| MX2022012260A (en) | 2020-03-31 | 2022-11-30 | Nuevolution As | Compounds active towards nuclear receptors. |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB753166A (en) * | 1953-05-22 | 1956-07-18 | Miles Lab | Improvements in or relating to substituted piperazines |
| US2993899A (en) * | 1958-03-31 | 1961-07-25 | Miles Lab | Acetylenically unsaturated piperazine derivatives |
| US3309370A (en) * | 1964-07-16 | 1967-03-14 | Miles Lab | Bicycloalkyl piperazine derivatives and process |
| FR2306694A1 (en) * | 1975-04-07 | 1976-11-05 | Parcor | DERIVATIVES OF PIPERAZINE |
| US4144346A (en) * | 1977-01-31 | 1979-03-13 | Janssen Pharmaceutica N.V. | Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles |
| US4163849A (en) * | 1978-03-17 | 1979-08-07 | Merck & Co., Inc. | Piperazinylpyrazines |
| JPS56118074A (en) * | 1980-02-22 | 1981-09-16 | Tanabe Seiyaku Co Ltd | Propane derivative and its preparation |
| US4339579A (en) * | 1980-12-29 | 1982-07-13 | American Home Products Corporation | 2,6-Bis-(pyrrolopyrazinyl)pyrazines |
| US5001125A (en) * | 1984-03-26 | 1991-03-19 | Janssen Pharmaceutica N.V. | Anti-virally active pyridazinamines |
| FR2573075B1 (en) * | 1984-09-14 | 1987-03-20 | Innothera Lab Sa | NEWS (PYRIDYL-2) -1 PIPERAZINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
| JP2576862B2 (en) * | 1986-03-05 | 1997-01-29 | 大塚製薬 株式会社 | Carbostyril derivative |
| DK111387A (en) * | 1986-03-05 | 1987-09-06 | Otsuka Pharma Co Ltd | CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES |
| AU639529B2 (en) * | 1987-03-04 | 1993-07-29 | Higuchi, Yoshinari | Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives |
| DE3803860A1 (en) * | 1988-02-09 | 1989-08-17 | Basf Ag | N, N'-DISUBSTITUTED PIPERAZINE |
| DK0385237T3 (en) * | 1989-03-03 | 1994-07-25 | Dainippon Pharmaceutical Co | 2- (1-Piperazinyl) -4-phenylcycloalkanopyridine derivatives, process for their preparation and pharmaceutical composition containing them |
| GB9012316D0 (en) * | 1990-06-01 | 1990-07-18 | Wellcome Found | Pharmacologically active cns compounds |
| JPH0971564A (en) * | 1995-07-06 | 1997-03-18 | Japan Tobacco Inc | Benzamidoxime derivative and its use in medicine |
| AU6318896A (en) * | 1995-07-06 | 1997-02-05 | Japan Tobacco Inc. | Benzamidoxime derivatives and medicinal use thereof |
| DZ2376A1 (en) * | 1996-12-19 | 2002-12-28 | Smithkline Beecham Plc | New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them. |
| JP3989102B2 (en) * | 1997-10-02 | 2007-10-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Condensed pyridine derivatives |
| DE69839887D1 (en) * | 1997-10-02 | 2008-09-25 | Eisai R&D Man Co Ltd | CONDENSED PYRIDINE DERIVATIVES |
| WO2000066578A1 (en) * | 1999-04-30 | 2000-11-09 | Pfizer Products Inc. | Compounds for the treatment of obesity |
| GB9926303D0 (en) * | 1999-11-05 | 2000-01-12 | Smithkline Beecham Plc | Novel compounds |
| GB9926302D0 (en) * | 1999-11-05 | 2000-01-12 | Smithkline Beecham Plc | Novel compounds |
| DE60022386T2 (en) * | 1999-12-16 | 2006-06-22 | Schering Corp. | SUBSTITUTED IMIDAZOLE AS NEUROPEPTIDE Y Y5 RECEPTOR ANTAGONISTS |
| FI20000480A0 (en) * | 2000-03-01 | 2000-03-01 | Orion Yhtymae Oyj | Quinoline and naphthalene derivatives as alpha-2 antagonists |
| EP2140864A3 (en) * | 2001-01-31 | 2010-01-27 | H.Lundbeck A/S | Use of GAL3 receptor antagonists for the treatment of depression and / or anxiety and compounds useful in such methods |
| ES2283768T3 (en) * | 2002-06-06 | 2007-11-01 | Novo Nordisk A/S | HEXAHYDROPIRROLO (1,2-A) PIRACINAS, OCTAHIDROPIRIDO (1,2-A) PIRACINAS AND DECAHYDROPIRACINO (1,2-A) SUBSTITUTED ACEPINES. |
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2003
- 2003-02-05 EP EP03701482A patent/EP1474401A2/en not_active Withdrawn
- 2003-02-05 CA CA002474214A patent/CA2474214A1/en not_active Abandoned
- 2003-02-05 MX MXPA04007612A patent/MXPA04007612A/en not_active Application Discontinuation
- 2003-02-05 JP JP2003565978A patent/JP4607458B2/en not_active Expired - Fee Related
- 2003-02-05 BR BR0307429-3A patent/BR0307429A/en not_active Application Discontinuation
- 2003-02-05 AU AU2003203148A patent/AU2003203148A1/en not_active Abandoned
- 2003-02-05 IL IL16285903A patent/IL162859A0/en unknown
- 2003-02-05 CN CNA038033607A patent/CN1628109A/en active Pending
- 2003-02-05 PL PL03372390A patent/PL372390A1/en not_active Application Discontinuation
- 2003-02-05 WO PCT/DK2003/000071 patent/WO2003066604A2/en active Application Filing
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2004
- 2004-07-16 ZA ZA2004/05694A patent/ZA200405694B/en unknown
- 2004-09-03 NO NO20043709A patent/NO328714B1/en not_active IP Right Cessation
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2010
- 2010-01-13 AU AU2010200135A patent/AU2010200135A1/en not_active Abandoned
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| AU2010200135A1 (en) | 2010-02-04 |
| EP1474401A2 (en) | 2004-11-10 |
| JP2005533747A (en) | 2005-11-10 |
| BR0307429A (en) | 2004-12-28 |
| NO20043709L (en) | 2004-09-03 |
| MXPA04007612A (en) | 2004-11-10 |
| WO2003066604A3 (en) | 2003-12-04 |
| IL162859A0 (en) | 2005-11-20 |
| ZA200405694B (en) | 2005-09-28 |
| CN1628109A (en) | 2005-06-15 |
| NO328714B1 (en) | 2010-05-03 |
| PL372390A1 (en) | 2005-07-25 |
| WO2003066604A2 (en) | 2003-08-14 |
| JP4607458B2 (en) | 2011-01-05 |
| CA2474214A1 (en) | 2003-08-14 |
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