CA2012852A1

CA2012852A1 - Method of inhibiting vasospasm and platelet aggregation resulting from angioplasty using thromboxane a receptor antagonists

Info

Publication number: CA2012852A1
Application number: CA002012852A
Authority: CA
Inventors: Miguel A. Ondetti; Martin L. Ogletree; Don N. Harris
Original assignee: Individual
Current assignee: Individual
Priority date: 1989-05-01
Filing date: 1990-03-22
Publication date: 1990-11-01
Also published as: GB2231795A; GB9009636D0; IT9020136A0; JPH02295922A; DE4013680A1; IT1240681B; IT9020136A1; FR2646351A1

Abstract

HA491 METHOD OF INHIBITING VASOSPASM AND PLATELET AGGREGATION RESULTING FROM ANGIOPLASTY USING THROMBOXANE A2 RECEPTOR ANTAGONISTS Abstract A method is provided for inhibiting vasospasm and platelet aggregation resulting from angioplasty by administering a thromboxane A2 receptor antagonist before, during and/or after the angioplasty procedure, which thromboxane A2 receptor antagonist is a 7-oxabicycloheptane prostaglandin analog.

Description

METHOD OF INHIBITING VASOSPASM AND PLATELET
AGGREGATION RESULTING FROM ANGIOPLASTY USING
~H.OM~L~O~y~ L_ ~CEPTOR ANTAGONISTS

S : :
The present invention relates to a method for inhibiting vasospasm and platelet aggregation resulting from angioplasty using thromboxane A2 receptor antagonist~, and is more particularly concerned with such a method using 7-oxabicyclo-prostaglandin analogs.

Percutaneous transluminal coronary angiopla~ty, or balloon catheter coronary angioplasty, (both referred to hereinafter as angioplasty) is a procedure for mechanically reshaping an artery so as to alleviate obstructive -~ lesions. Simply stated, the procedure involves introducing a catheter having a deflated balloon incorporated therein into an occluded artery and inflating the balloon in order to "reopen" the artery. ~his procedure has proven to be very successful in recent years and in many cases offers significant cost and safety advantages compared to alternative medical and surgical methods of treating occluded arteries.
European Patent Application 0,256,~05 discloses thromboxane receptor antagonists of the general formula 201Z8SZ~

oR2 ( CH2 ) nXWCOOR
<~
O Y
wherein W is straight or branched C1 7 alkylene;
X is cis or ~rans -CH=CH- or -CH2CH2-; and, Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which has 5-8 ring members and (a) optionally contains in the ring -O-, -S-, -SO2-, or -NR3 (where R3 is a hydrogen atom, C1 7 alkyl or aralkyl having a C1 4 alkyl portion); and/or (b) is optionally substituted by one or more C1 4 alkyl groups;
which are said to be useful, either singly or in combination with thromboxane synthase inhibitors, for the treatment of occlusive vascular diseases. Included in the series of vascular disorders listed is the use for peri- and post-operative complications following angioplasty.
Complications often associated with angioplasty are restenosis and acute thrombotic occlusion of the artery which has been opened.
This reduction in inside diameter of the artery and blockage thereof appear, in turn, to result from increased platelet aggregation and vasospasm. There are numerous theories attempting to explain the mechanism for platelet aggregation and vasospasm following angioplasty, and since the mechanisms are not completely understood, neither is the choice of suitable treatment.
Chesebro et al., in a paper entitled Restenosis After Arterial Angio~lasty: A
Hemorrheologic Res~onse to Injury~ Am. J. C~rdiol.

2(~1285:2 1987; 60:10B-16B, state that the region of the artery which has been dilated typically undergoes denudation of the endothelium resulting in immediate platelet growth and aggregation.
Chesebro et al. further disclose that vasoconstriction which occurs in the artery is directly related to the platelet deposition in that area. Chesebro et al. have found agents such as heparin, dipyridamole, aspirin, nitroglycerin and ibuprofen to be effective in reducing platelet-thrombus deposition. Several other agents, e.g. calcium channel blockers and thromboxane A2 receptor antagonists, were found to reduce vasospasm but had no effect on platelet aggregation at the dosages tested. Chesebro et al. additionally postulate that it is not clear that all platelet inhibition therapies will successfully alleviate angioplasty-induced restenosis.
Harker, in his article, Role of Platelets and Thrombosis in Mechanisms of Acute Occlusion and Restenosis After AngioPlastv, Am. J. Cardio 7 .
19~7; 60:20B-28B, reviews the numerous pathways responsible for mediating platelet deposition/
aggregation. Indeed, platelet aggregation probably involves thromboxane A2, adenosine diphosphate and platelet-activating factor pathways. Harker acknowledges that while reduction in vascular occlusion in a number of arterial disorders has been demonstrated by known pharmacologic modification of platelet behavior, the indication for the use of agents that inhibit platelet function for reducing restenosis after angioplasty is not clear. This seems to be so because of the lack of definitive knowledge of the pathogenesis of the restenosis process, and because of the theory that lesion formation resulting from mechanical injury, i.e. after angioplasty, may not be governed by the same mechanisms responsible for other stenosis occurrences.
The occurrence of vasospasm, i.e.
constriction of the artery, from angioplasty is similarly believed to be the result of a number of possible factors. For example, LeVeen et al. in AnqioPlastv-Induced VasosDasm in Rabbit Model, Mechanisms and Treatment, Investigative Radiol ogy 1985; 20:938-944, disclose that the causes of angioplasty-induced vasospasm are likely selected from 1) myogenic response, i.e. reflex arterial constriction from the str~tch of the arterial wall; 2) depletion of two otherwise-present vasodilating substances, prostacyclin (PGI2) and endothelial derived relaxing factor (EDRF), resulting from`the denudation of the endothelium by the catheter; 3) deposition of platelets which are known to release patent vasoconstrictors; and 4~ deposition of platelets which can cause thrombosis which may itself induce vasospasm.
LeVeen et al. found verapamil, a calcium channel blocker, to reverse established vasospasm but to be ineffective in prevention. Similarly, dazoxiben, a thromboxane synthase inhibitor, was found to reduce vasospasm, but not eliminate it or prevent it.
Although, the above-mentioned European Patent Application 0,256,805 discloses specific thromboxane receptor antagonists which are stated to be suitable for use with angioplasty, all 2(~Z85~

_5_ thromboxane receptor antagonists may not prove useful in this area of treatment. For example, to the extent thromboxane receptor antagonists inhibit blood coagulation, intramural hemorrhage in the treated vessel may be a possible adverse reaction. Further, use of thromboxane receptor antagonists could result in up regulation of platelet thromboxane receptors possibly leading to a thrombotic risk for the treated vessel following drug withdrawal. Also, it is believed that some thromboxane receptor antagonists may have significant agonist activity. In one published example, Throm. Res., 58:181, 1987, patients treated with BM 13,177 did develop angina and the drug had to be withdrawn from further study.
While platelet behavior modification agents (e.g., thromboxane receptor antagonists), vasodilators and the like may appear to be obvious choices for the treatment/prevention of restenosis and thrombotic occlusion resuIting from angioplasty, the plethera of possible mechanisms and unsuccessful trials as outlined above are hardly considered predictive o the success or failure of any given agent or class of agents.
Therefore, medicaments useful in inhibiting vasospasm and platelet aggregation resulting from angiopl~sty would be a useful addition to the medical art.

:~OlZ85~

In accordance with the present invention, a method is provided for inhibiting vasospasm and platelet aggregation resulting from angioplasty wherein a therapeutically effective amount of a thromboxane A2 receptor antagonist is systemically administered, such as orally or parenterally.
The term "thromboxane A2 receptor antagonist" as employed herein includes compounds which are so-called thromboxane A2 receptor antagonists, thromboxane A2 antagonists, thromboxane A2/prostaglandin endoperoxide antagonists, TP-receptor antagonists, or thromboxane antagonists except insofar as the compound is solely an inhibitor of thromboxane synthesis.
The thromboxane A2 receptor antagonist employed herein will be a 7-oxabicycloheptane prostaglandin analog and will include 7-oxabicyclo-heptane substi~uted diamide prostaglandin analogs as disclosed in U.S. Patent No. 4,663,336, 7-oxa-bicycloheptane substituted amino prostaglandin _7_ HA491 analogs as disclosed in U.S. Patent No. 4,416,896 and 7-oxabicycloheptane prostaglandin analogs as disclosed in U.S. Patent No. 4,537,981.
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
10 ~

(CH2)p-I--~-(CH2)q~I--lCI-R

including all stereoisomers thereof, wherein m is O
: to 4; A is -CH=CH- or -CH2-CH2-; n is 1 to 5; Q is -CH=CH-, -CH2~

OH Halo Halo /Halo -CH-, -CH-, -C-or a single bond; R is CO2H, CO2alkyl, CO2 alkali metal, CO2polyhydroxyamine salt, -CH2OH, N- N

~ N - N or -CNR4R5 H

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; Rl is H or lower 201Z85~

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, (1l)n~ (~I)n' (1l) lower alkyl-S-, aryl-S-, arylalkyl-S-, (1l)n~ (1l)n~ (1l)n~
aryl-S-alkyl-, alkyl-S-alkyl-, arylalkyl-S-alkyl (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl.
The 7-oxabicycloheptane substituted amino prostaglandin analogs suitable for use herein, as disclosed in U.S. Patent No. 4,416,896, have the formula * CH2-A-(CH2)ml~ CRa < i*
\~
~\ I ( CH2 )nl NH Ra : 25 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 Ra is lower alkyl, aryl, aralkyl, lower alkoxy, aralkoxy or G
-NH-C-Ra 2~)~Z85Z

wherein R2 is lower alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylamino, arylamino or aralkylamino.
The 7-oxabicycloheptane prostaglandin S analogs suitable for use herein, as disclosed in U.S. Patent No. 4,537,981, have the formula CH2-A-(CH2)m -X
< I l*

B-CH-Y
O OH

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 OEI;
,N - N
-C~
\ N - N

CO2Ra wherein Ra is H or lower alkyl; or O
CNH-~
wherein Z is H, lower alkyl, aryl, SO2-Q
(with Q1 being lower alkyl or aryl), o C-Q1, or ORb wherein ~ is H, and Y is alkyl, substituted alkyl; aryl-lower alkyl; alkenyl;
alkynyl, aryl; pyridyl; substituted pyridyl;

2~Z~S~

pyridyl-lower alkyl; thienyl, substituted thienyl;
thienyl-lower alkyl; cycloalkyl; cycloalkylalkyl;
substituted cycloalkylalkyl; or phenoxymethyl.
Preferred examples of thromboxane A2 receptor antagonists which may be employed herein include the 7-oxabicycloheptane compounds disclosed in U.S. Patent No. 4,537,981, especially, [lS-[la,2a(Z),3a(1E,3S*,4R*),4a]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid; the 7-oxabi-cycloheptane substituted amino-prostaglandin analogs disclosed in U.S. Patent No. 4,416,896, especially, [lS-[la,2a,(Z),3a,4a]]-7-[3-[[2-(phenylamino)carbonyl]hydrazino]methyl]-7-oxa-bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; the 7-oxabicycloheptane substituted diamide prostaglandin analogs disclosed in U.S. Patent No.
4,663,336, especially, [lS-[la,2a(Z),3a,4a]~-7-[3-[[[[(1-oxoheptyl)amino~acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid and the corresponding tetrazole, and [lS-[la,2a(Z),3a,4a]]-7-~3-[[[[(4-cyclohexyl-l-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid.
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., prior to, during and/or after the angioplasty process.

2~)1285Z

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, buffer, 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 from about 0.1 to about 2500 mg, preferably from about 5 to 200 mg/one to four times daily, may be administered in systemic dosage forms as described above for a prolonged period, that is, four weeks to six months, or longer, beginning at the time of the angioplasty procedure-.

2~)~285~

The following Examples represent preferred embodiments of the present invention:

Example 1 An injectable solution of thromboxane A2 receptor antagonist for intravenous use in the inhibition of vasospasm and platelet aggregation resulting from angioplasty is produced as follows:

[lS-[1~,2~(Z),3~,4~]]-7-[3-[[2-(phenylamino)carbonyl]hydrazino]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 29,548)2500 mg Methyl paraben 5 mg 15 Propyl paraben 1 mg Sodium chloride 25 g Water for injection qs. 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 presterilized vials which are then closed with presterilized rubber closures. Each vial contains a concentration of 75 mg of active ingredient per 150 mg of solution.

Example 2 An injectable for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty is prepared as described in Example 1 except that the thromboxane A2 receptor antagonist employed is [lS-[la,2a(Z),3a(1E,3S*,4R*),4a]]-7-[3-(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 inhibiting vasospasm and platelet aggregation resulting from angioplasty containing [lS-[la,2a(Z),3a,4a]]-7-[3-[[[[(1-oxo-heptyl)-amino]acetyl]amino]methyl]-7-oxabicyclo-[2.2.1]-hept-2-yl]-5-heptenoic acid (SQ 30,741) as the thromboxane A2 receptor antagonist is prepared as described in Example 1.

Example 4 An injectable for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty is prepared as described in Example 1 except that the thromboxane A2 receptor antagonist employed is [lS-[la,2a(Z),3a,4a]]-7-[3-[[[[(4-cyclohexyl-l-oxo-butyl)amino]acetyl]amino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 31,491).

2~)~285:;~

ExamPle 5 A thromboxane A2 antagonist formulation suitable for oral administration for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty is set out below.
1000 tablets each containing 400 mg of thromboxane A2 receptor antagonist are produced from the following ingredients.

[ls-[la~2a(z)~3a~4a]]-7-[3-t[[[( Oxoheptyl)amino]acetyl]amino]methyl]~
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ 30,741) 400 g Corn starch 50 g 15 Gelatine 7.5 g Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g The thromboxane A2 receptor antagonist and corn starch are admixed with an aqueous solution of the gelatin. The mixture is dried and ground to a find powder. The Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to form 1000 tablets each containing 400 mg of active ingredient.

2~)1Z8SZ

Exam~le 6 A thromboxane A2 antagonist tablet formulation for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty is prepared as described in Example 5 except that SQ 29,548 is employed as the thromboxane A2 receptor antagonist in place of SQ 30,741.

Exam~le 7 10 A thromboxane A2 antagonist tablet formulation for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty is prepared as described in Example 5 except that SQ 28,668 is employed in place of SQ 30,741.

Claims

What is claimed s:

1. A method for inhibiting vasospasm and platelet aggregation resulting from angioplasty in a mammalian species, which comprises adminis-tering to a mammalian species in need of such treatment an effective amount of a thromboxane A2 receptor antagonist, which thromboxane A2 receptor antagonist is a 7-oxabicycloheptane prostaglandin analog.

2. The method as defined in Claim 1 wherein the 7-oxabicycloheptane prostaglandin analog is a 7-oxabicycloheptane substituted diamide prostaglandin analog or a 7-oxabicyclo-heptane substituted amino prostaglandin analog.

3. The method as defined in Claim 1 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 R? 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.

4. The method as defined in Claim 2 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 hond; 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 (wherein n' is 0, 1 or 2), alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl.

5. The method as defined in Claim 2 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, aryl, aralkyl, lower alkoxy, aralkoxy or -NH-?-R?
wherein R? is lower alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylamino, arylamino or aralkylamino.

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

7. 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-[[[[(1-oxoheptyl)amino]acetyl]amino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or the corresponding tetrazole.

8. 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-cyclo-hexyl-1-oxobutyl)amino]acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

9. The method as defined in Claim 1 wherein the thromboxane A2 receptor antagonist has the name [lS-[la,2a(Z),3a,4a]]-7-[3-[[2-(phenyl-amino)carbonyl]hydrazino]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 is administered orally or parenterally.

11. The method as defined in Claim 1 wherein the thromboxane receptor antagonist is administered in single or divided doses of from about 0.1 to about 2500 mg/one to four times daily.