WO2005058292A1

WO2005058292A1 - New use in gastrointestinal disorders

Info

Publication number: WO2005058292A1
Application number: PCT/SE2004/001877
Authority: WO
Inventors: Anders Lehmann
Original assignee: Astrazeneca Ab
Priority date: 2003-12-19
Filing date: 2004-12-15
Publication date: 2005-06-30
Also published as: SE0303490D0

Abstract

The present invention relates to the use of a compound of formula I for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of a compound of formula I for the treatment of gastro-esophageal reflux disease, as well as for the treatment of regurgitation.

Description

NEW USE IN GASTROINTESTINAL DISORDERS

Field of the invention

The present invention relates to the use of certain compounds for the inhibition of transient lower esophageal sphincter relaxations. A further aspect of the invention is directed to the use of certain compounds for the treatment of gastro-esophageal reflux disease, as well as for the treatment of regurgitation.

Background of the invention

The lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".

Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Hollow y & Dent (1990)

Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.

The object of the present invention was to find a new way for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), thereby preventing reflux. More particularly the object of the invention was to find a new way of treating gastro-esophageal reflux disease (GERD), as well as a new way for the treatment of regurgitation in infants. Outline of the invention The present invention is directed to the use of compounds of formula I

wherein X is -S-, -S(O)-, -S(O)₂-, -S(O)₂NH-, -P(O)(OCH₃)-, -P(O)(OH)-, - NH-, -N(CH₃)-

, -NHC(O)NH-, C(O)-, -C(O)O-, -NHC(O)-, -CH(OH)-, -CH=N-, -CH=CH-, -CH₂NH- or

C(=NH)-;

R¹ is aryl or heteroaryl;

R² is hydrogen, OR⁴ or NR⁵R⁶; R⁴ is C C₈ alkyl or C₂-C₈ alkenyl;

R⁵ and R⁶ independently are hydrogen, Cι-C₈ alkyl or C(O)Cι-C₈ alkyl; and

R³ is hydrogen, cyano, heteroaryl, heterocycloalkyl, C(O)R⁷, OR⁸ orTSTR⁹R¹⁰;

R⁷ is OH, C C alkoxy, NH₂, NHCH₂C(O)OH or aryl;

R⁸ is hydrogen, Cι-C₈ alkyl, C(O)C C₄ alkyl or C(O)-aryl; and R⁹ and R¹⁰ independently are hydrogen, Cι-C₈ alkyl or C₂-C₄ alkenyl; with the proviso that when X is -C(O)- and R² and R³ are hydrogen or R² is H and R³ is 4- methoxy, R¹ is neither 1-naphthyl nor 4-methoxy-l-naphtyl; or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).

Aryl or heteroaryl is to be understood to include a six membered ring or a bicycle consisting of two condensed six-membered rings or one six-membered and one five- membered ring, wherein one or more C atoms may be replaced, independently of one another, by an atom selected from the group consisting of oxygen, nitrogen and sulfur. Examples include C₆-Cι₀ aryl, Cι-C heteroaryl, and C₆ aryl condensed to a five or six membered aliphatic or heteroaliphatic ring, e.g. naphthyl, 1,2,3,4-tetrahydronaphthalenyl, phenyl, indolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzothiazolyl, imidazolyl, benzimidazolyl, benzoxadiazolyl, benzotriazolyl, indanyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl.

Examples of heterocycloalkyl include piperidinyl, piperazinyl and morpholinyl.

It will be understood that the above defined compounds may bear substituents within their structure, e.g. one or more substituents selected from OH; nitro; halogen; cyano; COOH; C(O)NH₂; C(O)NHNHC(O)CH₃; C(NH₂)=NOH; C,-C₄ alkyl; S-Cι-C₄ alkyl; C C₈ alkoxy; C₅-C₁₀ aryl such as phenyl; Cι-C₄-heteroaryl such as oxadiazolyl; Cι_.-C₅-N- heterocycloalkyl such as morpholinyl or piperidinyl; C(O)O-Cι-C₄ alkyl orNR^πR¹² wherein R¹¹ and R¹² independently are hydrogen, Cι-C alkyl, C(O)NHO-Cι-C₄ alkyl, C(O)Cι-C₄ alkyl or SO₂-Cι-C₄ alkyl; which substituents again may be substituted by a substituent selected from OH; nitro; NH₂; Cι-C₄ alkyl; Cι-C₄ alkoxy; Cι.-C₄ alkoxy substituted by OH; C₃-C₆ cycloalkyl; N-(Cj-C₄ alkyl)₂; phenyl; or morpholinyl.

For example, in the meaning of R¹ aryl or heteroaryl may be unsubstituted or substituted by one or more substituents selected from OH; COOH; C(O)NH₂; nitro; halogen; cyano; C(NH₂)=NOH; Cι-C₄-N-heteroaryl; -Cs-N-heterocycloalkyl; Cι-C₄ alkyl; S-C,-C₄ alkyl; Cι-C₈ alkoxy and NR¹ *R¹² wherein R¹ ' and R¹² independently are hydrogen, C]-C₄ alkyl, C(O)NHO-d-C₄ alkyl, C(O)C C₄ alkyl or SO₂-Cι-C₄ alkyl; wherein Cι-C₄ alkyl, C_rC₈ alkoxy and Cj-Cs-N-heterocycloalkyl again may be unsubstituted or substituted by OH; Cι-C alkyl; Cι-C₄ alkoxy; d.-C₄ alkoxy substituted by OH; C₃-C₆ cycloalkyl; N-(Cι-C₄ alkyl)2; phenyl; or morpholinyl; in the meaning of R³ oxadiazolyl, piperazinyl or tetrazolyl may be substituted by methyl; in the meaning of R⁴ Q- alkyl may be unsubstituted or substituted by OH, C(O)O-Cj-C₄ alkyl, morpholinyl, piperidinyl, phenyl or oxadiazolyl; wherein phenyl and oxadiazolyl again may be unsubstituted or substituted by Cι-C alkyl, Cι-C₄ alkoxy, nitro, NH₂ or N(C C₄ lkyl)₂; in the meaning of R⁵ or R⁶ Cι-C₄ alkyl may be unsubstituted or substituted by morpholinyl; in the meaning of R³ Cι-C alkyl may be unsubstituted or substituted by C(O)OH, C(O)OCH₃, C(O)NHNHC(O)CH₃ or oxadiazole substituted by Cι-C₄ alkyl.

Compounds of formula I exist in free or salt, e.g. acid addition salt form. The invention is to be understood as including the compounds of formula I in free as well as in salt form, e.g. as trifluoroacetate or hydrochloride salt. Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt.

In formula I the following significances are examples of compounds, independently, collectively or in any combination or sub-combination:

(a) X is-S-, -S(O)- , -S(O)₂-, -S(O)₂NH-, -P(O)(OCH₃)-, -P(O)(OH)-, -NH-, -N(CH₃)-, - NHC(O)NH-, -NHC(O)-, -C(O)-, -C(O)O-, -CH(OH)-, -CH=N-, -CH=CH-, -CH₂NH- or - C(=NH)- ; particularly -NH-, -C(O)-, -C(O)O- or -CH₂NH-, more particularly -C(O)- or - C(O)O-;

(b) R¹ is phenyl, 4-methoxyphenyl, 2-hydroxy-3-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-[2-(morpholin-4-yl)ethoxy]-phenyl, 4-[3- (hydroxy)propoxy]phenyl, 4-butoxyphenyl, 3-(NHC(O)NHOCH₃)-4-pentoxyphenyl, 4- thiomethylphenyl, 4-acetamido-phenyl, naphthyl, 4-carboxynaphthyl, 4- aminocarbonylnaphthyl, 4-hydroxynaphthyl, 4-(C(NH₂) =NOH)-naphthyl, 4-fluoro- naphth-1-yl, 4-cyanonaphthyl, 3-nitro-naphth-l-yl, 4-nitro-naphth-l-yl, 3-amino-naphth-l- yl, 4-amino-naphth-l-yl, 4-dimethylamino-naphth-l-yl, 4-methoxy-naphth-l-yl, 4-[4- (hydroxy) butoxyjnaphthyl, 4-pentoxy-naphthyl, 4-[2-(morpholin-4-yl)ethoxy]naphthyl, 3-(dimethylamino)naphthyl, 3-methylsulfonamido-naphthyl, 4-methyl-sulfonamido- naphthyl, 4-(l,2,4-triazol-l-yl)-naphth-l-yl, 4-(lH-tetrazol- 5-yl)-naphthyl, 4-(pyrazol-l- yl)-naphthyl, 4-(imidazol-l-yl)-naphthyl, l,2,3,4-tetrahydronaphthalen-5-yl, indan-4-yl, indol-7-yl, quinolin-8-yl, quinolin-4-yl, quinolin-3-yl, quinolin-5-yl, isoquinolin-5-yl, isoquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-l-yl, l,2,3,4-tetrahydroquinolin-8-yl, 6- methoxy-l,2,3,4-tetrahydroquinolin-l-yl, 5-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl, 7- pentoxy-benzotriazol-4-yl, 5,7-dimethyl-2, l,3-benzothiadiazol-4-yl, 5-chloro-2, 1,3- benzothiadiazol-4-yl, 2,l,3-benzothiadiazol-4-yl, 2,l,3-benzoxadiazol-4-yl, 7-pentoxy- 2,1,3- benzoxadiazol-4-yl, 2-oxo-7-pentoxy-l,3-dihydro-benzimidazol-4-yl, 2- (T HCH₂phenyl)-7-pentoxy-benzimidazol-4-yl₅ 2-(NHCH2cyclohexyl)-7-pentoxy- benzimidazol-4-yl, 2-(NH(CH2)₃N(CH₂CH₃)2)-7-pentoxy-benzimidazol-4-yl, 2-

(NH(CH₂)₃CH₃)-7-pentoxy-benzimidazol-4-yl, 2-(4-methylpiperazin- 1 -yl)-7-pentoxy- benzimidazol-4-yl, 2-(NH(CH₂)₂OH)-7-pentoxy-benzimidazol-4-yl, 2- (NH(CH₂)2θ(CH2)2θH)-7-pentoxy-benzimidazol-4-yl, 2-methyl-7-pentoxy-benzimidazol- 4-yl, 7-pentoxybenzimidazol-4-yl; particularly naphthyl, 4-hydroxynaphthyl, 4-fluoro- naphth-1-yl, 4-cyanonaphth-l-yl, 4-nitro-naphth-l-yl, 4-dimethylamino-naphth-l-yl, 4- methoxy-naphth- 1 -y 1, 4-[4-(hydroxy)-butoxy]naphthyl, 4-( 1 ,2,4-triazol- 1 -yl)-naphth- 1 -yl, 4-(pyrazol- 1 -yl)-naphthyl, 4-(imidazol- 1 -yl)-naphthyl, 1 ,2,3 ,4-tetrahydronaphthalen-5-yl, indan-4-yl, quinolinyl, quinolin-8-yl, quinolin-4-yl, isoquinolin-5-yl, 7-pentoxy- benzotriazol-4-yl, 5-chloro-2, 1 ,3-benzothiadiazol-4-yl, 2-(NHCH₂phenyl)-7-pentoxy- benzimidazol-4-yl, 2-(NH(CH2)₃CH₃)-7-pentoxy-benzimidazol-4-yl or 7- pentoxybenzimidazol-4-yl, more particularly naphthyl, 4-fluoro-naphth-l-yl, 4- cyanonaphth-1-yl, 4-dimethylamino-naphth-l-yl, 4-(l,2,4-triazol-l-yl)-naphth-l-yl, 4- (imidazol-l-yl)-naphthyl, l,2,3,4-tetrahydronaphthalen-5-yl, indan-4-yl, quinolin-8-yl, isoquinolin-5-yl or 5-chloro-2,l,3 benzothiadiazol-4-yl; (c) R² is hydrogen, -O-(CH₂)₂CH₃, -O-(CH₂)₃CH₃, -O-(CH₂)₄CH₃, -O-(CH₂)₅CH₃₅ -O- (CH₂)₆CH₃, -O-(CH )₃CH(CH₃)₂, 2-(morpholin-4-yl)-ethoxy, 2-(piperidin-l-yl)-ethoxy, 2- (4- methoxyphenyl)ethoxy, 2-(phenyl)-ethoxy, 2-(4-nitrophenyl)-ethoxy, 2-(4- dimethylaminophenyl)-ethoxy, 2-(4 aminophenyl)-ethoxy, 2-(2-nitrophenyl)-ethoxy, 2-(2- aminophenyl)-ethoxy, 2-(2-dimethylaminophenyl)-ethoxy, 3-(morpholin-4-yl)-propyloxy, 3-(piperidin-l-yl)-propyloxy, -O-(CH₂)₃C(O)OCH₂CH₃, -O-(CH₂)₄C(O)OCH₂CH₃, -O- (CH2)₂OCH₂CH₃, -O-CH₂C(O)OCH₃, -O-CH₂(2-methyl)-oxadiazol-5-yl, -O-CH₂-(2- ethyl)-oxadiazol-5-yl, -O-CH₂-(2- propyl)-oxadiazol-5-yl, -OCH₂CH=CHCH₂CH₃ (Z) and (E), -O-(CH₂)₃OH, -O-(CH₂)₄OH, -O-(CH₂)₅OH, -N-[2-(morpholin-4-yl)-ethyl]-N- (CH₂)₃CH₃, -NH-(CH₂)₃CH₃, -NH-(CH₂)₄CH₃, -NHC(O)(CH₂)₃CH₃, -N(CH₃)(CH₂)₃CH₃ or -N(CH₃)(CH₂)₄CH₃; particularly hydrogen, -O-(CH₂)₂CH₃, -O-(CH₂)₃CH₃, -O- (CH₂)₄CH₃, -O(CH₂)₅CH3, -O-(CH₂)₃CH(CH₃)₂, 2-(morpholin-4-yl)-ethoxy, -O- CH₂CH=CHCH₂CH₃ (Z) and (E), -NH-(CH₂)₃CH₃, -NH-(CH₂) CH₃, -N(CH₃)(CH₂)₃CH₃ or-N(CH₃)(CH₂)₄CH₃; more particularly -O-(CH₂)₃CH₃, -O-(CH₂)₄CH₃, -O- (CH₂)₃CH(CH₃)₂, -O-CH₂CH=CHCH₂CH₃ (Z) and (E), -NH-(CH₂)₃CH₃, -NH-(CH₂)₄CH₃, -N(CH₃)(CH₂)₃CH₃ or -N(CH₃)(CH₂)₄CH₃;

(d) R³ is hydrogen, 7-OH, 8-OH, 7-OCH₃, 7-OCH₂C(O)OH, 7-OCH₂C(O)OCH₃, 7- OCH₂C(O)NHNHC(O)CH₃, 7-[-O-CH -(2-methyl)-l,3,4-oxadiazol-5-yl], 7-OC(O)CH₃, 7- OC(O)-naphthyl, 3-C(O)OH, 7-C(O)OH, 3-C(O)OCH₃, 7-C(O)NH₂, 8-OC(O)-naphthyl, 3- C(O)NHCH₂C(O)OH, 7-cyano, 6-NH₂, 7-NH₂, 6-N(CH₃)₂, 7-N(CH₃)₂, 6- NHCH₂CH=CH₂,

7-(piperazin-l-yl), 7-(4-methylpiperazin-l-yl), 7- (lH-tetrazol-5-yl), 7-(l-methyl)tetrazol-5-yl), 7-(2-methyl)tetrazol-5-yl) or 7-(2-methyl)- 1,3, 4-oxadiazol-5-yl; particularly hydrogen, 7-OΗ, 8-OH, 7-OC(O)CH₃ or 6- NHCH₂CH=CH₂; more particularly hydrogen, 7-OH or 7-OC(O)CH₃.

The compounds of formula I above can be prepared as described in WO02/42248 A2.

Consequently, the present invention is directed to the use of a compound of formula I for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).

A further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the prevention of reflux.

Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).

Effective prevention of regurgitation would be an important way of preventing, as well as curing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive. Thus, a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of regurgitation.

Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of lung disease.

Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the management of failure to thrive.

Still a further aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of asthma, such as reflux- related asthma.

Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of chronic laryngitis.

A further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such inhibition.

Another aspect of the invention is a method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such prevention.

Still a further aspect of the invention is a method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

Yet another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

Still a further aspect of the invention is a method for the treatment or prevention of asthma, such as reflux-related asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

Yet another aspect of the invention is a method for the treatment of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

Still a further aspect of the invention is a method for the treatment or inhibition of lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

Still a further aspect of the invention is a method for the management of failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I is administered to a subject in need of such treatment.

The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J, 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.

The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.

The wording "GERD", gastro-esophageal reflux disease, is defined in accordance with van Heerwarden, M.A., SmoutA.J.P.M., 2000; Diagnosis of reflux disease. Bailliere 's Clin. Gastroenterol. 14, pp. 759-774. Pharmaceutical formulations

For clinical use, the compounds of formula I 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 compounds of formula I 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 compound of formula I to be formulated is 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 of the invention 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 compound of formula I may be administered once or twice daily, depending on the severity of the patient's condition.

A typical daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated, 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. Biological evaluation

Screening for compounds active against TLESR

Adult Labrador retrievers of both genders, trained to stand in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are formed and the dogs are allowed to recover completely before any experiments are done.

Motility measurement

In brief, after fasting for approximately 17 h with free supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve, Adelaide, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures. The assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Adelaide, South Australia). An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.

When a baseline measurement free from fasting gastric/LES phase III motor activity has been obtained, placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein. Ten min after i.v. administration, a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg. Immediately following the meal, air is insufflated at a rate of 500 ml/min until a intragastric pressure of 10+1 mmHg is obtained. The pressure is then maintained at this level throughout the experiment using the infusion pump for further air infusion or for venting air from the stomach. The experimental time from start of nutrient infusion to end of air insufflation is 45 min. The procedure has been validated as a reliable means of triggering TLESRs.

TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s. The relaxation should not be preceded by a pharyngeal signal <2s before its onset in which case the relaxation is classified as swallow- induced. The pressure difference between the LES and the stomach should be less than 2 mmHg, and the duration of the complete relaxation longer than 1 s.

Inhibition of the number of TLESRs was calculated with regard to the five preceding control experiments for each dog, and the results as set out in Table 1 below were achieved.

EXAMPLES

Example 1

Naphtalen-l-yl-(4-pentyloxy-naphtalen-l-yl)-methanone (CA registry number: 432047-72- 8) was prepared according to the procedure described in WO 02/42248 (Example 1). The above naphtalene, herein referred to as: 432047-72-8, was tested on adult Labrador retrievers of both genders in accordance with the model described above.

Table 1

N= number of dogs tested.

The results shown in Table 1 above indicate that compounds of formula I are useful for the inhibition of TLESR, and thus for the treatment of GERD.

Claims

1. Use of a compound of formula I,

wherein X is -S-, -S(O)-, -S(O)₂-, -S(O)₂NH-, -P(O)(OCH₃)-, -P(O)(OH)-, - NH-, -N(CH₃)-, -NHC(O)NH-, C(O)~, -C(O)O-, -NHC(O)-, -CH(OH)-, -CH=N-, - CH=CH-, -CH₂NH- or -C(=NH)-; R¹ is aryl or heteroaryl; R² is hydrogen, OR⁴ or NR⁵R⁶; R⁴ is Cι-C₈ alkyl or C₂-C₈ alkenyl; R⁵ and R⁶ independently are hydrogen, Cι-C₈ alkyl or C(O)Cj-C₈ alkyl; and R³ is hydrogen, cyano, heteroaryl, heterocycloalkyl, C(O)R⁷, OR⁸ or NR⁹R¹⁰; R⁷ is OH, d-d alkoxy, NH₂, NHCH₂C(O)OH or aryl; R⁸ is hydrogen, Cι-C₈ alkyl, C(O)d- C₄ alkyl or C(O)-aryI; and R⁹ and R¹⁰ independently are hydrogen, Ci-d alkyl or C₂-C₄ alkenyl; with the proviso that when X is -C(O)- and R² and R³ are hydrogen or R² is H and R³ is 4-methoxy, R¹ is neither 1- naphthyl nor 4-methoxy-l-naphtyl; or a pharmaceutically acceptable salt or an optical isomer thereof; for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).

2. Use of a compound of formula I as defined in claim 1, wherein X is -C(O)-, R¹ is naphtyl, R² is -O-(CH₂) -CH₃ and R³ is hydrogen; or a pharmaceutically acceptable salt or an optical isomer thereof; for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs).

3. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).

4. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the prevention of reflux.

5. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, regurgitation.

6. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, asthma.

7. Use according to claim 6, wherein the asthma is reflux-related asthma.

8. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, chronic laryngitis.

9. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the treatment of, or prevention of, lung disease.

10. Use of a compound of formula I as defined in claim 1 or 2, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for managing failure to thrive.

11. Use according to any one of the preceding claims, wherein the daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subject to be treated.

12. A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I

wherein X is -S-, -S(O)-, -S(O)₂-, -S(O)₂NH-, -P(O)(OCH₃)-, -P(O)(OH)-, - NH-, -N(CH₃)-, -NHC(O)NH-, C(O)-, -C(O)O-, -NHC(O)-, -CH(OH)-, -CH=N-, - CH=CH-, -CH₂NH- or -C(=NH)-; R¹ is aryl or heteroaryl; R² is hydrogen, OR⁴ or NR⁵R⁶; R⁴ is Ci-Cg alkyl or C₂-C₈ alkenyl; R and R independently are hydrogen, Cι-C₈ alkyl or C(O)Cι-C₈ alkyl; and R³ is hydrogen, cyano, heteroaryl, heterocycloalkyl, C(O)R⁷, OR⁸ orNR⁹R¹⁰; R⁷ is OH, Cι-C₄ alkoxy, NH₂, NHCH₂C(O)OH or aryl; R⁸ is hydrogen, d-C₈ alkyl, C(O)Cι-C₄ alkyl or C(O)-aryl; and R⁹ and R¹⁰ independently are hydrogen, Cι-C₈ alkyl or C₂-C₄ alkenyl; with the proviso that when X is -C(O)- and R² and R³ are hydrogen or R² is H and R³ is 4-methoxy, R¹ is neither 1-naphthyl nor 4-methoxy-l-naphtyl; or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such inhibition.

13. A method according to claim 12, wherein, in the compound of formula I, X is - C(O)-, R¹ is naphtyl, R² is -O-(CH₂)₄-CH₃ and R³ is hydrogen.

14. A method for the treatment of gastro-esophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment.

15. A method for the prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such prevention.

16. A method for the treatment of, or prevention of, regurgitation, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.

17. A method for the prevention of, or treatment of, lung disease, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.

18. A method for managing failure to thrive, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such management.

19. A method for treatment or prevention of asthma, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.

20. A method according to claim 19, wherein the asthma is reflux-related asthma.

21. A method for treatment or prevention of chronic laryngitis, whereby a pharmaceutically and pharmacologically effective amount of a compound of formula I as defined in claim 12 or 13, or a pharmaceutically acceptable salt or an optical isomer thereof, is administered to a subject in need of such treatment or prevention.

22. A method according to any one of claims 12-20, wherein the daily dose of the compound of formula I is from 0.1 - 100 mg per kg body weight of the subj ect to be treated.