WO2004110429A1

WO2004110429A1 - Use of substituted chromans or thiocromans for the treatment of ibs

Info

Publication number: WO2004110429A1
Application number: PCT/SE2004/000960
Authority: WO
Inventors: Seth-Olov Thorberg
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-06-19
Filing date: 2004-06-16
Publication date: 2004-12-23
Anticipated expiration: 2005-12-19
Also published as: TW200509904A; SE0301795D0; AR044717A1

Abstract

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).

Description

USE OF SUBSTITUTED CHROMANS OR THIOCROMANS FOR THE TREATMENT OF IBS

Field of the invention

Background of the invention

Irritable bowel syndrome (IBS) can be defined in accordance with Thompson WG,

Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional

Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, Talley NJ, Thompson

WG, Whitehead WE, Coraziarri E, eds. Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, NA: Degnon Associates, Inc.;

2000:351-432 and Drossman DA, Corazziari E, Talley ΝJ, Thompson WG and Whitehead

WE. Rome II: A multinational consensus document on Functional Gastrointestinal

Disorders. Gut 45(Suppl.2), II1-II81.9-1-1999.

The etiology of this condition is unknown. There appears to be multiple factors that play a role in the pathogenesis of IBS including psychosocial disorders, genetic factors, dysmotility, post-acute gastrointestinal infection, abnormal brain-gut axis interactions and visceral hypersensitivity.

Currently existing therapy of IBS is largely empirical and directed towards relief of prominent symptoms. The most commonly used therapies still include bulking agents, antispasmodics and antidepressants.

Substituted 3-amino chromans or thiocromans are disclosed in WO91/09853 Al. Fluorogenated aminochromans, (R)-5-carbamoyl-8-fluoro-3-Ν,Ν-disubstituted-amino-3,4- dihydro-2H-l-benzopyrans in the form of free base or pharmaceutically acceptable salts thereof, are disclosed in WO95/11891 Al. Particular salts, such as (R)-3-N,N- dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen tartrate, such as the (2R,3R) form of the tartrate and particularly the monohydrate thereof, are disclosed in WO98/54166 Al .

The object of the present invention was to find a new way for the treatment of IBS.

Outline of the invention

It has now surprisingly been found that substituted 3-amino chromans or thiocromans as well as enantiomers and salts thereof, are useful for the treatment of IBS.

More particularly, the present invention is directed to the use of substituted 3-amino chromans or thiocromans according to formula I,

wherein (O)p

X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or Cι-C₆ alkyl; Ri is hydrogen, -C_ό alkyl or C₂-C₆ alkenyl; R₂ is hydrogen, - alkyl, C₂-C₆ alkenyl, Cι-C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -Cβ alkyl, C₂-C₆ alkenyl or C C₄ alkoxy;

Ri and R₂ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, -Ce alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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, CF₃, -Cβ alkyl, C₂-C₆ alkenyl or C₁-C₄ 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, CF₃, C_Ϊ-C₆ alkyl, C₂- C₆ alkenyl or -C alkoxy;

R₄ is hydrogen or halogen;

R₅ is hydrogen, Cι-C₆ alkyl or C₂-C₆ alkenyl; R₆ is Ci-C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₇ is hydrogen, hydroxy, chloro, bromo, Ci-C₆ alkyl, C₂-C₆ alkenyl, -C alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or CrC₄ alkoxy;

R₈ and R₉ are each independently hydrogen, -Cβ alkyl, C₂-C₆ alkenyl, 5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, C C₆ alkyl, C₂-C₆ alkenyl, -C₄ 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). Cι-C₆ 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. In one embodiment, alkyl groups have 1 to 4 carbon atoms.

C₂-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. In one embodiment, the alkenyl groups have 2 to 4 carbon atoms and one double bond.

-C₄ alkoxy in formula I above represents a straight alkoxy group having 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy or butoxy.

Cι-C alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R₂ 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, C₂-C₆ alkenyl e.g. allyl, propenyl, or C₁-C₄ alkoxy in meta and/or para position. Examples of suitable aryl groups in C₁-C₄ alkylaryl are phenyl, naphtyl, biphenyl, thienyl, furyl, pyrryl, pyrimidyl and pyrridinyl. In one embodiment, -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, CF₃, C C₆ alkyl, C₂-C₆ alkenyl or C C₄ 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, CF₃, C C₆ alkyl, C₂- C₆ alkenyl or -C₄ alkoxy; in the definition of R₃ in formula I represents either (i) substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyradazinyl, thiozolyl, isothiozolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinyl or morpholinyl or either (ii) substituted or unsubstituted quinolyl, isoquinolyl, quinazolyl, quinaxazolyl or indolyl.

5- or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S in the definition of R₇, R₈ and R₉ 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 R₂ or R₅ and R₆, or R₇ and R₈ 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.

When one or more stereocentre is present in the molecule, 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 . In a further embodiment, 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:

wherein R₁₀ is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R₁₂ is hydrogen; Rι₃ 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).

When one or more stereocentre is present in the molecule, 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.

In yet another embodiment, 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-Ν,Ν- 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.

Consequently, 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:

1- diarrhea predominant

2- constipation predominant 3- alternating bowel movements.

Abdominal pain or discomfort is the hallmark of IBS and is present in the three subgroups. 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:

1- Presence of abdominal pain or discomfort for at least 12 weeks (not necessarily consecutively) out of the preceding year

2- Two or more of the following symptoms: a) Relief with defecation b) Onset associated with change in stool frequency c) Onset associated with change in stool consistency

Pharmaceutical formulations

For clinical use, 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. Thus, 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. In the preparation of oral pharmaceutical formulations in accordance with the invention, 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. The mixture is then processed into granules or compressed into tablets.

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. These 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.

In one aspect of the present invention, 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.

Biological evaluation

Example 1.

Materials and methods

Chemical name R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-

2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)- tartrate monohydrate

Formula C18 H23 F N2 O2,

C22 H31 F N2 O9 (Tartrate monohydrate) Structure

Relative molecular weight 318.39 Tartrate 486.5

Test formulation Compound R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro- 2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)- tartrate monohydrate

Vehicle Sterile water

Stock concentration A fresh solution was prepared for each experiment on the same day. The concentration of the solution depended on the total animal weight, in order to keep a constant volume of administration. The compound was diluted in sterile water.

Additional chemicals and materials Halothane Pentobarbital

Test system

Justification for selection of test Isobaric colorectal distension is a test system used in system humans to assess visceral sensitivity and has, in some cases, been used as a diagnostic tool for IBS.

Species Rat Strain Wistar

Sex Male

Total No. of animals 16

Body weight range 250 - 350 g

Supplier Harlan, San Diego, CA, USA

Identification method Permanent marker on the tail

Acclimatisation The animals were allowed to acclimate to the animal facility for 1 week prior to surgery.

Housing conditions The rats were housed in. pairs with free access to food and water. A 12 hour light dark cycle (lights on at 6 am) was maintained.

Diet Purina rat chow Water Tap water Bedding Shavings Pre-treatment Surgery: Electrodes (teflon coated stainless steel,

AstraZeneca, Sweden) for electromyographic

(EMG) recording were stitched into the external oblique musculature, just superior to the inguinal ligament as previously described (Coutinho SV,

Plotsky PM, Sablad M, Miller JC, Zhou H, Bayati

Al, McRoberts JA, Mayer EA. Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am J

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.

Wounds were tested for tenderness to ensure complete recovery prior to testing. Participation in previous studies No

Study design

Dose 1 μmol/kg or 0.486 mg/kg

Volume of administration 0.25 ml/kg

Infusion/injection rate and/or time 3 s

Route and frequency of administration Subcutaneous, once daily for two consecutive days

Duration of treatment Two days

Number/group 8

Number of groups 2

Individual animal identification 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, II: 1, 11:2, 11:3, 11:4,

NoVreference No. 11:5, 11:6, 11:7, 11:8, 111:1, IH:2, 111:3, 1H:4, m:5, m:6,

Experimental procedures

Colorectal distension

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. Brain Res 1988; 450:153-169). Each distension lasted 20 seconds at four-minute inter-stimulus intervals. 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.

Water avoidance stress

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). Furthermore, water avoidance stress (WA) increases colonic motility as measured by fecal pellet output. Sham WA consists of placing rats in the same containers for 1 hour without water.

Experimental design The experiment used 2 groups of 8 rats. One group was subjected to WA stress and the other sham WA stress. Nisceromotor responses (NMRs) to phasic CRD (10 to 60 mmHg) were evaluated at baseline, immediately after WA or sham WA, and again 24 hours later. R-3-Ν,Ν-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate was injected subcutaneously (sc) at the dose of 1 μmol/kg, 15 minutes before the WA (or sham WA) stress, and again 30 minutes before the 24-hour measurements. With the first group of rats, the procedure was repeated two weeks later, except that vehicle (saline) was given in place of drug. Comparisons were made between the 2 treatment conditions (R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and vehicle) within the first group rats subjected to WA stress. For the second group of rats subjected to sham WA, comparisons were made between R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro- 2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate treated rats and historical control rats subjected to sham WA.

Data analysis

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 AΝONA followed by a Bonferroni post test comparisons (Fig. 1). In the second method, the difference between post WA or 24 hours responses and the baseline response at each pressure was calculated and comparisons were made using t-tests with corrections for between group errors using pooled variances at all pressures (Fig. 2). Errors in this analysis are standard errors of the difference (SEd). All other data is presented as mean ± SEM. A P<0.05 was considered statistically significant. Results

Inhibition of water avoidance stress-induced delayed hyperalgesia

As observed previously, subjecting male Wistar rats to 1 hour of WA stress did not affect the VMR immediately after the stress period, but did cause a significant increase in the response 24 hours later (Fig. 1; top left panel; P<0.05 by repeated measures ANOVA). Injection of 1 μmol/kg R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate sc 15 minutes before WA stress and 30 minutes before the 24 hour CRD series abolished the increase seen at 24 hours (Fig. 1; top right panel). Both the post WA and 24 hour VMRs tended to be smaller than the initial baseline VMR, but this was not significant. The effect of R-3-N,N- dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate compared to vehicle on post WA and 24 hour VMRs is more readily apparent in the difference plots (Fig. 2; top 2 panels respectively). R-3-N.N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate injected before WA stress tended to decrease the VMR immediately after WA, but the effect was not significant at any pressure (P>0.1). However 24 hours later, VMRs in the vehicle-treated group were increased relative to baseline responses at distension pressures >20 mmHg (Fig. 2, top right panel). Rats treated with R- 3-N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate before WA and again before the 24 hours measurement had significantly lower VMR responses compared to vehicle at distension pressures of 20, 40 and 60 mmHg (P<0.01).

No effect on visceral motor responses following sham water avoidance For vehicle treated rats, sham WA stress, in which rats are placed in dry tanks, had no effect on VMRs either immediately after sham stress or 24 hours later. (Fig. 1; bottom left panel). Injection of 1 μmol/kg R-3-Ν,Ν-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate sc 15 minutes before sham stress and 30 minutes before the 24 hour CRD series had no significant effect on the VMR immediately after sham stress or 24 hours later (Fig. 1; bottom right panel). Difference comparisons (Fig. 2; bottom 2 panels) failed to show any effect of R-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate on VMRs at either time.

Conclusions

1. R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate given at 1 μmol/kg 15 minutes before WA stress and again 30 minutes before the 24 hour assessment of the VMR to graded phasic CRD, completely blocks delayed stress-induced visceral hyperalgesia.

2. R-3-N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate at the same dose had no effect on VMRs to CRD following sham stress.

3. In rats given R-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5- carboxamide hydrogen (2R,3R)-tartrate monohydrate and WA stress, there was a reduction of the VMR relative to baseline responses at pressures greater than 20 mmHg, suggesting a possible analgesic effect of the compound.

The results shown in the Example above, supports that compounds of formula I are useful for the treatment of irritable bowel syndrome (IBS).

Clinical evaluation

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.

While the study investigates both male and female subjects, the primary assessment is based on women only. Exploratory analyses investigate the treatment effect in male subjects.

Inclusion criteria

1. An informed consent has been signed.

2. The subject is 18 - 70 years of age

3. 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:

- Relief with defecation,

- Onset associated with a change in stool frequency, or - Onset associated with a change in stool form.

5. 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.

6. Ability to complete the diary and the questionnaires

Inclusion criteria visit no 2 (randomisation) Patients with an average daily score of abdominal pain/discomfort during the run-in period of > 1.0 on a 5-graded scale (0=none, l=mild, 2= moderade, 3=intense, 4=severe).

Exclusion Criteria

1. The subject has clinical evidence of any other organic gastrointestinal disease.

2. The subject has a serious, unstable medical condition.

3. 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.

4. The subject has a history of alcohol or substance abuse within two years.

5. The subject has abnormal laboratory results.

6. The subject has been treated for a malignancy within the last 5 years

7. The subject has been diagnosed with lactose intolerance and it can explain their symptoms.

8. The subject has participated in a drug study within the last 30 days.

9. The subject has had previous gastric or intestinal surgery

10. 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.

12. Pregnancy, planned pregnancy or lactation.

Randomization is in blocks of 4 and is stratified based on primary baseline symptoms: constipation predominant, or diarrhea/other predominant.

Primary endpoint: Having adequate relief of abdominal pain/discomfort for two weeks out of four weeks for each of the three months. Based on weekly telephone interviews the patients will be asked to answer the following question: "hi the past seven days, have you had adequate relief of your IBS pain and discomfort?" Response choices: yes or no.

Claims

1. Use of a compound of formula I,

wherein

(O)p

is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or - alkyl;

R_\ is hydrogen, - alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, Cr alkyl, C₂-C₆ alkenyl, - alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -Ce alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C_rC₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR , 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or C1-C₄ 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₄ is hydrogen or halogen; R₅ is hydrogen, -C_δ alkyl or C₂-C₆ alkenyl;

R₆ is Cι-C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₇ is hydrogen, hydroxy, chloro, bromo, -C₆ alkyl, C₂-C₆ alkenyl, Ci-C₄ alkoxy;

NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, -Cβ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -C₆ alkyl, C₂-C₆ alkenyl, C1-C4 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).

2. Use according to claim 1 , wherein the IBS is diarrhea predominant IBS.

3. Use according to claim 1 , wherein the IBS is constipation predominant IBS .

4. Use according to claim 1 , wherein the IBS is alternating bowel movement predominant IBS.

5. Use of a compound of formula I,

wherein

(O)_p

X is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or C C₆ alkyl;

R! is hydrogen, -C₆ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, -Cβ alkyl, C₂-C₆ alkenyl, -C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, - alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, Cι-C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or C1-C4 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy;

R/_t is hydrogen or halogen;

R₅ is hydrogen, Cι-C₆ alkyl or C₂-C₆ alkenyl;

R₆ is Cι-C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₇ is hydrogen, hydroxy, chloro, bromo, - alkyl, C₂-C₆ alkenyl, - alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, -C₆ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl, C C 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 abdominal pain.

6. Use of a compound of formula I,

wherein

(0)_P

X is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or - alkyl;

Ri is hydrogen, Ci-Cβ alkyl or C₂-C6 alkenyl; R2 is hydrogen, - alkyl, C₂-C₆ alkenyl, -C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -Ce alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

Rt and R₂ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ 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 , Cι-C₆ alkyl, C₂-C₆ alkenyl or C₁-C₄ alkoxy;

R₄ is hydrogen or halogen;

R₅ is hydrogen, Cι-C₆ alkyl or C₂-C₆ alkenyl; R₆ is -C_ό alkyl or C₂-C₆ alkenyl; or

R₇ is hydrogen, hydroxy, chloro, bromo, Cι-C₆ alkyl, C₂-C₆ alkenyl, -C₄ alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, - alkyl, C₂-C₆ alkenyl, -C₄ 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 abdominal discomfort.

. Use of a compound of formula E,

wherein

R₁₀ is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; Rπ is hydrogen; R₁₃ 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).

8. Use according to claim 7, wherein said compound is the salt (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate.

9. Use according to claim 8, said compound being (R)-3-N,N-dicyclobutylamino-8 fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate.

10. Use according to any one of claims 7-9, wherein the IBS is diarrhea predominant IBS.

11. Use according to any one of claims 7-9, wherein the IBS is constipation predominant IBS.

12. Use according to any one of claims 7-9, wherein the IBS is alternating bowel movement predominant IBS.

13. Use of a compound of formula π,

wherein

Rio is n-propyl or cyclobutyl;

Rn is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; Ri₂ is hydrogen; R₁₃ is hydrogen or methyl; as well as optical isomers and pharmaceutically acceptable salts and solvates of the compounds of formula E or their optical isomers, for the manufacture of a medicament for the treatment of abdominal pain.

14. Use of a compound of formula π,

wherein

R₁₀ is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R₁₂ is hydrogen; Rι₃ 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 abdominal discomfort.

15. Use according to any one of claims 1-15, wherein the daily dose of the active agent is 0.1-1000 mg.

16. Use according to claim 15, wherein the daily dose of the active agent is 1-50 mg.

17. Use according to claim 16, wherein the daily dose of the active agent is 5-20 mg.

18. A method for the treatment of irritable bowel syndrome (IBS), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I

wherein

(O)p

X is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or - alkyl;

Ri is hydrogen, Cι-C₆ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, -C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, Ci-C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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 , Cι-C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or Cι-C₄ alkoxy;

R₄ is hydrogen or halogen;

R5 is hydrogen, Cι-C₆ alkyl or C₂-C₆ alkenyl;

R₆ is Cι-C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and R₆ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₇ is hydrogen, hydroxy, chloro, bromo, Cι-C₆ alkyl, C₂-C₆ alkenyl, C C₄ alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or C₁-C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, -Cβ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, C C₆ alkyl, C₂-C₆ alkenyl, Cι-C alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula I or their optical isomers; is administered to a subject in need of such treatment.

19. The method according to claim 14, wherein the IBS is diarrhea predominant IBS.

20. The method according to claim 14, wherein the IBS is constipation predominant

IBS.

21. The method according to claim 14, wherein the IBS is alternating bowel movement predominant IBS.

22. A method for the treatment of abdominal pain, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I

wherein (O)p

X is O or S; p is an integer 0, 1 or 2; R is hydrogen, fluoro or - alkyl;

Ri is hydrogen, -Cβ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, C C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, -Ce alkyl, C₂-C₆ alkenyl or d-C₄ alkoxy; Ri and R₂ may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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, CF₃, -C₆ alkyl, C₂-C₆ alkenyl or C₁-C₄ 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, CF₃, C C₆ alkyl, C₂-C₆ alkenyl or -C₄ alkoxy;

R₄ is hydrogen or halogen; R₅ is hydrogen, C C₆ alkyl or C₂-C₆ alkenyl;

R₆ is -C6 alkyl or C₂-C6 alkenyl; or

R₇ is hydrogen, hydroxy, chloro, bromo, Cι-C₆ alkyl, C₂-C₆ alkenyl, C C₄ alkoxy; NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or C C₄ alkoxy;

R₈ and R₉ are each independently hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, C C₆ alkyl, C₂-C₆ alkenyl, C C₄ alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula I or their optical isomers; is administered to a subject in need of such treatment.

23. A method for the treatment of abdominal discomfort, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I

wherein

(O)p

X is O or S; p is an integer 0, 1 or 2;

R is hydrogen, fluoro or - alkyl;

Ri is hydrogen, -Cβ alkyl or C₂-C₆ alkenyl;

R₂ is hydrogen, -Cβ alkyl, C₂-C₆ alkenyl, Cι-C₄ alkylaryl where aryl may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or C C₄ alkoxy;

R₃ is halogen, CN, CF₃, SO₃CF₃, N₃, NO₂, C C₆ alkyl, C₂-C₆ alkenyl, NH₂, NR₅R₆, COR₇, 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, CF₃, d-C₆ alkyl, C₂-C₆ alkenyl or -C₄ 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, CF₃, Cι-C₆ alkyl, C₂-C₆ alkenyl or d-C₄ alkoxy; R-j is hydrogen or halogen;

R₅ is hydrogen, Q-Cβ alkyl or C₂-C₆ alkenyl;

R₆ is Cι-C₆ alkyl or C₂-C₆ alkenyl; or

R₅ and Re may together form a 5- or 6- membered ring which may contain 1 or 2 heteroatoms selected from N, O or S; R₇ is hydrogen, hydroxy, chloro, bromo, Cι-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₄ alkoxy;

NR₈ R₉ or 5-or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by one or more of halogen, CN, CF , Cι-C₆ alkyl, C₂-C₆ alkenyl or C₁-C₄ alkoxy;

R₈ and R are each independently hydrogen, d-d alkyl, C₂-C₆ alkenyl, 5- or 6- membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S optionally substituted by halogen, CN, CF₃, d-C₆ alkyl, C₂-C₆ alkenyl, Cι-C₄ alkoxy, or may together form a 5- or 6- membered ring containing 1 or 2 heteroatoms selected from N, O or S; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula I or their optical isomers; is administered to a subject in need of such treatment.

24. A method for the treatment of irritable bowel syndrome (IBS), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II

wherein

R₁₀ is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R₁₂ is hydrogen; R₁₃ is hydrogen or methyl; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula II or their optical isomers; is administered to a subject in need of such treatment.

25. The method according to claim 24, wherein said compound is (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate.

26. The method according to claim 25, said compound being (R)-3-N,N- dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate.

27. The method according to any one of claims 24-26, wherein the IBS is diarrhea predominant IBS.

28. The method according to any one of claims 24-26, wherein the IBS is constipation predominant IBS.

29. The method according to any one of claims 24-26, wherein the IBS is alternating bowel movement predominant IBS.

30. A method for the treatment of abdominal pain, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula II

wherein

Rio is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R12 is hydrogen; Rι₃ is hydrogen or methyl; or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula II or their optical isomers; is administered to a subject in need of such treatment.

31. A method for the treatment of abdominal discomfort, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula π

wherein

Rio is n-propyl or cyclobutyl;

Rπ is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl; R12 is hydrogen; Rι₃ is hydrogen or methyl;

or an optical isomer or a pharmaceutically acceptable salt or solvate of the compounds of formula II or their optical isomers; is administered to a subject in need of such treatment.

32. The method according to any one of claims 18-31, wherein the daily dose of the active agent is 0.1-1000 mg.

33. The method according to claim 32, wherein the daily dose of the active agent is 1- 50 mg.

34. The method according to claim 33, wherein the daily dose of the active agent is 5-

20 mg.