Classifications

• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • 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
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

• the present invention relates to the use of certain glycol derivatives of xanthines, in medicine, particularly in the treatment and prophylaxis of irritable bowel syndrome and functional dispepsia.
• Irritable bowel syndrome is a disease diagnosed positively by the presence of clinical features meeting the Rome criteria and by the exclusion of organic pathology justifying the symptoms.
• the Rome criteria for irritable bowel syndrome include continuous or recurrent symptoms of: abdominal pain or discomfort that is releived by defaecation; and/or associated with a change in frequency of stool; and/or associated with a change in consistency of stool; and two or more of the following: altered stool frequency, altered stool form, passage of mucus, and bloating or feeling of abdominal distention. IBS symptoms are reported in up to 22% of the population, with prevalence inwomen.
• Certain pathophysiological mechanisms are known to lead to or aggravate irritable bowel syndrome, including abnormal motility, abnormal visceral perception, psychological distress and luminal factors irritating the small bowel or colon such as lactose, bile acids, short-chain fatty acids and food allergans.
• IBS may present as diahrrea-predominant, constipation-predominant or alternating diahrrea and constipation forms.
• dyspepsia is a distinct type of dyspepsia.
• the term "dyspepsia” is defined as the general condition of indigestion and as such encompasses a variety of distinct dyspeptic conditions.
• There are several recognized types of dyspepsia the most common being acid-related dyspepsia which is associated with excess gastric acidity and may lead to peptic ulcers, gastroesophageal reflux disease (GERD), and other conditions characterized by excess gastric acidity.
• Functional dyspepsia (FD) is not associated with excess gastric acidity. Rather, the primary pathophysiological causative factor for FD is unclear.
• FD is a visceral hypersensitivity state characterized by chronic or recurrent upper abdominal symptoms in the absence of any identifiable organic pathology, such as peptic ulceration, gastric cancer, chronic pancreatitis or GERD.
• identifiable organic pathology such as peptic ulceration, gastric cancer, chronic pancreatitis or GERD.
• the absence of identifiable organic pathology is established using conventional techniques including endoscopy, radiography, histology, and other techniques known to those skilled in the art.
• the primary symptoms of FD include upper abdominal pain or discomfort (often aggravated by food or milk or occurring after meals), early satiety (which can lead to weight loss or anorexia), nausea and vomiting, bloating, belching, and post-prandial fullness.
• FD has been divided into subtypes based upon the predominant symptom(s) observed in the patient. "Ulcer-like” FD is characterized primarily by pain. "Reflux-like” FD is primarily characterized by heartburn that is often alleviated by acid-suppressing agents. It is believed that most cases of reflux-like FD can actually be attributed to GERD, and is not actually FD because the condition can be associated with an organic pathology.
• FD “Dysm otility- 1 ike” FD is characterized primarily by discomfort, bloating, nausea, vomiting, early satiety, and post-prandial fullness. "Unspecified” FD refers to FD patients having symptoms that do not fit into the above categories. Typically FD patients exhibit symptoms across the various sub-types. The conventional treatment options for FD reflect the assumption that FD is attributable to the foregoing pathophysiological factors. The conventional treatment options for FD have proven to be of limited efficacy in many patients.
• n and n are independently integers from 0 to 10;
• X and Y are independently oxygen or sulphur
• a and B are independently methyl, branched C3_g alkyl, C3_s cycloalkyl or C3_g cycloal enyl; and salts, solvates and pharmaceutically acceptable esters and amides thereof; and their use in treatment of inflammatory diseases, immune disorders, septic shock, circulatory disorders and gastrointestinal inflammation, infection or damage.
• X is -0- or -NH-
• Q is (-CH2-) Pl (-O ⁇ C-)p where p is an integer of from 0 to 4;
• R 1 is hydrogen or methyl
• R 2 and R 3 independently represent 0 or S n is an integer of 1 to 50;
• R is hydrogen or methyl; and solvates and amides thereof; and their use in treatment of inflammatory conditions and immune disorders.
• Z represents a 5 or 6 membered cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl, said cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl optionally containing one or more heteroatoms selected from 0, N or S;
• R 1 represents hydrogen or methyl
• R 2 represents hydrogen, C1-12, alkyl, aryl, or aralkyl
• k represents 0 or 1 n represents an integer of 1 to 50;
• X represents -0-, -N(H)-, -N(C,-6alkyl)-, -N(C 3 -8cycloalkyl)-, -N(C ⁇ - 8 alkyl)(C 3 -8 cycloalkyl), - N[(CH 2 CH2 ⁇ ) m (C ⁇ -i2 alkyl, aryl, or aralkyl)]-, -CH2O-, -CH2NH-,
• p and p 1 independently represent an integer of from 0 to 4
• y and y' independently represent integers from 0 to 10;
• R 3 represents H, straight or branched Ci-i ⁇ alkyl (optionally substituted by phenyl, -CO- phenyl, CN, -CO(G- 3 ) alkyl, -C ⁇ 2(C ⁇ -3)alkyl, or containing one or more 0 atoms in the alkyl chain); C1-6 straight or branched alkenyl (optionally substituted by phenyl, -CO- phenyl,
• CN -CO(C ⁇ - 3 ) alkyl, -COzfCi-aJalkyl, or containing one or more 0 atoms in the alkyl chain); C1-6 straight or branched alkynyl or a group -C ⁇ -3alkyl -NR 8 R 9 wherein R 8 and R 9 are independently H, C ⁇ - 3 alkyl or together form a 5 or 6 membered heterocyclic group, optionally containing other heteroatoms selected from 0, N or S;
• R 4 and R 5 independently represent
• heterocyclic group or subsituted heterocyclic group including heteroaryl and substituted heteroaryl groups
• R 6 and R 7 independently represent 0 or S; with the proviso that when
• -R 2 represents H or Me
• -R 3 represents H
• -X represents 0 or NH
• -Z represents phenyl
• R 4 and R 5 do not both represent cyclohexyl; and solvates thereof, and their use in treatment of inflammatory diseases, immune disorders, septic shock, circulatory disorders and gastrointestinal inflammation, infection or damage.
• the present invention provides a method for the treatment or prophylaxis of irritable bowel syndrome in an animal, comprising administering a therapeutically effective amount of a compound of formula (I):
• Z is selected from the group consisting of Cs-ecycloalkyl, Csaryl, substituted Cs-ecycloalkyl, substituted Csaryl, 5- or 6-membered heterocyclic group, substituted 5- or 6- membered heterocyclic group, 5- or 6-membered heteroaryl and substituted 5- or 6-membered heteroaryl;
• R 1 is H or methyl;
• R 2 is H, C ⁇ -i2alkyl, aryl, or aralkyl;
• k is O or 1 ;
• n is an integer 1 to 50;
• X is selected from the group consisting of -0-, -N(H)-, -N(C ⁇ - 6 alkyl)-, -N(C 3 -8cycloalkyl)-, -N(C ⁇ -salkyl)(C3-8 cycloalkyl), and -N[(CH 2 CH20)m(Ci-i2 alkyl, aryl, or aralkyl)]-;
• m is 0-12;
• H straight or branched G- ⁇ alkyl wherein said alkyl may optionally be substituted with a functional group selected from the group consisting of phenyl, -CO-phenyl, CN, -CO(C ⁇ -3)alkyl, -C ⁇ 2(C ⁇ - 3 alkyl), and wherein said Ci-ualkyl may optionally have one or more 0 atoms in the alkyl chain; straight or branched C2-6alkenyl; straight or branched C2-ealkynyl; and
• R 8 and R 9 are each independently selected from the group consisting of H and C ⁇ -3alkyl or R 8 and R 9 together with the N to which they are bonded form a 5- or 6-membered heterocyclic group, optionally containing 1 or 2 other heteroatoms selected from the group consisting of 0, N and S;
• R 4 and R 5 are each independently selected from the group consisting of -C3-8cycloalkyl,
• R 6 and R 7 are each independently 0 or S; or a pharmaceutically acceptable solvate thereof.
• the present invention provides a method for the treatment or prophylaxis of functional dyspepsia in an animal.
• the method comprises administering to the animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable solvate thereof.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable solvate thereof for the preparation of a medicament for the treatment or prophylaxis of irritable bowel syndrome in an animal.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable solvate thereof for the preparation of a medicament for the treatment or prophylaxis of functional dyspepsia in an animal.
• the present invention provides a method for the treatment or prophylaxis of irritable bowel syndrome in an animal comprising administering to the animal a therapeutically effective amount of an endothelial cell adhesion molecule inhibitor.
• the present invention provides a method for the treatment or prophylaxis of functional dyspepsia in an animal comprising administering to the animal a therapeutically effective amount of an endothelial cell adhesion molecule inhibitor.
• the present invention provides the use of an endothelial cell adhesion molecule inhibitor for the preparation of a medicament for the treatment or prophylaxis of irritable bowel syndrome in an animal.
• the present invention provides the use of an endothelial cell adhesion molecule inhibitor for the preparation of a medicament for the treatment or prophylaxis of functional dyspepsia in an animal.
• Figure 1 is a graphical representation of the results of a study conducted in Zymosan- sensitized rats comparing the effect of (E)-4-(1 ,3-bis(cyclohexylmethyl)-1 ,2,3,6- tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid nonaethylene glycol methyl ether ester (1 12.5 and 25 mg/kg) versus vehicle. Results are reported as response to colorectal distention (CRD) (as a percent of control) with increasing dosage of 0, 12.5, and 25 mg/kg of compound (sensitized -- ⁇ --) as compared to baseline (— ⁇ --).
• CCD colorectal distention
• aryl refers to a carbocyclic group having 6-14 carbon atoms with at least one aromatic ring (e.g., phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e.g., 1 , 2, 3, 4,-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
• substituted aryl refers to aryl as defined above optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• functional groups e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• aralkyl refers to a G-i ⁇ alkyl that may be a straight or a branched alkyl group that is substituted by an aryl or substituted aryl group.
• heterocylic group refers to a saturated or partially unsaturated, non-aromatic group having from 5 to 12 members in a single ring (e.g. imidazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazylyl, thiadiazolyl, triazolyl or tetrazolyl) or multiple condensed rings (e.g.
• heterocyclic group can optionally be unsubstituted or substituted (i.e., a "substituted heterocyclic group") with e.g.
• halogen lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocyclic group, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• heteroaryl refers to a heterocyclic group as defined above in which at least one ring is aromatic.
• substituted heteroaryl refers to a heterocyclic group optionally substituted with one or more substituents including halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• cycloalkyl in reference to any of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic group, substituted heterocyclic group, heteroaryl and substituted heteroaryl refers to the total number of atoms (C, N, O and S) in the ring.
• a 6-membered aryl is phenyl and a 6-membered heteroaryl is pyridine.
• alkyl as used herein represents straight or branched hydrocarbon chains containing the indicated number of carbon atoms.
• alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and one or more double bonds, for example propenylene.
• cycloalkyl includes non-aromatic carbocyclic groups containing the specified number of carbon atoms and one or more double bonds, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane and includes bridged cycloalkyl groups, for example norbornyl.
• substituted alkyl and “substituted cycloalkyl” refer to alkyl and cycloalkyl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• functional groups e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
• solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula (I)) and a solvent.
• Solvents include water, methanol, ethanol, or acetic acid.
• the invention provides a compound of formula (I) wherein R 4 and R 5 are each independently selected from the group consisting of:
• the compound of formula (I) is defined where R 4 and R 5 are each independently aryl or substituted aryl.
• the compound of formula (I) is defined where R 4 and R 5 are each independently selected from the group consisting of a heterocyclic group, substituted heterocyclic group, heteroaryl and substituted heteroaryl groups.
• the compound of formula (I) is defined where R 3 is H or C ⁇ - 3 alkylNR 8 R 9 and R 8 and R 9 are each independently H or Ci-aalkyl.
• the compound of formula (I) is defined where R 3 is C ⁇ -3alkylNR 8 R 9 and R 8 and R 9 together with the N to which they are bonded form a 5 or 6 membered heterocyclic group, optionally containing 1 or 2 other heteroatoms selected from the group consisting of 0, N and S.
• the compound of formula (I) is defined where Z is selected from the group consisting of a Cs-ecycloalkyl, Csaryl, substituted Cs-scycloalkyl and substituted
• the compound of formula (I) is defined where Z is selected from the group consisting of a 5- or 6-membered heterocyclic group, substituted heterocyclic group, heteroaryl and substituted heteroaryl containing from one to three heteroatoms independently selected from 0, N or S.
• the compounds of formula (I) are defined where Z is a phenyl ring, thiophene ring or pyridine ring, more preferably phenyl.
• Z may be attached to Z in any suitable position.
• Z is phenyl, preferably this group is attached to the phenyl ring in the para position.
• the compounds of formula (I) are defined where R 1 is H or methyl.
• the compounds of formula (I) are defined where R 2 is H, methyl or ethyl.
• the compounds of formula (I) are defined where k is 1. In one embodiment, the compounds of formula (I) are defined wherein n is 5-50. A preferred set of compounds of formula (I) are defined where n is from 8 to 20, more preferably from 8 to 15. However in certain embodiments of the present invention, such as wherein R 3 is other than H, n may preferably be shorter than 8 to 20, such as 5 to 20. Similarly, when k is 0, n may preferably be shorter than 8 to 20, such as 5-20.
• Still another preferred set of compounds of formula (I) is defined where X is -0-, -N(H)-, -N(Ct- ⁇ alkyl)- ° r -N(C 3 -8cycloalkyl)-. More preferably, X is -0-, -N(H)- or -N(CH 3 )-.
• (-CH2-) P or (-CH CH-) P .
• compounds of formula I are defined where y and y' are both 1.
• the compounds of formula I are defined where R3 is methyl.
• R 4 and R 5 are each independently selected from the group consisting of G-salkyl, C3-scycloalkyl and aryl.
• R 4 and R s are each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, propyl, butyl, isopropyl, isobutyl, and phenyl.
• R 4 and R 5 are different
• R 4 and R B are the same.
• R 6 and R 7 are the same. More preferably, both R 6 and R 7 are 0.
• the present invention provides a compound of formula (I) as defined above wherein X is -0- and R 1 is H; of these, compounds wherein n is an integer of 8 to 20 are preferred, and those wherein n is an integer of 8 to 15 are more preferred.
• the invention also includes mixtures of compounds of formula (I) in any ratio wherein n varies.
• the present invention provides methods for the treatment or prophylaxis of gastrointestinal disorders, which methods comprise administering a therapeutically effective amount of a compound of formula (l-A):
• X is -0- or -NH-
• R 1 is H or methyl
• R 2 and R 3 are each independently 0 or S; n is an integer 1 to 50; and
• R is H or methyl; or a pharmaceutically acceptable solvate thereof.
• Particularly preferred compounds for use in the methods of the invention include: (E)-4-(l ,3-Bis(cyclohexylmethyl)-1 ,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- yOcinnamic Acid Decaethylene Glycol Methyl Ether Ester; (E)-4-(l ,3-Bis(cyclohexylmethyl)-1 ,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- yl)cinnamic Acid Nonaethylene Glycol Methyl Ether Ester; (E)-3-[l ,3-Bis(cyclohexylmethyl)-1 ,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic
• Nonaethylene Glycol Methyl Ether Ester 4-(1 ,3-bis(cyclohexylmethyl)-1 ,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)benzoic Acid
• Nonaethylene Glycol Methyl Ether Amide 4-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)benzoic Acid-
• Nonaethylene Glycol Methyl Ether Amide (E)-3-(1,3-Bis(cyclohexylmethyl)-1 ,2 I 3,6-tetrahydro-2 I 6-dioxo-9H-purin-8-yl)cinnamic Acid N-cyclopropylmethyl Nonaethylene Glycol Methyl Ether Amide ; (E)-4-(l,3-Bis(cyclohexylmethyl)-1 ,2,3 I 6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic
• More particularly preferred compounds for use in the methods of the present invention include: (E)-4-(l,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- yOcinnamic Acid Decaethylene Glycol Methyl Ether Ester; (E)-4-(l,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- yOcinnamic Acid Nonaethylene Glycol Methyl Ether Ester;
• Nonaethylene Glycol Methyl Ether Ester 4-(1 ,3-bis(cyclohexylmethyl)-1 I 2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)benzoic Acid
• Nonaethylene Glycol Methyl Ether Amide (E)-4-(l ,3-Bis(cyclohexylmethyl)-2,3,6,7-tetrahydro-2,6-dioxo-7-benzyl-l H-purin-8- yOcinnamic Acid Nonaethylene Glycol Methyl Ether Ester; (E)-4-(1 ,3-Bis(cyclohexylmethyl)-2 I 3,6,7-tetrahydro-2,6-dioxo-7-(2-oxo-2-phenylethyl)- 1 H-purin-8-yl)cinnamic Acid Nonaethylene Glycol Methyl Ether Ester;
• the present invention provides methods for the treatment or prophylaxis of irritable bowel syndrome or functional dyspepsia which comprises admininstering a therapeutically effective amount of (E)-4-(1 ,3-Bis(cyclohexylmethyl)- 1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid nonaethylene glycol methyl ether ester or a pharmaceutically acceptable solvate thereof.
• the compounds of the present invention are capable of existing as geometric and optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention.
• Q contains a double bond, compounds in the form of the
• the compounds employed in the present invention are cell adhesion molecule inhibitors, and preferably endothelial cell adhesion molecule inhibitors.
• cell adhesion molecule inhibitor includes compounds which specifically block or inhibit proteins on the surface of animal cells that mediate cell-cell binding.
• cell adhesion molecule inhibitor includes compounds which inhibit the expression of cell adhesion molecules.
• endothelial cell adhesion molecule inhibitor includes compounds which specifically block or inhibit the adhesive interactions of leukocytes and the endothelium. These compounds can be identified by performing the endothelial cell adhesion assay as decribed herein below. Preferably, the compounds have IC50 values in this assay of 500nM or less, more preferably 100nM or less and even more preferably 50nM or less.
• the term “endothelial cell adhesion molecule inhibitor” includes compounds which inhibit the expression of endothelial cell adhesion molecules. More preferably, the endothelial cell adhesion molecules include ICAM-1 (Intercellular adhesion molecuIe-1),
• the methods of the present invention involve treating or preventing irritable bowel syndrome, including diarrhea-predominant, constipation-predominant and alternating irritable bowel syndrome, and functional (non-ulcerative) dyspepsia by administering to an animal, a therapeutically effect amount of an endothelial cell adhesion molecule inhibitor, such as a compound of formula (I) or a solvate thereof.
• an endothelial cell adhesion molecule inhibitor such as a compound of formula (I) or a solvate thereof.
• the methods of the present invention may be employed for the treatment or prophylaxis of irritable bowel syndrome and functional dyspepsia in animals generally, and particularly in mammals such as humans.
• a therapeutically effective amount refers to an amount of an endothelial cell adhesion molecule inhibitor, e.g., a compound of formula (I), which is effective for the treatment or prophylaxis of the stated condition.
• a therapeutically effective amount of a compound of formula (I) for the treatment or prophylaxis of irritable bowel syndrome or functional dyspepsia is an amount effective for the treatment or prophylaxis of irritable bowel syndrome or functional dyspepsia.
• treatment refers to the partial or total elimination of symptoms in an afflicted animal.
• prophylaxis refers to the complete prevention of the condition in an animal as well as the reduction in severity and/or frequency of symptoms of the condition in an afflicted animal.
• an endothelial cell adhesion molecule inhibitor e.g., a compound of formula (I) or pharmaceutically acceptable solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient, and will ultimately be in the discretion of the attendent physician.
• a typical daily dose for the treatment of irritable bowel syndrome or functional dyspepsia may be expected to lie in the range of 0.005 mg/kg - lOOmg/kg, preferably 0.5-100 mg/kg, and most preferably 0.5-20 mg/kg. This dose may be administered as a single unit dose, as several separate unit doses or as a continuous infusion.
• An intravenous dose may be expected to lie in the range of 0.0025 mg/kg to 200 mg/kg and would typically be administered as an infusion.
• compositions comprising, as active ingredient, a compound of formula (I) or a pharmaceutically acceptable solvate thereof, together with at least one pharmaceutically acceptable carrier or excipient.
• pharmaceutical compositions may be used in the prophylaxis or treatment of irritable bowel syndrome and functional dyspepsia.
• the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
• the carrier may be a solid or liquid and the formulation is preferably formulated as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredients. If desired other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
• the methods of the present invention comprise administering a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable solvate thereof and alosetron or a pharmaceutically acceptable salt thereof.
• Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular, or intravenous), rectal, topical including transdermal, intranasal and inhalation administration.
• Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non- aqueous liquids; or as oil-in-water or water-in-oil emulsions.
• Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatine and glycerine or sucrose acacia.
• a flavoured base such as sugar and acacia or tragacanth
• pastilles comprising the active compound in an inert base, such as gelatine and glycerine or sucrose acacia.
• Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Additional formulations suitable for parenteral administration include formulations containing physiologically suitable co-solvents and/or complexing agents such as surfactants and cyclodextrins. Oil- in-water emulsions are also suitable formulations for parenteral formulations. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
• Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient in one or more solid carriers forming the suppository base, for example, cocoa butter.
• Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
• Suitable carriers for such formulations include petroleum jelly, lanolin, polyethyleneglycols, alcohols, and combinations thereof.
• the active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% w/w.
• Formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound with liquids or finely divided solid carriers or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
• a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
• Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers, or insufflators.
• a compound of formula (I) or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for the prophylaxis or treatment of irritable bowel syndrome or functional dyspepsia.
• the antiadhesion activity of compounds described herein was determined using a modification of the previously described method, Jurgensen, CH. et. al., J. Immunol.
• cytokine-stimulated human umbilical vein endothelial cells were assessed by quantitating the adherence of fluorescently-labelled (calcein-AM, Molecular Probes, Eugene, OR) leukocytes to endothelial cell monolayers. Activity was determined by calculating inhibition of cytokine-stimulated adhesion minus the basal adhesion (unstimulated).
• Rats were deeply anesthetized with pentobarbital sodium (45 mg/kg) administered intraperitoneally. Electrodes were stitched into the external oblique musculature for electromyographic (EMG) recording. Electrode leads were tunneled subcutaneously and exteriorized at the nape of the neck for future access. After surgery, rats were housed separately and allowed to recuperate for at least 3 days prior to testing.
• EMG electromyographic
• EMG activity produced by contraction of the external oblique musculature was quantified using Spike2 software (Cambridge Electronic Designs). Each distension trial lasted 60 seconds, and EMG activity was quantitated in 1 -second bins for 20 seconds before distension (baseline), during distention, and 20 seconds after distention. The increase in total number of recorded counts during distention is defined as the response.
• the animals were then briefly anesthetized with halothane, and zymosan (1 mL, 25 mg/mL) was instilled into the colon with a gavage needle inserted to a depth of about 7-8 cm, to produce inflammation and enhance the VMR to CRD.
• zymosan (1 mL, 25 mg/mL) was instilled into the colon with a gavage needle inserted to a depth of about 7-8 cm, to produce inflammation and enhance the VMR to CRD.
• responses to CRD were quantified as described above.
• Hyperalgesia is an altered sensory state of increased sensitivity to pain. Visceral hyperalgesia associated with the gastrointestinal tract may arise secondary to infection or inflammation. Such altered visceral sensation, as exemplified by increased sensitivity to colorectal distention, has been observed in patients with functional bowel disorders.

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