US 2004O266836A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0266836A1 Buhlmayer et al. (43) Pub. Date: Dec. 30, 2004 (54) ORGANIC COMPOUNDS Related U.S. Application Data (76) Inventors: Peter Buhlmayer, Arlesheim (CH); (60) Provisional application No. 60/330,337, filed on Oct. Randy Lee Webb, Flemington, NJ 18, 2001. (US)US Publication Classification Correspondence Address: (51) Int. Cl." ..................... A61K 31/455; CO7D 213/46; NOVARTS CO7D 211/82 CORPORATE INTELLECTUAL PROPERTY (52) U.S. Cl 514/355; 54.6/315 ONE HEALTH PLAZA 430/2 Oa - 1 - O - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - s EAST HANOVER, NJ 07936-1080 (US) (57) ABSTRACT The invention relates to a salt formed of at least one (21) Appl. No.: 10/493,040 AT-receptor antagonist having at least one acidic center and of at least one cardiovascular ingredient having at least one (22) PCT Filed: Oct. 17, 2002 basic center that can be used for treating cardiovascular diseases and conditions, their prophylaxis or delay of pro (86) PCT No.: PCT/EP02/11652 gression. US 2004/0266836 A1 Dec. 30, 2004 ORGANIC COMPOUNDS 0007. The term “basic center” whenever referred hereinto means a functional group able to gain a proton, for example, 0001. This invention relates to salts formed of an AT the basic amino function in e.g. alkylamines, Such as ??, or receptor antagonist and a cardiovascular ingredient, phar any basic heterocycles, Such as pyridines, pyrazines, or maceutical compositions thereof and methods of using Said piperidines. Salts to treat patients Suffering from cardiovascular diseases and related conditions. 0008. The term “patient” whenever referred to herein 0002. As cardiovascular diseases are leading causes of means mammals including humans. death in industrialised countries and as the majority of 0009. The term “additive effect” or “synergistic effect”, affected patients are middle aged, there exists an increasing respectively, whenever referred to herein, for example, may need for potent as well as easily administered drugs for the be defined using the following equations: therapy of cardiovascular diseases. Under the term cardio vascular diseases and related conditions commonly used in afA+b/B=1 means an additive effect the art as a generic term may be Summarized diseases or afA+b/B-1 means a synergistic or superadditive effect, conditions Such as e. g. hypertension, congestive heart failure, post myocardial infarction, angina pectoris, coronary 0010 where “A” and “B” are equieffective doses of the heart diseases, cardiac arrhythmia, atherosclerosis, endothe individual ingredients when each is present alone, “a” and lial dysfunction, renal diseases, e.g. acute and preferably “b' are the respective doses in the Salt according to the chronic renal disease, isolated Systolic hypertension, periph invention that give the effect level achieved by dose “A” eral vascular disease, hyperlipidemia, Stroke or end-organ alone or dose “B” alone. Reference is made to R.J. Tallarida. damage. Although drug classes as well as their combinations "Statistical analysis of drug combinations for Synergism', for the treatment of Said diseases and related conditions are Pain 1992; 49:93-97 and “Drug synergism and dose-effect well known and commonly used, the patient compliance is data analysis”, Editor, R. J. Tallarida, Chapman and Hall/ often reduced due to the complex therapeutic Schemes and CRC, New York, 2000. the high intake rates. 0011. It is expected that in the case of the salts according 0003. The present invention provides a unique concept, to the invention, effects will be assessed e.g. as changes in which is an alternative to fixed combinations. For the first blood pressure and more specifically, as antihypertensive time, combination salts of at least one AT receptor antago effects. Therefore, the two ingredients forming a Salt accord nist with at least one further basic cardiovascular active ing to the invention would be synergistic when their effects principle (ingredient) have been made. In a fixed combina are greater than that expected from the Sum of the individual tion, different active principles are Separately combined in a ingredients, especially at the same doses as in the Salt. The dosage unit form. In a conventional fixed combination, hypothesis to be tested is that the two active ingredients are acidic or basic active ingredients may react within the additive when given together. If they are not additive, then dosage unit form with pharmaceutical auxiliaries and addi an interaction has occurred that may result e.g. in a Super tives, e.g. by forming esters and the like. A prolonged additive response. With a careful experimental design, this Storage of corresponding dosage unit forms may result in an can be assessed using appropriate Statistical methods as increased amount of Side products. A dosage unit form referenced above, e.g. corresponding effects can be taken comprising a combination Salt formed of at least two active from dose-response-curves. principles is more stable and resistant to forming unwanted 0012. In addition to blood pressure, the measurements of Side products. Furthermore, combination Salts according to heart rate or neurohormones (plasma renin activity, aldos the present invention have improved properties. Corre terone or norepinephrine) may also be used to determine the sponding improved properties comprise Suitable and relationship between the Salt and their individual component improved therapeutic activities and pharmacodynamic drugs. effects. For example, the beneficial effects of a combination Salt formed of at least two active principles comprises a 0013 Finally, the determination of plasma levels of each broader therapeutic applicability, a potentiation or Syner component of the Salt can also be used to indicate a response, gism of the activity of one of the Salt components, an for example, additive or Synergistic, that is different from enhancement of the pharmacodynamic properties. A com that of the component parts. It is understood that a direct bination Salt can also be used to achieve therapeutic effects relationship exists between the amount of drug in the plasma even at Sub-therapeutic amounts of at least one active and the pharmacologic effect induced by the drug. There principle within a corresponding combination Salt. fore, drug levels of the component drugs contained within 0004. Accordingly, the invention provides salts formed of the Salt can be used, either alone or in conjunction with the at least one AT-receptor antagonist having at least one pharmacodynamic response to demonstrate an advantage of acidic center and of at least one cardiovascular ingredient the salt formulation over that of individual components of having at least one basic center. the Salt. 0014. The term “potentiation” shall mean an enhance 0005. The term “at least one” whenever referred to herein ment of a corresponding pharmacological activity or thera may define one, two or more units. peutic effect, respectively. Potentiation of one component 0006. The term “acidic center” whenever referred to within the combination Salt according to the present inven herein means a functional group able to split of a proton e.g. tion formed with another component within the combination the hydrogen atom of the carboxyl group, of the Sulphona Salt according to the present invention means that an effect mide group or that of the tetrazole ring of the AT-receptor is being achieved that is greater than that achieved with one antagonist. component alone. US 2004/0266836 A1 Dec. 30, 2004 0015 The term “synergistic effect” or “effect of “poten in EP 678503 and incorporated herein by reference. Espe tiation' is used in the context of this application to mean an cially preferred is the hemi-fumarate Salt thereof. enhanced responsiveness to the drug. For example, if the Salts according to the invention result in an improvement in 0023 Beta-blockers are known in the art. A beta blocker the absorption, with an increase in the plasma concentration preferably is a representative Selected from the group con of the AT-receptor blocker then the extent of e.g. blood Sisting of a Selective B1-blocker, Such as atenolol, bisoprolol preSSure lowering may be “potentiated” or greater than (especially the fumarate thereof), metoprolol (especially the hemi-(R,R)fumarate or fumarate thereof), furthermore, ace expected. butolol (especially the hydrochloride thereof), esmolol 0016. The pharmacodynamic properties of one active (especially the hydrochloride thereof), celiproplol (espe principle within the combination Salt of the present inven cially the hydrochloride thereof), taliprolol, or acebutolol tion can also be potentiated by the further active principle (especially the hydrochloride thereof), a non-Selective within the combination Salt of the present invention leading f-blocker, Such as Oxprenolol (especially the hydrochloride to Synergism or potentiation. thereof), pindolol, furthermore, propanolol (especially the hydrochloride thereof), bupranolol (especially the hydro 0017. The term “AT-receptor antagonist” (also called chloride thereof), penbutolol (especially the Sulphate Angiotensin-II-receptor antagonist) whenever referred here thereof), mepindolol (especially the Sulphate thereof), car into has to be understood to define those active ingredients teolol (especially the hydrochloride thereof) or nadolol, and that bind to the AT-receptor subtype of Angiotensin-II but a B-blocker with C-blocking