WO2009081219A1

WO2009081219A1 - Quinazoline derivatives as vanilloid receptor modulators

Info

Publication number: WO2009081219A1
Application number: PCT/IB2007/004039
Authority: WO
Inventors: Laxmikant Atmaram Gharat; Jitendra Maganbhai Gajera; Neelima Khairatkar-Joshi; Vidya G. Kattige
Original assignee: Glenmark Pharmaceuticals SA
Current assignee: Ichnos Sciences SA
Priority date: 2007-12-20
Filing date: 2007-12-20
Publication date: 2009-07-02
Anticipated expiration: 2010-06-20

Abstract

There are provided quinazoline derivatives of the compounds of the formula (I): which may be used as vanilloid receptor modulators. Various related methods, formulations, variants, and embodiments are provided.

Description

QUINAZOLINE DERIVATIVES AS VANILLOID RECEPTOR MODULATORS

TECHNICAL FIELD

The present patent application provides quinazoline derivatives, which may be used as vanilloid receptor (VR) 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 12: 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, 14 288 (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 irritancy 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- 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:

wherein Rl is independently chosen from hydrogen, C1-C5 alkyl, or C1-C5 perfluoroalkyl.

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 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.

The term "alkyl," whether used alone or as a part of another group, refers to a group or a substituent that includes a chain of carbon atoms. The chains of carbon atoms of the alkyl groups described and claimed herein may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted. In a non-limiting example, "C1-C5 alkyl" denotes an alkyl group having carbon chain with from 1 to 5 carbon atoms, inclusive, which carbon chain may be saturated or unsaturated, straight chain or branched, substituted or unsubstituted.

The term "aryl", whether used alone or as part of a substituent or a group, denotes a carbocyclic aromatic radical derived from an aromatic hydrocarbon. Non-limiting examples of an "aryl" radical include phenyl, naphthyl, diphenyl, fluorophenyl, methoxyethylphenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, tolyl, xylyl, and dimethylcarbamylphenyl. The "aryl" groups of the compounds described herein may be substituted by independent replacement of 1 to 3 of the hydrogen atoms on the carbocyclic aromatic skeleton with substituents including, but not limited to, halogen, —OH, --CN, mercapto, nitro, amino, substituted amino, (Cl-Cό)alkyl, (Cl-Cό)alkoxy, (Cl-Cό)alkylthio, (Cl-C6)alkylamino, halogenated (Cl-Cό)alkyl, formyl, (Cl-Cό)acyl, (Cl-Cό)alkoxyacyl, and (Cl-C6)acylamido, (Cl-C5)perfluoroalkyl, (Cl-C5)perfluoroalkoxy.

The term "heteroaryl", whether used alone or as part of a substituent group, is used to denote a cyclic aromatic radical having from five to ten ring atoms of which at least one ring atom is a heteroatom, i.e., it is not a carbon atom. An example is where there are from 1 to 4 heteroatoms in the ring structure selected from S, O, and N. The radical may be joined to the rest of the molecule via any of the ring atoms. Non-limiting examples of "heteroaryl" groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. The heteroaryl groups of the compounds described and/or claimed herein may be substituted by independent replacement of 1 to 3 hydrogen atoms of the aromatic skeleton with substituents including, but not limited to halogen, -OH, -CN, mercapto, nitro, amino, substituted amino, (Cl-Cό)alkyl, (Cl-Cό)alkoxy, (Cl-Cό)alkylthio, (Cl-C6)alkylamino, halogenated (Cl- C6)alkyl, formyl, (Cl-Cό)acyl, (Cl-Cό)alkoxyacyl, (Cl-C6)acylamido, aryl, (Cl- C5)alkylaryl, (Cl-C5)perfluoroalkyl, (C1-C5) perfluoroalkyl-aryl, and haloaryl.

The term "haloaryl" is used to denote a group comprised of an aryl group substituted with halogen atom, where aryl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is chlorophenyl. Halogen atom on aryl ring can present on ortho, meta or para position of the ring. The term "perfluoroalkylaryl" is used to denote a group comprised of an aryl group substituted with perfluoroalkyl group, where aryl and perfluoroalkyl groups are as defined above. An example of such group is trifluoromethylphenyl. Perfluoro group on aryl ring can present on ortho, meta or para position of the ring.

The term "alkylaryl" is used to denote a group comprised of an aryl radical and a carbon chain that connects the aryl radical to the rest of the molecule, for example benzyl group.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this application can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

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. As set forth above, the present patent application provides derivatives of compounds of the formula (I):

wherein Rl is independently chosen from hydrogen, C1-C5 alkyl, or C1-C5 perfluoroalkyl. In one preferred variant, Rl is 3-trifiuoromethyl. The compound may exist in the form of a racemic mixture or individual stereoisomers.

Particular examples of the derivatives of compounds of this embodiment are:

N-(3,4-dihydrospiro[chromene-2, 1 '-cyclobutan]-4-yl) -7-[3-(trifiuoromethyl)pyridin-2- yljquinazolin -4-amine;

(+) N-P^-dihydrospirofchromene-ljl'-cyclobutanJ^-yl) -7-[3-trifiuoromethyl) pyridin-2- yl]quinazolin -4-amine; and

(-) N-(3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl)- 7-[3-(trifiuoromethyl) pyridin-2- yl]quinazolin -4-amine.

The compounds of this embodiment may be prepared in any suitable manner. Scheme I below illustrates one chemical route to the derivatives of the compounds of this embodiment:

Scheme I

The appended Examples further illustrate preparation of the compounds of the formula (I).

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 4 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 4 herein below.

Also provided is a method for preventing, ameliorating or treating a vanilloid receptor 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 mediated disease, disorder or syndrome is a pain or inflammatory disease, disorder or syndrome mediated by vanilloid receptor 1 (VRl).

Diseases, conditions, and/or disorders that are modulated by vanilloid receptor 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, 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. In particular, also provided are the derivatives of the compounds of the formula (I) or formula (II) 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, 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.

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, 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 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 arid 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 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.

Example 1

N-(3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl) -7-[3-(trifluoromethyl)pyridin-2- yl]quinazolin -4-amine

Step 1 : 4-chloro-7-[3-(trifluoromethyl)pyridin-2-yl]quinazoline

This compound was prepared by using same procedure as described in X. Zheng et al. Bioorg. Med. Chem. Lett. 16 (2006) 5217 - 5221.

Step 2: 3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-amine

This compound was prepared by using same procedure as described in WO2007/042906.

Step 3: jV-(3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl) -7-[3-(trifluoromethyl) pyridin- 2-yl]quinazolin -4-amine

The stirred solution of 4-chloro-7-[3-(trifluoromethyl)pyridin-2-yl]quinazoline (1 Equ.) in IPA was added TEA (2 Equ.) and solution of 3,4-dihydrospiro[chromene-2,l'- cyclobutan] -4-amine (1.1 Equ.) in THF and refluxed at 90⁰C for 18 h. Solvent was evaporated . Diluted with DCM. Organic layer was washed with water, concentrated to get crude product. Further purified by column chromatography.

¹H NMR (DMSO- d_β): δ 1.7 - 1.9 (m, 2H); 2.11 - 2.39 (m, 6H); 5.9 (m, IH); 6.82 (m, 2H); 7.14 (m, 2H); 7.59 (d, IH, J = 8.1 Hz); 7.74 (m, 2H), 8.35 - 8.43 (m, 2H); 8.57 (s, IH); 8.71 (d, IH, J = 7.8 Hz); 8.94 (d, IH). IR (KBr) (cm^'1): 3427, 2931, 2342, 1626, 1567, 1433, 1318, 1276, 1232, 1166, 1118, 1085,

1028, 776, 753.

MS (M+H)⁺: 463.36 M. P. - 109 - 111 ⁰C.

Example 2

(+) N-(3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl) -7-[3-trifluoromethyl) pyridin- 2-yl]quinazolin -4- amine

This compound was prepared by using same procedure as described in example 1, except

(+)3,4-dihydrospiro[chromene-2,r-cyclobutan]-4-amine was used in step 2.

¹H NMR (DMSO- J₆): δ 1.13 - 1.22 (m, 2H); 1.77 - 1.83 (m, 2H); 2.13 - 2.30 (m, 4H); 5.91

(m, IH); 6.82 (m, 2H); 7.14 (m, 2H); 7.59 (d, IH, J = 6.6 Hz); 7.74 (bs, 2H), 8.35 - 8.43 (m,

2H); 8.58 (s, IH); 8.72 (d, IH); 8.94 (bs, IH).

IR (KBr) (cm¹): 3436, 2984, 2942, 1757, 1633, 1567, 1431, 1318, 1232, 1162, 1132, 1065,

1029, 900, 843, 777.

MS (M+H)⁺: 463.42 M. P. - 110 - 113 ⁰C.

Example 3

(-) N-(3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-yl)- 7- [3-(trifluoro methyl) pyridin- 2-yl|quinazolin -4- amine

This compound was prepared by using same procedure as described in example 1 , except (- )3,4-dihydrospiro[chromene-2,l'-cyclobutan]-4-amine was used in step 2. H NMR (DMSO- J₆): δ 1.13 - 1.22 (m, 2H); 1.7 - 1.9 (m, 2H); 2.1 - 2.3 (m, 4H); 5.9 (m, IH); 6.80 - 6.82 (m, 2H); 7.12 - 7.14 (m, 2H); 7.58 (d, IH, J = 8.1 Hz); 7.74 (bs, 2H), 8.35 - 8.43 (m, 2H); 8.57 (s, IH); 8.71 (d, IH, J = 6.9 Hz); 8.95 (bs, IH). IR (KBr) (Cm^"1): 3399, 2930, 2346, 1704, 1626, 1567, 1485, 1434, 1318, 1232, 1166, 1118,

1086, 1028, 891, 793, 753.

MS (M+H)⁺: 463.57 M. P. - 107 - 109 ⁰C.

The compounds described herein may be tested for their activity for vanilloid receptors 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 4: Screening; for TRPVl antagonist using the ⁴⁵CaI cium 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%. 4⁵Ca was used at a final concentration of 2.5 DCi/ml (⁴⁵Ca, ICN).

Assay buffer was composed of F-12 DMEM medium supplemented with 1.8 mM CaCl₂ (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-100, 0.5% deoxycholate and 0.1% Sodium dodicyl sulphate (SDS, 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 37⁰C in the presence of 5 % CO₂. Cells were then washed twice with 200 μl of assay buffer and re-suspended in 144μl of the same. Assay was carried out at 3O⁰C in total volume of 200 Dl. Test compounds were added to the cells fifteen minutes before addition of capsaicin. Final concentration of capsaicin in the assay was 300 nM. After 5 minutes of agonist treatment, drug was washed out and wells rinsed with 300 Dl of ice cold wash buffer 3X. The cells were lysed in 50μl lysis buffer for 20 min. 40 Dl of cell lysate was mixed with 150 Dl 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 ⁴⁵Ca uptake values were normalized over basal ⁴⁵Ca value. Data was expressed as % inhibition of ⁴⁵Ca uptake by test compound with respect to maximum ⁴⁵Ca uptake induced by capsaicin alone. IC₅₀ value was calculated from dose response curve by nonlinear regression analysis using GraphPadPRISM software. The activity results are given in Table.

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.

Claims

We claim:

1. A derivative which is a compound of the formula (I) and/or a pharmaceutically- acceptable salt or a solvate or a hydrate thereof:

wherein

Rl is independently chosen from hydrogen, C1-C5 alkyl, or C1-C5 perfluoroalkyl.

2. The derivative of claim 1, wherein Rl is 3-trifluoromethyl.

3. The derivative of claim 2, which is a racemic mixture.

4. The derivative of claim 1 ; which derivative has inhibitory activity with respect to a VR-I receptor equal to or greater than 10% as measured in a TRPVl assay.

5. A pharmaceutical composition comprising one or more derivatives of claim 1 and one or more pharmaceutically-acceptable excipients.

6. A pharmaceutical composition comprising one or more derivatives of claim 4 and one or more pharmaceutically-acceptable excipients.

7. A method of inhibiting vanilloid receptor 1 in a subject, said method comprising administering an effective inhibitory amount of one or more derivatives of claim 4 to said subject.

8. The method of claim 7, wherein said subject is a live cell.

9. The method of claim 8, wherein said subject is a mammal.

10. The method of claim 8, wherein said mammal is human.

11. A method for preventing, ameliorating or treating a vanilloid receptor mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a derivative according to claim 1.

12. The method of claim 1 1, wherein said wherein the vanilloid receptor mediated disease, disorder or syndrome is a pain or inflammatory disease, disorder or syndrome mediated by vanilloid receptor 1 (VRl).