Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
15632 Y
1 BACKGROUND OF THB INVENTION
3 Diuretics such as the thiazides and pyrazines are
4 useful as antihypertensive agents. However, these diuretics
tend to increase circulating plasma renin levels. This
6 increase in renin may be undesirable since it acts to reduce
7 the antihypertensive eEfect of the diuretic.
8 ~-adrenergic blocking agents are another class
9 of drugs which are effective in long term treatment of
hypertension. Propranalol, a ~-adrenergic blocking agent,
11 has been found to inhibit renal renin secretion in man and
12 in animals [New ~ngland Journal of Medicine 287, 1209-1213
13 tl972)J Prindolol, another ~-adrenergic blocking agent, has
14 been found ~o have antihypertensive effect when administered ~ -
alone and in combination with a thiazide diuretic [The
16 Medical Journal of ~ustralia 2, 309-312, (1972)]. The effect ~;
17 on hypertension of a combination of large doses of 4 differ-
18 ent ~-blocking agents (including a substituted 1,2,5-
19 thiadiazole) with a thiazide diuretic, has also been reported
(Postgraduate ~edical Journal 50, 253-259, May 1974).
21 U.S. 3,832,470, issued August 27, 1974, discloses a mixture
22 o~f a vasodilator and a ~-adrenergic blocking agent - South
23 African Patent 723,922 discloses a composition containing a
24 ~-adrenergic blocking agent, a vasodilator and a diuretic.
It has been discovered that administration of a
26 particular combination of a substituted 1,2,5 thladiazole
27 ~-adrenergic blocking agent and said diuretic to a hyper-
28 tensive animal (1) enhances the antihypertensive activity of
2g the diuretic and (2j reduces the severity of potassium loss
.. : .. :,: : ~
` _ _ 15632 IA
1 due to the diureticO
2 SUM~RY OF THE INVENTION
,
3 Composition comprising (lj a substituted 1,2,5
4 thiadiazole ~-blocking agent and (2) a thiazide and/or
pyrazine diuretic; and a method of treating a hypertensive
6 animal.
7 DESCRIPTION OF THE PREFERRED EMBODIMEN~S
8 An embodiment of the present invention are compo-
9 sitions containing:
A.) ~-blocking agents selected from:
11 (i) compounds having the ~ormula
12 OH
' H
13 R ~ O-CH2-CH-CH2 ~R
14 N ~N - ;~
16 wherein R is selected from hydrogen, halogen,
17 C3-C6 cycloalkyl, Cl-C4 alkyl, C2-C4 alkenyl,
18 phenyl, substituted phenyl, Cl-C5 alkoxy, hetero-
19 cycle, Cl-C4 alkylcarbamoyl, carbamoyl and ~ -
R -L-R - wherein R is selected from Cl-C3 alkyl,
21 phenyl and substituted phenyl, L is selected from
22 oxygen and sulfur and R is methyl or ethyl; and
23 R' is selected from Cl-C10 alkyl, C2-C6 alkynyl,
24 C2-C4 alkenyl, C3-C6 cycloalkyl, Cl-C4 alkylthio, ~
and heterocycle. ;
:.,,,,, :.. ..
26 tii) non-toxic pharmaceutically acceptable salts of
27 (i); and
28 (iii) mixtures containing (i) and (ii); and
29 B.) diuretic selected from: ,-
.:, ~,, .
~; 30 a.) thiazides and their pharmaceutically acceptable ~ ~ -
,"
\~ 31 salts
`~ - 2 - ;
, .,, . ~ , .
15632 IA
~f~
1 b.) amiloride and its pharmaceutically acceptable
2 salts and
3 c.) mixtures of (a) and (b).
4 The ~-blocking agents of the Formula I include
the individual optical isomers as well as the racemate. More
6 preferred Formula I compounds and salts are those wherein R
7 is hydrogen; halogen such as chlorine, bromine, fluorine
8 and the like; alkyl such as methyl, ethyl, propyl, t-butyl
9 and the like; alkenyl such as vinyl, allyl, methallyl and
the like: R2-L-R3- radical wherein R2 is alkyl such as ;
11 methyl, ethyl~ propyl; phenyl or substituted phenyl wherein
12 the substituents are selected from the group consisting of
13 halogen such as chlorine, bromine, fluorine and the like,
14 hydroxy, alkyl such as methyl, ethyl, propyl and the like, -
or alkoxy such as methoxy, ethoxy, propoxy and the like; L ~ ~-
16 is oxygen or sulfur and R is alkyl such as methyl and ethyl;
17 carbamoyl; alkylcarbamoyl wherein the alkyl moiety is
18 represented by methyl, ethyl, isopropyl, butyl and the like;
19 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclobexyl and the like; alkoxy such as methoxy, ethoxy,
21 propoxy, isopropoxy, butoxy, pentoxy and the like; phenyl
22 ~ or substituted phenyl wherein the substituen~s are selected
23 from the group consisting of one or more halogen such as
24 ~ chlorine, fluorine and the like, alkyl having from 1 to 3 -~
25~ ~carbons, and alkoxy having from 1 to 3 carbons, aralkyl
26 ~ wherein the alkyl moiety has from 1 to 4 carbons and the
27 aryl moiety can be unsubstituted or substituted with one or
28 more halogen such as chlorine, fluorine, bromine and the ~ -
29 like, alkyl having from 1 to 3 carbons, or alkoxy having ~ -
': ',''' "
'~ ~ 3 ~
: .:
- - 15632 IA
~3~
1 from 1 to 3 carbons; and a heterocyclic moiety such as
2 aziridinyl, azetidinyl, pyrrolidyl, p.iperidyl, hexahydro-
3 azepineo, morpholino, piperidino, thiazolidinyl, p-thiazinyl,
4 piperazinyl, thienyl, ~uryl and the like; R' is alkyl having
fr~m lupto about 10 carbons, pre~erably 1 to 6 carbons and
6 more preferably from 3 to 6 carbons such as isopropyl,
7 tert-butyl, 2,2-dimethylpropyl, hexyl and the like; alkenyl
8 such as allyl, vinyl, methalkyl and the like; or alkynyl
9 groups having from 2 to 6 carbons, such as -C~CH, propynyl,
butynyl, propargyl, hexynyl and the like;substituted alkyl :
11 wherein the substituents are selected from the group con-
12 sisting of hydroxy and halogen such as chl~rine, bromine
13 and the like; carboxy; alkoxy; alkylthio wherein the alkyl
14 moiety contains from 1 to 4 carbons; cycloalkyl such as . .
cyclopropyl, cyclohexyl, cyclopentyl and the like; and a
16 heterocyclic group such as pyrrolidinyl, piperazinyl, ~ - :
17 morpholino. thiazolidinyl, thienyl, furyl, thiazinyl and the : . :
18 like.
19 Representative Formula I compounds and their salts
which are useful in this invention are: . . .
21 3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5- .
22 thiadiazole :
23 (+)-3-chloro-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5- ; '
24 ~ ~thiadiazole hydrochloride -.
(-)-3-chloro-4-(3-methylamino-2~hydroxypropoxy)-1,2,5-
26 thiadiazole hydrochloride ..
27 3-bromo-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
, , - ~ .:
23 thiadiazole
29 (~)-3-bromo-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5- - .
thiadiazole hydrocyloride ~:;
, .'~,~'-
: _ 4 _ :
.,;, , .
15632 IA
l r~
3-bromo-4-(3-t butylamino-2-hydroxypropoxy)-1,2,5-
2 thiadiazole hydrochloride
3 3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-hydroxy-
4 propoxy)-1,2,5-thiadiazole
3 morpholino-4-(3-n-hexylamino-2-hydroxypropoxy)-1,2,5-
6 thiadiazole hydrogen maleate
7 (+)-3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
3 thiadiazole hydrogen maleate
9 (-)-3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
thiadiazole hydrogen maleate
11 3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
12 thiadiazole hydrochloride
13 3-N-t-butylcarbamoyl~4-(3-t-butylamino-2-hydroxypropoxy)-
14 1,2,5-thiadiazole -:
(+)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2 hydroxypropoxy)-
16 1,2,5-thiadiazole hydrochloride .
17 (-)-3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)~
18 1,2,5-thiadiazole hydrochloride :~
19 3-N-isopropylcarbamoyl-4-(3-isopropylamino-2-hydroxypropoxy)- . -
1,2,5-thiadiazole
21 (+?-3-N-isopropylcarbamoyl-4-(3-isopropylamino~2-hydroxy-
22 propoxy)-1,2,5-thiadiazole hydrochloride
23 (-)-3-N isopropylcarbamoyl-4-(3-isopropylamino-2-hydroxy-
24 ~propoxy)-1,2,5-thiadiazole hydrochloride
3-morpholino-4-~3-t~butylamino-2-hydroxypropoxy)-1,2,5-
26 : ~ thiadiazole benzoate
; 27 3-chloro-4-(3-isopropylami~o-2-hydroxypropoxy)-1,2,5- ~
~:28 thiadiazole : -
~; 3-bromo-4-(3-isopropylamino-2-hydroxypropoxy~-1,2,5- : :
31 thiadiazole ~
~ : .
. '~ '
: -
. . :, :. ": . .:: . . . . . . .. .. . .
15632Y
(t)-3-chloro-4-(3-isopropylamino-2-hydroxypropoxy)-1,2,5-
thiadiazoie
3-methyl-4-(3-n-butylamino-2-hydroxypropoxy)-1,2,5- .-
thiadiazole
3-ethoxy-4-(3-sec-butylamino-2-hydroxypropoxy)-1,2,5-
thiadiazole
and the like.
Especially preferred Formula I compounds are those in
which R is halogen, alkyl, alkoxy, phenyl, benzyl, morpholino,
piperazîno and piperidino and R' is alkyl, preferably C3-C6. A
most preferred Formula I compound is one where R is morphol,no,
R' is t-butyl, and more particularly the (-)isomer and pharma-
! ceutically acceptable salts thereof, especially the hydrogen
', maleate.
The pharmaceutically acceptable salts of Formula Icompounds are included as useful compounds in the present
invention. Any non-toxic, pharmaceutically acceptable salt of ;
Formula I compounds may be used. Representative examples of
these pharmaceutically acceptable salts are the hydrohalides,
~1l 20 e.g., hydrochlorides, hydrobromides, hydroiodides; the phos- ~-
1 phates, sulfates, oxalates, lactates, malates, maleates, -
,,,, " . ..
formates, acetates, succinates, tartrates, salicylates, - -~
~1 citrates, phenylacetates, benzoates, p-toluenesulfonates and
:'f
other salts su~h as those that provide relatively insoluble
products that afford a slow release of the active material, for
' '1 ' ' ~ :
`~f: example, a 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) and the
like,
The ~-blocking agents of Formula I and methods for
their preparation are described in U.S. 3,655,663, U.S.
3,729,469, U.S. 3,657,237, U.S. 3,718,647 and U.S. 3,812,182.
1 ,
- 6 -
, ,,, . , , - : ~ ;,
:. ,, .. ~. , :
15632Y
The diuretics used in the present invention include
(a) thiazides and their non-toxic pharmaceutically acceptable
salts (b) pyrazine and its non-toxic pharmaceutically accepta-
ble salts, and (c) mixtures of (a) and (b).
The thiazides comprise a 1,2,4 benzothiazine class of
compounds. They include compounds such as flumethiazide, benz-
thiazide, cyclopenthiazide, cyclothiazide, trichloromethiazide,
benzhydroflumethiazide, methylcyclothiazide, polythiazide,
thiabutazide, and the like and their non-toxic, pharmaceuti-
cally acceptable salts.
Preferred thiazides are those having the follo~ing
formulae:
... .. .
H2Ro25~ ? 2 2 ? ~
¦ and their pharmaceutically acceptable salts.
I The Formula II compound is chlorothiazide and the
Formula iII compound is hydrochlorothiazide. Salts of the
Formula Il and I I I compounds include those of alkali metals,
especially sodium. -
The thiazide diuretics, their use and methods for ;-
20~ their preparation are described in U.S. 29809,184, U.S.
: 3,025,2g2, U.S. 2,337,1699 U.S. 3,164,588 and U.S. 3,043,840.
i , . . . . . . ..
. .
~,, ~ : . .
~ "
:..................................................................... . .
~ ' :
`~ _ 7 _ ~ -
~ :'.',:
. , . ... . . ,.. ,.. , ,.. ,, . . , . , , ~ . .
15632 IA
.
~lD'~
1 The pyrazine diuretic has the formula
3 o
~ ll H ll
4 Cl ~ C-~-C-NH2
6 H2N ~ N ~ N~2
IV
7 The Formula IV compound is amiloride. The -
compound and its preparation are clescribed in Belgian
9 Patent 639,386. Amiloride is also useful as a non-toxic
pharmaceutically acceptable salt of inorganic acid, e.g.,
11 hydrohalo acid, phosphorus acid, suluric acid and the
12 like, and organic a¢id e.g., citric, tartaric, maleic,
13 sulfo~ic, phosphonic, malic; acetic, and the likeO A :
14 most preferred salt o amiloride is the hydrochloride~ -~
. . ,
dihydrate.
16 ~ Combinations containlng thiazide and pyrà~ine ;i
17 diure~ics ara also useful. Thé weight~ratios~of the ;
18 diuretics in these combinations can be varied. Generally .
19 weight ratios of diazine: thiazide from 1:1 to 1:10 .
~20~ are useful and a weight ratio~of~l:10 is~particularly -
21~ useful. In a pY~erred combination the diazine is ~ .
22~ amiloride hydrochlcr1de~(cr its~d~ihydrate) and the thiazide~ ~
23~ ~ rcchlorothia7lde - and~in;a most preferreù comblnation ~ -
4~ the~wèight~ratic of said amlloride said hydrcchlorothiaziùe~
25~ i5~1:10. These combinations are dlsclosed in U.5.~3,781,430.
26~ The compositions of the~present in~ention are
27~ administered in dose quantities of ~-adrenergic blocking ;~
2~ agent: diuretic in weight ratio of from about 1:15 to
29~ about~24~:1, pref rably about 1:12 to about 4:1 and more
30~ preersbly about 1:1 to about 4:1 and most preferably about ~ ;
8 -
~ 15632 IA
1 1:1 to about 1:10; a 1:125 1:5 ratio range is especially
2 preferred. The amount of ~-adrenergic blocking agent and
3 diuretic administered is varied. Generally, the ~-blocking
4 agent is administered in quantities ranging from 1-12 mg.
per kilogram of animal body weight while the diuretic is
6 administered in quantities ranging from about 0~5-15 mg.
7 per kilogram of animal body weight. A preferable administra-
8 tion quantity range for the ~-blocking agent is about 1-8
9 mg./kg/day and for the diuretic about 1-10 mg./kg./day.
The present compositions are useful for treating hyper
; 11 tension in animals (patients) to effect a decrease in blood
12 pressure. These compositions are administered in varying
13 dosages and for various periods of time as the treatment
14 requires.
It is to be understood, however, that the specific ~ -
i 16 dose level for any particular patient will depend upon a
17 variety of factors including the activity of the specific
18 compound employed, the age, body weight, general health,
19 sex, diet, time of administration, rate of excretion,
20 drug combination and the severity of the disease under-
~I . .
21 going therapy.
22 The compositions of the present invention may be
23 administered in any acceptable and recognized manner.
24 They are preferably administered orally in an acceptable
.~ ~ .. .
~ 25 dosage form. The compounds may be combined in a capsule.
i 26 The compositions may be provided in the form of tablets,;
27 said tablets may include other ingredients which are ordinar-
28 ily used to facilitate tablet formation, palatability, etc. ;~
29 The compositions may likewise be dissolved or dispersed in
`~ 30 a pharmaceutically acceptable carrier for administration
~ 31 ln a fluid form.
' ~:
_ g _
. ; .
. .. . . . .. . . . . . . . . . . .
.. ,.. : ~ . . - ~ ........................................ . .
1563~ IA
l The following examples illustrate but do not
2 limit the preparation o the various compositions of the
3 invention.
TABLE I
7 Ingredients Ex.l Ex.2 Ex.3 Ex.4 Ex.5 Ex.6
3-morpholino-4-~3-t- 10 10 10 5 5 5
9 butylamino-2-hydroxy-
propoxy)-1,2,5-thia-
diazole
. :-:,
11 Hydrochlorothiazlde 10 25 50 10 25 50 ~ -
12 Starch USP Corn 124 114 109 99 8~ 80
13 Microcrystalline134 129 109 ~5 85 54
Cellulose ~ ~;
14 Magnesium Stearate2 2 2
TOTAL (mg./tablet)280 280 280 200 200 200 ;~
l~ 3-morpholino-4-(3-t-butylamino-~-hydroxypropoxy)-1,2,5-thia-
17 diazole, hydrochlorothiazide, part of the corn starch and
18 mLcrocrystalline cellulose are mixed together, milled and
l9 granulated with part of the corn starch as starch paste.
The granulated mass is wet-sized, dried, dry milled, and
21 blended with the remain1ng corn starch and microcrystalline
22 cellulose, lubricated with magnesium stearate, and compressed
23 in;to tablets.
24~ Equivalent amounts of chlorothiazide or its sodium
;25 salt maybe su~stituted for the hydrochlorothiazide in the
26~ Table I formulation to prepare corresponding compositions.
27 ~ When other ~-adrenergic blocking agents such as
28 3-chloxo-4-(3~t-butylamino-2-hydroxypropoxy)-1,2,5-thia-
29 diazole, 3-(4-hydroxypiperidino)-4-(3-t-butylamino-2-
-- 10 -- '''
".'~':
.: . . :
~, . . .. . . .
15632 IA
1 hydroxypropoxy)-1,2,5-thladiazole, 3-piperazino-4-(3-t-
2 butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, 3-pipexi-
3 dino-4-(3-t~butylamino-2-hydroxypropoxy)-1,2,5-thiadia~ole,
4 3-N-isopropylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)-
1,2,5-thiadiazole, 3-N-isopropylcarbamoyl-4-(3-isopropyl-
6 amino-2-hydroxypropoxy)-1,2,5-thiadiazole, 3-methyl-4-(3-
7 t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, 3-
8 ethoxy-4-(3-t-butylamino-2-hydroxypropo~y)-1,2,5-thi~-
9 diazole or repxesentative salt thereof i5 substltuted ~or
3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
11 thiadiazole, there is obtained the corresponding com-
12 position.
13 TABLE II
14
,:
Ingredients Ex.7 Ex.8Ex.9Ex.10Ex.llEx.12
, ~
16 3-morpholino-4- 10 10 10 5 5 5
(3-t-butylamino-2-
17 hydroxypropoxy)-l,
2,5-thiadiazole
19 hydrogen maleate
19 Hydrochlorothiazide10 25 50 10 25 50
Starch USP Corn124114 109 99 84 80
21 Microcrystalline 134 129 109 85 85 54
Cellulose
22 Magnesium Stearate 2 2 2 1 1 1
23 TOTAh (mg./tablet)280 280 280 200 200 200
24 ~ 3-morpholino~4-(3-t-butylamino-2-hydroxypropoxy)-1,2~5-thia- `;
25 diazole hydrogen maleatedhydrochlorothiazide, part of the ~ ~
26 corn starch and microcrystalline cellulose axe mixed together, ~ -
27 milled and granulated with part of the corn starch as starch
28 paste. The granulated mass is wet-sized, dried, dry milled,
29 and blended with the remaining corn starch and microcrystal-
line cellulose, lubricated with magnesium stearate, and
, ~ :
-- 11 -- :;. , .,: ,.,
. ~ ....
,.' ' ' ' ' ' . ',
15632 IA
1 compressed into tablets.
2 Corresponding composi~ions are prepared when an
3 equivalent amount of amiloride or its hydrochloride
4 dihydrate is substituted for hydrochlorothiazide in Table
I l a
6 When othar optically active ~-adrenergic blocking
7 agents such as (-)-3-chloro-4-(3-t-butylamino-2-hydroxy-
propoxy)-1,2,5-thiadiazole hydrochloride, (-)-3-(4-hydroxy-
9 piperidino)-4-(3-t-hutylamino-2-hydroxypropoxy)-1,2,5-thia- : .
diazole hydrochloride, (-)-3-piperidino)-4-(3-t-butylamino- : .
11 2-hydroxypropoxy)-1,2,5-thiadiazole hydrogen maleate, (-)- ~ -
12 3-N-t-butylcarbamoyl-4-(3-t-butylamino-2-hydroxypropoxy)- .
13 1,2,5-thiadiazole hydrochloride, (-)-3-methyl-4-(3 t-
14 butylamino-2-hydroxypropoxy)-1,2,S-thiadiazole hydrochloride,
(-)-3-ethoxy-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
16 thiadiazole hydrochloride or ~-)-3-chloro-4-(3-t-butylamino-
17 2-hydroxypropoxy)-1,2,5-thiadiazole is substituted for 3-
18 morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thia-
19 diazole hydrogen maleate, there is obtained the correspond-
ing composition.
.1 .
!: I
i,
i
''1~ ' ,
.,: ~ . :
, 1~: ,, .
- 12 -
,, .
-'~."' :: ' '. , :: . . ~. ' i : . , .
-~ 15632 IA
J
1 TABLE III
_ , ., .. .. . ,.. __
3 Ingredients Ex.13EX.14 EX.15Ex.16Ex.17 EX.18
. . ., ~
4 3-morpholino-4- 10 10 10 5 5 5
3-t-butylamino-2- -
hydroxypropoxy)-1,2,
5-thiadiazole hydro-
6 gen maleate (racemate)
7 ~ydrochlorothiazide 10 25 50 10 25 50
8 Starch USP Corn 124 114 109 99 84 80
9 Microcrystalline 134 129 109 85 85 54
Cellulos~
Magnesium Stearate 2 2 2 1 1 1
11 TOTAL (mg./tablet) 280 280 280 200 200 200
12 -~3-morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2, 5-
13 thiadiazole hydrogen maleate (racemate), hydralazine, part
14 of the corn starch and microcrystalline cellulose are mixed
together, milled and granulated with part of the corn starch
16 as starch paste. The granulated mass is wet-sized, dried,
17 dry milled, and blended with the remaining corn starch and
18 microcrystalline cellulose, lubricated with magnesium
~19 stearate, and compressed into tablets. ;~
~ A mixture containing hydrochlorothiazide and
~ , .
21 amiloride hydrochloride dihydxate are substituted for hydro- ~ :
22~ chlorothiazide in Table IIX to~prepare corresponding
23~ ~compositions~
24 ~ When other optically active ~-adrenergic blocking
2~5~ agents such as racemic 3-chloro-4-(3-t-butylamino-2-h~droxy-
26 ~ propoxy)-1,2,5-thiadiazole hydroohloride, (-)-3-(4-hydroxy-
27 ~piperidino)-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5- ~;
28 thiadiazole citrate, (+)-3-piperidino~4-(3-t-butylamino-
29 2-hydroxypropoxy)-1,2,5-thiadiazole hydrochloride, racemic ~ -~
.:
~:: ~. ., ~ .
: ~
~ . ' . ,
:
~ 15532 IA
l 3-morpholino-4-(3-t butylamino-2-hydroxypropoxy)-1,2,
2 5-thiadiazole hydrobromide, (+)-3-N-t-butylcarbamoyl-4-
3 (3-t~butylaminG-2-hydroxypropoxy)-1,2,5-thiadiazole hydro-
4 chloride, (-)-3 methyl-4-(3-t-butylamino-2-hydroxypropoxy)-
1,2,5-thiadiazole acetate, (~)-3-ethoxy-4-(3-t-butyl-
6 amino-2-hydroxypropoxy)-1,2,5-thiadiazole phosphate, or
7 (+)-3-chloro-4-(3-t-butylamino-2-hydroxybukoxy)-1,2,5-thia-
8 diazole hydrochloride is substituted for racemic 3-morpholino-
9 4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole hydro-
gen maleate, with the hydrochlorothiazide or mixed
11 hydro~hlorothiazide/amiloride HCl-2H2O corresponding
12 compositions are obtained.
13 The effect of the compositions of the present
14 invention on blood pressure and plasma potassium was
determlned by an in vivo procedure utilizing adult beagle
i 16 dogs in which hypertension was produced by surgical modi-
17 ~ication of the kidney. The blood pressure and plasma
18 potassium level of these hypertensive dogs were measured
19 over a number of days before and after (twice a day) oral -~
administration (in gelatin capsules) of hydrochloro-
21 thiazide (HCTZ) and a combination of MCTZ and (-)-3-
22 morpholino-4-(3-t-butylamino-2-hydroxypropoxy)-1,2,5-
23 thiadiazole hydrogen maleate (~THM). The results obtained
24 from~a statistically designed set of experiments, using the
~ 2~5 aforesaid procedure, are tabulated below:
'f '
:'
- 14 - i
.~
15632 IA
~f~
1 TABLE A
2 : : .
3 EFFECT ON BLOOD PRESSURE ~ND PLASMA POTASSIUM
4 ~ :
No.
Of Days of Plasma 1 Blood 2
Test TreatmentDogs Treatment Potassium P essure :~-
6 A 1 Control 5 - 4.2 140
7 2 HCTZ-10 mg/kg/day 5 2 3.4 122
8 3 HCTZ-10 mg/kg/day 5 4 3.6 129 .
9 D 1 Control 5 - 4.3 132
2 HCTZ-10 mg/kg/day 5 2 4.1 114
THM-2.0 mg/kg/day
12 3 HCTZ-10 mg/kg/day 5 4 4.1 105 ~ ~ :
13 MTHM-2.0 mg/kg/day
14 B 1 Cont.rol (lactose) 4 - - 126
2 MTHM-1.0 mg/kg/day 4 2 _ 128
16 MTHM-1.0 mg/kg/day 4 4 - 133 1
17 3 MT~IM-4.0 mg/kg/day 4 2 137 - : :
18 : MTHM-4.0 mg/kg/day 4 4 - 141 ..
C 1 Control 6 : 3 4.5
M~M-2.0 mgjkg/day 12 3 5.0
millequivalen~s/liter :
2 mean arterial in mm/Hg
.~ : ,: .
'3
. ~ ~ 15 - ~:
.i~ ~ :, -"
~ ~ 15632 IA
.~ f ~
l Comparable results were obtained when comparing effect
2 on blood pressure and plasma potassium of 2.5 mg./kg/day
3 HCTZ with 2.5 mg./kg/day HCTZ + 2 mg./kg/day MTE~M and
4 2.5 mg./kg/day EICTZ + 8 my./kg/day MTHM. The data
presented in Table A, clearly shows taht the substituted
6 thiadiazole substantially enhances (1) the antihypertensive
7 effect of hydrochlorothiazide and (2) reduces the severity
8 of potassium loss produced by hydrochlorothiazide.
9 Other combinationsand dosages which have been
studies are MTHM/HCTZ at 1.0/2.5, 4.0/10.0 and 8.0/10.0
ll mg/kg/day; and MTEIM/HCTZ/amiloride hydrochloride dihydrate
12 at 1.0/2.5Ø25, 4.0/10.0/1.0, 8.0/10.0/1.0, and
13 10.0/25/2.5 mg/kg/day.
14 In addition to blood pressure reduction and plasma
potassium level maintained the HCTZ/MTHM compositions were
16 also found to reduce circulating renin levels.
:::
17 Analogous results are obtalned for other composi-
18 tions of the present invention as disclosed herein. Claims
l9 to th inven-tion follow.
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