IE19970487A1 - Ranolazine and related piperazines for use in the treatment of shock conditions - Google Patents

Abstract

ABSTRACT Piperazine derivatives, particularly ranolazine, are useful for treatment of tissues Oifig Na bPaitinni The Patents Office experiencing a physical or chemical insult, and specifically for treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.

Description

Field of the Invention The present invention relates to methods of treatment using ranolazine or another piperazine derivative compound of Formula I, particularly to methods of using ranolazine for treatment of tissues experiencing a physical or chemical insult, and specifically to methods of treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.

B r n ' n Ranolazine, i.e., :N—(2,6—dimethylphenyl)—4— [2—hydroxy—3-(2—methoxyphenoxy)propyl]—l—piperazine acetamide or l-[3—(2—methoxyphenoxy)hydroxypropyl]— 4-[(2,6—dimethylphenyl)aminocarbony1methyl]piperazine, and the dihydrochloride salt thereof, and the compounds of Formula I, are described in U.S. Patent No. 4,567,264. Ranolazine is disclosed as a calcium entry blocking compound useful in the treatment of cardiovascular diseases, such as, myocardial infarction, congestive heart failure, angina and arrhythmia.

One aspect of the present invention concerns a method of treating tissues experiencing a physical or chemical insult, by administering an effective amount of a compound of Formula I: (Formula I) and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N—optionally substituted is methyl, R4 R4 and R5 are each independently alkylamido, except that when R1 is not methyl; or R2 and R3 together form —OCH20—; R6, R7, R8, R9 and R10 hydrogen, lower acyl, aminocarbonylmethyl, are each independently cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino; R6 and R7 together form -CH=CH-CH=CE—; or R7 and R8 together form -ocazo-; R11 and R12 are each independently hydrogen or lower alkyl; and w is oxygen or sulfur.

In a preferred embodiment, the invention entails a method of treatment wherein the compound of Formula I is one in which R1 and R5 are methyl, particularly where R2, R3 R4 R11 and R12 are hydrogen, and more particularly where W is oxygen. Most preferred is the where R6 is method of treatment with ranolazine, R9 and R10 are hydrogen. i.e., methoxy and R7, R8, IE 97 0487 In another aSP€Ct, the present invention entails a method for Protecting the myocardium against global ischaemic damage induced by cardioplegia, which method comprises administering to a subject undergoing cardiac surgery. and/Or adding to the extra-corporeal circulation of such subject. an effective amount of a compound of Formula I, preferably ranolazine.

The invention also entails a method for protecting skeletal muscle against damage resulting, e.g., from trauma or subsequent to muscle or systemic diseases, which method comprises administering to a subject whose skeletal muscle is or is likely to be damaged an effective amount of a compound of Formula I, preferably ranolazine.

A further aspect of this invention entails a method for treating shock conditions (including cardiogenic shock). which method comprises administering to a subject experiencing shock an effective amount of a compound of Formula I, preferably ranolazine.

Still another aspect of this invention entails a method of protecting myocardial tissue against ischaemic damage in subjects with myocardial infarction, especially in patients who are waiting to receive treatment such as thrombolytic drugs or PTCA (percutaneous transthoracic coronary angioplasty), which method comprises administering to a subject suffefing fmmt orsusceotflfle to suffer from myocardial infarction or undergoino ?TCA an effective amount of a compound of Formula I, oreferably ranolazine.

Another aspect of the invention is a method for protecting neuronal tissue against ischaemia resulting from cardiac function impairment or from non—cardiac conditions (including protecting brain tissue against ischaemia—induced metabolic disorders), which method comprises administering to a subject suffering from or susceptible to suffer from neuronal tissue damage an IE 97 0487 €ffeCtiVe amount Of a compound of Formula I, preferably ranolazine.

In still another aspect, the present invention entails a method for preserving donor tissues used in transplants (protecting them from the deleterious effects of ischaemia), by administration to the donor, the recipient and/or by adding to the ez;yixQ perfusion fluid an effective amount of a compound of Formula I, preferably ranolazine or a pharmaceutically acceptable salt thereof, particularly for renal transplants, skin grafts, cardiac transplants, lung transplants, corneal transplants, and liver transplants.

In yet another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount (up to 5 mg/ml for liquid and semi—solid formulations) of a compound of Formula I, particularly ranolazine or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable excipient, such compositions being adapted for use in the methods of treatment of the present invention.

Another aspect of the invention entails methods of treatment by coadministration of a compound of Formula I together with another pharmaceutically active agent, such as thrombolytic agents [especially TPA (Tissue Plasminogen Activator) or streptokinase] or anti—anginals (such as beta blockers, including propranolol and timolol).

DETAILED DESCRIPTION OF THE INVENTIOH Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

As used herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, including: IE 97 0487 (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms.

As used herein, the term "q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

As used herein, the term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.

Preparation of ganglazine Ranolazine and the piperazine compounds of Formula I can be prepared, for example, as described in U.S. Patent No. 4,567,264.

Utilitv. Testing and Administration It has surprisingly been found that ranolazine is active in methods of treatment unrelated to its initially identified calcium entry blocking mechanism and cardioselective indications. Particularly interesting is the fact that ranolazine has now been found to protect tissues against ischaemia (improving cellular oxygen utilization efficiency) at doses that do not produce any cardiodepressant effects (see, Allely and Alps, supra; and Ferrangon, et a1., gupgaa) fieaeral Utility The piperazine compounds of Formula I, particularly ranolazine and the pharmaceutically acceptable salts thereof (preferably the dihydrochloride). are useful for IE 97 0487 treating tissues experiencing a physical or chemical insult. For example, such treatment can be for cardioplegia, or for hypoxic reperfusion injury to cardiac or skeletal muscles, or brain tissue. The compounds of Formula I, particularly ranolazine and its salts, are also useful for preserving (e.g., preventing deterioration of) donor tissues used in transplants, by administration to the transplant donor, to the transplant recipient, or by perfusion of the tissues to be transplanted, particularly for renal transplants, skin grafts, cardiac transplants, lung transplants, corneal transplants, and liver transplants.

Testing Protection against myocardial ischaemia can also be assessed via effectiveness to prevent ischaemia—induced increase in alpha-l adrenoceptor number in the myocardium. It is known that alpha-l adrenoceptor E9-270487 A detailed description is set IE 370487 . 3_3Q, 1612, 1985). description is set forth in Example 3.

The utility of compounds of Formula I, as exemplified by ranolazine, in organ transplant is demonstrated by administering the test compound to pigs before nephrectomy. and/or by adding the compound to the fluid used for flushing and storage of the organ and by A detailed assessing functionality of transplanted kidneys over a period of 14 days. Improvement of renal function in treated animals is assessed by measurement of the glomerular filtration rate and also by peak serum levels for creatinine and urea. Glomerular filtration is a well established indicator of renal function (see, e.g., Mudge and Weiner in Goodman and Gilman, 879, 7th Ed, 1985) and it is generally assessed by measurement of inulin and/or creatinine clearance (Ieztb9gx_gf_nedicing, 1088-93, l4th Ed., 1975 — Beeson and Mcbermott Editors). A detailed description is set forth in Example 4. followed by an infusion over the period of reperfusion, IE 970487 as described bY Alps, et a1., (Arzneim. Eorsch Drug Reg., 11, (1), 5, 868-876, 1983).

Administration Administration of ranolazine in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration of agents Thus, be, for example, orally, nasally, parenterally or for serving similar utilities. administration can topically, including by perfusion. Administration can be achieved in the form of solid, semi—solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, capsules, powders, solutions, suspensions, emulsions, creams, lotions, aerosols, ointments or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

The compositions will include a conventional pharmaceutical carrier or excipient and an effective amount of ranolazine or a pharmaceutically acceptable salt thereof, and in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Sustained release and slow release formulations for maintaining extended or constant dosage levels are also useful in the present invention.

Ranolazine can also be co—administered with other active agents, such as thrombolytic agents [especially TPA (Tissue Plasminogen Activator) or streptokinase] or anti—angina1s (such as beta blockers, including propranolol and timolol).

The preferred method of administration is parenteral, except for those cases when the subject must be pre-treated before surgery or when the subject must be maintained under therapy after acute episodes of ischaemia (in which instances it may be preferable to administer the composition orally).

IE 970482‘ _11_ Genera11Y» dePending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of the pharmaceutically active compound of this invention and 99% to lZ by weight of suitable pharmaceutical excipients. Preferably, the composition will be about 5 to 75% by weight of a pharmaceutically active compound, with the rest being suitable pharmaceutical excipients.

For liquid and semi—solid formulations, about 5 mg/ml is preferred as the maximum concentration for the active ingredient.

Oral administration entails using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such oral administration, a pharmaceutically acceptable, non—toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, Such compositions take the form of solutions, suspensions, sucrose, magnesium carbonate, and the like. tablets, capsules, powders, sustained release or slow release formulations and the like.

Preferably the oral compositions will take the form of a capsule or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrroli— done, gelatin, cellulose and derivatives thereof, and the like.

The active compounds may be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier of polyethylene aE9Z0487 _l2._ glycols (PEG) [e.g., PEG 1000 (96%) and PEG 4000 (4‘Z,)] or semi—synthetic glycerides (witepsol“, Suppocire”).

Another preferred mode of administration is parenterally. Liquid pharmaceutically administerable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound (about 0.5% to about %), as described above, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.

For preservation of tissues awaiting transplantation, a perfusion solution is preferred. Such solutions include an active compound in a carrier such as Eurocollins Solution (Fresenius, A.G., Bad Homburg, vdH, Germany), University of Wisconsin Fluid (Kalayoglu, M., et al., Iha_Lanaat, 1988 i, 617), phosphate buffered sucrose (see, e.g., Example 7E) and Hyperosmolar Citrate (Ross, et al., Transplantation, 1976, 498-501).

If desired, the pharmaceutical composition to be administered may also contain minor amounts of non—toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see R m n n' Ph rm 16th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1980). The composition to be administered will, in any event, contain a quantity of the active compound(s) in a pharmaceutically effective amount for relief of the particular condition being treated when administered in accordance with the teachings of this invention.

Example 7 describes oral and parenteral formulations containing ranolazine. Such formulations should not be IE 970487 Construed 33 narrowing the invention. In particular, parenteral formulations can be given as dilutions with perfusion fluids, dialysis fluids and/or fluids used to flush and store organs. It is also intended that the invention encompasses the possibility to associate ranolazine with other pharmaceutical agents, as co—prescription or by concomitant dissolution in fluids.

Dgsagg Generally, ranolazine is administered in a therapeutically effective amount, i.e., a dosage sufficient to effect treatment. The amount of active compound administered will, of course, be dependent on the subject treated, the subject's weight, the severity of the affliction, the route of administration and the judgement of the prescribing physician. However, absent sufficient time to weigh the foregoing factors in detail, e.g., in emergency situations, effective i.v. dosages range from about 0.05 to about 5 mg/kg for bolus injection followed by an infusion ranging from about 0.3 to about 30 mg/kg/hour. dosage ranges from about 0.1 to about 2.5 mg/kg and the Preferably, the i.v. bolus infusion dosage from about 1.5 to about 15 mg/kg/hour.

For an average 70 kg human, the i.v. bolus would range from about 3.5 to about 350 mg, or preferably, from about to about 105 mg. In other situations, the oral dosage is in the range of about 10 to about 1400 mg per day, preferably about 35 to about 1400 mg per day, more preferably about to about 700 mg/day, for an average kg human. For administration by perfusion fluid, a concentration of about 0.001 to about 5 g per litre is used, preferably about 0.005 to about 2.5 g per litre, and most preferably about 0.005 to about 0.1 g per litre; perfusion can continue from tissue removal from the donor until its use for transplantation.

IE 970487 EXAMPLES The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

EXAMPLE 1 Protection Against Cardiac Ischaemia This is an adaptation of the model described by Alps, et al., (Arzneim. Forsch Drug Res., 13, (l), 6, 868-876, 1983).

Eight male baboons were anaesthetized then randomly allocated to one of the two following groups: r A Four animals were subjected to 30 min. occlusion of II I I the left anterior descending coronary artery (LAD) followed by a reperfusion period of 5.5 hours. Venous plasma samples taken pre—thoracotomy, pre—LAD ligation and every hour during the reperfusion period were analyzed for CPK2 and LDHI iso-enzyme levels. loading dose of ranolazine (S00 ug/kg) intravenously min. before LAD ligation followed by a continuous infusion of 50 ug/kg/min. for a 6-hour period starting at LAD ligation time. _15_ RE T CPK2 iso-enzyme levels in plasma remained below the detection limits until the first hour post—infarction. LDHI plasma levels were identical at pre—surgery and pre—1igation times (pre—infarct period). Results, as reported in Table l, are expressed in international units of iso-enzyme per litre of plasma.

T l 1 > Time > Pre— > lhr Post- > 6hr Post— > > r Pr -in r r r ' n r rf i n) > > > > > > Control CPK2 > N.D. > 10.5 > 232.8 > > group LDH1 > 52.7 > — > 333.8 > > —————————————— ——> — —— -- > ———————— ——> > Tested CPK2 > N.D. > 11.0 > 28.5 > > group LDH1 > 53.0 - > 85.8 > > > > > > As shown above, ranolazine strongly inhibited the release of CPK2 and LDH1, such a result being indicative of an effective protection of the myocardial tissue against deleterious effects of ischaemia.

E LE Skeletal Muscle Protection Skeletal muscle protection was determined according to the experimental conditions as per Example 1, except that plasma samples were assayed for CPK3 and LDH5 iso—enzymes. The results are reported in Table 2.

|E970437 Table 2 > Time > > Post-reperfusion > > Group > Pre—surzerv > 6hr Post—infarct > ) > ) ) > Control CPK3 > 104.6 > 2016.5 > > group LDE5 > 30.0 > 212.0 > > --------------- --> ----------- -—> ————————————————— -—> > Tested CPK3 > 84.0 > 141.0 > > group LDH5 > 27.4 > 22.3 > Iso—enzyme levels are given in International Units per litre of plasma.

Thus, ranolazine clearly protected the muscle from surgery—induced damage.

This method has been described by Ferrandon et al., Br. J. Pharmacol., 21, 247P, 1988.

Male Sprague—Dawley rats were anaesthetized with pentobarbitone sodium (50 mg/kg, i p.). After injection of heparin (200 units i.v.) the thorax was opened, the heart removed with a length of aorta attached and then immersed in ice cold Krebs‘ solution (118 mM NaCl, 4.55 mM KC1, 1.2 mM KHZSO4, 1.2 mM MgSO4, 11.0 mM glucose, 20.0 mM NaHC03, 1.35 mM Caclz, pH 7.4). The heart was gently palpated to expel the blood. Hearts were then perfused with the above solution warmed to 37° C and gassed with 95% 02 and 5% C02 retrogradely via the aorta (Langendorff model) using a peristaltic pump set to deliver 14 ml/min. A microelectrode was introduced into the ventricular muscle wall and a lE970487 reference electrode placed in contact with the perfusion fluid 3cm above the heart. connected to a pH meter.

Hearts were perfused at 14 ml/min for a 15 min period to obtain a stable baseline ventricular pH. The aortic flow was then reduced to 1 ml/min for 15 min by decreasing the pump speed. the initial rate for 15 min.

The two electrodes were The flow was then restored to Values of coronary flow and ventricular pH were measured at 5 minute intervals.

After restoration of the initial flow rate measurements were made at 30 seconds, 1 minute and 5 min. Samples of coronary effluent were collected and stored on ice.

Infusions of ranolazine (1 pM) were started 10 min prior to reducing the flow rate and were continued for At the end of the the hearts dried at the remainder of the experiment. experiment the atria were removed and 75°C for 2 days.

Biochemical determination of lactate released into the coronary effluent was made using a spectrophotometric method. was obtained by reference to a standard curve.

The quantity of lactate contained in the samples Lactate release from the heart mass was calculated using the following formula: £lactate1(microMo1/ml) x coronarv flow (ml/min) dry weight of the heart (g) The results are reported in Tables 3 and 4. lE97o437 pH Modifications After 10 min Pre— of Fall in ischeamia low perfusion pH CONTROLS 7.36 6.77 0.59 RANOLAZINE 7.38 7.10 0.28 Thus, ranolazine inhibits the ischaemia—induced fall in pH by approximately 50%.

Lactate release modifications* > 2 min >> 5 min > 15 min >> 1 min > before >> after > after >> after Group > low perf. >> low perf. > low oerf. >> reperf > >> > >> CONTROLS > 0.6 >> 3.34 > 5.0 >> 17.4 > >> > >> 1 pM > >> > >> mmmAmmE> L2 >> 2A5 > 26 >> 80 > >> > >> *Values are expressed as micromoles of lactate released per minute in the coronary effluent by 1 g of dried heart.

Thus, the compounds belonging to this invention clearly reduced the sequelae of low flow perfusion.

'E970437 EXAMPLE 4 Protection For Organ Transplants Twenty left nephrectomised pigs were autotransplanted with their kidneys after preservation for 24 hours in phosphate buffered sucrose (PBS 140) and immediate contralateral nephrectomy followed the autotransplantation.

The quality of the preservation and post—transplant renal function were assessed by measurement of glomerular filtration rate (GFR) using inulin clearance on day 7.

Qrgup A gn=lQ2 placebo group The animals received placebo pre-treatment (bolus and infusion) commencing 5 min prior to left nephrectomy and lasting until the kidney was removed. then flushed with PBS 140 containing placebo before storage in PBS 140. was auto—transplanted.

The kidney was After 24 hours storage the kidney Gr B =10 r The animals received a bolus dose of ranolazine intravenously (0.85mg/kg) 5 min prior to nephrectomy followed by an infusion (0.25mg/kg/h) until the kidney The kidney was then flushed with PBS 140 solution containing ranolazine 0.5mg/l (made up immediately before flush) prior to storage. After 24 hours storage the kidney was auto—transplanted. was removed. _20_ Table 5 Group A Group B Glomerular filtration l6.4ml/min 56 6ml/min rate at day 7 Peak Serum Urea 43.4mm/1 28.SmM/l Peak Serum Creatinine l063pM/1 750uM/l The results shown in Table 5 demonstrate that organs preserved in a fluid containing ranolazine achieved superior functionality after transplantation as compared with the control group that did not receive ranolazine.

EXAnBLE_i Protection Against Brain Ischaemia Isoenzyme appearance in peripheral venous blood was determined according to the experimental conditions as per Example 1, except that plasma samples were assayed for CPKI. The results are reported in Table 6.

CPKI Levels .7 19.3 .8 19.9 CONTROL GROUP RANOLAZINE GROUP lE9704 IE 97 0487 _21_ Results are expressed in International Units per litre Of Plasma, and clearly demonstrate the protective role of ranolazine in cerebral ischaemia.

EXAMPLE 6 Protection Against Myocardial Ischaemia Male Sprague-Dawley rats were pentobarbitone— anaethetized and mechanically respired with room air. A left lateral thoracotomy was then performed and the left anterior descending coronary artery (LAD) was occluded for a period of 30 min. Control animals had the ligature placed in position but not tied.

Compounds (500 ug/kg ranolazine, saline vehicle) were administered either i.p. or i.v. 15 min prior to LAD ligation or i.p. for 3 days (twice a day) plus 15 min prior to occlusion.

At the end of the ischaemic period the ischaemic zone of the left ventricle was excised and analyzed for alpha-l—adrenoceptor density according to the method described by Williams et al. (gardiovascnlar Pharmacology, 3, 522, 1981). The apparent alpha—l-adrenoceptor density was calculated at 0.1 nM [3H]—prazosin and results were expressed as femtomole of receptors per mg of protein, as shown in Table 7.

These results demonstrate that ranolazine inhibits the ischaemia-induced increase in a—l adrenoreceptor density in rats left ventricle and is therefore useful to prevent tissue damage resulting from myocardial ischaemia. lE970487 Table 7 gram; mi; No. Animals Alpha-1 densitv Control 12 8.55 Ischaemia/Treated by saline vehicle only 12 16.30 Ischaemia/Treated by ranolazine i.p. 13 11 20 Ischaemia/Treated by ranolazine i.v. 9 9.71 Ischaemia/Treated by ranolazine i.p. 3 days 9 8.33 EXAMPLE 7 Formulations The following example illustrates the preparation of representative pharmaceutical formulations containing a compound of Formula I, as exemplified by ranolazine.

A. I.V. FORMULATION (low concentration) (ranolazine) 5.0 mg 0.5 g dextrose monohydrate 51.2 mg 5.1 g sodium hydroxide q.s. to pH 4 pH 4 water for injection to 1.0 ml 100 ml B. I.V. FORMULATION (high concentration) (ranolazine) 20.0 mg 2 8 dextrose monohydrate 39.4 mg 4 g sodium hydroxide q.s. to pH 4 pH 4 water for injection to 1.0 ml 100 ml IE 97 048 7 _23_ To prepare the I.V. formulations, ranolazine and dextrose monohydrate are dissolved into water (70 per cent of the final desired volume) then sodium hydroxide (l0N solution) is added under stirring until pH 4 and the volume is completed to 100 ml with water. filtered through a 0.2 micron membrane filter and The medium is packaged in ampoules or vials under sterile conditions.

Alternatively the medium can be filtered under non-sterile conditions, packed in ampoules then sterilized by autoclaving.

C. FILM COATED TABLET FORMULATION In r i n Bart: by weight ranolazine ECl (A) 80.0 microcrystalline cellulose (B) 16.5 polyvinylpyrrolidone (C) 1.0 crosscarmellose sodium (D) 2.0 magnesium stearate (E) 0.5 (A), (B) and half of (D) are mixed then (C) and (E) and the After careful water are added to allow wet granulation. remaining part of (D) are finally added. mix the granulated mixture is dried, formed into tablets containing up to 250 mg of active compound, and the tablets are film coated using white Opadry” following appropriate techniques.

E97068? _24_ D; CQNTRQLLED RELEASE FQEflULATIQN . Parts by weight ranolazine BASE (A) 90 microcrystalline cellulose (B) 10 The two above ingredients are dry mixed then water is added to form a wet mass adequate for extrusion then spheronisation (0.5 to 1.4 mm). Microspheres are coated with appropriate release—control1ing polymers then put into hard shell capsules containing up to 250 mg of active ingredient per unit.

E. EEBEDSIQN ILQID In r i n Parts by weight Ranolazine 20 mg Phosphate Buffered Sucrose: Sucrose 48.0 g Sodium Dihydrogen Phosphate 4.59 g Sodium Monohydrogen Phosphate 6.53 g Water For Injection (U.S P.) q.s. to 1000 ml The ingredients are dissolved in a portion of the water For Injection, and once dissolved, the remaining volume is made up with water For Injection. while the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted lE97o437 ._25_ without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process. process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (1)

1. WHAT IS QLAIMED IS: 1. A method of treating tissues experiencing a physical or chemical insult, by administering an effective amount of a compound of the formula: R R R R 011 R11 ? R8 w—cH2 -53; CH2-—N N—cH —c—N R3 H 3 0 R7 R6 H R12 R5 R4 or a pharmaceutically acceptable esters or acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 hydrogen, lower alkyl, lower alkoxy, cyano, are each independently trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N—optionally substituted alkylamido, except that when R1 is methyl, R4 methyl; or R2 and R3 together form —OCH2O—; R6, R7, R8, R9 and R10 hydrogen, lower acyl, aminocarbonylmethyl, is not are each independently cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di—lower alkyl amino; R6 and R7 together form -CH=CH—CH=CH—; or R7 and R8 together form —OCH2O-; R11 and R12 are each independently hydrogen or lower alkyl; and W is oxygen or sulfur. S 2. The method of Claim 1 wherein R1 and R are methyl. 4 ii The method of Claim 2 wherein R2, R3, R , R and R12 are hydrogen. 4. The method of Claim 3 wherein W is oxygen. :73. 8 The method of Claim 4 wherein R6 is methoxy and R , R , R9 and R10 are hydrogen, i e., ranolazine. 6. The method of Claim 1, comprising a method for protecting the myocardium against global ischaemic damage induced by cardioplegia, preferably wherein said method comprises systemically administering said compound to a subject undergoing cardiac surgery, or adding to the extra—corporeal circulation of such subject, an effective amount of said compound. 7. The method of Claim 1 comprising a method for protecting skeletal muscle against damage resulting from trauma or subsequent to muscle or systemic diseases. 8. The method of Claim l comprising a method for treating shock conditions, including cardiogenic shock. 9. The method of Claim 1 comprising a method for protecting neuronal tissue against ischaemia resulting from cardiac function impairment or from non-cardiac conditions, including protecting brain tissue against ischaemia—induced metabolic disorders. 10. The method of Claim 1 comprising a method for preserving donor tissues used in transplants, by administration to the donor, the recipient and/or by adding to the eg;yiyo perfusion fluid an effective amount of said compound, preferrably wherein the donor tissues are used in renal transplants, skin grafts, cardiac transplants. lung transplants, corneal transplants, or liver transplants. 11. The method of Claim 1 comprising a method of protecting myocardial tissue against ischaemic damage in subjects with myocardial infarction. 12. The method of any one of Claims 6-11 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof. 13. The method of Claim 1 comprising coadministration of said compound together with a second pharmaceutically active agent. 14. agent is TPA or streptokinase. The method of Claim 13 wherein said second 15. A pharmaceutical composition containing a therapeutically effective amount, up to 5 mg/ml for liquid and semi-solid formulations, of a compound of the formula: or a pharmaceutically acceptable esters or acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy. cyano. trif1“°r°methY1» halo. lower alkylthio. lower alkyl lOWer alkyl sulfonyl, N—optionally substituted alkylamido. except that when R1 sulfinyl, is methyl, R4 is not methyl; or 2 3 R6 an; R gtoggther form —OCH2O—; R 1 R , R . R and R10 are each independently hydrogen. lower acyl, aminocarbonylmethyl, CYaD0- 10W€f alkyl. lower alkoxy, trifluoromethyl, halo, lower alkylthio. lower alkyl sulfinyl, lower alkyl sulfonyl, di—lower alkyl amino; R; and R7 together form —CH~CH—CH=CH—; or R and R together form —C 420-; ll 12 . R are each independently hydrogen or lower alkyl; and W is oxygen or sulfur, admixed with at least one pharmaceutically acceptable excipient. 16. The pharmaceutical composition of Claim 25 wherein said compound is ranolazine. 17. A pharmaceutical composition substantially as hereinbefore described by way of Example. l8. A compound of the formula stated in any of claims l to 5, for use in the treatment of tissues experiencing a physical or chemical insult. l9. A compound as claimed in claim l8 for use in the treatment of the conditions specified in any of claims 6 to ll. 20. Use of a compound of the formula stated in any of claims 7 to 5 {OF “S9 in the DV€PaVatl0n Of a Dharmaceutical composition for treatment of tissues experiencing a physical or chemical insult. Dated this Zlst day of June, l990. TOMKINS & CO.,