MX2008007841A

MX2008007841A - Pyrazoles for the treatment of gerd and ibs

Info

Publication number: MX2008007841A
Application number: MX/A/2008/007841A
Authority: MX
Inventors: Bauer Udo
Original assignee: Astrazeneca Ab; Bauer Udo
Priority date: 2005-12-23
Filing date: 2008-06-17
Publication date: 2008-09-02

Abstract

The present invention relates to novel pyrazole derivatives having a positive allosteric GABAB receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use, optionally in combination with a GABAB agonist, for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS) . The compounds are represented by the general formula (I) wherein R1, R2, R3and Y are as defined in the description. For example, R1may be hydrogen or alkyl, R2may be hydrogen or alkyl, R3may be alkoxy and Y may be a carbonylamino linked substituent containing an aryl group.

Description

PIRAZOLES FOR THE TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE AND IRRITABLE BOWEL SYNDROME FIELD OF THE INVENTION The present invention relates to novel compounds that have a positive allosteric GABAB receptor (GBR) modulator effect, to methods for the preparation of the compounds and to their use for the inhibition of transient relaxations of the lower esophageal sphincter, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS).

BACKGROUND OF THE INVENTION The lower esophageal sphincter (LES) is prone to intermittent relaxation. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost in those moments, an event called "reflux". Gastroesophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy focuses on reducing the secretion of gastric acid, or on neutralizing the acid in the esophagus. The main mechanism behind the reflux has been considered to be dependent on a lower esophageal sphincter REF. : 193633 hypotonic However, recent research (for example, Holloway &Dent (1990) Gastroenterol, Clin. N. AMER. 1 9, pp. 51 7-535) has shown that the majority of reflux episodes occur during transient sphincter relaxations. lower esophageal (TLESR), that is, relaxations not triggered by swallowing. It has also been shown that gastric acid secretion is normally normal in patients with GERD. Consequently, there is a need for therapy that reduces the incidence of TLESR and thus prevents reflux. GABAB receptor agonists have been shown to inhibit TLESR, which is described in WO 98/11885 Al.

GABAB receptor agonists GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. The GABA receptors have traditionally been divided into GABAA and GABAB receptor subtypes. The GABAB receptors belong to the superfamily of G-protein coupled receptors (GPCRs). The most studied GABAB receptor agonist baclofen (4-amino-3- (p-chlorophenyl) butanoic acid, described in CH 449046) is useful as an antispastic agent. EP 356128 A2 describes the use of the GABAB receptor agonist (3-aminopropyl) methylphosphinic acid for use in therapy, in particular in the treatment of disorders of the central nervous system. EP 463969 Al and FR 2722192 Al describe 4-aminobutanoic acid derivatives having different heterocyclic substituents on carbon 3 of the butyl chain. EP 181833 Al discloses substituted 3-aminopropylphosphinic acids having high affinities towards GABAB receptor sites. EP 399949 Al describes (3-aminopropyl) methylphosphonic acid derivatives, which are described as potent GABAB receptor agonists. Still other (3-aminopropyl) methylphosphinic acids and (3-aminopropyl) phosphinic acids have been described in WO 01/41743 Al and WO 01/42252 Al, respectively. The structure-activity relationships of various phosphinic acid analogs with respect to their affinities for the GABAB receptor are described in J. Med. Chem. (1995), 38, 3297-3312. Sulfinic acid analogues and their GABAB receptor activities are described in Bioorg. & Med. Chem. Let t. (1998), 8, 3059-3064. For a more general review of GABAB ligands, see Curr. Med. Chem. -Cen tral Nervous System Agen ts (2001), 1, 27-42.

Positive allosteric modulation of GABAB receptors It has been reported that 2,6-di-tert-butyl-4- (3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (3,5-di-tert-butyl) -4- hydroxyphenyl) -2,2-dimethylpropanal (described in US 5,304,685) exert a positive allosteric modulation of native and recombinant GABAB receptor activity. { Society for Neuroscience, 30tb Annual Meeting, New Orleans, La., Nov. 4-9, 2000: Positive Allosteric Modulation of Native and Recombinant GABAB Receptor Activity, S. Urwyler et al., Molecular Pharmacol. (2001), 60, 963-971). It has been reported that N, N-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidin-4,6-diamine exerts positive allosteric modulation of the GABAB receptor (The Journal of Pharmacology and Experimental Therapeutics, 307 (2003), 322- 330). For a recent review on allosteric modulation of GPCRs, see: Expert Opin. Ther. Patents (2001), 11, 1889-1904.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (I) (i) where R1 represents hydrogen, C1-C10 alkyl; C2-C? 0 alkenyl; C2-C? or C3-C-cycloalkyl] alkynyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, SO3R7, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups or R1 represents aryl or heteroaryl, each optionally substituted by one or more of C? -C? C2-C alkenyl? 0; C2-C? alkynyl, C ciclo-C? alkoxy C 3 -CLC cycloalkyl, C 1 -C 10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used to define R1 may be further substituted by one or more of halogen (s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy , wherein the C? -C? alkyl or can be further substituted by one or two aryl or heteroaryl groups; R 2 represents hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy or C 1 -C 10 thioalkoxy, optionally substituted by one or more of C 1 -C 10 alkoxy, C 3 -C 0 cycloalkyl, C 1 -C 10 thioalkoxy C10, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, or R2 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl; C-C? o alkenyl; C2-C? alkynyl, C3-C? cycloalkyl, CC? alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, C0NR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R3 represents C? -C? 0 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, C0NR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents C? -C? alkyl, C-C10 alkenyl; C2-C? alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C? -C? thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid , C0NR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups or R3 represents aryl or heteroaryl, each optionally substituted by one or more of C? -C? Alkyl, C2-C? Alkenyl or alkynyl of C2-C? 0, C3-C cycloalkyl, C? -C? Alkoxy, C? -C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents amino, optionally mono- or disubstituted with C? -C10 alkyl, C2-C10 alkenyl, C2-C? alkynyl or C3-C? cycloalkyl; And represents R4 represents C? -C? Alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C? -C? 0 alkoxy; or C3-C? -cycloalkyl, each optionally substituted by one or more of C? -C? alkoxy, C3-C0 cycloalkyl, C? -C? thioalkoxy, halogen (s), hydroxy, mercapto , keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, COR10, nitrile, S02NR8R9, S02Rn, NR8S02R9, NR8C = ONR9 or one or two aryl or heteroaryl groups or R4 represents aryl or heteroaryl, each optionally substituted with one or more alkyl of C? -C10, C2-C10 alkenyl, C2-C? alkynyl, C3-C ?cycloalkyl, C?-C10 alkoxy, C-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, S02NR8R9, NR8S02R9, S03R7, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used to define R4 may be further substituted by one or more of halogen (s), C-C10 alkyl, C-alkoxy ~ C? O, C? -C? Or thioalkoxy alkoxy of C? -C? Or wherein C? -C? Alkyl or can be further substituted by one or two aryl or heteroaryl groups; R5 represents hydrogen, C? -C? Alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-Co cycloalkyl, each optionally substituted by one or more of C? -C10 alkoxy, C3-C10 cycloalkyl, C-C10 thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9 , C02R10, nitrile or one or two aryl or heteroaryl groups; or R 5 represents aryl or heteroaryl, each optionally substituted by one or more of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 1 alkoxy C? O, thioalkoxy of C? -Co, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R6 represents hydrogen, C? -C? Alkyl, C2-C? Alkenyl, or C2-C? Alkynyl; or C3-C6 cycloalkyl, each optionally substituted with one or more of C-C10 alkoxy, C3-C10 cycloalkyl, C? -C? thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid , CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R6 represents aryl or heteroaryl, each substituted by one or more of C? -C? alkyl, or alkenyl of C2-C10, C2-C10 alkynyl, C3-C10 cycloalkyl, C? -C10 alkoxy, C? -C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R5 and R6 together form a ring consisting of 3 to 7 atoms selected from C, N and 0, wherein the ring is optionally substituted with one or more of C? -C? alkyl, C2-C10 alkenyl, C2-C? alkynyl, C3-C ciclocycloalkyl, C?-C? alkoxy, C?-C? t thioalkoxy, halogen (s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl, or heteroaryl groups; R7 each independently represents Ci-Cio alkyl; R8 each independently represents hydrogen, C?-C10 alquilo alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally further substituted by one or more of halogen (s), C?-C? O alkyl, alkoxy C? ~ C] 0, or thioalkoxy of C? -C10; R9 each independently represents hydrogen, C? -C? Alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl can be further optionally substituted by one or more of halogen (s), C-C10 alkyl, C-alkoxy ? ~ C? O, or thioalkoxy of C? -C10; R10 each independently represents C? -C10 alkyl, optionally substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted optionally furthermore by one or more of halogen (s), C? -C? 0 alkyl, C-C10 alkoxy or C? -C10 thioalkoxy; R 11 represents C 1 -C 6 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally further substituted by one or more of halogen (s), C 1 -C 6 alkyl, C 1 alkoxy, C? Oo thioalkoxy of C? -C10; wherein each of alkyl, alkenyl, alkynyl and cycloalkyl can independently have one or more carbon atoms substituted for O, N or S; where none of the O, N or S is in a position adjacent to any other O, N or S; wherein each of alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl can independently have one or more carbon atoms substituted by fluoro; as well as pharmaceutically and pharmacologically acceptable salts thereof, and enantiomers of the compound of the formula (I) and salts thereof; except: 3-benzamido-1, 5-diphenyl-, ethyl ester of pyrazole-4-carboxylic acid and 2-propenamide, N- (4-acetyl-5-methyl-1H-pyrazol-3-yl) -3 -phenyl. In one embodiment of the present invention, R 1 represents C 1 -C 4 alkyl, optionally substituted by one or two heteroaryl groups. In another embodiment of the present invention, R1 represents aryl, optionally substituted by one or more of C? -C? alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C? -C10 alkoxy, C? -C10 thioalkoxy , SO3R7, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups. According to another embodiment of the present invention, R1 represents unsubstituted phenyl. In another embodiment of the present invention, R 2 represents C 1 -C 4 alkyl. In a further embodiment of the present invention, R1 and R2 form a ring consisting of 5 or 6 atoms selected from C, O and N. In one embodiment of the present invention, R3 represents C?-C4 alkoxy, optionally substituted by one or more of C? -C? thioalkoxy, C3-C? 0 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl groups or heteroaryl. According to another embodiment of the present invention, R3 represents C? -C? Alkyl, optionally substituted by one or more of C? -C? Alkoxy, C? -C? Thioalkoxy, or C3 cycloalkyl. C10, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02Rlt} , nitrile or one or two aryl or heteroaryl groups.

In another embodiment of the present invention, R4 represents C? -C7 alkyl, C2-C alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, optionally substituted by one or more of C? -C? Alkoxy or , C3-C? 0 cycloalkyl, C? -C10 thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile, amide, sulfonamide, urea or one or two aryl or heteroaryl groups, wherein the aryl or heteroaryl group used to define R4 can be further substituted by one or more of halogen (s), C? -C? alkyl, C? -C? alkoxy or C? -C? thioalkoxy. , wherein the C? -C? alkyl or can be further substituted by one or two aryl or heteroaryl groups. In a further embodiment of the present invention, R 4 represents C 1 -C 4 alkyl, optionally substituted by one or two aryl or heteroaryl groups. In a further embodiment of the present invention, R 4 represents C 1 -C 4 alkyl, substituted by one or two aryl or heteroaryl groups. In a further embodiment of the present invention, R4 represents aryl or heteroaryl, optionally substituted by one or more of C? -C10 alkyl, C2-C10 alkenyl, C2-C? Alkynyl, C3-CX0 cycloalkyl, alkoxy of C? -C? o, C? -C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8C0R9, C02R10, nitrile or one or two aryl or heteroaryl groups.

According to one embodiment of the present invention, R5 represents C? - alkyl. According to yet another embodiment of the present invention, R 5 represents methyl. In another embodiment of the present invention, R6 represents C? - alkyl. In another embodiment of the present invention, R6 represents methyl. In a further embodiment of the present invention, R5 and R6 form a ring consisting of 5 or 6 atoms selected from C, O and N. According to another embodiment of the present invention, Y represents According to another embodiment of the present invention, Y represents The present invention also relates to a compound according to claim 1, selected from 3- [(2,3-dihydro-l, 4-benzodioxin-2-ylcarbonyl) amino] -l-ethyl-l-pyrazole-4 ethyl carboxylate and ethyl l-ethyl-3- [(2-phenylbutanoyl) amino] -lH-pyrazole-4-carboxylate. The above compounds of formula (I) are useful as potent positive allosteric GABAB receptor modulators as well as agonists. The molecular weight of the compounds of formula (I) above is generally within the range of 300 g / mol to 700 g / mol. It should be understood that the present invention also relates to any and all tautomeric forms of the compounds of the formula (I). The general terms used in the definition of formula (I) have the following meanings: Alkyl of C? -C10 is a straight or branched alkyl group, having from 1 to 10 carbon atoms, for example, methyl, ethyl, -propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, hexyl or heptyl. The alkyl groups may contain one or more heteroatoms selected from O, N and S, ie, one or more of the carbon atoms may be substituted by this heteroatom. Examples of these groups are methyl ethyl ether, methyl ethylamine and methyl thiomethyl.

The alkyl group can be part of a ring. One or more of the hydrogen atoms of the alkyl group may be substituted by a fluorine atom.

Alkyl of C? -C4 is a straight or branched alkyl group having from 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl. The alkyl groups may contain one or more heteroatoms selected from 0, N and S, ie, one or more of the carbon atoms may be substituted by this heteroatom. Examples of these groups are methyl ethyl ether, methyl ethylamine and methyl thiomethyl. The alkyl group can be part of a ring. One or more of the hydrogen atoms of the alkyl group may be substituted by a fluorine atom. C2-C alkenyl is a straight or branched alkenyl group having 2 to 10 carbon atoms, for example vinyl, isopropenyl and 1-butenyl. The alkenyl groups may contain one or more heteroatoms selected from O, N and S, that is, one or more of the carbon atoms may be substituted by this heteroatom. One or more of the hydrogen atoms of the alkenyl group can be replaced by a fluorine atom. C2-C Al alkynyl is a straight or branched alkynyl group, having 2 to 10 carbon atoms, for example ethynyl, 2-propynyl and but-2-ynyl. The alkynyl groups may contain one or more heteroatoms selected from 0, N and S, ie, one or more of the carbon atoms may replace this heteroatom. One or more of the atoms Hydrogen in the alkynyl group can substitute a fluorine atom. Cycloalkyl of C3-C? 0 is a cyclic alkyl, having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl can also be unsaturated. The cycloalkyl groups may have one or more heteroatoms selected from O, N and S, that is, one or more of the carbon atoms may substitute this heteroatom. One or more of the hydrogen atoms of the cycloalkyl group can substitute a fluorine atom. C? -C? Alkoxy is an alkoxy group having 1 to 10 carbon atoms, for example methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentoxy, hexoxy or a heptoxy group. The alkoxy may be cyclic, partially unsaturated or unsaturated, such as in propenoxy or cyclopentoxy. The alkoxy can be aromatic, such as in benzyloxy or phenoxy. C? -C? Thioalkoxy is a thioalkoxy group having 1 to 10 carbon atoms, for example thiomethoxy, thioethoxy, n-thiopropoxy, n-thiobutoxy, thioisopropoxy, thioisobutoxy, secondary thiobutoxy, tertiary thiobutoxy, thiopentoxy, thiohexoxy or thioheptoxy. The thioalkoxy can be unsaturated, such as in thiopropenoxy or aromatic, such as in thiobenzyloxy or thiophenoxy. The term "aryl" is defined herein as a an aromatic ring having from 6 to 14 carbon atoms including both individual rings and polycyclic compounds, such as phenyl, benzyl or naphthyl. Polycyclic rings are saturated, partially unsaturated or saturated. The term "heteroaryl" as defined herein is an aromatic ring having 3 to 14 carbon atoms, including both individual rings and polycyclic compounds in which one or more of the ring atoms is either oxygen, nitrogen or sulfur, such as furanyl, thiophenyl or imidazopyridine. Polycyclic rings are saturated, partially unsaturated or saturated. Halogen (s) as used herein are selected from chlorine, fluorine, bromine or iodine. The term keto is defined herein as a divalent oxygen atom doubly bound to a carbon atom. The carbon atoms are present adjacent to the carbon atom to which the divalent oxygen is attached. When the compounds of the formula (I) have at least one asymmetric carbon atom, they can exist in various stereoiochemical forms. The present invention includes the mixture of isomers as well as the individual stereoisomers. The present invention also includes geometric isomers, rotational isomers, enantiomers, racemates and diastereomers When applicable, the compounds of the formula (I) can be used in neutral form, for example as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound in question. The compounds of the formula (I) are useful as modulators of positive allosteric GBR (GABAB receptor). A positive allosteric modulator of the GABAB receptor is defined as a compound that makes the GABAB receptor more sensitive to GABA and GABAB receptor agonists by binding to the GABAB receptor protein at a site different from that used by the endogenous ligand. The positive allosteric GBR modulator acts synergistically with an agonist and increases the potency and / or intrinsic efficiency of the GABAB receptor agonist.

It has also been shown that positive allosteric modulators that act on the GABAB receptor can produce an agonist effect. Therefore, the compounds of the formula (I) can be effective as full or partial agonists. A further aspect of the invention is a compound of the formula (I) for use in therapy. As a consequence of the GABAB receptor becoming more sensitive to GABAB receptor agonists after the administration of a positive allosteric modulator, observe an increased inhibition of transient lower esophageal sphincter relaxations (TLESR) for a GABAB agonist. In consecuense, the present invention is directed to the use of a positive allosteric GABAB receptor modulator according to formula (I), optionally in combination with a GABAB receptor agonist, in the preparation of a medicament for the inhibition of transient esophageal sphincter relaxations. lower (TLESRs). A further aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the prevention of reflux. Yet another aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment of gastroesophageal reflux disease (GERD). The effective management of regurgitation in babies could be an important way to prevent, as well as to cure lung diseases due to the aspiration of regurgitated gastric contents, and to manage the lack of development, among others due to excessive loss of ingested nutrients. Thus, a further aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment of pulmonary diseases. Another aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the management of lack of development. Another aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of asthma, such as asthma related to reflux. A further aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of laryngitis or chronic laryngitis. A further aspect of the present invention is a method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), in which a pharmacologically and pharmacologically effective amount of a compound of the formula (I), optionally in combination with an agonist of the GABAB receptor, is administered to a subject that requires this inhibition. Another aspect of the invention is a method for reflux prevention, with which a pharmaceutically and pharmacologically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of this prevention. A further aspect of the invention is a method for the treatment of gastroesophageal reflux disease (GERD), with which a pharmaceutical and pharmacologically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, it is administered to a subject who requires this treatment. Another aspect of the present invention is a method for the treatment or prevention of regurgitation, with which a pharmacologically and pharmacologically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject that requires this treatment. Yet another aspect of the invention is a method for the treatment or prevention of regurgitation in infants, with which a pharmacologically and pharmacologically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject that requires this treatment. A further aspect of the invention is a method for the treatment, prevention or inhibition of pulmonary disease, with which a pharmaceutically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject requiring this treatment. The lung disease that will be treated may be among others due to aspiration of regurgitated gastric contents. A further aspect of the invention is a method for managing lack of development, with which a pharmaceutically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject that requires this treatment. A further aspect of the invention is a method for the treatment or prevention of asthma, such as asthma related to reflux, with which a pharmacologically and pharmacologically effective amount of a compound of the formula (I), optionally in combination with an agonist of the GABAB receptor, is administered to a subject that requires this treatment. A further aspect of the invention is a method for the treatment or prevention of laryngitis or chronic laryngitis, with which a pharmaceutically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is admin to a subject that requires this treatment. A further embodiment is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment of a functional gastrointestinal disorder (FGD). Another aspect of the invention is a method for the treatment of a functional gastrointestinal disorder, with which an effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject suffering from of that condition. A further embodiment is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment of functional dyspepsia. Another aspect of the invention is a method for the treatment of functional dyspepsia, with which an effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject suffering from that condition. Functional dyspepsia refers to a pain or discomfort centered in the upper abdomen. The discomfort can be characterized by or combined with upper abdominal fullness, early satiety, inflation or nausea. Etiologically, patients with functional dyspepsia can be divided into two groups: 1- Those with an identifiable pathophysiological or microbiological abnormality of uncertain clinical relevance (for example, Helicobacter pylori gastritis, histological duodenitis, vesicular stones, visceral hypersensitivity, gastroduodenal dysmotility) 2- Patients without identifiable explanation for the symptoms. Functional dyspepsia can be diagnosed according to the following: At least 12 weeks, which do not have to be consecutive within the preceding 12 months of 1- Persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen) and 2- None evidence of organic disease (including upper endoscopy) likely to explain the symptoms; and 3- No evidence that dyspepsia is relieved exclusively by defecation or associated with the onset of a change in the frequency or shape of the stool. Functional dyspepsia can be divided into subsets based on patterns of distinctive symptoms, such as ulcer-type dyspepsia, dysmotility-type dyspepsia, and unspecified (non-specific) dyspepsia. Current therapy for functional dyspepsia is widely empirical and directed towards relief of prominent symptoms. The most commonly used therapies still include antidepressants. A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS). , such as IBS of predominant constipation, IBS of predominant diarrhea or IBS of predominant alternating bowel movements. A further aspect of the invention is a method for the treatment or prevention of irritable bowel syndrome (IBS), with which a pharmaceutical and pharmacologically effective amount of a compound of the formula (I), optionally in combination with a receptor agonist. GABAB, is administered to a subject in need of this treatment. IBS is defined herein as a chronic functional disorder with specific symptoms that include continuous or recurrent abdominal pain and discomfort accompanied by altered bowel function, commonly with abdominal inflation and abdominal distension. It is generally divided into three subgroups according to the predominant bowel pattern: 1- predominant diarrhea 2- predominant constipation 3- alternating intestinal movements. Abdominal pain or discomfort is the hallmark of IBS and is present in all three subgroups. The symptoms of IBS have been categorized according to the Rome criteria and subsequently modified to the Rome II criteria. This compliance to describe the symptoms of IBS has helped to achieve a consensus to designate and evaluate clinical studies of IBS. The diagnostic criteria of Rome II are: 1- Presence of abdominal pain or discomfort for at least 12 weeks (not necessarily consecutively) of the previous year 2- Two or more of the following symptoms: a) Relief with defecation b) Home associated with change in stool frequency c) Start associated with change in stool consistency. A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of CNS disorders, such as anxiety . A further aspect of the invention is a method for the 2- predominant constipation 3- alternating intestinal movements. Abdominal pain or discomfort is the hallmark of IBS and is present in all three subgroups. The symptoms of IBS have been categorized according to the Rome criteria and subsequently modified to the Rome II criteria. This compliance to describe the symptoms of IBS has helped to achieve a consensus to designate and evaluate clinical studies of IBS. The diagnostic criteria of Rome II are: 1- Presence of abdominal pain or discomfort for at least 12 weeks (not necessarily consecutively) of the previous year 2- Two or more of the following symptoms: a) Relief with defecation b) Home associated with change in stool frequency c) Start associated with change in stool consistency. A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of CNS disorders, such as anxiety. A further aspect of the invention is a method for the treatment or prevention of CNS disorders, such as anxiety, with which a pharmaceutically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of this treatment. A further aspect of the invention is the use of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of depression. A further aspect of the invention is a method for the treatment or prevention of depression, with which a pharmacologically and pharmaceutically effective amount of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject in need of this treatment. A further aspect of the invention is the use of a compound according to formula (I), optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment or prevention of dependence, such as alcohol dependence. or nicotine. A further aspect of the invention is a method for the treatment or prevention of dependence, such as alcohol dependence, with which a pharmaceutical and The pharmacologically effective compound of the formula (I), optionally in combination with a GABAB receptor agonist, is administered to a subject requiring this treatment. For the purpose of this invention, the term "agonist" should be understood as including full agonists as well as partial agonists, whereby a "partial agonist" should be understood as a compound capable of activating partial, but not completely, GABAB receptors. The word "TLESR", transient relaxations of the lower esophageal sphincter, is defined in the present according to Mittal, R.K. , Holloway, R.H., Penagini, R., Blackshaw, L.A., Dent, J., 1995; Transíent lower esophageal sphíncter relaxation. Gastroenterology 109, pgs. 601-610. The phrase "reflux" is defined as fluid from the stomach that is able to pass into the esophagus, since the mechanical barrier is temporarily lost in those cases. The word "GERD", gastroesophageal reflux disease, is defined according to van Heerwarden, M.A., Scout A.J.P.M., 2000; Diagnosis of reflux disease, Bailliere's Clin. Gastroenterol. 14, pgs. 759-774. Functional gastrointestinal disorders, such as functional dyspepsia, can be defined according to Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irving EJ, Mueller-Lissner SA. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, Talley NJ, Thompson WG, Whitiehead WE, Coraziarri E, eds., Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, VA: Degnon Associates, Inc .; 2000: 351-432 and Drossman DA, Corazziari E, Talley, NJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45 (Suppl.2), II1-II81.9-1-1999. Irritable bowel syndrome (IBS) can be defined according to Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irving EJ, Mueller-Lissner SA. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, Talley NJ, Thompson WG, Whitiehead WE, Coraziarri E, eds., Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, VA: Degnon Associates, Inc .; 2000: 351-432 and Drossman DA, Corazziari E, Talley, NJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45 (Suppl.2), II1-II81.9-1-1999. A "combination" according to the invention may be present as a "fixed combination" or as a "combination of parts kits".

A "fixed combination" is defined as a combination in which (i) a compound of the formula (I); and (ii) a GABAB receptor agonist are present in a unit. An example of a "fixed combination" is a pharmaceutical composition in which (i) a compound of the formula (I) and (ii) a GABAB receptor agonist are present in a mixture. Another example of a "fixed combination" is a pharmaceutical composition in which (i) a compound of the formula (I) and (ii) a GABAB receptor agonist are present in a unit without being in admixture. A "combination of kits of parts" is defined as a combination in which (i) a compound of the formula (I) and (ii) a GABAB receptor agonist are present in more than one unit. An example of a "combination of kits of parts" is a combination in which (i) a compound of the formula (I) and (ii) an agonist of the GABAB receptor are present separately. The components of the "combination of kits of parts" can be administered simultaneously, sequentially or separately, that is, separately or together. The term "positive allosteric modulator" is defined as a compound that makes a receptor more sensitive to receptor agonists by binding to the receptor protein at a site different from that used by the endogenous ligand. The term "therapy" and the term "treatment" they also include "prophylaxis" and / or prevention unless otherwise indicated. The terms "therapeutic" and "therapeutically" should be considered accordingly.

Pharmaceutical Formulations The compound of the formula (I) can be formulated alone or in combination with a GABAB receptor agonist. For clinical use, the compound of the formula (I), optionally in combination with a GABAB receptor agonist, is in accordance with the present invention suitably formulated in pharmaceutical formulations for oral administration. Likewise rectal, parenteral administration or any other route of administration can be contemplated by the person skilled in the art of formulations. Thus, the compound of the formula (I), optionally in combination with a GABAB receptor agonist, is formulated with a pharmaceutically and pharmaceutically acceptable carrier or adjuvant. The vehicle can be in the form of a solid, semi-solid or liquid diluent. In the preparation of oral pharmaceutical formulations according to the invention, the compound of the formula (I) to be formulated, optionally in combination with a GABAB receptor agonist, is mixed with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, derivatives of cellulose, gelatin or other 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 pellets or compressed into tablets. Soft gelatin capsules can be prepared with capsules containing a mixture of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, with vegetable oil, fat or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in combination with solid powder ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch. , amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration can be prepared (i) in the form of suppositories containing the active substances mixed with a neutral fat base; (ii) in the form of a rectal gelatin capsule containing a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in a mixture with a vegetable oil, paraffinic oil or other suitable vehicle for rectal capsules of jelly; (iii) in the form of a micro enema ready to use or (iv) in the form of a formulation of dry micro enema that will be reconstituted in a suitable solvent just before its administration. Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example, solutions or suspensions, containing a compound of the formula (I), optionally in combination with a GABAB receptor agonist, and the remainder of the formulation consists of in sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, these liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of a dry powder which will be reconstituted with a suitable solvent before use. Solutions for parenteral administration can be prepared as a solution of a compound of the formula (I), optionally in combination with a GABAB receptor agonist, in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and / or pH regulating ingredients and are supplied in single doses in the form of ampoules or flasks. Solutions for parenteral administration can also be prepared as a dry preparation that will be reconstituted with a suitable solvent extemporaneously before using. In one aspect of the present invention, a compound of the formula (I), optionally in combination with a GABAB receptor agonist, may be administered once or twice a day, depending on the severity of the patient's condition. A typical daily dose of the compounds of the formula (I) is 0.1 to 100 mg per kg of body weight of the subject to be treated, but this will depend on several factors such as the route of administration, the age and weight of the patient as well. as of the severity of the patient's condition.

Methods of Preparation The compounds according to formula (I) of the present invention, when Y = -NH-Z-R4 and wherein R1, R2, R3 and R4 are defined as above, Z is -S02-, -C (S) - or -C (O) -, can be prepared by the following general methods: Reaction scheme 1 X = reactive functionality (eg Cl) where aminoheteroaryls (I I) are converted efficiently in the, using electrophiles such as acyl chlorides, sulfonyl chlorides, carbamoyl chlorides, isocyanates or isothiocyanates (typically 1.0-2.0 equivalents) in organic solvents such as THF or the like. The reaction is carried out either in the presence of bases such as triethylamine and temperatures of 25-50 ° C or in the presence of polymer-supported diisopropylethylamine (PS-DIPEA; 1.5 - 3 equivalents) at room temperature 50 ° C with stirring for 4 - 18 hours. Filtration of the reaction mixture onto the nucleophilic anion exchange resin Isolute-NH2, elution with THF and evaporation under vacuum produces the desired products as oils or amorphous solids. For the compounds according to formula (I) of the present invention when Y the preparation is done according to familiar methods for the person skilled in the art. The aminopyrazoles (II) are prepared from the intermediates (III) by heating the reagent either with substituted hydrazines or hydrazine itself followed by alkylation of the unsubstituted pyrazoles thus generated with alkyl halides in the presence of a base such as sodium hydride. In these reactions, they are producing both regioisomers which can be separated by chromatography (as indicated in reaction scheme 2; literature: Australian J. Chem. 1985, 38, 221-230; Helvética Chimica Acta 1959, 42, 349-359). Intermediates (III) can be prepared by reacting (IV) with ethanol under Mitsunobu standard reaction conditions (Literature: D.L. Huges in Organic Reactions, Vol 42, pp. 335-656, 1992).

Reaction scheme 2 Intermediaries (IV) are accessible through known literature procedures. For example, ketonitriles can be converted into intermediates (IV) by reaction with diethyl phosphorocyanurate and carboxylic acids as described by Shiori (J. Org.

Chem. 1978, 43, 3631-3632), or by reaction with acid chlorides as described by Rappoport (J. Org. Chem. 1982, 47, 1397-1408) (see reaction scheme 3).

Reaction scheme 3 (IV) EXAMPLES Example 1 Synthesis of Ethyl 3- [(2,3-dihydro-l, 4-benzodioxin-2-ylcarbonyl) amino] -l-ethyl-lH-pyrazole-4-carboxylate The lH-pyrazole-4-carboxylate (0.03 mmole) was dissolved in 2 mL of dry THF. Then, PS-DIEA was added (25 mg, 009 mmol) followed by the acid chloride (0.07 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered through an isolute-NH 2 ion exchange column and the solvent was evaporated. The crude material was purified by flash chromatography using 30% EtOAc: heptane as an eluent to provide the desired product. Yield: 37.8%. H NMR (400 MHz, CDC13) d 10.27 (s, 1H), 7.79 (s, 1H), 7.18-7.08 (m), 7.00-6.86 (m), 4.86 (d, 1H), 4.66 (d, 1H), 4.40-4.15 (m), 1.53 ( t, 3H), 1.38 (t, 3H). MS m / z 346.12 (M + H) +.

Example 2 Synthesis of ethyl 3-amino-l-ethyl-lH-pyrazole-4-carboxylate (used as an intermediate) To a solution of ethyl 3-amino-1-pyrazole-4-carboxylate (0.96 mmol, commercially available from ACROS) in MeCN was added sodium hydride (60%, 46 mg) at room temperature. After 30 minutes of stirring, a solution of ethyl iodide (0.96 mmole) in MeCN was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The reaction was then stopped by the addition of water, followed by dichloromethane. The phases were separated using a phase separator. The organic phase was collected, dried over MsS04, the solvent was evaporated and the crude mixture was purified by flash chromatography using 30% EtOAc: heptane as an eluent to give a mixture of regioisomers which was used directly in the following stages of the synthesis without some additional separation. Yield: 68.2%, XH NMR (400 MHz, CDC13) d 7.64 (s, 1H), . 50 (s, 1H), 4.28-4.17 (m), 4.10-3.91 (m), 3.37-3.18 (m), 1.92 (s, 1H), 1.48-1.18 (m). MS m / z 184.15 (M + H) +. The following example was synthesized according to the examples described above.

Example 3 ethyl l-Ethyl-3- [(2-phenylbutanoyl) amino] -lH-pyrazole-4-carboxylate Yield: 33.4%,? H NMR (400 MHz, CDC13) d 9.14 (s, 1H), 7.43-7.20 (m), 4.28-4.07 (m), 3.44 (s, 1H), 2.36-2.16 (m), 1.98-1.75 (m), 1.47 (t, 3H), 1.29 (t, 3H), 0.93 (t, 3H). MS m / z 330.27 (M + H) +.

Analysis LC-MS analysis was carried out using a system Micromass 8 MUX-LTC ESP + probe, the purity being determined by UV detection of a single wavelength (254 nm). Chromatography was carried out on an XterraTM MS C8 column 3.5 um, 4.6x30 mm, 8 in parallel. The flow of 15 ml / min was divided over the 8 columns to give a speed of flow of 1.9 ml / min. The 10 minute chromatography gradient was as follows: Mobile Phase A: 95% ACN + 5% 0.010 M NH4OAc Mobile Phase B: 5% ACN + 95% 0.010 M NH4OAc 10 min. 0.0 min 0% A 8.0 min 100% A 9.0 min 100% A 9.1 min 0% A The NMR analysis was carried out at 400 MHz.

Biological evaluation Effects of the positive allosteric GABAB receptor modulator in a functional in vi tro assay The effect of GABA and baclofen on the release of intracellular calcium in CHO cells expressing the heterodimer of the GABAB receptor (IA / 2) was studied in the presence or absence of the positive allosteric modulator. The positive allosteric modulator according to the invention increased both the potency and the efficacy of GABA. The potency of the compounds, ie the ability of the compounds to reduce the EC50 of GABA was revealed by the concentration required to reduce the EC50 of GABA by 50%. These powers were similar to the power reported for CGP7930 (can be purchased from Tocris, Northpoint, Fourth Way, Avonmouth, Bristol, BSll 8TA, United Kingdom) by Urwyler et al. CGP7930 increases the GABA potency of an EC50 of about 170-180 nM to an EC50 of about 35-50 nM.

Experimental procedures Materials Culture medium of Nut mix F-12 cells (Ham), reduced serum medium OPTI-MEM I, fetal bovine serum (FBS), penicillin / streptomycin solution (PEST), geneticin, HEPES acid (4- ( 2-hydroxyethyl) -1-piperazinetanesulfonic (pH regulator), 1 M solution), 'Hank's Balanced Salt Solution (HBSS) and zeocin were from Life technologies (Paisley, Scotland); polyethyleneimine, probenicid, baclofen and? -aminobutyric acid (GABA) came from Sigma (St. Louis, E.U.A.); Fluo-3 AM was from Molecular Probes (Oregon, E.U.A.). The 4-amino-n- [2, 3- 3 H] butyric acid ([3 H] GABA) was from Arsham Pharmacia Biotech (Uppsala, Sweden).

Generation of cell lines expressing the GABAB receptor GABABRla and GABABR2 were cloned from human brain cDNA and subcloned into pCI-Neo (Promega) and pALTER-1 (Promega), respectively. A GABABRla-Gaqi5 fusion protein expression vector was constructed using the plasmid DNA of pCI-Neo-GABABRla and pLECI-Gaqi5 (Molecular Devices, CA). In order to make Gaq? 5 insensitive to pertussis toxin, Cys356 was mutated to Gly using standard PCR methodology with primers 5 '-GGATCCATGGCATGCTGCCTGAGCGA-3' (forward) and 5 '-GCGGCCGCTCAGAAGAGGCCGCCGTCCTT-3' (backward). The Gaq? 5mut cDNA was ligated into the BamHI and NotI sites of pcDNA3.0 (Invitrogen). The GABAB RIA coding sequence was amplified by PCR from pCI-Neo-GABABRla using the primers, 5'-GGATCCCCGGGGAGCCGGGCCC-3 '(forward) and 5'-GGATCCCTTATAAAGCAAATGCACTCGA-3' (backward) and subcloned into the BamHI site of pcDNA3.0-Gaq? 5mut. To optimize the Kozak consensus sequence of GABABR2, m mutagenesis was performed if you using the Altered Sites Mutagenesis kit according to the manufacturer's instruction (Promega) with the following primer, 5'-GAATTCGCACCATGGCTTCCC-3 '. The optimized GABABR2 was then restricted from pALTER-1 with Xho I + Kpn I and subcloned into the mammalian expression vector pcDNA3.1 (-) / Zeo (Invitrogen) to produce the final construct, pcDNA3.1 (- ) / Zeo-GABABR2. For the generation of stable cell lines, CHO-K1 cells were cultured in Nut mix F-12 medium (Ham) supplemented with 10% FBS, 100 U / ml penicillin and 100 μg / ml streptomycin at 37 ° C in a humidified C02 incubator. The cells were detached with 1 mM EDTA in PBS and 1 million cells were seeded in 100 mm petri dishes. After 24 hours the culture media were replaced with OptiMEM and incubated for 1 hour in a C02 incubator. For the generation of a cell line expressing the GABABRLA / GABABR2 heterodimer, plasmid DNA GABAßRla (4 μg), plasmid DNA GABABR2 (4 μg) and lipofectamine (24 μl) 'were mixed in 5 ml of OptiMEM and incubated for 45 minutes at room temperature. The cells were exposed to the transfection medium for 5 hours, which was then replaced with culture medium. Cells were cultured for an additional 10 days before selection agents were added (300 μg / ml hygromycin and 400 μg / ml geneticin). Twenty-four days after transfection, the classification of individual cells into 96-well plates by fLujo cytometry was carried out using a FACS Vantage SE (Becton Dickinson, Palo Alto, CA). After expansion, the functional response to the GABAB receptor was tested using the FLIPR assay described below. The clone with the highest functional response was collected, expanded and then subcloned by individual cell sorting. The clonal cell line with the highest peak response in FLIPR was used in the present study. For the generation of a stable cell line expressing GABABRla-Gaq? 5 fusion protein and DNA plasmid GABABr2, GABABRla-Gaq? 5mut (8 μg), plasmid DNA GABABR2 (8 μg) and lipofectamine (24 μl) were mixed in 5 ml of OptiMEM and incubated for 45 minutes at room temperature. The cells were exposed to the transfection medium for 5 hours, which was then replaced with culture medium. After 48 hours, the cells were detached and seeded in 6-well plates (2000 cells / well) and cultured in culture medium supplemented with geneticin (400 μg / ml) and zeocin (250 μg / ml). After 4 days, individual colony cells were harvested and transferred to a 24-well plate. After 10 days, the cell clones were seeded in T-25 flasks and cultured for another 16 days before they were tested for GABAB receptor mediated functional response. The clones that showed the highest peak response were collected and subcloned by seeding the cells in 6-well plates (1000 cells / well) and repeating the steps described above. The line of clonal cells that gave the highest peak response in FLIPR was used in the present study.

Measurement of GABAB receptor-dependent intracellular calcium release in FLIPR Measurement of GABAB receptor-dependent intracellular calcium release in the GABAB receptor Fluorescence imaging (FLIPR) was carried out as described by Coward et al., Anal. Biochem. (1999) 270, 242-248, with certain modifications. Transfected CHO cells were cultured in Nut Mix F-12 (HAM) with Glutamax-I and supplemented with 10% of 100 U / ml of penicillin and 100 μg / ml of streptomycin, 250 μg / ml of zeocin and 400 μg / ml of geneticin Twenty-four hours before the experiments the cells (35,000 cells / well) were seeded on 96-well black-walled poly-D-lysine coated plates (Becton Dickinson, Bedford, UK) in culture medium without selection agents. The cell culture medium was aspirated and 100 μl of Fluo-3 loading solution (4 μM Fluo-3, 2.5 mM probenecid and 20 mM Hepes in Nut Mix F-12 (Ham)) were added. After incubation for 1 hour at 37 ° C in a 5% C0 incubator, the dye solution was aspirated and the cells were washed twice with 150 μl of wash solution (2.5 mM probenecid and 20 mM Hepes in HBSS) followed by the addition of 150 μl of wash solution. The cells were then assayed in a fluorescence imaging plate reader (Molecular Devices Corp., CA, E.U.A.). The test compounds were diluted to 50 μM in HBSS containing 20 mM Hepes and 5% DMSO and added in a volume of 50 μL. Fluorescence was sampled every second for 60 s (10 s before and 50 s after the addition of the test compound) before GABA (50 μl 7.6 nM-150 μM) was added and the muereo continued every sixth second for an additional 120 seconds.

GTP? S [35 S] -GTP? S binding assays were carried out at 30 ° C for 45 minutes in membrane pH buffer (100 mM NaCl, 5 mM, 1 mM EDTA, 50 mM HEPES, pH 7.4) containing 0.025 μg / μl of membrane protein (prepared from the cell lines described above) with 0.01% bovine serum albumin (free of fatty acids), 10 μM of GDP, 100 μM of DTT and 0.53 nM [35S] -GTP? S (Amersham-Pharmacia Biotech) in a final volume of 200 μl. The non-specific binding is determined in the presence of 20 μM of GTP? S. The reaction was initiated by the addition of GABA at a concentration of between 1 mM and 0.1 nM in the presence or absence of the required concentration of PAM. The reaction was terminated by the addition of an ice-cold wash buffer (50 mM Tris-HCl, 5 mM MgCl2, 50 mM NaCl, pH 7.4) followed by rapid filtration under vacuum through glass fiber filters. Filtermat A (Wallac) (0.05% treated with PEI) using a Micro 96 Harvester (Skatron Instruments). The filters were dried for 30 minutes at 50 ° C, then a flashing paraffin pad was melted on the filters and bound radioactivity was determined using a 1450 Microbeta Trilux scintillation counter (Wallac).

Calculations Response curves to doses of GABA in the presence and absence of test compounds were constructed using the 4-parameter logistic equation, y = ymax + ((ymin- ymax) / 1 + (x / C) D), where C = EC5o and D = slope factor. The potency of PAM in GTP? S assays was determined by plotting the logarithmic EC5o for GABA against the logarithmic concentration of the positive allosteric modulator in the presence of which the measurement was carried out. Generally, the potency of the compounds of the formula (I) ranges from EC50s between 20 μM and 0.001 μM.

Effect of the compounds in the IBS model (colorectal distention) Colorectal distention (CRD) For CRD, a 3 cm polyethylene balloon with a connector catheter (made at home) is inserted into the distal colon, 2 cm from the base of the balloon to the anus, during anesthesia with mild isoflurane (Forene® , Abbott Scandinavia AB, Sweden). The catheter is fixed to the base of the tail with tape. At the same time, an intravenous catheter (Neoflon®, Becton Dickinson AB, Sweden) is inserted into a vein of the tail for administration of the compounds. Subsequently, the rats are placed in Bollman cages and allowed to recover from sedation for at least 15 minutes before beginning the experiments. During the CDR procedure, the balloons are connected to pressure transducers (P-602, CFM-k33, 100 mmHg; Bronkhorst Hi-Tec, Veenendal, The Netherlands). An adapted barostat (AstraZeneca, Molndal, Sweden) is used to control air inflation and pressure inside the balloon. An adapted computer software (PharmLab on-line 4.0.1) running on a standard PC is used to control the barostat and to perform data collection and storage. The distension paradigm generated by the barostat is achieved by generating pulse patterns in an analogue output channel. The use of CRD paradigms consisted of repeated phasic distensions, 12 times at 80 mmHg, with a pulse duration of 30 s at 5 minute intervals. Responses to CRD are evaluated by recording and quantifying phasic changes in intra-balloon pressure during distension pulses. The pressure oscillations during the isobaric inflation of the intracolonic balloon reflect abdominal muscle contractions associated with the distension procedure and, therefore, are considered a valid evaluation of the response visceromotor (VMR) associated with the presence of pain of visceral origin.

Data collection and analysis The value pressure signals are sampled at 50 Hz and then subjected to digital filtering. A high-pass filter at 1 Hz is used to separate the pressure changes induced by contractions from the slow variable pressure generated by the barostat. A resistance in the air flow between the pressure generator and the pressure transducer further increases the pressure variations induced by abdominal contractions of the animal. In addition, a 49-51 Hz band stop filter is used to remove line frequency interference. An adapted computer software (PharmLab off-line 4.0.1) is used to quantify the phasic changes of the balloon pressure signals. The average rectified value (ARV) of the balloon pressure signals is calculated for the period of 30 s before the impulse (baseline activity) and during the duration of the impulse (as a measure of the VMR at distension). When the impulse analysis is carried out, the first and second of each impulse is excluded since they reflect artefact signals produced by the barostat during inflation and deflation of the balloon and do not originate from the animal.

RESULTS The effect of positive allosteric modulators is examined in the RVM to isobaric CRD in rats. A paradigm consisting of 12 distensions at 80 mmHg is used. The compounds are administered at a dose of 1 to 50 μmol / kg and the VMR responses to CRD are compared to the vehicle control. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

Having described the invention as above, the content of the following claims is claimed as property: 1. A compound, characterized in that it has the general formula (I) ( wherein R1 represents hydrogen, C? -C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl or C3-C3 cycloalkyl, each optionally substituted by one or more of C? -C10 alkoxy, C3-C10 cycloalkyl, Ci-Cio thioalkoxy, S03R7, halogen (s), hydroxy , mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups or R1 represents aryl or heteroaryl, each optionally substituted by one or more of C? -C10 alkyl; C2-C alkenyl? 0; C 2 -C 0 alkynyl, C 3 -Cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 0 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used in defining R1 may be further substituted by one or more of halogen (s), C? -C? alkyl, C? -C? oo alkoxy or C? -C? thioalkoxy, wherein the C1-C10 alkyl can be further substituted by one or two aryl or heteroaryl groups; R 2 represents hydrogen, C 1 -C 6 alkyl, C 1 -C 10 alkoxy or C 1 -C 10 thioalkoxy, optionally substituted by one or more of C 1 -C 0 alkoxy, C 3 -C 10 cycloalkyl, C 1 -thioalkoxy C10, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, or R2 represents aryl or heteroaryl, each optionally substituted by one or more of C? -C? 0; C2-C2 alkenyl; C2-C? alkynyl, C3-C: cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R3 represents C1-C10 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents C1-C10 alkyl, C2-C6 alkenyl;
C2-C alkynyl 0; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups or R3 represents aryl or heteroaryl, each optionally substituted by one or more of C2-C2 alkyl, C2-C2 alkenyl, C2-C alkynyl C3-C10 cycloalkyl C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents amino, optionally mono- or disubstituted with C1-C10 alkyl, C2-C2 alkenyl, C2-C3 alkynyl or C3-C10 cycloalkyl; And represents
R4 represents C? -C10 alkyl; C2-C alkenyl? 0; C2-C alkynyl 0; C1-C10 alkoxy; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, COR10, nitrile, S02NR8R9, S02R, NR8S02R9, NR8C = ONR9 or one or two aryl or heteroaryl groups or R4 represents aryl or heteroaryl, each optionally substituted by one or more of C 1 -C 10 alkyl, C 2 -C 0 alkenyl, CC 0 alkynyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, S02NR8R9, NR8S02R9, SO3R7, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used to define R4 may be further substituted by one or more of halogen (s), C? -C? alkyl, C? -C10 alkoxy, C1-C10 alkoxy or C1-C10 thioalkoxy wherein the C1-C10 alkyl can be further substituted by one or two aryl or heteroaryl groups; R5 represents hydrogen, C? -C? Alkyl; C2-C alkenyl? 0; C2-C alkynyl 0; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C? -C? thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9 , NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R 5 represents aryl or heteroaryl, each optionally substituted by one or more of C 1 -C 6 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, C 3 cycloalkyl
CIO, C? -C? 0 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R 6 represents hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl; or C3-C ?cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R6 represents aryl or heteroaryl, each substituted by one or more of C1-C10 alkyl, C2-C2 alkenyl, C2-C3 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, thioalkoxy of C? -C10 halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R5 and R6 together form a ring consisting of 3 to 7 atoms selected from C, N, and O, wherein the ring is optionally substituted with one or more of C?-C10 alquilo alkyl, C al-C al al alkenyl, C2-C? alkynyl, C3-C10 cycloalkyl, C? -C? alkoxy, C? -C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R7 represents each independently alkyl of C? -C10, R8 each independently represents hydrogen, C? -C10 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally further substituted by one or more of halogen (s), C? C10, C? -C? Alkoxy, or C? -C? O thioalkoxy; R9 each independently represents hydrogen, C? -C? Alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be further optionally substituted by one or more of halogen (s), C? -C? 0 alkyl, C alkoxy?
C? O, or thioalkoxy of C? -C? O; R10 each independently represents C? -C? Alkyl, or optionally substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be further optionally substituted by one or more of halogen (s),
C? -C? 0, C? -C? Alkoxy or C? -C? O thioalkoxy; R 11 represents C 1 -C 6 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally further substituted by one or more of halogen (s), C 1 -C 6 alkyl, C 1 alkoxy, C? -Co thioalkoxy or C? -C? wherein each of alkyl, alkenyl, alkynyl and cycloalkyl can independently have one or more carbon atoms substituted for 0, N or S; where none of the O, N or S is in a position adjacent to any other 0, N or S; wherein each of alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl can independently have one or more carbon atoms substituted by fluoro; as well as pharmaceutically and pharmacologically acceptable salts thereof, and enantiomers of the compound of the formula (I) and salts thereof; except: 3-benzamido-1, 5-diphenyl-, ethyl ester of pyrazole-4-carboxylic acid and 2-propenamide, N- (4-acetyl-5-methyl-1H-pyrazol-3-yl) -3 -phenyl. 2. The compound according to claim 1, characterized in that R1 represents C? -C alkyl, optionally substituted by one or two heteroaryl groups. 3. The compound according to claim 1, characterized in that R1 represents aryl, optionally substituted by one or more of Ci-Cio alkyl, C2-C? Alkenyl, C2-C? Alkynyl, C3- cycloalkyl C?, C? -C? Alkoxy, C? -C? Thioalkoxy, S03R7, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two groups aryl or heteroaryl. 4. The compound according to claim 3, characterized in that R1 represents unsubstituted phenyl. 5. The compound in accordance with any of claims 1-4, characterized in that R2 represents C? -C4 alkyl. 6. The compound according to claim 1, characterized in that R1 and R2 form a ring consisting of 5 or 6 atoms selected from C, 0 and N. 7. The compound according to any of claims 1-6, characterized in that R3 represents C? -C alkoxy, optionally substituted by one or more of C? -C? Thioalkoxy, or C3 cycloalkyl. -C10, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups.
8. The compound according to any of claims 1-6, characterized in that R3 represents C? -C? Alkyl, optionally substituted by one or more of C? -C? Alkoxy, or C? -C thioalkoxy. C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups.
9. The compound according to any of claims 1-8, characterized in that R4 represents C? -C alkyl, C-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, optionally substituted by one or more of C? -C? alkoxy, C3-C10 cycloalkyl, Ci-Cio thioalkoxy, halogen (S), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile, amide, sulfonamide, urea or one or two aryl or heteroaryl groups, wherein the aryl or heteroaryl group used to define R4 may be further substituted by one or more of halogen (s), C1 alkyl -C10, C1-C10 alkoxy or C1-C10 thioalkoxy, wherein the C1-C10 alkyl may be further substituted by one or two aryl or heteroaryl groups.
10. The compound according to claim 9, characterized in that R4 represents C?-C4 alkyl, optionally substituted by one or two aryl or heteroaryl groups.
11. The compound according to claim 10, characterized in that R4 represents C1-C4 alkyl, substituted by one or two aryl or heteroaryl groups.
12. The compound according to any of claims 1-8, characterized in that R4 represents aryl or heteroaryl, optionally substituted by one or more of C1-C10 alkyl, C2-C2 alkenyl, C2-C alkynyl? 0, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups.
13. The compound according to any of claims 1-12, characterized in that R5 represents C? _4 alkyl.
14. The compound according to claim 13, characterized in that R 5 represents methyl.
15. The compound according to any of claims 1-14, characterized in that R6 represents CX-4 alkyl.
16. The compound according to claim 15, characterized in that R6 represents methyl.
17. The compound according to any of claims 1-12, characterized in that R5 and R6 form a ring consisting of 5 or 6 atoms selected from C, O and N.
18. The compound according to any of claims 1 -12, characterized in that Y represents
19. The compound according to any of claims 1-12, characterized in that Y represents
20. The compound according to claim 1, characterized in that it is selected from 3- [(2,3-dihydro-l, 4-benzodioxin-2-ylcarbonyl) amino] -l-ethyl-lH-pyrazole-4-carboxylate of ethyl and ethyl l-ethyl-3- [(2-phenylbutanoyl) amino] -lff-pyrazole-4-carboxylate. 21. A pharmaceutical composition characterized in that it comprises the compound according to any of; claims 1-20 and a pharmaceutically acceptable carrier or diluent. 22. A compound, characterized in that it has the general formula (I) (wherein R 1 represents hydrogen, C 1 -C 0 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl or C 3 -C 7 cycloalkyl, each optionally substituted by one or more Ci alkoxy; -Cio, cycloalkyl of C3-C? 0, thioalkoxy of C? -C? 0, S03R7, he? Logen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl groups or heteroaryl or R1 represents aryl or heteroaryl, each optionally substituted by one or more of C? -C? alkyl, C2-C? alkenyl, C2-C10 alkynyl, C3-cycloalkyl, d-alkoxy, Cio, thioalkoxy of C? -C? 0, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used in defining R1 may be further substituted by one or more halogen (s), C 1 -C 10 alkyl, C 1 -C 10 alkoxy or C 1 -C 10 thioalkoxy, wherein the C 1 -C 10 alkyl may be further substituted by one or two aryl or heteroaryl groups; R 2 represents hydrogen, Ci-Cβ alkyl, C 1 -C 10 alkoxy or C 1 -C 10 thioalkoxy, optionally substituted by one or more of Ci-Cio alkoxy, C 3 -C 0 cycloalkyl, C] -C thioalkoxy; or, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups, or R2 represents aryl or heteroaryl, each optionally substituted by one or more of Ci-alkyl; Cio; C2-C alkenyl? 0; C 2 -C 0 alkynyl, C 3 -C 6 cycloalkyl, Ci-Cι alkoxy, Ci-Cι thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R3 represents C? -C? 0 alkoxy, optionally substituted by one or more of Ci-Cio thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R 3 represents C 1 -C 10 alkyl, C 2 -C 0 alkenyl;
C2-C? alkynyl; or C3-C10 cycloalkyl, each onally substituted by one or more of C1-C10 alkoxy, C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups or R3 represents aryl or heteroaryl, each onally substituted by one or more of C1-C10 alkyl, C2-C2 alkenyl, C2-C alkynyl? , C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents amino, onally mono- or disubstituted with C1-C10 alkyl, C2-C2 alkenyl, C2-C3 alkynyl or C3-C10 cycloalkyl; And represents
R 4 represents C 1 -C 10 alkyl; C2-C2 alkenyl; C2-C? alkynyl; C1-C10 alkoxy; or C3-C10 cycloalkyl, each onally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, COR10, nitrile, S02NR8R9, S02Rn, NR8S02R9, NR8C = ONR9 or one or two aryl or heteroaryl groups or R4 represents aryl or heteroaryl, each onally substituted by one or more of C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, C3-C: cycloalkyl, or C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, S02NR8R9, NR8S02R9, S03R7, nitrile or one or two aryl or heteroaryl groups, wherein any aryl or heteroaryl group used to define R4 may be further substituted by one or more of halogen (s), C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkoxy or C 1 -C 10 thioalkoxy wherein the C 1 -C 10 alkyl can be further substituted by one or two aryl or heteroaryl groups; R5 represents hydrogen, C1-C10 alkyl; C2-C2 alkenyl; C2-C alkynyl 0; or C3-C ?cycloalkyl, each onally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R 5 represents aryl or heteroaryl, each onally substituted by one or more of C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, or C 3 cycloalkyl.
CLO, C? -C? Alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R 6 represents hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl; or C3-C] cycloalkyl], each onally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R6 represents aryl or heteroaryl, each substituted by one or more of C1-C10 alkyl, C2-C2 alkenyl, C2-C20 alkynyl, C3-C10 cycloalkyl, 1-C10 alkoxy, thioalkoxy of C1-C10, halogen (s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; or R 5 and R 6 together form a ring consisting of 3 to 7 atoms selected from C, N and 0, wherein the ring is onally substituted with one or more of C 1 -C 10 alkyl, C 2 -C 0 alkenyl, alkynyl of C2-C? 0, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen (s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR8R9, NR8COR9, C02R10, nitrile or one or two aryl or heteroaryl groups; R7 represents each independently alkyl of Ci-C10, R8 each independently represents hydrogen, C1-C10 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be onally further substituted by one or more of halogen (s), C? -C alkyl? or, C 1 -C 0 alkoxy, or C 1 -C 0 thioalkoxy; R9 each independently represents hydrogen, Ci-Cio alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be onally further substituted by one or more of halogen (s), C? -C? ? ~
C? O, or thioalkoxy of C? -C? O; R10 each independently represents C? -C? Alkyl, or optionally substituted by aryl or heteroaryl, wherein the aryl or heteroaryl may be further optionally substituted by one or more of halogen (s),
C? -C? O, C? -C? Alkoxy or C? -C? O thioalkoxy; R11 represents C? -C? Alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl can be optionally further substituted by one or more of halogen (s), C? -C? Alkyl or C? -C alkoxy. ? oo thioalkoxy of C? -C? o; wherein each of alkyl, alkenyl, alkynyl and cycloalkyl can independently have one or more carbon atoms substituted for 0, N or S; where none of the O, N or S is in a position adjacent to any other O, N or S; wherein each of alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl can independently have one or more carbon atoms substituted by fluoro; as well as pharmaceutically and pharmacologically acceptable salts thereof, and enantiomers of the compound of the formula (I) and salts thereof, for use in therapy. 23. Use of the compound according to any one of claims 1-20 or claim 22, optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the treatment of gastroesophageal reflux disease (GERD). 24. Use of the compound according to any one of claims 1-20 or claim 22, optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the prevention of reflux. 25. Use of the compound according to any one of claims 1-20 or claim 22, optionally in combination with a GABAB receptor agonist, in the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESRs). 26. Use of the compound according to any of claims 1-20 or claim 22, optionally in combination with a receptor agonist.
GABAB, in the manufacture of a medicine for the treatment of a functional gastrointestinal disorder.
27. The use according to claim 26, wherein the functional gastrointestinal disorder is dysfunctional dyspepsia.
28. Use of the compound according to any of claims 1-20 or claim 22, optionally in combination with a GABAs receptor agonist, in the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS).
29. The use according to claim 28, wherein the IBS is IBS of predominant constipation.
30. The use according to claim 28, wherein the IBS is IBS of predominant diarrhea.
31. The use according to claim 28, wherein the IBS is IBS of predominant alternating bowel movements.
32. A method for the treatment of gastroesophageal reflux disease (GERD), characterized in that a pharmaceutical and pharmacologically effective amount of a compound of the formula (I) according to any one of claims 1-20 or claim 22, optionally in combination with a GABA receptor agonist, is administered to a subject who requires this treatment.
33. A method for the treatment of a functional gastrointestinal disorder, characterized in that a pharmaceutical and pharmacologically effective amount of a compound of the formula (I) according to any one of claims 1-20 or claim 22, optionally in combination with an agonist of the GABAB receptor, is administered to a subject that requires this treatment.
34. A method for the treatment of irritable bowel syndrome (IBS), characterized in that a pharmaceutically effective amount of a compound of the formula (I) according to any one of claims 1-20 or claim 22, optionally in combination with a GABAB receptor agonist is administered to a subject who requires this treatment.