CA1088537A - Phenylpiperazinotetrahydronaphthols and derivatives - Google Patents
Phenylpiperazinotetrahydronaphthols and derivativesInfo
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- CA1088537A CA1088537A CA260,395A CA260395A CA1088537A CA 1088537 A CA1088537 A CA 1088537A CA 260395 A CA260395 A CA 260395A CA 1088537 A CA1088537 A CA 1088537A
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- compound
- tetrahydro
- piperazinyl
- methoxyphenyl
- naphthalenol
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Abstract
Abstract New compounds and the pharmaceutically acceptable acid addition salts thereof, which are useful hypotensive agents, have the structure wherein R1 is hydrogen, wherein X is alkyl of 1 to 12 carbon atoms or aryl, or wherein Y is lower alkyl or aryl; R2 is hydrogen, halogen, lower alkyl, hydroxy, alkoxy or ; R3 is hydrogen, halogen, lower alkyl, alkoxy alkyl-thio, trifluoromethyl or nitro; and n is 1, 2 or 3 wherein the terms lower alkyl, alkoxy and alkylthio refer to groups having 1 to 4 carbon atoms and the term aryl refers to phenyl or phenyl monosubstituted with lower alkyl, alkoxy or halogen.
Description
The present invention relates to new compounds, which have useful pharmacological properties, having the ~tructure (R2)n~X ~ ~
or a pharmaceutically acceptable acid addition salt thereof wherein Rl is hydrogen, X-~- wherein X is alkyl of 1 to 12 carbon atoms or aryl, or Y-NH-~- wherein Y is lower alkyl or aryls R2 is hydrogen, halogen, lower alkyl, hydroxy, alkoxy or X-~-0-; R3 is hydrogen, halogen, lower alkyl, alkoxy, alkylthio, trifluoromethyl or nitro; and n is 1, 2 or 3~
I wherein the terms lower alkyl, alkoxy and alkylthio refer ,.j . .
to groups having 1 to 4 carbon atoms and the term aryl refers to phenyl or phenyl monosub~tituted with lower alkyl~ alkoxy or halogen.
In formula I above and throughout the specification ;
the symbols are a~ defined above and in the following four paragraphs.
The term "lower alkyl n, as used throughout the spec~-,~ fication, refers to an alkyl group having 1 to 4 carbon atoms.
The terms "alkoxy" and "alkylthio", as u~ed throughout ~ the specification, refer to groups wherein the hydrocarbon `~ portion of the group has 1 to 4 carbon atoms.
,~i .
The term nhalogen~, as used throughout the specifica-tion, refers to fluorine, chlorine, bromine and iodine; chlorine and bromine are the preferred halogen~.
The term ~aryl", as used throughout the specification, refers to phenyl or phenyl monos~bstituted with lower alkyl, ~c~ ; alkoxy or halogen.
1~88S37 The phenylpiperazinotetrahydronaphthols of for-mula I, and the pharmaceutically acceptable acid addition salts thereof, are useful as hypotensive agents in mammals, e.g., domestic animals such as dogs, cats, etc. Daily doses of from 5 to 50 mg/kg, preferably about 5 to 25 mg/kg can be administered in single or divided doses orally or by injection.
The active compounds of the present invention are administered orally, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like.
Such compositions and preparationq should contain at least 0.1%
of active compound. m e percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 7S% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or prepara-tions according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 250 milligrams of active compound.
The compounds of formula I include those wherein the -~Rl and phenylpiperazino groups are in the cis and in the trans configurations.
~A130 The compounds of formula I, wherein Rl is hydroge~ and the -ORl and phenylpiperazino groups are in the trans configur-ation, can be prepared by reacting a 6,7-epoxy-5,6,7,8-tetra-hydronaphthalene derivative having the formula .
(R2 ) n~=D
with a piperazine derivative having the formula III
10 3 53 ~ ~
R3 .~ .
to yield a trans-phenylpiperazinotetrahydronaphthol having the .
formula IV OH
~ , The reaction can be run in an organic solvent or in a mixture : of organic solvents, preferably a mixture of an aromatic hydrocarbon and an alkanol (e.g., a mixture of xylene and méthanol). Reaction conditions are not critical, ~ut the ., .
reaction will prefera~ly be run at the reflux temperaturo of the solvent.
., ~. :
'' O
1~88537 The compounds of formula I wherein Rl is hydrogen, and the -ORl and phenylpiperazino groups are in the cis configura-tion, can be prepared by first reacting a 6,7-epoxy-5,6,7,8-tetrahydronaphthalene of formula II with sodium azide in the presence of ammonium chloride to yield a trans compound having the formula V ~ OH
(R2 ~ ~ 3 The reaction can be run in an organic solvent, preferably an ether such as 2-methoxyethanol.
Reduction of a trans compound of formula V yields the corresponding trans compound having the formula VI
~R2~B2 The reduction reaction can be run using gaseous hydrogen and a catalyst such as platinum oxide.
Reaction of a compound of formula VI with an acyl chloride yields a trans compound having the formula VII N-acy1 (~
The reaction can be run in an organic solvent, e.g., benzene, in the presence of alkali.
The sequential reaction of a trans compound of formula VII with thionyl chloride and a mineral acid, e.g., hydro-chloric acid, yields a cis compound having the formula VIII
~R2 ~ NN2 Reaction of a Q -3-amino-1,2,3,4-tetrahydro-2-naphtha-lenol of formula VIII with an N-(substituted phenyl)-N,N-bis-~-chloroethylamine having the formula `
IX ~ N(CH2CH2Cl)2 ~J
yields a cis-phenylpiperazinotetrahydronaphthol having the formula X
~ ~ OH
or a pharmaceutically acceptable acid addition salt thereof wherein Rl is hydrogen, X-~- wherein X is alkyl of 1 to 12 carbon atoms or aryl, or Y-NH-~- wherein Y is lower alkyl or aryls R2 is hydrogen, halogen, lower alkyl, hydroxy, alkoxy or X-~-0-; R3 is hydrogen, halogen, lower alkyl, alkoxy, alkylthio, trifluoromethyl or nitro; and n is 1, 2 or 3~
I wherein the terms lower alkyl, alkoxy and alkylthio refer ,.j . .
to groups having 1 to 4 carbon atoms and the term aryl refers to phenyl or phenyl monosub~tituted with lower alkyl~ alkoxy or halogen.
In formula I above and throughout the specification ;
the symbols are a~ defined above and in the following four paragraphs.
The term "lower alkyl n, as used throughout the spec~-,~ fication, refers to an alkyl group having 1 to 4 carbon atoms.
The terms "alkoxy" and "alkylthio", as u~ed throughout ~ the specification, refer to groups wherein the hydrocarbon `~ portion of the group has 1 to 4 carbon atoms.
,~i .
The term nhalogen~, as used throughout the specifica-tion, refers to fluorine, chlorine, bromine and iodine; chlorine and bromine are the preferred halogen~.
The term ~aryl", as used throughout the specification, refers to phenyl or phenyl monos~bstituted with lower alkyl, ~c~ ; alkoxy or halogen.
1~88S37 The phenylpiperazinotetrahydronaphthols of for-mula I, and the pharmaceutically acceptable acid addition salts thereof, are useful as hypotensive agents in mammals, e.g., domestic animals such as dogs, cats, etc. Daily doses of from 5 to 50 mg/kg, preferably about 5 to 25 mg/kg can be administered in single or divided doses orally or by injection.
The active compounds of the present invention are administered orally, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like.
Such compositions and preparationq should contain at least 0.1%
of active compound. m e percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 7S% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or prepara-tions according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 250 milligrams of active compound.
The compounds of formula I include those wherein the -~Rl and phenylpiperazino groups are in the cis and in the trans configurations.
~A130 The compounds of formula I, wherein Rl is hydroge~ and the -ORl and phenylpiperazino groups are in the trans configur-ation, can be prepared by reacting a 6,7-epoxy-5,6,7,8-tetra-hydronaphthalene derivative having the formula .
(R2 ) n~=D
with a piperazine derivative having the formula III
10 3 53 ~ ~
R3 .~ .
to yield a trans-phenylpiperazinotetrahydronaphthol having the .
formula IV OH
~ , The reaction can be run in an organic solvent or in a mixture : of organic solvents, preferably a mixture of an aromatic hydrocarbon and an alkanol (e.g., a mixture of xylene and méthanol). Reaction conditions are not critical, ~ut the ., .
reaction will prefera~ly be run at the reflux temperaturo of the solvent.
., ~. :
'' O
1~88537 The compounds of formula I wherein Rl is hydrogen, and the -ORl and phenylpiperazino groups are in the cis configura-tion, can be prepared by first reacting a 6,7-epoxy-5,6,7,8-tetrahydronaphthalene of formula II with sodium azide in the presence of ammonium chloride to yield a trans compound having the formula V ~ OH
(R2 ~ ~ 3 The reaction can be run in an organic solvent, preferably an ether such as 2-methoxyethanol.
Reduction of a trans compound of formula V yields the corresponding trans compound having the formula VI
~R2~B2 The reduction reaction can be run using gaseous hydrogen and a catalyst such as platinum oxide.
Reaction of a compound of formula VI with an acyl chloride yields a trans compound having the formula VII N-acy1 (~
The reaction can be run in an organic solvent, e.g., benzene, in the presence of alkali.
The sequential reaction of a trans compound of formula VII with thionyl chloride and a mineral acid, e.g., hydro-chloric acid, yields a cis compound having the formula VIII
~R2 ~ NN2 Reaction of a Q -3-amino-1,2,3,4-tetrahydro-2-naphtha-lenol of formula VIII with an N-(substituted phenyl)-N,N-bis-~-chloroethylamine having the formula `
IX ~ N(CH2CH2Cl)2 ~J
yields a cis-phenylpiperazinotetrahydronaphthol having the formula X
~ ~ OH
2~t~ ,1~" N~ ~;
The reaction can be run in an organic solvent, preferably a 20 lower alkanol, at elevated temperatures. The reaction does not go quickly, and may take up to a week to complete.
Alternatively, both CiS- and trans-phenylpiperazino-tetrahydronaphthols of formula I, wherein ~1 is hydrogen and R2 i8 alkoxy, can be prepared from the corresponding compound of formula I wherein R2 is hydroxy. The compound i8 reacted ~ with a diazoalkane in an organic solvent, preferably a lower -~ alkanol at a reduced temperature.
Reaction of a CiS- or trans-phenylpiperazinotetrahydro-naphthol of formula I (Rl is hydrogen) ~ith an acid anhydride 30 having the formula XI l in the presence of an organic base, e.g., pyridine, yields the corresponding cis or trans compound having the formula XII o O-C-X
~ ~ `N ~ ~
Reaction of a cis- or trans-piperazinotetrahydro-naphthol of formula I ~Rl is hydrogen) with an isocyanate 10 having the formula XIII Y-N=C=O
yields the corresponding cis or trans carbamate having the formula . Il :
XIV ~ O-C-NH-Y
2 ~/--\
The reaction can be run in an organic solvent, preferably a 20 polar organic solvent such as dimethylformamide or dimethyl-sulfoxide, in the presence of an organic base such as pyridine.
The 6,7-epoxy-5,6,7,8-tetrahydronaphthalene derivative~
of formula II can be prepared from naphthalene derivatives having the structure . XV ~ :
(R'2 ~ .
In formula XV and throughout the specification, R'2 can be hydrogen, halogen, lower alkyl, or hydroxy. ~ naphthalene derivative of 30 formula VII can be.reduced with a metal such as sodium or lithium, 1~130 in liquid ammonia containing an alkanol, such as ethanol, isopropanol, t-butanol, etc. to obtain a 5,8-dihydronaphtha- -~
lene derivative having the structure XVI ~ `
( 2) ~
:
To prepare the 5,8-dihydronaphthalene derivatives necessary for the preparation of compounds of formula I wherein R2 is alkoxy, the corre6ponding hydroxy derivative of formula XVI
i5 reac~ed with an alkyl halide to yield the alkoxy-5,8-dihydronaphthalene. The reaction is carried out in a polarorganic solvent, e.g., dimethylsulfoxide or dimethylformamide, in the presence of an alkali metal alkoxide, e.g., sodium methoxide or potassium ethoxide.
Reactian of a 5,8-dihydronaphthalene derivative having the structure XVII ~ ~, with m-chloroperbenzoic acid yields a 6,7-epoxy-5,6,7,8-tetra-hydronaphthalene derivative of formula ~I. The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene derivative in an organic solvent, ' e.g., ethyl acetate. The resulting mixture is added to a L~ mixture of ethyl ether and aqueous sodium bicarbonate and mixed to form the 6,7-epoxy-5,6,7,8-tetrahydronaphthalene derivative of formula II.
,. .::,:
~ Alternate procedures for the preparation of the compounds -~ of formula I will be apparent to those gkilled in the art.
For example, the compounds of formula I wherein R2 is alkoxy ;~ 30 can be prepared by reacting the corresponding hydroxy compounds :'' .~
wigh a diazoalkane and compounds of formula I wherein R2 is X-~-O- can be prepared by reacting the corresponding hydroxy compounds with an acid anhydride of formula XI.
The compounds of formula I can be utilized in the form of their pharmaceutically acceptable acid-addition salts.
These salts are readily formed by methods well known in the art. Exemplary salts are hydrohalides (e.g., hydrochloride and hydrobromide), nitrate, phosphate, borate, acetate, tar-trate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like.
The following examples are specific embodiments of this invention.
ExamP le -1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyPhenyl)--~iPerazlnyl]-2-naphthaleno r A solution Gf 4.12 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 4.81 g of l-~o-methoxyphenyl)-piperazine, and 1.53 ml of isopropyl alcohol in 20 ml of xylene is refluxed under nitrogen for 19 hours. The xylene is removed in vacuo and the residue triturated with ether to give 4.01 g of crude material. Two recrystallizations of this material from ethyl acetate yield 2.5 g of the title compound, melting point 182-183C.
ExamPle 2 tra~fi-li2,3;4-Tetrahydro-3-~4-phenyl-l-piperazinyl)-2 naDhtha eno A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydro-naphthalene, 8.91 g of N-phenylpiperazine, and 19 ml of i80-propanol in 50 ml of xylene is refluxed for five days. The xylene i~ removed in vacuo leaving a solid residue, which yields 9.9 g of crude material on trituration with isopropyl ether. Two recrystallizations from ethyl acetate yield 6.5 g of the title compound, melting point 152-154C.
Example 3 2i3,4-Tetrahydro-3-~4-(2-methoxyphenyl)-1-piperazinyl3--nap t a eno A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydro-naphthalene, 10.56 g of l-(o-methoxyphenyl)piperazine, and 19 ml of isopropanol in 50 ml of xylene i9 refluxed for five ~;~ days. The xylene is removed in vacuo leaving a solid residue, which on trituration with isopropyl ether gives 11.34 g of crude material. Two recrystallizations from ethyl acetate yield 7,0 g of the title compound, melting point 159-161C.
' _g_ ~ 8S37 Example 4 trans-5,6,7,8-Tetrahydro-7(and 6)-~4-(2-methoxyphenyl)-1-piperazinyl]-1,6(and 1,7)-naphthalenedlol A solution of 33.8 g of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol and 42 g of l-(_-methoxyphenyl)piperazine in 400 ml xy-lene is heated under reflux for 20 hours. On cooling, a large amount of solid precipitates and is removed by filtration to give 57.8 g of material. A thin layer chromatogram reveals two clean-ly separated spots. This is dissolved in a hot mixture of ethyl acetate-ethanol. On cooling, crystalline material is deposited.
This is recrystallized from ethyl acetate-ethanol and then from ethanol to give 7.7 g of trans-5,6,7,8-tetrahydro-6-[4-(2-meth-oxyphenyl)-l-piperazinyl]-1,7-naphthalenediol, melting point 199-201C.
~ The mother liquor from the harvesting above is concent-f rated. Recrystallizations from ethyl acetate give material still containing s~meof the slow moving isomer. This mixture (32 g) is chromatographed on 1 kg Activity III basic alumina. trans-5,6,7, 8-Tetrahydro-7-[4-12-methoxyphenyl)-1-piperazinyl]-1,6-naphthal-enediol (TLC pure) is eluted with chloroform. Ether is added to these fractions, and the material which crystallizes is harvested -~
and recrystallized from ethyl acetate-methanol to yield 14.0 g of trans-5,617,8-tetrahydro-7-[4-(2-methoxyphenyl)-l-piperazinyl]-l, , 6-naphthalenediol, melting point 218-220C.
Example 5 ~ans-1,2,3,4-Tetrahydro-8-methoxy-3-[4-(2-methoxyPhenyl)-l-piperazinyl]-2-naphthalenol A solution is 2.0 g of trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-l-piperazinyl]-1,7-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane.
The solution is stored at 0C for 48 hours. The solvent is re-moved in vacuo. The residue is dissolved in ethyl acetate, wash-ed with dilute sodium hydroxide solution and dried. The solvent is removed ln vacuo leaving an oil which crystallizes on tritur-ation with a small amount of ether. This is washed with isopro-pyl ether and recrystallized from ether to give 1.7 g of the title compound, melting point 123-125C.
Example 6 ~L~-1,2,3,4-Tetrahydro-5-methoxy-3-[4-(2-methoxyphenyl)-1-piE~er-az nY - -naP t a eno A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-l-piperazinyl3-1,6-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazometbane. ' $he solution is stored at 0C for 48 hours. The solvent is removed in _acuo, the residue is dissolved in ethyl acetate and washed with 10 dilute sodium hydroxide solution. After drying and removal of sol-vent in vacuo, an oil remains which crystallizes on trituration with a very small amount of ether. The crystalline material is wa~hed -with a small amount of isopropyl ether and recrystallized from ether-isopropyl ether to give 1.13 g of the title compound, melting point 138-141C.
Example 7 $~-1S2,3,4-Tetrahydro-3-[4- (2-methoxyphenyl)-1-piperazinvll-2,6-~an "-napnt a ene io A mixture of 20.4 g of 6,7-epoxy-5,6,7,8-tetrahydro-2-naph-thol acetate and 42.2 g of l-~o-methoxyphenyl)piperazine in 200 ml 20 xylene is heated under reflux overnight. After cooling, the mixture is taken to dryness in vacuo. The material is dissolved in benzene and chromatographed on 1 kg Activity III basic alumina. After elu-tion of fast moving material with beniene and benzene-chloroform mixture Isomer A (fractions 13-18,--17.9g) is eluted with chloroform and Isomer B (fractions 25-34, 17.lg~ is eluted with chloroform and S~ methanol in chloroform.
Fractions 14-16 (9.lg) are recrystallized from ethyl acetate-ethanol to give 5.34 g of material. This is recrystallized from a `~ large volume (~1.5 1) of methanol to give 4.55 g of material, melting -30 point 237-239C-Ethyl acetate is added to fractions 25-31 (13.2g) and the material which crystallizes is har-rested (8.64g?. This is recrystal-lized from a large volume of methanol (-3 1) to give 6.6S g of material, melting point 224-228C.
~1 ~0 Example 8 -5,6~7i8-Tetrahydro-7-[4-~2-methoxyphenyl)-1-piperazinyl]-~_-nap tha ene lO , iacetate es A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,6-naphthalenediol in 20 ml of pyridine is cooled in an ice bath and treated drop-wise with 2.2 ml of acetic anhydride. After standing for 2 days at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide and twice with water. The 10 ethyl acetate solution is dried over magnesium sulfate, fil-texed, and the solvent is removed in vacuo leaving 2.6 g of foam. Ether is added and the crystalline material that is deposited is harvested. This is recrystallized from ethyl acetate-isopropyl ether to give 1.88 g of the title compound, melting point 128-132C.
. ExamPle 9 -1,2,3,4-Tetrahvdro-3-(4-phenyl-1-piperazinyl)-2-naphtha-eno , acetate ester A solution of 1.0 g of trans-1,2,3,4-tetrahydro-3-(4-20 phenyl-1-piperazinyl)-2-naphthalenol in 10 ml of pyridine is cooled in an ice bath and treated dropwise with 0.68 ml of acetic anhydride. After standing overnight at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with dilute sodium hydroxide solution and twice with water. After drying over magnesium sulfate the solvent is removed in vacuo leaving 1.18 g of viscous material. A small amount of ether is added and on standing cry~talline material i~ deposited. This i9 recrystal-lized from isopropyl ether to give 0.9 g of the title compound, 30 melting point 70-75C.
Example 10 tr~n--5,6, 7,8-Tetrah dro-6-[4-(2-methoxypheny1)-1-piperazinxl]-1,7-napXthalenediol, diacetate ester A solution of 1.5 g of trans-5, 6, 7,8-tetrahydro-6-14-~2-methoxyphenyl)-1-piperazinyl~-1,7-naphthalenediol in 15 ml pyridine is cooled in an ice bath and treated dropwise with 1.65 ml of acetic anhydride. The mixture is left for about 16 hours at room temperature. The mixture is taken to near dryness ln vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide and twice -~
10 with water. After drying over magnesium sulfate, the solvent i5 removed in vacuo leaving 2.0 g of foam. On addition of ether-hexane the material crystallizes. This is recrystallized from ethyl acetate-hexane to give 1.6 g of the title compound, melting point 137-141C.
Example 11 trans-1,2,3,4-Tetrahvdro-5,8-dimethoXy-3-[4-(2-methOXYPhen~
;rPlPerazinyll-2-nap~thalenol~ acetate ester ~-~~
A solution of 920 mg of trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-t4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol -in 10 ml pyridine is cooled in an ice bath and treated dropwise with 0.44 ml of acetic anhydride. After standing for about 1-6 hours at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide solution and twice with water. After drying the solvent 16 removed in vacuo leaving aoo mg of foam. Ether is added and the material which crystallizes is recrystallized from ethyl acetate-hexane to give 0.70 g of the title compound, melting point 166-169C.
.
. . .
Example 12 trans-1,2,3,4-Tetrahydro-6 (or 7)-methoxy-3-14-(2-methoxyphenyl~-l-plperazlnyl~-2-naphthalenol A suspension of 1.0 g of trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2,6(or 2,7)-naphthalene-diol in 100 ml methanol is cooled in an ice bath and treated with an excess of freshly prepared solution of diazomethane in ether. The mixture is left in the refrigerator for about 16 hours. The next day the yellow color is gone but a con-siderable amount of insoluble material remains. The mixture ~
is stirred in an ice bath for 8 hours during which time more `~-diazomethane solution is added. After standing 16 hours at 5C the solution is nearly complete. After stirring with -~
cooling for 3 additional hours a few drops of acetic acid are added to discharge the yellow color. The solvent is removed in vacuo. The residue is dissolved in ethyl acetate, washed with dilute sodium hydroxide solution andthen water. After --drying, the solvent is removed in vacuo to give 1.05 g of foam. This yields crystalline material on addition of ether-isopropyl ether. Recrystallization from ethyl acetate-hexane yields 0.46 g of the title compound, melting point 129-131C. ~ -Example 13 dro-3-[4-(2-methoxyphenyl)-1-piperazin`1]-2,6 (or 2,7~-na~ _ trans-1,2,3,4-Tetrahydro-3-[4-(2-methoxyphenyl-1-piper-azinyl]-2,6 (or 2,7)-naphthalenediol (l.Og) is partially dis-solved in 10 ml of pyridine. The mixture is cooled in an ice bath an 1.1 ml acetic anhydride is added dropwise. After stirring for 1-2 hours at room temperature a clear solution is obtained. After standing for about 16 hours at room temperature the solvent is removed in vacuo. The residue is ;-.
-14- ~
HAl30 dissolved in ethyl acetate and washed with dilute sodium hydroxide solution and then twice with water. After drying, the solvent is removed in vacuo leaving a foam. Material crystallizes after the addition of hexane-ether. This is harvested and recrystallized from ether-hexane to give 0.85 g of the title compound, melting point 99-102C.
Example 14 2~L~a-n-~r-l~2~3)4-Tetrah~dro-3-[4-(2-methoxyphenyl)-l-piperazinyl]
or , -nap t a ene io , iacetate trans-1,2,3,4-Tetrahydro-3-l4-(2-methoxyphenyl)-l-10 piperazinyl]-2,6~or 2,7)-naphthalenediol (l.0 g) is partially dissolved in lO ml of pyridine. The mixture is cooled in an ice bath and 1.1 ml of acetic anhydride is added dropwise.
After stirring a few minutes at room temperature the mixture is a clear solution which is left for about 16 hours at room temperature. The solvent was renloved in _acuo, the residue is dissolved in ethyl acetate and wa~hed with dilute sodium hydroxide solution and twice with water. After drying, the solvent is removed in vacuo leaving a foam. After standing several days in ether-hexane, crystalline material is obtained.
20 This is recrystallized from ether-hexane to give l.0 g of the title compound, melting point 109-113C.
Example 15 -5~6~7~8-Tetrahydro-7-[4-~2-methoxyphenyl)-l-piperazin~l]
, , -na~ t a ene rio , A solution of 13.1 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-diacetoxynaphthalene and 29.8 g of l-(o-methoxyphenyl~-piperazine in 200 ml of xylene is refluxed under nitrogen for 48 hours. The reaction mixture is then cooled, the c~ystalline precipitate filtered, washed with ether, and dried in vacuo to afford lO.SS g of crude crystalline product. Recrystallization 101~8537 of 7.50 g of this material from ethyl acetate/ethanol gives 4.0 g of the title compound, melting point 222-224C.
Example 16 -1,2,3,4-Tetrah~dro-6(or 7)-methoxy-3-[4-(2-methoxypheny -P perazinY - -nap t a enol -~
A suspension of 1.0 g of trans-1,2,3,4-tetrahydro-3-14-(2-methoxyphenyl)-1-piperazinyl]-2,6 (or 2,7~-naphthalene-diol in 100 ml methanol is cooled in an ice bath and treated with an excess of a freshly prepared solution of diazomethane in ether. After standing for about 16 hours in a refrigerator the yellow color is gone but a considerable amount of insoluble material remains. More diazomethane solution is added ~in 3 portions) and the mixture is stirred for about 8 hours while cooling in an ice bath. After standing in a refrigerator for about 16 hours, the addition of more diazomethane and stirring i8 repeated. The third day the mixture is just stirred. After ~tanding in the cold for about 16 hour~ again nearly all the solld is gone. A ~ew drops of glacial acetic acid are added to dl8charge yellow color. The mixture is taken to dryness in vacuo. The residue i8 dissolved in warm ethyl acetate and washed with dilute sodium hydroxide solution and then with water.
After drying, the solvent is removed in vacuo to give 1.05 g of partially crystalline material. Ether is added and crystal-ltne material is harvested. Recrystallization from ethyl acetate-hexane gives 0.79 g of the title compound, melting point 148-150C.
Example 17 ~-5,6,7,8-Tetrahydro-7-r4-~2 ~ -A solution of 3.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyll-1,4,6-naphthalenetriol in 30 75 ml of pyridine and 25 ml of acetic anhydride is stored H~130 10~8537 at room temperature overnight. The solution is concentrated ln vacuo, the residue taken up in ether, washed with cold dilute sodium hydroxide, saturated sodium chloride, dried, and concentrated _ vacuo to an oil. Trituration with isopropyl ether gives 3.7 g of crude solid product. Two recrystallizations from ethyl acetate/hexane give 1.4 g of the title compound, melting point 168-170C.
Example 18 -1~2!3~4-Tetrahydro-5~8-dimethoxy-3-l4-(2-methoxyphenyl) -p perazlnY - -nap t a eno , propanoate ester trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-14-(2-methoxy-phenyl)-l-piperazinyl]-2-naphthalenol (6.0 g) is partially dissolved in 70 ml of pyridine. The mixture is cooled in an ice bath and treated dropwise with 3.9 ml of propionic anhy-dride. The mixture is clear after stirring at room temperature for 44 hour6. After taking to dryness Ln vacuo, the residue is dissolved in ethyl acetate and washed twice with cold dilute sodium hydroxide solution and twice with saturated sodium chloride solution. After drying, the solvent is removed ln vacuo leaving 7.35 g of foam. This is dissolved in ether. On 20 ~tanding 4.3 g of crystalline material is deposited. This is recrystallized from ether to give 2.9 g of the title compound, melting point 100-105C.
Example 19 -1 ~ 3~l-T2etrahxdhol5~8-dimethoxy-3-[4-(2-met-oxyphe-nyl) -plperazlny ]- -nap t a eno , utanoate ester trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-l-piperazinyl]-2-naphthalenol ~6.0 g) is partially dissolved in 70 ml of pyridine. The mixture is cooled in an ice bath and treated dropwise with 4.75 ml of but~ric anhydride.
30 After stirring for 2 days at room temperature the clear solution 108~537 is taken to dryness 1n vacuo. The residue is dissolved in ethyl acetate and washed twice with cold dilute sodium hydroxide solution and twice with saturated sodium chloride solution.
After drying, the solvent i8 removed in vacuo leaving 7.35 g of foam. ThiS is dissolved in isopropyl ether and after standing several days in the freezer, crystalline material is deposited. This is recrystallized from ether-hexane with a charcoal decolorization to give 2.75 g of the title compound, melting point 73-78C.
Example 20 10 ~ (and 5,7,8)-trimethoxy-3-[4-(2-met oxYphenyl)-l-pipera A solution of 3.4 g of 1,2,4-trimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.8 g of l-~o-methoxyphenyl)-piperazine, and 3.1 ml of isopropanol in 30 ml of xylene is heated under reflux for 5 days. After cooling the mixture iB taken to near dryness in vacuo. The residue contains fiome solids. Isopropyl ether is added and 2.6 g of solid is harvested. This i8 recrystallized from ethyl acetate with a charcoal decolorization to give 1.25 g of the title compound, 20 melting point 210-213C.
The mother liquor from the above crystallization of crude matérial is taken to dryness and the 4.8 g residue is dissolved in benzene and chromatographed on a 120 g column of basic alimina (Activity III). After elution of the ~aster moving isomer with benzene, the other isomer is eluted with benzene and 30~ ethy~ acetate in ~enzene. Isopropyl ether is added to fractions containing the second isomer to give 1.1 g of crystalline material. This is recrystallized from ethyl acetate to give 0.6 g of the title compound, melting point 30 167-170C.
.
~A130 xample 21 ~L~ 2~3~4-Tetrah~dro-6~7-dimethoxy-3-~4-(2-methoxyphenyl) -plperaziny -2-nap t a eno A solution of 2.94 g of 2,3-dimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.9 g of l-(o-methoxyphenyl)piperazine, and 1 ml of isopropanol in 30 ml of xylene is refluxed for 5 days. The reaction mixture is concentrated in vacuo, the residue taken up in ethyl acetate, and this is thoroughly extracted with dilute hydrochloric acid. The combined acid extracts are made basic with dilute sodium hydroxide solution, and this is 10 thoroughly extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated in vacuo to an oil, which gives 1.3 g of solid on trituration with ethyl acetate.
Recrystallization from ethyl acetate gives 600 mg of the title compound, melting point 172-174C.
Exam~le 22 tran~-3-[i-(2-Chloro heny1)-1-PiperazinY1]-1,2,3,4-tetrahydro-lmethoxY-2-naph~halenol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 9.83 g of o-chlorophenylpiperazine and 20 2 ml of absolute ethanol in 100 ml xylene is refluxed for 5 days.
The solution is then concentrated in vacuo, and the residue is triturated with ether to give 12.0 g of crude product. Recrystal-lization from ethanol/methanol gives the title compound, melting point 237-239DC.
Example 23 ,-1,2!3,4-Tetrahydro-S,a-dimethoxy-3-~4-(2-methylphenyl) l-plperazlnyl]-2-napht enol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 8.8 g of o-tolylpiperazine, and 2 ml of 30 absolute ethanol in 100 ml of xylene is refluxed for 4 days.
10~8537 The reaction mixture is cooled to room temperature, and the resulting crystalline solid is filtered off and washed with ether to give 15.2 g of crude product. Recrystallization from ethanol/methanol gives 4 g of the title compound, melting point 217-219C.
Example 24 trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-[3-(trifluoro-methyl)phenvl]-l-piperazinyl]-2-naphthalenol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(a,a,a-trifluoro-m-tolyl)piper-10 azine, and 2 ml of absolute ethanol in 100 ml of xylene isrefluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184-187C.
Example 25 -~La~-3-[4-[2-(EthYlthio)phenyl]-l-piperazinyl]-1,2,3,4-tetra-hydro-5,8-dimethoxy-2-naphthalenol A solution of 10.3 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 11.9 g of l-o-ethylmercaptophenyl-20 piperazine, and 2 ml isopropanol in 100 ml of xylene is heatedunder reflux for 6 days. ~he solution is taken to dryness in vacuo leaving partially crystalline material. ~fter trituration with isopropyl ether the crystalline material is harvested by filtration. Two recrystallizations from ethy} acetate give 9.45 g --of the title compound, melting point 171-173C.
Example 26 trans-l 2,3,4-Tetra ~ )-To a suspension of 3.98 g of trans-1,2,3,4-tetrahydro-30 5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol , _ ~n_ in 20 ml o~ N,N-dimethylformamide and lS ~1 of pyridine is added 2 ml of n-butyl isocyanante, and the resulting mixture is stirred -and heated at 100C for 6 hours. The resulting clear solution is concentrated ln vacuo and the residue is triturated with diiso-propyl ether to give 3.5 g of crude product. Two recrystalliza-tions from diisopropyl ether give 1.5 g of the title compound, melting point 105-108C.
Example 27 cis-1~2!3~4-TetrahYdro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-~perazlnyl]-2-naphthalenol 10 A. trans-3-Triazo-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol A mixture of 12.36 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 15.6 g of sodium azide, and 3.48 g of ammonium chloride in 162 ml 2-methoxyethanol and 24 ml water is stirred in a bath maintained at 80C+5 for 18 hours. The mixture i8 taken to dryness in _acuo. The solid i~ partially dissolved in water, some sodium chloride is added, and the product is extracted into chloroform, dried and freed of solvent in vacuo to give 15.2 g of solid azide.
B. trans-3-Amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naPhthalenol The crude azide is dissolved in 200 ml of absolute ethanol, treated with 0.8 g of platinum oxide, and hydrogenated on a Parr shaker for 24 hours. The bottle is vented and refilled with hydrogen every 15 minutes for the first hour, then once an hour for 6 hours before the mixture is left shaking for 16 -~ hours. After heating to dissolve precipitated material, the catalyst is removed by filtration and washed with hot ethanol.
The filtrate is taken tG dryness in vacuo leaving a waxy solid.
This is ~riturated with ethyl acetate/ether to give 11.5 g of ~olid amine.
,.
~0~537 C. trans-3-Amino-1,2,3,4-tetrahYdro-5,8-dimethoxy-2-naphthal- -enol ! hydrochloride (1:1) A solution of 3.7 g cf trans-3-amino-1,2,3,4-tetrahydro- ~
5,8-dimethoxy-2-naphthalenol in isopropanol is converted to the -hydrochloride salt by adding a solution of hydrogen chloride in isopropanol. The salt is precipitated by adding ether and --recrystallized twice from isopropanol to give 1.3 g of the title compound, melting point 213-216C.
D. trans-3-Benzamido-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphtha-lenol A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro- ~ ;
5,8-dimethoxy-2-naphthalenol, hydrochloride in 2 liters of water -is cooled in an ice bath and a solution of 40 g of benzoyl chlor- -ide in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0-5C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost imme- -diately. The mixture is stirred at 0-5C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo .
over phosphorous pentoxide to give 78.5 g of the title compound.
E. cis-3-Amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol The crude benzamido compound (78.5 g) is added in several ~ -portions to 180 ml of cold thionyl chloride. After the addition is complete the mixture is stirred at room temperature for 45 minutes and then heated at 50C for 2-1/2 hours. The thionyl chloride is removed in vacuo, and the residue is treated with -- ~- ,;
700 ml of 10~ hydrochloric acid and heated under reflux for about ~ -16 hours. Charcoal is added to the hot solution and this is filtered through a pad. On cooling, benzoic acid crystallize~ ~-from the filtrate and is removed by filtration. This filtrate is taken to near dryness -in vacuo leaving very viscous material.
~0~8537 This is dissolved in ethanol-methanol and again taken to dryness _ vacuo leaving a waxy solid. The crude hydrochloride is dis-solved in 200 ml water. This is extracted exhaustedly with ethyl acetate, and the a~queous layer is then made alkaline with sodium hydroxide. The solid free base is harvested by filtration, wash-ed with water and dried in vacuo to give 21.5 g of product. A
2.0 g sample of this is recrystallized from isopropanol with a charcoal decolorization to give 1.1 g of the title compound, melting point 193-196C.
F. cis-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyll-2-naphthalenol A solution of 2.23 g of c -3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol and 2.48 g of N-(o-methoxyphenyl)-N,N-b -~-chloroethylamine in 25 ml of n-butanol is heated in a small Parr bomb at 140-150C for 5 days. The cooled solution is taken to dryness in vacuo and the residue is diluted with water and made basic with dilute aqueous sodium hydroxide. This is thoroughly extracted with ethyl acetate, and the combined ext-racts are washed with saturated aqueous sodium chloride, dried, and concentrated in vacuo to give 3.5 g of a semi-solid material.
Trituration with ether yields 1.5 g of crude product.
A sample (2.6 g) of the above crude product is dissolved in chloroform and applied to an alumina column (75 g of Activity III, basic). Elution with chloroform (20 ml fractions) gives (fractions 3-5) l.S g of solid. Direct recrystallization of this material from ethyl acetate/methanol with charcoal decolor- -izations gives the analytical sample (0.92 g) melting point 198-199C.
Example 28 trans-1,2,3,4-Tetrahydro-3-(4-phenyl-1-piperazino)-2-naphthal-enol, benzoate ester Following the procedure of Example 9, but substituting benzoic anhydride for acetic anhydride, yields trans-1,2,3,4-~IA130 tetrahydro-3-~4-phenyl-1-piperazino)-2-naphthalenol, benzoate ester .
Example 29 trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-l-pi~erazino~-2-naphthalenol ! he~ylcarbamate Following the procedure of Example 26, but substituting phenyl isocyanate for n-butyl isocyanate, yields trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinol-2-naphthalenol, phenylcarbamate.
E~amPle 30 t~ -1,2t3,]4-Tetrahydro-5,8-dichloro-3-[4-(2-methoxyphenyl)-_-P Perazlno - -nap t a eno Following the procedure of Example 1, but substituting 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dichloronaphthalene for 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene yields trans-1,2,3,4-tetrahydro-5,8-dichloro-3-t4-(2-methoxyphenyl)-1-piper-azino]-2-naphthalenol.
Example 31 ~-1,2,3~4-T t ahydro-5,8-dimethyl-3-_t4-(2-methoxyphenyl)-l_Piperazino]-2-naphthalenol ~ -Foilowing the procedure of Example 1, but substituting 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethylnaphthalene for 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene yields trans-1,2,3,4-tetrahydro-5,8-dimethyl-3-[4-(2-methoxyphenyl3-1-piperazino]-2-naphthalenol.
The reaction can be run in an organic solvent, preferably a 20 lower alkanol, at elevated temperatures. The reaction does not go quickly, and may take up to a week to complete.
Alternatively, both CiS- and trans-phenylpiperazino-tetrahydronaphthols of formula I, wherein ~1 is hydrogen and R2 i8 alkoxy, can be prepared from the corresponding compound of formula I wherein R2 is hydroxy. The compound i8 reacted ~ with a diazoalkane in an organic solvent, preferably a lower -~ alkanol at a reduced temperature.
Reaction of a CiS- or trans-phenylpiperazinotetrahydro-naphthol of formula I (Rl is hydrogen) ~ith an acid anhydride 30 having the formula XI l in the presence of an organic base, e.g., pyridine, yields the corresponding cis or trans compound having the formula XII o O-C-X
~ ~ `N ~ ~
Reaction of a cis- or trans-piperazinotetrahydro-naphthol of formula I ~Rl is hydrogen) with an isocyanate 10 having the formula XIII Y-N=C=O
yields the corresponding cis or trans carbamate having the formula . Il :
XIV ~ O-C-NH-Y
2 ~/--\
The reaction can be run in an organic solvent, preferably a 20 polar organic solvent such as dimethylformamide or dimethyl-sulfoxide, in the presence of an organic base such as pyridine.
The 6,7-epoxy-5,6,7,8-tetrahydronaphthalene derivative~
of formula II can be prepared from naphthalene derivatives having the structure . XV ~ :
(R'2 ~ .
In formula XV and throughout the specification, R'2 can be hydrogen, halogen, lower alkyl, or hydroxy. ~ naphthalene derivative of 30 formula VII can be.reduced with a metal such as sodium or lithium, 1~130 in liquid ammonia containing an alkanol, such as ethanol, isopropanol, t-butanol, etc. to obtain a 5,8-dihydronaphtha- -~
lene derivative having the structure XVI ~ `
( 2) ~
:
To prepare the 5,8-dihydronaphthalene derivatives necessary for the preparation of compounds of formula I wherein R2 is alkoxy, the corre6ponding hydroxy derivative of formula XVI
i5 reac~ed with an alkyl halide to yield the alkoxy-5,8-dihydronaphthalene. The reaction is carried out in a polarorganic solvent, e.g., dimethylsulfoxide or dimethylformamide, in the presence of an alkali metal alkoxide, e.g., sodium methoxide or potassium ethoxide.
Reactian of a 5,8-dihydronaphthalene derivative having the structure XVII ~ ~, with m-chloroperbenzoic acid yields a 6,7-epoxy-5,6,7,8-tetra-hydronaphthalene derivative of formula ~I. The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene derivative in an organic solvent, ' e.g., ethyl acetate. The resulting mixture is added to a L~ mixture of ethyl ether and aqueous sodium bicarbonate and mixed to form the 6,7-epoxy-5,6,7,8-tetrahydronaphthalene derivative of formula II.
,. .::,:
~ Alternate procedures for the preparation of the compounds -~ of formula I will be apparent to those gkilled in the art.
For example, the compounds of formula I wherein R2 is alkoxy ;~ 30 can be prepared by reacting the corresponding hydroxy compounds :'' .~
wigh a diazoalkane and compounds of formula I wherein R2 is X-~-O- can be prepared by reacting the corresponding hydroxy compounds with an acid anhydride of formula XI.
The compounds of formula I can be utilized in the form of their pharmaceutically acceptable acid-addition salts.
These salts are readily formed by methods well known in the art. Exemplary salts are hydrohalides (e.g., hydrochloride and hydrobromide), nitrate, phosphate, borate, acetate, tar-trate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like.
The following examples are specific embodiments of this invention.
ExamP le -1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyPhenyl)--~iPerazlnyl]-2-naphthaleno r A solution Gf 4.12 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 4.81 g of l-~o-methoxyphenyl)-piperazine, and 1.53 ml of isopropyl alcohol in 20 ml of xylene is refluxed under nitrogen for 19 hours. The xylene is removed in vacuo and the residue triturated with ether to give 4.01 g of crude material. Two recrystallizations of this material from ethyl acetate yield 2.5 g of the title compound, melting point 182-183C.
ExamPle 2 tra~fi-li2,3;4-Tetrahydro-3-~4-phenyl-l-piperazinyl)-2 naDhtha eno A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydro-naphthalene, 8.91 g of N-phenylpiperazine, and 19 ml of i80-propanol in 50 ml of xylene is refluxed for five days. The xylene i~ removed in vacuo leaving a solid residue, which yields 9.9 g of crude material on trituration with isopropyl ether. Two recrystallizations from ethyl acetate yield 6.5 g of the title compound, melting point 152-154C.
Example 3 2i3,4-Tetrahydro-3-~4-(2-methoxyphenyl)-1-piperazinyl3--nap t a eno A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydro-naphthalene, 10.56 g of l-(o-methoxyphenyl)piperazine, and 19 ml of isopropanol in 50 ml of xylene i9 refluxed for five ~;~ days. The xylene is removed in vacuo leaving a solid residue, which on trituration with isopropyl ether gives 11.34 g of crude material. Two recrystallizations from ethyl acetate yield 7,0 g of the title compound, melting point 159-161C.
' _g_ ~ 8S37 Example 4 trans-5,6,7,8-Tetrahydro-7(and 6)-~4-(2-methoxyphenyl)-1-piperazinyl]-1,6(and 1,7)-naphthalenedlol A solution of 33.8 g of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthol and 42 g of l-(_-methoxyphenyl)piperazine in 400 ml xy-lene is heated under reflux for 20 hours. On cooling, a large amount of solid precipitates and is removed by filtration to give 57.8 g of material. A thin layer chromatogram reveals two clean-ly separated spots. This is dissolved in a hot mixture of ethyl acetate-ethanol. On cooling, crystalline material is deposited.
This is recrystallized from ethyl acetate-ethanol and then from ethanol to give 7.7 g of trans-5,6,7,8-tetrahydro-6-[4-(2-meth-oxyphenyl)-l-piperazinyl]-1,7-naphthalenediol, melting point 199-201C.
~ The mother liquor from the harvesting above is concent-f rated. Recrystallizations from ethyl acetate give material still containing s~meof the slow moving isomer. This mixture (32 g) is chromatographed on 1 kg Activity III basic alumina. trans-5,6,7, 8-Tetrahydro-7-[4-12-methoxyphenyl)-1-piperazinyl]-1,6-naphthal-enediol (TLC pure) is eluted with chloroform. Ether is added to these fractions, and the material which crystallizes is harvested -~
and recrystallized from ethyl acetate-methanol to yield 14.0 g of trans-5,617,8-tetrahydro-7-[4-(2-methoxyphenyl)-l-piperazinyl]-l, , 6-naphthalenediol, melting point 218-220C.
Example 5 ~ans-1,2,3,4-Tetrahydro-8-methoxy-3-[4-(2-methoxyPhenyl)-l-piperazinyl]-2-naphthalenol A solution is 2.0 g of trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-l-piperazinyl]-1,7-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane.
The solution is stored at 0C for 48 hours. The solvent is re-moved in vacuo. The residue is dissolved in ethyl acetate, wash-ed with dilute sodium hydroxide solution and dried. The solvent is removed ln vacuo leaving an oil which crystallizes on tritur-ation with a small amount of ether. This is washed with isopro-pyl ether and recrystallized from ether to give 1.7 g of the title compound, melting point 123-125C.
Example 6 ~L~-1,2,3,4-Tetrahydro-5-methoxy-3-[4-(2-methoxyphenyl)-1-piE~er-az nY - -naP t a eno A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-l-piperazinyl3-1,6-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazometbane. ' $he solution is stored at 0C for 48 hours. The solvent is removed in _acuo, the residue is dissolved in ethyl acetate and washed with 10 dilute sodium hydroxide solution. After drying and removal of sol-vent in vacuo, an oil remains which crystallizes on trituration with a very small amount of ether. The crystalline material is wa~hed -with a small amount of isopropyl ether and recrystallized from ether-isopropyl ether to give 1.13 g of the title compound, melting point 138-141C.
Example 7 $~-1S2,3,4-Tetrahydro-3-[4- (2-methoxyphenyl)-1-piperazinvll-2,6-~an "-napnt a ene io A mixture of 20.4 g of 6,7-epoxy-5,6,7,8-tetrahydro-2-naph-thol acetate and 42.2 g of l-~o-methoxyphenyl)piperazine in 200 ml 20 xylene is heated under reflux overnight. After cooling, the mixture is taken to dryness in vacuo. The material is dissolved in benzene and chromatographed on 1 kg Activity III basic alumina. After elu-tion of fast moving material with beniene and benzene-chloroform mixture Isomer A (fractions 13-18,--17.9g) is eluted with chloroform and Isomer B (fractions 25-34, 17.lg~ is eluted with chloroform and S~ methanol in chloroform.
Fractions 14-16 (9.lg) are recrystallized from ethyl acetate-ethanol to give 5.34 g of material. This is recrystallized from a `~ large volume (~1.5 1) of methanol to give 4.55 g of material, melting -30 point 237-239C-Ethyl acetate is added to fractions 25-31 (13.2g) and the material which crystallizes is har-rested (8.64g?. This is recrystal-lized from a large volume of methanol (-3 1) to give 6.6S g of material, melting point 224-228C.
~1 ~0 Example 8 -5,6~7i8-Tetrahydro-7-[4-~2-methoxyphenyl)-1-piperazinyl]-~_-nap tha ene lO , iacetate es A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,6-naphthalenediol in 20 ml of pyridine is cooled in an ice bath and treated drop-wise with 2.2 ml of acetic anhydride. After standing for 2 days at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide and twice with water. The 10 ethyl acetate solution is dried over magnesium sulfate, fil-texed, and the solvent is removed in vacuo leaving 2.6 g of foam. Ether is added and the crystalline material that is deposited is harvested. This is recrystallized from ethyl acetate-isopropyl ether to give 1.88 g of the title compound, melting point 128-132C.
. ExamPle 9 -1,2,3,4-Tetrahvdro-3-(4-phenyl-1-piperazinyl)-2-naphtha-eno , acetate ester A solution of 1.0 g of trans-1,2,3,4-tetrahydro-3-(4-20 phenyl-1-piperazinyl)-2-naphthalenol in 10 ml of pyridine is cooled in an ice bath and treated dropwise with 0.68 ml of acetic anhydride. After standing overnight at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with dilute sodium hydroxide solution and twice with water. After drying over magnesium sulfate the solvent is removed in vacuo leaving 1.18 g of viscous material. A small amount of ether is added and on standing cry~talline material i~ deposited. This i9 recrystal-lized from isopropyl ether to give 0.9 g of the title compound, 30 melting point 70-75C.
Example 10 tr~n--5,6, 7,8-Tetrah dro-6-[4-(2-methoxypheny1)-1-piperazinxl]-1,7-napXthalenediol, diacetate ester A solution of 1.5 g of trans-5, 6, 7,8-tetrahydro-6-14-~2-methoxyphenyl)-1-piperazinyl~-1,7-naphthalenediol in 15 ml pyridine is cooled in an ice bath and treated dropwise with 1.65 ml of acetic anhydride. The mixture is left for about 16 hours at room temperature. The mixture is taken to near dryness ln vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide and twice -~
10 with water. After drying over magnesium sulfate, the solvent i5 removed in vacuo leaving 2.0 g of foam. On addition of ether-hexane the material crystallizes. This is recrystallized from ethyl acetate-hexane to give 1.6 g of the title compound, melting point 137-141C.
Example 11 trans-1,2,3,4-Tetrahvdro-5,8-dimethoXy-3-[4-(2-methOXYPhen~
;rPlPerazinyll-2-nap~thalenol~ acetate ester ~-~~
A solution of 920 mg of trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-t4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol -in 10 ml pyridine is cooled in an ice bath and treated dropwise with 0.44 ml of acetic anhydride. After standing for about 1-6 hours at room temperature the mixture is taken to near dryness in vacuo. The residue is dissolved in ethyl acetate and washed with cold dilute sodium hydroxide solution and twice with water. After drying the solvent 16 removed in vacuo leaving aoo mg of foam. Ether is added and the material which crystallizes is recrystallized from ethyl acetate-hexane to give 0.70 g of the title compound, melting point 166-169C.
.
. . .
Example 12 trans-1,2,3,4-Tetrahydro-6 (or 7)-methoxy-3-14-(2-methoxyphenyl~-l-plperazlnyl~-2-naphthalenol A suspension of 1.0 g of trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2,6(or 2,7)-naphthalene-diol in 100 ml methanol is cooled in an ice bath and treated with an excess of freshly prepared solution of diazomethane in ether. The mixture is left in the refrigerator for about 16 hours. The next day the yellow color is gone but a con-siderable amount of insoluble material remains. The mixture ~
is stirred in an ice bath for 8 hours during which time more `~-diazomethane solution is added. After standing 16 hours at 5C the solution is nearly complete. After stirring with -~
cooling for 3 additional hours a few drops of acetic acid are added to discharge the yellow color. The solvent is removed in vacuo. The residue is dissolved in ethyl acetate, washed with dilute sodium hydroxide solution andthen water. After --drying, the solvent is removed in vacuo to give 1.05 g of foam. This yields crystalline material on addition of ether-isopropyl ether. Recrystallization from ethyl acetate-hexane yields 0.46 g of the title compound, melting point 129-131C. ~ -Example 13 dro-3-[4-(2-methoxyphenyl)-1-piperazin`1]-2,6 (or 2,7~-na~ _ trans-1,2,3,4-Tetrahydro-3-[4-(2-methoxyphenyl-1-piper-azinyl]-2,6 (or 2,7)-naphthalenediol (l.Og) is partially dis-solved in 10 ml of pyridine. The mixture is cooled in an ice bath an 1.1 ml acetic anhydride is added dropwise. After stirring for 1-2 hours at room temperature a clear solution is obtained. After standing for about 16 hours at room temperature the solvent is removed in vacuo. The residue is ;-.
-14- ~
HAl30 dissolved in ethyl acetate and washed with dilute sodium hydroxide solution and then twice with water. After drying, the solvent is removed in vacuo leaving a foam. Material crystallizes after the addition of hexane-ether. This is harvested and recrystallized from ether-hexane to give 0.85 g of the title compound, melting point 99-102C.
Example 14 2~L~a-n-~r-l~2~3)4-Tetrah~dro-3-[4-(2-methoxyphenyl)-l-piperazinyl]
or , -nap t a ene io , iacetate trans-1,2,3,4-Tetrahydro-3-l4-(2-methoxyphenyl)-l-10 piperazinyl]-2,6~or 2,7)-naphthalenediol (l.0 g) is partially dissolved in lO ml of pyridine. The mixture is cooled in an ice bath and 1.1 ml of acetic anhydride is added dropwise.
After stirring a few minutes at room temperature the mixture is a clear solution which is left for about 16 hours at room temperature. The solvent was renloved in _acuo, the residue is dissolved in ethyl acetate and wa~hed with dilute sodium hydroxide solution and twice with water. After drying, the solvent is removed in vacuo leaving a foam. After standing several days in ether-hexane, crystalline material is obtained.
20 This is recrystallized from ether-hexane to give l.0 g of the title compound, melting point 109-113C.
Example 15 -5~6~7~8-Tetrahydro-7-[4-~2-methoxyphenyl)-l-piperazin~l]
, , -na~ t a ene rio , A solution of 13.1 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-diacetoxynaphthalene and 29.8 g of l-(o-methoxyphenyl~-piperazine in 200 ml of xylene is refluxed under nitrogen for 48 hours. The reaction mixture is then cooled, the c~ystalline precipitate filtered, washed with ether, and dried in vacuo to afford lO.SS g of crude crystalline product. Recrystallization 101~8537 of 7.50 g of this material from ethyl acetate/ethanol gives 4.0 g of the title compound, melting point 222-224C.
Example 16 -1,2,3,4-Tetrah~dro-6(or 7)-methoxy-3-[4-(2-methoxypheny -P perazinY - -nap t a enol -~
A suspension of 1.0 g of trans-1,2,3,4-tetrahydro-3-14-(2-methoxyphenyl)-1-piperazinyl]-2,6 (or 2,7~-naphthalene-diol in 100 ml methanol is cooled in an ice bath and treated with an excess of a freshly prepared solution of diazomethane in ether. After standing for about 16 hours in a refrigerator the yellow color is gone but a considerable amount of insoluble material remains. More diazomethane solution is added ~in 3 portions) and the mixture is stirred for about 8 hours while cooling in an ice bath. After standing in a refrigerator for about 16 hours, the addition of more diazomethane and stirring i8 repeated. The third day the mixture is just stirred. After ~tanding in the cold for about 16 hour~ again nearly all the solld is gone. A ~ew drops of glacial acetic acid are added to dl8charge yellow color. The mixture is taken to dryness in vacuo. The residue i8 dissolved in warm ethyl acetate and washed with dilute sodium hydroxide solution and then with water.
After drying, the solvent is removed in vacuo to give 1.05 g of partially crystalline material. Ether is added and crystal-ltne material is harvested. Recrystallization from ethyl acetate-hexane gives 0.79 g of the title compound, melting point 148-150C.
Example 17 ~-5,6,7,8-Tetrahydro-7-r4-~2 ~ -A solution of 3.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyll-1,4,6-naphthalenetriol in 30 75 ml of pyridine and 25 ml of acetic anhydride is stored H~130 10~8537 at room temperature overnight. The solution is concentrated ln vacuo, the residue taken up in ether, washed with cold dilute sodium hydroxide, saturated sodium chloride, dried, and concentrated _ vacuo to an oil. Trituration with isopropyl ether gives 3.7 g of crude solid product. Two recrystallizations from ethyl acetate/hexane give 1.4 g of the title compound, melting point 168-170C.
Example 18 -1~2!3~4-Tetrahydro-5~8-dimethoxy-3-l4-(2-methoxyphenyl) -p perazlnY - -nap t a eno , propanoate ester trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-14-(2-methoxy-phenyl)-l-piperazinyl]-2-naphthalenol (6.0 g) is partially dissolved in 70 ml of pyridine. The mixture is cooled in an ice bath and treated dropwise with 3.9 ml of propionic anhy-dride. The mixture is clear after stirring at room temperature for 44 hour6. After taking to dryness Ln vacuo, the residue is dissolved in ethyl acetate and washed twice with cold dilute sodium hydroxide solution and twice with saturated sodium chloride solution. After drying, the solvent is removed ln vacuo leaving 7.35 g of foam. This is dissolved in ether. On 20 ~tanding 4.3 g of crystalline material is deposited. This is recrystallized from ether to give 2.9 g of the title compound, melting point 100-105C.
Example 19 -1 ~ 3~l-T2etrahxdhol5~8-dimethoxy-3-[4-(2-met-oxyphe-nyl) -plperazlny ]- -nap t a eno , utanoate ester trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-l-piperazinyl]-2-naphthalenol ~6.0 g) is partially dissolved in 70 ml of pyridine. The mixture is cooled in an ice bath and treated dropwise with 4.75 ml of but~ric anhydride.
30 After stirring for 2 days at room temperature the clear solution 108~537 is taken to dryness 1n vacuo. The residue is dissolved in ethyl acetate and washed twice with cold dilute sodium hydroxide solution and twice with saturated sodium chloride solution.
After drying, the solvent i8 removed in vacuo leaving 7.35 g of foam. ThiS is dissolved in isopropyl ether and after standing several days in the freezer, crystalline material is deposited. This is recrystallized from ether-hexane with a charcoal decolorization to give 2.75 g of the title compound, melting point 73-78C.
Example 20 10 ~ (and 5,7,8)-trimethoxy-3-[4-(2-met oxYphenyl)-l-pipera A solution of 3.4 g of 1,2,4-trimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.8 g of l-~o-methoxyphenyl)-piperazine, and 3.1 ml of isopropanol in 30 ml of xylene is heated under reflux for 5 days. After cooling the mixture iB taken to near dryness in vacuo. The residue contains fiome solids. Isopropyl ether is added and 2.6 g of solid is harvested. This i8 recrystallized from ethyl acetate with a charcoal decolorization to give 1.25 g of the title compound, 20 melting point 210-213C.
The mother liquor from the above crystallization of crude matérial is taken to dryness and the 4.8 g residue is dissolved in benzene and chromatographed on a 120 g column of basic alimina (Activity III). After elution of the ~aster moving isomer with benzene, the other isomer is eluted with benzene and 30~ ethy~ acetate in ~enzene. Isopropyl ether is added to fractions containing the second isomer to give 1.1 g of crystalline material. This is recrystallized from ethyl acetate to give 0.6 g of the title compound, melting point 30 167-170C.
.
~A130 xample 21 ~L~ 2~3~4-Tetrah~dro-6~7-dimethoxy-3-~4-(2-methoxyphenyl) -plperaziny -2-nap t a eno A solution of 2.94 g of 2,3-dimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.9 g of l-(o-methoxyphenyl)piperazine, and 1 ml of isopropanol in 30 ml of xylene is refluxed for 5 days. The reaction mixture is concentrated in vacuo, the residue taken up in ethyl acetate, and this is thoroughly extracted with dilute hydrochloric acid. The combined acid extracts are made basic with dilute sodium hydroxide solution, and this is 10 thoroughly extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated in vacuo to an oil, which gives 1.3 g of solid on trituration with ethyl acetate.
Recrystallization from ethyl acetate gives 600 mg of the title compound, melting point 172-174C.
Exam~le 22 tran~-3-[i-(2-Chloro heny1)-1-PiperazinY1]-1,2,3,4-tetrahydro-lmethoxY-2-naph~halenol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 9.83 g of o-chlorophenylpiperazine and 20 2 ml of absolute ethanol in 100 ml xylene is refluxed for 5 days.
The solution is then concentrated in vacuo, and the residue is triturated with ether to give 12.0 g of crude product. Recrystal-lization from ethanol/methanol gives the title compound, melting point 237-239DC.
Example 23 ,-1,2!3,4-Tetrahydro-S,a-dimethoxy-3-~4-(2-methylphenyl) l-plperazlnyl]-2-napht enol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 8.8 g of o-tolylpiperazine, and 2 ml of 30 absolute ethanol in 100 ml of xylene is refluxed for 4 days.
10~8537 The reaction mixture is cooled to room temperature, and the resulting crystalline solid is filtered off and washed with ether to give 15.2 g of crude product. Recrystallization from ethanol/methanol gives 4 g of the title compound, melting point 217-219C.
Example 24 trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-[3-(trifluoro-methyl)phenvl]-l-piperazinyl]-2-naphthalenol A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(a,a,a-trifluoro-m-tolyl)piper-10 azine, and 2 ml of absolute ethanol in 100 ml of xylene isrefluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184-187C.
Example 25 -~La~-3-[4-[2-(EthYlthio)phenyl]-l-piperazinyl]-1,2,3,4-tetra-hydro-5,8-dimethoxy-2-naphthalenol A solution of 10.3 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 11.9 g of l-o-ethylmercaptophenyl-20 piperazine, and 2 ml isopropanol in 100 ml of xylene is heatedunder reflux for 6 days. ~he solution is taken to dryness in vacuo leaving partially crystalline material. ~fter trituration with isopropyl ether the crystalline material is harvested by filtration. Two recrystallizations from ethy} acetate give 9.45 g --of the title compound, melting point 171-173C.
Example 26 trans-l 2,3,4-Tetra ~ )-To a suspension of 3.98 g of trans-1,2,3,4-tetrahydro-30 5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol , _ ~n_ in 20 ml o~ N,N-dimethylformamide and lS ~1 of pyridine is added 2 ml of n-butyl isocyanante, and the resulting mixture is stirred -and heated at 100C for 6 hours. The resulting clear solution is concentrated ln vacuo and the residue is triturated with diiso-propyl ether to give 3.5 g of crude product. Two recrystalliza-tions from diisopropyl ether give 1.5 g of the title compound, melting point 105-108C.
Example 27 cis-1~2!3~4-TetrahYdro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-~perazlnyl]-2-naphthalenol 10 A. trans-3-Triazo-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol A mixture of 12.36 g of 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene, 15.6 g of sodium azide, and 3.48 g of ammonium chloride in 162 ml 2-methoxyethanol and 24 ml water is stirred in a bath maintained at 80C+5 for 18 hours. The mixture i8 taken to dryness in _acuo. The solid i~ partially dissolved in water, some sodium chloride is added, and the product is extracted into chloroform, dried and freed of solvent in vacuo to give 15.2 g of solid azide.
B. trans-3-Amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naPhthalenol The crude azide is dissolved in 200 ml of absolute ethanol, treated with 0.8 g of platinum oxide, and hydrogenated on a Parr shaker for 24 hours. The bottle is vented and refilled with hydrogen every 15 minutes for the first hour, then once an hour for 6 hours before the mixture is left shaking for 16 -~ hours. After heating to dissolve precipitated material, the catalyst is removed by filtration and washed with hot ethanol.
The filtrate is taken tG dryness in vacuo leaving a waxy solid.
This is ~riturated with ethyl acetate/ether to give 11.5 g of ~olid amine.
,.
~0~537 C. trans-3-Amino-1,2,3,4-tetrahYdro-5,8-dimethoxy-2-naphthal- -enol ! hydrochloride (1:1) A solution of 3.7 g cf trans-3-amino-1,2,3,4-tetrahydro- ~
5,8-dimethoxy-2-naphthalenol in isopropanol is converted to the -hydrochloride salt by adding a solution of hydrogen chloride in isopropanol. The salt is precipitated by adding ether and --recrystallized twice from isopropanol to give 1.3 g of the title compound, melting point 213-216C.
D. trans-3-Benzamido-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphtha-lenol A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro- ~ ;
5,8-dimethoxy-2-naphthalenol, hydrochloride in 2 liters of water -is cooled in an ice bath and a solution of 40 g of benzoyl chlor- -ide in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0-5C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost imme- -diately. The mixture is stirred at 0-5C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo .
over phosphorous pentoxide to give 78.5 g of the title compound.
E. cis-3-Amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol The crude benzamido compound (78.5 g) is added in several ~ -portions to 180 ml of cold thionyl chloride. After the addition is complete the mixture is stirred at room temperature for 45 minutes and then heated at 50C for 2-1/2 hours. The thionyl chloride is removed in vacuo, and the residue is treated with -- ~- ,;
700 ml of 10~ hydrochloric acid and heated under reflux for about ~ -16 hours. Charcoal is added to the hot solution and this is filtered through a pad. On cooling, benzoic acid crystallize~ ~-from the filtrate and is removed by filtration. This filtrate is taken to near dryness -in vacuo leaving very viscous material.
~0~8537 This is dissolved in ethanol-methanol and again taken to dryness _ vacuo leaving a waxy solid. The crude hydrochloride is dis-solved in 200 ml water. This is extracted exhaustedly with ethyl acetate, and the a~queous layer is then made alkaline with sodium hydroxide. The solid free base is harvested by filtration, wash-ed with water and dried in vacuo to give 21.5 g of product. A
2.0 g sample of this is recrystallized from isopropanol with a charcoal decolorization to give 1.1 g of the title compound, melting point 193-196C.
F. cis-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyll-2-naphthalenol A solution of 2.23 g of c -3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol and 2.48 g of N-(o-methoxyphenyl)-N,N-b -~-chloroethylamine in 25 ml of n-butanol is heated in a small Parr bomb at 140-150C for 5 days. The cooled solution is taken to dryness in vacuo and the residue is diluted with water and made basic with dilute aqueous sodium hydroxide. This is thoroughly extracted with ethyl acetate, and the combined ext-racts are washed with saturated aqueous sodium chloride, dried, and concentrated in vacuo to give 3.5 g of a semi-solid material.
Trituration with ether yields 1.5 g of crude product.
A sample (2.6 g) of the above crude product is dissolved in chloroform and applied to an alumina column (75 g of Activity III, basic). Elution with chloroform (20 ml fractions) gives (fractions 3-5) l.S g of solid. Direct recrystallization of this material from ethyl acetate/methanol with charcoal decolor- -izations gives the analytical sample (0.92 g) melting point 198-199C.
Example 28 trans-1,2,3,4-Tetrahydro-3-(4-phenyl-1-piperazino)-2-naphthal-enol, benzoate ester Following the procedure of Example 9, but substituting benzoic anhydride for acetic anhydride, yields trans-1,2,3,4-~IA130 tetrahydro-3-~4-phenyl-1-piperazino)-2-naphthalenol, benzoate ester .
Example 29 trans-1,2,3,4-Tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-l-pi~erazino~-2-naphthalenol ! he~ylcarbamate Following the procedure of Example 26, but substituting phenyl isocyanate for n-butyl isocyanate, yields trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinol-2-naphthalenol, phenylcarbamate.
E~amPle 30 t~ -1,2t3,]4-Tetrahydro-5,8-dichloro-3-[4-(2-methoxyphenyl)-_-P Perazlno - -nap t a eno Following the procedure of Example 1, but substituting 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dichloronaphthalene for 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene yields trans-1,2,3,4-tetrahydro-5,8-dichloro-3-t4-(2-methoxyphenyl)-1-piper-azino]-2-naphthalenol.
Example 31 ~-1,2,3~4-T t ahydro-5,8-dimethyl-3-_t4-(2-methoxyphenyl)-l_Piperazino]-2-naphthalenol ~ -Foilowing the procedure of Example 1, but substituting 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethylnaphthalene for 6,7-epoxy-5,6,7,8-tetrahydro-1,4-dimethoxynaphthalene yields trans-1,2,3,4-tetrahydro-5,8-dimethyl-3-[4-(2-methoxyphenyl3-1-piperazino]-2-naphthalenol.
Claims (82)
1. A process for the preparation of a compound having the formula or a pharmaceutically acceptable acid addition salt thereof wherein R1 is hydrogen, wherein X is alkyl of 1 to 12 carbon atoms or aryl, or wherein Y is lower alkyl or aryl; R2 is hydrogen, halogen, lower alkyl, hydroxy, alkoxy or ; R3 is hydrogen, halogen, lower alkyl, alkoxy, al-kylthio, trifluoromethyl or nitro; and n is 1, 2 or 3; where-in the terms lower alkyl, alkoxy and alkylthio refer to groups having 1 to 4 carbon atoms and the term aryl refers to phenyl or phenyl monosubstituted with lower alkyl, alkoxy or halogen, which comprises reacting either (a) a compound of the formula with a compound of the formula to form a trans product of the formula or (b) a cis compound of the formula with a compound of the formula to form a cis product of the formula wherein R1 is hydrogen, and optionally, reacting said trans or cis product with either (c) an acid anhydride of the formula to form a cis or trans compound of the formula or (d) an isocyanate of the formula Y-N=C=O
to form a cis or trans compound of the formula and, where desired, forming a pharmaceutically acceptable acid addition salt thereof.
to form a cis or trans compound of the formula and, where desired, forming a pharmaceutically acceptable acid addition salt thereof.
2. The process in accordance with claim 1 wherein the OR1 group and the phenylpiperazino group are in the cis con-figuration.
3. The process in accordance with claim 1 wherein the OR1 group and the phenylpiperazino group are in the trans con-figuration.
4. The process in accordance with claim 1 wherein R1 is hydrogen.
5. The process in accordance with claim 1 wherein R1 is .
6. The process in accordance with claim 1 wherein R1 is .
7. The process in accordance with claim 1 wherein R2 is hydroxy.
8. The process in accordance with claim 1 wherein R2 is alkoxy.
9. The process in accordance with claim 1 wherein R2 is hydrogen.
10. The process in accordance with claim 1 wherein R3 is hydrogen.
11. The process in accordance with claim 1 wherein R3 is alkoxy.
12. The process in accordance with claim 1 wherein R2 and R3 are each methoxy.
13. The process in accordance with claim 1 wherein n is 1 or 2.
14. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
15. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-3-(4-phenyl-1-piperazinyl)-2-naphthalenol.
16. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
17. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperzinyl]-1,6-naphthalenediol.
18. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-piperazinyl]-1,7-naphthalenediol.
19. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-8-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
20. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
21. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2,6-naphthalenediol.
22. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2,7-naphthalenediol.
23. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,6-naphthalenediol, diace-tate ester.
24. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-3-(4-phenyl-1-piperazinyl)-2-naphthalenol, acetate ester.
25. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-piperazinyl]-1,7-naphthalenediol, diace-tate ester.
26. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, acetate ester.
27. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-6-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
28. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-7-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
29. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,4,6-naphthalenetriol.
30. The process in accordance with claim 1 wherein the compound prepared has the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,4,6-naphthalenetriol, tri-acetate ester.
31. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, propanoate ester.
32. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, butanoate ester.
33. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,6,8-trimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphtha-lenol.
34. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,7,8-trimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphtha-lenol.
35. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-6,7-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
36. The process in accordance with claim 1 wherein the compound prepared has the name trans-3-[4-(2-chlorophenyl)-1-piperazinyl]-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol.
37. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methylphenyl)-1-piperazinyl]-2-naphthalenol.
38. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-2-naphthalenol.
39. The process in accordance with claim 1 wherein the compound prepared has the name trans-3-[4-[2-(ethylthio)phenyl]-1-piperazinyl]-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol.
40. The process in accordance with claim 1 wherein the compound prepared has the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphtha-lenol, butylcarbamate.
41. The process in accordance with claim 1 wherein the compound prepared has the name cis-1,2,3,4-tetrahydro-5,8-di-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol.
42. A compound having the formula or a pharmaceutically acceptable acid addition salt thereof wherein R1 is hydrogen, wherein X is alkyl of 1 to 12 carbon atoms or aryl, or wherein Y is lower alkyl or aryl; R2 is hydrogen, halogen, lower alkyl, hydroxy, alkoxy or ; R3 is hydrogen, halogen, lower alkyl, alkoxy, al-kylthio, trifluoromethyl or nitro; and n is 1, 2 or 3; where-in the terms lower alkyl, alkoxy and alkylthio refer to groups having 1 to 4 carbon atoms and the term aryl refers to phenyl or phenyl monosubstituted with lower alkyl, alkoxy or halogen, whenever prepared according to the process of claim 1.
43. A compound as defined in claim 42 wherein the OR1 group and the phenylpiperazino group are in the cis configura-tion, whenever prepared according to the process of claim 2.
44. A compound as defined in claim 42 wherein the OR1 group and the phenylpiperazino group are in the trans config-uration, whenever prepared according to the process of claim 3.
45. A compound as defined in claim 42 wherein R1 is hydrogen, whenever prepared according to the process of claim 4.
46. A compound as defined in claim 42 wherein R1 is , whenever prepared according to the process of claim 5.
47. A compound as defined in claim 42 wherein R1 is , whenever prepared according to the process of claim 6.
48. A compound as defined in claim 42 wherein R2 is hydroxy, whenever prepared according to the process of claim 7.
49. A compound as defined in claim 42 wherein R2 is alkoxy, whenever prepared according to the process of claim 8.
50. A compound as defined in claim 42 wherein R2 is hydrogen, whenever prepared according to the process of claim 9.
51. A compound as defined in claim 42 wherein R3 is hydrogen, whenever prepared according to the process of claim 10.
52. A compound as defined in claim 42 wherein R3 is alkoxy, whenever prepared according to the process of claim 11.
53. A compound as defined in claim 42 wherein R2 and R3 are each methoxy, whenever prepared according to the pro-cess of claim 12.
54. A compound as defined in claim 42 wherein n is 1 or 2, whenever prepared according to the process of claim 13.
55. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 14.
56. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-3-(4-phenyl-1-piperazinyl)-2-naphthalenol, whenever prepared according to the process of claim 15.
57. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piper-azinyl]-2-naphthalenol, whenever prepared according to the process of claim 16.
58. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piper-azinyl]-1,6-naphthalenediol, whenever prepared according to the process of claim 17.
59. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-piper-azinyl]-1,7-naphthalenediol, whenever prepared according to the process of claim 18.
60. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-8-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 19.
61. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 20.
62. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-3-[4-(2-methoxyphenyl)-1-piper-azinyl]-2,6-naphthalenediol, whenever prepared according to the process of claim 21.
63. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-3-14-(2-methoxyphenyl)-1-piper-azinyl]-2,7-naphthalenediol, whenever prepared according to the process of claim 22.
64. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piper-azinyl]-1,6-naphthalenediol, diacetate ester, whenever pre-pared according to the process of claim 23.
65. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-3-(4-phenyl-1-piperazinyl)-2-naphthalenol, acetate ester, whenever prepared according to the process of claim 24.
66. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-6-[4-(2-methoxyphenyl)-1-pip-erazinyl]-1,7-naphthalenediol, diacetate ester, whenever pre-pared according to the process of claim 25.
67. The compound as defined in claim-42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-l-piperazinyl]-2-naphthalenol, acetate ester, when-ever prepared according to the process of claim 26.
68. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-6-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 27.
69. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-7-methoxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 28.
70. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-7-14-(2-methoxyphenyl)-1-piper-azinyl]-1,4,6-naphthalenetriol, whenever prepared according to the process of claim 29.
71. The compound as defined in claim 42 having the name trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piper-azinyl]-1,4,6-naphthalenetriol, triacetate ester, whenever prepared according to the process of claim 30.
72. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, propanoate ester, when-ever prepared according to the process of claim 31.
73. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, butanoate ester, when-ever prepared according to the process of claim 32.
74. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,6,8-trimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 33.
75. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,7,8-trimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 34.
76. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-6,7-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 35.
77. The compound as defined in claim 42 having the name trans-3-[4-(2-chlorophenyl)-1-piperazinyl]-1,2,3,4-tetra-hydro-5,8-dimethoxy-2-naphthalenol, whenever prepared accord-ing to the process of claim 36.
78. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methyl-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared accor-ding to the process of claim 37.
79. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-[3-(trifluoro-methyl)phenyl]-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 38.
80. The compound as defined in claim 42 having the name trans-3-[4-[2-(ethylthio)phenyl]-1-piperazinyl]-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthalenol, whenever prepared according to the process of claim 39.
81. The compound as defined in claim 42 having the name trans-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-napthalenol, butylcarbamate, whenever prepared according to the process of claim 40.
82. The compound as defined in claim 42 having the name cis-1,2,3,4-tetrahydro-5,8-dimethoxy-3-[4-(2-methoxy-phenyl)-1-piperazinyl]-2-naphthalenol, whenever prepared according to the process of claim 41.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA260,395A CA1088537A (en) | 1976-09-02 | 1976-09-02 | Phenylpiperazinotetrahydronaphthols and derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA260,395A CA1088537A (en) | 1976-09-02 | 1976-09-02 | Phenylpiperazinotetrahydronaphthols and derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088537A true CA1088537A (en) | 1980-10-28 |
Family
ID=4106768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA260,395A Expired CA1088537A (en) | 1976-09-02 | 1976-09-02 | Phenylpiperazinotetrahydronaphthols and derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1088537A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5151446A (en) * | 1989-09-25 | 1992-09-29 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
-
1976
- 1976-09-02 CA CA260,395A patent/CA1088537A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5151446A (en) * | 1989-09-25 | 1992-09-29 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
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Effective date: 19971028 |