CA1105475A - 1,2,3,4-tetrahydro-naphthalenes - Google Patents
1,2,3,4-tetrahydro-naphthalenesInfo
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- CA1105475A CA1105475A CA292,457A CA292457A CA1105475A CA 1105475 A CA1105475 A CA 1105475A CA 292457 A CA292457 A CA 292457A CA 1105475 A CA1105475 A CA 1105475A
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Abstract of the Disclosure:
The invension provides compounds of formula I, I
wherein R1 is, for example, hydrogen or alkanoyl of 1 to 20 carbon atoms; R2 is, for example, hydrogen, hydroxy, alkanoyl of 1 to 20 car-bon atoms, CF3SO2NH or CC13SO2NH; R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine; R4 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; and R6 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or (CH2)6-group, which compounds possess pharmacological activity, for example in she treatment of cardiac diseases and Parkin-son's disease.
The invension provides compounds of formula I, I
wherein R1 is, for example, hydrogen or alkanoyl of 1 to 20 carbon atoms; R2 is, for example, hydrogen, hydroxy, alkanoyl of 1 to 20 car-bon atoms, CF3SO2NH or CC13SO2NH; R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine; R4 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 8 carbon atoms; and R6 is, for example, hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or (CH2)6-group, which compounds possess pharmacological activity, for example in she treatment of cardiac diseases and Parkin-son's disease.
Description
~ 5475 case 100-~713 1,2,3,4-Tetrahydro-Naphthalenes The present invention relates to 1,2,3,4-tetrahydro-naphthalenes.
More particularly, this invention provides co~.pounds of formula I,
More particularly, this invention provides co~.pounds of formula I,
2 ~ J ~ \ I
~herein Rl is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -C0-(CH2)n-R7 group, n is from o to 5, R7 is a group of formula and each of Yl and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of ~ 100-~1713 1 to 4 carbon atoms or, when Yl and Y2 are bonded to adjacent carbon atoms, and Y2 together may be methylenedioxy, R2 is hydroyen, hydroxy, alkanoyloxy of 1 to S 20 carbon atoms, a O-CO-(CH2)n-R7 group wherein n and R7 are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkyl-sulphony1amino group of 1 to 4 carbon atoms, CF3SO2NH, CC13SO2NH, CH2O~I, 2 ( 2)n 7' 7 re as previously defined, or CH2-O-CO-R8, wherein R8 is hydroyen or alkyl of 1 to 1~ carbon atoms, R3 is hydroyen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydroyen, CH2OH, CH2O-CO-R~ o.r CH -O-CO-(CH ) -R wherein R and R
are as previously defined, R5 is hydroyen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or (CH2) -Rg, wherein n is as previously defined and Rg is a group of formula, ~ ~ 3 wherein each of Y3, Y4 and Y5 may, inde-pendently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, wherein R8 is as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined or, when Y3 and Y4 are bonded to adjacent carbon atoms, Y3 and Y~ together may be methyl-enedioxy, ~6 is hydrogen, alkyl of 1 to 4 carbon a-toms or, together with R5, a -(CH
-(CH2)5 or -(CH2)6- group;
lS whereby when two or more of the residues 1~ 2~ Y3~ Y~ and Y5 are a free or acylated OH- group, these groups are identical, or when R2 and R~ are both 35~7~
free or acylated CH2-OH groups, these groups are identical, with the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino solely substituted by alkyl or benzyl, and is other than a hetero-ring, excepting as follows:
a) when ORl is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when ORl is in position S and R2 is hydrogen, ~NR R can be NH or -NHCH
When R2, Yl, Y2, Y3, Y4 and Y5 are halogen, this is preferably ; fluorine o~ chlorine. Also provided by the invention are pharmaceutically acceptable acid addition salts of said co~unds of Fon~a I.
In the group -CO-(CH2)n-R7, n may be 0, 1, 2,
~herein Rl is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -C0-(CH2)n-R7 group, n is from o to 5, R7 is a group of formula and each of Yl and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of ~ 100-~1713 1 to 4 carbon atoms or, when Yl and Y2 are bonded to adjacent carbon atoms, and Y2 together may be methylenedioxy, R2 is hydroyen, hydroxy, alkanoyloxy of 1 to S 20 carbon atoms, a O-CO-(CH2)n-R7 group wherein n and R7 are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkyl-sulphony1amino group of 1 to 4 carbon atoms, CF3SO2NH, CC13SO2NH, CH2O~I, 2 ( 2)n 7' 7 re as previously defined, or CH2-O-CO-R8, wherein R8 is hydroyen or alkyl of 1 to 1~ carbon atoms, R3 is hydroyen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydroyen, CH2OH, CH2O-CO-R~ o.r CH -O-CO-(CH ) -R wherein R and R
are as previously defined, R5 is hydroyen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or (CH2) -Rg, wherein n is as previously defined and Rg is a group of formula, ~ ~ 3 wherein each of Y3, Y4 and Y5 may, inde-pendently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, wherein R8 is as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined or, when Y3 and Y4 are bonded to adjacent carbon atoms, Y3 and Y~ together may be methyl-enedioxy, ~6 is hydrogen, alkyl of 1 to 4 carbon a-toms or, together with R5, a -(CH
-(CH2)5 or -(CH2)6- group;
lS whereby when two or more of the residues 1~ 2~ Y3~ Y~ and Y5 are a free or acylated OH- group, these groups are identical, or when R2 and R~ are both 35~7~
free or acylated CH2-OH groups, these groups are identical, with the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino solely substituted by alkyl or benzyl, and is other than a hetero-ring, excepting as follows:
a) when ORl is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when ORl is in position S and R2 is hydrogen, ~NR R can be NH or -NHCH
When R2, Yl, Y2, Y3, Y4 and Y5 are halogen, this is preferably ; fluorine o~ chlorine. Also provided by the invention are pharmaceutically acceptable acid addition salts of said co~unds of Fon~a I.
In the group -CO-(CH2)n-R7, n may be 0, 1, 2,
3, 4 or 5, preferably 0. R7 may be phenyl. Alterna-tively, R7 may bP phenyl mono- or di-substituted with fluorine, chlorine, bromine or iodine. In another group of compounds, R7 may be phenyl mono- or di-substituted with alkyl of 1 to 4 caxbon atoms or alkoxy of 1 to 4 carbon atoms. When bonded to adjacent carbon atoms, Y1 and Y2 may form a methylenedioxy group.
Rl is preferably hydrogen.
7~i -` 100-d713 The ~roup -ORl is preferably in the 5-, 6- or 7- position.
R2 is preferably hydrogen, halogen or an alkylsuphonamylamino group, especially hydro~en.
R5 is preferably hydrogen, alkyl or a -(CH2)n-R9 gxoup.
In the group -(CH2)n-Rg, n may be 0, 1, 2, 3,
Rl is preferably hydrogen.
7~i -` 100-d713 The ~roup -ORl is preferably in the 5-, 6- or 7- position.
R2 is preferably hydrogen, halogen or an alkylsuphonamylamino group, especially hydro~en.
R5 is preferably hydrogen, alkyl or a -(CH2)n-R9 gxoup.
In the group -(CH2)n-Rg, n may be 0, 1, 2, 3,
4 or 5, preferably 2, and Rg is preferably a 3,4-dihydroxy or a 3,4-dimethoxyphenyl residue.
R6 is preferably hydrogen or methyl.
When Rl is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms. Alternatively, Rl may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms.
When R2 is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms. Alternatively, R2 may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms.
R2 may also be fluorine, chlorine~ bromine or iodine.
100-~713 When R2 is alkyl of 1 to 4 carbon atoms, this is preferably methyl. ~hen R2 is alkylsulphonylamino of 1 to 4 carbon atoms, this is preerably methyl-sulphonylamino. ~2 may be CF3SO2NH or CC13SO2NH. R2 may also be ~CH2OH. Alternatively, R2 may be the gro~p CH2~0-C0-(CH2) -R7 as previously defined. R2 can also be the group CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms. When R8 is alkyl, this may, for example, be of 15 to 19 carbon atoms or of 10 to 14 carbon atoms. Alternatively, R8 may be alkyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms. R8 may also be hydrogen.
R3 may be hydrogen. When R2 is chlorine, R3 ; may be hydrogen or chlorine.
R4 may be hydrogen. Alternatively, R4 may be CH2OH. R4 may be the group CH2O-CO-R8, wherein R8 is as previously defined. R4 may also be the group CH2-0-CO-(CH2)n-R7, wherein n and R7 are as previously defi~ed. R4 is preferably hydrogen or CH2OH.
R5 may be hydrogen or alkyl of 1 to 4 carbon 100-~713 a-toms. When R5 is cycloal]cyl of 3 to 8 carbon atoms, this is preferably of 5 or 6 carbon atoms.
R5 may be (CH2) ~Rg, wherein n and R9 are as previously defined. Rg may be phenyl. Alternatively, Rg may be phenyl substituted by the groups Y3, Y4 and Y5 as previously defined. Y3, Y~ and Y5 may, indepen-dently, be fluorine, chlorine, bromine or iodine.
Alternatively, each o Y3, Y4 and Y5 may, independently, be alkyl o 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. One or more of Y3, Y4 and Y5 may be O~.
In another group of compounds, one or more of Y3, Y4 and Y5 may be -O-COR8, wherein R~3 is as previously defined. In a further group of compounds, one or more 3 4 5 may be -o-co-(cH2) -R wh R7 are as previously defined. When bonded to adjacent carbon atoms, Y3 and Y4 together rnay be methylenedioxy.
R6 may be hydrogen. Alternatively, R6 may be alkyl of 1 to ~1 carbon atoms, for example, methyl.
R5 and R6 together may form a -(CH2)~-, -(CH2)5- or -(CH2)~6 group~
rrhe invention further provides a process Eor the production of a compound of formula I comprising, ~5~5 a) producing a compound of formula Ia, : R3 R2_ ~ ~ 4/ R5 Ia O~l 6 wherein R2 has the same significance as R2 with the exception of an alkanoyloxy or an -O~CO-(CH2)n-R7 group, S R5 has the same significance as R5 with the exception of a (C~I2)n-Rg group, wherein R9 contains an -O~COR8 or an ,; O CO (CH2 ) n~R7 residue, by convertin~ the alkoxy or benzyloxy group in a compound of formula II, to a hydroxy group by ether splitting, 11 ~ 4~ 5 II
Rl oO
wherein Rlo is alkyl of 1 to 4 carbon atoms or benzyl, and Rll has the same significance as R2 and, in _ g _ ~ 4~ 100~4713 `.' .
addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib, 3 ~ ~ R6 Ib wherein Ri is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, R2 has the same significance as R2 with the excepti.on of a free -OH group, and R5 has the same significance as R5 with the exception of a -(CH2)n--Rg group wherein the R9 group contains a free -OH group, by acylating a compound of formula III, R2 f~ N ~ III
with a reactive derivative of a carboxylic acid of ormula R8-COOH or R7~(CH2)n-cOoH~
or c) producing a compound of formula Ic, s .
R Ic : wherein R2" is h,vdrogen, hydroxy, fluorine/ chloxine, bromine or iodine, al~yl of 1 to 4 car-bon atoms or CH2OH, R4 is hydrogen or CH2OH, n' is from 1 to 5, and R9 has the same significance as Rg with the exception that Rg cannot contain an -O-COR8 or -O-CO-(CH2)~-R7 group~
by reducing a compound of formula Iy ~3 N-CO-(C~2)n~_l Rg and when desired, forming a pharmaceutically acceptable acld addition salt of the compound of Formula I so produced.
Process variant a) can be effected in known manner for the splitting of ethers. ~he reaction may suitably be effected by means of a cleaving agent such as hydriodlc acid, hydrobromic acid or hydrochloric acid, preferably in water or acetic acid, suitably at a ~ ~ S ~ ~ S 100-4713 tem~erature of from 0 to 100C, or boron tribromide, preferably in methylene chloride, suitably at a temper-ature of from 0 to 50C. When employing hydrochloric acid, the reaction is preferably effected at a pressure ; 5 of from 1 to 10 atm.
When Rlo is benzyl or when Rll is benzyloxy, the benzyl group can also be removed by catalytiC
hydrogenolysis. For these purposes, it is convenient to employ a noble metal catalyst, for example, a plat-inum catalyst, in quantities of from 2 to 10~ (w/v) and to ef~ect the reaction in ethanol.
In the case of the compounds of ~ormula I
wherein Y3, Y4 and/or Y5 is/are alkoxy, the appropriate starting material of formula II is selected in which Rlo is benzyl and the benzyl group is selectively removed.
Process variant b) can be effected according to known methods for the acylation of phenolic amino compounds. The acylation can, for example, be effected using an acylating agent, for example an acyl chloride or acid anhydrid~. The reaction may suitably be effected in trifluoroacetic acid at room temperature.
~ 100-~713 ',' Process variant c) can be effected according to known methods for the reduction of amides to amines.
Diborane or a complex me-tal hydride, e.g. LiAlH4, may advantageously be used as reducing agent. The reduction is preferably effected in an inert solvent such as tetrahydrofuran at temperatures of from 25 to75C. ~en R2" Y~, Y~ and~or Y5 is/are halogen, dibcrane should be used as the reducing agen~; otherwise, there is a possibility of at least par~ial removal of the halogen atoms from the benzene ring.
The resulting compounds of ~ormula I may ~e isolated and purified using conventional techniques.
Free base forms of the compound.s of formula I
may be converted into acid addition salt forms and vice versa in conventional manner The compounds of formula I can exist in the form of enantiomers or in racemate form. The racemates can be resolved into their optically active isomers in known manner.
The compounds of formula II, wherein R~ is hydrogen, are generally obtainable by known methods from known 5,6,7- or 8-alkoxy (or benzyloxy)~2-amino-100-~713 tetralines (or analogues thereof which can be prepared by known processes), which can have a second alkoxy or benzyloxy group in the benzene ring and which, if required, are already substituted by alkyl groups on the nitrogen atom~
When such compounds possess a free amino group in the 2- position, this group may be convérted into a -NR5R6 group by alkylation, arylation or aralkyl ation. The conversion can be effected according to known methods, e.g. by reductive alkylation or by means of an alkyl halide.
- The i.ntroduction of the substituents R2" and R3 can be effected as follows~
a) Introduction of an alkyl-, trifluoro- or trichloro-. methylsulphonamido group:
The alkoxyamino tetralines (wherein the amino group can, if recruired, be temporarily protected with an acyl group) used as starting materials are first nitrated according to known methods, e.g. with nitrous acid in methylene chloride, the resulting isomeric mixture separated chromatographically and the nitro-compound so obtained reduced to the corresponding amino 100~~713 derivative, e.g. by means of palladium on charcoal.
The amino compounds are finally conv~rted to the alkyl-trifluoro- or trichlorosulphonylamine derivatives by means of an alkyl- trifluoromethyl or trichloromethyl-3 sulphonyl halide.
b) Bromination, chlorination, iodination:
The starting materials of formula II, wherein Rll (and, where appropriate, R3) is chlorine, bromine or iodine, can be prepared by reacting the alkoxy-tetraline (wherein the amino group may be temporarily protected with an acyl group) with an appropriate halogenating agent. Suitable halogenating agents include, for example, sulphuryl chloride, bromine or iodine (in the presence of an equivalent quantity of ` 15 silver trifluoroacetate) in an inert solvent such as methylene chloride. The usual mixture of products, comprising compounds which have been halogenated in the o- or ~- position to the alkoxy group, is obtained and can be separated on Kieselgel.
c) Fluorination Alkoxyaminotetralines, which are substituted ~ 100-~713 r in the benzene ring with an -NH2 group [preparable as under a~, are employed as starting materials and are converted to the corresponding fluorine derivatives according to a Balz-Schiemann reaction. The starting S materials are thereby first diazotised, precipitated in the form of the fluoroborate, isolated and thermally decomposed .
d) Intxoduction of the C~12OH group:
The introduction of the CH2OH group may advan-tageously be effected vla formylation and subsequent reduction of the formyl group to the hydroxymethyl gro~p. Alkoxytetralines (wherein the amino group can, if required, be protected with an acyl group) are employed as starting materials. The formylation can be effected, for example, according to the Gatterman reaction, with hydrogen cyanide in the presence of a Frledel-Crafts catalyst. After separation of the isomers from the reaction mixture, the formyl group in the desired compound can be reduced to the hydroxy-methyl group, for example, with a reducing agent such as dlborane or LiAlH4 in an inert solvent such as tetrahydrofuran.
T
no-47l3 The compounds of formula II wherein R4 is a CH2O~I group, R3, R5 and ~6 are each hydrogen and Rll is hydrogen, alkyl, alkoxy or benzyloxy, can be obtained from the corresponding compounds of formula II wherein R4 is a COOH or a COOR (R - alkyl of 1 to 4 carbon atoms) group. These latter compounds are either known or can be produced by known methods for the preparation of a-amlno acids. For example, the compounds can be obtained from the corresponding tetralones by reaction 10 with potassium cyanide and ammonium carbonate and ~ub-sequent decomposition of the resulting hydantoin deriv-ative. The reduction of the compounds wherein R~ is a COOEI or COOR group to compounds wherein R4 is CH~OH may he effected in known manner for the reduction of a car~
15 bonyl group to a hydroxymethyl gxoup. The reduction can, for example, be efected with a reducing agant such as diborane or lithium aluminium hydride, in an inert solvent such as tetrahydrofuran or dioxane, at a temperature of from 0 to 100C. The reduction of the c~m-20 pounds of formula III, wherein R is alkyl, may suitably be ef~ected with a borohydride, pre~erably an alkali metal borohydride such as sodium borohydride, in etha-nol, tetrahydrofuran, dioxane or water.
_ 17 _ 100-~713 The introduction of the additional substitu-ents R3, Rll, R5 and ~6 in the compounds of formula II
wherein R~ is CH20~I can be effected in the same manner as for compounds wherein R~ is hydrogen. In most cases, the substitution will already have been effected in the earlier step, i.e. in the compounds wherein R~l is a COOE~ or a COOR group.
Compounds of formula II, wherein R11 and/or R4 are an acylated CH20H group, can be prepared by acylation, e.g. as described in process variant b), o the corresponding compounds wherein Rll and/or R4 are a free CH20H group.
The starting materials of formula IIl can be prepared in accordance with process variant a) or c).
The starting materials of formula IV can be produced by acylation of the corresponding unacylated compound with a reactive derivative of an acid of formula R9-(CH2)n,_l-cooH. Suitable reactive deriva-tives are, for example, acid chlorides or N-hydroxy~
succinimide esters.
In the following Examples, all temperatures are in degrees Celsius.
100-~713 EXA~IPLE 1: 2-Amino-1,2,3,4-tetr. 2-.
~ydrox~-met ~ hthalene a) 2-~mino-2-carboxy-lL2~3,4-tetrahydro~8-methoxy-_____.__ _______ __ _ _ ________ _______ __._ _ na~hthalene 28 g of potassium cyanide, followed by 76O5 g of a~nonium carbonate, are added to a suspension of 50 g of 8-methoxy~2-tetralone in 350 ml of isopropanol.
The mi~ture is stirred at 60 for 20 hours, cooled to room temperature, then 400 ml of wa-ter are addedI and the reac-tion mixture left to stand at 4 in order to crystallise. 8-Methoxy-2-spirohydantoin -tetraline crysta]lises out, with a melting point of 216-~17.
42 ml of a 40~ aqueous sodium hydroxide solution are added to a suspension of 21 g of 8-methoxy-2-spiro-hydrantoin tetraline in 130 ml of propylene glycol, and the reaction mixture heated, with stirring, for 2~ hours to 190. The cooled solution is decolourised with activated charcoal, adjusted to a pH of 1 with concen-trated hydrochloric acid, the resultin~ precipitate ~0 filtered off, and the mother liquor adjusted to a p~I
of 5.5 with a sodium bicarbonate/acetate acid buffer solu~ion. The ti~le compound which crystallises out " 100-4713 has melting point of 228-230 after isola~ion and drying.
b) 2-Amino-1~2,3,4-tetrahydro-8-methoxy-2-hydroxy-____~____ ____~~______ ___~________ ____ ___ _ methy1na~hthalene A suspension of 14.5 g of 2-amino-2-carboxy-1,2,3,4-tetrahydro-8-methoxynaphthalene in 400 ml of tetra-hydrofuran is added dropwise with stirring (under a ni-trogen atmosphere) to 525 ml of a l-molar solution of diborane in tetrahydrofuran~ The reaction solution is then boiled at reflux for 12 hours and cooled to room temperature. 400 ml of a solution of 2N hydrogen chloride in ethanol are added to the residue, the mix~
ture is boiled at reflux for 2 hours, the cooled solu-tion evaporated and the residue is shaken out with lN
aqueous sodium hydroxide/methylene chloride solu~ion.
The organic phase is evaporated to dryness, the residue chromatographed on silica gel with a mixture of lO~
ammonia-methylene chloride solution and methanol t9~
The title compound, which is in the form of an oil, is dissolved in ethanol/ether ~1:1) and, in order to con-vert the compound into the hydrochloride form, one equiv-alent of a 4N ethereal hydrogen chloride solution is added, and the mixture left to stand at 4 so as to : ~0 ~5~
100~~713 crystallise. The ti~le compound is obtained in the form of the hydrochloride. M.P. 153-154.
c) 2_Amino_lL2L_,~,4-tetrahydro-8-hxdroxy-2_hydr methylna~hthalene
R6 is preferably hydrogen or methyl.
When Rl is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms. Alternatively, Rl may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms.
When R2 is alkanoyl of 1 to 20 carbon atoms, this may, for example, be of 15 to 20 carbon atoms or of 10 to 14 carbon atoms. Alternatively, R2 may be alkanoyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms.
R2 may also be fluorine, chlorine~ bromine or iodine.
100-~713 When R2 is alkyl of 1 to 4 carbon atoms, this is preferably methyl. ~hen R2 is alkylsulphonylamino of 1 to 4 carbon atoms, this is preerably methyl-sulphonylamino. ~2 may be CF3SO2NH or CC13SO2NH. R2 may also be ~CH2OH. Alternatively, R2 may be the gro~p CH2~0-C0-(CH2) -R7 as previously defined. R2 can also be the group CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms. When R8 is alkyl, this may, for example, be of 15 to 19 carbon atoms or of 10 to 14 carbon atoms. Alternatively, R8 may be alkyl of 1 to 4 carbon atoms or of 5 to 9 carbon atoms. R8 may also be hydrogen.
R3 may be hydrogen. When R2 is chlorine, R3 ; may be hydrogen or chlorine.
R4 may be hydrogen. Alternatively, R4 may be CH2OH. R4 may be the group CH2O-CO-R8, wherein R8 is as previously defined. R4 may also be the group CH2-0-CO-(CH2)n-R7, wherein n and R7 are as previously defi~ed. R4 is preferably hydrogen or CH2OH.
R5 may be hydrogen or alkyl of 1 to 4 carbon 100-~713 a-toms. When R5 is cycloal]cyl of 3 to 8 carbon atoms, this is preferably of 5 or 6 carbon atoms.
R5 may be (CH2) ~Rg, wherein n and R9 are as previously defined. Rg may be phenyl. Alternatively, Rg may be phenyl substituted by the groups Y3, Y4 and Y5 as previously defined. Y3, Y~ and Y5 may, indepen-dently, be fluorine, chlorine, bromine or iodine.
Alternatively, each o Y3, Y4 and Y5 may, independently, be alkyl o 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms. One or more of Y3, Y4 and Y5 may be O~.
In another group of compounds, one or more of Y3, Y4 and Y5 may be -O-COR8, wherein R~3 is as previously defined. In a further group of compounds, one or more 3 4 5 may be -o-co-(cH2) -R wh R7 are as previously defined. When bonded to adjacent carbon atoms, Y3 and Y4 together rnay be methylenedioxy.
R6 may be hydrogen. Alternatively, R6 may be alkyl of 1 to ~1 carbon atoms, for example, methyl.
R5 and R6 together may form a -(CH2)~-, -(CH2)5- or -(CH2)~6 group~
rrhe invention further provides a process Eor the production of a compound of formula I comprising, ~5~5 a) producing a compound of formula Ia, : R3 R2_ ~ ~ 4/ R5 Ia O~l 6 wherein R2 has the same significance as R2 with the exception of an alkanoyloxy or an -O~CO-(CH2)n-R7 group, S R5 has the same significance as R5 with the exception of a (C~I2)n-Rg group, wherein R9 contains an -O~COR8 or an ,; O CO (CH2 ) n~R7 residue, by convertin~ the alkoxy or benzyloxy group in a compound of formula II, to a hydroxy group by ether splitting, 11 ~ 4~ 5 II
Rl oO
wherein Rlo is alkyl of 1 to 4 carbon atoms or benzyl, and Rll has the same significance as R2 and, in _ g _ ~ 4~ 100~4713 `.' .
addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib, 3 ~ ~ R6 Ib wherein Ri is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, R2 has the same significance as R2 with the excepti.on of a free -OH group, and R5 has the same significance as R5 with the exception of a -(CH2)n--Rg group wherein the R9 group contains a free -OH group, by acylating a compound of formula III, R2 f~ N ~ III
with a reactive derivative of a carboxylic acid of ormula R8-COOH or R7~(CH2)n-cOoH~
or c) producing a compound of formula Ic, s .
R Ic : wherein R2" is h,vdrogen, hydroxy, fluorine/ chloxine, bromine or iodine, al~yl of 1 to 4 car-bon atoms or CH2OH, R4 is hydrogen or CH2OH, n' is from 1 to 5, and R9 has the same significance as Rg with the exception that Rg cannot contain an -O-COR8 or -O-CO-(CH2)~-R7 group~
by reducing a compound of formula Iy ~3 N-CO-(C~2)n~_l Rg and when desired, forming a pharmaceutically acceptable acld addition salt of the compound of Formula I so produced.
Process variant a) can be effected in known manner for the splitting of ethers. ~he reaction may suitably be effected by means of a cleaving agent such as hydriodlc acid, hydrobromic acid or hydrochloric acid, preferably in water or acetic acid, suitably at a ~ ~ S ~ ~ S 100-4713 tem~erature of from 0 to 100C, or boron tribromide, preferably in methylene chloride, suitably at a temper-ature of from 0 to 50C. When employing hydrochloric acid, the reaction is preferably effected at a pressure ; 5 of from 1 to 10 atm.
When Rlo is benzyl or when Rll is benzyloxy, the benzyl group can also be removed by catalytiC
hydrogenolysis. For these purposes, it is convenient to employ a noble metal catalyst, for example, a plat-inum catalyst, in quantities of from 2 to 10~ (w/v) and to ef~ect the reaction in ethanol.
In the case of the compounds of ~ormula I
wherein Y3, Y4 and/or Y5 is/are alkoxy, the appropriate starting material of formula II is selected in which Rlo is benzyl and the benzyl group is selectively removed.
Process variant b) can be effected according to known methods for the acylation of phenolic amino compounds. The acylation can, for example, be effected using an acylating agent, for example an acyl chloride or acid anhydrid~. The reaction may suitably be effected in trifluoroacetic acid at room temperature.
~ 100-~713 ',' Process variant c) can be effected according to known methods for the reduction of amides to amines.
Diborane or a complex me-tal hydride, e.g. LiAlH4, may advantageously be used as reducing agent. The reduction is preferably effected in an inert solvent such as tetrahydrofuran at temperatures of from 25 to75C. ~en R2" Y~, Y~ and~or Y5 is/are halogen, dibcrane should be used as the reducing agen~; otherwise, there is a possibility of at least par~ial removal of the halogen atoms from the benzene ring.
The resulting compounds of ~ormula I may ~e isolated and purified using conventional techniques.
Free base forms of the compound.s of formula I
may be converted into acid addition salt forms and vice versa in conventional manner The compounds of formula I can exist in the form of enantiomers or in racemate form. The racemates can be resolved into their optically active isomers in known manner.
The compounds of formula II, wherein R~ is hydrogen, are generally obtainable by known methods from known 5,6,7- or 8-alkoxy (or benzyloxy)~2-amino-100-~713 tetralines (or analogues thereof which can be prepared by known processes), which can have a second alkoxy or benzyloxy group in the benzene ring and which, if required, are already substituted by alkyl groups on the nitrogen atom~
When such compounds possess a free amino group in the 2- position, this group may be convérted into a -NR5R6 group by alkylation, arylation or aralkyl ation. The conversion can be effected according to known methods, e.g. by reductive alkylation or by means of an alkyl halide.
- The i.ntroduction of the substituents R2" and R3 can be effected as follows~
a) Introduction of an alkyl-, trifluoro- or trichloro-. methylsulphonamido group:
The alkoxyamino tetralines (wherein the amino group can, if recruired, be temporarily protected with an acyl group) used as starting materials are first nitrated according to known methods, e.g. with nitrous acid in methylene chloride, the resulting isomeric mixture separated chromatographically and the nitro-compound so obtained reduced to the corresponding amino 100~~713 derivative, e.g. by means of palladium on charcoal.
The amino compounds are finally conv~rted to the alkyl-trifluoro- or trichlorosulphonylamine derivatives by means of an alkyl- trifluoromethyl or trichloromethyl-3 sulphonyl halide.
b) Bromination, chlorination, iodination:
The starting materials of formula II, wherein Rll (and, where appropriate, R3) is chlorine, bromine or iodine, can be prepared by reacting the alkoxy-tetraline (wherein the amino group may be temporarily protected with an acyl group) with an appropriate halogenating agent. Suitable halogenating agents include, for example, sulphuryl chloride, bromine or iodine (in the presence of an equivalent quantity of ` 15 silver trifluoroacetate) in an inert solvent such as methylene chloride. The usual mixture of products, comprising compounds which have been halogenated in the o- or ~- position to the alkoxy group, is obtained and can be separated on Kieselgel.
c) Fluorination Alkoxyaminotetralines, which are substituted ~ 100-~713 r in the benzene ring with an -NH2 group [preparable as under a~, are employed as starting materials and are converted to the corresponding fluorine derivatives according to a Balz-Schiemann reaction. The starting S materials are thereby first diazotised, precipitated in the form of the fluoroborate, isolated and thermally decomposed .
d) Intxoduction of the C~12OH group:
The introduction of the CH2OH group may advan-tageously be effected vla formylation and subsequent reduction of the formyl group to the hydroxymethyl gro~p. Alkoxytetralines (wherein the amino group can, if required, be protected with an acyl group) are employed as starting materials. The formylation can be effected, for example, according to the Gatterman reaction, with hydrogen cyanide in the presence of a Frledel-Crafts catalyst. After separation of the isomers from the reaction mixture, the formyl group in the desired compound can be reduced to the hydroxy-methyl group, for example, with a reducing agent such as dlborane or LiAlH4 in an inert solvent such as tetrahydrofuran.
T
no-47l3 The compounds of formula II wherein R4 is a CH2O~I group, R3, R5 and ~6 are each hydrogen and Rll is hydrogen, alkyl, alkoxy or benzyloxy, can be obtained from the corresponding compounds of formula II wherein R4 is a COOH or a COOR (R - alkyl of 1 to 4 carbon atoms) group. These latter compounds are either known or can be produced by known methods for the preparation of a-amlno acids. For example, the compounds can be obtained from the corresponding tetralones by reaction 10 with potassium cyanide and ammonium carbonate and ~ub-sequent decomposition of the resulting hydantoin deriv-ative. The reduction of the compounds wherein R~ is a COOEI or COOR group to compounds wherein R4 is CH~OH may he effected in known manner for the reduction of a car~
15 bonyl group to a hydroxymethyl gxoup. The reduction can, for example, be efected with a reducing agant such as diborane or lithium aluminium hydride, in an inert solvent such as tetrahydrofuran or dioxane, at a temperature of from 0 to 100C. The reduction of the c~m-20 pounds of formula III, wherein R is alkyl, may suitably be ef~ected with a borohydride, pre~erably an alkali metal borohydride such as sodium borohydride, in etha-nol, tetrahydrofuran, dioxane or water.
_ 17 _ 100-~713 The introduction of the additional substitu-ents R3, Rll, R5 and ~6 in the compounds of formula II
wherein R~ is CH20~I can be effected in the same manner as for compounds wherein R~ is hydrogen. In most cases, the substitution will already have been effected in the earlier step, i.e. in the compounds wherein R~l is a COOE~ or a COOR group.
Compounds of formula II, wherein R11 and/or R4 are an acylated CH20H group, can be prepared by acylation, e.g. as described in process variant b), o the corresponding compounds wherein Rll and/or R4 are a free CH20H group.
The starting materials of formula IIl can be prepared in accordance with process variant a) or c).
The starting materials of formula IV can be produced by acylation of the corresponding unacylated compound with a reactive derivative of an acid of formula R9-(CH2)n,_l-cooH. Suitable reactive deriva-tives are, for example, acid chlorides or N-hydroxy~
succinimide esters.
In the following Examples, all temperatures are in degrees Celsius.
100-~713 EXA~IPLE 1: 2-Amino-1,2,3,4-tetr. 2-.
~ydrox~-met ~ hthalene a) 2-~mino-2-carboxy-lL2~3,4-tetrahydro~8-methoxy-_____.__ _______ __ _ _ ________ _______ __._ _ na~hthalene 28 g of potassium cyanide, followed by 76O5 g of a~nonium carbonate, are added to a suspension of 50 g of 8-methoxy~2-tetralone in 350 ml of isopropanol.
The mi~ture is stirred at 60 for 20 hours, cooled to room temperature, then 400 ml of wa-ter are addedI and the reac-tion mixture left to stand at 4 in order to crystallise. 8-Methoxy-2-spirohydantoin -tetraline crysta]lises out, with a melting point of 216-~17.
42 ml of a 40~ aqueous sodium hydroxide solution are added to a suspension of 21 g of 8-methoxy-2-spiro-hydrantoin tetraline in 130 ml of propylene glycol, and the reaction mixture heated, with stirring, for 2~ hours to 190. The cooled solution is decolourised with activated charcoal, adjusted to a pH of 1 with concen-trated hydrochloric acid, the resultin~ precipitate ~0 filtered off, and the mother liquor adjusted to a p~I
of 5.5 with a sodium bicarbonate/acetate acid buffer solu~ion. The ti~le compound which crystallises out " 100-4713 has melting point of 228-230 after isola~ion and drying.
b) 2-Amino-1~2,3,4-tetrahydro-8-methoxy-2-hydroxy-____~____ ____~~______ ___~________ ____ ___ _ methy1na~hthalene A suspension of 14.5 g of 2-amino-2-carboxy-1,2,3,4-tetrahydro-8-methoxynaphthalene in 400 ml of tetra-hydrofuran is added dropwise with stirring (under a ni-trogen atmosphere) to 525 ml of a l-molar solution of diborane in tetrahydrofuran~ The reaction solution is then boiled at reflux for 12 hours and cooled to room temperature. 400 ml of a solution of 2N hydrogen chloride in ethanol are added to the residue, the mix~
ture is boiled at reflux for 2 hours, the cooled solu-tion evaporated and the residue is shaken out with lN
aqueous sodium hydroxide/methylene chloride solu~ion.
The organic phase is evaporated to dryness, the residue chromatographed on silica gel with a mixture of lO~
ammonia-methylene chloride solution and methanol t9~
The title compound, which is in the form of an oil, is dissolved in ethanol/ether ~1:1) and, in order to con-vert the compound into the hydrochloride form, one equiv-alent of a 4N ethereal hydrogen chloride solution is added, and the mixture left to stand at 4 so as to : ~0 ~5~
100~~713 crystallise. The ti~le compound is obtained in the form of the hydrochloride. M.P. 153-154.
c) 2_Amino_lL2L_,~,4-tetrahydro-8-hxdroxy-2_hydr methylna~hthalene
5 g of 2-amino~1,2,3,4--tetrahydro-8-methoxy-2-hydroxymethyl-naphthalene-hydrochloride are suspended in 100 ml of methylene chloride, and 6.8 ml o boron tribromide are added. The reaction solution is stirred for 4 hours at room temperature, then 10 ml of methanol are added, and the reaction mixture evaporated. The residue is freed from boron esters by boiling down S
times, each time with 50 ml of ethanol, then shaken out with a mixture of lN aqueous potassium bicarbonate solution and methylene chloride/isopropanol (2:1), and the resi-lS due of the dried concentrated organic phase is chro-matographed on silica gel with a mixture of 10% ammonia-methylene chloride solution and methanol (7:3). The title compound, which is obtained as a foam, is dis-solved in ethanol, ethereal hydrogen chloride solution is added, and the mixture left to stand at -10, whereby the title compound is obtained in the form o the hydrogen chloride. M.P. 191~193.
5~
EXAMPLE 2: 2-~nino-1,2,3,4-tetrah~ro-6-acetox methylnapllthalene 1 ml of acetyl chloride is added to a suspen-sion of 1 g of 2-amino-1,2,3,4-tetrahydro-6-hydroxy-2-hydroxymethylnaphthalene-hydrobromide in 12 ml of tri-fluoroacetic acid, whereupon the whole mixture immedi-ately goes into solution, and gas develops. The reaction mixture is then stirred for 1 1/2 hours at room temperature and lyophilised. The residue is rubbed with 50 ml of ether, suctioned off and washed with 50 ml of ether.
NMR Spectrum (CDC13): S = 1.7 t3H, s); 1.8 (3El, s);
2.2-3.3 (6El, m); 3.8 (2H, s);
times, each time with 50 ml of ethanol, then shaken out with a mixture of lN aqueous potassium bicarbonate solution and methylene chloride/isopropanol (2:1), and the resi-lS due of the dried concentrated organic phase is chro-matographed on silica gel with a mixture of 10% ammonia-methylene chloride solution and methanol (7:3). The title compound, which is obtained as a foam, is dis-solved in ethanol, ethereal hydrogen chloride solution is added, and the mixture left to stand at -10, whereby the title compound is obtained in the form o the hydrogen chloride. M.P. 191~193.
5~
EXAMPLE 2: 2-~nino-1,2,3,4-tetrah~ro-6-acetox methylnapllthalene 1 ml of acetyl chloride is added to a suspen-sion of 1 g of 2-amino-1,2,3,4-tetrahydro-6-hydroxy-2-hydroxymethylnaphthalene-hydrobromide in 12 ml of tri-fluoroacetic acid, whereupon the whole mixture immedi-ately goes into solution, and gas develops. The reaction mixture is then stirred for 1 1/2 hours at room temperature and lyophilised. The residue is rubbed with 50 ml of ether, suctioned off and washed with 50 ml of ether.
NMR Spectrum (CDC13): S = 1.7 t3H, s); 1.8 (3El, s);
2.2-3.3 (6El, m); 3.8 (2H, s);
6.4-7.0 (3H, m).
EX~MPLE 3: N-[2-(3,~-dimethoxyphenyl)ethYl]-2-methyl-amino-1,2,3,4-tetrahydro-6-hydro~yn lene-hYdrochloride ~.6 y of N-[2-(3,4-dimethoxyphenyl)acetyl]-2-methylamino-1,2,3,4-tetrahydxo-6-hydroxynaphthalene are suspended in 70 ml of tetrahydrofuran with stirring.
65 ml of a 1 Molar solution of diborane in tetrahydro-~5~L7~i 100-~713 furan are added dropwise and the reaction solution stirred fcr 3 hours at room temperature and finally for a further 3 hours at 60. An excess of 4N hydrochloric acid is added to the cooled reaction mixture. The mix-S ture is finally dried, methanol is added to the mixture, evaporated and the procedure repeated several times.
The residue which is then obtained is chromatographed on I~leselgel with methylene chlorideJmethanol (9:1).
The title compound which is isolated, is dissolved in methanol, methanolic hydrogen chloride is added, and the mixture evaporated to dryness. The residue is dis-solved in 50 ml of isopropanol and the title compound, in the ~orm of the hydrochloride, is precipitated by the addition of 300 ml of ether. M.P.: sinters at 95.
The N-[2-(3,4-dimethoxyphenyl)acetyl] 2-methylamino-1,2,3 r 4-tetrahydro-6~hydroxynaphthalene used as starting material is obtained by the reaction of 6~hydroxy-2-methylamino-1,2,3,4-tetrahydronaphth-alene with the hydroxysuccinimide ester of 3,4-dimethoxy-~
phenyl acetic acid in dimethyl~ormamide at room temper-ature.
The following compounds can be obtained in manner analogous to those described in the aforementioned Examples employing appropriate starting materials in appro~imately equivalent amounts.
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EX~MPLE 3: N-[2-(3,~-dimethoxyphenyl)ethYl]-2-methyl-amino-1,2,3,4-tetrahydro-6-hydro~yn lene-hYdrochloride ~.6 y of N-[2-(3,4-dimethoxyphenyl)acetyl]-2-methylamino-1,2,3,4-tetrahydxo-6-hydroxynaphthalene are suspended in 70 ml of tetrahydrofuran with stirring.
65 ml of a 1 Molar solution of diborane in tetrahydro-~5~L7~i 100-~713 furan are added dropwise and the reaction solution stirred fcr 3 hours at room temperature and finally for a further 3 hours at 60. An excess of 4N hydrochloric acid is added to the cooled reaction mixture. The mix-S ture is finally dried, methanol is added to the mixture, evaporated and the procedure repeated several times.
The residue which is then obtained is chromatographed on I~leselgel with methylene chlorideJmethanol (9:1).
The title compound which is isolated, is dissolved in methanol, methanolic hydrogen chloride is added, and the mixture evaporated to dryness. The residue is dis-solved in 50 ml of isopropanol and the title compound, in the ~orm of the hydrochloride, is precipitated by the addition of 300 ml of ether. M.P.: sinters at 95.
The N-[2-(3,4-dimethoxyphenyl)acetyl] 2-methylamino-1,2,3 r 4-tetrahydro-6~hydroxynaphthalene used as starting material is obtained by the reaction of 6~hydroxy-2-methylamino-1,2,3,4-tetrahydronaphth-alene with the hydroxysuccinimide ester of 3,4-dimethoxy-~
phenyl acetic acid in dimethyl~ormamide at room temper-ature.
The following compounds can be obtained in manner analogous to those described in the aforementioned Examples employing appropriate starting materials in appro~imately equivalent amounts.
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v r~ z . ._ . ._ _ ~ 47S 100-~713 The compounds of formula I exhibit pharmaco-logical activity. In particular, the compounds e~hibit activity for the treatment of heart conditions, such as cardiac failure and shock, increased blood pressure and Parkinson's disease, as indicated in standard tests, for example, in observations in the "open-chest" dog.
The compounds are therefore indicated ~or use in the treatment of heart conditions, such as cardiac failure and shock, increased blood pressure and Parkin-son's disease.
For these uses, an indicated daily dose is from about 5 to abou-t 200 mg, suitably from about 5 to about 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1 to about 100 mg, suitably from about 1 to about 50 mg, or in sustained release form.
The compounds o formula I may be administered in pharmaceutically acceptable acid addition salt form~
Such acid addition salt forms exhibit the same order o activity as the free base forms and are readily ~repared in conventional manner. Sultable acids for salt forma-_ zg ~ ~ S ~ 100-~7~3 '''`
tion inelude inor~anie aeids such as hydrochlorie and ; hyclxobromic acids and organic acids such as maleic acid.
The present invention also provides a pharma-ceutieal eomposition eomprising a eompound o~ Eormula I, in free base form or in pharmaceutieally acceptable acid addition salt form, in association with a pharma-ceutieally acceptable diluen~ or carrier. Such compo-sitions may be formulated in conventional manner and may, for example, be a solution or a eapsule.
In one group of compounds of formula I, as previously defined, Rl is hyarogenr alkanoyl of 1 to 13 carbon atoms or a group -CO (C~l2)n-R7 wherein n is from 0 to 5 and R7 is phenyl or phenyl monosubstituted w~th alkyl of 1 to 4 carbon atoms, R2 is hydrogen, hydro~y, alkanoyl of 1 to 13 carbon atoms or a group -O-CO-(CEI2) -R7 wh~rein n is from 0 to 5 and R7 is phenyl or phenyl monosubstituted with alkyl of 1 to 4 earbon atoms, R~ is -CEl2ORl wherein Rl is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group -CO-(CEI2)n-R7 wherein n is from 0 to 5 and R7 i5 phenyl or phenyl monosubstituted with alkyl of 1 to ~ carbon atoms, R5 is hydrogen or alkyl of 1 to 4 carbon atoms .
100--~713 and R6 is hydrogen or alkyl of 1 to 4 carbon atoms.
In a second group of compounds of formula I, as previously defined, R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a residue of formula Yl Y2'~
wherein each of Yl and Y2, which may be the same or different, is hydrogen, alkyl of 1 to 4 carbon atoms, alko~y of 1 to 4 carbon atoms, fluorine, chlorine or bromine and each of R2, R3, R4~ R5 and R6 is hydrogen.
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E~ ~ z æ æ z æ z z æ z z ~, oooooooooo O u~
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a x ~ x c, m x r r-l ~ t~ U~ U') CO' 1~ ~-- ~O ~O 10 CO CO ~
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~: o .~ o r-- co cr. o .~ ~
,~ _ _ 3~ 5~9¦!7$j .... __ __ ~r ~
~1 ~ ~al ~al ~ ~ O O O Or~ ~
U
~ ~ S, Q S,S: ~
X ~V ~ O Ot)t) O
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~ O ~~: ~ ~ O
C~ ~ X ~ 5 ~ ~-- ~`' 11 14 ~ o ~`~ D O`--In ~ ~o~
~; . o I ~ I I o 4 t` ~ r~l ~I 1` o . o ~ ~ I~ t--~' ~ ~ ~
~:C
... .... ~
~;~ ~ O O O
~ I .~ I rl r~l ~ ~ C X
H ~ --I r~l H ~ _ O ~ O ~r o o s~ ~ ~
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~0 ~r~ O 0~ ~ 0~
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O X O r~ D ~ 0~
v r~ z . ._ . ._ _ ~ 47S 100-~713 The compounds of formula I exhibit pharmaco-logical activity. In particular, the compounds e~hibit activity for the treatment of heart conditions, such as cardiac failure and shock, increased blood pressure and Parkinson's disease, as indicated in standard tests, for example, in observations in the "open-chest" dog.
The compounds are therefore indicated ~or use in the treatment of heart conditions, such as cardiac failure and shock, increased blood pressure and Parkin-son's disease.
For these uses, an indicated daily dose is from about 5 to abou-t 200 mg, suitably from about 5 to about 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1 to about 100 mg, suitably from about 1 to about 50 mg, or in sustained release form.
The compounds o formula I may be administered in pharmaceutically acceptable acid addition salt form~
Such acid addition salt forms exhibit the same order o activity as the free base forms and are readily ~repared in conventional manner. Sultable acids for salt forma-_ zg ~ ~ S ~ 100-~7~3 '''`
tion inelude inor~anie aeids such as hydrochlorie and ; hyclxobromic acids and organic acids such as maleic acid.
The present invention also provides a pharma-ceutieal eomposition eomprising a eompound o~ Eormula I, in free base form or in pharmaceutieally acceptable acid addition salt form, in association with a pharma-ceutieally acceptable diluen~ or carrier. Such compo-sitions may be formulated in conventional manner and may, for example, be a solution or a eapsule.
In one group of compounds of formula I, as previously defined, Rl is hyarogenr alkanoyl of 1 to 13 carbon atoms or a group -CO (C~l2)n-R7 wherein n is from 0 to 5 and R7 is phenyl or phenyl monosubstituted w~th alkyl of 1 to 4 carbon atoms, R2 is hydrogen, hydro~y, alkanoyl of 1 to 13 carbon atoms or a group -O-CO-(CEI2) -R7 wh~rein n is from 0 to 5 and R7 is phenyl or phenyl monosubstituted with alkyl of 1 to 4 earbon atoms, R~ is -CEl2ORl wherein Rl is hydrogen, alkanoyl of 1 to 13 carbon atoms or a group -CO-(CEI2)n-R7 wherein n is from 0 to 5 and R7 i5 phenyl or phenyl monosubstituted with alkyl of 1 to ~ carbon atoms, R5 is hydrogen or alkyl of 1 to 4 carbon atoms .
100--~713 and R6 is hydrogen or alkyl of 1 to 4 carbon atoms.
In a second group of compounds of formula I, as previously defined, R1 is hydrogen, alkanoyl of 1 to 13 carbon atoms or a residue of formula Yl Y2'~
wherein each of Yl and Y2, which may be the same or different, is hydrogen, alkyl of 1 to 4 carbon atoms, alko~y of 1 to 4 carbon atoms, fluorine, chlorine or bromine and each of R2, R3, R4~ R5 and R6 is hydrogen.
Claims (4)
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-(CH2)n-R7 group, n is from 0 to 5, R7 is a group of formula and each of Yl and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or, when Yl and Y2 are bonded to adjacent carbon atoms, Y1 and Y2 together may be methylenedioxy, R2 is hydrogen, hydroxy, alkanoyloxy of 1 to 20 carbon atoms, a -O-CO-(CH2)n-R7 group wherein n and R7 are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkyl-sulphonylamino group of 1 to 4 carbon atoms, CF3SO2NH, CC13SO2NH, CH2OH, CH2-O-CO-(CH2)n-R7, wherein n and R7 are as previously defined, ox CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms, R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydrogen, CH2OH, CH2O-CO-R8 or CH2-O-CO-(CH2)n-R7, wherein R7 and R8 are as previously defined, R5 is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms ox (CH2)n-R9, wherein n is as previously defined and R9 is a group of formula, wherein each of Y3, Y4 and Y5 may, inde-pendently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, where in R8 is as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined or, when Y3 and Y4 are bonded to adjacent carbon atoms, Y3 and Y4 together may be methyl-enedioxy, R6 is hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or -(CH2)6- group, whereby when two or more of the residues OR1' R2' Y3' Y4 and Y5 are a free or acylated OH- group, these groups are identical, cr when R2 and R4 are both free or acylated CH2-OH groups, these groups are identical, With the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino solely substituted by alkyl or benzyl, and is other than a hetero-ring, excepting as follows:
a) when ORl is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when ORl is in position 5 and R2 is hydrogen, -NR5R6 can be -NH2 or -NHCH3; or of a pharmaceutically acceptable acid addition salt thereof: which comprises a) producing a compound of formula Ia, Ia wherein R2 has the same significance as R2 with the exception of an alkanoyloxy or an -O-CO-(CH2)n-R7 group, R5 has the same significance as R5 with the exception of a (CH2)n-R9 group, wherein R9 contains an -O-COR8 or an -O-CO-(CH2)n-R7 residue, by converting the alkoxy or benzyloxy group in a com-pound of formula II, to a hydroxy group by ether splitting, II
wherein R10 is alkyl of 1 to 4 carbon atoms or benzyl, and R11 has the same significance as R2 and, in addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib, Ib wherein R? is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, R2 has the same significance as R2 with the exception of a free -OH group, and R5 has the same significance as R5 with the exception of a -(CH2)n-R9 group wherein the R9 group contains a free -OH group, by acylating a compound of formula III, III
with a reactive derivative of a carboxylic acid of formula R8-COOH or R7-(CH2)n-COOH, or e) producing a compound of formula Ic, IC
wherein R?" is hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 to 4 car-bon atoms or CH2CH, R? is hydrogen or CH2OH, n' is from 1 to 5, and R? has the same significance as R9 with the exception that R9 cannot contain an -O-COR8 or -O-CO-(CH2)n-R7 group, by reducing a compound of formula IV
IV
and when desired, forming a pharmaceutically acceptable acid addition salt of said compound of Formula I so produced.
wherein R1 is hydrogen, alkanoyl of 1 to 20 carbon atoms or a -CO-(CH2)n-R7 group, n is from 0 to 5, R7 is a group of formula and each of Yl and Y2 may independently be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or, when Yl and Y2 are bonded to adjacent carbon atoms, Y1 and Y2 together may be methylenedioxy, R2 is hydrogen, hydroxy, alkanoyloxy of 1 to 20 carbon atoms, a -O-CO-(CH2)n-R7 group wherein n and R7 are as previously defined, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, an alkyl-sulphonylamino group of 1 to 4 carbon atoms, CF3SO2NH, CC13SO2NH, CH2OH, CH2-O-CO-(CH2)n-R7, wherein n and R7 are as previously defined, ox CH2-O-CO-R8, wherein R8 is hydrogen or alkyl of 1 to 19 carbon atoms, R3 is hydrogen or, when R2 is chlorine, R3 may also be chlorine, R4 is hydrogen, CH2OH, CH2O-CO-R8 or CH2-O-CO-(CH2)n-R7, wherein R7 and R8 are as previously defined, R5 is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms ox (CH2)n-R9, wherein n is as previously defined and R9 is a group of formula, wherein each of Y3, Y4 and Y5 may, inde-pendently, be hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, -OH, -O-COR8, where in R8 is as previously defined, -O-CO-(CH2)n-R7, wherein n and R7 are as previously defined or, when Y3 and Y4 are bonded to adjacent carbon atoms, Y3 and Y4 together may be methyl-enedioxy, R6 is hydrogen, alkyl of 1 to 4 carbon atoms or, together with R5, a -(CH2)4-, -(CH2)5 or -(CH2)6- group, whereby when two or more of the residues OR1' R2' Y3' Y4 and Y5 are a free or acylated OH- group, these groups are identical, cr when R2 and R4 are both free or acylated CH2-OH groups, these groups are identical, With the condition that when R4 is hydrogen and R2 is hydrogen, OH, alkyl or an acylated OH group, -NR5R6 is other than free amino or amino solely substituted by alkyl or benzyl, and is other than a hetero-ring, excepting as follows:
a) when ORl is in position 6 and R2 is hydrogen, -NR5R6 can be NH2 or b) when ORl is in position 5 and R2 is hydrogen, -NR5R6 can be -NH2 or -NHCH3; or of a pharmaceutically acceptable acid addition salt thereof: which comprises a) producing a compound of formula Ia, Ia wherein R2 has the same significance as R2 with the exception of an alkanoyloxy or an -O-CO-(CH2)n-R7 group, R5 has the same significance as R5 with the exception of a (CH2)n-R9 group, wherein R9 contains an -O-COR8 or an -O-CO-(CH2)n-R7 residue, by converting the alkoxy or benzyloxy group in a com-pound of formula II, to a hydroxy group by ether splitting, II
wherein R10 is alkyl of 1 to 4 carbon atoms or benzyl, and R11 has the same significance as R2 and, in addition, may signify alkoxy of 1 to 4 carbon atoms or benzyloxy, b) producing a compound of formula Ib, Ib wherein R? is alkanoyl of 1 to 20 carbon atoms or -CO-(CH2)n-R7, R2 has the same significance as R2 with the exception of a free -OH group, and R5 has the same significance as R5 with the exception of a -(CH2)n-R9 group wherein the R9 group contains a free -OH group, by acylating a compound of formula III, III
with a reactive derivative of a carboxylic acid of formula R8-COOH or R7-(CH2)n-COOH, or e) producing a compound of formula Ic, IC
wherein R?" is hydrogen, hydroxy, fluorine, chlorine, bromine or iodine, alkyl of 1 to 4 car-bon atoms or CH2CH, R? is hydrogen or CH2OH, n' is from 1 to 5, and R? has the same significance as R9 with the exception that R9 cannot contain an -O-COR8 or -O-CO-(CH2)n-R7 group, by reducing a compound of formula IV
IV
and when desired, forming a pharmaceutically acceptable acid addition salt of said compound of Formula I so produced.
2. A compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1 wherein R1 is hydrogen and the -ORl group is at the 6-position on the ring, R2 is hydrogen, R3 is hydrogen, R4 is CH2OH, R5 is hydrogen, and R6 is hydrogen.
4. 2-Amino-1,2,3,4-tetrahydro-6-hydroxy-2-hydroxymethylnaphthalene, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH15353/76 | 1976-12-07 | ||
| CH1535376 | 1976-12-07 | ||
| CH82/77 | 1977-01-05 | ||
| CH8277 | 1977-01-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105475A true CA1105475A (en) | 1981-07-21 |
Family
ID=25683446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA292,457A Expired CA1105475A (en) | 1976-12-07 | 1977-12-06 | 1,2,3,4-tetrahydro-naphthalenes |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5384955A (en) |
| AT (1) | AT366361B (en) |
| CA (1) | CA1105475A (en) |
| DE (1) | DE2752659A1 (en) |
| DK (1) | DK527877A (en) |
| ES (1) | ES464747A1 (en) |
| FI (1) | FI773595A (en) |
| FR (1) | FR2373513A1 (en) |
| GB (1) | GB1597140A (en) |
| IE (1) | IE45929B1 (en) |
| IL (1) | IL53533A (en) |
| NL (1) | NL7713364A (en) |
| NZ (1) | NZ185884A (en) |
| PH (1) | PH13932A (en) |
| PT (1) | PT67365B (en) |
| SE (1) | SE7713471L (en) |
| SU (1) | SU927110A3 (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
| WO1980000251A1 (en) * | 1978-07-14 | 1980-02-21 | American Hospital Supply Corp | Derivatives of 2-amino-6,7-dihydroxytetrahydronaphthalene(adtn) |
| DE3062971D1 (en) | 1979-09-14 | 1983-06-09 | Sandoz Ag | Derivatives of tetraline, their preparation and medicaments containing these compounds |
| EP0033789B1 (en) * | 1980-01-30 | 1984-03-07 | American Hospital Supply Corporation | 2-alpha-methyl-dopaminimino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, its salts, and a process for preparation thereof |
| SE8004002L (en) * | 1980-05-29 | 1981-11-30 | Arvidsson Folke Lars Erik | THERAPEUTICALLY APPLICABLE TETRALIN DERIVATIVES |
| IL65501A (en) * | 1981-05-08 | 1986-04-29 | Astra Laekemedel Ab | 1-alkyl-2-aminotetralin derivatives,process for their preparation and pharmaceutical compositions containing them |
| AU8455082A (en) * | 1981-05-11 | 1982-12-07 | Folk Lars-Erik Arvidsson | Therapeutically useful tetralin derivatives iii,processes forpreparation and pharmaceutical preparations for such compounds |
| US4578403A (en) * | 1981-06-23 | 1986-03-25 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4559359A (en) * | 1981-06-23 | 1985-12-17 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4455317A (en) * | 1981-06-23 | 1984-06-19 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4454154A (en) * | 1981-06-23 | 1984-06-12 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4402974A (en) | 1981-06-23 | 1983-09-06 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| IT1218322B (en) * | 1982-06-10 | 1990-04-12 | Chiesi Farma Spa | 1,2,3,4-TETRAIDRONAFTALENE DERIVATIVES, PREPARATION PROCEDURE AND RELATED PHARMACEUTICAL COMPOSITIONS |
| US4448990A (en) * | 1982-11-16 | 1984-05-15 | Eli Lilly And Company | Hydroxyaminotetralincarboxamides |
| US4500545A (en) * | 1982-11-16 | 1985-02-19 | Eli Lilly And Company | Hydroxyaminotetralincarboxamides |
| US4722933A (en) * | 1985-12-20 | 1988-02-02 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
| US4743618A (en) * | 1983-01-03 | 1988-05-10 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
| US5177112A (en) * | 1983-01-03 | 1993-01-05 | Whitby Research, Inc. | Substituted 2-aminotetralins |
| US4657925A (en) * | 1984-08-13 | 1987-04-14 | Nelson Research & Development Co. | Method and compositions for reducing the intraocular pressure of mammals |
| US4564628A (en) * | 1983-01-03 | 1986-01-14 | Nelson Research & Development Co. | Substituted 2-aminotetralins |
| GB2157950B (en) * | 1984-05-04 | 1988-11-02 | Nelson Res & Dev | Selective d-2 dopamine receptor agonist |
| US5214156A (en) * | 1988-03-25 | 1993-05-25 | The Upjohn Company | Therapeutically useful tetralin derivatives |
| CA1331191C (en) | 1988-03-25 | 1994-08-02 | Bengt Ronny Andersson | Therapeutically useful tetralin derivatives |
| US5225596A (en) * | 1989-01-09 | 1993-07-06 | The Upjohn Company | Halo substituted aminotetralins |
| JP2931986B2 (en) * | 1989-02-17 | 1999-08-09 | 武田薬品工業株式会社 | Aralkylamine derivatives |
| SE8901889D0 (en) * | 1989-05-26 | 1989-05-26 | Astra Ab | NOVEL 8-SUBSTITUTED-2-AMINOTETRALINES |
| US5380748A (en) * | 1991-03-07 | 1995-01-10 | Zeria Pharmaceutical Co., Ltd. | Trialkylamine derivative and ameliorant for digestive tract movement containing the same |
| DK0923542T3 (en) * | 1996-05-31 | 2003-11-17 | Upjohn Co | Aryl-substituted cyclic amines as selective dopamine D3 ligands |
| IT1294931B1 (en) | 1997-09-22 | 1999-04-23 | Sigma Tau Ind Farmaceuti | DERIVATIVES OF 2-AMINOTETHRALIN PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, ACTIVE IN THE |
| AR054363A1 (en) * | 2005-05-23 | 2007-06-20 | Astrazeneca Ab | COMPOUNDS THAT DISPLAY MODULATORY ACTIVITY IN THE 5-HYDROXY-TRIPTAMINE 6 RECEIVER |
| RU2558145C1 (en) * | 2011-06-27 | 2015-07-27 | Шаньдунь Луе Фармасьютикал Ко., Лтд. | Method for industrial production of nitrogen-substituted amino-5,6,7,8-tetrahydronaphthol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1017359A (en) * | 1972-07-03 | 1977-09-13 | Frederic P. Hauck | Substituted cyclic polymethylene phenols |
-
1977
- 1977-11-25 DE DE19772752659 patent/DE2752659A1/en not_active Ceased
- 1977-11-28 DK DK527877A patent/DK527877A/en not_active Application Discontinuation
- 1977-11-28 FI FI773595A patent/FI773595A/en not_active Application Discontinuation
- 1977-11-29 SE SE7713471A patent/SE7713471L/en not_active Application Discontinuation
- 1977-12-02 NL NL7713364A patent/NL7713364A/en not_active Application Discontinuation
- 1977-12-05 ES ES464747A patent/ES464747A1/en not_active Expired
- 1977-12-05 IL IL53533A patent/IL53533A/en unknown
- 1977-12-05 IE IE2462/77A patent/IE45929B1/en unknown
- 1977-12-05 PT PT67365A patent/PT67365B/en unknown
- 1977-12-05 GB GB50477/77A patent/GB1597140A/en not_active Expired
- 1977-12-06 CA CA292,457A patent/CA1105475A/en not_active Expired
- 1977-12-06 JP JP14648577A patent/JPS5384955A/en active Granted
- 1977-12-06 SU SU772549950A patent/SU927110A3/en active
- 1977-12-06 FR FR7736662A patent/FR2373513A1/en active Granted
- 1977-12-06 NZ NZ185884A patent/NZ185884A/en unknown
- 1977-12-06 AT AT0871977A patent/AT366361B/en not_active IP Right Cessation
- 1977-12-07 PH PH20543A patent/PH13932A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ185884A (en) | 1980-04-28 |
| ATA871977A (en) | 1981-08-15 |
| IL53533A (en) | 1982-07-30 |
| NL7713364A (en) | 1978-06-09 |
| AT366361B (en) | 1982-04-13 |
| SE7713471L (en) | 1978-06-08 |
| IE45929B1 (en) | 1982-12-29 |
| GB1597140A (en) | 1981-09-03 |
| DE2752659A1 (en) | 1978-06-08 |
| FR2373513B1 (en) | 1980-08-22 |
| IL53533A0 (en) | 1978-03-10 |
| JPS5384955A (en) | 1978-07-26 |
| FR2373513A1 (en) | 1978-07-07 |
| IE45929L (en) | 1978-06-07 |
| ES464747A1 (en) | 1979-01-01 |
| PH13932A (en) | 1980-11-04 |
| JPS6214540B2 (en) | 1987-04-02 |
| DK527877A (en) | 1978-06-08 |
| FI773595A (en) | 1978-06-08 |
| PT67365A (en) | 1978-01-01 |
| SU927110A3 (en) | 1982-05-07 |
| PT67365B (en) | 1979-09-20 |
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