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WO2008011016A2 - Méthodes de traitement du reflux gastrooesophagien - Google Patents

Méthodes de traitement du reflux gastrooesophagien Download PDF

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Publication number
WO2008011016A2
WO2008011016A2 PCT/US2007/016183 US2007016183W WO2008011016A2 WO 2008011016 A2 WO2008011016 A2 WO 2008011016A2 US 2007016183 W US2007016183 W US 2007016183W WO 2008011016 A2 WO2008011016 A2 WO 2008011016A2
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Prior art keywords
aminomethyl
group
acetic acid
receptor agonist
baclofen
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PCT/US2007/016183
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WO2008011016A3 (fr
Inventor
Theodore T. Ashburn
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Dynogen Pharmaceuticals Inc
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Dynogen Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • Gastrointestinal motility regulates the orderly movement of ingested material through the gut to ensure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of GI contents. The normal GI motility pattern can be impaired by a variety of circumstances including disease and surgery.
  • disorders of gastrointestinal motility can include, for example, gastroparesis and gastroesophageal reflux disease (GERD).
  • GFD gastroparesis
  • Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea and vomiting.
  • Acute gastroparesis can be caused by, for example, drugs, viral enteritis and hyperglycemia and is typically managed by treating the underlying disease rather than the motility disorder. The most common underlying disease resulting in gastroparesis is diabetes.
  • GERD is a physical condition in which stomach contents (e.g, stomach acid) reflux or flow back from the stomach into the esophagus.
  • GERD is synonymous with GORD (gastro-osophageal reflux disease).
  • GORD gastro-osophageal reflux disease
  • the most common symptom of GERD is a burning sensation or discomfort behind the breastbone or sternum and is referred to as dyspepsia or heartburn. These symptoms can also mimic the symptoms of myocardial infarction or severe angina pectoris.
  • GERD GERD
  • Other symptoms of GERD include dysphagia, odynophagia, hemorrhage, water brash and respiratory manifestations such as asthma, recurrent pneumonia, chronic coughing, intermittent wheezing due to acid aspiration and/or stimulation of the vagus nerve, earache, hoarseness, laryngitis and pharyngitis.
  • Reflux episodes which result in GERD can occur both during the daytime (i.e., when the subject is in a waking state) and at nighttime (i.e., when the subject is in a non-waking state).
  • GERD occurring at nighttime is commonly referred to as nocturnal GERD.
  • Nocturnal GERD is distinct from daytime or diurnal GERD not only in the timing of the reflux episode, but in the severity of the damage which occurs as a result of the reflux. More specifically, nocturnal GERD, can be particularly damaging to the pharynx and larynx and a strong association between nocturnal GERD and asthma exists.
  • nocturnal GERD The increased damage associated with nocturnal GERD is due to a decrease in natural mechanisms which normally help protect against reflux (e.g., saliva production and swallowing), which occur when the patient is sleeping. This decrease leaves the esophagus more vulnerable to damage and can increase microaspiration.
  • reflux e.g., saliva production and swallowing
  • This decrease leaves the esophagus more vulnerable to damage and can increase microaspiration.
  • the body is in the recumbent position, eliminating the effect of gravity, which can clear gastric content from the esophagus. Sleep disorders are also associated with nocturnal GERD resulting in daytime sleepiness and a significant decrease in the overall quality of life.
  • GERD GERD subjects the esophagus to ulcer formation or esophagitis and can result in more severe complications such as, esophageal erosions, esophageal obstruction, significant blood loss and perforation of the esophagus.
  • Severe esophageal ulcerations occur in 20-30% of patients over age 65.
  • prolonged exposure of the esophageal mucosa to stomach contents can lead to a condition known as Barrett's Esophagus.
  • Barrett's Esophagus is an esophageal disorder that is characterized by replacement of normal squamous epithelium with abnormal columnar epithelium. This change in tissue character is important clinically not only as an indication of severe reflux, but as an possible precursor of adenocarcinoma of the lower esophagus.
  • GERD lower esophageal sphincter
  • TLESR transient lower esophageal sphincter relaxations
  • LESP lower esophageal sphincter resting pressure
  • GERD GERD sufferers
  • the frequency of TLSER can be much higher, for example, as high as eight or more times an hour and weakness of the LESP allows reflux to occur.
  • Other factors which can contribute to GERD include delayed stomach emptying and ineffective esophageal clearance.
  • GERD GERD The extent and severity of GERD depends not only on the presence of gastroesophageal reflux but on factors including the volume of gastric contents available to reflux, pH, identity and potency of the refluxed material, the interval that the refluxed material remains in the esophagus, salivary volume, frequency of swallows, whether or not the subject is supine or upright and the ability of the esophageal tissue to withstand injury and to repair itself after injury.
  • the present invention relates to a method of treating a gastrointestinal motility disorder in a subject in need of such treatment comprising coadministering an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a GABA receptor for example, GABA B receptor
  • the subject is a human.
  • the gastrointestinal motility disorder is GERD. More specifically, the GERD is nocturnal GERD.
  • the gastrointestinal motility disorder is gastroparesis.
  • the invention is also directed to a method of increasing esophageal motility in a subject in need thereof comprising coadministering to said subject an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a GABA receptor for example, GABA B receptor
  • the gastrointestinal motility disorder is gastroparesis.
  • the invention further relates to pharmaceutical compositions for use in therapy or prophylaxis, for example, in the treatment of a gastrointestinal motility disorder in a subject in need of such treatment or for increasing esophageal motility in a subject in need thereof.
  • the pharmaceutical compositions comprise an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the gastrointestinal motility disorder is GERD. More specifically, the GERD is nocturnal GERD.
  • the gastrointestinal motility disorder is gastroparesis.
  • the present invention is also directed to the use of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof described herein for the manufacture of a medicament for use in therapy or prophylaxis, for example, for the treatment of a gastrointestinal motility disorder in a subject in need of treatment or for increasing esophageal motility in a subject in need thereof.
  • GABA receptor for example, GABA B receptor
  • the gastrointestinal motility disorder is GERD. More specifically, the GERD is nocturnal GERD.
  • the gastrointestinal motility disorder is gastroparesis.
  • the present invention provides a method for treating a gastrointestinal motility disorder in a subject in need of such treatment comprising coadministering an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the present invention also provides a method for increasing esophageal motility in a subject in need thereof comprising coadministering an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the present invention further relates to pharmaceutical compositions for therapy or prophylaxis, for example for the treatment of a gastrointestinal motility disorder in subject in need of such treatment or for increasing esophageal motility in a subject in need thereof, comprises an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • a 5-HT 3 receptor agonists and the GABA receptor agonists that can be used in the present invention are described below.
  • compositions of the present invention can optionally contain a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • Pharmaceutically acceptable carriers can be aqueous or non-aqueous solvents.
  • Gastrointestinal motility disorders refers to disorders of the gastrointestinal tract wherein the normal orderly movement of ingested material through the gastrointestinal tract is impaired. Gastrointestinal motility disorders include, for example, gastroparesis and gastroesophageal reflux disease (GERD). Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea and vomiting. Acute gastroparesis can be caused by, for example, drugs, viral enteritis and hyperglycemia and is typically managed by treating the underlying disease rather than the motility disorder. The most common underlying disease resulting in gastroparesis is diabetes.
  • Gastroesophageal reflux is a physical condition in which stomach contents (e.g, stomach acid, enzymes and bile salts) reflux or flow back from the stomach into the esophagus. Frequent reflux episodes (e.g., two or more times per week) can result in a more severe problem known as gastroesophageal reflux disease (GERD).
  • GERD gastroesophageal reflux disease
  • GORD glycosophageal reflux disease
  • the most common symptom of GERD is a burning sensation or discomfort behind the breastbone or sternum and is referred to as dyspepsia or heartburn. These symptoms can also mimic the symptoms of myocardial infarction or severe angina pectoris.
  • GERD GERD
  • Other symptoms of GERD include dysphagia, odynophagia, hemorrhage, water brash and respiratory manifestations such as asthma, recurrent pneumonia, chronic coughing, chronic throat clearing, intermittent wheezing due to acid aspiration and/or stimulation of the vagus nerve, earache, hoarseness, sleep disturbances, daytime sleepiness, laryngitis and pharyngitis.
  • Reflux episodes which result in GERD can occur both during the daytime (i.e., when the subject is in a waking state) and at nighttime (i.e., when the subject is in a non-waking state).
  • GERD occurring at nighttime is commonly referred to as nocturnal GERD.
  • Nocturnal GERD is distinct from daytime or diurnal GERD not only in the timing of the reflux episode, but in the severity of the damage which occurs as a result of the reflux. More specifically, nocturnal GERD, can be particularly damaging to the pharynx and larynx and a strong association between nocturnal GERD and asthma exists.
  • the increased damage associated with nocturnal GERD is due to a decrease in natural mechanisms which normally help protect against reflux (e.g., saliva production, swallowing and appropriate angle of the gravity vector), which occur when the patient is sleeping.
  • This decreased defence mechanisms leave the esophagus more vulnerable to damage and can increase microaspiration.
  • the body while asleep the body is in the recumbent position, eliminating the effect of gravity, which can clear gastric content from the esophagus. Sleep disorders are also associated with nocturnal GERD resulting in daytime sleepiness and a significant decrease in the overall quality of life.
  • GERD GERD subjects the esophagus to ulcer formation or esophagitis and can result in more severe complications such as, esophageal erosion, esophageal obstruction, esophageal strictures, significant blood loss and perforation of the esophagus.
  • Severe esophageal ulcerations occur in 20-30% of patients over age 65.
  • prolonged exposure of the esophageal mucosa to stomach contents can lead to a condition known as Barrett's Esophagus.
  • Barrett's Esophagus is an esophageal disorder that is characterized by replacement of normal squamous epithelium with abnormal columnar epithelium. This change in tissue type is important clinically not only as an indication of severe reflux, but also as a precursor to adenocarcinoma of the lower esophagus.
  • treatment refers to a reduction in at least one symptom associated with a gastrointestinal motility disorder.
  • the subject having GERD can experience a reduction in any one ore more of the symptoms of dysphagia, odynophagia, hemorrhage, water brash, esophageal erosion, esophageal obstruction and respiratory manifestations such as asthma, recurrent pneumonia, coughing, chronic throat clearing, intermittent wheezing, earache, hoarseness, sleep disturbances, daytime sleepiness, laryngitis and pharyngitis.
  • increasing esophageal motility refers to increasing peristaltic waves and/or LES pressure.
  • Subjects in need of increasing esophageal motility include those suffering from GERD, including nocturnal GERD.
  • a "subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
  • companion animals e.g., dogs, cats and the like
  • farm animals e.g., cows, sheep, pigs, horses, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, and the like.
  • GABA receptor (for example, GABA B receptor) agonists are gamma- aminobutyric acid and compounds that are derived from or based on gamma- aminobutyric acid, i.e. GABA analogs.
  • GABA receptor agonists are either readily available or can be readily synthesized using known methods.
  • Exemplary GABA receptor agonists and their salts include baclofen, gabapentin, pregabalin, PD217,014 and other GABA analogs as described in U.S. Patent No. 4,024,175, U.S. Patent No. 5,563,175, U.S. Patent No. 6,316,638, U.S. Patent No. 6,545,022 Bl, PCT Publication No.
  • GABA agonists that can be used in the present invention include, but are not limited to, cis-(lS,3R)-( 1 -(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)- 3-methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9-
  • GABA agonists and fused bicyclic or tricyclic amino acid analogs of gabapentin that are useful in the present invention include: 1. Baclofen, represented by the following structure:
  • GABA analogs according to the following structure as described in U.S. Pat. No. 4,024,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof, wherein Ri is hydrogen or a lower alkyl radical and n is 4, 5, or 6;
  • GABA analogs according to the following structure as described in U.S. Pat. No. 5,563,175, or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof,
  • Ri to Rio are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; m is an integer of from O to 3; n is an integer from 1 to 2; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer from 1 to 3; t is an integer from 0 to 2; and u is an integer from 0 to 1 ;
  • GABA analogs as disclosed in PCT Publication No. WO 93/23383 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof; 8. GABA analogs as disclosed in Bryans et al. (1998) J. Med. Chem. 41 :1838-1845 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;
  • GABA analogs as disclosed in Bryans et al. (1999) Med. Res. Rev. 19:149-177 or salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, or derivatives thereof;
  • Ri and R 2 are independently hydrogen or hydroxy;
  • X is selected from the group consisting of hydroxy and Q*-G- where: G is -O-, -C(O)O- or -NH-;
  • Q* is a group derived from a linear oligopeptide comprising a first moiety D and further comprising from 1 to 3 amino acids, and wherein said group is cleavable from the amino acid compound under physiological conditions;
  • D is a GABA analog moiety
  • Z is selected from the group consisting of:
  • a substituted alkyl group containing a moiety which is negatively charged at physiological pH which moiety is selected from the group consisting of - COOH, -SO 3 H, -SO 2 H, -P(O)(OR 16 XOH), - OP(O)(OR 16 XOH), -OSO 3 H and the like, and where R 16 is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; and (ii) a group of the formula -M-Q X
  • R is hydrogen or a lower alkyl
  • to R 14 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl,- CO 2 H 5 -CO 2 Ri -ORi 5 wherein Rj 5 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and Ri to Re are not simultaneously hydrogen;
  • n is an integer as disclosed in U.S. Patent Application Serial No. 60/160725, including those disclosed as having high activity as measured in a radioligand binding assay using [3H]gabapentin and the ⁇ 2 ⁇ subunit derived from porcine brain tissue, or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof,
  • Rl and R2 are independently selected from H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbons atoms, phenyl and benzyl, subject to the proviso that, except in the case of a tricyclooctane compound of formula (XVII), Rl and R2 are not simultaneously hyrogen; and 15.
  • the GABA receptor agonists are selected from the group consisting of baclofen (both enantiomers), XP- 19986, gabapentin, pregabalin, PD217.014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9- (aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-
  • Serotonin also referred to as 5-hydroxytryptamine (5-HT)
  • 5-HT 5-hydroxytryptamine
  • 5-HTi 5-HTi
  • 5-HT 7 Currently, at least fourteen subtypes of serotonin receptors are recognized and delineated into seven families, 5-HTi through 5-HT 7 . These subtypes share sequence homology and display some similarities in their specificity for particular ligands. While these receptors all bind serotonin, they initiate different signaling pathways to perform different functions.
  • serotonin is known to activate submucosal intrinsic nerves via 5-HTi p and 5-HT4 receptors, resulting in, for example, the initiation of peristaltic and secretory reflexes.
  • serotonin is also known to activate extrinsic nerves via 5-HT 3 receptors, resulting in, for example, the initiation of bowel sensations, nausea, bloating and pain.
  • a review of the nomenclature and classification of the 5-HT receptors can be found in Neuropharm., 33: 261-273 (1994) and Pharm. Rev., 45:157-203 (1994).
  • 5-HT 3 receptors are ligand-gated ion channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization have been found to affect the regulation of visceral pain and colonic transit. Antagonism of the 5-HT 3 receptors has the potential to influence sensory and motor function in the gut.
  • 5-HT 3 receptor refers to naturally occurring 5-HT 3 receptors (e.g., mammalian 5-HT 3 receptors (e.g., human (Homo sapiens) 5-HT 3 receptors, murine (e.g., rat, mouse) 5-HT 3 receptors, feline (e.g., cat) 5-HT 3 receptors)) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring 5-HT 3 receptor (e.g., recombinant proteins).
  • the term includes naturally occurring variants, such as polymorphic or allelic variants and splice variants.
  • a 5-HT 3 receptor agonist refers to a substance (e.g., a molecule, a compound) which promotes (induces or enhances) at least one function characteristic of a 5-HT 3 receptor.
  • the 5-HT 3 receptor agonist binds the 5-HT 3 receptor (i.e., is a 5-HT 3 receptor agonist).
  • the agonist is a partial agonist. Partial agonist, as used herein, refers to an agonist which no matter how high of a concentration is used, is unable to produce maximal activation of the 5-HT 3 receptor.
  • a 5-HT 3 receptor agonist e.g., a 5-HT 3 receptor agonist
  • a 5-HT 3 receptor agonist can be identified and activity assessed by any suitable method.
  • the binding affinity of a 5-HT 3 receptor agonist to the 5-HT 3 receptor can be determined by the ability of the compounds to displace [ 3 H]granisetron from rat cortical membranes (Cappelli et al, J. Med. Chem., 42(9): 1556-1575 (1999)).
  • the agonist activity of the compounds can be assessed in vitro on, for example, the 5-HT 3 receptor-dependent [ l4 C]guanidinium uptake in NG 108-15 cells as described in Cappelli et al.
  • 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof described above in the section entitled "GABA Receptor Agonist” (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein).
  • GABA receptor for example, GABA B receptor
  • GABA Receptor Agonist e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein.
  • the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( 1 -(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3- methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l -aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen.
  • the 5-HT 3 receptor agonist is a thieno[3,2- bjpyridine derivatives such as those described in U.S. Patent No. 5,352,685, the entire content of which is incorporated herein by reference.
  • the 5-HT 3 receptor agonist activity is represented by Structural Formula I:
  • Ri represents hydrogen, a Ci-Ce alkyl group, a C 2 -Ce alkenyl group, a
  • R 2 represents hydrogen, a Ci-C 6 alkyl group, halogen, hydroxyl, a Ci-
  • Y represents -O- or N wherein R 3 represents hydrogen or a Ci -C ⁇ alkyl group; and A is represented by
  • n is an integer from 1 to about 4;
  • R 4 represents hydrogen, a Ci-C 6 alkyl group, a C 3 -Cs cycloalkyl group or a C 7 -Ci S aralkyl group or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide derivative thereof.
  • the 5-HT 3 agonist represented by the Structural Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein).
  • the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD214,017, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-(lR,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1 ]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.
  • baclofen both enatiomers
  • XP- 19986 gabapentin
  • pregabalin pregabalin
  • the GABA receptor agonist activity is baclofen. It is understood that when Rj of Structural Formula I is hydrogen, compounds having the tautomeric form represented by Structural Formula IA are included within the definition of Structural Formula I.
  • Structural Formula IA includes the tautomeric form represented by Structural Formula I when R
  • Formula I can be N-oxide derivatives.
  • Y represents -O- or
  • Ri represents hydrogen, a Ci-C ⁇ alkyl group, a Ce-Ci 2 aryl group, or a C 7 -
  • Ci8 aralkyl group R 2 represents hydrogen, a Ci-Ce alkyl group or halogen; and A is represented by wherein: n is 2 or 3; and R4 represents a Ci-C 6 alkyl group.
  • the 5-HT 3 receptor agonist is represented by
  • the 5-HT 3 receptor agonist is represented by structural Structural Formula V:
  • the 5-HT 3 agonist represented by the Structural Formula V or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein).
  • GABA receptor for example, GABA B receptor
  • GABA Receptor Agonist e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 therein.
  • the GABA receptor agonists are selected from the group consisting of baclofen (both enatiomers), XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis- (lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9- (aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-
  • the GABA receptor agonist activity is baclofen.
  • V is an N-oxide derivative.
  • Structural Formula V includes the tautomeric form depicted by Structural Formula VA:
  • Structural Formula VA includes the tautomeric form represented by Structural Formula V.
  • Structural Formula V has the (R) configuration at the designated chiral carbon the compound is referred to as: (R)-N-I- azabicyclo[2.2.2]pct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide which is understood to include the tautomeric form: (R)-N-I -azabicyclo[2.2.2]oct- 3-yl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide.
  • Structural Formula VA has the (R) configuration at the designated chiral carbon the compound is referred to as: (R)-N-I- azabicyclo[2.2.2]oct-3-yl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide, which is understood to include the tautomeric form: (R)-N- 1-azabicyclo [2.2.2]oct-3-yl-4,7- dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide.
  • the 5-HT 3 receptor agonist is a condensed thiazole derivative such as those described in U.S. Patent No. 5,565,479, the entire content of which is incorporated herein by reference.
  • the 5-HT 3 receptor agonist is represented by Structural Formula VI or a tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof:
  • R represents hydrogen, halogen, hydroxyl, a Ci-C ⁇ alkoxy group, carboxy, a Ci-C ⁇ alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;
  • ⁇ is a phenyl ring or a naphthalene ring
  • L is a direct bond or a C)-C O alkylene group
  • Li and L 2 are defined so that one is a direct bond and the other is: a) a Cj-C ⁇ alkylene group optionally containing an interrupting oxygen or sulfur atom therein; b) an oxygen atom or sulfur atom; or c) a Ci-Ce alkenylene group
  • Im represents a group having the formula: wherein:
  • Ri-Rs are the same or different each representing hydrogen or a Ci-C 6 alkyl group.
  • the compound according to Structural Formula VI is the same or different each representing hydrogen or a Ci-C 6 alkyl group.
  • ⁇ is a phenyl ring
  • Li is a direct bond
  • L 2 is an alkylene group or alkenylene group.
  • the 5-HT 3 agonist represented by Structural Formula VI or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist in the section entitled
  • GABA receptor for example, GABA B receptor
  • GABA Receptor Agonist e.g., the GABA agonists described in Section 1, 2, 3, 4,
  • the GABA receptor agonists are selected from the group consisting of baclofen, XP-19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3-methylcyclohexane)acetic acid, cis-(lR,3S)-(l-(aminomethyl)-3-methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l- aminomethyl)- (3,5-dimethylcyclohexane)acetic acid, (9-
  • the GABA receptor agonist activity is baclofen.
  • the 5-HT 3 receptor agonist is represented by Structural Formula VII:
  • the 5-HT 3 agonist represented by Structural Formula VII or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist described above in the section entitled "GABA Receptor Agonist” (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein).
  • GABA receptor for example, GABA B receptor
  • GABA Receptor Agonist e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein.
  • the GABA receptor agonists are selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(lS,3R)-( l-(aminomethyl)- 3- methylcyclohexane)acetic acid, cis-( 1R,3 S)-(I -(aminomethyl)-3- methylcyclohexane)acetic acid, l ⁇ ,3 ⁇ ,5 ⁇ -(l-aminomethyl)- (3,5- dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof. More preferably, the GABA receptor agonist activity is baclofen.
  • the 5-HT 3 receptor agonist is m-chlorophenylbiguanide (mCPBG) represented by the following structural formula:
  • the 5-HT 3 agonist mCPBG or a pharmaceutically acceptable salt, hydrate or solvate thereof can be used with a GABA receptor (for example, GABA B receptor) agonist described above in the section entitled "GABA Receptor Agonist" (e.g., the GABA agonists described in Section 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 therein).
  • GABA receptor agonists are selected from the group consisting of baclofen, XP- 19986, gabapentin, pregabalin, PD217,014, cis-(l S,3R)-( 1-
  • the compounds for use in the methods or compositions of the invention can be formulated for oral, transdermal, sublingual, buccal, parenteral, rectal, intranasal, intrabronchial or intrapulmonary administration.
  • the compounds can be of the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stea
  • Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions.
  • the liquid preparations can 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 p-hydroxy benzoates or sorbic acid).
  • 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
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorb
  • the compounds for use in the methods or compositions of the invention can be in the form of tablets or lozenges formulated in a conventional manner.
  • the compounds for use in the methods or compositions of the invention can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or infusion (e.g., continuous infusion).
  • injection or infusion for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or infusion (e.g., continuous infusion).
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents can be used.
  • the compounds for use in the methods or compositions of the invention can be in the form of suppositories.
  • tablets can be formulated in conventional manner.
  • intrabronchial or intrapulmonary administration conventional formulations can be employed.
  • the compounds for use in the methods or compositions of the invention can be formulated in a sustained release preparation.
  • the compounds can be formulated with a suitable polymer or hydrophobic material which provides sustained and/or controlled release properties to the active agent compound.
  • the compounds for use the method of the invention can be administered in the form of microparticles for example, by injection or in the form of wafers or discs by implantation.
  • Additional dosage forms suitable for use in the methods or compositions of the invention include dosage forms as described in U.S. Pat. No. 6,340,475, U.S. Pat. No. 6,488,962, U.S. Pat. No. 6,451,808, U.S. Pat. No. 6,340,475, U.S. Pat. No.
  • Additional dosage forms include those described in U.S. Pat. Application No. 20030147952, U.S. Pat. Application No. 20030104062, U.S. Pat. Application No. 20030104053, U.S. Pat. Application No. 20030044466, U.S. Pat. Application No. 20030039688, and U.S. Pat. Application No. 20020051820.
  • Additional dosage forms of this invention also include dosage forms as described in PCT Patent Application WO 03/35041 , PCT Patent Application WO 03/35040, PCT Patent Application WO 03/35029, PCT Patent Application WO 03/35177, PCT Patent Application WO 03/35039, PCT Patent Application WO 02/96404, PCT Patent Application WO 02/32416, PCT Patent Application WO 01/97783, PCT Patent Application WO 01/56544, PCT Patent Application WO 01/32217, PCT Patent Application WO 98/55107, PCT Patent Application WO 98/1 1879, PCT Patent Application WO 97/47285, PCT Patent Application WO 93/18755, and PCT Patent Application WO 90/11757.
  • the dosage forms of the present invention include pharmaceutical tablets for oral administration as described in U.S. Patent Application No. 20030104053.
  • the dosage forms of this invention include dosage forms in which the same drug is used in both the immediate-release and the prolonged-release portions as well as those in which one drug is formulated for immediate release and another drug, different from the first, for prolonged release.
  • This invention is particularly directed to dosage forms in which the immediate- release drug is at most sparingly soluble in water, i.e., either sparingly soluble or insoluble in water, while the prolonged-release drug can be of any level of solubility.
  • the prolonged-release portion of the dosage form can be a dosage form that delivers drug to the digestive system continuously over a period of time of at least an hour and preferably several hours and the drug is formulated as described in U.S. Patent Application No. 20030104053.
  • the immediate-release portion of the dosage form is either a coating applied or deposited over the entire surface of a unitary prolonged-release core, or a single layer of a tablet constructed in two or more layers, one of the other layers of which is the prolonged-released portion and is formulated as described in U.S. Patent Application No. 20030104053.
  • the supporting matrix in controlled - release tablets or controlled release portions of tablets is a material that swells upon contact with gastric fluid to a size that is large enough to promote retention in the stomach while the subject is in the digestive state, which is also referred to as the postprandial or "fed” mode.
  • This is one of two modes of activity of the stomach that differ by their distinctive patterns of gastroduodenal motor activity.
  • the "fed” mode is induced by food ingestion and begins with a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract. The change consists of a reduction in the amplitude of the contractions that the stomach undergoes and a reduction in the pyloric opening to a partially closed state.
  • the result is a sieving process that allows liquids and small particles to pass through the partially open pylorus while indigestible particles that are larger than the pylorus are retropelled and retained in the stomach.
  • This process causes the stomach to retain particles that are greater than about 1 cm in size for about 4 to 6 hours.
  • the controlled-release matrix in these embodiments of the invention is therefore selected as one that swells to a size large enough to be retropelled and thereby retained in the stomach, causing the prolonged release of the drug to occur in the stomach rather than in the intestines. Disclosures of oral dosage forms that swell to sizes that will prolong the residence time in the stomach are found in U.S. Pat. No. 6,448,962, U.S. Pat. No. 6,340,475, U.S.
  • coadministration refers to administration of an effective amount of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and an effective amount of a GABA receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • Coadministration encompasses administration of the 5-HT3 receptor agonist and the GABA receptor agonist in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of the 5-HT 3 receptor agonist and the GABA receptor agonist, or in multiple, separate capsules or tablets for each.
  • coadministration also encompasses use of each compound in a sequential manner in either order.
  • the compounds are administered sufficiently close in time to have the desired therapeutic effect.
  • the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile.
  • the 5-HT 3 receptor agonist and the GABA receptor agonist can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
  • Staggered release of agents can be accomplished in single composition using any suitable formulation technique such as those described above.
  • a variety of coating thicknesses and/or different coating agents can provide staggered release of agents from a single composition, and release at a desired location in the upper GI tract.
  • the separate compositions can be formulated to achieve the desired release profile.
  • the separate compositions can be formulated to release primarily in the duodenum rather than in the acidic environment of the stomach.
  • a variety of formulation techniques such as gastric retention techniques, coating techniques and the use of suitable excipients and/or carriers can be utilized to achieve the desired release.
  • An additional therapeutic agent can be used in the method of treating a gastrointestinal motility disorder or increasing esophageal motility and in compositions of the invention described herein.
  • Additional therapeutic agents suitable for use in the method of treating GERD and in compositions of the invention can be, but are not limited to, antacids, for example, TUMS ® and ROLAIDS ® .
  • the additional therapeutic agent will be one that is useful for treating the disorder of interest.
  • the additional therapeutic agent does not diminish the effects of the therapy and/or potentiates the effects of the primary administration.
  • an "effective amount” refers to an amount effective to obtain therapeutic or prophylactic effect without including unacceptable side effects.
  • therapeutic effect refers to inhibiting development of, or to alleviating the existing symptoms of the gastrointestinal motility disorder in the subject being treated or increaseing esopheal motility in a subject in need thereof. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and ED 5O (the dose that provides 50% of the maximal response and/or is therapeutically effective in 50% of the population).
  • the dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. The exact formulation, route of administration, and dosage is chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain desired therapeutic effects. In addition to the patient's condition and the mode of administration, the dose administered would depend on the severity of the patient's symptoms and the patient's sex, age and weight, the current medical condition of the patient and the nature of the gastrointestinal motility disorder being treated. In accordance with the present invention, an "effective amount" of a 5-HT 3 receptor agonist encompasses alone or in combination with a GABA receptor agonist to achieve therapeutic effect.
  • an "effective amount" of a GABA receptor agonist encompasses an amount effective to achieve therapeutic effect alone or in combination with a 5-HT 3 receptor agonist.
  • the amount is referred herein as a "sub-therapeutic" dose.
  • coadminstration of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect resulting from separate administration of a 5-HT 3 receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and a GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof alone.
  • An advantage of the synergistic effect of the combination therapy is the ability to use less of each agent than is needed when each is administered alone. As such, undesirable side effects associated with the agents are reduced (partially or completely). A reduction in side effects can result in increased patient compliance over current treatments.
  • Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)).
  • Sigmoid-Emax equation Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)
  • Loewe additivity Li. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)
  • the median-effect equation Chou, T.C. and Talalay, P., Adv. Enzy
  • continuous dosing refers to the chronic administration of a selected active agent.
  • as-needed dosing also known as “pro re nata” “prn” dosing, and “on demand” dosing or administration is meant the administration of a therapeutically effective dose of the compound(s) at some time prior to commencement of an activity wherein suppression of the gastrointestinal motility disorder would be desirable.
  • Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.
  • the combination therapy can be administered about one hour before sleep to treat nocturnal GERD.
  • drug administration or dosing is on an as-needed basis, and does not involve chronic drug administration.
  • as-needed administration can involve drug administration immediately prior to commencement of an activity wherein suppression of the symptoms of the GERD would be desirable, but will generally be in the range of from about 0 minutes to about 10 hours prior to such an activity, preferably in the range of from about 0 minutes to about 5 hours prior to such an activity, most preferably in the range of from about 0 minutes to about 3 hours prior to such an activity.
  • a suitable dose per day for each of the 5-HT 3 receptor agonist or the GABA receptor agonist for administration can be in .the range of from about 1 ng to about 10,000 mg, about 5 ng to about 9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 ⁇ g to about 3,500 mg, about 5 ⁇ g to about 3,000 mg, about 10 ⁇ g to about 2,600 mg, about 20 ⁇ g to about 2,575 mg, about 30 ⁇ g to about 2,550 mg, about 40 ⁇ g to about 2,500 mg, about 50 ⁇ g to about 2,475 mg, about 100 ⁇ g to about 2,450 mg, about 200 ⁇ g to about 2,425 mg,
  • Suitable doses per day for each of the 5-HT 3 receptor agonist or the GABA receptor agonist for administration include doses of about or greater than 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 ng, about 1 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 20 ⁇ g, about 30 ⁇ g, about 40 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 200 ⁇ g, about 300 ⁇ g, about 400 ⁇ g, about 500 ⁇ g (0.5 mg), about 1 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600
  • a suitable dose of 5-HT 3 receptor agonist can be in the range of from about 0.1 mg to about 100 mg per day, such as from about 0.5 mg to about 50 mg, for example, from about 1 mg to about 25 mg per day.
  • the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.
  • the suitable dose of the GABA receptor agonist can be in the range of from about 50 mg to about 5000 mg per day, such as from about 100 mg to about 2500 mg, for example, from about 500 mg to about 2000 mg per day.
  • the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day.
  • the amount of each dosage can be the same or different.
  • a per day dose of the compounds of the combination can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days etc.
  • the compounds for use in the method of the invention can be formulated in unit dosage form.
  • the term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. Suitable amounts for use in preparation of a unit dosage form are described above for both the 5-HT 3 receptor agonist and the GABA receptor agonist.
  • the unit dosage form can 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 can be the same or different for each dose.
  • the invention further includes a kit for treating a gastrointestinal motility disorder or for increasing esophageal motility.
  • the kit comprises a 5-HTj receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof and instructions for use with the GABA receptor agonist according to the method of the invention and optionally a device for administering the compounds of the invention.
  • the 5-HT 3 receptor agonist is present in the kit in a subtherapeutic dose.
  • the GABA receptor agonist is present in the kit in a sub-therapeutic dose.
  • the instructions direct administration of the GABA receptor agonist or a pharmaceutically acceptable salt, hydrate or solvate thereof in a sub-therapeutic dose.
  • the instructions direct administration of the compound having 5-HT 3 receptor agonist activity in a sub-therapeutic dose.
  • kits can be in separate dosage forms or combined in a single dosage form.
  • the instructional insert further includes instructions for administration with an additional therapeutic agent as described herein.
  • administration encompasses administration by different individuals (e.g., the subject, physicians or other medical professionals) administering the same or different compounds.
  • the term pharmaceutically acceptable salt refers to a salt of a compound . to be administered prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric.
  • Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
  • the active compounds disclosed can be prepared in the form of their hydrates, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like and as solvates.
  • suitable 5-HT 3 receptor agonists GABA receptor (for example GABA B receptor) agonist can be identified, for example, by screening libraries or collections of molecules using suitable methods.
  • Another source for the compounds of interest are combinatorial libraries which can comprise many structurally distinct molecular species.
  • Combinatorial libraries can be used to identify lead compounds or to optimize a previously identified lead.
  • Such libraries can be manufactured by well-known methods of combinatorial chemistry and screened by suitable methods.
  • An "aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and can optionally contain one or more units of unsaturation, e.g., double and/or triple bonds and/or one or more suitable substituents.
  • An aliphatic group can be straight chained, branched or cyclic. When straight chained or branched, an aliphatic group typically contains between about 1 and about 12 carbon atoms, more typically between about 1 and about 6 carbon atoms.
  • an aliphatic group typically contains between about 3 and about 10 carbon atoms, more typically between about 3 and about 8 carbon atoms, e.g., a cyclopropyl group, cyclohexyl group, cyclooctyl group etc.
  • Aliphatic groups can be alkyl groups (i.e., completely saturated aliphatic groups, e.g., a C]-Ce alkyl group, such as a methyl group, propyl group, hexyl group, etc.), alkenyl groups (i.e., aliphatic groups having one or more between about 3 and about 8 carbon atoms, e.g., a cyclopropyl group, cyclohexyl group, cyclooctyl group etc.
  • alkyl groups i.e., completely saturated aliphatic groups, e.g., a C]-Ce alkyl group, such as a methyl group, propyl group, hexyl group, etc.
  • alkenyl groups i.e., aliphatic groups having one or more between about 3 and about 8 carbon atoms, e.g., a cyclopropyl group, cyclohexyl group, cycloo
  • Aliphatic groups can be alkyl groups (i.e., completely saturated aliphatic groups, e.g., a Ci-Ce alkyl group, such as a methyl group, propyl group, hexyl group, etc.), alkenyl groups (i.e., aliphatic groups having one or more carbon-carbon double bonds, e.g., C 2 -Ce alkenyl group, such as a vinyl group, butenyl group, hexenyl group etc.) or alkynyl groups (i.e., aliphatic groups having one or more carbon-carbon triple bonds, e.g., a C 2 -C 6 alkynyl group, such as an ethynyl group, butynyl group, hexenyl group, etc.)- Aliphatic groups can optionally be substituted with a designated number of substituents, as described herein.
  • alkyl groups i.e., completely saturated aliphatic
  • Alkenylene group as used herein refers to the diatomic group having one carbon atom and one attached hydrogen. Suitable alkenylene groups include C 2 -C O alkenylene groups such as vinylene, propenylene, 1-methylvinylene, etc.
  • aromatic group also referred to as an "aryl group” as used herein includes carbocyclic aromatic groups, heterocyclic aromatic groups (also referred to as “heteroaryl”) and fused polycyclic aromatic ring systems as defined herein which can be optionally substituted with a suitable substituent.
  • a “carbocyclic aromatic group” is an aromatic ring of 5 to 14 carbons atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan.
  • Examples of carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, e.g., 1-naphthyl and 2-naphthyl; anthracenyl, e.g., 1- anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, e.g., 9-fluorenonyl, indanyl and the like.
  • a carbocyclic aromatic group is optionally substituted with a designated number of substituents, described below.
  • heterocyclic aromatic group (or “heteroaryl”) is a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • heteroaryl examples include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as ⁇ -pyridyl), 3-pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ⁇ -pyridyl); thienyl, e.g., 2- oxazoyl, 4-oxazoyl and 5- oxazoyl; isoxazoyl; pyrrolyl; pyridazinyl; pyrazinyl and the like.
  • pyridyl e.g., 2-pyridyl (also referred to as ⁇ -pyridyl), 3-pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ⁇ -pyridyl)
  • thienyl e.g., 2- oxazoyl,
  • Heterocyclic aromatic (or heteroaryl) as defined above can be optionally substituted with a designated number of substituents, as described below for aromatic groups.
  • a "fused polycyclic aromatic" ring system is a carbocyclic aromatic group or heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring.
  • Examples include, quinolinyl and isoquinolinyl, e.g, 2-quinolinyl, 3-quinolinyl, 4- quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1- isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7- isoquinolinyl and 8-isoquinolinyl; benzofuranyl, e.g., 2 -benzofuranyl and 3- benzofuranyl; dibenzofuranyl, e.g., 2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, e.g., 2-benzothienyl and 3-benzothienyl; indolyl, e.g., 2-indolyl and 3-indolyl;
  • aralkyl group is an alkyl group substituted with an aromatic group, preferably a phenyl group.
  • a preferred aralkyl group is a benzyl group.
  • Suitable aromatic groups are described herein and suitable alkyl groups are described herein.
  • An aralkyl group can optionally be substituted, and suitable substituents for an aralkyl group (substituted on the aryl, alkyl or both moieties) are described herein.
  • substitutable group can be a hydrogen atom which is replaced with a group other than hydrogen (i.e., a substituent group).
  • substituent groups can be present.
  • substituents can be the same or different and substitution can be at any of the substitutable sites on the group or moiety. Such means for substitution are well-known in the art.
  • alkyl groups e.g., Ci-C 6 alkyl groups
  • alkoxy groups e.g., Ci-C 6 alkoxy, such as a methoxy group, propoxy group, hexyloxy group etc.
  • a halogen or halo group F, Cl, Br, I
  • hydroxy, nitro, thio also referred to as mercapto
  • akylthio e.g., Ci-C 6 alkylthio
  • oxo -CN, -COH, -COOH
  • amino, N- alkylamino e.g., Ci-C 6 alkylamino
  • N,N-dialkylamino in which the alkyl groups can also be substituted
  • esters -C
  • N-oxide refers a functionality wherein an oxygen atom is bonded to the nitrogen of a tertiary amine.
  • Protected hydroxy 1 refers to a hydroxyl group in which the hydrogen atom of the hydroxy group has been replaced with a suitable hydroxy protecting group.
  • Suitable hydroxy protecting groups include but are not limited to, for example, benzyl, tert-butyl, acetyl, trifluoroacetyl, benzoyl and benzyloxycarbonyl.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • the compounds of the present invention When compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes either or both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the enantiomers can be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization (See, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC
  • diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step is required to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer.
  • the "R” forms of the compounds are substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
  • “S” forms of the compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R” forms.
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%.
  • the enantiomeric excess can be about 60% or more, such as about 70% or more, for example about 80% or more, such as about 90% or more.
  • the enantiomeric excess of depicted compounds is at least about 90%.
  • the enantiomeric excess of the compounds is at least about 95%, such as at least about 97.5%, for example, at least about 99% enantiomeric excess.
  • a compound of the present invention When a compound of the present invention has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers which are not mirror-images e.g., (S,S) and (R 5 S) are diastereomers.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of such compounds and mixtures thereof.
  • the efficacy of the combination therapy can be assessed through monitoring of the patient's symptoms. For example, an improvement in symptoms such as, hoarseness, cough, heartburn, asthma and overall quality of life can be assessed without the need for invasive testing.
  • patients receiving the combination therapy can be subjected to gastroesophageal testing, for example, esophageal manometry followed by ambulatory gastroesophageal pH monitoring.
  • gastroesophageal testing for example, esophageal manometry followed by ambulatory gastroesophageal pH monitoring.
  • This type of gastoesophageal testing can be conducted according to established protocols such as those found in Fackler et al, Gastroenterology 122(3): 625-632 (2002).
  • Esophageal Manometry Briefly, esophageal manometry is used to locate the LES of all study participants using the station pull-through technique. LES pressure and location are recorded by a computerized motility system such as Synectics Gastrosoft Polygram, Milwaukee, WI.
  • Ambulatory Gastroesophageal pH Monitoring Twenty-four hour pH level monitoring is then conducted in all study participants. Monitoring is performed with 2.1 mm monocrystalline pH catheters with 2 antimony electrodes separated by 15 cm (Medtronic Functional Diagnostics Zinetics, Inc., Salt lake City, UT). The reference electrode is internalized. The pH electrodes are calibrated at 37 EC in buffer solutions of pH 7 and pH 1 (Fisher Scientific, Fairlawn, NJ) before each study. After calibration, the pH probe apparatus is passed nasally and positioned such that the distal electrode is in the gastric fundus, 10 cm below the proximal border of the lower esophageal sphincter. The probe apparatus is secured to the nose and cheek to prevent dislodgment.
  • the pH electrodes are connected to a portable digital data recorder (Digitrapper Mark III Gold; Synectics) worn around the waist, which stores pH data samples every 4 seconds for up to 24 hours. Patients then return home with instructions to keep a diary recording meal times, time of lying down for sleep, and time of rising in the morning. Patients are encouraged to perform their normal daily activities, consume their customary diet without restrictions, and avoid sleeping for short periods during the day. They return the following day after a minimum of 18 hours to have their probes removed and their diaries reviewed.
  • a portable digital data recorder Digitrapper Mark III Gold; Synectics
  • Additional pH monitoring following onset of combination therapy is conducted at predetermined time points and the data compared and analyzed to determine the effectiveness among combination therapies and the effectiveness of combination therapy as compared to monotherapy with the components of the combination.
  • the ability of the combination therapy to suppress gastric acid can be assessed using the fundic pouch dog model. More specifically, following starvation overnight a dog is subjected to sterile ventrotomy under anesthesia using sodium pentobarbital (about 30 mg/kg, i.v.) and a fistula is attached to a part of the corpus ventriculi. After a two week recovery period, the dog is fixed to the Pavlov's stand, and gastric juice is collected every 15 minutes for about 4 hours under histamine stimulation (about 0.2 mg/kg/hr). A volume of each collected juice is recorded and the juice is titrated with 0.01 N NaOH using pH automatic measuring apparatus. The amount of gastric juice secreted in calculated as mEq/4hr. The combination therapy is then orally administered about one hour before histamine administration and gastric juice is collected and analyzed as described for the control group.
  • Comparison of the amount of gastric acid secreted for the Control and Treated Groups is conducted to assess the ability of the combination therapy to suppress gastric acid secretion.
  • Esophageal smooth muscle peristalsis and lower esophageal spincter (LES) pressure is recorded in vivo in a feline model, similar to the one used by Liu J, Pehlivanov N, and Mittal RK in a study, wherein baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats.
  • LES Esophageal smooth muscle peristalsis and lower esophageal spincter
  • g. Combination of MKC-733 and baclofen on LES pressure in response to 3 gastric distension.
  • MKC-733 is dissolved in 1.5% methylcellulose in distilled water and administered via intragastric infusion through a silicone line placed into the stomach parallel to the manometric catheter.
  • Baclofen is purchased from Sigma (St. Louis, MO) and fresh solution is made in saline prior to the experiments. Baclofen is administered intravenously.
  • Drugs are administered prior to the recording session. Each session starts with a 10- min recording of basal activity followed by 3 consecutive gastric distensions.
  • MKC- 733 is administered 15-minutes prior to initiating the recording.
  • the drug combination is administered as follows: MKC-733 via intragastric infusion and baclofen i.v. at 15-min of MKC-733 treatment.
  • the cats are allowed a minimum of 5 days for washout and recovery between the recording sessions.
  • LES pressure and induction of TLESRs by gastric distension The cats are fasted overnight and anesthetized with ketamine (75 mg per animal i.m.) Additional doses of ketamine are administered as needed throughout the experiment to maintain sedation but not alter the ability of the cat to swallow or the tone of the LES.
  • the animals are placed on a heating blanket (37 0 C) to maintain body temperature.
  • Distal esophageal motility and LES pressure is recorded manometrically by means of a water-perfused catheter assembly system (Arndorfer Inc. Greendale, WI) attached via pressure transducers to a minimally compliant hydraulic pump.
  • LES pressure is monitored using a Dent sleeve positioned within the LES, with the tip placed into the stomach.
  • the probe is constructed for cat esophageal manometry with a total distance of 4 cm between recording sites 0 (tip in the stomach) and 2, while the remaining sites (3, 4 and 5) are placed 2 cm apart with site 5 placed at 6 cm from the top of the sleeve.
  • the outputs from the pressure transducers are connected to bridge amplifiers and the signal from each manometric site is recorded using an 8 channel Power Lab (AD Instruments). Under these experimental conditions, the effect of gastric distension on LES pressure is studied by injecting 60 ml of air into the stomach.
  • Gastric distension is induced by air injected into the stomach using a hand-held syringe.
  • the recording session ensures the reproduction of the TLSRs reported by Liu et al Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 283(6): G 1276-81, where a gastric distension with 60 ml of air consistently induces a LES relaxation.
  • the air is injected within 5-10 s, kept in the stomach for a period of 60 s and then withdrawn using the syringe.
  • the volume of withdrawn air is measured and about 80-90 % of the injected air is recovered from the stomach after each gastric distension.
  • Gastric distensions is repeated 3 times in each animal. At least 2-min interval is allowed between distensions. According to the protocol, if an esophageal contraction occurs immediately after air injection, the distension is terminated by withdrawing air from the stomach and the data for LES pressure is disregarded.

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Abstract

L'invention porte sur une méthode de traitement les troubles de la motilité gastrointestinale consistant à coadministrer à un patient le nécessitant une quantité efficace d'un agoniste du récepteur 5-HT3 ou l'un de ses sels, hydrates, ou solvates pharmacocompatibles, et une quantité efficace d'un agoniste du récepteur GABA ou l'un de ses sels, hydrates, ou solvates pharmacocompatibles. L'invention porte également sur une méthode améliorant la motilité oesophagienne consistant à coadministrer à un patient le nécessitant une quantité efficace d'un agoniste du récepteur 5-HT3 ou l'un de ses sels, hydrates, ou solvates pharmacocompatibles, et une quantité efficace d'un agoniste du récepteur GABA ou l'un de ses sels, hydrates, ou solvates pharmacocompatibles.
PCT/US2007/016183 2006-07-18 2007-07-17 Méthodes de traitement du reflux gastrooesophagien Ceased WO2008011016A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086492A1 (fr) * 2007-01-11 2008-07-17 Xenoport, Inc. Formes galéniques orales à libération prolongée d'un promédicament de r-baclofène et procédés de traitement
WO2009096985A1 (fr) * 2008-02-01 2009-08-06 Xenoport, Inc. Formes posologiques orales particulaires à libération soustenue de promédicaments de (r)-baclofène et procédés de traitement correspondants
WO2010042759A2 (fr) 2008-10-08 2010-04-15 Kyphia Pharmaceuticals Inc Conjugués gaba et procédés d'utilisation de ceux-ci
US8424489B2 (en) 2008-07-21 2013-04-23 Kathleen Desrosiers Device and method for feeding domesticated animals
US10071068B2 (en) 2009-03-03 2018-09-11 Xenoport, Inc. Sustained release oral dosage forms of an R-baclofen prodrug

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040020056A (ko) * 2001-05-29 2004-03-06 디포메드 디벨롭먼트 리미티드 위식도 역류 질환 및 야간 위산분비의 치료 방법
EP1644043A1 (fr) * 2003-05-27 2006-04-12 ALTANA Pharma AG Combinaisons pharmaceutiques d'un inhibiteur de la pompe a protons et d'un compose modifiant la motilite gastro-intestinale
KR20060118421A (ko) * 2003-08-29 2006-11-23 다이노젠 파마세우티컬스, 인코포레이티드 위장 운동 장애의 치료에 유용한 조성물
US20050090554A1 (en) * 2003-09-12 2005-04-28 John Devane Treatment of gastroparesis and nonulcer dyspepsia with GABAB agonists
WO2007005780A2 (fr) * 2005-07-01 2007-01-11 Dynogen Pharmaceuticals, Inc. Compositions et procédés permettant de traite l'hypomotilité du système digestif et des troubles associés

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086492A1 (fr) * 2007-01-11 2008-07-17 Xenoport, Inc. Formes galéniques orales à libération prolongée d'un promédicament de r-baclofène et procédés de traitement
WO2009096985A1 (fr) * 2008-02-01 2009-08-06 Xenoport, Inc. Formes posologiques orales particulaires à libération soustenue de promédicaments de (r)-baclofène et procédés de traitement correspondants
US8424489B2 (en) 2008-07-21 2013-04-23 Kathleen Desrosiers Device and method for feeding domesticated animals
WO2010042759A2 (fr) 2008-10-08 2010-04-15 Kyphia Pharmaceuticals Inc Conjugués gaba et procédés d'utilisation de ceux-ci
US8268887B2 (en) 2008-10-08 2012-09-18 Feng Xu Drug conjugates and methods of use thereof
US9186341B2 (en) 2008-10-08 2015-11-17 Feng Xu GABA conjugates and methods of use thereof
EP3075722A1 (fr) 2008-10-08 2016-10-05 Xgene Pharmaceutical Inc Conjugués gaba et leurs procédés d'utilisation
US10478412B2 (en) 2008-10-08 2019-11-19 Xgene Pharmaceutical Inc. GABA conjugates and methods of use thereof
US10071068B2 (en) 2009-03-03 2018-09-11 Xenoport, Inc. Sustained release oral dosage forms of an R-baclofen prodrug

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