WO2010062959A1 - 5-ht4 receptor agonists for treating irritable bowel syndrome and colonic hypersensitivity - Google Patents

Abstract

The disclosure provides 5-HT4 receptor agonist compounds for treatment of functional bowel disorders, pain associated with bowel disorders, or colonic hypersensitivity. The 5-HT4 receptor agonist compounds have the following formula: (I)

Description

SELECTIVE 5-HT₄ RECEPTOR AGONIST FOR REDUCTION IN

COLONIC HYPERSENSITIVITY AND THE TREATMENT OF

IRRITABLE BOWEL SYNDROME

Cross-Reference to Related Applications This application claims priority from U.S. Provisional Patent Application Number

60/118,079, filed November 26, 2008.

BACKGROUND OF THE DISCLOSURE Field of the disclosure

The disclosure provides 5-HT₄ receptor agonist compounds for treatment of functional bowel disorders, pain associated with bowel disorders, or colonic hypersensitivity.

Description of the related art

Functional bowel disorders, such as irritable bowel syndrome (IBS), are common disorders characterized by frequently recurring symptoms of abdominal pain, bloating, and bowel dysfunction. It is now believed that the symptoms of IBS result from visceral hypersensitivity and sensitization within neuronal pathways involved in the bidirectional communication between the gut and the brain. It has been estimated that a minimum of 10- 20% of the United States population experience several of the symptoms of irritable bowel disorders. Moreover, greater than 30% of patients that recover from an acute infectious gastroenteritis also exhibit irritable bowel syndrome symptomatology. Although IBS is not known to lead to serious disease or excess mortality, it has a significant impact on patients' quality of life and social functioning.

The clinical presentation of IBS is quite diverse. Many of the patients report a wide range of colonic and extra-colonic symptoms. Symptoms of irritable bowel syndrome include abdominal cramping with pain that is concurrent with abnormal bowel habits in terms of frequency and appearance. Treatments for functional bowel disorders generally, and irritable bowel syndrome specifically, include modification of diet, psychological therapy, stress management, exercise, antidepressant and antianxiety medications, antidiarrheals, bile acid binding agents, anticholinergics, some experimental medications, and other pharmacological and non-pharmocological treatments. These treatments have only limited success and effectiveness and some have undesirable side effects.

It is well established that many IBS patients have a lower threshold to pain on distension of a balloon catheter in the gastrointestinal tract (GI), compared to healthy controls. Although no animal models of IBS exist, advances in the understanding of the pathophysiology of IBS have facilitated the development of preclinical models of visceral pain and visceral hypersensitivity in which equivalent stimulation techniques are employed. A model involving conscious animals in which visceral hypersensitivity in response to colorectal distension is investigated, one that closely resembles the exaggerated response to colorectal distension seen in IBS patients. The method of colorectal distension can be used to activate nociceptive neuronal pathways from the gastrointestinal tract that induces a protective reflex of abdominal muscle contraction. One method of measuring these contractions is via strain gauges in the abdomen and permits the study of agents to determine whether they inhibit nociception and visceral hypersensitivity.

Despite studies and postulates, however, chronic visceral pain of gastrointestinal origin is poorly understood and lacks an effective therapy. Thus, there is a need for improved treatment for visceral pain of gastrointestinal origin, functional bowel disorders and irritable bowel syndrome. SUMMARY OF THE DISCLOSURE hi a broad aspect, the disclosure provides 5-HT₄ receptor agonist compounds for treatment of functional bowel disorders, pain associated with bowel disorders, or colonic hypersensitivity.

Thus, one aspect of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, comprising administering a compound of the formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein the bonds at positions 3 and 4 are cis relative to each other;

L is -(C₁-C₆ alkyl)-, -(Ci-C₆ alkyl)-C(O)-, or -C(O)-(C₁-C₆ alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen,

Ci-C₄ alkoxy, or -OH, and wherein one carbon in the alkyl portion of L may be replaced by -N(Rg)-; Ri is halogen; R₂ is -NH₂, -NH(C₁-C₄ alkyl) or -N(C₁-C₄ alkyl)₂; R₃ is -OH or Cj-C₄ alkoxy;

R₄ is -H or -CH₃;

R₅ is -0-C₃-C₈ cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -O- heteroaryl, -N(R₉)-(C₀-C₆ alkyl)-C(O)-aryl, or -N(R₉)-(C₀-C₆ alkyl)-aryl, -N(R₉)-(C₀- C₆ alkyl)-C(O)-heteroaryl, or -N(R₉)-(C₀-C₆ alkyl)-heteroaryl, wherein each of the cyclic groups is optionally substituted at one or more substitutable positions with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, Ci-C₆ haloalkyl, C₁-C₆ haloalkoxy, -OH, hydroxy-Q-Q-alkyl, -NH₂, -NH(Cj-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)R_π, or -0-(C₀-C₆ alkyl)-C(O)Rn, methylsulfone, C₀-C₆-sulfonamide, or -NO₂; wherein

R₉ at each occurrence is independently -H or Ci-C₄ alkyl;

Rn is Ci-C₆ alkyl, -OH, or

Rn is C₁-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently

Ci-C₄ alkoxy, -NH₂, -NH(C₁-C₆ alkyl), -N(Ci-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)N(R₉)-heterocycloalkyl, -O-heterocycloalkyl,

-C₁-C₆(O)N(R₉)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1 , 2, or 3 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy- C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, -CO₂H, CF₃, or -OCF₃, the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C₆ alkyl, Ci-C₆ alkoxy, -OH, hydroxy-Ci-C₆ alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃; or Rn is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with

1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy-Ci-C₆ alkyl, C₁-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃; and

R₂₀ is C₁-C₆ alkoxy, or -OH; to a patient in need of such treatment.

Another aspect of the disclosure provides methods of testing a compound of the formula (I) for the treatment of colonic hypersensitivity, comprising:

(a) inducing colonic hypersensitivity in a mammal;

(b) administering the compound to the mammal; and

(c) assessing colonic sensitivity, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt or solvate thereof, wherein the bonds at positions 3 and 4 are cis relative to each other;

L is -(C₁-C₆ alkyl)-, -(Cj-C₆ alkyl)-C(O)-, or -C(O)-(Ci-C₆ alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, Ci-C₄ alkoxy, or -OH, and wherein one carbon in the alkyl portion of L may be replaced by -N(Rg)-; R₁ is halogen;

R₂ is -NH₂, -NH(C₁-C₄ alkyl) or -N(Cj-C₄ alkyl)₂; R₃ is -OH or Ci-C₄ alkoxy; R₄ is -H or -CH₃;

R₅ is -0-C₃-C₈ cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -O- heteroaryl, -N(R₉)-(C₀-C₆ alkyl)-C(O)-aryl, or -N(Rg)-(C₀-C₆ alkyl)-aryl, -N(Rg)-(C₀- C₆ alkyl)-C(O)-heteroaryl, or -N(Rg)-(C₀-C₆ alkyl)-heteroaryl, wherein each of the cyclic groups is optionally substituted at one or more substitutable positions with C₁-C₆ alkyl, Cj-C₆ alkoxy, halogen, Ci-C₆ haloalkyl, Ci-C₆ haloalkoxy, -OH, hydroxy-C₁-C₄-alkyl, -NH₂, -NH(Ci-C₆ alkyl), -N(Ci-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)Rn, or -0-(C₀-C₆ alkyl)-C(O)Rπ, methylsulfone, C₀-C₆-sulfonamide, or -NO₂; wherein

Rg at each occurrence is independently -H or Ci-C₄ alkyl; Rn is Ci-C₆ alkyl, -OH, or

Rn is Cj-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently C-C₄ alkoxy, -NH₂, -NH(C-C₆ alkyl), -N(Cj-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)N(Rg)-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C₆(O)N(Rg)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C₆ alkyl, Cj-C₆ alkoxy, -OH, hydroxy- Ci-C₆ alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, CF₃, or -OCF₃, the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C₆ alkyl, Cj-C₆ alkoxy, -OH, hydroxy-Q-Ce alkyl, C₁-C₆ alkoxycarbonyl, -CO₂H₅ -CF₃, or -OCF₃; or

R₁ ] is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C₆ alkyl, Cj-C₆ alkoxy,

-OH, hydroxy-Cj-C₆ alkyl, Cj-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃; and R₂₀ is C₁-C₆ alkoxy, or -OH.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Acetic Acid Induced-Colonic Hypersensitivity: Experiments to confirm that intracolonic acetic acid induces acute colonic hypersensitivity.

Figure 2. Effect of ATI-7505, 0.01 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 3. Effect of ATI-7505, 0.1 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 4. Effect of ATI-7505, 1.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 5. Effect of ATI-7505, 10.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity. Figure 6. Effect of ATI-7505, 30.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 7. Summary of the effect of ATI-7505 in rats with acetic acid-induced colonic hypersensitivity.

Figure 8. Effect of Cisapride, 10.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 9. Effect of Cisapride, 50.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 10. Effect of Cisapride, 100 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity. Figure 11. Summary of the effect of Cisapride, in rats with acetic acid-induced colonic hypersensitivity.

Figure 12. Post-Inflammatory Colonic Hypersensitivity: Experiments to confirm colonic hypersensitivity following recovery from an acute colitis. Figure 13. Effect of ATI-7505, 1.0 mg/kg p.o., in rats with acetic acid-induced colonic hypersensitivity.

Figure 14. Summary of the effect of ATI-7505, 1.0 mg/kg p.o., in two models of colonic hypersensitivity.

DETAILED DESCRIPTION OF THE DISCLOSURE

One embodiment of the disclosure provides a method of treating irritable bowel syndrome, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment of the disclosure provides a method of treating pain of gastrointestinal origin, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

Yet another embodiment of the disclosure provides a method treating colonic hypersensitivity, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. One embodiment of the disclosure provides a method according to any previous embodiments, wherein R₁ of formula (I) is -Cl.

Another embodiment of the disclosure provides a method according to any previous embodiments, wherein R₂ of formula (I) is -NH₂.

Yet another embodiment of the disclosure provides a method according to any previous embodiments, wherein R₃ of formula (I) is -OCH₃.

One embodiment of the disclosure provides a method according to any previous embodiments, wherein R₄ of formula (I) is -H.

Another embodiment of the disclosure provides a method according to any previous embodiments, wherein Rj, R₂, and R₃ of formula (I) have the following orientation on the phenyl ring:

One embodiment of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, comprising administering a compound of the formula (I), wherein R₁ is -Cl, R₂ is -NH₂, R₃ is -OCH₃, and R₄ is -H. In another embodiment the orientation OfR₁, R₂, and R₃ is as follows:

Yet another embodiment of the disclosure provides a method according to any previous embodiments, wherein R₂₀ of formula (I) is -OCH₃.

One embodiment of the disclosure provides a method according to any previous embodiments, wherein L of formula (I) is -(C₂-C₆ alkyl)-C(O)- or -(C₃-C₅ alkyl)-, wherein one carbon may be replaced by -N(Rg)-.

Another embodiment of the disclosure provides a method according to any previous embodiments, wherein L of formula (I) is -(C₂-C₆ alkyl)-C(O)-.

Another embodiment of the disclosure provides a method according to any previous embodiments, wherein R₅ of formula (I) is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl, each optionally substituted with -CH₃, -CH₂CH₃, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions with groups that are independently Cj-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, Q-C₄ haloalkoxy, -OH, hydroxy-Q-Q alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(Cj-C₄ alkyl)₂, -(C₀-C₆ alkyl)-C(O)R_n, or -NO₂, wherein R₁₁ is C₁-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently

C₁-C₄ alkoxy, -NH₂, -NH(Ci-C₄ alkyl), -N(C]-C₄ alkyl)₂, -(C₀-C₆ alkyl)- C(O)N(R₉)-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C₆ alkyl, Ci-C₆ alkoxy, -OH, hydroxy-CrCβ alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃.

One embodiment of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, comprising administering a compound of the formula (I), wherein L of formula (I) is -(C₂-C₆ alkyl)- C(O)-, and R₅ of formula (I) is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl, each optionally substituted with -CH₃, -CH₂CH₃, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions with groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, -OH, hydroxy-d-Q alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(C₁-C₄ alkyl)₂, -(C₀-C₆ alkyl)-C(O)Rj i , or -NO₂, wherein

R₁₁ is C₁-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkoxy, -NH₂, -NH(Ci-C₄ alkyl), -N(Ci-C₄ alkyl)_2j -(C₀-C₆ alkyl)- C(O)N(R₉)-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy-Ci-C₆ alkyl, C₁-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃.

Another embodiment of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, comprising administering a compound of the formula (I), wherein R₁ is -Cl, R₂ is -NH₂, R₃ is -OCH₃, R₄ is -H, L of formula (I) is -(C₂-C₆ alkyl)-C(O)-, and R₅ of formula (I) is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl, each optionally substituted with -CH₃, -CH₂CH₃, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions with groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, C₁-C₄ haloalkyl, Cj-C₄ haloalkoxy, -OH, hydroxy-Ci-C₄ alkyl, -NH₂, -NH(Ci-C₄ alkyl), -N(C₁-C₄ alkyl)₂, -(C₀-C₆ alkyl)-C(O)R_ϊ i , or -NO₂, wherein

R₁₁ is C₁-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkoxy, -NH₂, -NH(Cj-C₄ alkyl), -N(C₁-C₄ alkyl)₂, -(C₀-C₆ alkyl)- C(O)N(R₉)-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C₆ alkyl, Ci-C₆ alkoxy, -OH, hydroxy-d-C₆ alkyl, Cj-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃. Yet another embodiment of the disclosure provides a method according to any previous embodiments, wherein R₅ of formula (I) is heterocycloalkyl, which is selected from l-aza-bicyclo[2.2.2]oct-3-yl, and 8-aza-bicyclo[3.2.1]oct-3-yl, where the nitrogen in the 8- aza-bicyclo[3.2.1]oct-3-yl group is optionally substituted with -CH₃, Or-CH₂CH₃.

One embodiment of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the disclosure provides a method of treating irritable bowel syndrome, comprising administering this compound. In another embodiment, the disclosure provides a method of treating pain of gastrointestinal origin, comprising administering this compound, hi yet another embodiment, the disclosure provides a method of treating colonic hypersensitivity, comprising administering this compound. Another embodiment of the disclosure provides a method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, wherein the compound of formula (I) is compound known as ATI-7505, and has the following structure:

In one embodiment, the disclosure provides a method of treating irritable bowel syndrome, comprising administering ATI-7505. In another embodiment, the disclosure provides a method of treating pain of gastrointestinal origin, comprising administering ATI-7505. hi yet another embodiment, the disclosure provides a method of treating colonic hypersensitivity, comprising administering ATI-7505.

Another embodiment of the disclosure provides a method method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, wherein the compound of formula (I) is:

(35)- 1 -azabicyclo[2.2.2]oct-3-yl 6- {(3S,4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3 -methoxypiperidin- 1 -yl }hexanoate; (3S)-I -azabicyclo[2.2.2]oct-3-yl 6- {(3i?,4S)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino] -3 -methoxypiperidin- 1 -yl } hexanoate; (3i?)-l-azabicyclo[2.2.2]oct-3-yl 6-{(3i?,4S)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3 -methoxypiperidin- 1 -yl }hexanoate; 8-methyl-8-azabicyclo[3.2.1 ]oct-3-yl 6- {(35',4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino] -3 -methoxypiperidin- 1 -yl } hexanoate; 4-[({(3ιS^r,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl}acetyl)amino]benzoic acid; methyl 4-[( {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l - yl } acetyl)amino]benzoate; methyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)amino]benzoate; methyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)amino]benzoate; ethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)amino]benzoate; isopropyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidm-

1 -yl} acetyl)amino]benzoate;

2-methoxyethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl } acetyl)amino]benzoate;

2-pyrrolidin-l-ylethyl 4-[({(3<S',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}acetyl)amino]benzoate; 1 -methylpiperidin-4-yl 4-[( {(3S,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)amino]benzoate; 2-pyridin-2-ylethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)amino]benzoate; 2-(dimethylamino)ethyl 4-[({(35',4iϊ)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)amino]benzoate;

1 -methylpiperidin-3-yl 4-[( {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}acetyl)amino]benzoate;

2-morpholin-4-ylethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}acetyl)amino]benzoate; 1 ,4-dimethylpiperidin-4-yl 4-[( {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)amino]benzoate; 4-[({(35'₅4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl}acetyl)amino]benzoic acid; 2-oxo-2-(piperidin-4-ylamino)ethyl 4-[({(3iS',4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino] -3 -methoxypiperidin- 1 -yl } acetyl)amino]benzoate; l-({(35',4jR)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl} acetyl)piperidine-4-carboxylic acid; methyl l-({(35',4i?)-4-[(4-ammo-5-chloro-2-methoxybenzoyl)amino]-3-niethoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; methyl 1 -( {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin- 1 - yl } acetyl)piperidine-4-carboxylate; methyl 1 -( {(35',4i?)-4-[(4-amino-5-cnloro-2-methoxybenzoyl)amino]-3-methoxypiperidin- 1 - yl } acetyl)piperidine-4-carboxylate; ethyl l-({(35,4/?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; 2-methoxyethyl 1 -( {(35,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl } acetyl)piperidine-4-carboxylate; 4- {[(2- {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l - yl} ethyl)(methyl)amino]methyl}benzoic acid; methyl 4- { [(2- {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)ammo] -3 - methoxypiperidin-l-yl}ethyl)(methyl)amino]methyl}benzoate; methyl 4-{[(2-{(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}ethyl)amino]methyl}benzoate; isopropyl 4- {[(2- {(35^r,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} ethyl)amino]methyl}benzoate; ethyl 4- {[(2- {(35,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin- l-yl}ethyl)amino]methyl}benzoate Dihydrochloride; (3i?)-l -azabicyclo[2.2.2]oct-3-yl 4- {[(2- {(3,S,4i?)-4-[(4-ammo-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l-yl}ethyl)amino]carbonyl}benzoate; (R)-quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybeiizamido)-3- methoxypiperidin- l-yl)hexanoate;

6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-l-yl)hexanoic acid; or a pharmaceutically acceptable salt or solvate thereof. One embodiment of the disclosure provides a method according to any previous embodiments, wherein the compound of formula (I) is administered in a dose of about 0.01 mg/kg to about 50.0 mg/kg. In another embodiment, the dose is about 0.1 mg/kg to about 30 mg/kg. In yet another embodiment, the dose is about 1.0 mg/kg to about 30 mg/kg.

Pharmaceutical Compositions

In another aspect, the present disclosure provides compositions useful for treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity comprising compounds as described above with respect to any of formula (I) and an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use. The composition may optionally include one or more additional compounds.

When used to treat or prevent irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, the compounds described herein may be administered singly, as mixtures of one or more compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. The compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies. The compounds may be administered in the form of compounds per se, or as pharmaceutical compositions comprising a compound. Pharmaceutical compositions for treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity comprising the compound(s) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.

The compounds may be formulated in the pharmaceutical composition per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.

Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives. Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore^τ or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the compound, as is well known.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For rectal routes of administration, the compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver compound(s). Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.

The amount of compound(s) administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular compound(s) the conversation rate and efficiency into active drug compound under the selected route of administration, etc.

Determination of an effective dosage of compound(s) for a particular use and mode of administration is well within the capabilities of those skilled in the art. Effective dosages may be estimated initially from in vitro activity and metabolism assays. For example, an initial dosage of compound for use in animals may be formulated to achieve a circulating blood or serum concentration of the metabolite active compound that is at or above the activity of the particular compound as measured in as in vitro assay. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound via the desired route of administration is well within the capabilities of skilled artisans. Initial dosages of compound can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of the active metabolites to treat or prevent the various diseases described above are well-known in the art. Animal models suitable for testing the bioavailability and/or metabolism of compounds into active metabolites are also well-known. Ordinarily skilled artisans can routinely adapt such information to determine dosages of particular compounds suitable for human administration.

Dosage amounts will typically be in the range of from about 0.0001 mg/kg/day, 0.001 mg/kg/day or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the active metabolite compound, the bioavailability of the compound, its metabolism kinetics and other pharmacokinetic properties, the mode of administration and various other factors, discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) and/or active metabolite compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of compound(s) and/or active metabolite compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.

Definitions As used herein, the following terms are intended to have the following meanings:

"Alkyl" includes those alkyl groups containing from 1 to 10, preferably 1 to 6, carbon atoms. Alkyl groups may be straight, or branched. Examples of "alkyl" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-, sec- and tert-butyl, n-pentyl, iso-penyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, 3-ethylbutyl, n-octyl, n-nonyl, n-decyl and the like. Alkyl groups described without specifying branching encompass all possible isomers. For example, "propyl" includes n-propyl and iso-propyl, and ^ςcbutyl" includes n-butyl, iso-butyl, sec-butyl and tert-butyl.

The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10, preferably 2 to 6, carbons, and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.

The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10, preferably 2 to 6, carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Representative examples of aryl groups include phenyl, naphthyl, anthracenyl 1,2,3,4-tetrahydronaphthalene, indenyl, 2,3-dihydroindenyl, and biphenyl. Preferred examples of aryl groups are phenyl and naphthyl. Most preferred is phenyl.

The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term "cycloalkyl" as used herein means, means a monocyclic, bicyclic, or tricyclic ring system having only carbon atoms in the rings. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0³'⁷]nonane and tricyclo[3.3.1.1 ' ]decane (adamantane). The terms "halogen" or "halo" indicate fluorine, chlorine, bromine, and iodine.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where each halogen is independently F, Cl, Br or I. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafiuoroethyl, and 2-chloro-3-fluoropentyl. "Haloalkyl" includes perhaloalkyl groups, such as -CF₃ or -CF₂CF₃. Preferred halogens are F and Cl. Preferred haloalkyl groups contain 1-6 carbons, more preferably 1-4 carbons, and still more preferably 1-2 carbons. A preferred haloalkyl group is trifluoromethyl. "HaIo(Cj-C₆ alkyl)" denotes a haloalkyl having in the range of from 1 to 6 carbons.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, where each halogen is independently F, Cl, Br or I. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. "Haloalkoxy" includes perhaloalkoxy groups, such as CF₃. Preferred halogens are F and Cl. Preferred haloalkoxy groups contain 1-6 carbons, more preferably 1-4 carbons, and still more preferably 1-2 carbons. A preferred haloalkoxy group is trifluoromethoxy. "HaIo(Ci-C₆ alkoxy)" denotes a haloalkoxy having in the range of from 1 to 6 carbons.

The term "heteroaryl" as used herein, means a monocyclic or a bicyclic ring system containing at least one aromatic ring, where the aromatic ring contains at least one heteroatom selected from nitrogen, oxygen, and sulfur. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to an aryl (e.g., phenyl), or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocyclyl. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, purinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.

The term "heterocycloalkyl" as used herein, refers to a ring or ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein said heteroatom is in a non-aromatic ring and the ring system is attached to the parent group by a member of (one of) the non-aromatic ring(s). The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings, and/or phenyl rings. Thus, heterocycloalkyl groups suitable for the invention have at least 3 members, and may have up to 20 members. Preferred heterocycloalkyl groups have from 3 to 10 members. Certain more preferred heterocycloalkyl groups have from 8-10 members. Other more preferred heterocycloalkyl groups have 5 or 6 members. Representative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-l,4-benzodioxinyl, 2,3-dihydro-l -benzofuranyl, 2,3 -dihydro-1 -benzothienyl, 2,3-dihydro-lH-indolyl, and 1,2,3,4-tetrahydroquinolinyl,

2,3,4,4a,9,9a-hexahydro-lH-carbazoryl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl,

5a,6,7,8,9,9a-hexahydrodibenzo[b₅d]tbienyl, aza-bicyclo-octyl (e.g., l-aza-bicyclo[2.2.2]oct- 3-yl, 8-aza-bicyclo[3.2.1]oct-3-yl), aza-bicyclo-nonyl, and aza-bicyclo-decyl. The term "oxo" as used herein means a =0 group. Multivalent atoms, such as sulfur, may contain more than one oxo group.

The term "pharmaceutically acceptable salts" or "a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Preferred acid addition salts are the chloride and sulfate salts. In the most preferred aspect, structural and/or functional analogs of cisapride are administered as the free base or as the mono or dihydrochloride salt.

As used herein, the terms "treatment" and "treating" encompass prophylactic administration of the compound or a pharmaceutical composition comprising the compound ("prophylaxis") as well as remedial therapy to reduce or eliminate a disease or disorder mentioned herein. Prophylactic administration is intended for prevention of disorders and may be used to treat a subject that is at risk of having or suffering from one or more disorders mentioned herein. Thus, as used herein, the term "treatment", or a derivative thereof, contemplates partial or complete inhibition of the stated disease state, when an active ingredient of the invention is administered prophylactically or following the onset of the disease state for which such active ingredient of the is administered. "Prophylaxis" refers to administration of the active ingredient(s) to a mammal to protect the mammal from any of the disorders set forth herein, as well as others.

The term "therapeutically effective amount" refers to an amount necessary to achieve a derived therapeutic effect. Therapeutically effective amounts of structural and/or functional analogs of formula (I) are encompassed by the above-described dosage amounts and dose frequency schedule. Methods of Synthesis

The compounds described herein, as well as intermediates thereof, may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely used and/or adapted to synthesize active 5-HT₄ receptor agonist compounds can be found in international patent application no. PCT/USO5/OO51O filed January 7, 2005 (WO 05/068461), international patent application no. PCT/US06/26166 filed July 5, 2006 (WO 07/005951), and international patent application no. PCT/US06/34322 filed August 31, 2006 (WO 07/028073). Each of these prior publications is incorporated herein by reference.

Those having skill in the art will recognize that the starting materials and reaction conditions may be varied, the sequence of the reactions altered, and additional steps employed to produce compounds encompassed by the present disclosure. Skilled artisans will recognize that in some instances, during the synthesis of 5-HT₄ receptor agonist compounds and prodrugs thereof, the starting materials may include functional groups that require protection during synthesis. The exact identity of any protecting group(s) used will depend upon the identity of the functional group being protected, and will be apparent to these of skill in the art. In general, the need for such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to those skilled in the art of organic synthesis.

Examples

The method of treatment or method of testing of irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity of the disclosure is illustrated further by the following examples, which are provided for illustrative purposes and are not intended to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described in them.

Example 1:

The effect of ATI-7505 and Cisapride in a rat model of acetic acid-induced colonic hypersensitivity Animals: All experiments were performed on male Sprague Dawley rats purchased from Charles River (Wilmington, MA) and housed under controlled conditions (25°C, reverse 12 h light/dark cycle) with free access to food and water. Upon arrival, each rat was placed into a cage and acclimated to the animal facility for at least 7 days. Groups: The following groups of rats were tested: a. Naϊve, n = 8 b. Vehicle, 0.5% methylcellulose, 1.0 ml, p.o. n = 8 c. ATI-7505, 0.01 mg/kg, 1.0 ml, p.o. n = 8 d. ATI-7505, 0.1 mg/kg, 1.0 ml, p.o. n = 8 e. ATI-7505, 1.0 mg/kg, 1.0 ml, p.o. n = 8 f. ATI-7505, 10.0 mg/kg, 1.0 ml, p.o. n = 8 g. ATI-7505, 30.0 mg/kg, 1.0 ml, p.o. n = 8 h. Cisapride, 10.0 mg/kg, 1.0 ml, p.o. n = 7 i. Cisapride, 50.0 mg/kg, 1.0 ml, p.o. n = 7 j. Cisapride, 100 mg/kg, 1.0 ml, p.o. n = 4

Acclimatization: Following receipt from the vendor, rats were allowed to acclimate to the animal facility and recover from shipping stress for one week. Additionally, one week before colonic sensitivity testing, rats were brought to the laboratory to acclimate to the experimenter and laboratory conditions.

Fasting: Animals were fasted (food removed, free access to water) on wire-bottom metabolic cages for 16-18 hrs before receiving the TNBS enema and before undergoing colorectal distension procedures. Animals were rapidly moved from their home cage to a metabolic cage by lifting them at the base of the tail. Animals were removed from the metabolic cage in an identical manner. It was important that rats were fasted before TNBS enema and before colorectal balloon insertion to clear the colon of fecal pellets. Fecal pellets in the colon at the time of TNBS administration and instrumentation surgery increases the risk of perforating the colon. Wire-bottom metabolic cages decreased the likelihood of rats consuming fecal pellets during the fasting period.

Acetic Acid-Induced Colonic Hypersensitivity Model: Acetic acid-induced colonic hypersensitivity in rats has been described by Langlois et. al (Eur J Pharmacol. 1996 Dec 27;318(l):141-4), Plourde et al. (Am J Physiol. 1997 Jul;273(l Pt l):G191-6), Gunter et al. (Physiol Behav. 2000 May;69(3):379-82), and Greenwood-Van Meerveld et al. (Auton Neurosci. 2003 Feb 28;104(l):17-24; Neurogastroenterol Motil. 2006 Jan;18(l):76-86; Neurogastroenterol Motil. 2006 May;18(5):343^5)τ Simultaneous^{^}with^~~ colonic^{^}balloon insertion, a colonic catheter (PE 90 tubing) was inserted via the anus to the level of the mid- colon for the infusion of dilute acetic acid (1.5 ml, 0.6%). Following VMR instrumentation surgery, the acetic acid solution was slowly infused into the colon, which stimulated colonic hypersensitivity within 60 minutes. Drug or vehicle was then orally pre-dosed and colonic sensitivity was assessed as described.

Visceromotor Response (VMR) Instrumentation: Following an overnight fast (16-18 hrs), animals were prepped for surgical attachment of a strain gauge force transducer to the external oblique muscle. The surgeon wore a lab coat and gloves throughout the procedure. Anesthesia was induced via isoflurane inhalation (2-5%). Corneal reflex and toe-pinch were used throughout the procedure to access depth of anesthesia. The incision site was shaved followed by 3 alternating scrubs with betadine and alcohol. A small incision (< 2 cm) was made on the abdomen near midline and the strain gauge was sewn onto the external oblique muscle with 7 stitches using 3-0 nylon suture. The incision was closed using 3-0 nylon suture and analgesic and antibiotic cream was applied to the incision site. The strain gauge lead wires were looped around and attached to the animal's back using a single stitch. The colorectal balloon was inserted 11 cm into the distal colon and was held in place by taping the balloon catheter to the animal's tail. For the acetic acid-induced colonic hypersensitivity, an infusion line (PE 90) was inserted adjacently with the colonic balloon catheter. Animals were allowed to wake up and recover for 30 minutes before colonic sensitivity assessment began.

Colonic Sensitivity Assessment: Behavioral response to colorectal distension (CRD) was measured by counting the number of abdominal contractions recorded by a strain gauge transducer sutured onto the abdominal musculature. A 5 cm latex balloon catheter inserted via the anal canal 11 cm into the distal colon was used for performing CRD. Constant pressure (isobaric) tonic distensions were performed in a graded manner, i.e. the balloon was inflated to the desired pressure and then maintained for a period of 10-minutes during which time the number of abdominal muscle contractions was recorded to measure the level of colonic sensation. A 10-minute recovery was allowed between distensions. hi the acetic acid induced-colonic hypersensitivity model, 60 minutes following luminal acetic acid infusion (0.6%, 1.5 ml) and following a 30-minute oral pre-dose of either vehicle or drug (1.0 ml), rats underwent a single test CRD series. The series consisted of 10- minute distensions of 15-30-45-60 mmHg separated by 10-minute rest periods.

Drug Dosing: ATI-7505 and Cisapride were administered orally (p.o.) in a volume of 1 ml 0.5% methylcellulose vehicle at the doses previously listed. VMR testing was performed after a 30-minute pre-dose. Data and Statistical Analysis: To normalize the presentation of the VMR data between the two models of hypersensitivity, all treatments were expressed as percentage of maximum response (mean ± standard error of the mean (SEM)) in the naϊve animals or each pressure. Statistical significance, assigned if p < 0.05, was assessed between different treatments using a two-way analysis of variance (ANOVA) with a Bonferroni's post-test to determine differences between groups.

Results; As shown in Figure 1, 60-minutes following a luminal infusion dilute acetic acid, rats treated with vehicle demonstrate a robust hypersensitivity to colonic distension, shown as significant increases in the VMR at all distension pressures when compared to the naϊve group. Values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group. * p < 0.05, ^ttt p < 0.01 vs. naϊve, two-way ANOVA, Bonferroni post-test.

As shown in Figures 2-6, ATI-7505 demonstrated a dose-responsive inhibition of the elevated VMR with no effect at 0.01 mg/kg and a maximal effect at 1.0 mg/kg. In Figures 2- 6, values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group. As shown, there were no significant differences in the VMR response between the sensitized and ATI-7505 groups at any distension pressure. Figure 7 summarizes the effect of ATI-7505. In figure 7, values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group, f p < 0.05, fff p < 0.001 vs. naϊve (N); * p < 0.05, ** p < 0.01, *** p < 0.001 vs. sensitized (S), two-way ANOVA, Bonferroni post test. hi contrast to the ATI-7505, Cisapride did not significantly inhibit the VMR at either 10 or 50 mg/kg (Figure 8 and 9). hi figures 8 and 9, values represent the mean + SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group.

Additionally, at 100 mg/kg, Cisapride demonstrated a trend to worsen the acetic acid- induced hypersensitivity (Figure 10). Values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group. *** p < 0.001 vs. vehicle, two-way ANOVA, Bonferroni post test. Due to the effect of exacerbating the VMR, the investigation of the 100 mg/kg dose was stopped at n = 4. Example 2:

The effect of ATI-7505 in a rat model of post-inflammatory colonic hypersensitivity

Animals: as described in Example 1. Groups: The following groups of rats were tested: a. Naϊve, n = 8 b. Vehicle, 0.5% methylcellulose, 1.0 ml, p.o. n = 8 c. ATI-7505, 1.0 mg/kg, 1.0 ml, p.o. n = 8

Acclimatization: Following receipt from the vendor, rats were allowed to acclimate to the animal facility and recover from shipping stress for one week. Fasting: as described in Example 1.

Post-Inflammatory Model: Rats were fasted overnight prior to intracolonic dosing. On the day of dosing, animals were briefly anaesthetized with isoflurane (2%) and TNBS (50 mg/kg, 25% ethanol, 0.5 ml dose volume) was administered via a rectal dosing cannula to a distance of 8 cm from the anus. The solution was administered incrementally over the length of the colon. The intracolonic administration of TNBS induced an acute colitis that lasted for approximately one-week. As previously confirmed by morphological, histological and biochemical analysis, TNBS-induced inflammation peaks at day 3 post-enema and was completely healed by day 30. After 23 days, rats were acclimatized to the laboratory environment daily for 7 days. At 30 days post-TNBS dosing, after fasting for 16-18 hours, rats were brought to the laboratory for instrumentation and CRD.

Visceromotor Response (VMR) Instrumentation: as described in Example 1.

Colonic Sensitivity Assessment: In addition to the conditions described in Example 1, in the post-inflammatory model, a qualifying colorectal distension series was performed to determine the colonic sensitivity of each post-inflammatory rat: Three 30 mmHg distensions, with a 10-minute resting period separating distensions, were performed. If a rat failed to have a single 30 mmHg distention producing greater than 14 contractions during the qualifying series, the rat was deemed non-sensitized. Rats that qualified as sensitized then received vehicle or drug (1.0 ml - p.o.). After a 30-minute predose, the rats then underwent the test

CRD series consisting of 15-30-45-60 mmHg 10-minute distensions with 10-minute rest periods.

Drug Dosing: ATI-7505 was administered orally (p.o.) in a volume of 1 ml 0.5% methylcellulose vehicle at the doses previously4isted.

Data and Statistical Analysis: as described in Example 1. Results: As shown in Figure 12, vehicle treated rats demonstrated a significantly increased VMR at 30-60 rnmHg. Values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the naϊve group. ^tt p < 0.01, ^ttt p < 0.01 vs. naϊve, two-way ANOVA, Bonferroni post-test.

ATI-7505 at 1.0 mg/kg significantly inhibited the VMR at 45 and 60 mmHg (Figure 13). Values represent the mean + SEM for the number of abdominal contractions per 10- minute distension normalized as a % of the 60 mmHg response in the naϊve group. ** p < 0.01, *** p < 0.001 vs. sensitized, two-way ANOVA, Bonferroni post test. Figure 14 directly compares the two models of hypersensitivity and the common dose of 1.0 mg/kg ATI-7505. As shown, both models produced a similar level of hypersensitivity, as there were no significant differences between the models at any pressure. Additionally, the inhibition of the hypersensitivity by 1.0 mg/kg ATI-7505 was not significantly different between the two models. Values represent the mean ± SEM for the number of abdominal contractions per 10-minute distension normalized as a % of the 60 mmHg response in the matched vehicle group. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. matched vehicle, two-way ANOVA, Bonferroni post test.

The values illustrated in Figures 1-14 are listed in Tables 1-14:

Table 2: Vehicle (p.o.), Acetic Acid Model: Fig. 1-11

Table 4: ATI-7505, 0.1 mg/kg (p.o.), Acetic Acid Model: Fig. 3, 7

Table 11: Vehicle (p.o.), Post-Inflammatory Model: Fig. 12, 13

Table 13: Vehicle (p.o.), Acetic Acid Model: Fig. 14

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.

Claims

WE CLAIM:

1. A method of treating irritable bowel syndrome, pain of gastrointestinal origin, or colonic hypersensitivity, comprising administering a compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein the bonds at positions 3 and 4 are cis relative to each other;

L is -(C₁-C₆ alkyl)-, -(C₁-C₆ alkyl)-C(O)-, or -C(O)-(Ci-C₆ alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄ alkoxy, or -OH, and wherein one carbon in the alkyl portion of L may be replaced by -N(R₉)-;

R₁ is halogen;

R₂ is -NH₂, -NH(Ci-C₄ alkyl) or -N(C₁-C₄ alkyl)₂; R₃ is -OH or C₁-C₄ alkoxy; R₄ is -H or -CH₃; R₅ is -0-C₃-C₈ cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -O- heteroaryl, -N(Rg)-(C₀-C₆ alkyl)-C(O)-aryl, or -N(Rg)-(C₀-C₆ alkyl)-aryl, -N(Rg)-(C₀- C₆ alkyl)-C(O)-heteroaryl, or -N(Rg)-(C₀-C₆ alkyl)-heteroaryl, wherein each of the cyclic groups is optionally substituted at one or more substitutable positions with Ci-C₆ alkyl, Ci-C₆ alkoxy, halogen, Ci-C₆ haloalkyl, C₁-C₆ haloalkoxy, -OH, hydroxy-C₁-C₄-alkyl, -NH₂, -NH(C₁-C₆ alkyl), -N(Ci-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)R_π, or -0-(C₀-C₆ alkyl)-C(O)R_π, methylsulfone, C₀-C₆-sulfonamide, or -NO₂; wherein

R₉ at each occurrence is independently -H or Ci-C₄ alkyl; Rn is Ci-C₆ alkyl, -OH, or Rn is Ci-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently

C₁-C₄ alkoxy, -NH₂, -NH(Ci-C₆ alkyl), -N(Ci-C₆ alkyl)₂, -(C₀-C₆ alkyl)-C(O)N(R₉)-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C₆(O)N(Rg)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1 , 2, or 3 groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy- Cj-C₆ alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, CF₃, or -OCF₃, the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Ci-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy-Ci-C₆ alkyl,

C₁-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃; or

Rn is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₆ alkyl, Cj-C₆ alkoxy, -OH, hydroxy-d-Ce alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃; and

R₂₀ is C]-C₆ alkoxy, or -OH; to a patient in need of such treatment.

2. The method according to claim 1 for treating irritable bowel syndrome.

3. The method according to claim 1 for treating pain of gastrointestinal origin.

4. The method according to claim 1 for treating colonic hypersensitivity.

5. The method according to any one of claims 1 -4, wherein Ri is -Cl.

6. The method according to any one of claims 1 -5, wherein R₂ is -NH₂.

7. The method according to any one of claims 1-6, wherein R₃ is -OCH₃.

8. The method according to any one of claims 1 -7, wherein R₄ is -H.

9. The method according to any one of claims 1 -8, wherein Ri , R₂, and R₃ have the following orientation on the phenyl ring:

10. The method according to any one of claims 1-9, wherein R₂₀ is -OCH₃.

11. The method according to any one of claims 1-10, wherein L is -(C₂-C₆ alkyl)-C(O)- or -(C₃-C₅ alkyl)-, wherein one carbon may be replaced by -N(R₉)-.

12. The method according to any one of claims 1-11, wherein L is -(C₂-C₆ alkyl)-C(O)-.

13. The method according to any one of claims 1-12, wherein R₅ is -O-heterocycloalkyl, wherein the heterocycloalkyl group is selected from aza-bicyclo-octyl, aza-bicyclo-nonyl, and aza-bicyclo-decyl, each optionally substituted with -CH₃, -CH₂CH₃, piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions with groups that are independently C₁-C₄ alkyl, Cj-C₄ alkoxy, halogen, Cj-C₄ haloalkyl, Ci-C₄ haloalkoxy, -OH, hydroxy-Ci-C₄ alkyl, -NH₂, -NH(C₁-C₄ alkyl), -N(Cj-C₄ alkyl)₂, -(C₀-C₆ 3UCyI)-C(O)R₁ i , or -NO₂, wherein

R₁₁ is C₁-C₆ alkoxy, optionally substituted with 1 or 2 groups that are independently C₁-C₄ alkoxy, -NH₂, -NH(C₁-C₄ alkyl), -N(Ci-C₄ alkyl)₂, -(C₀-C₆ alkyl)- C(O)N(R₉)-heterocycloalkyl, or heterocycloalkyl, wherein the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C₆ alkyl, C₁-C₆ alkoxy, -OH, hydroxy-Ci-C₆ alkyl, Ci-C₆ alkoxycarbonyl, -CO₂H, -CF₃, or -OCF₃.

14. The method according to any one of claims 1-13, wherein R₅ is heterocycloalkyl, which is selected from l-aza-bicyclo[2.2.2]oct-3-yl, and 8-aza-bicyclo[3.2.1]oct-3-yl, where the nitrogen in the 8-aza-bicyclo[3.2.1]oct-3-yl group is optionally substituted with -CH₃, or -CH₂CH₃.

15. The method according to any one of claims 1-14, wherein the compound is:

or a pharmaceutically acceptable salt or solvate thereof.

16. The method according to any one of claims 1-14, wherein the compound is:

17. The method according to any one of claims 1-14, wherein the compound is: (3S)-I -azabicyclo[2.2.2]oct-3-yl 6- {(3S,4i?)-4-[(4-ammo-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l -yl}hexanoate;

(3,S)-l-azabicyclo[2.2.2]oct-3-yl 6-{(3i?,4_JS)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l-yl}hexanoate; (3i?)-l-azabicyclo[2.2.2]oct-3-yl 6-{(3i?,45)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l-yl}hexanoate; 8-methyl-8-azabicyclo[3.2. l]oct-3-yl 6- {(35,4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino] -3 -methoxypiperidin- 1 -yl } hexanoate; 4-[({(35',4i?)-4-[(4-ammo-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl}acetyl)amino]benzoic acid; methyl 4-[({(36^r,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl}acetyl)amino]benzoate; methyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl} acetyl)amino]benzoate; methyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)amino]benzoate; ethyl 4-[({(36',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)amino]benzoate; isopropyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-

1 -yl} acetyl)amino]benzoate;

2-methoxyethyl 4-[({(36',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl } acetyl)amino]benzoate;

2-pyrrolidin-l-ylethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl } acetyl)amino]benzoate; 1 -methylpiperidin-4-yl 4-[( {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)amino]benzoate; 2-pyridin-2-ylethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl } acetyl)amino]benzoate; 2-(dimethylamino)ethyl 4-[({(3₁S',4i?)-4-[(4-amino-5-chloro-2-niethoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl} acetyl)amino]benzoate; l-methylpiperidin-3-yl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl} acetyl)amino]benzoate; 2-morpholin-4-ylethyl 4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}acetyl)amino]benzoate;

1 ,4-dimethylpiperidin-4-yl 4-[( {(3S,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}acetyl)amino]benzoate;

4-[({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidm-l- yl}acetyl)amino]benzoic acid; 2-oxo-2-(piperidin-4-ylamino)ethyl 4-[({(35,4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l-yl}acetyl)amino]benzoate; 1 -( { (3 >S',4i?)-4-[(4-amino- 5 -chloro-2-methoxybenzoyl)amino] -3 -methoxypiperidin- 1 - yl} acetyl)piperidine-4-carboxylic acid; methyl l-({(3iS',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; methyl l-({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; methyl l-({(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; ethyl l-({(35^r,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l- yl } acetyl)piperidine-4-carboxylate; 2-methoxyethyl 1 -( {(35,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-1 -yl} acetyl)piperidine-4-carboxylate; 4- {[(2- {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-l - yl}ethyl)(methyl)amino]methyl}benzoic acid; methyl 4- {[(2- {(35',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl} ethyl)(methyl)amino]methyl }benzoate; methyl 4- {[(2- {(35',4i?)-4-[(4-ammo-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin-l-yl}ethyl)amino]methyl}benzoate; isopropyl 4- {[(2- {(3>S',4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3- methoxypiperidin- 1 -yl} ethyl)amino]methyl }benzoate; ethyl 4- {[(2- {(3₁S,4i?)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxypiperidin-

1 -yl} ethyl)amino]methyl}benzoate Dihydrochloride; (3i?)-l-azabicyclo[2.2.2]oct-3-yl 4-{[(2-{(3,S,4i?)-4-[(4-amino-5-chloro-2- methoxybenzoyl)amino]-3-methoxypiperidin-l-yl}ethyl)amino]carbonyl}benzoate; (R)-quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3- methoxypiperidin- 1 -yl)hexanoate; 6-((3 S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3 -methoxypiperidin- 1 -yl)hexanoic acid; or a pharmaceutically acceptable salt or solvate thereof.