ACRYLAMIDE DERIVATIVES AS VANILLOID RECEPTOR 1 MODULATORS

TECHNICAL FIELD

The present patent application provides acrylamide derivatives, which may be used as vanilloid receptor- 1 (VRl) modulators. In particular, the derivatives described herein are useful for treating or preventing diseases, conditions and/or disorders mediated by VRl receptors.

BACKGROUND

Pain perception or nociception is mediated by the peripheral terminals of a group of specialized sensory neurons, termed "nociceptors." A wide variety of physical and chemical stimuli induce activation of such neurons in mammals, leading to recognition of a potentially harmful stimulus. Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain. Moreover, chronic pain may be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at vanilloid receptors (VRl) to pain processing (see, e.g., V. Di Marzo et al., Current Opinion in Neurobiology U: 372-379 (2002)).

The lipophilic vanilloid, capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is believed to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VRl now known as TRPVl) (Caterina MJ, et.al, Science, H 288 (5464), 306-13 (2000)). Capsaicin is the main pungent component in hot pepper. Hot pepper has been used, for a long time, not only as a spice but also as a traditional medicine in the treatment of gastric disorders and when applied locally, for the relief of pain and inflammation. CAP has a wide spectrum of biological actions, and not only exhibits effects on the cardiovascular and respiratory systems but also induces pain and iπϊtancy on local application. CAP, however, after such induction of pain, induces desensitization, both to CAP itself and also to other noxious stimuli to stop the pain. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of VRl receptor activation is thought to be mediated by a capsaicin-

i

induced desensitization of the primary sensory afferent terminal. Based on this property, CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are either used or are under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorder.

VRl is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VRl in various systems are not properly understood at this time. Increasing number of animal studies have revealed the possible involvement of VRl receptors in various pathologies and based on such information VRl is now being considered as a molecular target for various indications.

One class of natural and synthetic compounds which modulate the function of Vanilloid Receptor (VRl) have been characterized by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. This class has been widely studied and is extensively reviewed by Szallasi and Blumberg. Various vanilloid agonists and antagonists have been developed for the treatment of pain. The agonists work through desensitizing the receptor while antagonists block its stimulation by (patho) physiological ligands. At present, various VR modulators have been characterized as VRl antagonists.

European Patent Publication No. EP 462761 discloses (benzopyranyl) phenylureas and related compounds as potassium channel activators and a method of using these and other compounds having potassium channel activating activity as antiischemic and/or antiarrhythmic agents.

PCT Publication No. WO 2003/080578 discloses heteroaromatic ureas as vanilloid receptor (VRl) modulators, in particular antagonists, for treating pain and/or inflammation. PCT Publication No. WO 05/007652 describes substituted quinolin-4yl-amine analogues useful in the treatment of conditions related to capsaicin receptor activation.

There is a need for better analgesics for the treatment of both acute and chronic pain, and the treatment of various neuropathic pain states. SUMMARY

In one aspect, there is provided a derivative which is a compound of the formula (I) and/or a pharmaceutically-acceptable salt or a solvate or a hydrate thereof:

(I),

wherein

R ¹ is selected from hydrogen or fluoro;

R ² is selected from pyridyl, furyl, thienyl, quinolinyl, or optionally substituted phenyl wherein substituents are chloro, methoxy or trifluoromethyl.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.

(2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3- phenylacrylamide (Compound No. 1),

(2E)-N-3,4-dihydrospiro[chromene-2,r-cyclobutan]-4-yl)-3- (4-methoxyphenyl) acrylamide(Compund No. 2),

(2E)-3-(4-chlorophenyl)-N -3,4-dihydrospiro[chromene-2, 1 '-cyclobutan] -4-yl)acryl amide(Compound No. 3),

(2E)-N-3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yl-3-(2-furyl) acryl amide(Compound No. 4),

(2E)-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-[4 -(trifluoro methyl)phenyl] acryl amide (Compound No. 5),

(2E)-N -3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yl-3-pyridin-3-ylacrylamide

(Compound No. 6),

(2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3- thien-2- ylacrylamide(Compound No. 7),

(2E)-N-(6-fluoro3,4-dihydrospiro[chromene-2,r-cyclobutan] -4-yl)-3-phenylacrylamide (Compound No. 8),

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,r-cyclobutan ]-4-yl)-3-(4-methoxy phenyl) acrylamide(Compound No. 9),

(2E)-3-(4-chlorophenyl)-N-(6-fluoro-3,4-dihydrospiro[chro mene-2,l'-cyclobutan]-4- yl)acrylamide (Compound No. 10),

(2E)-3-(2, 3 dimethoxyphenyl)-N-(6-fluoro-3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]- 4-yl)acryl amide (Compound No. 11),

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,r-cyclobutan ]-4-yl)-3-pyridin-3- ylacrylamide(Compound No. 12),

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,r-cyclobutan ]-4-yl)-3-pyridin-3- ylacrylamide(Compound No. 13).

In another aspect, there is provided a derivative which is a compound of the formula (I) and/or a pharmaceutically-acceptable salt or a solvate or a hydrate thereof, which derivative possesses inhibitory activity with respect to a VR-I receptor. Various embodiments and variants are provided.

In another aspect, there is provided a pharmaceutical composition that includes one or more derivatives described herein and one or more pharmaceutically-acceptable excipients.

In yet another aspect, there is provided a method of inhibiting vanilloid receptor 1 in a subject by administering an effective inhibitory amount of one or more derivatives described herein to the subject.

In yet another aspect, there is provided a method for preventing, ameliorating or treating a vanilloid receptor 1 mediated disease, disorder or syndrome in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more derivatives described herein.

It should be understood that the following detailed description is given by way of illustration only since various changes and modifications within the scope of the invention will be apparent to those skilled in the art and are intended to be encompassed within the scope of this invention. DETAILED DESCRIPTION

To describe the application, certain terms are defined herein as follows. The term "compound" is used to denote a molecule of unique, identifiable chemical structure. A compound may exist as a free species. Also, the free species form of the compound may form various salts, usually with external acids or bases.

The term "derivative" is used as a common term for the free species form of the compound and all its salts. Thus, the claim language "a derivative, which is a free species and/or a salt of the compound of the formula [I]" is used to define a genus comprising the free species compounds of the given formula and all the salts of the compounds of the given formula. The use of the term "and/or" is intended to indicate that, for a compound of a given chemical structure, a claim to a "derivative" covers the free species form and all of its salts, as well as the mixtures of free species and the salt forms.

The term "pharmaceutically-acceptable salts" is intended to denote salts that are suitable for use in human or animal pharmaceutical products. The use of the term "pharmaceutically-acceptable" is not intended to limit the claims to substances ("derivatives") found only outside of the body.

A "composition" may contain one compound or a mixture of compounds. A "pharmaceutical composition" is any composition useful or potentially useful in producing physiological response in a subject to which such pharmaceutical composition is administered. The term "pharmaceutically acceptable" with respect to excipients is used to define non-toxic substances generally suitable for use in human or animal pharmaceutical products.

The term "modulator" further refers to a compound that produces a response in a VR- 1 receptor. Examples of modulators are agonists and antagonists.

The term "treating" or "treatment" of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition;

(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or

(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

The term "subject" includes live cells, mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Pharmaceutically acceptable salts forming part of this invention include, for example, salts derived from inorganic bases, salts of organic bases, salts of chiral bases and salts of natural or synthetic amino acids.

Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

Compounds described herein may have one or more asymmetric carbon atoms and thus may occur as racemic mixtures, enantiomers and diastereomers. These compounds may also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present invention.

The derivatives described herein are modulators of vanilloid receptor 1 (VR-I). Preferably, the derivatives described herein, in particular the derivatives of compounds of the formula (I) have inhibitory activity with respect to vanilloid receptor 1. More preferably, the derivatives have VR-I inhibitory activity equal to or greater than 10% as measured in a TRPVl assay set forth in Example 14 herein below.

Also provided is a method of inhibiting vanilloid receptor 1 in a subject by administering an effective inhibitory amount of one or more derivatives described herein above to the subject. The preferred derivatives of compounds of the formula (I) have VR-I inhibitory activity equal to or greater than 10% as measured in a TRPVl assay set forth in Example 14 herein below.

Also provided is a method for preventing, ameliorating or treating a vanilloid receptor 1 mediated disease, disorder or syndrome in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more derivatives described herein above. Preferably, the vanilloid receptor 1 mediated disease, disorder or syndrome is a pain or inflammatory disease, disorder or syndrome. Diseases, conditions, and/or disorders that are modulated by vanilloid receptor 1 antagonists include, but are not limited to, migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease, inflammatory diseases such as pancreatitis, respiratory disorders (such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease), irritation of skin, eye or mucous membrane, dermatitis, and non-specific disorders such as fervescence, retinopathy, muscle spasms, emesis, dyskinesias or depression.

According to one embodiment, the disease, condition, and/or disorder is pain (such as acute pain, chronic pain, neuropathic pain, post-operative pain, in pain due to neuralgia (e.g. post herpetic neuralgia or trigeminal neuralgia), due to diabetic neuropathy, dental pain, and cancer pain. Additionally, VRl antagonists are useful in the treatment of inflammatory pain

conditions (e.g., arthritis and osteoarthritis), diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.

As indicated above, the derivatives described herein have vanilloid receptor antagonist (VRl) activity and are useful for the treatment or prophylaxis of certain diseases or disorders mediated or associated with the activity of vanilloid receptor 1 , including pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, emesis, stomach duodenal ulcer and pruritus.

Thus the invention also provides derivatives described herein for use as an active therapeutic substance, in particular in the treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor- 1. In particular, also provided are the derivatives of the compounds of the formula (I) or formula (H) for use in the treatment or prophylaxis of pain.

Further provided is a method of treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor 1, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of the present invention.

Also provided is the use of derivatives described herein in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor 1.

Also provided is a method for alleviating and/or treating migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntingdon's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease and inflammatory diseases such as pancreatitis, and in respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye

or mucous membrane, dermatitis, and in non specific disorders such as fervescence, retinopathy, muscle spasms, emesis, dyskinesias or depression. Specifically in multiple subtypes of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g. post herpetic neuralgia, trigeminal neuralgia; and in pain due to diabetic neuropathy or dental pain as well as in cancer pain. Additionally in the treatment of inflammatory pain conditions e.g. arthritis, and osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.

The derivatives described herein in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.

Also provided is a pharmaceutical composition that includes one or more derivatives of compounds of the formula (I) and/or the formula (II), and one or more pharmaceutically- acceptable excipients.

The pharmaceutical compositions include at least one derivative described herein and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition includes a therapeutically effective amount of the derivative described herein. The derivative may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

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, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of 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 include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical

composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 ^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

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

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.

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), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The compounds of the formula (I) may be prepared in any suitable manner. For example, the compound of the formula (I) may be prepared by coupling of the intermediate of the formula (III) with carboxylic acid derivative of the formula (IV):

To illustrate, the scheme below describes preparation of compounds of the formula

(I):

Ia Ib

Synthesis of Ib

O Malonic acid/

O piperidine

R' H 120-130 ⁰ C, 3-4hr R' OH

Synthesis of Ia

Raney Ni/ H ₂

NH ₇ OKHCI

The following Examples and Experimental procedures are merely illustrative, and compounds of the present application are not limited by the following embodiments in any case. A person skilled in the art can implement the present application at maximum by variously altering, not only in the following Examples but also in the claims of the present specification, and such alterations are included in claims of the present specification.

Examplel (2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-phe nylacrylamide

To a solution of trans-cinnamic acid (1.0 equiv. from Aldrich) in THF (10 mL) triethylamine

(2.0 equiv.) was added followed by addition of ethylchloroformate (1.5 equiv.) at room temperature. The resulting solution was stirred for 30-40 mins under nitrogen atmosphere. A solution of amine hydrochloride(intermediate 1) (1.01 equiv) and triethylamine (1.2 equiv.) in

THF (5.0 mL) was added with siring. Reaction mixture was stirred for 5-6 hr at room temperature. The residue obtained after removal of solvent was taken in water and extracted in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, the residue obtained after removal of solvent was purified through silica gel column using mixture of pet ether: ethyl acetate as an eluent to get pure product as white solid.

IR (KBr):3268, 3061, 2936, 1653, 1625, 1543, 1486, 1427, 1340, 1253, 1221, 1203, 1124,

1078, 998, 971, 819, 759cm ^"1 _.

¹ HNMR (300MHz, CDCl ₃ ): δl.6 (m, 2H), 1.8 (m, 2H), 2.2 (m, 2H), 2.4 (m, 2H), 5.4 (m, IH),

5.9 (d, IH), 6.4(d, IH), 6.75-6.95 (m, 2H), 7.1-7.2 (m, 3H), 7.3(d, 2H), 7.5(d,lH), 7.6-7.7

(d,lH).

[M+l] ⁺ : 320

MP: 195-196 ⁰ C

Example 2 (2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl)-3-(4 -methoxyphenyl) acrylamide

This compound was prepared as per the procedure given in example 1, using 4-methoxy phenyl acrylic acid (1.0 equiv, from Aldrich) and intermediate 1 (1.0 equiv.) to get compound as a white solid.

IR (KBr): 3268, 3061, 2936, 1653, 1625, 1543, 1486, 1427, 1340, 1253, 1221, 1203, 1124, 1078, 998,971,819,759cm ¹ _.

¹ HNMR (30OMHz ₅ CDCl ₃ ): δl.5(m,2H), 1.8(m,2H), 2.2(m,2H), 2.4(m,2H), 3.84(s,3H), 5.4(q,lH), 5.6-5.7(d,lH), 6.2-6.3(d,lH), 6.8-6.9 (d,4H),7.1(d,lH), 7.4(d,lH), 7.6(d,lH).

Example 3

(2E)-3-(4-chlorophenyl)-N -S^-dihydrospiroIchromene^.l'-cyclobutan] -4-yl)acryl amide

This compound was prepared as per the procedure given in example 1 , using 4-chloro phenyl acrylic acid (1.0 equiv, form Aldrich) and intermediate 2 (1.0 equiv) to get compound as a white solid.

IR (KBr): 3268, 3061, 2936, 1653,1625,1543,1486, 1427, 1340, 1253, 1221, 1203, 1124,

1078,998,971,819,759cm ^"1 _.

¹ HNMR(300MHz,CDCl ₃ ):δl.5(m,2H),1.8(m,2H),2.2(m,2H),2.4(m,2H),5.4(q,lH),

5.8(d,1H),6.3-6.4(d,1H),6.75(d,2H),7.1-7.2(d,3H), 7.3(d, 1H).7.4(d,1H),7.6(d,1H).

[M+l] ⁺ : 354

M.P.: 175-176 ⁰ C

Example 4

(2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3- (2-furyl) acryl amide

Step 1: 3-(l-benzofuran-2-yl) acrylic acid

This compound was prepared by the method described by Sinisterra, J.V. et al., Synthesis,

1985, 1097 (ester, nitrile) followed by the hydrolysis of the ester.

M.P.: 138-140°C (lit. ^{cited above} , 14O ⁰ C)

Step 2: (2E)-N-3,4-dihydrospiro[chromene-2,r-cyclobutan]-4-yl-3-(2-f uryl) acryl amide

This compound was prepared as per the procedure given in step 1 example, using furyl acrylic acid (1.0 equiv) and intermediate 2 (1.0 equiv)to get compound as off white solid.

IR(KBr): 3242, 3070,2926, 1657, 1627, 1546, 1496, 1427, 1326, 1272, 1226, 1212, 1168,

1124, 1068, 998, 971, 819, 759cm ^"1 _.

¹ HNMR(SOOMHZ ₅ CDCI ₃ ): δ 1.5 (m,2H), 1.8 (m,2H), 2.2 (m,2H), 2.4 (m,2H), 5.4 (q,lH), 5.6

(d,lH), 6.2-6.3 (d,lH), 6.45 (d,lH), 6.59 (d,lH), 6.8-6.9 (q,2H), 7.1-7.2 (m,5H), 7.4-7.5 (d,

2H).

[M+l] ⁺ : 310

Melting Point: 176-178 ⁰ C

Example 5

(2E)-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-[4 - (trifluoromethyl)phenyl]acryl amide

This compound was prepared as per the procedure given in step 1 example, using 4-(Trifluoromethyl) phenyl acrylic acid (1.0 equiv.; Aldrich) and intermediate 1 (1.0 equiv) to get compound as a white solid.

IR(KBr): 3242, 3070, 2926, 1657, 1627, 1546, 1496, 1427, 1326, 1272, 1226, 1212, 1168, 1124, 1068, 998, 971, 819, 759cm ^"1 _.

1HNMR(300MHz,CDCl ₃ ):61.5 (m, 2H),1.8 (m, 2H), 2.2 (m, 2H), 2.4(m, 2H), 5.4 (q,lH), 5.8 (d,lH),6.4(d,lH), 6.84-6.95(m,2H), 7.16-7.27(dd,2H), 7.63(s,4H),7.7 (d,lH). [M+l] :387.39 Melting Point: 170-172 ⁰ C

Example 6 (2E)-N -3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-pyridin-3 -ylacrylamide

Step 1: 3-pyridinyl acrylic acid

This compound was prepared by the method described by Panizzon, L., HeIv. Chim. Acta,

1941, 24, 24E.

Step 2: (2E)-N -3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-pyridin-3 -yl acrylamide

This compound was prepared as per the procedure given in example 1, using 3-pyridinyl acrylic acid (1.0 equiv) and intermediatel (1.0 equiv) to get compound as off white solid.

IR (KBr): 3233, 3276, 2929, 1655, 1622, 1556, 1535, 1487, 1351, 1230, 1130, 1024, 996,

980, 809, 747cm ^"1 _.

¹ HNMR (30OMHz ₅ CDCl ₃ ): δ 1.5 (m,2H), 1.8 (m,2H), 2.2 (m,2H), 2.4 (m,2H), 5.4 (q,lH), 6.0 (d,lH), 6.4-6.5 (d,lH), 6.8-6.9 (q, 2H), 7.1-7.32 (m, 3H), 7.6-7.7 (d, 2H), 7.7-7.8 (d, IH), 8.5 (d, IH), 8.76 (s, IH). [M+H] ⁺ : 320 MP: 176-178 ⁰ C

Example 7

(2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3- thien-2-ylacryIamide

Step 1: 2-thienyl acrylic acid

This compound was prepared by the method described by Tinnemans, A.H.A. et al., J.O.C.,

1978, 43, 2493-2500 (Me ester) followed by hydrolysis of the ester.

M.P. 238 ⁰ C (lit ^{dted above} 236-237 ⁰ C)

Step 2: (2E)-N-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl-3-thi en-2-ylacrylamide

This compound was prepared as per the procedure given in step 1 example, using 2-thienyl acrylic acid (1.0 equiv) and intermediate 1 (1.0 equiv) to get compound as a off white solid.

IR(KBr):3233, 3276, 2929, 1655, 1622, 1556, 1535, 1487, 1351, 1230, 1130, 1024, 996,

980, 809, 747cm ^"1 _.

1HNMR(3OOMHz,CDCl ₃ ): δ 1.5(m,2H), 1.8(m,2H), 2.2(m,2H), 2.4(m,2H), 5.4(q,lH), 5.6-

5.7(d,lH), 6.1-6.2(d,lH), 6.8-6.9(q,2H), 7.0 (m,2H), 7.0-7. l(d,2H), 7.1-7.3(m,4H), 7.8(d,lH).

Mass:325.43

MP: 177- 178 ⁰ C

Example 8 (2E)-N-(6-fluoro3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4 -yl)-3-phenylacrylamide

To a solution of trans-cinnamic acid (1.0 equiv from Aldrich) in THF (10 mL) triethylamine (2.0 equiv) was added followed by addition of ethyl chlorofdormate (1.5 equiv.) at room temperature. The resulting solution was stirred for 30-40 mins under nitrogen atmosphere. A

solution intermediate 2 (1.01 equiv in) and triethylamine (1.2 equiv.) in THF (5.0 mL) was added with siring. Reaction mixture was stirred for 5-6 hr at room temperature. The residue obtained after removal of solvent was taken in water and extracted in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, the residue obtained after removal of solvent was purified through silica gel column using mixture of pet ether: ethyl acetate as an eluent to get pure product as white solid.

IR (KBr):3268, 3061, 2936, 1653, 1625, 1543, 1486, 1427, 1340, 1253, 1221, 1203, 1124

1078, 998, 971, 819, 759cm ^"1 _.

¹ HNMR (300MHz, CDCl ₃ ): δl.6 (m, 2H), 1.8(m, 2H), 2.2(m, 2H), 2.4 (m, 2H), 5.4 (m, IH),

5.8(d, IH), 6.4(d, IH), 6.75-6.95 (m, 3H), 7.3-7.5 (m, 5H), 7.68-7.35(d, IH).

[M+] ⁺ : 337.3

M.P.: 185-186 °C

Example 9

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,l'-cyclobuta n]-4-yl)-3-(4-methoxy phenyl) acrylamide

This compound was prepared as per the procedure given in example 1 using 4-methoxy phenyl acrylic acid (1.0 equiv from Aldrich) and intermediate 2 (1.0 equiv) to get compound as white solid.

IR (KBr):3268, 3061, 2936, 1653,1625,1543,1486, 1427, 1340, 1253, 1221, 1203, 1124,

1078, 998, 971, 819,759cm ^"1 _.

¹ H NMR (300MHz, CDCl ₃ ):δl.5 (m, 2H),1.8 (m, 2H), 2.2 (m, 2H), 2.4(m,2H), 3.84 (s,3H),

4.1(q,lH), 5.4 (q,lH), 5.6-5.7 (d,lH), 6.4 (d, IH), 6.2-6.3 (d, 2H), 6.8-6.9 (d, 2H), 7. l(d, lH).7.4 (d, IH), 7.6 (d, IH).

[M+l] ⁺ : 398

MP: 139-141 ⁰ C

Example 10

(2E)-3-(4-chlorophenyl)-N-(6-fluoro-3,4-dihydrospiro[chro mene-2,l'-cyclobutan]-4- yl)acrylamide

This compound was prepared as per the procedure given in example 1 using 4-chloro phenyl acrylic acid (1.0 equiv from Aldrich) and intermediate 2 (1.0 equiv) to get compound as a white solid.

IR (KBr): 3268, 3061, 2936, 1653, 1625, 1543,1486, 1427,1340, 1253, 1221, 1203, 1124,

1078,998,971,819,759cm ^"1 _.

¹ HNMR (30OMHz ₅ CDCl ₃ ): δl.5 (m, 2H), 1.8 (m, 2H), 2.2 (m, 2H), 2.4 (m, 2H), 5.4 (q,lH),

5.8 (d,lH), 6.3-6.4 (d,lH),6.75 (d, 2H),6.8-6.9 (d, 2H), 7.3 (d, 1H).7.4 (d,lH),7.6(d,lH).

Example 11

(2E)-3-(2, 3 dimethoxyphenyl)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,l ^f -cyclobutan]-

4-yl)acryl amide

This compound was prepared as per the procedure given in step 1 example using 2,3- dimethoxycinnamic acid (1.0 equiv from Aldrich) and intermediate 2 (1.0 equiv) to get compound as white solid.

IR (KBr):3223, 2938, 2836, 1653, 1650, 1614, 1578, 1543, 1480, 1428 1270, 1221, 1203,

1073, 1078, 998, 812,759cm ^"1 _. .5(m,2H), 1.8(m,2H),2.2 (m,2H), 2.4(m,2H), 3.7(s,6H),

5.4(q,lH), 5.8(d,lH), 6.3-6.4(d,lH) 6.75(d,2H), 6.8-6.9(d,2H), 7.3(d, IH) ₅ 7.4(d,lH),

7.6(d,lH).

[M+l] ⁺ :398

M.P.: 139-141°C

Example 12

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,l'-cyclobuta n]-4-yl)-3-pyridin-3- ylacrylamide

This compound was prepared as per the procedure given in example 1, using 3-pyridinyl acrylic acid (1.0 equiv) and intermediate 2 (1.0 equiv) to get compound as off white solid.

IR (KBr):3233, 3276, 2929, 1655, 1622, 1556, 1535, 1487, 1351, 1230, 1130, 1024, 996,

980, 809, 747cm ¹

ηNMR(300MHz,CDCl ₃ ): δ 1.5(m,2H), 1.8(m,2H), 2.2(m,2H), 2.4(m,2H), 5.4(q,lH),

6.0(d,lH), 6.4-6.5(d,lH), 6.7-6.9 (m,3H), 7.32(s,lH), 7.6-7.7(d,2H), 7.7-7.8(d,lH),

8.5(d,lH), 8.76(s,lH).

[M+l] ⁺ : 339

M. P.: 147-148 ⁰ C

Example 13

(2E)-N-(6-fluoro-3,4-dihydrospiro[chromene-2,l'-cyclobuta n]-4-yl)-3-pyridin-3- ylacrylamide

This compound was prepared as per the procedure given in example 1, using 2-quinoline acrylic acid (1.0 equiv., prepared using the method described by Alberts, A.A. et al., J.A.C.S., 1935, 57, 1284-1287) and intermediate 2 (1.0 equiv) to get compound as off white solid. ¹ HNMR (300MHz, CDCl ₃ ): δ 1.5(m, 2H), 1.8 (m, 2H), 2.2(m,2H), 2.4(m,2H), 5.1(q,lH), 5.4(d,lH), 5.6-5.7 (d,lH), 6.3-6.4 (q, 2H), 6.7-7.00 (m, 6H), 7.3-7.4 (dd, 4H), 7.6-7.7(d,lH). [M+l] ⁺ : 389 MP: 195-196 ⁰ C

The compounds described herein may be tested for their activity for vanilloid receptor 1 following procedures known to a person of ordinary skill in the art. As example, the

following protocol was employed for testing compounds of the present invention. This protocol is illustrative and is not meant to limit to the scope of the present invention.

Example 14 Screening for TRPVl antagonist using the ⁴⁵ Calcium uptake assay

The inhibition of TRPVl receptor activation was followed as inhibition of capsaicin induced cellular uptake of radioactive calcium which represents calcium influx exclusively through the plasma membrane associated TRPVl receptor. Materials:

Stock solution of capsaicin was made in ethanol and test compounds in 100 % DMSO. Stock solutions were diluted to appropriate final concentrations in assay buffer keeping the final DMSO concentration between 0.1% and 0.55%. ⁴⁵ Ca was used at a final concentration of 2.5 μCi/ml ( ⁴⁵ Ca, ICN). Assay buffer was composed of F-12 DMEM medium supplemented with 1.8 mM CaCl ₂ (final cone.) and 0.1% Bovine serum albumin.(BSA from SIGMA)

Wash buffer was tyrodes solution supplemented with 0.1% BSA and 1.8 mM calcium. Lysis buffer contained 50 mM Tris-HCl, pH7.5, 150 mM NaCl, 1% Triton X-IOO, 0.5% deoxycholate and 0.1% Sodium dodicyl sulphate (SDS ₅ SIGMA ) Method:

Assay was carried out with some modifications the of procedure as described by Toth et.al.( See Toth A et. al, Life Sciences 73 p 487-498 ,2003)._Human TRPVl expressing CHO cells were grown in F-12 DMEM (Dulbecco's modified Eagle's medium -GIBCO ) medium with 10% FBS( fetal bovine serum Hyclone), 1% penicillin-streptomycin solution, 400 μg / ml of G-418. Cells were seeded 48 h prior to the assay in 96 well plates so as to get ~ 50,000 cells per well on the day of experiment. Plates were incubated at 37 ⁰ C in the presence of 5 % CO ₂ . Cells were then washed twice with 200 μl of assay buffer and re-suspended in 144 μl of the same. Assay was carried out at 30 ⁰ C in total volume of 200 μl. Test compounds were added to the cells fifteen minutes before addition of capsaicin. Final concentration of capsaicin in the assay was 250 nM. After 5 minutes of agonist treatment, drug was washed out and wells rinsed with 300 μl of ice cold wash buffer 3X. The cells were lysed in 50 μl lysis buffer for 20 min. 40 μl of cell lysate was mixed with 150 μl of Microscint PS, left overnight for equilibration. Radioactivity in samples was measured as counts per minute (cpm) using Packard Biosciences Top Count. The drug / vehicle / capsaicin treated ⁴⁵ Ca uptake values were normalized over basal ⁴⁵ Ca value. Data was expressed as % inhibition of

⁴⁵ Ca uptake by test compound with respect to maximum ⁴⁵ Ca uptake induced by capsaicin alone. IC ₅₀ value was calculated from dose response curve by nonlinear regression analysis using GraphPadPRISM software. The activity results are given in Table

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.