GB2217601A - Pharmaceutical combinations for the treatment of thrombotic disorders - Google Patents

Abstract

The use of both (i) a compound of formula (1) <IMAGE> wherein R<1> is a hydrogen atom or a methyl group; X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n is 1; or X is trans -CH=CH-, m is zero and n is 3; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which a has 5-8 ring members and (a) optionally contains in the ring -O-, -S-, -SO2- or NR<3a>; and/or (b) is optionally substituted by one or more alkyl groups; Alk is a straight or branched C1-5 alkyl chain; l is zero or 1; p is zero, 1, 2, 3 or 4; R<2> is a hydroxyl group or a group selected from -OCOR<3>, -CO2R<3>, -CONR<3>R<4>, -SO2NR<3>R<4> -NHCOR<3>, -NHSO2R<5>, -SO2R<5>, -SR<5>, -NR<3>R<4>, -COR<5>, NHCONR<3>R<4> and -NHCSNH2; R<3>, R<3a> and R<4>, which may be the same or different, represent a hydrogen atom or a C1-4alkyl or C7-10 aralkyl group; and R<5> is a C1-4 alkyl group; or a physiologically acceptable salt, solvate or cyclodextrin complex thereof and (ii) a thrombolytic agent in the therapy or prophylaxis of thrombotic disorders. Pharmaceutical compositions containing both (i) and (ii) are also described.

Description

PHARMACEUTICAL COMBINATIONS FOR THE TREATMENT or THROMBOTIC DISORDERS The present invention relates to a combination of a thrombolytic agent with certain thromboxane receptor blocking agents, to pharmaceutical formulations containing them, and to their use in human or veterinary medicine.

Blood clots are composed of fibrin which forms from its soluble precursor fibrinogen under the auction of the enzyme thrombin.

Mammalian plasma contains an enzymatic system capable of dissolving the fibrin in blood clots. In cases where the thrombolytic potential of the body is insufficient to remove intravascular thrombi it is often necessary to use exogenously administered thrombolytic agents.

However, although thrombolytic agents have been shown in human studies to rapidly dissolve blood clots, it has also been demonstrated that after administration the obstruction is not resolved or the obstruction re-occurs in a significant proportion of patients.

In EP-A-0296802 we describe compounds having the general formula (1 >

wherein R1 is 8 hydrogen atom or a methyl group; X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n is 1; or X is trans -CH=CH-, m is zero and n is 3; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which e has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, -SO2- or NR3; and/or (b) is optionally substituted by one or more alkyl groups; Alk is a straight or branched C15 alkyl chain; X is zero or 1; p is zero, 1, 2, 3 or 4;; R2 is a hydroxyl group or a group selected from -OCOR3, -C02R3, -CONR3R4, -S02NR3R4 -NHCOR3, -NHSO2R5, -S02R5, -SR5, -NR3R4, -COR5,-NHCONR3R4 and -NHCSNH2; R3, R38 and R4, which may be the same or different, represent a hydrogen atom or a C14 alkyl or C7-10 aralkyl group; and R5 is a C14 alkyl group; and the physiologically acceptable salts, solvates and cyclodextrin complexes thereof.

We have stated therein that such compounds inhibit thromboxane A2 and endoperoxide mediated aggregation of blood platelets and contraction of vascular muscle and are thus of particular interest as snti-thrombotic agents.

We have now found that it is beneficial to coadminister a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof. A compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof and a thrombolytic agent in combination therapy is therefore of interest for use in human and veterinary medicine, more particularly for use in the treatment or prophylaxis of thrombotic disorders. The benefit of co-administration of the two agents derives from the enhancement of therapeutic effect when both agents are used in the treatment or prophylaxis of such conditions.

Particular examples of thrombotic disorders are known in the art but include myocardial infarction, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism, stroke and peripheral vascular disease.

Thus, according to one aspect of the invention, we provide a method of treating thrombotic disorders in human or snimal subjects which comprises administering to the patient effective amounts of a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof.

It will be appreciated that the thrombolytic agent and the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof may be administered to the patient either simultaneously, sequentially or in combination. If there is sequential administration, the delay in administering the second of the active ingredients should not be such as to lose the benefit of a potentiated thrombolytic or anti-thrombotic effect of the combination of the active ingredients.

The thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof will preferably be administered to the patient simultaneously.

However, if simultaneous administration is not precticable, the active agents are preferably administered sequentially, the administration of one agent immediately followed by administration of the other agent.

When the two active agents are administered in this way the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof is conveniently given intravenously.

It may prove desirable for the patient to initially receive a loading dos of a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof followed by administration of both active agent as described just above.

It may also prove desirable to continue treatment with a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof to maximise inhibition of post-therapy reocclusion. Thus, for example, oral maintenance therapy can be continued, e.g. for six months.

In another aspect of the invention, therefore, we provide a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in the presence of each other in the patient for use in human or veterinary medicine, more particularly for use in the treatment or prophylaxis of thrombotic disorders.

In 8 further aspect of the invention we provide a combination of a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof.

In a yet further aspect of the invention we provide a combination of a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof for use in human or veterinary medicine, more particularly for use in the treatment or prophylaxis of thrombotic disorders.

In another aspect of the invention we provide the use of a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in the preparation of a medicament for the treatment or prophylaxis of thrombotic disorders in the human or animal body.

In using a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof accord to the present invention, it is preferable to employ them in the form of pharmaceutical formulations which may be in separate formulations or in a single combined formulation. However, in the latter formulation both active ingredients must of course be stable and mutually compatable in the particular formulation employed.

The present invention therefore also provides a pharmaceutical composition which comprises a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof together, where desirable, with one or more pharmaceutical carriers or excipients.

In another aspect of the invention we provide a pharmaceutical composition comprising a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof together, where desirable, with one or more pharmaceutical carriers or excipient for use in human or veterinary medicine, more particularly for use in the treatment of prophylaxis or thrombotic disorders.

The single combined composition may be prepared by admixture of the active ingredients together, where desirable, with one or more pharmaceutical carriers or excipients. Thus, in another aspect of the invention we provide a process for the preparation of a pharmaceutical composition which comprises mixing a thrombolytic agent and a compound of formula. (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof together, where desirable, with one or more pharmaceutical carriers or excipients.

When the thrombolytic agent and the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof are to be used as a single combined composition, the composition will generally be administered parenterally (e.g.

intramuscularly, subcutaneously, intraperitoneally or intravenously), and either by infusion or by bolus injection. Intravenous administration is the preferred route of administration for a single combined composition, the composition being preferably administered by infusion.

Parenteral formulations containing the thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in a single combined composition may be prepared in a similar manner to the preparation of formulations suitable for the thrombolytic agent or a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof per se. The parenteral formulations may be presented in the form of suspensions, solutions or emulsions in oil or aqueous vehicles which may optionally contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredients may be in powder form for reconstitution before use with a suitable vehicle, e.g. sterile pyrogen-free water.Formulations for injections may be presented in unit dosage form in ampoules, or in a multidose container with an sdded preservative, or in a suitable container for infusion.

As stated hereinbefore, the thrombolytic agent and the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof may be administered as two separate compositions. The thrombolytic agent will generally be in a form suitable for parenteral administration. The compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof may be used in various pharmaceutical formulations, especially for oral or parenteral administration.

It may be convenient to present the thrombolytic agent and the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof as a two container pack, one container containing the thrombolytic agent and the other containing the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof. The compounds may then be admixed immediately before administration or, if desired, may be administered separately either simultaneously or sequentially.

The invention also provides a thrombolytic agent and a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof and compositions containing them, in association with instructions for their use together in human or veterinary medicine, more particularly for their use together in the treatment or prophylaxis of thrombotic disorders.

It is to be understood that when the active agents are administered simultaneously, either in a single combined composition or separately, the appropriate composition will comprise an amount of a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof effective to inhibit platelet aggregation at the site of the occlusion during the period of thrombolytic therapy and an amount of the thrombolytic agent effective to lyse a target thrombotic occlusion.

It will be appreciated that any thrombolytic agent compatable with a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof may be used according to the present invention. Important thrombolytic agents for use according to the invention include the enzymes, plesminogen activators. Examples of suitable plasminogen activators include "kinases" such as streptokinase, streptokinase/plasminogen complex, urokinase and prourokinase, tissue plasminogen ectivator (hereinafter referred to as 't-PA') and the like.

It is to be understood that the term "thrombolytic agent" as used herein is intended to also generally cover agents which, when administered, cause an increase in fibrinolysis, for example through endogenous t-PA release. Such agents include vasopressin analogues, pentosan polysulphate and Protein C. Vasopressin analogues are generally well-known in the art and suitable vasopressin analogues for use according to the present invention include analogues described by A. M. A. Gader et. al. in The Lancet 1973, Volume 2, 1417-1418.

Pentosan polysulphate has been reported in the literature, for example in Thrombosis and Haemostasis 1985, 54 (4), 833-837 (N. A.

Marsh et. al.), and Protein C has been described in numerous publications including Thrombosis Research 41, 483-488 (1986) by C.

Sharon et. al.

The plasminogen activators streptokinase and urokinase are both commercially available for thrombolytic therapy and parenteral pharmaceutical formulations containing streptokinase or urokinase are well-known in the art. A particularly convenient urokinase for use according to the present invention is now commercially available as 'Breokinase' or 'Alphakinase'.

The term 'streptokinase/plasminogen complex' means herein any binary complex of streptokinase and plasminogen including blocked forms of the.streptokinase/plasminogen complex as described, for example, in EP-A-009879 and EP-A-0028489. Particularly important streptokinase/plasminogen complexes for use according to th8~present invention include binary complexes between streptokinase and plasminogen wherein the catalytic site essential for fibrinolytic activity is blocked by an acyl group. A particularly convenient streptokinase/plasminogen complex for use according to the present invention is now commercially available as 'Eminase'. The streptokinase/plasminogen complexes and parenteral pharmaceutical formulations containing them may be prepared according to methods described in the aforementioned European patent specifications.

The term 'prourokinase' means herein any single chain polypeptide substantially corresponding to the single chain precursor of urokinase SCUPA (single chain urinary plasminogen activator).

Important single chain polypeptides for use according to the present invention include those which are resistant to conversion to high or low molecular weight urokinase. Examples of suitable polypeptides are described in EP-A-139447, EP-A-200451, EP-A-236040 and EP-A-247674.

The prourokinase polypeptides and parenteral pharmaceutical formulations containing them may be prepared according to the methods described in the aforementioned European patent specifications or in EP-A-232544.

The term 't-PA' means herein any bioactive protein substantially corresponding to mammalian, and especially human, t-PA and includes forms with or without glycosylation. The t-PA may be one- or two-chain t-PA or a mixture thereof, although preferably the t-PA is in a single chain form for use according to the present invention. A number of t-PAs are known in the art, for example, those described in EP-A-41766, EP-A-93619, EP-A-112122, EP-A-113319, EP-A-117059, EP-A-117060, EP-A-173552, EP-A-174835, EP-A-178105, EP-A-225117, EP-A-225286, WO 86/01538, WO 86/05514, WO 86/05807, GB-A-2173804, GB-A-2176702, GB-A-2176703, GB-A-2184354 and GB-A-2189249. A particularly convenient t-PA for use according to the present invention is the human t-PA product now commercially available as 'Activase'.The t-PA and parenteral pharmaceutical formulations containing the t-PA may be prepared according to methods described in the aforementioned European and British patent specifications or in EP-A-123304, EP-A-143081, EP-A-156169, EP-A-211592, EP-A-217379, EP-A-218112, EP-A-232544 or WO 86/01104.

Particularly suitable thrombolytic agents for use according to the present invention are the plesminogen activators referred to above as "kinases" (i.e. plasminogen activators such as streptokinase, streptokinase/plasminogen complex, urokinase and prourokinase).

Streptokinase and acylated streptokinase/plasminogen complexes such as 'Eminase' are particularly suitable for use according to the present invention.

Suitable salts of a compound of formula (1) include acid addition salts derived from inorganic and organic acids such as hydrochlorides, hyrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 2-chlorobenzoates, p-toluenesulphonates, methanesulphonates, salicylates, fumarates, lactates, hydroxynaphthalenecarboxylates (e.g. l-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates) or furoates, or salts with suitable bases such as alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethylemmonium, 2-hydroxyethyidimethylammonium, piperazinium, N, N-dimethylpiperazinium, piperidinium, ethylenediammonium and choline) salts.A preferred salt of the compounds of formula (1) is the hydrochloride salt.

A preferred group of compounds of formula (1) for use according to the present invention are those of formula (2)

and the physiologically acceptable salts, solvates and cyclodextrin complexes thereof, wherein X is cis or trans -CH=CH- or -CH2CH2-, Y is a saturated heterocyclic amino group which has 5, 6 or 7 ring members and optionally contains in the ring -0-, Alk is a straight C1,3alkyl chain, p is zero, 1 or 2 and R2 is as defined in formula (1) above.

Preferred compounds of formula (2) are those in which R2 represents -OH, -C02H, -CONH2, -NHCOCH3, -NHS02CH3, -502NHCH3, -NHCONH2 or -S02CH3. Compounds of formula (2) in which the group (CH2)pR2 is attached at the ortho position of the phenyl group in the rest of the molecule are particularly preferred.

In general, preferred compounds of formulae (1) and (2) for use according to the present invention are those in which the carbon atom carrying thea -side chain (i.e. the -O(CH2)nX(CH2)mC02Rl group in formula (1) and the -OCH2XCH2CH2C02H group in formula (2)] is in the R configuration (including mixtures containing this isomer).

A preferred compound of formula (1) for use according to the present invention is [l (Z),2ss,5ss]-(+)-6-[[2-(hexahydro-lH-azepin-l- yl)-5-( (2'- (hydroxymethyl) (1,1 '-biphenyl]-4-yl]methoxy]cyclopentyl] oxy]-4-hexenoic acid and its physiologically acceptable salts, solvates and cyclodextrin (e.g. ss-cyclodextrin) complexes.

The compounds of formula (1) and physiologically acceptable salts, solvates and cyclodextrin complexes thereof and pharmaceutical compositions containing them may be prepared according to the methods described in EP-A-0296802.

The precise dose of the thrombolytic agent and the compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof to be administered will, of course, depend on a number of factors including, for example, the age and weight of the patient, the specific condition requiring treatment and its severity and the route of administration. An effective dose, however, in the case of a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof is likely to be in the range from 0.05 to 10 mg/kg body weight of patient, 1 to 4 times daily.

Dosages and dosage rates in the case of the thrombolytic agents will generally correspond with dosages and dosage rates one would use if administering the thrombolytic agent alone to treat the thrombotic disorder. In the case of streptokinase and urokinase effective dose regimes for a variety of thrombotic disorders are now well-established. In the case of a streptokinase/plasminogen complex a patient with a medium-sized thrombus will generally receive a daily dose of from 0.10 to 1.0 mg/kg body weight of patient either by injection in up to eight doses or by infusion. Dosages and dosage rates as described for urokinase are generally equally satisfactory for a prourokinase. Typically a protease-resistant prourokinase will be infused intravenously at a rate usually greater than about 4000 IU/kg/hr to achieve perfusion of an occluded artery or vein. In the case of t-PA an effective dose is likely to be in the range from 150,000 to 450,000 IU/kg/hr, although the dosage is likely to be less for some thrombotic conditions, such as deep vein thrombosis and acute stroke or for maintaining patency of the already reperfused coronary artery. In these situations, an effective amount of t-PA will generally be in the range from 7,000 to 36,000 IU/kg/hr.

Claims (13)

1. The use of (i) a compound of formula (1)

wherein R1 is a hydrogen atom or a methyl group; X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n is 1; or X is trans -CH=CH-, m is zero and n is 3; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which 8 has 5-8 ring members and (a) optionally contains in the ring -0-, -S-, 502 or -NR3a; and/or (b) is optionally substituted by one or more alkyl groups; Alk is a straight or branched C15 alkyl chain; k is zero or 1; p is zero, 1, 2, 3 or 4; R2 is a hydroxyl group or a group selected from -OCOR3, -C02R3, -CONR3R4, -SO2NRR4 -NHCOR3, -NHSO2R51 -SO2R5, -SO2R5,-SR5, -NR3R4, -COR5,-NHCONR3R4 and -NHCSNH2; R3, R3a and R4, which may be the same or different, represent a hydrogen atom or a C14 alkyl or C7-10 aralkyl group; and R5 is a C1 alkyl group; or a physiologically acceptable salt, solvate or cyclodextrin complex thereof and (ii) a thrombolytic agent in the manufacture of -medicaments for the use either separately or in combination of (i) and (ii) and in the presence of each other in the human body for the therapy or prophylaxis of thrombotic disorders.

2. The use according to Claim 1 in which the compounds (i) and (ii) are presented as separate compositions for said use.

3. A pharmaceutical composition which comprises both a compound (i) and a compound (ii) as defined in Claim 1.

4. The use or a composition according to any preceding claim in which compound (i) is [la(Z),2$,5ss]-(+)-6-[[2-(hexahydro-lH-azepin-l- yl)-5-[t2'-(hydroxymethyl) biphenyl]-4-yl]methoxy]cyclopentyl3 oxy]-4-hexenoic acid or a physiologically acceptable salt, solvate or cyclodextrin complex thereof.

5. The use or a composition according to any preceding claim in which compound (ii) is a kinase plasminogen activator.

6. The use or a composition according to any preceding claim in which compound (ii) is streptokinase.

7. The use or a composition according to any of Claims 1 to 5 in which compound (ii) is an acylated streptokinase/plasminogen complex.

8. The use according to any of Claims 1, 2, 4, 5, 6 and 7 in which a compound (i) is in a form suitable for oral or parenteral administration.

9. The use according to any of Claims 1, 2, 4, 5, 6, 7 and 8 in which a compound (i) is in a form suitable for intravenous administration.

10. A two-container pack for use in the therapy or prophylaxis of thrombotic disorders in humans, one of the containers containing a compound (i) and the other containing a compound (ii) as defined in the preceding claims.

11. A composition according to any of Clsims 3 to 7, or a pack according to Claim 10 or (i) or (ii) as defined in Claim 1 in association with instructions for the use of both (i) and (ii) in the therapy or prophylaxis of thrombotic disorders in humans.

12. The use of both compounds (i) and (ii) as defined in the preceding claims in the presence of each other in the human body in therapy.

13. The use of both compounds (i) and (ii) as defined in the preceding claims in the presence of each other in the human body in the therapy or prophylaxis of thrombotic disorders.