WO2010062959A1 - Agonistes de récepteur de 5-ht4 pour traiter le syndrome du côlon irritable et l’hypersensibilité du côlon - Google Patents

Agonistes de récepteur de 5-ht4 pour traiter le syndrome du côlon irritable et l’hypersensibilité du côlon Download PDF

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Publication number
WO2010062959A1
WO2010062959A1 PCT/US2009/065925 US2009065925W WO2010062959A1 WO 2010062959 A1 WO2010062959 A1 WO 2010062959A1 US 2009065925 W US2009065925 W US 2009065925W WO 2010062959 A1 WO2010062959 A1 WO 2010062959A1
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Prior art keywords
amino
alkyl
chloro
methoxypiperidin
methoxybenzoyl
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PCT/US2009/065925
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English (en)
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Johnson Watson Mcrorie
Russell David Spruell
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Aryx Therapeutics, Inc.
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Publication of WO2010062959A1 publication Critical patent/WO2010062959A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the disclosure provides 5-HT 4 receptor agonist compounds for treatment of functional bowel disorders, pain associated with bowel disorders, or colonic hypersensitivity.
  • IBS irritable bowel syndrome
  • IBS intra-bowel syndrome
  • 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.
  • IBS patients have a lower threshold to pain on distension of a balloon catheter in the gastrointestinal tract (GI), compared to healthy controls.
  • GI gastrointestinal tract
  • 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.
  • the disclosure provides 5-HT 4 receptor agonist compounds for treatment of functional bowel disorders, pain associated with bowel disorders, or colonic hypersensitivity.
  • 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):
  • L is -(C 1 -C 6 alkyl)-, -(Ci-C 6 alkyl)-C(O)-, or -C(O)-(C 1 -C 6 alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen,
  • R 4 is -H or -CH 3 ;
  • R 5 is -0-C 3 -C 8 cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -O- heteroaryl, -N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl, or -N(R 9 )-(C 0 -C 6 alkyl)-aryl, -N(R 9 )-(C 0 - C 6 alkyl)-C(O)-heteroaryl, or -N(R 9 )-(C 0 -C 6 alkyl)-heteroaryl, wherein each of the cyclic groups is optionally substituted at one or more substitutable positions with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, Ci-C 6 haloalkyl, C 1 -C 6 haloalkoxy, -OH, hydroxy-Q
  • R 9 at each occurrence is independently -H or Ci-C 4 alkyl
  • Rn is Ci-C 6 alkyl, -OH, or
  • Rn is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently
  • Ci-C 4 alkoxy -NH 2 , -NH(C 1 -C 6 alkyl), -N(Ci-C 6 alkyl) 2 , -(C 0 -C 6 alkyl)-C(O)N(R 9 )-heterocycloalkyl, -O-heterocycloalkyl,
  • heterocycloalkyl groups are optionally substituted with 1 , 2, or 3 groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -OH, hydroxy- C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or -OCF 3
  • the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C 6 alkyl, Ci-C 6 alkoxy, -OH, hydroxy-Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, -CF 3 , or -OCF 3
  • Rn is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with
  • R 20 is C 1 -C 6 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:
  • L is -(C 1 -C 6 alkyl)-, -(Cj-C 6 alkyl)-C(O)-, or -C(O)-(Ci-C 6 alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently halogen, Ci-C 4 alkoxy, or -OH, and wherein one carbon in the alkyl portion of L may be replaced by -N(Rg)-; R 1 is halogen;
  • R 2 is -NH 2 , -NH(C 1 -C 4 alkyl) or -N(Cj-C 4 alkyl) 2 ;
  • R 3 is -OH or Ci-C 4 alkoxy;
  • R 4 is -H or -CH 3 ;
  • R 5 is -0-C 3 -C 8 cycloalkyl, -O-heterocycloalkyl, heterocycloalkyl, aryl, -O-aryl, -O- heteroaryl, -N(R 9 )-(C 0 -C 6 alkyl)-C(O)-aryl, or -N(Rg)-(C 0 -C 6 alkyl)-aryl, -N(Rg)-(C 0 - C 6 alkyl)-C(O)-heteroaryl, or -N(Rg)-(C 0 -C 6 alkyl)-heteroaryl, wherein each of the cyclic groups is optionally substituted at one or more substitutable positions with C 1 -C 6 alkyl, Cj-C 6 alkoxy, halogen, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, -OH, hydroxy-C 1 -C 4
  • Rg at each occurrence is independently -H or Ci-C 4 alkyl; Rn is Ci-C 6 alkyl, -OH, or
  • Rn is Cj-C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C-C 4 alkoxy, -NH 2 , -NH(C-C 6 alkyl), -N(Cj-C 6 alkyl) 2 , -(C 0 -C 6 alkyl)-C(O)N(Rg)-heterocycloalkyl, -O-heterocycloalkyl, -Ci-C 6 (O)N(Rg)-heteroaryl, or heteroaryl, wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C 6 alkyl, Cj-C 6 alkoxy, -OH, hydroxy- Ci-C 6 alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, CF 3 , or -OCF 3 , the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen,
  • R 1 is -O-heterocycloalkyl wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, Cj-C 6 alkyl, Cj-C 6 alkoxy,
  • R 20 is C 1 -C 6 alkoxy, or -OH.
  • 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.
  • FIG 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 14 Summary of the effect of ATI-7505, 1.0 mg/kg p.o., in two models of colonic hypersensitivity.
  • 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 R 1 of formula (I) is -Cl.
  • Another embodiment of the disclosure provides a method according to any previous embodiments, wherein R 2 of formula (I) is -NH 2 .
  • Yet another embodiment of the disclosure provides a method according to any previous embodiments, wherein R 3 of formula (I) is -OCH 3 .
  • One embodiment of the disclosure provides a method according to any previous embodiments, wherein R 4 of formula (I) is -H.
  • Another embodiment of the disclosure provides a method according to any previous embodiments, wherein Rj, R 2 , and R 3 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 R 1 is -Cl, R 2 is -NH 2 , R 3 is -OCH 3 , and R 4 is -H.
  • R 1 is -Cl
  • R 2 is -NH 2
  • R 3 is -OCH 3
  • R 4 is -H.
  • the orientation OfR 1 , R 2 , and R 3 is as follows:
  • Yet another embodiment of the disclosure provides a method according to any previous embodiments, wherein R 20 of formula (I) is -OCH 3 .
  • L of formula (I) is -(C 2 -C 6 alkyl)-C(O)- or -(C 3 -C 5 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 -(C 2 -C 6 alkyl)-C(O)-.
  • R 5 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 -CH 3 , -CH 2 CH 3 , 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-C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 4 haloalkyl, Q-C 4 haloalkoxy, -OH, hydroxy-Q-Q alkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -N(
  • 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-C 6 alkyl, Ci-C 6 alkoxy, -OH, hydroxy-CrC ⁇ alkyl, Ci-C 6 alkoxycarbonyl, -CO 2 H, -CF 3 , or -OCF 3 .
  • 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 -(C 2 -C 6 alkyl)- C(O)-, and R 5 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 -CH 3 , -CH 2 CH 3 , piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions with groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C
  • R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2j -(C 0 -C 6 alkyl)- C(O)N(R 9 )-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-C 6 alkyl, C 1 -C 6 alkoxy, -OH, hydroxy-Ci-C 6 alkyl, C 1 -C 6 alkoxycarbonyl, -CO 2 H, -CF 3 , or -OCF 3 .
  • 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 R 1 is -Cl, R 2 is -NH 2 , R 3 is -OCH 3 , R 4 is -H, L of formula (I) is -(C 2 -C 6 alkyl)-C(O)-, and R 5 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 -CH 3 , -CH 2 CH 3 , piperidinyl, piperazinyl, and pyrrolidinyl, wherein the piperidinyl, piperazinyl, and pyrrolidinyl groups are optionally substituted at one or two positions
  • R 11 is C 1 -C 6 alkoxy, optionally substituted with 1 or 2 groups that are independently C 1 -C 4 alkoxy, -NH 2 , -NH(Cj-C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , -(C 0 -C 6 alkyl)- C(O)N(R 9 )-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-C 6 alkyl, Ci-C 6 alkoxy, -OH, hydroxy-d-C 6 alkyl, Cj-C 6 alkoxycarbonyl, -CO 2 H, -CF 3 , or -OCF 3 .
  • R 5 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 -CH 3 , Or-CH 2 CH 3 .
  • 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:
  • the disclosure provides a method of treating irritable bowel syndrome, comprising administering this compound.
  • 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:
  • the disclosure provides a method of treating irritable bowel syndrome, comprising administering ATI-7505.
  • the disclosure provides a method of treating pain of gastrointestinal origin, comprising administering ATI-7505.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • 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).
  • 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
  • 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 ⁇ 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.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • 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.
  • 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.
  • DMSO dimethylsulfoxide
  • 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.
  • Effective dosages may be estimated initially from in vitro activity and metabolism assays.
  • 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.
  • 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.
  • 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.
  • 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.
  • “propyl” includes n-propyl and iso-propyl
  • ⁇ c butyl includes n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • aryloxy means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • 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[3.3.1.0 3 ' 7 ]nonane and tricyclo[3.3.1.1 ' ]decane (adamantane).
  • 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 -CF 3 or -CF 2 CF 3 .
  • 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-C 6 alkyl) denotes a haloalkyl having in the range of from 1 to 6 carbons.
  • 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 CF 3 .
  • 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-C 6 alkoxy) denotes a haloalkoxy having in the range of from 1 to 6 carbons.
  • 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.
  • 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.
  • 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.
  • heterocycloalkyl 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.
  • 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.
  • 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
  • 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 e.g., aza-bicyclo-decyl.
  • 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.
  • structural and/or functional analogs of cisapride are administered as the free base or as the mono or dihydrochloride salt.
  • treatment 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.
  • 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.
  • 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.
  • 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-HT 4 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.
  • 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-HT 4 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.
  • 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.
  • VMR Visceromotor Response
  • 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.
  • 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.
  • CRD colorectal distension
  • 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 na ⁇ ve 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.
  • ANOVA analysis of variance
  • 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.
  • 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 na ⁇ ve group.
  • Figure 7 summarizes the effect of ATI-7505.
  • 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 na ⁇ ve group, f p ⁇ 0.05, fff p ⁇ 0.001 vs. na ⁇ ve (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).
  • 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 na ⁇ ve group.
  • Example 2 Example 2:
  • mice 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.
  • TNBS 50 mg/kg, 25% ethanol, 0.5 ml dose volume
  • VMR Visceromotor Response
  • 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.
  • ATI-7505 was administered orally (p.o.) in a volume of 1 ml 0.5% methylcellulose vehicle at the doses previously4isted.
  • 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 na ⁇ ve 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.
  • Table 11 Vehicle (p.o.), Post-Inflammatory Model: Fig. 12, 13
  • Table 13 Vehicle (p.o.), Acetic Acid Model: Fig. 14

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Abstract

La présente invention concerne des composés agonistes de récepteur de 5-HT4 pour le traitement de troubles intestinaux fonctionnels, de la douleur associée à des troubles intestinaux, ou l’hypersensibilité du côlon. Les composés agonistes de récepteur de 5-HT4 ont la formule suivante : (I)
PCT/US2009/065925 2008-11-26 2009-11-25 Agonistes de récepteur de 5-ht4 pour traiter le syndrome du côlon irritable et l’hypersensibilité du côlon WO2010062959A1 (fr)

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US8524736B2 (en) 2004-01-07 2013-09-03 Armetheon, Inc. Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders
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CN110950843A (zh) * 2019-11-28 2020-04-03 广东东阳光药业有限公司 取代的苯酰胺衍生物及其用途
CN113412817A (zh) * 2021-05-31 2021-09-21 成都中医药大学附属医院 提高成模率减少死亡率的ibs-d实验动物模型方法
US20210355116A1 (en) * 2018-11-05 2021-11-18 Renexxion, Llc Methods of producing naronapride trihydrate
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US8138204B2 (en) 2004-01-07 2012-03-20 Aryx Therapeutics, Inc. Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders
US8524736B2 (en) 2004-01-07 2013-09-03 Armetheon, Inc. Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders
US20100105727A1 (en) * 2007-03-16 2010-04-29 Dong-A-Pharm. Co., Ltd. Novel benzamide derivatives and process for the prepartion thereof
US9221790B2 (en) 2010-04-23 2015-12-29 Dong-A Pharm. Co., Ltd. Benzamide derivatives
US20210355116A1 (en) * 2018-11-05 2021-11-18 Renexxion, Llc Methods of producing naronapride trihydrate
US11498918B2 (en) * 2018-11-05 2022-11-15 Renexxion, Llc Methods for the treatment of gastro-intestinal disorders
US11643409B2 (en) 2018-11-05 2023-05-09 Renexxion, Llc Material for the treatment of gastro-intestinal disorders
US11827631B2 (en) 2018-11-05 2023-11-28 Renexxion, Llc Methods for the treatment of gastro-intestinal disorders
CN110950843A (zh) * 2019-11-28 2020-04-03 广东东阳光药业有限公司 取代的苯酰胺衍生物及其用途
CN110950843B (zh) * 2019-11-28 2022-12-27 广东东阳光药业有限公司 取代的苯酰胺衍生物及其用途
CN113412817A (zh) * 2021-05-31 2021-09-21 成都中医药大学附属医院 提高成模率减少死亡率的ibs-d实验动物模型方法
CN113412817B (zh) * 2021-05-31 2022-07-12 成都中医药大学附属医院 提高成模率减少死亡率的ibs-d实验动物模型方法

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