JPH02270826A - Composite for therapy of hypertension - Google Patents

Abstract

PURPOSE: To obtain a hypertension treating composition capable of lowering blood pressure, useful for mammalian hypertension, comprising a thromboxane A2 receptor antagonist. CONSTITUTION: This composition comprises a thromboxane A2 receptor antagonist. A 7-oxabicycloheptane prostaglandin analog such as a compound of formula I [A is CH=CH, etc.; B is CH=CH, etc.; m1 is 1-8; X is OH, CO2 Ra (Ra is H, etc.), a group of formula II, etc.; Y is an alkyl, a substituted alkyl, alkenyl, etc.] such as [1S [1α,2α (5Z), 3α (1E,3R,4S),4α]]-7-[3-(3-hydroxy-4-phenyl-1- pentenyl)-7-oxabicyclo[2,2,1]hept-2-yl]-5-heptenoic acid, etc., are preferably used as the antagonist.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a composition for treating hypertension, more specifically, a composition comprising tromphoxane A, a receptor antagonist (preferably a 7-oxabicyclohebutane prostagranone analogue) as an essential active ingredient. , relates to a composition that can be administered to a mammal to treat hypertension.

Structure and effects of the invention The present invention provides a therapeutically effective amount of thromboxane A.

The present invention provides a composition for treating hypertension in mammals comprising a receptor antagonist, which lowers blood pressure by administering the composition systemically, e.g., orally or parenterally, to mammals including humans over a treatment period. Seshime,
High blood pressure can be treated. The composition for treating hypertension according to the present invention includes thromboxane A, a receptor antagonist alone or together with an angiotensin converting enzyme inhibitor, a β-blocker, a diuretic, an endopeptidase inhibitor and/or human ANF 99- The active ingredient is a mixture of 126.

In addition, as "trompoxane A, receptor antagonist", so-called trompoxane Δ, receptor antagonist, trompoxane A, antagonist, trompoxane A, /brostaglandin entombreoquine antagonist, TP-receptor antagonist, or thromboxane Compounds that are referred to as xane antagonists (with the exception of those compounds that alone are inhibitors of thromboxane synthesis) are included.

The tronofoxane A antagonists that can be used in the present invention are specific inhibitors of the action of l.lompogizano A, and thus exert the desired effect of thromboxane A2 inhibition, while avoiding other undesirable non-specific effects. 10- Never occurs.

The thromboxane Δ2 receptor antagonist used in the present invention is 7
-Oxabicyclohebutane prostaglandin analogs are preferred, including the 7-oxabicyclohebutane-substituted diamido prostaglandin analogs disclosed in US Pat. No. 4,663,336; -Oxabicyclohebutane-substituted aminoprostagranone analogs, and U, S Patent No. 453798
No. 1 contains a butane prostagranone analog disclosed in 7-year-old Kisahinoku. Other 7-oxabicycloheptane prostagranone analogs include those obvious to those skilled in the art.

The 7-oxabicyclohebutane-substituted diamido prostagranone analogs disclosed in Patent No. 4,663,336 and suitable for use in the present invention have the formula: [wherein m is 0 to 4°A] is -CH-CH- or -CH2-CH, -.

n is 1 to 5; ? H Q is ~CH-CH-1-CHt-1-CT-(-R is-
co, tr, -CO7・alkyl, -〇〇.

・Alkali metal, -CO, ・Polyhydroquinamine salt,
-CH20H.

■1, lower alkyl, hydroquine, lower alkokino or aryl, I? ' and at least one of R5 excludes hydroquine or lower alkokino).

p is 1~71° R1 is H or lower alkyl.

q is 1 to 12° R2 is H or lower alkyl; and R3 is 1, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkokene, arylalkylamino, aryloxy, amino,
alkylamino, arylalkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkokinoalkyl, aryloxyalkyl or arylalkokynealkyl], and its stereoisomers Also includes.

The 7-oxabinoc[1-heptane-substituted aminoprostagranone analogs disclosed in the above U, S Patent No. 4,416,896 and suitable for use in the present invention are of the formula [where A is -
CH= CH- or -(CHt)y: ml is 1~
8゜n, is 0 to 5゜Ra is hydrogen or lower alkyl; and R1 is lower alkyl, aryl, aralkyl, lower alkoke, aralkoxy or =14-aryl, aralkyl, alkokino, arylamino,
aralkoxy, alkylamino, arylamino or aralkylamino], and includes stereoisomers thereof.

The 7-oxabicyclohebutane prostagranone analogs disclosed in Patent No. 4,537,981 and suitable for use in the present invention have the formula [where Δ and B may be the same or different; Δ is -C
H-CH- or -(CH,) 2-1I3 is -C)I
= CH-1 (CHJz- or -〇-: C-m+ is 1-8°X is -0H1), or -C-Nl-l-Z (where Z is H
.

lower alkyl, aryl, 5O3-Ql (Ql is ]1 lower alkyl or aryl), -C-Q, or -〇Rsi (Rsi is H), and Y is alkyl, substituted alkyl, aryl-lower Alkyl, alkenyl, alkynyl, aryl, pyrinol, substituted pyrinol, pyrite-lower alkyl, thienyl, substituted thienyl, thienyl-
lower alkyl, chloroalkyl, chloroalkylalkyl, substituted chloroalkylalkyl, or phenoxmethyl], and also includes stereoisomers thereof.

Preferred specific examples of thromboxane A and receptor antagonists that can be used in the present invention include U.S. Patent No. 45379.
7-oxahinochlorol\butane compound disclosed in No. 81,
In particular, [l5-41α, 2α (57,).

3α(1E,3R,4S),4α]]-7-[3-(3
-hydroquino-4-phenyl-I-penotenyl)-7-
Oxabicyclo[2,2,1]hept-2-yl] = 5
-Heptenoic acid: 7-oxabicyclohebutane-substituted aminoprostaglandin analogs disclosed in US Pat. No. 4'116896, especially [1S-[1α.

2α(5Z), 3α, 4α])-7-[3-[[2-(
phenylamino)carbonyl]hydrazino]methyl]-
7-Oxabicyclo[2,2,1]hept-2-ylco-5-heptenoic acid, the 7-oxabicyclohebutane-substituted diamide prostaglandin analogs disclosed in US Pat. No. 4,663,336, especially [1S-[1α , 2α (5Z)
, 3α, 4α]]-7-[3-[[[[(+-Ogisohebutyl)amino]acetyl]amino]methyl]~7-oxabicyclo[2,2,1]hept~2=ilco5-
Heptenoic acid or its corresponding tetrazole and [1S-
[1α, 2α(Z), 3α, 4α]]-7-[3-[[
[[(4-chlorohequinol-1-xobutyl)amine]acetylcoamino]methyl]-7-oxabicyclo[
2,2,1]hept-2-yl]-5-heptenoic acid.

Examples of other thromboxane A antagonists suitable for use in the present invention include, but are not limited to, the fenoquine alkyl carboxylic acids disclosed in Witsch et al., US Pat. No. 4,258,058, particularly 4-[2-(benzenesulfamido)ethyl]phenoquinacetic acid (Boarringer Mannheim, BMI 3177); sulfonamidophenylcarphonic acids, especially 4-[2- (4-Chlorobenzenesulfonamide) edylcophenylacetic acid (BMI 3505 from Boeringer Mannheim); US
Aryldioalkylphenylcarboxylic acids disclosed in Patent No. 4752676, especially 4-(3-((4-chlorophenyl)sulfonyl)propyl)hensenacetic acid, (E
)-5-[[[(pyrinonyl)[3-(trifluoromethyl)phenyl]methylenecoamino Joxo]pentanoic acid (R68 from Janssen Research Laboratories, Inc.)
070), 3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylinotol-2-yl]-2,2-tumedelpropionic acid (Merck-Frost glue) ,-655240,Eur,J
, Pharmacol, 135(2):193
．． (see March 17, 1987), s(z)-7-([
2,4,5-nos]-4-(2-hydroquinophenyl)
-2-trifluoromethyl-1゜3-nooxane-5-
yl) heptenoic acid (IC1185282, Brlt,,
1, Pharmacol, 90, (ProcSupp
l): 228P-Abs, March 1987), 5(
Z)-7-42,2-tmethyl-4-phenyl-1,3
-5-yl]heptenoic acid (ICr1
59995, Brlt, J., Pharmacol, 8
6 (Proc, Suppl): 808 P-
Δbs, December 1985), N, N'-His[7-(3-chlorohenzenaminosulfonyl)-1,
, 2,3,4-tetrahydroisoquinolylconosulfonylimito (SKF88046, Pharmacolo
gisL25 (3): I I GAbs, +17A
l) S, August 1983), [IC(Z)-2β,
5α] ~(+)-7-[5-[[(Ii′-hyphenyl)-4-yl]methochushroom-1-(4-morpholinyl)
-3-Oxonquabenzilt I-heptenoic acid (AH23848, C1rculation 72 from Glaxo)
(6): 1208.1985+2J1 Takesho), Ievallorphan allylpromide (CM321911Sanofi, I, ife
Sci, 3I(20-21):2261.19821
(see January 15), (Z, 2-endor 3-oxo)-
7-(3-acetyl-2-pinoclo[2,2,1]hebutyl-5-hepta-3Z-enoic acid, 4-phenyldiosemi-j)) L, Bazo:/(E P 092- Uni
v, Edinburgh, Brlt, J, Pharm.
acol, 84 (3): 595, March 1985).

In the practice of the present invention, thromboxane A, a receptor antagonist, is administered to mammals (e.g., monkeys, dogs, cats, rats,
It can be administered systemically to humans (such as humans) by oral or parenteral administration.

The nonvoxane Δ2 receptor antagonist may be formulated in conventional dosage forms, such as tablets, capsules, elixirs or injections. Such dosage forms may also include necessary carrier materials, excipients, lubricants, buffers, antimicrobial agents, fillers (e.g. mannitol), antioxidants (e.g. ascorbic acid or sodium sulfate), etc. Although oral dosage forms are preferred, parenteral dosage forms also give satisfactory results.

For such systemically administered formulations, from about 0.05 to
It can be administered over a long period of time, ie, as long as the hypertension persists, preferably in a single dose or in 2 to 6 divided doses of about 5 to 500 m in dual dosage form. These preparations can also be used as sustained-release preparations in which the above-mentioned doses are delivered twice a week, once a week, or once a week.

For the treatment of hypertension, lompoxan antagonists can also be combined with diuretics. Administration of a composition containing a mixture of an antidrug and a diuretic to mammals in need thereof.
As a J dose, about 30 to 60011 Kai, preferably about 30
~330jl@ of thromboxane antagonist, and about 15
~300B, preferably about 15-200ml of diuretic. Diuretics and deanodic diuretics (e.g. chlorodeacyt, hydrochlorodeacyt, flumethiat, hydroflumedianot, bentroflumethiat, mediclodianod, trichloromethat, polydeanod or henzdiazide) which are intended for such mixed use.
Also included are ethacrylic acid, ticlinafene, rirothalidone, furozamide, musolimine, bumetanit, triamterene, amiloride, spironolactone, and salts thereof.

In the treatment of hypertension, thromboxan recebuta antagonists are combined with angiotensin converting enzyme (ACE) inhibitors such as captogril, zofenopril, hononopril, enalapril, linnopril, (S)-i[6-amino-2-
[[Hydroquine (4-phenylbutyl)phosphinyl 1
Saikino]-1-oxohexyl]-1,-proline (S
Q29852), etc., and the dosage of the ACE inhibitor in this case is determined by Physicians.
For example, it is about 5 to 3500/day as described in the Desk Reference (PDR). The mixing weight ratio of the thromboxane antagonist and the He〇E inhibitor is approximately I
It is O~10.1.

In addition, in the treatment of hypertension, thromboxane receptor antagonists are used as neutral endopeptidase inhibitors or human A.
It can be administered in combination with NF99-126. Compositions containing such mixtures contain about 1 to 500 ffg/
day thromboxane antagonist and about + -lo o m9
/ky (body weight) noendopeptidase inhibitor or about 0
001-0, I mg/kg body weight) of Human ANF99-126.

Furthermore, in the treatment of hypertension, thromboxane receptor antagonists may be administered in combination with β-blockers such as propranocar, atrol, timolol maleate, metoprolol tartrate, labetalol hydrochloride, etc. The dosage of the blocking agent is as described in the PDR, for example about 1 to 500 ff days. In such a mixed use, the weight ratio of l-lomphoxane antagonist to β-blocker is about 1:10-10 I.

Furthermore, in the treatment of hypertension, thromboxane receptor antagonists are used in combination with calcium duct blockers, such as nitrobilinones such as nifedipine, nitrendipine, and nimodipine, phenylalkylamines such as verapamil, penzodiazebins such as nortiazem, and benzazepines. In this case, the amount of carunium duct blocking agent used is as described in PDH, for example, about 1
~10100Ox days. In such a mixed use, the weight ratio of the tromphoxane antagonist to the calcium duct blocker is about 1.
10-10 l.

Additionally, thromboxane receptor antagonists can be combined with direct vasodilators (e.g. hytralanone or minoxidil).
May be used in combination with

The following examples are preferred embodiments of the invention.

Example 1 An injection solution of trompoxane A, a receptor antagonist, for the treatment of hypertension by intravenous injection is prepared according to the following procedure.

Ascites [1S~[1α, 2α(5Z), 3α, 4α]]-7-
-[3-[[2-(phenylamino)carponylcohytranono]methylco-7-oxabicyclo[2,2,1]
hept-2-yl]-5-heptenoic acid (SQ29571
8) ・2500zy Methylparaben ・5xg Propylparaben ・・・・ I×g Sodium chloride 25g Water for injection (appropriate amount) ・・・・・ 5ρ Add the above thromboxane Δ, receptor antagonist, preservative and sodium chloride to 3Q water for injection Dissolve and then adjust the total volume to 5ρ. The solution is filtered through a sterile filter, aseptically filled into sterile vials, and closed with sterile rubber stoppers. Each vial is 75
It has the concentration of active ingredient B/15f)+(j) of the injection solution.

Example 2 The thromboxane A and receptor antagonist used were [1S-
[1α, 2α (5Z), 3α (I E, 3 R, 4S)
, 4α]]-7-[3-(3-hydroquino-4-phenyl-I-pentenyl)-7-oxabicyclo[22I-cohebutol-2-yl]-5-heptenoic acid (SQ28668
) An injection solution for use in the treatment of hypertension is produced according to the description in Example 1.

Example 3 Thromboxane A, [1S-[1
α, 2α(5Z), 3α, 4α]]-7-[3-[[[
[(1-oxoheptyl)amino]acetyl]amino]
Methyl]-7-iquizapinculo[2,2,1]hept-
An injection solution of thromboxane A, a receptor antagonist for the treatment of hypertension, containing 2-yl]-5-heptenoic acid (SQ3 (1741)) is prepared as described in Example 1.

Example 4 The thromboxane A and receptor antagonist used were [1S-
[1α, 2α(Z), 3α, 4α]]-7-[3-[[
[[(4-chloroquinol-1-oxobutyl)amino)acetyl]amino]methyl]-7-oxahinochlor[
2,2,1]hept-2-yl]-5-heptene = 26
= An injection solution for the treatment of hypertension is prepared as described in Example I, except that it is an acid.

Example 5 A L. rompoquizano A receptor antagonist formulation suitable for oral administration for the treatment of hypertension is shown below.

1000 tablets each containing 400H thromboxano A, a receptor antagonist are prepared from the following ingredients.

Group color [I S-
[1α, 2α(5Z), 3α, /Iα]]-7-[3-
[[[[(1-oxoheptyl)amino'acetyl]amino]methyl]-7-oxabinochloro[2,2,1]hept-2-yl]-5-heptenoic acid (SQ30741)
・ 400 cornstarch ・ 50 geladine
・75 Avicel (microcrystalline cellulose) 2
5 Magnenium Stearate 25 Mix the above thromboxane A, receptor antagonist and corn starch with an aqueous solution of gelatin.

The mixture is dried and ground into a fine powder. Achycel and then magnesium stearate are mixed while being crushed.

Next, this was compressed into tablets using a tablet molding machine to form 400i tablets.
1000 tablets are formed, each containing the active ingredient of i+.

Example 6 Thromboxane A, 5Q3074 as receptor antagonist
Thromboxane A2 receptor antagonist tablets for use in the treatment of hypertension are prepared as described in Example 5, except that 5Q29548 is used in place of 1.

Example 7 A thromboxane A2 receptor antagonist tablet for use in the treatment of hypertension is prepared as described in Example 5, except that 5Q28668 is used in place of SQ30741.

These thromboxane A2 receptor antagonist tablets also contain β-blockers such as propranocar or atenolol, enalapril, linnobril, zofenopril,
fosinopril or 5Q29852, E inhibitor, endopeptidase inhibitor or human ANF9
9-126, it is recognized that diuretics or vasodilators may be included.

Example 8 Suitable for oral administration for the treatment of hypertension,
Two receptor antagonist/calcium duct blocker formulations are shown below.

400H thromboxanoΔ2 receptor antagonist and 1
1000 tablets each containing 00xh nortiazem are prepared from the following ingredients.

Component - 1 layer [1S-[1α, 2α (5Z), 3α, 4α] 1-7-
[3-[[[[(1-oxoheptyl)aminocoacetyl]amino]methyl]-7-oxahinoclo[2,2,
1]Hept-2-yl]-5-heptenoic acid (SQ307
41) ・400 nordeazem ・・100 cornstarch ・50 geladine
75 Ahisel (microcrystalline cellulose) 2
5 Magnesium Stearate 2,5 Mix the above trompoxano antagonist, nortiazem and cornstarch with an aqueous solution of gelatin. Dry the mixture;
Grind into a fine powder. Achycel and then magnesium stearate are mixed while being coarsely crushed. This is then compressed in a tablet machine to form 1000 tablets each containing 500 mg of active ingredient.

Example 9 An injection solution used for administration of a calcium duct blocker and thromboxane A2 receptor antagonist is prepared according to the following procedure.

Component [IS-[1α, 2 α(5Z), 3 α, 4
α]Coco-7-[3-[[2-(phenylamino)carbonyl]hydrazino)methyl]-7-oxahincro[2,2,1]hept-2-yl]-5-heptenoic acid (
SQ29548) or 5Q307/II-2
500 Shoulder 9 Nifugonopino or Nordeazem・2500Mg Methylparahen・5mg Propylparaben・・Iπ9Thorium Chloride・25g Water for Injection (appropriate amount)
・ ・ 5f! 2. Calcium duct blocker, thromboxane A.

The receptor antagonist, preservative and sodium chloride are dissolved in 3Q of water for injection, then the volume is adjusted to 5p. The solution is filtered through a sterile filter and aseptically filled into sterile vials, which are then closed with sterile rubber stoppers.

Each vial has a concentration of 75Rg active ingredient/150Rp injection solution.

Example IO Trompoxane Δ2 antagonist used is US Pat. No. 425
8058, such as 4-[2-(benzenesulfamide)edyl)fubunoquine acetic acid, as described in Example 9.
Manufactures an injection solution used to treat hypertension.

Example 1■ Thromboxane A used, the antagonist being [1S-[1α,
2β(5Z), 3β, 4α]]-7-[3-[[[[(
4-Cyclohexol -oxobutyl)amino]acetyl]aminocomethyl]-7-oxabicyclo[22,
1] An injection solution for treating hypertension is prepared according to the description in Example 9, except that hept-2-yl 1-5-heptenoic acid is used.

Example I2 200xg 5Q32324 and 400xg 5Q30
1000 tablets, each containing 741, are prepared from the following ingredients:

Layout 1 (d-cis)-1(acetyloxy)-1,3,4゜5
-tetrahydro-4-(4-methoxyphenyl)-1-
[2-(Methylamino)ethyl]-6-0lifluoromethyl)-2H-1-benzazepin-2-one monohydrochloride (SQ32324)...200 SQ30741 -400 Lactose
... +00 Abyssel
+50 cornstarch
50 stearic acid magnenouno 2.5'' 2.5Q3232/1.5Q30741, lactose and ahycel are mixed and then blended with cornstarch. Add Magnenium Stearate. The dry mixture was compressed in a tablet machine into 1000 tablets (505 mg) each containing 200 Mg of active ingredient.
η). These tablets contain IC as a coloring agent.
+ - Methyl cellulose (Me
Coat with a solution of Lhocel E I 5 ). The resulting tablets are useful for treating hypertension.

Example 13 50 mg of captopril and 250 sites of 5Q3074
Two-piece #1 geladine capsules, each containing 1, are filled with a mixture of the following ingredients:

Trowel ″L 〃5Q30
741 ・250 Captopril
・・50 Magnenium Stearate ・7 Lactose (USP)
-193 The resulting capsules are useful for treating hypertension.

Example I4 An injection solution for use in the treatment of hypertension is manufactured according to the following procedure.

Outside (d-cis)-3-(acetyloxy)-1-[2-dimethylamino)ethyl]-1.3,4.5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoro methyl)-28-1-benzazepin-2-one monohydrochloride (SQ31765)...500+9 SQ30741 -250η Methylparaben...5H propylparaben
11g sodium chloride
・ 25g water for injection (amount) ・
5Q above 5Q31765.5Q30741. The preservative and sodium chloride are dissolved in 3 ρ water for injection, then the volume is adjusted to 5 (2).The solution is filtered through a sterile filter and aseptically filled into sterile vials, which are then closed with sterile rubber stoppers. t1 of 5Rρ] Contains injection liquid,
Its concentration is 1001 g of active ingredient per 1 Rρ of injection solution.

Example 15 A tronofoxan antagonist/β-blocker formulation suitable for oral administration for the treatment of hypertension, prepared as described in Example I, is shown below.

100 O1 [l!] each containing 400 ml of trompoxan antagonist and /IOzg of atrol! 11 tablets are made from the following ingredients:

Suction 1SQ30741
-400 Troll
40 cornstarch
50 Geradine 75 Avicel (microcrystalline cellulose) 25 Magnesium stearate 2535 Example I6 The following experiment demonstrates that thromboxane receptor antagonists lower blood pressure.

As a thromboxane receptor antagonist [IS-[1α
, 2α(5Z), 3α, 4α]]-7-[3-[[[[
(1-oxoheptyl)amino'acetyl]amino]methyl]-7-oxabicyclo[2,2,1]hept-2
-yl]-5-heptenoic acid (hereinafter referred to as SQ) or plumbo (hereinafter referred to as PLA) in a healthy 12
Three groups of human subjects (8 in the SQ treatment group, 8 in the PL
4 people in administration group A). One 50g of SQ
3°6 or 12x9/h after administration as a 1V pill
r injections were given over a period of 48 hours. The 48 hour average pharmacodynamic (PD) parameters are as follows:

(*P<0.05 vs, PLA) SQ specifically inhibited TXΔ,-mediated platelet aggregation ex vivo at low and high agonist (U46619) concentrations. Mean platelet T X measured ex vivo
A v receptor (r() affinity and density were unchanged. When R occupancy is ≥99%, SQ
emplate) increases hemostasis time, but R occupancy is 5
70% of the time it's not.

These results indicate that thromboxane receptor antagonists reduce diastolic blood pressure.

Patent Applicant: E.R. Squibb & Zands Innocoholated

Claims (1)

[Scope of Claims] 1. A composition for treating high blood pressure in mammals, comprising a thromboxane A_2 receptor antagonist. 2. The composition according to claim 1, wherein the thromboxane A_2 receptor antagonist is a 7-oxabicycloheptane prostaglandin analog. The composition according to claim 2, wherein the 3,7-oxabicycloheptane prostaglandin analog is a 7-oxabicycloheptane-substituted diamide prostaglandin analog or a 7-oxybicycloheptane-substituted aminoprostaglandin analog. . The 4,7-oxabicycloheptane prostaglandin analog has the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A and B may be the same or different, and A is -C
H=CH- or -(CH_2)_2-, B is -CH=
CH-, -(CH_2)_2- or -C≡C-m_1
is 1 to 8;
Here, Z is H, lower alkyl, aryl, SO_2-
Q_1 (Q_1 is lower alkyl or aryl), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or -OR^2_b (
R^2_b is H); and Y is alkyl, substituted alkyl, aryl-lower alkyl, alkenyl, alkynyl, aryl, pyridyl, substituted pyridyl, pyridyl-lower alkyl, thienyl, substituted thienyl, thienyl-
3. The composition according to claim 2, which is lower alkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, or phenoxymethyl, and also includes stereoisomers thereof. The 5,7-oxabicycloheptane-substituted diamide prostaglandin analog has the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, m is 0 to 4; A is -CH=CH- or -CH_2-CH_2 -;n
is 1 to 5; Q is -CH=CH-, -CH_2-, ▲ mathematical formula, chemical formula,
There are tables, etc.▼▲There are mathematical formulas, chemical formulas, tables, etc.▼,
▲There are mathematical formulas, chemical formulas, tables, etc.▼ or single bond; R is -CO_2H, -CO_2・alkyl, -CO_2
・Alkali metal, -CO_2, polyhydroxyamine salt, -CH_2OH, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R
^4 and R^5 are the same or different and are H, lower alkyl, hydroxy, lower alkoxy or aryl, R
at least one of ^4 and R^5 excludes hydroxy or lower alkoxy); p is 1 to 4; R^1 is H or lower alkyl; q is 1 to 12; R^2 is H or lower alkyl; and R ^3 is H, lower alkyl, lower alkenyl, lower alkynyl, aryl, arylalkyl, lower alkoxy, arylalkyloxy, aryloxy, amino,
Alkylamino, arylalkylamino, arylamino, ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, n' is 0
, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl] and also includes stereoisomers thereof. Compositions as described in Section. The 6,7-oxabicycloheptane-substituted aminoprostaglandin analog has the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is -CH=CH- or -(CH_2)_2
−; m_1 is 1 to 8; n_1 is 0 to 5; Ra is hydrogen or lower alkyl; and R^1_a is lower alkyl, aryl, aralkyl, lower alkoxy, aralkoxy, or ▲ Numerical formula, chemical formula, table, etc. ▼ (here So, R^2_
a is lower alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylamino, arylamino or aralkylamino]
The composition according to claim 3, which also includes stereoisomers thereof. 7. Thromboxane A_2 receptor antagonist is [1S-[
1α, 2α (5Z), 3α (1E, 3R, 4S), 4α
]]-7-[3-(3-hydroxy-4-phenyl-1
2. The composition of claim 1, wherein the composition is 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid. 8. Thromboxane A_2 receptor antagonist is [1S-
[1α, 2α(5Z), 3α, 4α]]-7-[3-[
Claim 1, which is [[[(1-oxoheptyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or its corresponding tetrazole. Compositions as described in Section. 9. Thromboxane A_2 receptor antagonist is [1S-
[1α, 2α(Z), 3α, 4α]]-7-[3-[[
[[(4-cyclohexyl-1-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo[
The composition according to claim 1, which is 2.2.1]hept-2-yl]-5-heptenoic acid. 10. Thromboxane A_2 receptor antagonist [1S-
[1α, 2α (5Z), 3α, 4α]) -7-[3-[
[2-(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2
2. The composition of claim 1, wherein the composition is 5-heptenoic acid. 11. The composition according to claim 1, comprising a mixture of a thromboxane A_2 receptor antagonist and a diuretic. 12. The composition according to claim 1, comprising a mixture of a thromboxane A_2 receptor antagonist and an angiotensin converting enzyme inhibitor. 13. The composition of claim 1, comprising a mixture of a thromboxane A_2 receptor antagonist and a β-blocker. 14. The composition according to claim 1, comprising a mixture of a thromboxane A_2 receptor antagonist and a calcium duct blocker. 15. The composition according to claim 1, comprising a mixture of a thromboxane A_2 receptor antagonist and a vasodilator. 16. The composition according to claim 13, wherein the β-blocker is atrol, propranocal, atenolol, timolol, metaprolol, acebutolol or labetalol. 17. Angiotensin converting enzyme inhibitors include captopril, enalapril, lisinopril, fosinopril, SQ
13. The composition of claim 12, which is 29852 or zofenopril. 18. Thromboxane A_2 receptor antagonist and endopeptidase inhibitor or human ANF99-126
A composition according to claim 1, comprising a mixture of.