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GB2087390A - 5,6,7,8-Tetrahydro-1,6 naphthyridine derivatives and their preparation - Google Patents

5,6,7,8-Tetrahydro-1,6 naphthyridine derivatives and their preparation Download PDF

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Publication number
GB2087390A
GB2087390A GB8132554A GB8132554A GB2087390A GB 2087390 A GB2087390 A GB 2087390A GB 8132554 A GB8132554 A GB 8132554A GB 8132554 A GB8132554 A GB 8132554A GB 2087390 A GB2087390 A GB 2087390A
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Prior art keywords
piperazinyl
naphthyridine
tetrahydro
group
general formula
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GB2087390B (en
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Nippon Kayaku Co Ltd
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Nippon Kayaku Co Ltd
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Priority claimed from JP55150719A external-priority patent/JPS5775983A/en
Priority claimed from JP56154863A external-priority patent/JPS5857379A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

5,6,7,8-Tetrahydro-1,6-naphthyridine derivatives for use in treating vertigo and as a central muscle relaxant have the general formula <IMAGE> wherein R1 and R2 are each hydrogen or a lower alkyl group or R1 and R2 are bonded together to form an alkylene group with 2 to 5 carbon atoms, R3 is hydrogen, a lower alkyl group, benzyl group or a phenyl group represented by the formula <IMAGE> in which R4 is hydrogen or halogen or a lower alkyl or lower alkoxy group, A is a linear or branched alkylene group with 2 to 4 carbon atoms, and Y is a diloweralkylamino 1-pyrrolidinyl, 1-loweralkylpyrrolidinyl, 1 -piperidinyl, 4-hydroxy-4-phenyl-1-piperidinyl, 4-hydroxy-4-(halogenphenyl)-1 -piperidinyl, 1-morpholinyl, 4-loweralkyl-1-piperazinyl, 4-benzyl-1 -piperazinyl, 4-pyridyl-1-piperazinyl group or a piperazinyl group represented by the formula <IMAGE> in which R5 is hydrogen or halogen, a lower alkyl, halogen substituted lower alkyl or lower alkoxy group. These compounds can be in the form of their non-toxic salts.

Description

SPECIFICATION 5,6,7,8-Tetrahydro-1 ,6-naphthyridine derivatives and their preparation The present invention relates to a novel 5,6,7,8-tetrahydro-l ,6-naphthyridine derivative valuable as an anti-vertiginous agent and/or a central muscle relaxant. The number of patients suffering from vertigo as the chief complaint has been increased owing to complicated social factors such as increase of old-age people, trafic accidents, labor accidents and air pollutions.
Accordingly, at the present, the vertigo is a disease which is often encountered in the fields of otolaryngology, internal medicine and gynecology. As the drug for vertigo, there have been used vasodilotors, tranquilizers, antihistamines, vitamins and metabolism activators according to the chief complaint and condition of patients. Among these drugs, betahistine and diphenidol having a relatively high selectivity to vertigo have been developed and used as the antivertiginous agent. However, they still have much to be improved in that betahistine is shortacting and that diphenidol has a hallusinogenic action as side effects. Thus, anti-vertiginous agent with much higher selectivity to vertigo and longer duraction of action should be developed urgently.
We previously found that a 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivative having a substituent such as an akyl or alkyenyl group on the nitrogen atom at the 6-position of the 5,6,7,8tetrahydro-1 ,6-naphthyridine ring has an excellent anti-vertiginous activity (see Ger. Offen.
2942065).
The 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivatives of the present invention have a linear or branched C2-C4 alkyl group substituted with a nitrogen as the substituent at the 6-position. The derivatives of the present invention are excellent over the compounds disclosed in Ger. Offen.
2942065 in the anti-vertiginous activity and have excellent properties as the anti-vertiginous agent of low toxicity and reduced side effects. Moreover, the compounds of the present invention have a prominent muscle relaxant action and depressant action on the anemic decerebrate rigidity. Namely, the compounds of the present invention is valuable also as the central muscle relaxant.
The compounds of the present invention are novel compounds having a chemical structure quite different from those of known central muscle relaxants.
The present invention relates to novel 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivatives represented by the following general formula (I):
wherein R, and R2 are each hydrogen, a lower alkyl group or R, and R2 are bonded together to form an alkylene group with 2 to 5 carbon atoms, R3 is hydrogen, a lower alkyl, benzyl group or a phenyl group represented by the formula
in which R4 is hydrogen, halogen, a lower alkyl or lower alkoxy group, A is a linear or branched alkylene group with 2 to 4 carbon atoms, and Y is a diloweralkylamino, 1-pyrrolidinyl, 1loweralkylpyrrolindinyl, 1-piperidinyl, 4-hydroxy-4-phenyl- 1 -piperidinyl, 4-hydroxy-4-(halogeno phenyl)- 1 -piperidinyl, 1-morpholinyl, 4-loweralkyl-1-piperazinyl, 4-benzyl-1 -piperazinyl, 4-pyridyl1-piperazinyl group or a piperazinyl group represented by the formula
in which R5 is hydrogen or halogen, a lower alkyl, halogen-substituted lower alkyl or lower alkoxy group.
In the compound represented by the above general formula (I), as the alkyl group having 1 to 4 carbon atoms for R, and R2, there can be mentioned, for example, methyl, ethyl, propyl and butyl groups, and as the alkylene group having 2 to 5 carbon atoms, which is formed by bonding of R, and R2, there can be mentioned, for example, ethylene, propylene, butylene and pentylene groups. As the lower alkyl group for R3, there can be mentioned, for example, methyl, ethyl and propyl groups. As the halogen atom for R4, there can be mentioned fluorine, chlorine, bromine and iodine atoms, as the lower alkyl group for R4, there can be mentioned methyl, ethyl, propyl and butyl groups, and as the lower alkoxy group for R4, there can be mentioned, for example, methoxy, ethoxy, propoxy and butoxy groups. The alkylene group as A may be branched if branching is possible.As the alkylene group for A, there can be mentioned
As the diloweralkylamino group for Y, there can be mentioned, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino and methylethylamino groups. As the 4-loweralkyl-1piperazinyl group for Y, there can be mentioned, for example, 4-methyl-1-piperazinyl, 4-ethyl-1piperazinyl, 4-propyl-1-piperazinyl and 4-butyl-1-piperazinyl groups. As the halogen atom for R5, there can be mentioned chlorine, bromine and fluorine atoms, as the lower alkyl group for R5, there can be mentioned methyl, ethyl, propyl and butyl groups, and as the lower alkoxy group for R5, there can be mentioned methoxy, ethyoxy, propoxy and butoxy groups.
Among compounds represented by the above general formula (I), those in which Y is a 4-(2pyridylpiperazinyl) group or a group
in which R5 is hydrogen, halogen, a lower alkyl group or a lower alkoxy group presented at the 2-position. A 2-loweralkoxy group, especially, are preferred from the pharmacological activities.
Preferred combinations of R1, R2, R3 and Y will now be described. When each of R, and R2 is hydrogen, R3 is hydrogen and Y is a piperazinyl group in which R5 is halogen, a lower alkyl or lower alkoxy group present at the 2-position. When at least one of R, and R2 is a lower alkyl group, R3 is hydrogen and Y is a piperazinyl group in which R5 is halogen, a lower alkyl or lower alkoxy group present at the 2-position. When R, and R2 are bonded together to form an alkylene group with 2 to 5 carbon atoms, R3 is hydrogen and Y is a pyridylpiperazinyl group or a piperazinyl group in which R5 is a lower alkoxy group present at the 2-position. In this case, a trimethylene or tetramethylene group is preferred as the alkylene group formed by bonding of R, and R2.
Typical instances of the compounds of the present invention are described below.
Compound No. Name 1 5,6,7, 8-Tetrahydro-6-(3-diethylaminopropyl)- 1, 6- naphthyridine 2 5,6,7,8,-Tetrahydro-6-(3-dimethylaminopropyl)-1,6 naphthyridine 3 5,6,7,8,-Tetrahydro-6-[2-(1-piperidinylethyl)] 1 ,6-naphthyridine 4 5,6,7,8,-Tetrahydro-6-[3-(1-piperidinylpropyl)] 1,6-naphthyridine 5 5,6,7,8,-Tetrahydro-6-[2-[4-(4-fluorophenyl)-1 piperazinyl]ethyl1 ,6-naphthyridine 6 5,6,7, 8-Tetrahyd ro-6-C3-[4-(fl uoroph enyl)- 1 pipernzinyl]prnpyl1 , 6-naphthyridine 7 5,6,7, 8-Tetrahyd ro-6-E3-C4-(2-ch loroph enyl)- 1 - piperazinyl]propyl]-1 , 6-naphthyridine 8 5,6,7,8-Tetrahydro-6-[3-[4-(3-chlorophenyl)-1 piperazinyl]propyl]-1 ,6-naphthyridine 9 5, 6, 7, 8-Tetrahydro-6-[3-[4-(4-chlorophenyl)-1 piperazinyl]propyl]-1 ,6-naphthyridine 10 5,6,7,8,-Tetrahydro-6-[3-[4-(2-tolyl)-1 piperazinyl]propyl]-1,6-naphthyridine 11 5,6,7,8,-Tetrahydro-6-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-1,6-naphthyridine 12 5,6,7,8,-Tetrahydro-6-[3-[4-(2-methoxyphenyl)-1 piperazinyl]propyl]-1,6-naphthyridine 13 5,6,7,8,-Tetrahydro-6-[3-[4-(3-trifluoromethyl phenyl)-1 -piperazinyl]propyl]1 ,6-naphthyridine 14 5,6,7,8,-Tetrahydro-6-[3-methyl-3-[4-(2-tolyl) 1-piperazinyl]propyl]-1,6-naphthyridine 15 5,6,7,8,-Tetrahydro-6-[2-[4-(2-ethoxyphenyl)-1 piperazinyl]ethyl]-1,6-naphthyridine 16 5,6,7,8,-Tetrahydro-6-[3-[4-(2-ethoxyphenyl)-1 piperazinyl]propyl]-1,6-naphthyridine 17 5,6,7,8,-Tetrahydro-6-[3-[4-hydroxy-4-phenyl-1 piperidinyl]propyl]-1,6-naphthyridine 18 5,6,7,8,-Tetrahydro-6-[3-[4-hydroxy-4-(4-chloro phenyl).. -piperidinyl]propyll-1 ,6-naphthyridine 1 9 5,6,7, 8-Tetrahydro-6-[[2-[4-(2-methoxyphenyl)-1 piperazinyl]-1-methyl]ethyl]-1,6-naphthyridine 20 5,6,7, 8-Tetrahydro-[2-[4-(2-methoxyphenyl)-1 piperazinyl]propyl]-1 ,6-naphthyridine 21 5,6,7,8,-Tetrahydro-6-[[3-[4-(2-methoxyphenyl)-1 piperazinyl 1 -methyl]propyl]-1 ,6-naphthyridine 22 5,6,7,8,-Tetrahydro-6-[[3-[4-(2-methoxyphenyl)-1 piperazinyl]-2-methyl]propyl]-1,6-naphthyridine 23 5,6,7, 8-Tetrahydro-6-[3-[4-(2-methoxyphenyl)- 1 piperazinyl]butyl]-1 ,6-naphthyridine 24 6-[(2-Diethylamino-l -methyl)ethyl]-5,6,7,8- tetrahydro-2-methyl-1,6-naphthyridine 25 6-(3-Diethylaminopropyl)-5,6,7,8-tetrahydro-2- methyl-1,6-naphthyridine 26 5, 6, 7, 8-Tetrahydro-2-methyl-6-[2-[4-(2-tolyl)- 1 piperazinyl]ethyl]-1 ,6-naphthyridine 27 6-2-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]ethyl] 5,6,7,8,-Tetrahydro-2-methyl-1,6-naphthyridine 28 5,6,7,8,-Tetrahydro-3-methyl-6-[2-(1-piperidinyl) ethyl]-1 ,6-naphthyridine 29 6-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl] 5,6,7,8-tetrahydro-3-methyl-1 ,6-naphthyridine 30 6-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl] 5,6,7,8,-Tetrahydro-3-methyl-1,6-naphthyridine 31 5,6,7,8,-Tetrahydro-2,3-trimethylene-6-[2-(4 phenyl- 1 -piperazinyllethyll-1 ,6-naphthyridine Compound No.Name 32 6-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl] 5,6,7,8,-tetrahydro-2,3-trimethylene-1,6 naphthyridine 33 1,2,3,4,6,7,8,9-Octahydro-2-(3-dimethylamino propyl)-benzo[b]-1,6-naphthyridine 34 2-(2-Diethylaminoethyl)-1 2,3,4,6,7,8, 9-octahydro- benzo[bF1 ,6-naphthyridine 35 2-[(2-Diethylamino-1 -methyl)ethyl]-1 2,3,4,6,7,8,9- octahydro-benzo[b]-1,6-naphthyridine 36 1 2,3,4,6,7,8, 9-Octahydro-2-[2-( 1 -pyrrolidinyl) ethyll-benzoCbl-l .6-naphthyridine 37 1,2,3,4,6,7,8,9-Octahydro-2-(2-diisopropylamino ethyl)-benzo[b]-1,6-naphthyridine 38 1,2,3,4,6,7,8,9-Octahydro-2-[2-(1-morphlinyl) ethyl]-benzo[b]-1,6-naphthyridine 39 1,2,3,4,6,7,8,9-Octahydro-2-[2-(4-methyl-1 piperazinyllethyll-benzoCbl-l ,6-naphthyridine 40 2-[2-(4-Benzyl- 1 -piperazinyl)ethyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6 naphthyridine 41 1,2,3,4,6,7,8,9-Octahydro-2-[2-(4-phenyl-1 piperazinyl)ethyl]-benzo[b]- 1,6-naphthyridine 42 1,2,3,4,6,7,8,9-Octahydro-2-[3-(4-phenyl-1 piperazinyl)propyl]-benzo[b]-1,6-naphthyridine 43 1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-tolyl)-1 piperazinyl]ethyl]-benzo[b]-1,6-naphthyridine 44 2-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6 naphthyridine 45 2-[2-4-(3-Chlorophenyl)-I -piperazi nyl]ethyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6 naphthyridine 46 2-[2-L4-(4-Ch lorophenyl)- 1 -piperazinyl]ethyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]- 1,6- naphthyridine 47 1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-methoxy phenyl)-1-piperazinyl]ethyl]-benzo[b]-1,6 naphthyridine 48 1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(4-methoxy phenyl)-1-piperazinyl]ethyl]-benzo[b]-1,6 naphthyridine 49 1,2,3,4,6,7,8,9-Octahydro-2-[3-[4-(2-methoxy- phenyl)- 1 piperazinyl]propyl]-benzo[b]- 1,6- naphthyridine 50 2-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6- naphthyridine 51 2-[[2-[4-(2-Ethoxyphenyl)-1 -piperazinyl-1 methyl]ethyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b] 1,6-naphthyridine 52 2-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]-propyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6 naphthyridine 53 2-[3-[4-(2-Ethoxyphenyl)-1 -piperazinyljpropyl]- 1,2,3,4,6,7,8,9-octahydro-benzo[b]- 1,6- naphthyridine 54 2-[[3-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]- 1 methyl]propyll-1,2,3,4,6,7,8,9-octahydro-benzo[b]- 1,6-naphthyridine 55 2-[[3-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]-2 methyl]propyl]-1,2, 3,4,6,7,8, 9-octahydro- benzo[bF1 ,6-naphthyridine Compound No.Name 56 2-[3-[4-(2-Ethoxyphenyl)-1-piperazinyl]butyl 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6 naphthyridine 57 1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-pyridyl)-1 piperazinyl]ethyl]-benzo[b] 1 , 6-naphthyridine 58 6-[2-[4-(2-Ethoxyphenyl)-1 -piperazinyl]ethyl] 5-methyl-5,6,7,8-tetrahydro- 1,6-naphthyridine 59 6-[2-[4-(2-Ethoxyphenyl)-1 -piperazinyl]ethyl]- 5-phenyl-5, 6,7,8-tetrahydro-l ,6-naphthyridine 60 6-(3-Pyrrolidinopropyl)-5-phenyl-5,6,7,8 tetrahydro-1,6-naphthyridine 61 6-[2-[2-( 1 -Methyl)pyrrolidinyl]ethyl]-5,6, 7,8- tetrahydro-1,6-naphthyridine 62 6-[3-(4-Methyl-1-piperazinyl)propyl]-5-phenyl- 5,6,7,8-tetrahydro- 1,6-naphthyridine 63 6-[2-(1 -Piperidino)ethyl]-5-(4-tolyl)-5,6,7,8- tetrahydro- 1 , 6-naphthyridine 64 6-[3-Diethylaminopropyl)-5-(4-tolyl)-5,6,7,8- tetrahydro-1 ,6-naphthyridine 65 6-(2-Diethylaminoethyl)-5-(3-chlorophenyl)- 5,6, 7,8-tetrahydro-l ,6-naphthyridine 66 6-[3-(4-Methyl-1 -piperazinyl)propyl]-5-(3- chlorophenyl)-5, 6,7,8-tetrahydro-l ,6-naphtyridine 67 6-(2-Pyrrolidinoethyl)-5-(4-chlorophenyl) 5,6,7,8-tetrahydro-1,6-naphthyridine 68 5-(4-Chlorophenyl)-6-[2-(1 -methyl-2-pyrrolidinyl) ethyl]-5,6, 7,8-tetrahydro-l, 6-naphthyridine 69 5-(2-Methoxyphenyl)-6-[2-(1-methyl-2 pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro-1,6 naphthyridine 70 5-(2-Methoxyphenyl)-6-[2-(4-methyl-1- piperazinyl)ethyl]-5,6,7,8-tetrahydro-1,6 naphthyridine 71 5-(4-Methoxyphenyl)-6-(2-diethylaminoethyl)- 5,6,7,8-tetrahydro-1,6-naphthyridine 72 5-(4-Methoxyphenyl)-6-(3-diethylaminopropyl)- 5,6,7,8-tetrahydro- 1,6-naphthyridine 73 7-Methyl-6-[2-[4-(2-ethoxyphenyl)-1 - piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,6 naphthyridine 74 7-Phenyl-6-[2-[4-(2-ethoxyphenyl)-1 piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,6 naphthyridine 75 8-Methyl-6-[2-[4-(2-ethoxyphenyl)-1 piperazinyl]ethyl-5,6,7,8-tetrahydro-1,6 naphthyridine 76 8-Benzyl-6-[2-[4-(2-ethoxyphenyl)-1 - piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,6 naphthyridine Among these compounds, for example, compounds Nos. 7, 8, 10, 11, 12, 15, 16, 20, 21, 22, 23, 26, 27, 28, 29, 30, 32, 42, 50, 51, 52, 53, 54, 55 and 56 are preferred as the antivertiginous agent, and compounds Nos. 15, 21, 26, 27, 29, 30, 50, 53, 54 are especially preferred as the anti-vertiginous agent. For example, compounds Nos. 3, 5, 7, 9, 11, 12, 13, 15, 19, 20, 23, 26, 27, 29, 30, 47, 49, 50 and 57 are preferred as the central muscle relaxant, and compounds Nos. 7, 11, 15, 19, 20, 26, 27, 29. 30, 47, 49 and 50 are especially preferred as the central muscle relaxant.
Processes for the preparation of compounds represented by the general formula (I) according to the present invention will now be described. The expression "equivalent(s)" herein means molar equivalent(s) unless specified otherwise.
The processes for the preparation of compounds of the present invention are roughly divided into the following 3 types.
(1) Process A:
wherein R1, R2, R3, A and Y are as defined and X is halogen.
(2) Process B:
wherein R1, R2, R3, A, Y and X are as defined above.
(3) Process C:
wherein R1, R2, R3 and Y are as defined above, and one of B and C is a carbonyl group and the other of B and C is a linear or branched alkylene group having 1 to 3 carbon atoms.
The respective processes will now be described in detail.
(1) Process A This process is suitable for the production of compounds of the general formula (i) in which the moiety A is -CH2CH2- or -CH2CH2CH2-.
More specifically, 1.0 equivalent of a S,6,7,8-tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (II) is reacted with 0.5 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, of a halogenated alkylamine derivative represented by the general formula (III) or a hydrohalogenic acid salt thereof in an inert solvent such as methanol, ethanol, propanol, tetrahydrofuran, acetone, toluene or dimethylformamide in the presence of at least 0.5 equivalent of a base, for example, an organic base such as triethylamine or pyridine, an inorganic base such as sodium hydroxide, sodium carbonate or potassium carbonate or an alkali metal derivative (in this case, it is preferred that the solvent is rendered anhydrous) such as sodium, sodium hydride or sodium amide, preferably in the presence of triethylamine, at a temperature in the range of from room temperature to a temperature approximating to the boilding point of the solvent for 1 to 20 hours. When a hydrohalogenic acid salt of the compound represented by the general formula (III) is used, better results can be obtained by further adding a base in an amount larger than the amount equivalent to the amount of the hydrohalogenic acid salt.Isolation of the intended compound of the general formula (I) from the reaction mixture is accomplished by removing the solvent from the reaction mixture by distillation, rendering the residue alkaline by addition of an aqueous solution of an alkaline substance such as sodium hydroxide or potassium carbonate, preferably a high-concentration aqueous solution of sodium hydroxide, and extracting the intended compound with a waterimmiscible organic solvent such as toluene, ether or chloroform. Purification of the product is accomplished by drying the extract, removing the solvent from the extract by evaporation and subjecting the oily residue to distillation under reduced pressure or by subjecting the extract to alumina column chromatography or silica gel column chromatography.When the intended compound is crystallized, the intended compound can be isolated and purified by performing recrystallization using an appropriate solvent.
As the 5,6,7,8-tetrahydro-l ,6-naphthyridine derivative of the general formula (II) that is used as the starting compound, there can be mentioned, for example, 5,6,7,8-tetrahydro-1,6- naphthyridine, 5,6,7, 8-tetrahydro-2-methyl- 1 , 6-naphthyridine, 5,6,7,8-tetrahydro-3-methyl-1,6- naphthyridine, 5,6, 7,8-tetrahydro-2,3-trimethylene-l .6-naphthyridine, 1 ,2, 3,4,6,7,8, 9-octahy- drn-benzoLb]-1 , 6-naphthyrid ine, 5,6,7,8-tetrahydro-5-methyl-l ,6-naphthyridine, 5,6,7,8-tetrahy- dro-5-phenyl- , 6-naphthyridine, 5,6,7,8-tetrahydro-5-(4-tolyl)- ,6-naphthyridine, 5,6,7,8-tet rahydro-5-(3-chlorophenyl)-l .6-naphthyridine.5,6,7,8-tetrahydro-5-(4-chlorophenyl)-1,6-na- phthyridine, 5,6,7,8-tetrahydro-5-(2-methoxyphenyl)-l ,6-naphthyridine. 5,6,7 ,8-tetrahydro-5-(4- methoxyphenyl)-1,6-naphthyridine, 5,6,7,8-tetrahydro-7-methyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-6-phenyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-8-methyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-8-benzyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-2-ethyl-1,6-naphthyridine, 5,6,7,8-tet rahydro-2-propyl- 1, 6-naphthyridine, 5,6,7, 8-tetrahydro-2-butyl- 1 , 6-naphthyridine, 5,6,7,8-tet- rahydro-3-ethyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-3-butyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-3-propyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-3-butyl-1,6-naphthyridine, 5,6,7,8-tetrahydro-2,3-trimethylene-1,6-naphthyridine, 1,2,3,4,6,7,8,9-octahydrobenzo[b]-1,6-naphthyridine and 5,6,7,8-tetrahydro-2,3-pentamethylene-1,6-naphthyridine, As the compound of the general formula (III), there can be mentioned, for example, 3dimethylaminpropyl chloride, 2-diethylaminoethyl chloride, 2-diethylamino-1 -methylethyl chloride, 3-diethylaminopropyl chloride, 2-diisopropylaminoethyl chloride, 2-(1 -pyrrolindinyl)ethyl chloride, 2( 1 -piperidinyl) ethyl chloride, 1-(2-chloroethyl)-4-(2-fluorophenyl)-1-piperazine, 1-(3chloropropyl)-4-(2-chlorophenyl)piperazine, 1 -(2-chloroethyl)-4-phenylpiperazine, 1-(3-chloropro- pyl)-4-phenylpiperazine, 1-(2-chloroethyl)-4-(2-chlorophenyl)piperazine, 1 -(2-chloroethyl)-4-(3- chlorophenyl)piperazine, 1-(2-chloroethyl)-4-(4-chlorophenyl)-piperazine, 1-(2-chloroethyl)-4-(2methyl-phenyl)piperazine, 1 -(2-chloroethyl)-4-(2-methoxyphenyl)piperazine, 1 -(2-chloroethyl)-4 (4-methoxyphenyl)piperazine, 1 -(3-chloropropyl)-4-(2-methoxyphenyl)piperazine, 1-(2-chloroethyl4-(2-ethoxyphenyl)piperazine, 1 -(3-chloropropyl-4-(2-ethoxyphenyl)piperazine and 1-(2-chloroe- thyl)-4-(2-pyridyl)piperazine, and hydrohalogenic acid salts thereof.
(2) Process B Also this process is suitable for the production of compounds of the general formula (I) wherein the moiety A is -CH2CH2- or -CH2CH2CH2-.
According to this process, 1.0 equivalent of 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (IV) is reacted with 0.5 50 3.0 equivalents, preferably 1.0 to 1.5 equivalents, of a secondary amine derivative represented by the general formula (V) or a hydrohalogenic acid salt thereof in an inert solvent such as methanol or ethanol in the presence of an excessive amount of a base, preferably in the presence of a base in an amount larger than the amount necessary for neutralizing the acid portion of the hydrohalogenic acid salt used as the reaction substrate, under heating and reflux for 1 to 20 hours.If isolation of the intented compound of the general formula (I) from the reaction mixture are carried out in the same manner as described above with respect to the process A, the intended 5,6,7,8-tetrahydro-1,6- naphthyridine derivative represented by the general formula (I) can be prepared substantially quantitatively. The reaction conditions, inert solvent and base to be adopted in this process are the same as those described hereinbefore with respect to the process A.
As the secondary amine derivative of the general formula (V) that is used in the present process B, there can be mentioned, for example, dimethylamine, diethylamine, dipropylamine, piperidine, 4-(4-fluorophenyl)- 1 -piperazine, 4-(2-fluorophenyl)-l-piperazine, 4-(2-chlorophenyl)- 1 - piperazine, 4-(3-bromophenyl)-1 -piperazine, 4-(3-chlorophenyl)- 1 -piperazine, 4-(4-chlorophenyl)1-piperazine, 4-(3-methylphenyl)- 1 -piperazine, 4-(2-methylphenyl)-1 -piperazine, 4-(2-ethylphe nyl)- 1 -piperazine, 4-(2-methoxyphenyl)-I -piperazine, 4-(3-methoxyphenyl)- 1 -piperazine, 4-(4-methoxyphenyl)-1-piperazine, 4-(2-ethoxyphenyl)-1-piperazine, 4-(3-trifluoromethylphenyl)-1-piperazine, 4-(2-chloromethylphenyl)-1-piperazine, 4-phenyl- 1 -piperazine, 4-methyl- 1 -piperazine, 4-ben zyl- 1 -piperazine, 4-(2-pyridyl)- 1 -piperazine, pyrrolidine, morpholine, 4-hydroxy-4-phenylpiperazine and 4-hydroxy-4-(4-chlorophenyl)-1 -piperazine, and these hydrohalogenic acid salts thereof.
The compound of the general formula (IV) that is used as the other reactant in the process B may be prepared according to the following two processes.
(i) The first process is represented by the following reaction formula (a):
wherein X1 and X, which may be the same or different, are halogen, and R1, R2, R3 and A are as defined above.
More specifically, a 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (II) is reacted with a dihalogeno compound represented by the general formula (VII) in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran, acetone, benzene, toluene, zylene or dimethylformamide in the presence of a base, for example, an organic base such as triethylamine or pyridine, an inorganic base such as potassium carbonate or sodium carbonate or an alkali metal derivative (in this case, it is preferred that the solvent be rendered anhydrous) such as metallic sodium, sodium hydride or sodium amide at a temperature of from room temperature to a temperature approximating to the boiling point of the solvent.A specific example of this process will now be described 1.0 equivalent of S,6,7,8-tetrahydro-1,6- naphthyridine is dissolved in anhydrous benzene, and 1.0 to 1.5 equivalents of oily sodium hydride is added to the solution and the mixture is refluxed for 30 minutes to 1 hour. Then, 1.0 to 1.5 equivalents of 1-bromo-2-chloroethane or 1-bromo-3-chloropropane is dropped to the reaction mixture and the reaction mixture is refluxed for 10 to 30 hours. Better results can be obtained according to the above procedures. After completion of the reaction, unreacted sodium hydride is decomposed by water or alcohol, and the reaction mixture is made acidic by addition of an acidic aqueous solution such as hydrochloric acid and the aqueous layer is extracted.The aqueous layer is made alkaline by an alkaline aqueous solution of sodium hydroxide or potassium carbonate, extracted with a water-immiscible organic solvent such as ether, benzene or toluene and dried. The solvent is then removed by evaporation under reduced pressure to give a derivative represented by the general formula (IV) in the form of an oily residue in a yield of 40 to 80%. Since the so obtained derivative represented by the general formula (IV is unstable, it is ordinarily used for reaction with a secondary amine of the general formula (V) directly without purification.
As the compound of the general formula (II) that is used for this reaction, there can be mentioned compounds described herein before with respect to the process A. As the dihalogeno compound of the general formula (VII), there can be mentioned, for example, 1-bromo-2chloroethane, 1,2-dibromoethane, 1,2-dichloroethane, 1 -bromo-3-chloropropane, 1,3-dibromo- propane, 1,3-dichloropropane, 1,2-dibromopropane, 1 ,3-dibromo-2-methylpropane and 1,3dibromo-3-methylpropane. From the viewpoint of the yield, it is preferred to use 1-bromo-2chloroethane, 1 -bromo-3-chloropropane, 1 -bromo-2-chloropropane and 1-bromo-3-chloro-3-me- thylpropane.
(ii) The second process is represented by the following reaction formula (b):
wherein R1, R2, R3, X, and A are as defined above.
The step Ol is first described. At this step, 1.0 equivalent of a 5,6,7,8-tetrahydro-1 6- naphthyridine derivative represented by the general formula (II) is reacted with 1.0 to 1.5 equivalents of a halogen compound represented by the general formula (VIII) in an inert solvent in the presence of 1.0 to 1.5 equivalents of a base at a temperature in the range of from room temperature to a temperature approximating to the boiling point of the solvent for 2 to 5 hours.
By this reaction, a derivative represented by the general formula (IX) can be obtained substantially quantitatively. The reaction condition, base, inert solvent and post isolation to be adopted at this step are the same as those described hereinbefore with respect to the process A.
As the compound of the general formula (II), there can be mentioned, for example, the same compounds as described hereinbefore with respect to the process A. As the compound represented by the general formula (VIII), there can be mentioned, for example, ethylenechlorohydrin, ethylenebromohydrin, 3-chloro-1 -propanol and 3-bromo-1-propanol. As the 5,6,7,8tetrahydro-1 ,6-naphthyridine derivative of the general formula (IX) obtained at the abovementioned step 01, there can be mentioned, for example, S,6,7,8Aetrahydro-6--(2-hydroxye- thyl)-2-methyl- 1,6-naphthyridine and 1,2,3,4,6,7,8,9-octahydro-6-(2-hydroxyethyl)-benzo[b]- 1 ,6-naphthyridine.
The step G2 will now be described. At this step 02 the hydroxyl group of the 5,6,7,8tetrahydro-1,6-naphthyridine derivative of the general formula (IX) obtained at the step Ol of the reaction formula (b) is chrolinated. More specifically, 1.0 equivalent of the derivative of the general formula (IX) is mixed under ice cooling with an excessive amount of thionyl chloride in the absence of a solvent and reaction is carried out at room temperature for 1 to 20 hours, or 1.0 equivalent of the derivative of the general formula (IX) is reacted with 1.0 to 3.0 equivalents of thionyl chloride in an inert solvent such as methylene chloride or chloroform at a temperature in the range of from room temperature to a temperature approximating to the boiling point of the solvent for 1 to 20 hours.After completion of the reaction, the reaction mixture is concentrated under reduced pressure to give the residue, and the residue is washed with ether or acetone and dissolved in an inert solvent such as methanol or ethanol. When the obtained solution is colored, the solution is decolorized with active charcoal, and recrystallized from methanol or ethanol to give a derivative represented by the general formula (IV) in a yeild of about 50 to about 80%. As the 5,6,7,8-tetrahydro-1,6-naphthyridine derivative of the general formula (IV) obtained at this step (b), there can be mentioned, for example, 6-(2 chloroethyl)-5,6,7,8-tetrahydro-2-methyl- , 6-naphthyridine dihydrochloride and 2-(2-chloroe thyl)- 1 2,3,4,6,7,8, 9-octahydrn-benz9b]-1 , 6-naphthyridine dihydrochloride.
(3) Process C This process is suitable for the preparation of compounds of the general formula (I) in which the moiety A is branched.
Namely, according to this process, the carbonyl group of the moiety B or C of a 5,6,7,8tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (VI) is reduced to give a compound represented by the general formula (I). An example of this process will now be described. At least 0.5 molar of a reducing reactant such as lithium aluminum hydride is suspended in an anhydrous ether solvent such as anhydrous ethyl ether or anhydrous tetrahydrofuran, and a solution of 1.0 equivalent of a derivative represented by the general formula (XI) in an an hydros ether solvent such as anhydrous ethyl ether or anhydrous tetrahydrofuran is dropped to the suspension with stirring at room temperature.After completion of the dropwise addition, the reaction mixture is further stirred for 1 to 2 hours at a temperature in the range of from room temperature to a temperature approximating to the boiling point of the solvent to complete reaction. The unreacted reducing reactant is decomposed with a small amount of water, and the precipitated colorless solid is removed by filtration. The filtrate is dried and the solvent is removed by evaporation under reduced pressure to give an intended 5,6,7,8tetrahydro-1,6-naphthyridine derivative represented by the general formula (I) in the form of a light yellow oil in a yeild of 60 to 90%.
The starting compound represented by the following general formula (Vl) will now be described.
In the general formula (VI), R1, R2, R3 and Y are as defined above. One of B and C is a carbonyl group, while the other of B and C is a linear or branched alkylene group having 1 to 3 carbon atoms, such as -CH2-, -CH(CH3)-, -CH2CH2- or -CH(CH3)CH2-.
This starting compound is prepared according to the following 4 processes to be selected appropriately according to the kind of the branched alkylene group.
(i) The first process is represented by the following reaction formula (c):
wherein R1, R2, R3 and Y are as defined above.
This process is suitable for the preparation of a compound of the general formula (VI) in which B is a carbonyl group and C is -CH(CH3)-.
The step ( G1 of the above reaction will now be described. At this step, 1.0 equivalent of a S,6,7,8-tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (II) is dissolved in an inert solvent such as methylene chloride or chloroform and 1.0 to 1.5 equivalents of a base such as triethylamine or pyridine is added to the solution. The mixture is cooled on an ice bath to a temperature of about 10"C, and then 1.0 to 1.5 equivalents of 2chloropropionyl chloride directly or in the form of a solution in an inert solvent such as methylene chloride or chloroform is added dropwise to the mixture. The mixture is stirred at room temperature for several hours. The reaction mixture is concentrated under reduced pressure and the residue is made acidic by addition of hydrochloric acid or the like and washed with a water-immiscible organic solvent such as toluene. The water layer is made alkaline under ice cooling with an alkaline aqueous solution of sodium hydroxide and extracted with a waterimmiscible organic solvent such as toluene or chloroform. The extract is dried and the solvent is removed by evaporation under reduced pressure. The obtained crystalline residue is recrystallized from an appropriate solvent such as ethyl ether or isopropyl ether to give a derivative represented by the general formula (X) in a yeild of 60 to 90%. As the compound of the general formula (II) that it used as the starting compound, there can be mentioned the same compounds as described herein before with respect to the process A.As the derivative of the formula (X) obtained at this step (1), there can be mentioned, for example, 2-(2-chloropropionyl) 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine.
The step Q2 of the above reaction will now be described. At this step, 1.0 equivalent of the derivative of the general formula (X) obtained at the above-mentioned step (3 and 1.0 to 1.5 equivalents of a secondary amine derivative represented by the general formula (V) are dissolved in an inert solvent such as methanol or ethanol and the solution is refluxed in the presence of a base such as triethylamine or pyridine for 10 to 100 hours. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and the residue is made acidic by addition of dilute hydrochloric acid and then washed with a water-immiscible organic solvent such as toluene.The water layer is made alkaline with an alkaline aqueous solution of sodium hydroxide under ice cooling and then extracted with a water-immiscible organic solvent such as toluene. The extract is dried and the solvent is removed by evaporation under reduced pressure to give a 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (Vla) in the form of an oily residue in a yield of 80 to 90%. As the compound represented by the general formula (V), there can be mentioned the same compounds as described hereinbefore with respect to the process B. As the derivative of the general formula (Vla) obtained at the step #, there can be mentioned, for example 2-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]propionyl]1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine.
Incidentally, if chloroacetyl chloride is used instead of 2-chloropyopionyl chloride at the step a a a compound of the general formula (VI) in which C is -CH2- is obtained.
(ii) The second process is represented by the following reaction formula (d):
wherein R1, R2, R3 and Y are as defined above.
This process is suitable for the preparation of compounds of the general formula (VI) in which B is -CH(CH3)- and C is a carbonyl group.
According to this process, 1.0 equivalent of a S,6,7,8-tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (II) is reacted with 1.0 to 1.5 equivalents of a 2chloropropionylamide derivative under the same conditions as described hereinbefore with respect to the step Q2of the above process (i) of the reaction formula (c). The isolation to be adopted at this step are carried out in the same manner as described hereinbefore with respect to the above step ), whereby a 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (Vlb) can be obtained in a yield of 60 to 80%. As the compound of the general formula (II), there can be mentioned the same compounds as described hereinbefore with respect to the process A.As the compound of the general formula (Vlb) obtained according to this process, there can be mentioned, for example, 2-[[2-[4-(2-ethoxyphenyl)-l -piperazinyll-l- methyl-2-oxo]ethyl]- 1 2,3,4,6,7,8, 9-octahydrobenzo[b]" 1 , 6-naphthyridine.
Incidentally, if a chloroacetylamide derivative is used instead of the 2-chloropropionylamide derivative, there can be obtained a compound of the general formula (Vl) in which B is -CH2-.
(iii) The third process is represented, for example, by the following reaction formula (e):
wherein R1, R2, R3 and Y are as defined above.
This process is suitable for the preparation of compounds represented by the general formula (Vl) wherein B is a carbonyl group and C is -CH(CH3)CH2-.
The reaction and isolation to be adopted at the step Xare carried out in the same manner as described hereinbefore with respect to the step Glof the process (i) except that crotonyl chloride is used instead of 2-chloropropionyl chloride, whereby a 5,6,7,8-tetrahydrn-1 ,6-naphthyridine derivative represented by the general formula (XII) can be obtained substantially quantitatively.
As the compound represented by the general formula (II), there can be mentioned the same compounds as described hereinbefore with respect to the process A. As the compound represented by the general formula (VII), there can be mentioned, for example, 2-(2-butenoyl) 1 ,2,3,4,6,7,8,9-octahydrn-benzob]-1 ,6-naphthyridine.
At the step (2), 1.0 equivalent of the 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivative of the general formula (XII) obtained at the step Glis reacted with 1.0 to 1.5 equivalents of a secondary amine derivative represented by the general formula (V) under reflux conditions in an inert solvent such as ethanol in the presence of a catalyst such as triethylamine, pyridine or Triton B for 24 to 72 hours, After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and the residue is made alkaline by addition of an alkaline aqueous solution of sodium hydroxide and then extracted with a water-immiscible organic solvent such as toluene or chloroform.The extract is dried and the solvent is removed by evaporation under reduced pressure to give a S,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (Vlc) in the form of an oily residue in a yield of 50 to 70%.
If purification is especially required, the obtained compound may be purified according to an ordinary purification method such as silica gel column chromatography. As the compound represented by the formula (V), there can be mentioned, for example, the same compounds as described hereinbefore with respect to the process (i). As the S,6,7,8-tetrahydro-1,6-naphthyri- dine derivative represented by the general formula (Vlc), there can be mentioned, for example, 2-[3-[4-(2-ethoxyphenyl)- 1 -piperazinyl]butyryl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthy- ridine.
Incidentally, if methacryl chloride is used instead of crotonyl chloride at the step Gi there can be obtained a compound represented by the following general formula (Vld):
wherein R1, R2, R3 and Y are as defined above.
(iv) The fourth process is represented, for example, by the following reaction formula (f):
wherein R1, R2, R3 and Y are as defined above.
This process is suitable for the preparation of compounds of the general formula (Vl) in which B is -CH(CH3)CH2- and C is a carbonyl group.
According to this process, 1.0 equivalent of a 5,6,7.8-tetrahydro-l ,6-naphthyridine derivative represented by the general formula (II) and 1.0 to 1.5 equivalents of a crotonyl amide derivative represented by the general formula (XIII) are subjected to the reaction and the isolation from the reaction mixture in the same manner as at the step G2of the process (iii), whereby a 5,6,7,8tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (Vle) is obtained in a yield of 70 to 90%. As the compound represented by the general formula (II), there can be mentioned the same compounds as described hereinbefore with respect to the process A.As the compound represented by the general formula (Vle), there can be mentioned, for example, 2 [[2-[4-(2-ethoxyphenyl)- 1 -piperazinyl]- 1 -methyl-3-oxo]propyl]-1 2,3,4,6,7,8, 9-octahydroben- zo[b]-1 ,6-naphthyridine.
If a methacrylamide of the formula
(XIV) is used instead of the crotonyl amide at this reaction, there can be obtained a compound represented by the following general formula (Vlf):
wherein R1, R2, R3 and Y are as defined above.
The compounds prepared according to the above-mentioned processes may be converted to pharmacologically acceptable acid addition salts, for example, inorganic acid salts such as hydrochlorides, sulfates and phosphates and organic acid salts such as maleates, fumarates, malonates, tertrates and citrates. Theoretically, some 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives of the present invention having at least one asymmetric carbon atoms, for example, compounds Nos. 14, 19, 20, 21, 22, 23, 24, 35,51,52, 54, 55, 56 and 61, include two optical isomers. In the present invention, not only racemic compounds but also optical isomers are included.Optically active compounds can be obtained from racemic compounds according to known procedures, for example, by forming a salt with an optically active acid, separating the formed two diastereomer salts and isolating optical isomers from the diastereomer salts.
The pharmacological tests adopted by us for evaluating the anti-vertiginous and muscle relaxant actions of the 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivatives represented by the general formula (I) and results of the tests made on typical compounds will now be described.
Pharmacological Tests (1) Anti-Vertiginous Action: It is known that the vertigo due to the peripheral labyrinth trouble is accompanied by the nystagmus. Accordingly adult cats were used, and the spontaneous nystagmus destroying labyrinth was subacutely caused in the cats to examine symptoms. Furthermore, mice were used, and the median lethal dose (LDso) were calculated.
Experimental Procedures: Experiments were use in adults cats weighing 2.0-4.0 kg. Under ether anesthesia, unilateral labyrinth of adult cats was destructed, and the spinal cord was trancected at C2 level. Artificial respiration was maintained throughout the experiment. The evaluation of the test compound was performed by the effect of this compound on frequency of the spontaneous nystagmus induced after recovery from anesthesia. The test compound was dissolved in a physiological saline and administered i.v.. The inhibition ratio (%) of nystagmus was calculated according to the formula (As 8) x 100 A wherein A represents the nystagmus frequency just before the administration of the compound and B represents the nystagmus frequency at the point of maximum response after the administration.Moreover, the duration of action was determined by measuring the time required for complete recovering of the nystagmus frequency. In order to evaluate the acute toxicity in mice (CRJ-ICR, d 7W), the test compound was administered intraperitoneally, and the median lethal dose (LD50) was determined by up and down method.
Results: The results obtained on typical compounds of the present invention are shown in Table 1.
Table 1 Nystagmus Inhibiting Action Inhibition Duration Amount Ratio Time Acute Toxicity Compound (mg/Kg) (%) (minutes) (LD50 mg/Kg) (7) difumarate 3 30-40 8 1 64 (8) difumarate 3 30 5 283 (9) difumarate 3 50 8 141 (10) difumarate 3 30-30 10 156 (11)difumarate 3 50-60 > 60 130 (12) difumarate 3 30-40 20 151 (15) difumarate 3 60-70 60 1 60 (16) difumarate 3 20-30 6 100-300 (20) difumarate 3 30-40 4 30-100 (21) ditartrate 3 40 30 100-300 (22) ditartrate 3 30 12 100-300 (23) ditartrate 3 20 20 100-300 (26) difumarate 3 25 60 11 7 (27) difumarate 3 75 60 11 9 (28)difumarate 3 15 10 611 (29)difumarate 3 65 35 119 (30) difumarate 3 75 40 68 (32) difumarate 3 20 20 74 (42) difumarate 3 35 20 1 59 (50) difumarate 3 75 > 240 223 (51) difumarate 3 25 2.5 128 (52) difumarate 3 15 3 180.3 (53) difumarate 3 35 30 200 (54) difumarate 3 65 20 200 (55) difumarate 3 45 5.5 146 (56) difumarate 3 45 4.5 222 (2) Muscle Relaxant Action: (2-1) Traction Test: According to the modified traction test of Courvoisier (S. Courvoisier, R. Ducrot and L. Julou, "Psychotropic Drugs", S. Garattini and V. Ghetti, Ed., Elsevier Publishing Co., Amsterdam, 1957, pages 373-391), ICR male mice (n = 6) were hanged down from a horizontally spread wire 2 mm in the diameter by the forelimbs, and the reaction of drawing up the hind legs (traction) was examined.Evaluation was made according to the following scoring: 0: walking on the wire 1: drawing up hind legs within 10 to 30 seconds 2: hanging for more than 30 seconds 3: falling within 10 to 30 seconds 4: falling within 3 to 10 seconds 5: falling within 0 to 3 seconds 6: quite incapable of hanging The test compound was dissolved in a physiological saline and subcutaneously administered.
The average score obtained 60 minutes after the administration is shown. To the control group, a phyiological saline and subcutaneously administered in an amount of 0.1 cc/lOg body weight. As a control substance, toluperisone hydrochloride was used. In order to evaluate the acute toxicity in mice, the test compound was administered intraperitoneally. ICR male mice were used, and the median lethal dose (LD50) was determined.
Results: Results of the tests made on typical compounds of present invention are shown in Table 2.
Table 2 Amount Scores after Acute Toxicity Compound (mg/Kg) 60 Minutes (LD50, mg/Kg) (5) difumarate 30 0.7 300 (7)difumarate 30 1.1 164 (9) difumarate 30 0.2 141 (11) difumarate 30 3.5 130 (12)difumarate 30 0.7 151 (13) difumarate 30 0.3 259 (15) difumarate 30 2.7 160 (19)ditartrate 30 3.5 30-100 (20) difumarate 30 3.2 30-100 (23) ditartrate 30 0.2 100-300 (26) difumarate 30 1.3 117 (27) difumarate 30 1.8 11 9 (29) difumarate 30 3.9 119 (30) difumarate 30 2.8 68 (32) difumarate 30. 1.8 74 (47) difumarate 30 3.5 136.6 (49) difumarate 30 1.5 207.1 (50) difumarate 30 3.2 223 (57) difumarate 30 0.4 149 Control - 0.0 Tolperisone hydrochloride (comparison) 30 0.0 207.1 ditto 100 1.3 207.1 (2-2) Effects on Anaemic Decerebrate Rigidity in Rats: According to the method of Fukuda et al. [H. Fukuda, T, Ito, S.Hashimoto and Y. Kudo, Japanese J. Pharmacol., 24, 810 (1974)], effects of the compounds of the present invention on the anaemic decerebrate rigidity in rats was examined. The rigidity is caused in the limbs, especially the forelimbs, by hyperexcitability of a-motoneurones, and these preparations are regarded as excellent models for examining abnormal exaggeration of muscle tonus such as muscle spasm. A test compund causing depression of this preparation may be considered to possess the central muscle relaxant activity through acting on the brainstem and spinal cord.
Experimental Procedures: Male Wister rats weighing 350 to 500 9 were used. Under ether anesthesia, a tracheal cannula was inserted, and bilateral common carotid arteries were ligated. The basal artery was cauterized by a bipolar coagulator (Model MICRO-1 C supplied by Mizuho Ika Kogyo) to stop the blood stream. The rat was fixed on their back and the forelimbs were caused to catch one end of a celluloid plate having strain gauges mounted on both the surfaces. The change of the resistance generated in correspondence to the force of pushing up the celluloid plate by rigidity of the forelimbs was recorded as the change of tension through a bridge circuit by an automatic balance recorder (Model R-12M supplied by Shimazu Seisakusho).
Depression ratio was calculated according to the following formula: average tension (g) for 10 minutes at peak period Depression ratio (%) = [100 - X 100] average tension (g) for 10 minutes before adminis tration Furthermore, the time required for complete recovery was measured as the duration of action.
As a control substance, Tolperisone was used. In order to evaluate the acute toxicity in mice, the compound was administered intraperitoneally. ICR male mice were used and, median lethal dose (LD50) was determined.
Results: Results of the tests made on typical compounds of the present invention are shown in Table 3.
Table 3 Contraction Highest Inhibition Acute Reaction Inhibition Duration Toxicity Amount Time Ratio Time (LD50, Compound (mg/Kg) (minutes) (%) (minutes) mg/Kg) (3) difumarate 1.0 30-45 13 > 60 300-1000 (5) difumarate 1.0 30-45 23 > 60 300 (7) difumarate 1.0 30-45 31 > 60 164 (11) difumarate 1.0 30-45 28 > 60 130 (12) difumarate 1.0 30-45 17 > 60 151 (15) difumarate 1.0 30-45 45 > 60 160 (19)ditartrate 1.0 30-45 35 > 60 30-100 (20)difumarate 1.0 30-45 37 > 60 30-100 (29) difumarate 1.0 30-45 27 > 60 11 9 (30) difumarate 1.0 30-45 28 > 60 68 (47) difumarate 1.0 30-45 20 > 60 136.6 (49) difumarate 1.0 30-45 6 > 60 207.1 (50) difumarate 1.0 30-45 > 60 223 Tolperisone hydrochloride (comparison) 2.5 0 6.0 0 207.1 ditto 5.0 5 47.0 20-30 207.1 From the pharmacological test results shown in Table 1, it is seen that the compounds of the present invention have an excellent inhibitory effect on nystagmus frequency and this effect is longlasting. Therefore, it will readily be understood that the compounds of the present invention are excellent as the anti-vertiginous agent. Moreover, from the results shown in Tables 2 and 3, it is seen that the compounds of the present invention are excellent over the known central muscle relaxant, Tolperizon, in the results of the traction teat and effect on the anaemic decerebrate rigidity test. Accordingly, it will readily be understood that the compounds of the present invention are excellent also as the central muscle relaxant.
The compounds of the present invention, represented by the general formula (I), can be administered by optional methods, for example, oral administration, injection, rectal administration and hypodermic administration. Doses for adults are changed according to the administration course and the administration frequency and also to whether the compounds are used as the anti-vertiginous agent or the central muscle relaxant, but the daily doses of the compounds of the present invention are oridinarily 1 to 500 mg and preferably 5 to 100 mg. As in case of conventional anti-vertiginous agents and central muscel relaxants, the compounds of the present invention can be administered to men in any optional preparation form. For example, in case of oral administrations, the compounds of the present invention can be used in the form of any tablets, capsules, granules and syrups.As the excipient to be used for manufacture of these drugs, there can be mentioned, for example, lactose, sucrose, mannitol, starch and amino acids.
In case of tablets, there may be used lubricants such as magnesium stearate and talc, disintegrating agents such as CMC calcium and Avicel, and binders such as polyvinyl pyrrolidone and hydroxypropyl cellulose.
The compound of the general formula (II) is prepared according to a process shown by the following reaction formula (g):
wherein R1, R2 and R3 are as defined above.
More specifically, a compound represented by the general formula (XV) is subjected to hydrogenation at about 30 to about 70"C in the presence of 1 to 10% of palladium adsorbed carbon as a catalyst in a solvent such as acetic acid, propionic acid, dilute hydrochloric acid or methanol, whereby a S,6,7,8-tetrahydro-1 ,6-naphthyridine derivative represented by the general formula (II) can be obtained substantially quantitatively.
The compound of the general formula (XV) used as the starting compound for the above reaction can be prepared according to the following four processes that are appropriately chosen and adopted according to the kind and position of the substituent R3.
(1) Process for Preparation of Compounds where R3 is Hydrogen: This process is represented by the following reaction formula (h):
wherein Ri and R2 are each hydrogen, R4, R5 and R6 are each hydrogen, when R, is a lower alkyl group, R2, R4 and R5 are each hydrogen and R6 is a lower alkyl group, when R2 is a lower alkyl group, R1, R4 and R6 are each hydrogen and R5 is a lower alkyl group, and when R, and R2 are bonded together to form an alkylene group having 2 to 5 carbon atoms, R4 is hydrogen and R5 and R6 are bonded together to form an alkylene group having 2 to 5 carbon atoms.
According to this process, 1.0 equivalent of a compound represented by the general formula (XVI) is mixed with 0.5 to 1.5 equivalents of N-benzyl-y-piperidone, and in the absence of a solvent, 1.0 to 30.0% of a salt such as ammonium acetate or piperidine acetate or a Lewis acid such as an hydros aluminum chloride or titanium tetrachloride is added as the catalyst. The mixture is reacted on an oil bath at 70 to 160"C for 10 to 48 hours. The intended product is isolated from the reaction mixture according to the following procedures. After completion of the reaction, 6N hydrochloric acid is added to the reaction mixture under ice cooling to adjust the pH value to 0.5 to 1.0, and the mixture is washed by extracting it several times with a waterimmiscible organic solvent such as toluene or benzene.Then, under ice cooling, an alkaline aqueous solution of sodium hydroxide is added to the water layer to adjust the pH value to 5.0 7.0, and extraction is carried out with a water-immiscible organic solvent such as benzene or toluene, and the extract is dried and the solvent is removed by distillation under reduced pressure. The obtained oily residue is purified by distillation under reduced pressure or by ordinary alumina or silica gel column chromatography to give a crude crystal of a 6-benzyl 5,6,7,8-tetrahydro-l ,6-naphthyridine derivative represented by the general formula (XVa). The crude crystal is recrystallized from an appropriate organic solvent such as ether or isopropyl ether. Thus, the intended compound is obtained in a yield of 20 to 70%. As the compound represented by the formula (XVI), there can be mentioned, for example, 4-amino-3-buten-2-one, 1-amino-i -penten-3-one, 1-amino-i -hexen-3-one, 1-amino-i -heptan-3-one, 3-amnoacrolein, 3amino-2-methylacrolein, 3-amino-2-ethylacrolein, 3-amino-2-propylacrolein, 3-amino-2-butylacrolein, 2-aminomethyleneeyclopentanone, 2-aminomethylenecyclohexanone and 2-amino-methylenecycloheptanone.
(2) Process for Preparation of Compounds where R3 is Presented at 5-Position: This process is represented by the following reaction formula (i):
wherein R3 and X are as defined above.
To a solution of a Grignard reagent of the general formula (XVII), which is obtained from a corresponding halogen compound and metallic magnesium in a non-protonic solvent such as anhydrous tetrahydrofuran, ether, monoglyme, diglyme or toluene according to an ordinary method, a 1 ,6-naphthyridine quaternary salt represented by the general formula (XVI) is added portionwise at O to 30"C, and the mixture is stirred at room temperature for 1 to 2 hours to give a derivative represented by the general formula (XVIII). Since this derivative is unstable, the obtained oily crude product is directly used for the reaction of the subsequent step G2 without isolation or purification.
At the step (2i, the derivative represented by the general formula (XVlll).is reduced by an ordinary catalytic reduction method in the presence of a catalyst such as platinum oxide, platinum, palladium or palladium-carbon, or the derivative is reduced by using a reducing agent such as sodium borohydride or sodium cyanoborohydride, whereby a derivative represented by the general formula (XVb) is obtained. As the solvent used for the reduction reaction with the reducing agent, there can be mentioned an alcoholic aqueous solution such as methanol/water or methanol/phosphoric acid buffer (pH = 7) and a weakly acidic organic solvent such as acetic acid/methanol.At this step, from the viewpoint of the yield, it is preferred that the reducing agent be used in an amount of 1 to 5 moles per mole of the derivative represented by the general formula (XVI II).
(3) Process for Preparation of Compounds where R3 is Presented at 7-Position: This process is represented by the following reaction formula (j):
wherein R3 is as defined aobve.
At the step #, 3-(N-benzylaminocarbonyl)-2-methylpyridine of the formula (IXI) obtained according to the method of Y. Sato et al. [Chemi. Pharm, Bull., 8, 427 (1 960)] is reduced to 3 (N-benzylaminomethyl)-2-methylpyridine of the formula (XX). As the reducing agent used for this reaction, there can be mentioned, for example, reducing compounds such as diborane, lithium aluminum hydride and sodium hydrobis (2-methoxy-ethoxy)aluminate. As the solvent, there are used non-protonic organic solvents such as ether, tetrahydrofuran and toluene.When diborane is used as the reducing agent, there may be adopted a method in which in an inert atmosphere such as a nitrogen current, the compound of the formula (XIX) is added to a solution of borane in tetrahydrofuran and reaction is carried out at a temperature in the range of from 0 C to a temperature approximating to the boiling point of the solvent for 2 to 3 hours. After completion of the reaction, an aqueous solution of a mineral acid such as hydrochloridc acid is added to the reaction mixture to decompose the formed borane complex, and the compound of the formula (XX) is isolated according to ordinary procedures.
At the step (2), , the compound of the formula (XX) obtained at the step Glis reacted with an aldehyde represented by the general formula (XXI) to obtain a compound represented by the general formula (XXII).
More specifically, the compound of the formula (XX) is gradually added to a non-protons organic solvent such as an hydros tetrahydrofuran, ether, monoglyme or diglyme in the presence of a strong base such as n-butyl lithium, sec-butyl lithium, phenyl lithium or lithium diisopropylamide at -70 to 0"C, preferably -70 to -50 C, and the mixture is stirred for about 1 hour at the above temperature. Then, at least 1 mole, preferably at least 3 moles, of an aldehyde of the formula (XXI) is gradually added to the mixture per mole of the compound of the formula (XX), and the resulting mixture is stirred for 1 to 2 hours to give an alcohol derivative represented by the general formula (XXII).
At the step G3 , the hydroxyl group of the derivative of the general formula (XXII) obtained at the step Di is halogenated with an ordinary halogenating agent such as thionyltchloride to give a compound represented by the general formula (XXIII).
More specifically, the compound of the general formula (XXII) is dissolved in a solvent such as chloroform, and a halogenating agent such as thionyl chloride is added to the solution and the reaction is carried out at O to 30'C for 2 to 3 hours.
At the step %, , the compound of the general formula (XXIII) obtained at the step G3is ring- closed to give a compound represented by the general formula (XVc).
More specifically, the compound of the general formula (XXIII) is dissolved or suspended in a solvent such as ethanol, and reaction is carried out in the presence of a base such as trimethylamine or triethylamine at a temperature in the range of from 30 C to a temperature approximating to the boiling point of the solvent for 1 to 2 hours.
(4) Process for Preparation of Compounds where R3 is Presented at 8-Position: This process is represented by the following reaction formula (k):
wherein R3 and X are as defined above.
in this process, 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine represented by the formula (XVa) is reacted with a compound represented by the general formula (XXIV) under the same conditions as adopted at the step (D2of the process (3) represented by the reaction formula (j).
Processes for the preparation of typical compounds of the present invention will now be described with reference to the following Examples that by no means limit the scope of the invention. The expression "percent" in the Examples means percent by weight unless otherwise specified.
Example 1 This example illustrates preparation of 6-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-5,6,7,8- tetrahydro-3-methyl-1,6-naphthyridine (compound No. 29).
In 30 ml of ethanol was dissolved 1.48 g (10 m mol) of 5,6,7,8-tetrahydro-3-methyl-1,6- naphthyridine, and 3.99 g (12 m mol) of 1-(2-chloroethyl)-4-(2-chlorophenyl)piperazine dihydrochloride and 4.7 ml (34 m mol) of trimethylamine were added to the solution and then the mixture was refluxed on an oil bath for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue and a 30% aqueous solution of sodium hydroxide was added to the residue to make it alkaline and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oily reside was purified by aklumina column chromatography (ether was used as an eluting solvent).When the obtained light yellow oil was allowed to stand still, the oil was crystallized. The obtained crude crystal was recrystallized from isopropyl ether to give 1.52 g (Y. 41.0%) of colorless prisms, m.p.
64-67"C.
NMR 8 (CDCl3): 2.27 (3H, s; CH3), 2.41-3.37 (16H, m; C7, Q-H and
3.67 (2H, s; C5-H), 6.73-7.48 (5H, m; C4-H and phenyl), 8.23 (iH, d, J= 1.5 Hz; C2-H) Mass (m/e) (rel. intensity): 372 (M+ + 2, 5.9). 370 (M+, 16.0), 230 (22.2), 211 (34.6), 209 (100), 175(13.4), 161(62.1) The fumaric acid salt of the so obtained free base was prepared, for example, according to the following procedures. More specifically, 0.951 g (8.2 m mol) of fumaric acid was dissolved in 110 ml of hot acetone, and a solution of 1.52 g (4.1 m mol) of the free base in 10 ml of acetone was added to the above solution under stirring. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were filtrated off and recrystallized from ethanol to give 1.8 g (Y: 75.0%) of a difumarate (C21H27CIN4 2C4H404) as colorless powdery crystals, m.p. 218-221'C (dec.).
The following compounds were prepared from corresponding starting compounds by the reaction in the same manner as described above.
5,6,7, 8-Tetrahydro-6-[2-(4-fluorophenyl)piperazinyl]ethyl- 1, 6-naphthyridine (compound No. 5), colorless prisms, m.p. 128-131"C.
Mass (m/e) rel. intensity: 340 (M+, 42.1), 216 (27.2), 204 (14.6), 193(100), 163(14.6), 147 (81.3) 5,6,7, 8-Tetrahydro-6-[3-[4-(2-chlornphenyl)pipernzinyl]prnpyl]-1 ,6-naphthyridine (compound No.
7), light yellow oil.
Mass (m/e) (rel. intensity): 372 (M+ + 2, 33.3), 370 (M+, 100), 211(26.7), 209 (56.7), 204(95.3), 147 (68.7) Difumarate (C21H27N4Cl.2C4H4O4): colorless powdery crystals, m.p. 169-171 C.
6-[(2-Diethylamino-1-methyl)ethyl]-5,6,7,8-tetrahydro-2-methyl-1,6-naphthyridine (compound No. 24), light yellow oil, b.p. 134-137 C (0.6 mmHg).
Mass (m/e) (rel. intensity): 261 (M+, 1.5), 175 (42.2), 160(2.7), 100 (100), 86 (4.5) Di-DL-Tartrate (C1 6H27N 2C4H606), hygroscopic powder.
6-(3-Diethylaminopropyl)-5, 6,7, 8-tetrahydro-2-methyl- 1,6-naphthyridine (compound No. 25), light yellow oil. b.p 1 34-1 38'C (0.7 mmHg).
Mass (m/e) (rel. intensity): 261 (M+, 16.0), 188 (27.6), 187 (23.0), 173 (33.4), 161 (32.4), 147 (14.0), 103 (25.6), 98 (29.9), 86 (100) Difumarate (C16H27N3.2C4H4O4), colorless powdery crystals, m.p 105.5-106.5 C 5,7,7,8-Tetrahydro-2-methyl-6-[2-[4-(2-tolyl)-1-piperazinyl]ethyl]-1,6-naphthyridine (compound No. 26), colorless prisms, m.p. 120.5-121.5 C.
Mass (m/e) (rel. intensity): 350 (M+, 14.2), 230 (7.1) 218(6.7), 201(8.2), 189 (100), 175 (18.9), 161(47.8) Fumarate (C22H30N4' 2C4H404), colorless powdery crystals, m. p. 212-213 C (dec.).
6-[2-[4-(2-ethoxyphenyl)- 1 -piperazinyl]ethyl]-5,6,7, 8-tetrahydro-2-methyl- 1 ,6-naphthyridine (compound No. 27), colorless prisms, m.p. 80.5-81.51 C.
Mass (m/e) (rel. intensity): 381 (M+, 18.4), 218(100), 204 (21.8), 190(23.7), 163 (22.4), 161(20) Difumarate (C23H32N40 2C4H404), colorless powdery crystals, m.p. 216-217 C (dec.).
5,6,7, 8-Tetrahydro-3-methyl-6-[2-( 1 -piperidinyl)ethyl]- 1,6-naphthyridine (compound No. 28), light yellow oil b.p. 155-159 C (0.4 mmHg).
Mass (m/e) (rel. intensity): 259 (M+, 9.1), 161 (14.8), 98 (100) Difumarate (C16H25N3.2C4H4O4), colorless powdery crystals, m.p. 213-214 C (dec.).
6-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-3-methyl-1,6-naphthyridine (compound No. 30), light yellow oil.
Mass (m/e) (rel. intensity): 380 (M+, 11.0), 220 (23.6), 219(100), 217(13.0), 206(17.7), 205(17.0), 189(14.4), 163(11.9), 161(14.2), 146 (14.3) Difumarate (C23H32N4.2C4H4O4), colorless powdery prisms, m.p. 200-201.0 C (dec.).
1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-tolyl)-1-piperazinyl]ethyl]-benzo[b]-1,6-naphthyridine (compound No. 43), colorless prisms, m.p. 120.5-121.5 C.
Mass (m/e) (rel. intensity): 390 (M+, 15.7), 230 (10.3), 201(100.0), 189 (100.0), 175(13.6) Difumarate (C25H34N4 2C4H404), colorless powdery prisms, m.p. 221.0-111.0 C (dec.).
2-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 44), colorless prisms, m.p. 85.0-86.0C.
Mass (m/e) (rel. intensity): 412 (M+ + 2, 3.3), 410 (M+, 8.2), 270 (15.3), 211 (21.6), 209 (61.2), 201(100) 2-[2-[4-(3-Chlorophenyl)-1-piperazinyl]ethyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 45), colorless needles, m.p. 113.0-114.0 C.
Mass (m/e) (rel. intensity): 412 (M+ + 2,2.2), 410 (M+, 6.3), 270 (11.6), 211 (4.9), 209 (14.8), 201(100) Difumarate (C24H31ClN4.2C4H4O4), colorless powdery crystals, m.p. 218-221 C (dec.).
2-[2-[4-(4-Chlorophenyl)-1-piperazinyl]ethyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 46), colorless needles, m.p. 163.0-164.0 C.
Mass (m/e) (rel. intensity): 412 (M+ + 2, 1.2), 410 (M+, 3.2), 270 (8.1), 211 (5.6), 209 (15.7), 201(100.0) Difumarate (C24H31CIN4 2C4H404), colorless powdery crystals, m.p. 194-195.5 C.
6-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl]-5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 59), colorless prisms, m.p. 111.5-113.0 C.
Mass (m/e) (rel. intensity): 442 (M+, 12.3), 223 (39.4), 220 (13.8), 219 (100), 206 (13.6) Di-DL-tartrate (C26H34N40 2C4H606), hygroscopic powder.
6-(3-Pyrrolidinopropyl)-5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 60), colorless prisms, m.p. 47.4-53.0 C.
Mass (m/e) (rel. intensity): 321 (M+, 31.5), 209 (60.8), 113(15.5), 111(23.8), 96 (13.7), 84 (100) Difumarate (C21H27N3.2C4H4O4), hydroscopic powder.
6-[2-(1-Piperidino)ethyl]-5-(4-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 63), colorless prisms, m.p. 82.3-87.6 C.
Mass (m/e) (rel. intensity): 335 (M+, 21.8), 237 (100), 223 (49.9), 98 (69.6) Difumarate (C22 H29 N32C4H404), m.p. 178-180 C (dec.).
5-(2-Methoxyphenyl)-6-C2-(4-methyl- 1 -piperazinyl)ethyl]-5, 6,7,8-tetrahydro-l, 6-naphthyridine (compound No. 70), light yellow oil.
Mass (m/e) (rel. intensity): 366 (M+, 29.4), 253 (100), 113(11.8) Di-DL-tartrate (C22H230N40 2C4H606), hygroscopic powder.
Example 2 This Example illustrates preparation of 2-[2-(4-(2-ethoxyphenyl)-1-piperazinyl]ethyl]- 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 50).
In 15 ml of ethanol was dissolved 1.2 g (6.4 m mol) of 1 ,2,3,4,6,7,8,9-octahydro-benzo[b]- 1,6-naphthyridine, and 2.2 g (6.4 m mol) of 1-(2-chloroethyl)-4-(2-ethoxyphenyl)piperazine dihydrochloride and 2 g (19.8 m mol) of triethylamine were added to the solution, and then the mixture was refluxed on an oil bath for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was made alkaline by addition of a 30% aqueous solution of sodium hydroxide and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 1.9 g (Y; 70.6%) of a light yellow oil.
NMR # (CDCl3): 1.46 (3H, t, J = 7.0 Hz; OCH2CH3), 1.67-2.15 (4H, m; C7-H and C8-H), 2.50-3.30 (20H, m; C3, C4, C6,
3.66 (2H, s; C1-H), 4.10 (2H, q; OCH2CH2), 6.70-7.30 (4H, m; phenyl), 7.29 (1H, s; C10-H) Mass (m/e) (rel. intensity): 420 (M+, 11.8), 219(100.0), 206 (15.6), 201 (33.6), 189 (12.2) Difumarate (C26H26N4O.2C4H4O4), colorless powdery crystals, m.p. 185.0-187.0 C.
The following compounds were prepared from corresponding starting compounds in the same manner as described above.
5,6,7,8-Tetrahydro-6-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]ethyl]-1,6-naphthyridine (compound No. 15), light yellow oil.
Mass (m/e) (rel. intensity): 366 (M+, 16.3), 220 (16.7), 219 (100, 206 (8.8), 204 (10.8), 189 (13.7), 163(14.2), 147 (10.3), 70 (17.6) Difumarate (C22H30N402C4H404), colorless prisms, m.p. 177-181 C (dec.).
6-[2-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]ethyl]5,6, 7,8-tetrahydro-2, 3-trimethylene-l ,6-naphthyri- dine (compound No. 31), colorless prisms, m.p. 105.0-107.5 C.
Mass (m/e) (rel. intensity): 362 (M+, 10.9), 256 (16.8), 187 (100), 175 (63.0) Difumarate (C23H30N4 2C4H404), colorless powdery crystals, m.p. 204.0-206.0 C.
6-[2-[4-(2-Ethoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-2,3-trimethylene-1,6-naphthyridine (compound No. 32), viscous oil.
Mass (m/e) (rel. intensity): 406 (M+, 5.0), 219 (100), 217 (10.0), 206 (9.3), 189 (9.8), 187 (40.3) Difumarate (C26H34N40 2C4H404), colorless powdery crystals, m.p. 1 98.0-200.0 C (dec.).
2-(3-Dimethylaminopropyl)-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine, (compound No. 33), light yellow oil. b.p. 158.0-164.0 C (0.1-0.2 mmHg) Mass (m/e) (rel. intensity): 2##M+, H27.0), 228 (29.2), 227 (31.4), 213 (28.6), 2## (29.2), 200 (26.5), 187 (100.0), 85 (65.4) Difumarate (C1 7H21N3 2C4H404), colorless powdery crystals, m.p. 203.0-206.0 C (dec.).
2-(2-Diethyleminoethyl)-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-aphthyridine (compound No.
34), light yellow oil, b.p. 161.0-164.0 C (0.55 mmHg).
Mass (m/e) (rel. intensity): 287 (M+, 8.1), 201 (61.7), 86 (100.0) Difumarate (C18H29N3 2C4H404), colorless powdery crystals, m.p. 158.5-160.0 C (dec.).
2-[(2-Diethylamino-1-methyl0ethyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 35), light yellow oil. b.p. 163.0-167.0 C (0.45 mmHg).
Mass (m/e) (rel. intensity): 301 (M+, 2.4), 215 (38.1), 100 (100.0) Di-DL-tartrate (C19H31N3.2C4H6O6), hygroscopic powder.
1,2,3,4,6,7,8,9-Octahydro-2-(2-diisopropylaminoethyl)-benxo[b]-1,6-naphthyridine (compound No. 37), light yellow oil. b.p. 175.0-182.0 C (0.4 mmHg).
Mass (m/e) (rel. intensity): 315 (M+, 30.5), 201 (52.4), 113(100.0) Di-DL-tartrate (C20H33N3.2C4H6O6), hygroscopic powder.
1,2,3,4,6,7,8,9-Octahydro-2-[2-(4-phenyl-1-piperazinyl)ethyl]-benzo[b]-1,6-naphthyridine (compound No. 41), colorless prisms, m.p. 125.0-127.0 c.
Mass (m/e) (rel. intensity): 376 (M+, 31.4), 270 (25.7), 201(100.0), 175(60.0) Difumarate (C24H32N4.2C4H4O4), colorless powdery crystals, m.p. 208.0-210.0 C (dec.).
1 ,2,3,4,6,7,8, 9-Octahydro-2-[3-(4-phenyl- 1 -piperazinyl)propyl]-benzo[b], 1 ,6-naphthyridine (compound No. 42), colorless needles, m.p. 83.0-83.5 C.
Mass (m/e) (rel. intensity): 390 (M+, 100), 258 (97.1), 213(27.1), 201 (91.2), 200 (38.2), 187(59.1), 175(34.4), 173 (25.9), 161(27.4), 132 (20.8) Difumarate (C25H24N4.2C4H4O4), colorless powdery crystals, m.p. 212.0-213.0 C (dec.).
1,2,3,4,6,7,8, 9-Octahydro-2-[2-[4-(2-methoxyphenyl)- 1 -piperazinyl]ethyl]-benzo[b]-1 , 6-naphthyridine (compound No. 47), light yellow oil.
Mass (m/e) (rel. intensity): 406 (M+, 17.5), 205 (100.0), 201 (37.5), 191(16.3) Difumarate (C25H34N40'2C4H404), colorless powdery crystals, m.p. 206.0-207. C (dec.).
1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-benzo[b]-1,6-naphthyridine (compound No. 48), colorless prisms, m.p. 127.0-128.5'C.
Mass (m/e) (rel. intensity): 406 (M+, 19.1), 205 (84.0), 203 (34.6), 201(100.0), 185 (36.5) Difumarate (C35H34N4O2C4H404), colorless powdery crystals, m.p. 119.0-201.5 C (dec.).
1,2,3,4,6,7,8,9-Octahydro-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]-benzo[b]-1,6-naphthyridine (compound No. 49), light yellow oil Mass (m/e) (rel. intensity): 420 (M+, 89.2), 257 (100.0), 201 (62.3), 191(47.3), 187 (34.2) Difumarate (C26H36N4O.2C4H4O4), colorless powdery crystals, m.p. 201.0-202.0 C (dec.).
2-[3-[4-(2-ethoxyphenyl)-1-piperqazinyl]propyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 53), light yellow oil.
Mass (m/e) (rel. intensity): 434 (M+, 69.3) 258 (100.0), 244 (22.7), 233 (29.6), 219 (28.3), 205 (32.0), 201 (70.5), 187 (35.0) Difumarate (C26H38N4O.2C4H4O4), colorless powdery crystals, m.p. 192.0-193.5 C (dec.).
1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-pyridyl-1-piperazinyl]ethyl]-benzo[b]-1,6-naphthyridine (compound No. 57), colorless prisms, m.p. 115.0-117.0 C.
Mass (m/e) (rel. intensity): 377 (M+, 36.9), 201 (96.6), 176 (100.0) Difumarate (C23H31N5.2C4H4O4), colorless powdery crystals, m.p. 205.0-208.0 C (dec.).
6-[2-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]ethyl]-5-methyl-5, 6,7, 8-tetrahydro- 1 6-naphthyrid ine (compound No. 58), light yellow oil.
Mass (m/e) (rel. intensity): 380 (M+, 14.8), 220 (19.3), 219 (100.0), 206 (8.3), 189 (9.8), 161(22.7) Di-DL-tartrate (C23H 32N40 2C4H6O6), hygroscopic powder.
6-(2-[2-(1 -Methyl)pyrrolidinyl]ethyl]-5, 6,7, 8-tetrahydro- 1, 6-naphthyridine (compound No. 61), light yellow oil.
Mass (m/e) (rel. intensity): 321 (M+, 6.9), 209 (25.6), 111 (64.5), 84 (100.0) Di-DL-tartrate (C21H27N3.2C4H6O6), hygroscopic powder.
6-[3-(4-Methyl-1-piperazinyl)propyl]-5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 62), light yellow oil.
Mass (m/e) (rel. intensity): 350 (M+, 100.0), 306 (16.3), 280(19.4), 209(28.6), 113(65.7) Difumarate (C22H30 N42C4H404), colorless powdery crystals, m.p. 186-189'C (dec.).
6-(3-Diethylaminopropyl)-5-(4-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 64), light yellow oil.
Mass (m/e) (rel, intensity): 337 (M+, 100.0), 264 (25.6), 223 (66.1), 113(44.6), 86 (100.0) Di-DL-tartrate (C22H31N3.2C4H6O6, hygroscopic powder.
6-(2-Diethylaminoethyl)-5-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No.
65), light yellow oil.
Mass (m/e) (rel. intensity): 345 (M+ + 2, 1.1)343 (M+, 1.5), 259 (2.4), 257 (7.0), 101 (6.0), 86 (100.0) Di-DL-tartrate (C20H26ClN3.2C4H6O6), hygroscopic powder.
6-[3-(4-Methyl-1-piperazinyl)propyl]-5-(3-chlorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 66), light yellow oil.
Mass (m/e) (rel. intensity): 386 (M+ + 2, 28.4), 384 (M+, 81.8), 342 (9.5), 340 (23.4), 316(9.1), 314(25.0), 113(100) Di-DL-tartrate (C22H29CI N4 2C4H606), hygroscopic powder.
6-[2-( 1 -Pyrrolidinyl)ethyl]-5-(4-chlorophenyl)-5, 6,7, 8-tetrahydro- 1 , 6-naphthyridine (compound No. 67), light yellow oil.
Mass (m/e) (rel. intensity): 343 (M+ + 2, 1.3), 341 (M+, 4.1), 259 (8.5), 257 (24.8), 99 (19.4), 84 (100) Di-DL-tartrate (C20H24ClN3.2C4H6O6, hygroscopic powder.
5-(4-Chlorophenyl)-6-[2-(1-methyl-2-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 68), light yellow oil.
Mass (m/e) (rel. intensity): 357 (M+ + 2, 3.7), 355 (M+, 10.3), 245 (2.8), 243 (8.1), 111 (53.8), 84 (100) Di-DL-tartrate (C21H26ClN3.2C4H6O6), hygroscopic powder.
5-(2-Methoxyphenyl)-6-[2-(1-methyl-2-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 69), light yellow oil.
Mass (m/e) (rel. intensity): 351 (M+, 12.9), 239 (56.7), 111 (100.0), 84(65. 7) Difumarate (C22H29N3 2C4H404), colorless powdery crystals, m.p. 148.0-168.0 C.
5-(4-Methoxyphenyl)-6-(2-diethylaminoethyl)-5, 6,7, 8-tetrahydro- 1 ,6-naphthyridine (compound No. 71), light yellow oil.
Mass (m/e) (rel. intensity): 339 (M+, 6.0), 253 (92.9), 239 (15.5), 86 (100) Di-DL-tartrate (C21H29N3O.2C4H6O6), hygroscopic powder.
5-(4-Methoxyphenyl)-6-(3-diethylaminopropyl)-5, 6,7, 8-tetrahydro- 1 6-naphthyridine (compound No. 72), light yellow oil.
Mass (m/e) (rel, intensity): 353 (M+, 62.3), 279 (21.3), 254 (15.8), 253 (13.2), 239 (63.6), 113(34.8), 86 (100.0) Di-DL-tartrate (C22H31N3O.2C4H6O6), hygroscopic powder.
7-Methyl-6-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 73), light yellow oil.
Mass (m/e) (rei. intensity): 380 (M+, 5.7), 219 (100.0), 206 (8.1), 204 (7.6), 161(20.9) 7-Phenyl-6-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 74), light yellow oil.
Mass (m/e) (rel. intensity): 442 (M+, 6.8), 223 (27.1), 219 (100.0), 210(18.2), 206 (52.6) 8-Methyl-6-[2-(2-ethoxyphenyl)-i -piperazinyl]ethyl]-5, 6,7, 8-tetrahydro-1 ,6-naphthyridine (compound No. 75), light yellow oil.
Mass (m/e) (rel. intensity): 380 (M+, 8.8), 219 (100.0), 206 (11.5), 204 (9.4), 189 (9.4), 161(9.4) Difumarate (C23H32N4O 2C4H404), colorless prisms, m.p. 161.0-163.0 C.
8-Benzyl-6-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]ethyl-5,6,7,8-tetrahydro-1,6-naphthyridine (compound No. 76), light yellow oil.
Mass (m/e) (rel. intensity): 456 (M+, 14.0), 237 (20.2), 234 (23.0), 219(100), 206 (27.0) Difumarate (C29H36N4O 2C4H404), colorless prisms, m.p. 125.0-127.0 C.
Example 3 This example illustrates preparation of 5,6,7,8-tetrahydro-6-[2-[4-(2-methoxyphenyl)piperazinyl]ethyl]-1,6-naphthyridine (compound No. 11).
(1) Preparation of 5,6,7,8-tetrahydro-6-(2-chloroethyl)-1,6-naphthyridine: In 150 ml of anhydrous benzene was dissolved 8.05 g (60 m mol) of 5,6,7,8-tetrahydro-1 6- naphthyridine, and 3.14 g (72 m mol) of about 60% oily sodium hydride was added to the solution. The mixture was refluxed on an oil bath for 1.5 hours. Then, a solution of 10.3 g (72 m mol) of 1 -bromo-2-chloroethane in 30 ml of anhydrous benzene was dropped to the reaction mixture, and the mixture was refluxed on an oil bath for 24 hours. After completion of the reaction, water was added to the reaction mixture under ice cooling to decompose unreacted sodium hydride. The reaction mixture was then made acidic by addition of 6N hydrochloric acid and the water layer was extracted.The water layer was washed with ether, the pH value was adjusted to about 9 by a 30% aqueous solution of sodium hydroxide and extracted with ether.
The ether layer was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 7.2 g (Y; 61.0%) of S,6,7,8-tetrahydro-6-(2- chloroethyl)-i ,6-naphthyridine in the form of a light yellow oil.
(2) Preparation of 5,6,7,8-tetrahydro-6-[2-[4-(2-methoxyphenyl)-piperazinyl]ethyl] 1,6-naphthyridine: In 25 ml of ethanol was dissolved 5.9 g (30 m mol) of 5,6,7,8-tetrahydro-6-(2-chloroethyl)1,6-naphthyridine obtained in (1) above, and 6.92 g (36 m mol) of 4-(2-methoxyphenyl)piperazine and 5.03 ml (36 m mol) of triethylamine were added to the solution. The mixture was refluxed on an oil bath for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue, and the residue was mixed with a 30% aqueous solution of sodium hydroxide and extracted with ether. The ether layer was dried over an hydros potassium carbonate, and the solvent was removed by evaporation under reduced pressure.The obtained oily residue was purified by silica gel column chromatography (a mixture of chloroform:ethanol (5:1) solvent was used as the eluting solvent) to give 5.98 g (Y; 56.6%) of a light yellow oil.
neat IR v cm-1: max 2930, 2800, 1580, 1495, 1450 NMR 8 (CDCl3): 2.6-3.3 (16H, m;
C7-H and C8-H), 3.35 (2H, s; C5-H), 3.87 (3H, s; CH3O), 6.92 (4H, s; phenyl), 7.00 (iH, dd, J32 = 4.5 Hz, J34 = 8.0 Hz, C3-H), 7.36 (1 H, dd, J42 = 2.5 Hz, J43 = 8.0 Hz; C4-H), 8.35 (1 H, dd, J23 = 4.5 Hz, J24 = 2.5 Hz; C2-H) Mass (m/e) (rel. intensity): 352 (M+, 11.1), 205 (100), 192(100), 175(12.7), 149 (10.6), 147 (8.4) Difumarate (C21 H28N4O2C4H404), colorless powdery crystals, m.p. 168.0-168.5 C (dec.).
The following compounds were synthesized from corresponding starting compounds in the same manner as described above.
5,6,7,8-Tetrahydro-6-(3-diethylaminopropyl)-1,6-naphthyridine (compound No. 1), colorless oil, b.p. 131-132'C 10.7 mmHg).
Mass (m/e( (rel. intensity): 247 (M+, 40.5), 174(37.7), 173(195,5), 159 (30.8), 147 (28.3), 113(33.0), 98 (22.6), 86 (100) 5,6,7,8-Tetrahydro-6-[2-(1-piperidinyl)ethyl]-1,6-naphthyridine (compound No. 3), colorless oil, b.p. 143-145 C (0.6 mmHg).
Mass (m/e) (rel. intensity): 245 (M+, 6.5), 147 (9.2), 98 (100) 5,6,7,8-Tetrahydro-6-(1-piperazinyl)propyl]-1,6-naphthyridine (compound No. 4), colorless oil.
b.p. 152-156 C (0.7 mmHg).
Mass (m/e) (rel. intensity): 259 (M+, 47.1), 98 (100) 5,6,7,8-Tetrahydro-6-[3-[4-(4-fluorophenyl)- 1 -piperazinyl]propyl]- 1,6-naphthyridine (compound No. 6), yellow oil.
Mass (m/e) (rel. intensity): 354 (M+, 100), 204 (58.1), 147 (39.5) Difumarate (C21H27N4F.2C4H4O4), colorless powdery crystals, m.p. 204.0-207.0 C.
5,6,7,8-Tetrahydro-6-[3-[4-(3-chlorophenyl)- 1 -piperazinyl]propyl]- 1,6-naphthyridine (compound No. 8), light yellow oil.
Mass (m/e) (rel. intensity): 372 (M+ + 2, 33.8), 370 (M+, 97,6), 230 (26.2), 211 (19.0), 209 (37.1), 204 (100), 147 (88.6) Difumarate (C21H27N4Cl2C4H4O4), colorless powdery crystals, m.p. 208.2-209.8 C (dec.).
5,6,7,8-Tetrahydro-6-[3-[4-(4-chlorophenyl)-1-piperazinyl]propyl]-1,6-naphthyridine (compound No. 9), light yellow oil.
Mass (m/e) (rel. intensity): 372 (M+ + 2, 33.9), 370 (M+, 88.5) 230 (25.9), 211(15.5), 209 (26.7), 204 (100), 147 (80.5) Difumarate (C21H27N4Cl.2C4H4O4), colorless powdery crystals, m.p. 210.5-212.7 C (dec.).
5,6,7,8-Tetrahydro-6-[3-[4-(2-methylphenyl)-1-piperazinyl]propyl]-1,6-naphthyridine (compound No. 10), light yellow oil.
Mass (m/e) (rel. intensity): 350 (M+, 68.1), 204(100), 189 (29.2), 175 (31.9), 159(22.6), 147 (70.9) Difumarate (C22H30N4,2C4H404), colorless powdery crystals, m.p. 176.0-179-0 C (dec.).
5,6,7,8-Tetrahydro-6-[3-[4-(2-methoxyphenyl)-1-piperazinyl]fpropyl]-1,6-naphthyridine (compound No. 12), light yellow oil.
Mass (m/e) (rel. intensity): 366 (M+, 100, 204 (70.3), 147 (34.2) Difumarate (C22H30N4O.2C4H4O4), colorless powsery crystals, m.p. 177.0-182.0 C.
5,6,7,8-Tetrahydro-6-[3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]propyl]-1,6-naphthyridine (compound No. 13), light yellow oil.
Mass (m/e) (rel. intensity): 404 (M+, 100), 243 (28.6), 230 (17.6), 204 (59.2), 147 (51.0) Difumarate (C22H37N4F3.2C4H404), colorless powdery crystals, m.p. 202.7-204.6oC (dec.).
5,6, 7,8-Tetrahydro-6-[3-(4-hydroxy-4-phenyl) 1 -piperazinyl]propyl]-1 ,6-naphthyridine (compound No. 17), light yellow oil.
Mass (m/e) (rel. intensity): 351 (M+, 18.1), 190(20.0), 189 (100), 172(22.0), 75 (24.2) DL-Tartrate (C22H29N4O.3/2C4H6O6). colorless powdery crystals, m.p. 98.0-103.0 C.
5,6,7,8-Tetrahydro-6-[3-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]propyl]-1,6-naphthyridine (compound No. 18), light yellow oil.
Mass (m/e) (rel. intensity): 387 (5.8), 386 (18.7), 385 (M+, 14.4), 384 (48.5), 225 (36.5), 223 (100, 174(33.1), 171 (6.5), 169 (18.7) DL-Tartrate (C22H29N4O3/2C4H6O6), colorless powdery crystals, m.p. 102.0-108.0 c.
Example 4 This Example illustrates preparation of 2-[2-(4-benzyl-1 -piperazinyl)ethyl]- 1,2,3,4,6,7,8,9- octahydro-benzo[b]-1,6-naphthyridine (compound No. 40).
(1) Preparation of 2-(2-hydroxy)ethyl- 1 ,2,3,4,6,7,8, 9-octahydro-benzo[b]- 1 ,6-naphthyridine: In 50 ml of ethanol were dissolved 5.0 g (26.6 m mol) of 1,2,3,4,6,7,8,9-octahydro- benzo[b]-1,6-naphthyridine, 5.0 g (39.9 m mol) of ethylene bromohydrin and 4.0 g (39.9 m mol) of triethylamine, and the solution was refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was made alkaline by addition of a 40% aqueous solution of sodium hydroxide and extracted with toluene.
The toluene extract was dried with an hydros potassium carbonate and the solvent was removed by distillation under reduced pressure. The obtained oily residue was subjected to distillation under reduced pressure to give 6.0 g (Y; 97.1%) of a light yellow oil, b.p. 181.0-183.0 C (0.35 mmHg).
neat IR v cm-1: max 3200 (OH) NMR 8 (CDCl3): 1.50-2.13 (4H, m; C7 and C8-H), 2.42-3.20 (10H, m; C3, C4 C6, C9 and NCH2CH2OH), 3.64 (2H, s; C,-H), 3.70 (1 H, s; OH, exchangeable), 3,73 (2H, t, J = 5.0 Hz; NCH2CH2OH), 6.98 (1H, s; C10-H) (2) Preparation of 2-(2-chloro)ethyl-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine dihydrochloride: Under ice cooling, 6.0 g (25.8 m mol) of 2-(2-hydroxy)ethyl-l .2,3,4,6,7,8,9-octahydro- benzo[b]-1,6-naphthyridine synthesized in (1) above was gradually added to 9.2 g (77.4 m mol) of thionyl chloride with stirring, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue, and the residue was washed with a small amount of ether, dissolved in ethanol and decolorized by active carbon. After removal of the active carbon, recrystallization from ethanol was directly carried out to give 5.8 g (Y; 69.5%) of colorless prisms, m.p.
208.0-211.0 C (dec.).
NMR # (D2O, I.S. DSS): 1.61-2.26 (4H, m; C7 and C8-H), 2.70-3.30 (4H, m; C6 and Q-H), 3.38-4.37 (8H, m; C3, C4 and NCH2CH2CI), 3.80 (2H, s; C1-H), 8.12 (1H, s; C,o-H) (3) Preparation of 2-[2-(4-benzyl- 1 -piperazi nyl)ethyl]- 1 2,3,4,6,7,8, 9-octahydro-benzo[b]- 1 ,6-na- phthyridine (compound No. 40): To 30 ml of ethanol were added 2.5 g (7.7 m mol) of 2-(2-chloro)ethyl-1,2,3,4,6,7,8,9- octahydro-benzo[b]-1,6-naphthyridine dihydrochloride synthesized in (2) above, 1.6 g (9.3 m mol) of 1-benzylpiperazine and 2.8 g (27.9 m mol) of triethylamine, and the mixture was refluxed for 2 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was made alkaline by addition of a 40% aqueous solution of sodium hydroxide and extracted with toluene. The toluene extract was dried and anhydrous potassium carbonate and the solvent was removed by distillation under reduced pressure. When the obtained oily residue was allowed to stand still, the oil was crystallized. The obtained crude crystals were recrystallized from petroleum ether to give 2.4 g (Y; 80.0%) of a colorless prisms, m.p. 57.0-59.0 C.
NMR # (CDCl3): 1.63-1.96 (4H, m; C7 and C8-H), 2.35-3.10 (20H, m; C3, C4, C6, C9 and
3.50 (2H, s; C1-H or CH2C6H5), 3.59 (2H, s; CH2C6H5 or C,-H), 6.96 (1 H, s; C,o-H), 7.29 (5H, s; phenyl) Mass (m/e) (rel. intensity): 390 (M+, 16.0), 299 (6.0), 215 (17.1), 201 (65.6), 187 (100) Difumarate (C2rjHs4N4 2C4H404) colorless powdery crystals, m.p. 229.0.-231.0 C.
The following compounds were synthesized from corresponding starting compounds in the same manner as described above.
5,6,7,8-Tetrahydro-6-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propyl]-1,6-naphthyridine (compound No. 16), light yellow oil.
Mass (m/e) (rel. intensity): 380 (M+, 22.0), 379 (64.3), 233(34.1), 217(34.1), 205 (51.2), 204 (100), 147 (75.6) Difumarate (C23H32N4O 2C4H404), colorless prisms, m.p. 138.0-141.5 C (dec.).
1.2,3,4,6,7,8, 9-Octahydro-2-[2-( 1 -pyrrolidinyl)ethyl]-benzo[b]- 1 , 6-naphthyridine (compound No.
36), colorless prisms, m.p. 71.0-72.0 C (dec.).
Mass (m/e) (rel. intensity): 285 (M+, 11.8), 201 (100), 84 (66.2) Difumarate (C,8H27N3 2C4H404), colorless powdery crystals, m.p. 193.0-196.0 C (dec.).
1 ,2,3,4,6,7,8, 9-Octahydro-2-[2-( 1 -morpholinyl)ethyl]-benzo[b)- 1 ,6-naphthyridine (compound No. 38), colorless prisms, m.p. 50.0-53.0 c.
Mass (m/e) (rel. intensity): 301 (M+, 3.7), 201(100), 100 (9.2) Difumarate (C,8H27N3O 2C4H404), colorless powdery crystals, m.p. 203.0-206.0 C (dec.).
1,2,3,4,6,7,8,9-Octahydro-2-[2-(4-methyl- 1 -piperazinyl)ethyl]-benzo[b]- 1,6-naphthyridine (compound No. 39), colorless prisms, m.p. 71.0-72.0 c.
Mass (m/e) (rel. intensity): 314 (M+, 13.0), 270 (4.4), 215(6.6), 201 (60), 113(100) Difumarate (C1gH30N4 2C4H404), colorless powdery crystals, m.p. 222.0-225.0 C (dec.).
Example 5 This Example illustrates preparation of 2-[[2-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-methyl]- 1,2, 3,4, 6,7,8, 9-octa hydro-benzo[b]-l ,6-naphthyrid ine (compound No. 51).
(1) Preparation of 1 (2-chloropropionyl)-4-(2-ethoxyphenyl)piperazine: In 150 ml of chloroform were dissolved 6.2 g (30 m mol) of l-(2-ethoxyphenyl)piperazine and 5.0 ml (36 m mol) of triethylamine, and the solution was cooled to a temperature of about 10 C under ice cooling with stirring and a solution of 4.6 g (36 m mol) of 2-chloropropionyl chloride in 30 ml of chloroform was gradually dropped to the above solution. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue, and the residue was made acidic by addition of dilute hydrochloric acid and washed with toluene. The aqueous layer was made alkaline by addition of a 40% aqueous solution of sodium hydroxide and extracted with toluene.
The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained crystalline residue was recrystallized from petroleum ether to give 6.2 g (Y; 73.6%) of colorless prisms, m.p. 68.0-68.5 C.
KBr IR v cm-': max 1645 (CO) NMR 8 (CDCl3): 1.45 (3H, t; OCH2CH3), 1.70 (3H, d; COCH(CH3)CI), 2.80-3.30 (4H, m;
3.50-4.10 (4H,
4.07 (2H, dd; OCH2CH3), 4.63 (1H, dd; COCH(CH3)CI) (2) Preparation of 2-[[2-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-methyl-2-oxo]ethyl]- 1,2,3,4,6,7,8,9-octahydro-benzo[b]- ,6-naphthyridine: In 80 ml of ethanol were dissolved 4.2 g (15 m mol) of 1-(2-chloropropionyl)-4-(2- ethoxyphenyl)piperazine synthesized in (1) above, 3.4 g (18 m mol) of 1,2,3,4,6,7,8,9 octahydro-benzo[b]-l,6-naphthyridine and 5.1 g (50 m mol) of triethylamine, and the solution was refluxed for 76 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was made acidic by addition of 3N hydrochloric acid and washed with toluene. The aqueous layer was made alkaline by addition of a 40% aqueous solution of sodium hydroxide under ice cooling and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 4.9 g (Y; 73.0%) of a light yellow oil.
KBr IR u cm-': max 1647 (CO) NMR 8 (CDCl3): 1.27 (3H, d, J = 7.0 Hz; NCH(CH3)CO), 1.40 (3H, t, J = 7.0 Hz; OCH2CH3), 1,60-2.10 (4H, m; C7 and C8-H), 2.40-3.30 (12H, m; C3, C4, C6, C9-H and phenyl
3.30-4.10 (7H, m; C,-H,
and NCH(CH3)CO), 4.03 (2H, q, J = 7.0 Hz;OCH2CH3), 6.50-7.30 (5H, m; C,o-H and phenyl) (3) Preparation of 2-[[2-[4-(2-ethoxyphenyl)- 1 -piperazinyl]-l -methyl]ethyl]- 1 ,2, 3,4,6,7,8, 9-oc- tahydro-benzo[b]-l ,6-naphthyridine (compound No. 51): In 80 ml of anhydrous ether was suspended 0.4 g (10.6 m mol) of lithium aluminum hydride, and a solution of 4.8 g (10.6 m mol) of 2-[[2-[4-(2-ethoxyphenyl)-1-piperazinyl]-1- methyl-2-oxo]ethyl] 1 ,2,3,4,6,7,8, 9-octahydro-benzo[b]-1 ,6-naphthyridine obtained in (2) above in 40 ml of anhydrous ether was dropped to the above suspension at room temperature with stirring. The mixture was then refluxed for 4 hours.After completion of the reaction, about 1 ml of water was added to the reaction mixture to decompose excessive lithium aluminum hydride.
The precipitated colorless solid was removed by filtration. The filtrate was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oily residue was purified by silica gel chromatography (a mixture of toluene:ethanol (5:1) solvent was used as the eluting solvent), and the obtained crude crystal was recrystallized from isopropyl ether to give 3l.0 g (Y; 64.8%) of colorless prisms, m.p. 122.0-123.0ïC.NMR # (CDCl3): 1.13 (3H, d, J = 7.0 Hz; NCH (CH3)CH2), 1.43 (3H, t, J = 7.0 Hz; OCH2CH3), 1.60-2.10 (4H, m; C7 and C8-H), 2.10-3.50 (19H, m; C3, C4, C6, C9-H and
3.77 (2H, s; C1-H), 4.05 (2H, q, J = 7.0 Hz; OCH2CH3), 6.70-7.10 (5H, m; C,o-H and phenyl) Mass (m/e) (rel. intensity): 434 (M+, 4.0), 219 (4.5), 214(16.8), 215(100) Difumarate (C27H38N4O 2C4H404), colorless powdery crystals, m.p. 129.0-131.0 C (dec.).
The following compound was synthesized from corresponding starting compounds in the same manner as described above.
5,6,7,8-Tetrahydro-6-[[2-[4-(2-methoxyphenyl)-1-piperazinyl]-1-methyl]ethyl]-1,6-naphthyridine (compound No. 19), viscous oil.
Mass (m/e) (rel. intensity): 366 (M+, 8.3). 206 (10.7), 205 (29.6), 162(15.4), 161(100) Difumarate (C22H30N4O 2C4H404), colorless powdery crystals, m.p. 94.9-96.0 C.
Example 6 This Example illustrates preparation of 2-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]-propyl]- 1 ,2,3,4,6,7,8,9-octahydrn-benzo[b]-i ,6-naphthyridine (compound No. 52).
(1) Preparation of 2-(2-chloro)propionyl- 1 2,3,4,6,7,8, 9-octahydro-benzo[b]-i , 6-naphthyridine In 100 ml of chloroform were dissolved 3.8 g (20 m mol) of i,2,3,4,6,7,8,9-octahydro benzo[b]-1 ,6-naphthyridine and 2.4 g (24 m mol) of triethylamine, and the solution was cooled to a temperature of about 10"C under ice cooling with stirring and a solution of 30 g (24 m mol) of thionyl chloride in 20 ml of chloroform was gradually dropped to the above solution.
The mixture was then stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue and the obtained residue was made acidic by addition of 3N hydrochloric acid and washed with toluene.
The water layer was made alkaline by addition of a 30% aqueous solution of sodium hydroxide with stirring and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained crude crystal was recrystallized from isopropyl ether to obtain 4.2 g (Y; 75.3%) of a colorless needles, m.p. 113.0-115.0 C.
KBr IR v cm-1: max 1644 (C=O) NMR S (CDCI3): 1.60-2.10 (4H, m; C7 and C8-H), 1.68 (3H, d, J= 7.0 Hz; CH3), 2.50-3.20 (6H,m; C4, C6 and C9-H), 3.88 (2H, t, J = 7.0 Hz; C3-H), 4.60 (1 H, q, J = 6.0 Hz; NCOCH(CH3)CI), 4.65 (2H, s;C1-H), 7.10 (1H, s; C,,-H) (2) Preparation of 2-[2-[4-(2-ethoxyphenyl)- 1 -piperazinyl]propionyl]-l ,2, 3,4, 6, 7, 8, 9-octahydro- benzo[b]-1 ,6-naphthyridine: To 80 ml of ethanol were added 4.2 g (15 m mol) of 2-(2-chloropropionyl)-1,2,3,4,6,7,8,9- octahydro-benzo[b]-l ,6-naphthyridine prepared in (1) above, 4.4 g (18 m mol) of 1-(2ethoxyphenyl)piperazine monohydrochloride and 3.6 g (36 m mol) of triethyl amine, and the mixture was refluxed for 76 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give residue, and the obtained residue was made acidic by addition of 3N hydrochloric acid and washed with toluene.The water layer was made alkaline by addition of a 30% aqueous solution of sodium hydroxide under ice cooling and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation to give 5.7 g (Y; 84.8%) of an oily product.
CHCl IR v 3 cm-': max 1635 (CO) NMR 8 (CDCl3): 1.27 (3H, d, J = 7.0 Hz; NCOCH(CH3)N), 1.50 (3H, t, J = 7.0 Hz; OCH2CH3), 1.60-1.90 (4H, m; C7 and C8-H), 2.50-3.20 (14H, m; C4, C6, C9-H and
3.30-4.30 (5H, m; C3-H, OCH2CH3, and NCOCH(CH3)N), 4.40-4.90 (2H, s;C1-H), 6.85 (4H, s; phenyl), 7.1 (1H, s; C,o-H) (3) Preparation of 2-[2-[4-(2-ethoxyphenyl)- 1 -piperazinyl]propyl]-i ,2,3,4,6,7,8, 9-octahydro-ben- zo[b]-i ,6-naphthyridine (compound No. 52): In 80 ml of anhydrous ether was suspended 0.45 g (11.9 m mol) of lithium aluminum hydride, and a solution of 5.36 g (11.9 m mol) of 2-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]propio- nyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine synthesized in (2) above in 40 ml of anhydrous ether was dropped to the above suspension. The mixture was then refluxed for 4 hours. After completion of the reaction, about 1 ml of water was added at room temperature to the reaction mixture to decompose excessive- lithium aluminum hydride. The precipitated colorless solid was removed by filtration, and the filtrate was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (a mixture of tolueneethanol (5:1) solvent was used as the eluting solvent) to give 3.10 g (Y; 59.7%) of a light yellow oil.
NMR # (CDCl3): 1.13 (3H, d, J = 7.0 Hz; HCH(CH3)), 1.43 (3H, t, J = 7.0 Hz; OCH2CH3), 1.60-2.00 (4H, m; C7 and C8-H), 2.30-3.30 (19H, m; C3, C4, C6, C9-H and
3.62 (2H, s; C1-H), 4.05 (2H, q, J = 7.0 Hz; OCH2CH3), 6.60-7.10 (5H, m; C10-H and phenyl) Mass (m/e) (rel. intensity): 434 (M+, 1.9), 234 (17.5), 233(100.0), 231(6.5) The DL-tartrate was prepared from the so obtained free base in the same manner as described in Example 4 except that DL-tartaric acid was used instead of fumaric acid.
Di-Dl-tartrate (C27H38N4O.2C4H6O6), colorless powdery crystals, m.p. 91.0-94.0 C.
The following compounds was synthesized from corresponding starting compounds in the same manner as described above.
2-[2-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]ethyl]-i 2,3,4,6,7,8, 9-octahydro-benzo[b]- 1 , 6-naphthyri- dine (compound No. 20), light yellow oil.
Mass (m/e) (rel. intensity): 366 (M+, 1.47), 219 (16.7), 218(100.0), 190(4.1) Difumarate (C22H30N4O-2C4H404), colorless powdery crystals, m.p. 120.0-122.0 C.
Example 7 This Example illustrates preparation of 2[[3-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-methyl]pro- pyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine (compound No. 54).
(1) Preparation of 1 -(crotonyl)-4-(2-ethoxyphenyl)piperazine In 150 ml of chloroform were dissolved 6.2 g (30 m mol) of 2-ethoxyphenylpiperazine and 3.0 ml (37 m mol) of.pyridine, and a solution of 3.8 9 (36 m mol) of crotonyl chloride in 30 ml of chloroform was dropped to the above solution under ice cooling with stirring at a temperature of about 10 C. Then, the mixture was further stirred for 1 hour at room temperature. After completion of the reaction, the liquid reaction mixture was concentrated under reduced pressure to give the residue, and the obtained residue was made acidic by addition of 3N hydrochloric acid and washed with toluene. The aqueous layer was made alkaline by addition of a 30% aqueous solution of sodium hydroxide under ice cooling and extracted with toluene.The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 7.91 g (Y; 95.9%) of a colorless oily product.
CHCI3 IR v cm-': max 1655 (C=O) NMR # (CDCl3): 1.45 (3H, t, J = 7.0 Hz; OCH2CH3), 1.87 (3H, dd, J = 1,5 Hz, J = 6.0 Hz; = CH-CH3), 3.04 (4H, t, J = 5.0 Hz; phenyl
3.78 (4H, t, J = 5.0 Hz;
4.06 (2H, q, J = 7.0 Hz; OCH2CH3), 6.26 (1H, dd, J= 1.5 Hz, J= 15.5 Hz; CO-CH=CHCH3), 6.60-7.13 (1H, m; CO-CH = CHCH3), 6.88 (4H, s; phenyl) (2) Preparation of 2-[[3-[4-(2-ethoxyphenyl)- 1 -piperazinyl]- 1 -methyl-3-oxo]propyl] 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine: In 10 ml of ethanol were dissolved 13.4 g (18 m mol) of i,2,3,4,6,7,8,9-octahydro- benzo[b]-1,6-naphthyridine and 4.1 g (15 m mol) of 1-(crotonyl)-4-(2-ethoxyphenyl)piperazine.
and a 40% ethanol solution of Triton B was added to the above solution and the mixture was refluxed for 48 hours. ("Triton" is a registered Trade Mark.) After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and the obtained residue was made alkaline by addition of a 30% aqueous solution of sodium hydroxide and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (a mixture of chloroform:ethanol (10:1) solvent was used as the eluting solvent) to give 5.0 g (Y; 71.4%) of a light brown gam.
CHCI3 IR v cm-': max 1625 (C=O) NMR 8 (CDCl3): 1.20 (3H, d, J = 6.0 Hz; NCH(CH3)), 1.45 (3H, t, J = 7.0 Hz; OCH2CH3), 1.63-2.10 (4H, m; C7 and C8-H), 2.22-3.23 (15H, m;C3, C4, C6, C9-H, NCH(CH2CO and phenyl
3.23-3.93 (6H, m; C,-H and
4.07 (2H, q, J = 7.0 Hz; OCH3CH3), 6.89 (4H, s; phenyl), 6.99 (iH, s; C,o-H) (3) Preparation of 2-[[3-[4-(2-ethoxyphenyl)-1-piperazinyl]-1 -methyl]propyl- 1,2,3,4,6,7,8,9-oc- tahydro-benzo[b]-1,6-naphthyridine (compound No. 54):: In 80 ml of anhydrous ether was suspended 0.38 g (10 m mol) of lithium aluminum hydride, and a solution of 4.6 g (10 m mol) of 2-[[3-[4-(2-ethoxyphenyl)-l -piperazinyl]-l -methyl-3- oxo]propyl]- 1 2,3,4,6,7,8, 9-octahydro-benzo[b]-1 , 6-naphthyridine synthesized in (2) above in 20 ml of anhydrous ether was gradually dropped to the above suspension with stirring at room temperature and the mixture was refluxed for 1 hour. After completion of the reaction, about 1 ml of water was added to the reaction mixture at room temperature to decompose excessive lithium aluminum hydride. The precipitated colorless solid was removed by filtration, and the filtrate was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 3.8 g (Y; 85.5%) of a light yellow oil.
NMR # (CDCl3): 1.07 (3H, d, J = 6.5 Hz; NCH(CH3)), 1.43 (3H,t, J = 7.0 Hz; OCH3CH3), i.6i-2.10(6H, m; C7, C8-H and NCH(CH3)CH2CH2N), 2.20-3.35 (19H, m; C3, C4, C6, C9-H and
3.65 (2H, s; C1-H), 4.03 (2H, q, OCH2CH3), 6.87 (4H, s; phenyl), 6.96 (iH, s; C,o-H).
Mass (m/e) (rel. intensity): 448 (M+, 82.2), 302 (31.1), 292 (61.5), 247 (55.2), 219 (100.0), 215 (43.5), 187 (65.9), 163 (37.0) Di-DL-tartrate (C28H40N4O 2C4H606), hygroscopic powder.
The following compound was synthesized from corresponding starting compounds in the same manner as described above.
5,6,7,8-Tetrahydro-6-[[3-[4-(2-methoxyphenyl)- 1 -piperazinyl]- 1 -methyl]-propyl]- 1 , 6-naphthyri- dine (compound No. 21), viscous oil.
Mass (m/e) (rel. intensity): 380 (M+, 64.2), 248 (42.7), 233 (33.5), 218(25.4), 204(100.0), 161(40.2) Di-DL-tartrate (C33 H 32N40 2C4H606), hygroscopic powder.
Example 8 This Example illustrates preparation of 2-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]-butyl]- 1 2, 3,4, 6, 7, 8, 9-octahydro-benzo[b]- 1,6-naphthyridine (compound No. 56).
(1) Preparation of 2-crotonyl-1, ,2,3,4,6,7,8, 9-octahydro-benzo[b]- 1 , 6-naphthyridine: In 100 ml of chloroform were dissolved 3.8 9(20 m mol) of 1,2,3,4,6,7,8,9-octahydro- benzo[b]-1 ,6-naphthyridine and 2 ml (25 m mol) of pyridine, and a solution of 2.5 9 (24 m mol) of crotonyl chloride in 30 ml of chloroform was dropped to the above solution under ice cooling with stirring at a temperature of about 1 0 C. The mixture was then stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and the obtained residue was made acidic by addition of 3N hydrochloric acid and washed with toluene.The water layer was made alkaline by addition of a 30% aqueous solution of sodium hydroxide under ice cooling and extracted with toluene.
The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The resulting crystalline residue was recrystallized from isopropyl ether to give 5.0 g (Y; 97.6%) of a colorless prisms, m.p. 82.0-85.0 C.
CHCI3 IR v cm-1: max 1653 (CO) NMR # (CDCl3): 1.50-2.12 (4H, m; C7 and C8-H), 1.92 (3H, dd, J = 1.0 Hz, J = 6.0 Hz; COCH = COCH3), 2.43-3.13 (6H, m; C4, C6 and C9-H), 3.87 (2H, t, J = 6.0 Hz; C3-H), 4.70 (2H, s;C1-H), 6.32 (1H, dd, J = 1.0 Hz, J = 15.0 Hz; COCH=CHCH3), 6.62-7.19 (1H, m; COCH =CHCH3), 7.10 (1H, s, C10-H) (2) Preparation of 2-[3-[4-(2-ethoxyphenyl)-i -piperazinyl]butyl]-i ,2,3,4,6,7,8,9-octahydro-ben- zo[b]-1,6-naphthyridine: In 10 ml of ethanol were dissolved 3.85 g (15 m mol) of 2-crotonyl-1 ,2,3,4,6,7,8,9 octahydro-benzo[b]-1,6-naphthyridine obtained in (1) above and 3.7 g (18 m mol) of 2ethoxyphenyl-piperazine, and 2 ml of a 40% methanol solution of Triton B was added to the above solution and the mixture was heated and refluxed for 24 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the residue, and the obtained residue was made alkaline by addition of a 30% aqueous solution of sodium hydroxide and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The resulting oily residue was purified by repeating silica gel column chromatography (a mixture of chloroform:acetone (10:1) solvent and a mixture of chloroform:methanol (10:1) solvent were used as the eluting solvent) to give 4.1 g (Y; 58.7%) of a light brown viscous oil.
CHCI3 IR v cm-1: max 1628 (CO) NMR # (CDCl3): 1.17 (3H, d, J = 6.0 Hz; NCH(CH3)), 1.45 (3H, t, J = 7.0 Hz; OCH2CH3), 1.63-2.10 (4H, m; C7 and C6-H), 2.23-3.59 (17H, m; C4, C6, C7-H and
3.59-4.27 (1 H, m; C3-H), 4.07 (2H, q, J = 7.0 Hz; OCH3CH3), 4.68 (2H, s; C1-H), 6.88 (4H, s; phenyl), 7.10 (1H, s;C10-H) (3) Preparation of 2[3-[4-(2-ethoxyphenyl)-1 -piperazinyl]butyl]-1 ,2,3,4,6,7,8,9-octahydro-ben- zo[b]-l ,6-naphthyridine (compound No. 56): In 80 ml of ahydrous ether was suspended 0.30 g (8 m mol) of lithium aluminum hydride and a solution of 3.70 g (8 m mol) of 2-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]butytyl]- 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine obtained in (2) above in 20 ml of anhydrous ether was dropped to the suspension with stirring at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, about 1 ml of water was added to the reaction mixture to decompose excessive lithium aluminum hydride, and was stirred for a while.The precipitated colorless solid was removed by filtration, and the filtrate was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 3.2 g (Y; 89.5%) of a light yellow oil.
NMR # (CDCl3): 1.05 (3H, d, J = 5.5 Hz: NCH(CH3)), 1.43 (3H, t, J = 7.0 Hz; OCH2CH3), 1.60-2.10 (6H, m; C7, C8-H and NCH2CH2CH(CH3)), 2.23-3.33 (19H, m; C3, C4, C6, C9-H
3.56 (2H, s; C,-H), 4.02 (2H, q; OCH2CH3), 6.88 (4H, s; phenyl), 6.95 (iH, s; C,o-H) Mass (m/e) (rel. intensity): 448 (M+, 39.4), 298 (25.3), 272 (86.1), 235 (26.3), 233 (25.5), 205 (32.8), 201 (100.0), 200 (56.9) Di-DL-tartrate (C28H40N4O 2C4H 606), hygroscopic powder.
The following compounds were synthesized from corresponding starting compounds in the same manner as described above.
5,6,7, 8-Tetrahydro-6-[[3-[4-(2-methoxyphenyl)- 1 -piperazinyl]butyl]- 1 ,6-naphthyridine (compound No. 23), viscous oil.
Mass (m/e) (rel. intensity): 380 (M+, 32.8), 244 (31.6), 219 (53.7), 218(88.1), 191(40.9), 147 (100.0), 146 (65.7) Di-DL-tartrate (C23H32N4O.2C4H6O6), hygroscopic powder.
5,6,7, 8-Tetrahydro-6-[[3-[4-(2-methoxyphenyl)- 1 -piperazinyl]-2-methyl]propyl- 1,6-naphthyridine (compound No. 22), viscous oil.
Mass (m/e) (rel. intensity): 380 (M+, 50.5), 244 (33.7), 233 (30.5), 218 (99.3), 204 (77.6), 191(31.3), 147 (100.0) Di-DL-tartrate (C23H32N4O.2C4H6O6), hygroscopic powder.
2-[[3-[4-(2-ethoxyphenyl)- 1 -piperazinyl]-2-methyl]propyl]- 1 ,2,3,4,6,7,8, 9-octahydro-benzo[b]- 1,6-naphthyridine (compound No. 55), light yellow oil.
Mass (m/e) (rel. intensity): 448 (M+, 72.3), 298 (26.9), 272 (100.0) 247 (26.2), 219 (36.9), 205 (20.5), 201 (60.9) Di-DL-tartrate (C36H40N402C4H606), hygroscopic powder.
Processes for the preparation of compounds represented by the general formula (II) will now be described with reference to the following Examples.
Example 9 This Example illustrates preparation of 1,2,3,4,6,7,8,9-octahydro-benzo[b]-1,6-naphthyridine.
(1) Preparation of 2-benzyl-1,2,3,4,6,7,8,9-octahydro-benzo[b]- 1,6-naphthyridine: To a mixture of 6.0 g (48.0 m mol) of 2-aminomethylenehexanone and 10.9 g (57. 6 m mol) of i-benzyl-4-piperidone was added 60.0 mg of anhydrous ammonium acetate as a catalyst, and the mixture was reacted at 130 C on an oil bath for 24 hours. After completion of the reaction, 6N hydrochloric acid was added to the reaction mixture to adjust the pH value to 0.5 and the reaction mixture was washed with chloroform. A 40% aqueous solution of sodium hydroxide was added to the water layer under ice cooling to adjust the pH value to about 2.0 and the mixture was washed several times with toluene.The pH value was adjusted to 6.0 to 7.0 by a 40% aqueous solution of sodium hydroxide and was extracted several times with toluene. The toluene extracts were dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The resulting oily residue was subjected to distillation under reduced pressure to give a light yellow oil, b.p. 150.0-157'C (0.4 mmHg).
When the obtained light yellow oil was allowed to stand, it was crystallized. The resulting crude crystals were recrystallized from isopropyl ether to give 5.5 g (Y; 41.0%) of colorless prisms, 113.0-114.0 C.
NMR # (CDCl3): 1.46-2.06 (4H, m; C7 and C8-H), 2.46-3.11 (8H, m; C3, C4, C6 and C9-H), 3.53 (2H, s; C1-H or CH2C6H5), 3.69 (2H, s; CH2C6H5 or C,-H), 6.92 (2H, s; CXo-H), 7.09-7.46 (5H, m; phenyl) Mass (m/e) (rel. intensity): 278 (M+, 70.8), 277 (100.0), 187 (66.7)158(27.9), 101 (41.7) (2) Preparation of 1,2,3,4,6,7,8, 9-octahydro-benzo[b]- 1 ,6-naphthyridine: In 100 ml of acetic acid was dissolved 10.2 g (36.7 m mol) of 6-benzyl-1,2,3,4,6,7,8,9- octahydro-benzo[b]-1 ,6-naphthyridine, and 2.0 g of 10% Pd-C was added to the solution and catalytic hydrogenation was carried ot at 50 to 60'C on an oil bath. After theoretical amount of hydrogen gas was adsorbed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The resulting residue was made alkaline by addition of a 40% aqueous solution of sodium hydroxide and extracted with toluene.The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The resulting crystalline residue was recrystallized from isopropyl ether to give 6.6 g (Y; 95.7%) of colorless prisms. m.p. 99.0-100.0 C.
NMR # (CDCl3): 1.50-2.26 (4H, m; C7 and C8-H), 2.05 (1 H, s; C2-H, exchangeable), 2.54-3.50 (8H, m; C3, C4, C6 and C9-H).
The following compounds were synthesized from corresponding starting compounds in the same manner as described above.
2-Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine, colorless prisms, m.p. 48.0-49.0 C.
NMR # (CDCl3): 1.95 (1 H, s; C6-H, exchangeable), 2.53 (3H, s; CH3), 2.66-3.35 (4H, m; C7 and C8-H), 3.98 (2H, s; C5-H), 6,92 (1 H, d, J = 8.0 Hz; C3-H), 7,23 (1 H, d, J = 8.0 Hz; C4-H) Mass (m/e) (rel. intensity): 148 (M+, 100.0), 147 (73.0), 119(36.5) 5,6,7,8-Tetrahydro-2,3-trimethylene-1,6-naphthyridine, colorless prisms, m.p. 93.0-94.0 C.
NMR # (CDCl3): 1.82 (1 H, s; NH, exchangeable), 2.15 (2H, quin, J = 7.0 Hz; -CH2CH2CH2-), 2.70-3.40 (8H, m;-CH2CH2CH2-, C7 and C8-H), 3.96 (2H, s; C5-H), 7.13 (1H, s; C4-H) Mass (m/e) (rel. intensity): 174(M+, 100.0), 173 (77.8), 159(11.9), 145 (75.9) Example 10 This Example illustrates preparation of 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine: (1) Preparation of 6-benzyl-5-methyl-5,6, 7,8-tetrahydro-l .6-naphthyridine: To 150 ml of a 1 M tetrahydrofuran solution of methyl magnesium bromide (150 m mol) cooled by an ice bath in a nitrogen atmosphere, 5.1 g (50 m mol) of 6-benzyl-1,6naphthyridinium bromide was gradually added, and the mixture was violently stirred for 10 minutes.After completion of the reaction, 300 ml of a 20% aqueous solution of ammonium chloride was gradually added to the reaction mixture with stirring, and tetrahydrofuran was removed by evaporation under reduced pressure and the floating residual oily substance was extracted with ether. The ether layer was dried over an hydros potassium carbonate and the solvent was removed by evaporation under reduced pressure to give 13.26 g of a crude oily product. This oily product was dissolved in 250 ml of methanol and 250 ml of a 0.5M phosphoric acid buffer solution (pH = 7.0) was added to the solution, and 1.9 g (50 m mol) of sodium borohydride was gradually added to the mixture under ice cooling and stirring.The mixture was stirred for about 10 minutes and methanol was removed by evaporation under reduced pressure, and the floating oily substance was extracted with ether. The ether layer was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained crude oily product was purified by distillation under reduced pressure to give 10.80 g (Y; 90.8%) of a colorless oily product, b.p. 141 .0-143.0 C (0.3 mmHg).
NMR # (CDCl3): 1.33 (3H, d, J = 7.0 Hz; CH3), 2.4-3.3 (4H, m; C7 and C8-H), 3.4-4.1 (3H, m; C5-H and CH2C6H5), 6.90 (1 H, dd, J32 = 4.5 Hz, J34 = 8.0 Hz; C3-H), 7.0-7.5 (6H, m; C4-H and C6Hs), 8.30 (1 H, dd, J23 = 4.5 Hz, J24 = 2.0 Hz; C2-H Mass (m/e) (rel. intensity): 238 (M+, 3.71, 224(19.5), 223 (100), 91(14.6) (2) Preparation of 5-methyl-5, 6, 7, 8-tetrahydro-1 , 6-naphthyridine: 6-Benzyl-8-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine obtained in (1) above was subjected to catalytic hydrogenation in the same manner as described in (2) of Example 9, whereby the intended compound was obtained substantially quantitatively in the form of a colorless oil, b.p.
81.0-86.0 C (0.5 mmHg).
NMR # (CDCl3): 1.45 (3H, d, J = 7.0 Hz; CH3), 1.78 (1H, broad s; NH, exchangeable), 2.70-3.60 (4H, m; C7 and C8-H), 4.10 (1 H, q, J = 7.0 Hz: C5-H), 7.07 (1 K, dd, J32 = 5.0 Hz, J34 = 8.0 Hz; C3-H), 7.47 (1 H, dd, J42 = 1.5 Hz, J43 = 8.0 Hz; C4-H), 8.37 (1H, dd, J23 = 5.0 Hz, J24 = 1.5 Hz; C2-H) Mass (m/e) (rel. intensity): 148 (M+, 6.7), 147 (9.5), 134(12.8), 133 (100.0), 118(10.7), 106 (11.1), 79 (7.7), 71.6(12.8) The following compounds were synthesized from corresponding starting compounds in the same manner as described above.
5-Phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine, colorless prisms, m.p. 135-136.5 C.
Mass (m/e) (rel. intensity): 210 (M+, 29.6), 209 (14.0), 133(100.0), 107 (18.8) 5-(4-Tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine, colorless needles, m.p. 96.0-98.0 C.
Mass (m/e) (rel. intensity): 224 (M+, 55.7), 223 (31.1), 133 (100.0), 107 (33.0) 5-(4-Chlorophenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine, colorless prisms, m.p. 87.0-92.0 C.
Mass (m/e) (rel. intensity): 246 (M+ + 2, 7.6) 244 (M+, 23.7), 243 (10.2), 133 (100.0), 107 (32.2) S-(3-Chlorophenyl)-S,6,7, 8-tetrahydro- 1 , 6-naphthyridine, colorless leaflets, m . p.
109.0-109.5 C.
Mass (m/e) (rel. intensity): 246 (M+ + 2, 6.9), 244 (M+, 20.6), 243 (6.5), 133 (100.0), 107 (15.5) 5-(4-Methoxyphenyl)-5,6, 8-tetrahydro- 1 ,6-naphthyridine, colorless prisms, m . p. 49.0-52.5 'C.
Mass (m/e) (rel. intensity): 240 (M+, 100), 239 (46,8), 133(96.5), 107 (65.2) S-(2-Methoxyphenyl)-5,6,7, 8-tetrahydro-1 , 6-naphthyridine, light yellow oil.
Mass (m/e) (rel. intensity): 240 (M+, 69.9), 239 (23.5), 133(100.0), 107 (40.9) Example 11 This Example illustrates preparation of 7-methyl-5,6,7,8-tetrahydro-1 ,6-naphthyridine: (1) Preparation of 3-benzylaminomethyl-2-methyipyridine: To 250 ml of a 2M tetrahydrofuran solution of borane (0.5 mole) cooled by ice cooling in a nitrogen atmosphere, a solution of 22.6 g (0.1 mole) of N-benzyl-2-methyl-nicotinamide in 250 ml of anhydrous tetrahydrofuran was gradually added. After the completion of the addition, the temperature was gradually elevated and the mixture was refluxed for 2 hours.After completion of the reaction, the liquid reaction mixture was cooled by an ice bath and 100 ml of 6N hydrochloric acid was added to the reaction mixture in a nitrogen atmosphere, and tetrahydrofuran was removed by distillation under ordinary pressure. The resulting aqueous solution was made alkaline by 40% NaOH and extracted with toluene, and the toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oily residue was purified by distillation under reduced pressure to give 18.5 g (Y; 87.3%) of colorless oil, b.p. 139.0-142.0 C (0.6 mmHg).
NMR # (CDCl3): 1.55 (1H, broad s; NH, exchangeable), 2.53 (3H, s; CH3), 3.73 (2H, s; 3-pyridyl-CH2NH or phenyl-CH2N), 3.81 (2H, s; phenyl-CH3N or 3-pyridyl-CH2NH),7.02 (1 H, dd, J56 = 4.5 Hz, J54 = 7.5 Hz; C5-H),7.32 (5H, s; CH2C6H5), 7.24 (1H, dd, J45 = 7.5 Hz, J46 = 2.0 Hz; C4-H), 8.35 (1H, dd, J65 = 4.5 Hz, J64 = 2.0 Hz;C6-H) Mass (m/e) (rel. intensity): 212 (M+, 100), 211 (25.8), 121(87.8), 106 (49.8), 107 (40.2), 94 (20.6), 91 (15.8) (2) Preparation of 3-(benzylaminomethyl)-2-(2-hydroxypropyl) pyridine: In a nitrogen atmosphere, 10.5 ml (75 m mol) of diisopropylamine was added to 200 ml of anhydrous tetrahydrofuran cooled to -70 C by dry ice-acetone, and 40 ml of a 1.5M hexane solution of butyl lithium (60 m mol) was gradually added and the mixture was stirred at -70 C for 10 minutes.Then, a solution of 5.3 9 (25 m mol) of 3-(benzylaminomethylene)-2methylpyridine in 50 ml of anhydrous tetrahydrofuran was gradually dropped to the above solution so that the temperature did not exceed -60 C The mixture was stirred at -70 C for 1 hour to form a brown solution. Then, 7.0 ml (125 m mol) of freshly distilled acetaldehyde was gradually added to the above solution so that the temperature did not exceed -50 C. The resulting light yellow solution was stirred at -70 C for 30 minutes. After completion of the reaction, 20 ml of methanol was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. The resulting residue was made acidic by addition of 6N hydrochloric acid and washed with toluene. The aqueous solution was made alkaline with 40% aqueous solution of sodium hydroxide, and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The resulting oily residue was subjected to distillation under reduced pressure to give 5.12 g (Y; 79.8%) of a light yellow oil, b.p. 1 65.0-1 69.0'C (0.3 mmHg).
NMR 8 (CDCl3): 1.36 (3H, d, J = 6.5 Hz;
2.93-3.13 (2H, m; 2-pyridyl
3.13-3.98 (2H, broad; OH and, NH, exchangeable), 3.73 (2H, s; 3-pyridyt-CH2NK or phenyl
3.82 (2H, s; 3-pyridyl-CH2NH or phenyl
3.98-4.53 (1H, m;
7.05 (1 H, dd; J54 = 7.5 Hz, J56 = 5.0 Hz; (C5-H), 7.33 (5H, -C6H6). 7.52 (1 H, dd, J46 = 2.0 Hz, J45 = 7.5 Hz; C4-H), 8.39 (1 H, dd, J65 = 5.0 Hz, J64 = 2.0 Hz;C6-H) Mass (m/e) (rel. intensity): 256 (M+, 5.7), 165 (28.5), 149 (100.0), 147 (36.4), 134(35.0), 107 (58.5), 106 (42.7) (3) Preparation of 3-(benzylaminomethyl)-2-(2-chloropropyl)pyridine dihydrochloride: In 20 ml of chloroform was dissolved 5.0 g (1 9.5 m mol) of3-(benzylaminomethy)-2-(2hydroxypropyl)pyridine obtained in (2) above, and 4.2 ml (58 m mol) of thionyl chloride was gradually added to the above solution under ice cooling with stirring so that the temperature did not exceed 20 C and the mixture was stirred at room temperature for 2 hours.After completion of the reaction, methanol was added to the reaction mixture under ice cooling with stirring to decompose unreacted thionyl chloride, and the resulting solution was concentrated under reduced pressure to give the residue. The obtained residue was dissolved in a methanol-ethanol mixed solvent and decolorized with a small amount of activated charcoal, and the solution was subjected to recrystallization to give 5.33 g (Y; 78.6%) of colorless prisms, m.p.
180.0-205.0 C.
NMR # (D2O) (DSS as ISS): 1.65 (3H, d, J = 6.5 Hz;
3.20-3.80 (2H, m; 2-pyridyl
4.10-4.46 (1H, m;
4.53 (2H, s; 3-pyridyl.
or phenyl
4.66 (2H, s; phenyl
or 3-pyridyl
7.66 (15H, s; -C6H5), 8.10(1K, dd, J56= 5.5 Hz, J64=8.5 Hz; C5-H), 8.65-8.97 (2H, m; C4 and C6-H) (4) Preparation of 6-benzyl-7-methyl-5, 6,7 ,8-tetrahydro-1 , 6-naphthyridine: To 120 ml of ethanol was added 13.9 g (40 m mol) of 3-benzylaminomethyl)-2-(2chloropropyl)pyridine dihydrochloride obtained in (3) above, and 22.3 ml (160 m mol) of triethylamine was added to the resulting suspension and the mixture was refluxed for 1 hour.
After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and the obtained residue was made alkaline by addition of 20% aqueous solution of sodium hydroxide and extracted with toluene. The toluene extract was dried over anhydrous potassium carbonate and the solvent was removed by evaporation under reduced pressure. The obtained oil residue was purified by distillation under reduced pressure to give 8.70 g ( 91.3%) of a light yellow viscous oil. b.p. 150.0-0 C (0.9 mmHg).
NMR # (CDCl3): 1l.20 (3H, d, J = 6.5 Hz;
2.37-3.50 (3H m; C7 and C8-H), 3.38 (1H, d, J = 13.0 Hz; C5-H), 3,67 (2H, s;
phenyl), 3.88 (1 H, d, J = 13.0 Hz; C5-H), 6.97 (1H, dd, J32 = 4.5 Hz, J34 = 7.5 Hz; C3-H), 7.11-7.53 (6H, m; C4-H and CH2C6H5), 8.37 (1 H, dd, J23 = 4.5 Hz, J24 = 2.0 Hz; C2-H) Mass (m/e) (rel. intensity): 238 (M+, 7.7), 223 (100.0), 147 (14.0), 91(54.2) (5) Preparation of 7-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine: 6-Benzyl-7-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine prepared in (4) above was subjected to catalytic hydrogenation in the same manner as described in (2) of Example 9, whereby the intended compound was obtained substanitially quantitatively.
NMR # (CDCl3): 1.26 (3H, d, J = 6.0 Hz;
2.88 (1H, s; > NH, exchangeable), 2.23-3.43 (3H, m; C7 and C8-H), 4.03 (2H, s; C5-H), 7.00 (1 H, dd, J32 = 4.5 Hz, J34 = 7.5 Hz; C3-H), 7.28 (1H, dd, J42 = 1.5 Hz, J43 = 7.5 Hz; C4-H), 8.34 (1H, dd, J33 = 4.5 Hz, J34 = 1.5 Hz; C2-H) Mass (m/e) (rel. intensity): 148 (M+, 6.7), 147 (7.1), 133(100.0) The following compound was prepared from corresponding starting compounds in the same manner as described above.
7-Phenyl-5,6,7,8-tetrahydro-1 ,6-naphthyridine, light yellow viscous oil. b.p. 165.0-i 68.O'C (0.45 mmHg).
Mass (m/e) (rel. intensity): 210 (M+, 100.0), 209 (24.9), 133 (34.4), 107 (33.3), 105(13.8) Example 12 This Example illustrates preparation of 8-benzyl-5,6,7, 8-te,rahydro-l ,6-naphthyridine.
(1) Preparation of 6.8-dibenzyl-5,6,7.8-tetrahydro-1,6-naphthyridine: In a nitrogen atmosphere, 10.5 ml (750 m mol) of diisopropylamine was added to 200 ml of anhydrous tetrahydrofuran cooled to -70oC by dry ice-acetone, and 40 ml of a 1.5M hexane solution of n-butyl lithium (60 m mol) was gradually added to the above solution. Then, a solution of 11.2 g (50 m mol) of 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine in 100 ml of anhydrous tetrahydrofuran was gradually dropped to the above solution so that the temperature did not exceed -60 C. The solution became immediately red. Then, the solution was stirred at -70 C for 2 hours.Then, 6.2 ml (52 m mol) of benzyl bromide was gradually dropped to the red solution so that the temperature did not exceed -55OC, and the mixture was stirred for 1 hour. After completion of the reaction, a small amount of ethanol was added to the reaction mixture and the solvent was removed by evaporation under reduced pressure to give the residue. A small amount of diisopropyl ether was added to the oily residue to crystallize. The resulting crude crystals were recrystallized from diisopropyl ether to give 10.4 g (Y; 66.0%) of colorless needles, m.p. 83.0-86.0 C.
NMR # (CDCl3): 2.25-3.96 (9H, m; aliphatic proton), 6.98 (1H, dd, J32 = 5.0 Hz, J34 = 7.5 Hz; C3-H), 7.13 (5H, s; > CHCH2C6H5), 7.20 (1H, overlapped with phenyl proton, C4-H), 7.35 (5H, s; NCH2C6H5), 8.45 (1 H, dd, J23 = 5.0 Hz, J24 = 2.0 Hz; C2-H) Mass (m/e) (rel. intensity): 314 (M+, 42.6), 223 (100.0), 222 (93.6), 195(23.8), 194(28.9), 133(21.3), 131(21.3), 91 (27.7) (2) Preparation of 8-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine: 6,8-Dibenzyl-5,6,7,8-tetrahydro-l .6-naphthyridine obtained in (1) above was subjected to catalytic hydrogenation in the same manner as described in (2) of Example, 9, whereby the intended compound was obtained substantially quantitatively in the form of a colorless oil, b.p.
145.0-150.0 C (0l.8 mmHg).
Mass (m/e) (rel. intensity): 224 (M+, 100.0), 195 (63.4), 194(60.7), 133 (62.1), 132(55.21 118(41.4) The following compound was synthesized from corresponding starting compounds in the same manner as described above.
8-Methyl-S,6,7,8-tetrahydro-i ,6-naphthyridine, colorless oil, m.p. 76-80"C (0.8 mmHg).
Mass (m/e) (rel. intensity) 148 (M+, 81.0), 147 (50.6), 133(25.3), 118(100.0)

Claims (23)

1. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the following general formula (I) or a non-toxic salt thereof:
wherein R1 and R2 are each hydrogen or a lower alkyl group or R1 and R2 are bonded together to form an alkylene group with 2 to 5 carbon atoms, R3 is hydrogen, a lower alkyl group, benzyl group or a phenyl group represented by the formula
in which R4 is hydrogen or halogen or a lower alkyl or lower alkoxy group, A is a linear or branched alkylene group with 2 to 4 carbon atoms, and Y is a diloweralkylamino, 1-pyrrolidinyl, 1 -loweralkylpyrrolidinyl, 1-piperidinyl, 4-hydroxy-4-phenyl- 1 -piperidinyl, 4-hydroxy-4-(halogenophenyl)-1 -piperidinyl, 1 -morpholinyl, 4-loweralkyl-i -piperazinyl, 4-benzyl-i -piperazinyl, 4-pyridyl1-piperazinyl group or a piperazinyl group represented by the formula
in which R9 is hydrogen or halogen, a lower alkyl, halogen-substituted lower alkyl or lower alkoxy group.
2. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative or non-toxic salt thereof according to claim 1, wherein Y is
in which R5 is hydrogen, halogen, a lower alkyl or lower alkoxy group.
3. A 5,6,7,8-tetrahydro-1 ,6-naphthyridine derivative or non-toxic salt thereof according to claim 1, wherein R, and R2 are each hydrogen or a methyl group or R1 and R2 are bonded together to form a trimethylene or tetramethylene group, R3 is hydrogen, a methyl, benzyl, phenyl, chlorophenyl, tolyl or a methoxyphenyl group, A is -CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2-, -CH(CH3)CH2CH2- or -CH2CH(CH3)CH2-, and Y is a dimethylamino, diethylamino, diisopropylamino, 1-pyrrolidinyl, 1 -methyl-2-pyrrolidinyl group, a 1 -piperidinyl, 4-hydroxy-4 phenyl- 1 -piperidinyl, 4-hydroxy-4-(4-chlorophenyl)- 1 -piperidinyl, 1 -morpholinyl, 4-methyl-i-pip- erazinyl, 4-benzyl-1 -piperazinyl, 4-(2-pyridyl)- 1 4-piperazinyl, 4-phenyl-1 -piperazinyl, 4-chlorophenyl-1-piperazinyl, 4-fluorophenyl-1-piperazinyl, 4-tolyl-l -piperazinyl, 4-trifluoromethylphenyl-1 - piperazinyl, 4-methoxyphenyl- 1 -piperazinyl or 4-ethoxyphenyl-i -piperazinyl group.
4. A 5,6,7,8-tetrahydro-i ,6-naphthyridine derivative or non-toxic salt thereof according to claim 3, wherein R3 is hydrogen and Y is a 1-piperidinyl, 4-(2-pyridyl)-l -piperazinyl, 4phenylpiperazinyl, 4-(2-chlorophenyl)-1-piperazinyl, 4-(3-chlorophenyl)-1-piperazinyl, 4-(2-tolyl)1 -piperazinyl, 4-(2-methoxyphenyl)-1 -piperazinyl or 4-(2-ethoxyphenyl)- 1 -piperazinyl group.
5. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative or non-toxic salt thereof according to claim 3, wherein each of R1, R3 and R3 is hydrogen, A is -CH2CH2- or -CK2CH2CK2-, and Y is a 4-(2-chlorophenyl)-1 -piperazinyl, 4-(3-chlorophenyl)- 1 -piperazinyl, 4-(2-tolyl)-1 -piperazinyl, 4 (2-methoxyphenyl)-1-piperazinyl or 4-(2-ethoxyphenyl)- 1 -piperazinyl group.
6. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative or non-toxic salt thereof according to claim 3, wherein one of R, and R2 is hydrogen and the other or R1 and R2 is a methyl group, P is hydrogen, A is -CH2CH2-, and Y is a 1-piperidinyl, 4-(2-chlorophenyl)-l -piperazinyl, 4-(2 tolyl)- 1 -piperazinyl or 4-(2-ethoxyphenyl)- 1 -piperazinyl group.
7. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative or non-toxic salt thereof according to claim 3, wherein R, and R2 are bonded together to form a trimethylene group, R3 is hydrogen, A is -CH2CH2-, and Y is a 4-(2-ethoxyphenyl)-1-piperazinyl group.
8. A S,6,7,8-tetrahydro-1 ,6-naphthyridine derivative or non-toxic salt thereof according to claim 3, wherein R, and R2 are bonded together to form a tetramethylene group, R3 is hydrogen, A is -CH2CH2-, -CH(CH3)CH2-, -CH3CH3CH2-, -CH(CH3)CH2CH2- or -CH2CH(CH3)CH2-, and Y is a 4-(2-pyridyl)- 1 -piperazinyl, 4-phenyl-1-piperazinyl, 4-(2-methoxyphenyl)- 1 -piperazinyl or 4-(2-ethoxyphenyl)-l -piperazinyl group.
9. 5,6,7,8-Tetrahydro-6-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-1,6-naphthyridine.
10. 5,6,7,8-Tetrahydro-6-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]ethyl]-1,6-naphthyridine.
11. 6-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-2-methyl-1,6-naphtyridine.
12. 6-[2-[4-(2-Chlorophenyl)-1-piperazinyl]ethyl]-5,6,7,8-tetrahydro-3-methyl-1,6-naphthyridine.
13. 1,2,3,4,6,7,8,9-Octahydro-2-[2-[4-(2-methoxyphenyl]-1-piperazinyl]ethyl]-benzo[b]-1,6naphthy ridine.
14. 2-[2-[4-(2-Ethoxyphenyl)- 1 -piperazinyl]ethyl]- 1 ,2,3,4,6,7,8, 9-octahydro-benzo[b]- 1,6-naphthyri dine.
15. Any one of Compound Nos 1 to 10, 12 to 14, 16 to 26, 28, 30 to 46, 48, 49 and 51 to 76 hereinbefore specified.
16. A compound as claimed in any one of the preceding claims for use in treating a human or animal for vertigo.
17. A compound as claimed in any one of claims 1 to 15 for use as a central muscle relaxant for a human or animal.
18. A process for the preparation of 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (I) as defined in claim 1 or a non-toxic salt thereof, which process comprises reacting a compound represented by the following general formula (II):
wherein P1, R2 and R3 are as defined in claim 1, with a compound represented by the following general formula (Ill): X-A-Y (III) wherein X is halogen and A and Y are as defined in claim 1, and optionally (a) converting a resulting derivative of the general formula (I) to a non-toxic salt thereof or (b) converting a resulting salt of a derivative of the general formula (I) to a derivative of the general formula (I) or to another, non-toxic, salt thereof.
19. A process for the preparation of a 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (I) as defined in claim 1 or a non-toxic salt thereof, which process comprises reacting a compound represented by the following general formula (IV):
wherein X represents halogen and P1, R2, R3 and A are as defined in claim 1, with a compound represented by the following general formula (V): H-Y (V) wherein Y is as defined in claim 1, and optionally (a) converting a resulting derivative of the general formula (I) to a non-toxic salt thereof or (b) converting a resulting salt of a derivative of the general formula (I) to a derivative of the general formula (I) or to another, non-toxic, salt thereof.
20. A process for the preparation of a 5,6,7,8-tetrahydro-l ,6-naphthyridine derivative represented by the general formula (I) as defined in claim 1 or a non-toxic salt thereof, which process comprises reducing the carbonyl group of a compound represented by the following general formula:
wherein one of B and C is a carbonyl group and the other other of B and C is a linear or branched alkylene group with 1 to 3 carbon atoms, and R,, R2, R3, and Y are as defined in claim 1, and optionally (a) converting a resulting derivative of the general formula (I) to a nontoxic salt thereof or (b) converting a resulting salt of a derivative of the general formula (I) to a derivative of the general formula (I) or to another, non-toxic, salt thereof.
21. A process for the preparation of a 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the general formula (I) as defined in claim 1 or a non-toxic salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 9.
22. A pharmaceutical composition comprising, as active ingredient, a compound as claimed in any one of claims 1 to 1 7 or which has been prepared by a process as claimed in any one of claim 18 to 21, together with a pharmaceutically acceptable excipient.
23. A 5,6,7,8-tetrahydro-1,6-naphthyridine derivative represented by the following general formula:
vvherein R, is hydrogen or a lower alkyl group and R2 is hydrogen, or R, and R2 together form an alkylene group with 2 to 5 carbon atoms, and R3 is hydrogen, a lower alkyl group, benzyl group or a phenyl group represented by the formula
in which R4 is hydrogen, halogen or a lower alkyl or lower alkoxy group, with the proviso that R1,R2 and R3 do not simultaneously represent hydrogen.
GB8132554A 1980-10-29 1981-10-29 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives and their preparation Expired GB2087390B (en)

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JP56154863A JPS5857379A (en) 1981-10-01 1981-10-01 5,6,7,8-tetrahydro-1,6-naphthyridine derivative and its preparation

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ES (1) ES8402589A1 (en)
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IT (1) IT8124760A0 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0997462A1 (en) * 1997-06-30 2000-05-03 Nippon Kayaku Kabushiki Kaisha Novel naphthyridine derivatives or salts thereof
EP1142892A1 (en) * 1998-12-16 2001-10-10 Nippon Kayaku Kabushiki Kaisha Processes for the preparation of novel naphthyridine derivatives
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis
US9040558B2 (en) * 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0997462A1 (en) * 1997-06-30 2000-05-03 Nippon Kayaku Kabushiki Kaisha Novel naphthyridine derivatives or salts thereof
EP0997462A4 (en) * 1997-06-30 2001-07-04 Nippon Kayaku Kk Novel naphthyridine derivatives or salts thereof
US6294547B1 (en) * 1997-06-30 2001-09-25 Nippon Kayaku Kabushiki Kaisha Naphthyridine deratives or salts thereof
EP1142892A1 (en) * 1998-12-16 2001-10-10 Nippon Kayaku Kabushiki Kaisha Processes for the preparation of novel naphthyridine derivatives
EP1142892A4 (en) * 1998-12-16 2003-09-17 Nippon Kayaku Kk Processes for the preparation of novel naphthyridine derivatives
US8604055B2 (en) 2004-12-31 2013-12-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9040558B2 (en) * 2004-12-31 2015-05-26 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9782407B2 (en) 2004-12-31 2017-10-10 Dr. Reddy's Laboratories Ltd. Substituted benzylamino quinolines as cholesterol ester-transfer protein inhibitors
US9199967B2 (en) 2011-08-18 2015-12-01 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (CETP) inhibitors
US9000007B2 (en) 2011-09-27 2015-04-07 Dr. Reddy's Laboratories Ltd. 5-benzylaminomethyl-6-aminopyrazolo [3, 4 -B] pyridine derivatives as cholesteryl ester-transfer protein (CETP) inhibitors useful for the treatment of atherosclerosis

Also Published As

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IT8124760A0 (en) 1981-10-29
ES516935A0 (en) 1984-02-16
DE3143016A1 (en) 1982-05-27
ES8402589A1 (en) 1984-02-16
GB2087390B (en) 1984-06-13

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