KR20130041539A - Chromane derivatives as trpv3 modulators - Google Patents

Abstract

PURPOSE: A chroman derivative as a TRPV3(transient receptor potential vanilloid) modulator is provided to prevent or treat diseases, symptoms, and/or disorders regulated by TRPV3. CONSTITUTION: A compound is denoted by chemical formula I. A pharmaceutical composition contains the compound of chemical formula I, a free base, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. A method for treating diseases, symptoms, and/or disorders regulated by TRPV3 comprises a step of administering therapeutically effective amount of the compound or the pharmaceutical composition to a subject. The diseases, symptoms, and/or disorders regulated by TRPV3 include pain, nocieceptive pain, toothache, cardiodynia caused by ischemic myocardium, pain caused by migraine, acute pain, chronic pain, neuropathic pain, postoperative pain, and pain caused by neuralgia.

Description

CHROMANE DERIVATIVES AS TRPV3 MODULATORS}

This application claims the benefit of priority over Indian Provisional Application No. 1274 / MUM / 2008, filed June 17, 2008, and US Provisional Application No. 61 / 078,603, filed July 7, 2008. Are all incorporated by reference in this specification as a whole.

The present patent application relates to Chromaman derivatives having transient receptor latent vanilloid (Transient Recept or Potential vanilloid 3, TRPV3) activity.

The movement of ions across the cell membrane is performed by specialized proteins. TRP channels are one large group of non-selective cation channels that function to help regulate ion flux and membrane potential. TRP channels are divided into six subgroups, including the TRPV group. TRPV3 is a member of the TRPV class of the TRP channel.

TRPV3 is a calcium permeable non-selective cation channel. In addition to calcium ions, the TRPV3 channel is permeable to other cations such as sodium. Thus, TRPV3 channels regulate membrane potential by controlling the influx of cations such as calcium and sodium ions. TRPV3 receptors are mechanically different from voltage-gated calcium channels. In general, voltage-gated calcium channels allow calcium influx from extracellular media in response to membrane depolarization resulting in elevated intracellular calcium levels or concentrations. Conversely, TRP The channel is nonselective, persistent, exhibits a more prolonged change in ionic temperature, and is ligand gated (regulated by chemicals such as 2-aminoethoxydiphenyl borate [2-APB], vanilloid and heat). These mechanical differences involve structural differences between voltage-switching and TRP channels. Thus, although many different channels play a role in regulating ion influx and membrane potential in response to different stimuli with different cell types, it is important to recognize the significant mechanical, functional, and mechanical differences among the different ion channel classes.

TRPV3 protein is derived from skin cells (Peier et. al . Science (2002), 296 , 2046-2049) and dorsal root ganglia, trigeminal ganglia, spinal cord and brain (Xu et) al . Nature (2002), 418 , 181-185; Smith et al. Nature (2002), 418 , 186-188). In keratinocyte cell lines, stimulation of TRPV3 causes the release of inflammatory mediators including interleukin-1. Thus, TRPV3 also plays an important role in inflammation and pain control due to the release of inflammatory stimuli. In particular, TRPV3 proteins used in screening assays for identifying compounds that modulate the function of TRPV3 protein in the present specification include, but are not limited to, human TRPV3, mouse TRPV3, rat TRPV3, and Drosophila TRPV3. US2004 / 0009537 (filed '537) discloses sequences corresponding to human, mouse and Drosophila TRPV3. For example, SEQ ID NOs 106 and 107 of the '537 application correspond to human nucleic acid and amino acid sequences, respectively.

TRPV3 function is primarily involved in the reception and delivery of pain. Thus, it is desirable to identify and prepare compounds that modulate one or more functions of TRPV3.

WO 2007/056124, WO 2008/140750 and WO 2008/033564 disclose TRPV3 modulators, in particular antagonists for the treatment of TRPV3 mediated various diseases.

In an effort to find better analgesics, there is still a need for therapeutic agents for TRPV3-mediated diseases, disorders and / or disorders.

summary

This patent application relates to compounds of formula (I):

A is a substituted or unsubstituted cycloalkyl, aryl, heteroaryl, or heterocyclic group;

Y is — (CHR ¹ ) _{r wherein} R ¹ is hydrogen, halogen, or substituted or unsubstituted alkyl;

X is hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, -OR ² , -NR ³ R ⁴ , -C (O) -R ³ , -C (O) OR ³ , -C (O) NR ³ R ⁴ , -S (O) _p NR ³ R ⁴ , or -S (O) _p R ³ ;

In each case R ³ And R ⁴ may be the same or different and is hydrogen, —OR ² , substituted or unsubstituted alkyl, alkenyl, cycloalkyl cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo Independently from a click group, or heterocyclylalkyl;

In each case R ² is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl Is selected;

'm' is an integer ranging from 0 to 2 including the boundary value;

'n' is an integer ranging from 0 to 2 including the boundary value;

'p' is an integer ranging from 0 to 2, including the boundary value; And

 'r' is an integer ranging from 0 to 2 including the boundary value.

Formula (I) structurally includes all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts conceivable from the disclosed general chemical structures.

According to one embodiment, specifically provided are compounds of formula (I), in which 'A' is substituted or unsubstituted aryl. In this embodiment, preferably 'A' is substituted or unsubstituted phenyl or naphthyl, wherein substituent (s) halogen (eg fluorine or chlorine), alkoxy (eg methoxy ), Or cycloalkoxy (eg cyclopentyloxy).

According to another embodiment, specifically provided are compounds of formula (I), in which 'A' is substituted or unsubstituted heteroaryl. In this embodiment, preferably, 'A' is substituted or unsubstituted thiazole, benzothiazole, quinoline or dibenzo [ b, d ] furan, wherein the substituent (s) halogen, alkyl (eg, Independently from methyl), alkoxy (eg methoxy), cycloalkoxy, or halophenyl (eg bromophenyl).

According to another embodiment, specifically provided are compounds of formula (I), in which 'Y' is CH ₂ , CH (CH ₃ ) or a bond.

According to another embodiment, specifically provided are compounds of formula (I), wherein the dashed line is a single bond or absence.

According to another embodiment, specifically X is halogen (eg fluorine or chlorine) or alkoxy (eg methoxy); And 'm' is 1. Provided are compounds of formula (I).

According to another embodiment, specifically provided are compounds of formula (I), in which 'n' is 1.

Exemplary compounds are shown below, which are illustrative and are not intended to limit the scope of the present invention.

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-methoxyphenyl) acetamide,

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-cyclopentyloxy-3-methoxybenzyl) acetamide,

2- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1- (4-methoxynaphthylmethyl) acetamide,

2- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -[(4-methoxydibenzo [ b , d ] furan-1- 1) methyl] acetamide,

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - [(1 S ) -1- phenylethyl] acetamide,

(2 E) -2- (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-ylidene) - N - [2- (cyclopentyloxy) phenyl] Acetamide,

N- (2-cyclopentyloxyphenyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide,

N- (2,6-difluorobenzyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide,

2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -quinolin-6-ylacetamide,

N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclo Butane] -4-yl) acetamide,

2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1-naphthylacetamide,

2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1,3-thiazol-2-ylacetamide and

2- (6-methoxy-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (6-methyl-1,3-benzothiazol-2- One) acetamide or

Analogs, tautomers, rheomers, geometric isomers, stereoisomers, enantiomers, diastereomers or pharmaceutically acceptable salts of compounds 1 to 13 are also included.

According to another embodiment, specifically provided are compounds of formula I or salts thereof which have an IC ₅₀ value of 10,000 nM and which inhibit the function of TRPV3. In another embodiment, specifically provided are compounds of Formula I or salts thereof that have an IC ₅₀ value of 1000 nM and which inhibit the function of TRPV3.

details

The present invention provides Chromaman derivatives usable as TRPV3 modulators and methods for synthesizing these compounds. Pharmaceutically acceptable salts, enantiomers, and diastereomers of the compounds disclosed herein are included independently of one another. Separately included are compounds that can be used in the treatment of diseases, conditions and / or disorders mediated by TRPV3 together with pharmaceutically acceptable carriers, excipients or diluents.

The present invention is defined by the claims, and is not limited to the following description. The terms used in the appended claims are as defined in this section unless specifically defined to be used differently.

The term "halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a linear or branched hydrocarbon chain radical having 1 to 8 carbon atoms, consisting solely of carbon and hydrogen atoms, which does not contain unsaturation, which is connected in a single bond with the rest of the molecule, eg For example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl ( tert -butyl). The term "C _{1 -6} alkyl" refers to alkyl chains having from 1 to 6 carbon atoms. Unless otherwise indicated or described, all alkyl groups described herein may be linear or branched, and may be substituted or unsubstituted.

The term "alkenyl" refers to an aliphatic hydrocarbon group comprising a carbon-carbon double bond, which may be a linear or branched chain having 2 to about 10 carbon atoms, for example ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Unless otherwise indicated or described, all alkenyl groups described herein may be linear or branched, and may be substituted or unsubstituted.

The term "alkynyl" refers to a linear or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having from 2 to about 12 carbon atoms (a radical having from 2 to about 10 carbon atoms is preferred). Such as ethynyl, propynyl and butynyl. Unless otherwise indicated or described, all alkynyl groups described herein may be linear or branched, and may be substituted or unsubstituted.

The term "alkoxy" refers to a saturated or aliphatic hydrocarbon radical, linear or branched, bonded to one oxygen atom linked to its core structure. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like. Unless otherwise indicated or described, all alkoxy groups described herein may be linear or branched, and may be substituted or unsubstituted.

The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic or spirobicyclic groups such as spiro (4,4) non-2-yl This is not restrictive. Unless otherwise indicated or described, all cycloalkyl groups described herein may be substituted or unsubstituted.

The term "cycloalkylalkyl" refers to a cyclic ring comprising radicals having from 3 to about 8 carbon atoms directly connected to the alkyl group. Cycloalkylalkyl groups can be linked to the main structure at any carbon atom of the alkyl group, thereby producing a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl. Unless otherwise indicated or described, all cycloalkylalkyl groups described herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a cyclic ring having at least one carbon-carbon double bond and comprising a radical having from 3 to about 8 carbon atoms, for example cyclopropenyl, cyclobutenyl and cyclopentenyl . Unless otherwise indicated or described, all cycloalkenyl groups described herein may be substituted or unsubstituted.

The term "aryl" means a carbocyclic aromatic system comprising one, two or three rings, which rings may be fused. When the rings are fused, one of the rings must be fully unsaturated and the fused ring can be fully saturated, partially unsaturated or fully unsaturated. The term “fused” means having two adjacent atoms in common with the primary ring (ie, shared) and the presence of a secondary ring (ie, linked or formed). The term "fused" is equivalent to the term "condensed". The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless otherwise indicated or described, all aryl groups described herein may be substituted or unsubstituted.

The term “arylalkyl” is an aryl group as defined above, such as —CH ₂ C ₆ H ₅ or —C ₂ H ₄ C ₆ H ₅ , directly bonded to an alkyl group as defined above.

The terms "heterocyclic ring" and "heterocyclic ring" "heterocyclic group" are stable 3- to 15-membered rings consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Point to a radical. For the purposes of the present invention, this heterocyclic ring radical may be a monocyclic ring, bicyclic ring or tricyclic ring system, which may comprise a fused, crosslinked or spirocyclic system and The nitrogen, phosphorus, carbon, oxygen or sulfur atoms of the click ring radical can optionally be oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; Ring radicals may be partially or fully saturated (ie, heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cynolinyl, diozolanyl, indolinyl, naphthyridinyl, per Hydroazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, putridinyl, purinyl, quinazolinyl, quinoxarinyl, quinolininyl, isoquinolinyl, tetrazolyl, Imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, Pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxoxazolidinyl, Morpholinyl, thiazolyl, thiazolinyl, thiazoridinyl, isothiazolyl, quinuclidinyl, isothiazoridinyl , Indolyl, isoindolinyl, indolinyl, isoindonilyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyra Neyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl group sulfoxide, thiamorpholinyl group sulfone, dioxaphosphol Anyl, oxadiazolyl, chromanyl and isochromenyl. Heterocyclic ring radicals can be linked to any hetero atom or carbon atom in the main structure, thereby creating a stable structure. Unless otherwise indicated or described, all heterocyclic rings described herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical bonded directly to an alkyl group. These heterocyclylalkyl radicals can be linked at any carbon atom to the alkyl group main structure, thereby producing a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. This heteroaryl ring radical may be linked to any heteroatom or carbon atom in the main structure, thereby producing a stable structure. Unless otherwise indicated or described, all heteroaryl groups described herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical bonded directly to an alkyl group. These heteroarylalkyl radicals can be linked at any carbon atom to the alkyl group main structure, thereby producing a stable structure.

Unless stated otherwise, the term "substituted" as used herein refers to substituted with one or more or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (= 0) , Thio (= S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or substituted Unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine, -COOR ^{x '} , -C (O) R ^x' , -C (S) R ^{x '} , -C (O) NR ^x' R ^{y '} , -C (O) ONR ^x' R ^{y '} , -NR ^x' CONR ^{y '} R ^z' , -N (R ^{x '} ) SOR ^{y '} , -N (R ^x' ) SO ₂ R ^{y '} ,-(= NN (R ^x' ) R ^{y '} ), -NR ^x' C (O) OR ^{y '} , -NR ^x' R ^{y '} , -NR ^{x '} C (O) R ^y' , -NR ^{x '} C (S) R ^y' , -NR ^{x '} C (S) NR ^y' R ^{z '} , -SONR ^x' R ^{y '} , -SO ₂ NR ^{x '} R ^y' , -OR ^{x '} , -OR ^x' C (O) NR ^{y '} R ^z' , -OR ^{x '} C (O) OR ^y' , -OC (O) R ^{x '} , -OC (O) NR ^{x '} R ^y' , -R ^{x '} NR ^y' C (O) R ^{z '} , -R ^x' OR ^{y '} , -R ^x' C (O) OR ^{y '} , -R ^x' C (O) NR ^{y '} R ^z' , -R ^{x '} C (O) R ^y' , -R ^{x '} OC (O) R ^y' , -SR ^{x '} , -SOR ^x' , -SO ₂ R ^{x '} And -ONO ₂ , wherein R ^{x ' ,} R ^y' and R ^{z '} are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Substituted or unsubstituted Unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Independently selected from a substituted heterocyclylalkyl ring, a substituted or unsubstituted heteroarylalkyl group, or a substituted or unsubstituted heterocyclic ring.

The term “treating or treating” a condition, disorder or symptom includes; or Preventing or delaying the development of clinical symptoms; (b) inhibiting a condition, disorder or symptom, ie, stopping or reducing the progression of the disease or at least one clinical or subclinical symptom thereof; Or (c) alleviating the disease, ie, reducing the condition, disorder or symptom or at least one clinical or subclinical symptom thereof.

The term “subject” includes mammals (especially humans) and other animals, such as livestock (eg pets including dogs and cats) and non-livestock animals (eg wild animals).

 A "therapeutically effective amount" means an amount of a compound that, when administered to a subject to be treated for a condition, disorder or condition, is sufficient to reveal such therapeutic effect. This “therapeutically effective amount” depends on the compound, the disease and its severity, and the age, weight, physical condition and responsiveness of the subject being treated.

The compounds described in this patent application may form salts. Examples of pharmaceutically acceptable salts that form part of this patent application include, but are not limited to, salts derived from inorganic base salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. For all compounds disclosed in formula (I), this patent application includes their stereoisomeric forms and mixtures thereof. To the extent that the prior art teaches the synthesis or separation of certain stereoisomers, the different stereoisomers of this patent application may be separated from one another by methods known in the art, or may be obtained by stereospecific or asymmetric synthesis. Can be. Tautomeric forms and compounds of the compounds described herein are also included.

Pharmaceutical composition

The pharmaceutical compositions provided herein comprise at least one compound described in the present specification and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the included pharmaceutical composition comprises a compound described in the present specification which is sufficient to inhibit the TRPV3 receptor in the subject.

Presumed subjects include mammals, including, for example, live cells and human mammals. The compounds of the present invention can be bound to pharmaceutically acceptable excipients (such as carriers or diluents), can be diluted by, or put in carriers which can be in the form of capsules, vesicles, paper or other containers.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, white clay, sucrose, dextrin, magnesium carbonate, sugars, Lower alkyl ethers of cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, Polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

The carrier or diluent may comprise a sustained release material in which glyceryl monostearate or glyceryl distearate alone or in admixture with a wax.

The pharmaceutical composition may comprise one or more pharmaceutically acceptable auxiliaries, wetting agents, emulsifiers, suspending agents, preservatives, salts for affecting osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents, or any combination thereof. . The pharmaceutical compositions of the present invention may be formulated for immediate release, sustained release or delayed release of the active ingredient after administration to a subject by techniques known in the art.

The pharmaceutical compositions described in the present specification can be prepared by conventional techniques known in the art. For example, the active compound may be mixed with the carrier, diluted with the carrier, or sealed in the carrier, and may be in the form of an ampoule, capsule, vesicle, paper, or other container. When the carrier acts as a diluent, the carrier can be a solid, semisolid or liquid substance that acts as a vehicle, excipient, or medium with respect to the active compound. The active compound may be adsorbed onto granular solid containers, for example vesicles.

The pharmaceutical compositions may be in conventional forms such as, for example, capsules, tablets, aerosols, solutions, suspensions or topical application products.

The route of administration can be any route that effectively delivers the active compound of the invention to an appropriate or predetermined site of action. Suitable routes of administration include, but are not limited to, oral, nasal, lung, oral, subdermal, intradermal, transdermal, intestinal, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, eye drops (eye drops) Solutions) or external (such as external ointments).

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), oral tablets, and lozenges. Tablets, dragees, or capsules with talc and / or carbohydrate carriers or binders and the like are particularly suitable for oral use. Liquid formulations include, but are not limited to, sterile injectable solutions such as syrups, emulsions, soft gelatins, and aqueous or non-aqueous liquid suspensions or solutions. Particularly suitable for runners are injection solutions or suspensions. Preferably it is an aqueous solution with the active compound dissolved in polyhydroxylated castor oil.

Appropriate doses of the compounds for use in the treatment of the diseases and disorders described herein can be determined by one skilled in the art. Therapeutic doses are generally identified through doses in human testing based on primary evidence derived from animal experiments. The dose should be sufficient to induce any therapeutic benefit without causing side effects. For example, the daily dose of the TRPV3 modulator may range from about 0.1 to about 30.0 mg / kg. Methods of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can be readily used and controlled by those skilled in the art. All variations and modifications are within the scope of the present invention.

How to treat

The present invention provides compounds and pharmaceutical agents useful for the treatment of diseases, conditions and / or disorders regulated by TRPV3. The present patent application also provides a method of treating a disease, condition and / or disorder regulated by TRPV3 in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

Diseases, conditions, and / or disorders controlled by TRPV3 include, but are not limited to, pain, nociceptive pain, toothache, heart pain resulting from ischemic myocardium, pain from migraine, acute pain, chronic pain, neuropathic pain, postoperative Pain, pain caused by neuralgia (eg, neuralgia or trigeminal neuralgia after shingles), pain caused by diabetic neuropathy, toothache and cancer pain, inflammatory pain conditions (eg arthritis and osteoarthritis), arthralgia, neuropathy, nerves Degenerative, retinopathy, neurotic skin disorders, stroke, bladder hypersensitivity, urinary incontinence, gastrointestinal disorders such as vulvar pain, sensitive bowel syndrome, gastro-esophageal reflux disease, enterocolitis, ileitis, gastric-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, inflammatory diseases such as pancreatitis, respiratory disorders such as allergic and non-allergic rhinitis, asthma or obstructive pulmonary disease, skin, eyes or Irritation of the membranes, dermatitis, pruritic conditions such as urinary pruritus, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory disorders, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis It is thought to include diabetes, obesity, urticaria, actinic keratosis, keratinocytes, alopecia, Ménière's disease, tinnitus, deafness, anxiety disorders, and benign prostatic hyperplasia. Diseases, conditions and / or disorders controlled by additional TRPV3 are described, for example, in WO2007 / 056124; Wissenbach, U. et al , Biology of the Cell (2004), 96 , 47-54; Nilius, B. et al ., Physiol Rev (2007), 87 , 165-217; Okuhara, DY et al , Expert Opinion on Therapeutic Targets (2007), 11 , 391-401; Hu, HZ et al , Journal of Cellular Physiology , (2006), 208 , 201-212, and the references included therein, all of which are incorporated into this specification for the purposes stated in their entirety.

General manufacturing method

Compounds described in this specification, including compounds of Formula (I) and specific examples thereof, are prepared using techniques known to those skilled in the art. The compounds described in this specification are prepared in the reaction sequence shown in Scheme 1. All possible stereoisomers are included within the scope of the present invention.

Starting materials for the following reaction schemes are commercially available or can be prepared by methods known to those skilled in the art or by the methods described in the specification. In general, the compounds according to the present invention can be prepared through the following scheme, all symbols are as described above.

Compounds of formula (I) may be prepared according to Scheme 1. Thus, 2-hydroxy acetophenone of formula (1) produces a spirocyclic ketone of formula (3) in the presence of a base such as pyrrolidine or piperidine in an alcoholic solvent, and the spiro of formula (3) Cyclic ketones are reacted with trialkyl phosphonoacetates of formula (4), wherein R is alkyl, of under Wittig reaction conditions to form acrylic acid esters of formula (5), R is alkyl. The compound of formula (5) is hydrolyzed and then catalytic hydrogenation (optional) to yield the compound of formula (6). The carboxylic acid of formula (6) is combined with the appropriate amine of formula (7) in the presence of a suitable coupling agent to prepare a compound of formula (I). Alternatively, the acid chloride intermediate (6) may be combined with an amine of formula (7) in the presence of a suitable base to prepare a compound of formula (I).

Experiment

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the present invention in any way, but merely illustrative. Accordingly, one of ordinary skill in the art appreciates that various modifications of the following examples, substituents, reagents or conditions can be made to further perform the experiments and examples.

Intermediate

Intermediate 1

(6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetic acid:

Step 1 : 6-chlorospiro [chromen-2,1'-cyclobutane] -4 ( 3H ) -one: 5'-chloro-2'-hydroxy acetophenone (5.0 g, in methanol (50 ml) 29.308 mmol) was added pyrrolidine (4.16 g, 58.616 mmol) followed by cyclobutanone (4.1 g, 58.616 mmol) at room temperature. The reaction mixture was heated to reflux under nitrogen for 14 hours. The solvent was evaporated under reduced pressure and the residue obtained was diluted with water (100 ml) and the mixture acidified to pH 4.0. The mixture was extracted with chloroform (3 x 100 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The residue obtained after solvent evaporation was purified by silica gel column chromatography and purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to give 6.3 g of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.69-1.88 (m, 5H), 1.96-2.04 (m, 1H), 2.88 (s, 2H), 6.91 (d, J = 9.0 Hz, 1H), 7.38 ( d, J = 6.6 Hz, 1H), 7.76 (s, 1H).

Step 2: ethyl (2 E) - (6- chloro-spiro [chromene -2,1'- cyclobutane] -4 (3 H) - ylidene) acetate, and anhydrous tetrahydrofuran (25 ml) was stirred and cooled in To this sodium hydride (431 mg, 17.897 mmol) mixture was added triethyl phosphonoacetate (4.03 g, 17.897 mmol) over 15 minutes. The reaction mixture was stirred for 30 minutes and then 6-chlorospiro [chromen-2,1′-cyclobutan] -4 ( 3H ) -one (2 g, 8.948 mmol) in anhydrous tetrahydrofuran was added. The reaction mixture was stirred for 24 h under nitrogen at the same temperature. The reaction mixture was diluted with methanol and water and the product extracted with ethyl acetate (3 x 100 ml). The organic layer was washed with water (100 ml), brine, dried (Na ₂ SO ₄ ) and concentrated to yield 3.54 g of crude product, which was used in the next step.

Step 3: (2 E) - ( 6- chloro-spiro [chromene -2,1'- cyclobutane] -4 (3 H) - ylidene) acetic acid in ethyl ethanol (30 ml) (2 E) - ( To a stirred solution of 6-chlorospiro [chromen-2,1'-cyclobutane] -4 ( 3H ) -ylidene) acetate (3 g, 10.22 mmol) was added 1N sodium hydroxide solution (30 ml) to room temperature. Added at. The reaction mixture was stirred for 2 hours at room temperature. The residue obtained after solvent evaporation under reduced pressure was acidified with 1 N HCl. The desired product was extracted with ethyl acetate (3 × 50 ml), washed with water (100 ml), brine, dried (Na ₂ SO ₄ ) and concentrated to give 2.6 g of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 3.96 (s, 2H), 6.36 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 9.3 Hz, 1H), 7.51 (s, 1H).

Step 4: (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) acetic acid: ethyl acetate (25 ml) (2 E) - (6-chloro-spiro To a stirred solution of [chromen-2,1′-cyclobutane] -4 ( 3H ) -ylidene) acetic acid (2.5 g, 9.444 mmol) was added 10% Pd / C (50 mg) at room temperature. The reaction mixture was stirred in a Paar hydrogenation apparatus at 40 psi hydrogen pressure for 12 hours. The reaction mixture was filtered through a celite bed, the filtrate was dried (Na ₂ SO ₄ ) and concentrated to give 2.45 g of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 2.09-2.21 (m, 2H), 2.29-2.38 (m, 1H), 2.99 (d , J = 13.2 Hz, 1H), 3.44 (br s, 1H), 6.73 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 9.3 Hz, 1H).

Intermediate 2

6-Fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetic acid:

The title compound was prepared in 4 steps from 5'-fluoro-2'-hydroxyacetophenone and cyclobutanone by a similar procedure as in Intermediate 1 to give a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.66-1.74 (m, 2H), 1.88-1.95 (m, 1H), 2.05-2.14 (m, 3H), 2.26-2.34 (m, 1H), 2.37-2.44 (m, 1H), 2.48-2.56 (m, 1H), 2.96 (dd, J = 4.2, 15.6 Hz, 1H), 3.35 (br s, 1H), 6.74-6.82 (m, 3H).

Intermediate 3

(6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetic acid:

Step 1 : 6-Hydroxyspiro [chromen-2,1'-cyclobutane] -4- ( 3H ) -one: The title compound was converted to 2 ', 5'-dihydroxy in pyrrolidine (10.79 ml) Prepared from acetophenone (10 g, 65.724 mmol) and cyclobutanone (13.29 ml, 131.44 mmol) by a similar procedure as in step 1 of intermediate 1 to give 10 g of product; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.63-1.73 (m, 2H), 1.84-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.23-2.33 (m, 2H), 6.85 (d , J = 8.7 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H).

Step 2 : 6-methoxyspiro [chromen-2,1′-cyclobutane] -4 ( 3H ) -one: 6-hydroxyspiro [chromen-2,1 in dry dimethylformamide (150 ml) To a stirred solution of '-cyclobutane] -4- ( 3H ) -one (8 g, 39.215 mmol) was added potassium carbonate (16.28 g, 117.64 mmol) and methyl iodide (4.88 ml, 78.431 mmol). The reaction mixture was added and stirred at room temperature under nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3x300 ml), and the combined organic layers were washed with water (3x100 ml), brine (60 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give 8.13 g of product; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.67-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.11-2.18 (m, 2H), 2.23-2.34 (m, 2H), 2.87 (s , 2H), 3.77 (s, 3H), 6.88 (d, J = 9.6 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H).

Step 3 : The final compound was prepared from 6-methoxyspiro [chromen-2,1'-cyclobutan] -4 ( 3H ) -one by a procedure similar to that of intermediate 1 step 2-4; ¹ H NMR (300 MHz, DMSO- d ₆ ) d 1.53-1.65 (m, 2H), 1.78 (br s, 1 H), 1.96-2.05 (m, 3H), 2.18-2.23 (m, 2H), 2.30- 2.39 (m, 1H), 2.93 (d, J = 15.9 Hz, 1H), 3.18 (br s, 1H), 3.64 (s, 3H), 6.64 (s, 2H), 6.75 (s, 1H).

Intermediate 4

1- [2- (cyclopentyloxy) -3-methoxyphenyl] methylamine hydrochloride:

Step 1 : 2- (cyclopentyloxy) -3-methoxybenzaldehyde oxime: hydroxylamine hydrochloride in a stirred solution of 2- (cyclopentyloxy) -3-methoxybenzaldehyde (3 g, 13.636 mmol) in ethanol (1.758 g, 27.277 mmol) and sodium hydroxide (18 ml, 34.091 mmol) aqueous solution were added. The reaction mixture was refluxed under nitrogen atmosphere for 6 hours. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with water. The product was extracted using chloroform (3x200 ml) and the combined organic layers were washed with water (3x100 ml), brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 3.12 g of The product was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.58-1.64 (m, 4H), 1.66-1.72 (m, 4H), 3.84 (s, 3H), 4.86 (br s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 8.43 (s, 1H).

Step 2 : 1- [2- (cyclopentyloxy) -3-methoxyphenyl] methanamine hydrochloride: 2- (cyclopentyloxy) -3-methoxybenzaldehyde oxime (3 g, in methanol (10 ml) To a stirred solution of 12.448 mmol), a catalytic amount of Raney nickel (0.30 g) was added at room temperature. The reaction mixture was stirred with a Paar hydrogenation apparatus at 50 psi hydrogen pressure for 3 hours. The reaction mixture was filtered through a celite bed, dried (Na ₂ SO ₄ ), filtered and concentrated to give crude product. The crude product was then dissolved in ethyl acetate and hydrochloric acid in ethyl acetate was added dropwise at 10 ° C. and stirred for 20 minutes and then filtered to dry to give 2.86 g of product, ¹ H NMR (300 MHz, DMSO- d ₆ ) d 1.57-1.63 (m, 4H), 1.65-1.72 (m, 4H), 3.81 (s, 3H), 3.94 (s, 2H), 4.90 (br s, 1H), 7.08 (s, 3H), 8.39 ( br s, 3H).

Intermediate 5

1- (4-methoxy-1-naphthyl) methylamine hydrochloride:

The title compound was prepared in two steps from 4-methoxy-1-naphthaldehyde (1 g, 5.376 mmol) by a similar procedure as in Intermediate 4 to afford 1.27 g of the product as a hydrochloride salt; ¹ H NMR (300 MHz, CDCl ₃ ) d 3.85 (s, 3H), 4.26 (s, 2H), 6.68 (d, J = 7.2 Hz, 1H), 7.40 (br s, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 6.6 Hz, 1H).

Intermediate 6

1- (4-methoxydibenzo [ b , d ] furan-1-yl) methylamine hydrochloride:

The title compound was prepared in two steps from 4-methoxy-dibenzo [ b , d ] furan-1-carbaldehyde (3 g, 13.274 mmol) by a similar procedure as in Intermediate 4 to give 2.97 g of the product as a hydrochloride. Obtained as a salt; ¹ H NMR (300 MHz, CDCl ₃ ) d 4.07 (s, 3H), 4.63 (s, 2H), 7.16 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 6.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H).

Example

3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2- methoxyphenyl) General procedure for the preparation acetamide derivatives:

Method A

To a stirred mixture of (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetic acid derivative (1.0 mmol) and arylamine hydrochloride (1.0 mmol) in dichloromethane 3- ( 3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (EDCI.HCl) (1.3 mmol), 1-hydroxybenzotriazole (HOBt) (1.3 mmol) and triethylamine (3.4 mmol) were added. . The reaction mixture was stirred for 12 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with water, extracted with chloroform, and the combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the product.

Method B

Step 1 : Oxalyl chloride (1.5 mmol) and catalytic amount in a stirred solution of (3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetic acid derivative (1.0 mmol) in dichloromethane N, N -dimethylformamide was added. The reaction mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. Solvent and excess oxalyl chloride were evaporated under reduced pressure to give acid chloride as a sticky solid which was used as such as a coupling reaction without further purification.

Step 2 : To a stirred and cooled mixture of arylamine (1.0 mmol) and triethylamine (1.7 mmol) in dichloromethane was added Step 1 intermediate (1.0 mmol) in dichloromethane at 0 ° C. over 15 minutes. The reaction mixture was cooled to room temperature and stirred for 2 hours under nitrogen at the same temperature. The reaction mixture was diluted with water and the product extracted with chloroform. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) filtered and concentrated in vacuo to afford the product.

Example  One

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-methoxyphenyl) acetamide:

The title compound was prepared from intermediate 1, 6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetyl chloride (230 mg, 0.812 mmol) in dichloromethane. (10 ml) 2-methoxyaniline (100 mg, 0.812 mmol) was prepared by coupling in the presence of triethylamine (225 μl, 1.624 mmol) as in Method B to give 159 mg of the product as an off-white solid. IR (KBr) 3301, 2941, 1656, 1542, 1247, 1030, 742 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.62-1.75 (m, 2H), 1.81-1.89 (m, 1H), 2.02-2.10 (m, 3H), 2.33-2.48 (m, 3H), 3.04 (dd , J = 4.8, 9.6 Hz, 1H), 3.50 (br s, 1H), 3.81 (s, 3H), 6.72 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.93-7.04 (m, 3 H), 7.14 (s, 1 H), 7.75 (br s, 1 H), 8.37 (d, J = 6.9 Hz, 1 H); ESI-MS ( m / z ) 372.25 (M + H) ⁺ .

Example  2

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-cyclopentyloxy-3-methoxy-benzyl) -acetamide:

The title compound was converted to intermediate 1 (207 mg, 0.828 mmol) and intermediate 4 (200 mg, 0.828 mmol) in EDCI.HCl (238 mg, 1.248 mmol), HOBt (190 mg, 1.242 mmol) and dichloromethane (5 ml). Prepared by coupling as in Method A in the presence of triethylamine (460 μl, 3.312 mmol) in 157 mg of the product as a white solid; IR (KBr) 3279, 2938, 1646, 1478, 1269, 1077 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.50-1.67 (m, 5H), 1.81-2.06 (m, 6H), 2.09-2.19 (m, 4H), 2.28-2.39 (m, 1H), 2.75-2.82 (m, 1H), 3.40 (br s, 1H), 3.83 (s, 3H), 4.47 (d, J = 6.0 Hz, 2H), 4.95 (br s, 1H), 6.03 (br s, 1H), 6.68 (d, J = 8.7 Hz, 1 H), 6.82-6.90 (m, 2 H), 6.95-7.04 (m, 3H); ESI-MS ( m / z ) 468.46 (M ⁻ H) ⁻ .

Example  3

2- (6-Chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutane] -4-yl) -N -1- (4-methoxynaphthylmethyl) acetamide:

The title compound was purified by intermediate 1 (178 mg, 0.671 mmol) and intermediate 5 (150 mg, 0.671 mmol) in EDCI.HCl (192 mg, 1.008 mmol), HOBt (154 mg, 1.008 mmol) and dichloromethane (5 ml). Prepared by coupling as in Method A in the presence of triethylamine (375 μl, 2.686 mmol) to afford 103 mg of the product white solid; IR (KBr) 3289, 2933, 1632, 1480, 1092, 760 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.42-1.68 (m, 5H), 1.80-1.85 (m, 1H), 2.03-2.16 (m, 3H), 2.74-2.81 (m, 1H), 3.44 (br s, 1H), 3.98 (s, 3H), 4.76-4.90 (m, 2H), 5.66 (br s, 1H), 6.65-6.73 (m, 2H), 6.96-7.04 (m, 2H), 7.33 (d , J = 8.7 Hz, 1H), 7.46-7.55 (m, 2H), 7.92 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H); ESI-MS ( m / z ) 434.40 (M ⁻ H) ⁻ .

Example  4

2- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -[(4-methoxydibenzo [ b , d ] furan-1- (L) methyl] acetamide:

The title compound was prepared by intermediate 1 (121 mg, 0.455 mmol) and intermediate 6 (100 mg, 0.379 mmol) in EDCI.HCl (109 mg, 0.569 mmol), HOBt (87 mg, 0.569 mmol) and dichloromethane (5 ml). Prepared by coupling as in Method A in the presence of triethylamine (158 μl, 1.138 mmol) to give 64 mg of the product white solid; IR (KBr) 3292, 2934, 1630, 1479, 1274, 747 cm ⁻¹ ; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.50-1.67 (m, 3H), 1.90-2.02 (m, 3H), 2.17-2.29 (m, 3H), 2.79 (dd, J = 4.8, 9.6 Hz, 1H ), 3.47 (br s, 1H), 4.05 (s, 3H), 4.83-4.98 (m, 2H), 5.68 (br s, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.91-7.04 ( m, 3H), 7.16 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H); ESI-MS ( m / z ) 475.90 (M) ⁺ .

Example  5

2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - [(1 S ) -1- phenylethyl] acetamide:

The title compound was diluted with acid chloride of intermediate 1 (117 mg, 0.412 mmol) and (5 ml) (s)-(α) -methylbenzylamine (50 mg, 0.412 mmol) in dichloromethane (172 μl, 1.238). mmol) in the presence of Method B to yield 98 mg of the product as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.52-1.61 (m, 4H), 1.85 (br s, 1H), 1.98-2.05 (m, 4H), 2.27-2.38 (m, 3H), 2.72 (br s , 1H), 3.42 (br s, 1H), 5.17 (br s, 1H), 5.69 (br s, 1H), 6.70 (d, J = 8.7 Hz, 1H), 7.00-7.09 (m, 2H), 7.31 (s, 5H).

Example  6

(2 E) -2- (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-ylidene) - N - [2- (cyclopentyloxy) phenyl] Acetamide:

Acetate The title compound was prepared from (2 E) - (6- chloro-spiro [chromene -2,1'- cyclobutane] -4 (3 H) - ylidene) acetate (intermediate 1, step 2) and 2- (cyclopentyl Oxy) aniline (120 mg, 0.681 mmol) (150 mg, 0.565 mmol) was converted to EDCI.HCl (163 mg, 0.851 mmol), HOBt (130 mg, 0.851 mmol) and (5 ml) triethylamine (157) in dichloromethane. Prepared by coupling as in Method A in the presence of .mu.l, 1.134 mmol) to give 95 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.53-1.65 (m, 8H), 1.74-1.90 (m, 4H), 2.22-2.30 (m, 2H), 2.47-2.57 (m, 2H), 3.50 (s , 2H), 4.67 (br s, 1H), 6.75 (d, J = 8.1 Hz, 2H), 6.85-6.96 (m, 2H), 7.04-7.10 (m, 2H), 8.32 (d, J = 7.8 Hz , 1H).

Example  7

N- (2-cyclopentyloxyphenyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide:

The title compound was prepared with acid chloride of intermediate 2 (121 mg, 0.451 mmol) and (5 ml) aniline (80 mg, 0.451 mmol) in 2- (cyclopentyloxy) dichloromethane in presence of triethylamine (188 μl , 1.353 mmol) in the same manner as in the method B to give 89 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.53-1.60 (m, 1H), 1.64-1.75 (m, 6H), 1.81-1.90 (m, 4H), 1.92-2.07 (m, 3H), 2.30-2.42 (m, 3H), 3.02 (dd, J = 4.8, 9.6 Hz, 1H), 3.52 (br s, 1H), 4.81 (br s, 1H), 6.74-6.81 (m, 2H), 6.87-7.04 (m , 4H), 7.76 (br s, 1 H), 8.36 (d, J = 8.1 Hz, 1 H).

Example  8

N- (2,6-difluorobenzyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide:

The title compound was prepared with acid chloride (250 mg, 0.931 mmol) and 2,6-difluorobenzylamine (133 μl, 1.117 mmol) in intermediate 2 (5 ml) triethylamine (388 μl, 2.793 mmol) in dichloromethane. Prepared by coupling as in Method B in the presence of 219 mg of product white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.58-1.70 (m, 3H), 1.79-1.89 (m, 1H), 2.00-2.07 (m, 2H), 2.16-2.21 (m, 2H), 2.29-2.39 (m, 1H), 2.75 (q, J = 5.1 Hz, 1H), 3.43 (br s, 1H), 4.51- 4.66 (m, 2H), 6.66-6.77 (m, 3H), 6.89 (t, J = 7.8 Hz, 2H), 7.19-7.29 (m, 1H).

Example  9

2- (6-Fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -quinolin-6-ylacetamide:

The title compound was prepared in Method B in the presence of acid chloride (110 mg, 0.409 mmol) and 6-aminoquinoline (65 mg, 0.451 mmol) of intermediate 2 in the presence of (5 ml) triethylamine (171 μl, 1.229 mmol) in dichloromethane. Prepared as a coupling to obtain 99 mg of product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.64-1.70 (m, 3H), 1.75-1.88 (m, 1H), 2.06-2.12 (m, 2H), 2.37-2.42 (m, 2H), 2.50-2.55 (m, 1H), 3.04 (dd, J = 4.8, 10.2 Hz, 1H), 3.57 (br s, 1H), 6.77-6.89 (m, 3H), 7.37-7.42 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 8.07 (dd, J = 7.8, 10.2 Hz, 2H), 8.40 (s, 1H), 8.82 (s, 1H).

Example  10

N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclo Butane] -4-yl) acetamide:

.

.

4- (4-bromophenyl) -1,3-thiazol-2-amine (122 mg, 0.679 mmol) in a stirred solution of intermediate 2 (100 mg, 0.399 mmol) in dimethylformamide (5 ml), followed by di Cyclohexyl carbodiimide (122 mg, 0.598 mmol) and N -hydroxysuccinimide (67 mg, 0.598 mmol) were added. The reaction mixture was heated to 80 ° C. under nitrogen for 24 hours. The reaction mixture was cooled to room temperature and the residue was filtered through celite bed. The product was extracted with ethyl acetate (3 × 50 ml) and the combined organic layers were washed with water, brine and dried (Na ₂ SO ₄ ). The crude product obtained under evaporation reduced pressure was purified by chromatography using 5% ethyl acetate in petroleum ether to give 79 mg of product as off white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.45-1.55 (m, 2H), 1.58-1.70 (m, 2H), 1.84-1.90 (m, 1H), 1.98-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.31-2.38 (m, 1H), 2.77 (dd, J = 4.2, 10.8 Hz, 1H), 3.40 (br s, 1H), 6.56 (d, J = 8.7 Hz, 1H), 6.72 -6.79 (m, 2H), 7.13 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 10.42 (br s, 1H).

Example  11

2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1-naphthylacetamide

The title compound was prepared in Method B in the presence of acid chloride (195 mg, 0.698 mmol) and 1-aminonaphthalene (100 mg, 0.698 mmol) of intermediate 3 in the presence of (5 ml) triethylamine (291 μl, 2.095 mmol) in dichloromethane. Prepared as a coupling to give 128 mg of product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.63-1.70 (m, 2H), 1.76-1.84 (m, 2H), 2.03-2.10 (m, 3H), 2.34-2.40 (m, 2H), 2.73-2.80 (m, 1H), 3.09 (q, J = 4.8 Hz, 1H), 3.60 (br s, 1H), 3.72 (s, 3H), 6.73-6.82 (m, 2H), 7.45-7.52 (m, 5H) , 7.66 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H).

Example  12

2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1,3-thiazol-2-ylacetamide:

The title compound was prepared with acid chloride of intermediate 3 (100 mg, 0.356 mmol) and 2-amino-1,3-thiazole (35 mg, 0.356 mmol) in dichloromethane (5 ml) triethylamine (149 μl, 1.068 mmol). ) Coupling in the presence of Method B to give 85 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.62-1.71 (m, 2H), 1.88 (br s, 1H), 2.05-2.12 (m, 3H), 2.30-2.41 (m, 2H), 2.59-2.67 ( m, 1H), 3.19 (q, J = 4.8 Hz, 1H), 3.58 (br s, 1H), 3.69 (s, 3H), 6.68-6.75 (m, 3H), 6.93-6.70 (m, 1H), 7.28-7.35 (m, 1 H).

Example  13

2- (6-methoxy-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (6-methyl-1,3-benzothiazol-2- 1) Acetamide:

The title compound was prepared with acid chloride (170 mg, 0.608 mmol) and 6-methyl-1,3-benzothiazol-2-amine (100 mg, 0.608 mmol) in intermediate 3 (5 ml) triethylamine in dichloromethane ( 254 μl, 1.826 mmol) was prepared by coupling as in Method B to give 80 mg of the product as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) d 1.60-1.68 (m, 3H), 1.86 (br s, 1H), 1.98-2.05 (m, 3H), 2.28-2.35 (m, 2H), 2.46 (s, 3H), 2.55-2.60 (m, 1H), 3.10 (q, J = 4.8 Hz, 1H), 3.55 (br s, 1H), 3.66 (s, 3H), 6.61 (br s, 1H), 6.69-7.77 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 7.53-7.60 (m, 2H). ESI-MS ( m / z ) 409.43 (M + H) ⁺ .

Pharmacological activity

Exemplary embodiments of the invention include Toth, A., Kedei, N., Wang, Y., and Blumberg, PM Life. Screen for TRPV3 activity by the modifications described in Sciences (2003), 73 , 487-498. Screening of the compounds can be carried out by other methods and procedures known in the art. Such screening methods are described in (a) Hu, H.-Z. meat al . J. Biol . Chem . (2004), 279 , 35741-35747; (b) Smith, GD et al . Nature (2002), 418 , 186-190; (c) Peier, AM et al . Science (2002), 296 , 2046-2049.

⁴⁵ calcium Up take  Using analysis TRPV3  Screening for Antagonists:

Inhibition of TRPV3 receptor activation was performed following 2-aminoethoxydiphenylborate (2-APB) induced radio calcium intracellular uptake. The test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 20 mM stock solution and then diluted using a plain batch with DMEM / F-12 containing 1.8 mM CaCl ₂ to obtain the desired concentration. The final concentration of DMSO in the reaction solution was 0.5% (v / v). Human TRPV3 expressing CHO cells were grown in DMEM / F-12 medium containing 10% FBS, 1% penicillin-streptomycin solution, 400 μg / ml G-418DMF. Cells were seeded 24 hours prior to analysis in 96 well plates to obtain ~ 50,000 cells per well on the day of the experiment. Cells were treated with test compounds for 10 minutes and then 2-APB was added for 4 minutes at a final concentration of 500 μM and 5 μi / ml ⁴⁵ Ca ⁺² f. Cells were washed, washed and digested with buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. Radioactivity in the digest was measured by Packardt Top count after liquid scintillant addition. Concentration response curves were plotted with the maximum% response obtained in the absence of test antagonist. IC ₅₀ values were calculated from concentration response curves by nonlinear regression analysis using GraphPad PRISM software.

The prepared compounds were tested using the analytical procedure described above and the results obtained are given in Table 1. % Inhibition at 1.0 μM and 10.0 μM concentrations is shown in Table 1 below.

Example Inhibition IC ₅₀ nM  1.0 μM 10.0 μM Example 1 26.3 94.2 - Example 2 61.6 92.9 725.3 Example 3 54.6 83.9 - Example 4 23.2 52.3 - Example 5 6.3 65.8 - Example 6 51.5 80.9 - Example 7 46.8 93.8 - Example 8 14.2 53.1 - Example 9 3.7 88.5 - Example 10 49.3 77.9 - Example 11 29.1 86.5 - Example 12 19.4 63.6 - Example 13 26.1 66.8 -

Claims (17)

Formula (I):

A is a substituted or unsubstituted cycloalkyl, aryl, heteroaryl, or heterocyclic group;
Y is — (CHR ¹ ) _{r wherein} R ^{1 is} hydrogen, halogen, or substituted or unsubstituted alkyl;
X is hydrogen, nitro, cyano, halogen, substituted or unsubstituted alkyl, -OR ² , -NR ³ R ⁴ , -C (O) -R ³ , -C (O) OR ³ , -C (O) NR ³ R ⁴ , -S (O) _p NR ³ R ⁴ , or -S (O) _p R ³ ;
In each case R ³ and R ⁴ may be the same as or different from each other, hydrogen, —OR ² , substituted or unsubstituted alkyl, alkenyl, cycloalkyl cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, hetero Independently from arylalkyl, heterocyclic group, or heterocyclylalkyl;
In each case R ² is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl Is selected;
'm' is an integer ranging from 0 to 2 including the boundary value;
'n' is an integer ranging from 0 to 2 including the boundary value;
'p' is an integer ranging from 0 to 2, including the boundary value; And
'r' is an integer ranging from 0 to 2 including the boundary value;
Of a compound or a pharmaceutically acceptable salt thereof.
The method of claim 1,
Y is-(CHR ¹ ) _r, wherein r is 0 to 2;
3. The method according to claim 1 or 2,
R ¹ is hydrogen or substituted or unsubstituted alkyl.
The method according to any one of claims 1 to 3,
A is substituted or unsubstituted aryl.
The method according to any one of claims 1 to 3,
A is substituted or unsubstituted heteroaryl.
The method of claim 1,
n is 1;
6. The method according to any one of claims 1 to 6,
2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-methoxyphenyl) acetamide,
2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (2-cyclopentyloxy-3-methoxybenzyl) acetamide,
2- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1- (4-methoxynaphthylmethyl) acetamide,
2- (6-chloro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -[(4-methoxydibenzo [ b , d ] furan-1- 1) methyl] acetamide,
2- (6-chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - [(1 S ) -1- phenylethyl] acetamide,
(2 E) -2- (6- chloro-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-ylidene) - N - [2- (cyclopentyloxy) phenyl] Acetamide,
N- (2-cyclopentyloxyphenyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide,
N- (2,6-difluorobenzyl) -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) acetamide,
2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -quinolin-6-ylacetamide,
N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] -2- (6-fluoro-3,4-dihydrospiro [chromen-2,1'-cyclo Butane] -4-yl) acetamide,
2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1-naphthylacetamide,
2- (6-methoxy-3,4-dihydrospiro [chromen-2,1'-cyclobutan] -4-yl) -N -1,3-thiazol-2-ylacetamide and
2- (6-methoxy-3,4-dihydro-spiro [chromene -2,1'- cyclobutane] -4-yl) - N - (6-methyl-1,3-benzothiazol-2- One) acetamide or
A compound which is a pharmaceutically acceptable salt thereof.
A compound according to any one of claims 1 to 7,
A pharmaceutical composition comprising a free base or a pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient.
The method of claim 8,
Pharmaceutical compositions wherein the pharmaceutically acceptable excipient is a carrier or diluent.
A method for preventing, alleviating or treating vanilloid receptor mediated diseases, disorders or syndromes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7. .
The method of claim 10,
Diseases, disorders or syndromes associated with TRPV3 function include pain, nociceptive pain, toothache, heart pain arising from ischemic myocardium, migraine pain, acute pain, chronic pain, neuropathic pain, postoperative pain, pain from neuralgia (Eg, neuralgia or trigeminal neuralgia after shingles), pain from diabetic neuropathy, toothache and cancer pain, inflammatory pain conditions (eg arthritis and osteoarthritis), arthralgia, neuropathy, neurodegeneration, retinopathy, neurosis Sexual skin disorders, stroke, bladder hypersensitivity, urinary incontinence, female vulva pain, gastrointestinal disorders such as sensitive bowel syndrome, gastro-esophageal reflux disease, enterocolitis, ileitis, gastric-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, Inflammatory diseases such as pancreatitis, respiratory disorders such as allergic and non-allergic rhinitis, asthma or obstructive pulmonary disease, irritation of skin, eyes or mucous membranes, dermatitis , Pruritic conditions, such as urethral pruritus, fever, muscle spasms, vomiting, dyskinesia, depression, Huntington's disease, memory disorders, limited brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity , Urticaria, actinic keratosis, keratinocytes, alopecia, Ménière's disease, tinnitus, deafness, anxiety disorders, and benign prostatic hyperplasia.
A method for preventing, alleviating or treating pain in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7.
The method of claim 12, wherein the pain is acute pain.
The method of claim 12, wherein the pain is chronic pain.
The method of claim 12, wherein the pain is post-operative pain.
A method for preventing, alleviating or treating neuropathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7.
A method for preventing, alleviating or treating inflammation in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7.