KR20040108784A - Hydroxy Tetrahydro-Naphthalenylurea Derivatives - Google Patents

Abstract

The present invention relates to tetrahydro-naphthalene derivatives and salts thereof useful as active ingredients in pharmaceutical formulations. The tetrahydro-naphthalene derivatives of the present invention have excellent activity as VR1 antagonists, prevent and treat diseases related to VR1 activity, especially urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthralgia, neuralgia, It is useful in the treatment of neuropathy, hyperalgesia, nerve damage, ischemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and COPD.

Description

Hydroxy tetrahydro-naphthalenylurea derivative {Hydroxy Tetrahydro-Naphthalenylurea Derivatives}

The vanilloid compound is characterized by having a vanylyl group or a sensory equivalent. Examples of various vanilloid compounds or vanilloid receptor modulators include vanillin (4-hydroxy-3-methoxy-benzaldehyde), guiacol (2-methoxy-phenol), gingeron (4- / 4-hydroxy- 3-methoxyphenyl / -2-butanone), eugenol- (2-methoxy4- / 2-propenyl / phenol) and capsaicin (8-methy-N-vanylyl-6-nonene-amide) have.

Among them, capsaicin, the main component of the pungent taste of red pepper, is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts with vanilloid receptors (VR1) that are prominently expressed at the nerve endings of afferent sensory fibers, including the cell body of the dorsal root ganglion (DRG) or the 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 has recently been cloned and is structurally related to Catrina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: Nature 389: 816-824, (1997), TRP (temporary receptor translocation) channel family. It was identified as a non-selective cation channel with six transmembrane domains. The binding of capsaicin with VR1 causes sodium, calcium and possibly potassium ions to move according to their concentration gradient, causing early depolarization and releasing neurotransmitters at the nerve endings. Thus, VR1 can be considered as a molecular integrator of chemical and physical stimuli that induce neuronal signals in pathological conditions or diseases.

Direct or indirect evidence indicating the relationship between VR1 activity and diseases such as pain, ischemia and inflammation is abundant (eg WO 99/00115 and 00/50387). In addition, it has been demonstrated that VR1 converts reflex signals related to overactive bladder in patients with impaired or abnormal spinal cord reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A Suppl): 36-52, 1997]. Desensitization of afferent nerves by depletion of neurotransmitters with VR1 agonists such as capsaicin has shown 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).

Antagonism of the VR1 receptor is expected to block the release of neurotransmitters, resulting in the prevention and treatment of conditions and diseases associated with VR1 activity.

Thus, VR1 receptor antagonists have chronic pain, neuropathic pain, postoperative pain, rheumatoid arthralgia, neuralgia, neuropathy, hyperalgesia, nerve damage, ischemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and COPD, incontinence (UI ), Such as urinary incontinence (UUI) and / or overactive bladder.

WO 00/50387 discloses compounds of the formula and pharmaceutically acceptable salts thereof having vanilloid agonist activity:

Where

X ^P is an oxygen or sulfur atom;

A ^P is -NHCH ₂ -or -CH _2- ;

R ^a is a substituted or unsubstituted C _1-4 alkyl group or R ^a1 CO—;

R ^a1 is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms or a substituted or unsubstituted aryl group having 6 to 10 carbon atoms;

R ^b 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 ^c is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, aminoalkyl, diacid monoester or α-alkyl acid;

Marked with "*" is a chiral carbon atom.

WO 2000/61581 discloses amine derivatives of the following formulas which are useful agents for diabetes, hyperlipidemia, atherosclerosis and cancer:

Wherein (R ', R ") is (F, F), (CF ₃ , H) or (iPr, iPr).

WO 00/75106 discloses compounds of the formulas which are agents useful in MMP-mediated diseases in mammals:

Where

Z is

ego,

R ⁹⁰ is hydrogen, C _1-12 alkyl, C _3-8 cycloalkyl, and the like, R ⁹¹ is amino-C _1-6 alkyl, aminocarbonyl-C _1-6 alkyl or hydroxyamino-carbonyl C _1-6 Alkyl;

R ⁹⁰ and R ⁹¹ are independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkylthio, C _1-6 alkoxy, fluoro, chloro, bromo, iodo and nitro.

WO 00/55152 discloses compounds of the formulas which are agents useful in the treatment of inflammation, immune related diseases, pain and diabetes:

Where

Ar ¹ is heterocycle;

Ar ² is tetrahydronaphti;

L and Q are as defined in their specification.

However, these references do not disclose simple hydroxy-tetrahydro-naphthalenyl-urea derivatives with VR1 antagonist activity.

There is a need for the development of compounds that have effective VR1 antagonist activity and that can be used for the prevention and treatment of diseases associated with VR1 activity, particularly urinary incontinence, urinary incontinence, overactive bladder, as well as pain and / or inflammatory diseases such as asthma and COPD. .

The present invention relates to hydroxy-tetrahydro-naphthalenylurea derivatives useful as active ingredients in pharmaceutical formulations. The hydroxy-tetrahydro-naphthalenylurea derivatives of the present invention have vanilloid receptor (VR) antagonist activity and prevent and treat diseases associated with VR1 activity, in particular urge incontinence, hyperactive bladder, chronic pain, neuropathic pain , Postoperative pain, rheumatoid arthralgia, neuralgia, neuropathy, hyperalgesia, nerve damage, ischemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

Urinary incontinence (UI) is an involuntary urine loss. Urinary incontinence (UUI) is one of the most common types of UI along with Stress Incontinence (SUI) caused by defects in the urethral obstruction mechanism. UUI is often associated with neurological disorders or diseases that cause nerve damage such as dementia, Parkinson's disease, multiple sclerosis, strokes and diabetes, but also occurs in individuals without such disorders. One common cause of UUI is an overactive bladder (OAB), a medical condition that refers to a frequent and urgent condition due to abnormal contraction and instability of the detrusor muscle.

Recently, many urinary incontinence drugs are commercially available to help the treatment of UUI. The treatment of OAB focuses on the development of anticholinergic agents and focuses on drugs that affect the control mechanisms of peripheral nerves or directly act on the contraction of bladder urination smooth muscle. These drugs can inhibit parasympathetic nerves that control bladder urination or have a direct spasm effect on the bladder detrusor. This results in decreased bladder internal pressure, increased dose, and decreased frequency of bladder contractions. Oral active anticholinergic agents such as propantelin (ProBanthine), tolterodine tartrate (Detrol) and oxybutynin (Ditropan) are the most commonly prescribed drugs. However, their most serious disadvantages are unacceptable side effects such as dry mouth, abnormal vision, constipation and central nervous system disturbances. These side effects result in low compliance. Dry mouth symptom alone causes 70% non-compliance of oxybutynin. The shortcomings of existing therapies underscore the need for new drugs with fewer side effects, effective, safe, and orally administrable.

The present invention provides hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomeric and stereoisomeric forms thereof, and salts thereof.

Where

X is

ego,

Y is a direct bond, ego,

R ¹ , R ² and R ³ are independently hydrogen, halogen, hydroxy, nitro, carboxy, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C _1-6 alkanoyl, C _1-6 alkanoylamino, carbamoyl, C _1-6 alkylcarbamoyl, cyano, or cyano, C _1-6 alkoxycarbonyl or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or when a phenoxy optionally substituted by C _1-6 alkyl, or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkylthio, and;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl or phenyl;

Z ¹ is hydrogen or C _1-6 alkyl;

Z ² is hydrogen, halogen or C _1-6 alkyl.

The hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomeric and stereoisomeric forms thereof, and salts thereof, show surprisingly good VR1 antagonist activity. They are therefore particularly suitable for the prevention and treatment of diseases associated with VR1 activity, in particular for the treatment of urinary incontinence and / or overactive bladder.

Preferably, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is

X ego,

Y is directly bonded or ego,

R ¹ , R ² and R ³ are independently hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C _1-6 alkanoyl, C _1-6 alkanoylamino, carbamoyl, C _1-6 alkylcarbamoyl, cyano, or cyano, C _1-6 alkoxycarbonyl or mono-, di- or tri-substituted by halogen, optionally C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or when a phenoxy optionally substituted by C _1-6 alkyl, or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkylthio, and;

R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl;

Z ¹ and Z ² are each hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is

X ego,

Y is directly bonded or ego,

R ¹ , R ² and R ³ are independently hydrogen, halogen, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, or cyano, C _1-6 alkoxy carbonyl or mono-, di- or tri-substituted by halogen, optionally C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or C _1-6 Phenoxy optionally substituted by alkyl or C _1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen;

R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl;

Z ¹ and Z ² are each hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is

X ego,

Y is directly bonded or ego,

R ¹ and R ² are independently hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy,

R ³ , R ⁴ and R ⁵ are each hydrogen;

Z ¹ and Z ² are each hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is

X ego,

Y is directly bonded or ego,

R ¹ and R ² are independently hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy,

R ³ , R ⁴ and R ⁵ are each hydrogen;

Z ¹ and Z ² are each hydrogen.

More preferably, the hydroxy-tetrahydro-naphthalenylurea derivative of Formula I is

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N- (3-chlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[3- (trifluoromethyl) phenyl] urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethyl) phenyl] urea,

Ethyl 3-({[(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl} amino) benzoate,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(1-naphthyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(2-naphthyl) urea,

N- (3,4-dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(4-isopropylphenyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(4-phenoxyphenyl) urea,

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea,

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea,

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N'-phenylurea,

N- (4-chlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[2- (trifluoromethyl) phenyl] urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethyl) phenyl] urea,

N- (3,4-dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethoxy) phenyl] urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethoxy) benzyl] urea,

N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(2,4,6-trimethoxybenzyl) urea,

N- (2,6-difluorobenzyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea,

N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethyl) benzyl] urea,

N-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethyl) benzyl] urea,

N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethoxy) benzyl] urea,

N-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethoxy) benzyl] urea,

N- [2- (4-chlorophenyl) ethyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, and

From the group consisting of N- [3-fluoro-4- (trifluoromethyl) benzyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea Is selected.

In the present invention, substituents generally have the following meanings unless stated otherwise:

"Alk" and "alkyl" in alkyl itself and in alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino are generally Linear or branched alkyl radicals of 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, exemplarily preferably methyl, ethyl, n-propyl, isopropyl, tert -Butyl, n-pentyl and n-hexyl.

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

Alkanoyl illustratively represents preferably acetyl and propanoyl.

Alkylamino refers to an alkylamino radical having 1 or 2 (independently selected) alkyl substituents, illustratively preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n- Pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino , Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl or alkylcarbamoyl denotes an alkylaminocarbonyl radical having 1 or 2 (independently selected) alkyl substituents, exemplarily preferably methylaminocarbonyl, ethylaminocarbonyl, n-propyl Aminocarbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl , N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl- Nn-pentylamino-carbonyl and Nn-hexyl-N-methylaminocarbonyl are shown.

Alkoxycarbonyl is illustratively preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy Cycarbonyl. The alkoxycarbonylamino is exemplarily preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxy Carbonylamino and n-hexoxycarbonylamino.

Alkanoylamino exemplarily denotes acetylamino and ethylcarbonylamino.

In cycloalkyl itself and in cycloalkylamino and cycloalkylcarbonyl cycloalkyl generally denotes a cycloalkyl group having from 3 to 8, preferably 5 to 7 carbon atoms, exemplarily preferably cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkylamino refers to a cycloalkylamino radical having one or two (independently selected) cycloalkyl substituents, illustratively preferably cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino Indicates.

Halogen represents fluorine, chlorine, bromine and iodine.

Preferably, the medicament of the present invention further comprises one or more pharmaceutically acceptable carriers and / or excipients.

The hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomeric and stereoisomeric forms thereof, and salts thereof include urge incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthralgia, neuralgia, nerves Treating diseases selected from the group consisting of conditions, hyperalgesia, nerve damage, ischemia, neurodegeneration and / or stroke, as well as inflammatory diseases such as asthma and COPD (since these diseases are also involved in VR1 activity) Or effective in preventing.

The compounds of the invention are often used in the form of pain associated with shingles, neuropathic pain and shingles neuralgia, painful diabetic neuropathy, neuropathic back pain, post-traumatic and postoperative neuralgia, neuralgia and other neuralgias due to nerve compression, phantom pain, Treatment and prevention of complex topical pain syndrome, infectious or semi-infectious neuropathy such as neuropathy associated with HIV infection, pain associated with central nervous system disorders such as multiple sclerosis or Parkinson's disease, spinal cord injury or traumatic brain injury, and pain after stroke It is used in addition to.

In addition, the compounds of the present invention are useful for the treatment of musculoskeletal pain, often in the form of pain associated with osteoarthritis or rheumatoid arthritis or other forms of arthritis and back pain.

In addition, the compounds of the present invention are useful for the treatment of cancer-related pain, including visceral or neuropathic pain associated with cancer or cancer treatment.

In addition, the compounds of the present invention are useful for the treatment of visceral pain, for example, pain associated with disorders of hollow viscera, such as gallbladder pain, pain associated with irritable bowel syndrome, pelvic pain, vulva pain, testicular pain or prostate pain.

The compounds of the invention are also useful for the treatment of pain associated with inflammatory lesions of joints, skin, muscles or nerves.

The compounds of the present invention are useful for the treatment of oral facial pain and headaches such as migraine or tension headaches.

Embodiments of the Invention

Compounds of formula (I) of the present invention may be prepared by the following methods [A], [B], [C], [D], [E], [F] or [G], but are not limited thereto. In some embodiments, one or more substituents, such as amino groups, carboxyl groups and hydroxyl groups, of compounds used as starting materials or intermediates are advantageously protected by protecting groups known to those skilled in the art. Examples of protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition)", Greene and Wuts, John Wiley and Sons, New York 1999.

Compounds of formula I (wherein X, Z ¹ and Z ² are the same as defined above) comprise compounds of formula II (wherein Z ¹ and Z ² are the same as defined above) and isocyanate III Of which X is the same as defined above).

The reaction can be carried out, for example, with 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); Ureas such as 1,3-dimethyl-2-imidazolidinone (DMI); Sulfoxide, such as dimethylsulfoxide (DMSO) and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction can be carried out in the presence of an organic base such as pyridine or triethylamine.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about room temperature to 100 ° C, but is not limited thereto. The reaction can be carried out usually for 30 minutes to 48 hours, preferably 1 to 24 hours.

Compounds of formula II and isocyanate III are commercially available or can be prepared using known techniques.

Compounds of formula (I) wherein X, Z ¹ and Z ² are as defined above may be selected from compounds of formula II (wherein Z ¹ and Z ² are as defined above) , After reacting with triphosgene, 1,1-carbonyldiimidazole (CDI) or 1,1'-carbonyldi (1,2,4-triazole) (CDT), Can be prepared by adding a compound of the same as defined above to the reaction mixture.

The reaction is for example 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, for example 1,3-dimethyl-2-imidazolidinone (DMI) and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 20 ° C. to 50 ° C., but is not limited thereto. The reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 hours.

Phosgene, diphosgene, triphosgene, CDI and CDT are commercially available and the compounds of formula IV are commercially available or can be prepared using known techniques.

Compounds of formula I (wherein X, Z ¹ and Z ² are as defined above) are compounds of formula II (wherein Z ¹ and Z ² are as defined above) and compounds of formula V Wherein L ₁ represents a halogen atom, such as a chlorine, bromine or iodine atom, followed by reaction, followed by addition of a compound of formula IV (wherein X is as defined above) to the reaction mixture can do.

The reaction is for example 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, for example 1,3-dimethyl-2-imidazolidinone (DMI) and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 30 ° C. to 120 ° C., but is not limited thereto. The reaction can usually be carried out for 1 to 48 hours, preferably for 2 to 24 hours.

The reaction can advantageously be carried out in the presence of a base comprising organic amines such as, for example, pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and the like. have.

Compounds of formula (V) are commercially available or can be prepared using known techniques.

Compounds of formula (I) wherein X, Z ¹ and Z ² are as defined above may be selected from compounds of formula IV (wherein X is as defined above) for phosgene, diphosgene, triphosgene, After reacting with 1,1-carbonyldiimidazole (CDI) or 1,1'-carbonyldi (1,2,4-triazole) (CDT), followed by formula II (wherein Z ¹ and Z ² Can be prepared by adding a compound of the same as defined above to the reaction mixture.

The reaction is for example 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); Ureas such as 1,3-dimethyl-2-imidazolidinone (DMI); Sulfoxide, such as dimethylsulfoxide (DMSO) and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 30 ° C. to 100 ° C., but is not limited thereto.

The reaction can be carried out usually for 30 minutes to 40 hours, preferably 1 to 24 hours.

Formula I compounds (IV) of (in the formula, X, Z ¹ and Z ² are the same also as defined above) compound and formula V (wherein, L ₁ a (wherein, X is the same also as defined above) Prepared by reacting a compound of silver chlorine, bromine or iodine atom, followed by addition of a compound of formula II (wherein Z ¹ and Z ² are as defined above) to the reaction mixture can do.

The reaction is for example 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, for example 1,3-dimethyl-2-imidazolidinone (DMI) and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 30 ° C. to 120 ° C., but is not limited thereto.

The reaction can usually be carried out for 1 to 48 hours, preferably for 2 to 24 hours.

The reaction can advantageously be carried out in the presence of a base comprising organic amines such as, for example, pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and the like. have.

Compounds of formula I 'wherein X and Z ² are as defined above can be prepared by the following procedure:

In step F-1, a compound of formula VII, wherein X and Z ² are as defined above, is substituted for a compound of formula VI in which Z ² is as defined above By using the compound, it can be prepared in a similar manner as described in the method [A], [B], [C], [D] or [E] for the preparation of the compound of formula (I).

In step F-2, the compound of formula VIII, wherein X and Z ² are as defined above, comprises a compound of formula VII, wherein X and Z ² are as defined above, It can be prepared by reacting with the same acid.

The reaction is for example 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; Alcohols such as methanol, ethanol; It may be carried out in a solvent including water and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 20 ° C. to 100 ° C., but is not limited thereto. The reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 hours.

In Step F-3, compounds of formula I '(, X and Z ² are the same as defined above in the formula) is hydrogenated to compound (also the same as that in the formula, X and Z ² are defined above) The compound of Formula VIII It can be prepared by reacting with a reducing agent such as sodium boron or lithium aluminum hydride.

The reaction is for example ether, for example diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; Aliphatic hydrocarbons such as n-hexane, cyclohexane; Aromatic hydrocarbons such as benzene, toluene and xylene; It may be performed in a solvent including alcohol, for example methanol, ethanol, isopropanol and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about -20 ° C to 50 ° C, but is not limited thereto. The reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 hours.

Compounds of formula I '' wherein X and Z ² are as defined above and Z ¹ is C _1-6 alkyl may be prepared by the following two steps.

In step F-4, a compound of formula IX wherein X and Z ² are as defined above and Z ³ is hydrogen or C _1-5 alkyl is selected from formula VIII wherein X and Z ² are Compounds as defined above can be prepared by reacting with a tri (C _1-6 alkyl) oxosulfonium salt, for example trimethyloxosulfonium iodide.

The reaction is for example ether, for example diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; Aliphatic hydrocarbons such as n-hexane, cyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about -20 ° C to 50 ° C, but is not limited thereto. The reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 hours.

In step F-5, a compound of Formula I '' wherein X and Z ² are as defined above and Z ¹ is C _1-6 alkyl is selected from Formula IX where X and Z ² Same as defined above, Z ³ can be prepared by reacting a compound of hydrogen or C _1-5 alkyl with a reducing agent such as sodium borohydride or lithium aluminum hydride.

The reaction is for example ether, for example diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; Aliphatic hydrocarbons such as n-hexane, cyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene and the like. Optionally, two or more solvents selected from the above can be mixed and used.

The reaction temperature can be arbitrarily set according to the compound to be reacted. The reaction temperature is usually about 20 ° C. to 50 ° C., but is not limited thereto.

The reaction can be carried out usually for 30 minutes to 10 hours, preferably 1 to 24 hours.

Compound VI is commercially available or can be prepared using known techniques.

The stereoisomeric form of formula (I), R form (la), wherein X, Z ¹ and Z ² are the same as defined above, is substituted for the compound of formula II with formula II-a (wherein Z ¹ and Z ² is the same as defined above for the preparation of the compounds of formula (I), by the use of compounds of formula (I), in a manner analogous to that described in the methods [A], [B], [C] can do.

The stereoisomeric form of Formula (I), the S form (I-a '), wherein X, Z ¹ and Z ² are the same as defined above, replaces the compound of Formula (II) Z ¹ and Z ² are the same as defined above, as described in the method [A], [B], [C], [D] or [E] for the preparation of the compound of formula (I). It can be manufactured in a similar way.

Compounds II-a or II-a 'can be prepared using known techniques.

When the compound of formula (I) or a salt thereof has an asymmetric carbon in its structure, its optically active compound and racemic mixture are also included in the scope of the present invention.

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

Acids forming acid addition salts include inorganic acids, such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl Sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.

Base addition salts include salts derived from inorganic bases such as, without limitation, ammonium hydroxide, alkali metal hydroxides, 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 compounds of the present invention or salts thereof can be modified depending on their substituents to form lower alkylesters or other known esters, and / or hydrates or other solvates. Such esters, hydrates and solvates are included within the scope of this invention.

The compounds of the present invention can be administered in oral form, such as, without limitation, conventional enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols and emulsions. . In addition, the compounds of the present invention can be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular and other forms known to those skilled in the pharmaceutical art. The compounds of the present invention can be administered transdermally in intranasal form via topical use of a suitable intranasal vehicle or using a transdermal delivery system known to those skilled in the art.

Dosage regimens in accordance with the use of the compounds of the invention include, without limitation, the age, weight, sex and medical condition of the subject, the severity of the disease to be treated, the route of administration, the level of metabolic and excretory function of the subject, the formulation employed, the specific used. It is selected by those skilled in the art in view of various factors including the compound and its salts.

The compounds of the present invention are preferably prepared with one or more pharmaceutically acceptable excipients prior to administration. Excipients are, for example and without limitation, inert materials such as carriers, diluents, flavors, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating materials.

Another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients that are compatible with the other ingredients of the pharmaceutical formulation and not deleterious to the subject thereof. Pharmaceutical formulations of the invention are prepared by combining one or more pharmaceutically acceptable excipients therefor with a therapeutically effective amount of a compound of the invention. In preparing the compositions of the present invention, the active ingredient may be mixed with a diluent or placed in a carrier and packaged in capsules, sachets, paper or other containers. The carrier may function as a diluent, which may be a solid, semisolid, or liquid substance that acts as a vehicle, or may be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, eg For example, it may contain up to 10% by weight of active compound and may be soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be a pharmaceutically acceptable non-toxic carrier for oral use such as without limitation lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose And the like, optionally disintegrants, such as, without limitation, corn, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, etc., and optionally binders, such as, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural And synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, wax, and the like, and optionally lubricants such as, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, acetic acid Sodium, sodium chloride, talc and the like.

In powder form, the carrier may be a finely divided solid mixed with the finely divided active component. The active ingredient may be mixed with the carrier having binding properties in suitable proportions and compacted into the shape and size desired to prepare a tablet. The powders and tablets preferably contain about 1 to about 99% by weight of the active ingredient, which is a novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melt wax and cocoa butter.

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

The active ingredient can also be dissolved in a suitable organic solvent, such as aqueous propylene glycol. Other compositions can be prepared by dispersing the finely divided active component in an aqueous starch or sodium carboxymethyl cellulose solution or a suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing unit dosages suitable for administration to a human or other mammal. The unit dosage form can be a capsule or tablet, or multiple capsules or tablets. A "unit dose" is a predetermined amount of an active compound of the invention, calculated to produce the desired therapeutic effect in combination with one or more excipients. The amount of active ingredient in unit dosages can be varied or adjusted to between about 0.1 and about 1000 milligrams or more, depending on the particular treatment involved.

Typical oral dosages of the invention are about 0.01 mg / kg / day to about 100 mg / kg / day, preferably 0.1 mg / kg / day to 30 mg / kg / day, most preferred when used for the described effects. Preferably from about 0.5 mg / kg / day to about 10 mg / kg / day. For parenteral administration, it has been proven according to the invention that it is generally advantageous to administer an amount of about 0.001 to 100 mg / kg / day, preferably 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 daily. In the case of transdermal administration, of course, it is administered continuously.

Although the present invention will be described by way of example, it should not be understood as limiting the scope and scope of the invention.

In the examples below, all quantitative data relate to weight percent unless otherwise indicated.

Mass spectra were obtained using electrospray (ES) ionization technology (micromass Platform LC). Melting point was not corrected. Shimadzu Phenomenex ODS column (4.6 mmΦ) flushing liquid chromatography-mass spectroscopy (LC-MS) data with a mixture of acetonitrile-water (9: 1 to 1: 9) at a flow rate of 1 ml / min. X 30 mm) was used to record on a micromass platform LC. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was used for all column chromatography separations. All chemicals were reagent grade, Sigma-Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyo co., Ltd., It was purchased from Arch corporation.

All starting materials are commercially available or can be prepared using the methods cited in the literature.

The effects of the compounds of the present invention were examined by the following analytical and pharmacological tests.

[Measurement of Capsaicin-Induced Ca ²⁺ Influx in Human VR1-transfected CHO Cell Lines] (Analysis 1)

(1) Formation of human VR1-CHOluc9aeq cell line

Human vanilloid receptor (hVR1) cDNA was cloned from a library of axonated dorsal root ganglions (WO 00/29577). The cloned hVR1 cDNA was composed of pcDNA3 vector and transfected with CHOluc9aeq cell line. The cell line contained the equarin and CRE-luciferase reporter genes as read signals. Transfections were selected medium (10% FCS, 1.4 mM sodium pyruvate, 20 mM HEPES, 0.15% sodium bicarbonate, 100 U / ml penicillin, 100 μg / ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg / ml Cloning by limiting dilution in DMEM / F12 medium (Gibco BRL) supplemented with G418. Ca ²⁺ uptake was examined in capsaicin-stimulated clones. High responder clones were selected and used for further experiments in the project. Human VR1-CHOluc9aeq cells were maintained in selection medium and inoculated with 1-2.5 × 10 ⁵ cells / flasks (75 mm ² ) every 3-4 days.

(2) Measurement of Ca ²⁺ inflow using FDSS-3000

Human VR1-CHOluc9aeq cells are suspended in the same culture medium as the selection medium, except G418, and in 384-well plates (black wall transparent base / flying nonn International) at a density of 1,000 cells per well. Seeding. After incubation for 48 hours, the medium was replaced with 2 μM Fluo (Fluo) in assay buffer (Hanks Balanced Salt Solution (HBSS), 17 mM HEPES (pH 7.4), 1 mM Probenecid, 0.1% BSA). ) -3 AM (Molecular Probes) and 0.02% Puronic F-127 and cells were incubated at 25 ° C. for 60 minutes. After washing twice with assay buffer, cells were incubated at 25 ° C. for 20 minutes with test compound or vehicle. After stimulation with 10 nM capsaicin, the mobility of cytoplasmic Ca ²⁺ was measured by FDSS-3000 (λ _ex = 488 nm, λ _em = 540 nm / Hamamatsu Photonics) for 60 seconds. The integral R was calculated and compared with the control.

[Measurement of Capsaicin-Induced Ca ²⁺ Influx in Primary Cultured Rat Dorsal Root Ganglion Neurons] (Analysis 2)

(1) Preparation of Rat Dorsal Ganglion Neurons

Neonatal Wister rats (5-11 days old) were sacrificed and dorsal root ganglia (DRG) removed. DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS (−) (Gibco BRL) for 30 minutes at 37 ° C., then half volume fetal bovine serum (FCS) was added and cells were separated. DRG neurons were resuspended in Ham F12 / 5% FCS / 5% Equine Serum (Gibco BRL), dispersed by repeated pipetting, and passed through a 70 μm mesh (Falcon). Culture plates were incubated at 37 ° C. for 3 hours to remove contaminant Schwann cells. Unattached cells were harvested and in the presence of 50 ng / ml recombinant rat NGF (Sigma) and 50 μM 5-fluorodeoxyuridine (Sigma) in laminin coated 384 well plates (Nunc) The cells were further incubated for 2 days at 1 × 10 ⁴ cells / 50 μl / well.

(2) Ca ²⁺ mobility analysis

DRG neurons were washed twice with HBSS supplemented with 17 mM HEPES (pH 7.4) and 0.1% BSA. Cells were washed three times after incubation at 37 ° C. for 40 min with 2 μM Fluor-3 AM (Molecula Probes), 0.02% PF127 (Gibco BRL) and 1 mM Probeneside (Sigma). Cells were incubated with VR1 antagonist or vehicle (dimethylsulfoxide) and then incubated with 1 μM capsaicin in FDSS-6000 (λ _ex = 480 nm, λ _em = 520 nm / Hamamatsu Photonics). Fluorescence changes at 480 nm were monitored for 2.5 minutes. The integral R was calculated and compared with the control.

[Institutional Bath Analysis Measuring Capsaicin-Induced Bladder Contraction] (Analysis 3)

Male wister rats (10 weeks old) were anesthetized with ether and sacrificed by cervical dislocation. The entire bladder is dissected and oxygenated modified Krebs-Henzel of the following composition (112 mM NaCl, 5.9 mM KCl, 1.2 mM MgCl ₂ , 1.2 mM NaH ₂ PO ₄ , 2 mM CaCl ₂ , 2.5 mM NaHCO ₃ , 12 mM glucose) It was added to a solution of Modified Krebs-Henseleit (pH 7.4). The contractile response of the bladder was studied as previously described (Maggi CA et al: Br. J. Pharmacol. 108: 801-805, 1993). Isotonic tension was recorded at a load of 1 g using the longitudinal strip of rat detrusor muscle. The bladder strips were equilibrated for 60 minutes before each stimulation. Contractile responses to 80 mM KCl were measured at 15 minute intervals until a reproducible reaction was obtained. The response to KCl was used as an internal standard to assess the maximum response to capsaicin. Prior to stimulation with 1 μM capsaicin (vehicle: 80% saline, 10% EtOH and 10% Tween 80), the strip was incubated with the compound for 30 minutes to examine the effect of the compound. One of the preparations prepared from the same animal was used as a control and the rest was used for the evaluation of the compound. The ratio of each capsaicin-induced contraction (ie, KCl-induced contraction) to internal standards was calculated and the effect of the test compound on capsaicin-induced contraction was evaluated.

[Measurement of Ca ²⁺ Influx in Human P2X1-transfected CHO Cell Lines]

(1) Preparation of human P2X1-transfected CHOluc9aeq cell line

Human P2X1-transfected CHOluc9aeq cell lines were formed, 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U / ml penicillin, 100 μg / ml streptomycin, 2 mM glutamine (Gibco BRL) ) And Dulbecco's modified Eagle's medium (DMEM / F12) supplemented with 0.5 units / ml apyrase (grade I, Sigma). The suspended cells were seeded ³ × 10 3/50 ㎕ / wells in each well of 384-well optical bottom black plates (fly neonkeu International). The cells were further incubated for 48 hours to attach to the plates.

(2) Measurement of intracellular Ca ²⁺ levels

P2X1 receptor agonist mediated increase in cytosolic Ca ²⁺ levels was measured using a fluorescent Ca ²⁺ chelating dye, Fluor-3 AM (Molecular Probes). Plated cells were washed twice with wash buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units / ml apiase) and loading buffer (1 μM in wash buffer) for 1 hour in the dark. Incubated in 40 μl of Fluor-3 AM, 1 mM probenside, 1 μM cyclosporin A, 0.01% Pluronic (Molecular Probes)). Plates were washed twice with 40 μl wash buffer and 5 μl 2 ', 3'-o- (2,4,6-trinitrophenyl) adenosine 5'-triphosphate (Molecular Probes) as test compound or reference. And 35 μl wash buffer were added to each well. After 10 more minutes of incubation in the dark, 200 nM α, β-methylene ATP agonist was added to initiate Ca ²⁺ migration. Fluorescence intensity was measured by FDSS-6000 (λ _ex = 410 nm, λ _em = 510 nm / Hamamatsu Photonics) at 250 msec intervals. Integral ratios were calculated from the data and compared to controls.

[Measurement of Capsaicin-Induced Bladder Contraction in Anesthetized Rats] (Analysis 4)

(1) animals

Female Sprague-Dawley rats (200-250 g / Charles River Japan) were used.

(2) catheter transplantation

Rats were anesthetized with 1.2 g / kg urethane (Sigma) intraperitoneally. The centerline was dissected to open the abdomen and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. At the same time, an inguinal incision was made and a polyethylene catheter (Hibiki, size 5) filled with heparin (Novo Heparin, Aventis Pharma) 2 IU / ml in saline (Otsuka) It was inserted into the onis artery.

(3) Cytometric Measurement

The bladder catheter was connected via a T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinjection pump (TERUMO). Saline was injected into the bladder at a rate of 2.4 ml / hr at room temperature. Bladder internal pressure was recorded continuously on a chart pen recorder (Yokogawa). Three or more reproducible urination cycles corresponding to 20 minutes of time were recorded prior to test compound administration and used as reference values.

(4) Administration of test compound and stimulation of bladder with capsaicin

Saline infusion was discontinued before compound administration. Test compound dissolved in a mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1: 1: 8, v / v / v) was administered at 10 mg / kg in the artery. . Two minutes after administration of the test compound, 10 μg of capsaicin (Nacalai Tesque) dissolved in ethanol was administered intraarterally.

(5) Analysis of bladder pressure measurement parameters

The relative increase in capsaicin-induced bladder internal pressure was analyzed from bladder intraocular pressure data. Capsaicin-induced bladder pressure was compared with maximum bladder pressure at urination without capsaicin stimulation. Test compound-mediated inhibition of increased bladder pressure was assessed using Student's t-test. It was interpreted as a significant difference when the probability level was less than 5%.

[Measurement of Overactive Bladder in Anesthetized Cystitis Rats] (Analysis 5)

(1) animals

Female Sprague-Dawley rats (180-250 g / Charles River Japan) were used. Cyclophosphamide (CYP) dissolved in saline was administered intraperitoneally at 150 mg / kg 48 hours before the experiment.

(2) catheter transplantation

Rats were anesthetized with 1.2 g / kg urethane (Sigma) intraperitoneally. The abdomen was opened to open the abdomen and a polyethylene catheter (Becton Dickinson, PE50) was implanted through the dome into the bladder. At the same time, the groin was dissected and a polyethylene catheter (Becton Dickinson, PE50) filled with saline (Otsuka) was inserted into the femoral vein. After emptying the bladder, the rats were left for 1 hour to recover from surgery.

(3) bladder internal pressure measurement

The bladder catheter was connected via a T-tube to a pressure transducer (Note-Spectramed Fitti Eltidy, DT-XXAD) and a microinjection pump (Terumo). Brine was injected into the bladder for 20 minutes at a rate of 3.6 ml / hr at room temperature. Bladder internal pressure was continuously recorded on a chart pen recorder (Yokogawa). Three or more reproducible urination cycles corresponding to a time of 20 minutes were recorded prior to test compound administration.

(4) Administration of Test Compound

Test compounds dissolved in a mixture of ethanol, Tween 80 (ICN Biomedical Inc.) and brine (1: 1: 8, v / v / v) were intravenously 0.05 mg / kg, 0.5 mg / kg or 5 mg / administered in kg. Three minutes after administration of the compound, saline (Nacalai task) was injected into the bladder at room temperature at a rate of 3.6 ml / hr.

(5) Analysis of bladder pressure measurement parameters

Bladder pressure measurement parameters were analyzed as described previously (Lecci A et al: Eur. J. Pharmacol. 259: 129-135, 1994). The bladder capacity calculated from the urination frequency calculated from the urination interval and the volume of saline injected up to the first urination was analyzed from the bladder manometry data. An unpaired Student's t-test was used to assess test compound-mediated inhibition of frequency and test compound-mediated increase in bladder capacity. It was interpreted as a significant difference when the probability level was less than 5%. Data were analyzed as mean ± SEM from 4 to 7 rats.

[Measurement of Acute Pain]

Acute pain on a hot plate was mainly measured in rats. Two variants of the hot plate test were used: In a typical variant, the animal was placed on a hot surface (52-56 ° C.) and the latency was measured until the animal exhibited nociceptive behavior, eg, walking or licking the feet. It was. Another variation was the increase in temperature of the heating plate on which the experimental animals were placed on the surface of the intermediate temperature. Subsequently, this surface was heated slowly but constantly until the animal began to lick the hind paws. The pain threshold was measured as the temperature reached when the hind feet began to lick.

Compounds were tested against vehicle treated controls. Substances were applied at different time points through different application routes (intravenous, intraperitoneal, oral, intratracheal, intraventricular, subcutaneous, intradermal, transdermal) prior to pain testing.

[Measurement of Persistent Pain]

Persistent pain was measured in the formalin or capsaicin test, mainly in rats. A solution of 1-5% formalin or 10-100 μg capsaicin was injected into one hind paw of the experimental animal. After application of formalin or capsaicin, the animal exhibited a nociceptive response such as poking, licking or biting the affected foot. Pain intensity was measured as the number of nociceptive responses within a time frame of 90 minutes or less.

Compounds were tested against vehicle treated controls. Prior to administering formalin or capsaicin, the substance was applied at different time points through different routes of application (intravenous, intraperitoneal, oral, intratracheal, intraventricular, subdermal, intradermal, transdermal).

[Measurement of Neuropathic Pain]

Neuropathic pain was induced primarily by different modifications of one sciatic nerve injury in rats. The surgery was performed under anesthesia. Loosening around the sciatic nerve produced a first modification of sciatic nerve injury (Bennett and Xie, Pain 33 (1988): 87-107). About half of the diameter of the sciatic nerve was tightened tightly to produce a second modification (Seltzer et al., Pain 43 (1990): 205-218). In the next variant, a group of models were used that tightly clamped or truncated the L5 and L6 spinal nerves, or only the L5 spinal nerves [KIM SH; CHUNG JM, AN EXPERIMENTAL-MODEL FOR PERIPHERAL NEUROPATHY PRODUCED BY SEGMENTAL SPINAL NERVE LIGATION IN THE RA, PAIN 50 (3) (1992): 355-363]. The fourth modification involves axonating two of the three terminal branches of the sciatic nerve (the tibia and the calf nerve), leaving the remaining calf nerve intact, whereas the last modification only axons the tibia branch and cuts the calf. And leaving the warm nerve intact. Animals in the control group were treated by apparent surgery.

After surgery, nerve damaged animals developed thermal hyperalgesia as well as chronic mechanical allodynia and cold allodynia. Mechanical allodynia may include pressure transducers (electronic von Frey Anesthesiometer, IITC Inc.)-Life Science Instruments, Woodland Hills, SA; Electronic Bourne Systems (Electronic von Frey System), Somedic Sales AB, Hoerby, Sweden). Thermal hyperalgesia is measured by a radiant heat source (Plantar Test, Ugo Basile, Comerio, Italy) or a cold plate at 5 to 10 ° C, where pain intensity is measured by counting the pain response of the affected hind paw. It was. After administration of acetone to the affected hind paws, cooling induced pain was further tested by counting the pain response or by measuring the duration of the pain response. In general, chronic pain was assessed by recording the activity of circadian rhythms (Surjo and Arndt, Cologne University, Cologne, Germany) and by recording differences in gait [foot print patterns; FOOTPRINTS program, Klapdor et al., 1997. A low cost method to analyze footprint patterns. J. Neurosci. Methods 75, 49-54.

Compounds were tested against apparent surgery and vehicle treated controls. Substances were applied at different time points through different application routes (intravenous, intraperitoneal, oral, intratracheal, intraventricular, subcutaneous, intradermal, transdermal) prior to pain testing.

[Measurement of Inflammatory Pain]

Inflammatory pain was induced primarily by injection of 0.75 mg of carrageenin or complete Freund's adjuvant in one hind paw. In animals, edema with thermal hyperalgesia as well as mechanical allodynia developed. Mechanical allodynia was measured by a pressure transducer (Electronic Bonne Frey Annesteciometer, IITC Inc. -Life Sciences Instruments, Woodland Hills, SA, USA). Thermal hyperalgesia was measured by a radiant heat source (Planta test, Ugo Basile, Comerio, Italy, Paw thermal stimulator, G. Ozaki, University of California, USA). For edema measurements, two methods were used. In a first method, animals were sacrificed and affected hind paws were compartmentalized and weighed. The second method involved the difference in foot volume by measuring water displacement in a volumetric flowmeter (Ugo Basile, Comerio, Italy).

Compounds were tested against vehicle treated controls without causing inflammation. Substances were applied at different time points through different application routes (intravenous, intraperitoneal, oral, intratracheal, intraventricular, subcutaneous, intradermal, transdermal) prior to pain testing.

[Measurement of Diabetic Neuropathic Pain]

Rats treated with a single intraperitoneal injection of streptozotocin 50-80 mg / kg developed severe hyperglycemia and mechanical allodynia within 1 to 3 weeks. Mechanical allodynia was measured by a pressure transducer (Electronic Bonn Frey Anestheometer, IITC Inc. -Life Sciences Instruments, Woodland Hills, SA).

Compounds were tested against diabetic and nondiabetic vehicle treated controls. Substances were applied at different time points through different application routes (intravenous, intraperitoneal, oral, intratracheal, intraventricular, subcutaneous, intradermal, transdermal) prior to pain testing.

The results of IC ₅₀ of capsaicin-induced Ca ²⁺ influx in human VR1-transfected CHO cell lines are shown in the Examples and the Tables of Examples below. The data corresponded to the compound obtained by solid phase synthesis and therefore corresponded to a purity level of about 40-90%. For practical reasons, compounds were classified into four classes of activity as follows:

IC ₅₀ = A (<or =) 0.1 μM <B (<or =) 0.5 μM <C (<or =) 1 μM <D

In addition, the compounds of the present invention showed good selectivity and strong activity in the other assays (2) to (5) described above.

Method of Preparation of Starting Compound

[Starting Compound A]

To a stirred solution of 8-amino-2-naphthol (50.0 g, 314 mmol) in tetrahydrofuran (1000 ml) was added di-t-butyldicarbonate (68.6 g, 314 mmol). The mixture was stirred at 70 ° C for 18 h. After cooling the mixture to room temperature, the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, followed by washing with a saturated aqueous solution of sodium carbonate, followed by water. The extracted organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitate was filtered and dried to give Nt-butoxycarbonyl-8-amino-2-naphthol (64.2 g, 79% yield).

Then, in a mixture of Nt-butoxycarbonyl-8-amino-2-naphthol (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 ml of anhydrous DMF at room temperature, iodoethane (42.3 g, 272 mmol) was added. The mixture was stirred at 60 ° C for 2 h. Water was added to the mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitate was collected and dried to give (7-ethoxy-naphthalen-1-yl) -carbamic acid t-butyl ester (47.9 g, yield 67.5%). .

Then to (7-ethoxy-naphthalen-1-yl) -carbamic acid t-butyl ester (47.9 g, 167 mmol) in 100 ml of 1,4-dioxane anhydride, 1,4-dioxane (100 4 N HCl in ml) was added. The mixture was stirred at rt for 2 h. Diisopropyl ether was added to the reaction mixture, and the precipitate was filtered off. Saturated sodium bicarbonate was added to the obtained solid, and the product was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 7-ethoxy-naphthalen-1-ylamine (27.0 g, yield 86.3%).

Then in a flask containing a mixture of 7-ethoxy-naphthalen-1-ylamine (1.80 g, 9.61 mmol) and t-butanol (2.13 g, 28.8 mmol) in tetrahydrofuran (20 ml) at -78 ° C. Liquid ammonia (300 ml) was collected. To the mixture was added lithium (0.200 g, 28.8 mmol) over 30 minutes and stirred at -78 ° C for 1 hour. Methanol and water were added and the mixture was stirred at rt for 16 h to evaporate ammonia. Ethyl acetate was added to the obtained residue. The organic layer was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (1.37 g, 76% yield).

[Starting Compound B]

To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 ml) is added 2N HCl aqueous solution (10 ml), 40 Stir at 1 ° C. for 1 h. Sodium carbonate was added to neutralize the mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.71 g, yield 78%). .

Sodium borohydride (0.030 g, 0.175 mmol) was then added to 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.050 g, 0.318 mmol) in methanol (10 ml) at 0 ° C. The mixture was stirred for 1 hour. The mixture was poured into water and the product extracted with ethyl acetate. The organic layer was washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (0.037 g, 71% yield). Obtained.

[Starting Compound C]

Stirred benzeneruthenium (II) chloride dimer (3.10 mg, 0.006 mmol) and (1S, 2R)-(-)-cis-1-amino-2-indanol (3.7 mg, 0.025 mmol) in degassed isopropanol The solution was heated at 80 ° C. under argon for 20 minutes. The mixture was added to a solution of 8-amino-3,4-dihydro-1H-naphthalen-2-one (50 mg, 0.310 mmol) in isopropanol (3 ml) at room temperature. A solution of potassium hydroxide (3.48 mg, 0.062 mmol) in isopropanol (1 ml) was added and the mixture was stirred at 45 ° C. for 1 hour. The mixture was passed through silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give chiral 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol enantiomer (33.0 mg, yield 65%).

[Starting Compound D]

A stirred solution of benzeneruthenium (II) chloride dimer (1.55 g) and (1S, 2R)-(-)-cis-1-amino-2-indanol (1.85 g) in degassed isopropanol (500 ml) After heating at 80 ° C. under argon for 20 minutes, it was cooled to room temperature. At room temperature the mixture is added to a solution of 8-amino-3,4-dihydro-1H-naphthalen-2-one (25.0 g) in isopropanol (700 ml) followed by potassium hydroxide (1.74 g in 300 ml of isopropanol prepared). ) Solution (dissolved at 45 ° C., preprepared and then cooled to room temperature). After stirring at 45 ° C. for 30 minutes, the mixture was cooled to room temperature, passed through a pad of silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane and treated with activated carbon for 10 minutes. After passing through a pad of silica gel, the mixture was concentrated under reduced pressure. The obtained product was recrystallized from dichloromethane to give (R) -8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (14 g, 56% yield) as red crystals.

(S) -8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol was obtained using (1R, 2S)-(+)-cis-1-amino-2-indanol. .

Then to a solution of (R) -8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (36.2 g) and pyridine (18.8 ml) in THF (850 ml) cooled to 0 ° C. Phenyl chloroformate (28.8 ml) was added. The mixture was stirred at rt for 3 h and then poured into ethyl acetate. The mixture was washed with aqueous NH ₄ Cl solution followed by water, and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Acetonitrile was added to the residue obtained, the precipitate was collected and washed with a mixture of acetonitrile and diisopropyl ether (2: 3) to obtain {(R) -7-hydroxy-5,6,7,8 -Tetrahydro-naphthalen-1-yl} -carbamic acid phenyl ester (33.0 g) was obtained.

Example 1-1

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea

This example was carried out according to the general method F.

4-chloro-3-trifluoromethyl-phenylisocyanate in a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84 mmol) in tetrahydrofuran (15 ml) (0.22 g, 1.0 mmol) was added. The mixture was stirred at rt for 1.5 h and poured into water. The product was washed with ethyl acetate, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N- (4-chloro-3-trifluoromethyl-phenyl) -N '-(7-ethoxy -5,8-dihydro-naphthalen-1-yl) urea (0.31 g, yield 89%) was obtained. Then N- (4-chloro-3-trifluoromethyl-phenyl) -N '-(7-ethoxy-5,8-dihydro-naphthalen-1-yl)-in tetrahydrofuran (20 ml)- To a solution of urea (0.21 g, 0.51 mmol) was added 1N aqueous hydrochloric acid solution (5 ml) and the mixture was stirred at 40 ° C. for 45 minutes. 10% aqueous sodium bicarbonate solution was added to neutralize the mixture, and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N- (4-chloro-3-tri-fluoromethyl-phenyl) -N '-(7-oxo-5,6,7,8 -Tetrahydro-naphthalen-1-ylurea (0.16 g, yield 85%) was obtained, followed by N- (4-chloro-3-trifluoromethyl-phenyl)-in methanol (10 ml) at 0 ° C. Sodium borohydride (0.04 g, 0.09 mmol) is added to N '-(7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl) urea (0.07 g, 0.18 mmol) and the mixture is Stirred for 30 minutes The mixture was poured into water and the product extracted with ethyl acetate The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the resulting product as a mixture of ethyl acetate / hexanes (1 / 2) Recrystallized from solution, N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) Urea (41 mg, yield 59%) was obtained.

In vitro active class: A

Example 1-2

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-{(R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl} urea

Racemic mixture of N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea ( 30.0 mg) was separated by chiral HPLC (Daicel OD column, n-hexane: 2-propanol = 98: 2) to give the corresponding R-isomer (8.3 mg). Chiral HPLC (ChiralCel OD 0.49 cm × 25 cm column, n-hexane / ethanol = 97/3, flow rate 1.5 ml / min) R-isomer was detected at 20.1 min.

Molecular Weight: 384.8

MS (M + H): 384

Example 1-3

N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-{(S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl} urea

Racemic mixture of N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea ( 30.0 mg) was separated by chiral HPLC (Dicel OD column, n-hexane: 2-propanol = 98: 2) to give the corresponding S-isomer (2.2 mg).

Chiral HPLC (chiralcel OD 0.49 cm × 25 cm column, n-hexane / ethanol = 97/3, flow rate 1.5 ml / min) S-isomer was detected at 17.6 min.

Molecular Weight: 384.8

MS (M + H): 384

Example 2-1

N-phenyl-N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea

This example was carried out according to general method A.

Phenyl isocyanate (14.6 mg, 0.123) in a solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (20.0 mg, 0.123 mmol) in 1,4-dioxane (1.0 ml) at room temperature mmol) was added. After the mixture was stirred for 16 hours, diisopropyl ether and hexanes were added. The precipitate was filtered and dried to give N-phenyl-N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea (17.8 mg, 51% yield).

Molecular Weight: 282.3

MS (M + H): 283

mp: 198-199 ° C

Active class: C

Using the starting material B and following a similar procedure as in Example 2-1, the compounds of Examples 2-2 to 2-41 were synthesized and tested.

Example 3-1

N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea chiral enantiomer

This example was carried out according to general method G.

4-chloro- in a solution of chiral 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol enantiomer (33.0 mg, 0.202 mmol) in 1,4-dioxane (3.0 ml) at room temperature 3-trifluoro-methyl-phenylisocyanate (44.8 mg, 0.202 mmol) was added. After the mixture was stirred for 16 hours, diisopropyl ether and hexanes were added. The precipitate was filtered off and dried to give chiral N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthal Renyl) urea (54.0 mg, 69% yield) was obtained. Enantiomeric excess (% ee) was measured using a chiralcel OD column (15% isopropanol in hexane as eluent, 1 ml / min).

Molecular Weight: 384.8

MS (M + H): 384

mp: 227-228 ° C

In vitro active class: A

Example 4-1

N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '-(4-trifluoromethoxy-benzyl) -urea

This example was carried out according to general method C.

7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (30.0 mg, 0.11 mmol) and 4-trifluoromethoxy-benzylamine in DMSO (1.0 ml) (21.3 mg, 0.11 mmol) was stirred at 100 ° C for 17 h. The reaction mixture was cooled to room temperature and water was added. The precipitate was filtered off and washed with water followed by acetonitrile to give N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '-(4-trifluoromethoxy- Benzyl) -urea (6.70 mg, yield 17%) was obtained.

In vitro active class: A

Example 4-2

N-{(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoromethoxy-benzyl) -urea

This example was carried out according to general method C.

(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (147.3 mg, 0.52 mmol) and 4-trifluorome in DMSO (1.5 ml) A mixture of oxy-benzylamine (99.4 mg, 0.52 mmol) was stirred at 150 ° C for 1.5 h. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water followed by brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to give N-{(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoro Romethoxy-benzyl) -urea (168.0 mg, yield 85%) was obtained.

In vitro active class: A

Chiral HPLC (chiralcel AD 0.49 cm × 25 cm column, n-hexane / ethanol = 90/10, flow rate 1.5 ml / min) R-isomer was detected at 17.7 min.

Example 4-3

N-{(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoromethoxy-benzyl) -urea

This example was carried out according to general method C.

(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (85.0 mg, 0.30 mmol) and 4-trifluorome in DMSO (1.0 ml) A mixture of oxy-benzylamine (57.4 mg, 0.30 mmol) was stirred at 150 ° C for 1.5 h. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to give N-{(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoro Romethoxy-benzyl) -urea (95.0 mg, yield 83%) was obtained.

In vitro active class: A

Chiral HPLC (chiralcel AD 0.49 cm × 25 cm column, n-hexane / ethanol = 90/10, flow rate 1.5 ml / min) S-isomer was detected at 13.2 min.

Example 4-4

N-{(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoromethyl-benzyl) -urea

This example was carried out according to general method C.

(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (150.0 mg, 0.53 mmol) and 4-trifluoro in DMSO (2.0 ml) A mixture of methyl-benzylamine (92.7 mg, 0.53 mmol) was stirred at 100 ° C for 1.5 h. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to give N-{(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoro Romethyl-benzyl) -urea (156 mg, yield 81%) was obtained.

In vitro active class: A

Chiral HPLC (chiralcel AD 0.49 cm × 25 cm column, n-hexane / ethanol = 90/10, flow rate 1.5 ml / min) R-isomer was detected at 16.2 minutes.

Example 4-5

N-{(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4-trifluoromethyl-benzyl) -urea

This example was carried out according to general method C.

(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0 mg, 0.35 mmol) and 4-trifluoro in DMSO (1.5 ml) A mixture of methyl-benzylamine (61.8 mg, 0.35 mmol) was stirred at 100 ° C for 1.5 h. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and diisopropyl ether to give N-{(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '-(4 Trifluoromethyl-benzyl) -urea (109 mg, 5% yield) was obtained.

In vitro active class: A

Chiral HPLC (chiralcel AD 0.49 cm × 25 cm column, n-hexane / ethanol = 90/10, flow rate 1.5 ml / min) S-isomer was detected at 11.7 min.

The compounds of Examples 4-6 to 4-54 were synthesized in a similar manner to Examples 4-1, 4-2, 4-3, 4-4 and 4-5.

Example 4-48

N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-{2- [4- (trifluoromethyl) phenyl] -ethyl} Urea

This example was carried out according to general method C.

7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0 mg, 0.35 mmol) and 2- (4-trifluoromethyl in DMSO (1.0 ml) A mixture of -phenyl) ethylamine (66.7 mg, 0.35 mmol) was stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to rt and the mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The raw material was stirred with diethyl ether, the precipitate was filtered off and dried in vacuo to give N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '. -{2- [4- (trifluoromethyl) phenyl] ethyl} urea (125 mg, 94% yield) was obtained.

Example 4-49

N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-{2- [4- (trifluoromethoxy) phenyl] -ethyl} Urea

This example was carried out according to general method C.

7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100 mg, 0.35 mmol) and 2- (4-trifluoromethoxy in DMSO (1.0 ml) A mixture of -phenyl) ethylamine (72.4 mg, 0.35 mmol) was stirred at 60 ° C for 2.5 h. The reaction mixture was cooled to rt and the mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The raw material was stirred with diethyl ether, the precipitate was filtered off and dried in vacuo to give N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '. -{2- [4- (trifluoromethoxy) phenyl] ethyl} urea (109 mg, 79% yield) was obtained.

Example 5-1

N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '-(4-trifluoromethoxy-phenyl) -urea

This example was carried out according to general method E.

8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (32.6 mg, 0.20 mmol) and (4-trifluoromethoxy-phenyl) -carbamic acid phenyl ester in DMSO (1.0 ml) 59.5 mg, 0.20 mmol) was stirred at 100 ° C for 1.5 h. The mixture was concentrated under reduced pressure, then purified by preparative HPLC to give N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '-(4-trifluoromethoxy- Phenyl) -urea (15.5 mg, yield 21%) was obtained.

In vitro active class: A

The compounds of Examples 5-2 to 5-24 were synthesized in a similar manner as in Example 5-1.

Claims (24)

Hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomeric or stereoisomeric forms thereof, or salts thereof. <Formula I> Where X is C _1-6 alkyl, ego, Y is a direct bond, ego, R ¹ , R ² and R ³ are independently hydrogen, halogen, hydroxy, nitro, carboxy, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C _1-6 alkanoyl, C _1-6 alkanoylamino, carbamoyl, C _1-6 alkylcarbamoyl, cyano, or cyano, C _1-6 alkoxycarbonyl or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or when a phenoxy optionally substituted by C _1-6 alkyl, or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkylthio, and; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, C _1-6 alkyl or phenyl; Z ¹ is hydrogen or C _1-6 alkyl; Z ² is hydrogen, halogen or C _1-6 alkyl. The method of claim 1, X ego, Y is directly bonded or ego, R ¹ , R ² and R ³ are independently hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C _1-6 alkanoyl, C _1-6 alkanoylamino, carbamoyl, C _1-6 alkylcarbamoyl, cyano, or cyano, C _1-6 alkoxycarbonyl or mono-, di- or tri-substituted by halogen, optionally C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or when a phenoxy optionally substituted by C _1-6 alkyl, or mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkylthio, and; R ⁴ and R ⁵ are independently hydrogen or C _1-6 alkyl; Z ¹ and Z ² are each a hydroxy-tetrahydro-naphthalenylurea derivative of formula I, tautomer or stereoisomeric form thereof, or salt thereof. The method of claim 1, X ego, Y is directly bonded or ego, R ¹ , R ² and R ³ are independently hydrogen, halogen, di (C _1-6 alkyl) amino, C _3-8 cycloalkylamino, C _1-6 alkoxycarbonyl, or cyano, C _1-6 alkoxy carbonyl or mono-, di- or tri-substituted by halogen, optionally C _1-6 alkyl, mono-, di-, or tri-halogen, optionally substituted by C _1-6 alkoxy, halogen or C _1-6 Phenoxy optionally substituted by alkyl or C _1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen; R ⁴ and R ⁵ are each hydrogen; Z ¹ and Z ² are each a hydroxy-tetrahydro-naphthalenylurea derivative of formula I, tautomer or stereoisomeric form thereof, or salt thereof. The method of claim 1, X ego, Y is directly bonded or ego, R ¹ and R ² are independently hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy, R ³ , R ⁴ and R ⁵ are each hydrogen; Z ¹ and Z ² are each a hydroxy-tetrahydro-naphthalenylurea derivative of formula I, tautomer or stereoisomeric form thereof, or salt thereof. The method of claim 1, X ego, Y is directly bonded or ego, R ¹ and R ² are independently hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy, R ³ , R ⁴ and R ⁵ are each hydrogen; Z ¹ and Z ² are each a hydroxy-tetrahydro-naphthalenylurea derivative of formula I, tautomer or stereoisomeric form thereof, or salt thereof. N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (3-chlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[3- (trifluoromethyl) phenyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethyl) phenyl] urea, Ethyl 3-({[(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl} amino) benzoate, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(1-naphthyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(2-naphthyl) urea, N- (3,4-dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(4-isopropylphenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(4-phenoxyphenyl) urea, N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N'-phenylurea, N- (4-chlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[2- (trifluoromethyl) phenyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethyl) phenyl] urea, N- (3,4-dichlorophenyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethoxy) phenyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethoxy) benzyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-(2,4,6-trimethoxybenzyl) urea, N- (2,6-difluorobenzyl) -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethyl) benzyl] urea, N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '-[4- (trifluoromethoxy) benzyl] urea, N- [2- (4-chlorophenyl) ethyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea, and N- [3-fluoro-4- (trifluoromethyl) benzyl] -N '-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea A hydroxy-tetrahydro-naphthalenylurea derivative of formula I of claim 1, a tautomeric or stereoisomeric form thereof, or a salt thereof. N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea, N- [4-chloro-3- (trifluoromethyl) phenyl] -N '-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea, N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethyl) benzyl] urea, N-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethyl) benzyl] urea, N-[(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethoxy) benzyl] urea, and Selected from the group consisting of N-[(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '-[4- (trifluoromethoxy) benzyl] urea A hydroxy-tetrahydro-naphthalenylurea derivative of formula I according to claim 1. A medicament comprising as an active ingredient a hydroxy-tetrahydro-naphthalenylurea derivative of claim 1, a tautomeric or stereoisomeric form thereof, or a physiologically acceptable salt thereof. The medicament of claim 8 further comprising one or more pharmaceutically acceptable excipients. The medicament according to claim 8, wherein the hydroxy-tetrahydro-naphthalenylurea derivative of formula I, tautomer or stereoisomeric form thereof, or physiologically acceptable salt thereof is a VR1 antagonist. The medicament according to claim 8 for the treatment and / or prevention of urological disorders or diseases. The medicine according to claim 11, wherein the urological disorder or disease is urge incontinence or an overactive bladder. The medicament according to claim 8 for the treatment and / or prevention of pain. The medicament according to claim 13, wherein the pain is chronic pain, neuropathic pain, postoperative pain, or rheumatoid arthralgia. The medicament according to claim 8 for the treatment and / or prevention of a disorder or disease associated with pain. The medicament according to claim 15, wherein the disorder or disease associated with pain is neuralgia, neuropathy, hyperalgesia, nerve damage, ischemia, neurodegeneration, or stroke. The medicament according to claim 8 for the treatment and / or prevention of an inflammatory disorder or disease. The medicament according to claim 17, wherein the inflammatory disorder or disease is asthma or COPD. Use of the compound of claim 1 for the manufacture of a medicament for the treatment and / or prevention of a urological disorder or disease. Use for the manufacture of a medicament for the treatment and / or prevention of pain of the compound of claim 1. Use of the compound of claim 1 for the manufacture of a medicament for the treatment and / or prevention of an inflammatory disorder or disease. A method of controlling urological disorders or diseases in humans and animals by administering an effective amount of at least one compound of claim 1 to antagonize VR1. A method of controlling pain in humans and animals by administering an effective amount of at least one compound of claim 1 to antagonize VR1. A method of controlling an inflammatory disorder or disease in humans and animals by administering an effective amount of at least one compound of claim 1 to antagonize VR1.