US3919230A - {62 -Naphthylmethyl piperazinyl derivatives - Google Patents

{62 -Naphthylmethyl piperazinyl derivatives Download PDF

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Publication number
US3919230A
US3919230A US440431A US44043174A US3919230A US 3919230 A US3919230 A US 3919230A US 440431 A US440431 A US 440431A US 44043174 A US44043174 A US 44043174A US 3919230 A US3919230 A US 3919230A
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United States
Prior art keywords
naphthylmethyl
piperazine
compounds
pyridyl
chemical compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US440431A
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English (en)
Inventor
Harlan F Hill
John J Lafferty
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SmithKline Beecham Corp
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SmithKline Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Corp filed Critical SmithKline Corp
Priority to US440431A priority Critical patent/US3919230A/en
Priority to ZA00750160A priority patent/ZA75160B/xx
Priority to JP50014791A priority patent/JPS50108278A/ja
Priority to GB453675A priority patent/GB1449802A/en
Priority to AU77840/75A priority patent/AU501049B2/en
Priority to CA219,288A priority patent/CA1042434A/en
Priority to IL46568A priority patent/IL46568A/xx
Priority to CH132675A priority patent/CH616678A5/de
Priority to ES434433A priority patent/ES434433A1/es
Priority to BE153056A priority patent/BE825178A/xx
Priority to NL7501362A priority patent/NL7501362A/xx
Priority to FR7503627A priority patent/FR2260353B1/fr
Priority to DE19752505002 priority patent/DE2505002A1/de
Priority to LU71803A priority patent/LU71803A1/xx
Priority to IE254/75A priority patent/IE40593B1/xx
Priority to HU75SI00001455A priority patent/HU171352B/hu
Priority to US05/596,872 priority patent/US3988457A/en
Application granted granted Critical
Publication of US3919230A publication Critical patent/US3919230A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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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)
US440431A 1974-02-07 1974-02-07 {62 -Naphthylmethyl piperazinyl derivatives Expired - Lifetime US3919230A (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
US440431A US3919230A (en) 1974-02-07 1974-02-07 {62 -Naphthylmethyl piperazinyl derivatives
ZA00750160A ZA75160B (en) 1974-02-07 1975-01-09 Novel compounds and compositions for treating parkinson's disease
GB453675A GB1449802A (en) 1974-02-07 1975-02-03 Piperazine derivatives and compositions containing them for treating parkinsons disease
AU77840/75A AU501049B2 (en) 1974-02-07 1975-02-03 Naphthylmethyl piperazines
CA219,288A CA1042434A (en) 1974-02-07 1975-02-03 Beta-naphthyl-methyl-piperazines
JP50014791A JPS50108278A (enrdf_load_stackoverflow) 1974-02-07 1975-02-03
ES434433A ES434433A1 (es) 1974-02-07 1975-02-04 Un procedimiento para preparar nuevos derivados de bnaftil-metil-piperazinilo.
CH132675A CH616678A5 (enrdf_load_stackoverflow) 1974-02-07 1975-02-04
IL46568A IL46568A (en) 1974-02-07 1975-02-04 -naphthylmethyl piperazine derivatives and compositions for treating parkinson's disease
BE153056A BE825178A (fr) 1974-02-07 1975-02-04 Nouveaux composes et compositions pour le traitement de la maladie de parkinson
FR7503627A FR2260353B1 (enrdf_load_stackoverflow) 1974-02-07 1975-02-05
NL7501362A NL7501362A (nl) 1974-02-07 1975-02-05 Anti-parkinson-verbindingen en - preparaten.
DE19752505002 DE2505002A1 (de) 1974-02-07 1975-02-06 Beta-naphthylmethyl-4-piperazine, verfahren zu ihrer herstellung und arzneimittel
LU71803A LU71803A1 (enrdf_load_stackoverflow) 1974-02-07 1975-02-06
IE254/75A IE40593B1 (en) 1974-02-07 1975-02-07 Novel piperazine derivatives and compositions containing them for treating parkinson's disease
HU75SI00001455A HU171352B (hu) 1974-02-07 1975-02-07 Sposob poluchenija proizvodnykh beta-naftil-metil-piperazina i farmacevticheskikh preparatov soderzhahhikh takie soedinenija
US05/596,872 US3988457A (en) 1974-02-07 1975-07-17 Novel compounds and compositions for treating Parkinson's disease

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US440431A US3919230A (en) 1974-02-07 1974-02-07 {62 -Naphthylmethyl piperazinyl derivatives

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US05/596,872 Division US3988457A (en) 1974-02-07 1975-07-17 Novel compounds and compositions for treating Parkinson's disease

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US (1) US3919230A (enrdf_load_stackoverflow)
JP (1) JPS50108278A (enrdf_load_stackoverflow)
AU (1) AU501049B2 (enrdf_load_stackoverflow)
BE (1) BE825178A (enrdf_load_stackoverflow)
CA (1) CA1042434A (enrdf_load_stackoverflow)
CH (1) CH616678A5 (enrdf_load_stackoverflow)
DE (1) DE2505002A1 (enrdf_load_stackoverflow)
ES (1) ES434433A1 (enrdf_load_stackoverflow)
FR (1) FR2260353B1 (enrdf_load_stackoverflow)
GB (1) GB1449802A (enrdf_load_stackoverflow)
HU (1) HU171352B (enrdf_load_stackoverflow)
IE (1) IE40593B1 (enrdf_load_stackoverflow)
IL (1) IL46568A (enrdf_load_stackoverflow)
LU (1) LU71803A1 (enrdf_load_stackoverflow)
NL (1) NL7501362A (enrdf_load_stackoverflow)
ZA (1) ZA75160B (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130646A (en) * 1975-07-25 1978-12-19 E. R. Squibb & Sons, Inc. 1,2,3,4-Tetrahydro-2-((4-(phenyl)-1-piperazinyl)methyl)-1-naphthalenols and derivatives and analogs thereof
US4148897A (en) * 1976-04-29 1979-04-10 Takeda Chemical Industries, Ltd. 1,2-Dihydronaphthalene derivatives and pharmaceutical composition
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
WO1984000752A1 (en) * 1982-08-11 1984-03-01 Eastman Kodak Co Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines and methods for their preparation and use
WO2000051547A3 (en) * 1999-03-03 2001-04-05 Merck & Co Inc Inhibitors of prenyl-protein transferase
CN107652156A (zh) * 2017-11-18 2018-02-02 辽宁科技学院 一种β‑甲基萘的结晶方法和装置

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3299067A (en) * 1963-11-19 1967-01-17 Science Union & Cie 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3299067A (en) * 1963-11-19 1967-01-17 Science Union & Cie 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130646A (en) * 1975-07-25 1978-12-19 E. R. Squibb & Sons, Inc. 1,2,3,4-Tetrahydro-2-((4-(phenyl)-1-piperazinyl)methyl)-1-naphthalenols and derivatives and analogs thereof
US4148897A (en) * 1976-04-29 1979-04-10 Takeda Chemical Industries, Ltd. 1,2-Dihydronaphthalene derivatives and pharmaceutical composition
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
WO1984000752A1 (en) * 1982-08-11 1984-03-01 Eastman Kodak Co Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines and methods for their preparation and use
US4620006A (en) * 1982-08-11 1986-10-28 Eastman Kodak Company Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines
WO2000051547A3 (en) * 1999-03-03 2001-04-05 Merck & Co Inc Inhibitors of prenyl-protein transferase
US6335343B1 (en) 1999-03-03 2002-01-01 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
CN107652156A (zh) * 2017-11-18 2018-02-02 辽宁科技学院 一种β‑甲基萘的结晶方法和装置
CN107652156B (zh) * 2017-11-18 2023-11-10 辽宁科技学院 一种β-甲基萘的结晶方法和装置

Also Published As

Publication number Publication date
AU501049B2 (en) 1979-06-07
JPS50108278A (enrdf_load_stackoverflow) 1975-08-26
GB1449802A (en) 1976-09-15
ES434433A1 (es) 1976-11-16
IL46568A (en) 1979-01-31
CA1042434A (en) 1978-11-14
IE40593L (en) 1975-08-07
HU171352B (hu) 1977-12-28
AU7784075A (en) 1976-08-05
DE2505002A1 (de) 1975-08-14
FR2260353A1 (enrdf_load_stackoverflow) 1975-09-05
IL46568A0 (en) 1975-04-25
CH616678A5 (enrdf_load_stackoverflow) 1980-04-15
IE40593B1 (en) 1979-07-04
LU71803A1 (enrdf_load_stackoverflow) 1975-06-24
FR2260353B1 (enrdf_load_stackoverflow) 1980-01-04
NL7501362A (nl) 1975-08-11
BE825178A (fr) 1975-08-04
ZA75160B (en) 1976-01-28

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