FR2646351A1 - USE OF AN ANTAGONIST OF THROMBOXANE A2 RECEPTORS FOR THE MANUFACTURE OF A MEDICAMENT FOR INHIBITING VASOSPASM AND THE PLATELET AGGREGATION RESULTING FROM ANGIOPLASTY - Google Patents

Abstract

To manufacture a medicament for inhibiting vasospasm and platelet aggregation resulting from angioplasty, a thromboxane A2 receptor antagonist which is a prostaglandin 7-oxabicycloheptane analog is used.

Description

t1 2646351

  USE OF A RECEPTOR ANTAGONIST

  THROMBOXANE A FOR MANUFACTURING

  OF A MEDICINE USED TO INHIBIT VASOSPASM

  AND THE RESULTING PLATELET AGGREGATION. ANGIOPLASTY

  The present invention relates to the use of thromboxane A2 receptor antagonists, and more particularly of 7-oxabicycloprostaglandins analogs, for inhibiting vasospasm and platelet aggregation.

resulting from angioplasty.

  Percum transluminal coronary angioplasty

  Balloon catheter or coronary angioplasty (both referred to hereinafter as angioplasty) is a technique for mechanically reshaping an artery to repair obstructive lesions. Simply put, this technique involves introducing a catheter, which has a deflated balloon incorporated, into an artery

  plugged and inflate the balloon to "reopen" the artery.

  This technique has proven to be very successful in the last

  years, and in many cases it presents advantages

  significant costs and safety in other methods

  medical and surgical treatment of blocked arteries. European patent application 0 256 805 discloses thromboxane receptor antagonists, of general formula oR2 '(CHE2) XWCOORI - n HO in which W is a linear C 1-7 or branched C alkylene group; X is a group -CH = CH- or -CH2CH2_ cis or trans; and, Y is a saturated heretocyclic amine group (attached to the cyclopentane nucleus via the nitrogen atom) whose cycle has 5 to 8 elements and (a) whose nucleus optionally contains -O-, -S- , -S02-, or -NR3 (R3 being a hydrogen atom, an alkyl radical in C1_7 or aralkyl having an alkyl part in CG1_4); and / or (b) which is optionally substituted by one or more C 1-4 alkyl radicals; which are said to be usable, either alone or in combination with thromboxane inhibitors

  synthase, for the treatment of ocular vascular disorders

  clusion. Included in the series of vascular disorders

  areas listed peri and postoperative complications

following angioplasty.

  Complications often associated with angio-

  Plasty are "restenosis" and acute thrombotic occlusion of the artery that has been opened. This reduction in the internal diameter of the artery and the blockage thereof

  themselves appear to be the result of an increase in the aggregate

  platelet and vasospasm. There are many theories that attempt to explain the mechanism of platelet aggregation and vasospasm following angioplasty, and since these mechanisms are not fully understood, the choice of an appropriate treatment is not. no

more.

  Chesebro et al., In an article entitled Restencsis After Arterial Angioplasty: A Hemorrheologic Response to Injury, Am. J. Cardiol., 1987; 60: 10B-16B, state that the region of the artery that has been dilated generally undergoes denudation of the endothelium resulting in immediate growth and aggregation of

  platelets. Chesebro et al. further reveal that the vaso-

  constriction that occurs in the artery is directly related to the deposition of platelets in this area. Chesebro et al.

  found that agents such as heparin, dipyri-

  damole, aspirin, nitroglycerin and ibuprofen have the effect of reducing platelet and thrombus dep8t. We have

  found that several other agents, for example the blo-

  calcium channel quorers and receptor antagonists

  thromboxane A2, reduced vasospasm but had no effect on platelet aggregation at the doses tested. Chesebro et al. further postulate that it is not clear that all platelet inhibition therapies

  successfully reduce restenosis induced by angioplasty.

  Harker, in his article titled Role of Platelets and Thrombosis in Mechanisms of Acute Occlusion

  and Restenosis After Angioplasty, Am. J. Cardiol. 1987; 60: 20B-

  28B, reviews the many avenues through which

  wind to make the deposit and aggregation of platelets. In fact, platelet aggregation likely involves thromboxane A2, ATP and platelet activating factors. Harker recognizes that, if the reduction of vascular occlusion in a number of arterial disorders has been demonstrated by a modification

  known pharmacological behavior of platelets, the indi-

  The cation for the use of agents that inhibit platelet function to reduce restenosis after angioplasty is unclear. This appears to be so due to the lack of definitive knowledge about the pathogenesis of the restenosis process and because of the theory that the formation of lesions resulting from injury

  mechanical, i.e. after angioplasty, may not

  not be governed by the same mechanisms as those that are

  responsible for other cases of stenosis.

  It is also thought that the occurrence of vaso-

  spasm, that is, narrowing of the artery, after angioplasty, is the result of a number of possible factors. For example, LeVeen et al., In Angioplasty-Induced

  Vasospasm in Rabbit Model, Mechanisms and Treatment, Investi-

  gative Radiology 1985; 20: 938-944, reveal that the causes

  of vasospasm induced by angioplasty are likely

  chosen between 1) - the myogenic response, ie a retre-

  reflex arterial cisse after extension of the wall

  arterial; 2) depletion of two vaso-dilata substances

  normally present, prostacyclin (PGI2) and endothelial relaxant factor (EDRF), resulting from the denudation of the endothelium by the catheter; 3) the

  deposit of platelets which, as we know, release vaso-cons-

  patient trictors; and 4) the deposition of platelets which can

  wind cause thrombosis, which in turn can induce vasospasm. LeVeen et al. found that the

  verapamil, which is a calcium channel blocker, reversible

  knows vasospasm after onset but was powerless to prevent it. Similarly, dazoxiben, a

  thromboxane synthase inhibitor, reduced vaso-

  spasm, 'but did not suppress or poke it.

  Although the above-mentioned European patent application 0 256 805 discloses specific antagonists of

  thromboxane receptors which are said to be suitable for use

  with angioplasty, all the antagonists of

  thromboxane receptors may not prove useful

  them in this processing area. For example - since thromboxane receptor antagonists inhibit blood clotting, intramural hemorrhage in the treated vessel may be an adverse reaction

  possible. In addition, the use of receptor antagonists

  Thromboxane levels could result in up-regulation of platelet thromboxane receptors - possibly leading to a risk of thrombosis for the vessel after treatment is stopped. It is also believed that certain thrombin receptor Ges antagonists may have significant agonist activity. In a published example, Throm. Res., 58: 181, 1987, patients treated with BM 13 177 have

  actually developed angina pectoris, and the subsequent study

  drug should be discontinued if behavioral modifiers

  platelets (the antagonists of the throm-

  boxane for example), vasodilators and similar substances may appear to be obvious choices for the treatment and / or prevention of restenosis and thrombotic occlusion resulting from angioplasty,

  the plethora of possible mechanisms and inconsistent testing

  Clutters, as noted above, do little to predict the success or failure of any given agent or family of agents. This is why drugs which can be used to inhibit vasospasm and platelet aggregation resulting from angioplasty would constitute a useful contribution.

to medical technology.

  The subject of the present invention is the use of

  tion of a thromboxane A2 receptor antagonist for the manufacture of a medicament for inhibiting the

  vasospasm and platelet aggregation resulting from angio-

  plasty. The term "receptor antagonist

  thromboxane A2 "11, as used herein includes the compounds

  which are called throm- receptor antagonists

  boxane A2, thromboxane A antagonists and endo-

2 2

  prostaglandin peroxides, TP receptor antagonists, or thromboxane antagonists, except insofar as the compound is only an inhibitor of the synthesis of

thromboxane.

  The thromboxane receptor antagonist

  To which is used here will be an analogue of 7-oxabicyclo-

  heptane prostaglandin and will include 7-oxa- analogs

  prostaglandins substituted bicycloheptane diamide which are described in US Patent No. 4,663,336,

  analogs of 7-oxabicycloheptane amino substituted prosta-

  glandines which are described in the US patent

  from America Na 4 416 896, and analogs of 7-oxabicyclo-

  heptane prostaglandins which are described in the patent of

  United States of America N 4- 537 981.

  The prostaglandin substituted 7-oxabicycloheptane diamide analogs which can be used here, as described in E.U.A. No 4 663 336, have the formula (CH 2) m-A- (CH2) n-Q-R * 2m2 1 "*

3 0 (CHE) -N-C- (CEH2) -NC-R3

  2 2 12 g including all their stereoisomers, formula in which m is a number from O to 4; A is -CH = CH- or -CH2-CH2-; n is a number from 1 to 5; Q is -CH = CH-, -CH2, OH Halo Halo Halo

-CH-, - H -, - C-

  or a single bond; R is C02H, CO2alkyl, CO2 alkali metal, CO2 polyhydroxyamine salt, -CH2 OH, O II or -CNR R5 o R and R5 are identical or different and are hydrogen or a lower alkyl group, hydroxy, lower alkoxy

  or aryl, at least one of R and R5 being other than a group-

  hydroxy or lower alkoxy; p is a number from 1 to 4; R is hydrogen or a lower alkyl radical; q is a number from 1 to 12; R is hydrogen or an alkyl radical

  inferior; and R3 is hydrogen or a lower alkyl radical

  laughing, lower alkenyl, lower alkynyl, aryl, aryl-

  alkyl, lower alkoxy, arylalkyloxy, aryloxy, amine, alkylamine, arylalkylamine, arylamine,

(> '() O

  aIkyl in1rieur $ -, aryl-S-, arzlalkyl-S-,

(O) '(O)' (O

() () n () n

  ary -S-alI- l - a kyl-, ar-lalkyl-S-alkyL? -

  (o n 'is 0, 1 or 2}, alkylam-1-noalkyle, arylamino-

  alkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl The prostaglandin-substituted 7-oxabicycloheptane amino analogs which can be used here, as described in the patent E.U.A. N 4 416 896, have the formula

: X j. î2 (CE.). l-C00R.

  o including all their stereoisomers, formula in which A is CH = CH or (CH2) 2; m1 is a number from 1 to

  8; n is a number from 0 to 5 ;; R is hydrogen or a radi-

  cal a; lower kyle; and R1 is a lower alkyl, aryl, aralkyl, lower alkoxy, aralkoxy or

0

fi 2

-NH-C-R

  a o R2 is a lower alkyl, aryl, aralkyl, a radical

  alkoxy, aryloxy, aralcoxy, alkylamine, arylamine or aralkyl-

amine.

  Analogs of 7-oxabicycloheptane prosta-

  glandins which can be used here, as described in the E.U.A. N 4,537,981, have the formula

** CH-A- (CH2) -X

  | B-cH-Y including all their stereoisomers, formula in which A and B may be the same or different and A is CH = CH or (CH2) 2; B is CH = CH, CeC or (CH2) 2; m1 is a number from 1 to 8; X is OH; A-N -Cv CO2Ra o R is hydrogen or a lower alkyl radical; 2a a or O

CNH-Z

  o Z is hydrogen, or a lower alkyl, aryl, SQ2-Q1 group (Q1 being a lower alkyl or aryl radical), t! C-Q1 or OR o Rb is hydrogen, and Y is an alkyl, b b or substituted alkyl radical; lower arylalkyl; alkenyl; alkynyl, aryl; pyridyle; substituted pyridyB; pyridyl-lower alkyl; thienyl, substituted thienyl '; thienyl-lower alkyl; cycloalkyl; cycloalkylalkyl; substituted cycloalkylalkyl;

or phenoxymethyl.

  Preferred examples of thromboxane A2 receptor antagonists which can be used here include 7-oxabicyclohepraneS which are described in E.U.A. N 4,537,981, especially acid [1S- [1E, 2C

  (Z), 3 (1E, 3S *, 4R *), 4J]] - 7- [3- (3-hydroxy-4-phenyl-1-pentenyl) -

  7-oxabicyclo [2.2.1] hept-2-yl] -5-hepténo! Que; the prostaglandin substituted amino 7oxabicycloheptane analogs which are described in the E.U.A. No. 4,416,896, in particular EIS-E acid [1,2 (Z), 3,4]] - 7- [3 [[2- (phenylamino) carbonyl] hydrazino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-heptenoic;

  analogs of 7-oxabicycloheptane diamide substituted pros-

  taglandins which are described in the E.U.A. NOT

  4,663,336, including acid [IS-E1I, 20 (Z), 3 ", 441] -7-E3-

  EEEE [[[(1-oxoheptyl) aminoaacetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2yl] -5-heptenoic and the corresponding tetrazole,

  and acid [1S-E [11, 2 (Z), 3O, 4] J1-7-e3- [E [E (4-cyclohexyl-1-

  oxobutyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-

2-yl] -5-heptenoic.

  Descriptions of the above-mentioned patents

  are incorporated here for reference.

  In the practice of the present invention, the thromboxane A2 receptor antagonist can be administered by the systemic route, for example by the oral or parenteral route, to mammalian species such as monkeys, dogs, cats, rats, men , etc., before, during and / or

after angioplasty.

  The thromboxane A receptor antagonist can be incorporated into a conventional dosage form,

  such as tablet, capsule, elixir or injectable product.

  The preceding dosage forms will also include the carrier, the excipient, the lubricant, the buffer, the antibacterial agent, the volume agent (such as mannitol), the anti-oxygen cells (ascorbic acid or sodium bisulfite), or similar products required. Oral dosage forms are preferred, but parenteral forms are all

also satisfactory.

  With regard to systemic formulas, single or divided doses of about 0.1 to about 2500 mg, preferably about 5 to 200 mg from one to four times a day, can be administered in systemic dosage forms such as than those described above for an extended period of time, i.e. four weeks to six months, or longer, starting

at the time of angioplasty.

  The following examples represent forms-

  preferred embodiments of the present invention.

Example 1

  An antagonist solution for injection is prepared.

  nist of thromboxane A2 receptors for intravenous use for the inhibition of vasospasm and platelet aggregation, from the following ingredients:

  Acid [1S- [1,2ô (Z), 3 (, 40]] - 7- [3 - [[2-

(phenylamino) carbonyljhydrazino] -

  methyl] -7-oxabicyclo [2.2.1] hept-2-ylJ-

  heptenoic (SQ 29 548) 2500 mg Methyl parahydroxybenzoate 5 mg Propyl parahydroxybenzoate I mg Sodium chloride 25 g Water for injection, sufficient to make 5 1 Dissolves the thromboxane A2 receptor antagonist, preservatives and chloride of sodium in 3 liters of water for injection, then the volume is brought to 5 liters. The scout is filtered on a sterile filter and aseptically filled with pre-sterilized vials that

  it is then closed with pre-closed rubber closures

  sterilized. Each ampoule contains a concentration of

  75 mg of active ingredient for 150 mg of solution.

Example 2

  A solution for injection is prepared for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty, as described in Example 1, except that the thromboxane A2 receptor antagonist is the acid [1S-E1,2K (Z), 3C

  (11E, 3S *, 4R *), 40 (] - 7-E3- (3-hydroxY --- phenyl-1-pentnyl) -7-oxa-

  bicyclo [2.2.1] hept-2-yl] -5-heptenoic (SQ 28 668).

Example 3

  A solution for injection of the thromboxane A2 receptor antagonist is prepared, as described in Example 1, for use in inhibiting

  vasospasm and platelet aggregation resulting from angio-

  plasty, containing acid [1S- [1O, 2 (C "Z), 3o, 4V]] - 7- [3-

  EE [[[[(1-oxoheptyl) -amino] acetyl] amino] methyl] -7-oxabioyclo-

  [2.2-1] -hept-2-yl] -5-heptenoic (SQ 30 741) as an antagonist

  nists of thromboxane A2 receptors.

Example 4

  A solution for injection 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 used is 1 [E1S- [1C, 2 "(Z), 3Y, 4]] -7-E3 - [[[C (4-cyclohexyl-1-oxobutyl) amino] acetyliamino] methyll-7oxabicyclo-E2.2.1] hept -2-yl] -5-heptenoic (SQ

31 491).

Example 5

  A thromboxane A2 antagonist formulation suitable for oral administration for use in inhibiting vasospasm and platelet aggregation

  resulting from angioplasty, is described below.

  1000 tablets, each containing 400 mg of thromboxane A2 receptor antagonist, are prepared from the following ingredients: Acid [E1S- [11,2 "(Z), 30, 4"]] - 7- [3- [ [[[(1-oxoheptyl) amino]

  acetyl] amino] methyl] -7-oxabicyclo [2.2.1] lhept-2-yll-5-hepténoi-

  as (SQ 30 741) 400 g Corn starch 50 g Gelatin 7.5 g Avicel (microcrystalline cellulose) 25 g Magnesium stearate 2.5 g il The thromboxane A2 receptor antagonist and corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground into a

  fine powder. We mix the Avicel, then the magnesium stearate-

  sium, with granulation. We then compress the mixture

  resulting in a tablet press to form 1000 com-

  awards each containing 400 mg of active ingredient.

Example 6

  A tablet formulation is prepared.

  of thromboxane A for use in inhibiting vasospasm and platelet aggregation resulting from angioplasty, as described in Example 5, except that SQ 29 548 is used as the antagonist

  thromboxane A2 receptors in place of SQ 30 741.

Example 7

  An antagc tablet formula is prepared

  of thromboxane A for use in inhibiting vasospasm and platelet aggregation resulting from angioplascia, as described in Example 5, except that SQ 28 668 is used in place of SQ 741.

Claims (9)

  1. Use of a thromboxane A2 receptor antagonist for the manufacture of a medicament for inhibiting vasospasm and platelet aggregation resulting from angioplasty in a mammalian species, said thromboxane A2 receptor antagonist being a   7-oxabicycloheptane prostaglandin analog.   2. Use according to claim 1, in which the analog of 7oxabicycloheptane prostaglandin is an analog of 7-oxabicycloheptane diamide substituted prostaglandin or an analog of 7-oxabicycloheptane amino substituted prostaglandin.   3. Use according to claim 1, in which the analog of 7oxabicycloheptane prostaglandin has the formula CH2-A- (C2) m -X B-CE-Y   o including all its stereoisomers, formula in which A and B can be identical or different and A is CH = CH or (CH2) 2; B is CH = CH, C-C or (CH2) 2; m1 is a number from 1 to 8; Xest OH; N - N N-N H   CO R o R is hydrogen or a lower alkyl radical; - 2a a or O I CNH-Z   o Z is hydrogen, or a lower alkyl or aryl group, SO2-Q1 (Q1 being a lower alkyl or aryl radical), II C-Q1, 2   or Zb o Rb is hydrogen and Y is an alkyl radical; substituted alkyl; aryl-lower alkyl; alkenyl; alkynyl, aryl; pyridyle; substituted pyridyl; pyridyl-lower alkyl; thienyl, substituted thienyl; thienyl-lower alkyl; cycloalkyl; cycloalkylalkyl; substituted cycloalkylalkyl; or phenoxymethyl.   4. Use according to claim 2, in which the prostaglandin substituted 7oxabicycloheptane diamide analog has the formula / ((C 2) -A- (CE) ,, - Q-R (1 * 1 * \ [(2 p: 1 1 il _ 2) q_ t12_ O R O   including all of its stereoisomers, formula in which m is a number from 0 to 4; A is -CH = CH- or -CH 2-CH2-; n is a number from 1 to 5; Q is CH = CH-, -CH2, OH Halo Halo Halo - & H-, -CH-, -C_   or a single bond; R is C0 2H, C02alkyl, C0 2 alkali metal, CO2 polyhydroxyamine salt, -CH20H, N - N 1 or S-N -CR _vs_:! QU_ lR4R5 H 4 5   o R and R are the same or different and are hydro-   gene or a lower alkyl, hydroxy, lower alkoxy or aryl group, at least one of R and -R5 being other than a hydroxy or lower alkoxy group; p is a number from 1 to 4; R is hydrogen or a lower alkyl radical; q is a number from 1 to 12; R is hydrogen or a lower alkyl radical; and R3 pst hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl, ary! alkyl, lower alkoxy, arylalkyloxy, aryloxy, amine, alkylamine, arylalkylamine, arylamine, (O) n, (O) n '( ) n 'alkyl infiur S - ,, r aIkyl riur S-, aryl-S-, arylalkyl-S-, (0) n, (0) I, I nt Il n aryl-S-alkyl-, alkyl-S- alkyl-, arylalkyl-S-alkyl   (o n 'is equal to 0, 1 or 2), alkylaminoalkyle, arylamino-   alkyl, arylalkylaminoalkyle, alkoxyalkyle, aryloxyalkyle or arylalkoxyalkyle. 5. Use according to claim 2, in which the prostaglandin substituted amino 7-oxabicycloheptane analog has the formula * * CH2-A- (CH2) ml COORa t * (CE2) n -NEH-Ri O including all of its stereo -isomers, formula in which A is CH = CH or (CH2) 2; m1 is a number from 1 to 8; n1 is a number from 0 to 5; R is hydrogen or a lower alkyl radical 1a; and R is a lower alkyl, aryl, aralkyl, lower alkoxy, aralkoxy or Il 2 radical -NH-C-R   2 a o R is a lower alkyl, aryl, aralkyl, a- radical   alkoxy, aryloxy, aralcoxy, alkylamine, arylamine or aralkyl- amine.   6. Use according to claim 1, wherein the thromboxane A receptor antagonist   is acid [lS- [lK, 20 (Z), 3 (1E, 3S *, 4R *), 4 &]] - 7- [3- (3-hydroxy-   4-phenyl-1-pentenyl) -7-oxabicyclo [2.2.1] hept-2-ylI-5-hepté noique.   7. Use according to claim 1, in which the thromboxane A_ receptor antagonist is [1S-E1i, 2 (Z), 3U, 44]] - 7-E3 [[EE (1-oxoheptyl) acid   amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yi] -5-   heptenoic or the corresponding tetrazole. 8. Use according to claim 1, wherein the thromboxane A2 receptor antagonist   is acid [1S- [1E, 20 (Z), 30,4O ']] - 7- [3 - [[E (4-cyclohexyl-1-   oxobutyl) aminolacetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept- 2-yl] -5-heptenoic.   9. Use according to claim 1, in which the thromboxane A2 receptor antagonist is [1S- [E1l, 2v (Z), 30C, 40q] -7- [3 [[2- (phenylamino) acid   carbonyl] hydrazino] methyl] -7-oxabicyclo [2.2.1] nept-2-yl] -5- heptenoic.