WO2004110429A1 - Utilisation de chromanes ou de thiocromanes substitues pour le traitement du syndrome du colon irritable - Google Patents

Utilisation de chromanes ou de thiocromanes substitues pour le traitement du syndrome du colon irritable Download PDF

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Publication number
WO2004110429A1
WO2004110429A1 PCT/SE2004/000960 SE2004000960W WO2004110429A1 WO 2004110429 A1 WO2004110429 A1 WO 2004110429A1 SE 2004000960 W SE2004000960 W SE 2004000960W WO 2004110429 A1 WO2004110429 A1 WO 2004110429A1
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alkyl
alkenyl
hydrogen
halogen
heteroatoms selected
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PCT/SE2004/000960
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Seth-Olov Thorberg
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Astrazeneca Ab
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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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the present invention relates to the use of substituted 3-amino chromans or thiocromans as well as enantiomers and salts thereof for the treatment of irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • IBS Irritable bowel syndrome
  • the object of the present invention was to find a new way for the treatment of IBS.
  • the present invention is directed to the use of substituted 3-amino chromans or thiocromans according to formula I,
  • X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or C ⁇ -C 6 alkyl; Ri is hydrogen, -C ⁇ alkyl or C 2 -C 6 alkenyl; R 2 is hydrogen, - alkyl, C 2 -C 6 alkenyl, C ⁇ -C 4 alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF 3 , -C ⁇ alkyl, C 2 -C 6 alkenyl or C C 4 alkoxy;
  • Ri and R 2 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;
  • R 3 is halogen, CN, CF 3 , SO 3 CF 3 , N 3 , NO 2 , -Ce alkyl, C 2 -C 6 alkenyl, NH 2 , NR 5 R 6 , COR 7 , 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , -C ⁇ alkyl, C 2 -C 6 alkenyl or C 1 -C 4 alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C ⁇ -C 6 alkyl, C 2 - C 6 alkenyl or -C alkoxy;
  • R 4 is hydrogen or halogen
  • R 5 is hydrogen, C ⁇ -C 6 alkyl or C 2 -C 6 alkenyl;
  • R 6 is Ci-C 6 alkyl or C 2 -C 6 alkenyl; or
  • R 5 and R 6 may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;
  • R 7 is hydrogen, hydroxy, chloro, bromo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, -C alkoxy;
  • R 8 and R 9 are each independently hydrogen, -C ⁇ alkyl, C 2 -C 6 alkenyl, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF 3 , C C 6 alkyl, C 2 -C 6 alkenyl, -C 4 alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula I or their optical isomers, for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • C ⁇ -C 6 alkyl in formula I above represents straight, branched and cyclic alkyl groups having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, ethylcyclopropyl or methylcyclobutyl.
  • alkyl groups have 1 to 4 carbon atoms.
  • C 2 -C6 alkenyl in formula I above represents straight or branched carbon atoms chains having 2 to 6 carbon atoms and containing one or two double bonds, for example allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl.
  • the alkenyl groups have 2 to 4 carbon atoms and one double bond.
  • -C 4 alkoxy in formula I above represents a straight alkoxy group having 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy or butoxy.
  • aryl may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R 2 in formula I represents an aryl residue having 3 to 12 carbon atoms in the aromatic ring and optionally 1 or 2 heteroatoms selected from N, O or S in the aromatic ring, bond by a straight or branched alkylen chain having 1 to 4 carbon atoms in the aliphatic chain.
  • the aromatic ring may be substituted by one or more of nitrile, trifluoromethyl, halogen such as fluoro, chloro, bromo, iodo, - alkyl, e.g. methyl, ethyl, propyl, C 2 -C 6 alkenyl e.g.
  • aryl groups in C 1 -C 4 alkylaryl are phenyl, naphtyl, biphenyl, thienyl, furyl, pyrryl, pyrimidyl and pyrridinyl.
  • -C alkylaryl groups are unsubstituted and substituted phenylalkyl groups wherein the alkyl group is a straight or branched alkyl having 1 to 4 carbon atoms and the aromatic ring may be substituted by one or more of fluoro, chloro, bromo, iodo, nitrile, trifluoromethyl, methyl or ethyl in meta and/or para position, such as example benzyl, phenethyl and phenylpropyl.
  • Halogen in formula I above represents fluoro, chloro, bromo or iodo.
  • 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S and being either (i) optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C C 6 alkyl, C 2 -C 6 alkenyl or C C 4 alkoxy or either (ii) fused at two adjacent carbon atoms to an aryl ring, said aryl ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF 3 , C C 6 alkyl, C 2 - C 6 alkenyl or -C 4 alkoxy; in the definition of R 3 in formula I represents either (i) substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyradazinyl
  • 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R 7 , R 8 and R 9 in formula I representing phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl and morpholinyl.
  • Examples of suitable 5- or 6-membered ring structures formed by R t and R 2 or R 5 and R 6 , or R 7 and R 8 respectively and the nitrogen atom and which may contain a further heteroatom selected from N, O or S are piperazine, morpholine, pyrrolidine, pyrrole, pyrroline, imidazole, imidazoline, imidazolidine, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine.
  • optical isomers may be present.
  • the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer.
  • the compounds or their optical isomers can also be in the form of solvates, e.g. hydrates.
  • the compounds of formula I can be synthesised in accordance with the procedure described in WO91/09853 Al .
  • the present invention is directed to the use of fluorogenated aminochromans, (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3 ,4-dihydro-2H- 1 • benzopyrans according to the formula II:
  • R 10 is n-propyl or cyclobutyl
  • R ⁇ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 12 is hydrogen;
  • R ⁇ 3 is hydrogen or methyl; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula II or their optical isomers, for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • optical isomers may be present.
  • the compounds according to formula II can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer.
  • the compounds or their optical isomers can also be in the form of solvates, e.g. hydrates.
  • the compounds of formula II can be synthesised in accordance with the procedure described in WO95/11891 Al.
  • a compound useful in accordance with the present invention is the salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5- carboxamide hydrogen tartrate, such as the salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate or the salt (R)-3- ⁇ , ⁇ - dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate.
  • These compounds can be synthesised in accordance with the procedure described in WO98/54166 A 1.
  • the present invention is directed to the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of IBS.
  • a further aspect of the invention is a method for the treatment of IBS, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • a further embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of diarrhea.
  • Another aspect of the invention is a method for the treatment of diarrhea, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • Yet another embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of diarrhea predominant IBS.
  • a further aspect of the invention is a method for the treatment of diarrhea predominant IBS, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • a further embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of constipation.
  • Another aspect of the invention is a method for the treatment of constipation, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • Yet another embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of constipation predominant IBS.
  • a further aspect of the invention is a method for the treatment of constipation predominant IBS, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • a further embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the inhibition of alternating bowel movements.
  • Another aspect of the invention is a method for the inhibition of alternating bowel movements, whereby an effective amount of a 3- amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject in need of such inhibition.
  • Yet another embodiment is the use of 3-amino chromans or thiocromans according to the above, as well as enantiomers and salts thereof, for the manufacture of a medicament for the treatment of alternating bowel movement predominant IBS.
  • a further aspect of the invention is a method for the treatment of alternating bowel movement predominant IBS, whereby an effective amount of a 3-amino chroman or thiocroman according to the above, or an enantiomer or a salt thereof, is administered to a subject suffering from said condition.
  • IBS is herein defined as a chronic functional disorder with specific symptoms that include continuous or recurrent abdominal pain and discomfort accompanied by altered bowel function, often with abdominal bloating and abdominal distension. It is generally divided into 3 subgroups according to the predominant bowel pattern:
  • IBS symptoms have been categorized according to the Rome criteria and subsequently modified to the Rome II criteria. This conformity in describing the symptoms of IBS has helped to achieve consensus in designing and evaluating IBS clinical studies.
  • the Rome II diagnostic criteria are:
  • the substituted 3-amino chromans or thiocromans are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
  • the substituted 3-amino chromans or thiocromans are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent.
  • the substituted 3-amino chromans or thiocromans to be formulated are mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
  • Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a compound according to the above in a pharmaceutically acceptable solvent.
  • solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials.
  • Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the substituted 3-amino chromans or thiocromans may be administered once or twice daily, depending on the severity of the patient's condition.
  • a typical daily dose of the substituted 3-amino chromans or thiocromans is from 0.1-1000 mg, being administered once, twice or three times daily, such as a dose of 1-50 mg or 5-20 mg twice daily, but this will depend on various factors such as the route of administration, the age and weight of the patient as well as of severity of the patient' s condition.
  • a typical daily dose per kg body weight of the subject to be treated per day is 0.01 to 10 mg.
  • Test formulation Compound R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro- 2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)- tartrate monohydrate
  • EMG EMG recording were stitched into the external oblique musculature, just superior to the inguinal ligament as previously described (Coutinho SV,
  • Physiol 2002; 282: G307-G316 The fistula housing the electrode leads was externalized through a 4-mm incision on the left side of the abdominal wall for future access. Following surgery, rats were housed in pairs and allowed to recuperate for at least 7 days.
  • the visceral stimulus employed was distension of the descending colon and rectum using a method that has been previously described (Ness TJ, Gebhart, GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res 1988; 450:153-169). Briefly, animals were lightly anesthetized with halothane and a flexible latex balloon (6 cm) lubricated with Surgilube (E. Fougera and Co., Melville, NY) was inserted intra-anally into the descending colon.
  • the balloon was positioned such that its end was 1 cm proximal to the anus and was secured in place by taping the balloon catheter to the base of the tail. Animals were allowed to recover from anesthesia for approximately 30 minutes. The balloon pressure was continuously monitored online with the aid of a customized pressure control device (AstraZeneca R&D, Molndal, Sweden). Colorectal distension (CRD) in awake rats results in contraction of the abdominal and hind limb musculature, recorded as EMG activity in the external oblique musculature (Ness TJ, Gebhart GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat.
  • EMG activity was recorded 20 s before CRD, 20 s during CRD and 20 s after termination of CRD. The EMG activity was rectified and the increase in the area under the curve (AUC) of EMG amplitude (over baseline) was recorded. Baseline responses to graded intensities of phasic CRD (2 * 60 mmHg, followed by 2 series of inflations to 10, 20, 40, 60 mmHg; total of 10 inflations) were obtained. The animals were then exposed to water avoidance (WA) stress for one hour. Responses to phasic CRD were obtained immediately after WA and again 24 hours later.
  • WA water avoidance
  • the rats were placed on a pedestal (8 x 8 x 10 cm) that is attached to the bottom of a Plexiglas tank (25 x 25 x 45 cm). The tank was filled with fresh tap water at room temperature within 1 cm of the top of the block.
  • This well-characterized test represents a potent psychological stressor with large elevations in blood levels of ACTH and corticosterone within 30 minutes (Million M, Tache Y, Anton P. Susceptibility of Lewis and Fischer rats to stress-induced worsening ofTNB-colitis: protective role of brain CRF. Am Physiol 1999; 276: G1027-G1036).
  • water avoidance stress increases colonic motility as measured by fecal pellet output. Sham WA consists of placing rats in the same containers for 1 hour without water.
  • Changes in the NMR at each pressure were calculated as the difference between the EMG response during the 20 sec distension less the EMG activity during the 20 s before distension. Nalues obtained at each pressure of inflation during the 2 distension series were averaged together and normalized as percentage of the baseline response at 60 mmHg.
  • the effect of stress on the NMR to CRD was analyzed by comparing the post stress measurements with the baseline measurements within the same group of animals. The data were analyzed in two ways. First the pressure-response curves were analyzed by repeated measure two-way A ⁇ ONA followed by a Bonferroni post test comparisons (Fig. 1).
  • VMRs in the vehicle-treated group were increased relative to baseline responses at distension pressures >20 mmHg (Fig. 2, top right panel).
  • Clinical evaluation is performed by a randomized, double blind, multi-center study in male and female subjects diagnosed with IBS according to the Rome II criteria. Doses of 5, 10 and 20 mg b.i.d. (twice daily) of a compound as herein above described, such as (R)-3- N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate is compared to placebo based on symptoms in a parallel design. A two week, run-in period is utilized for assessment of baseline symptom severity using daily diary cards. Based on a positive severity scale with a mean value of > 1, using a 5 graded scale (0-4), patients are randomised into a 12- weeks treatment phase. Visits are scheduled monthly along with weekly telephone interviews.
  • the subject is 18 - 70 years of age
  • the subject is an ambulatory outpatient. 4.
  • the subject has IBS according to the Rome II criteria:
  • At least 12 weeks or more, which need not be consecutive, in the previous 12 months of abdominal pain or discomfort that at least 2 of the following 3 features:
  • the subject has had a normal flexible sigmoidoscopy or colonoscopy within the past 5 years. If the subject is aged 50 or greater, he/she must have had a normal colonoscopy within the past 5 years.
  • the subject has clinical evidence of any other organic gastrointestinal disease.
  • the subject has a serious, unstable medical condition.
  • the subject has had a major psychiatric diagnosis or a suicide attempt within the last two years, including patients who have not been on stable medication for the psychiatric disorder for the last 6 month.
  • the subject has a history of alcohol or substance abuse within two years.
  • the subject has abnormal laboratory results.
  • the subject requires continuous treatment with SSRIs (selective serotonin reuptake inhibitor(s)). 11. The subject has taken tegaserod or alosetron within 14 days of study.
  • SSRIs selective serotonin reuptake inhibitor(s)
  • Randomization is in blocks of 4 and is stratified based on primary baseline symptoms: constipation predominant, or diarrhea/other predominant.

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Abstract

La présente invention concerne l'utilisation de chromanes ou de thiocromanes substitués en 3-amino, ainsi que des énantiomères et des sels correspondants destinés au traitement du syndrome du côlon irritable.
PCT/SE2004/000960 2003-06-19 2004-06-16 Utilisation de chromanes ou de thiocromanes substitues pour le traitement du syndrome du colon irritable WO2004110429A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009853A1 (fr) * 1989-12-22 1991-07-11 Aktiebolaget Astra Nouveaux derives du chroman et du thiochroman
EP0498590A1 (fr) * 1991-02-08 1992-08-12 Eli Lilly And Company 2-Amino-1,2,3,4-tétrahydronaphthalènes substitués au noyau
EP0579507A1 (fr) * 1992-07-17 1994-01-19 Eli Lilly And Company Dérivés de l'isoxazole pour le traitement du syndrome des intestins irritables
WO1995011891A1 (fr) * 1993-10-28 1995-05-04 Astra Aktiebolag Nouveaux (r)-5-carbamyl-8-fluoro-3-amino n,n disubstitues-3,4-dihydro-2h-1-benzopyrannes
WO1998054166A1 (fr) * 1997-05-30 1998-12-03 Astra Aktiebolag Nouveau sel

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009853A1 (fr) * 1989-12-22 1991-07-11 Aktiebolaget Astra Nouveaux derives du chroman et du thiochroman
EP0498590A1 (fr) * 1991-02-08 1992-08-12 Eli Lilly And Company 2-Amino-1,2,3,4-tétrahydronaphthalènes substitués au noyau
EP0579507A1 (fr) * 1992-07-17 1994-01-19 Eli Lilly And Company Dérivés de l'isoxazole pour le traitement du syndrome des intestins irritables
WO1995011891A1 (fr) * 1993-10-28 1995-05-04 Astra Aktiebolag Nouveaux (r)-5-carbamyl-8-fluoro-3-amino n,n disubstitues-3,4-dihydro-2h-1-benzopyrannes
WO1998054166A1 (fr) * 1997-05-30 1998-12-03 Astra Aktiebolag Nouveau sel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Irritable bowel syndrome (functional bowel)", MEDICAL ENCYCLOPEDIA, 11 July 2002 (2002-07-11), Retrieved from the Internet <URL:http://www.nlm.nih.gov/medlineplus/encyclopedia.html> *

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