CN1870999A - Alkynes I - Google Patents

Abstract

The present invention is directed to novel compounds of formula (I), to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of gastroesophageal reflux disease (GERD).

Description

Alkyne I

technical field

The present invention relates to novel compounds, processes for their preparation, use of the novel compounds in therapy and pharmaceutical compositions comprising the novel compounds.

Background technique

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors involved in the regulation and activity of many synapses in the central nervous system (CNS). Eight metabotropic glutamate receptor subtypes have been identified and subdivided into three groups based on sequence similarity. Group I includes mGluR1 and mGluR5. These receptors activate phospholipase C and increase neuronal excitability. Group II, which includes mGluR2 and mGluR3, and group III, which includes mGluR4, mGluR6, mGluR7, and mGluR8, inhibit adenylyl cyclase activity and reduce synaptic transmission. Several receptors also exist in different isoforms, which occur by alternative splicing (Chen, C-Y et al., Journal of Physiology (2002), pp. 538.3, 773-786; Pin, J-P et al., European Journal of Pharmacology (1999), 375, 277-294 pages; Bruner-Osborne, H et al., Journal of Medicinal Chemistry (200), 43, 2609-2645 pages; Schoepp, D.D, Jane D.E. Monn J.A., Neuropharmacology (1999), 38, pp. 1431-1476).

The lower esophageal sphincter (LES) tends to relax intermittently. As a result, because at this point the mechanical barrier is temporarily lost, fluid from the stomach can enter the esophagus, a phenomenon hereinafter referred to as "reflux".

Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal disorder. Current drug therapies are directed at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The primary mechanism of reflux has been thought to be due to hypotonia of the lower esophageal sphincter. However, eg Holloway & Dent (1990) Gastroenterol. Clin. N. Amer., 19, pp. 517-535 have shown that most reflux episodes occur during transient lower esophageal sphincter relaxation (TLESR), i.e. not triggered by swallowing relaxation. It has also been shown that gastric acid secretion is often normal in patients with GERD.

The problem to be solved by the present invention is to find new compounds useful in the treatment of GERD.

WO 01/16121 A1 discloses compound A-L-B, wherein A is a 5-, 6- or 7-membered heterocycle,

L is alkenylene, alkynylene or azo; and

B is hydrocarbyl; cycloalkyl; heterocycle (optionally containing one or more double bonds); or aryl. These compounds have been described as useful in, inter alia, cerebral ischemia, chronic neurodegeneration, psychiatric disorders, epilepsy and diseases of the pulmonary and cardiovascular systems.

WO 99/02497 A2 discloses compounds of the formula:

Wherein X can be an alkenylene or alkynylene group bound by an adjacent unsaturated carbon atom, or an azo group; R ⁵ can be an aromatic or heteroaromatic group. These compounds have been described as useful in, inter alia, epilepsy, cerebral ischemia and Alzheimer's disease.

WO 03/022846 A1 discloses in particular the compound 4-(4-pyridin-2-yl-but-3-ynyl)-benzonitrile. The compound is an intermediate in a process for the production of a compound useful in the treatment of cancer.

Contents of the invention

The present invention relates to novel compounds represented by general formula I:

in

R ¹ is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, wherein aryl or heteroaryl can be substituted by C ₁ -C ₄ alkyl;

R ² is selected from hydrogen and C ₁ -C ₄ alkyl;

R ³ is selected from hydrogen, C ₁ -C ₄ alkyl, F, CF ₃ , CHF ₂ and CH ₂ F;

^R4 is selected from hydrogen, F, _CF3 , _CHF2 , _CH2F and _CH3 ;

^R is selected from hydrogen and F;

^R is selected from hydrogen and F;

Q is selected from C ₁ -C ₄ alkyl, which is optionally substituted by C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy;

Y ¹ is selected from hydrogen; halogen; nitrile; C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkyl, wherein one or more hydrogen atoms of the alkyl can be replaced by fluorine atoms; benzyloxy; nitro in the para position; and C ₁ -C ₄ alkyl esters;

^Y2 _{is selected} from _the group consisting _of hydrogen; halogen; nitrile; _C1 - _C4 alkoxy; base ester;

^Y3 _{is selected} from _hydrogen ; _halogen ; nitrile; _C1 - _C4 alkoxy; base esters; or

Y ¹ and Y ² can form an aromatic or non-aromatic ring, which is optionally replaced by halogen, nitrile, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl (wherein one or more hydrogen atoms of the alkyl Can be substituted by fluorine atom), benzyloxy or C ₁ -C ₄ alkyl ester;

and pharmaceutically acceptable salts, hydrates, isoforms and/or optical isomers thereof, except 4-(4-pyridin-2-ylbut-3-ynyl)-benzonitrile.

The general terms used in the definition of formula I have the following meanings:

Halogen is chloro, fluoro, bromo or iodo.

C ₁ -C ₄ Alkyl is straight chain or branched chain alkyl, which each independently contains 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, or iso Propyl. In one embodiment, the alkyl group may contain one or more heteroatoms selected from O, N, and S. Examples of such groups are methyl ethyl ether, methyl ethyl amine, and dimethyl sulfide.

Cycloalkyl is a cyclic alkyl group each independently comprising 3, 4, 5 or 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

C ₁ -C ₄ alkoxy is alkoxy containing 1, 2, 3 or 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy or isopropoxy.

The term aryl as used herein refers to an aromatic ring having 6-14 carbon atoms, including monocyclic and polycyclic compounds, such as phenyl, benzyl or naphthyl.

The term heteroaryl as used herein refers to an aromatic ring having 5-14 carbon atoms, including monocyclic and polycyclic compounds, such as imidazopyridine, in which one or several ring atoms are oxygen, nitrogen or sulfur, such as furan base or thienyl.

Pharmaceutically acceptable salts of compounds of formula I and their isomers, hydrates and isoforms are also within the scope of the present invention.

Pharmaceutically acceptable salts of compounds of formula I are also within the scope of this invention. Such salts are, for example, salts with inorganic acids such as hydrochloric acid; alkali metal salts such as sodium or potassium salts; or alkaline earth metal salts such as calcium or magnesium salts.

The novel compounds of the present invention are useful in therapeutic applications. In one aspect of the invention, the compounds are useful for inhibiting transient lower esophageal sphincter relaxation (TLESR) and thereby for treating or preventing gastroesophageal reflux disease (GERD). In another embodiment, the compounds of the invention are useful for preventing reflux, treating or preventing reflux, treating or preventing asthma, treating or preventing laryngitis, treating or preventing pulmonary disease, and for treating failure tothrive.

Another aspect of the present invention is the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal diseases such as functional dyspepsia (FD). Another aspect of the present invention is the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as IBS with constipation, IBS with diarrhea, or IBS with alternating bowel movements.

Another aspect of the present invention is that the compound of formula I is used for inhibiting transient lower esophageal sphincter relaxation, for treating or preventing GERD, for preventing reflux, for treating or preventing reflux, for treating or preventing asthma , use in a medicament for the treatment or prevention of laryngitis, for the treatment or prevention of pulmonary diseases, and for the treatment of stunted growth.

Another aspect of the invention is a method of treating any of the disorders described above, comprising administering a pharmaceutically effective amount of a compound of formula I above to a subject suffering from said disorder.

In one aspect of the invention, the compounds of formula I are useful for the treatment and/or prevention of acute and chronic neurological and psychiatric disorders, anxiety, and chronic and acute pain disorders. In another aspect, the compounds are useful for the prophylaxis and/or treatment of pain associated with migraine, inflammatory pain, neuropathic pain such as diabetic neuropathy, arthritis and rheumatoid diseases, low back pain, postoperative Pain and pain associated with a variety of conditions including cancer, angina, renal or biliary colic, menstruation, migraine and gout.

The term "isomer" is defined herein as a compound of formula I that differs in the position and/or orientation of functional groups in the compound of formula I. "Orientation" refers to stereoisomers, diastereomers, regioisomers and enantiomers.

As used herein, the term "isoform" is defined as a compound of formula I that differs in the crystal lattice of the compound of formula I, such as a crystalline compound and an amorphous compound.

The term "TLESR", Transient lower esophageal sphincter relaxation, is used in this text according to Mittal, R.K, Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology, 109 , as defined on pages 601-610.

The word "reflux" is defined herein as fluid from the stomach being able to pass into the esophagus because the mechanical barrier is temporarily lost at this time.

The term "GERD", gastroesophageal reflux disease, is defined herein according to van Heerwarden, M.A., Smout A.J.P.M., 2000; Diagnosis of reflux disease. Baillière's Clin. Gastroenterol. 14, pp. 759-774.

Preparation

The compound of formula I above can be coupled by Sonogashira (Tetrahedron Letters, 1975, 50, 4467; S.Thorand, N .Krause J.Org.Chem., 1998,63,8551-8553; M.Erdélyi, A.Gogoll, J.Org.Chem., 2001,66,4165-4169) synthesis (Scheme 1):

Diagram 1

In cases where terminal alkyne B is not commercially available, terminal alkyne B is prepared via intermediate G, which can be obtained by one of two routes (Scheme 2). One route is by coupling aryl iodide C with allyl alcohol D in DMF at temperatures ranging from room temperature to 60 °C. Another route is by first reducing the carboxylic acid E to the alcohol F using lithium aluminum hydride in THF, starting at 0 °C and ending at reflux temperature, and then using Dess-Martin periodinane in DCM at room temperature to catalyze Alcohol F is oxidized to aldehyde G in the presence of an amount of trifluoroacetic acid.

Route 1:

Route 2:

Diagram 2

After obtaining aldehyde G, alkyne B is prepared as described in Scheme 3:

Aldehyde G was first converted to dibromoalkene by reaction of aldehyde G with tetrabromomethane and triphenylphosphine in DCM at room temperature. Elimination with lithium bis(trimethylsilyl)amide in THF at -78°C, followed by halogen-lithium exchange with n-butyllithium in THF/hexane at -78°C to room temperature , yielding the terminal alkyne B after quenching with water. Substance B was then used for Sonogashira coupling as described in Scheme 1.

Diagram 3

The advantage of this reaction sequence as shown in Schemes 1-3 is that it can be performed without purification of any intermediates; purification is only required after Sonogashira coupling.

Alternatively, the method via pyridine J can be used (Scheme 4):

Sonogashira coupling of aryl bromide A with ethynyl(trimethyl)silane I in the presence of a base such as triethylamine at temperatures ranging from room temperature to 60°C affords pyridine J. Pyridine J is then reacted with bromide K by heating at 60° C. for an appropriate time in the presence of tetrabutylammonium triphenyldifluorosilicate to give compounds of general formula I.

Diagram 4

In the above schemes 1, 2, 3 and 4, Q, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , Y ¹ , Y ² and Y ³ are as defined in the compound of formula I above.

Experiment details

DCM was dried over 3A molecular sieves. THF was distilled from Na/benzophenone just before use. All reactions were performed under a nitrogen atmosphere. All glassware was dried at 150°C for at least two hours immediately before use. A phase separator from International Sorbent Technology (IST) was used. Chromatography was performed on silica gel 60 (0.040-0.063 mm) or reverse phase chromatography on a C8 column. All NMR spectra were measured in delta-chloroform.

2-Bromo-6-picoline can be purchased from Aldrich, (PPh ₃ ) ₂ PdCl ₂ can be purchased from Avacado, Pd(OAc) ₂ can be purchased from Aldrich, CuI can be purchased from Fluka, 4-phenylbut-1-yne can be purchased from TCI. If not indicated otherwise, the chemicals used were commercially available and used without further purification.

pharmaceutical preparations

For clinical use, the compounds of formula I are suitably formulated according to the invention as pharmaceutical preparations for oral administration. Furthermore, rectal, parenteral or any other route of administration may also be considered by those skilled in the art of formulation. Accordingly, compounds of formula I are formulated together with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier can be in the form of a solid, semi-solid or liquid diluent.

When preparing oral pharmaceutical formulations according to the present invention, the compound of formula I to be formulated is mixed with solid powder components such as lactose, sucrose, sorbitol, mannitol, starch, pullulan, cellulose derivatives, gelatin or other suitable components, and mixed with disintegrants and lubricants such as magnesium stearate, calcium stearate, stearyl fumarate and polyethylene glycol wax. The mixture is then processed into granules or compressed into tablets.

Soft gelatin capsules may be prepared from capsules containing a mixture of one or more active compounds of the invention, vegetable oil, fat, or other suitable medium for soft gelatin capsules. Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, pullulan, cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the following forms: (i) in the form of suppositories comprising the active substance mixed with a neutral fatty base; in the form of gelatin rectal capsules mixed with a vehicle; (iii) in the form of pre-made micro-enemas; or (iv) in the form of dry micro-enemas for reconstitution with a suitable solvent immediately prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, for example, containing the active compound and the balance of the formulation comprising sugar or sugar alcohol; and solutions or suspensions in mixtures of ethanol, water, glycerol, propylene glycol, and polyethylene glycol. liquid. Such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agents, if desired. Liquid preparations for oral administration can also be prepared as dry powder for reconstitution with a suitable solvent before use.

Solutions for parenteral administration can be prepared as solutions of the compounds of the present invention in pharmaceutically acceptable solvents. These solutions may also contain stabilizing and/or buffering components and are dispensed as unit doses in ampoules or vials. Solutions for parenteral administration can also be prepared as dry preparations for reconstitution with a suitable solvent before use.

In one aspect of the 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 dosage of the compound of formula I is 0.1-10 mg per kilogram of body weight of the subject to be treated, but will depend on various factors such as the route of administration, the age and weight of the patient, and the severity of the patient's condition.

Example

Method A

Example 1

The preparation of 3-(3-chlorophenyl) propionaldehyde (compound 1):

Tetrabutylammonium chloride (6.95 g, 0.25 mol, 1.0 eq.) and sodium bicarbonate (5.25 g, 0.625 mmol, 2.5 eq.) were suitably dissolved in DMF (15 mL) under nitrogen. The mixture was cooled to 0 °C, followed by the addition of 3-chloroiodobenzene (5.96 g, 3.10 mL, 0.25 mol), then allyl alcohol (2.18 g, 2.56 mL, 0.375 mol, 1.50 eq.), and finally Pd (OAc) ₂ (0.168g, 7.5mmol, 0.03eq.), which was added in small portions. The mixture was stirred at 0°C for 0.5 hours and finally at room temperature for 16 hours. TLC indicated some 3-chloroiodobenzene remained. The reaction mixture was then heated at 50°C for 5 hours. TLC indicated that 3-chloroiodobenzene still remained, so heating was continued at 50°C for an additional 15 hours. Thereafter, DMF was evaporated under vacuum by heating at 40 °C for 8 hours.

Then, water (30 mL) was added and the black reaction mixture was extracted with pentane (4 x 30 mL). The combined pentane phases were dried over sodium sulfate and evaporated. 2.487 g (yield: 59%) of product were obtained.

TLC _Rf (heptane/AcOEt 4:1) = 0.17.

¹ H NMR (500MHz): 9.81(s, 1H), 7.24-7.17(m, 3H), 7.09-7.06(br d, 1H), 2.93(t, J=7.5Hz, 2H), 2.78(t, J = 7.5Hz, 2H).

¹³ C NMR (75 MHz): 200.5, 142.2, 134.0, 129.6, 128.2, 126.3, 126.2, 44.8, 27.6.

Method B

Example 2

Preparation of 3-(3-chlorophenyl)propanol (compound 2):

3-(3-Chlorophenyl)propanoic acid (0.923 g, 5.0 mmol) was dissolved in THF (12 mL) under nitrogen and cooled to 0 °C. Lithium aluminum hydride (0.380 g, 10.0 mmol, 2.0 eq.) was added in portions. The mixture was allowed to warm to room temperature and stirred at this temperature for 0.5 hours, then refluxed for 0.5 hours.

Then, the mixture was cooled and poured into a saturated solution of tartaric acid in ethanol (30 mL) at 0°C. A 1:1 mixture of sodium sulfate decahydrate and Celite was added (total volume 40 mL). The mixture was stirred at room temperature for 10 min then vacuum filtered through Celite with _Et2O (150 mL). The organic phase was evaporated. A mixture of colorless oil and some white crystals was obtained. EtOAc (10 mL) was added. This dissolved the oil but not the crystals which were filtered off and the mother liquor was concentrated. Thus, 0.832 g (yield: 98%) of a colorless oil was isolated.

¹ H NMR (300MHz): 7.22-7.14(m, 3H), 7.09-7.03(m, 1H), 4.29(s, 1H, br), 3.63(t, J=6.6Hz, 2H), 2.66(t, J=7.4Hz, 2H), 1.86(q, J=7Hz, 2H).

¹³ C NMR (75 MHz): 143.5, 133.6, 129.2, 128.1, 126.2, 125.6, 61.2, 33.5, 31.4.

Example 3

Preparation of 3-(3-methoxyphenyl)propanol (compound 3):

Prepared according to Method B above using 3-(3-methoxyphenyl)propanoic acid as starting material.

¹ H NMR (500MHz): 7.19(t, J=7.8Hz, 1H), 6.78(d, J=7.4Hz, 1H), 1H, 6.76(m, 2H), 3.77(s, 3H), 3.64(t , J=6.5Hz, 2H), 2.66 (t, J=7.8Hz, 2H), 2.11 (br s, 1H), 1.87 (br q, J=7.6Hz, 2H).

Example 4

Preparation of 3-(3-methylphenyl)propanol (Compound 4): Prepared according to Method B above using 3-(3-methylphenyl)propanoic acid as starting material.

¹ H NMR (500MHz): 7.24(t, J=7.5Hz, 1H), 7.10-7.04(m, 3H), 3.70(t, J=6.6Hz, 2H), 3.25(br s, 1H), 2.72( t, J=7.6Hz, 2H), 2.39(s, 3H), 1.93(br q, J=7.6Hz, 2H).

Method C

Example 5

Preparation of 3-(3-methoxyphenyl)propanal (Compound 5)

Dess-Martin periodide [1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzodoxol-3-(1H)-one] (1.01g , 2.38 mmol, 1.1 eq.) was dissolved in DCM (5 mL). 1 drop of trifluoroacetic acid was added at a temperature of 0 °C, followed by 3-(3-methoxyphenyl)propanol (0.360 g, 2.17 mmol) in DCM (3 mL). After stirring at room temperature for 20 h, the reaction mixture was transferred into 1M NaOH (10 mL) with _Et2O (25 mL). After stirring for 10 minutes, the organic phase was separated, then extracted with 1M NaOH (10 mL) and water (10 mL) respectively and dried over sodium sulfate. Obtained 0.276 g of crude product (77%) which was used in the next step without further purification.

¹ H NMR (300MHz): 9.63(s, 1H), 7.10-7.02(m, 1H), 6.70-6.58(m, 3H), 3.64(s, 3H), 2.78(t, J=7.4Hz, 2H) , 2.60 (t, J=7.4Hz, 2H).

¹³ C NMR (300 MHz): 200.9, 159.3, 141.6, 129.2, 120.2, 113.8, 111.1, 54.8, 44.8, 27.9.

Example 6

Preparation of 3-(3-methylphenyl)propanal (Compound 6): Prepared according to Method C above using 3-(3-methylphenyl)propanol as starting material.

¹ H NMR (300MHz): 9.83(br t, J=1.4Hz, 1H), 7.20(br t, J=7.3Hz, 1H), 7.07-6.98(m, 3H), 2.94(t, J=7.4Hz , 2H), 2.78(t, J=7.4Hz, 2H), 2.34(s, 3H).

Method D

Example 7

Preparation of 1-chloro-3-(4,4-dibromobut-3-en-1-yl)benzene (compound 7) (according to E.J.Corey, P.L.Fuchs Tetrahedron Letters 1972, No.36, 3769-3772 pages method)

Tetrabromomethane (4.89 g, 14.76 mmol, 2.0 eq.) was dissolved in DCM (45 mL), then cooled to 0 °C. Triphenylphosphine (3.87 g, 14.76 mmol, 2.0 eq.) was added. The orange solution was stirred for 3 min, then Zn (0.97 g, 14.76 mmol, 2.0 eq.) was added in small portions. After stirring for an additional 10 minutes, 3-(3-chlorophenyl)propanal (1.24 g, 7.38 mmol) in DCM (5 mL) was added. After a further 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 14 hours. Then, pentane (200 mL) was added to the reaction mixture to obtain a precipitate. The mixture was filtered and the insoluble portion was dissolved in DCM (40 mL) and precipitated again with pentane (200 mL). After filtering, the process is repeated again. The combined organic phases were evaporated. 2.562 g of crude product were obtained as an oil containing white crystals. NMR indicated a mixture of desired material and O= _PPh3 . The oily substance could be dissolved in 5 mL of ethyl acetate, while the crystals could not be dissolved. The crystals were filtered off and the mother liquor was concentrated. 2.106 g (yield: 87%) of material were obtained which, according to NMR analysis, did not contain O═PPh ₃ .

¹ H NMR (300MHz): 7.25-7.15 (m, 3H), 7.07-7.02 (d t, J ₁ =6.6Hz, J ₂ =1.7Hz, 1H), 2.69 (t, J = 7.4Hz, 2H), 2.38 (q, J=7.4Hz, 2H).

¹³ C NMR (75 MHz): 142.2, 136.8, 134.0, 129.6, 128.3, 126.3, 126.3, 89.9, 34.3, 33.4.

Example 8

Preparation of 1-methoxy-3-(4,4-dibromobut-3-en-1-yl)benzene (compound 8): starting from 3-(3-methoxyphenyl)propanal The starting material was prepared according to Method D above.

¹ H NMR (300MHz): 7.10(t, J=7.6Hz, 2H), 6.65(m, 2H), 6.30(t, J=7.2Hz, 1H), 3.68(s, 3H), 2.59(t, J =7.6Hz, 2H), 2.30(q, J=7.5Hz, 2H).

¹³ C NMR (75 MHz): 159.4, 141.8, 137.3, 129.2, 120.4, 113.9, 111.3, 89.3, 55.0, 34.4, 33.7.

Example 9

Preparation of 1-methyl-3-(4,4-dibromobut-3-en-1-yl)benzene (compound 9): using 3-(3-methylphenyl)propanal as starting material according to Prepared by Method D above.

¹ H NMR (500MHz): 7.22(t, J=7.75Hz, 1H), 7.08-7.0(m, 3H), 6.33(t, J=7.2Hz, 1H), 2.60(t, J=7.6Hz, 2H ), 2.32(q, J=7.6Hz, 2H), 2.37(s, 3H).

¹³ C NMR (125 MHz): 140.3, 137.6, 132.6, 129.0, 128.5, 126.9, 125.2, 89.3, 34.5, 33.6, 21.3.

Method E

Example 10

Preparation of 1-but-3-yn-1-yl-3-chlorobenzene (compound 10):

1-Chloro-3-(4,4-dibromobut-3-en-1-yl)benzene (1.106 g, 3.41 mmol) was dissolved in THF (5 mL) and cooled to -78 °C. Lithium bis(trimethylsilyl)amide (5.11 mL, 1.0 M in THF, 1.5 eq.) was added dropwise and the solution was stirred for 0.5 h. Then n-butyl lithium (5.05 mL, 1.6 M in hexane, 2.5 eq.) was added dropwise. The reaction mixture was stirred at -78 °C for 1 hour, then at room temperature for 1 hour, then quenched with water (20 mL). The organic phase was separated and the aqueous phase was extracted with _Et2O (2 x 20 mL). The combined organic phases were dried over sodium sulfate and evaporated. 0.541 g (yield: 96%) of crude product was obtained.

¹ H NMR (300MHz): 7.24-7.15(m, 3H), 7.11-7.05(m, 1H), 2.79(t, J=7.4Hz, 2H), 2.45(d t, J ₁ =7.4Hz, J ₂ = 2.6Hz, 2H), 1.97(t, J = 2.6Hz, 1H).

¹³ C NMR (125 MHz): 142.2, 134.0, 129.5, 128.5, 126.6, 126.4, 83.0, 69.2, 34.2, 20.2.

Example 11

The preparation of 1-but-3-yn-1-yl-3-methoxybenzene (compound 11): use 1-methoxy-3-(4,4-dibromobut-3-en-1-yl ) benzene as starting material was prepared according to method E above.

¹ H NMR (500MHz): 7.23(t, J=7.7Hz, 1H), 6.83(d, J=7.7Hz, 1H), 6.79(m, 2H), 3.82(s, 3H), 2.85(t, J =7.6Hz, 2H), 2.50(t d, J ₁ =7.6Hz, _J2 =2.6Hz, 2H), 2.00(t, J=2.6Hz, 1H).

¹³ C NMR (125 MHz): 159.5, 141.9, 129.3, 120.7, 114.1, 111.5, 83.7, 68.8, 55.0, 34.8, 29.6.

Example 12

Preparation of 1-but-3-yn-1-yl-3-methylbenzene (compound 12):

Prepared according to Procedure E above, starting from 1-methyl-3-(4,4-dibromobut-3-en-1-yl)benzene.

¹³ C NMR (75 MHz): 140.2, 137.8, 129.0, 128.1, 126.9, 125.2, 83.8, 68.7, 34.8, 21.4, 20.6.

Method F

Example 13

Preparation of 2-[4-(3-chlorophenyl)but-1-yn-1-yl]-6-methylpyridine (compound 13):

To 2-bromo-6-methylpyridine (0.054g, 0.31mmol) was added crude 1-but-3-yn-1-yl-3-chlorobenzene (0.057g, 0.35mmol, 1.10eq.), followed by (PPh ₃ ) ₂ PdCl ₂ (0.007 g, 0.01 mmol, 0.03 eq.) and triethylamine (0.50 mL). The mixture was stirred at 0 °C for 0.5 h under nitrogen. CuI (0.002 g, 0.01 mmol, 0.03 eq.) was then added and the mixture was allowed to warm to room temperature over about 0.5 hours, then heated at 60° C. for 12 hours. The material was filtered through a ₁ g plug of SiO2, rinsing with ethyl acetate (15 mL). Flash chromatography on silica gel eluting with pentane/ _Et2O 3:1 then 2:1 gave 0.027 g (yield: 34% relative to 2-bromo-6-picoline) .

TLC: _Rf (pentane/ _Et2O =2:1)=0.29.

¹ H NMR (300MHz): 7.41(t, J=7.8Hz, 1H), 7.21-7.03(m, 5H), 6.97(d, J=7.8Hz, 1H), 2.84(t, J=7.8Hz, 2H ), 2.63(t, J=7.8Hz, 2H), 2.46(s, 3H).

¹³ C NMR (75 MHz): 158.3, 142.2, 142.1, 136.2, 133.8, 129.4, 128.4, 126.4, 126.3, 123.8, 122.2, 89.2, 81.1, 34.1, 24.4, 21.3.

Example 14

The preparation of 2-[4-(3-methoxyphenyl)but-1-yn-1-yl]-6-methylpyridine (compound 14): using 2-bromo-6-methylpyridine and 1- But-3-yn-1-yl-3-methoxybenzene was prepared according to method F above as starting material.

¹ H NMR (500MHz): 7.50(t, J=7.6Hz, 1H), 2.23(t, J=7.8Hz, 1H), 7.18(d, J=7.7Hz, 1H), 7.06(d, J=7.8 Hz, 1H), 6.78(dd, _J1 =8.1Hz, _J2 =2.3Hz, 1H), 6.87-6.81(m, 2H), 3.80(s, 3H), 2.94(t, J=7.7Hz, 2H ), 2.72(t, J=7.7Hz, 2H), 2.55(s, 3H).

¹³ C NMR (75 MHz): 159.4, 158.4, 142.7, 141.9, 136.1, 129.2, 123.7, 122.0, 120.6, 114.0, 111.6, 89.6, 81.0, 55.1, 34.8, 24.5, 21.6.

Example 15

Preparation of 2-methyl-6-[4-(3-methylphenyl)but-1-yn-1-yl]pyridine (Compound 15): Using 2-bromo-6-methylpyridine and 1-butane -3-yn-1-yl-3-methylbenzene Prepared as starting material by Procedure F above.

¹ H NMR (300MHz): 7.51(t, J=7.7Hz, 1H), 7.21(t, J=7.4Hz, 1H), 7.19(t, J=7.4Hz, 1H), 7.10-7.01(m, 4H ), 2.93(t, J=7.7Hz, 2H), 2.72(t, J=7.7Hz, 2H), 2.55(s, 3H), 2.35(s, 3H).

¹³ C NMR (75MHz): 158.5, 142.8, 140.3, 137.8, 136.1, 129.1128.2, 126.9, 125.3, 123.7, 122.0, 89.6, 80.9, 34.8, 24.6, 21.7, 21.4.

Example 16

Preparation of 2-methyl-6-(4-phenylbut-1-yn-1-yl)pyridine (compound 16):

Prepared according to Method F above, starting from 2-bromo-6-picoline and 4-phenyl-but-1-yne.

¹ H NMR (300MHz): 7.46(t, J=7.6Hz, 1H), 7.33-7.19(m, 5H), 7.14(d, J=7.7Hz, 1H), 7.02(d, J=7.7Hz, 1H ), 2.95(t, J=7.6Hz, 2H), 2.71(t, J=7.6Hz, 2H), 2.52(s, 3H).

¹³ C NMR (75 MHz): 158.2, 142.6, 140.1, 135.9, 128.1 (high intensity), 126.0, 123.5, 121.8, 89.3, 80.8, 34.6, 24.4, 21.5.

Example 17

2-Methyl-6-[(trimethylsilyl)ethynyl]pyridine (compound 17):

6-Bromo-2-methylpyridine (0.516 g, 3.0 mmol) was mixed with ethynyl(trimethyl)silane (0.324 g, 3.3 mmol, 1.10 eq.) and (PPh ₃ ) ₂ PdCl ₂ was added at 0°C (0.063g, 0.09mmol, 0.03eq.) and triethylamine (1.21g, 1.67mL, 12.0mmol, 4.0eq.). The mixture was stirred at 0 °C for 0.5 h, then CuI (0.017 g, 0.09 mmol, 0.03 eq.) was added and the mixture was allowed to warm to room temperature within 15 min. After stirring at room temperature for 15 minutes, it was heated to 60° C., heating was maintained for 2 hours, and finally the mixture was left at room temperature for 16 hours. LC/MS indicated no bromide remained. Phosphate buffer (5 mL, 0.2M, pH 7) was added. DCM extraction (3 x 5 mL) was performed using a phase separator. The organic phases were combined and dried over sodium sulfate. After evaporation 0.623 g of product was obtained. Flash chromatography on silica gel isolated 0.320 g of material after eluting with 5% EtOAc in heptane followed by 10% EtOAc. (Yield: 56%).

TLC: _Rf (heptane/EtOAc=2:1)=0.56.

¹ H NMR (300MHz): 7.37(t, J=7.8Hz, 1H), 7.13(d, J=7.8Hz, 1H), 6.93(d, J=7.8Hz, 1H), 2.40(s, 3H), 0.14(s, 9H).

¹³ C NMR (75 MHz): 158.2, 141.8, 135.7, 124.0, 122.3, 103.5, 93.6, 24.2, -0.51.

Example 18

2-methyl-6-(5-phenylpent-1-yn-1-yl)pyridine (compound 18):

(according to the method of A.S.Pilcher, P.DeShong, J.Org.Chem., 1996, 61, pages 6901-6905)

2-Methyl-6-[(trimethylsilyl)ethynyl]pyridine (0.038g, 0.2mmol, 2.0eq.) with (3-bromopropyl)benzene (0.020g, 0.1mmol) and tetrabutyl Ammonium triphenyldifluorosilicate (0.081 g, 0.3 mmol, 1.5 eq.) was mixed and heated at 60° C. for 24 hours in a sealed vial. Subsequent LC/MS indicated the molecular weight of the product. Heating was continued at 60 °C for an additional 24 hours, but there was no change in LC/MS. Purification by flash chromatography on Si, using the pentane/ether fraction as eluent, first 6:1, then 4:1, afforded 0.008 g of product (yield: 17%).

TLC: _Rf (pentane/ _Et2O =4:1)=0.34.

¹ H NMR (500MHz): 7.50(t, J=7.8Hz, 1H), 7.32-7.25(m, 2H), 7.24-7.18(m, 4H), 7.06(d, J=7.8Hz, 1H), 2.78 (t, J=7.8Hz, 2H), 2.54(s, 3H), 2.45(t, J=7.4Hz, 2H), 1.96(q, J=7.4Hz, 2H).

Example 19

Preparation of (1-methyl-but-3-ynyl)-benzene

(1-Methyl-but-3-ynyl)-benzene was prepared according to Method E above, using (4,4-dibromo-1-methyl-but-3-enyl)-benzene as starting material.

¹ H NMR (400 MHz): 7.33 (m, 2H), 7.25 (m, 3H), 3.01 (m, 1H), 2.45 (m, 2H), 1.99 (t, 1H), 1.41 (d, 3H).

Example 20

Preparation of (4,4-dibromo-1-methyl-but-3-enyl)-benzene

(4,4-Dibromo-1-methyl-but-3-enyl)-benzene was prepared according to Method D above, using 3-phenyl-butyraldehyde as starting material.

Example 21

2-Methyl-6-(4-phenylpent-1-yn-1-yl)pyridine (compound 19)

This compound was prepared according to Method F above using (1-methylbut-3-ynyl)-benzene and 2-bromo-6-picoline as starting materials.

¹ H NMR: 7.49(t, 1H), 7.26(m, 5H), 7.14(d, 1H), 7.04(d, 1H), 3.11(m, 1H), 2.73(dd, 1H), 2.64(dd, 1H), 2.53(s, 1H), 1.44(d, 3H).

¹³ C NMR: 158.9, 145.9, 143.3, 136.4, 128.6, 127.1, 126.6, 124.1, 122.3, 89.3, 81.9, 39.2, 28.9, 24.7, 21.1.

biological evaluation

Functional evaluation of mGluR5 antagonism in mGluR5d-expressing cell lines

The properties of the compounds of the invention can be analyzed using standard assays for pharmacological activity. Examples of glutamate receptor assays are known in the art, for example, in Aramori et al., Neuron 8:757 (1992); Tanabe et al., Neuron 8:169 (1992); Miller et al., J. Neuroscience 15:6103 (1995); Balazs, et al., J. Neurochemistry 69:151 (1997). The methods described in these publications are incorporated herein by reference. Conveniently, compounds of the invention can be studied by means of an assay measuring intracellular calcium [Ca2 ⁺ ] _i flux in mGluR5 expressing cells (FLIPR), or another assay measuring turnover of inositol phosphate metabolism (IP3).

FLIPR test

Cells expressing human mGluR5d described in WO 97/05252 were seeded at a density of 100,000 cells per well on collagen-coated 96-well plates with clear bottom and black sides and experiments were performed 24 hours after seeding. All assays were performed in Fraction IV containing 127 mM NaCl, 5 mM KCl, 2 mM MgCl ₂ , 0.7 mM NaH ₂ PO ₄ , 2 mM CaCl ₂ , 0.422 mg/ml NaHCO ₃ , 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml BSA ( in pH 7.4 buffer. Cell cultures in 96-well plates were loaded for 60 minutes in the above buffer containing 0.01% pluronic acid (proprietary, non-ionic surfactant polyol-CAS: 9003-11-6 4 μM of the acetoxymethyl ester form of the fluorescent calcium indicator fluo-3 (Molecular Probes, Eugene, Oregon) in ). After the loading period, the fluo-3 buffer was removed and replaced with fresh assay buffer. FLIPR experiments were performed using a laser setting of 0.800 W and a CCD camera shutter speed of 0.4 s and excitation and emission wavelengths of 488 nm and 562 nm, respectively. Each experiment starts with 160 μl of buffer present in each well of the cell plate. 40 μl from the antagonist plate was added followed by 50 μl from the agonist plate. The interval between antagonist and agonist additions was 90 seconds. The fluorescent signal was sampled 50 times at 1 s intervals immediately after each of the two additions, followed by 3 samples at 5 s intervals. Response was measured as the difference between the peak heights of the response to the agonist, minus the background fluorescence within the sampling time. _IC50 determinations were performed using a linear least squares fitting procedure.

IP3 test

An additional functional assay for mGluR5d is described in WO 97/05252, which is based on the turnover of phosphatidylinositol metabolism. Receptor activation stimulates phospholipase C activity and causes increased formation of inositol 1,4,5,triphosphate (IP3).

GHEK stably expressing human mGluR5d was seeded on a 24-well poly-L-lysine-coated plate at 40×10 ⁴ cells/well, and the medium contained 1 μCi/well [3H]inositol.

Cells were cultured overnight (16 hours), then washed three times and incubated at 37°C in HEPES-buffered saline (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl ₂ ) supplemented with 1 unit/ml alanine aminotransferase and 2 mM pyruvate. , 0.1% glucose, 20 mM HEPES, pH 7.4)) for 1 hour. Cells were washed once in HEPES buffered saline and preincubated for 10 minutes in HEPES buffered saline containing 10 mM LiCl. Compounds were incubated in duplicate at 37°C for 15 minutes before addition of glutamate (80 μΜ) or DHPG (30 μΜ) and incubation for an additional 30 minutes. Reactions were stopped by adding 0.5 ml of perchloric acid (5%) to the reaction on ice and incubated at 4°C for at least 30 minutes. Samples were collected in 15 ml polypropylene tubes and the inositol phosphates were separated using ion exchange resin (Dowex AG1-X8 formate form, 200-400 mesh, BIORAD) columns. Isolation of inositol phosphates was first performed by eluting glycerylphosphatidylinositol with 8 ml of 30 mM ammonium formate. Total inositol phosphate was then eluted with 8 ml of 700 mM ammonium formate/100 mM formic acid and collected in scintillation vials. This eluate was then mixed with 8 ml of scintillant and [3H]inositol incorporation was determined by scintillation counting. The dpm counts from duplicate samples were plotted and _IC50 determinations were generated using a linear least squares fitting procedure.

abbreviation

BSA Bovine Serum Albumin

CCD Charge Coupled Device

CRC Concentration Response Curve

DHPG 3,5-Dihydroxyphenylglycine

DPM Decays per minute

EDTA ethylenediaminetetraacetic acid

FLIPR Fluorescent Imaging Plate Reader

GHEK Human Embryonic Kidney Containing GLAST

GLAST Glutamate/Aspartate Transporter

HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (buffer)

IP ₃ inositol triphosphate

Typically, compounds are active in the assays described above with _IC50 values of less than 10000 nM. In one aspect of the invention, the _IC50 value is less than 1 [mu]M. In another aspect of the invention, the _IC50 value is less than 100 nM.

Screening for compounds with anti-TLESR activity

Adult Labrador hounds of both sexes were used and trained to stand in a Pavlov spreader. A muco-to-skin esophagostomy was made and the dog was allowed to recover completely before proceeding to any trials.

Motility measurement

Briefly, after about 17 hours of fasting with free access to water, a multi-lumen cuff/side port assembly (Dentsleeve, Adelaide, South Australia) was introduced through the esophagostomy to measure the stomach, lower esophageal sphincter (LES) and esophagus pressure. The assembly was perfused with water using a low compliance pressure perfusion pump (Dentsleeve, Adelaide, South Australia). An air-perfused tube was passed in the oral direction to measure swallowing, and the pH was monitored 3 cm above the LES with an antimony electrode. All signals were amplified and recorded at 10 Hz on a personal computer. When baseline measurements of non-fasted gastric/LES phase III motor activity have been obtained, placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in the foreleg vein. Ten minutes after i.v. administration, the stomach was perfused with nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) at 100 ml/min through the central lumen of the module to a final volume of 30 ml/kg. After infusing a nutritional meal, air is infused at a rate of 500 ml/min until an intragastric pressure of 10±1 mmHg is obtained. The pressure was then maintained at this level throughout the experiment by further insufflation of air using a perfusion pump or removal of air from the stomach. The time from the start of infusion of the nutritious meal to the end of the air insufflation was 45 minutes. This method has been confirmed to be a reliable method for inducing TLESR.

TLESR is defined as a decrease in lower esophageal sphincter pressure (referenced to intragastric pressure) at a rate >1 mmHg/s. Relaxations should not have a pharyngeal signal ≤ 2 s before their onset, in which case relaxations are classified as induced by swallowing. The pressure difference between the LES and the stomach should be less than 2mmHg, and the duration of complete relaxation should be more than 1 second.

Biological Evaluation Example 1

2-[4-(3-Chlorophenyl)but-1-yn-1-yl]-6-methylpyridine (Compound 13) was prepared according to the method of Example 13 above. 2-[4-(3-Chlorophenyl)but-1-yn-1-yl]-6-picoline was tested on adult Labrador hounds of both sexes according to the constant pressure model described above.

Table 1.1 - Constant pressure model compound Dose [μmol/kg/h], perfused during 60 minutes Inhibition %±SEM(N) Compound 13 4 31±13(4)

N = number of dogs used in the test

Claims (16)

1. Compounds represented by formula I:

in R ¹ is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, wherein aryl or heteroaryl can be substituted by C ₁ -C ₄ alkyl; R ² is selected from hydrogen and C ₁ -C ₄ alkyl; R ³ is selected from hydrogen, C ₁ -C ₄ alkyl, F, CF ₃ , CHF ₂ and CH ₂ F; ^R4 is selected from hydrogen, F, _CF3 , _CHF2 , _CH2F and _CH3 ; ^R is selected from hydrogen and F; ^R is selected from hydrogen and F; Q is selected from C ₁ -C ₄ alkyl, which is optionally substituted by C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; Y ¹ is selected from hydrogen; halogen; nitrile; C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkyl, wherein one or more hydrogen atoms of the alkyl can be replaced by fluorine atoms; benzyloxy; nitro in the para position; and C ₁ -C ₄ alkyl esters; ^Y2 _{is selected} from _the group consisting _of hydrogen; halogen; nitrile; _C1 - _C4 alkoxy; base ester; ^Y3 _{is selected} from _hydrogen ; _halogen ; nitrile; _C1 - _C4 alkoxy; base esters; or Y ¹ and Y ² can form an aromatic or non-aromatic ring, which is optionally replaced by halogen, nitrile, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, benzyloxy or C ₁ -C ₄ alkane Substituted by ester, wherein one or more hydrogen atoms of C ₁ -C ₄ alkyl can be replaced by fluorine atoms; And its pharmaceutically acceptable salts, hydrates, isoforms and/or optical isomers, except 4-(4-pyridin-2-ylbut-3-ynyl)-benzonitrile. 2. Compounds represented by formula I:

in R ¹ is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, wherein aryl or heteroaryl can be substituted by C ₁ -C ₄ alkyl; R ² is selected from hydrogen and C ₁ -C ₄ alkyl; R ³ is selected from hydrogen, C ₁ -C ₄ alkyl, F, CF ₃ , CHF ₂ and CH ₂ F; ^R4 is selected from hydrogen, F, _CF3 , _CHF2 , _CH2F and _CH3 ; ^R is selected from hydrogen and F; ^R is selected from hydrogen and F; Q is selected from C ₁ -C ₄ alkyl, which is optionally substituted by C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; ^Y is selected from hydrogen, halogen, nitrile, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyl; Y ² is selected from hydrogen, halogen, nitrile, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyl; Y ^is selected from hydrogen, halogen, nitrile, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyl; And its pharmaceutically acceptable salts, hydrates, isoforms and/or optical isomers, except 4-(4-pyridin-2-ylbut-3-ynyl)-benzonitrile. 3. A compound of formula I according to claim 1 or 2, wherein R ¹ is hydrogen or C ₁ -C ₃ alkyl; ^R is hydrogen; ^R is selected from hydrogen and methyl; R ⁴ is hydrogen; ^R is hydrogen; ^R6 is hydrogen; Q is C ₁ -C ₂ alkyl, which is optionally substituted by C ₁ -C ₂ alkyl; ^Y is selected from hydrogen, chlorine, C ₁ -C ₂ alkoxy and C ₁ -C ₂ alkyl; and Y ^is selected from hydrogen, chlorine, C ₁ -C ₂ alkoxy and C ₁ -C ₂ alkyl; and ^Y3 is hydrogen. 4. The compound of claim 1, selected from the group consisting of: 2-[4-(3-chlorophenyl)but-1-yn-1-yl]-6-methylpyridine, 2-[4-(3-methyl Oxyphenyl)but-1-yn-1-yl]-6-picoline, 2-methyl-6-[4-(3-methylphenyl)but-1-yn-1-yl] Pyridine, 2-methyl-6-(4-phenylbut-1-yn-1-yl)pyridine and 2-methyl-6-(4-phenylpent-1-yn-1-yl)pyridine. 5. A compound according to any one of claims 1-4 for use in therapy. 6. A compound according to claim 5, wherein the therapeutic use is the treatment or prevention of gastroesophageal reflux disease. 7. Use of the compound of formula I or its pharmaceutically acceptable salt or optical isomer according to claim 1 or 2 in the preparation of a medicament for inhibiting transient lower esophageal sphincter relaxation. 8. Use of the compound of formula I or its pharmaceutically acceptable salt or optical isomer according to claim 1 or 2 in the preparation of a medicament for treating or preventing gastroesophageal reflux disease. 9. Use of 4-(4-pyridin-2-ylbut-3-ynyl)-benzonitrile or its pharmaceutically acceptable salt or optical isomer in the preparation of a medicament for inhibiting transient lower esophageal sphincter relaxation. 10. Use of 4-(4-pyridin-2-ylbut-3-ynyl)-benzonitrile or its pharmaceutically acceptable salt or optical isomer in the preparation of a medicament for treating or preventing gastroesophageal reflux disease. 11. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2 as an active ingredient, and a pharmacologically and pharmaceutically acceptable carrier. 12. The method for the compound of preparation formula I, wherein aryl bromide A

with alkyne B,

The coupling reaction is carried out at room temperature to 60°C in the presence of a base such as triethylamine and among them R ¹ is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, wherein aryl or heteroaryl can be substituted by C ₁ -C ₄ alkyl; R ² is selected from hydrogen and C ₁ -C ₄ alkyl; R ³ is selected from hydrogen, C ₁ -C ₄ alkyl, F, CF ₃ , CHF ₂ and CH ₂ F; ^R4 is selected from hydrogen, F, _CF3 , _CHF2 , _CH2F and _CH3 ; ^R is selected from hydrogen and F; ^R is selected from hydrogen and F; Q is selected from C ₁ -C ₄ alkyl, which is optionally substituted by C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; Y ¹ is selected from hydrogen; halogen; nitrile; C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkyl, wherein one or more hydrogen atoms of the alkyl can be replaced by fluorine atoms; benzyloxy; nitro in the para position; and C ₁ -C ₄ alkyl esters; ^Y2 is _selected from _the group _{consisting of} hydrogen; halogen; nitrile; _C1 - _C4 alkoxy; base ester; ^Y3 _{is selected} from _hydrogen ; _halogen ; nitrile; _C1 - _C4 alkoxy; base esters; or Y ¹ and Y ² can form an aromatic or non-aromatic ring, which is optionally replaced by halogen, nitrile, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, benzyloxy or C ₁ -C ₄ alkane Substituted by esters, wherein one or more hydrogen atoms of C ₁ -C ₄ alkyl can be replaced by fluorine atoms. 13. Compounds represented by formula B:

in R ¹ is selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, wherein aryl or heteroaryl can be substituted by C ₁ -C ₄ alkyl; R ² is selected from hydrogen and C ₁ -C ₄ alkyl; R ³ is selected from hydrogen, C ₁ -C ₄ alkyl, F, CF ₃ , CHF ₂ and CH ₂ F; ^R4 is selected from hydrogen, F, _CF3 , _CHF2 , _CH2F and _CH3 ; Q is selected from C ₁ -C ₄ alkyl, which is optionally substituted by C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; Y ¹ is selected from hydrogen; halogen; nitrile; C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkyl, wherein one or more hydrogen atoms of the alkyl can be replaced by fluorine atoms; benzyloxy; nitro in the para position; and C ₁ -C ₄ alkyl esters; ^Y2 is _selected from _the group _{consisting of} hydrogen; halogen; nitrile; _C1 - _C4 alkoxy; base ester; ^Y3 _{is selected from hydrogen} ; halogen; nitrile; _C1 - _C4 alkoxy; base esters; or Y ¹ and Y ² can form an aromatic or non-aromatic ring, which is optionally replaced by halogen, nitrile, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, benzyloxy or C ₁ -C ₄ alkane Substituted by esters, wherein one or more hydrogen atoms of C ₁ -C ₄ alkyl can be replaced by fluorine atoms. 14. A compound selected from the group consisting of 1-chloro-3-(4,4-dibromobut-3-en-1-yl)benzene; 1-methoxy-3-(4,4-dibromobutan- 3-en-1-yl)benzene; 1-methyl-3-(4,4-dibromobut-3-en-1-yl)benzene; 1-but-3-yn-1-yl-3- Chlorobenzene; and (4,4-dibromo-l-methyl-but-3-enyl)-benzene. 15. A method of inhibiting transient lower esophageal sphincter relaxation comprising administering to a subject in need of such inhibition an effective amount of a compound of formula I according to claim 1 or 2. 16. A method of treating or preventing gastroesophageal reflux disease comprising administering an effective amount of a compound of formula I according to claim 1 or 2 to a subject in need of such treatment or prevention.