JP2006516587A - Selective mGlu5 antagonists for the treatment of neuromuscular disorders of the lower urinary tract - Google Patents

Abstract

Compared to at least one of the metabotropic mGlu1 receptor, mGlu2 receptor and mGlu3 receptor, preferably compared to all three, the antagonist selective for metabotropic mGlu5 is a neuromuscular function of the lower urinary tract in mammals Useful in the preparation of a medicament for the treatment of failure. A variety of suitable compounds are disclosed. The medicament may contain a selective mGlu5 antagonist as the sole active ingredient or may contain one or more additional therapeutic agents for the treatment of lower urinary tract neuromuscular dysfunction in mammals. . Also provided are methods for identifying selective mGlu5 antagonists useful for treating neuromuscular dysfunction of the lower urinary tract in mammals.

Description

  The present invention relates to compounds having selective affinity for the mGlu5 subtype of metabotropic glutamate receptors, pharmaceutical compositions containing such compounds, and uses of such compounds and compositions.

Background of the Invention In mammals, urination is a complex process that requires the integrated action of the bladder, its internal and external sphincters, and the pelvic floor musculature. The neurological control of these muscles is under the control of the cerebral cortex at three levels—in the bladder wall or sphincter, in the autonomic ganglia of the spinal cord, and in the central nerve of the pontine micturition center of the medulla (bridge). Occurs in the system (De Groat, Neurology of Ircorance, Ciba Foundation Symposium 151: 27, 1990). Urination is due to contraction of the bladder detrusor muscle, which consists of interlacing smooth muscle fibers under the autonomic control of the parasympathetic nerve from the sacral spinal cord. A simple micturition reflex is formed by sensory nerves for pain, temperature and bloating running from the bladder to the sacral cord. However, the sensory tract from the bladder also reaches the pontine micturition center and generates nerve impulses that normally act to suppress the sacral spinal reflex arch that controls bladder emptying in the spinal cord. As a result, normal urination is initiated by spontaneous suppression of cortical inhibition of the reflex arch and relaxation of the pelvic floor and external sphincter muscles. These events are followed by detrusor contraction and urination.

  Functional abnormalities in the lower urinary tract (eg, dysuria, incontinence and enuresis) are common in the general population. Difficulty urinating includes urinary frequency, nocturnal polyuria, and urgency, and cystitis (including interstitial cystitis), prostatitis or benign prostatic hyperplasia (BPH) Affecting approximately 70% of older men), or by neurological disorders. Incontinence syndromes include stress urinary incontinence, urge urinary incontinence, overflow urinary incontinence, and mixed incontinences. Enuresis refers to involuntary outflow of urine at night or during sleep.

  Treatment of neuromuscular disorders of the lower urinary tract is typically also active against compounds that act directly on the bladder muscle (eg, flavoxate, PMC (Guarneri et al., Drugs of Today, 30:91, 1994) antispasmodics (Ruffman, J., Int. Med. Res. 16: 317, 1988)) or anticholinergic compounds (eg, oxybutynin (Andersson, Drugs 36: 477, 1988) and Tolerodine (Nilvebrant, Life Sci. 68: 2549, 2001)). The use of α1-adrenergic receptor antagonists for the treatment of BPH is also common (Lepor, Urology, 42: 4S3, 1993). Treatment of lower urinary tract disorders using α1-adrenergic receptor antagonists, including subtype selective antagonists, is described in US Pat. Nos. 5,990,114; 6,306,861; No. 591; No. 6,387,909; and No. 6,403,594. However, treatments involving direct suppression of the pelvic musculature, including the detrusor, have undesirable side effects (eg, dysuria, accommodation reflex paralysis, tachycardia and thirst) (Andersson, Drugs 35: 477, 1988). Thus, in a manner that preserves the normal function of the micturition mechanism via the peripheral or central nervous system, for example, using compounds that act on inhibitory impulses of the reflex arch of the sacral spinal cord and / or the pontine micturition. It is preferred to treat neuromuscular disorders of the urinary tract.

  Glutamate (an excitatory amino acid) exists in synapses throughout the central nervous system and is known to act on at least two types of receptors: ion channel and metabotropic glutamate receptors.

  Upon activation, ion channel glutamate receptors form ligand ion channels, thereby directly mediating neuronal electrical signaling, resulting in rapid and relatively large conductance changes in the postsynaptic membrane. Metabotropic glutamate receptors (mGluR) indirectly regulate electrical signaling by acting on intracellular metabolic processes mediated by G proteins. As a result, changes in post-synaptic cells mediated through mGluR are relatively slow over a period of time compared to the rate at which the effect is mediated through ion channel glutamate receptors, leading to rapid and large changes in neuronal membrane conductance. Not tied.

  Three subtypes of ion channel glutamate receptors (ie, NMDA, AMPA, and kainate subtypes) have been described.

  Eight subtypes of metabotropic glutamate receptors have been cloned. These subtypes are divided into three groups based on sequence similarity and pharmacological and biochemical properties: Group I mGluR (mGlu1 and mGlu5), Group II mGluR (mGlu2 and mGlu3) and Group III mGluR (mGlu4, mGlu6). , MGlu7 and mGlu8) (Spooren et al., Trends Pharmacol. Sci. 22: 331-337, 2001). Alternative splicing is a source of receptor diversity between group I and group III receptors.

  The structure of mGluR is reviewed in Hermans and Challis (Biochem. 359: 465-484, 2001). For Group I, the mGlu1 receptor in rats includes four isotypes, mGlu1a, mGlu1b, mGlu1c, mGlu1d (containing 1199, 906, 897 and 912 amino acids, respectively). These isotypes share a common N-terminal domain of 887 amino acids that binds to the C-terminal domain of 312 (mGlu1a), 19 (mGlu1b), 10 (mGlu1c) and 25 (mGlu1d) amino acids, respectively. Different C-terminal domains are created by alternative splicing. Similarly, there are three known human mGlu1 receptors, mGlu1a (1194 amino acids), mGlu1b (906 amino acids) and mGlu1d (908 amino acids). These human receptors contain a common 887 amino acid N-terminal domain that binds to the C-terminal domain of 307 (mGlu1a), 19 (mGlu1b) and 21 (mGlu1d) amino acids, respectively, made by alternative splicing.

  In terms of function, in all isoforms derived from either rat or human, the common N-terminal domain, in order from the N-terminus, is a typical G composed of an extracellular domain, seven transmembrane alpha helices. It includes a protein-coupled receptor transmembrane domain and the beginning of the intracellular domain. The variable C-terminal domain forms a second intracellular loop that completes the intracellular domain of each isotype. Ligand specific recognition and binding occurs in the extracellular domain. G protein binding is affected by intracellular domains and intracellular loops that bind to specific transmembrane α-helices. The ability to stimulate ligand affinity and the second messenger cascade is the same for the four subtypes.

  Known group I mGlu5 receptors in both humans and rats include the mGlu5a and mGlu5b subtypes. In both human and rat, mGlu5b contains a 32 amino acid insertion that is not present in subtype mGlu5a, 50 residues downstream from the end of the transmembrane domain in the C-terminal intracellular domain (ie, in the C-terminal direction). Type mGlu5b is different from subtype mGlu5a. The difference between this subtype is due to alternative mRNA splicing. Thus, rat mGlu5a is 1171 amino acids and mGlu5b is 1203 amino acids, and this difference is due to the inclusion of 23 amino acids at positions 876-907 of the mGlu5b receptor. Human mGlu5a is 1180 amino acids and mGlu5b is 1212 amino acids, and this difference is due to 32 amino acids at positions 877-908 of the mGlu5b receptor (Hermans et al., Biochem. J. 359: 465-484, 2001). ).

  For Group III receptors, alternative splicing involves two isoforms of the mGlu4 and mGlu7 receptors (ie, subtype “a” and “b”) and three isoforms of the mGlu8 receptor (ie, subtype “a”), respectively. , “B” and “c”) (Hermans et al., Biochem. J. 359: 465-484, 2001). In contrast, the mGlu6 receptor is currently known to have only one isotype (Hermans et al., Biochem. J. 359: 465-484, 2001). The rat and human mGlu4a receptors are both 912 amino acids long. Rats also produce a 983 amino acid long mGlu4b subtype due to alternative splicing replacing the last 64 amino acids of the mGlu4a subtype with a different set of 135 amino acids (Thomsen et al., Neuropharm., 36: 21-30). , 1997). Similarly, mGlu6, mGlu7a, mGlu7b, mGlu8a and mGlu8b have the same length in rats and humans: 877, 915, 922, 908 and 908 amino acids, respectively. In both mGlu7 and mGlu8 receptors, the “b” isoform produces a translational frame change relative to the “a” isoform, and the last 16 amino acids of mGlu7a and mGlu8a, respectively, with a different set of 23 or 16 amino acids, respectively. Due to alternative splicing leading to substitution (Corti et al., Eur. J. Neurosci, .10: 3629-3641, 1998). The mGlu8c subtype has been identified only in humans and is only 501 amino acids long. Out-of-frame insertion results in a stop codon before the first α-helix of the transmembrane domain; thus, the putative human mGlu8c protein represents the secreted isoform of the receptor (Malherbe et al., Brain Res. Mol. Brain Res., 67: 201-210, 1999).

Glutamate binding to Group I receptors results in G protein-mediated activation of phospholipase C and degradation of membrane phospholipids into chemical messenger inositol triphosphates and diacylglycerols. Inositol triphosphate releases Ca ²⁺ from the internal store. Consequently, group I mGluR activation typically mediates excitability or increases neuronal excitability.

  Glutamate binding at group II or III receptors induces G protein-mediated inhibition of adenylate cyclase. Inhibited adenylate cyclase activity results in decreased production of cyclic adenosine monophosphate. As a result, group II and group III mGluR activation typically mediates the suppression of synaptic transmission.

  The function of glutamate receptors in the micturition reflex pathway has been tested by administering drugs that block ion channel glutamate receptors. Intravenous administration of MK801, a noncompetitive blocker of the NMDA receptor, for example, reduced the strength of bladder contraction. MK801 also increased the micturition volume threshold in some experiments, but not in other experiments (deGroat, WC, et al., In: Nervous control of the neurological system, CA). Maggi (ed.), Harwood Academic Publishers, pp. 227-290, 1993).

  WO 00/63166 discloses tricyclic carbamic acid derivatives useful for the treatment of various diseases including urinary incontinence. These derivatives are disclosed to be agonists or antagonists of Group I mGlu receptors with specificity for the mGlu1 receptor.

  WO 01/32632 discloses pyrimidine derivatives useful for the treatment of various diseases including urinary incontinence. These derivatives have been disclosed as selective antagonists of the mGlu1 receptor that have at least 10-fold selectivity for the mGlu1 receptor over the mGlu5 receptor.

  WO 01/27070 discloses novel bisarylacetamides useful for the treatment of urinary incontinence, among other symptoms. These molecules are disclosed to be selective agonists or antagonists for the mGlu1 receptor.

  US Pat. No. 6,369,222 discloses heterocyclic azepinyl-pyrimidine derivatives useful for the treatment of urinary incontinence, among other conditions. These derivatives have been disclosed as antagonists of the mGlu1 receptor.

  Thus, these patent documents disclose mGlu1 receptor antagonists as useful for the treatment of urinary incontinence. However, none of these references provide experimental support for the treatment of urinary disease in either human patients or animal models of lower urinary tract disease.

  Patients with lower urinary tract symptoms often can respond to specific classes or subclasses of therapeutic agents. In addition, a patient may initially respond to a therapeutic agent but will not respond to that agent over time. Furthermore, if the therapeutic agent is administered at the concentration required to treat lower urinary tract symptoms, the patient may exhibit undesirable side effects. These side effects can be caused by changing the treatment to a different therapeutic agent, or by administering a low dose of two or more therapeutic agents to achieve a therapeutic effect (where one or more low doses are associated with each treatment). If the drug is used in monotherapy, it is insufficient to have a therapeutic effect).

  Accordingly, those skilled in the art understand the continuing need to identify new therapeutic agents in the treatment of lower urinary tract diseases. These novel therapeutics can be used to treat lower urinary tract diseases as monotherapy. Novel therapeutics treat patients who do not respond to one or more alternative therapeutics, patients who fail to respond to alternative therapeutics, or patients who benefit from combination medicine with two or more therapeutics Can be particularly useful.

  We tested the activity of selective mGlu1 and selective mGlu5 antagonists in a rat model useful for detecting activity against the lower urinary tract. Surprisingly, two commercially available antagonists selective for the mGlu1 receptor showed no effect, but good activity was found for antagonists selective for the mGlu5 receptor. Antagonists selective for Group II mGluR also showed no effect in the rat model. From these results, selective mGlu5 antagonists may be an effective means for treating lower urinary tract disorders.

The present invention
(A) binds to the mGlu5 receptor with an affinity of at least 10 ⁻⁶ M, and (b) an affinity that is at least 10 times stronger than the affinity that the compound binds to any one of the mGlu1 receptor, mGlu2 receptor or mGlu3 receptor. Of the compound that binds to the mGlu5 receptor,
Use is provided for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract.

  The compound preferably binds to the mGlu5 receptor with an affinity that is at least 10 times greater than the affinity that the compound binds to each of the mGlu1 receptor, mGlu2 receptor and mGlu3 receptor.

Furthermore, the compound is preferably
(C) binds to the mGlu5 receptor with an affinity that is at least 10 times stronger than the affinity that the compound binds to any one of the group III mGlu receptors.

  The selectivity of mGlu5 receptor over other mGlu receptors is more preferably at a 100-fold level.

  Neuromuscular dysfunction treated by drugs includes urinary urgency, overactive bladder, frequent urination, reduced urine compliance (decreased bladder storage capacity), cystitis (Including interstitial cystitis), incontinence, urine leakage, enuresis, difficulty urinating, urinary hesitancy, and difficulty in cavitation of the bladder.

  Preferably, the agent will be effective in reducing the frequency of bladder contractions due to bladder expansion that increases bladder capacity and the time interval between urination and subsequent urination.

  In a preferred embodiment, the selective mGlu5 antagonist has a structure represented by the following general formulas I-V:

  (1) Compounds of general formula I:

(here,
R ₁ is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkylamino, piperidino, carboxyl, esterified carboxyl, amidated carboxyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cyano, alkynyl, lower alkoxycarbonyl , Di- (lower) alkylamino, lower alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl, or N- (lower) alkyl-N-phenylcarbamoyl (wherein the N- (lower) alkyl and N-phenyl groups are substituted) Or independently substituted with a substituent selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl groups),
R ₂ is hydrogen, lower alkyl, carboxyl, esterified carboxyl, amidated carboxyl, lower hydroxyalkyl, hydroxyl, lower alkoxy or lower alkanoyloxy, lower alkoxycarbonyl, di- (lower) -alkylamino- ( Lower) alkanoyl, di- (lower) alkylaminomethyl, 4- (4-fluorobenzoyl) piperidin-1-yl-carbonyl, 4-tert-butyoxycarbonylpiperazin-1-yl-carbonyl, 4- (4-azido) 2-hydroxybenzoyl) piperazin-1-yl-carbonyl or 4- (4-azido-2-hydroxy-3-iodo-benzoyl) -piperazin-1-yl-carbonyl,
R ₃ is hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower hydroxyalkyl, di- (lower) alkylaminomethyl, morpholinocarbonyl or 4- (4-fluorobenzoyl) piperidin-1-yl-carbonyl Represents
R ₄ is hydrogen, lower alkyl, hydroxyl, lower hydroxyalkyl, lower aminoalkyl, (lower) alkylamino (lower) alkyl, di- (lower) -alkylamino (lower) alkyl, unsubstituted or hydroxy substituted. (Lower) alkyleneamino (lower) alkyl, lower alkoxy, lower alkanoyloxy, lower aminoalkoxy, (lower) alkylamino (lower) alkoxy, di- (lower) -alkylamino (lower) alkoxy, lower alkoxycarbonyl, carboxy (Lower) alkylcarbonyl, (lower) alkoxycarbonyl (lower) alkoxy, lower hydroxyalkyl, m-hydroxy-p-azidophenylcarbonylamino (lower) alkoxy, lower aminoalkoxy, phthalimide (lower) alkoxy, Unsubstituted (lower) alkyleneamino (lower) alkoxy, or (lower) alkyleneamino (lower) alkoxy, carboxyl, esterified carboxyl substituted with hydroxyl or 2-oxo-imidazolidin-1-yl group Represents amidated carboxyl, lower carboxyalkoxy or lower esterified carboxyalkoxy,
X ₁ is a lower alkenylene, lower haloalkenylene, lower alkynylene or lower haloalkynylene group (wherein each of the aforementioned groups is linked via a vicinal unsaturated carbon atom or an azo group (—N═N—)). ) And
R ₅ represents an aromatic or heteroaromatic group which may be unsubstituted or substituted with lower hydroxyalkyl, lower alkoxycarbonyl, lower alkanoyl, trifluoromethyl, trifluoromethoxy, trimethylsilylalkynyl, azide, lower aminoalkoxy , Di- (lower) -alkylamino (lower) alkoxy, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, lower alkanoylamino, benzylcarbonylamino, (lower) alkylaminocarbonyl Amino, (lower) alkoxycarbonylaminocarbonylamino, (lower) alkylsulfonyl, lower alkyl, halo, lower haloalkyl, lower haloalkoxy, lower alkenyl, lower alkyl Quinyl, unsubstituted phenyl, phenyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and trifluoromethyl groups, unsubstituted phenyl (lower ) Alkynyl, or phenyl (lower) alkynyl, hydroxyl, lower hydroxyalkyl, (lower) substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and trifluoromethyl groups Alkanoyloxy (lower) alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, lower amine alkoxy, (lower) alkylamino (lower) alkoxy, (lower) alkanoylamino (lower) alkoxy, N- ( Lower) -alkyl- N- (lower) -alkanoylamino (lower) alkoxy, unsubstituted phenoxy, or substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and trifluoromethyl groups Phenoxy, phenyl (lower) alkoxy or phenyl (lower) alkoxy (wherein the phenyl group is substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and trifluoromethyl groups) Acyl, carboxyl, esterified carboxyl, amidated carboxyl, cyano, carboxy (lower) alkylamino, esterified carboxy (lower) alkylamino, amidated carboxy (lower) alkyl Amino, phosphono (lower) alkylamino Esterified phosphono (lower) alkylamino, nitro, amino, lower alkylamino, di- (lower) -alkylamino, acylamino, N-acyl-N- (lower) -alkylamino, phenylamino, phenyl (lower ) Alkylamino, cycloalkyl (lower) alkylamino, or heteroaryl (lower) alkylamino, each of which is unsubstituted or substituted by lower alkyl-lower alkoxy-, halo- and / or trifluoromethyl Substituted with one or more substituents selected from:
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

  Compounds of formula I having basic groups can form acid addition salts, and compounds of formula I having acidic groups can form salts with bases.

  Compounds of the formula I having basic groups and further having at least one acidic group can also form internal salts.

  Partial and total salts, ie salts having 1, 2 or 3 (preferably 2) equivalents of base per mole of acid of formula I, or 1, 2 or 2 per mole of base of formula I Salts having 3 equivalents (preferably 1 equivalent) of acid are included in the present invention.

  Pharmaceutically acceptable salts can also be used for isolation or purification purposes. These are preferred because only pharmaceutically acceptable non-toxic salts are used for therapy.

When X ₁ is an alkenylene group, the trans configuration is preferred.

Preferred compounds of formula I are, independently or together:
X ₁ is a (C _2-4 ) alkenylene, (C _2-4 ) haloalkenylene, (C _2-4 ) alkynylene or (C _2-4 ) haloalkynylene group wherein each of the above groups is vicinal Connected via a saturated carbon atom)
R ₁ is hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) hydroxyalkyl, cyano, ethynyl, carboxy, (C _1-4 ) alkoxycarbonyl, di- (C _1-4 ) alkylamino, (C _1-6 ) alkylaminocarbonyl, or trifluoromethylphenylaminocarbonyl,
R ₂ is hydrogen, hydroxy, (C _1-4 ) alkyl, (C _1-4 ) hydroxyalkyl, (C _1-4 ) alkoxy, carboxy, (C _2-5 ) alkanoyloxy, (C _1-4 ) Alkoxycarbonyl, di ( _C1-4 ) alkylamino ( _C1-4 ) alkanoyl, di- ( _C1-4 ) alkylaminomethyl, 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy, 4 -Tert-butyloxycarbonyl-piperazin-1-yl-carbonyl, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carbonyl, or 4- (4-azido-2-hydroxy-3) -Iodobenzoyl) -piperazin-1-yl-carbonyl,
R ₃ is _{hydrogen, (C 1-4)} alkyl, _{carboxyl, (C 1-4) alkoxycarbonyl, (C 1-4) alkylcarbamoyl, (C 1-4)} hydroxyalkyl, di _{(C 1-4)} Alkylaminomethyl, morpholinocarbonyl or 4- (4-fluoro-benzoyl) piperidin-1-yl-carboxy;
R ₄ is hydrogen, hydroxyl, (C _1-4 ) alkoxy, carboxy, (C _2-5 ) alkanoyloxy, (C _1-4 ) alkoxycarbonyl, (C _1-4 ) aminoalkoxy, di (C _{1- 4)} alkylamino _{(C 1-4)} alkoxy, di _{(C 1-4)} alkylamino _{(C 1-4)} alkyl, carboxy _{(C 1-4) alkylcarbonyl, (C 1-4)} alkoxycarbonyl _{(C 1 -4} ) alkoxy, ( _C1-4 ) hydroxyalkyl, di ( _C1-4 ) alkylamino ( _C1-4 ) alkoxy or m-hydroxy-p-azidophenylcarbonylamino ( _C1-4 ) alkoxy. ,and,
R ₅ is a group of the following formula

(here,
Each of R _a and R _b is independently hydrogen, hydroxyl, halo, nitro, cyano, carboxy, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, hydroxy (C _1-4 ) alkyl, _{(C 1-4) alkoxycarbonyl, (C 2-7) alkanoyl, (C} 2 -C _{5) alkanoyloxy, (C 2-5)} alkanoyloxy _{(C 1-4)} alkyl, trifluoromethyl, trifluoromethoxy , Trimethylsilylethynyl, ( _C2-5 ) alkynyl, amino, azide, ( _C1-4 ) aminoalkoxy, ( _C2-5 ) alkanoylamino ( _C1-4 ) alkoxy, ( _C1-4 ) alkylamino ( C _1-4) alkoxy, di _{(C 1-4)} alkylamino _{(C 1-4) alkoxy, (C 1-4)} alkylamino, di _{(C 1 4)} alkylamino, mono-halo benzylamino, thienyl methylamino, thienylcarbonyl amino, trifluoromethyl phenylaminocarbonyl, _{tetrazolyl, (C 2-5)} alkanoylamino, benzylcarbonyl _{amino, (C 1-4)} alkylaminocarbonyl amino (C _1-4 ) represents an alkoxycarbonyl-aminocarbonylamino or (C _1-4 ) alkylsulfonyl group,
R _c is hydrogen, fluorine, chlorine, bromine, hydroxy, (C _1-4 ) alkyl, (C _2-5 ) alkanoyloxy, (C _1-4 ) alkoxy or cyano, and
R _d is hydrogen, halo or (C _1-4 ) alkyl)
It is what is.

More preferred compounds of formula I are
X ₁ is defined as above,
R ₁ is hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, cyano, ethynyl or di (C _1-4 ) alkylamino;
R ₂ is hydrogen, hydroxy, carboxy, (C _1-4 ) alkoxycarbonyl, di (C _1-4 ) alkylaminomethyl, 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy, 4-tert -Butyloxycarbonyl-piperazin-1-yl-carboxy, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -Piperazin-1-yl-carboxy;
R ₃ is as defined above,
R ₄ is hydrogen, hydroxy, carboxyl, (C _2-5 ) alkanoyloxy, (C _1-4 ) alkoxycarbonyl, amino (C _1-4 ) alkoxy, di (C _1-4 ) alkylamino (C _{1- 4)} alkoxy, di _{(C 1-4)} alkylamino _{(C 1-4)} alkyl or hydroxy _{(C 1-4)} alkyl, and R ₅ is a group of the formula

(here,
Each of R _a and R _b is independently hydrogen, halo, nitro, cyano, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, trifluoromethyl, trifluoromethoxy, or (C _{2 -5} ) alkynyl; and
R _c and R _d are as defined above)
It is what is.

  More preferred are 2-methyl-6- (phenylethynyl) -pyridine (MPEP) and 2-methyl-6- (2-phenylethenyl) -pyridine (SIB 1893).

  In certain embodiments, the present invention provides a compound having a structure represented by the following general formula IA:

(here,
R ′ is hydrogen or (C _1-4 ) alkyl, and
M represents a group of the following formula:

(Wherein R _aa , R _bb and R _cc are each independently hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, hydroxy, (C _1-4 ) hydroxyalkyl, cyano. Or halo,
R _dd is cyano or halo;
R _ee is hydroxyl, (C _1-4 ) alkyl or (C _1-4 ) alkoxy,
R _ff represents hydrogen or (C _1-4 ) alkyl;
R _gg and R _hh are hydrogen or together are the formulas ═O, ═CH—CN, ═N—OH, ═N—O— (C _1-4 ) alkyl, ═CH—PO _{3. [(C 1-4) alkyl] 2} or = _{CH-CO-R kk (where, R kk is (C 1-4)} alkoxy or _-NR ll _{R mm (wherein, R ll} and _{R mm} is Independently selected from hydrogen, (C _1-4 ) alkyl and phenyl);
Rii and Rjj are independently hydrogen, (C _1-4 ) alkyl or phenyl, and
V ₁ is (CH ₂ ) _n , CHR _nn (where n is 1, 2 or 3 and R _nn is hydroxyl, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) hydroxyalkyl, ( _C1-4 ) alkoxy ( _C1-4 ) alkyl, ( _C1-4 ) alkoxycarbonyl, carbamoyl, ( _C1-4 ) alkylcarbamoyl, phenyl, pyridyl, thienyl, or (R _oo , R _pp ) N-lower alkyl (where R _oo is hydrogen, (C _1-4 ) alkyl, (C _1-4 ) alkanoyl or benzoyl, and R _pp is hydrogen or ( C _1-4 ) alkyl)), or when R _gg and R _hh are each hydrogen, V ₁ is NR _qq, where R _qq is (C _1-4 ) Alkoxyca Boniru, benzyloxycarbonyl, benzoyl, _{thienyl, (C 1-4)} alkanoyl, carbamoyl, mono- - or di - _{(C 1-4)} - alkylcarbamoyl, or a _{phenylcarbamoyl,} any phenyl ring in _{R qq} is Optionally substituted with one or more halo, cyano, (C _1-4 ) alkyl, or (C _1-4 ) alkoxy groups).
Alternatively, the enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts thereof are provided.

  (2) A compound having a structure represented by the following general formula II (that is, II-A, II-B, or II-C):

(Where R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are independently of each other hydrogen, lower alkyl, lower alkoxy, — (CH ₂ ) _n -halo, — (CH ₂ ) _n —NR. _e R _f , — (CH ₂ ) _n —N (R _e ) —C (O) -lower alkyl, aryl or heteroaryl, which is unsubstituted or substituted with one or more lower alkyl groups Represents substituted);
B ₁ is the following

(here,
R ₁₁ represents hydrogen, lower alkyl, — (CH ₂ ) _n —C (O) OR _e , or halo;
R ₁₂ is hydrogen, lower alkyl, — (CH ₂ ) _n —C (O) OR _f , halo, nitro, or heteroaryl, which is unsubstituted or substituted with lower alkyl or cycloalkyl Represents);
R ₁₃ represents hydrogen, lower alkyl, — (CH ₂ ) _n —OH, — (CH ₂ ) _n —C (O) OR _g , or aryl;
R ₁₄ represents a lower alkyl group;
R ₁₅ represents hydrogen, lower alkyl, or halo;
R ₁₆ represents hydrogen or alkyl;
R ₁₇ represents — (CH ₂ ) _n —N (R _e ) C (O) -lower alkyl;
R ₁₈ represents hydrogen or a lower alkyl group;
R ₁₉ , R ₂₀ , R ₂₁ and R ₂₂ each independently represent hydrogen, lower alkyl, — (CH ₂ ) _n -halo, or lower alkoxy;
R ₂₃ , R ₂₄ and R ₂₅ each independently represent hydrogen, lower alkyl, — (CH ₂ ) _n -halo, or lower alkoxy;
R ₂₆ represents hydrogen or a lower alkyl group;
R ₂₇ represents hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from hydroxy and halo;
R ₂₈ represents hydrogen, lower alkyl, lower alkanoyl or nitro group;
R ₂₉ , R ₃₀ and R ₃₁ independently of one another represent hydrogen or lower alkyl;
R _e , R _f and R _g independently of one another represent hydrogen or lower alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
X ₂ is —CH ₂ —, —O— or —S—; and
Y ₁ represents —CH═ or —N═)
Represents)
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

Examples of compounds encompassed by Formula II-A include
1-methyl-2-phenylethynyl-1H-imidazole,
1-methyl-2- (4-methoxy-phenylethynyl) -1H-imidazole,
1-methyl-5-phenylethynyl-1H-imidazole, and 1-methyl-4-phenylethynyl-1H-imidazole, which may be included or excluded from Formula II.

  In certain embodiments, the present invention also provides compounds of the following general formulas II-B and II-C:

(Wherein R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ and R ₃₆ are independently of each other hydrogen, lower alkyl, — (CH ₂ ) _n -halogen, lower alkoxy, — (CH ₂ ) _n —NR. _{e R f, - (CH 2} ) n -N (R e) -C (O) - ( lower) alkyl, aryl or heteroaryl (which, unsubstituted or substituted, or one or more lower alkyl Represented by a residue);
R ₃₇ represents hydrogen, lower alkyl, — (CH ₂ ) _n —C (O) OR _e group or halogen;
R ₃₈ is hydrogen, lower alkyl, — (CH ₂ ) _n —C (O) OR _f , halogen, nitro or heteroaryl, which is unsubstituted or substituted with lower alkyl or cycloalkyl. Represents);
R ₃₉ represents hydrogen, lower alkyl, — (CH ₂ ) _n —OH, — (CH ₂ ) _n —C (O) OR _g or aryl,
R ₄₀ represents lower alkyl,
R ₄₁ represents hydrogen, halogen, or a lower alkyl group,
R ₄₂ represents hydrogen or alkyl,
R _e , R _f and R _g independently of one another represent hydrogen or lower alkyl; and
n = 0, 1, 2, 3, 4, 5 or 6),
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

Preferred compounds of formula II are those of formula II-A, where B ₁ represents B1. Examples of such compounds are not limited,
1-methyl-2-phenylethynyl-1H-imidazole,
2- (5-nitro-2-phenylethynyl-imidazol-1-yl) -ethanol,
2-phenylethynyl-lH-imidazole,
5- (3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl) -3-methyl [1,2,4] oxadiazole, and 3-cyclopropyl-5- (3,5- Dimethyl-2-phenylethynyl-3H-imidazol-4-yl) [1,2,4] oxadiazole.

Compounds of formula II-A in which B ₁ represents B2 (such as, but not limited to, 1-methyl-5-phenylethynyl-1H-imidazole) are also preferred compounds of formula II.

A compound of formula II-A where B ₁ represents B3 (such as, but not limited to, N- [2- (5-methoxy-2-phenylethynyl-1H-indol-3-yl) -ethyl] acetamide) Is also a preferred compound of formula II.

Compounds of formula II-A in which B ₁ represents B4 are also preferred compounds of formula II. Examples of such compounds are not limited,
3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta [a] naphthalene, and
3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta [a] naphthalene.
Compounds of formula II-A in which B ₁ represents B5 are also preferred compounds of formula II. Examples of such compounds are not limited,
1-chloro-3- (2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl) -propan-2-ol,
4-phenylethynyl-1H-imidazole,
1-methyl-4-phenylethynyl-1H-imidazole, and
1,2-dimethyl-5-nitro-4-phenylethynyl-1H-imidazole.

Compounds of formula II-A in which B ₁ represents B6 (such as, but not limited to, 1,3-dimethyl-5-phenylethynyl-1H-pyrazole) are also preferred compounds of formula II.

B ₁ represents B ₁ and R ₁₂ represents (CH ₂ ) _n —C (O) OR _f or heteroaryl (which is unsubstituted or substituted with lower alkyl or cycloalkyl) More preferred are compounds of formula II-A. Particularly preferred are those wherein R ₁₂ represents (CH ₂ ) _n —C (O) OR _f , where n is 0 and R _f is lower alkyl.

  (3) A compound having a structure represented by the following general formula III:

(here,
A ₁ represents a 5-, 6-, or 7-membered ring having the following structure:

(here,
At least one of W, X ₃ , Y ₂ and Z ₁ is a group (CR _h ) _p (where p is 1 or 2); and the remainder of W, X ₃ , Y ₂ and Z ₁ Are independently of each other O, N or S;
Each R _h is independently halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or substituted Not lower alkoxy, (lower) alkylcarbonyloxy, carboxyl, esterified carboxyl, amidated carboxyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cycloalkyl, mercapto, nitro , Carboxyl, carbamate, carboxamide, hydroxyl, ester, cyano, amine, amide, amidine, amide, sulfonyl, sulfonamide, or N- (lower) -alkyl-N-phenylcarbamoyl where each Nitrogen atoms are independently unsubstituted or independently substituted by lower alkyl, lower alkoxy, halo or trifluoromethyl) and q is 0, 1, 2, or 3),
L ₁ is a substituted or unsubstituted alkenyl, alkynyl or azo; and
B ₂ is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocyclic (optionally one or more double bonds Or substituted or unsubstituted aryl,
(Here, “substituted” means that one or more hydrogen atoms are hydroxyl, alkyl, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, Nitro, amino, N-substituted- or N, N-di-substituted amino, wherein one or both nitrogen atoms are independently alkyl, heterocycle, aryl (these are each required Or independently substituted with hydroxyl, alkyl or heterocyclic), or alkylamide, amidine, amide, carboxy, esterified carboxy, amidated Carboxy, carboxamide, carbamate, ester, sulfonyl, and sulfonamide groups, etc. Comprising means replaced group with substituents selected from the group)),
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

According to a particular embodiment of the invention, A ₁ contains a ring having at least one nitrogen atom located in the ring at a position adjacent to a carbon atom having a linking group as a substituent, 5-, 6- or 7 -Membered unsaturated heterocyclic group. The ring further contains 3, 4 or 5 independently variable atoms selected from carbon, nitrogen, sulfur and oxygen. A ₁ is pyridinyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, oxadiazinyl, isothiazolyl, thiazolyl, dioxazolyl, oxathiazolyl, oxathiazyl, It may be azepinyl, diazepinyl and the like. One skilled in the art will understand that there are multiple isomers for a chemical formula; each of the possible isomeric forms of the various empirical formulas described herein is contemplated by the present invention. . When the ring atom capable of changing is carbon, it has hydrogen or optionally halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, thiol, Substituted with nitro, carboxyl, ester, cyano, amine, amide, carboxamide, amidine, amide, sulfonamide, etc., but preferred embodiments have no substituents (ie q is 0), or And having the following substituents: halogen, (C _1-4 ) alkyl, (C _1-4 ) fluoroalkyl, aryl, and amine. Substitution at the Z ₁ position of the ring is also preferred.

According to a particular embodiment of the invention, A ₁ is a 5-, 6- or 7-membered ring containing nitrogen and sulfur atoms as ring members. Groups contemplated for use according to this embodiment of the present invention include A ₁ is isothiazol-3-yl (1,2-thiazol-3-yl), thiazol-4-yl (1,3,- Thiazol-4-yl), thiazol-2-yl (1,3-thiazol-2-yl), 1,2-thiazin-3-yl, 1,3-thiazin-4-yl, 1,4-thiazin- Examples include 3-yl, 1,3-thiazin-2-yl, thiazepinyl and the like. Preferred groups include A ₁ is isothiazol-3-yl (1,2-thiazol-3-yl), thiazol-4-yl (1,3-thiazol-4-yl), and thiazol-2-yl And (1,3-thiazol-2-yl).

According to another embodiment of the invention, A ₁ is a 5-, 6- or 7-membered ring containing nitrogen and oxygen atoms as ring members. Groups contemplated by this embodiment of the present invention include A ₁ as 1,2-oxazin-3-yl, 1,3-oxazin-4-yl, 1,4-oxazin-3-yl, 1,3 -Oxazin-2-yl, oxazol-2-yl, isoxazol-3-yl, oxazol-4-yl, oxazepinyl and the like. Preferred groups include those where A ₁ is oxazol-2-yl, isoxazol-3-yl, and oxazol-4-yl.

In still other embodiments of the invention, A ₁ is a 5-, 6- or 7-membered ring containing a nitrogen atom as a ring member. Groups contemplated by these embodiments include those where A ₁ is 2-pyridinyl and 2-pyrrolyl.

In still further embodiments of the invention, A ₁ is a 5-, 6- or 7-membered ring containing two nitrogen atoms as ring members. Groups contemplated by these embodiments include those where A ₁ is 3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl (1,3-diazin-4-yl), pyrazine-3 -Yl (1,4-diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl), pyrazol-3-yl (1,2-diazol-3-yl), imidazole- 4-yl (1,3-isodiazol-4-yl), imidazol-2-yl (1,3-isodiazol-2-yl), diazepinyl, 1,3-isodiazol-4-yl, 1,3-isodiazole- The thing which is 2-yl etc. is mentioned. Preferred groups are those in which A ₁ is 3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl (1,3-diazin-4-yl), pyrazin-3-yl (1,4- And those which are diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl), 1,3-isodiazol-4-yl and 1,3-isodiazol-2-yl.

According to yet another embodiment of the invention, A ₁ is a 5-, 6- or 7-membered ring containing 3 nitrogen atoms as ring members. Groups contemplated by these embodiments include A ₁ being 1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl, 1,2,4-triazin-3-yl 1,2,4-triazin-5-yl, 1,3,5-triazin-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, triazepinyl And the like. As preferred groups, A ₁ is 1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4- Examples thereof include triazin-5-yl, 1,3,5-triazin-2-yl, 1,2,3-triazol-4-yl, and 1,2,4-triazol-3-yl.

According to still other embodiments of the present invention, A ₁ is a 5-, 6- or 7-membered ring containing 4 nitrogen atoms as ring members. Groups contemplated in these embodiments include those where A ₁ is tetrazin-2-yl, tetrazin-3-yl, tetrazin-5-yl, tetrazolyl, tetrazepinyl, and the like. Preferred groups include those where A ₁ is tetrazolyl.

According to yet another embodiment of the present invention, A ₁ is a 5-, 6- or 7-membered ring containing as a ring member one sulfur atom and two nitrogen atoms. Groups contemplated by these embodiments include: A ₁ is 1,2,6-thiadiazin-3-yl, 1,2,5-thiadiazin-3-yl, 1,2,4-thiadiazin-3-yl 1,2,5-thiadiazin-4-yl, 1,2,3-thiadiazin-4-yl, 1,3,4-thiadiazin-5-yl, 1,3,4-thiadiazin-2-yl, 1 2,4-thiadiazin-5-yl, 1,3,5-thiadiazin-4-yl, 1,3,5-thiadiazin-2-yl, 1,2,4-thiadiazol-3-yl, 1,2 , 3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, thiadiazepinyl, etc. Is mentioned. As preferred groups, A ₁ is 1,2,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2,5- Those that are thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl.

According to yet another embodiment of the present invention, A ₁ is a 5-, 6- or 7-membered ring containing as a ring member one oxygen atom and two nitrogen atoms. Groups contemplated by these embodiments include 1,2,6-oxadiazin-3-yl, 1,2,5-oxadiazin-3-yl, 1,2,4-oxadiazin-3-yl, 1, 2,5-oxadiazin-4-yl, 1,2,3-oxadiazin-4-yl, 1,3,4-oxadiazin-5-yl, 1,3,4-oxadiazin-2-yl, 1,2, 4-oxadiazin-5-yl, 1,3,5-oxadiazin-4-yl, 1,3,5-oxadiazin-2-yl, 1,2,4-oxadiazol-3-yl, 1,2, 3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-5 And oxadiazepinyl, etc. . As preferred groups, A ₁ is 1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, Examples include 1,2,5-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl.

In yet another embodiment of the invention, A ₁ as ring member is 1 to 6 nitrogen atoms, and / or 1 to 6 carbon atoms, and / or 0 to 5 sulfur atoms, and / or 0 to 0. 5-, 6- or 7-membered rings containing 5 oxygen atoms.

Further, in certain embodiments, L ₁ is a linking group that connects groups A ₁ and B ₁ . L ₁ is selected from a substituted or unsubstituted alkenylene group, alkynylene group or azo group. Preferred compounds are those in which L ₁ is an alkenylene or alkynylene group containing 2 carbon atoms, most preferably alkynylene.

Further, in certain embodiments of the invention, B ₂ is a group that is bonded to group A ₁ via a bridging group L ₁ . Groups contemplated for use in the present invention are those wherein B ₂ is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, optionally one or more double bonds Substituted or unsubstituted heterocycles, substituted or unsubstituted aryl, and the like.

Preferred compounds are those in which B ₂ is a substituted or unsubstituted alkyl group, alkenyl group, dialkenyl group, trialkenyl group, alkynyl group, alkadiynyl group, alkatriynyl group, alkenylnyl group, alkadienyl group. ) Group, alkenediinyl group and the like, which is a substituted or unsubstituted hydrocarbyl.

B ₂ is a substituted or unsubstituted cycloalkyl group, cycloalkenyl group, cycloalkadienyl group, cycloalkatrienyl group, cycloalkynyl group, cycloalkadiynyl group, bicyclic hydrocarbon group (wherein More preferred are compounds that are substituted or unsubstituted cyclohydrocarbyl selected from such that the two rings have two common atoms). Particularly preferred compounds are those wherein B ₂ is cycloalkyl and cycloalkenyl having carbon atoms in the range of 4 to about 8. Exemplary compounds include cyclopropanyl, cyclopentenyl, and cyclohexenyl. Also particularly preferred are bicyclic hydrocarbon groups where the two rings have two atoms in common; exemplary compounds include indenyl, dihydroindenyl, naphthalenyl, and dihydronaphthalenyl.

Even more preferred are compounds wherein B ₂ is a substituted or unsubstituted heterocycle optionally containing one or more double bonds. Exemplary compounds include pyridyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, piperidinyl, isoxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Compound B ₂ is or substituted aryl-substituted are also preferred. Particularly preferred compounds are aryl and heterocycles in which the substituents optionally have further substituents (methyl, trifluoromethyl, cyclopropyl, alkoxy, halogen and cyano as described herein), A compound. Also preferred are compounds wherein B ₂ is a bicyclic heterocyclic group, where the two rings have two common atoms. Exemplary compounds include indolyl and isoquinolinyl.

The most preferred compounds of formula III are
3- (2-methylthiazol-4-yl) ethynylpyridine (MTEP);
2-methyl-4-[(E) -2-phenylethenyl] -1,3-thiazole;
4- (2-pyrimidinylethynyl) isoquinoline;
2- (3,4-dihydro-2-naphthalenylethynyl) pyridine;
4,6-dimethyl-2- (phenylethynyl) pyrimidine; and
2- (1-Cyclopenten-1-ylethynyl) -6-methylpyridine.

  (4) a compound having a structure represented by the following general formula IV,

(here,
n is 0, 1 or 2;
X ₄ is O, S, NH, or NOH,
R ₄₃ and R ₄₄ independently of one another represent hydrogen, CN, COOR _i , CONHR _i , (C _1-6 ) alkyl or tetrazole, or R ₄₃ and R ₄₄ together represent an oxo group Represents
R _i is hydrogen or (C _1-6 ) alkyl;
R ₄₅ is (C _1-6 ) alkyl, (C _2-6 ) alkenyl, (C _3-8 ) cycloalkyl, —CH ₂ OH, —CH ₂ O-alkyl, or —COOH;
Ar ₁ is an unsubstituted aromatic or heteroaromatic group, or (C _1-6 ) alkylamino, di- (C _1-6 ) -alkylamino, (C _1-6 ) alkoxy, carboxy, hydroxyl , Cyano, halo, trifluoromethyl, nitro, amino, (C _1-6 ) acylamino, (C _1-6 ) alkylthio, (C _1-6 ) hydroxyalkyl, (C _1-6 ) alkylsulfonyl, and ( C _1-6 ) an aromatic or heteroaromatic group substituted with one or more substituents selected from the group consisting of haloalkyl;
Z ₂ represents a group of the following formula

(here,
R ₄₆ and R ₄₇ each independently represent hydrogen, halogen, (C _1-6 ) alkoxy, —OAr ₁ , (C _1-6 ) alkyl, —CF ₃ , COOR _i , CONHR _i , —CN, — OH, COR _i , —S— (C _1-6 ) -alkyl, —SO ₂ — (C _1-6 ) -alkyl;
A ₂ is CH ₂ , O, NH, NR _i , S, SO, SO ₂ , CH ₂ —CH ₂ , CH ₂ O, CHOH or C (O) (where R _i is as defined above). Is)
B ₃ is CHR _i , C (R _i ) ₂ , (C _1-6 ) alkyl, C (O), —CHOH, —CH ₂ —O, —CH═CH, CH ₂ —C (O), CH _{2 -S, CH 2 -S (O} ), CH 2 -SO 2, -CHCO 2 R i, or is _{-CH-N (R i) 2} ( where _{R i,} are as defined above ); And
Het is a heterocycle such as furan, thiophene or pyridine)),
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

Preferred molecules are
3-[(3-bromobenzoyl) amino] -1- (1-indanyl) -3-methylpyrrolidin-2-one,
3-[(3-chlorobenzoyl) amino] -1- (3-chlorophenethyl) -3-methylpyrrolidine-2-thione,
3-[(3-Chlorobenzoyl) amino] -1- (1-indanyl) -3-methylpyrrolidin-2-thione, and 3-[(6-chloropyridin-2-yl) carboxamide] -1- (1 -Indanyl) -3-methylpyrrolidine-2-thione)
It is.
(5) a compound having a structure represented by the general formula V,

(here,
Ar ₂ is a heteroaryl group,
Ar ₃ is an aryl group (wherein
Ar ₂ and Ar ₃ may be represented by —F, —Cl, —Br, —I, —OR _j , —SR _j , —SOR _j , —SO ₂ R _j , —SO ₂ NR _j R _k , as necessary. _{-OCOR j, -OCONR j R k,} -NRCOR k, -NRCO 2 R k, -CN, -NO 2, -CO 2 R j, CONR j R k, -C (O) R j, -CH (OR _{j) R k, -CH 2 (} oR j), - R j and _{-A- (CH} 2) n _-NR j consists _{R k} is selected from the group substituted with one or more substituents (wherein Wherein R _j and R _k are independently selected from the group consisting of H, CF ₃ , (C _1-10 ) alkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, heterocycloalkyl, aryl. or, alternatively, _{R j} and _{R k} are joined to May form a C _1-5 methylene chain, _{and, A} is, CH 2, O, NH, S, SO, defined as SO _2, and, n is 1, 2, 3 or 4) ),
G ₁ is, -NH -, - S, -O -, - CO -, - CONH -, - CONHCH 2 -, CH 2 CONH -, - CH 2 NHNH -, - CH 2 NHNHCH 2 -, - C = NO _{-CH 2 -, - CH 2 NHCH} 2 -, CH 2 CH 2 NH-, NHCH 2 CO -, - NHCH 2 CHOH -, - NHCH 2 NHNH -, - or is selected from the group consisting of -NHCONH-, or G ₁ is cyclopentane, cyclopentadiene, furan, thiofuran, pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4-imidazoline, imidazole, pyrazoline, pyrazolidine, imidazolidine, oxazole, 2-oxazole, thiazole, isoxazole, Isothiazole, 1H-1,2,4-triazole, 1H-1,2,3-to Riazole, 1,2,4-oxathiazole, 1,3,4-oxathiazole, 1,4,2-dioxazole, 1,4,2-oxathiazole, 1,2,4-oxadiazole, 1, 2,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1H-tetrazole, cyclohexane, piperidine, Tetrahydropyridine, 1,4-dihydropyridine, pyridine, benzene, tetrahydropyran, 3,4-dihydro-2H-pyran, 2H-pyran, 4H-pyran, tetrahydrothiopyran, 3,4-dihydro-2H-thiopyran, 2H- Thiin, 4H-thiopyran, morpholine, thiomorpholine, piperazine, pyridazine, pyrimidine , Pyrazine, 1,2,4-triazine, 1,2,3-triazine, 1,3,5-triazine, or a cyclic group selected from the group consisting of 1,2,4,5-tetrazine groups )
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

Preferred groups Ar ₃ independently represent are phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl and benzonaphthenyl groups.

Preferred groups independently represented by Ar ₂ are thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzoimidazolyl, 3H-indolyl, indolyl, indazolyl, purinyl Quinolidinyl, isoquinolyl, quinolyl, phthalidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl, benzoyl, indolizinyl, indolizinyl, indolizinyl, indolizinyl. .

Both Ar ₃ is selected from the group consisting of phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl and benzonaphthenyl groups, and Ar ₂ is thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl , Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, indolinyl, indolidinyl, indolinyl More preferably, it is selected from the group consisting of isobenzofuranyl or chromenyl groups. Arbitrariness.

  In another embodiment, the compound of the present invention may be represented by the following formula VB:

(here,
X ₅ , Y ₃ , and Z ₃ are independently selected from the group consisting of N, O, S, C, and CO (wherein at least one of X ₅ , Y ₃ , and Z ₃ is A heteroatom);
Ar ₄ and Ar ₅ are independently 1-4 heteroatoms selected from the group consisting of N, O and S and phenyl, benzyl, 1-naphthyl, 2-naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl and Selected from the group consisting of condensed heterocyclic groups or heterocyclic groups containing an aromatic group selected from the group consisting of benzonaphthenyl (wherein Ar ₄ and Ar ₅ are optionally _{-F, -Cl, -Br, -I,} OR j, -SR j, -SOR j, -SO 2 R j, -SO 2 NR j R k, -OCOR j, -OCONR j R k, -NRCOR k _{, -NRCO 2 R k, -CN,} -NO 2, -CO 2 R j, -CONR j R k, -C (O) R j, -CH (OR j) R k, -CH 2 (OR _j ) —R _j and —A— (CH ₂ ) _n —NR _j R _k (where R _j and R _k are independently H, CF ₃ , (C _1-10 ) alkyl, cyclo alkyl, alkyl - aryl, alkyl - heteroaryl, heterocycloalkyl, or is selected from the group consisting of aryl, or R _j and R _k bonded to C ₁ - ₅ methylene chain may be formed, a Is defined as CH ₂ , O, NH, S, SO, SO ₂ , and n is 1, 2, 3, or 4) and is substituted with one or more substituents selected from the group consisting of )),
Alternatively, its enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable salts.

  The heterocyclic or fused heterocyclic group preferably consists of quinolyl, quinazolyl, quinoxalyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and pyrazyl A member selected from the group.

  In a preferred embodiment of the invention, the compound comprises 3- (2-pyridyl) -5- (3,5-dichlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5 (3-methoxyphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- [3 (trifluoromethyl) phenyl] -1,2,4-oxadiazole, 3- ( 2-pyridyl) -5- (3-methylphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxa Diazole, 3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, and 3- (2-quinolinyl) -5- (3-cyanophenyl ) -1,2,4-oxadiazole Is a member selected Ri.

  In another embodiment of this invention, the compound is 2- (3,5-dichlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2- (3-chlorophenyl) -4- (2- Pyridyl) -1,3-oxazole, 2- (3-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2- (3-cyanophenyl) -4- (5-methoxypyrido-2- Yl) -1,3-oxazole, 2- (3-cyanophenyl) -4- (2-quinolyl) -1,3-oxazole, 2- [3-chlorophenyl] -4- [pyridin-2-yl]- 1,3-oxazole, 2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, and 2- (3-nitrophenyl) -4- (2- Pyridyl) -1,3-oxazole Ranaru is a member selected from the group.

  The present invention also relates to general formulas I, IA, II-A, II-B, II-C, III, IV, VA, and VB (hereinafter “ Also included are enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, and pharmaceutically acceptable salts of the compounds of formula IV).

  The present invention also encompasses metabolites of compounds of formulas IV that are selective mGlu5 antagonists (hereinafter referred to as active metabolites).

  The present invention also contemplates prodrugs that are metabolized in the body to produce compounds of formula IV that are selective mGlu5 antagonists.

  One skilled in the art will appreciate that the compounds may contain one or more chiral centers and therefore exist as a racemic mixture. For many applications, it is preferable to perform a stereoselective synthesis and / or subject the reaction product to an appropriate purification step to produce a substantially optically pure material. . Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, such as procedures for purifying racemic mixtures into optically pure fractions. One skilled in the art will further appreciate that when a compound of the present invention is a compound that can be crystallized in different forms, the compound may exist in polymorphic forms. Suitable methods for identifying and isolating polymorphs are known in the art.

In yet another embodiment, the present invention provides a method for identifying compounds useful for the treatment of neuromuscular dysfunction of the lower urinary tract, including:
(A) individually measuring the binding affinity of a test compound for mGlu5 receptor, mGlu1 receptor and group II mGlu receptor;
(B) (1) binds to the mGlu5 receptor with an affinity of at least 10 ⁻⁶ M; and
(2) To identify test compounds that bind to the mGlu5 receptor with an affinity that is at least 10 times stronger than the affinity for the mGlu1 receptor and the group II mGlu receptor.

In certain embodiments, methods for identifying compounds useful for treating neuromuscular dysfunction of the lower urinary tract further include:
(C) individually measuring the ability of each of the compounds identified in steps (a) and (b) above to act as antagonists or inverse agonists at the mGlu5 receptor.

In yet another embodiment, the present invention provides a method for identifying a compound useful for treating neuromuscular dysfunction of the lower urinary tract, the method comprising:
(A) individually measuring the binding affinity of a test compound for mGlu5 receptor, mGlu1 receptor, group II and group III mGlu receptor;
(B) (1) binds to the mGlu5 receptor with an affinity of at least 10 ⁻⁶ M; and
(2) identifying a test compound that binds to the mGlu5 receptor with an affinity that is at least 10-fold greater than the affinity for the mGlu1 receptor, group II and group III mGlu receptors; and
(C) individually measuring the ability of each of the compounds identified in step (b) above to act as antagonists or inverse agonists at the mGlu5 receptor.

Preferably, the activity of the compound identified in steps (a), (b), and (c) of the foregoing method is evaluated, and the activity of the compound in the treatment of lower urinary tract disease in a human or animal model system. Confirm by. More preferably, compounds that exhibit activity in at least one of the following biological parameters are identified:
(1) suppression of volume-induced rhythmic bladder voiding contractions in anesthetized rats;
(2) Increase in bladder volume capacity in conscious rats.

  In certain embodiments, the present invention also relates to compounds identified by the aforementioned method.

  In certain embodiments, the aforementioned disorders are treated with selective mGlu5 antagonists by administering the antagonist in combination with a known antimuscarinic agent. Similarly, selective mGlu5 antagonists can be administered in combination with α1-adrenergic antagonists, whether or not they have BPH, for the treatment of lower urinary tract symptoms.

In a similar manner, a selective mGlu5 antagonist can be administered in combination with one or more antagonists of the 5-HT _1A receptor.

  In a similar manner, the selective mGlu5 antagonist is one or more of the enzyme cyclooxygenase (COX) and its derivatives (eg, NO-releasing COX ester or amide inhibitors) that may be selective or non-selective for the COX2 isozyme. It can be administered in combination with an inhibitor.

  The present invention relates to methods of using antagonists and / or inverse agonists of the mGlu5 receptor to treat neuromuscular dysfunction of the lower urinary tract. The mGlu5 receptor is preferably human mGlu5.

The present invention is based on the following findings of the present inventors:
i) Compounds that act as selective antagonists and / or inverse agonists of metabotropic glutamate receptors, mGlu5 receptors, block dose-dependent long-lasting bladder contractions when the bladder is filled to a threshold volume When this effect is over, the micturition reflex can be suppressed without affecting the intensity of bladder contraction;
ii) Compounds that act functionally as selective antagonists and / or inverse agonists of metabotropic glutamate receptors, mGlu5 receptors, are measured at a dose that does not impair bladder contractility, and bladder capacity capacity as measured by cystometry records And iii) compounds that act functionally as selective antagonists and / or inverse agonists of metabotropic glutamate receptors, mGlu5 receptors, can be measured in one urination and subsequent urination as measured in the cystometry record. The time interval between can be increased.

  Compounds of general formula I can be synthesized as described in publication WO 99/02497.

  The synthesis of compounds represented by formula IA is described in publication WO 02/062323.

  Compounds of general formulas II-A, II-B, and II-C may be synthesized as described in publication WO02 / 46166.

  Compounds of general formula III can be synthesized as described in publication WO 01/16121.

  Compounds of general formula IV can be synthesized as described in WO 00/69816.

  Compounds of general formula VA and VB can be synthesized as described in WO01 / 12627.

  The disclosures of US Patent Publications 2002/0128263 A1, 2002/0188128 A1, and 2003/0022907 A1 are hereby incorporated by reference. In certain embodiments, the compounds disclosed in the aforementioned US patent publications may be excluded from the claims.

  Pharmacological blocking of the mGlu5 receptor leads to a positive effect in the management of neuromuscular dysfunction in the lower urinary tract.

  The antagonists and / or inverse agonists of the present invention are compounds of formulas IV disclosed above, enantiomers, diastereomers, N-oxides, crystalline forms, hydrates, solvates or pharmaceutically acceptable of these compounds And active metabolites of these compounds having the same type of activity. Preferably, the compound of formula IV is a selective mGlu5 antagonist.

  An mGlu5 receptor antagonist is typically a substance that reduces or eliminates the effect of a ligand (agonist) that activates the mGlu5 receptor. The antagonist can be, for example, a chemical antagonist, a pharmacokinetic antagonist, a receptor block antagonist, a non-competitive antagonist or a physiological antagonist.

  A chemical antagonist is a substance that binds to the ligand in solution such that the antagonist is ineffective. A pharmacokinetic antagonist is one that effectively reduces its concentration at the site of action of the active agent, for example, by increasing the metabolic degradation rate of the active ligand. Antagonism by receptor block involves two important mechanisms: reversible competitive antagonism and irreversible or non-equilibrium competitive antagonism. Reversible competitive antagonism occurs when the dissociation rate of the antagonist molecule is high enough to effectively dissociate the chemical antagonist molecule from the receptor upon addition of the ligand. Of course, the ligand cannot evict the bound antagonist molecule, and vice versa. Irreversible or non-equilibrium competitive antagonism is when the antagonist dissociates very slowly from the receptor or does not dissociate at all, resulting in no change in antagonist occupancy when the ligand is applied To occur. Therefore, antagonism cannot be overcome. Non-competitive antagonism describes a situation where an antagonist blocks several points in the signal transduction pathway that results in the generation of a response by a ligand.

  Physiological antagonism is a term used to describe roughly the interaction of two substances that tend to counteract each other in the body. An antagonist can also be a substance that reduces or eliminates the expression of a functional mGlu5 receptor. Thus, an antagonist, for example, reduces or eliminates expression of a gene encoding mGlu5 receptor, reduces or eliminates translation of mGlu5 receptor RNA, reduces or eliminates post-translational modification of mGlu5 receptor protein, or insertion of mGlu receptor into the cell membrane. May be a substance that reduces or eliminates

  An inverse agonist of the mGlu5 receptor is a substance that preferentially binds to an inactive receptor (as compared to an agonist that preferentially binds to an active receptor) and thus eliminates stimulation of the receptor by the agonist.

  In general, the in vivo activity of inverse agonists is similar to that of antagonists, and for clarity, inverse agonists are defined herein as antagonists.

  Antagonists for use in the present invention can be relatively non-specific antagonists that are general mGlu5 receptor antagonists. Preferably, however, the antagonist selectively antagonizes Group I mGlu receptors. More preferably, the antagonist used in the present invention is a selective mGlu5 receptor antagonist. A selective mGlu5 receptor antagonist is one that antagonizes the mGlu5 receptor but weakly antagonizes other mGlu receptors or substantially does not antagonize at all. Most preferred antagonists are those that selectively antagonize the mGlu5 receptor at low concentrations, such as those that cause a level of antagonism of 50% or higher at a concentration of 1000 nM or less. Thus, a selective mGlu5 antagonist is at least 10 fold, at least 20 fold, at least 50 fold, at least about 100 fold, at least about 250 fold, at least about 500 fold, at least about 1000 fold over mGlu5 receptor over mGlu1 receptor. Can show high activity.

  Accordingly, selective mGlu5 antagonists have the following properties.

(1) Significant mGlu5 antagonist activity: Useful compounds preferably exhibit potency as antagonists (measured as IC ₅₀ or Ki) between 1000 and 0.1 nM. Without limiting the present disclosure, as described in more detail below, efficacy may be measured in vivo or in vitro by determining the antagonist activity of the compound (including cell extracts or extract fractions). . Inhibitory potency is, as a non-limiting example, using native or recombinant mGlu5 receptor, a constitutively expressed or derived enzyme, and an enzyme expressed in native or non-native species and / or cell types. Can also be measured (W. Sporen, Trends in Pharmacol. Sci. 23: 331-337, 2001).

  (2) Selectivity: Preferred compounds exhibit at least about 10-fold higher potency as antagonists against the mGlu5 receptor compared to each of the mGlu1 receptor and the group II mGlu receptor. About 20-fold, at least 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, at least about 1000-fold higher potency as an antagonist for the mGlu5 receptor compared to each of the mGlu1 receptor and Group II mGlu receptors The compound which shows is more preferable.

Accordingly, compounds belonging to this general class are suitable candidates for testing according to the methods taught below. Selectivity can be measured as the ratio of Ki or IC ₅₀ for different receptors.

Screening candidate compounds to identify those compounds that are useful in the practice of the present invention is, for example, without limitation:
1) one or more mGlu1 receptors or group II mGlu receptors, and optionally group III mGlu receptors, preferably at least one receptor of each of mGlu1 and group II mGlu group receptors, and optionally group III assessing antagonist potency and selectivity for the mGlu5 receptor compared to the mGlu receptor; and 2) pharmacological activity using one or more animal model systems for neuromuscular dysfunction of the lower urinary tract Including confirming.

Those commonly used in in vitro assays for assessing antagonist activity against metabotropic glutamate receptors are found, for example, in Carroll et al. (Mol Pharmacol 59: 965-973, 2001). In preferred embodiments, measurement of antagonist activity against metabotropic glutamate receptors is performed using one or more assays described in the examples set forth below. Using one or more of the assays, the antagonist activity of a test compound against metabotropic glutamate receptors can be measured for various isozymes, and 50% binding inhibitory concentration (IC ₅₀ ) is a regression analysis well known in the art, Alternatively, it can be calculated using an equivalent computerized method (Tallarida et al., Manual of Pharmacological Calculations. Springer-Verlag, pp. 10-12, 1981).

If a compound exhibits a selectivity ratio of at least 10 fold, ie an mGlu1 receptor or a group II mGlu receptor with an IC ₅₀ or Ki for mGlu5 of 1 or more, preferably of mGlu1 and group II mGlu receptors If it is at least 10 times lower than the IC ₅₀ or Ki for at least one receptor of each, it is considered a “selective” mGlu5 antagonist. More preferably, the selective mGlu5 antagonists described herein further exhibit a selectivity ratio of at least 10-fold for one or more group III mGlu receptors.

  Once a compound has been identified as a selective mGlu5 antagonist, its pharmacological activity can be confirmed using one or more animal model systems for neuromuscular dysfunction of the lower urinary tract.

  Animal model systems useful for measuring such pharmacological activity include, but are not limited to, volume-induced rheumatic bladder voiding contractions in anesthetized rats. In this method, the bladder is catheterized through the external urethra using a polyethylene tube filled with saline. The external urethra is then ligated and connected to a pressure recording device. The bladder is then filled with saline until reflex micturition occurs, after which the frequency of micturition contraction is measured for 15 minutes. Test compounds are then administered intravenously and their effects are then evaluated for 60 minutes. This method is described in more detail in Example 3 below and was originally used to confirm the predicted performance of selective mGlu5 antagonists for urinary tract disorders. This model has been confirmed by the use of various reference standards (Guarneri et al., Pharmacol. Res. 27: 173-187, 1993).

  Other animal models useful for evaluating the activity of selective mGlu5 antagonists on the lower urinary tract are presented in Examples 4-5 of this application. These are intravesical pressures of bladder activity in conscious rats with the device in place to measure bladder pressure during continuous infusion of saline or highly diluted acetic acid into the bladder Based on measurement records. These methods are widely used and accepted by researchers in the art and are approximately 5 hours after administration of the test compound by continuous monitoring of bladder performance and evaluation of micturition interval and peak micturition pressure. Predict the infusion period.

A “metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized” generally refers to the process by which a particular substance changes in the body. Briefly, all compounds present in the body are manipulated by enzymes in the body to induce energy and / or to remove them from the body. Certain enzymes cause certain structural changes in the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase is activated to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. It catalyzes the transfer of glucuronic acid molecules. Further information on ^{metabolism, The Pharmacological Basis of Therapiutics, 9} th Edition, McGraw-Hill (1996), can be obtained from the pages 11-17.

  Metabolites of the compounds disclosed herein include administration of the compound to the host and analysis of the tissue sample from the host, or incubation of the compound in vitro with liver cells and analysis of the resulting compound. It can be identified by either. Both methods are well known.

  A “prodrug” of a compound disclosed herein is an inactive substance that changes to the active form of the disclosed compound in vivo when administered to a mammal.

In certain embodiments, lower urinary tract disease is treated by administering a selective mGlu5 antagonist in combination with one or more additional class of receptor antagonists. In a preferred embodiment, the selective mGlu5 antagonist is administered in combination with an antagonist of α1-adrenergic, 5-HT _1A or muscarinic receptor.

  In a further embodiment, the lower urinary tract disease is a selective mGlu5 antagonist, one or more inhibitors of a cyclooxygenase enzyme that can inhibit both COX1 and COX2 isozymes, or can be selective for COX2 isozymes, and NO thereof Treated by administration in combination with a donor derivative.

  Examples of antimuscarinic drugs for combination administration with selective mGlu5 antagonists are oxybutynin, tolterodine, darifenacin and temiverine.

  Selective mGlu5 antagonists can be administered in combination with α1-adrenergic antagonists for the treatment of lower urinary tract symptoms, whether or not they are associated with BPH. Preferred α1-adrenergic antagonists suitable for combined administration with selective mGlu5 antagonists are, for example, prazosin, doxazosin, terazosin, alfuzosin, and tamsulosin. Additional α1-adrenergic antagonists suitable for combination administration with selective mGlu5 antagonists are US Pat. Nos. 5,990,114; 6,306,861; 6,365,591; 387,909; and 6,403,594.

Examples of 5-HT _1A antagonists that can be administered in combination with a selective mGlu5 antagonist are described in Leonardi et al. Pharmacol. Exp. Ther. 299: 1027-1037, 2001 (eg, Rec 15/3079), US Pat. No. 6,071,920, and other phenylpiperazine derivatives are described in WO99 / 06383 and October 2002 7 As described in pending US patent application Ser. Nos. 10 / 266,088 and 10 / 266,104 filed on the same day. Additional 5-HT _1A antagonists include DU-125530 and related compounds described in US Pat. No. 5,469,942 and lobarzotan and related compounds described in WO 95/11891. Each of the foregoing is a non-limiting example of a 5-HT _1A antagonist that can be administered in combination with a selective mGlu5 antagonist.

  Examples of selective COX2 inhibitors that can be administered in combination with a selective antagonist of the mGlu5 receptor are, without limitation, nimesulide, meloxicam, rofecoxib, celecoxib, parecoxib and valdecoxib. Additional examples of selective COX2 inhibitors are described in, but not limited to, US Pat. No. 6,440,963. Examples of non-selective COX1-COX2 inhibitors include, but are not limited to, acetylsalicylic acid, niflumic acid, flufenamic acid, enfenamic acid, meclofenamic acid, tolfenamic acid, thiaprofenic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, fluprofen, Indomethacin, acemetacin, progourmetacin, ketorolac, diclofenac, etodolac, sulindac, fenthiazac, tenoxicam, lornoxicam, cynoxicam, ibuproxam, nabumetone, tolmethine, amtormethine. Thus, each of the foregoing is a non-limiting example of a COX inhibitor that can be administered in combination with a selective mGlu5 antagonist.

  Examples of derivatives of COX inhibitors that can be administered in combination with a selective mGlu5 antagonist have nitric acid (nitrooxy) or nitrite groups that can release NO in vivo, such as those shown in WO 98/09948, for example. It is a derivative of a COX inhibitor.

Chemical Definitions The following definitions generally apply to the compounds described herein, unless otherwise defined in specific cases.

  Alkyl groups can be straight or branched and can have 1 to 12 carbon atoms. Those having 1 to 6 carbon atoms, preferably those having 1 to 4 carbon atoms are preferred, and may also be indicated as lower alkyl groups. These meanings are maintained in more complex groups such as haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, and the like.

  An alkenyl group can be straight or branched and can have 2 to 12 carbon atoms. These can have more than one carbon-carbon double bond. Those having 2 to 6 carbon atoms, preferably those having 2 to 4 carbon atoms are preferred, and may also be indicated as lower alkenyl groups.

  Alkynyl groups can be straight or branched and can have 2 to 12 carbon atoms. These can have more than one carbon-carbon triple bond. Those having 2 to 6 carbon atoms, preferably those having 2 to 4 carbon atoms are preferred, and may be represented as lower alkynyl groups.

  The term “alkenylene” is linear or branched having at least one carbon-carbon double bond and having 2 to 12 carbon atoms (lower alkenyl groups have 2 to 6 carbon atoms). Refers to a divalent alkenyl group of the chain.

  The term “alkynylene” is a straight or branched chain having at least one carbon-carbon triple bond and having 2 to 12 carbon atoms (lower alkenyl groups have 2 to 6 carbon atoms). Of the divalent alkynyl group. Ethynyl is preferred.

  The term “hydrocarbyl” refers to straight or branched monovalent and divalent groups derived from saturated or unsaturated groups containing only carbon and hydrogen atoms and having 1 to 12 carbon atoms. This term includes alkyl groups, alkenyl groups, dialkenyl groups, trialkenyl groups, alkynyl groups, alkadiynyl groups, alkatriynyl groups, alkenine groups, alkadienyne groups, alkenedyne groups, etc. Is included.

  Cycloalkyl groups have 3 to 20 carbon atoms in one or more rings. If more than one ring is present, these rings may be fused or attached at one carbon atom as a spirane. Monocyclic cycloalkyl groups having 3 to 7 carbon atoms are preferred and may be designated as lower cycloalkyl groups.

  Cycloalkenyl groups have 3 to 20 carbon atoms in one or more rings. If more than one ring is present, these rings may be fused or attached at one carbon atom as a spirane. These are not as many as aromatics, but have more than one carbon-carbon double bond. Monocyclic cycloalkenyl groups having 3-7 carbon atoms are preferred and may be designated as lower cycloalkenyl groups.

  Cycloalkynyl groups have 3 to 20 carbon atoms in one or more rings. If more than one ring is present, these rings may be fused or attached at one carbon atom as a spirane. These have more than one carbon-carbon triple bond. Monocyclic cycloalkynyl groups having 3 to 7 carbon atoms are preferred and may be designated as lower cycloalkynyl groups.

  The term “cyclohydrocarbyl” refers to a cyclic (ie, containing a ring) monovalent group derived from a saturated or unsaturated group containing only carbon and hydrogen atoms and having 3 to 20 carbon atoms. Exemplary cyclohydrocarbyl groups include cycloalkyl groups, cycloalkenyl groups, cycloalkadienyl groups, cycloalkatrienyl groups, cycloalkynyl groups, cycloalkadiynyl groups, spiro hydrocarbon groups (where The two rings are joined by one atom that is the only member common to the two rings (eg, spiro [3.4] octanyl, etc.), bicyclic hydrocarbon groups (where two The rings are bonded and have two atoms in common) (eg bicyclo [3.2.1] octane, bicyclo [2.2.1] hept-2-ene, norbornene, decalin, etc.), etc. Is mentioned.

  The term “acyl”, whether used alone or in terms such as “acylamino”, refers to a group provided by the remainder after removal of a hydroxy from an organic acid.

  The term “alkanoyl” refers to a straight or branched alkyl chain attached to a carbonyl group. However, this term also includes the formyl group. Lower alkanoyl groups have 1 to 5 carbon atoms and include in particular formyl, acetyl and propanoyl groups.

  Halogen means a fluorine, chlorine, bromine or iodine atom. The combining term halo is interpreted similarly. Haloalkyl specifically includes single or multiple halogen substitutions, particularly trifluoromethyl and 2,2,2-trifluoroethyl.

  The term “aryl”, alone or in combination, includes a carbocyclic aromatic system comprising one, two or three rings, where such rings may be linked in a pendant manner or fused. ). The term “aryl” includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

  The terms “heterocycle” and “heterocyclic” have similar meanings and have one or more heteroatoms (eg, N, O, S) as part of the ring structure and 3-20 A ring-containing group having a ring atom of Heterocyclic groups can be saturated, partially unsaturated including one or more double bonds, or fully unsaturated. A fully unsaturated heterocyclic group may also be referred to as a heteroaryl group. Heterocyclic groups can contain 1, 2 or 3 rings. If the heterocyclic group contains 2 or 3 rings, these rings can be attached in any configuration (ie, fused or spiro configuration). Examples of the heterocyclic group include, but are not limited to, a monocyclic heterocyclic group containing 1 to 4 nitrogen atoms (eg, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); 1 to 2 oxygen atoms and Saturated 3-6 membered heteromonocyclic groups (eg morpholinyl etc.) and bicyclic heterocyclic groups (eg azabicycloalkanyl and oxabicycloalkyl groups) containing 1 to 3 nitrogen atoms; 1 Unsaturated 3-6 membered heteromonocyclic groups (eg thiazolyl etc.) containing 2 sulfur atoms and 1 to 3 nitrogen atoms, imidazolyl, pyrimidinyl, isothiazolyl and isoxazolyl groups. The foregoing is a non-limiting example. Additional examples of “heterocyclic” groups are provided herein. The term “substituted heterocycle” refers to a heterocycle that further bears one or more substituents as described above.

  Preferred heteroaryl groups are monocyclic and have 5-7 ring atoms, of which 1-4 are heteroatoms selected from oxygen, sulfur and nitrogen. Examples include furyl, pyrrolyl, thienyl, 1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1H- [1 , 2,4] triazolyl, 4H- [1,2,4] triazolyl, 1H- [1,2,3] triazolyl, 2H- [1,2,3] triazolyl, 4H- [1,2,3] triazolyl [1,2,4] oxadiazolyl, [1,3,4] oxadiazolyl, [1,2,3] oxadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, [1,2,3,4] oxatriazolyl, [1,2,3,5] oxatriazolyl, 1,3-thiazolyl, 1,2-thiazolyl, 1H-pentazolyl, pyridyl, pyrazinyl, pyri Jiniru, pyridazinyl, indolyl and quinolinyl. Such a heterocyclic group is preferred also when condensed with an aryl group. Examples of such fused bicyclic groups include benzofuran and benzothiophene.

Pharmaceutical Compositions The present invention further includes pharmaceutical compositions comprising selective mGlu5 antagonists, such as compounds that are one of formulas IV, or enantiomers, diastereomers, N-oxides, crystalline forms thereof , Hydrates, solvates, active metabolites, or pharmaceutically acceptable salts thereof, which are selective mGlu5 antagonists. The pharmaceutical composition may be, for example, a pharmaceutically acceptable carrier or diluent, a flavoring agent, a sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing agent, a colorant, a disintegrant, an excipient. It may contain one or more excipients such as stabilizers, plasticizers, edible oils, such as excipients, lubricants, absorption enhancers, fungicides and the like.

  Suitable pharmaceutically acceptable carriers or diluents are ethanol, water, glycerol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, phosphate buffered saline, PPG2 myristylpropio. Including, but not limited to, nates, magnesium carbonate, potassium phosphate, vegetable oils, animal oils, and solketals.

  Suitable binders include: starch; gelatin; natural sugars such as glucose, sucrose and lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth, plant gum, sodium alginate; carboxymethylcellulose; polyethylene glycol; wax Including, but not limited to.

  Suitable suspending agents include but are not limited to bentonite.

  Suitable dispersing and suspending agents include, but are not limited to, synthetic and natural gums such as plant gums, tragacanth, acacia, alginate, dextran; sodium carboxymethylcellulose; methylcellulose; polyvinylpyrrolidone; and gelatin.

  Suitable disintegrants include, but are not limited to, starches such as corn starch; methylcellulose; agar; bentonite; xanthan gum;

  Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

  Suitable edible oils include but are not limited to cottonseed oil, sesame oil, coconut oil and peanut oil.

  Examples of further additives include but are not limited to sorbitol, talc, stearic acid and dicalcium phosphate.

Unit Dosage Forms
Pharmaceutical compositions include tablets, pills, capsules, boluses, powders, granules, sterile parenteral solutions, sterile parenteral suspensions, sterile parenteral emulsions. Dosage units such as liquids (sterile parental emulsions), elixirs, tinctures, metered aerosols or liquid sprays, drops, ampoules, autoinjector devices or suppositories It can be formulated as a form. Unit dosage forms are used for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or insufflation, transdermal patches, and lyophilized compositions Can be done. In general, any delivery of active ingredient that results in systemic availability of the active ingredient may be used. Preferably the unit dosage form is an oral dosage form, most preferably a solid oral dosage form, and thus preferred dosage forms are tablets, pills, and capsules. Parenteral formulations are also preferred.

  Solid unit dosage forms can be prepared by mixing an active agent of the present invention with a pharmaceutically acceptable carrier and other desired additives as described above. The mixture is generally mixed until a homogeneous mixing of the active agent of the present invention is achieved, and the carrier and other desired additives are shaped (ie, the active agent is uniformly dispersed throughout the composition). ) In this case, the composition is formed as a dry or wet granule.

  Tablets or pills may be coated or otherwise formed to form unit dosage forms with a delayed and / or sustained action (eg, controlled release and delayed release unit dosage forms). It can be prepared by a method. For example, a tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of a layer or envelope over the former. The two components can be separated by an enteric layer that helps to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum or to be delayed in release.

  Biodegradable polymers for controlling the release of active agents include polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogel crosslinks or Amphiphilic block copolymers are included, but are not limited to these.

  For liquid dosage forms, the active agents or their physiologically acceptable salts are dissolved, suspended or milked with substances usually used as necessary (eg, solubilizers, emulsifiers or other adjuvants). It becomes turbid. Solvents for active combinations and the corresponding physiologically acceptable salts may include water, physiological salt solutions, or alcohols (eg, ethanol, propanediol or glycerol). In addition, sugar solutions such as glucose or mannitol solutions can be used. Mixtures of the various solvents mentioned can also be used in the present invention.

  Transdermal dosage forms are also contemplated by the present invention. The transdermal form is a diffusion transdermal system (transdermal patch) that uses either a fluid reservoir or a drug-in-adhesive matrix system. obtain. Other transdermal dosage forms include, but are not limited to, topical gels, lotions, ointments, transmucosal systems and devices, and iontophoretic (electrical diffusion) delivery systems. Transdermal dosage forms can be used for delayed and sustained release of the active agents of the present invention.

  The pharmaceutical compositions and unit dosage forms of the invention for parenteral administration (and particularly by injection) generally comprise a pharmaceutically acceptable carrier as described above. A preferred liquid carrier is vegetable oil. The injection can be, for example, intravenous, epidural, intrathecal, intramuscular, intraluminal, intratracheal or subcutaneous.

  The active agents can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  The active agents of the present invention can also be coupled with soluble polymers such as targetable drug carriers. Such polymers include, but are not limited to, polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol, and polyethyleneoxypolylysine substituted with palmitoyl residues.

Administration The pharmaceutical composition or unit dosage form of the present invention can be administered by various routes such as oral, enteral, intravenous, subcutaneous intramuscular, transdermal, transmucosal (including rectal and buccal) and inhalation routes. But are not limited to these.

  Preferably, oral or transdermal routes are used (ie, solid or liquid formulations, or skin patches, respectively).

  A pharmaceutical composition or unit dosage form containing an effective amount of the present invention may be obtained from E.I. J. et al. McGuire, “Campbell's UROLOGY”, 5th Ed 616-638, 1986, W. B. Administration to animals (preferably humans) in need of treatment of lower urinary tract neuromuscular dysfunction as described in the Saunders Company, and to patients suffering from any physiological dysfunction associated with defects in glutamate receptor function Can be done. Such dysfunction includes, but is not limited to, central nervous system disorders such as depression, anxiety, eating disorders, sexual dysfunction, addiction and related problems.

  As used herein, the term “effective amount” refers to an amount that produces a measurable improvement in at least one symptom or parameter of a particular disorder. In a preferred embodiment, the compound comprises urinary urgency, overactive bladder, frequent urination, reduced urinary compliance (reduced bladder storage capacity), cystitis (interstitial) Urinary tract disorders such as incontinence, incontinence, urine leakage, enuresis, difficulty urinating, urinary hesitancy and difficulty in cavitation of the bladder.

  The pharmaceutical composition or unit dosage form of the present invention is defined by routine trials taking into account the guidelines given above to obtain optimal activity while minimizing toxicity or side effects for a particular patient. Can be administered according to the dosing and dosing regimen to be administered. However, such fine-tuning of the treatment regime is a routine measure in view of the guidelines provided herein.

  The dosage of the active agent of the present invention can vary depending on various factors such as the underlying disease state, individual condition, weight, sex and age, and the method of administration. Effective amounts for treating a disorder can be determined by empirical methods known to those skilled in the art, for example, establishing a matrix of dosage and frequency and comparing experimental units or groups of subjects at each point in the matrix. Can be easily determined. The exact amount administered to a patient will vary depending on the condition and severity of the disorder and the health condition of the patient. Measurable improvements in symptoms or parameters can be measured by those skilled in the art or reported to the physician by the patient. It is understood that any clinically or statistically significant attenuation or improvement of any symptom or parameter of urinary tract disorder is within the scope of the present invention. A clinically significant attenuation or improvement means perceptible to the patient and / or physician.

  For example, a single patient can simultaneously suffer from several symptoms of dysuria (eg, urgency and excessive urination frequency or both), which can be alleviated using the methods of the present invention. In the case of incontinence, reducing the frequency or amount of undesired urination is considered an advantageous effect of the treatment method.

  The amount of drug administered is in the range of about 0.01 to about 25 mg / kg / day, preferably about 0.1 to about 10 mg / kg / day, and most preferably 0.2 to about 5 mg / kg / day. possible. The pharmaceutical formulations of the present invention need not necessarily contain an entire amount of an agent that is effective in treating the disorder, and therefore an effective amount is such that multiple doses of such pharmaceutical formulations It is understood that this can be achieved by administration of

  In a preferred embodiment of the invention, the compound is formulated in a capsule or tablet, preferably contains 25-500 mg of the compound of the invention, and preferably 25-1000 mg, preferably for relief of incontinence and dysfunction. Is administered to the patient at a total daily dose of 150-500 mg, most preferably about 350 mg.

  A pharmaceutical composition for parenteral administration contains from about 0.01% to about 100% by weight of the active agent of the present invention relative to 100% by weight of the total pharmaceutical composition.

  In general, transdermal dosage forms contain from about 0.01% to about 100% by weight of the active agent of the present invention relative to 100% by weight of the total dosage form.

The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dose may be administered in divided doses. In addition, co-administration or continuous administration with other compounds for the treatment of the disorder may be desired. One or more selective mGlu5 antagonists may be combined with, for example, one or more antimuscarinic, α ₁ -adrenergic antagonists, 5-HT _1A receptor antagonists or COX inhibitors, or NO-releasing derivatives thereof. Can be administered. Antimuscarinic agents, α ₁ -adrenergic antagonists, 5-HT _1A receptor antagonists, COX inhibitors and their NO releasing derivatives are shown above, but are not limited.

  For combination treatment where the compounds are in separate dosage formulations, the compounds can be administered at the same time, or each can be administered on separate staggered occasions. For example, a selective mGlu5 antagonist can be administered in the morning and an antimuscarinic compound can be administered in the evening, and vice versa. Additional compounds can also be administered at specific intervals. The order of administration includes the patient's age, weight, sex and medical condition; severity and etiology of the disorder being treated, route of administration, patient renal and liver function, patient treatment history, and patient responsiveness Depends on various factors. The determination of the order of administration can be finely tuned, and such fine-tuning is routine, given the guidelines given herein.

Use-Methods for Treatment
While not wishing to be bound by theory, it is believed that administration of an mGlu5 receptor antagonist prevents unwanted activity of the sacral reflex and / or cortical mechanisms that control micturition. Accordingly, it is contemplated that a wide range of lower urinary tract neuromuscular dysfunction (including but not limited to dysuria, incontinence and enuresis (overactive bladder)) can be treated using the compounds of the present invention. The Urination disorders include frequent urination, nocturnal polyuria, urgency, decreased urinary compliance (decreased bladder storage capacity), difficulty in hollowing out the bladder (ie less than optimal urine volume during urination) Is released). Incontinence syndrome includes stress incontinence, urge incontinence, and enuresis incontinence, and mixed forms of incontinence. Enuresis refers to involuntary outflow of urine at night or during sleep.

  The compounds of the present invention may also be useful in the treatment of central nervous system disorders resulting from glutamatergic dysfunction.

Examples The following examples illustrate the invention described herein without limiting it in any way.

Example 1: Affinity of selected antagonists for mGlu receptor subtypes Radioligands in mGlu1, mGlu5 and Group II (mGlu2; mGlu3) and Group III (mGlu4; mGlu6-8) mGluRs in rat brain Binding assay.

Method a) Preparation of the membrane:
Male Sprague Dawley rats (200-300 g, Charles River, Italy) were killed by cervical dislocation, the forebrain (cortex, striatum and hippocampus) and cerebellum were replaced with a Polytron homogenizer (Kinematica). Used and homogenized (2 × 20 seconds) in 50 volumes of 50 mM cold Tris buffer (pH 7.4). The homogenate was centrifuged at 48,000 × g for 15 minutes, resuspended in 50 volumes of the same buffer, incubated for 15 minutes at 37 ° C., and centrifuged and resuspended twice more. The final pellet was frozen and stored at −80 ° C. until use.

b) Binding assay:
i) mGlu1:
In the experimental section, pellets from rat cerebellum were loaded with 150-200 volumes of 20 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), 2 mM MgCl ₂ , 2 mM CaCl ₂ at pH 7.4. And resuspended. The membrane was incubated with approximately 7.5 nM [ ³ H] quiscaric acid in the presence or absence of competing agents for 60 minutes at 25 ° C. in a final volume of 1 ml. Non-specific binding was measured in the presence of 10 μM quiscaric acid (Hinoet al., Neurochem. Int. 38, 277-285, 2001).

ii) mGlu5:
In the experimental section, the pellet from the rat forebrain was resuspended in 100 volumes of 20 mM HEPES, 2 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4. The membrane was incubated with 4 nM [ ³ H] MPEP in the presence or absence of competing agents for 60 minutes at 25 ° C. in a final volume of 1 ml. Non-specific binding was measured in the presence of 10 μM MPEP (Spoorene et al., Trends Pharmacol Sci. 22, 331-337, 2001).

iii) Group II (mGlu2 + mGlu3):
In the experimental section, the pellet from the rat forebrain was resuspended in 250 volumes of 20 mM HEPES, 2 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4. The membranes were incubated with 1 nM [ ³ H] LY341495 in the presence or absence of competing agents for 30 minutes at 0 ° C. in a final volume of 1 ml. Nonspecific binding was measured in the presence of 1 μM LY341495 (Wrightt et al., J. Pharmacol. EXP. Ther. 298: 453-460, 2001; Mutelet al., J. Neurochem. 75, 2590-2601, 2000). did.

iiii) Group III (mGlu4 + mGlu6 + mGl7 + mGlu8):
In the experimental section, pellets from rat cerebellum were resuspended in 100-200 volumes of 10 mM HEPES (pH 8), 1.2 mM MgCl ₂ , 110 mM NaCl and 0.3 mM phenylmethylsulfonyl fluoride (PMSF). The membrane was incubated with approximately 20 nM [ ³ H] L-AP4 in the presence or absence of competing agents for 30 minutes at 25 ° C. in a final volume of 1 ml. Non-specific binding was measured in the presence of 100 μM L-serine-O-phosphate (L-SOP) (Hudtoff et al., Br. J. Pharmacol. 124, 971-977, 1998).

  Incubation was stopped by the addition of cold Tris buffer (pH 7.4) and rapid filtration through a Filtermat 1204-401 (Wallac) filter pretreated with 0.5% polyethyleneimine. The filter was then washed with cold buffer and the radioactivity retained on the filter was measured by liquid scintillation spectrometry.

Data Analysis Inhibition of specific binding of radioligands by test compounds is described by the non-linear curve fitting program Allfit (then-linear curve-fitting program Allfit) (De Lean et al., Am. J. Physiol. 235, E97-E102, 1978). ) Was used to estimate the 50% inhibitory concentration (IC ₅₀ ). IC ₅₀ values were converted to affinity constants (Ki) by the equation of Cheng & Prusoff (Biochem. Pharmacol. 22, 3099-3108, 1973). Data were expressed as the mean ± SE of pK _i (−log Ki).

Results Table 1 shows the affinity for Group I (mGlu1, mGlu5) or Group II (mGlu2 + mGlu3) receptors measured experimentally for various antagonists. Table 2 shows the values reported in the literature for the affinity and activity of several of the compounds shown in Table 1 for various mGluR subtypes.

Binding of [ ³ H] MPEP to mGlu5 subtype and [ ³ H] LY341495 to mGlu2 + mGlu3 subtype in the rat forebrain membrane was saturable and high affinity (K _d : respectively 10.4 and 2.5 nM).

The most potent inhibitors of the specific binding of [ ³ H] MPEP to the mGlu5 receptor were MTEP and MPEP itself. As reported by various literature as shown in Table 2, SIB 1893 exhibits weaker affinity, whereas all other compounds are inactive until reaching 1 μM.

AIDA and LY367385 have been reported as selective mGlu1 receptor antagonists (see Table 2). In our experimental conditions, only LY367385 significantly replaced [ ³ H] quiscaric acid from its binding site.

The specific binding of [ ³ H] LY341495 to the group II (mGlu2 + mGlu3) receptor was displaced with high affinity by the ligand itself, whereas all other compounds were inactive until reaching 1 μM.

Table 1
Binding affinity of selected antagonists for group I (mGlu1, mGlu5) and group II (mGlu2 + mGlu3) receptor subtypes

Table 2
In the absence of radioligand binding data reported in the literature, binding affinity for the mGluR subtype , IC ₅₀ and pK _b values obtained in different functional models are given. Values are given in μM.
ND = not measured.

References for Table 2
1) Gasparini et al., Neuropharmccology 38: 1493, 1999.
2) Varney et al., Pharmacol. Exp. Ther. 290: 170, 1999.
3) Hermans et al., Br. Pharmacol. 126: 873, 1999.
4) Moroni et al., J: Pharmacol. Exp. Ther. 281: 721, 1997.
5) Clark et al., Biorg. Med. Chem. 7: 2777, 1997.
6) Kingston et al., Neuropharmacology 34: 887, 1995.
7) Johnson et al., Neuropharmacology 38: 1519, 1999.

Example 2 Measurement of Inositol Phosphate Accumulation To determine the mode of action (agonist, antagonist or inverse agonist) of a test compound at mGlu5 and mGlu1 receptors, the concentration dependence of stimulation of inositol phosphate production in response to glutamate was varied Of CHO-K1 cells expressing mGlu1 or mGlu5 receptor, compared in the presence and absence of test compound itself.

Measurement of inositol phosphate (IP) accumulation in CHO-K1 transfected cells was performed by labeling the cells with 4 μCi / ml myo- [ ³ H] inositol overnight, followed by Carrolllet al. (Mol Pharmacol 59: 965-973, 2001). The cells are pre-incubated for 1 hour with glutamate degrading enzymes (1 U / ml glutamate / pyruvate / transaminase) and 2 mM pyruvate to prevent the possible effects of glutamate released from the cells.

  Stimulation is then performed for 30 minutes in a medium containing 10 mM LiCl and various concentrations of agonist (glutamic acid) or the compound to be tested. When investigating the activity of an antagonist, the test compound is added to the cell culture 20 minutes before the agonist is added and further incubated for 30 minutes in the presence of the agonist.

  Incubation is stopped by rapid washing with ice-cold buffer and addition of ice-cold perchloric acid. The inositol monophosphate fraction was separated from the neutral extract on an ion exchange minicolumn.

  Results are shown as the ratio of radioactivity collected in the IP fraction to radioactivity recovered from solubilized cell membranes.

  The normalized IP formation ratio is compared to that obtained with the submaximal Glu concentration used in the described experiment and is referenced as 100%.

Example 3: Method of effect on rhythmic bladder-voiding contractions induced by bladder filling in anesthetized rats Female Sprague-Dawley rats (registered trademark Crl: CD ) weighing 225-275 g (SD) IGSBR, Charles River Italy) was used. The animals are housed with food and water freely available and in a 12-hour alternating light-dark cycle at 22-24 ° C. for at least 1 week, except during the experiment. Forcibly maintained. The activity on rhythmic bladder-micturition contraction was determined by the method of Dray (Dray J., Pharmacol. Methods, 13: 157, 1985) with some modifications as in Guarneri (Guarneri, Pharmacol. Res., 27: 173, 1993). Evaluated according to. Briefly, rats are anesthetized by subcutaneous injection of 1.25 g / kg (5 ml / kg) urethane, followed by a catheter through the urethra using PE50 polyethylene tubing filled with physiological saline in the bladder. Inserted. The catheter was then tied in place with a ligature around the mouth of the external urethra and connected to a conventional pressure transducer (Statham P23 ID / P23XL). Intravesical pressure was continuously displayed on a chart recorder (Battaglia Rangoni KV 135 with DCI / TI amplifier). The bladder was then filled with increasing volumes of warm (37 ° C.) saline via a recording catheter until reflex bladder-micturition contraction occurred (usually 0.8-1.5 ml). For intravenous injection of the bioactive compound, a PE50 polyethylene tube filled with physiological saline was inserted into the jugular vein.

  From the intravesical pressure measurement chart, the number of contractions recorded before treatment (basal value) and 15 minutes after, and the average width of these contractions (average height of peak in mmHg) were evaluated.

  Since most compounds have the effect of starting relatively quickly and leading to complete cessation of bladder contraction, the biological activity is reduced by the duration of bladder quiescence (ie, the length of time during which no contraction occurs). It was easily evaluated by measuring. The effect on bladder contraction width was assessed by comparing these (when contraction resumed) with the width observed before treatment.

To compare the efficacy of a test compound in inhibiting bladder deflation, an effective dose (ED _10min ) that abolished bladder contraction for 10 minutes was calculated by linear regression analysis using the least squares method did.

  Morphine was also tested as a standard for this model.

Results Rapid bloating of the bladder in urethane anesthetized rats resulted in a series of rhythmic bladder-micturition contractions, a feature of which has been described (Magi et al., Brain Res. 380: 83, 1986; Maggi et al. , J; Pharmacol. Exp. Ther., 230: 500, 1984). The frequency of these contractions is related to the sensory afferent arm of reflex micturition, and the integrity of the micturition center, while their width is the reflex referent arm. ) Depends on the function. The results obtained after administration of the compounds of the invention are shown in Tables 3 and 4.

  Compounds of the invention selective for the mGlu5 subtype (MTEP, MPEP, SIB 1893) have been found to be active as inhibitors of isovolumetric voicing contractions in rats. At the resumption of contraction, no difference in contraction width was observed compared to before treatment.

  In contrast, compounds that showed selectivity for the mGlu1 subtype (AIDA, LY 367385) as well as compounds selective for the Group II mGlu receptor (LY 341495) were inactive.

  In summary, the compounds of the invention inhibited the micturition reflex by inhibiting bladder contraction by potency related to its affinity for the mGlu5 subtype and, depending on the dose. Furthermore, they did not reduce the width of the bladder contraction. This reducing effect, which can result in potentially lower bladder contractility and undesirable retention of residual urine in the bladder after micturition, is not characteristic of the compounds of the present invention.

Table 3
Effects after intravenous administration on rhythmic bladder-voiding contractions The data are for bladder quiesce (blade loss time (minutes)) after administration of a given dose. ) The mean value ± SEM of the duration.

Table 4
Effects after intravenous administration on rhythmic bladder-voiding contractions Data are extrapolated dose (ED _10min ) and 95 Indicates the% confidence limit.

n.a. = not active; no significant decrease in peak height

Example 4 Method of Effect on Intravesical Pressure Parameters in Conscious Rats Male Sprague Dawley rats [registered trademark Crl: CD (SD) IGS BR] weighing 300-400 g supplied by Charles River Italy were used. The animals were housed with free access to food and water and were forced to maintain a 12 hour light / 12 hour dark cycle at a temperature of 22-24 ° C. except during the experiment. In order to quantify urodynamic parameters in conscious rats, intravesical pressure measurement studies were performed according to a previously reported procedure (Guarneri et al., Pharmacol. Res. 24: 175, 1991).

  Briefly, the rats were anesthetized by intraperitoneal administration of 3 ml / kg Equithensin solution (pentobarbital 30 mg / kg and chloral hydrate 125 mg / kg) and placed supine. A midline incision approximately 10 mm long was made in the abdominal wall, shaved and cleaned. The bladder is gently separated from the attached tissue, emptied, and then cannulated through an incision in the bladder cavity using a polyethylene cannula (inner diameter 0.58 mm, outer diameter 0.96 mm), which is permanently And sutured with silk thread. For bolus intravenous injection, a similar polyethylene tube filled with saline containing sodium heparin (40 IU / ml) was inserted into the jugular vein. The cannula was placed externally through a subcutaneous tunnel in the retroscapular area, where it was connected to a plastic adapter to avoid the risk of removal by the animal. For drug testing, the rats were used on the first day after transplantation.

  On the day of the experiment, the rats were placed in a modified Bollman cage [ie, a restriction cage that is large enough to allow the rat to take a normal crouched posture but narrow enough to prevent rotation]. After a stabilization period of about 20 minutes, the free end of the bladder cannula is placed through a T-tube for continuous infusion of warm (37 ° C) saline solution into the bladder at a constant rate of 0.1 ml / min. It was connected to a pressure transducer (Statham P23 XL) and a peristaltic pump (Gilson minipuls 2). Intraductal pressure signals during infusion of saline into the bladder were continuously recorded in a polygraph (Rectigraph-8KSan-ei with a BM614 / 2 amplifier from Biomedica Mangoni) and Urodynamic parameters were evaluated: bladder volume capacity (BVC) and micturition pressure (MP). BVC (ml) is defined as the volume of saline injected into the bladder that is necessary to induce detrusor contraction that results in micturition. MP (mmHg) is defined as the maximum intravesical pressure caused by contraction during micturition. Basal BVC and MP values were evaluated as the average of the values observed in the cystometry chart recorded during the first 30-60 minutes. The infusion was discontinued at this point in the assay and the test compound was administered either intravenously via a jugular vein catheter or orally via a gastric tube. The resumed bladder infusion and changes in BVC and MP were evaluated from the mean values obtained in the intravesical pressure charts observed during 1, 2, 3, 4 and 5 hours after treatment. The compound was administered by intravenous and oral routes of administration in amounts of 1 ml / kg and 2 ml / kg, respectively. Control animals received the same amount of vehicle corresponding to 8% dimethylformamide and 8% Tween 80 aqueous solution (final concentration) for intravenous administration or 0.5% aqueous solution for oral administration.

  Under the given test conditions, measuring BVC is equivalent to measuring urination interval time.

Statistical analysis All data were expressed as mean ± standard error. Similar to BVC and MP Δ values (difference in ml or mmHg) (BVC or MP minus basal value at time “x”), the percent change in BVC and MP relative to the basal value is also shown for each rat / time. evaluated. In the figure, the data was evaluated as percent change when compared to the basal value.

  Similar to Δ values, statistical analysis of BVC and MP values was performed using S.P. A. S. / STAT software, version 6.12. Differences when comparing values at various times with basal values were evaluated based on original BVC and MP data, whereas differences in vehicle and active treatment efficacy were based on BVC and MP Δ values. evaluated.

Results The time course of the effect of the intravenous dose of the test compound is shown in FIGS. 3 and 10 mg / kg i. v. MPEP administered at a dose of 50 mg / kg i.e. v. It was found that SIB 1893 administered at a dose of 1 was effective in increasing bladder volume capacity (FIG. 1). The 10 mg / kg dose of MPEP recorded a significant increase in BVC, both compared to the basal value and compared to the value recorded in the control group. SIB 1893 significantly increased BVC only in comparison to basal values. Both compounds elicited only a mild effect on the micturition pressure, with a statistically significant difference to the changes observed in control animals (Figure 2). MPEP administered orally at doses of 3-10 and 30 mg / kg was significant at doses of 10 mg / kg or higher and induced a dose-dependent increase in BVC (FIG. 3).

  The time course of the effect of orally administered MPEP dose on MP is shown in FIG. MPEP significantly reduced MP compared to values observed at doses of 10 and 30 mg / kg in the control group. The change in MP over time was significantly different from that observed in the control group only at the 30 mg / kg dose.

Example 5: Method of effect on intravesical pressure parameters in conscious rats injected with dilute acetic acid into the bladder after oral administration The method used was that described in Example 4. Basal BVC and MP values were evaluated as the average of the values observed in the cystometry chart recorded during the first 30-60 minutes. At this point in the study, the infusion was discontinued and the test compound was administered orally via a gastric tube. Replace warm saline with dilute acetic acid (0.2%) and resume infusion into the bladder, and record changes in BVC and MP to intravesical pressure at 1, 2, 3 and 4 hours after treatment. The average value obtained in the measurement chart was evaluated by comparison with the base value. The compound was administered in an amount of 2 ml / kg and the control animals were orally received the same amount of vehicle (0.5% aqueous solution of methocel).

Statistical analysis Statistical analysis of the data was performed as reported in Example 4.

Results The time course of the effect of the dose of test compound is shown in FIGS. When administered orally at 10 mg / kg, MPEP is effective in antagonizing the decrease in bladder capacity capacity induced by injecting acid into the bladder without affecting micturition pressure (Figure 6). (FIG. 5). Its activity in this model system was similar to that of the known anti-inflammatory drug indomethacin.

CONCLUSION The mGlu receptor provides a mechanism by which glutamate can be tuned or precisely matched at the same synapse, which triggers a fast synaptic response via ion channel receptors at the synapse. A growing body of evidence, for example, indicates that the mGlu5 receptor regulates the NMDA receptor in the positive direction and that the two receptors are co-expressed in most neurons. Show. This is because the mGlu receptor produces a relatively subtle adjustment of the glutamate system in the CNS when compared to other approaches such as non-selective NMDA receptor antagonists that produce a range of side effects that cannot be tolerated by humans. Suggests representing a pharmacological target.

  Furthermore, the wide diversity and heterogeneous distribution of mGluR subtypes for the development of pharmacological agents that selectively interact with mGluRs contained in only one or a limited number of CNS functions. Provide opportunities.

  The results of the present invention clearly demonstrate that selective antagonists of mGlu5 have a desired effect at the bladder level and increase bladder capacity without adversely affecting bladder contractility. These compounds are also highly active in the presence of cystitis, indicating that they may be effective therapeutics in different forms of overactive bladder.

FIG. 1 shows vehicle (circle) and 3.0 and 10 mg / kg of compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) or 50 mg / kg of 2-methyl-6- (2-phenylethenyl) pyridine. FIG. 6 shows the time course change of bladder volume capacity (BVC) in rats after intravenous administration of (SIB 1893) (square). The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group. FIG. 2 shows the vehicle (circle) and 3.0 and 10 mg / kg of the compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) or 50 mg / kg of 2-methyl-6- (2-phenylethenyl) pyridine ( 2 shows the time course of micturition pressure (MP) in rats after intravenous administration of SIB 1893) (squares). The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group. FIG. 3 shows the time course of BVC in rats after oral administration of vehicle (circle) or 3.0, 10 or 30 mg / kg of compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) (square). Show. The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group. FIG. 4 shows the time course of MP in rats after oral administration of vehicle (circle) or 3.0, 10 or 30 mg / kg of compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) (square). Show. The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group. FIG. 5 shows that after oral administration of vehicle (circle), 10 mg / kg of compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) (square; left panel) or 1 mg / kg indomethacin (square; right panel) 2 shows the time course of BVC in rats injected with dilute acetic acid into the bladder. The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group. FIG. 6 shows oral administration of vehicle (circle) and 10 mg / kg of compound 2-methyl-6 (phenylethynyl) pyridine (MPEP) (square; left panel) or 1 mg / kg indomethacin (square; right panel). Later, MP changes over time in rats injected with dilute acetic acid into the bladder are shown. The data represents the percentage change relative to the basal value at different times after treatment. n = number of rats / group.

Claims (23)

Compounds having the following general formula I:

(here,
X ₁ represents a lower alkenylene, lower haloalkenylene, lower alkynylene or lower haloalkynylene group, each of which is linked via a vicinal unsaturated carbon atom or an azo group (—N═N—);
R ₁ is a hydrogen atom or lower alkyl, lower hydroxyalkyl, lower alkylamino, piperidino, carboxy, esterified carboxy, amidated carboxy, lower alkoxy, lower haloalkyl, lower haloalkoxy, cyano, alkynyl, lower alkoxy Carbonyl, di- (lower) alkylamino, lower alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl, or N- (lower) alkyl-N-phenylcarbamoyl group (each of the N- (lower) alkyl and N-phenyl groups) Is independently unsubstituted or has a lower alkyl, lower alkoxy, halogen or trifluoromethyl substituent),
R ₂ represents a hydrogen atom or lower alkyl, carboxyl, esterified carboxyl, amidated carboxyl, lower hydroxyalkyl, hydroxyl, lower alkoxy or lower alkanoyloxy, lower alkoxycarbonyl, di- (lower) -alkylamino- (Lower) alkanoyl, di- (lower) alkylaminomethyl, 4- (4-fluorobenzoyl) piperidin-1-yl-carbonyl, 4-tert-butyroxycarbonylpiperazin-1-yl-carbonyl, 4- (4- Azido-2-hydroxybenzoyl) piperazin-1-yl-carbonyl or 4- (4-azido-2-hydroxy-3-iodo-benzoyl) -piperazin-1-yl-carbonyl group;
R ₃ is a hydrogen atom or lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower hydroxyalkyl, di- (lower) alkylaminomethyl, morpholinocarbonyl or 4- (4-fluorobenzoyl) piperidin-1-yl- Represents a carbonyl group,
R ₄ is a hydrogen atom or lower alkyl, hydroxyl, lower hydroxyalkyl, lower aminoalkyl, (lower) alkylamino (lower) alkyl, di- (lower) -alkylamino (lower) alkyl, unsubstituted or hydroxy substituted (Lower) alkyleneamino (lower) alkyl, lower alkoxy, lower alkanoyloxy, lower aminoalkoxy, (lower) alkylamino (lower) alkoxy, di- (lower) -alkylamino (lower) alkoxy, lower alkoxycarbonyl, Carboxy (lower) alkylcarbonyl, (lower) alkoxycarbonyl (lower) alkoxy, lower hydroxyalkyl, m-hydroxy-p-azidophenylcarbonylamino (lower) alkoxy, lower aminoalkoxy, phthalimide (lower) alcohol Xy, unsubstituted (lower) alkyleneamino (lower) alkoxy, or (lower) alkyleneamino (lower) alkoxy, carboxyl, esterified by hydroxyl or 2-oxo-imidazolidin-1-yl group Carboxyl, amidated carboxyl, lower carboxyalkoxy or lower esterified carboxyalkoxy groups, and
R ₅ is an aromatic or heteroaromatic group (which may be unsubstituted or
Nitro, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, benzylcarbonylamino, azide, amino, halo, monohalobenzylamino, acyl, Acylamino, lower alkyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, lower haloalkoxy, lower aminoalkoxy, lower alkylsulfonyl, lower alkylamino, di- (lower) -alkylamino, lower alkenyl, lower alkenyloxy, lower alkylenedi Oxy, lower alkynyl, trimethylsilylalkynyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanoylamino, lower alkanoyloxy (Lower) alkylamino (lower) alkoxy, di- (lower alkyl) -amino (lower) alkoxy, (lower) alkanoylamino (lower) alkoxy, N- (lower alkyl) -N- (lower alkanoyl) -amino (lower ) Alkoxy, (lower) alkylaminocarbonylamino, (lower) alkoxycarbonylaminocarbonylamino, (lower) alkanoyloxy (lower) alkyl, N-acyl-N- (lower alkyl) amino, esterified carboxy, amidation Carboxy, carboxy (lower) alkylamino, esterified carboxy (lower) alkylamino, amidated carboxy (lower) alkylamino, phosphono (lower) alkylamino and esterified phosphono (lower) alkylamino Group, select from Or substituted with one or more substituents,
And / or one or more of phenyl, phenoxy, phenyl (lower) alkoxy, phenyl (lower) alkenyl, phenyl (lower) alkynyl, phenylamino, phenyl (lower) alkylamino, cycloalkyl (lower) alkylamino or hetero Substituted with an aryl (lower) alkylamino group, each of which is unsubstituted or substituted with one or more lower alkyl, lower alkoxy, halo and / or trifluoromethyl groups Represents)),
Alternatively, the enantiomers, diastereoisomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable of such compounds For the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. X ₁ is a (C ₂ -C ₄ ) alkenylene, (C ₂ -C ₄ ) haloalkenylene, (C ₂ -C ₄ ) alkynylene or (C ₂ -C ₄ ) haloalkynylene group, each of which is a vicinal unsaturated carbon Connected through an atom)
R ₁ is a hydrogen atom, or (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) hydroxyalkyl, cyano, ethynyl, carboxy, (C ₁ -C ₄ ) Represents an alkoxycarbonyl, di (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₆ ) alkylaminocarbonyl, or trifluoromethylphenylaminocarbonyl group;
R ₂ is a hydrogen atom or hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) hydroxyalkyl, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₂ -C ₅ ) alkanoyloxy, ( C ₁ -C ₄₎ alkoxycarbonyl, di _(C 1 -C ₄₎ alkylamino _(C 1 -C ₄₎ alkanoyl, di _(C 1 -C ₄₎ alkyl aminomethyl, 4- (4-fluorobenzoyl) - piperidine -1-yl-carbonyl, 4-t-butyloxycarbonyl-piperazin-1-yl-carbonyl, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carbonyl, or 4- (4 Represents -azido-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carbonyl group;
R ₃ is a hydrogen atom, or (C ₁ -C ₄ ) alkyl, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkylcarbamoyl, (C ₁ -C ₄ ) hydroxyalkyl, Represents a di (C ₁ -C ₄ ) alkylaminomethyl, morpholinocarbonyl or 4- (4-fluoro-benzoyl) piperidin-1-yl-carbonyl group;
R ₄ is a hydrogen atom or hydroxy, (C ₁ -C ₄ ) alkoxy, carboxy, (C ₂ -C ₅ ) alkanoyloxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino (C ₁ -C ₄ ) alkoxy, di _(C 1 -C ₄₎ alkylamino _(C 1 -C ₄₎ alkoxy, di _(C 1 -C ₄₎ alkylamino _(C 1 -C ₄₎ alkyl, carboxy _(C 1 -C ₄₎ alkylcarbonyl, ( C ₁ -C ₄ ) alkoxycarbonyl (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C ₄ ) alkyl, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkoxy or m-hydroxy- p- azidophenyl carbonylamino _(C 1 -C ₄₎ alkoxy group, and,
R ₅ is a group of the following formula

(here,
Each of R _a and R _b is independently a hydrogen or halogen atom, or hydroxy, nitro, cyano, carboxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, hydroxy (C ₁ -C _{4) alkyl, (C} 1 -C _{4) alkoxycarbonyl, (C} 2 -C _{7) alkanoyl, (C} 2 -C _{5) alkanoyloxy, (C} 2 -C ₅₎ alkanoyloxy _(C 1 -C ₄ ) alkyl, trifluoromethyl, trifluoromethoxy, _{trimethylsilylethynyl, (C} 2 -C ₅₎ alkynyl, amino, azido, amino _(C 1 -C _{4) alkoxy, (C} 2 -C ₅₎ alkanoylamino _{(C 1} - C _{4) alkoxy, (C} 1 -C ₄₎ alkylamino _(C 1 -C ₄₎ alkoxy, di _(C 1 -C ₄₎ alkylamino _(C 1 -C _{4) alkoxy, (C} 1 -C ₄₎ alkylamino, di _(C 1 -C ₄₎ alkylamino, mono-halo benzylamino, thienyl methylamino, thienylcarbonyl amino, trifluoromethyl phenylaminocarbonyl, Tetrazolyl, (C ₂ -C ₅ ) alkanoylamino, benzylcarbonylamino, (C ₁ -C ₄ ) alkylaminocarbonylamino (C ₁ -C ₄ ) alkoxycarbonyl-aminocarbonylamino, or (C ₁ -C ₄ ) alkyl Represents a sulfonyl group,
R _c represents a hydrogen, fluorine, chlorine or bromine atom, or hydroxy, (C ₁ -C ₄ ) alkyl, (C ₂ -C ₅ ) alkanoyloxy, (C ₁ -C ₄ ) alkoxy or a cyano group, and,
R _d represents a hydrogen or halogen atom or a (C ₁ -C ₄ ) alkyl group)
Represents
Use according to claim 1 of a compound of general formula I. X ₁ is a (C ₂ -C ₄ ) alkenylene, (C ₂ -C ₄ ) haloalkenylene, (C ₂ -C ₄ ) alkynylene or (C ₂ -C ₄ ) haloalkynylene group, each of which is a vicinal unsaturated carbon Connected through an atom)
R ₁ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, ethynyl or di (C ₁ -C ₄ ) alkylamino group;
R ₂ is a hydrogen atom or hydroxy, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, di (C ₁ -C ₄ ) alkylaminomethyl, 4- (4-fluorobenzoyl) -piperidin-1-yl-carbonyl, 4-t-butoxycarbonyl-piperazin-1-yl-carbonyl, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carbonyl or 4- (4-azido-2-hydroxy-3-iodo) Represents a benzoyl) -piperazin-1-yl-carbonyl group;
R ₃ is a hydrogen atom, or (C ₁ -C ₄ ) alkyl, carboxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkylcarbamoyl, hydroxy (C ₁ -C ₄ ) alkyl, di _(C 1 -C ₄₎ alkyl aminomethyl, morpholinocarbonyl or 4- (4-fluoro - benzoyl) - represents a carbonyl group - piperidin-1-yl;
R ₄ is a hydrogen atom or hydroxy, carboxy, (C ₂ -C ₅ ) alkanoyloxy, (C ₁ -C ₄ ) alkoxycarbonyl, amino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkyl. Represents an amino (C ₁ -C ₄ ) alkoxy, di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl or hydroxy (C ₁ -C ₄ ) alkyl group; and
R ₅ is a group of the following formula

(here,
Each of R _a and R _b is independently a hydrogen or halogen atom, or nitro, cyano, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy or _(C 2 -C ₅₎ an alkynyl group;
R _c represents a hydrogen, fluorine, chlorine or bromine atom, or hydroxy, (C ₁ -C ₄ ) alkyl, (C ₂ -C ₅ ) alkanoyloxy, (C ₁ -C ₄ ) alkoxy or a cyano group; and,
R _d represents a hydrogen or halogen atom or a (C ₁ -C ₄ ) alkyl group)
Represents
Use according to claim 1 of a compound of general formula I.   Use according to claim 1 of 2-methyl-6- (phenylethynyl) -pyridine (MPEP).   Use according to claim 1 of 2-methyl-6- (2-phenylethenyl) -pyridine (SIB 1893). Compounds having the following general formula IA

(here,
R ′ represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, and
M is a group of the following formula

(Wherein R _aa , R _bb and R _cc are each independently a hydrogen or halogen atom, or (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) represents a hydroxyalkyl, hydroxy or cyano group,
R _dd represents a halogen atom or a cyano group,
R _ee represents hydroxy, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy group,
R _ff represents a hydrogen atom or a (C ₁ -C ₄ ) alkyl group,
Either R _gg and R _hh both represent a hydrogen atom or they are taken together to form the formula ═O, ═CH—CN, ═N—OH, ═N—O— (C ₁ -C _{4) alkyl, = CH-PO 3 [(} C 1 -C 4) _{alkyl] 2} or = _{CH-CO-R kk (where, R kk is, (C} 1 -C ₄₎ alkoxy or -NR _ll R _mm, where R _ll and R _mm are independently selected from hydrogen, (C ₁ -C ₄ ) alkyl and phenyl;
Each of Rii and Rjj independently represents a hydrogen atom, a (C ₁ -C ₄ ) alkyl group or a phenyl group, and
V ₁ is (CH ₂ ) _n (where n is 1, 2 or 3), or CHR _nn (where R _nn is hydroxyl, (C ₁ -C ₄ ) alkyl, (C _1- C ₄ ) alkoxy, (C ₁ -C ₄ ) hydroxyalkyl, (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, carbamoyl, (C ₁ -C ₄ ) alkylcarbamoyl, phenyl, pyridyl, thienyl, _or, (R _oo, in _R pp) N-lower alkyl _{(wherein, R oo} is _{hydrogen, (C} 1 -C _{4) alkyl, (C} 1 -C ₄₎ alkanoyl Or benzoyl and R _pp is hydrogen or (C ₁ -C ₄ ) alkyl), or when R _gg and R _hh are each hydrogen, V ₁ is NR _{q q} (where R _qq is (C ₁ -C ₄ ) alkoxycarbonyl, benzyloxycarbonyl, benzoyl, thienyl, (C ₁ -C ₄ ) alkanoyl, carbamoyl, mono- or di- (C ₁ -C ₄ ) Alkyl-carbamoyl or phenylcarbamoyl, and any phenyl ring in R _qq is optionally one or more halogen, cyano, (C ₁ -C ₄ ) alkyl, or (C ₁ -C ₄ ) may have an alkoxy substituent)
Represents)
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. Compounds of general formula II-A

(Wherein R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are each independently a hydrogen atom or lower alkyl, lower alkoxy, — (CH ₂ ) _n -halo, — (CH ₂ ) _n. —NR _e R _f , — (CH ₂ ) _n —N (R _e ) —C (O) —, (lower) alkyl, aryl or heteroaryl groups (which are unsubstituted, 1 or Substituted with the above lower alkyl groups);
B ₁ is the following

(here,
R ₁₁ represents a hydrogen or halogen atom, or a lower alkyl or — (CH ₂ ) _n —C (O) OR _e group,
R ₁₂ is hydrogen, lower alkyl, — (CH ₂ ) _n —C (O) OR _f , halo, nitro, or heteroaryl, which is unsubstituted or substituted with lower alkyl or cycloalkyl Represents);
R ₁₃ represents hydrogen, lower alkyl, — (CH ₂ ) _n —OH, — (CH ₂ ) _n —C (O) OR _g , or aryl;
R ₁₄ represents a lower alkyl group;
R ₁₅ represents a hydrogen or halogen atom or a lower alkyl group;
R ₁₆ represents a hydrogen atom or an alkyl group;
R ₁₇ represents — (CH ₂ ) _n —N (R _e ) —C (O) -lower alkyl,
Each of R ₁₈ , R ₂₆ , R ₂₉ , R ₃₀ and R ₃₁ independently represents a hydrogen atom or a lower alkyl group;
Each of R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ and R ₂₅ independently represents a hydrogen atom or a lower alkyl, — (CH ₂ ) _n -halo, or a lower alkoxy group;
R ₂₇ represents a hydrogen atom, a lower alkyl group, or a lower alkyl group having a hydroxy and / or halogen substituent;
R ₂₈ represents a hydrogen atom or a lower alkyl, lower alkanoyl or nitro group;
Each of R _e , R _f , and R _g independently represents a hydrogen atom or a lower alkyl group;
n is 0 or an integer from 1 to 6;
X ₂ represents an oxygen or sulfur atom or a methylene group; and
Y ₁ represents a nitrogen atom or a methine group)
Represents)
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. B ₁ represents B ₁ and R ₁₂ is substituted with (CH ₂ ) _n —C (O) OR _f , unsubstituted heteroaryl, or one or more lower alkyl or cycloalkyl 8. Use according to claim 7 of compound II-A, representing heteroaryl. R ₁₂ is, represents -C (O) O- lower alkyl, Use according to claim 8 of the compound II-A. Compounds of general formula II-B or II-C

(Here, each of R ₃₂ , R ₃₃ , R ₃₄ , R ₃₅ and R ₃₆ is independently a hydrogen atom or lower alkyl, — (CH ₂ ) _n -halogen, lower alkoxy, — (CH ₂ ) _N -NR _e R _f ,-(CH ₂ ) _n -N (R _e ) -C (O)-(lower) alkyl, aryl or heteroaryl group (which is unsubstituted or 1 or Substituted with more lower alkyl residues);
R ₃₇ represents a hydrogen or halogen atom, or a lower alkyl or — (CH ₂ ) _n —C (O) OR _e group;
R ₃₈ is a hydrogen or halogen atom, or a lower alkyl- (CH ₂ ) _n —C (O) OR _f , nitro or heteroaryl group (which is unsubstituted or substituted with lower alkyl or cycloalkyl Represents substituted);
R ₃₉ represents a hydrogen atom or lower alkyl, — (CH ₂ ) _n —OH, — (CH ₂ ) _n —C (O) OR _g or an aryl group,
R ₄₀ represents a lower alkyl group,
R ₄₁ represents a hydrogen or halogen atom or a lower alkyl group,
R ₄₂ represents a hydrogen atom or an alkyl group,
Each of R _e , R _f and R _g independently represents a hydrogen atom or a lower alkyl group; and
n is 0 or an integer of 1 to 6),
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. Compounds having the general formula III

(here,
A ₁ represents a 5-6- or 7-membered ring having the following structure:

(here,
At least one of W, X ₃ , Y ₂ and Z ₁ is a group (CR _h ) _p (where p is 1 or 2); and the remainder of W, X ₃ , Y ₂ and Z ₁ Are each independently O, N or S;
Each R _h is independently halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, substituted or substituted Not lower alkoxy, (lower) alkylcarbonyloxy, carboxyl, esterified carboxyl, amidated carboxyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cycloalkyl, mercapto, nitro , Carboxyl, carbamate, carboxamide, hydroxyl, ester, cyano, amine, amide, amidine, amide, sulfonyl, sulfonamide, or N- (lower) -alkyl-N-phenylcarbamoyl where each Nitrogen atoms are independently unsubstituted or substituted with lower alkyl, lower alkoxy, halo or trifluoromethyl) and q is 0, 1, 2 or 3) ,
L ₁ is a substituted or unsubstituted alkenyl, alkynyl or azo; and
B ₂ is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocyclic (optionally one or more double bonds Or substituted or unsubstituted aryl,
(Here, “substituted” means that one or more hydrogen atoms are hydroxyl, alkyl, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino , N-substituted- or N, N-di-substituted amino (wherein one or both nitrogen atoms are independently alkyl, heterocycle, aryl (each of which is optionally And further independently substituted with hydroxyl, alkyl or heterocycle)), or alkylamide, amidine, amide, carboxy, esterified carboxy, amidated carboxy, carboxamide A substituent selected from the group consisting of a carbamate, an ester, a sulfonyl, and a sulfonamide group Means replaced group)),
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract.   Use according to claim 11 of 3- (2-methylthiazol-4-yl) ethynylpyridine (MTEP). Compounds of general formula IV

(here,
n is 0, 1 or 2;
X ₄ is O, S, NH, or NOH,
Each of R ₄₃ and R ₄₄ independently represents a hydrogen atom or a cyano, COOR _i , CONHR _i , (C ₁ -C ₆ ) alkyl or tetrazolyl group, or R ₄₃ and R ₄₄ are Together represent an oxo group,
R _i represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,
R ₄₅ represents a carboxy, hydroxymethyl, alkoxymethyl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₃ -C ₈ ) cycloalkyl group,
Ar ₁ is an unsubstituted aromatic or heteroaromatic group, or one or more (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) -alkylamino, (C _1- C ₆₎ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, nitro, _{amino, (C} 1 -C _{6) acylamino, (C} 1 -C _{6) alkylthio, (C} 1 -C ₆₎ hydroxyalkyl, ( C ₁ -C ₆₎ alkylsulfonyl, and / _or, an aromatic or heteroaromatic group having a _(C 1 -C ₆₎ haloalkyl substituent,
Z ₂ represents a group of the following formula

(here,
R ₄₆ and R ₄₇ are independently hydrogen or halogen atom, or cyano, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkoxy, —OAr ₁ , (C ₁ -C ₆ ) alkyl, COOR _i , CONHR _i , COR _i , (C ₁ -C ₆ ) -alkylthio or (C ₁ -C ₆ ) -alkylsulfonyl group,
A ₂ is CH ₂ , O, NH, NR _i , S, SO, SO ₂ , CH ₂ —CH ₂ , CH ₂ O, CHOH or C (O) (where R _i is as defined above). Is)
B ₃ is CHR _i , C (R _i ) ₂ , (C ₁ -C ₆ ) alkyl, C (O), —CHOH, —CH ₂ —O, —CH═CH, CH ₂ —C (O), CH ₂ —S, CH ₂ —S (O), CH ₂ —SO ₂ , —CHCO ₂ R _i , or —CH—N (R _i ) _2, where R _i is as defined above. Is); and
Het is a heterocycle such as furan, thiophene or pyridine)),
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. Compounds of general formula VA below

(here,
Ar ₂ represents a heteroaryl group,
Ar ₃ represents an aryl group (wherein
Ar ₂ and Ar ₃ are optionally -F, -Cl, -Br, -I, -OR _j , -SR _j , -SOR _j , -SO ₂ R _j , -SO ₂ NR _j R _k , _{-OCOR j, -OCONR j R k,} -NRCOR k, -NRCO 2 R k, -CN, -NO 2, -CO 2 R j, CONR j R k, -C (O) R j, -CH (OR _j ) substituted with one or more substituents selected from the group consisting of R _k , —CH ₂ (OR _j ), —R _j and —A— (CH ₂ ) _n —NR _j R _k (here Wherein R _j and R _k are independently selected from the group consisting of H, CF ₃ , (C ₁ -C ₁₀ ) alkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, heterocycloalkyl, aryl. Luke, or, _{R j} and _{R k} are binding It may form a _{C 1-5} methylene chain and, _{and, A} is, CH 2, O, NH, S, SO, defined as SO _2, and, n is 1, 2, 3 or 4 is there)),
G ₁ is, -NH -, - S, -O -, - CO -, - CONH -, - CONHCH 2 -, CH 2 CONH -, - CH 2 NHNH -, - CH 2 NHNHCH 2 -, - C = NO _{-CH 2 -, - CH 2 NHCH} 2 -, CH 2 CH 2 NH-, NHCH 2 CO-, NHCH 2 CHOH -, - NHCH 2 NHNH -, - or is selected from the group consisting of -NHCONH-, or, G ₁ is cyclopentane, cyclopentadiene, furan, thiofuran, pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4-imidazoline, imidazole, pyrazoline, pyrazolidine, imidazolidine, oxazole, 2-oxazole, thiazole, isoxazole, iso Thiazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole Azole, 1,2,4-oxathiazole, 1,3,4-oxathiazole, 1,4,2-dioxazole, 1,4,2-oxathiazole, 1,2,4-oxadiazole, 1, 2,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1H-tetrazole, cyclohexane, piperidine, Tetrahydropyridine, 1,4-dihydropyridine, pyridine, benzene, tetrahydropyran, 3.4-dihydro-2H-pyran, 2H-pyran, 4H-pyran, tetrahydrothiopyran, 3,4-dihydro-2H-thiopyran, 2H- Thiine, 4H-thiopyran, morpholine, thiomorpholine, piperazine, pyridazine, pyrimidine, pyrazine, 1 2,4-triazine, 1,2,3-triazine, 1,3,5-triazine, or a divalent cyclic group derived from 1,2,4,5-tetrazine)
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract. Ar ₃ is phenyl, benzyl, naphthyl, fluorenyl, Antoreniru, indenyl, represents a phenanthrenyl or benzonaphthenyl group, Use according to claim 14 of a compound V-A. Ar ₂ is thiazolyl, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazolyl, benzimidazolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl 16. A use according to claim 14 or claim 15 of compound VA representing, phthalidinyl, naphthyridinyl, quinazolinyl, cinazolinyl, isothiazolyl, quinoxalinyl, indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl or chromenyl group . Compound having the following general formula V-B

(here,
X ₅ , Y ₃ , and Z ₃ are independently selected from the group consisting of N, O, S, C, and CO (wherein at least one of X ₅ , Y ₃ , and Z ₃ is heterogeneous) Atoms);
Ar ₄ and Ar ₅ are each independently heterocyclic and 1-4 heteroatoms selected from the group consisting of N, O and S, and phenyl, benzyl, 1-naphthyl, 2-naphthyl and fluorenyl. And selected from the group consisting of condensed heterocyclic groups containing an aromatic group selected from the group consisting of anthrenyl, indenyl, phenanthrenyl and benzonaphthenyl (wherein Ar ₄ and Ar ₅ are optionally _{Te, -F, -Cl, -Br, -I} , OR j, -SR j, -SOR j, -SO 2 R j, -SO 2 NR j R k, -OCOR j, -OCONR j R k, - _{NRCOR k, -NRCO 2 R k,} -CN, -NO 2, -CO 2 R j, -CONR j R k, -C (O) R j, -CH (OR j) R k, -C _{2 (OR j)} -R j and _{-A- (CH 2) n -NR j} R k ( where, _{R j} and _{R k} are _{independently, H, CF 3, (C} 1 -C 10) alkyl , Cycloalkyl, alkyl-aryl, alkyl-heteroaryl, heterocycloalkyl, aryl, or R _j and R _k may combine to form a C _1-5 methylene chain. , A is defined as CH ₂ , O, NH, S, SO, SO ₂ , and n is 1, 2, 3, or 4), one or more substituents selected from the group consisting of )),
Alternatively, an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable salt of such a compound, Use for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract.   The heterocyclic or condensed heterocyclic group is selected from the group consisting of quinolyl, quinazolyl, quinoxalyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and pyrazyl. 18. Use according to claim 17 of selected compound V-B. (A) binds to the mGlu5 receptor with an affinity of at least 10 ⁻⁶ M, and (b) an affinity that is at least 10 times stronger than the affinity that the compound binds to any one of the mGlu1, mGlu2 or mGlu3 receptors. And binds to the mGlu5 receptor,
Use of a compound for the preparation of a medicament for the treatment of neuromuscular dysfunction of the lower urinary tract.   20. The use according to claim 19, wherein the compound binds to the mGlu5 receptor with an affinity that is at least 10 times stronger than the affinity to bind each of the mGlu1 receptor, mGlu2 receptor and mGlu3 receptor.   21. The compound of claim 19 or claim 20, wherein (c) the compound binds to the mGlu5 receptor with an affinity that is at least 10 times greater than the affinity that the compound binds to any one of the group III mGlu receptors. use. (A) measuring the binding affinity of one or more test compounds to the mGlu5 receptor and one or more mGlu1 receptors or group II mGlu receptors;
(B) (1) binds to the mGlu5 receptor with an affinity of at least 10 ⁻⁶ M; and
(2) identifying a test compound that binds to the mGlu5 receptor with an affinity that is at least 10 times greater than the affinity for the mGlu1 receptor or the group II mGlu receptor;
A method for identifying a compound useful for treating neuromuscular dysfunction of the lower urinary tract in a mammal. Individually measuring the binding affinity of the one or more test compounds for one or more group III mGlu receptors; and
Identifying a test compound that binds to the mGlu5 receptor with an affinity 10 times stronger than its affinity for the group III mGlu receptor;
23. The method of claim 22, further comprising:

Images