Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 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,
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
100-4713
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~
100-4713
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.
-- 5 -- -
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
-- 7 --
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
100-4713
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,
R3
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
HO 6
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,
-- 10 -
s
100-4713
.
R Ic
HO 6
: 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.
- 12 -
7X
~ 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-
- 13 -
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.
- 16 -
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.
- 18 -
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
19 --
" 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~
- 100-4713
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-
- 22 -
~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.
100- ~1713
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-- 2~ -
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100-4713
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- 25 -
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~ 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
- 30-
.
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.
- - 31 -
