阅读说明：本技术 σ-1受体激动剂收缩期血压疗法 (Sigma-1 receptor agonist systolic blood pressure therapy ) 是由 C·U·密斯令 于 2018-11-28 设计创作，主要内容包括：一种用于降低对使用一种或多种药物的抗高血压疗法展现抗性的患者的收缩期血压的方法,所述方法包括以有效提供选自谷值坐位收缩期、24小时动态收缩期和最大昼夜收缩期血压的一个或多个血压参数的至少约3mmHg降低的剂量和频率向所述患者施用<Image he="70" wi="447" file="DDA0002512652980000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A method for reducing systolic blood pressure in a patient who exhibits resistance to antihypertensive therapy with one or more drugs, comprising administering to the patient a dose and frequency effective to provide a reduction of at least about 3mmHg in one or more blood pressure parameters selected from the group consisting of trough sitting systolic, 24 hour dynamic systolic, and maximum circadian systolic blood pressure)

1. A method of treating isolated systolic hypertension, comprising administering to a subject in need thereof a therapeutically effective amount of a 2-73.

2. The method of claim 1, wherein the therapeutically effective amount of a2-73 is between 1mg and 60 mg.

3. The method of claim 2, wherein the therapeutically effective amount of a2-73 is between 30mg and 50 mg.

4. The method of claim 3, wherein the therapeutically effective amount of A2-73 is administered orally.

5. The method of claim 2, wherein the therapeutically effective amount of a2-73 is between 3mg and 5 mg.

6. The method of claim 5, wherein the therapeutically effective amount of A2-73 is administered intravenously.

7. Use of a2-73 in the manufacture of a medicament for the treatment of isolated systolic hypertension.

8. The medicament of claim 7, comprising a2-73 and a pharmaceutically acceptable carrier.

9. A method for reducing isolated systolic blood pressure in a subject in need thereof, the method comprising administering a2-73 to the patient at a dose and at a frequency effective to provide a reduction of at least about 3mmHg of one or more blood pressure parameters selected from the group consisting of valley sitting systole, 24 hour dynamic systole, and maximum circadian blood pressure, wherein the subject exhibits resistance to antihypertensive therapy with one or more antihypertensive drugs other than a 2-73.

10. A method for reducing isolated systolic blood pressure in a subject in need thereof, the method comprising administering a2-73 in combination with an antihypertensive drug to the patient at a dose and frequency effective to provide a reduction of at least about 3mmHg of one or more blood pressure parameters selected from the group consisting of valley sitting systolic, 24 hour dynamic systolic, and maximal circadian systolic blood pressure.

11. The method of claim 9 or claim 10, wherein the antihypertensive medication is selected from the group comprising: beta blockers, thiazide diuretics, ACE inhibitors, and calcium channel blockers.

12. The method of claim 11, wherein the beta blocker is selected from the group comprising: propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, ICI-118,551 and SR 59230A.

13. The method of claim 11, wherein the thiazide diuretic is selected from the group consisting of: chlorthalidone, hydrochlorothiazide, methyclothiazide, metolazone, indapamide, bendroflumethiazide, polythiazide, and hydroflumethiazide.

14. The method of claim 11, wherein the ACE inhibitor is selected from the group consisting of: enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, captopril and zofenopril.

15. The method of claim 11, wherein the calcium channel blocker is selected from the group consisting of: amlodipine, clindipine, clevidipine, felodipine, isradipine, lercanidipine, levamlodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, diltiazem, and verapamil.

Technical Field

The present disclosure generally relates to methods for reducing systolic blood pressure in a patient exhibiting resistance to antihypertensive therapy with one or more drugs, comprising administering to the patient a therapeutically effective amount of tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine hydrochloride.

Background

Sigma-1 receptors are calcium-sensitive endoplasmic reticulum chaperones associated with the maintenance of cellular calcium levels and proper protein folding. This receptor is believed to be important for maintaining cellular homeostasis in the presence of cellular stress and inflammation. Several studies have demonstrated that sigma-1 receptor stimulation promotes neuroprotection, neuroplasticity, cardioprotection and renal protection.

2-73 (hereinafter "a 2-73"), tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine hydrochloride, is a combined sigma-1 receptor agonist with the reported muscarinic (M1-M4) receptor activity. A2-73 was studied in phase I and IIa clinical trials as a therapeutic agent for the treatment of Alzheimer's disease and human patients were found to be well tolerated. In rats, sigma-1 receptor stimulation has been reported to promote endothelial and neuronal nitric oxide synthase activation and nitric oxide production, resulting in vasodilation and potentially mediating a drop in Blood Pressure (BP). M3receptor stimulation has been reported to trigger nitric oxide mediated central vasodilation. One report found that antagonists of M3 lowered blood pressure. (Kario et al, "Sleep-predominant lowering of hypertension by inhalation of a novel muscarinic M3receptor antagonist while sleeping: a novel 'bronchial anti-hypertension' strategy to target the lungs in hypertension with chronic obstructive pulmonary disease (Sleep-dependent lower of arterial hypertension by a novel approach of pulmonary targeting of a novel mucosal M3receptor antagonist), hypertension study (HYPERTENS RES.) 2008. 4: 31(4) 817-21. doi: 10.1291/hypertension.31.817). Drug-induced pairStimulation of such receptors may further contribute to changes in Blood Pressure (BP) in a given subject. Historically, clinical trials and clinical practice have placed more emphasis on Diastolic Blood Pressure (DBP) levels. Early reports defined DBP as the basis for detection and treatment, with 180/85mmHg blood pressure being unacceptable for treatment under later guidelines. Systolic hypertension, often considered as a result of major arteriosclerosis and loss of elasticity, is considered as an inevitable consequence of aging. DBP is often considered to be a function of peripheral resistance. SBP generally continues to rise with age while DBP stabilizes or falls. The end result is called Isolated Systolic Hypertension (ISH), which is generally understood to mean systolic blood pressure above 140mm Hg.

Treatment of ISH with thiazine diuretics and calcium antagonists or calcium channel blockers has been reported. Reference is made to therapeutic treatment with chlorothiadone (and optionally including atenolol or reserpine), nitrendipine, nifedipine, eprosartan and hydrochlorothiazide. In addition, ACE inhibitors, AT1 blockers, spironolactone (spironolactone), and opatricide (omapatrilate) are candidate therapeutic agents.

Disclosure of Invention

The present disclosure provides a method of treating isolated systolic hypertension comprising administering to a subject in need thereof an effective amount of a 2-73. The disclosure also includes the use of a2-73 in the manufacture of a medicament for the treatment of isolated systolic hypertension.

The present disclosure additionally includes a pharmaceutical composition for treating isolated systolic hypertension comprising a2-73 and a pharmaceutically acceptable carrier. Pharmaceutical compositions comprising a2-73 can be formulated for oral administration or, where appropriate, for administration by intravenous injection.

The present disclosure also includes a method for reducing systolic blood pressure in a subject in need thereof, the method comprising administering a2-73 to the subject at a dose and frequency effective to provide a reduction of at least about 3mmHg of one or more blood pressure parameters selected from the group consisting of valley sitting systole, 24 hour dynamic systole, and maximum circadian blood pressure, wherein the subject exhibits resistance to antihypertensive therapy with one or more antihypertensive drugs other than a 2-73.

Any of the methods disclosed herein for reducing systolic blood pressure may involve administering a2-73 in combination with another one or more antihypertensive drugs selected from beta blockers, thiazide diuretics, ACE inhibitors, and calcium channel blockers. Combinations may include simultaneous or separate administration schedules for each of the administered drugs.

A2-73 is used in a therapeutically effective amount of about 1mg to about 60 mg. In some aspects, the therapeutically effective dose is from about 30mg to about 50mg, particularly for oral administration. In other aspects, the therapeutically effective dose is about 3mg to about 5mg, particularly for intravenous administration. The present disclosure contemplates that a therapeutically effective dose can be administered at least once daily. In other aspects, a2-73 is administered according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period wherein a therapeutically effective dose of the pharmaceutical composition is administered to the patient, and thereafter, (b) a rest period. In some aspects, the administration period and the discontinuation period have the same duration or different durations. In some aspects, the administration period and the alternating withdrawal period are within a range from a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, and 14 days.

Drawings

Figure 1 is a graph of systolic blood pressure readings of 32 human patients of both genders adjusted for BP measurement time, gender, age, body mass index and prior or concurrent use of antihypertensive drugs across multiple follow-up visits.

Detailed Description

Various aspects of the disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is for illustration purposes only. A person skilled in the relevant art will recognize that other components and configurations may be used without parting from the spirit and scope of the disclosure.

It should be understood at the outset that although illustrative implementations of one or more aspects are illustrated below, the disclosed methods may be implemented using any number of techniques. The present disclosure should in no way be limited to the illustrative implementations, drawings, and techniques illustrated herein, but may be modified within the scope of the appended claims along with their full scope of equivalents.

In the following discussion and in the claims, the terms "include" and "comprise" are used in an open-ended fashion, and thus should be interpreted to mean "including, but not limited to. Various features described in greater detail below will become apparent to those skilled in the art with the benefit of this disclosure upon reading the following detailed description and by referring to the accompanying drawings.

According to one aspect of the present disclosure, a2-73 can be produced by feeding isopropanol to a solution of tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine free base in ethyl acetate. The ethyl acetate was removed by distillation and the remaining isopropanol solution containing tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine free base was filtered to be clear. Aqueous hydrochloric acid (1.1 eq) was charged to a solution of isopropanol and the crystalline tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine hydrochloride (a2-73) formed was isolated by filtration and dried under vacuum at 55 ℃ for 3 days.

The safety of A2-73 has been demonstrated in a randomized, placebo-controlled, single ascending dose phase 1A 2-73 study in 22 healthy male volunteers. (see Ole Voges, Ingo Weigmann, Norman Bitterlich, ChristophSchinder and Christopher Missling, "Phase 1 Dose Escalation Study to Study Safety, Tolerability and Pharmacokinetics of ANAVEX2-73 in healthy male Subjects (A Phase 1 Dose assessment Safety, Tolerability, and Pharmacokinetics of ANAVEX2-73 in Healthy Male Subjects)," Central nervous System Peak conference in 2014 (CNS Summit 2014), Boca Raton, FL, the entire disclosure of which is incorporated herein by reference). Incremental single oral doses of 1mg, 10mg, 30mg, 40mg, 50mg and 55mg of a2-73 were safe and well tolerated in healthy subjects. No serious adverse events occurred. The maximum tolerated dose and the minimum intolerant dose were defined as 55mg and 60mg, respectively, based on the frequency and intensity of non-therapeutic emergency adverse events. At the highest dose, adverse events observed included moderate and reversible dizziness and headache common in drugs targeting the central nervous system. Blood pressure and resting heart rate, as well as other clinical parameters like vital signs and 12-lead Electrocardiogram (ECG), do not show any clinically relevant or dose-dependent changes. The pharmacokinetics of A2-73 were found to be suitable for daily oral administration.

The present disclosure relates generally to pharmaceutical compounds and compositions for treating high Systolic Blood Pressure (SBP). More particularly, the present disclosure relates to the use of pharmaceutical compositions containing a2-73 for the treatment of high SBP.

SBP is therapeutically reduced by the methods as described herein. Blood pressure is determined by any of a variety of methods known in the art, including by blood pressure measurement. Blood pressure is typically measured in a seated or dynamic subject.

Another measure of blood pressure is "24 hour ambulatory" blood pressure. The "24-hour dynamic" systolic or diastolic BP is the average of systolic or diastolic measurements taken repeatedly over the course of a 24-hour period in a dynamic subject.

The "maximum circadian" systolic or diastolic BP is a measure of the highest systolic or diastolic blood pressure recorded over a 24-hour period. Without being bound by any particular theory, it is believed that the maximum circadian BP reflects a peak of the natural circadian blood pressure cycle, which typically occurs in the morning, e.g., between about 5 a.m. and about 11 a.m. Typically, the second peak occurs during the evening, for example between about 5 pm and 10 pm. This bimodal waveform circadian dynamic BP mode may be particularly characteristic of refractory hypertension.

A common feature of refractory hypertension is that the nocturnal (defined herein as 2200 to 0600) mean systolic activity BP is about 10% lower than the daytime (defined herein as 0600 to 2200) mean systolic activity BP. The parameter referred to herein as "day/night dynamic BP ratio" (expressed as a percentage) is calculated as (daytime average-nighttime average)/daytime average × 100. The circadian dynamic bp (ABP) pattern with daily/night ABP ratios less than about 10% is sometimes referred to as "non-arytenoic ABP".

As discussed herein, in some aspects, a subject patient receiving a2-73 who exhibits a therapeutic systolic blood pressure reduction according to the methods of the invention is a subject who exhibits resistance to antihypertensive therapy with one or more drugs other than a 2-73.

An unexpected drop in Systolic Blood Pressure (SBP) has now been found in a clinical study with a post-hoc evaluation, which was observed in a clinical trial with A2-73 for phase IIa of Alzheimer's disease. BP was measured at four time points during the study period: 1) screening for entry day, 2) the first day of treatment with oral or intravenous drugs (BP measurements were obtained prior to drug administration), 3) day 25 of treatment (when patients switched to oral or intravenous administration of whatever formula they had not previously received), and 4) day 36 (end of phase IIa study part a). Statistical analysis included a paired t-test comparing the BP change across each measurement, and multivariate linear mixed effect modeling (adjusted for time of measurement, gender, age, body mass index, and use of antihypertensive drugs) to account for intra-individual repeat measurements over time.

Thirty-two Alzheimer's disease patients were involved in phase IIa trials. The mean age was 69.5 (standard deviation [ SD ]9.8) years, 60% were males, the mean body mass index was 26.5(SD 3.9) kg/m2, and 50% were taking antihypertensive drugs at the time of screening. In an unadjusted analysis, a significant drop in SBP was compared between the first measurement (mean SBP 143.3, SD 19.7, mmHg) and all subsequent measurements (p ═ 0.007, 0.001, and 0.007, respectively). There was an average 8.7(SD 3.0) mmHg SBP reduction between the first and second measurements (i.e., immediately prior to the first treatment), but there was no significant reduction in comparing the second measurement to all subsequent measurements (p ═ 0.120 and 0.972, respectively). In the multivariate tuning model (fig. 1), there was no significant difference in SBP between the first and second reads (p ═ 0.211). However, as shown in fig. 1, there is a significant drop in SBP between the first read and other subsequent reads (p ═ 0.048 and 0.008, respectively). It should be noted that no patient reported any change in their antihypertensive regimen while participating in the trial.

There was no previous report of finding a decrease in SBP after treatment with sigma-1 receptor agonists. Such drugs therefore provide a novel mechanism for reducing systolic BP, which is useful in the treatment of isolated systolic hypertension. The efficacy of a2-73 is presented graphically in fig. 1, presenting repeated systolic BP readings adjusted for BP measurement time, gender, age, body mass index and use of antihypertensive drugs across follow-up visits. The beneficial effects of reducing systolic blood pressure include patients who exhibit resistance to many existing classes of antihypertensive drugs and therefore represent a significant advance in the treatment of high systolic blood pressure.

In some aspects, a combination dose comprising a2-73 and at least one beta blocker such as propranolol (propanolol) ((RS) -1- (1-methylethylamino) -3- (1-naphthoxy) propan-2-ol), bucindolol (butricinol) (2- [ 2-hydroxy-3- [ [2- (1H-indol-3-yl) -1, 1-dimethyl-ethyl ] amino ] propoxy ] benzonitrile), carteolol (carteolol) ((RS) -5- [3- (tert-butylamino) -2-hydroxypropoxy ] -3, 4-dihydroquinolin-2 (1H) -one), carvedilol (carvediol) (±) [3- (9H-carbazol-4-yloxy) -2(1H) -one), is expected to reduce SBP -hydroxypropyl ] [2- (2-methoxyphenoxy) ethyl ] amine), labetalol (labetalol) ((RS) -2-hydroxy-5- [ 1-hydroxy-2- [ (4-phenylbutan-2-yl) amino ] ethyl ] benzylamide), nadolol (nadolol) (rel- (2R, 3S) -5- { [ (2R) -3- (tert-butylamino) -2-hydroxypropyl ] oxy } -1, 2, 3, 4-tetrahydronaphthalene-2, 3-diol), oxprenolol (oxprenolol) ((RS) -1- [2- (allyloxy) phenoxy ] -3- (isopropylamino) propan-2-ol), penbutolol (penbutolol) ((S) -1- (tert-butylamino) -3- (2-cyclopentyl) propan-2-ol) Phenoxy) propan-2-ol), pindolol (pindolol) ((RS) -1- (1H-indol-4-yloxy) -3- (isopropylamino) propan-2-ol), sotalol (sotalol) ((RS) -N- {4- [ 1-hydroxy-2- (propan-2-ylamino) ethyl ] phenyl } methanesulfonamide), timolol (timolol) ((S) -1- (tert-butylamino) -3- [ (4-morpholin-4-yl-1, 2, 5-thiadiazol-3-yl) oxy ] propan-2-ol), acebutolol (acebutolol) ((RS) -N- { 3-acetyl-4- [ 2-hydroxy-3- (propan-2-ylamino) propoxy ] benzene-2-ol) (RS) -2- {4- [ 2-hydroxy-3- (propan-2-ylamino) propoxy ] phenyl } acetamide), betaxolol ((RS) -1- {4- [2- (cyclopropylmethoxy) ethyl ] -phenoxy } -3- (isopropylamino) propan-2-ol), bisoprolol ((RS) -1- {4- [ (2-isopropoxyethoxy) methyl ] phenoxy } -3- (isopropylamino) propan-2-ol), celiprolol ((RS) -N' - { 3-acetyl-4- [3- (tert-butylamino) -2-hydroxypropoxy ] phenyl } -N, n-diethylurea), metoprolol ((RS) -1- [4- (2-methoxyethyl) phenoxy ] -3- [ (propan-2-yl) amino ] propan-2-ol), nebivolol (nebivolol) (1RS, 1 ' RS) -1, 1 ' - [ (2RS, 2 ' SR) -bis (6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-yl) ] -2, 2 ' -iminodiethanol or 1- (6-fluoro chroman-2-yl) - { [2- (6-fluoro chroman-2-yl) -2-hydroxy-ethyl ] amino } ethanol or 2, 2 ' -azanediyl bis (1- (6-fluoro chroman-2-yl) ethanol) or 1- (3-fluoro chroman-2-yl) ethanol 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-yl) -2- { [2- (6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-yl) -2-hydroxyethyl ] amino } ethan-1-ol or a combination thereof), esmolol (esmolol) ((RS) -3- {4- [ 2-hydroxy-3- (propan-2-ylamino) propoxy ] phenyl } propanoic acid methyl ester), butaxamine (butaxamine) ((1S, 2S) -1- (2, 5-dimethoxyphenyl) -2- (tert-butylamino) propan-1-ol), ICI-118,551 (3- (isopropylamino) -1- [ (7-methyl-4-yl) -1-ol) -indanyl) oxy ] butan-2-ol) and SR 59230A ((2S) -1- (2-ethylphenoxy) -3- { [ (1S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl ] amino } propan-2-ol).

In other aspects, a combination dose comprising a2-73 and at least one thiazide diuretic such as chlorthalidone (chlorothalidone) ((RS) -2-chloro-5- (1-hydroxy-3-oxo-2, 3-dihydro-1H-isoindol-1-yl) benzene-1-sulfonamide), hydrochlorothiazide (6-chloro-1, 1-dioxo-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide), methylchlorothiazide (6-chloro-3- (chloromethyl) -2-methyl-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide), metolazone (methoxazone) (7-chloro-2-methyl-4-oxo-3-o-tolyl-1, 2, 3, 4-tetrahydroquinazoline-6-sulfonamide), indapamide (indapamide) (4-chloro-N- (2-methyl-2, 3-dihydroindol-1-yl) -3-sulfamoyl-benzylamide), bendroflumethiazide (3-benzyl-1, 1-dioxo-6- (trifluoromethyl) -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide), polythiazide (6-chloro-2-methyl-3- { [ (2), 2, 2-trifluoroethyl) thio ] methyl } -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide) and hydrofluorothiazine (1, 1-dioxo-6- (trifluoromethyl) -3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide).

In other aspects, a combination dose comprising a2-73 and at least one ACE inhibitor such aS enalapril (enalapril) ((2S) -1- [ (2S) -2- { [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino } propionyl ] pyrrolidine-2-carboxylic acid), ramipril (ramipril) ((2S, 3aS, 6aS) -1- [ (2S) -2- [ [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino ] propionyl ] -3, 3a, 4, 5, 6, 6 a-hexahydro-2H-cyclopenta [ b ] pyrrole-2-carboxylic acid), or a combination dose comprising a2-73 and at least one ACE inhibitor such aS, Quinapril (quinapril) ((3S) -2- [ (2S) -2- [ [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino ] propanoyl ] -3, 4-dihydro-1H-isoquinoline-3-carboxylic acid), perindopril (perindopril) ((2S, 3aS, 7aS) -1- [ (2S) -2- { [ (2S) -1-ethoxy-1-oxopent-2-yl ] amino } propanoyl ] -octahydro-1H-indole-2-carboxylic acid), lisinopril (lisinopril) ((2S) -1- [ (2S) -6-amino-2- [ [ (1S) -1-carboxy-3-phenylpropyl ] amino ] propanoyl ] -octahydro-1H-indole-2-carboxylic acid), lisinopril (2S) -1- [ (2S) -6-amino-2- [ [ (1S) -1-carboxy-3-phenylpropyl ] amino ] Hexanoyl ] pyrrolidine-2-carboxylic acid), benazepril (benazepril) (2- [ (3S) -3- [ [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino ] -2-oxo-4, 5-dihydro-3H-1-benzazepin-1-yl ] acetic acid), imidapril (imidapril) ((4S) -3- [ (2S) -2- [ [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino ] propionyl ] -1-methyl-2-oxoimidazolidine-4-carboxylic acid), trandolapril (trandolapril) ((2S, 3aR, 7aS) -1- [ (2S) -2- { [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino } propanoyl ] -octahydro-1H-indole-2-carboxylic acid), cilazapril (cilazapril) ((4S, 7S) -7- [ [ (2S) -1-ethoxy-1-oxo-4-phenylbutan-2-yl ] amino ] -6-oxo-1, 2, 3, 4, 7, 8, 9, 10-octahydropyridazino [1, 2-a ] diazepine-4-carboxylic acid), fosinopril (fosinopril) ((2S, 4S) -4-cyclohexyl-1- [2- [ hydroxy (4-phenylbutyl) phosphoryl ] acetyl ] pirepin-yl) Pyrrolidine-2-carboxylic acid), captopril (captopril) ((2S) -1- [ (2S) -2-methyl-3-sulfanylpropionyl ] pyrrolidine-2-carboxylic acid) and zofenopril (zofenopril) ((2S, 4S) -1- [ (2S) -3-benzoylsulfanyl-2-methylpropiono ] -4-phenylsulfanylpyrrolidine-2-carboxylic acid).

In other aspects, a combination dose comprising a2-73 and at least one calcium channel blocker such as amlodipine (amlodipine) ((RS) -2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester), clinodipine (clinidipine) (3- (E) -2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-phenyl-2-propenyl ester 5-2-methoxyethyl ester), clevidipine (clevidipine) ((RS) -4- (2, 3-dichlorophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 5-O- (butyryloxymethyl) ester 3-O-methyl ester), felodipine (felodipine) ((RS) -4- (2, 3-dichlorophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester), isradipine (isradipine) (4- (2, 1, 3-benzooxadiazol-4-yl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-methyl ester 5-propan-2-yl ester), lercanidipine (lercanidipine) ((RS) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 2[ (3, 3-diphenylpropyl) (methyl) amino ] -1, 1-dimethylethyl ester methyl ester), levamlodipine (levamiodipine) ((S) -2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester), nicardipine (nicardipine) (2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 2- [ benzyl (methyl) amino ] ethyl ester methyl ester), Nifedipine (3, 5-dimethyl 2, 6-dimethyl-4- (2-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate), nimodipine (nimodipine) (3- (2-methoxyethyl) 2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate 5-propan-2-yl ester), nisoldipine (nisoldipine) (isobutyl methyl 2, 6-dimethyl-4- (2-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylate), nitrendipine ((RS) -2, 6-dimethyl-4- (m-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester), diltiazem (diltiazem) (cis- (+) -acetic acid [2- (2-dimethylaminoethyl) -5- (4-methoxyphenyl) -3-oxo-6-thia-2-azabicyclo [5.4.0] undec-7, 9, 11-trien-4-yl ] ester) and verapamil (verapamil) ((RS) -2- (3, 4-dimethoxyphenyl) -5- { [2- (3, 4-dimethoxyphenyl) ethyl ] - (methyl) amino } -2-propan-2-yl valeronitrile).

In a related aspect, contemplated dosing regimens include administering to a subject a pharmaceutical composition comprising a2-73 on at least a daily basis. Twice daily administration is also expressly contemplated, and daily dosing as described herein can be divided into two equal doses. Administration may be once or twice daily for a period of at least 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days, or indefinitely for more than 30 days for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or longer. In other aspects, a2-73 is administered according to an intermittent dosing regimen of at least one or two cycles, each cycle comprising (a) a dosing period wherein a therapeutically effective dose of the pharmaceutical composition is administered to the patient, and thereafter, (b) a rest period. In some aspects, the administration period and the discontinuation period have the same duration or different durations. In some aspects, the administration is at least daily during a dosing period.

In some aspects, the administration period and the withdrawal period are within a range from a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, and 14 days. From the foregoing, it will be appreciated that various combinations of administration and withdrawal period lengths are contemplated and may be modified as necessary for the responsiveness of the patient. As a simple example, the dosing period and alternate rest period regimen may each be 1 day, as follows: day 1 dose/day 2 withdrawal/day 3 dose/day 4 withdrawal, etc. It is also noted that administration periods between about 1 and 12 days alternate with drug withdrawal periods between about 1 and 12 days in any combination, with particular reference to 12 days of administration periods and 12 days of drug withdrawal periods. An intermittent dosing regimen is usefully employed wherein the therapeutically effective amount of the pharmaceutical composition of a2-73 is from about 1mg to about 60mg and especially from about 30mg to about 50mg, especially for oral dosage forms. Doses of A2-73 of about 3mg to about 5mg are also contemplated, particularly for intravenous administration.

It will be appreciated that the dosage and time course of administration may vary depending on the characteristics and responsiveness of the subject. Blood pressure can be readily monitored using any method known in the art.

All values and ranges disclosed herein can vary by some amount. Whenever a numerical range with a lower limit and an upper limit is disclosed, any number and any included range within the range is specifically disclosed. In particular, each range of values (having the form "from about a to about b" or, equivalently, "from about a to b" or, equivalently, "from about a-b") disclosed herein is to be understood as stating each and every number and range encompassed within the broader range of values.

The compositions disclosed herein are employed individually or in combination in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier materials, which are suitable for parenteral, enteral (e.g., oral or inhalation), or topical application and which do not deleteriously react with the active composition. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, saline solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates (e.g., lactose, amylose, or starch), magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, perfume oils, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and/or aromatic substances and the like, which do not deleteriously react with the active composition. The pharmaceutical preparations can also be combined with other active agents, such as vitamins, if desired.

In some aspects, the dosage form includes instructions for use of such compositions. For parenteral applications, particular mention may be made of injectable preparations, sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants, including suppositories. Ampoules, vials or syringe barrels are convenient unit doses. By "unit dosage form" is meant a single administration entity. For example, single tablets, capsules, dragees or lozenges, suppositories or syringes.

Also for enteral applications, particularly suitable are tablets, dragees, liquids, drops, suppositories or capsules. Syrups, elixirs and the like may be employed, with a sweetening vehicle. Sublingual and buccal forms are also noted.

Sustained or direct release compositions, such as liposomes or those in which the active ingredient is protected by a differentially degradable coating (e.g., by microencapsulation, multiple coatings, etc.) can be formulated. It is also possible to freeze-dry the new composition and use the obtained lyophilisate, for example for the preparation of a product for injection.