TW200418798A - Selective mGlu5 antagonists for treatment of neuromuscular dysfunction of the lower urinary tract - Google Patents

Abstract

Antagonists that are selective for the metabotropic mGlu5 receptor over at least one of the metabotropic mGlu1 receptor, mGlu2 receptor and mGlu3 receptor, and preferably selective over all three thereof, are useful for the preparation of medicaments for the treatment of neuromuscular dysfunction of the lower urinary tract in mammals. A wide variety of suitable compounds is described. The medicament may contain the selective mGlu5 antagonist as the sole active agent, or may also contain one or more additional therapeutic agents for the treatment of neuromuscular dysfunction of the lower urinary tract in mammals. Also provided are methods of identifying selective mGlu5 antagonists that are useful for treating neuromuscular dysfunction of the lower urinary tract in mammals.

Description

200418798 发明, Description of the invention: L · j ^ rf j | FIELD OF THE INVENTION The present invention relates to ^ (^ "subtype compounds with selective affinity for subtypes, and pharmaceutical compositions containing the same And the use of this compound and composition. C Previous 3 Background of the Invention In mammals, urination is a complex process that requires the overall function of the bladder, its internal and external sphincter, and the pelvic floor. Neural control of these muscles Occurs at three levels-the bladder wall or sphincter, the autonomic ganglia of the spinal cord, and the medullary (pontine) pontine urination center (PMC) central nervous system. This is controlled by the cerebral cortex (De Groat, < Incontinence, Ciba Foundation Symposium 151 : 27, 1990) 〇I5 Urination results from the contraction of the urinary detrusor muscles, which are composed of staggered smooth muscle fibers under the control of the parasympathetic autonomic nerve of the sacral spinal cord. The sensory nerves of temperature and swelling are formed from the bladder to the sacral cord. However, the sensory bundles from the bladder also reach the pontine voiding center, causing the After the impulse is generated, it normally acts on the spine to inhibit the recommended cone reflex arc that controls bladder emptying. As a result, normal urination is caused by the inhibition of the cortical inhibition of the reflex arc and relaxation of the pelvic floor and external sphincter muscles. Beginning. This temple event is followed by the contraction of detrusor muscles and dysuria. The lower urinary tract functions are not normal, such as dysuria, urinary incontinence and enuresis. The 5 common diseases are dysuria, including frequent urination, nocturia and urine. Acute and may be caused by cystitis (including intermittent cystitis), prostatitis or benign prostatic hypertrophy (BPH), or neurological disorders affecting approximately 70% of older men. Symptoms of urinary incontinence include stress urinary incontinence Urgent urinary incontinence, spill urinary incontinence, and mixed urinary incontinence. Enuresis means involuntary urination at night or while sleeping. Treatment of neuromuscular disorders of the lower urinary tract typically involves the administration of direct action on the bladder muscle Compounds, such as flavonide, are an antispasmodic (Ruffman, J "/ Val. Med and from 16: 317, 1988) and also act on PMC (Gu arneri et al., Drw, c / 7b, y, 30:91, 1994), or oxybutynin (Andersson, Drwgs 36: 477, 1988) and tolterodine (Nilvebrant, 5W) 68: 2549, 2001). It is also common to use al-adrenoceptor antagonists to treat BPH (Lepor, ep / π / 叹, 42: 483, 1993). US Patent No. 5,990,114 6,306,861; 6,365,591; 6,387,909; and 6,403,594 indicate that αΐ-adrenergic receptor antagonists (including subtype selective antagonists) are used to treat lower urinary tract disorders. However, treatments that involve the direct suppression of pelvic muscle tissue including detrusor muscles can have unwanted side effects such as incomplete urination, modulated reflex mochi, fast heartbeat and dry mouth (Andersson, Drw% 35: 477, 1988). Therefore, the preferred method of treating neuromuscular disorders of the lower urinary tract is to 'use the effect through the peripheral or central nervous system to restore normal urination in a manner that affects the inhibitory nerve impulses such as the recommended cone reflex arc and / or the pontine urinary center. Mechanism of functional compounds. Glutamate, an excitatory amino acid, is found in synapses of the central nervous system 200418798. It is known to act on at least two receptor types: ionophilic and metabotropic facial amino acid receptors. Upon activation, the ionic surface amino acid receptor forms a ligand-gated ion channel, which directly regulates the electronic signals of nerve cells and produces rapid and relatively large conduction changes on the postsynaptic membrane. Metabotropic facial amino acid receptors (mGluRs) indirectly regulate electronic signals through G-proteins affecting intracellular metabolic processes. Therefore, compared to the rate of action of the ionic surface amino acid receptor, the change in post-synaptic cells regulated by mGluRs is relatively slow for a period of time, so it will not be linked to nerve membrane conduction quickly and in large quantities. Change. Read 10 Two types of ionophilic glutamate receptors have been described, namely NMDA, AMPA and kainate subtypes. Eight metabotropic glutamate receptor subtypes have been selected. These subtypes are divided into three groups based on sequence similarity and pharmacological and biochemical characteristics (Spooren et al., 7Vm Office P / zarmaw / · & z · 22: 331-337, 2001): Group 15 I Group mGluRs (mGlu 1 and mGlu5), group II mGluRs (mGlu2 and mGlu3) and group III mGluRs (mGlu4, mGlu6, mGlu7, and mGlu8). Alternative splicing is the origin of the diversity of receptors in groups I and III. Origin 0 There are comments on the structure of mGluRs in the literature of Hermans and Challis. 20 On J. 359: 465-484, 2001). Regarding group I, the rat mGlul receptors include four isoforms of mGlula, mGlulb, mGlulc, and mGluld, which contain 1199, 906, 897, and 912 amino acids, respectively. This isotype shares a common N-terminal region with 887 amino acids and is connected to each of the 7 amino acids with 312 (mGlula), 19 (mGlulb), 10 (mGlulc) and 25 (mGluld). C-terminal region. The different c-terminal regions are generated by alternative splicing. Similarly, three human mGiu 1 receptors are known, namely mGlu 1 a (1194 amino acids), mGlulb (906 amino acids), and mGluld (908 amino acids). These human receptors contain a common 5 team end region with 887 amino acids and are connected to each other by alternative splicing, with 307 (mGlula), 19 (mGlulb) and 21 (mGluld) amine groups. C-terminal region of the acid. In terms of function, when all homogens from rats or humans are counted sequentially from the N-terminus, the common N-terminus region contains a 10-cell outer region and one composed of 7 transmembrane α- The beginning of a typical G-protein-coupled bilayer transmembrane region and an intracellular region formed by a helix. The variable end region forms a second intracellular loop, which completes the intracellular regions of each isotype. Ligand-specific recognition and binding occurs in extracellular regions. G-protein binding is accomplished by linking the intracellular region of a specific transmembrane alpha-helix to the intracellular loop. 15 For the four subtypes, their ligand affinity and ability to stimulate the second message ladder response are the same. Type VII mGlu5 receptors known in both humans and rats include mGlu5a and mGlu5b subtypes. In both humans and rats, the subtype Giu5b differs from the subtype mGlu5a in that mGlu5b swims 50 residues (ie, toward the C-terminus) 20 from the terminal end of the transmembrane region, and the C-terminal intracellular region It contains an insert of 32 amino acids, which is not present in the subtype mGluSa. The differences between the subtypes arise from alternative mRNA splicing. According to this, rat mGlu5a has 1171 amino acids, and 111 (} 11: 15 | 3 has 1203 amino acids. This difference is because the mGlu5b receptor contains the 32 amino groups at positions 876_907. Human. 8 200418798 111〇1115 & has 1180 amino acids, and 111〇11151) has 1212 amino acids, this difference is because the mGlu5b receptor contains the 32 amino acids (Hermans at positions 877-908) et al., 359: 465-484, 2001). With regard to group III, alternative splicing resulted in two types of isoforms (i.e., subtypes "a" and "b") on mGlu4 and mGlu7 receptors, and three types of isotypes (i.e., subtypes) on mGlu8 receptors. a "," b ", and" c ") (Hermans et al., J._359: 465_484, 2001). In contrast, mGlu6 receptors are currently known to have only a single isotype (Hermans et al., * / · 359: 465-484, 2001). Both rat and human mGlu4a receptors have 912 amino acids. Rat Xin 10 also produced 983 amino acid long mGlu4b isoforms. This is due to the fact that different 135 amino acid groups replaced the last 64 amino acids of the mGlu4a isoform during alternative splicing (Thomsen et al ·, 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 15 amino acids, respectively. In both mGlu7 and mGlu8 receptors, the "b" homogeneous body has been altered relative to the "a" homogeneous body due to alternative splicing, resulting in 23 or 16 different amino acid groups replacing mGlu7a and mGlu8a, respectively. The last 16 amino acids (Corti, et al., P. wr. J. iVei / rosc /., 10: 3629-3641, 1998). The mGlu8c isoform is found only in humans and it is only 501 amino acids long. 20—An out-of-framework insert generates a stop code in front of the first alpha helix in the transmembrane region, so the predicted human mGlu8c protein may be equivalent to secreting homologous receptors (Malherbe, et al., And team Mo /. And team, 67: 201-210, 1999.) The binding of glutamic acid to group I receptors will generate G-protein-activated activated phosphorus 9 200418798 lipase c and break membrane phospholipids into chemical signals Inositol triphosphate and glycerin dioxin. Diacetic acid releases Ca from the internal storage tank. As a result, the activation of group I mGluRs mainly regulates neuronal excitation or increases neuronal excitement. 5 Glutamate binding to group II or III receptors will cause inhibition of G-protein regulation, making adenylyl cyclase. Inhibition of adenylate cyclase activity results in reduced production of cyclic adenylate (cAMP). As a result, activation of the ^ and 砠 groups mainly regulates the inhibition of synaptic transmission. The function of urinary excitatory receptors in the urination reflex pathway has been detected by administering drugs that block the ionophilic glutamic acid receptors. For example, MK 801, a non-competitive blocker of NMDA receptors, is administered intravenously, which reduces the magnitude of bladder contraction. MK 801 also increases the threshold of micturition volume in some experiments, but it will not be used in its dagger test (deGroat, WC, et al., In: control of the urogenital system, CA Maggi (ed.), Harwood 15 Academic Publishers, pp. 227-290, 1993) WO 00/63166 discloses tricyclic aminocarboxylic acid derivatives for treating different diseases including urinary incontinence. This disclosure discloses that these derivatives are synergists or antagonists of the first receptor, and are specific to the mGliil receptor. WO 01/32632 discloses 20 pyrimidine derivatives for treating different diseases including urinary incontinence. This disclosure discloses that these derivatives are selective antagonists of mGlul receptors, and the selectivity of mGlul receptors & mGlu5 receptors is at least 10 times higher. ^ WO 01/27070 discloses a novel diarylacetamide, which is used in the treatment of urinary incontinence among other diseases. This reveals that these molecules are selective synergists or antagonists of mGlul receptors. 10 200418798 US 6369222 discloses heterocyclic azacortyl "close-bite derivatives, which are used in the treatment of urinary incontinence, among other diseases. This disclosure discloses that these derivatives are antagonists of mGlul receptors. Therefore, these published patents Reveal the secretion of 1111 receptors can be used to treat urinary incontinence. However, these documents do not provide experimental support for the treatment of urinary incontinence in human patients or in animal models with lower urinary tract diseases. Patients often respond to a specific or sub-type of therapeutic agent. On the other hand, patients may initially respond to a therapeutic agent, but after a period of time become unresponsive to the agent. In addition, 10 When administered in concentrations for the treatment of lower urinary tract conditions, patients may show unwanted side effects. These side effects can be achieved by changing to different therapeutic agents' or by administration of two or more lower therapeutic effects. Doses of the therapeutic agent to reduce or overcome, wherein the one or more lower doses are not sufficient to achieve a therapeutic effect when the respective therapeutic agents are used alone. 15 Accordingly, one Those skilled in the art should be aware of the continuing need to identify novel therapeutic agents for the treatment of lower urinary tract diseases. This novel therapeutic agent can be used alone to treat lower urinary tract diseases. New therapeutic agents can be specifically used to treat one or two Patients who did not respond to multiple alternative therapeutic agents, became unresponsive to alternative therapeutic agents, or were suitable for combination therapy with two or more therapeutic agents. 20 We have tested mGlu 1 in a rat model for detecting activity on the lower urinary tract Selectivity and activity of mGlu5 selective antagonists. Surprisingly, it has been surprisingly found that mGlu5 receptor-selective antagonists have good activity, whereas two commercially available antagonists that are selective for mGlul receptors have not been shown. Effects. Device-selective antagonists of group II mGluRs have also shown effects in rat models11. Based on these results, mGlu5 selective antagonists may become effective tools for treating lower urinary tract disorders. Mingne j Summary of the invention The present invention provides the use of a compound for the preparation of a medicament for treating neuromuscular dysfunction of the lower urinary tract, the compound (a) The affinity for binding to the mGlu5 receptor is at least 10-6m, and (b) the affinity for binding to the mGlu5 receptor is stronger than the affinity of the compound for binding to one of the 1111011 receptor 'mGlu2 receptor or the mGlu3 receptor At least 10 times. Preferably, the compound has an affinity for binding to the mGlu5 receptor that is at least 10 times stronger than the affinity of the compound for binding to each of the mGlul receptor, mGlu2 receptor, or mGlu3 receptor. Additionally, the compound is preferably 0) The binding affinity to mGlu5 receptors is at least 10 times stronger than the binding affinity of the compound to one of the mGlu receptors in group in. Better selectivity to mGlu5 receptors is 100 times more than other mGlu receptors. Level. The neuromuscular dysfunction to be treated with this agent can be urgency, overactive bladder, frequent urination, decreased bladder compliance (decreased bladder storage capacity), cystitis (including intermittent cystitis), urinary incontinence, urine leakage , Enuresis, difficulty urinating, slow urination, and difficulty in emptying the bladder. Appropriately, as the bladder dilates to increase bladder capacity and the time interval between urination and the next urination, the agent will effectively reduce the frequency of bladder contraction 200418798. In the preferred embodiment, the structures represented by Formulae 1 to V. The mGlu5 selective antagonist has the following general formula compounds, or its isomers and non-image isomers: Compounds, crystalline forms, hydrates, solvates prodrugs or pharmaceutically acceptable salts: pharmacologically active generation

Among them: R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower amine group, brigade 10 σ 疋 group, slow group, esterified rebel group, fluorenated fluorenyl group, lower alkoxy group, lower 1¾ alkyl, lower 12¾ alkyl, cyano, alkynyl, lower alkyl, bis- (lower) alkylamino, lower alkylaminocarbonyl, trifluoromethylbenzylaminocarbonyl, or N- ( Lower) alkyl-N-phenylaminofluorene, the N- (lower) alkyl and N-phenyl radicals are unsubstituted or independently substituted by a group selected from the group consisting of 15 Substituted groups: lower alkyl, lower alkoxy, i element and trifluorofluorenyl groups, R2 represents hydrogen, lower alkyl, carboxyl, esterified carboxyl, fermented carboxyl, lower hydroxyalkyl, Hydroxyl, lower alkoxy or lower alkylsulfonyloxy, lower alkoxycarbonyl, di- (lower) -alkylamino- (lower) alkylfluorenyl, di 20- (lower) alkylaminomethyl, 4- (4-fluorophenylfluorenyl) -piperidin-1-yl-daiyl, 4-fluorenyl-butyloxycarbonylpiperazin-1-yl-carbonyl, 4- (4-azido-2-hydroxyphenylfluorene)醯 13 200418798 radical)-sigma qin-1 -yl-jiki or 4- (4-pentazine-2- surname -3 -Alkyl-benzyl)-Lukhan-1-yl-Weiji 'represents hydrogen, lower alkyl, carboxyl, lower alkoxycarbonyl, lower alkylaminoformamidine, lower hydroxyalkyl, di- ( Lower) alkylaminomethyl, morpholino 5 carbonyl or 4- (4-fluorobenzylidene) piperidin-1-yl-carbonyl, 'R4 represents hydrogen, lower alkyl, hydroxyl, lower hydroxyalkyl, Lower amine alkyl, (lower) alkylamino (lower) alkyl, di- (lower) alkylamino (lower) alkyl, unsubstituted or substituted with (lower) alkyleneamine (lower) ) Alkyl, lower alkoxy, lower alkanoyloxy, lower amine alkoxy, (lower) alkylamine-10 group (lower) alkoxy, di- (lower) -alkylamino (lower) alkane Oxy, lower alkoxycarbonyl, carboxy (lower) alkoxy, (lower) alkoxycarbonyl (lower) alkoxy, lower hydroxyalkyl, m-hydroxy-o-azidophenylcarbonyl (lower) alkane Oxy, lower amine alkoxy, benzodiamidino (lower) alkoxy, unsubstituted (lower) alkyleneamine (lower) alkoxy or hydroxyl or 2-side oxygen-imidazole (Lower) alkane substituted with alkyl-15 Amine (lower) alkoxy, carboxyl, esterified carboxyl, fluorinated carboxyl, lower carboxyalkoxy or lower g-carboxylated alkoxy, where X stands for lower alkenyl, lower i Fluorenyl, lower alkynyl, or lower halidene groups, wherein each of the foregoing groups is connected via a vicinal unsaturated 20 and a carbon atom, or an azo group (-N = N-) , And R5 represents an aromatic or heteroaromatic group, which is unsubstituted or substituted with one or more * substituents selected from: lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylfluorenyl, trifluoro Fluorenyl, trifluoromethoxy, trimethylsilylalkynyl, azide, lower amine alkoxy, di- (lower) -alkylamino (lower) alkoxy 14 200418798, mono-i-benzene Methylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, lower alkylamino, benzylamino, (lower) alkylaminocarbonyl (Lower) alkoxycarbonylamine carbonylamino, (lower) alkanesulfonyl, lower alkyl 'dentyl, lower i-alkyl, lower haloalkoxy 5oxy, lower alkenyl, low Alkynyl, unsubstituted phenyl or one or more-substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and trifluoromethyl groups Phenyl, unsubstituted phenyl (lower) alkynyl, or one or more substituents selected from the group consisting of lower alkyl, lower alkyl, halo, and trifluoromethyl groups Substituted phenyl_ 10 (lower) alkynyl, hydroxy, lower hydroxyalkyl, (lower) alkylfluorenyloxy (lower) alkyl, lower alkoxy, lower alkenyloxy, lower alkylene dioxy Base, lower alkylalkoxy, lower amine alkoxy, (lower) alkylamino (lower) alkoxy, (lower) alkylamino (lower) alkoxy, N- (lower) -alkyl -N- (lower) _ Bake amine (lower) alkoxy, unsubstituted phenoxy or be substituted by one or more of 15 from lower alkyl, lower alkoxy, _ and trifluoro Phenoxy, phenyl (lower) alkoxy or phenyl (lower) alkoxy substituted by a substituent of a group of methyl groups, wherein the phenyl group is selected from one or more of Low-level Lu Shaoji, Substituted by substituents of the group consisting of lower alkoxy group, A group and triII methyl group, alkynyl group, carboxyl group, esterified Wei group, acid aminated 20 carboxyl group, cyano group, carboxyl (Lower) alkylamino, esterified carboxyl (lower) alkylamine, fluorenated carboxyl (lower) alkylamine, phosphine (lower) alkylamine, esterified phosphine (lower) Amine, Nitro, Amine, Lower Amine, Di- (Lower) -Alkylamino, Amido, N-Amino-N- (Lower) -Alkylamino, Aniline, Phenyl (Lower ) Alkylamino, cycloalkyl (lower) alkylamino or heteroaryl (lower) alkylamine 15 200418798 groups each of which may be unsubstituted or lower alkyl-lower alkoxy-, -And / or tri-It methyl. Compounds of formula I having a base group can form acid addition salts, and compounds of formula I having an acid group can form salts with bases. Compounds of formula I having a base group and at least one acid group may also form internal salts. The present invention includes partial and total salts, that is, salts having 1,2, or 3, preferably 2 equivalents of base per mole of acid, or 2 or 3 per mole of base, preferably 1 equivalent of acid salt. It is also possible to use pharmaceutically unacceptable 10 salts for isolation or purification purposes. However, only pharmaceutically acceptable, non-toxic salts can be used therapeutically, so it is preferred. When X! Represents an alkenyl group, a reverse configuration is preferred. Preferred compounds of formula I are those which, independently or together, have the following: 15 χι represents (C2 · 4) alkenyl, (C2-4) iarylene, (C2 · 4) arynyl or (C2_4) _ Alkynyl groups in which each of the above groups is connected through a vicinal unsaturated carbon atom 'K is hydrogen, (Cm) alkyl, (Cm) alkoxy, (Cm) hydroxyalkyl, gas Group, ethynyl group, carboxyl group, (Cm) alkoxycarbonyl group, di- (Cm) -alkylamino group, 20-aminoamino group, or trifluoromethylphenylamino group, which is hydrogen, hydroxyl, ( Cl-4) alkyl, (Cm) via alkyl, alkyl, carboxyl, (C2_5) alkanoyloxy, (Cm) alkoxycarbonyl, di < Ci 4)-amine (Ci_4) , Bis- (Ci · 4) -alkylaminomethyl, 4- (4-fluorobenzylmethyl) -piperidin-1-yl-carboxyl, 4-fluorenyl-butyloxycarbonyl-piperazine-1 -Yl-carbonyl, 16 200418798 4- (4-pentino-2- via benzoate) -pyr-1-yl-weiyl or 4- (4-phenyl-2- vial-3- Moth methanoyl) -Qin-1 -yl carbon-based 'R3 is hydrogen, (Ci_4) alkyl, carboxyl, (Cm) alkoxycarbonyl, (Cm) alkylaminoformamidine, ((^ _4 ) Hydroxyalkyl, di- (Cm) -alkylaminomethyl, 5 Weiji morpholino or 4- (4-gas-yl - benzyl groups stuffed - yl betray '

R4 is hydrogen, hydroxyl, (Cm) alkoxy, carboxyl, (C2.5) alkanoyloxy, (Cm) alkoxycarbonyl, (Cm) amine alkoxy, di- (Cm) -alkylamino (Cm) alkoxy, dialkylamino ((^ _4) alkyl, carboxy (Cm) alkylcarbonyl, (Cm) alkoxycarbonyl (Cm) alkoxy, (CN4) hydroxyalkyl, di- (Cm ) -Alkylamino (Cm) 10 alkoxy or m-hydroxy_o-azidophenylcarbonylamino (Cm) alkoxy, and R5 is a group having the formula

Heart and heart are independently hydrogen, hydroxyl, halo, nitro, cyano, 15 carboxyl, (Cm) alkyl, ((^ _4) alkoxy, hydroxyl ((^ _4) alkyl, ((^ _4) Alkoxycarbonyl, (C2.7) alkylfluorenyl, (C2.5) alkylfluorenyloxy, (C2_5) alkylfluorenyloxy (Ci_4) alkyl, trifluoromethyl, trifluoromethoxy , Trimethylsilyl ethynyl, (c2.5) alkynyl, amine, azide, (Cw) amine alkoxy, (c2_5) 17 200418798 alkylamido (Cw) alkoxy, ( Cm) alkylamino ((^ _4) alkoxy, di- (Cw) -alkylamino (C ^) alkoxy, (C ^) alkylamino, di- (C ^)-alkylamino, Monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C2_5) alkylamino, benzylamino, ((^ _4) 5 alkylaminocarbonylamino (Cm) alkoxycarbonyl-aminocarbonylamino or (Ci_4) alkylsulfonyl,

Rc is hydrogen, fluoro, alkynyl, molyl, meridian, (Ci_4) alkyl, (C2_5) alkanoyloxy, (Cm) alkoxy or cyano, and Rd is hydrogen, halo, or ( Cm) alkyl. 10 More preferably, the compound of formula I is as defined above and has the following: · is hydrogen, (Cm) alkyl, (Cm) alkoxy, cyano, ethynyl, or di- (Ci_4) -carbamine R2 is hydrogen, hydroxy, carboxyl, (Cm) alkoxycarbonyl, di- (Cm) -alkylaminomethyl, 4- (4-muryl-benzoic acid) -coryl-1-yl-end Base, 4-hetero-butyl 15 oxoyl-ninja-1 -yl-endyl, 4- (4-fengmuryl-2-benzoyl) -nithyl

-1-yl-carboxyl or 4- (4-azido-2-hydroxy-3-iodo-benzylidene) -piperazin-1-yl-weiyl 'R3 is as defined above, R4 is hydrogen, Hydroxyl group, carboxyl group, (C2.5) alkylamino group, (Cm) alkyloxycarbonyl group 20, amino group (Cm) alkoxy group, di- (C ^)-alkylamino group (Cm) alkoxy group, Di- (Cm) -alkylamino (Cm) alkyl or hydroxy (Cm) alkyl, and R5 is a group having the formula

Or 〇-

Rd 18 200418798 of which

Ra and Rb are each independently hydrogen, i-group, nitro, cyano, (Cw) alkyl, (Cu) alkoxy, trifluoromethyl, trifluoromethoxy or (C2_5) alkynyl; and Re and Rd is as defined above. 5 More preferred are 2-methyl-6- (phenylethynyl) pyridine (MPEP) and 2-methyl-6- (2-styrylpyridine (SIB 1893).

In specific embodiments, the present invention provides a compound having a structure represented by Formula I-A, or a mirror image isomer, non-image isomer thereof, N-oxide, crystal form, hydrate, solvate, pharmacology Active metabolites, prodrugs or 10 pharmaceutically acceptable salts. R, C three C-M

Ι-Α where R 'is hydrogen or (Cm) alkyl, and M is a group of formula 15

among them

Raa, Rbb and Rec are each independently hydrogen, (Ci-4) alkyl, (Ci_4) oxy, hydroxyl, (Ci_4) hydroxyalkyl, cyano or halo,

Rdd is cyano or halo, 19 200418798

Ree is hydroxy, (Cm) alkyl or (Cm) alkoxy,

Rff is hydrogen or (C ^) alkyl,

Rgg and Rhh are hydrogen or together form a group of the formula: = 〇, = CH-CN, = N_OH, alkyl, ^ CH-PO ^ Cm) alkyl] 2 5 or = CH-CO-Rkk, where Rkk is (Cm) alkoxy or -NRuRmm, where:

Ru and Rmm are independently selected from hydrogen, (Cm) alkyl and phenyl,

Rn and Ry are independently hydrogen, (Ci_4) alkyl or phenyl, and

Vi is (CH2) n, CHRnn, where η is di 2 or 3, Rnn is hydroxyl, (Cμ) alkyl, (Cm) alkoxy, (Ci_4) hydroxyalkyl, (Cm) alkoxy (Cm) Alkyl, _10 (Cm) alkoxycarbonyl, aminoformamidine, ((^ _4) alkylaminoformamidine, phenyl, arodinyl, thienyl, or (R_RPP) N-lower alkyl, where R ... is hydrogen, (Cm) alkyl, (Cm) alkyl or benzamyl and Rpp is hydrogen or (Cm) alkyl, or assuming that Rgg and Rhh are each hydrogen, Vi may also be NRqq, Rqq is (Cm) alkoxycarbonyl, benzyloxycarbonyl, benzamidine, thienyl, (Cm) alkylamido, amine 15-methylformamidine, mono- or di- (Cm) -alkylaminoformamidine, or Phenylaminomethane, any phenyl ring in Rqq is optionally substituted with one or more halo, cyano, (Ci_4) alkyl or (Cm) alkyloxy groups. (2) Formula Compounds of II structure (ie II-A, II-B or II-C), or their mirror isomers, non-image isomers, N-oxides, crystalline forms, hydrates, _ 20 solvates, pharmacology Active metabolites, prodrugs or pharmaceutically acceptable salts:

20 200418798 where R6, R7, ruler 8, ruler 9 and Ri〇 independently represent hydrogen, lower courtyard, lower alkoxy,-(CHJrrli group,-(CH2) n_NReRf,-(CH2) nN (Re)- C (0)-(lower) alkyl, aryl or heteroaryl 'which is unsubstituted or substituted with one or more 5 lower alkyl groups;

Bi stands for

among them

Rll represents hydrogen, lower radical,-(CH2) nC (0) 0Re or halo, 10 Ri2 represents nitrogen, lower radical,-(CH2) nC (0) 0Rf, radical, stone radical or heteroaryl radical, which Unsubstituted or substituted with lower or cycloalkyl;

Ris represents hydrogen, lower alkyl,-(CH2) n-OH,-(CH2) n-C (〇) 〇Rg or aryl;

Rl4 substituted lower alkyl; 15 Rl5 represents hydrogen, lower alkyl or radical;

Rl6 represents hydrogen or alkyl;

Rn represents-(CH2) n-N (Re) -C (0) _ lower alkyl; R18 represents hydrogen or lower alkyl; 21 200418798

Rl9, R2G, R] 1 and R22 independently represent nitrogen, lower alkyl,-(CH2) n-halo or lower alkyl; R23, R24, and R25 independently represent hydrogen and lower halogen. ,-(CH2) n_ halo or lower alkyl; 5 R26 represents hydrogen or lower alkyl; R27 represents hydrogen, lower alkyl or lower alkyl substituted by one or more substituents selected from the group consisting of alkyl or halo R28 represents hydrogen, lower alkyl, lower alkyl or nitro; R29, R3G, and R31 independently represent hydrogen or lower alkyl; 0 Re, Rf, and Rg independently represent hydrogen or lower courtyard; η Is 0, 1, 2, 3, 4, 5 or 6; χ2 is -CH2-, -〇- or _s_; and Υι is -CH = or -N =. Examples of compounds of formula II-A are 5-methyl-2-phenylethynyl-1H-imidazole, 1-methyl-2- (4-methoxy-phenylethynyl) -1H-imidazole, 1-methyl Iso-5-benzyl, as well as 1-methyl-4-phenylethynylimidazole, may be contained within or excluded from the formula η. 〇 In a specific embodiment, the present invention also relates to compounds having the general formulae ^^ and ^ /, or mirror image isomers, non-image isomers, N-oxides, ..., type a, hydrated Substances, solvates, pharmacologically active metabolites, prodrugs or pharmaceutically acceptable salts: 22 200418798

II-B

II-C where

32 '~' R34, R35, and R% independently represent hydrogen, lower alkyl, 5- (CH2) n- 素, lower alkoxy, 〆CH2) n-NReRf, C (0)-(lower ) Alkyl, aryl or heteroaryl, which is unsubstituted or substituted with one or more lower alkyl residues; R37 represents hydrogen, lower alkyl,-(CH2) n_c (〇) 〇RA halogen; R38 represents hydrogen , Lower alkyl,-(CH2) rrC (0) ORf, halogen, nitro 10 or heteroaryl, which are unsubstituted or substituted with one or more lower alkyl or cycloalkyl;

R39 represents hydrogen, lower alkyl,-(CH2) n_OH,-(CH2) nC (0) 0Rg or aryl; R40 represents lower alkyl; R4i represents hydrogen, halogen or lower alkyl; and R42 represents hydrogen Or burning

Re, 1 ^ and \ independently of each other represent hydrogen or lower alkyl; and n = 0, 1, 2, 3, 4, 5, or 6 0. Preferred compounds of formula II are compounds of formula II_A, in which the compounds are substituted. 23 200418798 Examples of this compound (but not limited to) are as follows, 1-methyl-2-phenylethynyl-1H-imidazole, 2- (5-stoneshothyl-2-phenylethynyl-12 m sigma-1- ) -Ethoxy, 2-phenylethynyl-1Η-imidazole, 5 5- (3,5-dimethyl-2-phenylethynyl-3Η-imidazol-4-yl) -3-methyl ·-[ 1,2,4] oxadiazole, and bad propyl-5- (3,5-dimethyl-2-phenethylacryl-3H-methylsal-4-yl)-[1,2,4 ] Oxadiazole. Also preferred compounds of formula II are compounds having II-A, where I represents a compound of B2, such as, but not limited to, 1-methyl-5-phenylethynyl-1H-imidazole. Also preferred compounds of formula II are compounds having II-A, wherein I represents B3, such as, but not limited to, N- [2- (5-methoxy-2-phenylethynyl-1H-indole-3-yl) -Ethyl] acetamide. Also preferred compounds of formula II are compounds with Π-A, wherein h represents compound 15 of B4, such as but not limited to 3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta [ a] Naphthalene and 3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta [a] naphthalene. Also preferred compounds of formula II are compounds with Π-A, where I represents B5, such as, but not limited to, Dong 20 1-amino-3- (2-methyl-5-nitro-4-phenylethynyl- Imidazolyl) -prop-2-ol, '4-phenylethynyl-1H-imidazole, 1-methyl-4-phenylethynyl-1H-imidazole, and 1,2-dimethyl-5-nitro -4-phenylethynyl-1H-imidazole. 24 200418798 A compound of formula II which is also preferred is a compound having II-A, which represents B6, such as, but not limited to, 1,3-dimethyl-5-phenylethynyl-1H-pyrazole. A more preferred compound is Formula Π-A, wherein B represents B1 and R12 represents (CH2) n-C (0) ORf or a heteroaryl group, which is unsubstituted or substituted with a lower alkyl group or a cycloalkyl group. A particularly preferred compound is Ru for (CH2) n-C (0) ORF, where n is 0 and Rf is a lower alkyl group. (3) A compound represented by the general formula III or its mirror isomer, non-mirro isomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug, or pharmaceutically acceptable Salts: 10 A1 L1-B2 ΠΙ where eight! Is a 5-, 6_ or 7-membered ring with the following structure:

Wherein at least one of 15 W, X3, Y2, and B1 is a group (CRh) p, where pSi or 2; and W, X3, Y2, and the rest of Y are each independently 0, N, or s; Each Rh is independently halogen, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted lower alkoxy group, (lower) Alkoxyloxy, carboxyl, carboxyl esterified 20, fluorenated carboxyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cycloalkyl, fluorenyl, nitro, Carboxyl, aminocarboxylic acid, amine, amine, ester, cyano, amine, acid amine, amidine, 25 200418798 amido, sulfoamido, sulfonamide (lower) -alkyl-N-phenylamine Methyl formamidine, wherein each nitrogen atom is independently unsubstituted or substituted with lower alkyl, lower alkanoyl, halo or trifluoromethyl and where q is 0, 1, 2 or 3; L! Is substituted Or unsubstituted alkenyl, alkynyl, or azo; and 5 B2 is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted Heterocyclic ring, which optionally contains one or more double bonds or substituted or unsubstituted aryl groups, ~ where "substituted" means a radical group in which one or more hydrogen atoms are selected from Substituted by substituents of the following groups: hydroxyl, alkanoyl, alkoxy, mercapto, aryl, heterocyclic, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl Group, nitro group, amine group, N-substituted- or N, N-di, substituted amine group 'in which one or two nitrogen atoms are independently selected from halo group, heterocyclic ring, aryl group, etc. It is further independently substituted with a hydroxyl group, an alkyl group or a heterocyclic ring, or a substituted amine, a sulfonium group, a sulfonylamino group, a carboxyl group, an esterified sulfonyl group, an acidified carboxyl group, a carbamide, an amine group Ester esters, esters, sulfonyl and sulfa groups. According to a specific embodiment of the present invention, the eight-one is a 5-, 6-, or 7-membered unsaturated heterocyclic group containing a ring on the ring adjacent to a carbon atom bearing a linking group as a substituent. Has at least one nitrogen atom. The ring goes one further step <20 and contains 3, 4 or 5 independently different atoms selected from carbon, nitrogen, and oxygen. So 'a can be. Than Ji base, Mi σ sitting base, violate Qin base, mouth. Definite-base, ° zozolyl,. Biazinyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, oxo, oxo, σ, oxo, oxo, oxo Base, ° azozolyl, dioxazolyl, oxa σ azozolyl, cyano ° aziridine 'aza 26 fluorenyl, diaza fluorenyl and the like. Those skilled in the art will recognize that there are many isomers of a single chemical formula; the present invention also considers the possibility of each possible isomer to form various empirical chemical formulas described herein. When the variable ring atom is carbon, it possesses hydrogen, or is optionally substituted by: halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, thio, nitro, carboxy , Ester, cyano, amine, amidine, carbamide, amidine, amido, sulfonamide, etc. The preferred embodiment is that it does not have a substituent (that is, q is 0) or has the following substituents: halogen, ( Cm) alkyl, (Cm) fluoroalkyl, aryl and amine. Substitutions in the position of the ring are also preferred. According to a specific embodiment of the present invention, the eighth is a-, 6-, or 7-membered ring, and members of the ring contain a nitrogen atom and a sulfur atom. The groups considered for use in this embodiment of the present invention include those in which Ai * isothiazol-3-yl (1,2-thiazol-3-yl), thiazole-4-yl (1,3, -thiazole- 4-yl), thiazol-2-yl (1,3-thiazol-2-yl), 1,2-thiazinyl, 1,3-thiazin-4-yl, 1,4-thiazin-3- Radicals, 1,3-thiazin-2-yl, thiazinofluorenyl, and the like. A preferred group includes isothiato-3-yl (1,2-fluoren-3-yl), hydrazone-4-yl (1,3-sialyl-4-yl), and σ Sail-2-yl (1,3-thiazol-2-yl) group. According to other embodiments of the present invention, the Ai * 5-, 6-, or 7-membered ring, the members of which ring contain a nitrogen atom and an oxygen atom. The groups considered in this embodiment of the invention include those in which AH, 2-oxazin-3-yl, 1,3-oxazol-4-yl, 1,4- ° oxazin-3-yl, 1 , 3-sigmaoxan-2-yl, sigmaoxan-2-yl, isoxaoxetyl, oxazol-4-yl, oxazacrotyl and the like. A better group includes these Αι 疋 ° 恶 ° -2--2-, iso. evil. A group of a 3--3-yl group and an oxal-4-yl group. In yet another embodiment of the present invention, ba is a 5-, 6-, or 7-membered ring, and a member of the ring 5f contains a nitrogen atom. The groups considered in these examples include those in which a pyridyl group and a 2-σpyrrolyl group are mentioned. 10_ ^ In a further embodiment of the present invention, the member on A々5 ·, 6_, or 7-membered ring contains two nitrogen atoms. The groups considered in these examples include those in which M3 is Qinji (1,2,2 dioxan · 3 · base), t-determined 4-yl (1,3 · 2harle I, kibbi- 3-base (K-two-three-three-thickness. Dingdongji (1,3_-two-three- 2-yl), Bishal || (1,3_isodiasialyl), imidazosyl (0,3_isobisawasyl), diazafluorenyl, m isos-4-yl, 1,3-isodiasyl And other groups. Preferred groups include Αα3-pyridazinyl (1,2-diazine j group), κ-cardio group (in the case of dioxan), and other groups. 4, diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl), 1,3-isoisialyl | ', 15 $ According to yet another embodiment of Shu Mingzhi, ~ is a 5-, 6-, or 7-membered ring, and the shellfish on the% contains three nitrogen atoms. The groups considered in these examples include those in which Al is U, 3-triazine_4-yl, 1,2,4-triazolyl, U, 4_ triazyl-1, U, 4 · Tri Groups such as hydrazine H1,3,5-triazin-2-yl, U, 3-triazol-4-yl, I'2'4 —wow · 3 ·, triazine, and the like. Preferred groups include the triazine-like group, the u-sense triazine group, the 124_triazine 20 1 group, the U, 4-triazine_ 5- group, the triazine 1 group, U, 3. Trisalyl-4-yl, 1,2,4-triazol-3-yl. / ^ According to yet another embodiment of the invention, ~ is a 5-, 6-, or 7-membered ring, and the member on the% contains four nitrogen atoms. The groups considered in these examples include those in which Al is a tetrafluoren-2-yl group, a tetrazine I group, a tetramethyl-5-yl group, a tetrazolyl group, a tetraazathiol group, and the like . Preferred groups are those in which Al is a tetrazole group. According to another embodiment of the present invention, 乂 is a 5-membered or 7-membered ring, and the ring on the ring contains a sulfur atom and two nitrogen atoms. The groups considered in these examples include those in which A i is U, 6H-3-, ⑶ · 巷-嗅 3 基, U, 4 tetrazinyl, U2, 5H, and ^ ° gm U'4H5_ group, u, 4_n2_ group, 12,4_ thia: azinyl, U, 5-thiadiazin-4-yl, U, 5-thiadiazin-2-yl, u, 4_ Tuzu 3 bases 1,2,3-〇saidixal_4_base, 13,4

The groups of thiadiazolyl, U, 4-thiadiazol-5-yl, thiadiazepine, and the like include the following groups: ^ Exclamation groups of bisalyl, U, 44 bisalyl · 2, 1,2,5 · 嗔 H, and thiadiazol-5-yl. According to yet another embodiment of the present invention, ^ is a 5_, 6 •, or 7 · M ring, and members of the ring contain one oxygen atom and two nitrogen atoms. The groups considered by such Example 15 include these

Oxadiazine_3-yl, ι, 2,4-oxadiazine_3_yl, 丨 dioxadiazine_4_yl, 丨 di ^ oxadiazine-4-yl, 1,3,4_oxazine Diazin-5-yl, 1,3,4-oxadiazin-2-yl, 1,2,4-oxadiazin-5-yl, 1,3,5-oxadiazin-4-yl, l , 3,5-oxadiazin-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol | yl, 1,3, 'oxadiazol-2-yl Group, 1,2,5-20 σoxadiazolyl, 2,4, oxadiazol-5-yl, oxadiazepine and the like. Preferred groups include the oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,5- ° oxadiazol_3-yl and 1,2,4-oxadiasial-5-yl groups. According to yet another embodiment of the present invention, 丨 is a ^, 6_, or 7-membered ring, and members of the 29 200418798 ring contain one to up to six nitrogen atoms, and / or one to up to six carbon atoms, And / or zero to up to five sulfur atoms, and / or zero to up to five oxygen atoms. Further, in a specific embodiment, L! Is a linking group which connects 5 groups eight 1 and ^. L! Is selected from a substituted or unsubstituted alkenyl group, an alkynyl group or an azo group. Preferred compounds are those in which 1 ^ is an alkenyl or alkynyl group containing two carbon atoms. The alkynyl group is optimal. Further, 'in a specific embodiment, B2 is connected to the group VIII through a bridging group L1. The radical groups considered for use in the present invention are such that b2 is a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted cyclic hydrocarbon group, a substituted or unsubstituted heterocyclic ring, any of which It optionally contains one or more double bonds, substituted or unsubstituted aryl groups, and the like. Preferred compounds are those where B2 is a substituted or unsubstituted hydrocarbyl group selected from a substituted or unsubstituted alkyl group, an alkenyl group, a dienyl 15 group, a dienyl group Group, alkynyl group, chain dialkynyl group, chain trialkynyl group, alkenynyl group, alkadienynyl group, alkenediynyl group, etc. Wait. _ More preferred compounds are those in which B2 is a substituted or unsubstituted cycloalkyl group selected from a substituted or unsubstituted cycloalkyl group, a cycloalkenyl-20 group, a cyclodifluorenyl group, Cyclopyridinyl group, cyclaphthyl group, cycladic group, a bicyclic hydrocarbon group, in which two rings have two identical atoms, etc .: and other compounds. It is particularly preferred that the 1 is a compound having a cycloalkyl group and a cycloalkenyl group ranging from 4 to at most about carbon atoms. Exemplary compounds include cyclopropane, cyclopentenyl and cyclohexyl. Also particularly preferred are bicyclic nicotinyl groups, 30 200418798 where two rings have two identical atoms: exemplified compounds include indenyl, dihydroindenyl, naphthyl and dihydronaphthyl. Still more preferred compounds are those wherein &amp; is a substituted or unsubstituted hetero ring, which optionally contains one or more double bonds. Exemplary compounds include pyridinyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, piperidine, isosoryl, pyrazinyl, tramidinyl, alphabisazinyl, and the like And other compounds. Also preferred compounds are those in which B2 is substituted or unsubstituted aryl. Particularly preferred compounds are those wherein the substituents are an aryl group and a heterocyclic ring, which optionally further have the substituents described herein, methyl, trifluoromethyl, cyclopropyl, alkoxy, 10 halogen and cyano . Also preferred compounds are those in which B2 is a bicyclic heterocyclic group, wherein one ring has two identical atoms. Exemplary compounds include indadodol and isoline. The most preferred compound of formula III is as follows: 3- (2-methylthiazolebenzyl) acetylene pyridine (MTEP); 15 2-methyl_4 _ [(E) -2-phenylethenyl] _1,3-σ plug α-Side; 4- (2-pyrimidinylethynyl) isofluorinate; 2- (3,4-monohydro-2-naphthylethynyl). ratio. Benzene; 4,6-Dimethyl-2- (benzylethynyl). dense. And 2- (1-cyclopenten-1-ylethynyl) methylpyridine. 20 (4) Compounds having the structure of general formula IV 総, or mirror image isomers, money image isomers, N · oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs, or Pharmaceutically acceptable salts: 31 200418798

Where η is 0, 1 or 2; χ4 is 〇, S, ΝΗ or ΝΟΗ; 5 R43 and R44 are each independently hydrogen, CN, COORi, CONHRi, (Ci_6) alkyl, tetrafluorene or R43 and R44 together Represents a pendant oxygen group;

Ri is hydrogen or (Cw) alkyl; R45 is (Ci-6) alkyl, (C2_6) alkenyl, (C3_8) cycloalkyl, -CH2OH, -CH20-alkyl or -COOH; 10 An is not A substituted aromatic or heteroaromatic group, or an aromatic or heteroaromatic group substituted with one or more substituents selected from the group consisting of: (Cm) alkylamino, di- (Cw) -Alkylamino, (Cw) alkoxy, carboxyl, loryl, gas, ifi, dimethyl, pinyl, amine, (Ci_6) amino, (Ci_6) sulfur Base, (Ci-6) Luo Zhigan, (Ci-6) burning base and (Ci_6) halogen burning base; 15

Z2 represents a group of the formula

32 200418798 wherein R46 and R47 are each independently hydrogen, halogen, (CU6) alkoxy, -OAn, (Ck) alkyl, -CF3, COORi, CONHRi, -CN, -OH, CORi, -SJC ^ ) · Alkyl, -SOHCm) -alkyl; 5 A2 is CH2, 0, NH, NRI, S, SO, S02, CH2-CH2, CH20, CHOH or C (O), where Ri is as defined above ; B3 is CHRi, C (Ri) 2, (C ^) alkyl, C (O), -CHOH, -CH2-0, -CH = CH, CH2-C (0), CH2-S, CH2-S (0), CH2-S02, -CHCC ^ or -CH-N (Ri) 2, as defined herein; and 10 Het is a heterocyclic ring, such as furan, thiophene, or pyridine. The preferred molecules are: 3-[(3-Bromobenzyl) aminoindanyl) _3_methylσ than pyrrolidine-2_fluorene, 3-[(3_chlorobenzyl) amino chloride Phenethyl) _3_methylpyrrolidine 15 __Thionone, 3-[(3-Gas benzamidine) amino] berberindenyl) _3_fluorenyl. Pyrrolidine-2-sulfide is homologous and 3-[(6-chloropyridin-2-yl) carboxamidoindanyl) -3-methylpyrrolidine-2-thione. 20 (5) A compound having a structure represented by the general formula V, or a mirror image isomer, non-image isomer thereof, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug or pharmacy Acceptable salt. Αγ2-〇ϊ-Αγ3 ν α where 33 200418798

Ar2 is a heteroaryl group,

Ar3 is an aryl group, here

Ar2 and An are optionally substituted with one or more substituents selected from the group consisting of: -F, _C1, -Br, -I, -〇 &amp;, _ $ &amp;, 5- S02Rj, -S02NRjRk, -OCORj, -〇CO〇NRjRk, nrc〇r "-NRC02Rk, -CN, _N02, _C〇2Rj, c〇NRjRk, c (〇) Rj -CH (ORj) Rk, -CH / ORj), -Rj, and _MCH2VNRRk, where R and Rk are independently selected from the group consisting of: H, CF3, (q alkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl Group, heterocycloalkyl group, aryl group, or 10 or &amp; and ^ can be combined to form a Cl · 5 methylene chain, and A is defined as c: h2, 0, NH, S, SO, S02, and η are 1 , 2, 3, or 4,

Gi is selected from the group consisting of: _NH_, _s, _〇_, _c〇_, -CONH_, -C0NHCH2_, -CH2C〇NH-, -CH2NHNH-, -ch2nhnhch2-, -C = NO-CH2 -, -CH2NHCH2-, 5'CH2CH2NH-, -nhch2c0-, -NHCH2CHOH- ,, NHCH2NHNH_, -NHCONH-, or 〇1 is a ring group selected from the group consisting of cyclopentane, Cyclopentadiene, furan, thiofuran, d-pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4-imidazoline, imidazole, pyrazoline, pyrazolidine, imidazolidine, oxazole, 2_ Oxazole, thiazole, isoxazole, 20 isothiazole, your 1,2,4 · triazole, 1,2,3-triazole, H4-oxothiazole, ^ 4- ^ oxazole, 1, 4, 2-dioxazole, 1,4,2-oxothiazole, 丨 '' oxadiazole, 丨 '' soil sitting, 1,2,5-σoxa sitting, 1,2,5-mouth stopper Twenty sits, 1,3,4-mouth evil sits, 1,3,4_ cetozole, tetrozole, cyclohexane, piperidine, tetrahydropyridine, 1,4_dihydropyridine &quot; Pyrene, pyridine, benzene, tetrahydropyran, 3,4_digas_2 // _ pyran, pyran, 34 200418798 5 10 4H , Dihydro-2 Thiopyran, 2 / f_thiin, You-Thiodimolin, Thiomorphin, Lithium, Pyridazine, Qian "Bihuan, Qin 1,2,3-Diphon, 1,3,5_Triazine And 12,4,5-tetrazine groups. The preferred groups represented by ^ are independently phenyl, benzyl, naphthyl, alkynyl, enenyl, r-fluorenyl, phenanthryl and benzonaphthyl A fluorenyl group, a preferred group represented by ΑΓ2 is independently an alkynyl group, an M group, a "pyranyl group, a 2 fluorenyl group, a fluorenyl group, and the like. Bisyl, sialyl &quot; bisyl ", bisyl, stilbyl, stilbyl, base, benzene, benzene, stilbene, 3 //-, base, ahyl, ten dollar, base, Fluorenyl, isomeryl, lindenyl, azinyl, naphthyl, ~ pure, base, isomer, quinoline, ahru, "«, benzene, phenyl, benzoyl , Isobenzofuranyl and chromenyl.

15 20 is more preferably selected from the group consisting of phenyl, benzyl 'naphthyl, myrtle, anthrenyl, indenyl, phenanthryl, and benzonaphthylene groups, the same 2 is selected from the group consisting of: radian, rananyl, ° lananyl, 2 基. It is called base, sulfophenyl, scale base "Misalyl" than "Sialyl" &quot; Bisyl, fluorenyl, pyridyl, pyrazinyl, benzopyridyl, benzimidyl, 3 // ... Fluorenyl, fluorenyl, sulfonyl, sulfonyl, heterophilin, fluorenyl, fluorenyl, naphthyl sulfonyl, solubilizing group, isosalyl, 4 fluorenyl , Benzofluorenyl, native sigmafuranyl, isobenzosigmafuranyl, and chromenyl groups.

In yet another embodiment, the present invention may be a compound represented by Formula V7, or a mirror image isomer, non-image isomer thereof, a team oxide, a crystalline form, a hydrazine, a lotion, an eroli active metabolism Substances' prodrugs or pharmaceutically acceptable salts 35 200418798:

X5, Y3, and Z3 are independently selected from the following,

5 s, C and CO 'where at least one of χ5 and coffee is: sub-N, °, An and Α independently selected from the group consisting of 〇 Heterocyclic heterocycles 3 or heterocyclic groups with heteroatoms in the group consisting of S, and selected from phenyl, benzyl, 亍 laugh, 暴, 2-naphthyl, Silk, anthrenyl, benzyl, phenanthryl and benzonaphthylen group of 10 fresh aromatic groups' where Aι * 4 and Ars are optionally composed of one or more groups consisting of subordinate households Substituted by a group of substituents: -F, -a, _Br, _; [, -SORj, -S02Rj, _S02NRjRk, -OCORj, _〇c〇NRjRk -NRCORk, -NRC〇2Rk, -CN, -N〇2 -C02Rj, _c〇NRjI ^ k -C (0) Rj, -CH (0Rj) Rk, -CH2 (〇Rj) -Rj, and _A- (CH2) n-NRjRk;

15 where Rj and Rk are independently selected from the group consisting of: H, CF3, (Cl_10) alkyl, bad courtyard, alkyl-square, alkyl-heteroaryl, heterocycloalkyl , Aryl, or Rj and Rk can be combined to form a Cw methylene chain, A is defined as CH2, 0, NH, S, SO, S02, and η is 1, 2, 3, or 4. 20 The heterocyclic or fused heterocyclic group is preferably a member selected from the group consisting of fluorenyl, oxazoline, oxoxaline, 2-pyrimidinyl, 4- Mouth-dense σ basis, definite basis, 2-σι ± * σ basis, 3- ° ratio 0 basis, 4-σ ratio σ basis, and 36 ^ 18798 α-pyrazolyl. In a preferred embodiment of the present invention, the compound is a member selected from the group consisting of 3- (2..pyridinyl) -5- (3,5-diphenylphenyl) -1, 2,4-oxadiazole, 3- (2-pyridyl) _5- (3-methoxyphenyl) -1,2,4- ° oxadiatidine, 3- (2-σϋϋdingyl) -5- [ 3- (trifluoro · methyl) phenyl] -1,2,4-oxadiazole, 3- (2-methylpyridyl) -5- (3-methylbenzene.yl) · 1,2, 4-oxadiazole, 3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadi. Sit, 3- (5-methoxypyridin-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole and 3-oxo-2-fluorinyl) -5- (3 -Cyanophenyl) -1,2,4-oxadiazole. _ 10 In other embodiments of the present invention, the compound is a member selected from the group consisting of: 2_ (3,5-difluorophenyl) -4- (2-arimidinyl) -1,3 -Oxazole, 2- (3-Gaphenyl) -4- (2-.pyridinyl) -1,3-oxazole, 2- (3-methoxyphenyl) -4- (2-. Pyridyl M, 3-oxazole, 2. (3-cyanophenyl) -4- (5-methoxypyridin-2-yl) -1,3-oxazole, 15 2- (3-cyanophenyl)- 4- (2-fluorinyl) -1,3-oxazole, 2- [3-aerophenyl] -4 decapyridin-2-yl] -1,3-oxazole, 2- (2,5 , 6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole and 2- (3_stonestilylphenyl) -4- (2- ° to σ amidyl) -1,3- ° The present invention also includes mirror images of compounds having the general formula I, Ι-Α, ΙΙ-Α, ΙΙ-Β, II-C, III, IV, VA, and VB (hereinafter referred to as "Formula IV") 20 isomers, non-image isomers, N-oxides, crystalline forms, hydrates, solvates, pharmacologically active metabolites, prodrugs or pharmaceutically acceptable salts, which are selected by the mGlu5 receptor The present invention also includes metabolites of compounds of formula IV, which are selective antagonists of mGlu5 receptors, hereinafter referred to as Sexual metabolites. 37 200418798 The present invention also considers the possibility of prodrugs, which are metabolized in the body to produce compounds of formula IV, which are selective antagonists of mGlu5 receptors. Those skilled in the art should recognize the previous The compounds mentioned may contain one or more palm centers and may therefore exist as racemic mixtures. 5 For the purposes of many applications, it is preferred to carry out stereoselective synthesis and / or to treat the reaction products with appropriate purification steps in order to Production of substantially optically pure substances. Suitable stereoselective synthetic steps for the production of optically pure substances are well known techniques, such as the steps used to purify racemic mixtures into optically pure fractions. Those skilled in the art should further appreciate The invented compound may exist in a polymorphic form, wherein the compound can be crystallized into different forms. Suitable methods for identifying and isolating polymorphisms are known techniques. In other embodiments, the present invention provides A method for identifying compounds for treating lower urinary tract neuromuscular dysfunction, comprising: (a) individual measurement The binding affinity of the test compound for the mGiu5 receptor, mGlul receptor and the group 15 II group mGlu receptor; (b) According to the test compound, (1) the binding affinity for the mGlu5 receptor is at least 10-6M , And (2) the affinity of binding to the mGlu5 receptor is at least 10 times stronger than the affinity of the mGlu 丨 receptor and the group II mGlu receptor. 20 In the specific example, it is used to identify and treat the lower urinary tract The method of neuromuscular dysfunction compounds further comprises () the ability of each mouthpiece identified in the above steps (i) and (ii) to act as an antagonist or counteract each other individually. In the example, the present invention provides a method for identifying a compound for the treatment of the 38 urinary neuromuscular dysfunction, which comprises: ⑷ individually measuring the test compound against the heart receptor, mGiui receptor, group III and I_mGlu receptor binding affinity; (b) Identification of these test compounds, which: (1) binding affinity to mGlu5 receptor is at least 10.0M, and (2) comparison of affinity binding to mGlu5 receptor ㈤⑺, the mGlu receptors of the nth and mth groups are at least 10 times stronger and each compound identified in step (b) individually / then is blocked on mGlu5 receptor || Fortunately, the activity of the compound identified in steps (a), (b), and (c) of the above method can be evaluated by evaluating the compound in a human or animal model. The activity of treating the lower urinary tract in the system is determined. Preferably, the identified oral substance exhibits activity in at least one of the following biological parameters: Rhythmic bladder contraction; ； increase the bladder volume of rat towels Capacity. In specific embodiments, the invention also relates to compounds identified by the methods mentioned above. In specific κ% cases, mGlu5 selective antagonists can be combined with known antagonists by administering the antagonist. Drug lords to treat the disorders mentioned above.

Similarly, mG1U5 selective antagonists can be administered in combination with ai-adrenergic antagonists to treat lower urinary tract money, whether the tubing is related to BPH. In a similar manner, mGlu5 selective antagonists can be administered in combination with one or more 5-HTiA 200418798 receptor antagonists. In a similar manner, mGki5 selective antagonists can be combined with one or more enzyme% oxidase (cox) inhibitors (which can be selective or non-selective to cox2 isozymes) or their derivatives (such as esters or Phenamine inhibitor 5 preparation) combined administration. · Brief illustration of the diagram Qin Figure 1 shows the intravenous administration of a vehicle (circle), 3.0 and 10 mg / kg of 2-methyl-6- (phenylethynyl) pyridine (MPEP) compound or 50 mg / Changes in the volume of 10-cysteic capacity (BVC) of rats with time after 2 kg of 2-methyl-6- (2-styryl) pyridine (SIB 1893) compound (square). The data show the percentage change from the base value at different time points after treatment. n = number of rats / group. Figure 2 shows the intravenous administration of a vehicle (circle), 2-methyl-6- (phenylethynyl) pyridine (MPEP) compound of 30 and 10111 § / 1 ^ or 50 mg / kg of 2 Changes in micturition pressure (MP) versus time in rats after methyl 15-6- (2-benzylvinyl) pyridine (SIB 1893) compound (square). The data show the percentage change from the base value at different time points after treatment. η = number of rats / group. Figure 3 shows the rats after oral administration of a vehicle (circles), 3.0, 10, or 30 mg / kg of 2-fluorenyl-6- (phenylethynyl hupridine (MPEP) compound (square)). Change of S1-20 BVC with respect to time. The data show the percentage change from the base value at different time points after treatment. Η = number of rats / group. * Figure 4 shows the oral administration vehicle (circles) Changes in MP over time in rats after 2-methyl-6- (phenylethynyl) pyridine (MPEp) compound (square) at 3.0, 10, or 30 mg / kg. Data show that at different times after treatment Point 40 200418798 Percent change from base value. Η = number of rats / group. Figure 5 shows the oral administration of vehicle (circle), 10 mg / kg of 2-methyl-6- (phenylethynyl) pyridine (MPEP) Compound (square; left) or 1 mg / kg indomethacin (square; right), changes in BVC over time in rats with bladder infusion and dilute 5 release of acetic acid. The data show the percentage change from the base value at different time points after treatment. Η == number of rats / group. Figure 6 shows Administration with a vehicle (circle), 2-methyl-6- (phenylethynyl ratio ^ (MPEP) compound at 10 mg / kg (square; left picture) or 10 indomethacin at 1 mg / kg (square) ; Right)), changes in MP versus time in rats with bladder infusion and dilute acetic acid. The data show the percentage change from the base value at different time points after treatment. Η = number of rats / group .

I: Embodiment] I Detailed description of the preferred embodiment 15 The present invention relates to a method for treating lower urinary tract neuromuscular dysfunction using antagonists and / or anti-acting agents of mGlu5 receptors. The mGlu5 receptor is preferably human mGlu5. The present invention is based on our findings as follows: As a metabotropic glutamate receptor, mGlu5 receptor on the function, one of the primary antibodies * 丨 # or anti-allergic compounds can inhibit urination reflex, It causes dose-dependent long-lasting blocking of the bladder contractile force when filled to the threshold volume, and does not affect the amplitude of the bladder contraction when the effect stops; U) Force acts as a metabotropic facial amino acid receptor, mGlu5 receptor, Choice of compounds: Oral anti-J and / or anti-allergic compounds can increase the bladder volume and volume measured by intravesical pressure measurement at a dose that does not impair the contraction of the bladder 41 240818798; β and out) Functionally acts as a metabotropic facial amino acid receptor, mGki5 receptor, a compound of selective antagonists and / or anti-allergic agents, and increases the one and the next urination measured by the bladder pressure 5 assay Time interval. · Compounds of general formula I can be synthesized in the manner described in WO 99/02497. The synthetic manner of the compound represented by Formula I-A is described in WO 02/062323 publication. 10 Compounds of general formulae II-A, II_B and Il · C can be synthesized by the method described in WO 02/46166. Compounds of general formula III can be synthesized in the manner described in the publication WO 01/16121. Compounds of the general formula IV can be synthesized by the method described in WO 00/69816. Compounds of the general formula V-A and V-B can be synthesized by the method described in WO 01/12627. Authors U.S. Patent Publications 2002/0128263 A1, 2002/0188128 A1, and 2003/0022907 A1 are incorporated herein by reference. In the specific example 20, the compounds disclosed in the U.S. publication may be excluded from the scope of patent application. / Pharmacological blockade of mGlu5 receptors has a positive effect on the management of lower urinary tract neuromuscular dysfunction. The antagonists and / or anti-allergic agents of the present invention are related to the above-mentioned compounds of formula 1_ 乂 化 42 200418798, including mirror image isomers, non-image isomers, team oxides, crystalline forms, hydrates Substances, solvates or pharmaceutically acceptable salts, and active metabolites of these compounds, which have the same type of activity. Preferably, the compound of formula ι-ν is a selective antagonist of mGlu5. 5 mGlu5 receptor antagonist is a substance that reduces or destroys the role of the ligand (synergist) that primarily activates the mGlu5 receptor. The antagonist may be, for example, a chemical antagonist, a pharmacokinetic antagonist, an antagonist blocked by a receptor, a non-competitive antagonist, or a physiological antagonist. A chemical antagonist is a substance in which the antagonist binds 10 ligands in solution so that the ligands lose their effect. A pharmacokinetic antagonist is an antagonist that can effectively reduce the concentration of an active drug at its site of action, for example, by increasing the metabolic degradation rate of the active ligand. Antagonism by receptor_blocking involves an important mechanism. Reversible competitive antagonism and irreversible or non-equilibrium competitive resistance. Reversible competitive antagonism occurs when the resolution of the coffin antimolecules is fast enough that when the ligand is added, the ligand effectively replaces the chemical antagonist on the receptor. Of course, the ligand will not drive out a bound antagonist, and vice versa. Irreversible or non-equilibrium competitive antagonism occurs when the rate at which the antagonist decomposes from the bilayer is slow or incomplete, resulting in no change in the 'knotting agent' occupancy when the ligand is administered. Therefore, this antagonism is insurmountable. Non-competitive antagonism illustrates the situation where antagonists block certain points in the signal transmission pathway that cause the ligand to respond. / The term "physiological antagonism" is used to non-strictly explain the interaction of two substances' and their opposite effects tend to cancel each other out in the body. Antagonists can also be substances that reduce or disrupt the performance of functional H1G1U5 receptors. Therefore, 43 antagonists can be as reduced or destroyed

It is in an inactive state (a substance with the synergist phase C which preferentially binds to the recipient ’s synergist will preferentially bind to the active state of the receptor), so it avoids the stimulation of the synergist emitter_. Generally speaking, the activity of anti-allergens in vivo is similar to that of antagonists. For clarity, the anti-allergens will be defined as cumin-resistant agents in this application. The antagonist used in the nutritional invention can be a relatively non-specific antagonist, which is a general antagonist of the mGh! 5 receptor. However preferred are antagonists which selectively antagonize the mGlu receptors of group I. More preferably, the antagonist mGlu5 receptor selective antagonist used in the present invention. The mGiu5 receptor selective antagonist is an antagonist that antagonizes the mGlu5 receptor, but it does not antagonize the other 1110111 receptors only weakly or substantially. The best antagonists are those which selectively antagonize the mGlu5 receptor at low concentrations, for example, which result in an antagonistic level of 50% or more at a concentration of 1,000 nM or less. Therefore, mGlu5 selective antagonists can exhibit at least 10 times, at least 20 times, at least 50 times, at least about 100 times, at least about 250 times, at least about 20 500 times on the mGlu5 receptor than on the mGlul receptor, At least 1,000 times more potent. Accordingly, the mGlu5 selective antagonist has the following characteristics. (1) Wasted wG / n5 # Ronghuo) ¾: The compound that can be used preferably exhibits an antagonistic strength between 1000 and 0.1 nM (measurement of IC5G or Ki). Without limiting the disclosure of the present invention, as described in more detail below, the strength can be determined by determining the antagonistic activity of the compound in vitro or in vivo (including fragments of cell death extracts or extracts). Inhibition strength can also be determined using natural or recombinant mGlu5 receptors, enzymes that have been expressed or induced in nature, and enzymes that have been expressed in natural or unnatural species and / or cell types (W. 5 Sporen, Trends in Pharmacol. Sci. 23: 331_337, 2001), the above non-limiting examples. (2) Chosen dance: Compared to each mGlul receptor and the π group mGlu receptor, the better compound exhibits at least about 10-fold stronger antagonistic power against the mGlu5 receptor. Compared to each mGlul receptor and group II mGlu receptors, the better compounds show about 20 times, at least 50 times, at least about 100 times, at least about 250 times, at least about The antagonistic strength is about 500 times, at least about 1,000 times stronger. Accordingly, compounds of this general type are suitable to be selected for testing the methods taught below. Selectivity can be measured for different receptors or 1 (:: 50 ratio. Screening of candidate compounds to identify compounds that can be used in the practice of the present invention 15 include involving, for example, but not limited to: 1) evaluation compared In one or more of the "receivers" or the 11th group 111 (} 111 receptors and optionally the III group mGlu receptors, preferably compared to at least one mGlu 1 and 11th group mGlu receptor groups And optionally each of the mGlu receptors of the claw group, their antagonistic strength and selectivity to mGlU5 receptors; 20 and: '2) use of one or more for lower urinary tract neuromuscular dysfunction The animal model system is used to determine their pharmacological activities. In vitro analysis methods commonly used to evaluate the antagonistic activity on the metabotropic facial amino acid receptor can be found in the literature of scholars such as Carroll (Tick 45 200418798 P / zamaco / 59: 965-973, 2001). In a preferred embodiment, the antagonistic activity on a metabotropic glutamate receptor is one or more of the analytical methods described in the examples below. Done. Use one or more of these methods of analysis' Determining the antagonistic activity of a test compound on different isoforms on a metabotropic glutamate receptor, and regression analysis or equivalent computer methods familiar in the art * (Tallarida et al., Manual of ·

Pharmacologic Calculations. Springer-Verlag, pp. 10-12, 1981) to calculate the 50% inhibitory binding concentration (IC50). Provided that the compound exhibits a selectivity ratio of at least 10 times, that is | 10 IC50 or Ki at least 10 times lower for mGlu5 than for one or more melons "receptors or group n mGlu receptors" or preferably for at least An IC50 or Ki derived from mGlul and the parental organ of the 11th group 111111, this compound is considered a selective mGlu5 antagonist. More preferably, the mGlu5 selective antagonist described herein further exhibits a selectivity ratio of at least 10 times to one or more Group III mGlu receptors. Once a compound has been identified as a selective mGlu5 antagonist, its pharmacological activity can be determined using an animal model system for neuromuscular dysfunction of the lower urinary tract. Available animal model systems for measuring this pharmacological activity are, but are not limited to, volume-induced rhythmic urinary bladder contractions in anesthetized rats. This method is to use a polyethylene tube filled with physiological saline to pass through the external urethra to the bladder. ^ After that, the external urethra is tied up and connected to a pressure recording device. Then 'fill the bladder until reflex urination contraction occurs. After that, the frequency of the row was measured over 15 minutes. However, the test compound 46 200418798 was administered intravenously, and its effect was continued for 60 minutes. This method is explained in more detail in Example 3 below, and it is the first method to determine the predicted quality of mGlu5 selective antagonists in urinary tract disorders. This model has been validated by using different reference standards (Guarneri et al., Corps 5 Res, 27: 173-187, 1993). Examples 4-5 of this application provide other useful alternatives for evaluating mGlu5 selective antagonism Animal model of lower urinary tract activity. They are based on bladder activity recorded by bladder pressure measurement in conscious rats, which are constructed to measure bladder pressure during continuous perfusion of bladder with saline or very dilute acetic acid. These methods are widely used and accepted by researchers in this technical field, and predict the infusion period of about 5 hours after the administration of the test drug by continuously monitoring the bladder performance and evaluating the interval between micturition and peak micturition pressure. A "metabolite" of a compound disclosed herein is a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" means a biologically active derivative of a compound that is present in the compound Formed when metabolized. The term "metabolic" means the sum of the treatments through which a particular substance changes in vivo. In short, in order to drive energy and / or remove compounds from the body 'all compounds present in the body are processed by the enzyme 20 in the body. Specific enzymes cause specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucofuranosyltransferase catalyzes the conversion of activated glucuronic acid molecules into aryl alcohols, alcohols, carboxylic acids, amines, and free sulfur hydrogen. (sulphydryl) group. Information on the progress of the generation can be obtained from ‘Heart Suppression / Ru Zhan &lt; 47 200418798

Therapeutic ^^ 9th Edition, McGraw-Hill (1996)? Pages 11-17. The metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing a tissue sample of the host or by culturing the compound with liver cells in vitro and analyzing the resulting compound. Both methods are · Techniques familiar in this technical field. The "prodrug" of the compound disclosed herein is an inactive substance that, when administered to a dairy animal, is converted into the active form of the disclosed compound in vivo.

I 10 In a particular embodiment, it is used to treat lower urinary tract disease by administering a mGlu5 selective antagonist in combination with-or multiple additional types of receptor antagonists. In a preferred embodiment, the mGlu5 transgenic antagonist is a combination of leptin, 5-HT1A or a muscarinic receptor antagonist. In the progressive embodiment, it is by administering a mGlU5 selective antagonist I5 agent in combination with one or more cyclooxygenase enzyme inhibitors (which can inhibit both illusion and COX2 isoenzymes or alternatively, c 〇2 isoenzyme and its NO provider derivatives to treat lower urinary tract diseases /, # Examples of anti-muscarinic drugs administered in combination with mGlu5 selective antagonists are chlorinated hydrochloride, tolterodine, and dafida Nasin (darifen ^ and telmirine-20 temiverine). Wide mGlu5 selective antagonists can be administered in combination with α1_adrenergic antagonists to treat lower urinary tract symptoms, regardless of whether they are related to tadpoles. Suitable for MGlu5 selective antagonists are best administered with adrenergic antagonists such as prazosin, dozozin, terazosin, and ephra Alfuzosin and tamsulosin 〇 Other αΐ-adrenergic antagonists suitable for combination administration with mGlu5 selective antagonists are described in US Patent Nos. 5,990,114; 6,306,861; 6,365,591; 6,387,909 No .; with No. 6,403,594. 5 with mGlu5 Examples of selective antagonists combined with 5-HT! A antagonists can be found in the following literature: Leonardi et al., Exp. 77 ^ r. 299: 1027-1037, 2001 (eg Rec 15/3079), United States Patent No. 6,071,920, other piperazine derivatives described in WO 99/06383, and U.S. Patent Application Nos. 10 / 266,088 10 and 10 / 266,104 filed on October 7, 2002. Additional 5-HT1A antagonists include DU-125530 and related compounds described in U.S. Patent No. 5,469,942, and related compounds described in robalzotan and WO 95/11891. Each of the above can be selected with mGlu5 Non-limiting examples of 5-ΗΊΠA antagonists administered in combination with sexual antagonists. 15 Examples of COX2 selective inhibitors that can be administered in combination with selective antagonists of mGlu5 receptors are, but are not limited to, nimesulide (nimesulide), meloxicam, rofecoxib, celecoxib, parecoxib, and valdecoxib. Additional selective inhibition of COX2 Examples of agents are described in, but are not limited to, US Patent No. 6,44〇, 963 Examples of non-selective inhibitors of COX1-COX2 are, but are not limited to, acetosalicylic acid, niflumic acid, flufenamic acid, enfenamic acid, Meclofenamic acid, tolfenamic acid, thiaprophenic acid, ibuprofen, 49 200418798 naproxen, ketoprofen ), Flurbiprofen, furprofen, indomethacin, acemethacin, proglumethacin, ketorolac, diclofenac, Etodolac, sulindac, fentiazac, tenoxicam, lornoxicam, cynnoxicam, broson, (ibuproxam), nabumetone, tolmetin, amtolmetin. Accordingly, each of the aforementioned selective antagonists in combination with a COX inhibitor is a non-limiting example. Xin 10 An example of a derivative of a COX inhibitor that can be administered in combination with a selective antagonist of mGlu5 is a cox inhibitor derivative having a nitrate (nitrooxy) or nitrite group, such as WO98 / 〇9948 Provided in the body, can release NO in vivo. Chemical definition 15 _ In addition to the definition of a specific example, the following meanings apply to the compounds described herein. An alkyl group can be straight or branched and has 1 to 12 carbon atoms. With Xin From 1 to 6 carbon atoms? , Preferably from 1 to 4 carbons are preferred, and may be referred to as low, and alkynyl groups. These meanings are retained in more complex groups such as halogenated alkoxy, fluorenyl, thio, amine, diamine, and the like. The m-Woyl group may be a straight bond or a branched chain and has 2 to 12 carbon atoms. Basins can have more than one carbon_carbon double bond. With 2 to 6 carbon atoms, it is more preferable to have one carbon, and it may be referred to as a lower alkenyl group. 50 200418798 An alkynyl group can be straight or branched and has 2 to 12 carbon atoms. These may have more than one carbon-carbon triple bond. Having 2 to 6 carbon atoms, preferably 2 to 4 carbons are preferred, and may be referred to as a lower alkynyl group. The term "alkenyl" means a straight or branched chain divalent alkenyl group, having at least one carbon-carbon double bond and having 2 to 12 carbon atoms (lower-level free radicals having 2 to 6 carbon atoms) Alkenyl group). The term "alkynyl" means a straight or branched chain divalent alkynyl group having at least one carbon-carbon triple bond and having 2 to 12 carbon atoms (with 2 to 6 A lower alkynyl group of a carbon atom). Ethynyl is preferred. The term "hydrocarbyl" means a straight or branched chain monovalent and bivalent radical group, which is saturated or unsaturated by containing only carbon and hydrogen atoms Derived from a group with 丄 to 12 carbon atoms. The term includes alkyl groups, alkenyl groups, dienyl groups, dienyl groups, alkynyl groups, chain diblock groups , Trialkynyl group, alkenyne group, alkadienyne group, alkenediyne group, etc. Cycloalkyl group in one or more rings It has 3 to 20 carbon atoms. When there is more than one ring, the rings can be combined with each other, or spirocyclic hydrocarbons can be connected through a carbon atom parameter. Among them, 3 to 7 carbon atoms A monocyclic cycloalkyl group is preferred and can be referred to as a lower cycloalkyl group. The 20-cycloalkenyl group has 3 to 20 carbon atoms in one or more rings. When more than one ring These rings can be dense with each other, or they can form a spiro ring fe through a carbon atom / link ,,,, etc. It can have more than one carbon-carbon double bond, but not as much as aromatic. A monocyclic cycloalkenyl group having 3 to 7 carbon atoms is preferred and can be referred to as a lower cycloalkenyl group. 51 200418798% of an alkynyl group has 3 to 20 carbons in one or more rings Atoms. When there are more than one ring, the rings can be dense with each other, or spirocyclic hydrocarbons are connected through a carbon atom. They can have more than one carbon-carbon triple bond. A monocyclic cycloalkynyl group is preferred and can be referred to as a lower cycloalkynyl group 5. The term "cyclic hydrocarbon group" means a cyclic (ie, ring-containing) monovalent radical group consisting of only carbon Derived from a saturated or unsaturated group of a hydrogen atom, having 3 to 20 carbon atoms. Examples of the cyclic hydrocarbon group include a cycloalkyl group, a cycloalkenyl group, a cyclodienyl group, a cyclotrienyl group, a cycloalkynyl group, a cyclodiyne group, a spirohydrocarbyl group Group, in which two rings are linked by a single atom, the single atom is the sole common member of the two rings (such as spiro [3.4] octyl, etc.), a bicyclic hydrocarbon group, in which two rings are linked together and Has two common atoms (such as bicyclic [3 · 2 · 1] octane, bicyclo [2.2.1] hept-2-ene, norbornene, decalin, etc.) and so on. 15 The term "fluorenyl", whether used alone or in a term such as "fluorenyl", represents a free radical provided by a residue after removal of a hydroxyl group from an organic acid. · The term "burning St group" means a straight or branched alkyl chain attached to a carbonyl group. However, 'this term also includes a methyl group. Lower alkyl groups have from 1 to 2.05 Disk atoms and specifically include methyl, ethyl, and propyl groups. Halogen means fluorine, gas, bromine, or iodine atoms. The combined term halo has similar meanings: i-alkyl specifically includes a single or Plural substitutions, and specifically including trifluoromethyl and 2,2,2-trifluoroethyl. The term "aryl" when used alone or in combination means to contain one, two, or three 52 200418798 The Fang tribe, which was born in the middle and the middle, produced ^ brother /, 7% of this finding <can be attached together or ancestral together in a hanging manner. The term "Fang-Fang Zhi Bao 3 plugs such as phenyl, naphthyl , Tetrahydro * group, Inman and Diphenyl aromatic radical groups. 5 10 A The term "heterocyclic," which is synonymous with "heterocyclic", means that it has-or more fluorene atoms (such as N, 0, S) as part of the ring structure and has 3 to fibrous ring atoms. The ring-containing free radical group. The heterocyclic group may be saturated, partially or completely unsaturated with one or more double bonds. The fully unsaturated heterocyclic group may also be called heteroaromatic Radicals. Heterocyclic radicals can contain one, two or three rings. When heterocyclic radicals contain two or three rings, the rings can be attached to any structure, such as fused or helical The radicals of heterocycles include, for example, but are not limited to, monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms (such as orbityl, imidazolidinyl, piperidinyl, piperazinyl, etc.) ; Saturated 3 to 6-membered heterocyclic monocyclic groups (such as manganyl, etc.) containing 丨 to 2 oxygen atoms and 1 to 3 nitrogen atoms, and bicyclic heterocyclic groups such as azabicyclic alkyl and 15 groups of oxabicyclic alkyl groups; unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (such as thiazolyl, etc.), imidazolyl, pyrimidinyl, isothiazolyl Different The evil sigma group. The above &amp; and are non-limiting examples. "Heterocyclic, additional examples of groups are described here. The term "substituted heterocyclic ring" means that the heterocyclic ring further has one or more substituents as described above. 20 Preferred heteroaryl radicals are monocyclic and have 5 to 7 ring atoms, of which 1 To 4 are heteroatoms selected from oxygen, sulfur and nitrogen. Examples are furyl, pyrrolyl, thienyl, 1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H- ° ratio. Base, 4Η-α oxazolyl, ι, 2-oxazolyl, ι, 3-chrysalyl, 1Η- [1,2,4] triazolyl, 4Η- [1,2,4] triazolyl , 1Η_ [1,2,3] triazolyl, 53 200418798 211- [1,2,3] triazolyl, 411-1 [1,2,3] triazolyl, [1,2,4] oxadi Oxazolyl, [1,3,4] σoxadiσ sitting group, [1,2,3] σoxa dibasic group, 1H-tetraσ sitting group, 2H-tetrasialyl, [1,2,3, 4] σ evil three σ base, [1, 2, 3, 5] σ evil trisialyl, 1, 3-1. Sitting group, 1, 2-α sialyl, 1 Η-penta η sitting group, σ Compared with fluorenyl, roaring group, sigma stilbyl group, dadyl group, sigma group and 5 fluorinyl group. Also preferred are heterocyclic radical groups which are fused with aryl radical groups. Examples of combined bicyclic radicals include benzofuran and benzothiophene. Pharmaceutical composition The present invention further provides a pharmaceutical composition comprising a mGlu5 selective 10 antagonist, such as a compound having one of formulas ι-ν or a mirror isomer, non-mirro isomer, N-oxide, Crystals, hydrates, solvates, active metabolites or pharmaceutically acceptable salts, which are selective antagonists of mGlu5. Pharmaceutical compositions may include one or more excipients, such as a pharmaceutically acceptable carrier Or diluent, flavor, sweetener, preservative, dye, 15 binding agent, suspending agent, dispersant, colorant, disintegrating agent, excipient, lubricating agent, absorption enhancer, bactericide, etc., stabilizer , Plasticizer, edible oil. Suitable pharmaceutically acceptable carriers or diluents include, but are not limited to, ethanol, water, glycerin, aloe vera gel, allantoin, glycerin, vitamin A and E oils, minerals. Oils, phosphate buffers, ppG2 myristyl propionate, strontium carbonate potassium, vegetable oils, animal oils, and solketal. Suitable binding agents include, but are not limited to, · starch; gelatin; such as glucose , Sucrose and lactose natural Corn sweeteners; natural and synthetic gums such as acacia gum, tragacanth gum, vegetable gum, sodium alginate; carboxymethyl cellulose, polyethylene glycol; soil, etc. 54 200418798 Suitable suspending agents include , But not limited to: bentonite. Suitable dispersing and suspending agents include, but are not limited to: synthetic and natural gums such as vegetable gum, tragacanth gum, acacia gum, alginic acid, and dextran; carboxymethyl cellulose Sodium salt; methyl cellulose; polyvinylpyrrolidone; and gelatine. * Suitable dispersants include, but are not limited to, starches such as corn starch; _ methyl cellulose; agar; bentonite; yellow Suitable lubricants such as virgin rubber include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium gasification, and the like. | 10 Suitable cooking oils include, but are not limited to: cottonseed oil, sesame oil, coconut oil, and peanut oil. Examples of additional additives include, but are not limited to, sorbitol, talc, stearic acid, and calcium hydrogen phosphate. Single dosage form 15 The pharmaceutical composition can be formulated into a single dosage form such as a bond, pill, capsule, large pill, powder, granule, sterile parenteral solution, sterile parenteral suspension, sterile parenteral latex, tincture, elixir, Metered aerosols or liquid sprays, drops, ampoules, automatic injection devices or suppositories. This single dosage form can be used for oral, parenteral, intranasal, sublingual or rectal administration, or 20 by inhalation or insufflation, transdermal patches, and lyophilized compositions. In general, any system that utilizes active ingredients to achieve system delivery can be used. Preferably, the single dosage form is an oral dosage form, and the most preferred is a solid oral dosage form; therefore, the preferred dosage forms are pills, pills, and capsules. Non-oral formulations are also preferred. 55 200418798 A solid single dosage form can be prepared by mixing the active agent of the present invention with a pharmaceutically acceptable carrier and any other desired additives as described above. The mixture is typically mixed until a homogeneous mixture of the active agents of the invention is obtained and the carrier and any other desired additives are formed, i.e., the active agents are uniformly distributed throughout the composition. In this case, the composition can form dry or wet particles. Lozenges or pills can be overcoated or they can be prepared in a single dosage form with delayed and / or sustained action such as controlled release and delayed release single dosage forms. For example, the lozenge or pill may contain an internal dose and an external 10 dose component, the latter in the form of a layer or shell overlying the former. The two components can be separated by an enteric layer that prevents decomposition in the stomach and allows the internal component to pass through completely into the duodenum or delay release. Biodegradable polymers used to control the release of the active agent include, but are not limited to, polylactic acid, polyεcaprolactone, polybutyric acid, polyorthoester 15, polyacetal, polydihydropyridine Crosslinked or amphiphilic block copolymers of polyan, polycyanoacrylate and hydrogel. For liquid dosage forms, the active substance or a physiologically acceptable salt thereof is optionally dissolved, suspended or emulsified with a commonly used substance such as a solubilizer, emulsifier or other adjuvant. Solvents available for the active composition and corresponding physiologically acceptable salts include water, physiological saline or alcohol, such as ethanol, propylene glycol, or glycerol. Additionally, sugar solutions such as glucose or mannitol solutions can also be used. Various mentioned mixtures can also be used in the present invention. The invention also considers the possibility of transdermal dosage forms. Transdermal dosage form 56 200418798 is a diffusive transdermal system using a liquid reservoir or a matrix system of a drug in an adhesive. Other transdermal dosage forms include, but are not limited to, topical gels, lotions, ointments, transmucosal systems and devices, and iontophoresis (electrical diffusion) delivery systems. Transdermal dosage forms can be used for delayed release as well as sustained release of the active agent of the present invention. · The pharmaceutical group of the present invention for parenteral administration and especially for parenteral administration. Forms and single dosage forms typically include a pharmaceutically acceptable carrier as described above. The preferred liquid carrier is vegetable oil. Injections can be, for example, intravenous, epidural, intracerebrospinal, intramuscular, intraluminal, intratracheal, or subcutaneous. ίο The active agent can also be administered in the form of microlipid delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Microlipids can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. The active agents of the present invention may also be combined with soluble polymers such as targetable pharmaceutical carriers. This polymer includes, but is not limited to, 15 ° ketones per polyethylene, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamine phenol, and palmitoyl residues. Substituted poly (ethylenoxy) polyionine. The pharmaceutical composition or single dosage form of the present invention can be administered via various routes such as, but not limited to, oral, enteral, intravenous, intramuscular, subcutaneous, transdermal, transmucosal (including rectum and buccal) And administration by inhalation route. : It is preferred to use the oral or transdermal route (ie, in solid or liquid formulations or skin patches, respectively). An effective amount of the pharmaceutical composition of the present invention or a single dosage form can be administered 57 200418798 Animals in need of treatment of lower urinary tract neuromuscular dysfunction, preferably humans (according to EJ McGuire in "Campbell's UROLOGY ,, 5th Ed. 616 -638, 1986, as described in the WB Saunders Company) and 5 people suffering from any physiologically dysfunction related to glutamate receptor function impairment. This specialized dysfunction includes, but is not limited to, such as anxiety, Anxiety disorders, * eating disorders, sexual dysfunction, addiction and related problems. Central nervous system disorders. The term "effective amount" as used herein means a measurable improvement that can produce at least one symptom or specific disorder parameter The amount of the amount. In the preferred embodiment | 10 'the compound can be used to treat such things as urgency, overactive bladder, frequent urination, decreased bladder compliance (decreased bladder storage capacity), cystitis (including intermittent cystitis), Urinary tract disorders with urinary incontinence, leaking urine, enuresis, dysuria, delayed urination, and difficulty in emptying the bladder. Specific patient toxicity or side effects15 are minimized, and the pharmaceutical composition or single dose of the present invention can be administered according to the dosage and dosing schedule defined by the testing procedures in accordance with the guidelines provided above. However, the subtleties of this treatment regimen Adjustments are generally made in accordance with the guidelines provided herein. The dosage of the active agent of the present invention may vary according to various factors such as the underlying disease condition, body condition, weight, sex and age, and the mode of administration. The effective amount for treating disorders can be easily determined by empirical methods familiar to those skilled in the art, for example, by establishing a matrix diagram of dose and frequency of administration and comparing it with the early groups or experimenters at various points in the matrix. The correct amount administered to a patient will vary with the severity and severity of the disorder and the physical condition of the person 58 200418798. The measurable improvement in any symptom or parameter can be described by the person skilled in the art or the patient's description of the doctor Decision. It should be understood that a clinical or statistically significant reduction in any symptom or parameter of urinary tract disorders Or improvement falls within the scope of the present invention. Clinically significant reduction or improvement means that the patient and / or doctor can feel it. For example, an individual patient may suffer from many symptoms of dysuria, such as urgency and frequency Urine or both, these conditions can be alleviated using the methods described here. As for urinary incontinence, any reduction in the frequency or undesired leakage of urine is considered to be beneficial to this treatment method. Amount of medication administered The range may be between about 0.01 to about 25 mg / kg / day, preferably between about 0.1 to about 10 mg / kg / day and most preferably between 0.2 to about 5 mg / kg / day. It can be understood that the pharmaceutical formulation of the present invention does not necessarily include the entire amount required for effective treatment of the disorder, because this effectiveness can be achieved by administering this pharmaceutical formulation multiple times. In a preferred embodiment of the present invention, the compound is formulated as a capsule or lozenge for reducing urinary incontinence and dysfunction. The capsule or lozenge preferably contains 25 to 500 mg of the compound of the present invention, and is preferably administered. The total daily dose to the patient is 25 to 1000 mg, preferably 150 to 500 mg, and most preferably about 350 mg. The total pharmaceutical composition is counted at 100% by weight for pharmacy for parenteral administration. The composition contains from about 0.01% to about 100% by weight of the active agent of the present invention. Generally, a transdermal dosage form contains from about 0.01% to about 100% by weight of active agent relative to 100% of the total weight of the dosage form. 59 200418798 The pharmaceutical composition or a single dosage form can be administered in a single dose for one day or in divided doses throughout the day. In addition, co-administration or sequential administration of other compounds for the treatment of disorders is also desirable. One or more mGlu5 selective antagonists can be combined with, for example, one or more anti-pyridine, an α-adrenergic antagonist, a 5-αTα receptor antagonist, or a COX inhibitor or a> ^ release derivative thereof. Vote for. Examples of anti-pyridine, α1_adrenergic antagonists, 5_ΗΤια receptor antagonists, COX inhibitors and their purchased and released derivatives have been described above, but they are not restrictive. When the compounds used in combination therapy are in separate formulations, the compounds may be administered simultaneously or staggered. For example, a selective mGlu5 antagonist can be administered in the morning and an anti-muscarinic compound can be administered in the evening, and vice versa. Additional compounds can also be administered on a specific schedule. The order of administration depends on various factors, including the patient's age, weight, gender, and health status; the severity and etiology of the disorder to be treated, the route of administration, the patient's kidney and liver function, the patient's treatment history, and the patient's Respond. The order of dosing can be fine-tuned, and this fine-tuning is generally based on the guidelines provided here. The method of treatment is not intended to be limited by theory. It is believed that administration of mGlu5 receptor antagonists can prevent unwanted recommended cone reflexes and / or control the activity of the cortical mechanism of urination. Therefore, it is expected that a wide range of lower urinary tract neuromuscular dysfunction can be treated with the compounds of the present invention, including, but not limited to, dysuria, urinary incontinence, and enuresis (overactive bladder). Difficult urination includes frequent urination, nocturia, urgency, decreased bladder compliance (decreased bladder storage capacity), and difficulty in emptying the bladder, that is, the volume of urine excreted below the optimal amount during urination. Symptoms of urinary incontinence include stress insufficiency of 60 K, forced urinary incontinence, leaky urinary incontinence, and mixed urinary incontinence. Enuresis means involuntary urination at night or while sleeping. The compounds of the present invention can also be used to treat dysfunction of facial amino acid dysfunction caused by central nervous system disorders. 5 Examples The following examples illustrate the invention described herein, but should not be used to limit the invention. In Example 1, the affinity of the anti-agent for mGhi quag-g type in the rat brain, radioligands on mGlul, mGlu5 and group II (mGlu2; mGlu3) 10 and group HI (mGlu4; mGlu6_8) mGluRs Combined analysis. Method a) Preparation of calendar: Male Sprague Dawley rats (200-3 00g, Charles River, Italy) were sacrificed by cervical dislocation, using a Politron homogenizer 15 (Kinematica), 50 mM cold 50 mM trimethylol The forebrain (cerebral cortex, striatum, and hippocampal gyrus) and cerebellum were homogenized in aminomethane buffer pH 7.4 (2x20 sec). Centrifuge the homogenate at 48,000xg for 15 minutes. _ Resuspend it in 50 volumes of the same buffer, incubate at 37 ° C for 15 minutes, then centrifuge and resuspend again. Freeze and store the final pellet at -80 ° C until use. b) Binding analysis: · i) mGlul · · In the experimental part, the pellet from rat cerebellum was resuspended in a 150-200 volume of 20 mM N-2-via ethyl travel σqin-N'-2- Ethanesulfonic acid (HEPES), 2 mM MgCl2, 2 mM CaCl2, pH 7.4. 61 200418798 The membrane and [3H] of about 7.5 nM were used to incubate gentisine in the final 1 ml volume at 25t for 60 minutes in the absence of or in the presence of competing drugs. Non-specific binding was determined in the presence of 10 μM gentisine (Hinoi et al., Neurochem. Int. 3, 277-2S5, 2QQV). 5 ii) mGlu5: In the experimental part, the pellet from rat forebrain was resuspended in 100 volumes of 20 mM HEPES, 2 mM MgCl2, 2 mM CaCl2, pH 7.4. The membrane was incubated with 4 nM [3H] MPEP in the final 1 ml volume for 60 minutes at 25 ° C in the absence or presence of competing drugs. Non-specific binding was determined in the presence of 10 μM MPEP (spooren et 10 al ·, 7 &gt; 2nd Office 5W · 22, 331-337, 2001).

iii) Group II (mGlu2 + mGlu3): In the experimental part, the pellet from rat forebrain was resuspended in 250 volumes of 20 mM HEPES, 2 mM MgCl2, 2 mM CaCl2, pH 7.4. Let the membrane be related to 1 nM

[3H] LY341495 was incubated at 0 ° C for 30 minutes at a final volume of 15 ml in the presence or absence of competing drugs. Non-specific binding is determined in the presence of 1 μM LY341495 (Wright et al., J. Wuping 77 ^. 298: 453-460, 2001; Mutel et al.? J. Neurochem. 75, 2590-2601, 2000) 〇iiii) Group III (mGlu4 + mGlu6 + mGlu7 + mGlu8): In terms of 20 points in the experimental section, the pellet from rat cerebellum was resuspended in a 100-200 volume of 10 mM HEPES, pH 8, 1.2 mM MgCl2 , 110 mM NaCl and 0.3 mM benzylsulfonium fluoride (PMSF). The membrane was incubated with about 20 nM [3H] L-AP4 in the final volume of 1 ml in the absence of or in the presence of competing drugs at 25 ° C for 30 minutes. Non-specific binding is determined in the presence of 100 μM L-serine-O-scalylate 62 200418798 (L-SOP) (Hudtloff et aL, Valence J. Pharmacol 124, 971-977, 1998) ° The incubation was stopped by adding cold trimethylolaminomethane buffer pH 7.4, and quickly filtered through a 0.5% polyethyleneimine pre-treated water filter pad 1204-401 (Wallac) 5 filter. The filter was then washed with cold buffer and the radioactivity remaining on the filter was counted with a liquid scintillation spectrometer. Data analysis was performed by using the non-linear curve adaptation program Allfit to analyze the specific binding inhibition of the radioligand of the test compound to assess the inhibitory concentration 50% value 10 (IC50) (De Lean et al. 5 Am. J. Physiol 235 , E97-E102, 1978). The Cheng &amp; Prusoff program was used to convert the ic50 value into an affinity constant (Ki) CSbc / zem · P / zar surface α / · 22, 3099-3108, 1973). Data are presented as the average quality of pKi (-log Ki) soil SE. 15 Table 1 shows the experimentally determined affinity of various antagonists for Group I (mGlul, mGlu5) or Group II (mGlu2 + mGlu3) receptors. Table 2 provides the reported affinity and activity values for the specific compounds provided in Table 1 for different mGluR isoforms # in the literature. On the rat forebrain, the binding of [3H] MPEP to the mGlu5 isoform and 20 [3H] LY341495 to the mGlu2 + mGlu3 isoform is saturable and has high affinity (Kd: 10.4 and 2.5 nM, respectively). : [3H] The strongest inhibitor of specific binding of MPEP to mGlu5 receptors is MTEP and MPEP itself. SIB 1893 shows a weaker affinity, but all other compounds are still inactive to 1 μM, as shown in Table 2, which is also reported by the same publication as 63 200418798. AIDA and LY367385 have been reported as selective antagonists of mGlul receptors (see Table 2). In the experimental results of the present invention, only LY367385 significantly replaced [3H] with gentisine from its binding position. The specific binding of [3H] LY341495 to the group II (mGlu2 + mGlu3) receptor was replaced by the high affinity of the ligand itself, while all other compounds remained inactive to 1 μM.

Table 1 Binding affinities of selected antagonists to group I (mGlulmGlu5) and group II 10 (mGlu2 + mGlu3) receptor subtypes. Group I and Group II compoundsrnGluj Ki (μΜ) mGlu5 Ki (μΜ) mGlu2 + + mGlu3 Ki (μΜ) MTEP 0.040 MPEP &gt; 10 0.015 &gt; 1 SIB 1893 &gt; 10 0.859 &gt; 10 AIDA &gt; 10 &gt; 10 &gt; 10 LY 367385 6 &gt; 10 &gt; 1 LY 341495 = 10 &gt; 10 0.004 64 200418798 Table 2 Binding affinities reported in literature for mGluR isoforms. When radioligand binding data are not available, the ICw and pKb values obtained with different power jealousy models are provided. Values are expressed in μM. 5 5 ND = Not measured. Group [Group II Group Itl Compound MGlUia mGlU5a mGlu2 MG1u3 mGlu4a mGlu6 MGlu? MGlus MPEP &gt; 100 (IC50) 1 0.032 (ICso) 1 &gt; 100 (ICso) 1 ND &gt; 100 (ICso) 1 &gt; 100 (ICso) 1 &gt; 100 (ICso) 1 &gt; 100 (ICso) 1 SIB 1893 &gt; 30 (IC5〇) 2 0.3 (IC5〇) 2 &gt; 30 (IC5〇) 2 ND &gt; 30 (IC50) 2 &gt; 30 (IC5〇) 2 &gt; 30 (IC5〇) 2 &gt; 30 (IC5〇) 2 AIDA 3.4 (pKb) 3 &gt; 1000 (IC5〇) 4 Weak homogeneity, potency ND &gt; 1000 (IC5 〇) 4 ND ND ND LY367385 8.8 (IC5〇) 5 &gt; 100 (IC5〇) 5 ND ND ND ND ND ND LY341495 6.8 (IC5〇) 6 8.2 (IC5〇) 6 0.002 (Ki) 7 0.001 (Ki) 7 22 (IC50) 6 ND 0.99 (IC50) 6 0.173 (IC50) 6 Table 2 References 1) Gasparini et al., Neuropharmacology 38: 1493, 1999. 2) Varney et al.? J. Pharmacol. Exp. Ther. 290: 170,

10 1999. 3) Hermans et al.? Br. J. 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 · 15 6) Kingston et al ·, Neuropharmacology 34: 887, 1995 · 7) Johnson et al.? Neuropharmacology 38: 1519, 1999. 65 Example 2 The determination is to determine the mode of action of the test compound on the mGlu5 and mGlu 1 receptors (synergists, antagonists or anti-allergists), and to compare the performance of mGlul or mGlu5 receptors in the absence and presence of different concentrations of the test compound itself. The concentration of phosphoinositide was measured in 5 CH0_K1 cells in response to glutamic acid stimulation. In cells transfected with (: 1 * 10-10), the cells were marked overnight with 40 (^ / 1111 muscle- [3: «] muscle crest, and then inositol phosphate was measured according to the method of Carroll et al. (IP) accumulation 59: 965-973, 2001). Pre-incubate the cells with residual amine 10 acid-decomposing enzyme (1U / ml glutamate pyruvate transaminase) and 2 1111 ^ propionic acid for 1 hour. In order to avoid the effect of surface amino acids that may be released from these cells. Then, stimulate in a medium containing 10 mM LiCl and different concentrations of the equivalent agent (glutamic acid) or the compound to be tested for 30 minutes. 15 When studying the activity of antagonists, test compounds are added to cell culture 20 minutes before the addition of the synergist, and further incubated for 30 minutes in the presence of the synergist. Quickly wash with ice-cold buffer and add ice-cold To stop incubation. Separate the inositol monophosphate segment from the neutralized 20 extract on an ion exchange microcolumn. As a result, the radioactivity collected in the IP segment was recovered from the lysed cell membrane. The ratio between radioactivity is expressed. The normalized IP formation ratio Compared with the one obtained in the experiment described below, which is the second largest Glu concentration (as 100%). 66 200418798 Example 3 Rhythmic selected urination contraction due to bladder filling in anesthetized rats The above method of action uses female Sprague-Dawley rats (Crl: 5 CD @ (SD) IGS BR, Charles River Italia) weighing 225-275g. This animal is kept in a house where food and water can be obtained freely. And at 22-24 ° C, forcibly changing the daytime-· 12-hour night period, at least 丨 weeks, except during the experimental period. According to Dray (Dray J ·, P / zama⑺ / · 13: 157, 1985), and According to Guarneri (Guarneri, 27: 173, 1993), a number of modified methods were used to evaluate the activity on rhythmic bladder urination and contraction. In short, 'subcutaneous injection of 1.25 g / kg (5 ml / kg) The rats were anesthetized with urinary fever, and then the bladder was intubated through the urethra with a PE50 polyethylene tube filled with physiological saline. The catheter was tied with a knot to an appropriate place in the external urethral sphincter and connected to a conventional pressure transducer (Statham P23 ID / P23 XL). 15 consecutive pressures in the bladder Presented on a chart recorder (Battaglia Rangoni KV 135 with DCI / TI amplifier). After that, the bladder was filled through the recording catheter by increasing the volume of warm (37 ° C) saline until the reflective bladder-expulsion contraction occurred. ( (Typically 0.8-1.5 ml). For intravenous injection of bioactive compounds, a PE50 polyethylene tube filled with physiological saline was inserted into the jugular vein. 20 From the intravesical pressure chart to evaluate the number of contractions 15 minutes before treatment (basic value) and post-treatment_ and the average amplitude of these contractions (average height of spikes;: · mmHg) 〇Because most compounds produce The bladder contraction completely stopped at the beginning, so biological activity (ie, the length of time during which no contraction occurred) is generally measured by measuring the duration of bladder inactivity. The effect on the magnitude of bladder contraction is evaluated by comparing the magnitude of the bladder contraction (when the contraction restarts) with the size of the treatment observed. To compare the strength of the test compound in inhibiting bladder emptying contraction, a linear regression of the least square difference was used to calculate the equivalent dose that caused the contraction to disappear for 10 minutes (ED1 Gmin). Morphine was also tested as a reference standard for this model. Results The rapid expansion of the bladder in urethane-anesthetized rats can cause a series of rhythmic urinary bladder contractions, which has been described in the literature (Maggi et al., Brain Res. 380: 83, 1986; Maggi et al. J. Pharmacol. Exp. 772er., 230: 500, 1984). The frequency of these contractions is related to the reflexive urination sensation of the afferent arm and the urination center as a whole, and their magnitude depends on the function of the reflex exit arm. The results after administration of the compounds of the present invention are shown in Tables 3 and 4. The compounds of the present invention (mteP, MPEP, SIB 1893), which are selective for the mGlu5 isoform, were found to be active in rats with isovolemic urination contraction inhibitors. Compared to the shrinkage observed before treatment, there was no difference in the shrinkage observed when the shrinkage recovered. In contrast, compounds showing selectivity to mGlul subtypes (AIDA, LY 367385) and compounds showing selectivity to group II mGlu receptors (LY 341495) were not active. In summary, the compound of the present invention inhibits urination reflex by blocking bladder contraction. The blocking strength is related to its affinity for the niGlu5 subtype and it is related to the amount of South j 200418798. In addition, they do not reduce the magnitude of bladder contraction. The lowering effect which may lead to lower bladder contractility and undesired retention of residual urine in the bladder after urination is not a feature of the present invention.

• r 69 200418798 Table 3 Effect of intravenous administration on rhythmic urinary bladder contraction. The data represent the mean ± SEM (time for which the contraction disappears; minutes) during the period of bladder inactivity after a given dose. Compound dose (pg / kg iv ·) Rat bladder contraction inactivity time (minutes) MTEP 30 5 5.52 ± 1.09 100 6 8.73 ± 2.11 300 6 13.90 ± 2.10 1000 5 20.96 ± 4.66 MPEP 30 5 3.90 ± 1.37 100 19 7.09 ± 1.04 300 16 12.64 ± 1.72 1000 9 22.46 ± 5.35 SIB 1893 1000 5 4.44 ± 1.05 2000 5 8.00 ± 0.78 3000 6 15.57 ± 1.34 AIDA 1000 5 1.50 ± 0.54 3000 4 2.33 ± 1.44 10000 4 2.35 ± 0.50 LY 367385 3000 4 1.00 ± 0.29 10000 4 1.95 ± 0.30 LY 341495 100 4 2.45 ± 1.39 300 4 4.48 ± 1.31 1000 4 4.65 ± 2.11 Morphine 10 10 2.76 ± 0.93 30 10 6.89 ± 2.11 100 10 13.83 ± 2.40 300 10 18.17 ± 3.60

70 200418798 Table 4 Effect on rhythmic bladder contraction after intravenous administration. The data represent the extrapolated dose (discontinuation of contraction) (EDiQmin) for 10 minutes of inactive bladder and its 95% confidence interval. Compound ED10min Effect of 蚪 hydroxy㈣ 95% CL on contraction amplitude MTEP 106 49-228 na MPEP 150 91-248 na SIB 1893 1928 1612-2306 na AIDA &gt; 10000--LY367385 &gt; 10000--LY 341495 &gt; 1000- -Morphine 50 28-89 na 5 na = No activity; no significant reduction in peak height Example 4 Effect on parameters of bladder pressure in conscious rats Rats using Charles River Italia with 300_400 g bw 10 male Sprague-Dawley rats [Cd: CD @ (SD) IGS BR]. The animals were kept in a house with free access to food and water, and maintained at a temperature of 22-24 # ° C for a period of 12 hours during the day and 12 hours during the night, except during the experiment. In order to quantify the urinary tract dynamics parameters of conscious rats, intravesical pressure studies were performed according to previously reported procedures (Guarneri et al ·, '15 / Tzarmaco /. 7? From 24:75, 1991) 〇: · The time between the rats was anesthetized by intraperitoneal administration of 3 ml / kg of Equitensin solution (30 mg / kg of pentobarbital and 125 mg / kg of hydrazine). Supine posture. Cut a clean abdominal wall from the hair 71 200418798 Cut about 10 mm long midline. The bladder was carefully separated from the adsorbed tissue and emptied, and then a polyethylene catheter (0.58 mm inner diameter, 0.96 mm outer diameter) was intubated into the bladder body through an incision, and it was permanently sutured with a silk thread. For the purpose of intravenous high-dose intravenous injection, a similar polyethylene catheter filled with sodium bicarbonate solution containing sodium heparin (40 IU / ml) was inserted into the jugular vein. The catheter exits through a subcutaneous channel in the retroscapular area, where it is connected to a plastic adapter to avoid the danger of removal by the animal. When tested for the drug, the rat can be used for one day after implantation. On the day of the experiment, the rat was placed in a modified BOUman cage, a 10-limit cage, which was large enough to allow the rat to assume a normal crouching posture, but narrow enough to prevent it from turning. After a stabilization time of about 20 minutes, the free tip of the bladder catheter was connected to a pressure transducer (Statham P23XL) through a T-shaped tube and connected to a continuous infusion of warm saline ( 37 ° C) to the peristaltic pump (Gilson minipuls 2) inside the bladder. The intraluminal pressure signal during the 15 saline injection into the bladder was continuously recorded on a variety of wavegraphs (Rectigraph-8K San-ei with BM614 / 2 amplifier from Biomedica Mangoni). _ Estimate two urinary tract dynamic parameters: bladder volume capacity (BVC) and urination pressure (MP). BVC (unit ml) is defined as the volume required for nasal diaphragm 20 detrusor contraction followed by urination caused by saline infusion into the bladder. MP (in mmHg) is defined as the maximum intravesical pressure caused during urination. The obtained basic BVC 'and MP values are the average of the values observed in the intravesical pressure chart recorded during the first 30-60 minutes. At the time of analysis, the infusion was interrupted and the test compound was administered intravenously by a jugular catheter or orally by a gastric tube. The bladder was reinfused and changes in BVC and Mp were evaluated from the mean values obtained in the intravesical pressure maps observed during 2, 3, 4 and 5 hours after treatment. The volume of the compound administered intravenously and orally was 1 ml / kg and 2 ml / kg, respectively. Animals in the control group received the same amount of vehicle, corresponding to 8% dimethylformamide and 80 / 〇Tween 80 aqueous solution (final concentration) when administered intravenously, or 05% when administered orally. Methylcellulose (methocel) in water. Under given test conditions, the measurement of BVC is equivalent to the measurement of the interval between micturitions. 10 Statistical analysis All data are expressed as mean ± standard deviation. For each rat / time, the percentage change of BVC and MP relative to the base value, and the delta value of BVC and MP (BVC or MP at time "X" minus the base value) (the difference is in ml or mmHg) ). In the figure, the data is expressed as a 15% change from the base value. S.A.S./STAT software, version 6.12 was used for statistical analysis of BVC and MP values and △ value. The difference between the effect of the vehicle and the active treatment is evaluated by the Δ value of B V C and MP, and the difference between the values at different times relative to the base value is evaluated by the original BVC and MP data. 20 Results The effect of intravenous administration of the test compound over time is shown in Figures 1 and 2. It was found that intravenous administration of MPEP at doses of 3 and 10 mg / kg and intravenous administration of SIB 1893 at doses of 50 mg / kg were effective in increasing bladder volume and capacity (Figure 1). Compared with the basal value and the value recorded in the control group, record 73 200418798 to MPEP significantly increased BVC at a dose of 10 mg / kg. SIB 1893 only significantly increased BVC when compared to the base value. Both compounds caused only a slight effect on micturition pressure, and there were statistically significant differences in the changes observed in the control group animals (Figure 2). The MPEP dose was administered orally; in the M0 and 30 5 mg / kg2 experiments, a significant and dose-dependent increase in BVC was caused at doses of 10 mg / kg or more (Figure 3). The effect of oral administration of MPEP on time changes in MP is shown in Figure 4. Compared to the values observed in the control group, MPEP significantly reduced Mp at doses of 10 and 30 mg / kg. The change in Mp reduction with time was only significantly different from the control group at a dose of 310 mg / kg. Example 5 Distinguishment of acetic acid that is released by the blue-to-blue bladder infusion. The effect on the parameters of bladder pressure. Method The method used is described in Example 4. The calculated base BVC and 15 MP values are the average of the values observed in the intravesical pressure map recorded during the first 30-60 minutes. At the time point of the test, the infusion is discontinued and the test compound is administered orally by month &amp; Re-infuse the bladder, replace warm saline with dilute acetic acid (0.2%), and evaluate relative to the base value from the average values obtained in the intravesical pressure maps at 1, 2, 3, and 4 hours after treatment Changes in BVC and 20MP. The volume of the compound to be administered orally was 2 ml / kg, and the animals in the control group received the same amount of vehicle (0.5% / 0 methyl cellulose in water). Statistical analysis The statistical analysis of the material was performed by the method described in Example 4. Results 74 Figures 5 and 6 show the effect of the test compound administered over time. When administered orally at a dose of 10 mg / kg, MPEp effectively antagonized the decrease in bladder volume caused by acid infusion (Figure 5), but had no effect on urination pressure (Figure 6). The activity of this model is similar to that of the known anti-inflammatory drug indomethacin. 5 Conclusions The mGlu receptor provides a mechanism by which glutamic acid can modulate or fine-tune the activity of the same synapses that cause rapid synaptic responses through ionophilic receptors. More and more evidence points out that, for example, mCHu5 receptors positively regulate NMDA fork benefits, and that two receptors are commonly expressed on most neurons. This implies that when compared to other methods such as non-selective NMDA receptor antagonists that have many intolerable side effects in humans, the mGiu acceptance state represents an arrogant target that is used in the CNS for the chuamine system Produces relatively subtle adjustments. In addition, the wide diversity of mGluR isoforms and their heterologous distribution15 provide an opportunity to build agents that can selectively respond to mGluRs that are involved in only one or limited CNS function. The results of the present invention clearly demonstrate that mGlu5 selective antagonists impart desired effects at the bladder level and increase bladder capacity without negatively affecting bladder contraction. These compounds also have a significant effect in the presence of bladder inflammation, showing that they may be effective treatment tools for different forms of overactive bladder. I: Brief description of the drawing 3 Figure 1 shows the intravenous administration of a vehicle (circle), 3.0 and 10 mg / kg of 2 · methyl-6- (phenylethyl fast S) At ^ (MPEP) compound or 5 Changes in bladder volume capacity (BVC) with respect to time in rats after 2-mg 75 200418798-6- (2-styryl) pyridine (SIB 893) compound (square) at 0 mg / kg. The data show the percentage change from the base value at different time points after treatment. n = number of rats / group. 5 Figure 2 shows the intravenous administration of a vehicle (circles), 3.0 and 10 mg / kg of 2-methyl-6- (phenylethynyl) pyridine (MPEP) compound or 50 mg / kg of 2-methyl · Changes in urinary pressure (MP) versus time in rats after -6- (2-styryl) pyridine (SIB 893) compound (square). The data show the percentage change from the base value at different time points after treatment. η = number of rats / group. Read 10 Figure 3 shows BVC in rats after oral administration of vehicle (circle), 3.0, 10, or 30 mg / kg of 2-methyl-6- (phenylethynyl) pyridine (MPEP) compound (square) Relative to time. The data show the percentage change from the base value at different time points after treatment. n = number of rats / group. Figure 4 shows that after oral administration of a vehicle (circle), 30, 10, or 3010 § /] ^ 15 2 · methyldong (phenylethynyl) σbipyridine (MPEP) compound (square), Changes in MP over time in rats. The data show the percentage change from the base value at different time points after treatment. η = number of rats / group. Figure 5 shows the oral administration vehicle (circle), 10 mg / kg t2-methyl-6- (benzylethynyl) (MPEP) compound (square; left) or 20 mg of 1 ind. ° Changes in BVC over time in rats with bladder infusion and dilute release of acetic acid after indomethacin (square; right). The data show the percentage change from the base value at different time points after treatment. n = number of rats / group. Figure 6 shows the oral administration of a vehicle (circle), mg / kg of 2-methyl 76 200418798-6- (phenylethynyl) pyridine (MPEP) compound (square; left) or 1 mg / kg of indole Changes in MP over time in bladder infused and diluted acetic acid rats after indomethacin (square; right). The data show the percentage change from the base value at different time points after treatment. η = number of rats / group. [Representative symbol table for main elements of the diagram] (none)

77

Claims (2)

Scope of patent application: Use for the preparation of a compound for the treatment of lower urinary tract neuromuscular dysfunction. The compound has the general formula I or a mirror image isomer, a non-image isomer, an N-emulsion, and a crystalline form. , Hydrates, solvates, pharmacologically active metabolites, prodrugs or pharmaceutically acceptable salts: (I) wherein: Xl represents a lower alkenyl group, a lower halidenylenyl group, a lower alkenyl group, or a lower i-alkynyl group, each of which is connected via a cyclic unsaturated carbon atom or an azo group (-N = n-), Ri represents a hydrogen atom or a lower alkyl group, a lower hydroxyalkyl group, a lower alkylamino group, a piperidinyl group, a carboxyl group, an esterified carboxyl group, an amidated carboxyl group, and a lower alkyloxy group , Lower alkynyl, lower alkynyl, cyano, alkynyl, lower alkoxycarbonyl, di- (lower) alkylamino, lower alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl, or N- (Lower) alkyl-N-phenylaminoformamidine groups, each of which is independently unsubstituted or has a lower alkyl, lower alkyl Oxy, halogen, or trifluorofluorenyl substituents, representing a hydrogen atom or a lower alkyl group, a carboxyl group, an esterified carboxyl group, a fluorinated alkyl group, a lower alkyl group, a methyl group, a lower alkyl group, or a lower alkyl group Alkyloxy, lower alkoxycarbonyl, di- (lower) -alkylamino- (lower) 200418798 alkyl, bis- (lower) alkylaminomethyl, 4- (4-fluorobenzyl) )- Piperidin-1-yl-Weikyl, 4-inflammo-butyloxoyl-1-yl-quinyl, 4- (4-azanitro-2-hydroxybenzyl) -piperazine- 1-yl-carbonyl or 4- (4-azido-2-hydroxy-3-iodo-benzylidene) -piperazin-1-yl-carbonyl group, 5 R3 represents a hydrogen atom or a lower alkyl group , Carboxyl, lower alkoxycarbonyl,% lower alkylaminoformamidine, lower hydroxyalkyl, di- (lower) alkylaminomethyl ·, morpholinocarbonyl or 4- (4-fluorobenzyl) Piperidin-1-yl-carbonyl group, R4 represents a hydrogen atom or a lower alkyl group, a meridian group, a lower meridian group, a lower -10 alkylamine group, a (lower) alkylamino group (lower) alkyl group, and a di- (Lower) -alkylamino (lower) alkyl, unsubstituted or substituted with (lower) alkylene (lower) alkyl, lower alkoxy, lower alkyl fluorenyloxy, lower amine alkoxy (Lower) alkylamino (lower) alkoxy, di- (lower) -alkylamino (lower) alkoxy, lower alkoxycarbonyl, carboxyl (lower) alkylcarbonyl, (lower) 15 (Lower) alkoxy, lower hydroxyalkyl, m-hydroxy-o-azidophenylcarbonylamino (lower) alkoxy, lower amine Benzalimidate (lower) alkoxy, unsubstituted (lower) elongation amine (lower) 41 Alkoxy or substituted with a hydroxyl group or 2-oxo-azazolidine small group-group (Lower) alkyleneamine (lower) alkoxy, carboxyl, esterified carboxyl, fluorene -20 aminated carboxyl, lower carboxyalkoxy or lower esterified carboxyalkoxy groups, And ^ Rs represents an aromatic or heteroaromatic group, which is unsubstituted or substituted with one or more substituents selected from the group consisting of: nitro, hydroxyl, carboxyl, cyano, trifluoromethyl, trifluoromethyl Oxy, 79 200418798 thiophenemethylamino, thiophenecarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, phenylfluorenylcarbonylamino, azide, amine, halo, monohalobenzene Amido, acid, S &amp; amino, lower alkyl, lower alkyl, lower hydroxyalkyl, lower alkoxy, lower haloalkoxy, lower amine alkoxy 5 radical, lower alkanesulfonyl, lower Alkylamino, di- (lower) -alkylamino, A lower alkenyl, lower alkenyloxy, lower elongyl dioxy, lower alkynyl, trimethyl Silylalkynyl, lower alkoxycarbonyl, lower alkynyl, lower alkynyl, lower alkynyloxy, (lower) alkylamino (lower) alkoxy, di- (lower alkyl) -amine (Lower) alkoxy, (lower) alkoxy-10 amino (lower) alkoxy, N- (lower alkyl) -N- (lower alkyl) -amino (lower) alkoxy, (Lower) alkylaminocarbonylamino, (lower) alkoxycarbonylaminocarbonylamino, (lower) alkylfluorenyloxy (lower) alkyl, N-fluorenyl-N- (lower alkyl) -amino , Esterified carboxyl group, fluorenated carboxyl group, carboxyl (lower) alkylamine group, esterified carboxyl (lower) alkylamine group, fluorinated carboxyl 15 (lower) alkylamine group, phosphine (Lower) alkylamino groups and esterified phosphine (lower) amine groups, and / or substituted with one or more of the following: phenyl, phenoxy, phenyl (lower) alkoxy, phenyl (Lower) alkenyl, phenyl (lower) alkynyl, aniline, phenyl (lower) alkylamino, cycloalkyl (lower) alkylamino or heteroaryl Each of them is unsubstituted or the ring is lowered by one or more Lower alkyl, lower alkoxy, halo, and / or trifluoromethyl 'groups are substituted. 2. For the purpose of applying for item 1 of the patent scope, which has a compound of the general formula I, 80 200418798 Xi represents (C2-4) alkenyl, (C2_4) haloalkenyl, (C2_4) alkynyl, or ( C2_4) 1S alkynyl groups, each of which is connected through a cyclic unsaturated carbon atom, the heart represents a hydrogen atom or (Cm) alkyl, (Cm) alkoxy, (Cm) hydroxy5 alkyl, cyano Group, ethynyl, carboxyl, (Ci-4) alkoxycarbonyl, di- (Cm) alkylamino, (C ^) alkylaminocarbonyl or trifluoromethylphenylaminocarbonyl group, R2 Represents a hydrogen atom or a hydroxyl group, (C ^) alkyl, (Cw) hydroxyalkyl, (Cm) alkoxy, carboxyl, (C2_5) alkanoyloxy, (Cm) alkoxycarbonyl, 10 di (Cm) Alkylamino (Cm) alkylamido, bis (Cm) alkylaminomethyl, 4- (4-aminobenzyl) -bromo. Ding-1-yl-jiki, 4-year-old-butyloxyweilyl-mother call-1_yl-daikyl, 4- (4-fengqiyl-2- via benzyl) -luff-1 -Yl-Weiji or 4- (4-fengfengyl-2-meryl-3-moth benzyl) -branth-1-yl-fluoranyl group, 15 R3 represents a hydrogen atom or (Cm ) Alkyl, carboxyl, (Cm) alkoxycarbonyl, (Cm) alkylaminoformamidine, (CV4) hydroxyalkyl, bis (Cm) alkylaminomethyl, morpholinocarbon or 4- ( 4-amino-benzyl)-♦. A -1 -yl-fluorenyl group, R4 represents a hydrogen atom or a hydroxyl group, (Ci-4) alkoxy, carboxyl, (C2_5) _20 alkylfluorenyloxy, (Cm) alkoxycarbonyl, amine (Cm) alkoxy, bis (Cm) alkylamino (Cm) alkoxy, bis ((^ _ 4) alkylamino (Cm) alkyl, carboxy (Cm) 'alkylcarbonyl, (Ci_4) alkoxycarbonyl (Ci_4) alkoxy, hydroxy (Cm) alkyl, bis (Cw) alkylamino (Cw) alkoxy or m-hydroxy-o-azidophenylcarbonylamino (Cw) alkoxy group, And 81 200418798 R5 represents a group of the formula Where Ra and Rb each independently represent a hydrogen or halogen atom or a hydroxyl group, a nitro group, a 5 cyano group, a carboxyl group, a (Cm) alkyl group, a (Cm) alkoxy group, a hydroxy (Cm) alkyl group, and a (Cm) alkoxycarbonyl group (C2_7) alkylfluorenyl, (C2_5) alkylfluorenyloxy, (C2-5) alkylfluorenyloxy (Cm) alkyl, trifluoromethyl, trifluoromethoxy, trimethylsilyl Ethynyl, (C2_5) alkynyl, amine, azide, amine (Cm) alkoxy, (C2_5) alkamino (Cm) alkoxy, (Cm) alkamino (&lt; ^ _ 4 ) 10 alkoxy group, (C1.4) amine group (Ci_4) alkoxy group, (Ci_4) amine group, di (Cm) alkylamino, mono-benzylamino, thienylamino, thiophenecarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C2_5) alkylamino, benzyl Carbonylamino, (Cm) alkylaminocarbonylamino (Cm) alkoxycarbonyl-aminecarbonylamino or (Cm) alkanesulfonyl groups, 15 Re represents a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl group, ( Cm) alkyl, (C2_5) alkanoyloxy, (Cm) alkoxy or cyano group, and Rd represents a hydrogen or halogen atom or (C ^) alkyl group. 3. For the purpose of applying for item 1 of the patent scope, which has a compound of general formula I, in 82 200418798, Xi represents (C2_4) alkenyl, (C2_4) haloalkenyl, (C2_4) alkynyl, or (C2_4 ) Haloalkynyl groups, each of which is connected through a cyclic unsaturated carbon atom; 5 ratio represents a hydrogen atom or (C ^) alkyl, (Ci_4) alkoxy, cyano, ethynyl or Di (Cm) alkylamino group; R2 represents a hydrogen atom or a hydroxyl group, a carboxyl group, a (C ^) alkoxycarbonyl group, a bis (Cm) alkylaminomethyl group, 4- (4-fluorobenzyl) group- Piperidin-1-yl-carbonyl, 4-tert-butoxyfluorenyl-bromo-1-yl-genyl, 4- (4-fengoyl-2- via benzamidine 10yl)- Travelling -1 -yl-pyridyl or 4- (4-pyridyl-2 -pyridyl-3-mothylbenzyl) -Nitro-1-yl-jikiyl group ^ R3 represents hydrogen Atom or (Cm) alkyl, carboxyl, (Cm) alkoxycarbonyl, (Cm) alkylaminoformamidine, hydroxy (Cm) alkyl, bis (Cm) alkylaminomethyl, morpholinyl or 4- (4-Fluoro-benzyl) -σ-Cyen-1-yl-I-yl 15 groups; R4 represents a hydrogen atom or a hydroxyl group, a carboxyl group, a (c2_5) alkylfluorenyloxy group, a (Cm) alkyl group Oxycarbonyl, amine (Cm) alkane Oxygen, di (Cm) alkylamino (Cm) alkoxy · yl, di (C! -4) alkylamino (Cm) alkyl or hydroxy ((^ _ 4) alkyl group, and 20 R5 represents the following Formula group k or wherein 83 200418798 Ra and Rb each independently represent a hydrogen or halogen atom or a nitro, cyano, trifluoromethyl, trifluoromethoxy, (Cm) alkyl, (Ci_4) alkoxy, or (C2_5) Alkynyl groups; Rc represents hydrogen, fluorine, chlorine or bromine atoms or hydroxyl groups, (Cb4) alkyl, (C2_5) 5 alkylfluorenyloxy, (Ci.4) alkoxy or cyano groups, and Rd Represents a hydrogen or halogen atom or a (Cm) alkyl group. 4. For the purpose of applying for item 1 of the patent scope, it has 2-methyl-6- (phenylethynyl) mouth ratio (MPEP). 5. For the purpose of applying for item 1 of the patent scope, it has 2-methyl-6- (2-styrene 10yl) pyridine (SIB 1893). 6. —Use of a compound for preparing a medicament for treating lower urinary tract neuromuscular dysfunction, the compound having the general formula I-A or a mirror image isomer, non-image isomer, N-oxide, crystal Type, hydrate, solvate, pharmacologically active metabolite, prodrug or pharmaceutically acceptable salt: R · C three c—M 15 Ι-Α Where R 'represents a hydrogen atom or a (Cm) alkyl group, and M represents a group having the formula 84 200418798 where Raa, Rbb and Rcc each independently represent a hydrogen or halogen atom or (Ci_4) alkyl, (Cm) alkoxy, (C ^) hydroxyalkyl, hydroxyl or cyano group, Rdd represents an ifigen atom Or cyano group, 5 Ree represents a hydroxyl group, (Cm) alkyl or (Cm) alkoxy group, Rff represents a hydrogen atom or (C ^) alkyl group, and Rgg and Rhh both represent a hydrogen atom or Together form a group of the formula: = 0, = CH-CN, = N-OH, ^ N-CKCm) alkyl, sCH-POJCCm) alkyl] 2 or = CH-CO-Rkk, where Rkk is ( Ci-4) alkoxy or _ 10 -NRuRmm, wherein Ru and the ruler are independently selected from hydrogen, (Cm) alkyl and phenyl, Rn and Ry each independently represent a hydrogen atom, (Cp4) alkyl group or phenyl group ^, and 乂 1 Yes ((: 112) 11, where η is 1, 2 or 3 or CHRnn, where Rnn is 15 hydroxyl, (Cm) alkyl, (Cm) alkoxy, (Cm) hydroxyalkyl, (Cm) alkoxy (CN4) alkyl, (Cm) alkoxycarbonyl, aminoformamidine, (Cm) alkylaminosulfonium, phenyl, pyridyl, thienyl, or (R_RPP) N-lower_alkyl, where R Is hydrogen, (Cm) alkyl, (Cm) alkylfluorenyl or benzamyl and Rpp is hydrogen or (Ci_4) alkyl, or assuming that Rgg and Rhh are each hydrogen 'y 20 Vi may also be NRqq, Where Rqq is (Ci-4) alkoxycarbonyl, benzyloxycarbonyl, benzamidine, thienyl, (Cm) alkylfluorenyl, aminoformamidine, mono-, or di- (Cm) -alkyl -Aminoformamidine or phenylaminoformamidine, any phenyl ring in Rqq optionally has one or more halogen, cyano, (Cm) alkyl or (Ci-4) alkyloxy substituents. 85 200418798 7. — A compound for the preparation of a medicament for treating lower urinary tract neuromuscular dysfunction This compound has the general formula Π-A or its mirror isomer, non-mirro isomer, N-oxide, crystalline form, hydrate, solvate, pharmacologically active metabolite, prodrug or pharmaceutically acceptable Salts: R6, R7, R8, R9 and R10 each independently represent a hydrogen atom or a lower alkyl group, a lower alkoxy group,-(CH2) n-halo group,-(CH2) n-NReRf,-(CH2) nN (Re) -C (0)-(lower) alkyl, aryl or heteroaryl group, 10 of which is unsubstituted or substituted with one or more lower alkyl groups; represents Where Rn represents hydrogen or a halogen atom or a lower alkyl group or a 15-(CH2) n_C (0) 0Re group; 86 R12 represents hydrogen, a lower alkyl group,-(CH2) nC (0) 0Rf, an i group, a nitro group, or Heteroaryl, which is unsubstituted or substituted with lower alkyl or cycloalkyl; R13 represents hydrogen, lower alkyl,-(CH2) n-OH,-(CH2) n_C (0) 0Rg or aryl; R14 Represents a lower alkyl group; R15 represents a hydrogen or halogen atom or a lower alkyl group; R16 represents a hydrogen atom or an alkyl group; Rn represents-(CH2) nN (Re) -C (0) -lower alkyl; R18, R26, R29, R3G, and R31 each independently represent a hydrogen atom or a lower alkyl group; R19, R20, R2I, R22, R23, K · 24, and R25 each independently represent a hydrogen atom or a lower alkyl group,-( CH2) n-halo or lower alkoxy group; R27 represents a hydrogen atom, a lower alkyl group or a lower alkyl group having a radical and / or a halogen substituent; R28 represents a hydrogen atom or a lower alkyl group, Lower alkylfluorenyl or nitro group; Re'Rf and Rg each independently represent a hydrogen atom or a lower alkyl group; 11 is 0 or an integer from 1 to 6; X2 represents an oxygen or sulfur atom or a methylene group Group; and Y1 Table nitrogen atom or a methine group. For example, for the purpose of applying for scope 7 of the patent, it has a compound III-A, wherein Bl represents β1 and R12 represents (CH2) nC (0) 0Rf, an unsubstituted heteroaryl group or one or more lower alkyl or ring Alkyl-substituted heteroaryl. 200418798 9. As for the application in the scope of patent application No. 8, it has the compound Π-A, wherein Ri2 represents -C (0) 0-lower alkyl. 10. Use of a compound for preparing a medicament for treating lower urinary tract neuromuscular dysfunction, the compound having the general formula II-B or IIC or a mirror image isomer, non-image isomer, N-oxide , Crystalline, hydrate, solvate, pharmacologically active metabolite, prodrug or pharmaceutically acceptable salt: 10 of which R32, R33, R34, R35 and R36 each independently represent a hydrogen atom or a lower alkyl group,-(CH2) n-halogen, lower alkyloxy group,-(cH2) n_NReRf,-(CH2) nN (Re) -C ( 0)-(lower) alkyl, aryl or heteroaryl groups, which are unsubstituted or substituted with one or more lower alkyl residues; 15 Rs7 represents a hydrogen or halogen atom or a lower alkyl,-(CH2) nC (0) 0Re group; R38 represents hydrogen or halogen atom or lower alkyl,-(CH2) nC (0) QRfm heteroaryl group, which is unsubstituted or substituted with lower alkyl or cycloalkyl; 88 200418798 represents hydrogen atom or lower alkyl, _ (CH2) n-OH,-(CH2) nC (0) 〇Rg or aryl group; R4〇 represents lower alkyl group; Rn represents hydrogen or halogen atom or lower 5 R42 represents a hydrogen atom or an alkyl group; Re, Rf and Rg each independently represent a hydrogen atom or a lower alkyl group; and η is an integer of 0 or 1 to 6. 11. Use of a compound for preparing a medicament for treating lower urinary tract neuromuscular dysfunction, the compound having the general formula II or its mirror isomer, non-mirro isomer, N-oxide, crystalline form, hydration Substances, solvates, pharmacologically active metabolites, prodrugs or pharmaceutically acceptable salts: A1-^-B2 jjj Ai represents a 5-, 6-, or 7-membered ring with the following structure: Where at least one of W, X3, 1 and 21 is a group (CRh) P, where ρ is 1 or 2; and W, &amp;, γ2, and the remainder of ZM are each independently 0, N, or S; each Rh Independently, i element, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic ring, lower or lower substituted alkoxy group substituted by 89 200418798, ( Lower) Burned alkoxy, weidyl, esterified weidyl, fluorenated endyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cycloalkyl, mercapto , Nitro, carboxyl, carbamate, carbamide, hydroxy, ester, cyano, 5 amine, amidine, amidine, amido, sulfofluorenyl, sulfonamide, or N- (lower) _alkyl ' -N-phenylaminoformamidine, wherein each nitrogen atom is independently unsubstituted or substituted with lower alkyl, lower alkyl, iS or trifluoromethyl and wherein q is 0, 1, 2 or 3; b is a substituted or unsubstituted alkenyl, alkynyl or azo; and 10 B2 is a substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclic group , Substituted or unsubstituted heterocyclic rings, which optionally contain one or more double bonds or substituted or unsubstituted aryl groups, where "substituted" means a radical group in which one or more hydrogens Atoms are substituted by substituents selected from the group consisting of: 15 groups, alkyl, alkoxy, thio, aryl, heterocyclic, heterocyclic, trifluoromethyl, pentafluoroethyl , Cyano, cyanomethyl, nitro, amine, N-substituted- or N, N-di-substituted amine 'wherein one or two nitrogen atoms are independently φ alkyl, heterocyclic, aryl , Each of which is optionally further independently substituted by a hydroxyl group, an alkyl group or a heterocyclic ring, or substituted by an acid amine, a lung group, an amino group, a Wei group, a carboxyl group that is converted to S, and an amidine group. Carboxyl, carbamide, amine Y formate, esters, sulfonyl and sulfonamide groups, etc., 12. As the application of the scope of patent application ⑽, it has 3_ (2_methyl shot_4_ ) Acetylpyridine (MTEP) 13. Use of a compound for the preparation of 90 doses of a drug for treating lower urinary tract neuromuscular dysfunction, the compound having the general formula IV or Enantiomers, diastereomers, N- oxides, crystalline forms, hydrates, solvates, pharmaceutically active metabolites, the precursor of the drug, or a pharmaceutically acceptable salt thereof: Wherein η is 0, 1 or 2; X4 is 0, S, ΝΗ or ΝΟΗ; R43 and R44 each independently represent a hydrogen atom or a cyano group, COORi, CONHRi, (Cr6) alkyl or a tetrazole group, or R43 Together with R44 represents a side oxygen group; Ri represents a hydrogen atom or a (Cw) alkyl group; R45 represents a carboxyl group, a methylol group, an alkoxymethyl group, a (C ^) alkyl group, a (C2_6) alkenyl group, ( C3.8) a cycloalkyl group; An represents an unsubstituted aromatic or heteroaromatic group, or has one or more (C ^) alkylamino groups, di- (C ^)-alkylamine groups, ( C ^) alkoxy, carboxyl, hydroxy, cyano, i-group, trifluoromethyl, nitro, amine, amino-amino, (Ci-6) sulfanyl, (Ck) sulfanyl, (Ck ) Sulfuryl and / or (C ^) !! aromatic or heteroaromatic groups of alkyl substituents; z2 represents a group of the formula 200418798 r wherein R46 and R47 each independently represent a hydrogen or halogen atom or a cyano group, a hydroxy group, a trifluoromethyl group, a (Cu) alkoxy group, -OAn, a (Cw) alkyl group, COORi, CONHRi, CORi, ( ~) _Alkylthio or (D-alkanesulfonyl) group; A2 is CH2, 0, NH, NRI, S, SO, S02, CH2-CH2, CH20, CHOH or C (O), here Ri is as defined above; B3 is CHRi, C (Ri) 2, (Cw) alkyl, C (O), -CHOH, 10_ch2-〇, -CH = CH, CH2-C (0), CH2-S, CH2_S (0), CHrSOyCHCO ^ or -αΊ-N (Κ) 2, where Ri is as defined above; and et doped%, such as squeak, fenphen, or bar. Fixed. 15 14.- A compound for the preparation of a compound for the treatment of dysfunction of the lower urinary tract nervous system, the compound having or its mirror, non-mirror isomers, N_oxide, crystals'-soil, synthesis Compounds,, compounds, pharmacologically active metabolites, prodrugs, or pharmaceutically acceptable _ Ar2—G 「Ar3 ν · a solitary where 20Ah represents a heteroaryl group, 92 200418798 Ah represents an aryl group Group, where Aq and Ah are optionally replaced by one or more substituents selected from the group consisting of: -F, _a, _Br, 4, _〇Rj, _SR, -SORj, -S02Rj , -S02NRjRk, -〇c〇Rj, -〇c〇NRjRk 5 NRC0Rk, _NRC02Rk, -CN, · ν〇2, -C02Rj, -C0NRjRk, -C (0) Rj, _CH (〇Rj) Rk '_CH2 ( 〇Rj), -Rj, and -A- (CH2) n-NRjRk, where R ^ Rk is independently selected from the group consisting of: Η, CF3, (Cw) group, cycloalkyl, alkyl _Aryl, alkyl-heteroaryl, heterocycloalkyl'aryl, or ^ and ^ can be combined to form a 10 Ci-5 methylene chain, and A is defined as CH2, 0, NH, S, SO, S〇2 and η are 1, 2, 3 or 4, Gi is free to choose Groups formed by columns: -NH_, -S, -Ο-, -CO_, -CONH-, -CONHCH2-, -CH2CONH-, -CH2NHNH-, -CH2NHNHCH2_, -C = NO-CH2-, 15 -CH2NHCH2 -, -CH2CH2NH-, -NHCH2CO-, -NHCH2CHOH-, -NHCH2NHNH-, -NHCONH-, or Gi is a divalent ring radical derived from: cyclopentane, cyclopentadiene, sigmafuran , Thio squeam, .17 houses, σ bilo, 2-misoline, 3-taste mouthline, 4-mazeline, taste °, sitline, roar, spit-flavor, ° Evil 20 oxazole, 2-oxazole, thiazole, isoxazole, isothiazole, l / fl, 2,4-triazole, 1 / ί-1, 2, 3-triazole, 1, 2, 4-oxazole Thiazole, 1,3,4-oxothiazole, 1,4,2-dioxan, 1,4,2- °°° C, 1,2,4- ° oxadiazal, 1,2,4-嗟 two saliva, 1,2,5-σ evil two 11 sitting, 1,2,5- ° plug two saliva, 1,3,4-noise two saliva, 1,3,4-diasis, 1 world four Samarium, cyclohexane, slightly fixed, tetrahydro ° specification, 1,4-dihydro ° specification, σ ratio 唆, 93 200418798 benzene, tetrazine, 3,4_diazine-2 // _0 ratio, 2 //-11 ratio, 4 ^ 1-11 ratio, tetrahydrothio °° ratio, 3,4-dihydro-2 // • thio °° ratio 2thiin, 4 //-thio ° biran, morphine, thiomorphine, travelazine, vocal, ° dense, σΛσqin, 1, 2, 4_ triazine, 1, 2, 3, 3 Azine, 1,3,5-triazine or 1,2,4,5-tetrazine. r 5 15. The use according to item 14 of the scope of patent application, which has the compound VA, in which Ar3 represents phenyl, phenylfluorenyl, naphthyl, fluorenyl, anthrenyl, indenyl, phenanthryl or benzonaphthylene Group. 16. For applications in which the scope of patent application is No. 14 or 15, it has compound V-A, of which Ar2 stands for sale. Soryl, succinyl, ° biranyl, 2 //-bilocyl, ° plug 10 phenyl, σbilocyl, flavor. Sitting group, σ ratio salyl group, phenyl group, ° ratio ° Qinyl group, ° melidyl group, pyridazinyl group, benzothiazolyl group, benzimidazolyl group, 3 / /-indolyl group, called h doryl, σ primer Junki, Purinyl, σ-Qinyl, Iso-Quinyl, I-Qinyl, 酜 σ-Qinyl, Naphthyl, Sialinyl, ° Zeng Lin-Qi, Iso-Q11 , Indole [sigma] yl, isoindolyl, benzo [sigma] phenenyl, benzouranyl, 15 isobenzofuranyl or tryphenyl groups. 17. —Use of a compound for preparing a medicament for treating lower urinary tract neuromuscular dysfunction, the compound having the general formula VB or a mirror image isomer, a non-image isomer, an N-oxide, a crystalline form, Hydrates, solvates, pharmacologically active metabolites, prodrugs or pharmaceutically acceptable salts: VB where X5, Ya3, and 23 are independently selected from the group consisting of: 94 20 N, 0, S, C, and co, which make X5 and mZ3 at least heteroatoms; Ah and Aq independently selected From the group consisting of: a heterocyclic or fused heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, 0, and S, and selected from Aromatic moieties of the group consisting of phenyl, benzyl, benzoyl 2-naphthyl, alkoxy, anthryl, benzyl, phenanthryl, and benzocaimine, and their A Is optionally replaced by a substituent of the group consisting of: -F, _C1, office, 4, -0Rj, -SR ", -SORj, -S02Rj, -S02NRjRk, -OCORj, -Oconr ^ _NRC〇Rk, _NRC〇2Rk, -CN, -N〇2, _C〇2Rj, -c〇NRjRk, -C (〇) Rj, -CH (ORj) Rk, CH2 (〇Rj> Rj, and _A_ ( CH2) n_NRjRk; where Rj and Rk are independently selected from the group consisting of: H, CF3, (Cno) alkyl, cycloalkyl, alkyl-aryl, alkyl_heteroaryl, heterocyclic Alkyl, aryl, or Rj and Rk can be combined to form a C1-5 methylene chain. Meaning CH2, 0, NH, S, SO, S02, and η is 1, 2, 3, or 4. 18. For the purpose of claim 17 in the scope of patent application, it has the compound VB, wherein the heterocyclic or fused The heterocyclic group is preferably selected from the group consisting of fluorinyl, oxazolinyl, oxoxalinyl, 2-pyrimidinyl, 4-¾11fluorenyl, 5-¾, fluorenyl, 2_. Ratio. Definite base, 3-tr specific bite base, 4- ° specific angle base and ° specific angle base. 19. Use of a compound for preparing a drug for treating lower urinary tract neuromuscular dysfunction Compound 200418798 (a) has an affinity for binding to the mGlu5 receptor of at least 10'6 M, and (b) has an affinity for binding to the mGlu5 receptor than that of the compound to one of the mGlu 1 receptor, mGlu2 receptor, or mGlu3 receptor The binding affinity of the compound is at least 10 times stronger. 5 20 · If the application in the scope of patent application No. 19 has a binding affinity of the compound and the mGlu5 receptor than each compound and mGlul receptor, mGlu2 receptor or mGlu3 receptor A binding affinity is at least 10 times stronger. 21. If it is used for the purposes of item 19 or 20 of the patent application, it has The compound additionally has a binding affinity of kappa 10 (c) to the mGlu5 receptor that is at least 10 times stronger than the binding affinity of the compound to one of the mGlu receptors in group Π. 22.-Identification identified for use in treating mammals Method of a compound of urinary neuromuscular dysfunction comprising (a) determining the binding affinity of one or more test compounds for an mGlu5 receptor and one or more 11101111 receptors or a group II mGlu receptor; (b) identification test Compounds that (1) have an affinity for binding to the mGlu5 receptor of at least 10-6m, and (2) have an affinity for binding to the mGlu5 receptor that is at least stronger than that of the claw receptor or the group II mGlu receptor 10x. 20 23. The method of claim 22 in the scope of patent application, further comprising the individual test &quot; Hai—or test compound binding affinity to one or more group III mGlu receptors, and identifying the test compound and mGlu5 receptor The binding affinity is at least 10 times stronger than that of the group III mGlu receptor. 96