WO2008087461A2 - Use of kynurenic acid and derivatives thereof in the treatment of conditions of the gastrointestinal tract accompanied by hypermotility and inflammation or gout or multiple sclerosis - Google Patents

Use of kynurenic acid and derivatives thereof in the treatment of conditions of the gastrointestinal tract accompanied by hypermotility and inflammation or gout or multiple sclerosis Download PDF

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WO2008087461A2
WO2008087461A2 PCT/HU2008/000005 HU2008000005W WO2008087461A2 WO 2008087461 A2 WO2008087461 A2 WO 2008087461A2 HU 2008000005 W HU2008000005 W HU 2008000005W WO 2008087461 A2 WO2008087461 A2 WO 2008087461A2
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inflammation
straight
hydrogen atom
group
kyna
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WO2008087461B1 (en
WO2008087461A3 (en
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László VÉCSEI
Mihály BOROS
József KASZAKI
Ferenc FÜLÖP
József TOLDI
István SZATMÁRI
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Szegedi Tudományegyetem
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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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • kynurenic acid and derivatives thereof in the treatment of conditions of the gastrointestinal tract accompanied by hypermotility and inflammation or gout or multiple sclerosis
  • the subject of the invention is the use of kynurenic acid (KYNA) and its derivatives in the manufacture of a medicament for the treatment of conditions characterized by pathophysiological conditions of the gastrointestinal tract accompanied by increased motility and an elevated activity of the enzyme xanthine oxidoreductase (XOR), and further for the treatment of gout or multiple sclerosis.
  • KYNA kynurenic acid
  • XOR xanthine oxidoreductase
  • the enteric nervous system has an especially important role in the prevention of the inflammatory diseases of the GI tract and their complications, because various causative agents are particularly dangerous to the ENS in consequence of the enormous surface of the gastrointestinal (GI) tract.
  • the ENS is a system of tightly connected neurons and ganglia situated in all layers of the tissues throughout the whole length of the GI tract. As a result of the peripheral position of these neurons, they are not so well protected from the noxious effects as the neurons of the central nervous system (CNS) under the protection of the blood-brain barrier.
  • Toxic agents arriving via the circulation can impair the function of the ENS which can lead to disturbances of the regulation of the bowel function, and hence to acute colon obstruction, a frequent surgical emergency situation with high morbidity and mortality rates, despite optimal peri- and postoperative care.
  • the most important complications of the impaired passage accompanying acute colon obstruction are dysfunctions of the motility and the resultant inflammatory reactions.
  • the kynurenine pathway the main pathway in the metabolism of tryptophan, can be activated by free radicals and cytokines and can modify the activities of the enzymes involved in the tryptophan-kynurenine conversion.
  • the components of the kynurenine metabolism may have both harmful and protective effects in the CNS.
  • One of the main products of this pathway is quinolinic acid, a known agonist of N-methyl-D- aspartate (NMDA) sensitive glutamate receptors.
  • kynurenic acid 4-hydroxy-quinoline-2-carboxylic acid
  • NMDA glutamate receptor subtype NMDA glutamate receptor subtype
  • kynurenic acid also has an inhibitory effect on the alpha7-nicotine type acethyl-choline receptors.
  • KYNA Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progress in Neurobiology 2001; 64: 185- 218) KYNA can reduce excitotoxic injuries of neurons under both in vitro and in vivo conditions.
  • Overall quinolinic acid and its metabolites may display neurotoxic effects, while KYNA can be protective in the CNS.
  • Glutamatergic neurotoxicity has been observed on the neurons of the ENS, both in intact bowel preparations and in cultures of myenteric ganglia.
  • KYNA free radical-scavenging and XOR-inhibiting effects of the NMDA antagonist KYNA result in a reduced level of inflammation in the mucosa. Additionally, KYNA exerts a motility-reducing effect in hypermotilitic and inflammatory conditions of the GI tract. Further, the agents with potent anti-inflammatory effects in the GI tract generally also possess a therapeutic effect in treatments for CNS diseases, including multiple sclerosis.
  • the object of the present invention is the use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the GI tract or gout.
  • the object of the of the present invention is the use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the GI tract or gout or inflammatory conditions of the
  • Ri is hydroxy, NHR 2 , NR 2 R 2 or C 1-10 straight or branched alkoxy or glyceryl group;
  • R 2 is hydrogen atom or C 1-10 straight or branched alkyl group;
  • R 3 -R 6 are independently of each other hydrogen atom, halogen atom, C 1-10 alkyl, C 2-10 alkenyl or alkynyl group optionally substituted with a halogen atom.
  • general formula (I) includes compounds in which R 1 is hydroxy, NHR 2 , NR 2 R 2 or C 1-5 straight or branched alkoxy or glyceryl group; R 2 is hydrogen atom or C 1-5 straight or branched alkyl group; R 3 -R 6 are independently of each other hydrogen atom, halogen atom, C 1-5 alkyl, C 2-5 alkenyl or alkynyl group optionally substituted with a halogen atom and pharmaceutically acceptable salts thereof.
  • general formula (I) includes compounds, in which R 1 is hydroxy, NH 2 , NH-(C 1-5 straight or branched alkyl) or C 1-5 straight or branched- alkoxy or glyceryl group; R 2 is hydrogen atom; R 3 -R 6 are independently of each other hydrogen atom, halogen atom or CF 3 group.
  • the particularly preferred compounds are selected from the group consisting of KYNA (4- hydroxy-quinoline-2-carboxylic acid) and salts, amides or esters thereof, such as the glycerine esters that can be applied for medical use.
  • the compounds of general formula (I) appear to be especially, however not exclusively, suitable for use in the manufacture of a medicament for the treatment of acute bowel inflammation, Crohn's disease, colitis ulcerosa, diseases with post-ischemic reperfusion injuries of the gastrointestinal tract, irritable bowel syndrome, chronic colon inflammation, abdominal inflammations and increased motility of the bowels, gout and multiple sclerosis. Such applications form the closer subject of the invention.
  • the compounds of general formula (I) can be produced by customary methods, which are well known for the person skilled in the art (e.g. by the procedures mentioned below:
  • Salts with higher solubility as compared with the original or basic compounds can be especially suitable for medical use.
  • These salts may contain pharmaceutically acceptable anionic or cationic components.
  • the salts appropriate for medical use are those formed by inorganic acids, e.g.
  • hydrochloric acid hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid, and also salts formed by organic acids such as acetic acid, benzosulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, /?-toluenesulfonic acid and tartaric acid.
  • organic acids such as acetic acid, benzosulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, /?-toluenesulfonic acid and tartaric acid.
  • Basic salts appropriate for medical use are the ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts containing cationic amine derivatives.
  • the plots demonstrate the median values and the 25 th (lower whisker) and 75 th (upper whisker) percentiles, * p ⁇ 0.05 within groups vs baseline values, x p ⁇ 0.05 between groups vs sham-operated group values, # p ⁇ 0.05 between KYNA- treated group vs obstructed group values.
  • SMA superior mesenteric artery
  • the plots demonstrate the median (horizontal line in the box) and the 25 th (lower whisker), and 75 th (upper whisker) percentiles.
  • the plots demonstrate the median values and the 25 th (lower whisker) and 75 th (upper whisker) percentiles, * p ⁇ 0.05 within groups vs baseline values, x p ⁇ 0.05 between groups vs sham-operated group values, * p ⁇ 0.05 between KYNA- treated group vs obstructed group values.
  • the plots demonstrate the median values and the 25 th (lower whisker) and 75 th (upper whisker) percentiles, * p ⁇ 0.05 within groups vs baseline values, x p ⁇ 0.05 between groups vs sham- operated group values, # p ⁇ 0.05 between KYNA-treated group vs obstructed group values.
  • the plots demonstrate the median values and the 25 th (lower whisker) and 75 th (upper whisker) percentiles, * p ⁇ 0.05 within groups vs baseline values, x p ⁇ 0.05 between groups vs sham-operated group values, * p ⁇ 0.05 between KYNA-treated group vs obstructed group values.
  • Hemodynamic parameters were monitored continuously and registered with a computerized data-acquisition system (Haemosys 1.17; Experimetria Ltd., Budapest, Hungary).
  • the total peripheral vascular resistance (TPR) was calculated via the standard formula.
  • the level of the obstruction was marked by placing a silicone tourniquet catheter around the mid-transverse colon, keeping the neurovascular connections intact (obstruction was established by tightening the tourniquet).
  • Strain gauge transducers (Experimetria Ltd., Budapest, Hungary) were sutured with an atraumatic technique onto the antimesenteric side of the bowel wall to measure the oral colonic motility at 10 cm distances from the occlusion point.
  • the transducers were connected to an SG-M bridge amplifier and the signals were continuously recorded by a computerized data-acquisition system (Haemosys 1.17; Experimetria Ltd, Budapest, Hungary).
  • the sampling time was 10 min each, with a sampling frequency of 500 Hz; the signal analysis was performed off-line.
  • Large bowel motility indices were determined by calculating the area under the motility curve as a function of time. The time integral of the motility curve, as motility index, was used to estimate the neurogenic function of the intestine.
  • the amplitude and frequency of the giant migrating contractions (GMCs) were calculated, and the tone of the colon was given by the mean value of the minima in the motility curve.
  • GMCs giant migrating contractions
  • Plasma nitrite/nitrate (NOx) level measurements Heparinized blood samples were centrifuged at lOOOg at 4 °C, and the plasma was stored at -20 0 C. The measurement of plasma NO x level was measured by a literature method. (Moshage H, Kok B, Huizenga JR, Jansen PL: Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 1995; 41: 892-896)
  • the activity of XOR was measured in homogenized colon biopsies by a fluorometric kinetic assay based on the conversion of pterine to isoxanthopterine in the presence (total XOR) or absence (xanthine oxidase (XO) activity) of the electron acceptor methylene blue.
  • XO xanthine oxidase
  • mice were randomly allotted to one or other of four groups. Surgery was followed by a recovery period for cardiovascular stabilization, and the baseline variables were then determined during a 30-min control period.
  • KYNA nonspecific glutamate receptor antagonist
  • tissue samples were taken from the proximal part of the large bowel (close to the hepatic flexure) for determination of the activities of MPO, XO and xanthine dehydrogenase (XDH, a marker enzyme of the ATP degradation).
  • FIG. 2 demonstrates the changes in TPR.
  • TPR did not change synif ⁇ cantly in the sham- operated groups either with or without KYNA treatment, whereas it gradually decreased after colon obstruction.
  • the treatment with the nonselective NMDA receptor antagonist inhibited the obstruction-induced decrease in TPR.
  • the changes 300 min after obstruction onset were statistically significant.
  • Figure 3 presents the changes in flow of the superior mesenteric artery (SMA).
  • SMA superior mesenteric artery
  • KYNA administration resulted in a transient, significant increase in SMA blood flow.
  • the colon obstructed group (3) was characterized by a slow and gradual decrease of the flow which reached a significant level as compared to the sham- operated group by the end of the experiment.
  • Figure 4 demonstrates the changes in activity of XO and XDH in the colon.
  • the XO and XDH activities did not differ significantly.
  • the activity of the superoxide anion-producing XO was significantly increased after the obstruction, which the literature indicates to be a sign of the hypoxemic condition.
  • the activity of XDH was also elevated significantly in the obstructed group, indirectly indicating an accumulation of hypoxanthine as an end-product of ATP degradation.
  • the KYNA treatment therapy significantly inhibited the obstruction-induced increases in the XO and XDH activities.
  • FIG 5 demonstrates the changes in activity of MPO, a marker enzyme of leukocyte accumulation in tissues.
  • MPO a marker enzyme of leukocyte accumulation in tissues.
  • the KYNA treatment induced a significant decrease in the MPO activity of the large bowel as compared with the nontreated obstructed group.
  • the colon motility index shown in Figure 6 depends on the amplitude and the frequency of the GMCs.
  • the increase in the amplitude in the group with colon obstruction, demonstrated in Figure 7 therefore correlates with the increase in motility index in the same group. Definite increases in motility index and amplitude were registered in response to the obstruction and the changes were significant as compared with both the baseline values and the data for the sham-operated group.
  • the total inhibitory effect of 5 mM KYNA was determined in fluorometric kinetic assays.
  • Table 1 demonstrates the dose-dependent XOR-inhibitory effect of KYNA, which was detected via the luminol-dependent chemiluminescence of the free radicals derived from the xanthine/XO reaction (the reactive compound consisted of 200 ⁇ M luminol + 10 mU XO and 5 ⁇ M xanthine in a volume of 1 ml).
  • Table also demonstrates the dose-dependent inhibitory effect of allopurinol, a specific XO inhibitor. It can be stated that KYNA and allopurinol both exerted inhibitory effects on the XO activity. The solvent of the KYNA did not influence this reaction.
  • the protective effects of KYNA in the ENS are based on prevention of the production of free radicals resulting from XO and inhibition of the activation of leukocytes. Further in vitro experiments disclosed that the effect of KYNA is based partially on a specific, dose-dependent inhibitory effect through substrate analogy and partially on scavenging effects.
  • KYNA can be used in the manufacture of a medicament for the treatment of pathophysiological conditions of the GI tract accompanied by increased motility and an elevated activity of XOR and for the the treatment of gout or multiple sclerosis.
  • a drug containing KYNA appears to be especially, however not exclusively, suitable for the treatment of:
  • KYNA derivatives with general formula (I) can be administered into the organism by various routes e.g. i.v. or per orally.
  • the necessary daily amount of an active KYNA derivative of general formula (I) primarily depends on the specific compound actually used, but additionally on other factors, e.g. the method of the dosage, and the age and condition of the patient.
  • the adequate human dose of KYNA will generally fall in the range 1-100 mg (bodyweight kg) "1 daily, depending on the method of administration (i.v. or orally).
  • the customary human dose in the event of i.v. application is usually in the range 10-50 mg (bodyweight kg) "1 , and preferably approximately 25 mg (bodyweight kg) "1 .
  • the daily dosage leads to relatively constant blood concentration. This can be achieved by dividing the necessary daily dose into two, three, four or more doses or by administering a continuous infusion for a longer period or a sustained release dosage form of the active substance.
  • a compound of general formula (I) or a physiologically functional derivative thereof will be mixed with one or more therapeutically acceptable vehicles or with other auxiliary substances and in some cases with other active substances.
  • the medicaments will be materials that can be administered by oral, rectal, nasal, local (e.g. transdermal, buccal or sublingual), vaginal, parenteral (e.g. subcutaneous, intramuscular, intravenous or intradermal), etc. routes.
  • the medicaments will be manufactured in appropriate daily doses by the conventionally used methods of drug production.
  • the active substance will be mixed with a vehicle containing one or more supplementary components.
  • the active substance will usually be mixed regularly and evenly with the fluid vehicle or finely distributed solid material or mixture, and thereafter the mixture will be further shaped if necessary.
  • orally applicable medicaments according to the invention can be presented in physically separate dosage units of previously defined amounts of the active substance, e.g. in form of tablets, capsules, cachets, powders or granulates; aqueous or nonaqueous ⁇ e.g. alcoholic) solutions or suspensions; or in the form of oil-in- water or water-in-oil type liquid emulsions. Tablets can be produced if necessary by the admixture of one or more vehicles, and extrusion or moulding.
  • Compressed tablets may be made, for instance, in such a way, known to a person skilled in the art, that a free-flowing active agent in a powder or granulated formis mixed with a binder (povidone, gelatine or hydroxypropylmethyl cellulose), glidant, inert diluents, preservative, disintegrating agents ⁇ e.g. sodium starch-glycolate or crospovidone), surfactant or dispersing agents, and by means of an appropriate apparatus is compressed to tablets.
  • Moulded tablets are produced by pouring powdered agents wetted with inert, liquid diluents into appropriately shaped form.
  • Tablets can if necessary be supplied with a coating or mark, and converted into forms ensuring the sustained or regulated release of the active agent with the desired release profile, e.g. by admixture of hydroxypropylmethyl cellulose in varying proportions. Tablets, if so required, can be supplied with an enterosolvent coating, thereby ensuring the release of the agent in parts of the GI tract differing from the stomach.
  • Forms of medicaments convenient for parenteral administration may contain antioxidants, buffers, bacteriostatic agents, and an aqueous or nonaqueous, isotonic sterile injection solution which makes the product isotonic to the recipient's blood; or an aqueous or nonaqueous sterile suspension which consists of suspending and thickening agents, e.g. liposomes or other microparticle systems, for delivery of the active agent to the blood components or to one or more organs.
  • Products can be presented in the form of closed containers, e.g. ampoules or tubes including a unit dose or multiple doses stored in a lyophilised state, to which it is sufficient to add before use the appropriate sterile liquid vehicle, e.g.
  • kits suitable for the preparation of injections. Ready-to-use injections and suspensions can be produced from the sterile powders, granulates and tablets described above.
  • Advantageous unit-dose products may contain the above-described daily dose or unit, the daily divided dose, or an appropriate fraction of that.
  • Therapeutic products covered by the invention naturally contain, in addition to the vehicles mentioned above, other vehicles conventionally used in pharmaceutical production, depending on the form of the product in question, e.g. an oral dosing product may further contain sweetening agents, thickening agents and flavouring agents.
  • the active substance may be prepared by any known procedure. (KYNA preparation for instance: Spath, Monatsh, 1921; 42: 89; WaId, Joullie, J Org Chem 1966; 31: 3369) KYNA, as a natural compound, and its claimed derivatives may have substantially more moderate side-effect profiles than those of the synthetic molecules applied to date in the required indications, which signifies an absolute advantage from the aspect of the patient.
  • anaphylaxis and drug interactions can develop as side-effects of regularly applied allopurinol (a purine derivative XO inhibitor) in rheumatoid arthritis (gout) therapy.
  • allopurinol a purine derivative XO inhibitor
  • Dermato- and hypersensitivity reactions, GI symptoms may appear as undesirable side-effects.
  • Such side-effects may be expected to be avoidable via treatment with KYNA derivatives.
  • Steroidal anti-inflammatory treatment can be accompanied by particularly serious side- effects in the therapy of GI inflammation (colitis ulcerosa, irritable bowel syndrome, etc.), but the side-effects of non-steroidal antiinflammatories can additionally be diminished via therapy with KYNA derivatives.

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Abstract

The subject of the invention is the use of kynurenic acid (KYNA) and its derivatives and physiologically acceptable salts of the general formula (I) in the manufacture of a medicament for the treatment of conditions characterized by pathophysiological conditions of the GI tract accompanied by increased motility and an elevated activity of the enzyme xanthine oxidoreductase (XOR), and further for the treatment of gout or multiple sclerosis. The meanings of the substituents of general formula (I) are defined in the claims.

Description

Use of kynurenic acid and derivatives thereof in the treatment of conditions of the gastrointestinal tract accompanied by hypermotility and inflammation or gout or multiple sclerosis
TECHNICAL FIELD
The subject of the invention is the use of kynurenic acid (KYNA) and its derivatives in the manufacture of a medicament for the treatment of conditions characterized by pathophysiological conditions of the gastrointestinal tract accompanied by increased motility and an elevated activity of the enzyme xanthine oxidoreductase (XOR), and further for the treatment of gout or multiple sclerosis.
BACKGROUND OF THE INVENTION
Protection of the enteric nervous system (ENS) has an especially important role in the prevention of the inflammatory diseases of the GI tract and their complications, because various causative agents are particularly dangerous to the ENS in consequence of the enormous surface of the gastrointestinal (GI) tract. The ENS is a system of tightly connected neurons and ganglia situated in all layers of the tissues throughout the whole length of the GI tract. As a result of the peripheral position of these neurons, they are not so well protected from the noxious effects as the neurons of the central nervous system (CNS) under the protection of the blood-brain barrier. Toxic agents, arriving via the circulation can impair the function of the ENS which can lead to disturbances of the regulation of the bowel function, and hence to acute colon obstruction, a frequent surgical emergency situation with high morbidity and mortality rates, despite optimal peri- and postoperative care. The most important complications of the impaired passage accompanying acute colon obstruction are dysfunctions of the motility and the resultant inflammatory reactions. (Madl C, Druml W: Systemic consequences of ileus. Best Pract Res Clin Gastroenterol 2003; 17: 445-456; Bauer AJ, Schwarz NT, Moore BA, Turler A, Kalff JC: Ileus in critical illness: mechanisms and management. Curr Opin Crit Care 2002; 8: 152-157; Tδrnblom H, Abrahamsson H, Barbara G, Hellstrom PM, Lindberg G, Nyhlin H, Ohlsson B, Simren M, Sjδlund K, Sjovall, H, Schmidt PT, Ohman L: Inflammation as a cause of functional bowel disorders. Scand J Gastroenterol 2005; 40: 1140-1148) During the pathophysiological inflammatory processes of the GI tract (e.g. colitis), elevated plasma levels of glutamate receptor agonist and antagonist kynurenine metabolites can be detected. (Forrest CM, Youd P, Kennedy A, Gould SR, Darlington LG, Stone TW: Purine, kynurenine, neopterin and lipid peroxidation levels in inflammatory bowel disease. J Biomed Sci. 2002; 9: 436-442; Forrest CM, Gould SR, Darlington LG, Stone TW: Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease. Adv Exp Med Biol. 2003; 527: 395-400)
The kynurenine pathway the main pathway in the metabolism of tryptophan, can be activated by free radicals and cytokines and can modify the activities of the enzymes involved in the tryptophan-kynurenine conversion. (Mackay GM, Forrest CM, Stoy N, Christofides J, Egerton M, Stone TW, Darlington LG: Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eur J Neurol 2006; 13: 30-42.) The components of the kynurenine metabolism may have both harmful and protective effects in the CNS. (Stone TW, Mackay GM, Forrest CM, Clark CJ, Darlington LG: Tryptophan metabolites and brain disorders. Clin Chem Lab Med. 2003; 41: 852-859)One of the main products of this pathway is quinolinic acid, a known agonist of N-methyl-D- aspartate (NMDA) sensitive glutamate receptors.
Another important metabolite in this pathway is 3-hydroxykynurenine, which can cause neuronal injury by producing free radicals. The other main pathway in the metabolism of tryptophan leads to the synthesis of kynurenic acid (KYNA; 4-hydroxy-quinoline-2-carboxylic acid), which is an effective antagonist of the strychnine-insensitive glycine receptors, an NMDA glutamate receptor subtype, and kynurenic acid also has an inhibitory effect on the alpha7-nicotine type acethyl-choline receptors. (Perkins MN, Stone TW: An iontophoretic investigation of the action of convulsant kynurenines and their interaction with the endogenous excitant kynurenic acid. Brain Res 1982, 247: 184-187; Stone TW: Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progress in Neurobiology 2001; 64: 185- 218) KYNA can reduce excitotoxic injuries of neurons under both in vitro and in vivo conditions. (Faden AI, Demediuk P, Panter SS, Vink R: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989, 244: 798-800). Overall quinolinic acid and its metabolites may display neurotoxic effects, while KYNA can be protective in the CNS. (Vecsei L, Miller J, Macgarvey U, Beal MF: Effects of kynurenine and probenecid on plasma and brain tissue concentrations of kynurenic acid. Neurodegeneration 1992, 1: 17-26; Kiss C, Vecsei L: Neuroprotection and the kynurenine system. In: Kynurenines in the brain: from experiment to clinics, (ed) Vecsei L; pp. 173- 191 Nova Sciences Publishers, New York, 2005.) Little is known of the details of glutamate neurotransmission in the ENS. It has been reported that a high proportion of neurons in the peripheral nervous system express glutamate receptors, and the facilitation mediated by glutamate can modulate the cholinergic neurotransmission. The presence and expression of NMDA-sensitive glutamate receptors have been detected on the cholinergic neurons of the ENS. Glutamate probably acts as an excitatory neurotransmitter in this case. (Liu MT, Rothstein JD, Gershon MD, Kirchgessner A: Glutamatergic enteric neurons. J Neurosci 1997; 17: 4764-4784; Kirchgessner AL: Glutamate in the enteric nervous system. Curr Opin Pharmacol 2001; 1: 591-596). Glutamatergic neurotoxicity (necrosis and apoptosis) has been observed on the neurons of the ENS, both in intact bowel preparations and in cultures of myenteric ganglia. (Kirchgessner AL, Liu MT, Alcantara F: Excititoxicity in the enteric neurvous system, J Neurosci 1997; 17: 8804-8816)
These data indicate that the phenomenon of excitotoxicity can occur in the ENS and the increased activities of the enteral glutamate receptors can be involved in the impairments of the GI tract caused by obstruction, by a lack of oxygen or by ischemia. The inflammatory character of the process is proven by the fact that the activation of the glutamate receptors leads to an increased level of intracellular calcium (Ca2+), which ensures the possibility of the enhanced activity of Ca2+ dependent enzymes, such as XOR. It was earlier demonstrated (Palasthy Z, Kaszaki J, Lazar J, Nagy S, Boros M: Intestinal nitric .oxide synthase activity changes during experimental colon obstruction. Scand J Gastroenterol 2006; 41: 910-918) that the early phase of acute colon obstruction is characterized by a significant increase in proximal colon motility and by a hyperdynamic circulatory reaction (the main feature of which is a decrease in total peripheral vascular resistance). The latter phenomenon refers to the gradual increase in the inflammatory processes during the ileus. The enhanced motility observed has been suggested to be a result of the glutamatergic facilitation in the ENS during the early phase of acute colon obstruction. The possibility of excitatory neuronal injury and glutamate-mediated facilitation arises in the case of acute colon obstruction, and we therefore set out to test compounds that had not been investigated previously in the indications in question.
AIM OF THE INVENTION In accordance with the above-mentioned findings, our aims are to develop new possibilities for the pharmaceutical treatment of conditions of the GI tract accompanied by hypermotility and inflammation, because of the demand for improvement of the currently applied therapy and for the reduction of the side-effects. Further, our aim was to find active substances for the treatment of gout and multiple sclerosis.
SUMMARY OF THE INVENTION
We experienced that the free radical-scavenging and XOR-inhibiting effects of the NMDA antagonist KYNA result in a reduced level of inflammation in the mucosa. Additionally, KYNA exerts a motility-reducing effect in hypermotilitic and inflammatory conditions of the GI tract. Further, the agents with potent anti-inflammatory effects in the GI tract generally also possess a therapeutic effect in treatments for CNS diseases, including multiple sclerosis.
In human studies with stable relapsing-remitting multiple sclerosis the kynurenic acid levels of the CSF was lower compared to healthy controls (Rejdak, K., Bartosik-Psujek, H., Dobosz, B., Kocki, T., Grieb, P., Giovannoni, G., Turski, W.A., Stelmasiak, Z. (2002)) Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients (Neurosci. Lett. 331:63-65).
DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is the use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the GI tract or gout.
In another aspect the object of the of the present invention is the use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the GI tract or gout or inflammatory conditions of the
CNS, including multiple sclerosis. In the general formula (I)
Figure imgf000006_0001
(I)
Ri is hydroxy, NHR2, NR2R2 or C1-10 straight or branched alkoxy or glyceryl group; R2 is hydrogen atom or C1-10 straight or branched alkyl group; R3-R6 are independently of each other hydrogen atom, halogen atom, C1-10 alkyl, C2-10 alkenyl or alkynyl group optionally substituted with a halogen atom.
In a preferred embodiment general formula (I) includes compounds in which R1 is hydroxy, NHR2, NR2R2 or C1-5 straight or branched alkoxy or glyceryl group; R2 is hydrogen atom or C1-5 straight or branched alkyl group; R3-R6 are independently of each other hydrogen atom, halogen atom, C1-5 alkyl, C2-5 alkenyl or alkynyl group optionally substituted with a halogen atom and pharmaceutically acceptable salts thereof. In a further preferred embodiment general formula (I) includes compounds, in which R1 is hydroxy, NH2, NH-(C1-5 straight or branched alkyl) or C1-5 straight or branched- alkoxy or glyceryl group; R2 is hydrogen atom; R3-R6 are independently of each other hydrogen atom, halogen atom or CF3 group.
The particularly preferred compounds are selected from the group consisting of KYNA (4- hydroxy-quinoline-2-carboxylic acid) and salts, amides or esters thereof, such as the glycerine esters that can be applied for medical use.
Figure imgf000006_0002
Formula 1.
KYNA (4-hydroxy-quinoline-2-carboxylic acid) Within the above general definition, the compounds of general formula (I) appear to be especially, however not exclusively, suitable for use in the manufacture of a medicament for the treatment of acute bowel inflammation, Crohn's disease, colitis ulcerosa, diseases with post-ischemic reperfusion injuries of the gastrointestinal tract, irritable bowel syndrome, chronic colon inflammation, abdominal inflammations and increased motility of the bowels, gout and multiple sclerosis. Such applications form the closer subject of the invention.
The compounds of general formula (I) can be produced by customary methods, which are well known for the person skilled in the art (e.g. by the procedures mentioned below:
Spath, Monatsh, 1921; 42: 89; WaId, Joullie, J Org Chem 1966; 31: 3369).
Salts with higher solubility as compared with the original or basic compounds can be especially suitable for medical use. These salts may contain pharmaceutically acceptable anionic or cationic components. According to the invention, the salts appropriate for medical use are those formed by inorganic acids, e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid, and also salts formed by organic acids such as acetic acid, benzosulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, succinic acid, /?-toluenesulfonic acid and tartaric acid.
Basic salts appropriate for medical use are the ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), and salts containing cationic amine derivatives.
Legends to Figures Figure 1. Representative motility curves computer-edited from data registered with two strain gauge transducers. The minimum points of the curve were connected by the computer. This line represents the tone of the colon.
Figure 2. Changes in total peripheral vascular resistance (TPR) in the sham-operated (n=6; open squares), KYNA-treated sham-operated (n=6; closed circles with dashed line), colon- obstructed (n=6; empty diamonds), and KYNA-treated colon-obstructed (n=6 open circles with dashed line) groups of dogs. The plots demonstrate the median values and the 25th (lower whisker) and 75th (upper whisker) percentiles, * p<0.05 within groups vs baseline values, x p<0.05 between groups vs sham-operated group values, # p<0.05 between KYNA- treated group vs obstructed group values.
Figure 3. Changes in superior mesenteric artery (SMA) blood flow in the sham-operated (n=6; open squares), KYNA-treated sham-operated (n=6; closed circles with dashed line), colon- obstructed (n=6; empty diamonds), and KYNA-treated colon-obstructed (n=6; open circles with dashed line) groups of dogs. The plots demonstrate the median values and the
25th (lower whisker) and 75th (upper whisker) percentiles, * p<0.05 within groups vs baseline values, x p<0.05 between groups vs sham-operated group values, p<0.05 between KYNA-treated group vs obstructed group values.
Figure 4. Changes in activity of xanthine oxidase (XO; white boxes) and xanthine dehydrogenase (XDH; gray boxes) (μmol (mg protein)'1 min"1) in colonic tissue from sham-operated (n=6; empty box), sham-operated + KYNA-treated (n=6; left striped box), colon-obstructed (checked box), and colon-obstructed + KYNA-treated (n=6; right striped box) groups of dogs. The plots demonstrate the median (horizontal line in the box) and the 25th (lower whisker), and 75th (upper whisker) percentiles. x p<0.05 between groups vs sham-operated group values, p<0.05 between KYNA-treated groups vs obstructed group values.
Figure 5. Changes in activity of myeloperoxidase (MPO), (mU (mg protein)"1) in colonic tissue from sham-operated (n=6; empty box), sham-operated + KYNA-treated (n=6; left striped box), colon-obstructed (checked box), and colon-obstructed + KYNA-treated (n^β; right striped box) animals. Samples were harvested at the end of the experiments (at the 7th hour of the obstruction). The plots demonstrate the median (horizontal line in the box) and the 25th (lower whisker), and 75th (upper whisker) percentiles. x p<0.05 between groups vs sham-operated group values, p<0.05 between KYNA-treated groups vs obstructed group values.
Figure 6. Changes in motility index of the proximal colon in the sham-operated (n=6; open squares), KYNA-treated sham-operated (n=6; closed circles with dashed line), colon- obstructed (n=6; empty diamonds), and KYNA-treated colon-obstructed (n=6; open circles with dashed line) groups of dogs. The plots demonstrate the median values and the 25th (lower whisker) and 75th (upper whisker) percentiles, * p<0.05 within groups vs baseline values, x p<0.05 between groups vs sham-operated group values, * p<0.05 between KYNA- treated group vs obstructed group values.
Figure 7. Changes in amplitude of giant migrating contractions (GMCs) of the proximal colon in the sham-operated (n=6; open squares), KYNA-treated sham-operated (n=6; closed circles with dashed line), colon-obstructed (n=6; empty diamonds), and KYNA- treated colon-obstructed (n=6; open circles with dashed line) groups. The plots demonstrate the median values and the 25th (lower whisker) and 75th (upper whisker) percentiles, * p<0.05 within groups vs baseline values, x p<0.05 between groups vs sham- operated group values, # p<0.05 between KYNA-treated group vs obstructed group values.
Figure 8. Changes in tone of the proximal colon in the sham-operated (open squares), KYNA-treated sham-operated (n=6; closed circles with dashed line), colon-obstructed (n-6; empty diamonds), and KYNA-treated colon-obstructed (n=6; open circles with dashed line) groups. The plots demonstrate the median values and the 25th (lower whisker) and 75th (upper whisker) percentiles, * p<0.05 within groups vs baseline values, x p<0.05 between groups vs sham-operated group values, * p<0.05 between KYNA-treated group vs obstructed group values.
Description of the examinations
In anesthetized male and female inbred dogs, properties of KYNA which had already been proved to be effective in the CNS were examined with regard to their action on parameters of the GI tract regulated by the ENS, such as the motility and vascular regulation, and on the signs of inflammation of the mucosa, such as the activity of some of the most important free radical- producing enzymes (such as XOR and myeloperoxidase (MPO)).
The experiments included observations the changes in the motility pattern after KYNA treatment under normal conditions and in animals subjected to acute obstruction of the colon. Besides the systemic hemodynamic parameters, the colon motility was monitored for 7 hours in sham-operated animals and in animals with colon obstruction with or without KYNA treatment (50 mg kg-1 i.v.) at 3 hours. Tissue samples were utilized to measure the activities of XOR and MPO (a marker of leukocyte accumulation). Methods
Hemodynamic parameters were monitored continuously and registered with a computerized data-acquisition system (Haemosys 1.17; Experimetria Ltd., Budapest, Hungary). The total peripheral vascular resistance (TPR) was calculated via the standard formula. The level of the obstruction was marked by placing a silicone tourniquet catheter around the mid-transverse colon, keeping the neurovascular connections intact (obstruction was established by tightening the tourniquet). Strain gauge transducers (Experimetria Ltd., Budapest, Hungary) were sutured with an atraumatic technique onto the antimesenteric side of the bowel wall to measure the oral colonic motility at 10 cm distances from the occlusion point. The transducers were connected to an SG-M bridge amplifier and the signals were continuously recorded by a computerized data-acquisition system (Haemosys 1.17; Experimetria Ltd, Budapest, Hungary). The sampling time was 10 min each, with a sampling frequency of 500 Hz; the signal analysis was performed off-line. Large bowel motility indices were determined by calculating the area under the motility curve as a function of time. The time integral of the motility curve, as motility index, was used to estimate the neurogenic function of the intestine. The amplitude and frequency of the giant migrating contractions (GMCs) were calculated, and the tone of the colon was given by the mean value of the minima in the motility curve. (Huge A, Kreis ME, Jehle EC, Ehrlein HJ, Starlinger M, Becker HD, Zittel TT: A model to investigate postoperative ileus with strain gauge transducers in awake rats. J Surg Res 1998; 74: 112-118) This evaluation and these calculated parameters are demonstrated by Figure 1.
■ The frequency of contractions, as the number of bowel contractions under 1 min.
■ The muscle tone, as the mean value of the minima in the motility curve.
■ The amplitude of contractions, as the difference of the peak value and the minima values of the contraction wave.
■ The motility index, as the time integral of the motility curve.
Biochemical measurements
Plasma nitrite/nitrate (NOx) level measurements Heparinized blood samples were centrifuged at lOOOg at 4 °C, and the plasma was stored at -20 0C. The measurement of plasma NOx level was measured by a literature method. (Moshage H, Kok B, Huizenga JR, Jansen PL: Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 1995; 41: 892-896)
Tissue MPO activity
The activity of MPO, a marker of tissue leukocyte infiltration, was measured via colon biopsies by a literature method. (Kuebler WM, Abels C, Schuerer L, Goetz AE: Measurement of neutrophil content in brain and lung tissue by a modified myeloperoxidase assay. Int J Microcirc 1996; 16: 89-97)
XOR activity
The activity of XOR was measured in homogenized colon biopsies by a fluorometric kinetic assay based on the conversion of pterine to isoxanthopterine in the presence (total XOR) or absence (xanthine oxidase (XO) activity) of the electron acceptor methylene blue. (Beckman JS, Parks DA, Pearson JD, Marshall PA, Freeman BA: A sensitive fluorometric assay for measuring xanthine dehydogenase and oxidase in tissues. Free Rad Biol Med 1989; 6: 607-615)
Experimental groups and protocol The animals were randomly allotted to one or other of four groups. Surgery was followed by a recovery period for cardiovascular stabilization, and the baseline variables were then determined during a 30-min control period. Group 1 (n=5) served as sham-operated control, while in group 2 (n=5) the animals were treated at 180 min with the nonspecific glutamate receptor antagonist KYNA (Sigma Chem. USA; 50 mg kg"1 iv in 0.7 ml min"1 iv infusion for 30 min in 20 ml 0.1 M NaOH with the pH adjusted to 7.2-7.4). Dose-response effects were investigated in pilot rat studies. In groups 3 (n=6), and 4 (n=5), complete large bowel obstruction was induced by tightening the tourniquet. The animals in groups 1 and 3 were treated with the vehicle for KYNA, while in group 4 KYNA was administered 180 min after the onset of obstruction. The animals were observed for 420 min, the beginning of obstruction denoting 0 min. Changes in colonic motility and hemodynamic parameters were registered hourly; blood samples were taken from the portal vein for the measurement of plasma NOx levels at 0, 60, 180, 300 and 420 min in the post-occlusion period. At the end of the experiment, tissue samples were taken from the proximal part of the large bowel (close to the hepatic flexure) for determination of the activities of MPO, XO and xanthine dehydrogenase (XDH, a marker enzyme of the ATP degradation). Results
There were no differences in baseline values for any of the observed parameters. KYNA did had no effect on the blood pressure.
Figure 2 demonstrates the changes in TPR. TPR did not change synifϊcantly in the sham- operated groups either with or without KYNA treatment, whereas it gradually decreased after colon obstruction. The treatment with the nonselective NMDA receptor antagonist inhibited the obstruction-induced decrease in TPR. The changes 300 min after obstruction onset were statistically significant. Figure 3 presents the changes in flow of the superior mesenteric artery (SMA). In the sham-operated animals, KYNA administration resulted in a transient, significant increase in SMA blood flow. The colon obstructed group (3) was characterized by a slow and gradual decrease of the flow which reached a significant level as compared to the sham- operated group by the end of the experiment. There was no increase in the flow in the group subjected to colon obstruction and KYNA treatment. Figure 4 demonstrates the changes in activity of XO and XDH in the colon. In the treated and non-treated sham-operated groups, the XO and XDH activities did not differ significantly. The activity of the superoxide anion-producing XO was significantly increased after the obstruction, which the literature indicates to be a sign of the hypoxemic condition. The activity of XDH was also elevated significantly in the obstructed group, indirectly indicating an accumulation of hypoxanthine as an end-product of ATP degradation. The KYNA treatment therapy significantly inhibited the obstruction-induced increases in the XO and XDH activities.
Figure 5 demonstrates the changes in activity of MPO, a marker enzyme of leukocyte accumulation in tissues. After obstruction induction, the MPO activity increased significantly in the proximal colon. The KYNA treatment induced a significant decrease in the MPO activity of the large bowel as compared with the nontreated obstructed group. The colon motility index shown in Figure 6 depends on the amplitude and the frequency of the GMCs. The increase in the amplitude in the group with colon obstruction, demonstrated in Figure 7 therefore correlates with the increase in motility index in the same group. Definite increases in motility index and amplitude were registered in response to the obstruction and the changes were significant as compared with both the baseline values and the data for the sham-operated group. The administration of KYNA prevented the increases in motility index and amplitude evoked by the obstruction. As demonstrated in Figure 8, the tone of the proximal colon after creation of the obstruction was significantly decreased relative to the baseline values, but there were no significant changes relative to the sham-operated group. At the same time, the tone of the colon did not decrease in the colon obstructed group which received KYNA treatment. Moreover, a significant increase in tone was observed in the sham-operated, KYNA- treated group as compared with the nontreated sham-operated group. Besides in vivo determination, the inhibitory effects of KYNA on the XOR activity and free radical-scavenging capacity were examined under in vitro circumstances. The total inhibitory effect of 5 mM KYNA was determined in fluorometric kinetic assays. Table 1 demonstrates the dose-dependent XOR-inhibitory effect of KYNA, which was detected via the luminol-dependent chemiluminescence of the free radicals derived from the xanthine/XO reaction (the reactive compound consisted of 200 μM luminol + 10 mU XO and 5 μM xanthine in a volume of 1 ml). Table also demonstrates the dose-dependent inhibitory effect of allopurinol, a specific XO inhibitor. It can be stated that KYNA and allopurinol both exerted inhibitory effects on the XO activity. The solvent of the KYNA did not influence this reaction.
Table 1.
Figure imgf000013_0001
It seemed possible that KYNA exerts a neuroprotective effect with regard to both substrate analogy and a free radical-scavenging feature. Further in vitro examinations were therefore performed on the effects of KYNA on the luminol-dependent chemiluminescence generated by H2O2 (the reactive mixture consisted of 1 mM H2O2 and 6 μM EDTA), and on the luminol-dependent chemiluminescence (200μM luminol + 1 ml reactive compound) of free radicals, generated in the Udenfried reaction (production of free oxygen radicals from the mixture of 1 mM H2O2 + 500 μM ascorbic acid + 10 μM Fe2+ + 6 μM EDTA). The results on both free radical-producing systems verified the free oxygen radical- scavenging feature and efficacy of KYNA.
Table 2.
Figure imgf000014_0001
In conclusion, the protective effects of KYNA in the ENS are based on prevention of the production of free radicals resulting from XO and inhibition of the activation of leukocytes. Further in vitro experiments disclosed that the effect of KYNA is based partially on a specific, dose-dependent inhibitory effect through substrate analogy and partially on scavenging effects.
In summary, we have shown that a specific influence on changes in colon motility can be achieved by the administration of KYNA in cases of conditions accompanied by hypermotility. Besides the motility-reducing effect of KYNA, we have demonstrated its inhibitory effects on the activity of the enzyme XO, and on the production of free oxygen radicals, and also its anti-inflammatory effect. The glutamate receptor antagonist KYNA affords pharmacologically exploitable possibilities in the treatment of diseases of the GI tract accompanied by hypermotility and inflammation and even in the treatment of gout and multiple sclerosis
Thus, KYNA can be used in the manufacture of a medicament for the treatment of pathophysiological conditions of the GI tract accompanied by increased motility and an elevated activity of XOR and for the the treatment of gout or multiple sclerosis.More specifically, a drug containing KYNA appears to be especially, however not exclusively, suitable for the treatment of:
■ acute bowel inflammation
■ Crohn's disease ■ colitis ulcerosa
■ diseases with post-ischemic reperfusion injuries of the gastrointestinal tract
■ irritable bowel syndrome
■ chronic colon inflammation
■ abdominal inflammations and increased motility of the bowels, ■ gout
■ multiple sclerosis
As claimed in the invention, KYNA derivatives with general formula (I) can be administered into the organism by various routes e.g. i.v. or per orally. The necessary daily amount of an active KYNA derivative of general formula (I) primarily depends on the specific compound actually used, but additionally on other factors, e.g. the method of the dosage, and the age and condition of the patient. The adequate human dose of KYNA will generally fall in the range 1-100 mg (bodyweight kg)"1 daily, depending on the method of administration (i.v. or orally). The customary human dose in the event of i.v. application is usually in the range 10-50 mg (bodyweight kg)"1, and preferably approximately 25 mg (bodyweight kg)"1.
It can be advantageous if the daily dosage leads to relatively constant blood concentration. This can be achieved by dividing the necessary daily dose into two, three, four or more doses or by administering a continuous infusion for a longer period or a sustained release dosage form of the active substance.
For manufacture of a medicament according to the invention, a compound of general formula (I) or a physiologically functional derivative thereof (henceforward the active substance) will be mixed with one or more therapeutically acceptable vehicles or with other auxiliary substances and in some cases with other active substances. The medicaments will be materials that can be administered by oral, rectal, nasal, local (e.g. transdermal, buccal or sublingual), vaginal, parenteral (e.g. subcutaneous, intramuscular, intravenous or intradermal), etc. routes.
The medicaments will be manufactured in appropriate daily doses by the conventionally used methods of drug production. During the production, the active substance will be mixed with a vehicle containing one or more supplementary components. For manufacture of the products, the active substance will usually be mixed regularly and evenly with the fluid vehicle or finely distributed solid material or mixture, and thereafter the mixture will be further shaped if necessary.
The various routes of administration may exhibit various individual advantages. For example, orally applicable medicaments according to the invention can be presented in physically separate dosage units of previously defined amounts of the active substance, e.g. in form of tablets, capsules, cachets, powders or granulates; aqueous or nonaqueous {e.g. alcoholic) solutions or suspensions; or in the form of oil-in- water or water-in-oil type liquid emulsions. Tablets can be produced if necessary by the admixture of one or more vehicles, and extrusion or moulding. Compressed tablets may be made, for instance, in such a way, known to a person skilled in the art, that a free-flowing active agent in a powder or granulated formis mixed with a binder (povidone, gelatine or hydroxypropylmethyl cellulose), glidant, inert diluents, preservative, disintegrating agents {e.g. sodium starch-glycolate or crospovidone), surfactant or dispersing agents, and by means of an appropriate apparatus is compressed to tablets. Moulded tablets are produced by pouring powdered agents wetted with inert, liquid diluents into appropriately shaped form. Tablets can if necessary be supplied with a coating or mark, and converted into forms ensuring the sustained or regulated release of the active agent with the desired release profile, e.g. by admixture of hydroxypropylmethyl cellulose in varying proportions. Tablets, if so required, can be supplied with an enterosolvent coating, thereby ensuring the release of the agent in parts of the GI tract differing from the stomach.
Forms of medicaments convenient for parenteral administration may contain antioxidants, buffers, bacteriostatic agents, and an aqueous or nonaqueous, isotonic sterile injection solution which makes the product isotonic to the recipient's blood; or an aqueous or nonaqueous sterile suspension which consists of suspending and thickening agents, e.g. liposomes or other microparticle systems, for delivery of the active agent to the blood components or to one or more organs. Products can be presented in the form of closed containers, e.g. ampoules or tubes including a unit dose or multiple doses stored in a lyophilised state, to which it is sufficient to add before use the appropriate sterile liquid vehicle, e.g. water suitable for the preparation of injections. Ready-to-use injections and suspensions can be produced from the sterile powders, granulates and tablets described above. Advantageous unit-dose products may contain the above-described daily dose or unit, the daily divided dose, or an appropriate fraction of that.
Therapeutic products covered by the invention naturally contain, in addition to the vehicles mentioned above, other vehicles conventionally used in pharmaceutical production, depending on the form of the product in question, e.g. an oral dosing product may further contain sweetening agents, thickening agents and flavouring agents. The active substance may be prepared by any known procedure. (KYNA preparation for instance: Spath, Monatsh, 1921; 42: 89; WaId, Joullie, J Org Chem 1966; 31: 3369) KYNA, as a natural compound, and its claimed derivatives may have substantially more moderate side-effect profiles than those of the synthetic molecules applied to date in the required indications, which signifies an absolute advantage from the aspect of the patient. For example, anaphylaxis and drug interactions (cytostatics, theophylline, cyclosporine, coumarin derivatives, ampicillin, amoxicillin, etc.) can develop as side-effects of regularly applied allopurinol (a purine derivative XO inhibitor) in rheumatoid arthritis (gout) therapy. Dermato- and hypersensitivity reactions, GI symptoms (nausea and vomiting) may appear as undesirable side-effects. Such side-effects may be expected to be avoidable via treatment with KYNA derivatives.
Steroidal anti-inflammatory treatment can be accompanied by particularly serious side- effects in the therapy of GI inflammation (colitis ulcerosa, irritable bowel syndrome, etc.), but the side-effects of non-steroidal antiinflammatories can additionally be diminished via therapy with KYNA derivatives.

Claims

Claims
1. Use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof, wherein
Figure imgf000018_0001
G)
■ R1 is hydroxy, NHR2, NR2R2 or C1-10 straight or branched alkoxy or glyceryl group;
■ R2 is hydrogen atom or C1-1O straight or branched alkyl group;
■ R3-R6 are independently of each other hydrogen atom, halogen atom, C1-10 alkyl, C2-10 alkenyl or alkynyl group optionally substituted with a halogen atom, in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the gastrointestinal tract or gout.
2. Use of kynurenic acid derivatives of general formula (I) and pharmaceutically acceptable salts thereof, wherein
Figure imgf000018_0002
(I)
R1 is hydroxy, NHR2, NR2R2 or a C1-10 straight or branched alkoxy or glyceryl group; R2 is a hydrogen atom or a C1-10 straight or branched alkyl group; ■ R3-R6 are independently of each other hydrogen atom, halogen atom, C1-10 alkyl, C2-10 alkenyl or alkynyl group optionally substituted with a halogen atom, in the manufacture of a medicament for the treatment of conditions characterized by hypermotility and inflammation of the gastrointestinal tract or gout or inflammatory conditions of the CNS, including multiple sclerosis.
3. Use according to claim 1 or 2, wherein the condition to be treated is selected from are acute bowel inflammation, Crohn's disease, colitis ulcerosa, diseases with post-ischemic reperfusion injuries of the GI tract, irritable bowel syndrome, chronic colon inflammation, abdominal inflammation and increased motility of the bowels, gout and multiple sclerosis.
4. Use according to claims 1 to 3, wherein in the general formula (I)
■ R1 is hydroxy, NHR2, NR2R2 or C1-5 straight or branched alkoxy or glyceryl group;
■ R2 is hydrogen atom or C1-5 straight or branched alkyl group; ■ R3-Re are independently of each other hydrogen atom, halogen atom, Cj-5 alkyl, C2_5 alkenyl or alkynyl group optionally substituted with a halogen atom.
5. Use according to claims 1 to 4, wherein, in the general formula (I)
■ R1 is hydroxy, NH2, NH-(C1-5 straight or branched alkyl) or C1-5 straight or branched- alkoxy or glyceryl group;
■ R2 is hydrogen atom;
" R3-R6 are independently of each other hydrogen atom, halogen atom or CF3 group.
6. Use according to claims 1 to 5, wherein the compound of general formula (I) is kynurenic acid (4-hydroxyquinoline-2-carboxylic acid), or a pharmaceutically acceptable salt, ester or amide thereof, such as the glyceryl ester.
7. Method for treating conditions characterized by of hypermotility and inflammation of the GI tract, gout or multiple sclerosis, characterized by administering the patient kynurenic acid derivatives of the general formula (I) or pharmaceutically salts thereof, wherein
Figure imgf000020_0001
G)
■ Rj is hydroxy, NHR2, NR2R2 or C1-10 straight or branched alkoxy or glyceryl group;
■ R2 is hydrogen atom or C1-10 straight or branched alkyl group;
■ R3-R6 are independently of each other hydrogen atom, halogen atom, C1-10 alkyl, C2-5 alkenyl or alkynyl group optionally substituted with a halogen atom.
8. Method of claim 1, characterized in that the condition or disease to be treated is acute bowel inflammation, Crohn's disease, colitis ulcerosa, diseases with post-ischemic reperfusion injuries of the GI tract, irritable bowel syndrome, chronic colon inflammation, abdominal inflammation and increased motility of the bowels, gout and multiple sclerosis.
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