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WO2008035356A2 - Nouveaux ligands de récepteur cannabinoïde, compositions pharmaceutiques les contenant, et procédé associé à leur préparation - Google Patents

Nouveaux ligands de récepteur cannabinoïde, compositions pharmaceutiques les contenant, et procédé associé à leur préparation Download PDF

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Publication number
WO2008035356A2
WO2008035356A2 PCT/IN2007/000119 IN2007000119W WO2008035356A2 WO 2008035356 A2 WO2008035356 A2 WO 2008035356A2 IN 2007000119 W IN2007000119 W IN 2007000119W WO 2008035356 A2 WO2008035356 A2 WO 2008035356A2
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WO
WIPO (PCT)
Prior art keywords
pyrazole
dihydrochromeno
dichlorophenyl
dimethyl
carboxamide hydrochloride
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PCT/IN2007/000119
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English (en)
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WO2008035356A3 (fr
Inventor
Sachin S. Chaudhari
Abraham Thomas
Srinivas Gullapalli
Ashok Bhausaheb Kadam
Mangesh Jagannath Pawar
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Glenmark Pharmaceuticals Limited
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Publication of WO2008035356A2 publication Critical patent/WO2008035356A2/fr
Publication of WO2008035356A3 publication Critical patent/WO2008035356A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor (such as pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).
  • CBDl cannabinoid 1
  • CBD2 cannabinoid 2
  • the endogenous cannabinoid system comprises two main receptors, CBl and CB2, and a number of ligands including anandamide and virodhamine which demonstrate the greatest activity at the cannabinoid receptor (Jonathan A. W. & Louis J A, Obes Man., 5-19, 2005).
  • Anandamide which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extra cellular space and activates CBl cannabinoid receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of ⁇ - aminobutyric acid or glutamate through inhibition of calcium channels, while simultaneously interfering with vesicle release and activating potassium channels.
  • anandamide is prone to rapid enzymatic hydrolysis. This represents a serious drawback in its use as a drug because, inter alia, substances which are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.
  • CBl receptors are predominantly located in the brain and other neurons, while CB2 receptors are predominantly located in immune cells. Stimulation of these receptors is known to affect the central and peripheral action on lipid and glucose metabolism in adipose tissue and most notably, helps to regulate food intake, energy balance and nicotine dependence as well as regulate fear and anxiety.
  • CBl agonists or antagonists increase or decrease the motivation to work for palatable ingesta (Gallate J E and McGregor I S, Psychopharmacology, 142, 302-308, 1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur. J, Pharmacol, 370, 233-240, 1999).
  • Cannabinoids appear to directly stimulate eating by actions on appetitive processes, making food stimuli more salient and rapidly inducing eating even in satiated animals (Williams C M and Kirkham TC, Physiol. Behav., 76, 241-250, 2002).
  • CB receptor mediated syndromes diseases or disorders which include appetite, metabolism, diabetes, obesity, glaucoma associated intra-ocular pressure, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth disorders, eye- '-" ⁇ diseases, allergies and allergic reactions, pain, anxiety, psychotic afflictions, pathological states of brain, gastrointestinal disorders, nausea, vomiting, giddiness, urinary and fertility problems, cardiovascular diseases, neuroinflarnmatory pathologies, diseases of the central nervous system, neurodegenerative syndromes, diseases and disorders, sleep disorders, dermatological disorders, leukocyte activation-associated disorder, autoimmune diseases, nephrological pathologies, delayed or immediate hypersensitivity, infectious parasitic, and viral and bacterial diseases.
  • CB receptor mediated syndromes diseases or disorders which include appetite, metabolism, diabetes, obesity, glaucoma associated intra-ocular pressure, mood disorders, seizures, substance abuse, learning disorders,
  • CB modulators have been characterized as agonists, inverse agonists or antagonists to CBl and/or CB2 receptors.
  • These modulators include naphthalen- l-yl-(4-pentyloxynaphthalen-l-yl) methanone (SAB-378), 4-(2,4-dichlorophenylamino)-N- (terahydropyran-4-yl)methyl-2-trifluoromethylbenzamide (GW-842166X), N-(l-piperidinyl)- 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3 -carboxamide (SRl 41716A), 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl-4,5-dihydro-l/i-pyrazole- 1 -carboxamide (SLV-319), and
  • modulators have reached advanced stages of clinical trials for the treatment of pain, neurodegenerative disorders, psychotic disorders, neurological syndromes, diseases or disorders, eating disorders, Alzheimer's disease, alcohol dependency, diabetes, obesity and/or smoking cessation.
  • U.S. Patent No. 6,906,080 discloses tricyclic derivatives of pyrazolecarboxylic acid of formula (A) (shown below), methods for preparing the compounds of formula (A) and pharmaceutical compositions containing them.
  • the compounds of formula (A) are active on cannabinoid CBl receptors.
  • X— Y— represents — CH 2 - S(O) P — or — S(O) P — CH 2 - ; and Ri represents an NR 2 R 3 group.
  • WO 97/29079 WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04 /69837, WO 04/058145, WO 04/26301, WO 04/058744, and WO 04/096763.
  • the present invention relates to CBl receptor antagonists or inverse agonists of general formula (I):
  • Z is -O-, -S(O) m - or -NR e - ;
  • R and R are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a protecting group or R 1 and R 2 taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to
  • R 3 and R 4 are independently hydrogen or Ci -6 alkyl optionally substituted with halogen, or R 3 and R 4 taken together with the carbon atom to which they are attached may form a carbonyl
  • R 3 and R 4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NR e or
  • Preferred is a compound of formula (I) where Z is O;
  • a compound of formula (I) where R 3 and R 4 taken together with the carbon atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least one heteroatoms selected from O, NR e or S(O) n ,; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclobutyl; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclopentyl; Further preferred is a compound of formula (I) where -CR 3 R 4 is cyclohexyl; Further preferred is a compound of formula (I) where R 1 is hydrogen Further preferred is a compound of formula (I) where R 2 is 2, 4-Difluorophenyl Further preferred is a compound of formula (I) where R 1 and R 2 taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic
  • R 5 is hydrogen, -0R a , halo or cyano.
  • Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof.
  • the present invention should not be construed to be limited to them.
  • 35 ⁇ G-Piperidino- 1 -(2,4-dichlorophenyl)-7-iodo- 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3- carboxamide hydrochloride, 36. iV3-Azepanyl-l-(2,4-dichlorophenyl)-7-iodo-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride,
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and optionally together with one or more pharmaceutically acceptable excipients, diluents, carriers or mixture thereof.
  • the compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by cannabinoid receptors and in particular CBl and /or CB2 receptor modulators. These compounds are particularly useful in the treatment of appetite disorders, metabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social disorder, mood disorders, seizures, substance abuse, learning disorders, cognition, disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth, pain or neurodegenerative related syndromes, disorders or diseases.
  • Yet another aspect of the invention provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid (CB) receptor and in particular CBl and /or CB2 receptor modulators in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • CBD cannabinoid
  • cannabinoid (CB) receptor modulator is CBl or CB2 receptor modulator.
  • CB receptor modulator is agonist, antagonist, partial agonist or inverse agonist.
  • cannabinoid receptor mediated disease is obesity or dyslipidemia mediated by cannabinoid receptor 1 (CBl).
  • the disease, condition or disorder is selected from appetite disorder, metabolism disorder, cardiovascular disease, catabolism disorder, diabetes, obesity, dyslipidemia, glaucoma- associated intraocular pressure, social related disorder, mood disorder, seizures, substance abuse, learning disorder, cognition disorder, memory disorder, organ contraction, muscle spasm, respiratory disorder, locomotor activity disorder, movement disorder, immune disorder (such as autoimmune disorder), inflammation, cell growth, pain and neurodegenerative related syndrome, disorder and disease.
  • the present invention also discloses combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention.
  • the present invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
  • the present invention further provides intermediates of formula 2 useful for the preparation of compounds of formula I:
  • the present invention further provides intermediates of formula 5 useful for the preparation of compounds of formula I:
  • aryl refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydr ⁇ napthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • heterocyclic ring refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepanyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from the alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl ⁇ tert- butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., spiro(4.4) non-2 -yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkylaryl refers to a cyclic ring-containing radical, having 3 to about 8 carbon atoms, directly attached to an aryl group.
  • Non-limiting examples of such groups include phenylcyclopropyl, phenylcylobutyl and phenyl cyclopentyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • substituent on “substituted alkyl” is "substituted aryl”
  • substituent on "substituted aryl” cannot be “substituted alkenyl”.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-f ⁇ >-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers. All the stereoisomers of compounds described herein are within the scope of this invention. Racemic mixtures are also encompassed within the scope of this invention.
  • tautomers refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention.
  • prodrug refers to compounds, which are an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes.
  • ester refers to compounds, which are formed by reaction between an acid and an alcohol with elimination of water. Ester can be represented by the formula RCOOR'.
  • polymorph refers to a specific crystalline form of a compound.
  • cannabinoid receptor refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including CBl and/or CB2 receptors, that may be bound by a cannabinoid modulator compound of the present invention.
  • modulator further refers to the use of a compound of the invention as a CB (e.g., CBl and/or CB2) receptor agonist, partial agonist, antagonist or inverse-agonist.
  • treating or “treatment” of a state, disorder or condition includes:
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
  • 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 salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-
  • salts include acid addition salts (where appropriate) such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartarates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartarates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with standard low molecular weight solvents by methods known in the art.
  • the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • the compound of the present invention 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.
  • 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, hydroxymethyl cellulose 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 osmotic 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 methods known in the art.
  • compositions of the present invention 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).
  • 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 ampule, capsule, sachet, paper, or other container.
  • 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.
  • 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.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approximately 9 mg Mywacett 9-40 T and approximately 0.9 mg acylated monoglyceride
  • 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.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and/or prevention of diseases, conditions and/or disorders modulated by a cannabinoid (CB) receptor, especially those modulated by the CBl or CB2 receptor including those discussed below.
  • CBD cannabinoid
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid receptor (CB), and in particular the CBl or CB2 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • CBD cannabinoid receptor
  • Diseases, conditions, and/or disorders that are modulated by a CB receptor include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain (such as neuropathic pain) and neurodegenerative related syndromes, disorders and diseases.
  • Appetite related syndromes, disorders or diseases include, but are not limited to, obesity, overweight conditions, anorexia, bulimia, cachexia, dysregulated appetite and the like.
  • Obesity related syndromes, disorders or diseases include, but are not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like.
  • Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity.
  • Metabolism related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemias, arteriosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders (disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like.
  • Diabetes related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.
  • Catabolism related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilator dependency; cardiac dysfunction, e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.
  • Ophthalmic diseases include, but are not limited to, glaucoma, glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g. conjunctivitis).
  • Social or mood related syndromes, disorders or diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).
  • depression including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, cognitive disorders and the like).
  • Substance abuse related syndromes, disorders or diseases include, but are not limited to, drug abuse and drug withdrawal.
  • Abused substances include, but are not limited to, alcohol, amphetamines (or amphetamine like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing.
  • the compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance- induced anxiety or mood disorder.
  • the present invention further provides a method of treating nicotine dependency, addiction, withdrawal or aiding in the cessation or lessening of tobacco in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
  • dementias are diseases that include memory loss and additional intellectual impairment separate from memory.
  • the compounds and pharmaceutical compositions of the present invention are also useful in treating cognitive impairments related to attentional deficits, such as attention deficit disorder.
  • Muscle spasm syndromes, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.
  • Locomotor activity and movement syndromes, disorders or diseases include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.
  • Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract, chronic obstructive pulmonary disorder, emphysema, asthma, bronchitis and the like.
  • Kidney dysfunction nephritis which can be treated with the modulators of the present invention includes, but is not limited to, mesangial proliferative glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).
  • Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease
  • Cell growth related syndromes, disorders or diseases include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.
  • Pain related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, dental pain, menstrual cramps, labor pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, (e.g.
  • diabetic neuropathy sciatica, non specific lower back pain, fibromyalgia; HIV -related neuropathy; post herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions), hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, thyroiditis and the like.
  • Neurodegenerative related syndromes, disorders or diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical injury collateral to traumatic head or brain injury, brain inflammation, eye injury or stroke and the like.
  • Suitable pharmaceutical agents include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase- 1 (1 I ⁇ -HSD type 1) inhibitors, peptide YY 3-36 or analogs thereof, MCR-4 agonists, cholecystol ⁇ nin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor
  • anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, 11 ⁇ -hydroxy steroid dehydrogenase- 1 (1 I ⁇ -HSD
  • anorectic agents such as a bombesin agonist
  • neuropeptide- Y receptor antagonists such as a bombesin agonist
  • thyromimetic agents such as a bombesin agonist
  • dehydroepiandrosterone or an analog thereof glucocorticoid receptor agonists or antagonists, orexin receptor antagonists
  • glucagon-like peptide- 1 (GLP-I) receptor agonists GLP-I
  • DPP-IV dipeptidyl peptidase IV
  • ciliary neurotrophic factors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y.
  • the present invention preferably provides a combination product or medicament comprising one or more compounds described herein and one or more of other therapeutic agents for treating disease, disorder or condition described in this invention.
  • the instant invention preferably discloses combination product or medicament comprising one or more compounds described herein and one or more of antiobesity agent, ACAT inhibitor, PDE IV inhibitor, DPP IV inhibitor, antidiabetic agent, dyslipidemic agent, CETP inhibitor, HMG-CoA reductase inhibitor, fibrate, guggle lipid or other CBl or CB2 modulator for treating disease, disorder or condition described in this invention.
  • anti-obesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY 3-36 or an analog thereof (including the complete peptide YY), and pseudoephedrine.
  • compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.
  • Anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874; and PYY 3-36 (including analogs) can be prepared as described in U.S. Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All of the above recited references are incorporated herein by reference.
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (NeurontinTM).
  • Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).
  • AA Alcohol Anonymous
  • antihypertensive agents include antihypertensive agents; antidepressants (e.g., fluoxetine hydrochloride (ProzacTM); cognitive improvement agents (e.g., donepezil hydrochloride (AirceptTM.) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine); antipsychotic medications (e.g., ziprasidone (GeodonTM), risperidone (RisperdalTM), and olanzapine (ZyprexaTM)); insulin and insulin analogs (e.g., LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH 2 ; sulfonylureas and analogs thereof: chloropropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide ® , glimepiride, repaglinide, meglitinide
  • the compounds of the present invention may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.
  • Pyrazole carboxylic acid of the formula 5 where R 5 is cyano group or heterocycle derived from cyano group may be prepared as shown in Scheme 4.
  • Aromatic cyanation of intermediate 4 where X is Br, I, or OSO 2 CF 3 with transition metal cyanides or trimethylsilyl cyanide (TMSCN) in presence of a suitable Pd(O) catalyst affords intermediate 12 (Chatani N. et al J. Org. Chem. 1986, 51(24), 4714-4716).
  • Selective ester hydrolysis of 12 affords pyrazole acid 5.
  • the cyano group can be transformed to a heterocycle, eg. tetrazole, prior to hydrolysis to pyrazole acid 4 (Koguro K. et al Synthesis, 1998, 6, 910).
  • the compound of formula 4 where X is protected hydroxyl group can be converted to free hydroxyl group by using a suitable reagent such as trimethylsilyl iodide boron tribromide or 48 % HBr in acetic acid.
  • a suitable reagent such as trimethylsilyl iodide boron tribromide or 48 % HBr in acetic acid.
  • X is a benzyloxy group
  • catalytic hydrogenolysis affords the phenolic derivative.
  • the phenolic hydroxyl group can be realkylated with a suitable alkyl or fluoroalkyl halide (eg. CHF 2 Cl) and subsequently hydrolysed to the pyrazole acid of the general formula 5.
  • [ 3 H]CP55940 was used as the radioligand to bind the CBl receptor present in a rat brain membrane preparation which can be displaced by unlabeled ligands having affinity to the CBl receptor.
  • the assay was performed according to the modified method of Thomas et ah, 1998 (J. Pharmacol. Exp. Ther. 285: 285-292).
  • the total reaction mixture 250 ⁇ l contains Tris-BSA buffer (50 mM 2-amino-2-(hydroxymethy I)- 1,3 -propanediol, pH 7.4 with 1.5 % bovine serum albumin) or unlabeled WIN55212-2 (1 ⁇ M) or test samples (1 ⁇ M), [ 3 H]CP55940 (0.8 nM) and 100 ⁇ g of rat brain membrane.
  • the non-specific binding was defined by 1 ⁇ M of WIN55212-2.
  • the assay mixture was incubated at 37 0 C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.
  • [ 3 H]CP55940 was used as the radioligand to bind human CBl receptors expressed on the membranes from CHO cells (the hCBl-CHO cell line was generated in- house) which can be displaced by unlabeled ligands having affinity to the CBl receptor.
  • the assay was performed according to the modified method of Ross et al., 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 ⁇ l in poly- ethyleneimine (PEI) (0.2 %) pre-coated Millipore GFB (Glass Fibre-B) filter plates. 1.0 mM stocks of test compounds were prepared in DMSO and tested at a final concentration of 300 nM. The non-specific binding was determined by 0.5 ⁇ M CP-55,940.
  • PEI poly- ethyleneimine
  • Millipore GFB Glass Fibre-B
  • the reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabeled CP-55,940 (0.5 ⁇ M) or test samples, [ 3 H]CP55940 (0.75 nM ) and 50 ⁇ g of human CBl receptor preparation.
  • Tris-BSA buffer 50 mM Tris, 5 mM MgCl 2 , 1 mM EDTA, pH 7.4 with 0.1 % BSA
  • unlabeled CP-55,940 0.5 ⁇ M
  • test samples [ 3 H]CP55940 (0.75 nM )
  • [ 3 H]CP55940 (0.75 nM )
  • the results of the assay are shown in the Tables 1 - 6.
  • Examples 1-98 represent preferred embodiments of the present invention. It should be understood that there may be other embodiments which fall within the scope and spirit of this invention.
  • Specific methods adopted for the coupling reaction of pyrazole carboxylic acids 5 with amines 6 have been given in Scheme 5-10. However, the coupling reaction can be performed using various other approaches known in the literature. For example, activation of carboxylic acid 5 with various activating reagents (thionyl chloride, oxalyl chloride, DCC 5 CDI and the like) followed by treatment with amines of the general formula 6 affords compounds of the general formula I.
  • activating reagents thionyl chloride, oxalyl chloride, DCC 5 CDI and the like
  • Step 1 Ethyl 2-oxo-2-(4-oxo-3,4-dihydro-2H-3-chromenyl)acetate: A solution of 2,3- dihydro-4i/-chromen-4-one (5.0 g, 33.8 mmol) in THF (50 niL) was added dropwise (30 min) to a stirred and cooled (-78 0 C) solution of 20 % lithium bis(trimethylsilyl)amide [LHMDS] (31.10 niL, 37,0 mmol) in THF under nitrogen atmosphere. This mixture was allowed to warm up to -40 0 C and maintained at -40 to -30 °C for 30 min.
  • LHMDS lithium bis(trimethylsilyl)amide
  • Step 2 Ethyl l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A solution of Step 1 intermediate (4.0 g, 16.1 mmol) in absolute ethanol (30 mL) was treated with 2,4-dichlorophenylhydrazine (2.35 g, 16.1 mmol) in one portion with stirring under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The yellow solid separated out was collected by filtration, rinsed with cold ethanol and dried to afford 6.0 g of the desired hydrazone.
  • Step 3 l-(2,4-Dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid: To a solution of Step 2 intermediate (5.50 g, 14.0 mmol) in methanol (80 mL) was added IN potassium hydroxide (KOH) (30 mL) and the mixture was refluxed for 1.0 h under stirring. The methanol was evaporated under reduced pressure and the residue was diluted with water (100 mL) and the mixture was acidified with IN hydrochloric acid (HCl) to pH 2.0.
  • KOH potassium hydroxide
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride: The Step 3 intermediate (100 mg, 0.3 mmol) was dissolved in anhydrous THF (5 mL) under nitrogen atmosphere. 1-aminopiperidine (30 mg, 0.3 mmol), triethylamine (141 mg, 1.40 mmol), and benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate [BOP] (147 mg, 0.3 mmol) was added and the reaction mixture was allowed to stir at room temperature under nitrogen atmosphere for 3 h.
  • the reaction mixture was diluted with EtOAc (15 mL) and the layers were separated.
  • the aqueous layer was extracted with EtOAc (2 x 20 mL) and combined organic extracts were washed with IN sodium hydroxide (NaOH) (25 mL) and dried over anhydrous Na 2 SO 4 .
  • the residue obtained after evaporation of the solvent was purified on a silica gel column using 20 % EtOAc in hexane to afford 98 mg of the product as an off-white solid.
  • the free base 98 mg (0.221 mmol) was dissolved in EtOAc (1 mL), cooled to 0 0 C and 12 % HCl in EtOAc (3 mL) was added to result in a white solid.
  • Examples 2 to 6 were prepared from l-(2,4-Dichloropheny I)-1, 4-dihydrochromeno [4,3- c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 1 and the appropriate amines (Refer to Table 1) according to the procedure mentioned in Example 1, Step 4.
  • Step ⁇ 4 N3-Piperidino-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 2.56 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 67 mg of the product as a white solid; IR (KBr) 3393, 2932, 1690, 1509, 1382, 1360, 1140, 807, 747 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.60-1.78 (m, 2H), 1.77 (s, 3H) 5 1.84 (s, 3H), 1.90-2.02 (m, 4H), 3.42-3.61 (m, 4
  • Examples 8 to 11 were prepared using l-(2,4-Dichlorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 7 and appropriate amines (Refer to Table 1) according to the coupling procedure described in Step 4, Example 1.
  • Example 12 iV3-Piperidino-6-chloro-l-(2,4-dichlorophenyl)-l,4-dihydrochromeno[4,3-c]pyrazole-3- carboxamide hydrochloride
  • Step 1 Ethyl 2-(8-chloro-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 8- chloro-4-chromanone (3.1O g, 16.97 mmol) in T ⁇ F was reacted with diethyl oxalate (2.49 g, 16.97 mmol) in the presence of 20 % L ⁇ MDS in T ⁇ F (15.62 mL, 18.67 mmol) as described in Example 1, Step 1 to give 3.88 g of the compound as yellow liquid which solidifies on standing; IR (KBr) 3423, 2980, 1723, 1598, 1475, 1286, 1237, 1144, 1072, 1008 cm "1 ; 1 H N
  • Example 13 and 14 were prepared using 6-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 12 and appropriate amines (Refer to Table 2) according to the procedure mentioned in Example 12, Step 4.
  • Step 4 ⁇ G-Piperidino- ⁇ -chloro- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochro- meno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (62 mg, 0.146 mmol) with 1 -aminopiperidine (16 mg, 0.160 mmol) using BOP reagent (77 mg, 0.175 mmol) and triethylamine (74 mg, 0.73 mmol) as described in Example 1, Step 4 gave 40 mg of the product as a white solid; IR (KBr) 3436, 2919, 2850, 1680, 1509, 1452, 1244, 1111, 813 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.62-1.78 (m, 2H), 1.78 (s, 3H), 1.86 (s, 3H), 1.93-2.02 (m, 4H), 3.
  • Step 1 Ethyl 2-(6-bromo-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 6- bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (7.35 g, 28.81 mmol) was reacted with diethyl oxalate (4.21 g, 28.81 mmol) in the presence of 20 % LHMDS in THF (26.5 mL, 31.69 mmol) as described in Example 1, Step 1 to give 8.21 g of the compound as a dark yellow semi-solid; IR (neat) 3087, 2872, 1727, 1590, 1466, 1282 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.32-1.43 (m, 3H), 1.57 (s, 3H), 1.62 (s, 3H), 4.32-4.42 (m, 2H), 4.93 (s,
  • Step 2 Ethyl 8-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Step 1 intermediate (2.0 g, 5.64 mmol) was reacted with 2,4- dichlorophenylhydrazine (1.0 g, 5.64 mmol) in ethanol (50 mL) as described in Example 1, Step 2 to give 1.45 g of the product as a brown solid; IR (KBr) 3423, 2976, 1732, 1606, 1411, 1252 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.42-1.47 (m, 3H), 1.79 (s, 3H), 1.85 (s, 3H), 4.40- 4.48 (m, 2H) 5 6.49 (s, IH), 6.82-6.85 (m, IH) 3 7.24-7.27 (m, IH), 7.49-7.
  • Step 3 8-Bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydrochromeno [4,3 -c]pyrazole- 3-carboxylic acid:.
  • Step 4 7V3-Piperidino-8-bromo- 1 -(2,4-dichlorophenyl)-4,4-dimethyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (24 mg, 0.24 mmol) using BOP reagent (113 mg, 0.25 mmol) and triethylamine (108 mg, 1.07 mmol) as described in Example 1, Step 4 gave 56 mg of the product as an off-white solid; IR (KBr) 3421, 2936, 2629, 1703, 1509, 1381, 1439, 1245 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.85 (br s, 2H), 1.68 (s, 3H), 1.76 (s, 3H), 1.87-1.93 (m 4H), 3.45 (br s
  • Examples 20 and 21 were prepared from Ethyl 2-(7-chloro-4-oxo-3,4-dihydro-2H-3- chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and subsequent coupling of the acid obtained with 1-aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
  • Step 4 N3-Piperidino-l-(2,4-difluorophenyl)-7-iodo-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (130 mg, 0.27 mmol) with 1-aminopiperidine (30 mg, 0.297 mmol) using BOP reagent (130 mg, 0.297 mmol) and triethylamine (136 mg, 1.35 mmol) as described in Example 1, Step 4 gave 80 mg of the product as an off-white solid; IR (KBr) 3422, 2940, 1698, 1603, 1520, 1441, 1382, 1263, 1197, 984, 828, cm '1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.32 (br m, 2H), 1.57 (br m, 4H), 1.66 (s, 3H), 1.75 (
  • Examples 23 to 28 were prepared from Ethyl 2-(7-iodo-2,2-dimethyl-4-oxo-3,4- dihydro-27J-3-chromenyl)-2-oxoacetate and the appropriate hydrazines (Refer to Table 2) followed by hydrolysis and coupling of subsequent acid with 1 -aminopiperidine according to the procedure described in Example 1, Steps 2, 3 and 4.
  • Examples 30 and 31 were prepared from 7-Chloro-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 29 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Examples 33 and 34 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 32 and appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Step 3 l-(2,4-Dichlorophenyl)-7-fluoro-4,4-dimethyl-l ,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 4.64 mmol) using IN KOH (9.26 mL) in methanol (18 mL) as described in Example 1, Step 3 gave the 0.817 g of the acid as an off-white solid; IR (KBr) 3444, 2974 ⁇ 2851, 1719, 1586, 1490, 1382, 1279, 1068, 822 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.82 (br s, 3H), 1.85 (br s, 3H) 5 6.10 (br m, IH), 6.20-6.40 (m, 2H), 7.40-7.58 (m, 2H), 7.63 (br m, IH).
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-fluoro-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (350 mg, 1.52 mmol) with 1-aminopiperidine (167 mg, 1.67 mmol) using triethylamine (770 mg, 7.60 mmol) and BOP reagent (642 mg, 1.52 mmol) as described in Example 1, Step 4 gave 127 mg of the product as an off-white solid; IR (KBr) 3421, 2945, 2550, 1705, 1621, 1515, 1453, 1384, 1210, 1138, 1064, 981, 816 cm “1 ; 1 H NMR (SOO MHZ, CD 3 OD) ⁇ 1.60-1.90 (m, 8H), 1.90-2.13 (m, 4H), 3.10-3.58 (m, 4
  • Examples 40 to 44 were prepared from 7-Chloro ⁇ l-(2,4-dichlorophenyl) ⁇ 4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 39 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1 , Step 4.
  • Step 4 N3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (115 mg, 0.25 mmol) and triethylamine (106 mg, 1.05 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3428, 3084, 2950, 1645, 1500, 1380, 1400, 1230, 725 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.44-1.64 (m, 2H) 3 1.77 (s, 3H) 3 1.75-1.85 (m, 4H) 3 1.85 (s, 3H) 3 3.10-3.
  • Examples 46 to 49 were prepared from 7-Bromo-l-(2,4-dichlorophenyl)-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 45 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example I 3 Step 4.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-iodo-4,4-dimethyl-l,4-dihydiO- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (94 mg, 0.21 mmol) and triethylamine (98 mg, 0.97 mmol) as described in Example 1, Step 4 gave 102 mg of the product as an off-white solid; IR (KBr) 3368, 3060, 2935, 1690, 1600, 1504, 1381, 1234, 1063, 810 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.55-1.58 (m, 2H), 1.68 (s, 3H), 1.75 (s, 3H), 1.86-1.90 (m, 4H),
  • Examples 51 and 52 were prepared from l-(2,4-Dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 50 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
  • Example 55 iV3-Piperidino-l-(2,4-dichlorophenyI)-7-isopropyl-4,4-dimethyl ⁇ l,4 dihy drochromeno [4,3-c] py razole-3-carboxamide hydrochloride Step 1: Ethyl (7-isopropyl-2,2-diniethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl)oxoacetate: 7- isopropyl-2,2-dimethyl-2,3-dmydro-4H-chromen-4-one (3.10 g, 14.20 mmol) was reacted with diethyl oxalate (2.07 g, 14.20 mmol) in the presence of 20 % LHMDS in THF (14.24 mL, 17.04 mmol) as described in Example 1, Step 1 to give 2.60 g of the compound as a brown oil; IR (neat) 2965,
  • Step 4 N3-Piperidino-7-(/ert-butyl)-l -(2,4-dichlorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride : Coupling reaction of Step 3 intermediate (270 mg, 0.61 mmol) with 1-aminopiperidine (67 mg, 0.67 mmol) using BOP reagent (0.30 g, 0.67 mmol) and triethylamine (0.31 g, 3.10 mmol) as described in Example 1, Step 4 gave 65 mg of the product as a white solid ; IR (KBr) 2964, 1698, 1618, 1455, 1215, 1099, 984, 756 cm '1 ; 1 H NMR (300 MHz, DMSO-fife) ⁇ 1.19 (s, 9H), 1.41 (br m, 2H), 1.73 (br s, 6H), 1.78
  • Step 1 Ethyl 7-cyano-l-(2,4-dichlorophenyl)-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl l-(2,4-dichlorophenyl)-7-iodo-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate (600 mg, 1.10 mmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) in triethylamine (6 mL) was treated with trimethylsilyl cyanide (165 mg, 1.66 mmol) at room temperature followed by reflux for 2 h to afford 390 mg of the compound as a white solid; IR (KBr) 2985, 2228, 1733, 1581, 1412, 1259, 1188, 971, 8
  • Step 4 N3 -Piperidino- 1 -(2,4-dichlorophenyl)-7-methoxy- 1 ,4-dihydrochromeno [4,3 - c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.26 mmol) with 1-aminopiperidine (28 mg, 0.28 mmol) using BOP reagent (136 mg, 0.31 mmol) and triethylamine (130 mg, 1.28 mmol) as described in Example 1, Step 4 gave 70 mg of the product as a white solid; IR (KBr) 3434, 2929, 1701, 1625, 1484, 1299, 1268, 1165, 1108, 837, 801 cm '1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.66 (br s, 2H), 1.90-2.01 (m, 4H), 3.50 (br m, 4H), 3.74 (br s,
  • Examples 61 and 62 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 60 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example 1, Step 4.
  • Step 1 Ethyl 2-(7-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-3-chromenyl)-2-oxoacetate: 7-methoxy-2,2-dimethyl-2,3-dihydro-4/f-chromen-4-one (5.68 g, 27.54 mmol) was reacted with diethyl oxalate (4.02 g, 27.54 mmol) in the presence of 20 % LHMDS in THF (25.5 mL, 30.29 mmol) as described in Example 1, Step 1 to give 4.16 g of the compound as a pale yellow solid; IR (KBr) 2980, 1735, 1671, 1608, 1443, 1276 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.30-1.44 (m, 3H), 1.50-1.62 (m, 6H), 3.84 (s, 3H), 4.35-4.4.43 (m, 2H), 4.88 (
  • Step 3 l-(2,4-Dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylic acid: Hydrolysis of Step 2 intermediate (1.20 g, 2.68 mmol) using IiV KOH (6 mL) in methanol (20 mL) as described in Example 1, Step 3 gave the 1.02 g of the acid as a white solid; IR (KBr) 2939, 1695, 1615, 1434, 1201, 1071 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.82 (s, 3H), 1.86 (s, 3H), 3.76 (s, 3H), 6.26-6.38 (m. 2H), 6.25 (s, IH), 7.46- 7.53 (m, 2H), 7.64 (s, IH).
  • Step 4 iV3-Piperidino-l-(2,4-dichlorophenyl)-7-methoxy-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.23 mmol) with 1-aminopiperidine (26 mg, 0.26 mmol) using BOP reagent (126 mg, 0.28 mmol) and triethylamine (120 mg, 1.19 mmol) as described in Example 1, Step 4 gave 30 mg of the product as a white solid; IR (KBr) 3399, 2943, 1644, 1618, 1434, 1204, 1138 cm '1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.52-1.56 (m, 2H), 1.66 (s, 3H), 1.73 (s, 3H), 1.83-1.87 (m, 4H), 3.33 (br s, 4H), 3.
  • Examples 64 to 69 were prepared from l-(2,4-Dichlorophenyl)-7-methoxy-4,4- dimethyl-l,4-dihydrochromeno[4,3-c]-pyrazole-3-carboxylic acid, Step 3 intermediate, Example 63 and the appropriate amines (Refer to Table 3) according to the coupling procedure described in Example 1, Step 4.
  • Step 1 Ethyl 2-(7-benzyloxy-2,2-dimethyl-4-oxo ⁇ 3,4-dihydro-2H-3-chromenyl)-2- oxoacetate: 7-Benzyloxy-2,2-dimethyl-4-chromanone (15.0 g, 53.12 mmol) (See Synth. Commun.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl)-7-benzyloxy-4,4-dimethyl-l ,A- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.40 mmol) with 1 -aminopiperidine (44 mg, 0.44 mmol) using BOP reagent (241 mg, 0.48 mmol) and triethylamine (204 mg, 2.02 mmol) as described in Example 1, Step 4 gave 215 mg of the product as a white solid; IR (KBr) 3420, 2932, 1707, 1621, 1452, 1360, 1271, 1137, 978, 734 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.45 (br s, 2H), 1.72 (br s, 4H), 1.79 (br s, 6H), 3.26 (br
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-7-hydroxy-4,4-dimethyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: A stirred solution of Ethyl 7-benzyloxy-l-(2,4-dichlorophenyl)- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate, Example 73, Step 2 (500 mg, 0.96 mmol) and sodium iodide (NaI) (157 mg, 1.05 mmol) was treated dropwise with trimethylsilyl chloride (114 mg, 1.05 mmol) in acetonitrile (5 mL) at room temperature and refluxed for 15 h.
  • NaI sodium iodide
  • Step 2 Ethyl l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: A stirred solution of Step 1 intermediate (500 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.31 mmol) in dry DMF was purged with dichlorofiuoromethane gas at 80 0 C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 4 iV3-Piperidino-l-(2,4-dichlorophenyl)-7-difluoromethoxy-4,4-dimethyl-l,4- dihydrochromeno[4 5 3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (100 mg, 0.22 mmol) with 1-aminopiperidine (24 mg,0.24 mmol) using BOP reagent (117 mg, 0.26 mmol) and triethylamine (111 mg, 1.10 mmol) as described in Example 1, Step 4 gave 48 mg of the product as a white solid; IR (KBr) 3410, 2939, 1687, 1535, 1457, 1382, 1274, 1181, 1049, 990, 816 cm “1 ; 1 H NMR (300 MHz, CD 3 OD) ⁇ 1.48 (br m, 2H), 1.78 (br m, 7H), 1.85 (br s, 3H), 2.95
  • Examples 72 to 74 were prepared from l-(2,4-Dichlorophenyl)-7-difluoromethoxy- 4,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid, Step 3 intermediate, Example 71 and the appropriate amines (Refer to Table 3) according to the coupling procedure mentioned in Example I 5 Step 4.
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-7-(3-chlorophenyl)-l,4-dihydrochromeno-[4,3- c]pyrazole-3-carboxylate: A solution of Step 2 intermediate, Example 36 (200 mg, 0.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.01 rnmol) in dimethoxyethane (DME) (10 mL) was treated with 3-chlorophenylboronic acid (67 mg, 042 mmol) followed by solution of sodium carbonate (Na 2 CO 3 ) (45 mg, 0.42 mmol) in water (5 mL).
  • DME dimethoxyethane
  • Step 3 N3 -Piperidino-7-(3 -chlorophenyl)- 1 -(2,4-dichlorophenyl)- 1 ,4- dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 2 intermediate (100 mg, 0.21 mmol) with 1-aminopiperidine (23 mg, 0.23 mmol) using BOP reagent (112 mg, 0.25 mmol and triethylamine (107 mg, 1.05 mmol) as described in Example 1, Step 4 gave 55 mg of the product as an off-white solid; IR (KBr) 3411, 2942, 2858, 1698, 1537, 1390, 1265, 1188, 1140, 1007, 977, 749 cm “1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.40 (br s, 2H), 1.70 (br s, 4H), 3.08 (br s,
  • Step 1 Ethyl l-(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl-l,4-dihydrochromeno[4,3- c]pyrazole-3-carboxylate: Coupling reaction of Step 2 intermediate, Example 50, (0.20 g, 0.37 mmol) with phenylboronic acid (65 mg, 0.42 mmol) using tetrakis(triphenyl- phosphine)palladium(O) (22 mg, 0.02 mmol) in DME (4 mL) followed by solution OfNa 2 CO 3 (45 mg, 0.42 mmol) in water (2 mL) according to the procedure described in Example 76, Step 1 afforded 155 mg of the compound as an off-white solid; IR (KBr) 3019, 2400, 1619, 1518, 1420, 1218, 772, 669 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇
  • Step 3 N3 -Piperidino- 1 -(2,4-dichlorophenyl)-4,4-dimethyl-7-phenyl- 1 ,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (90 mg, 0.19 mmol) with 1-aminopiperidine (21 mg, 0.21 mmol) using BOP reagent (93 mg, 0.21 mmol) and triethylamine (96 mg, 0.95 mmol) as described in Example 1, Step 4 gave 40 mg of the product as an off-white solid; IR (KBr) 3414, 2931, 2855, 1700, 1498, 1259, 1140, 1098, 982, 888, 817, 763 cm “1 ; 1 H NMR (300 MHz, DMSO-4) ⁇ 1.39 (br s, 2H), 1.67 (br s, 4H), 1.76 (s, 3H), 1.
  • Examples 78 to 82 were prepared from Step 2 intermediate, Example 51 and the appropriate phenylboronic acids (Refer to Table 4) followed by hydrolysis and subsequent coupling of the acid with 1-aminopiperidine according to the procedure described in Example 77, Steps 1, 2 and 3.
  • Step 2 iV3-Piperidino-l-(2 5 4-dichlorophenyl)-7-(3-pyridyl-4,4-dimethyl-l,4-dihydro- chromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: A stirred solution of Step 1 intermediate (150 mg, 0.30 mmol) and 1-aminopiperidine (36 mg, 0.36 mmol) in anhydrous THF (2 mL) was treated with 20% LHMDS in THF (0.38 niL, 0.46 mmol). The resulting mixture was stirred at room temperature for 5 h.
  • Step 1 Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,r-cyclobutan]-3- yl)oxoacetate: 7-chlorospiro[criromene-2,l'-cyclobutan]-4(3/J)-one (Kabbe H. J. et al Synthesis 1978, 886-887; Bergmann et al. J. Med Chem.
  • Step 4 iV3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane] - 1 ,4-dihydrochromeno [4,3 -c]pyrazole-3 -carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (70 mg, 0.16 mmol) with 1-aminopiperidine (180 mg, 0.18 mmol) using BOP reagent (79 mg, 0.18 mmol) and triethylamine (81 mg, 0.80 mmol) as described in Example I 5 Step 4 gave 28 mg of the product as an off-white solid; IR (KBr) 3400, 2925, 1636, 1409, 1216, 1044, 759, 669 cm “1 ; 1 H NMR (300 MHz, OMSO-d 6 ) ⁇ 1.39 (br s, IH), 1.68 (br s, 4H), 2.00-2.
  • Step 1 Ethyl (7-bromo-4-oxo-3 ,4-dihydrospiro [chromene-2, 1 '-cyclobutan] -3 -yl)oxoacetate : 7-Bromospiro[chromene-2,l'-cyclobutan]-4(3H)-one (Kabbe H. J. et al .Synthesis 1978, 886-887; Bergmann et al. J. Med. Chem.
  • Step 2 Ethyl 7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l-cyclobutane]-l,4- dihydrochromeno[4,3-c]pyrazole-3-carboxylate: Step 1 intermediate (3.0 g, 8.17 mmol) was reacted with 2,4-dichlorophenylhydrazine (1.20 g, 8. 20 mmol) in ethanol (5 mL) as described in.
  • Step 4 iV3-Piperidino-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,r- cyclobutane]-l ,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.445 mmol) with 1 -aminopiperidine (49 mg, 0.490 mmol) using BOP reagent (0.215 mg, 0.49 mmol) and triethylamine (225 mg, 2.22 mmol) as described in Example " 1, Step 4 gave 150 mg of the product as a white solid; IR (KBr) 3412, 2945, 2334, 1696, 1507, 1266, 1102, 978, 803 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.42 (br s, 2H), 1.73 (br s, 4H), 2.06-2.
  • Step 1 Ethyl (7-iodo-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclobutan]-3-yl)oxoacetate: 7-iodospiro[chromene-2,r-cyclobutan]-4(3#)-one (Kabbe H. J. et al. Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem.
  • Step 4 N3-Piperidino-l-(2,4-dichlorophenyl) 7-iodo-spiro[chromene-4,l '- cyclobutane]-l ⁇ -dihydrochromeno ⁇ S-cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (200 mg, 0.342 mmol) with 1-aminopiperidine (349 mg, 0.376 mmol) using BOP reagent (182 mg, 0.410 mmol) and triethylamine (0.173 g, 1.71 mmol) as described in Example 1, Step 4 gave 168 mg of the product as a white solid; IR (KBr) 3410, 2944, 2297, 1694, 1505, 1401, 1266, 1192, 1065, 977, 803 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ k) ⁇ 1.38 (br s, IH), 1.66 (br s, 4
  • Step 1 Ethyl (7-chloro-4-oxo-3,4-dihydrospiro[chromene-2,l '-cyclopentan]-3-yl)oxoacetate: 7-chlorospiro[chromene-2,l'-cyclopentan]-4(3//)-one (Kabbe H. J. et al .Synthesis 1978, 886- 887; Bergmann et al. J. Med Chem.
  • Step 4 N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chiOmene-4,r-cyclopentane]- l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride: This compound was prepared by the coupling reaction of Step 3 intermediate (0.154 mg, 0.34 mmol) with 1- aminopiperidine (38 mg, 0.37 mmol) using BOP reagent (0.166 g, 0.37 mmol) and triethylamine (0.17 g, 1.71 mmol) as described in Example 1, Step 4; IR (KBr) 3411, 2944, 2857, 1690, 1509, 1457, 1411, 1261, 1183, 981, 862, 815 cm “1 ; 1 H NMR (300 MHz, DMSO- d 6 ) ⁇ 1.37 (br s, 2H), 1.64 (br s, 4H),
  • Step 4 N3 -Piperidino-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' -cycl'o- pentane]-l ⁇ -dihydrochromeno ⁇ -cjpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (93 mg, 0.19 mmol) with 1 -aminohomopiperidine (25 mg, 0. 21 mmol) using BOP reagent (92 mg, 0.
  • Step 1 Ethyl (7-difluoromethoxy-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclopentane]-3- yl)oxoacetate: 7-difluoromethoxy-spiro[chromene-2,r-cyclopentan]-4(3/i)-one (9.0 g, 33.5 mmol) was reacted with diethyl oxalate (5.4 g, 36.9 mmol) in the presence of 20 % LHMDS in THF (33.0 mL, 40.2 mmol) as described in Example 1, Step 1 to give 7.08 g of the compound; IR (neat) 3382, 2963, 1732, 1685, 1614, 1445, 1254, 1057, 857 cm '1 ; 1 H NMR (300 MHz, DMSO-40 ⁇ 1.26 (m, 3H), 1.75-1.91 (m, 8H), 4.35 (m, 2H),
  • Step 4 N3-Piperidino-7-chloro-l-(2,4-dichlorophenyl)-spiro[chromene-4,l '-cyclo- hexaneJ-l ⁇ -dihydrochromeno ⁇ -cJpyrazole-S-carboxamide hydrochloride: Coupling reaction of Step 3 intermediate (0.55 g, 1.18 mmol) with 1 -aminopiperidine (0.13 g, 1.3 mmol) using BOP reagent (0.57 g, 1.3 mmol) and triethylamine (0.60 g, 5.
  • Step 4 N3 -(Piperidino)-7-bromo- 1 -(2,4-dichlorophenyl)-spiro [chromene-4, 1 ' - cyclohexane]-l,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide hydrochloride Coupling reaction of Step 3 intermediate (200 mg, 0.39 mmol) with 1-aminopiperidine (49 mg, 0.43 mmol) using BOP reagent (208 mg, 0.47 mmol) and triethylamine (199 mg, 1.96 mmol) as described in Example 1, Step 4 gave 145 mg of the product as an off-white solid; IR (KBr) 3410, 2929, 1688, 15.05, 1227, 979, 838 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ ) ⁇ 1.40 (br s, 2H), 1.57-1.94 (m, 13H), 2.26 (br s
  • Example 94 iV3-(l-Azepanyl)-7-bromo-l-(2,4-dichlorophenyl)-spiro[chromene-4,l'-cyclohexane]- 1 ,4-dihydrochromeno [4,3-c] py razole-3-carboxamide hydrochloride
  • This compound was prepared from Step 3 intermediate, Example 91 and 1- aminohomopiperidine according to the coupling procedure described in Example 1, Step 4;
  • 1 H NMR 300 MHz, DMSO- d 6 ) ⁇ 1.37 (br s, 2H), 1.58 (br s, 6H), 1.76 (br s, 6H), 1.91-1.95 (m, 2H), 2.21-2.29 (m, IH), 2.41-2.50 (m, IH), 3.31 (br
  • Step 1 Ethyl 2-[7-chloro-l-(4-methylphenylsulfonyl)-4-oxo-l,2,3,4-tetrahydro-3- quinolinyl]-2-oxoacetate: 7-chloro-l-(4-methylphenylsulfonyl)- 1,2,3, 4-tetrahydro-4- quinolinone (Johnson et al J. Am. Chem.

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Abstract

La présente invention concerne de nouveaux modulateurs de récepteur cannabinoïde, notamment les modulateurs des récepteurs cannabinoïdes 1 (CB1) ou cannabinoïdes 2 (CB2). Cette invention a aussi pour objet l'utilisation de ces modulateurs dans le traitement de maladies, conditions et/ou troubles modulés par un récepteur cannabinoïde (tel que la douleur, les troubles neurodégénératifs, les troubles alimentaires, la perte ou la régulation du poids, et l'obésité).
PCT/IN2007/000119 2006-09-20 2007-03-21 Nouveaux ligands de récepteur cannabinoïde, compositions pharmaceutiques les contenant, et procédé associé à leur préparation WO2008035356A2 (fr)

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WO2009010824A1 (fr) * 2007-07-13 2009-01-22 Glenmark Pharmaceuticals, S.A. Ligands des récepteurs vanilloïdes
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010049366A1 (fr) * 2008-10-27 2010-05-06 Glaxo Group Limited Composés tricycliques comme modulateurs des récepteurs de glutamates
WO2011058149A1 (fr) 2009-11-13 2011-05-19 Merck Serono S.A. Dérivés tricycliques de pyrazolamine
WO2015196759A1 (fr) * 2014-06-23 2015-12-30 Tocopherx, Inc. Composés de pyrazole utilisés en tant que modulateurs de fshr et leurs utilisations
KR20160021817A (ko) * 2013-06-24 2016-02-26 메르크 파텐트 게엠베하 Fshr의 조절인자로서의 피라졸 화합물 및 이의 용도
US11939328B2 (en) 2021-10-14 2024-03-26 Incyte Corporation Quinoline compounds as inhibitors of KRAS

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WO2009010824A1 (fr) * 2007-07-13 2009-01-22 Glenmark Pharmaceuticals, S.A. Ligands des récepteurs vanilloïdes
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010049366A1 (fr) * 2008-10-27 2010-05-06 Glaxo Group Limited Composés tricycliques comme modulateurs des récepteurs de glutamates
WO2011058149A1 (fr) 2009-11-13 2011-05-19 Merck Serono S.A. Dérivés tricycliques de pyrazolamine
US10081637B2 (en) * 2013-06-24 2018-09-25 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof
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KR20160021817A (ko) * 2013-06-24 2016-02-26 메르크 파텐트 게엠베하 Fshr의 조절인자로서의 피라졸 화합물 및 이의 용도
US20160152626A1 (en) * 2013-06-24 2016-06-02 Henry Yu Pyrazole compounds as modulators of fshr and uses thereof
JP2016523865A (ja) * 2013-06-24 2016-08-12 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Ｆｓｈｒの調節剤としてのピラゾール化合物及びその使用
US11365199B2 (en) 2013-06-24 2022-06-21 Merck Patent Gmbh Pyrazole compounds as modulators of FSHR and uses thereof
KR102318498B1 (ko) * 2013-06-24 2021-10-27 메르크 파텐트 게엠베하 Fshr의 조절인자로서의 피라졸 화합물 및 이의 용도
KR20170033314A (ko) * 2014-06-23 2017-03-24 토코피알엑스, 인크. Ｆｓｈｒ의 조절제로서의 피라졸 화합물 및 이의 용도
WO2015196759A1 (fr) * 2014-06-23 2015-12-30 Tocopherx, Inc. Composés de pyrazole utilisés en tant que modulateurs de fshr et leurs utilisations
JP2017524733A (ja) * 2014-06-23 2017-08-31 トコフェレックス， インコーポレイテッド Ｆｓｈｒのモジュレータとしてのピラゾール化合物およびその使用
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