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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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  • C07—ORGANIC CHEMISTRY
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  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups
  • C07C279/32—N-nitroguanidines
• • 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
  • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/38—Amides of thiocarboxylic acids
  • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
  • C07D339/02—Five-membered rings
  • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid

Definitions

• the present invention relates to unique salts of trimebutine and N- monodesmethyl trimebutine, and their corresponding stereoisomers, having improved analgesic properties useful in the treatment of visceral pain in general and more particularly in the treatment of conditions characterized by abdominal pain, for example, in patients with intestinal diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), diabetic gastroparesis, and dyspepsia.
• intestinal diseases such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), diabetic gastroparesis, and dyspepsia.
• Trimebutine [3,4,5-trimethoxybenzoic acid 2-(dimethylamino)-2- phenylbutylester and its maleate salt] has been used in many countries since 1969 for the treatment of functional bowel disorders, including IBS.
• the efficacy of trimebutine to relieve abdominal pain has been demonstrated in various clinical studies (see, for example, Ghidini et al (1986) Single drug treatment for irritable colon: Rociverine versus trimebutine maleate. Curr Ther Res 39: 541 -548).
• Trimebutine has proved to be effective in the treatment of both acute and chronic abdominal pain in patients with functional bowel disorders, especially IBS, at doses ranging from 300 to 600 mg/day. It is also effective in children presenting with abdominal pain.
• trimebutine On the gastrointestinal tract are mediated in part via (i) an agonist effect on peripheral mu, kappa and delta opiate receptors and (ii) release of gastrointestinal peptides such as motilin and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and glucagon. Further, trimebutine accelerates gastric emptying, induces premature phase 111 of the migrating motor complex in the intestine and modulates the contractile activity of the colon. Recently,
• DMSLegal ⁇ D54688 ⁇ 00001 ⁇ 2632164vl 1 trimebutine has also been shown to decrease reflexes induced by distension of the gut lumen in animals to modulate visceral sensitivity.
• Nitric oxide (NO) been recently been shown to exert many antiinflammatory effects, including reduction of leukocyte adherence to the vascular endothelium (Gauthier et al (1994) Nitric oxide attenuates leukocyte- endothelial interaction via P-selectin in splanchnic ischemia-reperfusio ⁇ . Am J Physiol 267: G562-G568) and suppression of production of various chemotactic factors (Walford and Loscalzo (2003) Nitric oxide in vascular biology. J Thromb Haemost V. 2112-2118). Further, incorporation of an NO-releasing moiety into certain drugs such as NSAIDs, acetaminophen and ursodexycholic acid has been shown to enhance activities of these drugs and reduce toxicity relative to the parent drug.
• Hydrogen sulfide is another type of gaseous mediator that may exert anti-inflammatory effects. Recently it has been shown that H 2 S releasing agents exhibit analgesic activity in models of visceral pain (Distrutti et al (2005) Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KAT P channels. J Pharmacol Exp Ther 316: 325-335. Further, H 2 S has been shown to be a smooth muscle relaxant in intestinal tissues (see Teague, B. et al. (2002) The Smooth Muscle Relaxant effect of Hydrogen Sulfide In Vitro: Evidence for a Physiological Role to Control Intestinal Contractility. Br. J. Pharmacol. 137: 139-145.
• trimebutine is significantly enhanced when salts of trimebutine or N- monodesmethyl trimebutine and their corresponding stereoisomers are formed with various NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moieties.
• administration of these NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing salts of trimebutine and N-monodesmethyl trimebutine results in improved analgesic properties when compared to trimebutine (trimebutine maleate) or its metabolite N-monodesmethyl trimebutine alone and when compared to the NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moiety alone.
• These salts are particularly useful in the treatment of conditions characterized by abdominal pain such as such as irritable bowel syndrome, inflammatory bowel disease, diabetic gastroparesis, dyspepsia and the like.
• salts of trimebutine (TMB) and its active metabolite N- desmethyl trimebutine (Nor-TMB) and their corresponding stereoisomers (R)- TBM, (S)-TMB 1 (fl)-Nor-TBM and (S)-Nor-TBM, are provided, said salts being formed using NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moieties.
• the TMB and Nor-TMB salts of the present invention are superior to TMB and Nor-TMB alone and to an NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moiety alone in reducing visceral pain associated with colorectal distension.
• the NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moieties alone did not appear to have any significant effects on visceral pain associated with colorectal distension when administered alone.
• the salts of the present invention are useful in alleviating pain associated with any disorder of the digestive system that is associated with abdominal pain.
• salts of the invention have the following general formula:
• X is a NO-releasing, H 2 S-releasing or combined NO- and H 2 S-releasing moiety.
• X is selected from the group consisting of:
• any non-toxic, effective NO-releasing, H2S-releasing or combined NO- and H 2 S-releasing moiety can be used in the present invention.
• Preferred compounds are those of the following formulae:
• novel combined NO- and H 2 S-releasing moieties are provided having the general formula ' , nitroarginine-R, preferably:
• R is an H 2 S-releasing moiety.
• R is selected from the group consisting of 5-p-hydroxyphenyl-1 ,2-dithione-3-thione, cysteine, and 4-(thiocarbamoyl) benzoic acid.
• a method for treating visceral pain in a subject in need of such treatment comprising administering to the subject a visceral pain relieving amount of a compound of the present invention.
• the visceral pain is abdominal pain.
• the abdominal pain is due to intestinal diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), diabetic gastroparesis, and dyspepsia.
• Figure 1 shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle and trimebutine maleate.
• Figure 1(b) shows the colorectal pressure (mmHg) in a rat model of visceral pain perception using vehicle and trimebutine maleate alone.
• Figure 2(a) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle and nitroarginine alone.
• Figure 2(b) shows the colorectal pressure (mmHg) in a rat model of visceral pain perception using vehicle and nitroarginine alone.
• Figure 3(a) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle and trimebutine nitroargininate (salt I).
• Figure 3(b) shows the colorectal pressure (mmHg) in a rat model of visceral pain perception using vehicle and trimebutine nitroargininate (salt I).
• Figure 4(a) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle or trimebutine nitroargininate (salt I), with or without pretreatment with L-NAME.
• Figure 4(b) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle or trimebutine nitroargininate (salt I), with or without pretreatment with methylene blue.
• Figure 5(a) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle, trimebutine maleate and trimebutine thiocarbamoylbenzoate (salt III).
• Figure 5(b) shows the perception score (AWR Score) in a rat model of visceral pain perception using vehicle and thiocarbamoylbenzoate (TBZ) alone.
• Figure 6 is a bar graph showing H 2 S generation of 4-(thiocarbamoyl) benzoic acid (TBZ) and 5-(4-amino-phenyl)-[1 ,2]dithiole-3-thione (ADT-OH).
• the compounds of the present invention contain two active moieties, (1) either TMB or Nor-TMB, or their stereoisomers, and (2) an NO-releasing moiety, an H 2 S-releasing moiety, or combined NO- and H 2 S-releasing moieties ' .
• the salts of the present invention can be made using known starting materials and reagents.
• Compounds of the present invention may be utilized for the treatment of visceral pain, such as abdominal pain, associated with various diseases, including, but not limited to, Crohn's disease, ulcerative colitis, irritable bowel syndrome, infectious colitis ⁇ e.g., pseudomembranous colitis such as Clostridium difficile colitis, salmonella enteritis, shigella infections, yersiniosis, cryptospiridiosis, microspridial infections, and viral infections), radiation-induced colitis, colitis in the immunocompromised host, diabetic gastroparesis and dyspepsia.
• infectious colitis ⁇ e.g., pseudomembranous colitis such as Clostridium difficile colitis, salmonella enteritis, shigella infections, yersiniosis, cryptospiridiosis, microspridial infections, and viral infections
• radiation-induced colitis colitis in the immunocompromised host, diabetic gastroparesis and dyspepsia.
• subjects may be administered compounds of the present invention at any suitable therapeutically effective and safe dosage, as may be readily determined within the skill of the art. These compounds are, most desirably, administered in dosages ranging from about 1 to about 2000 mg per day, in a single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.1 to about 100 mg/kg, preferably between about 5 and 90 mg/kg, and more preferably between about 5 and 50 mg/kg, is most desirable.
• Variations may nevertheless occur depending upon the weight and conditions of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such large doses are first divided into several small doses for administration throughout the day.
• the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which will depend upon the route of administration.
• These pharmaceutical compositions can be prepared by conventional methods, using compatible, pharmaceutically acceptable excipients or vehicles. Examples of such compositions include capsules, tablets, transdermal patches, lozenges, troches, sprays, syrups, powders, granulates, gels, elixirs, suppositories, and the like, for the preparation of extemporaneous solutions, injectable preparations, rectal, nasal, ocular, vaginal etc.
• a preferred route of administration is the oral and rectal route.
• tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting
• compositions of similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
• preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
• the active ingredient may be combined with sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
• the dosage form can be designed for immediate release, controlled release, extended release, delayed release or targeted delayed release.
• the definitions of these terms are known to those skilled in the art.
• the dosage form release profile can be effected by a polymeric mixture composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition. Without wishing to be bound by theory, it is believed that the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange; osmosis or combinations thereof.
• a solution of an active salt in either sesame or peanut oil or in aqueous propylene glycol can be employed.
• the aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic.
• the aqueous solutions are suitable for intravenous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
• DMSU8-l ⁇ 054688VXXX)I ⁇ 2632164vl 14 was dissolved in water and 1N NaOH was slowly added to obtain 2-(2-amino-3- mercapto-propionyiamino)-5-nitroguanidino-pentanoic acid (b) as a white solid which was recovered by filtration.
• Rats male, Wistar, 200- 250 g, obtained from Charles River, Monza, Italy
• Rats were housed in plastic cages and maintained under controlled conditions with 12-hours light/dark cycle with lights on at 7.00 AM. Tap water and standard laboratory chow were freely available.
• rats were individually trained by spending 2-3 hours per day in a plexiglass cage for 2-3 days. It allowed them to adjust to a movement-restriction environment. Food was withheld for 12 hours before colorectal distension (CRD) recording were performed.
• CCD colorectal distension
• rats were sedated with ether inhalation and a 2 cm long latex balloon was inserted intrarectally 2 cm from the anal verge and fixed at the base of the tail.
• the balloon was connected via a double-barreled cannula to a pressure transducer to continuously monitoring the rectal pressure by a computer (PowerLab PC, A.D. Instruments, Milford, MA, USA) and to a syringe for inflation/deflation of the balloon.
• the rats were then housed in a small cage (20 x 8 x 8 cm) on an elevated PlexiglasTM platform and allowed to wake up and adapt for 1 hour. After recovery from sedation, animals underwent the CRD procedure and behavioral responses were tested. The night before the experiments, the balloons were inflated and left overnight so the latex stretched and the balloons became compliant.
• AWR abdominal withdrawal reflex
• the AWR is an involuntary motor reflex similar to the visceromotor reflex, but it has the great advantage that, in contrast to the latter, it does not require abdominal surgery to implant recording electrodes and wires in the abdominal muscle wall which may cause additional sensitization (see Ness, TJ. and Gebhart, G. F. (1990) Pain 41 : 167-234, incorporated herein by reference).
• Measurement of the AWR consisted of visual observation of the animal response to graded CRD by blinded observer and assignment of an AWR score according with the behavioral scale as previously described in Al-Chaer, E.D. et al.
• grade 0 corresponds to no behavioral response to CRD
• grade 1 corresponds to brief head movement at the onset of the stimulus followed by immobility
• grade 2 corresponds to a mild contraction of abdominal muscles although the rats does not lift the abdomen off the platform
• grade 3 corresponds to a strong contraction of the abdominal muscles with the lifting of the abdomen off the platform
• grade 4 corresponds to a severe contraction of the abdominal muscle manifested by body arching and the lifting of the abdomen and of the pelvic structures and scrotum.
• trimebutine maleate, nitroarginine and trimebutine nitroargininate were determined using a total of 15 fasting rats.
• trimebutine maleate, nitroarginine and trimebutine nitroargininate could reduce pain induced by CRD, after the first sequence of CRD (vehicle-treated), 5 rats were treated with trimebutine maleate at a dose of 10 mg/kg i.p., nitroarginine at a dose of 6 mg/kg or trimebutine nitroargininate at the dose of 16 mg/kg i.p., after
• Figures 1 (a), 2(a) and 3(a) show that trimebutine nitroargininate is more effective than either trimebutine maleate or nitroarginine in reducing visceral pain in response to colorectal distension. However, none of the compounds were particularly effective in reducing intrarectal pressure, as shown in Figures
• trimebutine nitroargininate is useful in treating abdominal pain associated with various inflammatory conditions of the alimentary tract, as well as functional gastrointestinal disorders such as irritable bowel syndrome, dyspepsia, etc., that are characterized by increased visceral nociception (with or without accompanying inflammation).
• Example 11 Experiments were carried out as described in Example 11 , except that groups of 5 rats each were treated with vehicle, trimebutine maleate (10 mg/kg), or with equimolar doses of trimebutine thiocarbamoylbenzoate (salt III) or thiocarbamolybenzoate alone.
• Figures 5(a) and 5(b) show that trimebutine thiocarbamoylbenzoate is more effective than either trimebutine maleate or thiocarbamoylbenzoate in reducing visceral pain in response to colorectal distension.
• trimebutine thiocarbamoylbenzoate is useful in treating abdominal pain associated with various inflammatory conditions of the alimentary tract, as well as functional gastrointestinal disorders such as irritable bowel syndrome, dyspepsia, etc., that are characterized by increased visceral nociception (with or without accompanying inflammation).
• DMSUg-] ⁇ O5 «88 ⁇ OOOOl ⁇ 2632164vl 38 corresponding vehicle-treated group.
• the alpha ( ⁇ ) represents a significant decrease in H 2 S synthesis as a result of incubation in the presence of PAG.

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