WO2007142581A1

WO2007142581A1 - Combination product for the treatment or prevention of dyslipidaemia

Info

Publication number: WO2007142581A1
Application number: PCT/SE2007/000549
Authority: WO
Inventors: Richard Skelly
Original assignee: Astrazeneca Ab
Priority date: 2006-06-07
Filing date: 2007-06-07
Publication date: 2007-12-13

Abstract

A combination therapeutic product which comprises rosuvastatin calcium and a compound of formula I: [Chemical formula should be inserted here. Please see paper copy] The combinations of the invention are useful in a method for the treatment or prevention of dyslipidaemia, and/or in a method for the treatment or prevention of atherosclerosis, and/or in a method for the treatment or prevention of adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) and peripheral arterial occlusive disease). The invention also relates to a pharmaceutical composition comprising such combinations and to the use thereof in the manufacture of a medicament for use in the treatment of dyslipidaemia, or in the manufacture of a medicament for use in the treatment or prevention of atherosclerosis, or in the manufacture of a medicament for the treatment or prevention of adverse cardiovascular complications associated with atherosclerosis.

Description

Combination product for the treatment or prevention of dyslipidaemia

The present invention relates to a combination therapeutic product comprising rosuvastatin calcium (marketed under the trade name Crestor^®) and a compound of formula I as defined herein. The combinations of the invention are useful in a method for the treatment or prevention of dyslipidaemia, and/or in a method for the treatment or prevention of atherosclerosis, and/or in a method for the treatment or prevention of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) and peripheral arterial occlusive disease). The invention also relates to a pharmaceutical composition comprising such combinations and to the use thereof in the manufacture of a medicament for use in the treatment or prevention of dyslipidaemia, or in the manufacture of a medicament for use in the treatment or prevention of atherosclerosis, or in the manufacture of a medicament for the treatment or prevention of one or more adverse cardiovascular complications associated with atherosclerosis. Dyslipidaemia is a disorder of lipoprotein metabolism, which can include the over production or deficiency of certain lipoproteins. Dyslipidaemia is often characterised by hypercholesterolaemia (elevated levels of low-density lipoprotein cholesterol (LDL-C)), hypertriglyceridaemia, and a reduction in the levels of high-density lipoprotein cholesterol (HDL-C). The underlying cause of the dyslipidaemia may be as a consequence of a condition such as obesity, metabolic syndrome or Type 2 diabetes.

Hypercholesterolemia is a major risk factor for atherosclerosis, which is associated with coronary artery disease (including angina pectoris, myocardial infarction and mortality), stroke (including cerebro vascular accident and transient ischaemic attack) and peripheral arterial occlusive disease. The magnitude of hypercholesterolaemia may have consequences for the therapy, but in general, any reduction of elevated plasma cholesterol levels results in an improvement in the risk profile. Diet is an essential first step for the management of hypercholesterolaemia, but the therapeutic potential of drug therapy is significantly larger. Several types of drug therapy for hypercholesterolaemia are currently available.

Rosuvastatin calcium (chemical name: bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(memylsulfonyl)aπimo]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt) belongs to a group of agents commonly known as "statins". Statins are inhibitors of the enzyme HMG CoA reductase, and lower blood cholesterol levels by inhibiting cholesterol synthesis in the liver. It is well known that statins are effective agents for lowering LDL-C, and multiple clinical trials have demonstrated that the reduction of this form of cholesterol alone can result in a significant reduction in the occurrence of coronary artery disease.

However, there remains a need for new and improved treatments for the management of dyslipidaemia in certain patient populations in which the reduction of LDL-C alone is not sufficient to reduce the risk of atherosclerosis and its associated adverse cardiovascular complications. In particular there is a need to provide improved treatment regimes for the treatment or prevention of atherosclerosis and its associated adverse cardiovascular complications in patients with conditions such as mixed dyslipidaemia and dyslipidaemias associated with metabolic syndrome or obesity, which all typically require the treatment of raised LDL-C and triglyceride levels, as well as the management of reduced levels of high- density lipoprotein cholesterol (HDL-C). There is also a need for improved treatment regimes for treating dyslipidaemia in patients with Type 2 diabetes, which is typically requires raised triglyceride levels and reduced HDL-C levels to be managed.

The combination therapeutic product of the present invention seeks to provide such an improved treatment for the management of the aforementioned conditions by combining the particular statin - rosuvastatin calcium - with a compound of formula I. The present invention makes use of compounds of formula I. An example of such a a compound of formula Ind its preparation is described in US 6,147,250, the entire contents of which are incorporated herein by reference.

It is anticipated that the combination products of the present invention will have a beneficial or synergistic effect on the treatment or prevention of dyslipidaemia, and/or the treatment or prevention of atherosclerosis, and/or the treatment or prevention of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) and peripheral arterial occlusive disease). It is particularly anticipated that the combination product of the present invention will have a beneficial or synergistic effect on the treatment of mixed dyslipidaemia and dyslipidaemia associated with metabolic syndrome, obesity and Type 2 diabetes.

According to one aspect of the invention, a combination therapeutic product is provided which comprises rosuvastatin calcium and a compound of formula I:

(D

wherein: R_a, Rb, R₀, and Ra are independently hydrogen, hydroxy, alkoxy, alkoxy amide, alkenyl, alkynyl, acyloxy, acyl amino, alkoxycarbonyl amino, thiol, alkylthiol, alkyl amϊno_; alkyl-NHR, alkyl-NR₂, cyano, COOH, COOR, C(O)NR, C(O)NR₂, C(O)NH₂, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the Ra, R_b, Rc and Rd groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, hydroxy and acyloxy;

R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-C(O)(O-alkyl), alkyl-C(O)(O-aryl), heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, carbohydrate group, -(CHa)-Re, -C(O)-Rg, and

-C(O)-(CH₂VRh, wherein n is O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R₈ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR₃ -CH(OH)R_h, hydroxy, C(O)NH₂, C(O)NHR, C(O)NR₂, wherein R is as defined above;

Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

R_h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)R_h, hydroxy, O-ρhosρhate, C(O)NH₂, C(O)NHR, C(O)NR₂, wherein R is as defined above, or, Re, Rg, and Rh can independently be C(O)-spacer-SO₃H, C(O)-spacer-SO₃M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO₃H₂, C(O)-sρacer-PO₃M₂, C(O)-spacer-PO₃HM, C(O)-spacer-PO₄H, C(O)- spacer-PO^, SO₃M, -PO₃H₂, -PO₃M₂, -PO₃HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)-spacer-[O(C_1-3 alkyl)_p]n, wherein n is as defined above and p is 1, 2, or 3, -[0(Ci_-3 alkyl)p]_n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl and spacer is a group selected from the group consisting of -(CH₂)_n , -(CH₂)_n -CO-, -(CH₂)_n -N-, -(CH₂)_n -0-, -(CH₂)* S, -(CH₂O)-,-(OCH₂)-,-(SCH₂)_, -(CH₂S),-(aryl-O)-, -(O-aryl)-, - (alkyl-O)- and -(O-alkyl)-, wherein n is as defined above; The term "alkyl", as used above, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of Ci to Qo, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexy]methyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. The term "lower alkyl", as used above, refers to a Ci to C₅ saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.

The term "alkylene", as used above, refers to a saturated hydrocarbon radical of straight or branched configuration made up of from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2- propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like. The alkylene group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. The term "-(CH₂)_n -", as used above, represents a saturated hydrocarbon radical of straight chain configuration. The term "n" is defined as 0-10.

The term "aryl", as used above, refers to phenyl, biphenyl, or naphthyl. The term "aralkyl", as used above, refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above. The term "alkaryl", as used above, refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above. In each of these groups, the alkyl group can be optionally substituted as described above and the aryl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate. Specifically included within the scope of the term "aryl" are phenyl; naphthyl; 3,4,5-trihydroxyphenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4- methylphenyl; 3,5-di-tertiarybutyl-4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-l -naphthyl; 4-tertiarybutylphenyl; and the like. Specifically included within the scope of the term "aralkyl" are phenylmethyl; phenylethyl; 2-methyl-l-naphthylmethyl, 2-naphthylmethyl; A- chlorophenylmethyl; and 4-tertiarybutylphenylmethyl and the like.

The term "halo", as used above, includes chloro, bromo, iodo, and fluoro. The term "alkoxy", as used above, refers to a moiety of the structure -O-alkyL wherein alkyl is as defined above.

The term "acyl", as used above, refers to a group of the formula C(O)R', wherein R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above, or a pharmaceutically acceptable salt thereof. According to an aspect of the invention the compound according to formula I is butanedioic acid, mono[4-[[l-[[3,5-bis(14-dimethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6- bis( 1 , 1 -dimethylethyl)phenyl]ester.

According to an aspect of the invention combination there is provided for a therapeutic product which comprises rosuvastatin calcium and butanedioic acid, mono[4-[[l-[[3,5-bis(l,l- drmethylethyl)-4-hydroxyphenyl]thio]-l-methylethyl]thio]-2,6-bis(l,l- dimethylethyl)phenyl] ester.

It is to be understood that term "a combination therapeutic product" used herein envisages the simultaneous, sequential or separate administration of the components of the combination. Thus, in one aspect of the invention, "a combination therapeutic product" envisages simultaneous administration of the rosuvastatin calcium and a compound of formula I. In a further aspect of the invention, "a combination therapeutic product" envisages sequential administration of those agents. In another aspect of the invention, "a combination therapeutic product" envisages separate administration of those agents. Where the administration of those agents is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial or synergistic effect of the combination therapy.

Thus, for the avoidance of doubt, the present invention provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, or a pharmaceutically-acceptable salt thereof, for use simultaneously, sequentially or separately for the treatment of dyslipidaemia.

The present invention further provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, or a pharmaceutically-acceptable salt thereof, for use simultaneously, sequentially or separately for the treatment of hypercholesterolaemia.

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, or a pharmaceutically-acceptable salt thereof, for use simultaneously, sequentially or separately for the treatment dyslipidaemia associated with metabolic syndrome, obesity or Type 2 diabetes. The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, or a pharmaceutically-acceptable salt thereof, for use simultaneously, sequentially or separately for the treatment of atherosclerosis.

The present invention further provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I as defined herein, or a pharmaceutically- acceptable salt thereof, for use simultaneously, sequentially or separately for the treatment of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke and peripheral arterial occlusive disease). As previously stated, it is believed that the combination product of the present invention will provide a beneficial or synergistic effect on the treatment or prevention of dyslipidaemia, and/or the treatment or prevention of atherosclerosis, and/or the treatment or prevention of one or more adverse cardiovascular complications associated with atherosclerosis. The combination product of the present invention is also thought to be particularly suited to the treatment of of mixed dyslipidaemia and dyslipidaemia associated with metabolic syndrome, obesity and Type 2 diabetes. According to the present invention, a combination treatment is defined as affording a "synergistic effect" if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose. For example, the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with rosuvastatin calcium or a particular compound of formula I₃ as defined herein alone. Further, the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to rosuvastatin calcium or a particular compound of formula I₃ defined herein alone. In addition, the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component is dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to or better than that achievable on dosing conventional amounts of either one of the components of the combination treatment. In particular, synergy is deemed to be present if the conventional dose of the rosuvastatin calcium or a particular compound of formula I as defined herein may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side-effects than those that occur when conventional doses of each component are used. Thus, in a further aspect the present invention provides a combination therapeutic product which comprises rosuvastatin calcium and a compound of formula I.

In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of dyslipidaemia which comprises rosuvastatin calcium and a compound of formula I. In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of hypercholesterolaemia which comprises rosuvastatin calcium and a compound of formula I.

In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of atherosclerosis which comprises rosuvastatin calcium and A compound of formula I.

In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) or peripheral arterial occlusive disease), said product comprising rosuvastatin calcium and A compound of formula I.

In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of mixed dyslipidaemia which comprises rosuvastatin calcium and a compound of formula I. In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of dyslipidaemia associated with obesity which comprises rosuvastatin calcium and a compound of formula I.

In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of dyslipidaemia associated with metabolic syndrome which comprises rosuvastatin calcium and a compound of formula I. In a further aspect, the present invention provides a combination therapeutic product for use in the synergistic treatment or prophylaxis of dyslipidaemia associated with Type 2 diabetes, which comprises rosuvastatin calcium and a compound of formula I.

In another aspect, the present invention provides, a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of dyslipidaemia.

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of hypercholesterolemia. The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of atherosclerosis.

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) or peripheral arterial occlusive disease).

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of mixed dyslipidaemia.

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of dyslipidaemia associated with obesity.

The present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of dyslipidaemia associated with metabolic syndrome. In a further aspect, the present invention also provides a combination therapeutic product comprising rosuvastatin calcium and a compound of formula I, for use simultaneously, sequentially or separately for the synergistic treatment or prophylaxis of dyslipidaemia associated with Type 2 diabetes.

A combination therapeutic product of the invention may be administered in the form of a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition which comprises rosuvastatin calcium and a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt thereof, in conjunction or admixture with a pharmaceutically-acceptable diluent or carrier

It will be appreciated that the pharmaceutical composition according to the present invention includes a pharmaceutical composition which comprises rosuvastatin calcium and a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier. Such a composition conveniently provides the combination therapeutic product of the invention for simultaneous use in the treatment or prophylaxis of breast cancer. A pharmaceutical composition according to the present invention also includes separate compositions comprising a first composition comprising rosuvastatin calcium and a pharmaceutically-acceptable diluent or carrier, and a second composition comprising a compound of formula I as hereinbefore defined and a pharmaceutically-acceptable diluent or carrier. Such a composition conveniently provides the combination therapeutic product of the invention for sequential or separate use. Conveniently, such a pharmaceutical composition of the invention comprises a kit comprising a first container with a suitable composition comprising the rosuvastatin calcium and a second container with a suitable composition comprising a compound of formula I.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions; for example for use within a transdermal patch), for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous, intramuscular or intravascular dosing) or as a suppository for rectal dosing. Preferably the compositions of the invention are in a form suitable for oral use, for example as tablets or capsules. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutically-acceptable diluents or carriers that are well known in the art. Suitable pharmaceutically-acceptable diluents or carriers for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl rj-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

According to a preferred version of this aspect of the present invention there is provided a pharmaceutical composition as defined hereinbefore comprising rosuvastatin calcium and the compound of formula I, in conjunction or admixture with a pharmaceutically- acceptable diluent or carrier.

The amount of each active ingredient of the present combination therapeutic product in such pharmaceutical compositions will necessarily vary depending upon the host treated and the particular route of administration.

For the rosuvastatin calcium component, a tablet or capsule formulation intended for oral administration will generally contain, for example, from about 0.1 to 100 mg, particularly, from about 1 to 50 mg, of active ingredient. For example, a conventional tablet formulation may be used for daily oral administration containing 5, 10, 20 or 40 mg of active ingredient. For the compound of formula I, the dose will of course vary depending on the therapeutic effect desired and the route of administration. In general, it is envisaged that a conventional tablet formulation may be used for daily oral administration containing 5-1000 mg of active ingredient.

For a single dosage form, the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Unit dosage forms may for example contain about 5 mg to about 500 mg of active ingredient. Alternatively each active ingredient may be combined separately with one or more excipients to produce a two-part dosage form. In the latter event the pharmaceutical composition of the invention comprises a kit comprising a first container with a suitable composition containing the rosuvastatin calcium and a second container with a suitable composition containing the compound of formula I. Such a kit may, for example, allow the physician to select the appropriate amounts of each active ingredient and the sequence and timing of the administration thereof. Those skilled in the art of treating breast cancer patients can readily select the appropriate conventional amounts of each active ingredient and a suitable dosing schedule. According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of dyslipidaemia. According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of dyslipidaemia comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment. According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of hypercholesterolaemia. According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of hypercholesterolaemia comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment. According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of atherosclerosis.

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of atherosclerosis comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) and/or peripheral arterial occlusive disease).

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of one or more adverse cardiovascular complications associated with atherosclerosis (e.g. hypertension, angina pectoris, myocardial infarction, stroke (including cerebro vascular accident and transient ischaemic attack) and/or peripheral arterial occlusive disease) comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of mixed dyslipidaemia.

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of mixed dyslipidaemia comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of dyslipidaemia associated with obesity.

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of dyslipidaemia associated with obesity comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of dyslipidaemia associated with Type 2 diabetes.

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of dyslipidaemia associated with Type 2 diabetes comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

According to a further aspect of the invention there is provided the use of the combination therapeutic product as defined hereinbefore or of the pharmaceutical composition as defined hereinbefore for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal, such as a human, for the treatment or prophylaxis of dyslipidaemia associated with metabolic syndrome.

According to a further aspect of the invention there is provided a method for the treatment or prophylaxis of dyslipidaemia associated with metabolic syndrome comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product or pharmaceutical composition as hereinbefore defined to a warm-blooded animal, such as a human, in need of such treatment.

Claims

1. A combination therapeutic product which comprises rosuvastatin calcium and a compound of formula I:

CO

wherein:

R_a, R_b, R_c, and R_d are independently hydrogen, hydroxy, alkoxy, alkoxy amide, alkenyl, alkynyl, acyloxy, acyl amino, alkoxycarbonyl amino, thiol, alkylthiol, alkyl amino, alkyl-NHR, alkyl-NR₂, cyano, COOH, COOR, C(O)NR, C(O)NR₂, C(O)NH₂, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R₃, R_b, R₀ and Ra groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, hydroxy and acyloxy; R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-C(θχθ-alkyl), alkyl-C(O)(O-aryl), heteroaryl, substituted heteroaryl, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members;

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, carbohydrate group, -(CH₂)-Rs, -C(O)-Rg, and -C(O)-(CH₂)_n-Rh, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R_s is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rh, hydroxy, C(O)NH₂, C(O)NHR, C(O)NR_2, wherein R is as defined above; Rg is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR₅ NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R_h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, -CH(OH)Rh, hydroxy, O-phosphate, C(O)NH₂, C(O)NHR, C(O)NR₂, wherein R is as defined above; or R₆, Rg, and R_h can independently be C(0)-spacer-SO₃H, C(O)-spacer-SO₃M, wherein M is a metal used to form a pharmaceutically acceptable salt, for example, sodium, C(O)-spacer-PO₃H₂, C(O)-spacer-PO₃M₂, C(O)-spacer-PO₃HM, C(O)-spacer-PO₄H, C(O)-sρacer-PO₄M, SO₃M, - PO₃H₂, -PO₃M₂, -PO₃HM, cyclic phosphates, polyhydroxyalkyl, carbohydrate groups, C(O)- spacer-[O(C_1-3 alkyl)_p]_n, wherein n is as defined above andp is 1, 2, or 3, -[0(C_1-3 alkyl)_p]_n, carboxy lower alkyl, lower alkylcarbonyl lower alkyl, N,N-dialkyl amino lower alkyl, pyridyl lower alkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl, N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl and spacer is a group selected from the group consisting of -(CH₂)_n , -(CH₂)_n -CO-, -(CH₂)_n— N-, - (CHa)_n-O-, -(CHz)_n S, -(CH₂O)-,-(OCH₂)-,-(SCH₂), -(CH₂S),-(aryl-O)-, -(O-aryl)-, -(alkyl-O)- and -(O-alkyl)-, wherein n is as defined above, or a pharmaceutically acceptable salt thereof.

2. A combination therapeutic product which comprises rosuvastatin calcium and butanedioic acid, mono[4-[[l-[[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl]thio]-l- methylethyl]thio]-2,6-bis(l,l-dimethylethyl)phenyl]ester.

3. A pharmaceutical composition suitable for use in the synergistic treatment of dyslipidaemia which comprises a combination therapeutic product according to claim 1 or claim 2 in association with a pharmaceutically-acceptable excipient or carrier.

4. The use of a combination therapeutic product according claim 1 or claim 2 a pharmaceutical composition according to claim 3, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of dyslipidaemia.

5. A method for the treatment or prophylaxis of dyslipidaemia comprising simultaneously, sequentially or separately administering an effective amount of a combination therapeutic product according to claims 1 or 2 or pharmaceutical composition according to claim 3 to a warm-blooded animal such as a human in need of such treatment.