CN1918157B - Stereoisomeric compounds and methods of treating gastrointestinal and central nervous system disorders - Google Patents

Abstract

The present invention relates to stereoisomeric compounds of formula (X): wherein the variables are as defined herein, and are safe and effective for the treatment of a variety of gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux disease, and related conditions combination. The compositions of the present invention are also useful in the treatment of a variety of conditions related to the central nervous system.

Description

Stereoisomeric compounds and methods of treating gastrointestinal and central nervous system disorders

This application claims priority to US Provisional Patent Application No. 60/534,892, filed January 7, 2004, and US Provisional Patent Application No. 60/560,938, filed April 9, 2004.

Background technique

Cisapride (cisapride) belongs to benzamide derivatives, and its parent compound is metoclopramide. U.S. Patent Nos. 4,962,115 and 5,057,525 (inventor "Van Daele", the entire contents of which are incorporated by reference) disclose the N-(3-hydroxy-4-piperidenyl)benzidine of cisapride amides. According to Van Daele, these compounds, their pharmaceutically acceptable acid addition salts, and their stereochemical isomers all stimulate motility of the gastrointestinal system.

As a class of drugs, benzamide derivatives have a variety of significant pharmacological effects. The remarkable pharmacological activity of benzamide derivatives is due to their effects on the nervous system regulated by the neurotransmitter serotonin. The action of serotonin, and thus the pharmacological properties of benzamide derivatives, has been indirectly demonstrated over the years in a wide range of applications under various conditions. Therefore, this study aimed to locate the sites of serotonin production and storage, as well as the location of serotonin receptors in humans, in order to confirm the relationship between these locations and various disease states or conditions.

In this regard, it has been found that the major production and storage sites of serotonin are the enterochromaffin cells of the gastrointestinal mucosa. Serotonin has also been found to strongly stimulate intestinal peristalsis by stimulating intestinal smooth muscle, accelerating intestinal transit, and reducing absorption time, similar to what occurs in diarrheal states. This stimulating effect is also associated with nausea and vomiting.

Due to their ability to modulate the serotonin nervous system in the gastrointestinal tract, many benzamide derivatives are potent antiemetics and are often used to control vomiting during cancer chemotherapy or radiotherapy, especially when using highly emetic compounds such as cisplatin hour. This effect is almost certainly the result of substances called 5HT ₃ receptors (whose canonical designation in the scientific literature is serotonin M-receptor) blocking the action of serotonin (5HT) at a specific site of action. Chemotherapy and radiation therapy may cause nausea and vomiting due to release of serotonin from damaged enterochromaffin cells in the gastrointestinal tract. Release of the neurotransmitter serotonin not only stimulates afferent vagal fibers (ie, initiates the gag reflex), but also stimulates serotonin receptors in the chemoreceptor-evoked area of the brain in the area postrema. Whether benzamide derivatives act on the central nervous system (CNS), peripheral nervous system, or both, the anatomical location of their action is unknown. (Barnes et al., J. Pharm. Pharmacol. 40:586-588, 1988). Like other benzamide derivatives, cisapride may act as an effective antiemetic due to its ability to modulate serotonin activity at _5HT3 receptors.

The second significant effect of benzamide derivatives is to increase the activity of gastrointestinal smooth muscle through the front of the small intestine through the esophagus, thereby promoting the transit of the esophagus and small intestine, promoting gastric emptying, and increasing the tension of the esophageal sphincter (Decktor et al., Eur.J Pharmacol. 147:313-316, 1988). Although benzamide derivatives are not themselves cholinergic receptor agonists, the above-mentioned effects on smooth muscle may be suppressed by muscarinic receptor blockers (such as atropine) or tetrodotoxin-like neurotransmission inhibitors that affect sodium channels. blocked. A similar blocking action of serotonin contractility in the small intestine has been reported. Recently, it was believed that the major smooth muscle effects of benzamide derivatives are the result of agonism on a new class of serotonin receptors, called _5HT4 receptors, located on the interneurons of the myenteric plexus of the intestinal wall. Agonism of these receptors results from the binding of acetylcholine to its receptors on the smooth muscle membrane, which in turn enhances the release of acetylcholine from the parasympathetic terminals of surrounding smooth muscle fibers. The smooth muscle membrane is the real motor of muscle contraction.

A discussion of various 5HT receptors, including the 5HT ₄ receptor, can be found in US Patent Nos. 6,331,401 and 6,632,827, the entire contents of which are hereby incorporated by reference.

Initially, cisapride was used to treat gastroesophageal reflux disease (GERD). The disease is characterized by regurgitation of food from the stomach into the esophagus. One of the most important factors in the pathogenesis of gastroesophageal reflux disease is the reduction of the pressure barrier caused by the failure of the lower esophageal sphincter. Lower esophageal sphincter failure may result from basal depression, sphincter relaxation, or an unbalanced increase in intragastric pressure. Other factors in the pathogenesis of the disease include delayed gastric emptying, insufficient esophageal emptying due to impaired peristalsis, and corrosive reflux substances that may damage the esophageal mucosa. Cisapride is thought to strengthen the anti-reflux barrier and improve esophageal emptying by increasing lower esophageal sphincter pressure and enhancing peristaltic contractions.

Due to its prokinetic effect, cisapride is also used in the treatment of dyspepsia, gastroparesis, constipation, postoperative ileus and intestinal pseudo-obstruction. Dyspepsia is a condition characterized by impaired digestive function or capacity, which may be a symptom of major gastrointestinal dysfunction, or a complication of other diseases such as appendicitis, gallbladder disorders, or malnutrition. Gastroparesis is gastric paralysis caused by abnormal gastric motility or complications of diabetes, progressive sclerosis, anorexia nervosa, or myotonic dystrophy. The condition of constipation is characterized by infrequent or difficult evacuation due to conditions such as intestinal muscle contractility or intestinal spasms. Postoperative ileus is a blockage in the bowel after surgery due to muscle damage. Intestinal pseudo-obstruction is characterized by constipation, colic pain, and vomiting, but there is no evidence of mechanical obstruction.

Drug toxicity is an essential consideration in the treatment of humans and animals. Toxicity (side effects) from taking medicines can range from low-grade fever to death. Drug therapy is justified only when the positive effects of the treatment options outweigh the potential risks of the associated treatments. The physician's balancing considerations include the qualitative effects of the medication used, the quantitative effects, and the corresponding consequences that would result if the medication were not provided to the individual. Other considerations include the patient's medical condition, stage of disease progression, medical history, and any known drug-related side effects.

Drug elimination is usually the result of drug metabolic activity and subsequent drug excretion from the body. Metabolic activity can occur within blood vessels and/or in cellular metabolic areas or organs. The liver is the main site of drug metabolism. Metabolic processes can be divided into synthetic reactions and non-synthetic reactions. In non-synthetic reactions, the drug undergoes chemical changes through oxidation, reduction, hydrolysis, or any combination of the above processes. These processes are collectively referred to as first-stage reactions.

In a second-stage reaction (also known as a synthesis reaction or a conjugation reaction), the parent drug or an intermediate metabolite thereof is combined with an endogenous substrate to form an addition or conjugation product. Metabolites formed during synthetic reactions are usually more polar and biologically inactive. Therefore, these metabolites are more readily excreted via the kidneys (in urine) or liver (in bile). Synthetic reactions include glucuronidation, amino acid conjugation, acetylation, sulfoconjugation and methylation.

More than 90% of the dose of cisapride is metabolized by oxidative N-dealkylation on the piperidine nitrogen or by aromatic hydroxylation on the 4-fluorophenoxy or benzamide ring.

Serious side effects have been found when administered to humans with cisapride, including CNS disturbances, increased systolic blood pressure, interactions with other drugs, diarrhea and abdominal cramps, among others. In addition, intravenous administration of cisapride has been reported to have other side effects not seen with its oral route (Stacher et al. [1987] Digestive Diseases and Sciences 32(11): 1223-1230). These side effects are believed to be caused by metabolites produced by the oxidative dealkylation or hydroxylation of aromatic hydrocarbons of a compound that is produced in the cytochrome P450 detoxification system. Cisapride is also listed in a number of adverse drug/drug interactions as a result of metabolism by the cytochrome P450 system.

From July 1993 to December 1999, cisapride (PROPULSID, Janssen Pharmaceutica Products, L.P.) was reported to be associated with at least 341 cases of severe arrhythmia. These arrhythmias include ventricular tachycardia, ventricular fibrillation, torsades de pointes, and long QT syndrome. A total of 80 deaths have been reported. Because of these side effects, the product was automatically withdrawn from the U.S. open market, and the drug is now only available through the Research Use Restricted Access Program.

5HT ₄ with prokinetic effects due to cardiac side effects (long QT prolongation, tachycardia, torsades de pointes) and adverse drug interactions due to hepatic cytochrome P-450 metabolism Receptor agonists are limited in terms of safety. Such GI prokinetic agents without these susceptibilities would be extremely valuable in several therapeutic areas, including GERD and gastric emptying disorders. Certain cisapride derivatives have been described in US Patent No. 6,552,046 and WO 01/093849 (hereby incorporated by reference in their entirety), however, compounds with better properties are always desirable.

It has now been found that certain stereoisomers of an esterified structural and/or functional analogue of cisapride have unique and particularly advantageous properties.

Contents of the invention

The present invention provides compounds and compositions of structural formula (X), which are stereoisomeric esterified cisapride analogues, which are used to safely and effectively treat various gastrointestinal diseases, including but not limited to, gastroparesis, gastric Esophageal reflux and related conditions. The compounds of the present invention are also useful in the treatment of a variety of conditions related to the central nervous system.

Compounds of the present invention include compounds of structural formula (X) and pharmaceutically acceptable salts thereof:

in,

The chemical bonds at the 3-position and 4-position are cis to each other;

L is -(C ₁ -C ₆ alkyl)-(in one aspect, is -(C ₃ -C ₅ alkyl)-), -(C ₁ -C ₆ alkyl)-C(O)-, or - C(O)-(C ₁ -C ₆ alkyl)-, wherein each alkyl group can be optionally substituted by 1 or 2 groups independently halogen, C ₁ -C ₄ alkoxy or -OH substitution, wherein one carbon atom of the alkyl part of L can be replaced by N(R ₉ );

R ₁ is halogen;

R ₂ is amino, NH(C ₁ -C ₄ alkyl) or N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl);

R ₃ is OH or C ₁ -C ₄ alkoxy;

R ₄ is H or methyl; and

R ₅ is -OC ₃ -C ₈ cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -N(R ₉ )-(C ₀ -C ₆ alkyl )-C)O)-aryl or -N(R ₉ )-C ₀ -C ₆ alkyl-aryl, -O-heteroaryl, -N(R ₉ )-C ₁ -C ₆ (O) -heteroaryl or -N(R ₉ )-C ₀ -C ₆ alkyl-heteroaryl, wherein each cyclic group may be unsubstituted or may be substituted at one or more substitutable positions , where the substituent is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxyl, hydroxyl-C ₁ - C ₄ alkyl, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkyl) -C(O)R ₁₁ , or -OC ₀ -C ₆ alkyl)-C(O)R ₁₁ , methanesulfonyl, C ₀ -C ₆ sulfamoyl or NO ₂ ; where

Each occurrence of R ₉ is independently hydrogen or C ₁ -C ₄ alkyl;

R ₁₁ is C ₁ -C ₆ alkyl, OH, or

R ₁₁ is C ₁ -C ₆ alkoxy, which may be optionally substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ - C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkyl) -C(O)N(R ₉ )-heterocycle Alkyl, -O-heterocycloalkyl, -C ₁ -C ₆ (O)N(R ₉ )-heteroaryl, or heteroaryl, wherein

A heterocycloalkyl group may be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, hydroxy -C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ ;

The heteroaryl group may be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, hydroxy- C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ ;

R ₁₁ is -O-heterocycloalkyl, wherein heterocycloalkyl can be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ ; and

R ₂₀ is C ₁ -C ₆ alkoxy (preferably C ₁ -C ₄ alkoxy, more preferably methoxy), or hydroxyl.

The present invention also relates to compositions comprising at least one compound of formula (X) and at least one pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

The compound of structural formula (X) can be used for treating or preventing gastroesophageal reflux disease, and sufficiently reducing the side effects of taking cisapride. These side effects include, but are not limited to, diarrhea, abdominal cramps, increased blood pressure, and increased heart rate.

In addition, the compounds and compositions of the invention may be used to treat emesis and other conditions including, but not limited to, dyspepsia, gastroparesis, constipation, postoperative ileus and intestinal pseudo-obstruction, and the like. It has the added benefit of reducing the side effects associated with taking cisapride.

Advantageously, the compounds of the invention are ligands for the _5HT4 receptor and, therefore, can be used to treat pathologies mediated through this receptor. These receptors are located in multiple regions of the central nervous system, and modulation of these receptors can be used to achieve modulation of the CNS.

Advantageously, the present invention provides therapeutic benefit by providing stereoisomeric compounds containing ester moieties that do not impair the therapeutic efficacy of these compounds, but render them more susceptible to degradation by plasma and/or cytosolic esterases, thus avoiding the The cytochrome P450 drug detoxification system that causes side effects of cisapride reduces the incidence of such side effects.

The present invention further provides a method for the treatment of gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, postoperative ileus and intestinal pseudo-obstruction and related conditions, which comprises using a therapeutically effective amount of a compound of structural formula (X) in need of such Individual administration of a treatment.

Advantageously, the therapeutic compound of the present invention is stable in storage, and its metabolic mechanism is safer than other drugs; therefore, the compound of the present invention has a lower incidence of side effects and toxicity when used.

In a further aspect, the invention relates to breakdown products (preferably metabolic breakdown products) formed when therapeutic compounds of the invention are subjected to the action of esterases. As described herein, these breakdown products can be used to monitor the clearance of a therapeutic compound from a patient.

In yet a further aspect, the invention provides methods for the synthesis of the therapeutic stereoisomeric compounds of the invention, as well as intermediates useful in the preparation of compounds of interest.

Description of drawings

Figure 1 is a concentration-response curve of 5-HT ₄ receptor agonists ATI-7505, serotonin, cisapride and ATI-7500.

Figure 2 is a graph of gastric emptying in a fed dog. Data shown are normalized to MMC regression values mean transit control time. Values represent mean + standard error of 5 dogs. *p<0.05 vs. transport control

Figure 3 is a metabolic map of ATI-7505 and ATI-7500 in the presence and absence of the CYP450-dependent cofactor NADPH. Graphs show mean and standard deviation of ATI-7505 and ATI-7500 concentrations in μM. ATI-7505 concentrations (2 μM) were incubated with human microsomal protein (1 mg) in the presence or absence of the NADPH regeneration system (cofactor).

Detailed ways

In a further aspect, the present invention relates to compounds of structural formula (X), wherein

R ₅ is -OC ₃ -C ₈ cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, wherein said heterocycloalkyl group is selected from piperidinyl, piperazinyl, pyrrolidinyl, Azabicyclo-octyl, which in certain embodiments is azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azabicyclo-nonyl, nitrogen Heterobicyclo-decyl, indolinyl, morpholinyl, thiomorpholinyl, S, S-dioxothiomorpholinyl, and imidazolidinyl, -O-aryl, -N( R ₉ )-C(O)-aryl, or -N(R ₉ )-C ₀ -C ₆ alkyl-aryl, wherein each cyclic group may be unsubstituted, or may be in one or more Substitutable position is substituted, where the substituent is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, hydroxyl , hydroxy-C ₁ -C ₄ -alkyl, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -C( O)R ₁₁ , or NO ₂ ; where

Each occurrence of _R is independently hydrogen or C ₁ -C ₄ alkyl; and

R ₁₁ is C ₁ -C ₆ alkyl, hydroxyl, or

R ₁₁ is C ₁ -C ₆ alkoxy, which may be optionally substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ - C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -C(O)N(R ₉ )-heterocycloalkyl, heterocycloalkyl, or heterocycloalkyl Aryl, of which

The heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo-octyl, in some embodiments, it is azabicyclo[2.2 .2] octyl, azabicyclo[3.2.1]octyl, azabicyclo-nonyl, azabicyclo-decyl, wherein said heterocycloalkyl group can optionally be replaced by 1 , 2 or 3 substituents, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, hydroxyl-C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ ,

The heteroaryl group is selected from pyridyl, pyrimidinyl, quinolinyl, isoquinolyl, and indolyl, wherein the heteroaryl group can be optionally substituted by 1, 2 or 3 groups, where The substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ or OCF ₃ ; or

R ₁₁ is -O-heterocycloalkyl, wherein heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, azabicyclo-octyl, and in certain embodiments, its Azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azabicyclo-nonyl, azabicyclo-decyl, and tetrahydrofuranyl, wherein each heterocycloalkane The radical group may be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ .

In another aspect, the invention provides compounds of structural formula (X), wherein R ₁ is chloro.

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₂ is amino.

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₃ is methoxy.

In another aspect, the present invention provides compounds of structural formula (X), wherein R ₄ is H or methyl.

In yet another aspect, the present invention provides compounds of formula (X), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H or methyl.

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H, and L is -(C ₄ -C ₆ alkyl) -C(O)-.

In another aspect, the present invention provides a compound of formula (X), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention relates to compounds of formula (XI), which are compounds of formula (X) wherein L is -(CH ₂ ) ₅ -C(O)-:

In yet another aspect, the present invention provides compounds of formula (XI), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H or methyl.

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R is _-O -heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of azabicyclo-octyl,

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R is _-O -heterocycloalkyl, wherein the heterocycloalkyl group is selected from azabicyclo-octyl, and in certain embodiments, It is 1-azabicyclo[2.2.2]oct-3-yl or 8-azabicyclo[3.2.1]oct-3-yl, azabicyclo-nonyl, azabicyclo-decane A group, wherein the nitrogen of the aza can be optionally substituted by methyl or ethyl;

_R4 is H or methyl.

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R is _-O -heterocycloalkyl, wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl, or pyrrolidinyl, which Each may be unsubstituted, or substituted at 1 or 2 positions, where the substituents are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, C ₁ -C ₄ Haloalkyl (in one aspect it is CF ₃ ), C ₁ -C ₄ haloalkoxy (in one aspect it is OCF ₃ ), hydroxy, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl), -(C ₁ -C ₆ alkyl) -C(O)R ₁₁ , or NO ₂ and R ₄ is H or methyl.

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R is _-O -heterocycloalkyl, wherein the heterocycloalkyl group is selected from indolinyl, morpholinyl, thiomorpholine , S, S-dioxothiomorpholinyl and imidazolidinyl, each of which may be unsubstituted or substituted at 1 or 2 positions, where the substituents are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, C ₁ -C ₄ haloalkyl (in one aspect, it is CF ₃ ), C ₁ -C ₄ haloalkoxy (in one aspect, it is OCF ₃ ), hydroxyl, hydroxyl-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl), - (C ₀ -C ₆ alkyl)-C(O)R ₁₁ , or NO ₂ ; and R ₄ is H or methyl.

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R ₅ is -O-phenyl, N(R ₉ )-(C ₀ -C ₆ alkyl)-C(O)-phenyl, or -N(R ₉ )-C ₀ -C ₄ alkyl-phenyl, wherein the phenyl group is substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, halogen, C ₁ -C ₄ haloalkyl (in one aspect, it is CF ₃ ), C ₁ -C ₄ haloalkoxy (in one aspect, it is OCF ₃ ), hydroxy, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl), -(C ₀ -C ₆ alkyl base)-C(O)R ₁₁ , or NO ₂ ; R ₄ and R ₉ are independently H or methyl.

In another aspect, the invention provides compounds of structural formula (XI), wherein _R4H is hydrogen.

In yet another aspect, the present invention provides compounds of structural formula (XI), wherein R ₁₁ is C ₁ -C ₆ alkoxy, which may be optionally substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkyl base)-C(O)N(R ₉ )-, heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl , wherein the heterocycloalkyl group can be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl , hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ or OCF ₃ .

In another aspect, the present invention provides compounds of structural formula (XI), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention provides compounds of formula (XII), i.e., compounds of formula (X) having the formula:

wherein R ₁₅ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl (in one aspect, it is CF ₃ ), C ₁ -C ₆ haloalkane Oxy (in one aspect it is OCF ₃ ), hydroxy, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), methanesulfonyl, C ₀ -C ₆ -sulfamoyl, or NO ₂ , R ₁₆ is H or -O-(C ₀ -C ₆ alkyl) -C(O) R ₁₁ . In another aspect, R ₁₅ is H.

In yet another aspect, the present invention provides compounds of structural formula (XII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is hydroxyl.

In yet another aspect, the present invention provides compounds of structural formula (XII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is C ₁ -C ₆ alkoxy, which may optionally be replaced by 1 or 2 substituents here are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ - C ₆ alkyl), -(C ₀ -C ₆ alkyl)-C(O)N(R ₉ )-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of azabi Cyclooctyl, which in certain embodiments is 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza Bicyclo-nonyl, azabicyclo-decyl, wherein the azanitrogen can be optionally substituted by methyl or ethyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein heterocycloalkyl The group can be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, hydroxyl-C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ , R ₄ and R ₉ are independently H or methyl. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁₅ is hydrogen, R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy.

In another aspect, the present invention provides compounds of structural formula (XII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is C ₁ -C ₆ alkoxy, which may optionally be replaced by 1 or 2 Group substitution, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, and indolyl, wherein the heterocycloalkyl group can be optionally is substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ , R ₄ and R ₉ are independently H or methyl. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁₅ is hydrogen, R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XII), wherein at least one of R ₄ and R ₉ is H.

In another aspect, the present invention provides compounds of structural formula (XII), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention provides compounds of formula (XIII), i.e., compounds of formula (XII) of formula:

wherein R ₁₅ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl (in one aspect, it is CF ₃ ), C ₁ -C ₆ haloalkane Oxy (in one aspect it is OCF ₃ ), hydroxy, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), or methylsulfonyl, C ₀ -C ₆ -sulfamoyl, NO ₂ , R ₁₆ is H or -O-(C ₀ -C ₆ alkyl) -C(O) R ₁₁ . In another aspect, R ₁₅ is H.

In yet another aspect, the present invention provides compounds of structural formula (XIII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is OH, C ₁ -C ₄ alkoxy (on the other hand, it is C ₁ -C ₃ alkoxy), or C ₁ -C ₂ alkoxy-C ₁ -C ₃ alkoxy-. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides a compound of structural formula (XIII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is a substituted C ₁ -C ₄ alkoxy group, where the substituents are amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), aza-bicyclo-octyl, in certain embodiments, its 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, azabicyclo-nonyl, azabicyclo-decane wherein the azanitrogen may be optionally substituted by methyl or ethyl; and _R is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, or -(C ₀ -C ₆ alkane base)-C(O)NH-pyridin-4; in another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides a compound of structural formula (XIII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is amino, -NH(C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) substituted C ₁ -C ₄ alkoxy. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides a compound of structural formula (XIII), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or - (C ₀ -C ₆ alkyl)-C(O)NH-pyridin-4-yl substituted C ₁ -C ₄ alkoxy. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XIII), wherein at least one of R ₄ and R ₉ is H.

In another aspect, the present invention provides compounds of structural formula (XIII), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention provides compounds of formula (XIV), i.e., compounds of formula (X) having the formula:

wherein R ₁₅ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl (in one aspect, it is CF ₃ ), C ₁ -C ₆ haloalkane Oxy (in one aspect it is OCF ₃ ), hydroxy, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), methanesulfonyl, C ₀ -C ₆ -sulfamoyl, or NO ₂ , R ₁₆ is H or -O-(C ₀ -C ₆ alkyl) -C(O) R ₁₁ . In another aspect, R ₁₅ is H.

In yet another aspect, the present invention provides compounds of structural formula (XIV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is OH, C ₁ -C ₄ alkoxy (in another aspect, it is C ₁ -C ₃ alkoxy), or C ₁ -C ₂ alkoxy-C ₁ -C ₃ alkoxy-. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy. In yet another aspect, at least one of _R and _R is H.

In yet another aspect, the present invention provides a compound of structural formula (XIV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is a substituted C ₁ -C ₄ alkoxy group, where the substituents are amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), aza-bicyclo-octyl, in certain embodiments, its 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, azabicyclo-nonyl, azabicyclo-decane wherein the azanitrogen may be optionally substituted by methyl or ethyl; and _R is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, or -(C ₀ -C ₆ alkane base)-C(O)NH-pyridin-4 base. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides a compound of structural formula (XIV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is amino, -NH(C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) substituted C ₁ -C ₄ alkoxy. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides a compound of structural formula (XIV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or - (C ₀ -C ₆ alkyl)-C(O)NH-pyridin-4-yl substituted C ₁ -C ₄ alkoxy. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XIV), wherein at least one of R ₄ and R ₉ is H.

In another aspect, the present invention provides compounds of structural formula (XIV), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention provides compounds of structural formula (XV), i.e., compounds of structural formula (X) having the following structural formula:

where n is 1 or 2.

In yet another aspect, the present invention provides compounds of formula (XV), wherein R ₄ is H or methyl, R ₁₁ is OH, C ₁ -C ₄ alkoxy (in another aspect, it is C ₁ -C ₃ alkoxy group), or C ₁ -C ₂ alkoxy-C ₁ -C ₃ alkoxy-. In another aspect, _R4 and _R11 are as defined above, _R1 is chloro; _R2 is amino; _R3 is methoxy. In yet another aspect, at least one of _R and _R is H.

In yet another aspect, the present invention provides compounds of structural formula (XV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is a substituted C ₁ -C ₄ alkoxy group, where the substituents are amino, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), aza-bicyclo-octyl, in certain embodiments, its 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, azabicyclo-nonyl, azabicyclo-decane wherein the azanitrogen may be optionally substituted by methyl or ethyl; and _R is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -C(O)NH-pyridine -4 bases. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XV), wherein R ₄ and R ₉ are independently H or methyl, and R ₁₁ is amino, -NH(C ₁ -C ₆ alkyl), or -N (C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) substituted C ₁ -C ₄ alkoxy. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XV), wherein R ₄ is independently H or methyl, and R ₁₁ is a substituted C ₁ -C ₄ alkoxy group, where the substituent is aza-bicyclic -octyl, which in certain embodiments is 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza Bicyclo-nonyl, azabicyclo-decyl, wherein the azanitrogen may be optionally substituted by methyl or ethyl; and _R is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(C ₀ -C ₆ alkyl)-C(O)NH-pyridin-4. In another aspect, R ₄ , R ₉ and R ₁₁ are as defined above, R ₁ is chloro; R ₂ is amino; R ₃ is methoxy.

In yet another aspect, the present invention provides compounds of structural formula (XV), wherein two or more of the aforementioned aspects are combined.

In another aspect, the present invention provides compounds according to any one of structural formulas (X), (XI), (XII), (XIII), (XIV) or (XV), wherein R ₁ , R ₂ and R ₃ are on the benzene ring The above position is as follows:

In another aspect, the present invention provides compounds according to any one of structural formulas (X), (XI), (XII), (XIII), (XIV) or (XV), wherein the bond at position 3 is in the "S" configuration , the bond at position 4 is in the "R" configuration.

In yet another aspect, the present invention provides compounds according to any one of structural formulas (X), (XI), (XII), (XIII), (XIV) or (XV), wherein R ₁ , R ₂ and R ₃ are in the benzene The positions on the ring are as follows:

And the bond at position 3 is "S" configuration, and the bond at position 4 is "R" configuration.

In another aspect, the present invention provides compounds according to any one of structural formulas (X), (XI), (XII), (XIII), (XIV) or (XV), wherein the bond at position 3 is in the "R" configuration , the bond at position 4 is in the "S" configuration.

In another aspect, the present invention provides compounds according to any one of structural formulas (X), (XI), (XII), (XIII), (XIV) or (XV), wherein R ₁ , R ₂ and R ₃ are on the benzene ring The above position is as follows:

And the bond at position 3 is in "R" configuration, and the bond at position 4 is in "S" configuration.

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H, and R ₁ , R ₂ and R ₃ are on the benzene ring The above position is as follows:

and

L is -(C ₃ -C ₅ alkyl)-, one of the carbon atoms may be replaced by -N(R ₉ )- or -(C ₂ -C ₆ alkyl)-C(O)-. In yet another aspect, R ₁ , R ₂ and R ₃ are as defined above and their positions on the benzene ring are as described above, R ₄ is as defined above, R ₅ is -O-heterocycloalkyl, wherein The heterocycloalkyl group is selected from aza-bicyclo-octyl, which in certain embodiments is 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo [3.2.1] Oct-3-yl, aza-bicyclonyl, azabicyclo-decyl, wherein the aza-nitrogen can be optionally replaced by methyl or ethyl, piperidinyl, piperazinyl, and Pyrrolidinyl substitution, wherein piperidinyl, piperazinyl and pyrrolidinyl can be unsubstituted, or can be substituted at 1 or 2 positions, where the substituents are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy _, halogen, C ₁ -C 4 haloalkyl, C ₁ -C ₄ haloalkoxy, hydroxyl, hydroxy-C ₁ -C ₄ alkyl, amino, -NH(C ₁ -C ₄ Alkyl), -N(C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), -(C ₀ -C ₆ alkyl) -C(O)R ₁₁ or NO ₂ , where

R ₁₁ is C ₁ -C ₆ alkoxy, which may be optionally substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ - C ₆ alkyl), -N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), -C(O)N(R ₉ )-heterocycloalkyl, or heterocycloalkyl, wherein The heterocycloalkyl group is selected from azabicyclo-octyl, in some embodiments, it is 1-azabicyclo[2.2.2]oct-3-yl, 8-azabicyclo Cyclo[3.2.1]oct-3-yl, azabicyclo-nonyl, azabicyclo-decyl, wherein the azanitrogen may be optionally substituted by methyl or ethyl; and _R is H or methyl Base, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl; wherein the heterocycloalkyl group can be optionally substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ .

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H, and R ₁ , R ₂ and R ₃ are on the benzene ring The above position is as follows:

并且

and

L is -(C ₃ -C ₅ alkyl)-, one of the carbon atoms may be replaced by -N(R ₉ )- or -(C ₂ -C ₆ alkyl)-C(O)-. In yet another aspect, R ₁ , R ₂ and R ₃ are as defined above and their positions on the benzene ring are as described above, R ₄ is as defined above and R ₅ is heterocycloalkyl selected from nitrogen Hetero-bicyclo-octyl, which in certain embodiments is 1-azabicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3- radical, aza-bicyclononyl, azabicyclo-decyl, wherein the azanitrogen may be optionally substituted by methyl or ethyl.

In yet another aspect, the present invention provides compounds of structural formula (X), wherein R ₁ is chlorine; R ₂ is amino; R ₃ is methoxy; R ₄ is H, and R ₁ , R ₂ and R ₃ are on the benzene ring The above position is as follows:

并且

and

L is -(C ₃ -C ₅ alkyl)-, one of the carbon atoms may be replaced by -N(R ₉ )- or -(C ₂ -C ₆ alkyl)-C(O)-. In yet another aspect, R ₁ , R ₂ and R ₃ are as defined above, and their positions on the benzene ring are as described above, R ₄ is as defined above, and R ₅ is -N(R ₉ )-C ₀ -C ₄ alkyl-aryl or -N(R ₉ )-(C ₀ -C ₆ alkyl)-C(O)-aryl, where the aryl group can be unsubstituted, or can be in 1 or multiple substitutable positions, where the substituents are C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy , Hydroxy, Hydroxyalkyl, Amino, -NH(C ₁ -C ₆ Alkyl), -N(C ₁ -C ₆ Alkyl)(C ₁ -C ₆ Alkyl), -(C ₀ -C ₆ Alkyl group)—C(O)R ₁₁ , or NO ₂ . In yet another aspect, the aryl group is phenyl substituted by -(C ₀ -C ₆ alkyl)-C(O)R ₁₁ , which may also be optionally substituted by 1 or 2 groups, where The substituents of are independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, CF ₃ , OCF ₃ , hydroxyl, hydroxyalkyl, amino, -NH(C ₁ -C ₄ alkyl ), -N(C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), or NO ₂ , wherein

R ₁₁ is C ₁ -C ₆ alkoxy, which may be optionally substituted by 1 or 2 groups, where the substituents are independently C ₁ -C ₄ alkoxy, amino, -NH(C ₁ - C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -(C ₀ -C ₆ alkyl) -C(O)N(R ₉ )-heterocycle Alkyl, or heterocycloalkyl, wherein said heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein said heterocycloalkyl group can optionally is substituted by 1, 2 or 3 groups, where the substituents are independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, hydroxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, -CO ₂ H, CF ₃ , or OCF ₃ . In a preferred aspect, the -(C ₀ -C ₆ alkyl)-C(O)R ₁₁ group is attached at the 4-position of the benzene ring.

In yet another aspect, the directions of the keys on the 3rd and 4th digits are as follows:

In a preferred aspect, the orientation of the bonds on positions 3 and 4 is as follows:

The present invention further provides a method for treating vomiting, dyspepsia, gastroparesis, constipation, intestinal pseudo-obstruction, gastroesophageal reflux disease or postoperative ileus, the method comprising using a therapeutically effective amount of a compound of structural formula (X) or a salt thereof Administer to patients in need of such treatment.

The present invention provides compounds that are more easily degraded by plasma and/or cytoplasmic esterases than cisapride, thereby avoiding side effects associated with cytochrome P450 metabolism.

Advantageously, the therapeutic compounds of the invention are stable in storage, but have a relatively short half-life in physiological environments; thus, the compounds of the invention have a low incidence of side effects and toxicity when administered.

In a preferred aspect of the invention there are provided therapeutic stereoisomeric compounds useful in the treatment of gastroesophageal reflux disease which contain ester groups which are readily degraded by esterases thereby breaking down the compound and facilitating its efficient elimination from the individual being treated. In preferred aspects, therapeutic stereoisomeric compounds are metabolized by first-stage drug detoxification systems.

In a further aspect, the invention relates to the breakdown products (preferably metabolic breakdown products, ie, metabolites, typically acids of the parent ester) formed when the therapeutic compounds of the invention are subjected to the action of esterases. The presence of these breakdown products in urine or plasma can be used to monitor the elimination of the therapeutic compound from the patient.

Degradation of compounds of the invention by esterases is particularly advantageous for drug metabolism because esterases are ubiquitous and their activity does not depend on age, sex or disease state to the same extent as oxidative hepatic drug metabolism.

The invention further provides a method of treating a disease such as gastroesophageal reflux disease comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one stereoisomeric and/or functional analogue of cisapride. In particular aspects, the present invention provides stereoisomeric structural and/or functional analogs of cisapride and pharmaceutical compositions of these esterified compounds.

The present invention further provides materials and methods for treating emesis and other disorders including but not limited to dyspepsia, gastroparesis, constipation and intestinal pseudo-obstruction with substantially reduced side effects associated with the administration of cisapride.

In a preferred aspect of the present invention, there is provided a stereoisomeric compound useful for the treatment of gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, postoperative ileus and intestinal pseudo-obstruction, said compound containing An ester group that breaks down the compound and facilitates its efficient elimination from the individual being treated.

The present invention further provides methods for the synthesis of the unique and advantageous compounds of the present invention. In particular, methods for the production and purification of such stereoisomeric compounds are taught. Methods for introducing ester moieties and for making and purifying stereoisomers are well known to those skilled in the art and can be readily performed by those skilled in the art using the guidance provided herein.

preferred compound

In a preferred aspect, the present invention provides isolated stereoisomers of Compound I having 3 chiral centers.

6-[4-(4-Amino-5-chloro-2-methoxy-benzamido)-3-methoxy-piperidin-1-yl]-hexanoic acid-1-aminoheterobicyclo[ 2.2.2] Oct-3-yl ester

Compound I

There are two chiral centers in cisapride and norcisapride (norcisapride), which are in the cis configuration in the active drug.

(±)-cisapride (±)-norcisapride

Thus, for example, the pharmaceutically active norcisapride is a racemic mixture of two cis enantiomers.

(-)-Norcisapride (+)-Norcisapride

In one aspect, the invention particularly relates to configurations at the third chiral center of the quinine alcohol moiety. Elimination of this group converts to the acid metabolite (referred to herein as ± compound II).

Compound II

The preferred stereoisomers of compound I according to the invention are prepared by combining quinine alcohol in the R or S configuration with (+)- or (-)-norcisapride to give structures III, IV, V and VI compound of.

(3R, 4S, 3'R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]- Hexanoic acid-1-azabicyclo[2.2.2]oct-3-yl ester

Compound III: (-)(R)-Compound I

(3S, 4R, 3'R)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]- Hexanoic acid-1-azabicyclo[2.2.2]oct-3-yl ester

Compound IV: (+)(R)-Compound I

(3R,4S,3'S)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid -1-Azabicyclo[2.2.2]oct-3-yl ester

Compound V: (-)(S)-Compound I

(3S,4R,3'S)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid -1-Azabicyclo[2.2.2]oct-3-yl ester

Compound VI: (+)(S)-Compound I

In preferred aspects, the invention relates to stereoisomerically separated compounds, and compositions comprising the same. Isolated stereoisomeric forms of compounds of the invention are substantially free of one another (ie, in stereoisomeric excess). In other words, compounds of the "R" configuration contain almost no compounds of the "S" configuration, and therefore, are in stereomeric excess to the "S" configuration. In contrast, compounds of the "S" configuration contain almost no compounds of the "R" configuration and, therefore, are in stereomeric excess to the "R" configuration. In one aspect of the invention, the isolated stereoisomeric compound has a stereoisomeric excess of at least about 80%. In preferred aspects, the compounds have a stereoisomeric excess of at least about 90%. In a more preferred aspect, the compounds have a stereoisomeric excess of at least about 95%. In a further preferred aspect, the compounds have a stereoisomeric excess of at least about 97.5%. In the most preferred aspect, the compounds have a stereoisomeric excess of at least about 99%. Similarly, the "(+)" and "(-)" forms of the compounds also have stereoisomeric excess.

As described herein, the different stereoisomers possess specific, unexpected properties that may be advantageously used in treatments tailored to specific conditions. Thus, for example, compounds containing the (3'R)-isomer in the quinuclidinyl ester moiety (i.e., compounds III and IV) are rapidly metabolized by esterases in human plasma; The isomeric compounds (ie compounds V and VI) are metabolized much more slowly.

Thus, the (3'R)-isomer of compound I can be used when rapid onset of action is preferred, such as pulse therapy in patients with acute gastroparesis or acute gastroesophageal reflux disease. Another advantage of rapid esterase metabolism to a much less active metabolite (ie compound II) is that it has a very low potential for drug-drug interactions and toxicity. Therefore, these short-acting (R)-isomers could be advantageously used as intravenous formulations for the treatment of gastroesophageal reflux disease in premature neonates, who cannot metabolize the drug like adults because their CYP450 system is not fully developed. Drugs that are rapidly metabolized by systems other than CYP450, such as the esterase system, are of great advantage in neonates. On the other hand, the (3'S)-isomer of compound I is most suitable for the treatment of chronic symptoms of the same disease, for example, gastroparesis in stable diabetic patients or cancer patients, or chronic paralysis in patients requiring drug effects lasting for 24 hours. Gastroesophageal reflux disease.

In addition to their differences in metabolic rate, these single isomers have different 5- _HT4 receptor binding abilities and thus also exhibit different activities and thus have different therapeutic uses. Therefore, in the order of decreasing 5- _HT receptor binding ability, the isomers can be classified as follows (the binding constant Ki value is in brackets): Compound IV (1.4nM), Compound VI (3.4nM), Compound III (28nM) , and compound V (72 nM). These binding experiments were performed using radioisotope labeling methods described in standard textbooks and can be readily repeated by those skilled in the art of molecular biology.

Conclusions based on these considerations: When the 3 and 4 positions are in cis to each other, compound I is a mixture of 4 isomers consisting of two pairs of enantiomers. The first pair of enantiomers is (+)(R)-compound I and (-)(S)-compound I (compounds IV and V respectively), the second pair of enantiomers is (-)( R)-compound I and (+)(S)-compound I (compound III and VI respectively). Within each pair of enantiomers, each single enantiomer differs in its properties in terms of rates of esterase hydrolysis and 5- _HT receptor binding. These different properties give them the advantageous therapeutic use that each is not interchangeable, ie it is specific for each isomer and it does not apply to racemic mixtures. These differences in receptor binding and these differences in metabolic rates are unpredictable and impossible to dissect these properties when testing racemic mixtures.

definition

As used herein, the term "alkyl" includes those alkyl groups having the specified number of carbon atoms. Alkyl groups can be straight chain, or branched. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl and analog. If the number of carbon atoms is not specified, the "alkyl" moiety has 1 to 6 carbon atoms.

The term "alkoxy" represents an alkyl group of the indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy include, for example, methoxy, ethoxy, propoxy, isopropoxy.

"Aryl" refers to an aromatic carbocyclic group having a single ring (eg, a benzene ring), which may be optionally fused or linked to other aromatic or non-aromatic rings. "Aryl" includes multiple fused rings (at least one of which is aromatic, such as 1,2,3,4-tetrahydronaphthyl, naphthyl, and wherein each ring can optionally be replaced by a radical as described below monosubstituted, disubstituted or trisubstituted) and unfused polycyclic rings such as biphenyl or binaphthyl. The preferred aryl of the present invention is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, or 6 , 7,8,9-Tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are phenyl, biphenyl and naphthyl. Phenyl is most preferred. Aryl groups herein may be unsubstituted or, as specifically indicated, substituted in one or more substitutable positions with various groups. For example, these aryl groups may be optionally substituted with, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, nitrile, nitro, amino, mono( C ₁ -C ₆ )alkylamino, di(C ₁ -C ₆ )alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino-(C ₁ -C ₆ )alkyl, mono(C ₁ -C ₆ )alkylamino-(C ₁ -C ₆ )alkyl or di(C ₁ -C ₆ )alkylamino -(C ₁ -C ₆ )alkyl.

The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen atom, and optionally further substituted with at least one other halogen atom, wherein each halogen atom is independently F, Cl, Br or I. Preferred halogens are F or Cl. Preferred haloalkoxy groups contain 1-6 carbon atoms, more preferably 1-4 carbon atoms, most preferably 1-2 carbon atoms. "Haloalkoxy" includes perhaloalkoxy groups such as OCF ₃ or OCF ₂ CF ₃ .

The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur. A heteroaryl ring can be fused or attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoindolyl, Quinolinyl, quinazolinyl, quinoxalinyl, naphthyridine, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizyl, indazolyl, benzo Thiazolyl, benzimidazolyl, benzofuryl, furyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl , isothiazolyl, 1,5-naphthyridine, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isochromanyl tetrahydrofuran Base, isobenzothienyl, isobenzothienyl, benzoxazinyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahydrothiophenyl, purinyl, benzodioxol Alkenyl, triazinyl, pteridyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, dihydrobenzoisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydro Benzoisothiazinyl, benzopyranyl, benzothiopyranyl, chromone, chroman-4-one, pyridyl N-oxide, tetrahydroquinolyl, Dihydroquinolinyl, dihydroquinolinonyl (dihydroquinolinonyl), dihydroisoquinolinonyl (dihydroisoquinolinonyl), dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinone, benzo Dioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl-N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl -N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl N-oxide, quinoxalinyl N -oxide, naphthyridine N-oxide, imidazolyl N-oxide, isoxazolyl-N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizyl N-oxide, indazolyl-N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazole Azolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, indolyl, pyrrolyl, furyl, thienyl, and imidazolyl. More preferred heteroaryl groups include pyridyl, pyrrolyl and indolyl. A heteroaryl group herein may be unsubstituted or, as specifically indicated, substituted in one or more substitutable positions with various groups. For example, these heteroaryl groups may be optionally substituted with, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, nitrile, nitro, amino, mono (C ₁ -C ₆ )alkylamino, di(C ₁ -C ₆ )alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ haloalkoxy, amino-(C ₁ -C ₆ )alkyl, mono(C ₁ -C ₆ )alkylamino-(C ₁ -C ₆ )alkyl or di(C ₁ -C ₆ )alkyl Amino-(C ₁ -C ₆ )alkyl.

The term "heterocycloalkyl" refers to a ring or ring system containing a heteroatom preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is located in a non-aromatic ring. Heterocycloalkyl rings may optionally be fused or attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/or benzene rings. Preferred heterocycloalkyl groups are 3 to 7 membered rings. More preferred heterocycloalkyl groups are 5 to 6 membered rings. Examples of heterocycloalkyl groups include, for example, aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, Morpholinyl S-oxide, thiomorpholinyl S, S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl , tetrahydrothiophenyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S, S-dioxide, oxazolidinone, dihydropyrazolyl, di Hydrogen pyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothiophenyl S-oxide, tetrahydrothiophenyl S, S-dioxide compounds and higher thiomorpholino S-oxides. Preferred heterocycloalkyl groups include aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, thiomorpho Linyl, S, S-dioxothiomorpholinyl, morpholinyl and imidazolidinyl. More preferred heterocycloalkyl groups include aza-bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidine base and morpholinyl. A heterocycloalkyl group herein can be unsubstituted or, as specifically indicated, substituted at one or more substitutable positions with various groups. For example, these heterocyclic groups may be optionally substituted with, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, nitrile, nitro, amino, mono( C ₁ -C ₆ )alkylamino, di(C ₁ -C ₆ )alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino-(C ₁ -C ₆ )alkyl, mono(C ₁ -C ₆ )alkylamino-(C ₁ -C ₆ )alkyl or di(C ₁ -C ₆ )alkylamino -(C ₁ -C ₆ )alkyl, or =O.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids and bases and organic acids and bases. Since the compounds of the present invention are basic, salts can be prepared from pharmaceutically acceptable, non-toxic acids. Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention include acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, gluconic acid, glutamine acid, hydrobromic acid, hydrochloric acid, isethanoic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, Tartaric acid, p-toluenesulfonic acid and similar. Preferred acid addition salts are chlorides and sulfates. In the most preferred aspect, the structural and/or functional analogue of cisapride is administered as the free base or as the monohydrochloride or dihydrochloride salt.

As used herein, the terms "treatment" and "treating" include prophylactic administration ("prophylaxis") of a compound or a pharmaceutical composition comprising the compound as well as salvage treatment to alleviate or eliminate a disease or disorder referred to herein. Prophylactic administration is intended to prevent a disease and it can be used to treat a subject at risk of having or having one or more of the diseases mentioned herein. Therefore, as used herein, the term "treatment" or its derivatives means that when the active ingredients of the present invention are administered prophylactically, or after the onset of the disease state in which these active ingredients are administered, partially or completely Inhibiting said disease state. "Prophylaxis"means the administration of an active ingredient to a mammal to protect the mammal from any of the diseases described herein, as well as other diseases.

The term "therapeutically effective dose" refers to the amount necessary to obtain the desired therapeutic effect, for example: 1) an amount sufficient to alleviate reflux disease; 2) an amount sufficient to alleviate nausea and vomiting; 3) an amount sufficient to alleviate diseases caused by gastric motility dysfunction quantity. The dosage and frequency tables above include therapeutically effective amounts of structural and/or functional analogs of cisapride.

A "mammal" can be, for example, a mouse, rat, pig, horse, rabbit, sheep, cow, cat, dog or human. In preferred aspects, the mammal is a human.

The term "individual" refers to a single mammal administered a compound of the invention. A "mammal" can be, for example, a mouse, rat, pig, horse, rabbit, sheep, cow, cat, dog or human. In preferred aspects, the mammal is a human.

The term "esterified cisapride" refers to therapeutic compounds of the invention that are structural and/or functional analogs of cisapride that contain hydrolyzable groups (typically esters) that do not reduce the therapeutic benefit provided by these compounds ability, but makes these compounds easier to be degraded by esterases (especially plasma and/or cytoplasmic esterases), thereby reducing the interaction of cisapride compounds with the cytochrome P450 drug detoxification system. The esterase-mediated metabolism of the esterified cisapride compound reduces the effect of the cytochrome P450 drug detoxification system in the metabolism of cisapride, and reduces or eliminates the side effects caused by cisapride.

As used herein, the term "structural analog" means that the described compound has the same structural features as the parent compound. For example, structural analogs of cisapride may share one or more structural features with the parent compound of cisapride (for example, substituted aromatic rings connected to the piperidine ring through an amide linker), but also differ in structure, such as , including or missing one or more chemical moieties.

As used herein, the term "functional analog" means that the compound in question has the same functional properties as the parent compound. For example, a functional analog of cisapride may share few, if any, structural features in common with cisapride, but perform a similar function, eg, a 5- _HT4 agonist.

The term "side effect" includes, but is not limited to, gastrointestinal disturbances such as diarrhea, abdominal cramps, and borborygmi; fatigue; headache; increased systolic blood pressure; death; ventricular tachycardia; ventricular fibrillation; torsades de pointes Ventricular tachycardia and long QT syndrome; increased heart rate; neurological and CNS disturbances; and interactions of cisapride with concomitant use of other drugs such as, but not limited to, digoxin, diazepam, alcohol , acenocoumarol, cimetidine, ranitidine, acetaminophen, and propranolol.

As used herein, the term "gastroesophageal reflux disease" refers to the onset and symptoms of those conditions that cause food in the stomach to back up into the esophagus.

As used herein, the terms "inducing an antiemetic effect" and "antiemetic treatment" refer to the alleviation or prevention of the symptoms of nausea and vomiting caused by or associated with emetic chemotherapy or radiotherapy for cancer.

As used herein, the term "treating diseases caused by gastric motility dysfunction" refers to the treatment of symptoms and conditions associated with gastric motility dysfunction, including but not limited to gastroesophageal reflux disease, dyspepsia, gastroparesis, constipation, postoperative bowel Obstruction and intestinal pseudo-obstruction.

As used herein, the term "prokinetic" means to enhance motility of the gastrointestinal tract, thereby enhancing movement through the gastrointestinal tract.

The term "dyspepsia" is used to refer to impairment of digestive capacity or function, which may result in major gastrointestinal dysfunction, or as a complication of or resulting from other disorders such as appendicitis, gallbladder disease, or malnutrition.

The term "gastroparesis" is used to refer to gastric paralysis caused by abnormal motility of the stomach, or as a complication of a disease such as diabetes, progressive sclerosis, anorexia, or myotonic dystrophy.

The term "constipation" is used to refer to a condition of poor or difficult excretion resulting from a condition such as intestinal muscle contractility or intestinal spasm.

The term "post-operative ileus" as used herein refers to a blockage in the bowel due to decreased muscle tone following surgical procedures.

As used herein, the term "bowel pseudo-obstruction" refers to a condition characterized by constipation, colic, and vomiting, but no evidence of mechanical obstruction.

Compound Preparation

The chemical synthesis of various cisapride analogues can be carried out according to the methods described in the following documents, modified by introducing ester groups at positions convenient for the synthesis of the disclosed compounds: European Patent Published April 13, 1983 Application No. 0,076,530 A2, U.S. Patent Nos. 4,962,115 and 5,057,525, and Daele et al., Drug Development Res. 8:225-232 (1986), the entire contents of which are incorporated herein by reference. Exemplary, non-limiting synthetic schemes for certain esterified cisapride analogs of the invention are described in WO 01/093849.

The present invention is further illustrated by the following examples, which are not intended to limit the scope or spirit of the invention to the specific methods described in these examples. Those skilled in the art will recognize that starting materials may be varied and additional steps may be employed to prepare compounds encompassed by the invention, as described in the following Examples. Those skilled in the art will also recognize that it may be necessary to use different solvents or reagents to achieve the above transformations. In some cases, it may be necessary to protect reactive functional groups to achieve the above transformations. In general, the need for such protecting groups, and the conditions necessary for attachment and removal of such protecting groups, will be apparent to those skilled in the art of organic synthesis. When protecting groups are used, a deprotection step may be required. Suitable protecting groups and methods of protection and deprotection, such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known in the art and highly regarded in the art.

Unless otherwise noted, all reagents and solvents were of standard commercial grade and used without further purification. Suitable atmospheres for carrying out the reaction, such as air, nitrogen, hydrogen, argon, and the like, will be apparent to those skilled in the art.

Example 1

Preparation of 6-[4R-(4-amino-5-chloro-2-methoxy-benzoylamino)-3S-methoxy-piperidin-1-yl]-hexanoic acid-1-azabicyclo [2.2.2] Oct-3'R-yl ester dihydrochloride (ATI-7505 dihydrochloride)

Step 1: Resolution of racemic norcisapride

Dissolve (-)-dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) in ethanol, and filter to remove insoluble particles. Separately, racemic cisapride (about 0.8 parts by weight) was dissolved in a mixture of ethanol and water, followed by filtration. The filtrate was heated to about 75°C, and then the (-)-DBT solution was added. Stirring at this temperature for about 30 minutes, the mixture was slowly cooled to 5°C over several hours and the product salt was collected by vacuum filtration and washed with an ethanol/water mixture. The wet cake was recrystallized with ethanol/water by heating to about 79°C, cooling to about 5°C (as above). The product was collected by vacuum filtration and washed with an ethanol/water mixture to give the product as a wet cake.

The wet cake product was suspended in water and the pH was adjusted to about 12 with 7% (W/W) aqueous NaOH. The resulting suspension was stirred at room temperature for about 3 hours, then vacuum filtered and the solid material washed with water and dried in vacuo. The product is then retreated with (-)-DBT in the same manner as described above to form the salt. The isolated salt was then neutralized with aqueous NaOH as described above. The product was isolated by filtration and dried to give (+)-norcisapride base (about 0.25 parts by weight). The e.e. value was about 100% (+)-norcisapride by chiral HPLC analysis. The optical rotation was about +5° (methanol; 25° C., 589 nm), confirming norcisapride as the dextro isomer.

Step 2: Coupling with ethyl 6-bromohexanoate

(+)-Norcisapride (about 1 part by weight), potassium carbonate (about 0.48 parts by weight) and potassium iodide (about 0.063 parts by weight) were suspended in anhydrous USP ethanol. To this suspension was slowly added ethyl 6-bromohexanoate (about 0.76 parts by weight) at room temperature. The mixture was heated to reflux until the reaction was complete. After cooling to room temperature, the reaction mixture was filtered to remove inorganic solids and the like, and the filtrate was concentrated under reduced pressure to half its original volume. The crude product was slowly added to cold water (about 13 parts by weight) with rapid stirring, and the product precipitated out. The precipitate was vacuum filtered, washed with water, then dissolved in absolute ethanol, slowly added to cold water and reprecipitated twice as described above. The resulting wet cake was washed with n-heptane, resuspended in ethyl acetate/n-heptane (1:9; v/v), stirred for about 1 hour, filtered, and vacuum-dried to obtain 0.73 parts by weight of white Solid coupling product.

Step 3: Coupling with (R)-3-hydroxyninol and formation of dihydrochloride

Suspend the ester (1 part by weight) and (R)-3-hydroxyninol (about 1.12 parts by weight) in toluene, then slowly add titanium(IV) ethoxide (about 0.5 parts by weight). The mixture was heated to about 91°C under nitrogen flow and the flask was partially evacuated through a distillation apparatus to form an azeotrope to remove ethanol. Additional toluene was added if necessary to maintain a minimum solvent volume in the flask. The reaction was considered complete after about 33 hours.

The mixture was cooled to room temperature and extracted 5 times with water. The organic layer was concentrated under reduced pressure, and the resulting residue was redissolved in EtOH/iPrOH (approximately 1:1 v/v), then filtered through a 0.45 micron filter to remove any particulates. Concentrated hydrochloric acid was slowly added to the filtrate with stirring, and the desired product was precipitated as the dihydrochloride salt. The resulting suspension was stirred at room temperature for several hours, collected by vacuum filtration and rinsed with EtOH/iPrOH (1:1; v/v) to yield 0.53 parts by weight of the crude product salt.

The crude dihydrochloride was resuspended in ethanol, heated to reflux for more than 1 hour, and then cooled to room temperature. The product was collected by vacuum filtration, rinsed with ethanol, and air dried. The solid was resuspended in ethanol and heated to about 55°C to obtain a clear solution, then warm isopropanol was added and the mixture was allowed to cool slowly to room temperature and the product precipitated out. The resulting suspension is stirred for several hours, then vacuum filtered, washing with e.g. isopropanol. The product was dried under vacuum, first at room temperature for several hours, then at about 55°C to constant weight.

Example 2

Preparation of (R)-quinuclidin-3-ol-6-((3S,4R)-4-(4-amino-2-chloro-6-methoxybenzamide)-3-methoxypiperidine -1-yl)hexanoate

Step 1: Synthesis of ethyl 4-(dibenzylamino)-3-methoxypiperidine-1-carboxylate (1):

To a DMF solution of racemic ethyl 4-amino-3-methoxypiperidine-1-carboxylate (1 molar part), benzyl bromide (about 2.2 molar parts), potassium carbonate (about ) and potassium iodide (about 0.2 molar parts). The reaction solution was heated to 80°C. After 6 hours, slowly add water to dilute the reaction solution (about 12 parts by volume), and extract with, for example, ethyl acetate. The organic layer was washed with brine, then dried over _{anhydrous Na2SO4} . Then it was filtered and the solvent was concentrated to obtain orange-yellow oil 1 (1 mole part).

Step 2: Synthesis of N,N-dibenzyl-3-methoxypiperidin-4-amine (2):

To the solution of 1 was added NaOH (about 10 mole parts) in isopropanol, the mixture was stirred, and it was heated to reflux. After about 3 hours to about 5 hours, the reaction solution was cooled to room temperature, and the alcohol solvent was removed by rotary evaporation. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . Then filtration and concentration of the solvent gave a crude oil which was purified with _SiO2 ( _{CH2Cl2 :} MeOH: _NH4OH ; (approx.) 15:1:0.01) to give 2.

Step 3. Synthesis of (3S,4R)-N,N-dibenzyl-3-methoxypiperidin-4-amine (3):

Dissolve (-)-dibenzoyl-L-tartaric acid (about 1.2 parts by weight) in ethanol, and then slowly add the solution of 2 (about 1 part by weight). The solution was gradually heated and then cooled to room temperature, causing the salt product to crystallize. The salt product was filtered and washed with EtOH/ _H2O , then suspended in water and basified by adding aqueous NaOH (7%, wt/wt) to adjust the pH to 12. The suspension was vigorously stirred at room temperature, and the solid was separated by filtration, washed with water, and dried in vacuo to obtain cis-isomer 3.

Step 4. Synthesis of ethyl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidin-1-yl)hexanoate (4):

To a solution of 3 (1 molar part) in DMF was added ethyl bromohexanoate (about 1.2 molar parts), potassium carbonate (about 1.4 molar parts) and potassium iodide (about 0.2 molar parts). The reaction solution was then heated to 80°C. After 8 hours, slowly add water to dilute the reaction solution (about 12 parts by volume), and extract with ethyl acetate. The organic layer was washed with brine, then dried over _{anhydrous Na2SO4} . It was then filtered and the solvent was concentrated to give the crude product. This was purified on _SiO2 to give the alkylated product 4.

Step 5. Synthesis of (R)-quinuclidin-3-ol-6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidin-1-yl)hexanoate ( 5):

To a mixture of 4 (1 molar part) and (R)-(-)-3-quinine alcohol (1 molar part) in toluene was added tetraethoxytitanium. The reaction mixture was charged to a dean-stark apparatus and then heated to 90°C with partial vacuum (adding more toluene if necessary to maintain necessary solvent levels). The mixture was cooled to room temperature, the reaction solution was diluted with ethyl acetate, and water was added to the resulting mixture. The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. After SiO _purification , enantiomerically enriched 5 was obtained.

Step 6. Synthesis of (R)-quinuclidin-3-ol-6-((3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate (6):

A solution of 5 (1 molar part) in ethanol was added to a reaction flask containing palladium on carbon (ca. 0.2 molar part). The mixture was evacuated of air, and the mixture was subjected to hydrogenolysis conditions using a _H2 atmosphere. After the reaction was complete, the palladium was filtered off through a pad of celite and washed with ethanol. The filtrate was concentrated by rotary evaporation to afford 6.

Step 7. Synthesis of (R)-quinuclidin-3-ol-6-((3S,4R)-4-(4-amino-2-chloro-6-methoxybenzamide)-3-methoxy (Piperidin-1-yl)-hexanoate (7):

To a THF solution such as ethyl chloroformate (1 molar part) was added portionwise at 0°C with benzoic acid (1 molar part). The mixture was warmed to room temperature for 1 h, then cooled to 0 °C and a solution of 6 (1 molar part) was added dropwise. The reaction solution was then warmed to room temperature. Upon completion, the reaction was quenched by adding saturated aqueous NaHCO ₃ and extracted with EA. The organic layer was _washed with brine and dried over anhydrous _Na2SO4 , filtered and concentrated to give the desired product 7.

Example 3

Another optional ATI-7505 synthesis method:

Under acidic conditions, 1-benzylpiperidin-4-one (1) and hydrobromic acid are reacted in the presence of acetic acid to produce N-benzyl-3-bromopiperidin-4-one (2). Treatment of 2 with sodium methoxide and methanol solution affords 1-benzyl-4,4-dimethoxypiperidin-3-one (3). (The presence of the β-amino group makes the Favorskii reaction impossible.) Methylation of the hydroxyl group with a hydride base affords compound 4 by treatment with methyl iodide in the presence of the solvent DMF.

Subsequent acetal hydrolysis with 1% sulfuric acid under heated conditions gave piperidine 5, which was then reductively aminated in methanol using e.g. sodium cyanoborohydride and ammonium acetate to give 1-benzyl-3 -Methoxypiperidin-4-amine (6). At this stage, chiral resolution techniques can be used on 6. This can be carried out, for example, using (-)-DBT or other variants of tartaric acid in the presence of a suitable solvent to give compound 7 specifically asymmetrically pure. The primary amine in 7 can be Boc group protected using Boc anhydride in the presence of THF solvent to afford 8. The debenzylation reaction was achieved by hydrogenolysis using Pd/C in methanol under an atmosphere of hydrogen at atmospheric pressure, providing a platform for the alkylation step. Treatment with 6-bromocapronitrile in the presence of weak base and DMF affords compound 10. Conversion of the nitrile to the ester using (R)-quinine alcohol under dilute acid conditions afforded 11. Subsequent removal of the Boc group with TFA yields the free amine, which can be coupled with the requisite benzoic acid in the presence of a coupling reagent such as ethyl chloroformate to yield the enantiomerically pure material ATI- 7505.

Alternatively, compound 9 can be alkylated with ethyl 6-bromohexanoate in the presence of a weak base. Subsequent removal of the Boc group yields compound 13. Titanium-catalyzed transesterification of 13 using (R)-quinine alcohol and titanium tetraethoxide in toluene solvent yielded ATI-7505. Carlsburg esterase hydrolyzes the S-configured ester, leaving the unreacted R-configured ester. Thus, treatment of the diastereomeric mixture of 14 with Carlsburg esterase also yielded ATI-7505.

Example 4

As described in U.S. Patent No. 6,147,093, or J. Jacques, A. Collet and S.H. Wilen (Wiley InterScience, New York, NY) "Enantiomers, Racemates and Resolutions", or S.H. Wilen et al., Tetrahedron (1977) 33:2725 According to the method, (+) and (-)-norcisapride can be prepared from the racemic mixture of norcisapride using conventional means such as optical resolution acid to resolve the enantiomers.

Collection by preparative column chromatography followed by evaporation of the solvent afforded the four isomers in milligram quantities. This method can be used to prepare small quantities of samples for analysis and characterization. This is a standard separation method routinely employed by analytical laboratories to isolate and characterize metabolites.

A possible route for the synthesis of compound IV, compound VI and (+)-compound II using (+)-norcisapride as starting material is illustrated below. The synthetic routes of compound III, compound V and (-)-compound II are the same, except that they use (-)-norcisapride as the starting material.

Example 5

(+)-Preparation of Compound II Ethyl Ester

A mixture of equimolar (+)-norcisapride and ethyl 6-bromohexanoate (1 equiv _each ), the KI of the catalyst, and _K2CO3 (2 equiv) in DMF was heated to 60 °C for several hours , or until TLC analysis indicated that the reaction was complete. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed _sequentially with water, 10% aqueous LiCl and brine, then dried over _Na2SO4 . Concentration afforded (+)-compound II ethyl ester.

(+)-Preparation of Compound II

A mixture of crude (+)-compound II ethyl ester obtained above (1 equiv), KOH (2M, 5 equiv) in MeOH and THF (enough to dissolve) was stirred at room temperature for about 1-2 hours. MeOH and THF were removed in vacuo and the residue was diluted with water. Wash with an organic solvent such as EtOAc. The pH of the aqueous layer was adjusted to ~5 using HCl. The precipitate was filtered off and dried to obtain (+)-compound II.

Preparation of compound IV and compound VI

A mixture of (+)-compound II (1 eq), (R)-(-)-3-quinine alcohol hydrochloride (1 eq), EDAC (1 eq) and DMAP (1 eq) in DMF was Heat at about 50°C overnight. After cooling and diluting with water, the mixture is purified by chromatography or crystallization to give compound IV. Similarly, using (S)-(+)-quinine alcohol hydrochloride, compound VI is obtained.

The following compounds were mainly prepared according to the methods and procedures described above. Compound names were generated using ChemDraw Ultraversion 8.03 (obtained from Cambridgesoft Corporation) or ACD Nameprosoftware, version 6.0.

(3S)-1-azabicyclo[2.2.2]oct-3-ol-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl )amino]-3-methoxypiperidin-1-yl}hexanoate;

(3S)-1-azabicyclo[2.2.2]oct-3-ol-6-{(3R,4S)-4-[(4-amino-5-chloro-2-methoxybenzoyl )amino]-3-methoxypiperidin-1-yl}hexanoate;

(3R)-1-azabicyclo[2.2.2]oct-3-ol-6-{(3R,4S)-4-[(4-amino-5-chloro-2-methoxybenzoyl )amino]-3-methoxypiperidin-1-yl}hexanoate;

8-methyl-8-azabicyclo[3.2.1]oct-3-ol-6-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzyl Acyl)amino]-3-methoxypiperidin-1-yl}hexanoate;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid methyl ester;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid methyl ester;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid methyl ester;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Ethyl amino]benzoate;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Isopropyl amino]benzoate;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid (2-methoxyethyl) ester;

2-Pyrrolidin-1-ylethanol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy piperidin-1-yl}acetyl)amino]benzoate;

1-methylpiperidin-4-ol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy (Piperidin-1-yl}acetyl)amino]benzoate;

2-pyridin-2-ylethanol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiper Pyridin-1-yl}acetyl)amino]benzoate;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid (2-(dimethylamino)ethyl) ester;

1-methylpiperidin-3-ol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy (Piperidin-1-yl}acetyl)amino]benzoate;

2-morpholin-4-yl-ethanol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy (Piperidin-1-yl}acetyl)amino]benzoate;

1,4-Dimethylpiperidin-4-ol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3 -Methoxypiperidin-1-yl}acetyl)amino]benzoate;

4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl) Amino]benzoic acid;

2-oxo-2-(piperidin-4-ylamino)ethanol-4-[({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl) Amino]-3-methoxypiperidin-1-yl}acetyl)amino]benzoate;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Pyridine-4-carboxylic acid;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Methyl pyridine-4-carboxylate;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Methyl pyridine-4-carboxylate;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Methyl pyridine-4-carboxylate;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Ethyl pyrene-4-carboxylate;

1-({(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl}acetyl)piper Pyridine-4-carboxylic acid (2-methoxyethyl) ester;

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl} Ethyl)(methyl)amino]methyl}benzoic acid;

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl} Ethyl)(methyl)amino]methyl}benzoate;

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl} Ethyl)amino]methyl}benzoic acid methyl ester;

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl} Ethyl)amino]methyl}benzoate isopropyl;

4-{[(2-{(3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-1-yl} Ethyl)amino]methyl}benzoic acid ethyl ester dihydrochloride;

(3R)-1-azabicyclo[2.2.2]oct-3-ol-4-{[(2-{(3S, 4R)-4-[(4-amino-5-chloro-2-methyl Oxybenzoyl)amino]-3-methoxypiperidin-1-yl}ethyl)amino]carbonyl}benzoate;

(R)-quinuclidin-3-ol-6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidine- 1-yl)-hexanoate; or

6-((3S,4R)-4-(4-Amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoic acid.

Formulation, Administration and Use

The dosing frequency and route of administration of the disclosed compounds are similar to those already used in the art and known to those skilled in the art (see, e.g., Physicians' Desk Reference, 54th Ed., Medical Economics Company, Montvale, NJ, 2000).

Dosage sizes of cisapride structural and/or functional analogs for the prevention or treatment of the acute or chronic diseases and/or disorders described herein will vary with the severity of the condition being treated and the route of administration. Dosage and possibly frequency of administration will also vary according to the age, weight and response of the individual patient. Typically, for the conditions described herein, the total daily dosage of a structural and/or functional analog of cisapride is from about 1 mg to about 200 mg in single or divided doses. Preferably, the daily dosage will be from about 5 mg to about 100 mg in single or divided doses, more preferably the daily dosage should be from about 5 mg to about 75 mg in single or divided doses. Preferably, the administration is 1 to 4 times a day. When treating a patient, one should start with a lower dose, which may be from about 5 mg to about 10 mg, and gradually increase to about 50 mg or higher depending on the patient's overall response. It is further recommended that children, patients over 65 years of age, and those with renal or hepatic impairment use a low dose initially and adjust it based on individual response and blood levels. It will be apparent to those skilled in the art that in some cases it may be necessary to use dosages outside these ranges. Furthermore, it should be noted that the clinical or treating physician will know how and when to interrupt, adjust or discontinue therapy based on the individual patient's response.

The compounds of the present invention may be formulated according to known methods for the preparation of pharmaceutical compositions. Formulations are described in several references that are well known and readily available to those skilled in the art. For example, "Remington's Pharmaceutical Science" by E.W. Martin describes formulations that may be used in conjunction with the present invention. In general, the compositions of the present invention are formulated so that an effective amount of the biologically active compound is combined with a suitable carrier to facilitate effective administration of the composition.

Compositions of the present invention include compositions such as suspensions, solutions, and elixirs; or, where oral solid formulations such as powders, capsules, and tablets are preferred over oral liquid formulations, carriers such as starch, Sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like. A preferred oral solid formulation is a capsule. The most preferred oral solid formulation is a tablet. Preferred amounts of active ingredient (ie, structural and/or functional analogs of cisapride) in solid dosage forms are about 5 mg, 10 mg, and 25 mg.

In addition, acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

The pharmaceutical compositions disclosed herein may be subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, for example packeted tablets, capsules, and paper or plastic containers, or powders in vials or ampoules. Also, the unit dosage form can be a liquid-based formulation, or formulated for association with solid food products, such as chewing gum, or as a lozenge.

In addition to the conventional dosage forms described above, the compositions of the present invention may also be administered by controlled release means and/or delivery devices, such as those described in U.S. Patent Nos. , the entire disclosure of which is hereby incorporated by reference.

Any suitable route of administration may be used to provide the patient with an effective dose of the structural and/or functional analogue of cisapride. For example, oral administration, rectal administration, parenteral administration (subcutaneous, intramuscular, intravenous), transdermal administration and the like may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, patches and the like.

In one aspect, the present invention provides a method for treating gastroesophageal reflux disease in a mammal while substantially reducing side effects associated with administration of cisapride, the method comprising administering a therapeutically effective amount of a structural and/or functional analogue of cisapride, or Pharmaceutically acceptable salts thereof are administered to persons in need of such treatment. Preferably, the present invention provides a method of treating gastroesophageal reflux disease in a human.

In another aspect, the present invention provides a composition for treating a human suffering from gastroesophageal reflux disease comprising a therapeutically effective amount of a structural and/or functional analog of cisapride, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a method for antiemetic effects in a mammal with substantially reduced side effects associated with the administration of cisapride, the method comprising administering a therapeutically effective amount of a structural and/or functional An analog, or a pharmaceutically acceptable salt thereof, is administered to a mammal in need of such treatment. Preferably, said mammal is a human.

In another aspect, the present invention relates to an antiemetic composition for treating a mammal in need of antiemetic treatment, comprising a therapeutically effective amount of a structural and/or functional analogue of cisapride, or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention includes a method for treating diseases caused by gastric dysmotility, the method comprising using a therapeutically effective amount of cisapride structural and/or functional analogues, or pharmaceutically acceptable salts thereof for the treatment of gastric dysmotility administration to mammals. Diseases caused by gastric dysmotility include, but are not limited to, dyspepsia, gastroparesis, constipation, postoperative ileus, and intestinal pseudo-obstruction. Preferably, said mammal is a human.

The observation that cisapride enters the central nervous system and binds to _5HT receptors suggests that cisapride may have centrally mediated effects. Cisapride is a potent ligand for _5HT4 receptors located in several regions of the central nervous system. Modulation of the serotonin system has various behavioral effects. Accordingly, the compounds of the present invention are useful in the treatment of: 1) cognitive impairment, including but not limited to Alzheimer's disease; 2) behavioral abnormalities, including but not limited to schizophrenia, mania, obsessive-compulsive disorder, and Psychoactive substance use disorders; 3) mood disorders, including but not limited to depression and anxiety; 4) autonomic function control disorders, including but not limited to essential hypertension and sleep disturbances.

Therefore, the present invention also provides a method for treating cognitive impairment, behavioral abnormalities, emotional disorders or autonomic function control disorders in mammals, the method comprising using a therapeutically effective amount of cisapride structural and/or functional analogues, or its pharmaceutically acceptable Receive salt administration. Preferably, said mammal is a human.

ATI-7505 binds with high affinity to 5- _HT4 receptor

5- _HT4 receptors are known to be the major receptor subtype in the gut involved in the prokinetic activity of cisapride. ATI-7505 binds the 5-HT ₄ receptor with high binding affinity and low nanomolar IC ₅₀ . As shown in Table 1, the affinity of ATI-7505 to the 5- _HT4 receptor is 18 times higher than that of cisapride and at least 360 times higher than that of ATI-7500, the main metabolite of ATI-7505.

Table 1.

5- _HT4 receptor binding

n _H , Hill Coefficient

5-HT ₄ receptor standard control antagonist [ ³ H]GR113808 (0.70nM)

ATI-7505 is a highly potent partial agonist of the human 5- _HT4 receptor

ARYx is based on the in vitro assay of adenylyl cyclase stimulation in cells engineered to stably express the human 5- _HT4 receptor. ATI-7505 proved to be a highly effective 5-HT ₄ receptor agonist, while its main metabolite ATI-7500 was relatively weak (Figure 1 and Table 2). The estimated _EC50 of ATI-7505 (4nM) was approximately 10-fold lower than that of cisapride (49nM) and approximately 100-fold lower than that of ATI-7500 (395nM). Based on its estimated _Emax value, ATI-7505 has 85% potency of 5-HT (serotonin) (Table 2), suggesting that ATI-7505 is a partial agonist of the _HT4 receptor.

Table 2.

Human 5-HT ₄ Receptor Potency and Potency (Intrinsic Activity)

EC ₅₀ , the concentration that results in a maximal 50% increase in adenylyl cyclase activity

_p EC50, negative logarithm of _EC50

ATI-7505 promotes gastric emptying in fed dogs

To characterize the effect of ATI-7505 on gastric emptying, a postprandial model experiment was performed in conscious dogs equipped with metered sensors in the stomach and small intestine. The purpose of this experiment was to measure the time required for migrating motor contractions (MMCs) to return to baseline levels after solid food ingestion. Drug-induced shortening of MMC time indicates an early end of digestion time due to accelerated gastric emptying. Immediately after completion of MMC in the small and middle intestine, intravenous infusions of different doses of the experimental drug (vehicle, ATI-7505 or cisapride) were given over 20 minutes. At the end of the drug infusion, allow the dog to eat. Intestinal contraction recordings were started at least 60 min before the start of the drug infusion to establish the fasted state and determine the onset of MMC in the duodenum, and continued until at least 30 min after the recovery of the duodenal MMC. The quantitative comparison of the experimental results was based on MMC recovery time as an index of gastric emptying after digestion of solid food. As summarized in Figure 2, ATI-7505 significantly shortened MMC recovery time, which indicates an acceleration of gastric emptying in normally fed dogs. Cisapride exhibits a similar mode of action.

ATI-7505 increases motility activity in stomach and small intestine with negligible effect on colonic activity

The kinetic activity of ATI-7505 relative to cisapride in the stomach, small intestine and colon was evaluated in fasted, conscious dogs. The specific objective was to determine the dose size of ATI-7505 (IV and OP) that most closely mimics the pattern and magnitude of inotropic activity induced by typical therapeutic doses of cisapride in dogs (0.5 mg/kg IV; 1 mg/kg PO).

Both ATI-7505 and cisapride resulted in prokinetic activity in the dog gut when administered by IV and PO. Onset of action is typically within 1-2 minutes and 25-30 minutes following IV and PO administration, respectively. The effects of ATI-7505 on gastric and small intestinal motility were similar to those of cisapride. Similar to cisapride, ATI-7505 appears to cause a dose-dependent stimulation of antrum and intestinal contractility with relatively little effect on colonic motility. The prokinetic effect induced by ATI-7505 in the upper GI tract was accompanied by a small but significant (p<0.05) increase in the frequency of giant migrating contractions (GMC).

ATI-7505 was not associated with the development of retrograde giant transitional constriction (RGC). Similar to cisapride, ATI-7505 had minimal effects on migrating motor contraction (MMC) features in the gastric antrum and in the proximal, central, and terminal small bowel. For MMC frequency and phase III duration, only one significant difference was noted: PO ATI-7505 increased the frequency of MMCs in the proximal small intestine compared to controls. Dogs tolerated the IV and PO doses of ATI-7505 well and showed no side effects such as diarrhea, anorexia, or weight loss.

Overall, the results show that ATI-7505 is approximately twice as potent as cisapride on a mg/kg basis. In addition, the effect of ATI-7505 was similar to that of cisapride, consistent with a mechanism related to promoting the release of acetylcholine from enteric neurons, rather than directly relaxing muscle movement. In conclusion, ATI-7505 increased gastric and small intestinal motility in a cisapride-like manner with minimal or no effect on colonic motility.

The metabolism of ATI-7505 is independent of CYP450

Based on pooled human microsomal data, ATI-7505 biotransforms into a single metabolite, ATI-7500, which does not undergo further metabolism. Conversion of ATI-7505 to ATI-7500 is independent of NADPH. Therefore, the main biotransformation pathway of ATI-7505 is independent of CYP450 enzymes.

ATI-7505 does not inhibit CYP450 enzymes

To test the potential of ATI-7505 and/or its major metabolite ATI-7500 as CYP450 inhibitors, the two molecules were screened using Gentest Supersomes ^TM .

Consistent with the results of published reports, cisapride has significant inhibitory activity against CYP450 enzyme isoforms CYP3A4 and 2D6, and has a lower degree of inhibitory effect on 2C9. ATI-7505 and its major metabolite ATI-7500 showed no significant inhibitory effect against any of the three CYP450 isomers, nor against other panels of isomers known to play a role in drug metabolism mechanisms Significant inhibitory effect.

ATI-7505 has negligible affinity for cardiac channel I _Kr

The rapidly activating delayed rectifier potassium (K ⁺ ) current in humans (human I _Kr ) is a K ⁺ channel encoded by the human-ether-a-go-go-related gene (hERG). It is known that cisapride causes QT prolongation by blocking I _Kr , therefore, it is of great significance to determine whether ATI-7505 and ATI-7500 have an important inhibitory effect on human I _Kr . The test system was mammalian HEK-293 cells expressing hERG K ⁺ channels, in which potassium currents were measured by whole-cell patch clamp technique. The order of IC ₅₀ values was: cisapride (9.5 nM) > ATI-7505 (24,521 nM) > ATI-7500 (204,080 nM) (Table 3). Overall, the results indicate that ATI-7505 is significantly less likely to cause arrhythmias than cisapride, and that ATI-7505 and ATI-750 have negligible affinity for the human I _Kr channel.

table 3.

Inhibition of I _Kr activity

Data normalized to % control tail I _Kr (current elicited by no drug or vehicle present)

ATI-7505 does not cause important electrophysiological changes in the guinea pig heart

The cardiac electrophysiological effects of ATI-7505 were tested in isolated perfused guinea pig hearts. The study examined ATI-7505, ATI-7500 and cisapride, all tested at concentrations up to 10,000 nM. The no-observed-effect level (NOEL) was defined as the highest concentration of test compound that did not exhibit a response significantly different from baseline (p<0.05). The following 6 cardiac parameters were tested: (1) QT interval; (2) _MAPD90 ; (3) SA interval; (4) QRS interval; (5) AH interval; and (6) HV. Although ATI-7505 is a weak regulator of cardiac electrophysiological parameters, its metabolite ATI-7500 is completely electrophysiologically inactive (Table 4). For all 6 cardiovascular parameters, the NOEL of ATI-7500 was greater than 10,000nM. Since the combined NOEL of cisapride for the six cardiac parameters measured was 10 nM and the combined NOEL of ATI-7505 was 1,000 nM, ATI-7505 does not appear to have the ability of cisapride to modulate cardiac electrophysiological parameters. Overall, the results suggest that ATI-7505 is significantly safer than cisapride in terms of its potential to cause important cardiac electrophysiological fluctuations.

Table 4.

Electrophysiological Parameters of Isolated Perfused Guinea Pig Hearts

All molecules were assayed at 10, 100, 1,000 and 10,000 nM baselines.

Significant differences (p<0.05) from baseline were observed when molecules were measured 10-fold higher, except for values reported as >10,000 nM.

Metabolism in Human Microsomal Preparations

The metabolism of these compounds in pooled human microsomes was studied in the presence and absence of the cytochrome P-450 coenzyme NADPH, the disappearance of the parent and the corresponding acid metabolites (i.e. the corresponding compound II isomers) Appears for real-time monitoring.

As shown in Figure 5, compounds III and IV were rapidly hydrolyzed by lipase into their respective metabolites (+) and (-)-compound II. Since the rate of hydrolysis is independent of the presence of NADPH, which is an essential cofactor for CYP450 action, metabolism is not dependent on CYP450. In contrast, (±)-S compounds V and VI appeared to be fairly stable over time under the same conditions. In this experiment, the amount of substrate (compounds III, IV, V and VI) remaining in the reaction after 5, 60 and 90 minutes was evaluated by a secondary HPLC-MS method. This remaining amount is associated with the appearance of the metabolite compound II. The total amount of remaining substrate and compound II is constant over time and is equal to the amount of starting material at time zero, thus suggesting that hydrolysis is the only metabolic reaction occurring.

Metabolism in fresh human blood

The test compound was dissolved in DMSO to make a 12.5 mM stock solution, and diluted with water to a final concentration of 2.5 mM (DMSO/H ₂ O=20/80). Fresh blood was collected from 3 donors into heparinized tubes and stored on ice until incubation. Aliquots of blood from each donor were pipetted into 1.5 mL centrifuge tubes, which were pre-incubated in a shaking water bath at 37°C for 5 minutes. Reactions were initiated by adding 10 [mu]L of the appropriate stock solution of the test compound to each tube (final concentration 100 [mu]M). After 0, 5, 15, 30 and 60 minutes, acetonitrile (750 mL) was added to terminate the incubation, centrifuged at 12,000 rpm for 2 minutes, and the supernatant was analyzed by an Agilent 1100 HPLC system. Separation was performed on a Keystone IntersilODS2, 250 X 4.6mm, 5m column. The aqueous mobile phase consisted of 20 mM ammonium acetate buffer (pH 5.7) and the organic phase acetonitrile. The following gradient was used: initially eluting with 20% acetonitrile for 1 minute. The acetonitrile concentration was increased linearly to 90% over the next 8 min and held for 1 min. The system was then returned to initial conditions for 1 minute and held for 4 minutes to prepare for the next injection. The absorbance at 240, 254 and 290 nM was detected, and the peak area of the parent peak was determined. Results are expressed as the remaining amount of starting compound and data are analyzed kinetically using WinNonLin. The half-life of each compound is shown in Table 6.

Table 6

It should be understood that the embodiments and aspects described herein are for illustrative purposes only, and those skilled in the art will recognize various changes or changes, which are included in the spirit of the application and the appended claims and within range. Furthermore, all patents, patent applications, provisional applications and publications cited herein are hereby incorporated by reference in their entirety to the extent they are not inconsistent with the express teachings of this specification.

The invention and the manner and means of making and using it are described herein sufficiently, clearly, concisely and accurately to enable any person skilled in the relevant art to make and use the invention. It will be appreciated that modifications may be made to the preferred aspects of the invention without departing from the spirit and scope of the invention as described in the claims. To particularly point out and distinctly claim the inventive subject matter, this document concludes with the following claims.

Claims (20)

1. A compound selected from the group consisting of

(3R, 4S, 3' R) -6- [4- (4-amino-5-chloro-2-methoxy-benzoylamino) -3-methoxy-piperidin-1-yl ] -hexanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester.

2. A compound selected from the group consisting of

(3S, 4R, 3' R) -6- [4- (4-amino-5-chloro-2-methoxy-benzoylamino) -3-methoxy-piperidin-1-yl ] hexanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester.

3. A compound selected from the group consisting of

(3R, 4S, 3' S) -6- [4- (4-amino-5-chloro-2-methoxy-benzoylamino) -3-methoxy-piperidin-1-yl ] -hexanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester.

4. A compound selected from the group consisting of

(3S, 4R, 3' S) -6- [4- (4-amino-5-chloro-2-methoxy-benzoylamino) -3-methoxy-piperidin-1-yl ] -hexanoic acid 1-aza-bicyclo [2.2.2] oct-3-yl ester.

5. The compound according to claim 2, wherein the compound is in the form of the dihydrochloride salt, and pharmaceutically acceptable salts thereof.

6. A composition comprising a compound of claim 1.

7. A composition comprising a compound of claim 2.

8. A composition comprising a compound of claim 3.

9. A composition comprising a compound of claim 4.

10. A composition comprising a compound of claim 5.

11. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

12. A composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

13. A composition comprising a compound according to claim 3 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

14. A composition comprising a compound according to claim 4 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

15. A composition comprising a compound according to claim 5 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

16. A composition comprising the composition of claim 6 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

17. A composition comprising the composition of claim 7 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

18. A composition comprising the composition of claim 8 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

19. A composition comprising the composition of claim 9 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

20. A composition comprising the composition of claim 10 and a pharmaceutically acceptable excipient, adjuvant, carrier or solvent.

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