WO2012166909A1

WO2012166909A1 - Compositions and methods for treating breathing control disorders or diseases

Info

Publication number: WO2012166909A1
Application number: PCT/US2012/040195
Authority: WO
Inventors: James C. Mannion; Scott L. Dax; Richard Woodward; Vita Ozola
Original assignee: Galleon Pharmaceuticals, Inc.
Priority date: 2011-06-03
Filing date: 2012-05-31
Publication date: 2012-12-06

Abstract

The present invention includes a method of treating a breathing control disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (+)-ketodoxapram or a solvate thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially free of (— )-ketodoxapram or a solvate thereof.

Description

TITLE OF THE INVENTION

Compositions and. Methods for Treating Breathing Control Disorders or Diseases

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is entitled to priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 61/492,988. filed June 3, 201 1, all of which is hereby incorporated by reference in its entirety herein,

BACKGROUND OF THE INVENTION

Normal control of breathing is a complex process that in v olves, in part, the body's interpretation and response to chemical stimuli such as carbon dioxide, pH and oxygen levels in blood, tissues and the brain. Breathing control is also affected by other factors such as wakefulness (i.e., whether the patient is awake or sleeping), emotion, posture and vocalization. Within the brain medulla, there are respirator}' control centers that interpret various feedforward and feedback signals that affect respiration and issues commands to the muscles that perform the work of breathing. Key muscle groups are located in the abdomen, diaphragm, pharynx and thorax.

Sensors located centrally and peripherally then provide input to the brain's central respiration control areas that enables response to changing metabolic requirements.

For example, ventilation sufficient to meet the body's metabolic needs is maintained primarily by the body's rapid response to changes in carbon dioxide levels (C0₂). Increased C0₂ levels signal the body to increase breathing rate and depth, resulting in higher blood oxygen levels and subsequent lower blood C0₂ levels. Conversely , low CO_?, levels can result in periods of hyponea (decreased breathing) or, in the extreme case, apnea (no breathing) since the stimulation to breathe is diminished. This is what happens w^rhen a person hyperventilates.

There are many diseases in which loss of normal breathing control is a primary or secondary feature of the disease. Examples of diseases with a primary loss of breathing control are apneas (central, mixed or obstructive; where the breathing repeatedly stops for 10 to 60 seconds) and congenital central hypoventilation syndrome. Secondary loss of breathing control may be due to chronic cardiopulmonary diseases (e.g., heart failure, chronic bronchitis, emphysema, and

. { - impending respiratory failure}, excessive weight (e.g., obesity-hypoventilation syndrome), certain drugs (e.g., anesthetics, sedatives, anxiolytics, hypnotics, alcohol, and narcotic analgesics and/or factors that affect the neurological system (e.g., stroke, rumor, trauma, radiation damage, and ALS). In chronic obstructive pulmonary diseases where the body is exposed to chronically high levels of carbon dioxide, the body adapts to the lower pH by a kidiiey mediated retention of bicarbonate, which has the effect of partially neu tralizing the CCVpH respiratory stimulation. Thus, the patient is unable to mount a normal ventilatory response to changes in metabolic demand,

Sleep disordered breathing is an example of where abnormalities in the control of breathing lead to a seriou s and prevalent disease in humans. Sleep apnea is characterized by frequent periods of no or partial breathing. Key factors that contribute to these apneas include anatomical factors (such as obesity), decreased hypercapnic and hypoxic ventilatory responses (e.g., decreased response to high carbon dioxide and low oxygen levels, respectively) and loss of "wakefulness" (e.g., drive to pharyngeal dilator muscles).. Apneic events result in hypoxia (and the associated oxidative stress) and eventually severe cardiovascular consequences (high blood pressure, stroke, heart attack).

Estimates for U.S. individuals afflicted with conditions wherein there is compromised respiratory control include sleep apneas (15-20 millions); obesity- hypoventilation syndrome (5-10 millions); chronic heart disease (5 millions); chronic obstractive pulmonary disease (COPD)/chroiiic bronchitis (10 millions); drag- induced, hypoventilation (2-5 millions); and mechanical ventilation weaning (0.5 million).

Racemic l -ethy{-4-(2-(moiphilin- -yl)efhyf)-33-diphenyl-pym)lid.in- -one (commonly known as doxapram) is a known respiratory stimulant, marketed, under the name of Dopram™.

doxapram Doxapram lias a strong, dose-dependent effect on stimulating respiration (breathing) in animals (Ward & Franko, 1962, Fed. Proc. 21 :325).

Administered intravenously, doxapram causes an increase in tidal volume and respiratory rate. Doxapram is used in intensive care settings to stimulate respiration in patients with respiratory failure and to suppress shivering after surgery. Doxapram is also useful for treating respiratory depression in patients who have taken excessive doses of opioid drugs such as buprenorphine and fail to respond, adequately to treatment with naloxone. However, use of doxapram in the medical setting is hampered by side effects, such as high blood pressure, panic attacks, tachycardia (rapid heart rate), tremor, convulsions, sweating, vomiting and the sensation of "air hunger." Doxapram may not be used in patients with coronary heart disease, epilepsy and high blood pressure.

The C-4 carbon in the structure of doxapram is a chiral center, and thus there are two distinct enantiomers associated with this molecule: the (+)-enantiomer and the (— )-enantionier. The concept of enantiomers is well known to those skilled in the art. The two enantiomers have the same molecular formula and identical chemical connectivity but opposite spatial "handedness." The two enantiomers are a mirror image of each other but are not superimposable.

Chiral molecules have the unique property of causing a rotation in the original plane of vibration of plane-polarized light. Individual enantiomers are able to rotate plane-polarized light in a clockwise (dextrorotary; the (+)-enantiomer) or counter clockwise (levorotatory; the (— )-enantiomer) manner. For a specific combination of solvent, concentration and temperature, the pure enantiomers rotate plane-polarized light by the same number of degrees but in opposite directions.

A racemic mixture or a "racemate" is a term used, to indicate the mixture of essentially equal quantities of enantiomeric pairs. Racemic mixtures are devoid of appreciable optical activity due to the mutually opposing optical activities of the individual enantiomers. Apart from their interaction with polarized light, enantiomers may differ in their phy sical, chemical and pharmacology activities, but such differences between enantiomers are largely unpredictable. Recent attempts have been made to develop pure enantiomers as new drags, based on previously marketed racemic drags (Nunez et al., 2009, Curr. Med. Chem. 16(16):2064-74). Development of an individual enantiomer as a novel drag, based on the already used racemate, requires the de novo p armacokinetic, pharmacological and toxicological characterization of each enantionier, since its properties may differ substantially and unpredictably from those of the racemate.

Doxapram is marketed and medically used, as a racemate, Doxapram has been previously separated into its pure enantiomers using methods such as chirai high-performance chromatography (Chankvetadze et al., 1996, J. Pharm. Biomed. Anal. 14: 1295-1303; Thunberg et al., 2002, J. Pharm. Biomed. Anal. 27:431 -39), and chirai capillary electrophoresis (Christians & Hoizgrabe, 2001. J. Chromat. A 91 1 :249-57). Using in silico methods, the enantiomers of doxapram were predicted to have identical oral bioavailability (Moda et al, 2007, Bioorg. Med. Chem. 15:7738- 45).

ketodoxapram

Ketodoxapram (4-[2-( l-ethyl-5-oxo-4,4-diphenyl-pyrrolidin-3-yl)- ethyl]-morphoiin~3~one) was found to be one of the major metabolites of doxapram in adults and newborn infants (Robson & Prescott, 1979, Br. J. Clin. Pharmacol, 7:81 - 87; Aranda et al., 1987, Pediatr. Res. 21 :357). Ketodoxapram was shown to have comparable pharmacological potency to doxapram and cause overt CNS stimulation in lambs (Bairam et al, 1991 , Resp. Phys. 86:345-54). Ketodoxapram appears to have fewer adverse effects but slightly shorter effect on baseline minute ventilation than doxapram (Bairam et al., 1990, Ped. Res. 28(2): 142-46).

There is a need in the art for novel chemical compounds that can be used to restore all or part of the body's normal breathing control system in response to changes in C0₂ and/or oxygen, with minimal side effects. Such compounds would be of benefit in decreasing the incidence and severity of breathing control disturbances. The present invention addresses and meets these needs. BRIEF SUMMARY OF THE INVENTION

The invention includes a composition comprising (-f-)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (— )-ketodoxapram or a solvate thereof,

In one embodiment, the (-H)-ketodoxapram or solvate thereof has enantiomeric purity of at least about 95%, In another embodiment, the

(+)-ketodoxapram or solvate thereof has enantiomeric purity of at least about 97%, In yet another embodiment, the (+)-ketodoxapram or solvate thereof has enantiomeric purity of at least about 99%. In yet another embodiment, the composition further comprises at least one pharmaceutically acceptable carrier.

The invention also includes a method of preventing or treating a breathing control disorder or disease in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (— )-ketodoxapram or a solvate thereof.

In one embodiment, the (+)-ketodoxapram or solva te thereof has at least about 95% enantiomeric purity. In another embodiment, the (+)-ketodoxapram or solvate thereof has at least about 97% enantiomeric purity. In yet another embodiment, the (- )-ketodoxapram or solvate thereof has at least about 99% enantiomeric purity. In yet another embodiment, the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventiiation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, and liypercapnia. In yet another embodiment, the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. In yet another embodiment, the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease. In yet another embodiment, the at least one additional compound is selected from the group consisting of an opioid, sedative, anesthetic, acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid, and an ampakine. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. In yet another embodiment, the subject is a mammal. in yet another embodiment, the mammal is a human, in yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

The invention also includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (— )-ketodoxapram or a solvate thereof.

In one embodiment, the (+)-ketodoxapram or solvate thereof has at least about 95% enantiomeric purity. In another embodiment, the (+)-ketodoxapram or solvate thereof has at least about 97% enantiomeric purity. In yet another embodiment, the (+)-ketodoxapram or solvate thereof has at least about 99% enantiomeric purity. In yet another embodiment, the subject is further administered a composition comprising at least one additional compound useful for preventing destabilization of or stabilizing the breathing rhythm. In yet another embodiment, the at least one additional compound is selected from the group consisting of an opioid, sedative, anesthetic, acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotonergic modulator, a cannabinoid, and an ampakine. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. In yet another embodiment, the subject is a mammal. In yet another embodiment, the mammal is a human. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

The invention also includes a method of preparing (H-)-ketodoxapram. The method comprises reacting (R)-l-ethyl-4-(2-iodoethyl)-3,3-diphenylpyrrolidin-2- one with morpholin-3-one in a solvent to yield (-H)-doxapram.

In one embodiment, morpholin-3-one is pretreated with a strong base to form the corresponding anion of morpholin-3-one. In another embodiment, the strong base comprises sodium hydride. In yet another embodiment, the solvent comprises Ν,Ν-dimethylformamide (DMF). In yet another embodiment, (R)-l -ethyl- 4-(2-iodoethyl)-3,3-diphenylpyrrolidin-2-one is prepared from (R)-2-( l- ethylpyrrolidin-3-yl)-2,2-diphenylacetic acid. In yet another embodiment, (R)-2-(l- ethylpyrrolidin-3-yl)-2,2-diphenylacetic acid is contacted with acetic anhydride and sodium iodide to yield (R)-l-ethy3-4-(2-iodoethyl)-3,3-diphenylpyrro3idio-2-one. In yet another embodiment, (R)-2-(l-ethylpyrrolidin-3-yl)-2,2~diphenyIacetic acid is prepared by hydrolyzing (R)-2-(l -ethylpyrrolidin-3-yl)-2,2-diphenylacetonitrile. In yet another embodiment, the hydrolyzing comprises treatment with a sulfuric acid solution and a hydrobromic acid solution. In yet another embodiment. (R)-2~(l~ ethylpyi olidin-3-yl)-2,2-diphenylacetonitrile is prepared by reacting (R)-3-chloro-l - ethylpyrrolidine with an anion of diphenylacetonitrile. In yet another embodiment, (R.)-3-chloro-l-ethylpyrrolidine is prepared by chlorinating (S)-l-ethylpyrrolidin-3-ol. In yet another embodiment, the chlorinating comprises treating (S)-l-ethylpyrrolidin- 3-ol with thionyi chloride. In yet another embodiment, (S)-l-ethylpyrrolidin-3-ol is prepared by reducing (S)-l -acetylpyrrolidin-3-yl acetate. In yet another embodiment, (S)- l-acetylpyrroIidin-3-yl acetate is prepared by acetylating (S)-3- hydroxypyrrolidine. In yet another embodiment, preparing (R)-2-(l -ethylpyrrolidin- 3-yl)-2,2-diphenylacetonitriie comprises: converting (R)-l-ethy3pyrroiidin-3-ol to a nucleophilically labile hydroxyl derivative, and reacting the derivative with an anion of diphenylacetonitrile to yield (R)-2-(l-ethylpyrrolidin-3-yl)-2,2- diphenylacetonitrile.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of preferred embodiments of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and

instrumentalities of the embodiments shown in the drawings.

Figure 1 is a graph illustrating the chiral HPLC trace for the first eluting peak derived from the resolution of ketodoxapram.

Figure 2 is a graph illustrating the chiral HPLC trace for the second eluting peak derived from the resolution of ketodoxapram.

Figure 3 is a graph illustrating the chiral HPLC trace for racemic ketodoxapram. Figure 4, comprising Figures 4A-4D, are graphs illustrating the effects of the (+)-enantiomer of ketodoxapram (Cmpd 19) on the respirator)'- rate (4A), tidal volume (4B), minute volume (4C) and 5 min average change in minute volume (4D) respectively, in anesthetized rats (n=4). Vehicle and (R)-4-[2-(l-ethyl-5-oxo-4,4- diphenyi-pyrrolidin-3-yl}-eihyl]-morpholin-3-one ( 1, 3, and 10 mg/kg) were administered intravenously to urethane anesthetized rats.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to the unexpected discovery that the (+)-enantiomer of ketodoxapram displays most or all the desired beneficial pharmacological activity associated with the racemic ketodoxapram.

In another aspect, the present invention relates to the unexpected discover}' that the (— )-enantiomer of ketodoxapram is essentially devoid of activity in stimulating ventilation or reversing respiratory depression, and moreover produces a number of acute side effects that were not detected as the same doses with (+)- ketodoxapram, such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, and production of cardiac arrhythmias and death.

The present invention includes a pharmaceutical composition comprising the (+)-enantiomer of (4-[2-(l -ethyl-5-oxo-4,4-diphenyl-pyrrolidin-3-yl)- ethylj-morpholin-3-one), also known as (+)-ketodoxapram, or a solvate thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially free of (— -)-ketodoxapram or a solvate thereof.

The present invention also includes a method of preparing (+)- ketodoxapram, wherein (+)-ketodoxapram is essentially free of (—) -ketodoxapram.

The present inv ention also includes a method of treating a breathing control disease or disorder in a subject in need thereof. The breathing control disease or disorder includes, but is not limited to, respiratory depression (induced by anesthetics, sedatives, anxiolytic agents, hypnotic agents, alcohol, and analgesics), sleep apnea, apnea of prematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (COPD). The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (+)-ketodoxapram or a solvate thereof, and a pharmaceutically acceptable carrier, wherein the composition is essentially tree of (— )-ketodoxapram or a solvate thereof.

Definitions

As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, animal pharmacology, and organic chemistry are those well-known and commonly employed in the art.

As used herein, the articles "a" and "an" refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

A "subject", as used therein, can be a human or non-human mammal.

Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is human.

As used herein, the term "doxapram" refers to l -ethyl-4-(2-(morphiiin- 4-yl)ethyl)-3,3-diphenyl-pyrrolidin-2-one, or a solvate thereof. Unless otherwise noted, "doxapram" refers to racemic doxapram, which comprises an essentially equimolar mixture of the two enantiomers of doxapram (the (+)-enantiomer and the (— )-enantiomer).

As used herein, a "solvate" of a compound refers to a combination of the compound and at least one solvent. In one embodiment, the solvate comprises water. In another embodiment, the solvate comprises an organic solvent, such as, but not limited to, DMSO, ethanol, «-propanol or isopropanol.

As used herein, the "(+)-doxapram" and "(— )-doxapram" enantiomers are defined in terms of the order in which they are eiuted from ehiral HPLC column, defined as: (a) a CHIKALPAK*" AY 20μηι column, with 3cm internal diameter x 25cm length, using ethanol with 0.2% DMEA (dimethylet ykmine) and C0₂ as mobile phase, in a ratio of 15:85 (v/v), with a flow rate of 85 g/min, a column temperature of 35°C, and UV detection at 220 nm; or (b) a CHXRALPAK^® AY-H 5μτη column, with 3cm internal diameter x 25cm length, using ethanol with 0.2% DMEA and CO_?, as mobile phase, in a ratio of 15:85 (v/v), with a flow rate of 85 g/min, a column temperature of 35°C, and UV detection at 220 nra. Under either condition, the (— )-doxapram enantiomer has a shorter elution/retention time from the column than the (+)-doxapram enantiomer. The nomenclature "(+)-doxapram" should not be construed to imply that this enantiomer rotates the vibrational plane of plane-polarized light in a clockwise manner under all possible combinations of solvent, temperature and concentration. Similarly, the nomenclature "(— )-doxapram" should not be construed to imply that this enantiomer rotates the vibrational plane of plane -polarized light in a counter-clockwise manner under all possible combinations of solvent, temperature and concentration.

As used herein, the "(+)-ketodoxapram" and "(— Vketodoxapram" enantiomers are defined in terms of the corresponding (-t-)-doxapram and (—-)- doxapram. (+)-Ketodoxapram has the same absolute stereochemistry as (+)- doxapram, and (— )-ketodoxapram has the same absolute stereochemistry as (— -)- doxapram. The nomenclature "(H-)-ketodoxapram" should not be construed to imply that this enantiomer rotates the vibrational plane of plane-polarized light in a clockwise manner under all possible combinations of solvent, temperature and concentration. Similarly, the nomenclature "(—Vketodoxapram" should not be construed to imply that this enantiomer rotates the vibrational plane of plane- polarized light in a counter-clockwise manner under all possible combinations of solvent, temperature and concentration.

As used herein, the term "enantiomeric purity" of a given enantiomer over the opposite enantiomer indicates the excess % of the given enantiomer over the opposite enantiomer, by mole. For example, in a mixture comprising about 80% of a given enantiomer and about 20% of the opposite enantiomer, the enantiomeric purity of the given enantiomer is about 60%.

As used herein, the term "essentially free of as applied to a given enantiomer in a mixture with the opposite enantiomer indicates that the enantiomeric purity of the given enantiomer is higher than about 80%, more preferably higher than about 90%, even more preferably higher than about 95%, even more preferably higher than about 97%, even more preferably higher than about 99%, even more preferably higher than about 99.5%, even more preferably higher than about 99.9%, even more preferably higher than about 99.95%, even more preferably higher than about 99.99%>. Such purity determination may be made by any method known to those skilled in the art, such as chirai HPLC analysis or chiral electrophoresis analysis.

In a non-limiting embodiment, the following terminology used to report blood gas measurements is well known to those skilled in the art and may be defined as such: minute ventilation (MV) is a measure of breathing volume per unit time and is given herein as mL/min; pC0₂ is partial pressure of carbon dioxide (gas) in (arterial) blood measured in mmHg (millimeters of Hg units); p0₂ is partial pressure of oxy gen (gas) in (arterial) blood measured in mmHg (millimeters of Hg units); Sa0₂ is the percentage of oxygen saturation (dissolved oxygen gas) which correlates to the percentage of hemoglobin binding sites in the bloodstream occupied by oxygen.

As used herein, the term ED₅₀ refers to the effective dose that produces a given effect in 50 % of the subjects.

As used herein, a "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

As used herein, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

As used herein, an "effective amount" or "therapeutically effective amount" of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered. The term to "treat," as used herein, means reducing the frequency with which symptoms are experienced by a patient or subject or administering an agent or compound to reduce the severity with which sy mptoms are experienced.

As used herein, "treating a disease or disorder" means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein.

As used herein, the term "adverse events" (AEs) or "adverse effects" refer to a change in normal behavior or homeostasis and refers to observed or measured effects in animals such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, production of cardiac arrhy thmias and death. As used herein, the term "about" will be understood by persons of ordinary skill in the art and will van' to some extent on the context in v/hich it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term "about" is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.

Compositions of the Invention

In one aspect, the invention includes a composition comprising

(+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (— )-ketodoxapram or a solvate thereof.

In one embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 90%, In another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 95%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 97%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99%. In yet another embodiment, the enantiomeric purity of the (-t-)-ketodoxapram or a solvate thereof is at least about 99.5%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.9%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.95%. In yet another embodiment, the enantiomeric purit of the (+)-ketodoxapram or a solvate thereof is at least about 99.99%. In yet another embodiment, the composition further comprises at least one pharmaceutical carrier.

Racemic ketodoxapram or a solvate thereof may be prepared using any of the methods disclosed in the chemical literature. A non-limiting synthetic scheme is represented in Scheme 1.

( ί j-Ketodoxapram or a solvate thereof that is essentially free of (~-)-ketodoxapram or a solvate thereof may he prepared by chiral resolution of racemic doxapram, using a method such as chiral chromatography (in a non-limiting example, chiral HPLC).

Synthesis

The (-i-)-enantiomer of ketodoxapram or a salt thereof may be prepared using from optically enriched or pure pyrroiidinol or hydroxyproline. A non-limiting synthetic scheme is represented below.

Scheme 2 The present invention includes a method of preparing (+)- ketodoxapram, comprising reacting (R)-l-ethyl-4-(2-iodoethyl)-3,3- diphenylpyrrolidin-2-one with morpholin-3-one in a solvent to yield (+)-doxapram.

In one embodiment, morpholin-3-one is pretreated with a strong base. In another embodiment, the base comprises sodium hydride. In yet another embodiment, the solvent comprises Ν,Ν-dimethyiformamide (DMF). In yet another embodiment, (R)~ 1 -ethyl-4-(2-iodoethyl)-3 ,3-diphenyfpyrrolidin-2-one is prepared from (R)-2-(l -ethylpyrrolidin-3-yl)-2,2-diphenylacetic acid. In yet another embodiment, (R)-2-(l-ethylpyrrolidin-3-yl)-2,2-diphenylacetic acid is contacted with acetic anhydride and sodium iodide to yield (R)-l-ethy3-4-(2-iodoethyl)-3,3- diphenylpyrrolidin-2-one. In yet another embodiment, (R)-2-(l-ethylpyrrolidin-3 -yl)~ 2,2-diphenylacetic acid is prepared by hydrolyzing (R)-2-(l-ethylpyrrolidin-3-yl)-2,2- diphenyiacetonitrile. In yet another embodiment, the hydrolyzing comprises treatments with, sulfuric acid solution and hydrobromic acid solution. In yet another embodiment. (R)-2~(l~ethylpyrrolidin~3-yl)-2,2-diphenylacetonitrile is prepared by reacting (R)-3-chloro-l-ethylpyrfolidine with an anion of diphenylacetonitrile. In yet another embodiment, (R)-3-chloro-l-ethy3pyrrolidine is prepared by chlorinating (S)- l -ethylpyrroiidin-3-ol. In yet another embodiment, the chlorinating comprises treating (S)-l-ethylpyrrolidin-3-ol with thionyl chloride. In yet another embodiment, (S)- 1 -ethylpyrrolidin-3-o] is prepared by reducing (S)- 1 -acetylpyrrolidin-3-yl acetate. In yet another embodiment, (S)-l-acetylpyrro1idin-3-yl acetate is prepared by aeetyiating (S)-3-hydroxypyrrolidine.

In another embodiment, (R)-l -ethylpyrrolidin-3-ol may be converted to a tosylate, mesylate or other nucleophilically labile hydroxy! derivative known in the art, and alkylated with the anion of diphenylacetonitrile to afford, by inversion of configuration, (R)-2-(l -ethylpyrrolidin-3-yl)-2,2-diphenylacetonitrile. This compound may be further derivatized to yield (+)-ketodoxapram as described above.

The (— )-enantiomer of ketodoxapram enantiomer may be obtained using the same procedures outlined herein, utilizing (R)-3-hydroxypyrrolidine, (S)- l- ethylpyrrolidin-3-ol or (S)-3-chloro-l-ethylpyrfolidine as starting materials.

Salts

The compounds described herein may form salts with acids, and such salts are included in the present invention. In one embodiment, the salts are pharmaceutically acceptable salts. The term "salts" embraces addition salts of free acids that are useful within the methods of the invention. The term "pharmaceutically acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinifcy, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or composition of compounds useful within the methods of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, dibenzoyltartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoie, phenyiaeetic, mandelic, embonic (pamoic), methanesulfonic, ethanesuifonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β- hydroxybutyric, salicylic, galactaric and galacturonic acid.

Methods

In one aspect, the present invention relates to the unexpected discovery that the (+)-enantiomer of ketodoxapram or a solvate thereof displays most or all the desired beneficial pharmacological activity associated with the ventilatory stimulant effects, and positive effects on arterial blood gases, of racemic ketodoxapram.

In another aspect, the present invention relates to the unexpected discovery that the (— )-enantiomer of ketodoxapram or a solvate thereof is essentially devoid of activity as a ventilator}' or respiratory stimulant, but unexpectedly produces adverse side effects, such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, production of cardiac arrhythmias and death.

Therefore, the experiments disclosed in the present invention suggest that a composition comprising ( + j-keodoxapram or a solvate thereof, wherein the composition is essentially free of (-— )-ketodoxapram or a solvate thereof, may be administered to a subject who is prone to or suffers from a breathing control disorder or disease in order to prevent, treat or mitigate the breathing control disorder.

Admi istration of a composition comprising (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (—-)-ketodoxapram or a solvate thereof, is unexpectedly advantageous over administration of racemic ketodoxapram or a solvate thereof because ( +j-ketodoxapram or a solvate thereof has most or all the desired beneficial pharmacological respiratory stimulant activity, together with positive effects on arterial blood gases, associated with racemic ketodoxapram but with significantly reduced adverse side effects compared to administration of racemic ketodoxapram or a solvate thereof.

A composition comprising (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (^■— )-ketodoxapram or a solvate thereof, is useful within the methods of the invention.

In one aspect, the present invention includes a method of preventing or treating a breathing control disorder or disease in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical composition comprising (+)-ketodoxapram or a solvate thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially tree of (— -)-ketodoxapram or a solvate thereof.

In one embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 90%. In another embodiment, the enantiomeric purity of the (-H)-ketodoxapram or a solvate thereof is at least about 95%. in yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 97%. In yet another embodiment, the enantiomeric purity of the (H-)-ketodoxapram or a solvate thereof is at least about 99%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.5%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.9%. In yet another embodiment, the enantiomeric purity of the (-t-)-ketodoxapram or a solvate thereof is at least about 99.95%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.99%.

In one embodiment, the breathing control disorder or disease is selected from the group consisting of narcotic-induced respiratory depression, sleep apnea, apnea of prematurity, obesiiy-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (CGPD). In yet another embodiment, the subject is further administered at least one additional compound useful for treating the breathing control disorder or disease. In yet another embodiment, the at least one additional compound is selected from the group consisting of an opioids, sedative (such as midazolam), anesthetic (such as propofol or a barbiturate), acetazolamide, almitrine, theophylline, caffeine, mefchylprogesterone and related compounds, a serotinergic modulator, a cannabinoid (such as dronabinol), and an ampakine. In yet another embodiment, the composition is administered to the subject in conjunction with the use of a mechanical ventilation device or positive airway pressure device. In another embodiment, the subject is a human. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

In another aspect, the present invention includes a method of preventing destabilization of or stabilizing breathing rhythm in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical composition comprising (+)-ketodoxapram or a solvate thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially tree of (— -)-ketodoxapram or a solvate thereof.

In one embodiment, the enantiomeric purity of die (+)-ketodoxapram or a solvate thereof is at least about 90%. In another embodiment, the enantiomeric purity of the (-H)-ketodoxapram or a solvate thereof is at least about 95%. in yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 97%. In yet another embodiment, the enantiomeric purity of the (H-)-ketodoxapram or a solvate thereof is at least about 99%. In yet another embodiment, the enantiomeric purity of the ( f)-ketodoxapram or a solvate thereof is a t least about 99.5%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.9%. In yet another embodiment, the enantiomeric purity of the (-t-)-ketodoxapram or a solvate thereof is at least about 99.95%. In yet another embodiment, the enantiomeric purity of the (+)-ketodoxapram or a solvate thereof is at least about 99.99%.

In one embodiment, the subject is further administered at least one additional compound useful for preventing destabilization of or stabilizing the breathing rhythm. In. yet another embodiment, the at least one additional compound is selected from the group consisting of an opioids, sedative (such as midazolam), anesthetics (such as propofoi or a barbiturate}, acetazolamide, almitrine, theophylline, caffeine, methylprogesterone and related compounds, a serotonergic modulator and an ampakine. In another embodiment, the composition is administered to the subject in conjunction with the use of a mechanical ventilation device or positive airway pressure device. In yet another embodiment, the subject is a mammal including but not limited to a human, mouse, rat, ferret, guinea, pig, monkey, dog, cat, horse, cow, pig and other farm animals. In yet another embodiment, the subject is a human. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route. Combination Therapies

In one embodiment, the compound (+)-ketodoxapram or a solvate thereof is useful in the methods of present invention in combination with at least one additional compound useful for treating breathing control disorders or diseases.

These additional compounds may comprise compounds of the present invention or compounds, e.g., commercially available compounds, known to treat, prevent, or reduce the symptoms of breathing control disorders. In one embodiment, the combination of the compound (+)-ketodoxapram or a solvate thereof and at least one additional compound useful for treating breathing control disorders has additive. complementary or synergistic effects in the treatment of disordered breathing, and in the treatment of sleep-related breathing control disorders.

In a non-limiting example, the compound (+)-ketodoxapram or a solvate thereof ma be used in combination with one or more of the following drugs: an opioid, sedative (such as midazolam), anesthetics (such as propofol or barbiturate), acetazolamide, almirrine, theophylline, caffeine, methylprogesterone and related compounds, serotinergic modulator, cannabinoid (such as dronabinol) and compounds known as ampakines. Non-limiting examples of ampakines are the pyrrolidine derivative racetam drugs such as piracetara and aniracetam; the "CX-" series of drugs which encompass a range of benzoylpiperidine and benzoylpyrrolidine structures, such as CX-516 (6-(piperidin-l-yl-carbonyl)quinoxaline), CX-546 (2,3-dihydro-l,4- benzodioxin-7-yl-(l -piperidyl)methanone), CX-614 (2H,3H,6aH-pyrrolidino(2, 1 - 3',2 1 ,3-oxazino-(6',5'-5,4)benzo(e) 1 ,4-dioxan- 10-one), CX-691 (2, 1 ,3- benzoxadiazol-6-yl-piperidin- 1 -yl-rnethanone), CX-717, CX-701, CX-1739, CX- 1763, and CX-1837; benzothiazide derivatives such as cyclothiazide and IDRA-21 (7-chloro-3-methyl-3,4-dihydro-2H-l ,2,4-benzothiadiazine 1 , 1 -dioxide);

biarylpropylsulfonamides such as LY-392,098, LY-404, 187 (N-[2-(4*-cyanobipheny1- 4~yl)propyl]propane-2 -sulfonamide), LY-451,646 and LY-5Q3.430 (4'- {(IS)-l-fiuoro- 2-[(isopropylsulfonyl)amino]- i -methylethy! } -N-methylbiphenyl-4-carboxamide).

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-E„_;ax equation (Holford & Scheiner,

19981 , Clin. Pharmacokmet. 6: 429-453 ), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol 1 14: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Pharmaceutical Compositions and Formulations

The invention also encompasses the use of pharmaceutical compositions of the compound (+)-ketodoxapram or a solvate thereof to practice the methods of the invention, wherein the compositions are essentially free of (— )- ketodoxapram or a solvate thereof.

Such a pharmaceutical composition may consist of the compound (+) -ketodoxapram or a solvate thereof alone, wherein the compositions is essentially free of (— -)-ketodoxapram or a solvate thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the compound (+)- ketodoxapram or a solvate thereof, wherein the compositions is essentially free of (— ketodoxapram or a solvate thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The compound ( +j-ketodoxapram may be present in the pharmaceutical composition in the form of a physiologically acceptable solvate, such as in combination with a physiologically acceptable solvent, as is well known in the art.

In an embodiment, the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In another embodiment, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 500 mg/kg/day.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will van', depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intravenous or another route of administration. A composition useful within the methods of the invention may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal. Other contemplated formulations include projected nanoparticies, liposomal preparations, and

immunologically-based formulations. The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.

Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for admi istration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the in vention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.

In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a

pharmaceutically acceptable carrier. Pharmaceutically acceptable earners, which are useful, include, but are not limited to, glycerol, water, saline, ethanoi and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

The carrier may be a solvent or dispersion medium containing, for example, water, ethanoi, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or poiyalcohols such as mannitoi and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absoiption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants,

preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g.. analgesic agents.

As used herein, "additional ingredients" include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives;

physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and

pharmaceutically acceptable polymeric or hydrophobic materials. Other "additional ingredients" which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

The composition of the in vention may comprise a preservati ve from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment.

Examples of preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

The composition preferably includes an antioxidant and a chelating agent which inhibit the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, aipha-tocopherol and ascorbic acid in the preferred range of about 0.01 % to 0.3% and more preferably BHT in the range of 0.03% to 0.1 % by weight by total weight of the composition. Preferably, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Particularly preferred chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition which may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are the particularly preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanoi, polyoxyethylene sorbitol monooieate, and polyoxyethylene sorbitan monooieate, respectively). Known emulsifying agents include, but are not limited to, lecithin, and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para- hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, tractionated vegetable oils, and mineral oils such as liquid paraffin.

Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as poiyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of

incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

Administration/Dosing

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the patient either prior to or after the onset of a breathing control disorder event. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophy lactic situation.

Administration of the compositions of the present invention to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a breathing control disorder or disease in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex. weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 0.01 and 50 nig/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

The compound can be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered , in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.

Actual dosage levels of the acti ve ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the

pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceuticai vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of breathing control disorders in a patient.

In one embodiment, the compositions of the invention are administered to the patient in dosages that range from one to five times per day or more. In another embodiment, the compositions of the in vention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physical taking all other factors about the patient into account.

Compounds of the invention for administration may be in the range of from about 1 _,ug to about 7,500 mg, about 20 μg to about 7,000 mg, about 40 ,ug to about 6,500 mg, about 80 fig to about 6,000 mg, about 100 g to about 5,500 mg, about 200 .g to about 5,000 mg, about 400 ,ug to about 4,000 mg, about 800 \ig to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1 ,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound of the invention is from about 0.5 ig and about 5,000 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1 ,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.

Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of breathing control disorder in a patient.

The term "container" includes any receptacle for holding the pharmaceutical composition. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged

pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound's ability to perform its intended function, e.g., treating, preventing, or reducing a breathing control disorder in a patient. Routes of Administration

Routes of administration of any of the compositions of the invention include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, ( transurethral, vaginal (e.g., trans- and perivaginal!}'), (intranasal, and (transrectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. Other formulations suitable for oral administration include, but are not limited to, a powdered or granular

formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharrnaceuticaliy excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.

Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patents Nos. 4,256, 108; 4,160,452; and 4,265,874 to form osmotical!y controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents; fillers; lubricants; disintegrates; or wetting agents. If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Coiorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric ΟΥ-Λ Type, OY-PM Type and OPADRY™ White,

32K18400).

Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a

pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycollate. Known surface-active agents include, but are not limited to, sodium lauryi sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pre -gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation." For example, solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.

U.S. Patent No. 5, 169,645 discloses directly compressible wax- containing granules having improved flo properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt.

The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds useful within the methods of the invention, and a further layer providing for the immediate release of one or more compounds useful within the methods of the invention. Using a wax/ H- sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

Parenteral Administration

As used herein, "parenteral administration'" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous (single dose or infusion), intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1 ,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

Topical Administration

An obstacle for topical administration of pharmaceuticals is the stratum coraeum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells. One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.

Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oii-in-water or water-m-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically administrabie formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N-me thy 1-2 -pyrroli d o e.

One acceptable vehicle for topical delivery of some of the compositions of the invention may contain liposomes. The composition of the liposomes and their use are known in the art (for example, see Constanza, U.S. Patent No. 6,323,219).

In alternative embodiments, the topically active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, buffering agents, preservatives, and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the stratum corneum with respect to a composition lacking the permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or -methyl-2-pyrrolidone, are known to those of skill in the art. In another aspect, the composition may further comprise a hydrotropic agent, which functions to increase disorder in the structure of the stratum corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.

The topically active pharmaceutical composition should be applied in an amount effective to affect desired changes. As used herein "amount effective" shall mean an amount sufficient to cover the region of skin surface where a change is desired. An active compound should be present in the amount of from about 0.0001 % to about 15% by weight volume of the composition. More preferable, it should be present in an amount from about 0.0005% to about 5% of the composition; most preferably, it should be present in an amount of from about 0.001% to about 1% of the composition. Such compounds may be synthetically-or naturally derived.

Buccal Administration

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein.

Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. The examples of formulations described herein are not exhaustive and it is understood that the invention includes additional modifications of these and other formulations not described herein, but which are known to those of skill in the art.

Rectal Administration

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation. Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 20^CC) and which is liquid at the rectal temperature of the subject (i.e., about 37°C in a healthy human). Suitable

pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various giycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.

Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389,

5,582,837, and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952,

20030104062, 20030104053, 20030044466, 20030039688, and 20020051820.

Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01 /56544, WO 01 /32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/1 1757.

Controlled Release Formulations and Drug Delivery' Systems

Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology. In some cases, the dosage forms to be used can be provided as slo or controlled-release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps and capiets, which are adapted for controlled-release are encompassed by the present invention.

Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled-release component" in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.

In certain embodiments, the formulations of the present invention may^¬ be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds ma be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticies, for example, by injection or in the form of wafers or discs by implantation.

In a preferred embodiment of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense to refer to a drag formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drag formulation that provides for release of the drag immediately after drag administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drag administration. In one aspect of the in vention, a method of treating a patient lacking normal breathing comprises administering the composition useful within the invention as described herein, and additionally treating the patient using a device for treatment of a lack of normal breathing. Such devices include, but are not limited to, ventilation devices, CPAP and BiPAP devices.

Mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. Mechanical ventilation is typically used after an invasive intubation, a procedure wherein an endotracheal or tracheostomy tube is inserted into the airway. It is normally used in acute settings, such as in the ICU, for a short period of time during a serious illness. It may also be used at home or in a nursing or rehabilitation institution, if patients have chronic illnesses that require long-term ventilation assistance. The main form of mechanical ventilation is positive pressure ventilation, which works by increasing the pressure in the patient's airway and thus forcing air into the lungs. Less common today are negative pressure ventilators (for example, the "iron lung") that create a negative pressure environment around the patient's chest, thus sucking air into the lungs. Mechanical ventilation is often a life- saving intervention, but carries many potential complications including

pneumothorax, airway injury, alveolar damage, and ventilator-associated pneumonia. For this reason the pressure and volume of gas used is strictly controlled, and reduced as soon as possible. Types of mechanical ventilation are: conventional ventilation, high frequency ventilation, non-invasive ventilation (non-invasive positive pressure pentilation or NIPPV), proportional assist ventilation (PAV), adaptive support ventilation (ASV) and neurally adjusted ventilatory assist (NAVA).

Non-invasive ventilation refers to all modalities that assist ventilation without the use of an endotracheal tube. Non-invasive ventilation is primarily aimed at minimizing patient discomfort and the complications associated with invasive ventilation, and is often used in cardiac disease, exacerbations of chronic pulmonary- disease, sleep apnea, and neuromuscular diseases. Non-invasive ventilation refers only to the patient interface and not the mode of ventilation used; modes may include spontaneous or control modes and may be either pressure or volume modes. Some commonly used modes of NIPPV include:

(a) Continuous positive airway pressure (CPAP): This kind of machine has been used mainly by patients for the treatment of sleep apnea at home, but now is in widespread use across intensive care units as a form of ventilation. The CP AP machine stops upper airway obstruction by deli vering a stream of compressed air via a hose to a nasal pillow, nose mask or full-face mask, splinting the airway (keeping it open under air pressure) so that unobstructed breathing becomes possible, reducing and/or preventing apneas and hypopneas. When the machine is turned on, but prior to the mask being placed on the head, a flo of air comes through the mask. After the mask is placed on the head, it is sealed to the face and the air stops flowing. At this point, it is only the air pressure that accomplishes the desired result. This has the additional benefit of reducing or eliminating the extremely loud snoring that sometimes accompanies sleep apnea.

(b) Bi-level positive airway pressure (BIPAP): Pressures alternate between inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure (EPAP), triggered by patient effort. On many such devices, backup rates may be set, which deliver IPAP pressures even if patients fail to initiate a breath.

(c) Intermittent positive pressure ventilation (IPPV), via mouthpiece or mask.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that, wherever values and ranges are provided herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly , ail values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only , and the invention is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein.

Materials:

Unless otherwise noted, all remaining starting materials were obtained from commercial suppliers and used without purification. Example 1 :

4-r2- i-Ethyl-5-oxo-4^-diphenyl-pyrrolidin-3-yr)-ethyl1-morpholin-3-one (9)

1 2

3-Chloro-l-ethylpyrroUdine (2)

l-Ethylpyrro3idin-3-ol (1) (10.00 g, 86.82 mmol) was added with cooling to SOCI₂ ( 5 mL). The reaction mixture was heated at reflux for 1 li. After cooling a K₂CO₃ solution (50%) (-150 niL) was added, and the resulting suspension was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with water (200 mL), dried over a?S0₄, and concentrated. The residue was distilled in vacuo to give 8.22 g (71%) of 3-chloro-l-ethylpyrrolidine (2). 400 MHz ¹ H NMR (CDCI₃, ppm) 4.40-4.33 (1H, m) 3.05 ( 1H, dd, J 10.7. 6.4 Hz) 2.77-2.69 (2H, m) 2.64-2.47 (3H, m) 2.45-2.35 (1H, m) 2.10-2.01 (1 H, m) 1 .09 (3H, t, J=7.2 Hz), ESI-MS (m/z): ⁺.

(l-Elhyl-pyirolidw-3-yl)-diphenyl-acelonitrile (4)

A solution of diphenylacetonitrile (3) (9.88 g, 51.13 mmol) and sodium amide (2.20 g, 56.40 mmol) in dry toluene (30 mL) was heated at reflux for 2 h. The reaction mixture was cooled to the room temperature. Sodium iodide (9.20 g, 61.38 mmol) and 3-chloro-l-ethyl-pyrrolidine (2) (8.20 g, 61.38 mmol) were added, and the reaction mixture was heated at 110 °C for 20 h. Water (100 mL) was added, and the resulting suspension was extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with water (150 mL), brine (150 mL) and dried over Na₂SG₄. The volatiles were removed in vacuo; the residue was purified by flash column chromatography using gradient elution from CH₂Cl₂ MeOH (99: 1) to CH₂Cl₂ MeOH (4: 1) to give l~ethyl-pyrrolidin-3-yl)-diphenyl-acetonitrile (4) (11.48 g, 77%). 400 MHz Π NMR (CDCI₃, ppm) 7.46-7.40 (4H, m) 7.35-7.28 (4H, m) 7.27-7.21 (2H, m) 3.49-3.40 (1H, m) 3.00 (1 H, ddd, J=8.8, 8.8, 3.2 Hz) 2.80 (1 H, dd, J=9.5, 7.3 Hz) 2.52-2.35 { 1 1 m) 2.27-2,21 (1H, m) 2.15-2.04 (1H, m) 1 ,86-1.77 (1H, m) 1,04 (3H, t, 7.2 Hz), ESI-MS (m/z): 291 [M+H]^÷.

2~(l~Ethyl-pyrrolidin~3~yl)~2,2-diphenyl-acet mide (5) A solution of ( l-ethyl-pyrrolidin-3-yl)-diphenyl-acetonitrile (4) (1 1.38 g, 39.19 mmol) in 70% H₂S0₄ (45 mL) was heated at 120 °C for 4 h. The reaction mixture was poured on ice, made basic with 50 % NaOH, and extracted with CH₂C1₂ (3 x 125 mL). The combined organic extracts were washed with water ( 150 mL) and dried over Na₂S04. The volatiles were removed in vacuo to give 2-( l-ethyl- pyi olidin-3-yl)-2,2-diplienyl-acetamide (5) (1 1.10 g, 92%). 400 MHz i t NMR (CDCI3, ppm) 7.56 (IH, br s) 7.42-7.37 (2H, m) 7.32-7.16 (8 H, m) 5.65 (IH, s) 3.49- 3.39 ( IH, m) 2.80-2.66 (2H, ) 2.59-2.51 (IH, ) 2.51-2.32 { 1 1. m) 1.94 (2H, q, =7.3 Hz) 1.02 (3H, t, J 7.3 Hz). ESI-MS (m/z): 309 [ - ! l j .

(l-Elhyl-pyrrolidin-3-yl)-diphenyl-acelic acid (6)

A solution of 2-(l-ethyl-pyrrolidin-3-yl)-2,2-diph.enyI-acetamide (5) (5.00 g, 16.21 mmol) in 48% HBr (50 mL, water solution) was heated at 120 °C for 48 h. The cooled solution was first made basic via the addition of 50 % NaOH solution and then acidified to pH 3 by adding KHSO₄. The resulting mixture was extracted with. CH₂C1₂ (3 x 75 mL). The combined organic extracts were dried over Na₂SC>₄ and concentrated. The residue was treated with hexanes to produce a solid, and then filtered to give (l-ethyl-pyrfolidin-3-yl)-diphenyl-acetic acid (6) in quantitative yield, which was used in the next step without purification, ESI-MS (m z): 310 [Μ+Ή]^".

l-Ethyl-4-(2-iodo-ethyl)-3,3-diphenyl-pyrrolidin-2-one (7)

A mixture of ( l-ethyl-pyrrolidin-3-yl)-diphenyl-acetic acid (6} (5.0 g, 16.16 mmol) , Nal (4.84 g, 32.32 mmol) and acetic anhydride (2.7 mL) in 2-butanone was heated at reflux for 1 h. Additional acetic anhydride (2.7 mL) was added, and the mixture was refiuxed for another h. The reaction mixture was cooled and filtered. The filtrate was evaporated and the residue was crystallized from EtOH to give 4.40 g (65%) of l-ethyl-4-(2-iodo-ethyl)-3,3-diphenyl-pyrrolidin-2-one (7). 400 MHz Ή NMR (CDC1₃, ppm) 7.57-7.53 (2H, m) 7.37-7.31 (2H, m) 7.30-7.17 (4H, m) 6.88- 6.84 (2H, m) 3.64-3.54 (1 H, m) 3.53 (I H, dd, J=8.9, 7.3 Hz) 3.47-3.38 (2H, m) 3.23 (I H, ddd. 1=10.0, 6.4, 4.4 Hz) 3.04-2.94 (2H, m) 2.02-1,92 ( H i . m) 1.23 (3H, t, J=7.3 Hz) 1.19-1.09 ( i l l . m). ES1-MS (m/z): 420 [M+Hf .

4-[2-(l-EthyI-5-oxo-4,4-diphenyl-pyrrolidm-3-yl)-ethyI]-mo (9)

A solution of morpholm-3-οηε (8) (1.57 g, 15.50 mmol) in DMF (10 mL) was added to a stirred suspension of NaH (60% suspension in mineral oil) (685 mg, 17.05 mmol) in DMF (15 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. l-Ethyl-4-(2-iodo-ethyl)-3,3-dipheriyl-pyiTolidiri-2-one (7) (6.50 g, 15.50 mmol) in DMF (40 mL) was then added in portions, and the mixture was stiired at room temperature for a further 20 h, then poured into water, and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with water (3 x 125 mL), then with a brine solution and lastly, dried over Na₂S0₄. The product was purified by flash column chromatography using gradient elution from CH₂Cl₂/EtOH (99: 1) to

CH₂Cl₂/EtOH (9: 1) to give 5.30 g (87%) of keto-doxapram 9. 400 MHz I I- NM R (CDC13, ppm) 7.48-7.43 (2H, m) 7.35-7.29 (2H, m) 7.28-7.16 (4H, m, overlapped with CDC13) 6.94-6.89 (2H, m) 4.17 (I H, d, J=16.6 Hz) 4.12 (1H, d, J=16.6 Hz) 3.90- 3.79 (2H, m) 3.71-3.60 (2H, m) 3.60-3.51 (IH, m) 3.43-3.33 (IH, m) 3.28-3,07 (51 ! . m) 1.72-1.61 (IH, m) 1.19 (3H, t, J=7.2 Hz) 1.00-0.88 (I H, m). ESI-MS (m/z): 393 | Μ · 1 ! | . Example 2:

Chromatographic Separation of Ketodoxapram

The operating conditions used for the separation process are as follows. The column was C^'f U RALPAK AD (5 urn, 4.6 mm ID x 250 mm). The mobile phase was EtOH with 0.1 % TEA (triethylamine). The flow rate was 1 mL/min at 30 °C. The temperature of the column was kept at room temperature, and LJV detection was performed at 230 nm.

A solution of racemic ketodoxapram (2.3 g) was injected onto the chromatographic column using the conditions illustrated above. The appropriate fractions collected from the chromatographic process were concentrated to dryness. After solvent removal, the products were dried to obtain two fractions: the first eluent, in a total of 0.974 g, with a recovery yield of 84.7% and an enantiomeric excess of 99.9%; the second eluent, in a total of 0.0995 g, with a recovery yield of 86.5% and an enantiomeric excess of 98.2%.

Example 3:

Chiral Synthesis of (+)-Ketodoxapram via {S)-3-hydroxypyrroj idine

17 18 19

Scheme 3 (S)-I-Eihylpyrrolidin-3-ol (12)

To a solution of (S)-3-hydroxypyrrolidine hydrochloride (10) (5.0 g, 40.46 mmoi) and pyridine (18.6 mL, 230,62 mmof) in CH₂C1₂ (250 mL), acetyl chloride (6.06 mL, 84.97 mmol) in CH₂C1₂ (15 mL) was added in a dropwise manner at 0°C under an argon atmosphere. After stirring at room temperature for 4 h, the reaction mixture was washed with water (50 mL) and then with saturated NaHC0₃ solution (2 x 50 mL). The aqueous extracts were saturated with NaCl and then extracted with CH₂C1₂ (3 x 100 mL). The combined organic extracts (CH₂C1₂) were dried (Na₂S0₄) and evaporated. The obtained product (S)-3-acetoxy-l - acetylpyrrolidine (11) was dissolved in diethyl ether (100 mL) and added to a stirred suspension of L1AIH₄ (6.27 g; 165.3 mmol) in Et₂0 (120 mL) at 0 °C. After stirring for 5 h at room temperature, the reaction mixture was cooled to 0 °C and quenched by the successive additions of H₂0 (2.6 mL), NaOH solution (4 M, 2.0 mL), and H₂Q (7.8 mL). After stirring vigorously at room temperature for 4 h, the resulting white precipitate was removed by filtration, and washed on the filter with Et₂0 (2 x 50 mL) and then with CH₂C1₂ (2 x 50 mL). The combined filtrates were collected, dried (anhydrous Na^SC^ , filtered and evaporated to yield product (S)- 1 -ethylpyrrolidin-3- oi (12) (3.6 g, 77%), which was used in the next step without purification. 400 MHz ^lll NMR (COCK, ppm) 4.28 (1 H, ddd, j 9.8. 5.2, 2.5 Hz} 2,93 (1 H, br s} 2.84-2.78 (1 H, m) 2.61 (1 H, dd, J=10.1 , 2.2 Hz) 2.48-2.45 (1H, m) 2.43 (2H, q, J=7.2 Hz) 2.25- 2.09 (2H, m) 1.71-1.59 (1H, m) 1.05 (3H, t, J=7.2 Hz).

(R)-3-Chloro- 1 -elhylpyrrolidine ( 13 )

(S)-l -Ethylpyrrolidin-3-oI (12) (10.00 g, 86.82 mmol) w^ras added with cooling to SOC1? (15 mL). The reaction mixture was heated at reflux for 1 h. After this time, a K₂C0₃ solution (50%,—150 mL) was added with cooling and the resulting suspension was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with water (200 mL), dried over anhydrous Na₂S0₄ and concentrated. The residue was distilled in vacuo (b.p. 54-55 °C, 18-20 mmHg) to yield (R)-3-chloro-l-ethylpyrrolidine (13) (6.30 g, 54%). 400 MHz Ti NMR (CDCI3, ppm) 4.41 -4.34 (1H, m) 3.05 (1H, dd, J=10.7, 6.4 Hz) 2.79-2,69 (2H, m) 2.64-2,46 (3H, m) 2.46-2.36 (1H, m) 2.1 1-2.02 ( 1H, m) 1.10 (3H, t, J=7.3 Hz). ES1-MS (m/z): 134, 136 [M+H]⁺. (R)-2-(l-EthyIpyrroIidin-3-yI)-2,2-diphenylacetoniirile (IS)

A solution of diphenylacetonitrile (14) (872 mg, 4.51 mmol) and sodium amide (229 mg, 5.86 mmol) in dry toluene (7 mL) was heated at reflux for 2 h. The reaction mixture was cooled to the room temperature, and then sodium iodide (743 mg, 4.96 mmol) and (R)-3-chloro-l-ethyl-pyrrolidine (13) (663 mg, 4.96 mmol) were added. The reaction mixture was heated at 110 °C for 20 h. After this time, water (15 mL) was added and the resulting suspension was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with water (50 mL}, then with a brine solution (50 ml.) and dried over anhydrous Na₂S(¼. The voiatiles were removed in vacuo and the residue was purified by flash column chromatography

(gradient elution from CH₂Cl₂/MeOH: 99: 1 (v/v) to CH₂Cl₂/MeOH: 4: 1 (v/v)) to yield (R)-2-(l -ethy]pyrrolidin-3-y])-2,2-diphenylacetonitrile (15) (900 mg, 69%). 400 MHz Ή-NMR (CDCI₃, ppm) 7.46-7.40 (4H, m) 7.35-7.27 (4H, m) 7.27-7.21 (2H, m) 3.49- 3.40 (1H, m) 3.00 (IH, ddd, J 8.6. 8,6, 3.1 Hz) 2.80 (1H, dd, J=9.5, 7.4 Hz) 2,56-2.35 (3H, m) 2.25 ( 1H, dd, .! 9.5. 9.5 Hz) 2.16-2.04 ( 1H, m) 1.86-1.77 (1H, m) 1.04 (3H, t, j 7.2 Hz). ESI-MS (m z): 291 [ V! ! ί j .

(R)-2-(l-Elhylpyrrolidin-3-yl)-2,2-diphenylacetamide (16)

A solution of (R)-(l-ethyl-pyrrolidin-3-yi)-diphenyiacetonitrile (15) (893 mg, 3.07 mmol) in 70% H₂S0₄ (12 mL) was heated at 120 °C for 4 h. The reaction mixture was poured on ice, made basic with 50 % NaOH. and then extracted with CH₂C1 (3 x 15 mL). The combined organic extracts were washed with water (20 ml.) and dried over anhydrous Na₂S(¼. The voiatiles were removed in vacuo to yield (R)-2-(l-eihylpyi o]idin-3-yl)-2,2-diplienylacetamide (16) (850 mg, 90%). 400 MHz ^!H NMR (CDCI₃, ppm) 7.62 (1H, br s) 7.42-7.38 (2H, m) 7.32-7.16 (8 H, m)

5.50 (1 H, s) 3.48-3.39 (1H, m) 2.77 ( 1H, d, J=9.7, 5.9 Hz) 2.71 -2.65 ( 1H, m) 2.59-

2.51 (1 H, m) 2.50-2.32 (3H, m) 1 .96-1.89 (2H, m) 1.02 (3H, t, J=7.3 Hz). ESI-MS (m/z): 309 j Vl I l | . (R)~2-(I-Ethy!pyrroildin-3-yI)~2, 2-diphenylacetic acid (17)

A solution of (R.)-2-(l -ethyf-pyrrolidin-3-yf)-2,2-dipheny1acetamide (16) (850 mg, 2,76 mmol) in HBr (30 mL. 48% aqueous solution) was heated at 120 °C for 48 h. After cooling, the solution was made basic with 50 % NaOH solution, then acidified to pH 3 by KHSO . The resulting mixture was extracted with CH₂C1₂ (3 x 15 mL-). The combined organic extracts were dried over anhydrous Na₂S0₄ and concentrated. To the resultant residue, hexanes (20 mL) were slowly added to produce a solid which was filtered to yield (R)-(l -ethy]-pyrroli.din-3-y].)- diphenyiacetic acid (17) in quantitative yield, which w^ras used in the next step without purification. ESI-MS (m/z): 310 [M+H] .

(R)-l-Ethyl-4-(2 o<hethyl)-3,3-diphenylpyrrolidin-2-one (18)

A mixture of (R)-(l-ethyl-pyrrolidm-3-yl)-diphenylacetic acid (17)

(2.76 mraol) , NaT (827 rag, 5.52 mmol) and acetic anhydride (2.0 mL) in 2-butarione (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled and filtered.

The filtrate was evaporated and the resultant residue was crystallized from EtOH to yield 1.00 g (86%) of (¾)-l -ethyl-4-(2-iodo-ethyl)-3,3-diphenylpy-rolidin-2-one (18).

400 MHz Ή NMR (CDC1₃, ppm) 7.57-7.53 (2H, m) 7.37-7.3 (2H, m) 7.30-7.17

(4H, m) 6.88-6.84 (2H, m) 3.64-3.54 (IH, m) 3.53 (1H, dd, J=8.9, 7.3 Hz) 3.47-3.38 (2H, m) 3.23 ( 1H, ddd, .! 1 0.0. 6.4, 4.4 Hz) 3.04-2.94 (2H, ) 2.02-1.92 ! H i. m) 1.23

(3H, t, J 7.3 Hz) 1 .19-1.09 ( 1 1 1. m). ESI-MS (m/z): 420 [M+H] .

(R)-4-[2-(l-Eihyl-5-oxo-4A-diphenyi-pyrreii (19)

The (-i-)-enantiomer of 4-[2-( 1 -ethy3-5-Qxo-4,4-diphenyl-pyrroiidin-3- yl)-ethy]]-morpholin-3-one (19) was prepared from the (+)-enantiomer of l-eihyl-4- (2~iodo-ethyl)~3,3-diphenylpyrrolidin-2-one (18), morpholin-3-one, sodium hydride in DMF, as described in Example 1.

Example 4:

Effects of ( )-4-[2-(l -Ethyl-5-oxo-4,4-di henyl- yrrolidin-3-yl)-ethyll-moφholin-3- one (19) on respiration rate, tidal volume, minute volume and 5-min average change in min u te v ol ume. in rat

General Methods:

Adult male Sprague Dawiey rats (250-350 g body weight; Harlan, Indianapolis, IN, USA) were anesthetized with isoflurane in oxygen. The femoral vein was cannulated to administer compounds. Body temperature was maintained between 36.0 and 37.2 °C throughout the experiment. The cervical portion of the trachea was cannulated and the attached to a rat-sized pneumo tachometer for measuring tracheal airflow. After surgical instrumentation was complete, isoflurane was slowly discontinued while urethane (1.8 g kg) was administered intravenously over 10-15 minutes to maintain anesthesia. Rats were permitted to breathe spontaneously and inspire 100% oxygen. At least 30-45 minutes after discontinuing isoflurane, baseline tracheal airflow was recorded for 20-30 minutes prior to compound administration. Vehicle and test compound were administered intravenously over 15-25 seconds and at a constant volume (1 mL/kg). At least 15- min elapsed between each dose of compound administered. Tracheal airflow was recorded continuously before, during and after compound administration. Tidal volume was derived from the integral of airflow and respiratory rate was derived from the number of inspirator}'^' cycles per minute. Minute volume was calculated as the product of tidal volume and respiratory rate.

Results:

Compared to vehicle, (R.)-4-[2-(l -ethy]-5-oxo-4,4-diphenyl-pyrrolidin- 3-yi)-ethyl]-morpholin-3-one dose-dependently increased both respirator}' rate and tidal volume, and their product, minute volume.

The disclosures of each and ever}' patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this in vention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A composition comprising (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (— )~ketodoxapram or a solvate thereof.

2. The composition of claim 1 , wherein the (+)-ketodoxapram or solvate thereof has enantiomeric purity of at least about 95%,

3. The composition of claim 2, wherein the (+)-ketodoxapram or solvate thereof has enantiomeric purity of at least about 97%,

4. The composition of claim 3. wherein the (+)-ketodoxapram or sol vate thereof has enantiomeric purity of at least about 99%.

5. The composition of claim 1, further comprising at least one pharmaceutically acceptable carrier.

6. A method of preventing or treating a breathing control disorder or disease in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (-— )-ketodoxapram or a solvate thereof.

7. The method of claim 6, wherein the (+)-ketodoxapram or solvate thereof has at least about 95% enantiomeric purity.

8. The method of claim 7, wherein the (+)-ketodoxapram or solvate thereof has at least about 97% enantiomeric purity.

9. The method of claim 8, wherein the (+)-ketodoxapram or solvate thereof has at least about 99% enantiomeric purity.

10. The method of claim 6, wherein the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventifation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, and hypercapnia.

11. The method of claim 10, wherein the respirator}' depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.

12. The method of claim 6, wherein the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease.

13. The method of claim 12, wherein the at least one additional compound is selected from the group consisting of an opioid, sedative, anesthetic, acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotonergic modulator, a cannabinoid, and an ampakine.

14. The method of claim 6, wherein the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject.

15. The method of claim 6, wherein the subject is a mammal.

16. The method of claim 15, wherein the mammal is a human.

17. The method of claim 6, wherein the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

1 8. A method of preventing destabiiization or stabilizing breathing rhythm in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+)-ketodoxapram or a solvate thereof, wherein the composition is essentially free of (—-)-ketodoxapram or a solvate thereof.

19. The method of claim 18, wherein the (+)-ketodoxapram or solvate thereof has at least about 95% enantiomeric purity.

20. The method of claim 19, wherein the (+)-ketodoxapram or sol vate thereof has at least about 97% enantiomeric purity.

21. The method of claim 20, wherein the (+)-ketodoxapram or solvate thereof has at least about 99% enantiomeric purity.

22. The method of claim 18, wherein the subject is further administered a composition comprising at least one additional compound useful for preventing destabilization of or stabilizing the breathing rhythm,

23. The method of claim 22, wherein the at least one additional compound is selected from the group consisting of an opioid, sedative, anesthetic, acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotonergic modulator, a cannabinoid, and an ampakine.

24. The method of claim 1 8, wherein the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device.

25. The method of claim 18, wherein the subject is a mammal

26. The method of claim 25, wherein the mammal is a human.

27. The method of claim 18, wherein the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

28. A method of preparing (+)-ketodoxapram, comprising reacting (R)-l-ethyl-4-(2-iodoethyl)-3,3-diphenylpyrrolidin-2-one with morpholin-3-one in a solvent to yield (+)-doxapram.

29. The method of claim 28, wherein moTpholin-3-one is pretreated with a strong base to form the corresponding anion of morpholin-3-one.

30. The method of claim 29, wherein the strong base comprises sodium hydride,

31. The method of claim 29, wherein the solvent comprises N,N- dinie thy I formamide (DMF) ,

32. The method of claim 28, wherein (R)-l-ethyl-4-(2-iodoethyl)-

3,3-diphenyIpyrroridin-2-one is prepared from ( )-2-( l-ethylpyrrolidin-3-yl)-2,2- diphenylacetic acid.

33. The method of claim 32, wherein (R)-2-(l -ethylpyrrolidin-3- yi)-2,2-dipbenylacetic acid is contacted with acetic anhydride and sodium iodide to yield (R)-l~ethyl-4-(2-iodoethyl)-3,3-diphenylpyrrolidin~2-one.

34. The method of claim 32. wherein (R)-2-(l -et ylpyrrolidin-3 - yl)-2,2-diphenylacetic acid is prepared by hydrolyzing (R)-2-(l-ethylpyrfolidin-3-yl)- 2 ,2 -diph eny I ace toni tril e .

35. The method of claim 34, wherein the hydrolyzing comprises treatment with a sulfuric acid solution and a hydrobromic acid solution.

36. The method of claim 34, wherein (R)-2-(l-ethyipyrrolidin-3- yl)-2,2-diphenylacetonitrile is prepared by reacting (R)-3-chloro-l-ethylpyrrolidine with an anion of diphenylacetonitrile.

37. The method of claim 36, wherein (R)-3-ehloro-l- ethylpyrrolidine is prepared by chlorinating (S)-l-ethylpyrrolidin-3-ol.

38. The method of claim 37, wherein the chlorinating comprises treating (S)-l-ethylpyrrolidin-3-ol with thionyl chloride.

39. The method of claim 37, wherein (S)-l-ethylpyrrolidin-3-ol is prepared by reducing (S)-l-acetylpyrro3idin-3-yl acetate.

40. The method of claim 39, wherein (S)-l-acety]pyrrolidin-3-y1 acetate is prepared by acetylating (S)-3-hydroxypyrro1idine.

41. The method of claim 34, wherein preparing (R)-2-(l- eihylpyrrolidin-3-yl)-2,2-diphenylacetonitrile comprises: converting (R)-l - ethy3pyrrolidm-3-ol to a nucleophifically labile liydroxyl derivative, and reacting the derivative with an anion of diphenylacetonitrile to yield (R)~2-(l-ethylpyrrolidin~3- yl)-2,2-diphenylacetonitrile.