Note: Descriptions are shown in the official language in which they were submitted.
7~
S P E C I ~ I C A T I O N
4-AMI~-0 T~TRAHYDRO-2-NAPHT~OIC ACID DERIVATIVES
Technical Field And Disclosure Of Invention
This invention~relates to novel and therapeutical-
ly useful 4-amino-1,2,3,4-tetrahydro-2-naphtho~c acid
derivatives of the formula:
N~R
Xn ~55 ~ COR
and salts thereof, wherein X is halogen atom, i~e~
fluorine, chlorine, bromine or iodine; n is l or 2; R
is hydroxy group, lower alkoxy group, e g. methoxy~
lo ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.
or amino group; and R is hydrogen atom, lower alkanoyl
group, a.g. acetyl, propionyl, isopropionyl~ butyryl,
isobutyryl, etc. or carbamoyl group.
Japanese Patent Publication No. 43-22097 (19683~
Chem. Pharm. Bull.~ 14, 324 (1966) and J. Med. Chem.,
2 , 1105 (1978) make ~lention of co~lpounds ~seful as an
intermediate for the synthesis of a certain ki~d of
analgesics, which compounds are represented by the
formula:
. ~
~3~
7HR
1' ' `
COR
wherein X' is hydrogen atom or methoxy group, Rl is
hydroxy group or lower alkoxy group, and R is
hydrogen or lower alkanoyl group.
The present inventors ha~e synthesi~ed a variety
of the derivatives having gamma-aminobutyric acid
(hereinafter abbreviated as GABA) moiety in their
structure and investigated into their usefullnass.
As a result, this invention has bee~ accomplished on
the basis of the new finding that the compounds of the
10 invention unexpectedly have potent diUretic and blood
pressure lowering actions~ although they show little
protecting effects on the functions in which only the
- central ner~ous system participates such as convuLsions
or fatal convulsions induced by a GABA antagonist such
15 as bicuculline or picrotoxin.
To the contrary, with the aforementioned known
~- ~ea~
compounds these actions are extremely ~e~ or substan-
tially ara not found.
The compounds of ~ormula (I) wherein R i5
20 hydrogen can be produced for example by the following
Methods 1 to 3:
Method 1
.
,
-- 3 --
~ lethod of reducing an o.~ime compound of the
formula:
NOH
~ CORl (II)
- wherein ~ n and Rl are the same as defined above.
Preferably, catalytic reduction is carried out in the
presence of a metallic catalyst such as Rarley nickelg
platinum oxide or palladium carbon in an inert solvent,
preferably a lower alkanol such as methanol~ ethanol or
the like or a lower alkanoic acid such as acetic acid,
if desired in the presence of ammonia for prevention of
possible polymerization~at a t~mperature of room tempe-
ra~ure to 150 C, preferably 50 to 100 C-under normal
- pressure or 50 to 150 atm of hydro~en. Here, hydrogen
or hydrazine may be used as a hydrogen source.
Otherwise, the reduction may be carried out by the u9e
of metallic sodium in liquid ammonia containing methanol
or by the use of both hydrochloric acid or acetic acid
and zinc or tin.
plethod 2
~lethod of subjecting a compound of the formulao
xn~l COEl
3'7
-- 4
to ammonolysis iII water or lower alkanol~ wherein X~ n
and Rl are the same as defined above, and Y is halogen
atom, methylsulfonyloxy group, p-toiyls~lfonyloxy group
or the like of the reactive residue.
Method 3
Method of subjecting a compound of the formula:
o
Xn ~ (IV)
to Leukart reaction~ wherein ~ n and Rl are the same
as defined above~ That is, a compound of formula (IV)
and urea, ammonium formate or the like undergo fusion
reaction in the presence of formic acid at 150 - 200 C
and the resulting product is hydrolyzed to give the
intended compounds~
The compounds of formula (I) wharein R is hydrogen
are allowed to react with a reactive deri~ative of lower
alkanic acid such as acid halide, acid anhydride or the
like to give the compounds of ~ormula (I) wherein R i5
lower alkanoyl group. They are allowed to react with
pot~ssium cyanate or sodium cyanate in an a~ueous lower
alkanol to giv~ the compounds of formula ~I) wherein R
is carbamoyl.
The compoun~ of formula ~I) wherein Rl is hydroxy
group are allowed to e~terify with a lower alkanol in
the presence of mineral acid such as hydrochloric acid
. ,i
~3~
5 --
or sUlfu~ic acid to give the compounds of formula (I)
wherein R is lower aLkoxy. The ester compounds thus
obtained or their free carboxylic acids are allowed to
react with ammonia to give the compounds of for~ula (I)
wherein R is amino.
The N-lower alkanoyl compounds and the estex
compounds or the amido compounds each of *ormula (I)
are subjected to hydrolysis to give, reversely, the
amino compounds and the free carboxylic acids of
formula (~), respecti~ely.
The compounds of formula (I) of this in~ention
produced in this way are present in the form of dia-
stereoisomers, with their tetralin ring containing
asymmetric carbon atoms at the 2- and 4-positions.
When the mixture of the diastereoisomers is fused
under heatirg at 60 to 200 C~ preferably 100 to 140 ~C~
the 2,4-cis isomer (simply referred to as "cis-isomer")
causes ring closure to form 1,4-me~hano-2-benzazepin-3
one derivative of the formula :
Xn ~,,`~L (v)
wherein X and n are the same as above.
Since the compound of formula (V) is neutral, the 2,4-
trans isomer (simply referred to as "trans-isomer")
~an be isolated by the extraction with acid or alkali
. . .
~L2 3~ d
The compounds of ~ormula (Y) can be converted, upon
hydrolysis by acid or alkali, into the cis-isomer of
amino-acid.
The cis-isomer and the trans-isomer thus separated
are respective ra^emates~ and the racemates can be
separated into respective optically active isomers,
for example by optically resolving the ester compounds
with an optically active cabroxylic acid~ e.g. tartaric
acid, dibenzoyltartaric acid, camphorsulfonic acid,
diacetyltartaric acid, phenylsuccinic acid, mandelic
acid, malic acid, lactic acid, etc. or the amino-
protected carboxylic acid compound with an optically
active base (e.g. natural alkaloid such as brucine,
quinine, cinchonidine, etc., optically active a-phenethyl-
amine, a-amino acid ester, etc.).
Where a carboxylic acid compound of formula ~II),
(III) or (IV) optically active at the 2-position is used,
respective optical isomers can be obtained only through
the foregoing proced~re of separation into the cis-isomer
and the trans-isomer.
The compounds (I) of the invention may be~ if
desired, treated with acid (e.g. inorganic acid such as
hydrochloric acid, sulfuric acid, phosphoric acid, nitric
acid, or organic acid such as acetic acid3 oxalic acid,
maleic acid, fumaric acid, lactic acid, citric acid7 etc.)
or with inorganic base (e.g. sodium hydroxide, so~ium
bicarbonate, potassium hydroxide~ calciunl hydroxide,
. "
37
-- 7 --
etc.) to form their acid or base adducts.
As ~ill be apparent from the description above~
the compounds (I) of this invention include all of the
diastereoisomers, cis-isomers, transisomers and optically
active isomers and salts of them.
The diuretic activity of the compounds ~I~ accordi~g
to this invention will be shown hereinbelow. The trans-
i(somers have more potent activity than the cis-isomers.
Test Method
~ccording to the method of Lipschitz et al (W. L.
Lipschit~, ~. Haddian, A. Kerpsser : J. Pharmacol. Exp.
Therap., 7~, 97 (1943)), groups each of 6 male ~istar
rats (weighing 180 to 220 g) were used. In precondi-
tioning, they were not fed witll any food for 18 hours
15 and further with any food and water for 3 hours.
Test group o* the rats was orally administered with
solution or suspension of the test compounds of this
invention in isotonic saline at a dosagè of 25 m~/kg
and was placed in metabolism cagss, and urine of them
20 was collected in the course of 6 hours.
The diuretic activity is calculated by the following
equation in terms of increment percentaga of the test
group to control group:
jAverage urine amount~ ~Aver~ge urine amount~
'f test group / ~of control group
__ _ -- _ x 1 0 0
(A~erage urine amount of control group)
- = increment percentage
:~37~
-- 8 --
Results
,. ~
Compound Increment
(Example No.) (~)
l(a) 737
. 2 410
3 . ~00
~0
. 7 362
14 ~25
16 441
17 436
!1~ 354
,_ 19 241 _ I
Under the same test conditions above, 4-amino-1,2,
3,4-tetrahydro-2-naphthoic acid hydrochloride, methyl
trans-4-amino-1,2,3,4-tetrahydro-2-naphthoate hydro-
chloride, ethyl trans-4-amino-6,7-dimethoxy-1~2~3,4-
tetrahydro-2-napllthoate hydrochloride dis not sho-~ any
results significantly different from the control group.
With G~BA per se, the diuretic activity could not be
found even at a high dosage of 1000 mg~kg.
- Blood pressure lowering action due to the compound
of Example la ~lich is typical of this invention is
shown in the folLowing:
.Test ~lethod
(1) Experiment with Spontaneous ~Iypertensive Rats (SHR)
Spontaneous hypertensive male rats (SHR) of 28 to
30 weeks age were used for the experiment and blood
press~re was measured according to tail compressi~g
methvd~ These rats were preliminarily divided into
~3~4~;~
control group and test group (six rats/one group) so
that both the groups have the same mean blood pressure.
A suspension of the test compound in 0,5 ~ methyl~
cellulose solution was administered orally to ths test
group at a dosage of 2 m~/kg and after 1~ 5, 7 and 9
hours blood pressure was measured, Dosage required for
lowering the blood pressure value before the administ-
ration by 20 mm Hg was determined.
(2) Experiment with DOCA ~ypertensive Rats
10 According to the method of Willard, male Wistar
rats o~ 8 weeks age were made DOC~ ~deoxycorticoste-
rone acetate) hypertensive rats by operation and among
them, rats whose blood pressure values a~ter 6 weeks
had reached upward of 150 mm Hg were used as test
animal,
The experiment was carried out in the ~ame
conditions as thoAe of SHR above.
Results
SHR DOCA
ED20 (mg/kg, p.o.)
6~5
In both the Experiments, the blood pressure
lowering action was gra~ually and slowly exhibited and
its maximum effect was exerted 7 to 9 hour after the
administration of the test compound.
The compounds of formula (I) of this invention
can be administered orally or parenterally as pharma-
ceutical composition by the co-rlbination with a suitable,
conventional pharmac~utically acceptable carrierO
~ 10 - ~37~
The pharmaceutical composition may be the form of
tablets, capsules, granules, powders, injectable
solutions or the like.
The daily dose of the compounds (I) for human
adults ranges usually f rom about 10 mg to about 500 ~g
f or oral administration in single dose or multiple
doses~ b-lt may vary depending on the age~ weight and/
or conditions of disease to be treated and response to
the medication.
The in~ention will be hereinafter described more
concretely by the following examples; but they are not
to be construed as limiting the invention.
Example 1
~à) A solution of 265 g of ethyl 7,8-dichloro-4-
hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate (m.p. 133
- 135 C) i~ 1 ~ of ethanol is charged into 3~-autoclave
and 130 m~ of 12 ~ ethanolic ammonia and 27 g of Raney
nickel are added thereto to reduce with hydrogen under
pressure of 65 atm at an inner temperature of 75 C.
The hydrogen upta~e is completed in about 3 hours, and
then the whole is allowed to cool. The catalyst i~
filtered o~f and the filtrate is concentrated. Ethyl
acetate is added to the residue and cooled. Crystals
are deposited and collected by filtration to give 75 g
of 6,7-dichloro-1,4-methano-2,3,4,5-tetrahydro-1}~-2
benzazepin-3-one, m.p. 1~6 - 200 C, which is ring-
closure product of t~e foregoing cis-isomer. The
filtrate solution is washed with water once, dried and
concentrated under heating on oil-bath at 130 C for 3
hours. After cooling, ethyl acetate is added and the
deposited crystals are collected by filtration to
recover an additional 14 g of the ring-closure isomer.
The filtrate solution is diluted with 1 ~ of ethyl
acetate and 1~0 m~ of 20 ~ a~ueous hydrochloric acid
is added with stirring, whereupon white needles
separate out. The crystals are collected by suction
filtration to give 76 g of crude ethyl trans-4-amino-
7,8-dichloro-1~2,3,4-tetrahydro-2-naphthoate hydro-
chloride. The aqueous layer of the filtrate`solution
is separated, the organic layer is extracted with
water several times and the aqueous layers combined
are saturated with sodium chloride. -An additional 23
g of crystalline product is recovered. The product,
when recrystallized from ethanol, sho~s a m. p. of 249
- 251 C (decomposition).
(b) Ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetra-
hydro-2~naphthoate, when opticall~ resolved by di- -
benzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid,
affords optically activo dextro- and lovo-iSomerS 9
respectivelyO
Hydrochloride of dextro-isomer
Z5 m.p. 209 - 213 C ~a3D = ~ 38.~ (1 ,o~ methanol)
~Iydrochloride of levo-i~omer
m.p. 2~8 - 213 C ~a ~D = ~ 37 . 4 ( 1 ~, methanol)
~ , . .
.
~74~2
- 12 _
Example 2
A suspension of 29 g of 6,7-dichloro-1,4-methano-
2,3,4,5-tetrahydro-lH-2-benzazepin-3-one in 300 m~ o~
20 ~ hydrochloric acid is hydroly~ed by heating with
stirring for 40 hours. After cooling~ crystals are
precipitated and collected by filtration to give 32 g
of crude cis-4-amino-7,8-dichloro-1,2,3,4-tetrahydro-
2-naphthoic acid hydrochloride. To the crude product
is added 500 m~ of ethanol, and dry hydrochloric acid
gas is introduced gently with stirring under reflu~
for 8 hours. After cooling, crystals are deposited~
separated by filtration and recrystallized from 95 ~
ethanol to give 2~ g of ethyl cis-4-amino-7,8-dichloro-
1,2,3,4-tetrahydro-2-napllthoate hydrochl~ride having
a m. p. of 239 - 245 C (decon~position) a~ white
needles.
~xample 3
A solution of 60 g of methyL 6,7-dichloro-4-
~ hydroxyimino-l,Z,3,4-tetrahydro-2-naphthoate in 300 m~
of methanol and 300 m~ of 10 ~ ammonia-methanol is
hydrogenated at 60 atm of hydro~en in the presence of
Reney nickel. Ile~ting is conducted at 70 ~ 80 C with
stirring for 7 hours. After cooling, the catalyst is
filtered off and the solven~ is distilled off. Acetone
is added to t~le semi~solid residue and cooled. The
precipitated crystals are collected by filtration to
give 17 g of 7,8-dichloro-1~4-lnethallo-~,3,4,5-tetra-
~: .
~3~4~
- 13 -
hydro~ 2-benzaZepin-3-one~ m.p. 215 - 217 C.
The mother liquor is concentrated~ heated at 110 -
120 C for 2 hours and cooled followed by crystalliza-
tion from acetone. Upon filtration, additional 3 g of
ring-closure product is obtained. The mother liquor
is concentrated, and ethyl acetate and 100 m~ of 10
aqueous hydrochloric acid are added and stirred well.
White needles are deposited and collected by filtra-
tion to gi~e 10 g of methyl trans-4-amino-6,7-dichloro-
1,2,3,4-tetrahydro-2-naphthoate hydrochloride in the
crystalline form. From the mother liquor~ a further
3 g of the product i9 recovered. The product, upon
recrystallization from methanol, gives white needles
having a ~I.p. of 262 - 263 C (decompositio~).
Example 4
Into a solution of 3. G g of methyl trans-4-amino-
6,7-dichloro-1,~,3,4-tetrahydro-2-naphthoate hyd~o-
chloride in 50 m~ of methanol and 15 ~ o~ 28 ~ aqueous
ammonia, ammonia gas is blew at 30 - 40 C for 8 hours.
The solvent is distilled off and water is added. The
precipitated crystals are separated by filtration and
dissolved in methanol and to -the solution i9 added
methanolic hydrochloric acid. Crystals are deposited,
separated by suction filtration and recrystallized
from methanol to give 1.6 g of trans-4-amino-6,7-
dichloro-1,2,3,4-tetrahydro-2-naphthalene carboxamlde
hydrochloride hav~ng a In . p . of above 280 C.
3~ 2
- 14 ~
Example 5
To a solution of 1.5 g of methyl trans-4-amino-
6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate in 20 m~
of pyridine is added 10 m~ of acetic anhydride under
ice-cooling, and the reactant is allowed to stand
overnight. The reaction solution is concentrated and
to the resulting residue is added water. Deposited
crystals are separated by suction filtration and
recrystallized from ethanol to gi~e 1.5 g of methyl
trans-4-acetamide-6,7-dichloro-1~2,3,4-tetrahydro-2-
naphthoate~ m.p. 182 - 184 CC.
Example 6
Into 100 m~ of 50 ~ methanol~ 3.1 g of methyl
trans-4-6,7-dichloro-1,2,3,4-tetrahydro-Z-naphthoate
hydrochloride is dissolved under warming~ and to the
solution is added dropwise a solution of l.Z g of
potassium cyanate in 10 m~ o~ water. After the drop~
wise addition~ the system is made to react at ~0 C
for 2 hours and cooled with ice. Deposite~ crystals
are separated by filtration, washed with water, and
recrystallized from a ~lixture of methanol and acetone
to give 1.7 e of methyl trans-~7-dichloro-4-ureido-
1,2,3,4-tetrahydro-2-naphthoate h~ving a ~.p~ of 227 -
229 C.
The fo110wing compounds are produced in a similar
manner to E~amples 1 to 6.
7. ~lethyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-2-
~2379c~
- 15
naphthoate hydrochloride, m.p 229 - 231 C
8. Methyl cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-
naphthoate hydrochloride 1/2 hydrate, m.p. 218 -
219 C (decomposition)
9. Cis-4-amino-6-chloro-1,2,3,4-tetrahydro-2-naphthoic
acid hydrochloride, m.p. 269 - 271 C (deco~position)
10. Ethyl trans-4-amino-6-chloro-1,2,3,4-tetrahydro-
2-naphtho~te hydrochloride~ m.p. 199 - 200 C
11. Trans-4-amino-6-chloro-1,2~3~4-tetrahydro-2-
naphthoic acid hydrochloride, m.p~ 283 - 285 C
12. Methyl trans-4-amino-7-chloro-1,2,3,4-tetrahydro-
2-naphthoate hydrochloride~ m.p. 215 - 218 C
13. Cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-
naphthoic acid hydrochloride~ m.p. 2j6 - 257 C
15 14. Trans-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-2-
naphthoic acid llydrochloride~ m.p. 283 285 C
15. ~thyl cis-4-amino-6,7-dichloro-1,2,3,4-tetrahydro-
2-naphthoate hydrochloride, m.p. 222 - 223 C
16. Ethyl trans-4-amino-6,7-dichloro-1~2~3,4-tetra-
20 hydro-2-na~htho~te hydrochloride, m.p. 234 - 236 C
17. Methyl trans-4-amino-7,8-dichloro-1,2,3~4-tetra-
hydro-2-naphthoate hydrochloride, m.p. 247 - 250 C
(decomposition~
18. ~lethyl cis-4-amino-7 9 8-dichloro-1,2,3~4-tetrahydro-
25 2-naphthoate hydrochloride~ m.p 240 - 242 C
(decomposition)
19. Bu~yl trans-4-amino-7,8-dichloro-1,2,314-tetrahydro-
~3791~2
- 16 _
2-naphthoate hydrochloride, m.p. 163 - 167 C
20. Ethyl trans-4-amino-6-fluoro-1,2,3,4-tetrahydro-
2-naphthoate hydrochloride, m.p. 211 - 213 C
21. Ethyl trans-4-amino-6-bromo-1~2,3~4-tetrahydro-
2-naphthoate
The invention has been fully e~plained in the
description and examples given above, but any ~aria-
tions and modifications of it may be made without
departing from the spirit and scope of the invention.
