GB2093837A - Aminoalkyl substituted 1,2,3,4- tetrahydronaphthalenes - Google Patents
Aminoalkyl substituted 1,2,3,4- tetrahydronaphthalenes Download PDFInfo
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- 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
- C07D295/16—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 acylated on ring nitrogen atoms
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Abstract
Aminoalkyl-mono or disubstituted naphthalenes represented by the formula <IMAGE> wherein R, R1 and R2 each are the same or different members of the group consisting of hydrogen, hydroxy, loweralkoxy or halo, with the limitation that at least one of R, R1 or R2 must be other than hydrogen except in the case where R3 or R4 are phenyl-loweralkyl or substituted phenyl-loweralkyl, or R1 and R2 or R and R1 together can form a methylene bridge; n is 1 to 4; and R3 and R4 are the same or different members of the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweracyl, benzyl, phenyl-loweralkyl, substituted phenyl-loweralkyl or R3 and R4 are taken together to form a piperazino, piperidino or morpholino moiety, and the pharmaceutically acceptable acid addition salts thereof. By their ability to interact specifically with various types of adrenergic and dopaminergic tissue receptors, these compounds are useful as therapeutic agents in the treatment of hypertension.
Description
SPECIFICATION Am inoa Ikyl Substituted 1 ,2,3,4-tetrahydronaphthalenes
The present invention provides novel amino-alkyl-mono or disubstituted 1,2,3,4- tetrahydronaphthaienes represented by the formula
wherein R, R, and R2 each are the same or different members of the group consisting of hydrogen, hydroxy, loweralkoxy or halo, with the limitation that at least one of R, R1 or R2 must be other than hydrogen except in the case where R3 or R4 are phenyl-loweralkyl or substituted phenyl-loweralkyl, or
R, and R2 or R and R, together can form a methylene bridge; n is 1 to 4; and R3 and R4 are the same or different members of the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweracyl, benzyl, phenyl-loweralkyl, substituted phenyl-loweralkyl or R3 and R4 are taken together to form a piperazino, piperidino or morpholino moiety, and the pharmaceutically acceptable salts thereof.
The term "loweralkoxy" as used herein, refers to alkoxy groups containing from 1 to 6 carbon atoms, i.e., methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.
The term "loweralkyl" refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms, i.e. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, 3-methylpentyl, nhexyl, etc.
The term "halo" as used herein, refers to chloro, bromo, fluoro and iodo.
The term "haloloweralkyl" refers to loweralkyl groups as defined above, substituted with one or more halo groups, i.e., chloromethyl, trifluoromethyl, a-bromoethyl, p-chioroethyl, etc.
The term "loweracyl" refers to acyl groups represented by the formula
wherein R5 is loweralkyl.
The term "pharmaceutically acceptable acid addition salts" refers to the nontoxic acid addition salts of the compounds of this invention which can be prepared in situ during the final isolation and purification or by separately reacting the free base with a suitable organic or inorganic acid.
Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, olease, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate and the like. It will be apparent to those skilled in the art that, depending upon the number of available amino groups for salt formation, the salt of this invention can be per-N-salts.
The compounds of the present invention are useful as antihypertensive agents when administered orally to hypertensive patients at dosages of from about 1 to 500 mg. administered preferably in divided dosages of two to three times a day, alone, or in combination with a diuretic agent.
The above compounds can easily be prepared from the corresponding (di)alkoxy-1,2,3,4tetrahydro-1 -naphthalenone by converting the latter to the corresponding 1 -hydroxy- 1 -aminomethyl derivative which is readily reduced to the desired 1-aminomethyl-(di)-alkoxytetraline. Heating with a strong inorganic acid leads to the above (di)hydroxy compounds.
The following examples further illustrate the present invention:
Example 1
Preparation of 1-a mino-6,7-dimethoxy-1 -hydroxy-1 ,2,3,4-tetrahydronaphthalene Hydrochloride
A mixture of 20 g. of 6,7-dimethoxy-1 -tetralone, 11.5 g. of trimethylsilyl cyanide and 20 mg. of zinc iodide in 1 6 ml. of benzene is heated and stirred at 600 C. until an infrared spectrum shows the absence of the carbonyl bond or about 5 hours. This solution is then dropwise added to a solution of 8.4 g. of lithium aluminum hydride in 250 ml. of ether. After refluxing for two hours, 10 ml. of 1 5% aqueous sodium hydroxide and 1 5 ml. of water are added in sequence. Stirring for 20 minutes is followed by the addition of chloroform and filtration.The filtrate is concentrated and ether is added, precipitating 20.3 g. (87% of theory) or 1 -aminomethyl-6,7-dimethoxy-1 -hydroxy-1 ,2,3,4- tetrahydronaphthalene; m.p. 1 07-90C.
A solution of 1 5.39 g. of this compound in 140 ml. of methanol containing 8.29 g. of concentrated HCI is treated with gaseous hydrogen in the presence of 5 g. 10% palladium-on-carbon at room temperature. After 20 hours, the catalyst is filtered off, the filtrate is evaporated and the residue is crystallized from isopropanol/ether, producing 14.2 g. (85%) of 1 -aminomethyl-6,7-dimethoxy- 1,2,3,4-tetrahydronaphthalene hydrochloride; m.p. 209-11 0C.
Example 2
Preparation of 1-isopropylaminomethyl-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene Hydrochloride
The compound of Example 1 (2.58 g.) is hydrogenated in 5 ml. of acetone and 95 ml. of ethanol in the presence of 1.4 g. sodium acetate trihydrate and 0.15 g. of platinum oxide at 3 atmospheres hydrogen pressure at room temperature. The mixture is then filtered and the filtrate is evaporated. The residue is taken up in water and treated with potassium hydroxide and chloroform. The organic layer is dried over K2CO3 and evaporated. The residue is crystallized from isopropanolic HCI to yield 2.71 g.
(91%) of 1 -isopropylaminomethyl-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride; m.p.
186-80C.
Example 3
Preparation of 1 -dimethylaminomethyl-6,7-dimethoxy-l .2,3,4-tetrahydronaphthalene Hydrochloride
By replacing the acetone/ethanol mixture of Example 2 with 2.2 ml. of 37% aqueous formaldehyde, 0.6 g. of 5% Pd/C and 84 ml. of methanol, an 81% yield of 1 -dimethylaminomethyl-6,7 dimethoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride is obtained, m.p. 203--50C.
Example 4
Preparation of 1 -benzylaminomethyl-6.7-dimethoxy-l ,2,3,4-tetrahydronaphthaiene Hydrochloride
When replacing the formaldehyde of Example 3 with benzaldehyde and using Pt/C catalyst, the corresponding 1 -benzylaminomethyl-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride is obtained in a yield of 88%; m.p. 1 43--5 OC.
Example 5
Preparation of 1 -(N-benzyl-N-methylaminomethyl)-6,7-dimethoxy-1 ,2,3, tetrahydronaphthalene Hydrochloride
Hydrogenation of the material of Example 4 by the method of Example 3 produces 1 -(N-benzyl N-methylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride, melting at 1 76--9 OC., in a yield of 86%.
Example 6
Preparation of 1-methylaminomethyl-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene Hydrochloride
When the compound of Example 5 is treated with H2 in the presence of a palladium-on-carbon catalyst, the benzyl group is eliminated, leaving 1 -methylaminomethyl-6,7-dimethoxy-1 ,2,3,4- tetrahydronaphthalene hydrochloride in a yield of 90%, m.p. 242--40 C.
Example 7
Preparation of 1 -[N-( 1 -p-methoxyphenyl)-2-propylaminomethyl]-6,7-dimethoxy-1 ,2,3, tetrahydronaphthalene HCI
By using the process of Example 4 but replacing the benzaldehyde used there with the equivalent amount of p-methoxybenzyl methyl ketone, one obtains 1-[N-(1-p-methoxyphenyl)-2 propylaminomethyl]-6,7-dimethoxy- 1 ,2,3,4-tetrahydronaphthalene HCI in a yield of 64%; m.p. 147- 51 C.
Example 8
Preparation of 1-[N-(1-p-methoxyphenyl)-3-butylaminomethyl]-6,7-dimethoxy-1,2,3,4- tetrahydronaphthalene HCI
When replacing the ketone used in Example 7 with p-methoxyphenethyl methyl ketone, one obtains 1 -[N-( 1 -p-methoxyphenyl)-3-butylaminomethyl]-6,7-dimethoxy- 1 ,2,3,4- tetrahydronaphthalene HCI in a yield of 62%; m.p. 1 15--90C.
Example 9
Preparation of 1 -propionylaminomethyl-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene The free base of the compound of Example 1 (5.28 g. of the HCI salt) is dissolved in 50 ml. of ether. While cooling, 5.2 g. propionic anhydride is added and the solution is kept one hour at room temperature while 1 -propionylaminomethyl-6,7-dimethoxy- ,2,3,4-tetrahydronaphthalene crystallizes out in a yield of 5.172 g. (or 91%); m.p. 1 03-50C.
Example 10
Preparation of 1 -propionylaminomethyl-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI
The entire amount of this material is refluxed 6 hours with 1.50 g. LiAIH4 in 60 ml.
tetrahydrofuran, followed by slowly adding 2 ml. 25% NaOH and 3 ml. water. The product is isolated in usual fashion and converted to the HCI salt with isopropanolic HCI, producing 3.732 g. 1 -(N- propylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCl; m.p. 195-7 0C.
Example 11
Preparation of 1 -( N-propyl-N-propionylamino-6,7-dimethoxy-1,2,3,4-tetrahydronåphthalene By repeating the process of Example 9 with the material of Example 10, one obtains 1 -(N-propyl N-propionylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene as a liquid in a yield of 90%, after neutralizing any excess propionic anhydride and extracting the product with ether.
Example 12
Preparation of 1 -(N,N-dipropylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI
Repeating the procedure of Example 10 with 3.58 g. of the product of Example 11 produces 3.35 g. of 1 -(N,N-dipropylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI which is an amorphous, white powder after solvent evaporation under high vacuum.
Example 13(a)
Preparation of 1 -a minomethyl-6,7-tetrahydronaphthalene Hydrobromide
Upon refluxing 3 g. of the product of Example 1 for five hours in 50 ml. of 48% aqueous hydrobromic acid in a nitrogen atmosphere, evaporating the solvent under vacuum and crystallizing the residue from isopropanol, 3.52 g. (90%) of 1 -aminomethyl-6,7-dihydroxy-1 ,2,3,4- tetrahydronaphthalene hydrobromide is obtained. This salt melts at 98-1 000C. and contains one molecular equivalent of isopropanol in the crystal.
Example 13(b)
Preparation of 1-isopropylaminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene Hydrobromide
By repeating the procedure with the isopropyl analog of Example 2, 1 -isopropylaminomethyl-6,7- dihydroxy-1 ,2,3,4-tetrahydronaphthalene hydrobromide is obtained; m.p. 207-90C.
Example 14(a)
Preparation of 5,6-methylenedioxy-1 ,2,3,4-tetrahydronaphthalenone To a solution of 41.7 g. of 5,6-dihydroxy-1 ,2,3,4-tetrahydro-1 -naphthalenone [Chem. Pharm.
Bull. Tokyo, 25(4), 637 (1977)] in 180 ml. dimethylsulfoxide under nitrogen is added 94 g. finely powdered K2CO3, followed by 1 50 g. methylene diiodide. The mixture is stirred at 650C. for two hours before ice is added. The resulting solid is filtered, washed with cold water and cold ether. It is then dissolved in CHCl3, the solution is extracted with 10% aqueous KOH and dried over MgSOJcharcoal.
The solution is evaporated and the residue is crystallized from acetonitrile to give 26.56 g. 5,6- methylenedioxy-1 ,2,3,4-tetrahydronaphthalenone; m.p. 1 32-60C. A second, impure crop is obtained, it is purified by extraction with ether to produce an additional 4.96 g. of the material; m.p. 1 35--7 OC.
Example 14(b)
Preparation of 1-aminomethyl-1-hydroxy-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalene A mixture of 10 g. 5,6-methylenedioxy-1 ,2,3,4-tetrahydro-1 -naphthalenone, 1 5 ml. benzene, 7.6 g. trimethylsilylcyanide, 20 mg. Znl2, 50 mg. AIC13 is stirred at 620C. for 5 hours. This solution is then added dropwise to 6.2 g. LiAIH4 in 250 ml. ether, and refluxed for three hours, followed by the dropwise addition of 10 ml. water and, in turn, 1 5 ml. 20% NaOH. After stirring, 250 ml. chloroform is added and the solids are removed by filtration.The solution is evaporated and ether is added to give 8.63 g. 1 -aminomethyl-1 -hydroxy-5,6-methylenedioxy-1 ,2,3,4-tetrahydronaphthalene; m.p. 140- 2"C.
Example 14(c)
Preparation of 1-aminomethyl-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalene HCI
The described product is dissolved in 100 ml. methanol containing 4.8 ml. concentrated HCI and the mixture is hydrogenated over 1.0 g. 20% Pd/C at room temperature for 18 hours and at 550C. for 4 hours. Filtration, evaporation of the filtrate and addition of isopropanolic HCI produces 8.36 g. 1 - aminomethyl-5,6-methylenedioxy-1 ,2,3,4-tetrahydronaphthalene HCI; m.p. 254--60C.
Examples 15-20 The method of Example 1 3 is used on various materials exemplified above. The new dihydroxy hydrobromides are listed below by reference to their dimethoxy starting material together with their melting points and yields.
Dihydroxy
Example No of Example m.p. Yield
15 3 245-70C. 96% 1 6 4 amorphous 87% 1 7 5 amorphous
18 6 208-90C. 94%
19 7* amorphous 98%
20 8* amorphous 93%
*MeO-group of Examples 7 and 8 also exchanged for HO-group.
Example 21
Preparation of 1 -[4-(2-hydroxyethyl)-1 piperazinylcarbonyl]-6,7-dimethoxy-1 2,3,4- tetrahydronaphthalene Hydrochloride 6,7-Dimethoxy-4-oxo-1 ,2,3,4-tetrahydronaphthalene-1 -carboxylic acid [J. Brown et al., J. Org.
Chem. 42 (24) 3984, 1977] is hydrogenated in methanol in the presence of 5% palladium-on-carbon.
After filtration of the catalyst, the filtrate is evaporated and the residue recrystallized in alcohol to yield 6.7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene-1 -carboxylic acid. This material is converted with PCI3 to the corresponding acid chloride which, in turn, is reacted with N-(2-hydroxyethyl)-piperazine to yield 1 -[4 (2-hydroxyethyl)- 1 -piperazinylcarbonyl]-6,7-dimethoxy- ,2,3,4-tetrahydronaphthalene hydrochloride. This material is reduced in ether with LiAIH4 to the corresponding 1 -[4-(2-hydroxyethyl)piperazinylmethyl]compound.
Example 22
By following the procedure of Example 13 with the compound of Example 21, the 6,7-dihydroxy
1 -[4-(2-hydroxyethyl)- 1 -piperazinyl methyl]-1 ,2,3,4-tetrahydronaphthalene hydrobromide is obtained.
In similar fashion, the following compounds are made, using the procedure of Examples 1, 9 or 21, and Example 13: 1 -(N-morpholinomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride and the
corresponding 6,7-dihydroxy compound; 1 -(N-trifluoroacetylaminomethyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI; 2,2,2-trifluoroethylaminomethyl-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI and its
6,7-dihydroxy analog; 1 -(N-tert.butylaminocarbonyl)-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI which is
reduced with diborane in tetrahydrofuran for two hours to 1 -(N-tert.butylaminomethyl)-6,7 dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI;;
1 -[(4-methyl-1 -piperazinyl)-methyl]-6,7-dimethoxy- 1,2,3,4-tetrahydronaphthalene dihydrochloride and the corresponding 6,7-dihydroxy analog;
1 -[N-(4-methoxyphenethyl)-aminomethyl]-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI
and its dihydroxy analog; 1 -[3-(4-methoxyphenyl)-propylaminomethyl]-6,7-dimethoxy-1 ,2,3,4-tetrahydronaphthalene HCI
and its trihydroxy analog salts.
Example 23
A mixture of 20 g. of 5,6-dimethoxy-1 ,2,3,4-tetrahydro-1 -naphthalene, 11.5 g. of trimethylsilyl cyanide, 20 mg. of zinc iodide and 16 ml. benzene is heated to 600 C. under stirring until the infrared spectrum shows the absence of a carbonyl bond, or about 5 hours. The solution is then dropwise added to a solution of 8.4 g. lithium aluminum hydride in 250 ml. ether. After refluxing for two hours, 10 ml.
of 1 5% aqueous sodium hydroxide is added dropwise followed by 1 5 ml. water. After stirring for 20 minutes, chloroform is added, the precipitate is filtered off, and the organic solution is concentrated, before ether is added to complete the crystallization of 21.5 g. (93% theory) of 1-aminomethyl-5,6- dimethoxy-1 -hydroxy-1 ,2,3,4-tetrahydronaphthalene; m.p. 138--400C.
(a) A solution of 13.59 g. of this compound in 140 ml. methanol and 8.29 g. of concentrated HCI is hydrogenated in the presence of 5 g. 10% palladium-on-carbon for 20 hours at room temperature.
After removal of the catalyst, the filtrate is evaporated and the residue is crystallized from isopropanol/ether to give 13.64 g. (43%) of 1 -aminomethyl-5,6-dimethoxy-1 ,2,3,4- tetrahydronaphthalene hydrochloride; m.p. 249-51 C.
(b) By following the procedures of Examples " 6, the corresponding 1 -(N-methyl-aminomethyl analog of the above is obtained; m.p. 202-40C.
Example 24
(a) The hydrochloride of Example 23(a) is converted to the free base and dissolved in 50 ml.
ether. Under cooling, 5.2 g. of propionic anhydride is added and the solution is subsequently held at room temperature for one hour whereby l-propionylam 1-propionylaminomethyl-5,6-dimethoxy-1,2,3,4- tetrahydronaphthalene crystallizes in a yield of 9.56 g. (89%); m.p. 1 03-50C.
(b) This material is refluxed with 0.087 mole of borane in 140 ml. tetrahydrofuran for 2 hours.
After cooling, 26 ml. of 6 N HCI is added dropwise and the solution is refluxed for 45 minutes and then evaporated. The residue is treated in turn with aqueous KOH, water and ether. The organic layer is dried over K2CO3 and again evaporated. The residue is converted to the HCI salt with HCI in isopropyl alcohol to yield 9.346 g. (90%) of 1-propylaminomethyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene
HCI; m.p. 203-50C.
Example 25
Preparation of 1-(N-propyl-N-propionyl)-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene
Repeating the procedure of Example 24(a) with 6.52 g. of the product of 24(b) and separating the acylated derivative from the solution by stirring the reaction mixture with 15% aqueous KOH for 20 minutes followed by ether extraction produces 6.30 g. (92%) of 1 -(N-propyl-N-propionyl)-5,6 dimethoxy-1 ,2,3,4-tetrahydronaphthalene. The LiAIH4 reduction produces 6.25 g. (77%) of 5,6 dimethoxy-l -(N,N-dipropylaminomethyl)-l ,2,3,4-tetrahydronaphthalene HCI; m.p. 149-51 OC.
Example 26(a)
Preparation of 5,6-dihydroxy-1-(N,N-dipropylaminomethyl)-1,2,3,4-tetrahydronaphthalene
Hydrobromide.
In a nitrogen atmosphere, 3.98 g. of the HCI salt of Example 25 is refluxed with 50 ml. 48% hydrobromide acid for 5 hours. The solvent is then removed In vacuo and the residue is crystallized from isopropanol, producing 3.75 g. (90%) of 5,6-dihydroxy- 1 -(N,N-dipropylaminomethyl)-1 2,3,4- tetrahydronaphthalene hydrobromide; m.p. 1 55-1 600 C.
Example 26(b)
Preparation of 1-(N,N-dimethyl)-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene Hydrochloride
By following the procedure of Example 3 and Example 26(a) with the compound of Example 23, the corresponding 1-(N,N-dimethyl) analog, m.p.246-8 C. is obtained.
Example 26(c)
Preparation of 5,6-dihydroxy-1-(N-methylaminomethyl)-1,2,3,4-tetrahydronaphthalene HBr
When using the compound of Example 23(b) in the method shown in Example 26(a), 5,6- dihydroxy-1 -(N-methylaminomethyl)-1,2,3,4-tetrahydronaphthalene HBr is obtained; m.p. 238- 400C.
Example 26(d)
Preparation of 5,6-dihydroxy- 1 -(2-propyla minomethyl)-1,2,3,4-tetrahydronaphthalene HBr
In the fashion of Example 2 and the above, 5,6-dihydroxy-1 -(2-prnpylaminomethyl)-1 ,2,3,4- tetrahydronaphthalene HBr is obtained; m.p. 226-90C.
Example 26(e)
Preparation of 1 -aminomethyl-5.6-dihydroxy-l .2,3.4-tetrahydronaphthalene HBr
By using the above method directly with the compound of Example 23(a), 1 -aminomethyl-5,6- dihydroxy-1,2,3,4-tetrahydronaphthaiene HBr is obtained; m.p. 21 1-130C.
Example 27(a)
Preparation of 5,6-dimethoxy-[4-p-methoxyphenyl-2-butylaminomethyl]-1,2,3,4- tetrahydronaphthalene HCI
By using the procedure of Example 4 with the compound of Example 23(a) and the ketone used in
Example 8 produces the compound shown in Example 8 except that the methoxy groups are in the 5and 6-positions, i.e., 5,6-dimethoxyo-methoxyphenyI-2-buWIaminomethyH-1 ,2,3,4tetrahydronaphthalene HCI; m.p.206-8 C.
Example 27(b)
Preparation of 5,6-dihydroxy-[4-p-hydroxyphenyl-2-butylaminomethyl]-1,2,3,4- tetrahydronaphthalene HBR
Demethylation as shown in Example 26(a) produces 5,6-dihydroxy-(4-p-hydroxyphenyl-2 butylaminomethyl)-1 ,2,3,4-tetrahydronaphthalene HBr; m.p. 1 85-950C.
Example 28
Preparation of 1 -( N-propyl-N-phenethyl)-, 1 -(N-propyl-N-phenylpropyl)- or 1-(N-propyl-N- isobutyl)-aminomethyl-5,6-dihydroxy-1 ,2,3,4-tetrahydronaphthalene Salts
Following the sequence of steps depicted in Examples 25 and 26, the compound of Example 24 is converted to the 1 -(N-propyl-N-butyl)-, the 1 -(N-propyl-N-ethyl)- and the 1 -(N-propyl-N-pentyl)- aminomethyl-5,6-dihydroxy-1 ,2,3,4-tetrahydronaphthalenes via the corresponding 5,6-dimethoxy1 ,2,3,4-tetrahydronaphthalenes. In the case of the pentyl analog, the anhydride of Example 25 is preferably replaced by an equimolar amount of pentanoyl chloride.
Using the equimolar amount of phenylacetyl chloride, phenylpropionyl chloride or isobutyryl chloride, the above procedures lead to 1 -(N-propyl-N-phenethyl)-, 1 -(N-propyl-N-phenylpropyl)- or 1 (N-propyl-N-isobutyl)-aminomethyl-5,6-dihydroxy-1 ,2,3,4-tetrahydronaphthalene salts via the corresponding 5,6-dimethoxy-1 ,2,3,4-tetrahydronaphthalenes.
Example 29
Preparation of 1-aminomethyl-1-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthalene and 1 aminomethyl-5-methoxy-1 ,2,3,4-tetrahydronaphthalene Hydrochloride
Twenty-five g. of 5-methoxy-1 -tetraione are dissolved in dry benzene and placed under a nitrogen atmosphere. After adding 30 mg. zinc iodide and 1 9 ml. trimethylsilyl cyanide, the mixture is heated at 60-650C. for 6.5 hours and then allowed to cool to room temperature overnight with stirring. The dark solution is then added dropwise to a diethyl ether slurry of 12.5 g. lithium aluminum hydride maintained at OOC. under nitrogen. Upon complete addition, the mixture is heated to reflux and maintained at this temperature for 3.5 hours.The reaction is then cooled to OOC. and quenched (12.5 ml. H20 followed by 12.5 ml. 1 5% NaOH; then 35 ml. H20). After filtering the mixture and evaporation of the filtrate, 28 g. 1 -aminomethyl-1 -hydroxy-5-methoxy-1 ,2,3,4-tetrahydronaphthalene is obtained.
The entire batch of this crude material is dissolved in a mixture of 240 ml. methanol and 20 ml.
hydrochloric acid, and hydrogenated in the presence of 1 5 g. Pd/charcoal (50% wet) at 500 C. and 3 atmospheres for 24 hours. The solvent is concentrated until a solid separates. This solid is filtered and crystallized from CH3OH/Et2O to yield 16 g. 1-aminomethyl-5-methoxy-1 ,2,3,4-tetrahydronaphthalene hydrochloride; m.p. 242-30C.
Example 30
Preparation of 1 -aminomethyl-5-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr
The product (1.5 g.) from Example 29 is added to methylene chloride and cooled to -780C.
under N2. A solution of 2.36 ml. boron tribromide in CH2Ci2 is added dropwise. The reaction mixture is stirred at -780C. and allowed to slowly warm to room temperature overnight.
The reaction mixture is then cooled to OOC. and 10 ml. methanol is added dropwise. The solution is evaporated to dryness and recrystallized from CH3CN affording a white solid, identified as 1 aminomethyl-5-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr; m.p. 180-81 0 C.
Example 31
Preparation of 1 -[N,N-dimethylJaminomethyl6-methoxy-1 ,2,3,4tetrahydronaphthalene HCI
The product (2 g.) from Example 29 is hydrogenated at room temperature with 0.4 g. 5% Pd/C in 10 ml. methanol, 5 ml. formalin and 1.2 g. sodium acetate trihydrate at 3 atmospheres H2 pressure and room temperature. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in methylene chloride and aqueous KOH is added. The organic layer is separated, dried over
Na2SO4, filtered and evaporated, affording an oil. The oil is taken up in a minimum amount of methanol and added dropwise to ethereal HCI.The hydrochloride salt is filtered and recrystallized from CH3CN/CH3OH, yielding 1 -[N,N-dimethyl]aminomethyl-5-methoxy- I ,2,3,4-tetrahydronaphthalene HCI; m.p. 255--60C.
Example 32
Preparation of 1 -(N-isopropyl)-aminomethyl-5-methoxy-l ,2.3,4-tetrahydronaphthalene HCI
The product (2 g.) from Example 29 is hydrogenated as in Example 31 except that the formalin is
replaced with acetone (5 ml.). Workup as in Example 31 yields 1-(N-isopropyl)-aminomethyl-5- methoxy-1 ,2,3,4-tetrahydronaphthalene HCI; m.p. 181820 C.
Example 33
Preparation of 1 -( N,N-dimethylaminomethyl )-5-hydroxy-1 ,2,3,4tetrahydrnnaphthalene HCI
The product (2.1 g.) of Example 31 is treated with 2 ml. BBr3 as in Example 30. The hydrobromide salt is converted into the hydrochloride salt by boiling the former with 30 ml. methanolic HCI in an
open flask for 1 5 minutes, followed by cooling, producing crystals of 1 -(N,N-dimethylaminomethyl)-5- hydroxy-1 ,2,3,4-tetrahydronaphthalene HCl; m.p. 277-780C.
Example 34
Preparation of 1-( N-isopropylaminomethyl)-5-hydroxy-l .2,3.4-tetrahydronaphthalene HBr
The product from Example 32, when treated with BBr3, as in Example 30 yields 1 -(N isopropylaminomethyl)-5-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr; m.p. 289--900C.
Example 35(a)
Preparation of 1 -aminomethyl-6-methoxy-l ,2,3,4-tetrahydronaphthalene HBr
Using the procedure of Example 29, but replacing the 5-methoxy-1 -tetralone with 6-methoxy-1 - tetralone yields 1 -aminomethyl-6-methoxy-1 ,2,3,4-tetrahydronaphthalene HCI; m.p. 1 92--40 C.
Example 35(b)
Preparation of 1 -aminomethyl-6-hydroxy-1 ,2,3,4-tetrahydronaphthalene HCI
Subsequent treatment in accordance with Example 30 yields 1 -aminomethyl-6-hydroxy-1 2,3,4- tetrahydronaphthalene HCI; m.p. 1 756c C.
Example 36
Preparation of 1 -( I\I,N-di methyla minomethyl)-6-methoxy-1 ,2,3,4-tetrahydronaphthalene HCI
Using the product from Example 35(a) and the procedure of Example 31 furnishes 1 -(N,N dimethylaminomethyl)-6-methoxy-1 ,2,3,4-tetrahydronaphthalene HCI; m.p. 234-5 0C.
Example 37
Preparation of 1 -(N,N-dimethylaminomethyl)-6-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr
The product from Example 36 is treated with BBr3 as in Example 30 and affords 1 -(N,N dimethylaminomethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalene HBr; m.p. 260-61 OC.
Example 38
Preparation of 1 -(N-2-propylaminomethyl )-6-methoxy-1 ,2,3,4-tetrahydronaphthalene HCI
Using the product from Example 35(a) and the procedure from Example 32 affords 1-(N-2 propylaminomethyl)-6-methoxy-1 ,2,3,4-tetrahydronaphthalene HCI; m.p. 21 7-1 80C.
Example 39
Preparation of 1 -(N-2-propylaminomethyl)-6-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr
The product from Example 38, when treated with BBr3 as in Example 30, affords 1 -(N-2 propylaminomethyl)-6-hydroxy-1 ,2,3,4-tetrahydronaphthalene HBr; m.p. 278--79 OC.
Example 40
The capacity of the new compounds to stimulate or inhibit adrenergic and/or dopaminergic functions by their interaction with specific tissue receptors is demonstrated in standard pharmacological tests involving isolated animal tissues in vitro as well as the whole animals in vivo.
The adrenergic a-agonisUc effect is shown as the capacity of the compound to produce a concentration-dependent contraction of the isolated rabbit aorta strip which is blockable by prazosin, a typical a-antagonist. The measure of this effect is expressed as ED50, a dose of the compound which produces 50% of the maximal attainable contraction of the tissue. The a-antagonistic effect is shown as an inhibition of the contraction of the isolated rabbit aorta produced by norepinephrine or phenylephrine, an a-agonist in this test system. This test shows no measurable a-agonistic activity for the compound of Example 26(a); the analogous compound of Example 26(b) shows an EDso value of 83x10-7 molar.
On the other hand, the compound of Example 26(a) is an a-antagonist, while the above dimethyl analog has virtually no a-antagonistic effect. The other compounds of Example 26 also show dopaminergic activity. This is demonstrated by their capacity to increase renal blood flow in the dopamine-like manner in the anesthetized dogs under conditions of a- and /3-blockade produced by premedication with phenoxybenzamine and propranolol. Among the a-agonists are the compounds of
Examples 1, 16, 26(b), 26(c), 26(e) and 29. The a-antagonists include the compounds of Examples 4, 7, 19, 26(d) and 27.
As shown above, some of the compounds of the shown structure act preferentially on aadrenergic receptors; the alkoxy compounds tend to show somewhat weaker activity, but in each instance they serve as intermediates for making the more highly active hydroxy compounds. The pronounced and often pure a-adrenergic activity is a unique feature of these disubstituted compounds.
Many of the described compounds show an unusual and beneficial combination of adrenergic and dopaminergic action, applicable to certain cardiovascular conditions.
Other compounds of the shown structure act preferentially on p-adrenergic receptors while lacking meaningful a-sympathetic effects. The adrenergic p-agonistic effect is shown as the capacity of the compound to produce a concentration-dependent chronotropic and inotropic response in isolated guinea pig atria which is blockable by propranolol, a typical p-antagonist. The measure of this effect is expressed as ED50, a dose of the compound which produces 50% of the maximal attainable response of the tissue. The p-antagonistic effect is shown as an inhibition of the chronotropic and inotropic response of the isolated guinea pig atria to norepinephrine, a p-agonist in this test system.
While the above examples refer to only dimethoxy tetralones, it will be obvious to those skilled in the art that 5,6-dibutoxytetralone or 6,7-diisopropoxytetralone and the like can be used as the starting materials, resulting of course, in the corresponding diloweralkoxy derivatives of the above formula.
Upon using the procedure of Examples 13 or 26, the corresponding dihydroxy compounds shown above will be obtained.
The new compounds can be administered in any pharmaceutically acceptable form to warmblooded animals, i.e. as an oral, intramuscular, intravenous, infusable dosage form or as a buccal or nasal spray. For oral dosage forms, a dose of 0.01-10 mg./kg. produces prompt adrenergic effects; the corresponding i.m. or i.v. dose is between 1,us. and 10 mg./kg.; spray and infusable solutions or suspensions preferably contain between 1 and 50 ,ug./ml.
Oral dosage forms can be made in the usual fashion: about one-half of 50 g. cornstarch is milled together with 10 g. of the compounds of the above structure and 220 g. of caicium phosphate dibasic dihydrate. This blend is milled until homogeneous and passed through a 40-mesh screen. The remaining portion of the cornstarch is granulated with water, heated and mixed with the above drug blend in a hot air oven at 500 C. and sifted through a 16-mesh screen. These granules are then mixed with 1 6 g. of talcum powder, 4 g. of magnesium stearate and 0.8 g. of combined coloring and flavoring additives. The mixture is blended to homogeneity, passed through a 30-mesh screen and blended for another 1 5 minutes. This blend is compressed into tablets weighing approximately 310 mg. using a 9/32" standard covex punch resulting in tablets of a hardness of 7-9 with each tablet containing 10 mg. of the drug. In a similar fashion, tablets weighing 600 mg. containing 250 mg. of drug can be prepared, preferably in a tableting machine producing bisected tablets.
Claims (29)
1. A compound of the formula
wherein R, R1 and R2 each are the same or different members of the group consisting of hydrogen, hydroxy, loweralkoxy or haio, with the limitation that at least one of R, R, or R2 must be other than hydrogen except in the case where R3 or R4 are phenyl-loweralkyl or substituted phenyl-loweralkyl, or
R1 and R2 or R and R1 together can form a methylene bridge; n is 1 to 4; and R3 and R4 are the same or different members of the group consisting of hydrogen, loweralkyl, haloloweralkyl, loweracyl, benzyl, phenyl-loweralkyl, substituted phenyl-loweralkyl or R3 and R4 are taken together to form a piperazino, piperidino or morpholino moiety, and the pharmaceutically acceptable acid addition salts thereof.
2. A compound of Claim 1 wherein R and Ri are hydroxy, R2 and R3 are hydrogen and R4 is loweralkyl or loweracyl.
3. The compound of Claim 2 wherein R4 is 2-propyl.
4. The compound of Claim 3 wherein R4 is methyl.
5. A compound of Claim 1 wherein R and R1 are hydroxy and R3 and R4 each are loweralkyl.
6. The compound of Claim 5 wherein R3 and R4 each are methyl.
7. The compound of Claim 5 wherein R3 and R4 each are iso-propyl.
8. The compound of Claim 1 wherein R, R1 and R2 are hydrogen, and R3 or R4 is phenylloweralkyl or substituted phenyl-loweralkyl.
9. A compound according to Claim 1 wherein n=2 and R and R1 are hydroxy.
10. The compound according to Claim 9 wherein R3 is hydrogen and R4 is
wherein X is hydrogen or loweralkyl.
11. The compound of Claim 9 wherein R3 is hydrogen and R4 is
wherein X is hydrogen or loweralkyl.
12. The compound of Claim 9 wherein R3 is hydrogen and R4 is benzyl.
13. The compound of Claim 9 wherein R2, R3 and R4 are hydrogen.
14. The compound of Claim 9 wherein R2 is hydrogen and R3 and R4 are propyl.
1 5. The compound of Claim 9 wherein R2 and R3 are hydrogen and R4 is 2-propyl.
16. The compound of Claim 9 wherein R2 and R3 are hydrogen and R4 is
wherein X is hydrogen or loweralkyl.
1 7. The compound of Claim 9 wherein R2 and R3 are hydrogen and R4 is
wherein X is hydrogen or loweralkyl.
18. A compound according to Claim 1 wherein n is 1.
19. A compound according to Claim 18 wherein R2 is hydroxy or loweralkoxy.
20. The compound of Claim 19 wherein R2 is methoxymethyl and R3 and R4 are hydrogen.
21. The compound of Claim 18 wherein R1 is hydroxy or loweralkoxy.
22. The compound of Claim 21 wherein R is methyl and R3 and R4 are hydrogen.
23. A composition with adrenergic activity in pharmaceutical dosage form containing a compound of the structure
wherein R is hydrogen or loweralkyl, R3 is hydrogen, loweralkyl or haloloweralkyl, R4 is hydrogen, loweralkyl, benzyl, loweracyl, an optionally hydroxy or alkoxy substituted phenyl-loweralkyl, or R3 and
R4 together with the nitrogen form a morpholine or a substituted piperazine ring, m is 1 or 2 with the proviso that when m is 2, the RO-- groups are attached to adjacent carbons of the aromatic ring, and their nontoxic acid addition products, together with a pharmaceutically acceptable diluent.
24. A composition according to Claim 23 wherein m is 2 and said RO-- groups are attached to the 5- and 6-positions.
25. A composition according to Claim 23 wherein m is 2 and said RO-- groups are attached to the 6- and 7-positions.
26. The composition according to Claim 23 in oral dosage form.
27. The composition according to Claim 26 wherein m=2 and said RO-- groups are attached to the 5- and 6-positions.
28. The composition according to Claim 26 wherein m is 2 and said RO-- groups are attached to the 6- and 7-positions.
29. A compound as claimed in Claim 1 and prepared substantially according to any one of
Examples 1 to 39 herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23930081A | 1981-03-02 | 1981-03-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2093837A true GB2093837A (en) | 1982-09-08 |
| GB2093837B GB2093837B (en) | 1985-04-24 |
Family
ID=22901558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8204254A Expired GB2093837B (en) | 1981-03-02 | 1982-02-12 | Aminoalkyl subsituted 1,2,3,4-tetrahydronaphtalenes |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS57167945A (en) |
| GB (1) | GB2093837B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0164697A2 (en) * | 1984-06-09 | 1985-12-18 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| GR900100423A (en) * | 1989-05-31 | 1991-10-10 | Abbott Lab | Dopamine agonists |
| US5086074A (en) * | 1988-01-15 | 1992-02-04 | Abbott Laboratories | 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes |
| US5128362A (en) * | 1988-01-15 | 1992-07-07 | Abbott Laboratories | 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes |
| WO1994000441A1 (en) * | 1992-06-26 | 1994-01-06 | Farmitalia Carlo Erba S.R.L. | N(hetero)-aryl-n(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity |
| US5334628A (en) * | 1984-06-09 | 1994-08-02 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| US5807889A (en) * | 1992-12-09 | 1998-09-15 | H. Lundbeck A/S | Aminomethylindans, -benzofuranes and -benzothiophenes |
| US6235789B1 (en) | 1994-09-12 | 2001-05-22 | Takeda Chemical Industries, Ltd. | Benzocycloalkene compounds, their production and use |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1221639A (en) * | 1983-05-13 | 1987-05-12 | Abbott Laboratories | Method of producing a.sub.2-adrenergic receptor agonist activity |
| FR2658818B1 (en) * | 1990-02-27 | 1993-12-31 | Adir Cie | NOVEL DERIVATIVES WITH NAPHTHALENIC STRUCTURE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| KR20030070768A (en) * | 2002-02-26 | 2003-09-02 | (주)리드젠 | PREPARATION OF N-(4-t-BUTYLBENZYL)-N-METHYL-1-NAPHTHYLMETHYLAMINE HYDROCHLORIDE AND PURIFICATION THEREOF |
| EP2303851A1 (en) * | 2008-06-27 | 2011-04-06 | H. Lundbeck A/S | Novel phenolic and catecholic amines and prodrugs thereof |
-
1982
- 1982-02-12 GB GB8204254A patent/GB2093837B/en not_active Expired
- 1982-03-02 JP JP57031856A patent/JPS57167945A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5200423A (en) * | 1984-06-09 | 1993-04-06 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| EP0164697A3 (en) * | 1984-06-09 | 1987-04-29 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| US5021458A (en) * | 1984-06-09 | 1991-06-04 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives and fungicides containing the same |
| EP0164697A2 (en) * | 1984-06-09 | 1985-12-18 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| US5334628A (en) * | 1984-06-09 | 1994-08-02 | Kaken Pharmaceutical Co., Ltd. | Amine derivatives, processes for preparing the same and fungicides containing the same |
| US5086074A (en) * | 1988-01-15 | 1992-02-04 | Abbott Laboratories | 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes |
| US5128362A (en) * | 1988-01-15 | 1992-07-07 | Abbott Laboratories | 1-aminomethyl-1,2,3,4-tetrahydronaphthalenes |
| GR900100423A (en) * | 1989-05-31 | 1991-10-10 | Abbott Lab | Dopamine agonists |
| EP0474767A4 (en) * | 1989-05-31 | 1992-07-08 | Abbott Laboratories | Dopamine agonists |
| EP0474767A1 (en) * | 1989-05-31 | 1992-03-18 | Abbott Lab | Dopamine agonists. |
| WO1994000441A1 (en) * | 1992-06-26 | 1994-01-06 | Farmitalia Carlo Erba S.R.L. | N(hetero)-aryl-n(hetero)-tetralin-alkyl-piperazine having serotoninergic, dopaminergic and adrenergic activity |
| US5807889A (en) * | 1992-12-09 | 1998-09-15 | H. Lundbeck A/S | Aminomethylindans, -benzofuranes and -benzothiophenes |
| US5972964A (en) * | 1992-12-09 | 1999-10-26 | H. Lundbeck A/S | Aminomethylindans, -benzofurans and -benzothiophenes |
| US6235789B1 (en) | 1994-09-12 | 2001-05-22 | Takeda Chemical Industries, Ltd. | Benzocycloalkene compounds, their production and use |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2093837B (en) | 1985-04-24 |
| JPS57167945A (en) | 1982-10-16 |
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| PG | Patent granted |