BACKGROUND ART Vanilloid compounds are characterized by the presence of vanillyl group or a functionally equivalent group. Examples of several vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2- methoxy-phenol), zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanon), eugenol (2-methoxy4-/2-propenyl/phenol), and capsaicin (8-methy-N-vanillyl-6- noneneamide).

Among others, capsaicin, the main pungent ingredient in"hot"chili peppers, is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts with vanilloid receptors (VR1), which are predominantly expressed in cell bodies of dorsal root ganglia (DRG) or nerve endings of afferent sensory fibers including C- fiber nerve endings [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D: The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 21: 531-543,1998]. The VR1

receptor was recently cloned [Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: Nature 389: 816-824, (1997) ] and identified as a nonselective cation channel with six transmembrane domains that is structurally related to the TRP (transient receptor potential) channel family. Binding of capsaicin to VR1 allows sodium, calcium and possibly potassium ions to flow down their concentration gradients, causing initial depolarization and release of neurotrans- mitters from the nerve terminals. VR1 can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit neuronal signals in a patho- logical conditions or diseases.

There are abundant of direct or indirect evidence that shows the relation between VR1 activity and diseases such as pain, ischaemia, and inflammatory (e. g., WO 99/00115 and 00/50387). Further, it has been demonstrated that VR1 transduce reflex signals that are involved in the overactive bladder of patients who have damaged or abnormal spinal reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl) : 36-52,1997]. Desensitisation of the afferent nerves by depleting neurotransmitters using VR1 agonists such as capsaicin has been shown to give promising results in the treatment of bladder dysfunction associated with spinal cord injury and multiple sclerosis [ (Maggi CA: Therapeutic potential of capsaicin-like molecules-Studies in animals and humans. Life Sciences 51: 1777-1781,1992) and (DeRidder D; Chandiramani V; Dasgupta P; VanPoppel H; Baert L; Fowler CJ: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup. J. Urol. 158: 2087- 2092,1997)].

It is anticipated that antagonism of the VRl receptor would lead to the blockage of neurotransmitter release, resulting in prophylaxis and treatment of the condition and diseases associated with VR1 activity.

It is therefore expected that antagonists of the VR1 receptor can be used for prophylaxis and treatment of the condition and diseases including chronic pain,

neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incon- tinence, inflammatory disorders, urge urinary incontinence (UUI), and/or overactive bladder.

WO 2000/50387 discloses the compounds having a vanilloid agonist activity represented by the general formula: wherein; XP is an oxygen or sulfur atom; AP is-NHCH2-or-CH2- ; Ra is a substituted or unsubstituted Cl 4 alkyl group, or RalCO-; wherein Ra'is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms; Rb is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom; R is a hydrogen atom, an alkyl group having 1 to 4 carbon atom, an aminoalkyl, a diacid monoester or.-alkyl acid; and the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts.

WO 2000/61581 discloses amine derivatives represented by the general formula: wherein (R', R") represent (F, F), (CF3, H), or (iPr, iPr) as useful agents for diabetes, hyperlipemia, arteriosclerosis and cancer. WO 2000/75106 discloses the compounds represented by the general formula:

wherein Z represents

in which R90 is hydrogen, C l2 alkyl, C3-8 cycloalkyl, or the like, and R91 is amino- C1-6 alkyl, aminocarbonyl-Cz 6 alkyl, or hydroxyaminocarbonyl Cl 6 alkyl ; and R90 and R91 are independently selected from the group consisting of H, C1-6 alkyl, C1- 6 alkylthio, C,-6 alkoxy, fluoro, chloro, bromo, iodo, and nitro; as useful agents for treating MMP-mediated diseases in mammals.

However, none of these reference discloses simple urea derivatives having pharmaceutical activity.

The development of a compound having effective VR1 antagonistic activity and the use of such compound for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urge urinary incontinence and/or overactive bladder have been desired.

SUMMARY OF THE INVENTION This invention is to provide urea derivatives of the formula (1), their tautomeric and stereoisomeric form, and salts thereof :

X is C,-6 alkyl substituted by phenyl or naphthyl (wherein said phenyl and naphthyl are optionally substituted by Roll, Rl2 and Rl3), aryl or heterocyclic ring, wherein said aryl and heterocyclic ring are optionally substituted by Rl l, Rl2 and R" and are selected from the group consisting of phenyl, naphthyl, pyridyl, carbazolyl, fluorenyl, thienyl, pyrimidyl, benzodioxolyl, indazolyl, and quinolyl, in which R", R12 and Rl3 independently represent hydrogen, halogen, C1-6 alkyl, mono-, di-, or tri-halogen substituted C,-6 alkyl, nitro, cyano, C1-6 alkoxy, hydroxy, piperidino, furyl, thienyl, benzyloxy, anilino, naphthyl, C1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, C-6 alkylamino, di (Cl alkyl) amino, C1-6 alkoxy- carbonyl, benzyl, phenoxy, C1-6 alkyl substituted phenoxy, pyridyl, halogen substituted phenoxy, C1-6 alkylthio, Ci-6 alkanoyl, C-6 alkanoylamino, hydroxy substituted C,-6 alkyl, mono-, di-, or tri-halogen substituted CI-6 alkyloxy, or phenyl optionally substituted by one to three substituents, in which the substituents are each different or identical and selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, pyridyl, mono-, di-, or tri- halogen substituted C,-6 alkyl, nitro, cyano, benzyloxy, thienyl, C, 6alkanoyl, C,-6

alkoxycarbonyl, C-6 alkylthio, di (C1-6 alkyl) amino, and Ci. alkylamino, mono, di, or tri halogen substituted C1-6 alkyloxy; Ru ils hydrogen, R2 is hydrogen, R3 is hydrogen, or R2 and R3 together form- (CH2) m- (wherein m represents 1,2, 3 or 4), or R1 and R3 together form-(CH2)n- (wherein n represents 1,2, or 3); R4 is hydrogen, halogen, C1-6 alkoxy, hydroxy, C1-6 alkoxy substituted benzyl- oxy, sulfamoyl, C1-6 alkylsulfamoyl, di (CI-6 alkyl) sulfamoyl, di (CI-6 alkyl) aminoC1-6 alkylene sulfamoyl, hydroxy C,-6 alkyl piperazinosulfonyl, C-6 alkylsulfonylamino, nitro, amino, C1-6 alkanoylamino, C1-6 alkoxy 6 alkyleneoxy, R is hydrogen, halogen, Cl alkoxy, hydroxy, Cl alkoxy substituted benzyloxy, sulfamoyl, C1-6 alkylsulfamoyl, di (Cl-6 alkyl) sulfamoyl, di (C1-6 alkyl) amino C, 6alkylene sulfamoyl, hydroxy C,-6 alkyl piperazinosulfonyl, C1-6 alkylsulfonylamino, nitro, amino, C1-6 alkanoylamino, C1-6 alkoxyC1-6 alkyleneoxy, or R4 and R5 together form -O-(CH2)-O-; and R6 is hydrogen, halogen, C1-6 alkyl, mono-, di-, or tri-halogen substituted C,-6 alkyl, nitro, cyano, C1-6 alkoxy, hydroxy, C1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, C1-6 alkylamino, di (Cl 6 alkyl) amino, C,-6 alkoxycarbonyl, phenyl, benzyl, phenoxy, halogen substituted phenoxy, C1-6 alkylthio, C1-6

alkanoyl, C alkanoylamino, hydroxy substituted C,-6 alkyl, mono-, di-, or tri-halogen substituted C,-6 alkoxy.

The urea derivatives of formula (I), their tautomeric and stereoisomeric form, and salts thereof surprisingly show excellent VR1 antagonistic activity. They are, therefore suitable especially for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urge urinary incontinence and/or overactive bladder.

Alkyl per se and"alk"and"alkyl"in alkoxy, alkanoyl, alkylthio, alkylamino, alkyl- aminocarbonyl, alkylaminosulphonyl, alkylsulphonylamino, alkoxycarbonyl, alkoxy- carbonylamino, alkylcarbamoyl and alkanoylamino represent a linear or branched alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, iso- propoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkanoyl illustratively and preferably represents acetyl and propanoyl.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n- hexyl-amino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N- methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

Alkylaminocarbonyl or alkylcarbamoyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylamino-

carbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl, n-pentylamino- carbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylamino- carbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N- isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N- n-pentylamino-carbonyl and N-n-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxy- carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxy- carbonyl and n-hexoxycarbonyl. Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.

Alkanoylamino illustratively and preferably represents acetylamino and ethyl- carbonylamino.

Halogen represents fluorine, chlorine, bromine and iodine.

Aryl per se and in arylamino and in arylcarbonyl represents a mono-to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, and more prefer- ably from 6-10 carbon atoms, optionally substituted with one or more substituents.

Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, biphenyl, fluorenonyl and the like.

Heterocyclic ring refers to a 3-to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems and may be partially or fully saturated or aromatic. Examples of such rings include, but are not limited to thienyl, benzothienyl, furanyl, benzofuranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, isothiazolyl, thiazolyl,

oxazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thiadiazolyl, benzothiadiazolyl, oxadiazolyl, benzothiazolyl, indolyl, carbazolyl, quinolinyl, isoquinolinyl, benzodioxolyl, indazolyl, indazolinolyl and the like This invention is also to provide a method for treating or preventing a disorder or disease associated with VR1 activity in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the urea derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.

Further this invention is to provide a use of the urea derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament. Preferably, said medicament is suitable for treating or preventing a disorder or disease associated with VR1 activity.

The compounds of the present invention surprisingly show excellent VR1 activity.

They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat VR1 related diseases.

More specifically, since the urea derivatives of the present invention inhibit VR1, they are useful for treatment and prophylaxis of diseases as follows: urinary incontinence, overactive bladder, chronic pain, neuropathic pain, post- operative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and inflammatory disorders In one embodiment, the compounds of formula (I) are those wherein: Y is 1-i ;

X is phenyl optionally substituted by R, R12 and R13, phenyl C1-6 alkyl (wherein said phenyl is optionally substituted by R", R12 and R13), or naphthyl optionally substituted by Roll, Rl2 and R", in which R", R12 and Rl3 independently represent hydrogen, halogen, C-6 alkyl, mono-, di-, or tri-halogen substituted C1-6 alkyl, nitro, C,-6 alkoxy, C1-6 alkoxycarbonyl, phenoxy, C-6 alkylthio, or C1-6 alkanoyl.

In another embodiment, the compounds of formula (I) are those wherein: Y is 1-i ; Rl is hydrogen; R2 is hydrogen; and R3 is hydrogen.

In another embodiment, the compounds of formula (I) are those wherein: Y is I-i ; X is phenyl optionally substituted by Roll, R and R13, phenyl C1-6 alkyl (wherein said phenyl is optionally substituted by R", R'2 and R13), or naphthyl optionally substituted by R'l, R and R13, in which R", R12 and R13 independently represent hydrogen, halogen, C1-6 alkyl, mono-, di-, or tri-halogen substituted C1-6 alkyl, nitro, C1-6 alkoxy, C1-6 alkoxycarbonyl, phenoxy, Cri-6 alkylthio, or C1-6 alkanoyl.

Rl is hydrogen; and

R2 and R3 together form- (CH2) ,- (wherein m represents 1,2, 3 or 4).

In another embodiment, the compounds of formula (I) are those wherein: Y is I-i ; Rl and R3 together form -(CH2)n- (wherein n represents 1,2, or 3) and R2 is hydrogen. alternatively, the urea derivative of formula (I) can be those wherein: Y is I-ii ; is hydrogen, halogen, C1-6 alkyl, mono-, di-, or tri-halogen substituted C1-6 alkyl, phenyl, or C1-6 alkoxy.

In another embodiment, the compounds of formula (I) are those wherein: y is X is C1-6 alkyl substituted by phenyl or naphthyl (wherein said phenyl and naphthyl are optionally substituted by Roll, Rl2 and Ri3), aryl or Heterocyclic ring, wherein said aryl and Heterocyclic ring are optionally substituted by R11, R12 and Rl3 and are selected from the group consisting of phenyl, naphthyl,

pyridyl, carbazolyl, fluorenyl, thienyl, benzodioxolyl, indazolyl, and quinolyl, R6 is hydrogen, halogen, C-6 alkyl, mono-, di-, or tri-halogen substituted Cl 6 alkyl, phenyl, or C, 6 alkoxy.

The preferable compounds of the present invention are as follows: N- (4-hydroxy-3-methoxybenzyl)-N'- (4-isopropylphenyl) urea; N- (4-hydroxy-3-methoxybenzyl)-N'- (1-naphthyl) urea; N- (3, 4-dichlorophenyl)-N'- (4-hydroxy-3-methoxybenzyl) urea; N- (3-chloro-4-methylphenyl)-N'- (4-hydroxy-3 methoxybenzyl) urea; N- (4-hydroxy-3-methoxybenzyl)-N'- (4-phenoxyphenyl) urea; N- [2-chloro-5- (trifluoromethyl) phenyl]-N'- (4-hydroxy-3- methoxybenzyl) urea; N-(3-chlorphenyl)-N'-(4-hydroxy-3-methoxybenzyl) urea; N- (4-chlorophenyl)-N'- (4-hydroxy-3-methoxybenzyl) urea; N- [4-chloro-3- (trifluoromethyl) phenyl]-N'- (4-hydroxy-3- methoxybenzyl) urea; N-(4'-chloro-1,1'-biphenyl-3-yl)-N'-(4-hydroxy-3-metoxybenzy l) urea; N-[2-(2-hydroxyethyl)phenyl]-N'-[4'-(methylsulfanyl)-1,1'-bi phenyl-3- yl] urea; N- [2- (2-hydroxyethyl) phenyl]-N'- (4'-nitro-1, 1'-biphenyl-3-yl) urea; N-(4'-acetyl-1,1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; Ethyl3'-[( {[2-(2hydroxyethyl) phenyl] amino} carbonyl) amino] - 1, 1'-biphenyl-4-carboxylate ; N-[2-(2-hydroxyethyl) phenyl]-N'-[2'-(trifluoromethyl)-1, 1'-biphenyl-3- yl] urea; N- (2'-chloro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N- [2- (2-hydroxyethyl) phenyl]-N'- [3- (l-naphthyl) phenyl] urea;

N- [2- (2-hydroxyethyl) phenyl] -N'- [4'- (trifluoromethyl)-1, 1'-biphenyl-3- yl] urea; N- (4', 6-dichloro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N-(2', 5'-dichloro-1, 1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; N-(2',4'-dichloro-1,1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; N-(3', 4'-difluoro-1, 1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; N- (4'-fluoro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N- [2- (2-hydroxyethyl) phenyl]-N'- (3'-nitro-1, 1'-biphenyl-3-yl) urea; N- [4'- (benzyloxy)-3'-fluoro-1, 1'-biphenyl-3-yl]-N'- [2- (2- hydroxyethyl) phenyl] urea; N- (4'-chloro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N-(2', 5'-dimethyl-1, 1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; N-[2-(2-hydroxyethyl)phenyl]-N'-[4'-(trifluoromethoxy)-1,1'- biphenyl-3- yl] urea ; N- (4'-chloro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl)-3- methoxyphenyl] urea; N- (3'-fluoro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N- (3'-chloro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea; N-(2', 5'-difluoro-1, 1'-biphenyl-3-yl)-N'-[2-(2-hydroxyethyl) phenyl] urea; and N- (3'-chloro-4'-fluoro-1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea.

Preferably, the medicaments of the present invention further comprise one or more pharmaceutically acceptable carrier and/or excipients.

EMBODIMENT OF THE INVENTION The compound of the formula (I) of the present invention can be, but not limited to be, prepared by either of the methods [A], [B] and [C] below. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are ad-

vantageously protected by a protecting group known to those skilled in the art.

Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition) "by Greene and Wuts, John Wiley and Sons, New York 1999.

[Method A]

The compound [1-a] wherein X and R6 are the same as defined above, can be prepared by the reaction of a substituted 2- (2-aminophenyl) ethanol [II] (wherein R6 is the same as defined above) and isocyanate of the formula [VI] (wherein X is the same as defined above).

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as 1,3- dimethyl-2-imidazolidinone (DMI) ; sulfoxides such as dimethylsulfoxide (DMSO); and others.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 30 °C to 100 °C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.

The compound [1-b], [I-c] and [1-d] wherein X, R4 and R5 are the same as defined above, can be prepared using substituted benzylamines [III], substituted tetrahydro- isoquinolines [IV] and substituted tetrahydro-naphthalenylamine [V] as starting material, respectively, by the same method as for the compound [1-a].

[Method B] Alternatively, the compound [1-a] (wherein X and R6 are the same as defined above) can be prepared by reacting a substituted 2- (2-aminophenyl) ethanol [II] and carbamate of the formula [VII] (wherein X is the same as defined above and Y represents phenyl).

The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as 1,3- dimethyl-2-imidazolidinone (DMI) ; sulfoxides such as dimethylsulfoxide (DMSO); and others.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20 °C to 100 °C. The reaction may be conducted for, usually, 30 minutes to 40 hours and preferably 1 to 24 hours.

The compound [1-b], [I-c] and [1-d] wherein X, R4 and R5 are the same as defined above, can be prepared using substituted benzylamines [III], substituted tetrahydro- isoquinolines [IV] and substituted tetrahydro-naphthalenylamine [V] as starting material, respectively, by the same method as for the compound [I-a].

[Method C] The compound [1-a] can be prepared by reacting amine of the formula [VIII] (wherein X is the same as defined above) and 1, 1'-carbonyldi (1, 2,4-triazole) (CDT) [IX], and

then adding substituted 2- (2-aminophenyl) ethanol [II] to the reaction mixture. The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane ; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as 1,3- dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others.

The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20 °C to 50 °C.

The reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The compound [1-b], [1-c] and [1-d] wherein X, R4 and R5 are the same as defined above, can be prepared using substituted benzylamines [III], substituted tetrahydro- isoquinolines [IV] and substituted tetrahydro-naphthalenylamine [V] as starting material, respectively, by the same method as for the compound [1-a].

The substituted 2- (2-aminophenyl) ethanols [II], substituted benzylamines [III], substituted tetrahydroisoquinolines [IV], substituted tetrahydro-naphthalenylamine [V], Isocyanates [VI], carbamates [VII], amine [VIII] and CDT [IX] are commercially available or can be prepared by the use of known techniques or by method described in the examples.

When the compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e. g. , geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention.

When the compound shown by the formula (1) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane, and the like. Examples of inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols

and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using trans- dermal delivery systems well-known to those of ordinary skilled in the art.

The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.

The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.

Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions,

solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxy- methyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. An "unit dose"is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about O. Olmg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to 100mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.

EXAMPLES The present invention will be described as a form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

Mass spectra were obtained using electrospray (ES) ionization techniques (micro- mass Platform LC). Melting points are uncorrected. Liquid Chromatography-Mass spectroscopy (LC-MS) data were recorded on a Micromass Platform LC with Shimadzu Phenomenex ODS column (4.6 mm X 30 mm) flushing a mixture of acetonitrile-water (9: 1 to 1: 9) at 1 ml/min of the flow rate. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 lem)) was used for all column chromatography separations. All chemicals were reagent grade and were purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd. , Tokyo kasei kogyo co. Ltd. , Arch corporation.

The effect of the present compounds were examined by the following assays and pharmacological tests.

[Measurement of capsaicin-induced Ca2+ influx in the human VR1-transfected CHO cell line] (Assay 1) (1) Establishment of the human VR1-CHOluc9aeq cell line Human vanilloid receptor (hVRI) cDNA was cloned from libraries of axotomized dorsal root ganglia (W02000/29577). The cloned hVRI cDNA was constructed with pcDNA3 vector and transfected into a CHOluc9aeq cell line. The cell line contains aequorin and CRE-luciferase reporter genes as read-out signals. The transfectants were cloned by limiting dilution in selection medium (DMEM/F12 medium (Gibco BRL) supplemented with

10% FCS, 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 llg/ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg/ml G418). Ca2+ influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments in the project. The human VRl-CHOluc9aeq cells were maintained in the selection medium and passaged every 3-4 days at 1-2. 5x105 cells/flask (75 mm2).

(2) Measurement of Ca2+ influx using FDSS-3000 Human VR1-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384-well plates (black walled clear-base/Nalge Nunc International). Following the culture for 48 hrs the medium was changed to 2 uM Fluo-3 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% BSA) and the cells were incubated for 60 min at 25°C. After washing twice with assay buffer the cells were incubated with a test compound or vehicle for 20 min at 25°C. Mobilization of cytoplasmic Ca2+ was measured by FDSS-3000 (Rex=488nm) kem=540nm/Hamamatsu Photonics) for 60 sec after the stimulation with 10 nM capsaicin. Integral R was calculated and compared with controls.

[Measurement of the capsaicin-induced Ca2+ influx in primary cultured rat dorsal root ganglia neurons] (Assay 2) (1) Preparation of rat dorsal root ganglia neurons New born Wister rats (5-11 days) were sacrificed and dorsal root ganglia (DRG) was removed. DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS (-) (Gibco BRL) for 30 min at 37°C, then a half volume of fetal calf serum (FCS) was added and the cells were spun down. The DRG neuron cells

were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated pipetting and passing through 70 J. m mesh (Falcon).

The culture plate was incubated for 3 hrs at 37°C to remove contaminating Schwann cells. Non-adherent cells were recovered and further cultured in laminin-coated 384 well plates (Nunc) at 1x104 cells/50 pl/well for 2 days in the presence of 50 ng/ml recombinant rat NGF (Sigma) and 50 pM 5-fluoro- deoxyuridine (Sigma).

(2) Ca2+ mobilization assay DRG neuron cells were washed twice with HBSS supplemented with 17 mM HEPES (pH 7.4) and 0.1% BSA. After incubating with 2 uM fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL) and 1 mM probenecid (Sigma) for 40 min at 37°C, cells were washed 3 times. The cells were in- cubated with VR1 antagonists or vehicle (dimethylsulphoxide) and then with 1 uM capsaicin in FDSS-6000 (Rex=480nm, Rem=520nm/Hamamatsu Photonics). The fluorescence changes at 480nm were monitored for 2.5 min.

Integral R was calculated and compared with controls.

[Organ bath assay to measure the capsaicin-induced bladder contraction] (Assay 3) Male Wistar rats (10 week old) were anesthetized with ether and sacrificed by dislocating the necks. The whole urinary bladder was excised and placed in oxygenated Modified Krebs-Henseleit solution (pH 7.4) of the following compo- sition (112mM NaCI, 5.9mM KCI, 1. 2mM MgCl2, 1. 2mM NaH2PO4, 2mM CaCl2, 2. 5mM NaHCO3, 12mM glucose). Contractile responses of the urinary bladder were studied as described previously [Maggi CA et al: Br. J. Pharmacol. 108: 801-805, 1993]. Isometric tension was recorded under a load of 1 g using longitudinal strips of rat detrusor muscle. Bladder strips were equilibrated for 60 min before each stimulation. Contractile response to 80 mM KCl was determined at 15 min intervals until reproducible responses were obtained. The response to KCl was used as an

internal standard to evaluate the maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with compounds for 30 min prior to the stimulation with 1 ViM capsaicin (vehicle: 80% saline, 10% EtOH, and 10% Tween 80). One of the preparations made from the same animal was served as a control while the others were used for evaluating compounds. Ratio of each capsaicin-induced contraction to the internal standard (i. e. KCl-induced contraction) was calculated and the effects of the test compounds on the capsaicin-induced contraction were evaluated.

[Measurement of Ca2+ influx in the human P2Xl-transfected CHO cell line] (1) Preparation of the human P2X1-transfected CHOluc9aeq cell line Human P2X1-transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12) supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 pg/ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I, Sigma). The suspended cells were seeded in each well of 384-well optical bottom black plates (Nalge Nunc International) at 3 x 103/50 1ll/well. The cells were cultured for following 48 hrs to adhere to the plates.

(2) Measurement of the intracellular Ca2+ levels P2X1 receptor agonist-mediated increases in cytosolic Ca2+ levels were measured using a fluorescent Ca2+ chelating dye, Fluo-3 AM (Molecular Probes). The plate- attached cells were washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 u. l of loading buffer (1 ; j. M Fluo-3 AM, 1 mM probenecid, 1 M cyclosporin A, 0.01% pluronic (Molecular Probes) in washing buffer) for 1 hour in a dark place. The plates were washed twice with 40 u. l washing buffer and 35 ul of washing buffer were added in each well with 5 il of test compounds or 2', 3'-o-(2, 4,6-trinitrophenyl) adenosine 5'-

triphpsphate (Molecular Probes) as a reference. After further incubation for 10 minutes in dark 200 nM a, (3-methylene ATP agonist was added to initiate the Ca2+ mobilization. Fluorescence intensity was measured by FDSS-6000 (kex=410nm, em=510nm/Hamamatsu Photonics) at 250 msec intervals. Integral ratios were calculated from the data and compared with that of a control.

[Measurement of capsaicin-induced bladder contraction in anesthetized rats] (Assay 4) (1) Animals Female Sprague-Dawley rats (200-250 g/Charles River Japan) were used.

(2) Catheter implantation Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.2 g/kg. The abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (Hibiki, size 5) filled with 2 IU/ml of heparin (Novo Heparin, Aventis Pharma) in saline (Otsuka) was inserted into a common iliac artery.

(3) Cystometric investigation The bladder catheter was connected via T-tube to a pressure transducer (Viggo- Spectramed Pte Ltd, DT-XXAD) and a microinjection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 2.4 ml/hr. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, corresponding to a 20-minute period, were recorded before a test compound administration and used as baseline values.

(4) Administration of test compounds and stimulation of bladder with capsaicin The saline infusion was stopped before administrating compounds. A testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1: 1 : 8, v/v/v) was administered intraarterially at 10 mg/kg. 2min after the administration of the compound 10 pg of capsaicin (Nacalai Tesque) dissolved in ethanol was administered intraarterially.

(5) Analysis of cystometry parameters Relative increases in the capsaicin-induced intravesical pressure were analyzed from the cystometry data. The capsaicin-induced bladder pressures were compared with the maximum bladder pressure during micturition without the capsaicin stimulation.

The testing compounds-mediated inhibition of the increased bladder pressures was evaluated using Student's t-test. A probability level less than 5% was accepted as significant difference.

Results of IC 50 of capsaicin-induced Ca2+ influx in the human VR1-transfected CHO cell line are shown in Examples and tables of the Examples below. The data corresponds to the compounds as yielded by solid phase synthesis and thus to levels of purity of about 40 to 90%. For practical reasons, the compounds are grouped in four classes of activity as follows: IC5o=A 0. 1uM<B 0. 5nM<C 1 uM<D The compounds of the present invention also show excellent selectivity, and strong activity in other assays (2)- (4) described above.

Preparing method of starting compounds: [Starting compound A] 7-methoxy-1, 2,3, 4-tetrahydro-6-isoquinolinol An ethanol (15 ml) solution of aminoacetaldehyde diethyl acetal (2.66 g, 20.0 mmol) and vanillin (3.04 g, 20.0 mmol) was added to a suspension of platinum (prepared by reduction of 0.2 g of platinum oxide) in ethanol (20 ml). The mixture was stirred under a hydrogen atmosphere at room temperature for 4 hrs. The catalyst was removed and the solvent was evaporated under reduced pressure. The residue was dissolved in 6N HCl (150 ml) and Pd/C (2. 0g, 10%) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hrs. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was collected and washed with ethanol to give 7- methoxy-1,2, 3,4-tetrahydro-6-isoquinolinol (0/75 g, 25%).

[Starting compound B] 6-methoxy-1, 2,3, 4-tetrahydro-7-isoquinolinol Starting material B was prepared by the same method as for starting material A, using isovanillin instead of vanillin. 6-methoxy-1, 2,3, 4-tetrahydro-7-isoquinolinol (0.03g, 35%).

starting compound C] 7-nitro-1, 2,3, 4-tetrahydro-1-naphthalenamine A mixture of 7-nitro-1-tetralone (1.91 g, 10.0 mmol), titanium (IV) tetraisopropoxide (5.9 ml, 20.0 mmol), ammonium chloride (1.07 g, 20.0 mmol) and triethylamine (2.8 ml, 20.0 mmol) in ethanol (20 ml) was stirred for 16 hrs at room temperature.

Sodium tetrahydroborate (0.57 g, 15. 0 mmol) was added and the reaction mixture was stirred for another 7 hrs at room temperature. 2M aqueous ammonia (30 ml) was added and after filtration of the inorganic precipitate, extraction was carried out with diethylether. The organic layer was then extracted with 2M HCI. The HCl solution was washed with diethylether and then treated with 2M NaOH. Extraction with diethylether was carried out. The organic layer was washed with brine, dried over Na2S04 and then concentrated to give 7-nitro-1, 2,3, 4-tetrahydro-1-naphthalenamine (0.25 g, 20%)

[Starting compound D] 4- (aminomethyl)-1-methoxy-2- [ (4-methoxybenzyl) oxy] benzene MeO o mew MeO : o Met HO OH ci OH OH MeO [step 1] Met mes MeO MeO [step 2] Ns \ N [step 3] Me0 Me0 Step 1: To a suspension of 3-hydroxy-4-methoxybenzyl alcohol (2.00 g, 13.0 mmol) and K2CO3 (2.13 g, 13.6 mmol) in acetone (80 ml) was added methoxybenz- chloride (2.13 g, 13.6 mmol). The reaction mixture was stirred at 60 °C for 16 hrs. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOEt/water. Extraction was carried out with AcOEt and the organic layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure to give {4-methoxy-3- [ (4- methoxybenzyl) oxy] phenyl} methanol (quantitative yield).

Step 2: To a mixture of {4-methoxy-3- [ (4-methoxybenzyl) oxy] phenyl} methanol (1.00 g, 3.7 mmol) and 1, 8-diazabicyclo [5.4. 0] undec-7-ene (0.61 g, 4.0 mmol) in toluene (18 ml) was added diphenylphosphinyl azide (1.10 g, 4.0 mmol) at 0°C. The mixture was stirred at room temperature for 4 hrs.

Water was added and extraction was carried out with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was passed through a silica gel plug

(hexane: AcOEt = 1: 1) and the filtrate was concentrated under reduced pressure to give 4- (azidomethyl)-1-methoxy-2- [ (4-methoxybenz- yl) oxy] benzene (1.00 g, 92%) which was used for the next step without any further purification.

Step 3: To a solution of 4- (azidomethyl)-1-methoxy-2- [ (4-methoxybenz- yl) oxy] benzene (1.00 g, 3.3 mmol) in THF (33 ml) was added triphen- ylphosphine (2.63 g, 10.0 mmol) and water (0.25 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hrs and then concentrated under reduced pressure. The residue 4-(aminomethyl)-1- methoxy-2- [ (4-methoxybenzyl) oxy] benzene was used in the reaction with isocyanates following method A without any further purification.

[Starting compound El (3-{[tert-butyl (dimethyl) silylloxy}-4-methoxyphenyl) methanamine Me I t-Bu-Si-CL. ll l Mu MeO Me Me HOCHO Me t. Bu-Si-O. . CHO I Me0 Me [step Me I/ Mu0 MeO Ms r. MeO " Me Step 2] Me t-Bu-Si-O OH t-Bu| iO>/<OH | e IMe Me I/ t-Bu-Si-O t'B N Si-O NHZ JLJ''' MeO [step 3] Me I 3 Me Me0 Me0 MeO-r [step 4] Step 1: To a solution of 3-hydroxy-4-methoxybenzaldehyde (3.00 g, 19.7 mmol) and imidazole (1.61 g, 23.7 mmol) in DMF (40 ml) was added t-butyldi- methylsilylchloride (3.12 g, 20.7 mmol) at 0°C. The reaction mixture was

stirred at room temperature for 4 hrs and then diluted with diethylether. The organic layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure. The residue product was used in the next step without any further purification.

Step 2: To a solution of 3- { [tert-butyl (dimethyl) silyl] oxy}-4-methoxybenzaldehyde (5.25 g, 19.7 mmol) was added NaBH4 (0.75 g, 19.7 mmol) and the reaction mixture was stirred at room temperature for 16 hrs. Saturated NH4Cl solution was added and the solvent was removed under reduced pressure.

The residue was extracted with AcOEt and the organic layer was washed with brine and dried over Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane: AcOEt = 9: 1-3: 1) to give (3- { [tert-butyl (dimethyl) silyl] oxy}-4- methoxyphenyl) methanol (4.51 g, 85%).

Step 3: To a mixture of (3-{[tert-butyl (dimethyl) silyl] oxy}-4-methoxyphenyl) meth- anol (1.00 g, 3.7 mmol) and 1, 8-diazabicyclo [5.4. 0] undec-7-ene (0.60 g, 3.9 mmol) in toluene (18 ml) was added diphenylphosphinyl azide (1.08 g, 3.9 mmol) at 0°C. The mixture was stirred at room temperature for 4 hrs.

Water was added and extraction was carried out with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was passed through a silica gel plug (hexane: AcOEt = 1: 1) and the filtrate was concentrated under reduced pressure to give [5- (azidomethyl)-2-methoxyphenoxy] (tert-butyl) dimeth- ylsilane (1.09 g, quantitative) which was used for the next step without any further purification.

Step 4: To a solution of [5- (azidomethyl)-2-methoxyphenoxy] (tert-butyl) dimethyl- silane (1.09 g, 3.7 mmol) in AcOEt (20 ml) was added 10% Pd/C (0.10 g) and the reaction mixture was stirred at room temperature for one day under a hydrogen atmosphere. The catalyst was removed by filtration and the

filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and hexane to give (3-{[tert-butyl (dimeth- yl) silyl] oxy}-4-methoxyphenyl) methanamine which was used in the next step without any further purification.

[Starting compound F] [3- (methoxymethoxy) phenyl] methanamine Me 'NH2 HO CN Me00 CN Me00 3.-10 1 ici [step z Step 1: To a solution of 3-hydroxybenzonitrile (5.00 g, 42.0 mmol) and N, N-diiso- propylethylamine (8.14 g, 63.0 mmol) in CH2CI2 (100 ml) was added chlorodimethyl ether (4.06 g, 50.4 mmol) at 0°C. The reaction temperature was allowed to rise to room temperature over 30 minutes. The mixture was then stirred at room temperature for 3 hrs. The mixture was then washed with water, dried over Na2SO4 and then concentrated under reduced pressure. 3- (methoxymethoxy) benzonitrile (4.24 g, 62%) was obtained as clear oil.

Step 2: To a cooled (0°C) suspension of lithiumaluminiumhydride (0.84 g, 22.1 mmol) in THF (50 ml) was added dropwise a solution of 3- (meth- oxymethoxy) benzonitrile (3.00 g, 18.4 mmol) in THF (10 ml). The re- action mixture was stirred at 0°C for 1 hr and then at room temperature for 3 hrs. A 5 N NaOH solution was added dropwise at 0°C and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in AcOEt. This was washed with water, dried over Na2SO4, and then concentrated under reduced pressure to give [3- (methoxymethoxy) phenyl] methanamine (1.78 g, 58%).

[Starting compound G] 8-amino-5,6, 7, 8-tetrahydro-2-naphthalenol NH2 HO NOH NH2 MeO MeO Me /I [step 2] I/ [step 1] [step 3] 4 NH2 HO Step 1: A mixture of 7-methoxy-1-tetraline (5.00 g, 28.4 mmol), hydroxylamine hydrochloride (5.92 g, 85.1 mmol) and potassium carbonate 12.94 g, 93.6 mmol) in methanol (100 ml) was heated to reflux and stirred for 16 hrs.

The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Water was added to the residue and extraction was carried out with AcOEt. The organic layer was dried over Na2SO4 and then concentrated to give 7-methoxy-3, 4-dihydro-1 (2H) - naphthalenone oxime (5.51 g, quantitative).

Step 2: To a suspension of Pd/C (10%) in methanol (10 ml) was added a catalytic amount of acetic acid and 7-methoxy-3, 4-dihydro-1 (2H) -naphthalenone oxime (2.00 g, 10.5 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hrs. The Pd catalyst was removed and the filtrate was concentrated under reduced pressure. Water was added to the residue and extraction was carried out with AcOEt. The organic layer was dried over Na2SO4 and then concentrated to give of 7-methoxy-1, 2,3, 4- tetrahydro-1-naphthalenamine (2.00 g, quantitative).

Step 3: To a solution of 7-methoxy-1, 2,3, 4-tetrahydro-1-naphthalenamine (0.20 g, l. l mmol) in CH2CIz (5 ml) was added boron tribromide (1.5 ml, 1M solution in CH2Cl2) at 0°C. Water was then added to the reaction mixture and extraction was carried out with AcOEt. The organic layer was dried over Na2SO4, concentrated under reduced pressure to give 8-amino- 5,6, 7,8-tetrahydro-2-naphthalenol (0.18 g, 98%) [Starting compound H] 1- (3'-amino-1, 1'-biphenyl-4-yl) ethanone To a stirred solution of 3-bromoaniline (0.344 g, 2.00 mmol) and [Pd (PPh3) 4] (0.069 g, 0.06 mmol) in DMF was added a 2N solution of sodium carbonate (1.5 ml).

4-acetylphenylboronic acid (0.656 g, 4.00 mmol) was added and the mixture was stirred at 90 °C for 16 hrs. The reaction mixture was then washed with water and dried over MgS04. The solution was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer chromatography on silica gel (CHC13) to give 1- (3'-amino-l, l'-biphenyl-4-yl) ethanone (0.25 g, 60 %). [Starting compound I] 4-amino-1, 1'-biphenyl \ \ ----0 N-ZZ zz", 0\ + I/+ HO N B [step 1] II R oh ou \ \ H2N Step 1: To a stirred mixture of [Pd (PPh3) 4] (0.069 g, 0.06 mmol), K3PO4 (0.636 g, 3.00 mmol) and 4-iodonitrobenzene (0.498 g, 2.00 mmol) in DMF was added phenylboronic acid (0.243 g, 2.00 mmol) and the mixture was stirred at 100 °C for 6 hrs. The reaction mixture was then washed with water and dried over MgS04. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (5% AcOEt-Hexane) to give 4-nitro-l, l'-biphenyl (0. 28 g, 69%).

Step 2 : To a solution of 4-nitro-1, 1'-biphenyl (0.275 g, 1.40 mmol) in ethanol (30 ml) was added Pd/C (0.050 g, 10% with 51.5% water) and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-amino-1, 1'-biphenyl (0. 21g, 88%)

[Starting compound J] 3'-methoxy-1, 1'-biphenyl-3-amine To a stirred solution of 3-bromoanisole (0.374 g, 2.00 mmol) and [Pd (PPh3) 4] (0.069 g, 0.06 mmol) in DMF was added a 2N solution of sodium carbonate (1.5 ml). 3-aminophenylboronic acid (0.548 g, 4.00 mmol) was added and the mixture was stirred at 90 °C for 16 hrs. The reaction mixture was then washed with water and dried over MgS04. The solution was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer chromatography on silica gel (CHC13, IPE: Hexane = 1: 1) to give 3'-methoxy-1, 1'-biphenyl-3-amine (0.28 g, 92 %).

[Starting compound K] 3-(2-thienyl) aniline To a stirred mixture of [Pd (PPh3) 4] (0.069 g, 0.06 mmol), K3PO4 (0.636 g, 3. 00 mmol) and 2-bromothiophene (0.343 g, 2.00 mmol) in DMF was added 3- nitrophenylboronic acid (0.335 g, 2.00 mmol) and the mixture was stirred at 100 °C for 6 hrs. The reaction mixture was then washed with water and dried over MgS04.

The solution was concentrated under reduced pressure and the resulting residue was dissolved in ethanol (30 ml). Pd/C (0.050 g, 10% with 51.5% water) was added and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered and the filtrate was concentrated to give 3- (2-thienyl) aniline (0.35 g, 86 %).

[Starting compound L] 2- [2-amino-4- (trifluoromethyl) phenyl] ethanol NH2 HO CF3 MeO MeO N MeO- \ \ \ Me0 /Me0 I/ CF3 O [step 2] CFs F X ¢ j L \ CF3 ON+'O OtN+'O NH2 Me0 Hp HO [step 4] HO CF3 CF3 Step 1: To a suspension of 60% sodium hydride in THF/DMF (30 ml, 1: 1) was added dimethyl malonate (2.000 g, 9.57 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for another 30 minutes. 4- fluoro-3-nitro benzotrifluoride was added and the reaction mixture was stirred for 16 hrs at room temperature. A saturated NH4Cl solution was added the mixture was extracted with AcOEt. The organic layer was washed with brine and dried over Na2S04. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane: AcOEt = 7: 1-3: 1) to give dimethyl 2- [2- nitro-4- (trifluoromethyl) phenyl] malonate (1.784 g, 58%).

Step 2: A mixture of 2- [2-nitro-4- (trifluoromethyl) phenyl] malonate (1.780 g, 5. 55 mmol), LiCI (0.47 g, 11. 11 mmol) in DMSO/water (DMSO 10 ml,

water 0.10 ml) was heated to 100 °C and stirred for 5 hrs. After cooling to room temperature, AcOEt was added and the solution was washed with brine. The organic layer was washed with brine and dried over Na2S04. and then concentrated under reduced pressure. The solution was concentrated under reduced pressure and the resulting residue was triturated with ethyl ether/hexane. Collected to give methyl [2-nitro-4- (trifluoromethyl) phen- yl] acetate (0.546 g, 37%).

Step 3: To a solution of methyl [2-nitro-4- (trifluoromethyl) phenyl] acetate (0.546 g, 2.07 mmol) in CH2C12 (25 ml) was added a 0.9M hexane solution of DIBAH (6.90 ml) at-78°C. The reaction temperature was allowed to rise to 0°C and was stirred for 2 hrs. The reaction was then quenched with iPrOH/H2O and diluted with AcOEt. Si02 was added to the mixture and stirring was continued for another 1 hr. The mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. The obtained crude residue (0.454 g, 93%) was used in the next step without any further purification.

Step 4: To a solution of 2- [2-nitro-4- (trifluoromethyl) phenyl] ethanol in methanol (20 ml) was added Pd/C (0.050 g, 10%). The solution was stirred at room temperature under a hydrogen atmosphere for 20 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2- [2-amino-4- (trifluoromethyl) phenyl] ethanol. The obtained product was used as starting material without any further purification.

[Starting compound M] 2- (5-fluoro-2-aminophenyl) ethanol INH2 HO F O§N+'O ON+'O NH2 N Me HO \ HO / [step 11 [step 2] F F F Step 1: To a stirred mixture of 5-fluoro-2-nitrotoluene (0.300 g, 1.93 mmol) and paraformaldehyde (0.023 g, 0.77 mmol) in DMSO (3.0 ml) was added sodium phenoxide trihydrate (0.010 g, 0.06 mmol). The reacting mixture was heated to 60°C and stirred for 1 hr. The resulting mixture was diluted with AcOEt and washed with dil. HCI, water and then brine. The organic layer was dried over Na2S04. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane: AcOEt = 3 : 1) to give 2- (5-fluoro-2-nitro- phenyl) ethanol.

Step 2: A mixture of 2- (5-fluoro-2-nitrophenyl) ethanol (0.123 g, 0.664 mmol), Fe powder (0.300 g, 5.37 mmol) and NH4C1 (0. 100 g, 1.86 mmol) in EtOH/Water (EtOH 8 ml, water 0.4 ml) was stirred at 90°C for 1 hr. After cooling to room temperature, AcOEt was added and the mixture was filtered through a celite pad. The filtrate was concentrated and the residue was dissolved in AcOEt, washed with water and then brine and dried over MgS04. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography

(hexane : AcOEt = 1: 2) to give 2- (5-fluoro-2-aminophenyl) ethanol. (0.09 g, 87%) Other starting materials are commercially available or can be prepared according to methods reported in the literature.

Example 1-1; N- (4-hydroxy-3-methoxybenzyl)-N'- (4-isopropylphenyl) urea This example was performed according to said method A.

To a stirred solution of 4- (aminomethyl)-2-methoxyphenol hydrochloride (50.0 mg, 0.26 mmol) and triethylamine (26.68 mg, 0.26 mmol) in 1,4-dioxane (1.5 ml) was added a solution of 4-isopropylphenyl isocyanate (38.3 mg, 0.24 mmol) in 1,4- dioxane (1.4 mL) at room temperature. The reaction mixture was warmed to 50 °C, and stirred for 20 hrs at the same temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography (MeOH: CHC13 = 1: 20) to give N- (4-hydroxy-3-methoxybenzyl)- N'- (4-isopropylphenyl) urea (21 mg, 25%). mp 156 °C ; Molecular weight 314. 39 Activity grade: A Example 1-2; <BR> <BR> N- (3, 4-dichlorophenyl)-N'- [2- (2-hydroxyethyl) phenyl] urea This example was performed according to the general method A.

A solution of 2- (2-aminophenyl) ethanol (30.0 mg, 0.22 mmol) and 3,4-dichloro- phenylisocyanate (41.1 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) was stirred at 50 °C for 18 hrs. The reaction mixture was cooled to room temperature and diluted with diisopropylether. The precipitate was collected and then washed with'Pr20 to give N- (3, 4-dichlorophenyl)-N'- [2- (2-hydroxyethyl) phenyl] urea (48.9 mg, 69%). mp 188-190 °C ; Molecular weight 325.20 Activity grade: A Example 2-1; N- (4'-chloro-1, 1'-biphenyl-3-yl)-N'- (4-hydroxy-3 methoxybenzyl) urea This example was performed according to said method B.

A mixture of 4- (aminomethyl)-2-methoxyphenol hydrochloride (50.0 mg, 0.26 mmol) and phenyl 4'-chloro-1, 1'-biphenyl-3-ylcarbamate (85.4 mg, 0.26 mmol) in DMSO (0.5 ml) was heated to 90°C and stirred for 16 hrs. Water was then added and extraction was carried out with AcOEt. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt: hexane = 2: 3) to give N- (4'-chloro-1, 1'- biphenyl-3-yl)-N'- (4-hydroxy-3 methoxybenzyl) urea (65.0 mg, 64%) m. p. 153. 4°C Molecular weight 382.85 Activity grade: A Example 2-2; N- [2- (2-hydroxyethyl) phenyl]-N'- [3 (trifluoromethoxy) phenyl] urea This example was performed according to the general method B.

A solution of 2- (2-aminophenyl) ethanol (80.1 mg, 0.58 mmol) and phenyl 3- (tri- fluoromethoxy) phenylcarbamate (165.3 mg, 0.56 mmol) in DMSO (2.0 mL) was stirred at 90 °C for 1 hr. The reaction mixture was cooled to room temperature and diluted with AcOEt. The solution was washed with IN HCI, IN NaOH and brine dried over Na2SO4. The solution was then concentrated under reduced pressure, and

the residue was triturated with diisopropylether to give N- [2- (2-hydroxy- ethyl) phenyl]-N'- [3 (trifluoromethoxy) phenyl] urea (70.5 mg, 37%). mp 160-161 °C ; Molecular weight 340.30 Activity grade: A Example 3-1; N- (1, 1'-biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea This example was performed according to the general method C.

To a solution of 1, l'-biphenyl-3-amine (37.0 mg, 0.22 mmol) in THF (2.0 ml) was added 1'-carbonyldi (1, 2,4-triazole) (35.9mg, 0.22 mmol). 2- (2-aminophenyl) ethanol (30.0 mg, 0.22 mmol) was added and the mixture was stirred at 55°C for 18 hrs. After cooling to room temperature, the mixture was diluted with water and ethylalcohol and the resulting precipitate was collected and washed to give N- (l, l'- biphenyl-3-yl)-N'- [2- (2-hydroxyethyl) phenyl] urea (20.8 mg, 29%). mp 196-198 °C Molecular weight 332.41 MS (M+H): 333 Activity grade: A According to procedures similar to any one of the Examples 1 to 3 above, the following compounds were synthesized and tested.

Table 1 Ex. No MOLSTRUCTU RE MW M+ 1 melting hVR 1 point class HN HNs 6 HN 392, 45873 393 ND C "o/\ ° \/ c-o - its-0 HN han 7 HN 410, 44916 411 ND C "o/\ ° \/ 0 c0 /cl3 HN ) =0 8 HN 302, 39806 303 ND C HN Eut, C HN 9 HN'0 256, 30697 257 ND C Foc Ex. No MOLSTRUCTURE MW Mt1 me t ng bVR 1 ho'as HAN \ 0 I 10 HN""0 CH3 286, 33346 287 ND C Hic HN HN 11 HN>O 274, 2974 275 ND C HIC HAN S 1 12 8HßN O 3 332, 42455 333 ND C I HN H3CI 0 HN" HN 13 WO 266, 33346 287 ND C "dz H3C'0 CwO I/ Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HO'AU 1 14 ICWN ° CH3 316, 35995 317 ND C 1 3 0 HN HNja F 15 CH3 WO 304, 32389 305 ND C I 0 CHO Han \ S 1 16 HN.'0 316, 38152 317 ND C 0 0 HN 17 HN 0 270, 29043 271 ND C 0 zu Ex. No MOLSTRUCTURE MW M+ elting hVR1 point class HO CH, I 18 HN 300, 31692 301 ND C 0 0 F HN 19 HN ; O 288, 28086 289 ND C 0 0 CH3 HN'as"CH3 20 1 358, 46279 359 ND C N 0 0 HN- CH3 HN 21 312, 3717 313 ND C Fc, om 0 Ex. No MOLSTRUCTURE MW M+ melting hVR1 point class licit un HAN HIC 22 342, 39819 343 NDc 113C-0 foc 0 CL3 HO 23 1 330, 36213 331 ND C N 0 0 NH \-NH NU NH 24 286, 33346 287 ND C 0 0J Ritz cl3 I NH 25 316, 35995 317 ND C ou 0 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class cl3 OH xi 0\/nu 26 NH 332, 42455 333 ND C 0 ou F L, r 27 NH 304, 32389 305 ND C 0 oJ 0- HO HN 28 HO 242, 27988 243 ND C N 0 H HN S 29 HON/to CH3 288, 37097 289 ND C I H Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN"/aO HN \ 0 30 H0\\% 4\N/40 272, 30637 273 ND C 9 H HN HN 31 Ho 260, 27031 261 ND C H 0 H HN/X\SoCH3 HN""S 32 Xd HN 0 318. 39746 319 ND B I hou HO HNZO 33 CH XNXO 272, 30637 273 ND C I 0 HO | T melting hVR1 Ex. No MOLSTRUCTURE MW M+1 melting class point class / HN "0' CH3 HN.'0 34 8H XNX0 302, 33286 303 133 C 0 HO / HN \ i SCH3 35 HNX0 318, 39746 319 ND C HO XI HN 36 HN-0 272, 30637 273 ND C HO , AJ HNJAS, CH3 HN \ I SCH3 37 306, 8166 307 ND C H 0 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN 38 G NO 260, 72551 261 ND C I H / / HN 39 290, 752 291 ND C /F HNja F HN 40 278, 71594 279 ND C H HN/Sz Hs HN \ i SCH3 41 Cl 341, 26163 341 ND C H Cl HO 42) HO 295, 17054 295 ND B H CA G Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN\o, CH3 HN" 0 43 325, 19703 325 ND B H ci HO 44 dz 313, 16097 313 ND B ci HN aS,, CH 3 HNS 45 F 290, 362 291 ND C H 0 ICRH H HN 46 \tuf L 244. 27091 245 ND C H . CK HN" 0" 47 F 274, 2974 275 ND C H Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN 48 262, 26134 263 ND C T"° / HN) $\SCH3 49 tf H 308, 35243 309 ND C I H F HN 10 F : C 262, 26134 263 ND C Ru 0 F / HN 51 F 292, 28783 293 ND C H F /F HN""or 52 F 280, 25177 281 ND C 0 F Ex. No MOLSTRUCTURE MW Mol melting hVR1 point class HN HN 53 HN'0 314, 36273 177. 5 C 0 ci / HAN F F 54 HNAO F 384, 78862 201 B HO a F F IF 0 NH 55 NH 374, 74978 193 A NU OH OH NyN, a zon lu 56 1°/290, 2968 211-212 C 0 I CH, OH Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class N H D 57 302, 33286 144 C 0 CH, I L ; H3 OH Ck'N"O H H 56 nu nib 317, 3039 180 C 0 CH OH cl CH, fuzz 0., NH 59 NH 314, 34401 315 ND C NU OH Oh H3C CH3 0 n J L. J 60 N 300, 36055 211 C U) CRH CH, Holz C3 0 0 \ NN \ 61 I H H 330, 34341 331 ND C Ho/0 0 CL, UH3 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class X H3. O CH, 0 Oh 62 300, 36055 184 C H3Cx 9 ° HO Br 0 63 N 351, 2024 203 B N H H3C\ 0 HO ci 0 fez ONH i 0 NH 64 nu 351, 74893 180 B NH H3C, 0 OH Ex. No MOLSTRUCTURE MW M+l melting hVR1 point class 0 zur 1, 0 OH 0 NH 65 335, 29433 208 C nu CIO Oh FH I, O.. NH 0 NH 66 nu 335, 29433 184 B NH / OH % a 0 nu 67 nu 351, 74893 195Z C NH CJ OH melting hVR1 Ex. No MOLSTRUCTURE MW | M+1 melting hVR1 point class Ber O. NH NH 68 365, 22949 195Z B zozo OH OU IF a HN 69 XN ; O 400, 78802 401 ND B HO Zu 0y NH 0 . NH 0 NH I NH 70 322, 36691 149 A \ OH CH3 0 Il o J L JJL. Ha HO HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class H CH Cl 3 0 1 J 1 D L 72 UTN N 314, 38764 217 C H H /cl3 Ho c3 CH3 0 N.'N \ G 320, 77849 321 ND A H H Ha HO ci C3 0 74 CH3 j 3 341, 19643 342 ND ? Ho) N H H H HO HO CH3 0 if 5 NN 290, 2968 291 ND B H H F Ho 0, 0 76 0 y NH 364, 40455 364 ND A NH 0 OH Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class oh 77 nu 300, 36055 301 ND B NH Oh OH CH 1 78 HO y F 400, 78802 130 B HN FI là'F ce CH3 0 IB Ho Ci HO HA F CH3 0 CH 0 0 >H Ht 374, 74978 375 ND A u N'kN HO HO zea zur ZON H 81 306, 7514 307 ND A Hic 0 HO l melting hVR1 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class N H If /0/ 82 8H, OH 286, 33346 181 B \ c3 I H H STY NyN, a 83 ci 306, 7514 210 A 0 1 UT 3 OH 0 F F OH 0 NH 84 N 433, 8396 ND ND B N JE. FUN NU F 85 447, 86669 448 ND C 0=S=0 I H C, NH Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class F F F H ON \/CI N 86 461, 89378 ND ND C O=S=O 0=so I H3CNCH3 F F F N 87 504, 96263 505 ND C 0=S=0 I HAN H3C'N I Ure -"1 3 \/ B 451, 54655 452 ND C 0 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class o Ao O-NH 89 N 536, 65504 537 ND C Zu HA HO HO HNy 0 'Y 90 438, 3464 439 ND C HAN HIC foc H) C 0 91 HNt0 437, 52146 438 ND C N HN vs 0 H, C Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class F) XNyO \ any 0 HN\/0 N 92 447, 86669 448 ND B han °S S Br HN 93 NFo 424, 31931 425 ND C zon \\ N , c FI 'F ci 94 il + 413, 78675 414 ND C 1+ Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0, 0 0 NH 95 qu 437, 52146 ND ND C N \ Zu o S\ o i FC-N /CRI CRI v HAN 96 HN 0 F 383, 80389 178 C HAN a F F F HN 97 0 425, 84153 426 ND C HN 0 F13C- Ex. No MOLSTRUCTURE MW M+l melting hVR1 point class ci F HN F 98 HNXO 356, 75036 175-177 A HO 0 I HN v 99 HN'\0 348, 40515 133-135 A HO I/ L o I 0 100 HN 0 328, 3711 152-153 B HO CH3 CH han \ HN 101 298, 38824 149-150 B Ho HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HUM HN 102 HN/tO 306, 36751 195-197 B HO HO HN- 103 HO 349, 23009 198-200 B HAN HO 104 <O 290, 752 173-175 C HO HO HN \ G 105 HN'0 290, 752 188-190 C HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class CL HN 106 HN. 0 290, 752 185-187 C HO I HAN F 107 HN/4O F 324, 30535 173-175 B HO F F F F HN 108 HNXO 324, 30535 178-180 B HO Ci HN cl 109 325, 19703 214-216 B HN 0 HO Ex. No MOLSTRUCTURE MW M+ melting hVR1 point class o ici. 0 I. NO0 han N 110 H 335, 74953 178 C Ho a F 0 0 I N : 0 H N I_ 111 HO 0 319, 29493 185 C N' 0 112 HAN N 319, 29493 183 C H ° fY' ci 0 1- HN NXN 113 HO lt3 Õ 335, 74953 170 B Br 0 HN Nit 114 HO H 335, 203 208 C \ EX No MOLSTRUCTURE MW M+1 melting hVR1 point class oYy HN- HAN N 115 HO CH3 298, 38824 243 C OH HN N H 116 HO CH3 284, 36115 226 C 0 0 Han N 117 HO H 298, 34461 177 C xi HN N H 11B X CHS 126 C 0 0 ut3 Ex. No MOLSTRUCTURE MW M+ melting hVR1 point class F HN 119 ! 288, 32449 141-143 C Ho HA F HN 120 288, 32449 160-162 C HA HA F F 121 HN 288, 32449 165-167 C HN 0 HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class CH3 /NwCH3 HN HN 122 299, 37582 187-188 C HO HA un HN HN 123 ! 284. 36115 186-188 C Ho HO IN HN 124 284, 36115 148-150 C HN 0 HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class CH3 125 HN 284, 36115 181-183 C HN- HO HOu HN HN 126 304, 77909 183-185 C HO ho CK 0' 127 HN 300, 36055 175-177 C HN'0 HO Ex. No MOLSTRUCTURE MW M+ melting hVR1 point class Han 128 HN. 0 256, 30697 385 ND C HO HO-CF I HN \ CH3 HN"0 129 HO 270, 33406 186 C han HAZY HN-0' F HN-'0 130 HO 274, 2974 275 ND C HN", aF HN 131 HN 10 274, 2974 183 C HO Ex. No MOLSTRUCTURE MW M+1 | melting hVR1 point class HN"AF 132 HN/4O 274, 2974 166 C HO HN/9/ HN CK, 133 Han"0 284, 36115 181 C HO HAN Han \ 134 il O CH3 286, 33346 154 C HO H\ i HN 0 135 HNXO CH 266, 33346 169 C HO melting hVR1 Ex. No MOLSTRUCTURE MW M+1 point class /I OC \ HN 136 HN/tO 286, 33346 186 C HO ci ci HN 137 HN"r) 325, 19703 326 ND C HO Xi HN 138 HN'0 325, 19703 326 N D C HO cri HNY HO 0 139 Zozo 325, 19703 326 ND C HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class CH 3 0 0 140 HN 328, 3711 329 ND C HN 0 HO HO I I HN 141 4 332, 40575 333 ND C Ho HA H3 H3c HN 142 HNXO CH 340, 46951 344 ND C Cru 3 ! CH," Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class FI F HAN HN 143 HN. 0 358, 75038 359 ND C HO "zu cri F HN 144 HOo 358, 75038 359 ND B HO F F HN) a HN 145 HN 292, 28783 174-C 176Z HA HN 0 146 HN 0 300, 36055 C 114Z HO CH3 Ex. No MOLSTRUCTURE MW M+1 melting'hVR1 point class 0 1. N HO 147 301, 3045 112-114 C Ho Ho Y HNa 148 HN""0 304, 77909 195-196 B HO I HN 149 ; 0 306, 36751 1988z C 191Z HO H HN 150 HN. 0 316 35995 189-190 C HO Ex. No MOLSTRUCTURE MW M melting hVR1 point class H, CY Han 0 151 O > 157-156 C HO F F F F F han HN 152 HN'0 324, 30535 180-182 C HO OH H H 153 M 70, 3 < Il oh OH Nu N 154 y 326, 18461 194 C 0 ion C ! Ex. No MOLSTRUCTURE MW M+1 melting hVR1 oh OH H H 155 O v 334, 42169 176 C 0 OH N N 156 NyN,, a 302, 39806 176-177 C 0 s CH3 HN HN-0 346, 43284 162-164 C HO H, J LJ HO HN''0 158 HO 346, 43284 164-166 B / x. No MOLSTRUCTURE MW M+ melting hVR1 point class H HN"N HN 159 HN/tO 347, 42042 150-151 C HO HAN HN \ 160 HO \ 346, 40515 190-191 C HO HNIO Ho "°Y " HO I : s1 162 325, 19703 326 ND C Ho HO Ex. No MOLSTRUCTURE MW M+ melting hVR1 point class 0 /fizz HN CH3 163 328, 3711 326 ND C Ho HAN HN 164 320, 3946 204 C han 0 Ho HA N CH3 Han 165 o 321, 38218 207 C HO HO HN 166 322, 36691 212 C Ho ho I Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class OH I 167 Han 322, 36691 188Z C HN''0 HO rY" HN 168 ! 339, 44115 188 C HO HA \ I 169"7 344, 4169 >250 A Han 0 HO x. No MOLSTRUCTURE MW C M+1 melting hVR1 point class HN 170 HNX0 \NzCH3 375, 4746 326 ND A I HO X CH3 HN'AO"O I HN 0 171 HN 0 348, 40515 145-146 A HO r CH3 0 N HN N 172 H 373, 45866 224-226 A HO Hic HO HN \ 173 HN O 362, 43224 178-180 B HO x. HNJS MW M+1 y mVin point class Han \ 0 174 362, 43224 146-148 A Holz Chez HN HN 175 HN'\0 362, 43224 170-172 C HO I/ 0 HN CH3 176 HNAo 362, 43224 116684z A ho Ho / Zu u T H HN CH3 HN'< ! ur-3 t HN O 366, 52369 369 ND C HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0 1. No i 178 HN 377, 40328 378 ND B HN'0 Ha au HN F HN F 179 HN"0 292, 28783 162-164 C HO F HO F HN F 180 HN I'0 292, 28783 188-189 B HO /cl3 HN F HN-F 181 HN 0 288, 32449 184-186 C HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN F I 182 HN"0 292, 28783 159-161 C HO F F HN 183 HN'I0 310, 27826 172-174 C HO F F Han F F 184 ; o 342, 29578 158-A 161Z HO Br I F HN 185 HN 0 403, 20138 161-164 A HO Ex. No MOLSTRUCTU RE MW M+ 1 melting hVR1 point class N HN go HAN F F ho Ho 1. 15 d F HN 187 HNAO 369, 30288 149-150 B Holz CHO I F HAN F HN"y 188 X0 354, 33184 161-162 A HN- HO F ZU F/\F 189 HN 0 342, 29578 150-152 C HO Ex. No MOLSTRUCTURE MW M+i meiting hVR1 point class /F HNaa HN \ G 190 HNAO 308, 74243 193-194 B HO I H/ N HN cl 191 A, 315, 76188 186-187 B HO I/ F HN 192 ! 350, 39618 197 B HO HAN XI HN \ 193 HNIko F 350, 39618 351 ND A HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class han \ 194 HNXO uCi 366, 85078 367 ND A HO 0 ruz 0 H 195 HO 366, 85078 175 A ici HN HN N H 196 HO ci 366, 85078 153 A Han N HAN N H "Htfl 197 HO 360, 45993 167 A CH3 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0"CH3 HN N H ''HlfS 198 HO 392, 45873 170 B 3 HAN HN \ 199 HN""0 0 F F 368, 38661 169 A HO i HN 200 HN ; 0 uCH, 346, 43284 178 A Ha HAN I HN 201 332, 40575 194 B HN 0 HO Ex. No MOLSTRUCTURE MW M+1 meiting hVR1 point class HAN Han \ 202 HN.'0 366, 85078 185 B HO s HN 203 HN 0 338, 43151 195 A HO HAN HN \ 204 HN O O 362, 43224 166 A I HO uH3 XI HN \ 205 H3 362, 43224 130 B HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN \ 206 HN 0 "S 378, 49684 379 191 A I H0< CH3 I Han I 207 HNI 0 F 368, 38661 369 181 A HO F. XI F HN \ opq 208 HNX0 0 368, 38661 369 169 A HOX F 0 a HN HAN N 2 401, 29581 142 A ci Ex. No MOLSTRUCTURE MW M M meitlng hVR1 point class han n F 210 HN F 350, 39618 171-172 A HO HN " v I 211 HNXO 9 350, 39618 188 A HA HAN I HN \ 212 HNA0 N 333, 39333 178. 9 C HO F F "INN 213 HNA0 t 368, 38661 369 150 A HO F I Ex. No MOLSTRUCTURE MW Mol melting hVR1 point class 0 HN- 214 HO 382, 46629 113 A 0 HN N 215 HO b TF 384, 84121 176 A ci 0 ION, HN N 216 Cl 401, 29581 180 A 0 HN N ci 217 H/I 401, 29581 184 A Ci Ex. No MOLSTRUCTURE MW M+1 | melting hVR1 point class ci HAN 1 HN 218 HNXO ci 401, 29581 170-172 A HO / , CL3 HN 219 HNXO 316, 35995 186-187 C HO HN"'CCO) xi un 220 HN'"0 300, 31692 183-184 C HO H H I HN 221 HNA0 296, 33152 234-236 C HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0 tj HN/tNH HO 222 400, 40413 198 A F F 0 HAN N 223 H 401, 29581 166 A ni I cul han \ 224 HN ; 0 < 374, 44339 205 A Ho CH3 HAN HN \ 225 HNAO 9 404, 46988 196 A HO 0 I r 0 HN 0 226 HN CH 404, 46988 133 A Ho Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0 0-CH3 0 I HAN N 227 HO H 392, 45873 141-143 A 0 /cl3 UT3 0 CHO HNXN v 228 HO H 396, 87727 126-129 A ci HN ,-o 229 HOs, 10 377, 40328 197-198 A HO Ho HN "ruz 230 HN o 357, 41563 180-182 A Ho ho N 0/cl3 HO J 231 Ou 392, 45873 180-181 C HN 0 HO CH3 HA Ex. No MOLSTRUCTURE MW M+l melting hVR1 point class i HN i 232 HN''0 \ I 357, 41563 186-187 A HO ION I HN HN'0 CI 233 HO 434, 84916 185-187 B F F F /I OF 1 11. \ 234 HN10 377, 40328 188 A HO 0. ICH3 HN 1 235 HN/40 9 360, 42267 158-160 A op Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HNY 236 HN 0 \ 0 I 456, 52145 181-182 A HO F 0 HN \ I CH3 237 HN/tO two 422, 48522 81-83 B "0 H3C, O UN3 I 0 HN N 238 HO H 400, 40413 180 A F F F F F 0 HN N H 239 HO 416, 40353 166 A F 0 O F HN H 240 HO % 0 416, 40353 184 A L) F F melting hVR1 Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0 HNNY 241 HO H FF 400, 40413 153 A fez F Han 242 HN/tO V 362, 43224 163 A HO 0 H3C HN- WN 243/to 336, 43151 159 A HO Xi Xi HN G 244 366, 85078 178 B Ho HA Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class HN \ I/ 245 HN''0 CI 401, 29581 191-193 B HO HAN Han \ zizi HN-'0/CI 246 HO 401, 29581 209-211 C HN ! o 247 HN 0 322, 36691 190 A HO ci zizi 248 HN 0 CH3 HO Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class / HAN HN I F 249 HN/4O \CI 384, 84121 180 A HoL HO HN 250 HN 0 384, 84121 369 177 B HO F Han \ HN'0/CI 251 ! 396, 87727 385 195 A HO 0 1 CL3 2 2 HN'\ 0/G 252 384, 84121 397 187 B HO F F Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class 0 HN'k N 253 Jt/344 4169 182-183 A HO ci XI ja ; F N F 254 HOy 426, 7488 427 201 B HO F / F F FW F l F F 255 N'0 437. 6464 438 209 A HO Br ci 0 N Nazi F 256 HO F F 372, 7775 373 201 A ' H3C HC Ex. No MOLSTRUCTURE MW M+1 melting hVR1 point class Ci Jazz ja ; F F/\F N. 0 257 434, 8492 435 173 B HO O I I-N, 258 N N I 352, 3595 353 213 A HO /F I F 3