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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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Prior art keywords
naphthylmethyl
piperazine
compounds
pyridyl
chemical compound
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US440431A
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Harlan F Hill
John J Lafferty
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SmithKline Beecham Corp
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SmithKline Corp
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Priority to US440431A priority Critical patent/US3919230A/en
Priority to ZA00750160A priority patent/ZA75160B/en
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 JP50014791A priority patent/JPS50108278A/ja
Priority to IL46568A priority patent/IL46568A/en
Priority to ES434433A priority patent/ES434433A1/en
Priority to CH132675A priority patent/CH616678A5/de
Priority to BE153056A priority patent/BE825178A/en
Priority to FR7503627A priority patent/FR2260353B1/fr
Priority to NL7501362A priority patent/NL7501362A/en
Priority to DE19752505002 priority patent/DE2505002A1/en
Priority to LU71803A priority patent/LU71803A1/xx
Priority to IE254/75A priority patent/IE40593B1/en
Priority to HU75SI00001455A priority patent/HU171352B/en
Priority to US05/596,872 priority patent/US3988457A/en
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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
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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
    • C07D295/02—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)

Abstract

Beta -Naphthylmethyl piperazinyl derivates having antiParkinsonism activity prepared by condensation of Beta chloromethylnaphthalene with the appropriate substituted piperazine.

Description

United States Patent [191 Hill et al.
B-NAPHTHYLMETHYL PIPERAZINYL DERIVATIVES [75] Inventors: Harlan F. Hill, Narberth; John J.
Lafferty, Levittown, both of Pa. [73] Assignee: SmithKline Corporation,
Philadelphia, Pa. {22] Filed: Feb. 7, i974 [2!] Appl. No.: 440,431
[52] US. Cl. 260/256.4 N; 260/268 BC; 260/268 PH; 424/250; 424/25l [5 [1 Int. Cl. C07D 2.39/24 [58] Field ol Search 260/2564 N. 268 BC 56] References Cited UNITED STATES PATENTS 3.299.067 1/1967 Regnier et a]. 260/2564 N Nov. 11, 1975 OTHER PUBLICATIONS Sokolova et ul.. Chemical Abstracts." Vol. 73. I970. Col. 25398f.
Ass/slum E.mminer-Jan1es H. Turnipseed Auume Age/H ur Firm-Joseph A. Marlino; Richard D. Foggio; William H. Edgenon [57] ABSTRACT ,B-Naphthylmethyl piperuzinyl derivates having 1mm Purkinsonism activity prepared by condensation of [:l-chloromethylnaphthalene with the appropriate suhstituted piperazine.
7 Claims, N0 Drawings fl-NAPHTHYLMETHYL PIPERAZINYL DERIV AT IVES terized by hypokinesia, akinesia, tremor and rigidity of the limbs. Parkinsonism is believed to be brought about by imbalance in the biochemical systems in the brain between the dopaminergic and cholinergic neural pathways. ln patients suffering from Parkinsonism, a depletion of dopamine in the brain is observed which is the result of progressive degeneration of nigro-striatal dopaminergic neurons.
Prior to the present invention, there has been a great need for compounds and compositions which produce anti-Parkinsonism activity without having limiting side effects. It is well known that L-dopa, a potential source of brain dopamine, has clinical utility in treating Parkinsonism. 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. However, 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.
It is therefore the object of the present invention to provide dopaminergic-like compounds for the treatment of Parkinsons disease which do not possess the limiting side effects of L-dopa.
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. These lesions destroy the source of the neurotransmitter dopamine in the caudate but leave the caudate cell bodies and their dopamine receptors intact. Activation of these receptors by drugs which produce contralateral rotation, with respect to the lesioned side of the brain, is used as a measure of central dopaminergic activity of the drug.
Compounds which are known to be clinically effective in controlling Parkinsonism, such as, for example, L-dopa and apomorphine, are also effective in the rat turning model. These compounds directly activate the dopamine receptors and cause contralateral rotation of the lesioned rat.
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
L-dopa when tested in the above modified Ungerstedt test.
The compounds of this invention are represented by the following general structural formula:
Formula I in which:
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. However, it is apparent to one skilled in the art that well ltnown nuclear substituents may be incorporated on the phenyl, pyridyl or pyrimidinyl rings. Such substituents may be, for example, lower alltyl, lower alkoxy, hydroxy or halogen. These substituted compounds are used as are the parent compounds.
Advantageous compounds of this invention are represented by the above structural formula when R represents C-pyridyl or C-pyrimidinyl and R, represents hydrogen.
The compounds of Formula I are prepared according to the following synthetic procedure:
in which R and R, are as defined above.
The method is carried out using readily available starting materials and gives excellent yields of the end product. Where certain compounds desired for use as starting materials are not available, they can be prepared by methods described in the literature and well known to the art for preparing analogous compounds as described in the examples. Thus as shown above, a substituted chloromethylnaphthalene is reacted with the appropriate piperazinyl derivative in the presence of an organic solvent, such as, for example, dimethylformamide and an acid binding agent such as sodium or potassium carbonate, and heated to yield the desired compound. Alternatively 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. Exemplary of such organic salts are those with maleic. fumaric, benzoic, ascorbic. pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic. acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic. stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids as well as with the 8-halotheophyllines, for exam ple. S-chlorotheophylline and S-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acids. These salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.
The 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. Preferably 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. Exemplary of solid carriers are lactose, terra alba, talc, sucrose, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary of liquid carriers are syrup, peanut oil. olive oil, water and the like. Similarly, 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. Thus if a solid carrier is used 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. If a liquid carrier is used, 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.
The following examples illustrate the preparation of specific compounds having anti-Parkinsonism activity. However, this should not be construed as a limitation of the invention since other variations will be obvious to those skilled in the art.
EXAMPLE I To a mixture containing 5.0 g. of B-chloromethylnaphthalene, 3.0 g. of sodium carbonate and ml. of dimethylformamide is added 4.6 g. of pyrimidinylpiperazine. The mixture is stirred and heated on a steam bath for approximately 2 hours. The mixture is then cooled, filtered and the filtrate is concentrated to a small volume in vacuo. The residue is washed with water and crystallized from ethanol to yield l-(B-naph- 4 thylmethyl)-4-(Z-pyrimidinyl)-piperazine melting point of l09-l10 C.
An ethereal solution of the free base is treated with hydrogen chloride to yield the hydrochloride salt.
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.
having a An acetone solution of the free base is reacted with succinic acid to yield the succinate salt.
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 5 Similarly using the above procedures, 9.8 g. of l-(3- chlorophenyl)piperazine used as a starting material yielded l-(B-naphthylmethyl)-4-(m-chlorophenyl)piperazine having a melting point of l l4l l5 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 9 To a suspension of 2.7 g. of lithium aluminum hydride in 75 ml. ofdry ether is added dropwise a solution containing 5.5 g. of 6-methyl-2-naphthoic acid in 75 ml. of dry ether. The mixture is refluxed for three hours, cooled, and treated with l0% sodium hydroxide solution. The mixture is then filtered and dried to yield 6-methyl-2-naphthalenemethanol.
20.3 g. of 6-methyl-2-naphthalenemethanol is dissolved in 100 ml. of dry benzene and to this solution is added 30 ml. of thionyl chloride. The solution is stirred for about l hour and concentrated to yield 2- chloromethyl-fi-methylnaphthalene.
A mixture of ll.0 g. of 2-chloromethyl-6-methylnaphthalene, 7.0 g. of sodium carbonate and 10.0 g. of
2-pyridylpiperazine in 75 m1. of dimethylformamide is stirred for 6 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated. The precipitate is then washed with water and crystallized from ethanol to yield l-(6-methyl-B-naphthylmethyl)-4-(2-pyridyl)- 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 l 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.
What is claimed is:
l. A chemical compound of the formula or a pharmaceutically acceptable acid addition salt thereof in which:
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. A chemical compound in accordance with claim I in which R, is hydrogen.
3. A chemical compound in accordance with claim 2 in which R is pyridyl.
4. A chemical compound in accordance with claim 2 in which R is pyrimidinyl.
5. A chemical compound in accordance with claim 2 in which R is phenyl.
6. A chemical compound in accordance with claim 3 in which R is a 2-pyridyl.
7. The chemical compound of claim 6 in the form of a free base.
* =8 IF II

Claims (7)

1. A CHEMICAL COMPOUND OF THE FORMULA
2. A chemical compound in accordance with claim 1 in which R1 is hydrogen.
3. A chemical compound in accordance with claim 2 in which R is pyridyl.
4. A chemical compound in accordance with claim 2 in which R is pyrimidinyl.
5. A chemical compound in accordance with claim 2 in which R is phenyl.
6. A chemical compound in accordance with claim 3 in which R is a 2-pyridyl.
7. The chemical compound of claim 6 in the form of a free base.
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
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 (en) 1974-02-07 1975-02-03
GB453675A GB1449802A (en) 1974-02-07 1975-02-03 Piperazine derivatives and compositions containing them for treating parkinsons disease
CH132675A CH616678A5 (en) 1974-02-07 1975-02-04
ES434433A ES434433A1 (en) 1974-02-07 1975-02-04 {62 -Naphthylmethyl piperazinyl derivatives
IL46568A IL46568A (en) 1974-02-07 1975-02-04 -naphthylmethyl piperazine derivatives and compositions for treating parkinson's disease
BE153056A BE825178A (en) 1974-02-07 1975-02-04 NEW COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARKINSON'S DISEASE
NL7501362A NL7501362A (en) 1974-02-07 1975-02-05 ANTI-PARKINSON COMPOUNDS AND PREPARATIONS.
FR7503627A FR2260353B1 (en) 1974-02-07 1975-02-05
DE19752505002 DE2505002A1 (en) 1974-02-07 1975-02-06 BETA-NAPHTHYLMETHYL-4-PIPERAZINE, THE METHOD FOR MANUFACTURING IT AND MEDICINAL PRODUCTS
LU71803A LU71803A1 (en) 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 (en) 1974-02-07 1975-02-07 Process for preparing derivatives of the beta-naphtyl-methyl-piperazine and pharmaceutical preparations containing such compounds
US05/596,872 US3988457A (en) 1974-02-07 1975-07-17 Novel compounds and compositions for treating Parkinson's disease

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US440431A US3919230A (en) 1974-02-07 1974-02-07 {62 -Naphthylmethyl piperazinyl derivatives

Related Child Applications (1)

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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

Publications (1)

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US3919230A true US3919230A (en) 1975-11-11

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

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

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 (en) * 2017-11-18 2018-02-02 辽宁科技学院 A kind of method for crystallising and device of β methyl naphthalenes

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 (en) * 2017-11-18 2018-02-02 辽宁科技学院 A kind of method for crystallising and device of β methyl naphthalenes
CN107652156B (en) * 2017-11-18 2023-11-10 辽宁科技学院 Crystallization method and device of beta-methylnaphthalene

Also Published As

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

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