DERIVES DU 2-AMINO-6, 7-DIHYDROXYTETRAHYDRO- NAPHTHALENE (ADTN)

DERIVATIVES OF 2-AMINO-6, 7-DIHYDROXYTETRAHYDRO- NAPHTHALENE (ADTN)

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
This invention provides derivatives of 2-amino-6,7-dihy-
droxytetrahydronaphthalene (ADTN) represented by the formula
<IMG>
wherein R is OH, alkyloxy, hydroxyalkyl or acyloxy, and R' is an
arylalkyl where the aryl group is benzyl, substituted benzyl,
phenyl or substituted phenyl and the alkyl group is a straight
or branched chain alkyl having one to twenty carbon atoms; and
the pharmaceutically acceptable salts thereof.
These derivatives of 2-amino-6,7-dihydroxytetrahydro-
naphthalene are useful as inotropes.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing N-arylalkyl derivatives of
2-amino-6,7-dihydroxy-tetrahydronaphthalene of the formula:
<IMG> (I)
wherein:
R is OH, alkyloxy, hydroxyalkyl, or acyloxy, and R' is an
arylalkyl where the aryl group is benzyl; benzyl substituted by
an alkoxy, acyloxy, or hydroxy group; phenyl; phenyl or sub-
stituted by alkoxy, acyloxy, or hydroxy group; and the alkyl
group is a straight or branched chain alkyl having 1 to 20
carbons; and the pharmaceutically acceptable salts thereof
comprising:
(a) reacting a solution of hydroxyl-protected 2-amino-
6,7-dimethoxy-1,2,3,4- tetrahydronaphthalene with ketone or
aldehyde and NaCNBH3;
(b) acidifying the solution resulting from step (a);
(c) recovering the N-arylalkyl derivatives so formed;
and
(d) where required, converting the product to a
pharmaceutically acceptable salt.
2. A process as claimed in claim 1, wherein R is OH,
and R' is an arylalkyl of the formula
<IMG>
3. A process as claimed in claim 1, wherein R is OCH3
11

and R' is an arylalkyl of the formula
<IMG>
4. A process as claimed in claim 1, wherein R is
acetyloxy and R' is an arylalkyl of the formula
<IMG>
5. A process as claimed in claim 1, wherein R is OH and
R' is an arylalkyl of the formula
<IMG>
6. A process as claimed in claim 1, wherein R is OH and
R' is an arylalkyl of the formula
<IMG>
7. A process as claimed in claim 1, wherein R is OCH3
and R' is an arylalkyl of the formula
<IMG>
12

8. A compound of tile formula
<IMG>
wherein R is OH, an alkyloxy, hydroxyalkyl, or an acyloxy; and
R' is an arylalkyl where the aryl group is benzyl; benzyl
substituted with an alkoxy, acyloxy or hydroxy group; phenyl
or phenyl substituted with an alkyloxy, acyloxy, or hydroxy
group, and the alkyl group is a straight or branched chain
alkyl having one to twenty carbon atoms; and the pharmaceutica-
lly acceptable salts thereof, whenever prepared by the process
of claim 1 or by an obvious chemical equivalent thereof.
9. A compound of the formula (I) as defined in claim
1, wherein R is OH, and R' is an arylalkyl of the formula
<IMG>
and pharmaceutically acceptable salts, whenever prepared by
the process of claim 2 or by an obvious chemical equivalent
thereof.
10. A compound of the formula (I) as defined in claim 1,
wherein R is OCH3, and R' is an arylalkyl of the formula
<IMG>
and pharmaceutically acceptable salts, whenever prepared by
the process of claim 3 or by an obvious chemical equivalent
thereof.
13

11. A compound of the formula (I) as defined in claim 1,
wherein R is acetyloxy and R' is an arylalkyl of the formula
<IMG>
or a pharmaceutically acceptable salt, whenever prepared by
the process of claim 4, or by an obvious chemical equivalent
thereof.
12. A compound of the formula (I) as defined in claim 1,
wherein R is OH and R' is an arylalkyl of the formula
<IMG>
or a pharmaceutically acceptable salt, whenever prepared by
the process of claim 5, or by an obvious chemical equivalent
thereof.
13. A compound of the formula (I) as defined in claim 1,
wherein R is OH and R' is an arylalkyl of the formula
<IMG>
or a pharmaceutically acceptable salt, whenever prepared by
the process of claim 6, or by an obvious chemical equivalent
thereof.
14. A compound of the formula (I) as defined in claim 1,
wherein R is OCH3 and R' is an arylalkyl of the formula
<IMG>
14

or a pharmaceutically acceptable salt, whenever prepared by
the process of claim 7, or by an obvious chemical equivalent
thereof.

Description

:~5030Z
DERIVATIVES OF 2-AMINO-6,7-DIHYDROXYTETRAHYDRO-
NAPHTHALENE (ADTN)
-
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to derivatives of 2-amino-6,7-
dihydroxytetrahydronaphthalene (ADTN) and, more particularly, to
N-arylalkyl derivatives of 2-amino-6,7-dihydroxytetrahydro-
naphthalene (ADTN) characterized by formula (I)
R ~ ~HRI
wherein R is OH, alkyloxy, hydroxyalkyl or acyloxy, and Rl is an
arylalkyl where the aryl group i8 benzyl, sub~tituted benzyl,
phenyl or substituted phenyl and the alkyl group i9 a ~traight
or branched chain alkyl having one to twenty carbon atoms; and
the pharmaceutically acceptable salts thereof.
The term "alkyloxy" as used herein refers to oxygenated
straight or branched chain radicals containing one to ten carbon
atoms, as illustrated by, but not limited to, methoxy, ethoxy,
butoxy and the like.
The term "hydroxyalkyl" as used herein refers to hydroxy-
lated straight or branched chain radicals containing one to ten
carbon atoms, as illustrated by, but not limited to 2-propanol,
3-propanol and the like.
The term "aryl" as used herein refers to benzyl, sub-
stituted benzyl, phenyl and substituted phenyl where the sub-
stituents of benzyl and phenyl include loweralkyl, hydroxy,
alkoxy, acyloxy and the like.
The term "alkyl N refers to straight and branched chain
alkyl radicals having from one to twenty carbon atoms such as
methyl, n-amyl, 3-methyl-2-octyl, 2-nonyl and 2-tetradecyl.
The term "acyloxy" as used herein refers to acetoxy,
propionyloxy, butyryloxy and the like.
The term "pharmaceutically acceptable salteN refers to
acid addltlon salts prepared by reactlng the basic amines of
this invention with an organic or inorganic acld, or by reactlng
the amine salts with the salt of an appropriate acid. Represen-
tative salts which are so formed include the hydrochloride,
hydrobromide, 8ul fate, bisulfate, acetate, oleate, laurate,
~ q~
:~ ,. . . .

115~)30Z
benzoate, phosphate, citrate, maleate, succinate, tartrate and
napsylate salts of the amine~.
The present compounds, i.e., N-arylalkyl derivatives of
2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN), may be pre-
pared by reductive aminations of the protected (ADTN) which may
be prepared by a modification of the preparation reported by
J. G. Cannon et al. (J. Med Chem., 20, p. 1111 (1977)) and as
illustrated in Scheme 1 below.

1~5~)30Z
~ /
~ U~
O O Hl
~ 1' H
U
` I
~ ~
U ~ ,~,0
~ ~ 0/ ~0
O _ O :1 ~
+
Z . ,,~
_I N 0
N ~ q~
U~
~ O"~ 0~ 0~ 0~ -
U~
-- 3 --
1~

~150302
The preparation of the pre~ent derivatives by reductLve
aminations of the protected (ADTN) i8 carried out with the appro-
priate ketones and aldehydes.
Generally, in the preparation of the present derivatives,
there is, initially, a ~olution of 2-amino-6,7-dimethoxy-1,2,3,4-
tetrahydronaphthalene (VI) in dry methanol is treated with the
appropriate ketone or aldehyde and NaCNBH3 under a nitrogen at-
mosphere. The mixture is then stirred for 72 hours whereupon
concentrated HCl is added dropwise until the mixture becomes
acidic. The methanol i8 removed on a rotary evaporator and the
mixture is extracted with ether. The aqueou~ mixture is made
basic to a pH greater than 12.0 with ~olid KOH and the mixture
is extracted with ether. The combined extracts are dried (MgSO4)
and the ~olvent i~ removed on a rotary evaporator. The products
are dissolved in CHC13 and hydrogen chloride is bubbled in the
solvent removed on a rotary evaporator. The products are
crystallized in isopropanol and then isolated.
The compounds of the present invention that can be
prepared by the reductlve aminations of the protected ~ADTN) and
represented by formula (I) include:
R ~ ~R'
(I)
a) 2(3-p-hydroxyphenyl-1-methylpropyl) amino-6,7-dihy-
droxy-1,2,3,4-tetrahydronaphthalene where R is OH
and R' is represented by the formula
2 H2 ~ OH
'~

~1503()2
b) 2-(3-p-hydroxyphenyl-1-methylpropyl) am~no-6,7-
dimethoxy-1,2,3,4-tetrahydronaphthalene where R
is OCH3 and R' is represented by the formula
2CH2 ~ OH
c) 2-diacetoxy-a-methyl dopaminimino~6,7-diacetoxy-1,
2,3,4-tetrahydronaphthalene whexe R is CH3CO- and
R' i~ represented by the formula
CH3 OCCH3
CHCH2~01CICH3
d) 2-a -methyl dopamlnimino-6,7-dihydroxy-1,2,3,4-
tetrahydronaphthalene where R i~ OH and R' is
represented by the formula
OH
CHCH2 ~ ~
e) 2-Dopaminimino-6,7-dihydroxy-1,2,3,4-tetrahydro-
,naphthalene where R is OH and R' is represented
by the formula
OH
2CH2 ~ H
.,~

,, ~ 11 1 ''' '
~150302
(f) 2-dlmethoxy- a-methyl dopaminimino-6,7-dimethoxy-
-1,2,3,4-tetrahydronapHthalene where R i~ OCH3
and R~ i8 represented by the formula
CHCH2 ~ OCH3
The compounds of the present invention exhibit inotropic
activity in warm-blooded animals at a dosage ranging from about
10.0 ug/kg to about 60.0 ug/kg of the body weight daily.
The following examples will further illustrate the
present invention.
EXAMPLE 1
Preparation of 6,7-dimethoxy-2-methoxyimino-1,2,3,4-
tetrah~dronapthalene ~V)
A mixture of 0.56 g (6.7 mmol) of methoxylamine hydro-
chloride and 6.5 ml (6.5 mmol) of a lM aqueous solution of NaOH
was added to 0.689 g t3.34 mmol) of 6~7-dimethoxy-2-tetralone
(IV). While under a nitrogen atmosphere the mixture was warmed
to ca. 100 for lS minutes and then kept at 40 using an infra-
red lamp for 18 hour~. Water wa~ added to the mixture which
was then extracted wibh ether. The combined extracts were dried
~MgS04) and the solvent was removed on a rotary evaporator,
affording 0.700 g ~89.2%) of brown oil: nmr ~CDC13) ~ 2.~-2.9
~m,4H), 3.32 ~S, lH), 3.57 ~S, lH), 3.73 (S, 6H), 3.78 (S, 3H),
6.4-6.6 (m, 2H). The compound was used without further purifica-
tion.
EXAMPLE II
Preparation of 2-amino-6,7-dimethoxy-1,2,3,4-
tetrahvdronaPhthalene (VI)
2-amino-6,7-dlmethoxy-1,2,3,4-tetrahydronapthalene (VI).
A solution of 0.700 g (2.98 mmol) of V in 20 ml of
~0 dry THF was treated with 5.0 ml ~-5.0 mmol) of a lM borane/THF
301ution while under a nitrogen atmosphere. The solution was
heated to reflux for 6 hours and was then quenched with water.
The AqueOUs mlxture was extracted with CHC13, the aomblned
~ki

1150302
extracts were dried and hydrogen chloride was bubbled into the
~olution. The ~olvent wa~ removed on a rotary evaporator,
leavlng 0.775 g of o~f-white qolid. CyrstallLzation from
isopropanol afforded 0.469 g (64.8%) of off-white product:
mp. 83-86C (lit. 85-87C).
EXAMPLE III
Preparation of ADTN Derivatives by
Reductive Amination of Protected ADTN
In the preparation of the derivatives, the general
procedure wa~ as follows: A solution of 1 mmol of VI in 2 ml
of dry methanol was treated with 1 mmol of the appropriate
ketone or aldehyde and 1.05 mmol of NaCNBH3 under a nitrogen
atmo~phere. The mixture was stirred for 72 hours whereupon
concentrated HCl wae added dropwi~e untll the mlxture became
acldlc. The methanol was removed on a rotary evaporator, the
mixture was extracted with ether. The aqueous mixture was
made baRic (pH ~12) with solid KOH and the mixture was extract-
ed with ether. The combined extracts were dried (MgS04) and
the solvent was removed on a rotary evaporator. The products
were dissolved in CHC13, hydrogen ch}oride was bubbled in and
the solvent was removed on a rotary evaporator. Crystalliza-
tion of the products was carried out in isopropanol and the
compounds were isolated. The compounds produced and the date
of their preparation are as follows:
(a) 2-(3-p-hydroxyphenyl-1-methylpropyl) amino-6,7-
dihydroxy -1,2,3,4-tetrahydronaphthalene: The compound was
isolated in 43% yield: mp. 236-237C, nmr (CD30D) ~ 1.3-1.7
(m, 3H), 1.7-3.8 (m, 12H), 6.43 (S, 2H), 6.65 (d, J-= 7Hz, 2H),
7.00 (d, J s 7 Hz, 2H).
Calcd for C20H26N03Br: C, 58.63; H, 6.42; N, 3.43.
Found: C, 58.54: H, 6.39; N, 3.37.
(b) 2-(3-p-hydroxyphenyl-1-methylpropyl) amino-6,7-
dimethoxy-1,2,3,4-tetrahydronaphthalene: The compound was
isolated in 91% yield: mp. 230-232C (d); nmr (CDC13)~ 1.13
(d, J - 6 Hz, 3H), 1.3-2.2 (m, 4H), 2.2-3.2 (m, 8H), 3.73
(S, 6H), 4.82 (S, 2H), 6.47 (m, 2H), 6.75 ~m, 4H, J ~ 8 Hz).
Calcd for C22H30No3cl: C, 67.41; H, 7.46~ N, 3.57.
Found: C, 67.18s H, 7.72; N, 3.46.
(c) 2-diacetoxy- ~-methyl dopaminimlno-6,7-diacetoxy-
1,2,3,4-tetrahydronaphthalene: A solution of 0.200 g of 2-~ -
methyl dopaminimino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene

~15030Z
(d) in 1 ml of trifluoroacetic acld and 1 ml of acetyl chlorlde
was warmed to ca. 80 for 0.5 h. The solvent was evaporated
and crystallization of the solid from ethanol afforded 0.140 g
(50.4%) of product: mp. 192-194CS nmr (CD30D) ~ 1.15
(d, J 3 6 Hz, 3H), 2.10 (S, 12H), 2.6-3.9 (m, lOH), 6.8-6.9
(m, 2H), S .03 (S, 3H).
Calcd for C27H32NO8Br: C, 56.06; H, 5.58; N, 2.42.
Found: C, 56.19; H, 5.40; N, 2.26.
(d) 2-a-methyl dopaminimino-6,7-dihydroxy-1,2,3,4-
tetrahydronaphthalene: The compound was isolated in 57~ yield;
nmr (CD30D) ~ (1.32, d, J - 6 Hz, 3H), 1.5 - 4.Q (m, lOH)
6.4-6.8 (m, SH).
(e) 2-dimethoxy- a-methyl dopaminimino-6,7-dimethoxy-
1,2,3,4-tetrahydronaphthalene: The compound was isolated in 35%
yieldS mp. 224-229C; ir (KBr) 3480, 3020-2650, 1612, 1590 cm 1.
EXANPLE IV
I-notr~e~c, ChrohotroPic and Prèssor/Depressor Activities
The following tests were conducted:
In anesthetlzed, open-chested dogs, instrumented with
a Walton-Brodie strain gauge to measure cardiac contractile
force, a ventricular catheter to measure left ventricular dP/dt
and an aortic catheter to measure diastolic blood pressure and
heart rate. Contractile force and L.V. dP/dt are indices of
cardiac contractility and provide information on the inotropic
state of the heart. The experimental standard drugs are com-
pared by normalizing pressor/depressor and heart rate responses
to a given inotropic effect. Cardioselective inotropic-~agents
will produce minimal diastolic pressure changes for any given
inotropic effect. Likewise, inotropic selective agent4 will
produce minimal heart rate changes for any given inotropic
effect.
In the data summary below, compounds A-F are:
Compound Name
A 2-(3-p-hydroxyphenyl-1-methylpropyl) amino-
6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene
B 2-(3-p-hydroxyphenyl-1-methylpropyl) amino-
6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene
- 8 -

l~SV302
,~ ~
C 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-
naphthalene
D (+)-4-(2(3-p-hydroxyphenyl-1-methylprop~l)
amino) ethyl-1,2-benzenediol (Dobutamine~:
Li 1 ly)
E 4-(2-aminoethyl)-1,2-benzenediol (Dopamine)
F 4-(1-hydroxy-2-((1-methylethyl)-amino)ethyl)-
1,2- benzenediol (Isoproterenol)
Inotropic Potency* (means + SEM)
Compound NCF50 CF1oo dP/dt75 dP/dt150
A 1157.6 333.1 261.8 756.0
B 256.3 197.6 125.4 358.6
C 544.9 + 3.3118.3 + 34.7~0.4 + 3.1 75.6 + 5.3
0 61.4 + 0.2 4.4 ' 0.2 4.0 + 0.6
E 69.1 + 1.01~.6 + 2.7 9.9 + 0.7 23.7 + 3.0
F 60.04 _ 0.010.09 -+ 0.020.04 _ 0.01 0.14 _ 0.05
*ug/l~g required to produce 50 and 100,' increase in cardiac contractile
force (CF) and 75 and 15G% increase in left ventricular dP/dt
(dP/dt).
Cardioselectivit~* (means + SEM)
Compound NCF50 CF1oo dP/dt75 dP/dt150
A 1 -17 -27 -23 -40
B 2 -13 57 37 75
C 531 + 9 61 + 10 30 ~ 5 51 + 5
D 63 + 1 4 + 3 4 + 1 3 + 3
E 6-20 + 6 -12 + 9 -20 + 7 -10 + 8
F 6-6 + 2 -15 + 2 -6 + 2 -16 + 2
*Change in diastolic blood pressure obtained at CF50, CF1oo, dP/dt75,

115030Z
1~ ,,
InotroPic Selectivity* (means _ SEM)
Compound N CF50 CFloo dP/dt75 dP/dt150
A 1 5 14 10 27
2 -1~ 15 ~ 32
C 5-12 + 9 21 + 17 -12 + 10 5 + 8
D 6 3 + 1 17 ~ 5 3 + 1 13 + 2
E 6 5 + 5 12 + 5 5 + 6 13 T 6
F 614 + 2 34 + 3 14 + 1 41 + 5
*Change in heart rate obtained at CF50, CFloo; dP/dt75, dP/dt150
.,
.