CA1042434A - Beta-naphthyl-methyl-piperazines - Google Patents
Beta-naphthyl-methyl-piperazinesInfo
- Publication number
- CA1042434A CA1042434A CA219,288A CA219288A CA1042434A CA 1042434 A CA1042434 A CA 1042434A CA 219288 A CA219288 A CA 219288A CA 1042434 A CA1042434 A CA 1042434A
- Authority
- CA
- Canada
- Prior art keywords
- piperazine
- compound
- beta
- pyridyl
- pyrimidinyl
- 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
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
.beta.-Naphthylmethyl piperazinyl derivates having anti-Parkinsonism activity prepared by condensation of .beta.-chloro-methylnaphthalene with the appropriate substituted piperazine.
.beta.-Naphthylmethyl piperazinyl derivates having anti-Parkinsonism activity prepared by condensation of .beta.-chloro-methylnaphthalene with the appropriate substituted piperazine.
Description
~4 ~ ~ 3~
1 Thls invention relates to novel ~-naphthylmethyl piperazinyl derivatives having valuable pharmacodynamic activity. More specifically, the compounds of this invention possess anti-Parkinsonism activity.
Parkinson's disease is a neurological disorder characterized 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. In 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 Parkin- -sonism. 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 com-pound in the treatment of Parkinsonism due in part to its limiting sicle 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 Parkinson's 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 lhe
1 Thls invention relates to novel ~-naphthylmethyl piperazinyl derivatives having valuable pharmacodynamic activity. More specifically, the compounds of this invention possess anti-Parkinsonism activity.
Parkinson's disease is a neurological disorder characterized 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. In 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 Parkin- -sonism. 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 com-pound in the treatment of Parkinsonism due in part to its limiting sicle 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 Parkinson's 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 lhe
-2- ~
-- . . ~, , , ~ - .
-, ~ - . .
.-- . . . . . . . .
1~ 4 ~
1 corresponding side effects by employing a modified standard animal pharmacolo~ical test p]^ocedure reported by Un~erstedt et al., in Brain Research 24, 1970, 485-493. This test dis-closes 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 6~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, i~ used as a measure of central dopaminergic activlty 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 intraperitone-ally. The dose corresponding to 500 contralateral rotations per two hours is obtained and assigned as the RD500.
A preferred compound of this invention is 1~
naphthylmethyl)-4-(2-pyridyl) piperazine which produced
-- . . ~, , , ~ - .
-, ~ - . .
.-- . . . . . . . .
1~ 4 ~
1 corresponding side effects by employing a modified standard animal pharmacolo~ical test p]^ocedure reported by Un~erstedt et al., in Brain Research 24, 1970, 485-493. This test dis-closes 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 6~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, i~ used as a measure of central dopaminergic activlty 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 intraperitone-ally. The dose corresponding to 500 contralateral rotations per two hours is obtained and assigned as the RD500.
A preferred compound of this invention is 1~
naphthylmethyl)-4-(2-pyridyl) piperazine which produced
-3-. ~ ~
- .:
~ V~;~43~
an RD500 of mg.~kg. as compared to 22.6 mg./kg. for L-dopa when tested in t~e a~ov~ modi~ed Ungerstedt test.
The compounds of this in~rention are represented by the following general structural fc)rmula:
Formulcl 1 1 ~ \
in w~i~h R represents phenyl, C-pyridyl or C-pyrimidinyl;
Rl represents hydrogen, lower alkyl of 1-5 carbon atoms, straight or branched chain, hydroxy, lower alkoxy of 1-5 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 known nuclear ~ -substituents may be incorporated on the phenyl, pyridyl or pyrimidinyl rings. Such substituents may be, for example, lower alkyl, lower alkoxy, hydroxy or halogen. These sub- ~
stituted compounds are used as are the parent compounds. ~ ~ -Advantageous compounds of this invention are repre-sented by the above structural formula when R represents -C-pyridyl or C-pyrimidinyl and Rl represents hydrogen.
The compounds of Formula 1 are prepared according to the following synthetic procedure:
' `~'
- .:
~ V~;~43~
an RD500 of mg.~kg. as compared to 22.6 mg./kg. for L-dopa when tested in t~e a~ov~ modi~ed Ungerstedt test.
The compounds of this in~rention are represented by the following general structural fc)rmula:
Formulcl 1 1 ~ \
in w~i~h R represents phenyl, C-pyridyl or C-pyrimidinyl;
Rl represents hydrogen, lower alkyl of 1-5 carbon atoms, straight or branched chain, hydroxy, lower alkoxy of 1-5 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 known nuclear ~ -substituents may be incorporated on the phenyl, pyridyl or pyrimidinyl rings. Such substituents may be, for example, lower alkyl, lower alkoxy, hydroxy or halogen. These sub- ~
stituted compounds are used as are the parent compounds. ~ ~ -Advantageous compounds of this invention are repre-sented by the above structural formula when R represents -C-pyridyl or C-pyrimidinyl and Rl represents hydrogen.
The compounds of Formula 1 are prepared according to the following synthetic procedure:
' `~'
4 ~
. . - . .. ,. . - ~- ~ . .
~CH2Cl ~\ DMF/Na2CO
Rl ~ + H ~ /N-R - 3 Rl ~ CH2 ~ -R
in which R and Rl are as defined above.
The method is carried out using readlly available starting materials and gives excellent yields of the end product. ~here 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 pre-paring 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, dimethyl-formamide and an acid binding agent such as sodium or potassium carbonate, and heated to yield the desired compound~ Alterna- -tively the unsubstituted piperazine can be reacted with ~ ~ -?0 ~-chloromethylnaphthalene to form ~ (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 abo-ve-defined bases formed wlth 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,
. . - . .. ,. . - ~- ~ . .
~CH2Cl ~\ DMF/Na2CO
Rl ~ + H ~ /N-R - 3 Rl ~ CH2 ~ -R
in which R and Rl are as defined above.
The method is carried out using readlly available starting materials and gives excellent yields of the end product. ~here 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 pre-paring 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, dimethyl-formamide and an acid binding agent such as sodium or potassium carbonate, and heated to yield the desired compound~ Alterna- -tively the unsubstituted piperazine can be reacted with ~ ~ -?0 ~-chloromethylnaphthalene to form ~ (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 abo-ve-defined bases formed wlth 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,
-5-.. . . ..
104~4~4 1 bismethylenesalicylic, methanesulfonic, ethanedisulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconlc, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acet~c acids as well as with the 8-halotheophyllines, for example3 8-chloro~ ;
theophylline and 8-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 in~-ention 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 pharma-ceutical practices. The substituted ~-naphthylmethyl plperazinyl derivatives will be present in an amount to produce anti-Parkinsonism activity. Preferably the dosage unit forms will contain the compounds of Formula 1 in an amount of from about 10 mg. to about 100 mg., advant~geously from about 25 mg. to about 50 mg. Most advantageously equal -~
daily doses are administered one to four times daily to pro~
vide 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, gelatin3 agar, pectin, acacia, magnesium stearate, ste~ric acid~ and the like. Exemplary of liquid carriers are syrup, peanut oil ~34~2434 1 ollve oil, water and the like. Similarly, the carrier as diluent can include any time delay materl~l well known to the art such as glyceryl monostearate or ~lyceryl distearate alone or with a wax.
S A wide variety of pharmaceutical forms can be employed. Thus if a solld 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 25 mg. to about 1 g. If a liquid carrier is used9 the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile in~ectable liquid such as an ampule, or an aqueous liquid suspension.
The followin~ 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.
~0 To a mixture containing 5.0 g. of ~chloromethyl~
naphthalene, 3.0 g. of sodium carbonate and 30 ml. of dimethylformamide is added 4.6 g. of pyrimidinylpiperazine~
The mixture is stirred and heated on a steam bath for approximately two 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-(~-napthylmethyl)-4-(2-pyrimidinyl)~
piperazine having a melting point of 109-110 C.
An ethereal solution of the free base is treated with hydrogen chloride to yield the hydrochloride salt :~.0~2434 A mixture containing 7.0 g. of ~-chloromethyl-naphthalene, 6.56 g. of 2-pyridylpiperazlne and 4.4 g. of so~ium carbonate in 40 ml. of dimethylformamide is stirred on a steambath for 90 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-(~-napthylmethyl)-4-(2-pyridyl)piperazine having a melting point of 124-126 C.
An acetone solution of the free base is reacted with succinic acid to yield the succinate salt.
A mixture of 10.0 g. of ~-chloromethylnapthalene,
104~4~4 1 bismethylenesalicylic, methanesulfonic, ethanedisulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconlc, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acet~c acids as well as with the 8-halotheophyllines, for example3 8-chloro~ ;
theophylline and 8-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 in~-ention 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 pharma-ceutical practices. The substituted ~-naphthylmethyl plperazinyl derivatives will be present in an amount to produce anti-Parkinsonism activity. Preferably the dosage unit forms will contain the compounds of Formula 1 in an amount of from about 10 mg. to about 100 mg., advant~geously from about 25 mg. to about 50 mg. Most advantageously equal -~
daily doses are administered one to four times daily to pro~
vide 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, gelatin3 agar, pectin, acacia, magnesium stearate, ste~ric acid~ and the like. Exemplary of liquid carriers are syrup, peanut oil ~34~2434 1 ollve oil, water and the like. Similarly, the carrier as diluent can include any time delay materl~l well known to the art such as glyceryl monostearate or ~lyceryl distearate alone or with a wax.
S A wide variety of pharmaceutical forms can be employed. Thus if a solld 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 25 mg. to about 1 g. If a liquid carrier is used9 the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile in~ectable liquid such as an ampule, or an aqueous liquid suspension.
The followin~ 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.
~0 To a mixture containing 5.0 g. of ~chloromethyl~
naphthalene, 3.0 g. of sodium carbonate and 30 ml. of dimethylformamide is added 4.6 g. of pyrimidinylpiperazine~
The mixture is stirred and heated on a steam bath for approximately two 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-(~-napthylmethyl)-4-(2-pyrimidinyl)~
piperazine having a melting point of 109-110 C.
An ethereal solution of the free base is treated with hydrogen chloride to yield the hydrochloride salt :~.0~2434 A mixture containing 7.0 g. of ~-chloromethyl-naphthalene, 6.56 g. of 2-pyridylpiperazlne and 4.4 g. of so~ium carbonate in 40 ml. of dimethylformamide is stirred on a steambath for 90 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-(~-napthylmethyl)-4-(2-pyridyl)piperazine having a melting point of 124-126 C.
An acetone solution of the free base is reacted with succinic acid to yield the succinate salt.
A mixture of 10.0 g. of ~-chloromethylnapthalene,
6.0 g. of sodium carbonate and 9.0 g. of phenylpiperazine in 60 ml. of dimethylformamide is stirred under nitrogen on a steambath for five hours. The reaction mixture is then cooled and filtered. The filtrate is concentrated and stirred with ice water. The formed precipitate is filtered off~
dissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1~
napthylmethyl)-4-(phenyl)piperazine having a melting point of ;
226-228 C.
Employing the procedure outlined above and using 10.9 g. of 1-~4-methoxyphenyl)piperazine as a starting material in place of phenylpiperazine yielded l-(~naphthyl~
methyl)-4-(4-methoxyphenyl)piperazine having a melting point of 117-118 C.
EXAMPLE 5 ~ -Similarly using the above procedures, 9,8 gO of i~34~4~4 1 1-(3-chlorophenyl)piperazine used as a starting material yielded l-(~-naphthylmethyl)-4 (m-chlorophenyl)piperazine having a melting point of 114-L15 C.
A solution of 2.0 g. of 1-(~-naphthylmethyl)~4-(4-methoxyphenyl)piperazine as prepared in Example 4 in 100 ml. of hot 48% hydrogen bromide is refluxed for two hours.
The solution is then cooled and filtered. The collected precipitate is then recrystallized from isobutyl alcohol to yield the dihydrobromide salt of 1-(~-naphthylmethyl)-4-(4-hydroxyphenyl)piperazine having a melting point of 225-227 C.
A solution of 20.0 g. of ~-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 10% sodium hydroxide. The basic solution is extracted with chloroform and the fractions are combined, washed w~lth water and dried. The oily material is distilled to give ~-(napthylmethyl)piperazine.
A mixture of 4.5 g. of ~-(naphthylmethyl)piperazine9 2.6 g. of 2-chloro-3-hydroxypyridine and 2.~ g. of sodium carbonate in 50 ml. of dimethylformamide is stirred on a steam-bath for four hours. The mixture is cooled and filtered. The ~ ;
filtrate is stirred with ice water and the formed precipitate is filtered, clissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to form the hydrochloride salt of 1-(~-naphthylmethyl)-4-(3-hydroxy-2-pyridyl)piperazine.
' `
..9_ - - -, , , . . .-.
-: ' . ~ - .: . :
~4Z~3~L
To a mixture of 4.50 g. of l~ napthylmethyl)-piperazine(as prepared ~n Example 7), 2.5 g. of 2-chloro~5 hydroxypyrimidine in 30 ml. of dimethylformamide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for six hours. The mixture is cooled and filtered and the filtrate concentrated to ~ small volume in vacuo. The con~
centrate is diluted with 100 ml. of water and the insoluble material is washed with water and hexane to yield 1~ 0 napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine.
EXA~PLE 9 To a suspension of 2.7 g. of lithium aluminum hydride in 75 ml. of dry ether i8 added dropwise a solution containing 5.5 g. of 6~methyl-2~naphthoic acid in 7S ml. of dry ether. The mixture i8 refluxed for three hoursJ cooled, and treated with 10% ~odium hydroxide solution. The mixture is then iltered snd dried to yield 6-methyl-2-naphthalene-methanol, 20.3 g. of 6-methyl-2~naphthslenemethanol is dissol~ed in lOO ml. of dry benzene and to this solution ls added 30 ml. of thionyl chlorida. The solution i8 stirred for about one hour and concentrated to yi~lt 2~chloromethyl=
6-methylnaphthalene.
A mixture of 11.0 ~. o~ 2-chloromathyl~6~methyl~
naphthalene, 7~0 g. o~ ~o~ium csrbonat~ And 10~0 g. of 2-pyrldylpiperaz~ne in 75 ml. of dimethylformamide 1~ stirred for 9iX hour~, The r~actlon mixt~re i~ coolQd~ 11~ered and the ~iltrate i9 concentr~t~. The p~ecipl~at~ i~ th~n w~hed with water snd crystallized ~ra~ ~hanol ~o yi~ld l~ mQ~hyl~
~-naphthylmethyl)~4~(2~pyridyl)p~per~8in~.
, - - ..
~4Z43~
In like manner using the procedure of Example 9, 5-methoxy-2-naphthoic acid and 7-chloro-2-naphtholc acid were employed as starting materials in place of 6-methyl~2 naphthoic acid to yield respectively 10(5 methoxy~
naphthylmethyl)-4-(2-pyridyl)piperazine, (7~chloro~naphthyl~
methyl)-4-(2-pyridyl)piperazine.
A solution of 3.4 g, of 1-(5-methoxy-~-naphthyl~
methyl)-4-(2-pyridyl)piperazine in lOO ml. of 48% hydrogen bromide is refluxed for three hours. The mixture is cooled~
concentrated and treated with sodium carbonate~ The mixture is extracted with chloroform and the chloroform extractions are dried to yield 1-(5-hydroxy-~-naphthylmethyl)~4-(2 15 pyridyl)piperazine.
EX~MPLE 12 Ingredients Mgo /Tablet ~ naphthylmethyl)-4-(2-pyridyl)piperazine 25 mg~
Calcium sulfate dihydrate 100 mg.
20 Sucrose 25 mg~
Starch 15 mg~
Talc 5 mg Stearic acid 3 mgO
The sucrose, calcium sulfate and l~ naphthyl~
methyl)-4-(2-pyridyljpiperazine are thoroughly mixed and granulated with hot 10% gelatin solutionO The wetted mass is passed through a #16 U. S. standard mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a #20 U. S. standard mesh screenO These granules are then mixed with starch, talc and stearic acid7 .. . .
i~4;~43~
l passed through a #60 U. S. standard mesh screen and compressed into tablets.
One tablet is administered four times a dayO
In~redients M~/Capsule ~ naphthylmethyl)-4-(2-pyrimidinyl)piperazine 50 mg~
Lactose 200 mg~
The above ingredients are thoroughly mixed and filled into a #2 hard gelatin capsuleO
l() One capsule is administered twic Q a dayO ;
:'0 ~. , 3(l ~ ~ '' - ,... .
dissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1~
napthylmethyl)-4-(phenyl)piperazine having a melting point of ;
226-228 C.
Employing the procedure outlined above and using 10.9 g. of 1-~4-methoxyphenyl)piperazine as a starting material in place of phenylpiperazine yielded l-(~naphthyl~
methyl)-4-(4-methoxyphenyl)piperazine having a melting point of 117-118 C.
EXAMPLE 5 ~ -Similarly using the above procedures, 9,8 gO of i~34~4~4 1 1-(3-chlorophenyl)piperazine used as a starting material yielded l-(~-naphthylmethyl)-4 (m-chlorophenyl)piperazine having a melting point of 114-L15 C.
A solution of 2.0 g. of 1-(~-naphthylmethyl)~4-(4-methoxyphenyl)piperazine as prepared in Example 4 in 100 ml. of hot 48% hydrogen bromide is refluxed for two hours.
The solution is then cooled and filtered. The collected precipitate is then recrystallized from isobutyl alcohol to yield the dihydrobromide salt of 1-(~-naphthylmethyl)-4-(4-hydroxyphenyl)piperazine having a melting point of 225-227 C.
A solution of 20.0 g. of ~-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 10% sodium hydroxide. The basic solution is extracted with chloroform and the fractions are combined, washed w~lth water and dried. The oily material is distilled to give ~-(napthylmethyl)piperazine.
A mixture of 4.5 g. of ~-(naphthylmethyl)piperazine9 2.6 g. of 2-chloro-3-hydroxypyridine and 2.~ g. of sodium carbonate in 50 ml. of dimethylformamide is stirred on a steam-bath for four hours. The mixture is cooled and filtered. The ~ ;
filtrate is stirred with ice water and the formed precipitate is filtered, clissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to form the hydrochloride salt of 1-(~-naphthylmethyl)-4-(3-hydroxy-2-pyridyl)piperazine.
' `
..9_ - - -, , , . . .-.
-: ' . ~ - .: . :
~4Z~3~L
To a mixture of 4.50 g. of l~ napthylmethyl)-piperazine(as prepared ~n Example 7), 2.5 g. of 2-chloro~5 hydroxypyrimidine in 30 ml. of dimethylformamide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for six hours. The mixture is cooled and filtered and the filtrate concentrated to ~ small volume in vacuo. The con~
centrate is diluted with 100 ml. of water and the insoluble material is washed with water and hexane to yield 1~ 0 napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine.
EXA~PLE 9 To a suspension of 2.7 g. of lithium aluminum hydride in 75 ml. of dry ether i8 added dropwise a solution containing 5.5 g. of 6~methyl-2~naphthoic acid in 7S ml. of dry ether. The mixture i8 refluxed for three hoursJ cooled, and treated with 10% ~odium hydroxide solution. The mixture is then iltered snd dried to yield 6-methyl-2-naphthalene-methanol, 20.3 g. of 6-methyl-2~naphthslenemethanol is dissol~ed in lOO ml. of dry benzene and to this solution ls added 30 ml. of thionyl chlorida. The solution i8 stirred for about one hour and concentrated to yi~lt 2~chloromethyl=
6-methylnaphthalene.
A mixture of 11.0 ~. o~ 2-chloromathyl~6~methyl~
naphthalene, 7~0 g. o~ ~o~ium csrbonat~ And 10~0 g. of 2-pyrldylpiperaz~ne in 75 ml. of dimethylformamide 1~ stirred for 9iX hour~, The r~actlon mixt~re i~ coolQd~ 11~ered and the ~iltrate i9 concentr~t~. The p~ecipl~at~ i~ th~n w~hed with water snd crystallized ~ra~ ~hanol ~o yi~ld l~ mQ~hyl~
~-naphthylmethyl)~4~(2~pyridyl)p~per~8in~.
, - - ..
~4Z43~
In like manner using the procedure of Example 9, 5-methoxy-2-naphthoic acid and 7-chloro-2-naphtholc acid were employed as starting materials in place of 6-methyl~2 naphthoic acid to yield respectively 10(5 methoxy~
naphthylmethyl)-4-(2-pyridyl)piperazine, (7~chloro~naphthyl~
methyl)-4-(2-pyridyl)piperazine.
A solution of 3.4 g, of 1-(5-methoxy-~-naphthyl~
methyl)-4-(2-pyridyl)piperazine in lOO ml. of 48% hydrogen bromide is refluxed for three hours. The mixture is cooled~
concentrated and treated with sodium carbonate~ The mixture is extracted with chloroform and the chloroform extractions are dried to yield 1-(5-hydroxy-~-naphthylmethyl)~4-(2 15 pyridyl)piperazine.
EX~MPLE 12 Ingredients Mgo /Tablet ~ naphthylmethyl)-4-(2-pyridyl)piperazine 25 mg~
Calcium sulfate dihydrate 100 mg.
20 Sucrose 25 mg~
Starch 15 mg~
Talc 5 mg Stearic acid 3 mgO
The sucrose, calcium sulfate and l~ naphthyl~
methyl)-4-(2-pyridyljpiperazine are thoroughly mixed and granulated with hot 10% gelatin solutionO The wetted mass is passed through a #16 U. S. standard mesh screen directly onto drying trays. The granules are dried at 120 F. and passed through a #20 U. S. standard mesh screenO These granules are then mixed with starch, talc and stearic acid7 .. . .
i~4;~43~
l passed through a #60 U. S. standard mesh screen and compressed into tablets.
One tablet is administered four times a dayO
In~redients M~/Capsule ~ naphthylmethyl)-4-(2-pyrimidinyl)piperazine 50 mg~
Lactose 200 mg~
The above ingredients are thoroughly mixed and filled into a #2 hard gelatin capsuleO
l() One capsule is administered twic Q a dayO ;
:'0 ~. , 3(l ~ ~ '' - ,... .
Claims (8)
1. A process for preparing a compound of the formula:
or a pharmaceutically acceptable acid addition salt thereof in which:
R is phenyl, pyridyl or pyrimidinyl; and R1 is hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy, comprising reacting a compound of the formula:
in which R1 is defined above with a compound of the formula:
in which R is defined above.
or a pharmaceutically acceptable acid addition salt thereof in which:
R is phenyl, pyridyl or pyrimidinyl; and R1 is hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy, comprising reacting a compound of the formula:
in which R1 is defined above with a compound of the formula:
in which R is defined above.
2. A process in accordance with Claim 1 in which the reaction is carried out in an organic solvent.
3. A process in accordance with Claim 2 in which a binding agent is present.
4. The process of Claim 1 for preparing 1-(.beta.-napthylmethyl)-4-(2-pyridyl)-piperazine which comprises reacting .beta.-chloromethyl-napthalene with 2-pyridylpiperazine.
5. The process of Claim 1 for preparing 1-(.beta.-napthyl-methyl)-4-(2-pyrimidinyl)-piperazine which comprises reacting .beta.-chloromethyl-napthalene with pyrimidinylpiperazine.
6. A chemical compound having the formula:
or a pharmaceutically acceptable acid addition salt thereof in which:
R is phenyl, pyridyl or pyrimidinyl; and R1 is hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy, whenever said compound is prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
or a pharmaceutically acceptable acid addition salt thereof in which:
R is phenyl, pyridyl or pyrimidinyl; and R1 is hydrogen, lower alkyl, halogen, hydroxy or lower alkoxy, whenever said compound is prepared by the process of Claim 1 or an obvious chemical equivalent thereof.
7. The compound 1-(.beta.-napthylmethyl)-4-(2-pyridyl)-piperazine or an acid addition salt thereof whenever said compound is prepared by the process of Claim 4 or an obvious chemical equivalent thereof.
8. The compound 1-(.beta.-napthylmethyl)-4-(2-pyrimidinyl)-piperazine or an acid addition salt thereof whenever said compound is prepared by the process of Claim 5 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US440431A US3919230A (en) | 1974-02-07 | 1974-02-07 | {62 -Naphthylmethyl piperazinyl derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1042434A true CA1042434A (en) | 1978-11-14 |
Family
ID=23748733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA219,288A Expired CA1042434A (en) | 1974-02-07 | 1975-02-03 | Beta-naphthyl-methyl-piperazines |
Country Status (16)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (6)
| 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 |
| JPS52133993A (en) * | 1976-04-29 | 1977-11-09 | Takeda Chem Ind Ltd | 1.2-dihydronaphthalene derivatives and method of preparing the same |
| US4367335A (en) * | 1981-08-03 | 1983-01-04 | Mead Johnson & Company | Thiazolidinylalkylene piperazine derivatives |
| US4620006A (en) * | 1982-08-11 | 1986-10-28 | Eastman Kodak Company | Acid salts of 1-(cyanoalkyl)-4-guanylpiperazines |
| EP1165013A4 (en) | 1999-03-03 | 2002-08-07 | Merck & Co Inc | Inhibitors of prenyl-protein transferase |
| CN107652156B (en) * | 2017-11-18 | 2023-11-10 | 辽宁科技学院 | Crystallization method and device of beta-methylnaphthalene |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL127996C (en) * | 1963-11-19 |
-
1974
- 1974-02-07 US US440431A patent/US3919230A/en not_active Expired - Lifetime
-
1975
- 1975-01-09 ZA ZA00750160A patent/ZA75160B/en unknown
- 1975-02-03 JP JP50014791A patent/JPS50108278A/ja active Pending
- 1975-02-03 CA CA219,288A patent/CA1042434A/en not_active Expired
- 1975-02-03 GB GB453675A patent/GB1449802A/en not_active Expired
- 1975-02-03 AU AU77840/75A patent/AU501049B2/en not_active Expired
- 1975-02-04 IL IL46568A patent/IL46568A/en unknown
- 1975-02-04 BE BE153056A patent/BE825178A/en not_active IP Right Cessation
- 1975-02-04 ES ES434433A patent/ES434433A1/en not_active Expired
- 1975-02-04 CH CH132675A patent/CH616678A5/de not_active IP Right Cessation
- 1975-02-05 NL NL7501362A patent/NL7501362A/en not_active Application Discontinuation
- 1975-02-05 FR FR7503627A patent/FR2260353B1/fr not_active Expired
- 1975-02-06 LU LU71803A patent/LU71803A1/xx unknown
- 1975-02-06 DE DE19752505002 patent/DE2505002A1/en not_active Ceased
- 1975-02-07 IE IE254/75A patent/IE40593B1/en unknown
- 1975-02-07 HU HU75SI00001455A patent/HU171352B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL46568A0 (en) | 1975-04-25 |
| AU7784075A (en) | 1976-08-05 |
| BE825178A (en) | 1975-08-04 |
| IL46568A (en) | 1979-01-31 |
| CH616678A5 (en) | 1980-04-15 |
| AU501049B2 (en) | 1979-06-07 |
| LU71803A1 (en) | 1975-06-24 |
| GB1449802A (en) | 1976-09-15 |
| JPS50108278A (en) | 1975-08-26 |
| ZA75160B (en) | 1976-01-28 |
| FR2260353A1 (en) | 1975-09-05 |
| IE40593L (en) | 1975-08-07 |
| NL7501362A (en) | 1975-08-11 |
| ES434433A1 (en) | 1976-11-16 |
| FR2260353B1 (en) | 1980-01-04 |
| HU171352B (en) | 1977-12-28 |
| US3919230A (en) | 1975-11-11 |
| IE40593B1 (en) | 1979-07-04 |
| DE2505002A1 (en) | 1975-08-14 |
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