CA2007896A1

CA2007896A1 - Method of treating hypertension using a thromboxane a2 receptor antagonist and new combinations

Info

Publication number: CA2007896A1
Application number: CA002007896A
Authority: CA
Inventors: A.K. Gunnar Aberg; Lawrence Friedhoff
Original assignee: Individual
Current assignee: Individual
Priority date: 1989-02-06
Filing date: 1990-01-16
Publication date: 1990-08-06
Also published as: JPH02270826A; GB2227664A; GB9002194D0; FR2642649A1; IT9019256A0; IT9019256A1; DE4003392A1; IT1238082B

Abstract

Abstract METHOD OF TREATING HYPERTENSION

AND NEW COMBINATIONS

A method is provided for treating hypertension by administering a thromboxane A2 receptor antagonist which preferably is a 7-oxabicycloheptane prostaglandin analog. In addition, new combinations are provided containing a thromboxane A2 receptor antagonist and a beta blocker, an angiotensin converting enzyme inhibitor, a diuretic, an endopeptidase inhibitor or human ANF 99-126.

Description

20~B96 ~A492 METHOD OF TREATING HYPERTENSION
USING A THRO~OXANE A2 R~3CEPTOR ANTAGONIST
AND NEW COMBINAT I O

The present invention relates to a me~lod for treating hypertension by administering a thromboxane A2 receptor antagonist, which preferably is a 7-oxabicycloheptane prostaglandin analog, and to new combinations containi~g a thromboxane A2 receptor antagonist.

In accordance with the present invention, a method is provided for treating hypertension wherein a therapeutically effective amou~t of a ` thromboxane A2 receptor antagonist is systemically administered, such as orally or parenterally, to reduce blood pressure in mammals, including humans, during the period of treatment.
In addition, in accordance with the present invention, new combinations are provided, for treating h~pertension, containing a thromboxane A2 receptor antagonist and an angiotensin converting .~ 25 enzyme inhibitor, a beta blocker, a diuretic, an endopeptidase inhibitor anCVor human ANF 99-126.
The term "thromboxane A2 receptor ~ antagonist" as employed herein includes ompounds :
. which are so called ~hromboxane A2 receptor 30 antagonists, thromboxane A2 antagonists, ~ :

.~ "' ., -thromboxane A2/prostaglandin encloperoxide ;~ antagonists, TP-receptor antagonists, or thromboxane antagonists except insofar as the compound is solely an inhibitor of thromboxane synth~sis.
Thromboxane A2 antagonists which may be employed herein are specific inhibitors of the actions of thromboxane A2 and therefore produce t~e desired ef~ect of throm~oxa~e A2 inhibition without causing other non-specific effects that ` may be undesirable.
The thromboxane A2 receptor antagonist employed herein will preferably be a 7-oxabicyclo-heptane prostaglandin analog and will include 7-oxabicycloheptane substituted diamide prosta-glandin analogs as disclosed in U.S. Patent No.
4,663,336, 7-oxabicycloheptane substitutecl amino prostaglandin analogs as disclosed in U.S. Patent No. 4,416,896 a~d 7-oxabicycloheptane prostaglandin analogs as di~closed in U.S. Patent No. 4,537,981.
; Other 7-oxabicycloheptane prostaglandin analogs may be included as will be apparent to one skilled in the art.
The 7-oxabicycloheptane substituted diamide prostaglandin analogs suitable for use herein, as disclosed in U.S. Patent No. 4,663,336, have the . formula (CH2)m~A~(CH2)n Q

< 1*/

(CH2~p-N - C-(c~2)q-N ~C-R3 O R O R O

:; :
:' ~,'.

, ,~ ' '1. ' " ' , ' '' , . .'~ ~' ' . ' , . :
~1 ' . . ' '.':, ~ ' ' , ' ' , HA~92 including all stereoisomers thereof, wherein m is 0 to 4; A is -CH-CH- or -C~2-CH~-; n is 1 ~o 5; Q is ~CH=CH-, -CH2-, IH H~alo Halo~ ~Halo -C~ CH-, -C-.
or a single bond; R is CO2H, CO2alkyl, CO2 alkali metal, C02polyhydroxyamine salt, -CH20H, : ~N -N
~ ~ or ~NR4R5 ' ~' ; wherein R4 and R5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl at least one of R4 and R5 being other than hydroxy .
a~d lower alkoxy; p is 1 to 4; Rl is H or lo~er 20 alkyl; g is 1 to 12; R2 is H or lower alkyl; and R3 is H, lower alkyl, lower alkenyl, lower : alkynyl, aryl, arylalkyl, lower alkoxy, ~-arylalkyloxy, aryloxy, amino, alkylamino, arylalkylamino, arylamino, :
(Il)n ()n' (Il)n :~
lowex alkyl-S-, aryl-S-, arylalkyl-S-, ()n (,)n (I~n aryl-S-alkyl-, alkyl-S-alkyl-, arylalkyl-i~-alkyl (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl.

:
. . .

2~7~396 _4_ ; The 7-oxabicycloheptane subs~itu~ed amino prostaglandin analogs suitable for use herein, as disclosed in U.S. Patent No. 4,416,896, have the formula ~H2-A- ( C'}~2 )ml CRa *~

~ H2 )rl ~~H~Ra and including all stereoisomers thereof, wherlein A is C~=CH or (CH2)2; m1 is 1 to 8; n1 is 0 ,! to 5, Ra is H or lower alkyl, and Ra is lower alkyl, aryl, aralkyl, lower alkoxy, aralkoxy or O
a 20 wherein R2a is lower alkyl, aryl, aralkyl, alkoxy, ~` aryloxy, aralkoxy, alkylamino, arylamino or aralkylamino.
:~ The 7-oxabicycloheptane prostaglandin analogs suitable for use herein, as disclosed in 25 U.S. Patent No. 4,537,981, have the formula ~2-A-(C~2)m -X

B-CH~Y
o OH

.

.,~
,.`~
.
, . ~ . .

., . :. . ' ' ' ' ' ' ' ' ' ' ' ' ' . . " ', .;`.~': . . , : - ' . ,, , ~ : ,. .: .. . . . :; ;:
.

~ 2t~ 7~96 ~:

_5_ and including all stereoisomers th~reof, wherein A
and B may be the same or differe~nt and A is cH=CH or (c~2)2; B is CH=CH, c--c or (~H2)2; m1 is 1 to 8;
X is OH;
N~-N
c~ il N--N

: 10 CO2Ra wherein Ra is H or lower alkyl; or ' O :
:: It CNH-Z
. wherein Z is H, lower alkyl, aryl, SO2-Q~
; (with Q1 being lower alkyl or aryl), -I~ .
C-Q , " 1 ,~ .
or O~ wherein ~ is H, and Y is alkyl, ..
;. substituted alkyl; aryl-lower alkyl; alkenyl; , ~;
alkynyl, aryl; pyridyl; substituted pyridyl; ~-20 pyridyl-lower alkyl; thienyl, substituted thienyl; :~.
thienyl-lower alkyl; cycloalkyl; cycloalkylalkyl;
substituted cycloalkylalkyl; or phenoxymethyl.
. Preferred exc~mples of thromboxane A2 receptor antagonists which may be employed herein 25 include the 7-oxabicycloheptane compounds disclosed ~ :
in U.S. Patsnt No. 4,537,981, especially, [lS-[la,2a(5Z),3a(1E,3R,~S~,4a]]-7-~3-(3-hydroxy-4-phenyl-l-pentenyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid; the 7-oxabicycloheptane :~
substituted amino-prostaglandin analog~ disclosed in U.S. Patent No. 4,416,896, especially, ~lS- :~
: [ la, 2~,(5Z),3~, 4a ~ ] - 7- [ 3 - ~ [ 2-(phenyl~mino)carbonyl]
hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-. ~'.
.,~. - . .
. . .

.. . . . ,, .. . , . ~ .,. . . ,. ., :. . . . , .~- .. .

heptenoic acid; the 7-oxabicycloheptane substituted diamide prostaglandin analogs di~closed in U.S. ~.
Patent No. 4,663,336, especially, [1S-[1~,2al5Z), 3a,4~]]-7-[3-[[[[(1 oxoheptyl)amino~acetyl]amino]
; 5 methyl]-7-oxabicyclo[2.2.1]hept-.2-yl~-5-heptenoic acid and the corresponding tetrazole, and [lS-[la,2a(Z),3a,4~]]-7-[3-[[[[(4-cyclohexyl-1-; oxobutyl)amino]acetyl]amino~methyl]-7-oxabicyclo~
[2.2.1Jhept-2-yl]-5-heptenoic acid.
Examples of other such thromboxane A2 antagonists suitable for use herein include but are not limited to the phenoxyalkyl carboxylic aci.ds disclosed in U. S. Patent No. 4,258,058 to Witte et al, especially 4-[2-(benzenesulfamido)ethyl]phenoxy-: 15 acetic acid, (BM 13,177 - Boehringer Mannheim), the sulphonamidophenyl carboxylic acids disclosed in U. S. Patent No. 4,443,~77 to Witte et al, especially 4-[2-(4-chlorobenzenesulfonamido)-, ethyl]phenylacetic acid, ~BM 13,505, Boehringer Mannheim) the arylthioalkylphenyl carboxylic acids disclosed in U. S. Patent No. 4,752,676 espscially 4-(3-((4-chlorophenyl)sulfonyl)propyl)benzeneacetic acid, (E)-5-[~[(pyridinyl)[3-(trifluoro-methyl)phenyl]methylene]amino]oxy]pentanoic acid also referred to as R68,070 - Janssen Research Laboratories, 3-[1-(4-chlorophenylmethyl)-5-fluoro-3-~ethylindol-2-yl]-2,2-dimethylpropanoic acid [(L-655240 Merck-Frosst) Eur. J. Pharmacol.
135(2):193, 17 Mar. 87], 5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenylj-2-trifluoromethyl-1,3-dioxan-5-yljheptenoic acid (ICI 185282, Brit. J.
:: Pharmacol 90 (Proc. Suppl):228 P-Abs., Mar. 87), 5(Z)-7 [2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl3-, . . .

. ~ , . . ~
.' ' ' ',: . : " , :
' ., ' ' ., ',:. . ' . ' ' ;
.... ~
. . . . .. .

HA~92 heptenoic acid (ICI 159995~ Brit. J. Pharmacol. 86 (Proc. suppl):808 P-Abs., Dec. 85~, N,N'-bis~7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4- -tetrahydro-isoquinolyl]disulfonylimide (SKF 88046, ~ 5 Pharmacologist 25(3):116 Abs, 117 Abs, Aug. 83), ; [la(Z)-2~,5a]-(+~-7-[5-[[(1,1'-biphenyl)-4-yl]-methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (A~ 23848 - Glaxo, Circulation 72(6):1208, Dec. 85, levallorphan allyl bromide (CN 32,191, Sanofi, Life Sci. 31 (20-21):2261, 15 ,~
; ~ov. 82), (Z,2-endo-3-oxo)-7-(3 acetyl-2-bicyclo-[2.2.1]heptyl-5-hepta-3Z-enoic acid, 4-phenylthiosemicarbazone (EP092 - Univ.
Edinburgh, Brit, J. Pharmacol. 84(3):595, Mar. 85).
The disclosures of the above-mentioned patents are incorporated herein by reference.
In carrying out the method of the present invention, the thromboxane A2 receptor antagonist may be administered systemically, such as orally or parenterally, to mammalian species, such as monkeys, dogs, cats, rats, humans, etc.
The thromboxane A2 receptor antagonist may be incorporated in a conventional dosage form, such as a tablet, capsule, elixir or injectable.
The above dosage forms will also include the necessary carrier material, excipient, lubricant, bufer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
With regard to such systemic formulations, single or divided doses of rom about 0.5 to about . ' .
: .

2~37B96 ~A492 2500 mg, preferably from about 5 to 500 mg one to six times daily, may be administered in systemic dosage forms as described above for a prolonged period, that is, for as long as hypertension continues. Sustained release forms of such ; formulations which may provide such amounts biweekly, weekly, monthly and the lik~ may also be employed.
The thromboxane antagonist can al90 be formulated with a diuretic for the treatment of hyper~ension. A combination product comprising thromboxane antagonist and a diuretic can be a~ministered in an effective amount which comprises a totally daily dosage of about 30 to 600 mg, preferably about 30 to 330 mg of thromboxane antagonist, and about 15 to 300 mg preferably about 15 to 200 of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylclo~hiazide, trichloromethiazide, polythiazide or benzthiazide as well as ethacrynic acid, tricrynafen, chlorothalidone, furosamide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds.
In treating hyperten~ion, the thromboxane receptor antagonists may be administered in combination with an angiotensin-converting enzyme (ACE) inhibitor such as captopril, zofenopril, - fosinopril, enalapril, lisinopril, (S)~1-[6-amino-~ .

- :," ~, " , . ,:

, , : ; , .

2~ 396 _ 9~

2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29,852) etc. employing the ACE inhibitor in an amount as indicated in the Physicians Desk Reference (PDR), for example, from about 5 to about 350 mg per day. Such combination would be at a weight ratio of thromboxane antago~ist to ACE i~libitor of from about 1:1~ t~ about 10:1.
; The thromboxane receptor antagonists can ; 10 also be administered in combination with a neutral endopeptidase inhibitor or with human ANF 99 -126 in treating hypertension. Such combination would contain the ~hromboxane antagonist at from about 1 to about 500 mg per day and an endopepti-dase inhibitor of from about 1 to about 100 mg per kg of body weight or the human ANF 99 - 126 at from about 0.001 to about 0.1 mg per kg of body weight.
In addition, in treating hypertension, the thromboxane receptor antagonists may be employed in combination with a beta blocker such as propranolol, ~adolol, timolol maleate, metoprolol tartrate, labetalol hydrochloride and the like employing ~he beta blocker in amounts as indicated in the PDR such as in an amount of from about 5 to about 350 mg per day. Such a combination would be at a weight ratio of thromboxane antagonist to beta blocker of from about l:lO to about 10:1.
The thromboxane receptor antagonist, in treating hypertension, may also be used in combination with a calcium channel blocker such as dihydropyridines such as niedipine, nitrendipine, nimodipine, phenylalkylamines such as verapamil, benzothiazepines such as diltiazem and ., .
.. , ' '' ~ . . . ., ;. . : . .. ..

'~ , . . ., , . ., ,, ' ,;. j, , . ~ ,: ,. .

2~:37B96 ~A492 --10~

benzazepines and the like employing the calcium channel blockex in amounts as indicated i~ the PDR
such as in an amount of from about 1 to about 1000 mg per day. Such a combination would be at a weight ratio of thromboxane antagonist to calcium channel blocker of from about 1:10 to about 10:1.
- The thrombo~ane receptor antagonist may also be employed in combination with direct vasodilators such as hydrala~ine or minoxidil.

` ~Q~g6 :
~A492 ~he following ~xamples represent preferred embodiment~ of the pr~sent invention.

Example 1 An injectable solution of ~hromboxane A2 receptor antagonist for intravenous use in treating hypertension is produced as follows:

[lS;[la,2a(5Z),3a,4a]]-7-[3~[[2-~phenylamino)carbonyllhydra7.ino]-methyl]-7-oxabicyclo[2.~.l]hept-2-yl~-5-heptenoic acid (SQ 29,548)2500 mg Methyl paraben S mg - Propyl paraben l mg 15 Sodium chloride 25 g Water for injection gs. 5 1.

: The thromboxane A2 receptor antagonist,preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre~terilized vials which are then closed with presterilized rubber cloaures. Each vial contains a concentration of 75 mg of active ingredient per 150 ml of solution.

Exam~le 2 An injectable for use in treating hypertension is prepared as described in Example 1 except that the thromboxane A~ receptor antagonist employed is [lS-[la,2a(5Z),3a(1E,3R,4S),4a]] 7-[3-.~ ' .

. ~ .. . . . . .

. : . . . ~ , ; -.. . .. .. , . ~ . , . ;

~37l~6 (3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 28,668).

ExamPle 3 An injectable solution of thromboxane A2 receptor antagonist for use in treating hypertension containing [lS-[1~, 2a ( 5Z ), 3a, 4a ] ] -7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic ac:id (SQ
30,741) as the thromboxane A2 receptor antagonist is prepared as described in Example 1.

Example 4 An injectable for use in treating hyperten~ion is prepared as described in E,xample 1 except that the thromboxane A2 receptor antagonist employed is [lS-[la,2~(Z),3a,4a]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.
Example 5 , A thromboxane A2 antagonist formulation suitable ~or oral administration for use in ;; treating hypertension is set out below.
1000 tablets each containing 400 mg of thromboxane A2 recepkor antagonist are produced from the following ingredie~ts.
. . . .
[lS-[la,2a(5Z),3a,4~]]~7-[3-[[[[(1-Oxoh~ptyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 30,741) 400 g Corn Starch 50 g Gelatin 7.5 g :' .

Avicel (microcrystalline cellulose) 2S g Magnesium stearate 2.5 g The thromboxane A2 receptor antagonist and corn starch are admi~ed with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate axe admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 400 mg of active ingredient.

Example 6 A thromboxane A2 antagonist tablet : formulation for use in treating hypertension is prepared as described in Example 5 except that SQ
29,548 is employed as ~he thromboxane A2 r.eceptor antagonist in place of SQ 30,741.
.~ , Exam~e 7 A thromboxane A2 antagonist tablet ; formulation for use in treating hypertension is prepared as described in Example 5 except that SQ
28,668 is employed in place of SQ 30,741.
It will also be appreciated that the above thro~boxane A2 antago~ist formulations may also include a beta blocker such a~ propranolol or atenolol, an ACE i~libitor such a~ enalapril, lisinopril, zofenopril, fosinopril or SQ 29,852, an endopeptidase inhibitor or human ANF 99-126, a diuretic or a vasodilator.
~.

.. . .. .

'',.,' ' ,,., '" '' , : , ` 2~7139Ç~

Example 8 A thromboxane receptor A2 antagonist-calcium channel blocker formulat:Lon suitable for oral administration for treating h~pertension is set out below.
1000 tablets each contain:Lng 400 mg of thrombo~ane A2 antagonist and 100 mg diltiazem are produced from the following ingredients.

[lS-[la,2a(5Z),3a,4a]]-7-[3-~[[[(1-Oxoheptyl)amino]acetyl]amino~methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid (SQ 30,741) 400 g Diltiazem 100 g 15 Corn starch 50 g Gelatin 7.5 g Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g The thromboxane antagonist, diltiazem and corn starch are admi~ed with an aqueous solution of ; the gelatin. The mixture is dried and ground to a fine powder. The ~vicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 500 mg of active ingredients.

Example 9 An injectable solution for use in administexing calcium channel blocker and thromboxane A2 receptor antagonist is produced as follows:

.' .

~ , .

` 2~7~6 [lS-[1~2~(5Z),3a,4~]]-7-[3-[[2-(phenylamino)carbonyl]hydrazino]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 29,548) 5 or SQ30,741 2500 mg Nifedipine or diltiazem2500 mg : Methyl paraben 5 mg Propyl paraben 1 mg Sodium chloride 25 g :. 10 Water for injection qs. 5 1.

The calcium channel blocker, thromboxane A~
antagonist, preservatives and sodium chloride are :dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into presterilized vials which are then closed with presterilized rubber closures.
Each vial contains a concentration of 75 mg of active ingredient per 150 ml of solution.

ExamPle 10 ~ n injectable for use in treating hypertension is prepared as described in Example 9 25 except that the thromboxane ~2 antagonist employed . i~ the phenoxyalkyl carboxylic acid 4-[2-(benzene-sulf~mido)ethyl]phenoxyacetic acid, disclosed in U. S. Patent No. 4,258,058.

Example 11 An injectable for use in trPating hypertension is prepared as described in Example 9 . .
.. .

: :

,' ' '`'~' '' .' ' ': '. . 1'.'.'. .'. . '. . ' ' ` '' ' "'"' ;' .
. . . :' - \~
Z~78~6 EA~92 except that the thromboxan2 A2 antagonist employed is [lS-[la,2~(Z),3~,4~]~-7-[3-[[[[(4-cyclohe~yl~
l-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]~5-heptenolc acid.
i Example 11 ~ -1000 tablets each containing 200 mg of SQ 32,324 and 400 mg SQ 30,741 are produced from the following ingredients:

(d-cls)-3-(acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-[2-(methylamino)ethyl]-6-(trifluoro-methyl)-2H-1-benzazepin-2-one, monohydrochloride salt (SQ 32,324) 200g SQ 30,741 400g Lactose lOOg Avicel 150g Corn starch 50g 20 Magnesium stearate 5g .
SQ 32,324, SQ 30,741, lactose and Avicel are admixed, then blended with the corn starch.
Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg tablets each containing 200 mg of active ingredient.
The tablets are coated with a solution of Methocel E 15 (methyl cellulose) including as a color a lake ,; containing yellow #~. The resulting tablets are useful in treating hypertension.

~' :
, ' .
.'' , :` .

, .,',~, -.. , 7~ 6 Example 12 Two piece #l gelatin capsules each containing 50 mg of captopril an~l 250 mg of SQ
30,741 are filled with a mixture of the following ingredients:

SQ 30,7`41250 mg Captopril 50 mg Magnesium stearate 7 mg 10 UsP lactose 193 mg.

The resulting capsules are useful in treating hypertension.

lS Example 13 An inject~ble solution for u~e in treating hypertension is produced as follows:

(d-cis3~3-(acetyloxy)-1-[2-dimethyl-amino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl) 6-~txifluoromethyl)-2H-1-benzazepin-2-one, monohydro-chloride (SQ 31,765) 500 mg SQ 30,741 25Q mg 2~ Me~hyl paraben 5 mg Propyl paraben 1 mg.
Sodium chloride 25 g Water for injection qs. 5 1.

SQ 31,765, SQ 30,74~, preservatives and sodium chloride are dissolved in 3 liters of water ., ., : , ,:

Z0~7B96 H~492 -~

for injection and then the volumle is brought ~p to 5 liters. The solu~ion is filt~rled through a sterile filter and aseptically filled into presterilized vials which are th,_n closed with .. 5 presterilized rubber closures. Each vial contains 5 ml of solutio~ in a c:oncentration of 100 mg of active ingredient per ml of solution for injection.

Example 14 A thromboxane antagonist-beta blocker ::
formulation suitable for oral administration for treating hypertension prepared as described in Example 1, is set out below.
1000 tablets each containing 400 mg of ; 15 thromboxane antagonist and 40 mg nadolol are produced from the following ingredients.

SQ 30,741 400 g Nadolol 40 g 20 Corn star~h 50 g Gelatin 7-5g '. Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g , :
Examle 15 ` The following experiment demonstrates that a thromboxane receptor antagonist decreases blood pressure.
A thromboxane receptor antagonist ; 30 [lS-[la,2a(5Z),3~,4~]]-7-[3-~[[[(1-oxoheptyl)- :
~ amino]acetyl]amino]methyl~-7-oxabicyclo-: ' : ' ~
~, .
:.'.

.- . . . .

~C~

--19 - .

[2.2.1~hept-2-yl] 5-heptenoic acid (SQ), or placebo (PLA) was given to 3 groups of 12 healthy human subjects (8 per group received SQ and 4 PLA). SQ was given as a single 50 mg IV bolus followed by an infusion of 3, 6 or 12 mg/hr for 48 hours. ~ean pharmacodynamic (PD) parameters at 48 hours were:

% Decrease Max. % ~% IncreasePlatelet Bleeding Aggregation Dose Diastolic BPTime low hiqh PLA -14~3 22~15 -9+11 -7~6 3 -20~3 156$55* 98~4* 89~17*
6 -18+3 111~19~ 100+0* 76i7*
12 ~28+~* 122i34~ lOOiO~ 88il6*
(*p<O.05 vs. PLA) SQ specifically inhibited TXA2-mediated platelet aggregation ex vivo at low and high agonist (U46619) concentrations. Mean platelet TXA2 receptor (R) affinity and density measured ex vivo were not changed. SQ increased template bleeding time when R occupancy was ~99% but not when R occupancy was ~70%.
From the above, it is seen that the thromboxane receptor antagonist reduced diastolic blood prescure.

:

,, .:
~..

Claims

What we claim is:

1. A method for treating hypertension in a mammalian species, which comprises administering to a mammalian species in need of such treatment a blood pressure lowering effective amount of a thromboxane A2 receptor antagonist.

2. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist is a 7-oxabicycloheptane prostaglandin analog.

3. The method as defined in Claim 2 wherein the 7-oxabicycloheptane prostaglandin analog is a 7-oxabicycloheptane substituted diamide prostaglandin analog or a 7-oxabicycloheptane substituted amino prostaglandin analog.

4. The method as defined in Claim 2 wherein the 7-oxabicycloheptane prostaglandin analog has the formula and including all stereoisomers thereof, wherein A and B may be the same or different and A
is CH=CH or (CH2)2; B is CH=CH, C?C or (CH2)2; m1 is 1 to 8; X is OH;

;

CO2Ra wherein Ra is H or lower alkyl; or ?NH-Z

wherein Z is H, lower alkyl, aryl, SO2-Q1 (with Q1 being lower alkyl or aryl), ?-Q1, or OR? wherein R2 is H, and Y is alkyl; substituted alkyl; aryl-lower alkyl; alkenyl; alkynyl, aryl;
pyridyl; substituted pyridyl; pyridyl-lower alkyl;
thienyl, substituted thienyl; thienyl-lower alkyl;
cycloalkyl; cycloalkylalkyl; substituted cycloalkylalkyl; or phenoxymethyl.

5. The method as defined in Claim 3 wherein the 7-oxabicycloheptane substituted diamide prostaglandin analog has the formula including all stereoisomers thereof, wherein m is 0 to 4; A is -CH=CH- or -CH2-CH2-; n is 1 to 5; Q
is -CH=CH-, -CH2, , , .

or a single bond; R is CO2H, CO2alkyl, CO2 alkali metal, CO2polyhydroxyamine salt, -CH2OH, or -?R4R5 wherein R4 and R5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl at least one of R4 and R5 being other than hydroxy and lower alkoxy; p is 1 to 4; R1 is H or lower alkyl; q is 1 to 12; R2 is H or lower alkyl; and R3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, arylalkyloxy, aryloxy, amino, alkylamino, arylalkylamino, arylamino, lower alkyl-, aryl-, arylalkyl-, aryl--alkyl-, alkyl--alkyl-, arylalkyl--alkyl (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl.

6. The method as defined in Claim 3 wherein the 7-oxabicycloheptane substituted amino prostaglandin analog has the formula and including all stereoisomers thereof, wherein A
is CH=CH or (CH2)2; m1 is 1 to 8; n1 is 0 to 5, Ra is H or lower alkyl; and R? is lower alkyl, axyl, aralkyl, lower alkoxy, aralkoxy or -NH-?-R2 wherein R? is lower alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylamino, arylamino or aralkylamino.

7. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist is [1S-[1.alpha.,2.alpha.(5Z),3.alpha.(1E,3R,4S),4.alpha.]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

8. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist has the name [1S-[1.alpha.,2.alpha.(5Z),3.alpha.,4.alpha.]]-7-[3-[[[[(1-oxoheptyl) amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]

hept-2-yl]-5-heptenoic acid or the corresponding tetrazole.

9. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist has the name [1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid.

10. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist has the name [1S-[1.alpha.,2.alpha.(5Z),3.alpha.,4.alpha.]]-7-[3-[[2-(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]
hept-2-yl]-5-heptenoic acid.

11. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist is administered orally or parenterally.

12. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is administered in single or divided doses of from about 0.5 to about 2500 mg/one to four times daily.

13. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is employed in combination with a diuretic.

14. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is employed in combination with an angiotensin-converting enzyme inhibitor.

15. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is employed in combination with a beta-blocker.

16. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is employed in combination with a calcium channel blocker.

17. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is employed in combination with a vasodilator.

18. A new pharmaceutical combination comprising a thromboxane receptor antagonist and a beta blocker.

19. The combination as defined in Claim 18 wherein the beta blocker is nadolol, propranolol, atenolol, timolol, metaprolol, acebutolol or labetalol.

20. A new pharmaceutical combination comprising a thromboxane A2 receptor antagonist and an angiotensin converting enzyme inhibitor.

21. The combination as defined in Claim 20 wherein the angiotensin converting enzyme inhibitor is captopril, enalapril, lisinopril, fosinopril, SQ 29,852 or zofenopril.

22. A new pharmaceutical combination comprising a thromboxane A2 receptor antagonist and an endopeptidase inhibitor or human ANF 99-126.

23. A new pharmaceutical combination comprising a thromboxane A2 receptor antagonist and a diuretic or an endopeptidase inhibitor.