Classifications

• • 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
  • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
  • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
  • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
• • 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
  • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/06—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
  • C07D295/073—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • 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
  • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

• L-dopa a potential source of brain dopamine
• the L-dopa is a precursor of dopamine and is decarboxylated in the brain to form dopamine, thereby raising the levels of dopamine in patients who are deficient in it.
• L-dopa does not qualify as an ideal compound in the treatment of Parkinsonism due in part to its limiting side effects, such as, for example, nausea, emesis and anorexia.
• the compounds of this invention have been demonstrated as having anti-Parkinsonism activity without the corresponding side effects by employing a modified standard animal pharmacological test procedure reported by Ungerstedt et al., in Brain Research 24, 1970, 485-493.
• This test discloses a drug induced rotation of rats having extensive unilateral lesions of the substantia nigra. Briefly, the test comprises the quantitative recording of rotational behavior in rats after o-hydroxydopamine lesions of the nigrostriatal dopamine system.
• a unilateral brain lesion in the left substantia nigra causes the dopamine receptor in the left caudate to become hypersensitive subsequent to the resulting degeneration of the nigral cell bodies.
• Rotational activity is defined as the ability of a compound to produce 500 contralateral rotations during a two-hour period after administration, usually intraperitoneally. The dose corresponding to 5.00 contralateral rotations per two hours is obtained and assigned as the RD
• a preferred compound of this invention is l-(fl-naphthylmethyl)-4-(2-pyridyl) piperazine which produced an RD of 8 mgJltg. as compared to 22.6 mgJltg. for
• R represents phenyl, C-pyridyl or C-pyrimidinyl
• R represents hydrogen. lower alltyl of l-S carbon atoms, straight or branched chain, hydroxy, lower alkoxy of l-5 carbon atoms, or halogen.
• the pharmacodynamically active compounds of this invention have the basic structure of Formula 1.
• substituents may be incorporated on the phenyl, pyridyl or pyrimidinyl rings.
• substituents may be, for example, lower alltyl, lower alkoxy, hydroxy or halogen. These substituted compounds are used as are the parent compounds.
• the unsubstituted piperazine can be reacted with fl-chloromethylnaphthalene to form B-(naphthylmethyl)piperazine which in turn can be reacted with the appropriately reactive R moiety.
• the invention also includes nontoxic pharmaceutically acceptable addition salts of the above-defined bases formed with organic and inorganic acids. Such salts are easily prepared by methods known to the art.
• the base is reacted with either the stoichiometric amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
• aqueous miscible solvent such as acetone or ethanol
• aqueous immiscible solvent such as ethyl ether or chloroform
• organic salts are those with maleic. fumaric, benzoic, ascorbic. pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic.
• novel compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like by incorporating the appropriate dose of a compound of Formula 1 with carriers according to the accepted pharmaceutical practices.
• the substituted [3- naphthylmethyl piperazinyl derivatives will be present in an amount to produce anti-Parkinsonism activity.
• the dosage unit forms will contain the compounds of Formula I in an amount of from about l mg. to about 100 mg, advantageously from about 25 mg. to about 50 mg. Most advantageously equal daily doses are administered one to four times daily to provide a daily dosage regimen of from about 10 mg. to about 400 mg.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, talc, sucrose, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
• liquid carriers are syrup, peanut oil. olive oil, water and the like.
• the carrier as diluent can include any time delay material well known to the art such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• a wide variety of pharmaceutical forms can be employed.
• a solid carrier the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
• the amount of solid carrier will vary widely but preferably will be about mg. to about I g.
• a liquid carrier the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule, or an aqueous liquid suspension.
• EXAMPLE 2 A mixture containing 7.0 g. of B-chloromethylnaphthalene, 6.56 g. of Z-pyridylpiperazine and 4.4 g. of sodium carbonate in 40 ml. of dimethylformamide is stirred on a steambath for minutes. The reaction mixture is filtered and the filtrate stirred with ice water. The precipitate was filtered and recrystallized from isobutyl alcohol to yield l-(B-napthylmethyl)-4-(2- pyridyl)piperazine having a melting point of l24l26 C.
• EXAMPLE 3 EXAMPLE 4 Employing the procedure outlined above and using 10.9 g. of l-(4-methoxyphenyl)piperazine as a starting material in place of phenylpiperazine yielded l-(B- naphthylmethyl)-4-(4-methoxyphenyl)piperazine having a melting point of ll7-l l8 C.
• EXAMPLE 6 A solution of 2.0 g. of l-(B-naphthylmethyl)-4-(4- methoxyphenyl)piperazine as prepared in Example 4 in ml. of hot 48% hydrogen bromide is refluxed for 2 hours. The solution is then cooled and filtered. The collected precipitate is then recrystallized from isobutyl alcohol to yield the dihydrobromide salt of l-(B-naphthylmethyl)-4-(4-hydroxyphenyl)piperazine having a melting point of 225227 C.
• EXAMPLE 7 A solution of 20.0 g. of B-chloromethylnaphthalene, 17.9 g. of piperazine dihydrochloride and 22.0 g. of piperazine hexahydrate in 55 ml. of methanol is refluxed for two hours. The solution is then cooled and filtered and the filtrate concentrated. The resulting solid is taken up in water and treated with l0% sodium hydroxide. The basic solution is extracted with chloroform and the fractions are combined, washed with water and dried. The oily material is distilled to give B-(napthylmethyl)piperazine.
• a mixture of 4.5 g. of B-(naphthylmethyl)piperazine, 2.6 g. of 2-chloro-3-hydroxypyridine and 2.8 g. of sodium carbonate in 50 ml. of dimethylformamide is stirred on a steambath for 4 hours.
• the mixture is cooled and filtered.
• the filtrate is stirred with ice water and the formed precipitate is filtered, dissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to form the hydrochloride salt of l-(B-naphthylmethyl)-4-(3-hydroxy-2-pyridyl)piperazine.
• EXAMPLE 8 To a mixture of 4.50 g. of l-(,6'napthylmethyl )-piperazine (as prepared in Example 7), 2.5 g. of 2-chloro-5- hydroxypyrimidine in 30 ml. of dimethylformarnide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for 6 hours. The mixture is cooled and filtered and the filtrate concentrated to a small volume in vacuo. The concentrate is diluted with I ml. of water and the insoluble material is washed with water and hexane to yield l-(B-napthylmethyl)-4-(5-hydroxy-2- pyrimidinyl)piperazine.
• EXAMPLE 10 In like manner using the procedure of Example 9, 5- methoxy-Z-naphthoic acid and 7-chloro-2-naphthoic acid were employed as starting materials in place of 6- methyl-Z-naphthoic acid to yield respectively l-(S- methoxy-B-naphthylmethyl)-4-(Z-pyridyDpiperazine, (7-chloro-B-naphthylmethyl)-4-(2-pyridyl)piperazine.
• EXAMPLE I EXAMPLE l2 ingredients MgJTablet i-(,B-naphthylmethyl)-4-(2-pyridyllpiperazine 25 mg. Calcium sulfate dihydrate I00 mg. Sucrose 25 mg. Starch 15 mg. Talc 5 mg. Stearic acid 3 mg.
• EXAMPLE l3 Ingredients MgJCapsulc l-(B-naphthylmethyl)-4-( 2-pyrimidinyl)piper- 50 mg. azinc Lactose 200 mg.
• the above ingredients are throughly mixed and filled into a No. 2 hard gelatin capsule.
• One capsule is administered twice a day.
• R is phenyl, pyridyl or pyrimidinyl; and R, is hydrogen, lower alkyl having from one to five carbon atoms, halogen, hydroxy or lower alkoxy having from one to five carbon atoms. 2.
• R is hydrogen.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)

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Cited By (6)

Citations (1)

• 1974
  • 1974-02-07 US US440431A patent/US3919230A/en not_active Expired - Lifetime
• 1975
  • 1975-01-09 ZA ZA00750160A patent/ZA75160B/xx unknown
  • 1975-02-03 JP JP50014791A patent/JPS50108278A/ja active Pending
  • 1975-02-03 GB GB453675A patent/GB1449802A/en not_active Expired
  • 1975-02-03 CA CA219,288A patent/CA1042434A/en not_active Expired
  • 1975-02-03 AU AU77840/75A patent/AU501049B2/en not_active Expired
  • 1975-02-04 ES ES434433A patent/ES434433A1/es not_active Expired
  • 1975-02-04 BE BE153056A patent/BE825178A/xx not_active IP Right Cessation
  • 1975-02-04 CH CH132675A patent/CH616678A5/de not_active IP Right Cessation
  • 1975-02-04 IL IL46568A patent/IL46568A/xx unknown
  • 1975-02-05 FR FR7503627A patent/FR2260353B1/fr not_active Expired
  • 1975-02-05 NL NL7501362A patent/NL7501362A/xx not_active Application Discontinuation
  • 1975-02-06 LU LU71803A patent/LU71803A1/xx unknown
  • 1975-02-06 DE DE19752505002 patent/DE2505002A1/de not_active Ceased
  • 1975-02-07 IE IE254/75A patent/IE40593B1/xx unknown
  • 1975-02-07 HU HU75SI00001455A patent/HU171352B/hu unknown

Patent Citations (1)

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