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  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• This invention relates to novel chroman compounds, pharmaceutical compositions containing such compounds, and methods of treating beta-3 adrenoreceptor-mediated conditions with such compositions.
• Adrenoreceptors are sites on effector organs that are innervated by postganglionic adrenergic fibers of the sympathetic nervous system, and are classified as either alpha-adrenergic or beta-adrenergic receptors.
• Alpha-adrenergic receptors respond to norepinephrine and to such blocking agents as phenoxybenzamine and phentolamine, whereas beta-adrenergic receptors respond to epinephrine and to such blocking agents as propranolol.
• Beta-adrenergic receptors are sub-classified as beta-1 , beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation causes cardiostimulation, whereas beta- 2 stimulation causes bronchodilation and vasodilation.
• Beta-3 receptors are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis and energy expenditure.
• Agonists of beta-3 adrenoreceptors are known to be useful in the treatment of hyperglycemia (diabetes) and obesity in mammals, as well as in the treatment of gastrointestinal disorders and neurogenetic inflammation (U.S. Patent No. 5,561,142). Additionally, they are known to lower triglyceride and cholesterol levels and to raise high- density lipoprotein levels in mammals (U.S. Patent No. 5,451 ,677). Accordingly, they are useful in the treatment of conditions- such as hypertriglyceridemia, hypercholesterolemia, and in lowering high-density lipoprotein levels.
• the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.
• R is independently
• phenyl optionally substituted with CO 2 C ⁇ -C 4 -alkyl, CO 2 H, halo, or
• C C 10 alkyl or C 3 -C 8 cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C r C ⁇ o alkyl, C C ⁇ 0 alkoxy, C C 0 alkylthio, CO 2 C C 4 -alkyl, and CO 2 H, and when two R 1 groups are attached to N as NR 1 R 1 , these R 1 groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
• R 3 is hydrogen, C C 10 alkyl, or COR 2 ;
• R 4 is hydrogen, C C 10 alkyl, C 1 -C 1 0 alkyl-phenyl, or C C 10 alkyl-pyridyl;
• R 5 is hydrogen or COOH
• phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or
• phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms each optionally substituted by C C 4 alkyl, CN, NO 2 , CO-C C 4 alkyl, C1-C 4 alkoxy, or
• a is O, 1, 2, 3, 4, or 5; b is 0, 1, or 2; d is 1, 2, or 3; e is 1 or 2;
• C J -C-J O alkyl means straight or branched chain alkyl groups having from one to about ten carbon atoms, which may be saturated, unsaturated, or partially saturated.
• groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, as well as vinyl, allyl, propynyl, butenyl, butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl, and the like.
• C 1 -C 10 haloalkyl means straight or branched chain alkyl groups having from about one to about ten carbon atoms where any C-C bond may be saturated or unsaturated, the alkyl groups being substituted at any available carbon atom with one or more halogen atoms, and includes such groups as trifluoromethyl, trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and the like.
• C,-C ⁇ 0 alkoxy means straight or branched chain alkoxy groups having from one to about ten carbon atoms where any C-C bond may be saturated or unsaturated, and includes such groups as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tenSbutoxy, and the like.
• 0,-C ⁇ o alkylthio means straight or branched chain alkylthio groups having from one to about ten carbon atoms where any C-C bond may be saturated or unsaturated, and includes such groups as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, ter.-butyl.hio, and the like.
• C 3 -C 8 cycloalkyl means saturated mono cyclic alkyl groups of from 3 to about 8 carbon atoms, and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• Halo includes fluoro, chloro, bromo, and iodo, unless specifically stated otherwise.
• R, R 2 , Ar, and Y each include any 5- or 6-membered saturated or unsaturated heterocyclic group having any combination of one or more N, S, or O atoms with the point of attachment being at any available position on the heterocyclic ring. Where there is more than one heteroatom in a single cyclic group, each heteroatom shall be chosen independently of any other heteroatom, in each occurrence, with the proviso that any single heterocyclic ring may not contain more than two oxygen or sulfur atoms.
• moieties include such 5-membered heterocylic groups as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl, dithiolanyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, tri
• Ar and Y also each include phenyl fused to any 5- or 6-membered heterocyclic ring described above to form a bicyclic moiety, which may be saturated or unsaturated and may have any combination of one or more N, S, or O atoms with the point of attachment being any at available position on the phenyl ring.
• phenyl fused 5-membered heterocyclic groups as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl, benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl, benzothiadiazolyl, benzopyrazolinyl, and the like.
• It also includes such phenyl fused 6-membered heterocyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
• Ar also includes phenyl fused to any 5- or 6-membered heterocyclic ring to form a bicyclic moiety as described above, which is further fused on the heterocyclic ring to a second phenyl ring, forming a tricyclic system, with the point of attachment to the core structure of the compound of Formula I being at any available position of the first phenyl ring.
• Ar also includes any 5- or 6-membered saturated or unsaturated heterocyclic ring having any combination of one or more N, S, or O atoms as described above, which is further fused to a phenyl ring, with the point of attachment to the core molecule of Formula I being at any available position on the heterocyclic ring.
• phenyl-fused with 5-membered hetero-bicyclic moieties as benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl, indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl, benzopyrazolinyl and the like.
• phenyl-fused with 6-membered hetero-bicyclic groups as quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
• CrC-jo-alkyl-phenyl means saturated straight or branched chain alkyl groups having from one to about ten carbon atoms where the phenyl moiety is attached at any available position on the alkyl group.
• moieties include benzyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4- phenylhexyl, and the like.
• C C ⁇ o-alkyl-pyridyl means straight or branched chain saturated alkyl groups having from one to about ten carbon atoms where the pyridyl moiety is attached at any available position on the alkyl group.
• the pyridyl group may be attached to the alkyl group from any available position on the pyridine ring.
• Examples of these include pyridyl, 2-(2-pyridyl)ethyl, 3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl, 1-methyl-2-(3-pyridyl)- ethyl, 5-(3-pyridyl)-pentyl, 4-(4-pyridyl)-hexyl, and the like.
• S(O) b -phenyl-CO 2 R 1 means a phenylthio, a phenylsulfinyl, or a phenylsulfonyl group, where the CO 2 R 1 moiety is attached at any available position on the phenyl ring.
• any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety.
• NR 1 R 1 may represent
• the present invention includes compounds of Formula I wherein Y is halo; R 6 ; SR 1 ; S(O) b -phenyl-CO 2 R 1 ; or phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , C C-ioCOR 2 , phenyl, or tetrazolo.
• Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , phenyl, or tetrazolo; and d is 1 or 2.
• Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O, optionally fused to a phenyl ring; each cyclic moiety being optionally substituted with one or more substituents independently selected from COR 2 , halo, NO 2 , OR 1 , R 1 , SR 1 , SO 2 NR 1 R 7 , NR 1 R 1 , d-C ⁇ COR 2 , phenyl, or tetrazolo; d is 1 or 2; and Ar is phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N; or a 5- or 6- membered heterocycle containing one or
• Another set of compounds of Formula I includes those compounds wherein Y is phenyl optionally fused to one or two phenyl rings or to a 5- or 6-membered heterocycle containing one or more heteroatom each independently selected from N, S, and O; or a
• the present invention specifically includes the following compounds:
• Representative salts of the compounds of Formula I include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
• acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
• Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and ⁇ /-methyl-D-glucamine.
• basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
• diamyl sulfates long chain halides such as decyl, lauryl
• esters in the present invention are non-toxic, pharmaceutically acceptable esters such as alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-d-Cs alkyl may be used, although methyl ester is preferred.
• the compound of Formula I may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formula I compound. The appropriate anhydride is reacted with the alcohol in the presence of an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N ⁇ /-dimethylaminopyridine.
• an acylation catalyst such as 1,8-bis[dimethylamino]naphthalene or N ⁇ /-dimethylaminopyridine.
• An appropriate carboxylic acid may be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of ⁇ /, ⁇ /-carbonyldiimidazole with pyridine.
• a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and optionally, an acylation catalyst. Esterification may also be reached using the appropriate carboxylic acid in the presence
• Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.
• an acylation catalyst such as 4-DMAP or pyridine.
• Sensitive or reactive groups on the compound of Formula I may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art.
• the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R,S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
• the configurational isomers of Formula I in which both the hydroxyl group attached to the side chain containing the Ar-X- moiety and the (CH 2 ) d group attached to the dihydrochromenyl ring are above the plane, as depicted below, are preferred.
• protecting groups may be required for the synthesis of compounds containing certain substituents.
• a description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
• compounds of Formula I wherein R 3 is H may be selectively protected, for example, as a carbamate derivative obtained by, for example, treatment with a reagent such as di-tert- butyl dicarbonate or other means known in the art. After purification, the carbamate group can easily be removed by treatment with an acid such as HCI or trifluoroacetic acid by means known in the art.
• Formula I compounds may be prepared by standard techniques known in the art and by known processes analogous thereto.
• three such standard methods may be used, the selection of which may be based, among other considerations, upon the availability of the required individual starting materials. These three methods are illustrated in Reaction Schemes 1 , 2, and 3 below.
• each variable may be any moiety within that variable's definition may be synthesized according to Reaction Scheme 1 wherein an appropriate epoxide 1a_ or chlorohydrin lb (preparation of la is described in WO 99/32475) is coupled with the appropriate amine 2 (preparation of 2 is described below in Reaction Schemes 12, 13, and 14).
• This reaction of Reaction Scheme 1 is typically carried out in an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about -10°C to reflux.
• an aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in an alcohol such as ethanol, isopropanol, or propanol at temperature from about -10°C to reflux.
• R 3 is other than hydrogen
• compounds in which R 3 is other than hydrogen may be prepared by reaction of compound I in which R 3 is H, by selective N-alkylation of N- acylation reactions with known compounds of formula R 3 -halo (where R 3 is acyl or alkyl) or [R 3 ] 2 ⁇ (where R 3 is acyl). Protection of the hydroxyl group, for example as a TBDMS ether, may be required prior to N-alkylation reactions; O-deprotection is carried out under standard conditions well known in the art.
• Reaction of an aldehyde of Formula 4 (preparation described below in Reaction Scheme 9) with an amino alcohol of Formula 3 (preparation described in WO 98/32475) followed by reduction gives the desired transformation to Formula la compounds.
• Compounds in which R 3 is other than hydrogen may be prepared by reaction of compound la in which R 3 is H by selective N- alkylation or N-acylation reactions with known compounds of formula R 3 -halo (where R 3 is alkyl or acyl) or [R 3 ] 2 ⁇ (where R 3 is acyl). Protection of the hydroxyl group, for example, as a TBDMS ether, may be required prior to N-alkylation reactions. O- deprotection is carried out under standard conditions well known in the art.
• Reaction Scheme 4 shows that compounds of Formula I or Formula la where Y is any alkenyl, cycloalkenyl, phenyl, or a 5-or 6-membered heterocyclic ring may be prepared from compounds of Formula I or Formula la where Y is a halogen, using the following additional methods described below.
• a compound of Formula I, wherein Y is iodo may be prepared by Reaction Scheme 1 using corresponding starting materials 2 or 4, where Y is iodo, each of which may be prepared by Reaction Schemes 12 or 9, respectively.
• the resulting Formula I compound is then protected by standard methods to give a compound of Formula 7a.
• the compound of Formula 7a is then converted to the boronic ester 8, which is then subjected to Suzuki coupling reactions with a halo-Y compound, in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4.
• a halo-Y compound in which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or 6-membered heterocycle to provide Formula 7 compounds as shown in Reaction Scheme 4.
• Deprotection of Formula 7 compounds by acid or fluoride-catalyzed hydrolysis provides the corresponding Formula I compounds.
• l-Y palladium catalyst e.g., Pd(dppf)CI 2 or Pd(OAc) 2 /(Di-t-butylphosphino)biphenyl
• the coupling may also be performed in the reverse manner, that is, a boronic ester derivative 10 prepared from a halophenyl compound 9 may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5 to give Formula lb compounds.
• a boronic ester derivative 10 prepared from a halophenyl compound 9 may be added to the iodo compound of Formula 7b, as shown in Reaction Scheme 5 to give Formula lb compounds.
• Formula I compounds in which Y is an aryl group further substituted by a S(O) b R 2 or NHS(O) b R 2 group may be prepared by elaboration of the corresponding Formula 7 compounds in which Y is an aryl group substituted by CO 2 H as shown in Reaction Scheme 6.
• R 1 and R 4 are as described above, may be prepared by a sequence shown in Reaction Scheme 7.
• the iodo compound of Formula 7a may be converted to the carboxylic acid of Formula 7c by palladium-catalyzed carboxylation. This may then be coupled with an amino acid using standard peptide synthesis techniques, deprotected and hydrolyzed to give compounds of Formula Ic. This method may be repeated to give Formula I compounds where Y is
• Pd catalyst e.g.,
• Other Formula I compounds wherein Y is NR 1 R 1 may be prepared from the nitro compound of Formula Id by reduction to e followed by dialkylation with the appropriate alkylating agents, such as R 1 -halo, R 1 -OTs, or R 1 -OMs to jf (Reaction Scheme7).
• R' lower alkyl
• Reaction Scheme 9 shows how other Formula I compounds in which Y is S(O) b Ph-CO 2 R 1 and b is 0 may be prepared by diazotization of je and nucleophilic displacement with a arylthiol to give arylthioethers of Formula Ih.
• Oxidation of the Formula Ih compound with mCPBA or Oxone ® gives the Formula li compound in which
• Formula I compounds in which Y is SR 1 may be similarly prepared by methods analogous to Reaction Scheme 9, by substituting HSR 1 in place of the arylthiol in the first step.
• oxidizing agent e.g., mCPBA or Oxone' ®
• the salts and esters of the Formula I compounds of the invention may be readily prepared by conventional chemical processes.
• the epoxides la of Reaction Scheme 1 are commercially available or may be prepared according to one of the many procedures described in the literature known to those skilled in the art.
• the epoxides of formula la may be prepared by the reaction of an aryl methyl ketone with a selective halogenating agent such as NBS, followed by ketone reduction with, for example, sodium borohydride to a give a chlorohydrin lb (a halo alcohol). Base-catalyzed cyclization of this alcohol with, for example, potassium carbonate, gives the epoxides of formula la.
• the amino alcohols 3 may be prepared by ring opening of the epoxides la with a nitrogen nucleophile, such as phthalimide, in the presence of a base to form an intermediate which may be cleaved or hydrolyzed as described in WO 98/32475. This sequence is general for conversion of epoxides of formula la to the amino alcohols of formula 3.
• Synthesis of aldehyde starting materials of Formula 4 may be accomplished from the carboxylic acid of Formula 5 by reduction with borane followed by oxidation, for example, under Swern conditions as shown in Reaction Scheme 10. This method is compatible with a wide variety of Y groups, although in some cases, a protecting group may also be employed and removed in a subsequent step.
• REACTION SCHEME 10 reduction e.g.,
• the carboxylic acids of Formula 5 are generally available from the known unsubstituted chroman carboxylic acid 5a (WO 99/32476) by various aromatic substitution reactions at the 6-position of the chroman ring and further elaboration of these products.
• halogenation e.g., iodination
• 5a gives the 6-iodo compound 5b
• nitration gives predominantly the 6-nitro analog 5c (U.S. Patent No. 6,051,586) as shown in Reaction Scheme 11.
• Compounds of Formula 5 where Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle may be prepared by Suzuki coupling of a halo-Y group to an iodo chroman boronic ester 12 prepared from the iodo chroman acid 5b.
• Formula 14 and then reduction by hydrogenation gives the desired Formula 2a compounds.
• Formula 2 amines in which R 3 is other than H may be prepared by standard alkylation or acylation methods known in the art.
• Formula 2 amines in which Y is other than hydrogen or halo may be prepared by palladium-catalyzed coupling reactions on the N-protected amine of Formula 15a followed by deprotection, as shown in Reaction Scheme 14.
• Formula 2 amines prepared in this way in which the Y group is substituted by an acid, ester, alcohol, ketone, sulfide, or nitro group may provide additional Formula 2 amines by manipulation of those functional groups by directed hydrolysis, esterification, reduction, oxidation, or reduction reactions of the Y group.
• the amine 2c after protection, may be directly substituted at the 6- position of the chroman under Friedel-Crafts alkylation conditions to provide the compounds of Formula 15 in which Y is any alkyl or cycloalkyl group.
• Y is an optionally substituted alkanoic acid group (15c) is shown in Reaction Scheme 15.
• ⁇ 0 R' lower alkyl
• Alcohol intermediates of Formula H in which Y is other than hydrogen or halo may also be prepared from the iodo alcohol ⁇ a by the previously described Suzuki coupling methodology as shown in Reaction Scheme 16. This may be accomplished either directly or via a 4-step sequence involving protection of the alcohol to 16a, for example, as a .-butyldimethylsilyl ether, conversion of the iodide to the boronic ester, Suzuki coupling to 16, and finally deprotection to 11.
• halo-Y compounds used in Reaction Schemes 12, 14, and 16 where halo is iodo, chloro, or bromo and Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5- or 6- membered heterocycle are either commercially available or synthesized by standard methods known to those skilled in the art.
• One such standard method is direct halogenation of compounds of formula H-Y which are either commercially available or known in the art.
• Other methods include the functional group conversion of HO-Y or H 2 N-Y compounds to halo-Y or TfO-Y compounds by standard substitution methods.
• R 7 lower alkyl or substituted phenyl
• heterocyclic intermediates 17 and 18 used to prepare 9b and 9c are accessible by standard methods from acyclic materials. Three examples of such heterocycles are shown in Reaction Schemes 18, 19, and 20.
• Celite ® diatomaceous earth filter agent ® Celite Corp.
• HPLC-electrospray mass spectra were obtained using a Hewlett- Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.
• Combinatorial/parallel reactions were carried out in 8-mL glass vials with Teflon- lined screw caps, or in a polypropylene reaction block consisting of a 8x12 matrix of ninety-six 2.0-mL reaction wells, with each reaction well incorporating a 15-45 micron polyethylene frit.
• Reaction blocks of this type are commercially available as FlexChemTM reactor blocks from Robbins Scientific Corporation, Sunnyvale, CA. The reactor blocks are sealed with rubber gaskets and a clamping device, and can be heated with mixing by rotation in an oven (Robbins Scientific).
• [(2 ?)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine hydrochloride (Example 10, 3.52 g, 10.83 mmol) was dissolved in THF (20 mL), and treated with 0.91 g (10.83 mmol) of sodium bicarbonate in 2 mL of water, followed by the addition of 2.36 g (10.83 mmol) of di-.-butyldicarbonate. The resulting solution was allowed to stir for 16 hours at room temperature. At this point the solution was concentrated in vacuo and the resulting residue was treated with water and extracted with ethyl acetate.
• a reaction mixture containing [(2f?)-6-iodo-3,4-dihydro-2H-chromen-2- yl]methanol (Example 8, 5 g, 17.2 mmol, 1.0 eq), .er.-butyldimethylsilyl chloride (20.6 mmol, 1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL) was stirred at 27°C overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether.
• the resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na 2 CO 3 (2 M, 26 mmol, 10.5 eq.) was added and the solution was heated at 85°C overnight.
• the product mixture was allowed to cool to room temperature, water was added and the two phase mixture was extracted with ethyl acetate.
• the combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexane: ethyl acetate 10:1).
• the purified product was dissolved in THF (10 mL) and tetrabutylammonium fluoride (1 M, 5 mL) was added in a single portion.
• the methanol was removed by rotary evaporation, and the resulting crude was partitioned between ethyl acetate and water.
• the aqueous layer was adjusted to pH 7 with 1N aqueous sodium hydroxide, and the layers were separated.
• the organic layer was washed with brine, dried (MgSO 4 ), and concentrated in vacuo to a dark oil.
• the reaction was quenched with addition of methanol (12 mL) and 2 M hydrochloric acid (95 mL), and then the resulting solution was heated at reflux for 1 hour.
• the reaction was cooled to room temperature and then the solution was adjusted to pH 9 using 1 M aqueous sodium hydroxide.
• the mixture was diluted with brine (500 mL) and the layers were separated.
• the aqueous layer was extracted with ethyl acetate (2 x 200 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo.
• Example 38 Method A. Preparation of terf-butyl (2R)-2-(r.erf-butyl(dimethvnsilvnoxyl-2-(3- pyridinyllethyl ⁇ r(2/ : ?)-6-iodo-3.4-dihvdro-2 - -chromen-2-vnmethyl>carbamate
• Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 eq.) were added, and the mixture was stirred vigorously under argon at 85°C overnight.
• the reaction was cooled and filtered through a pad of Celite ® with the aid of ethyl acetate.
• the filtrate was transferred to a separatory funnel where the layers were separated.
• the organic layer was concentrated in vacuo to remove excess solvents, and the resulting oil was dissolved in ethyl acetate.
• the ethyl acetate solution was extracted with a 1 :1 solution of saturated aqueous sodium bicarbonate and water.
• Triphenylphosphine (0.04 g, 0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol, 0.05 equivalent) were added, and the mixture was stirred vigorously under argon at 85 °C overnight.
• the reaction was cooled and filtered through a pad of Celite ® with the aid of ethyl acetate.
• the filtrate was transferred to a separatory funnel where the layers were separated.
• the organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel flushed with ethyl acetate followed by elution with 95:5 chloroform/methanol.
• Example 73 By employing the methods described in Example 73 and by using the compound of Example 70 with the appropriate amide or sulfonamide as starting materials, the following were similarly prepared and characterized:
• the mixture was diluted with 1.0 mL H 2 O and purified via preparative HPLC (gradient of 100:0 0.1 % TFA/H 2 0:acetonitrile to 30:70 0.1 % TFA/H 2 0:acetonitrile).
• Example 86 The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3- ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCI in
• Example 85 By using procedure described in Example 85, the compounds of Example 178 and Example 81 were coupled to provide the desired compound.
• Example 183 To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in ⁇ /, ⁇ /-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g). The reaction mixture was stirred at 60°C for 16 hours. The mixture was diluted with distilled water (2 mL) and extracted with ethyl acetate (3x2 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as clear oil (0.076 g, 74%). LC- MS: 705.3 (MH + ), retention time: 4.01 min.
• Example 183 To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in ⁇ /, ⁇ /-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0
• Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4- bromo-2-fluorobenzoic acid. (1.0 g, 4.6 mmol) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (1.36 mL, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine.
• Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous ⁇ /, ⁇ -dimethylformamide and was heated at 85°C for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4x), dried (MgSO 4 ), and concentrated in vacuo to a crude oil.
• Phenylmethyl 4- ⁇ (2R)-2-[([(2 ?)-2- ⁇ [(1,1-dimethylethyl)(dimethyl)silyl]oxy ⁇ -2-(3- pyridinyl)ethyl] ⁇ [(1 ,1-dimethylethyl)oxy]carbonyI ⁇ amino)methyl]-3,4-dihydro-2 -/-chromen-
• the carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCI in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane.
• Example 85 By using the procedure described in Example 85, the compounds of Example 200 and Example 178 were coupled to provide the desired compound.
• Example 204 Preparation of methyl 5- ⁇ (2R)-2-r(benzylamino)methyll-3,4-dihydro-2/- -chromen-6-yl)-4'- methyl-1 , 1 '-biphenyl-2-carboxylate
• Example 204 To a solution of the compound of Example 204 (0.18 g, 0.38 mmol, 1.0 eq.) in isopropanol (4.0 mL) were added the compound of Example 1 (0.09 g, 0.57 mmol, 1.5 eq.) and potassium carbonate (0.16 g, 1.13 mmol, 3.0 eq.) at room temperature. The reaction mixture was allowed to heat up at 95°C for 16 hours. The mixture was diluted with distilled water (6 mL) and extracted with ethyl acetate (3x6 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by HPLC yielded the intermediate as a colorless oil.
• Example 212 was converted to the title compound.
• Example 217 Preparation of A/-benzyl- ⁇ /-(r(2/ : ?)-6-bromo-3,4-dihvdr
• ⁇ /-benzyl[(2f?)-3,4-dihydro-2H-chromen-2- yl]methanamine hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L formic acid. The suspension was cooled to 16°C, then bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes, maintaining the reaction temperature between 15 and 16°C. After 70 minutes, a HPLC probe indicated the reaction to be complete. To the reaction mixture was then added 15.6 L water (temperature increased to 21 °C). The light reaction mixture was then stirred for 30 minutes at room temperature, then the product was filtered and washed with 3.9 L water.
• the reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and the residue was coated on silica.
• the silica coated product was purified on the MPLC (Biotage) with 30-100% ethyl acetate in hexanes then 2% methanol in methylene chloride to afford 796 mg (1.09 mmol, 63%) of product.
• Example 249 Method A. Preparation of 4-r(2 ?)-2- r(2R)-2-hvdroxy-2-.3-pyridinv ⁇ ethyllaminolmethvn- 3.4-dihvdro-2H-chromen-6-yll-N-(2-pyrimidinyl)benzenesulfonamide
• Example 312 was converted to the title compound.
• Example 316 80 mg, 0.135 mmol
• benzene sulfonyl chloride 41 mg, 0.233 mmol
• pyridine 1.5 mL
• the reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate.
• the crude product was coated on silica and purified on the MPLC (Biotage) with
• Example 318 was converted to the title compound.
• Example 281 To a stirred solution of Example 281 (45 mg) in dichloroethane (10 mL), were added Et 3 N (0.014 mL) and 4-methylphenyl isocyanate (0.013 mL). Stirring was continued at room temperature over a 2-3 hour period. The solvent was removed under reduced pressure. Crude product was purified by combiflash column chromatography to give the free base of the desired product (27 mg, 50% yield). This material was treated with HCI (4 M) in dioxane and stirred at room temperature overnight. The solvent was removed under reduced pressure to provide the crude product, which was purified by preparative HPLC to provide the title compound.
• the reaction was heated at 50°C for 13 hours and then cooled to room temperature.
• the reaction was diluted carefully with brine (50 mL) and diethyl ether (3x70 mL), then filtered to remove the solids.
• the aqueous layer was extracted with diethyl ether (3x70 mL), and the combined organic layers were washed with brine (50 mL) and dried over Na 2 SO , filtered, and concentrated in vacuo to afford the product 3,4-dimethylphenyl oxirane as a light yellow oil (1.15 g, yield 78%).
• 6-(4-methoxycarbonylphenyl)-(R)-chroman-2-methyIamine and 3,4-dimethylphenyl oxirane were reacted by following the procedure described above to provide 4-[(2R)-2-( ⁇ [2-(3,4-dimethylphenyl)-2-hydroxyethyl]amino ⁇ methyl)-3,4- dihydro-2 - -chromen-6-yl]benzoic acid as the trifluoroacetate salt (17 % yield).
• Examples 342-354 were prepared.
• the product was prepared from ferf-butyl (2/ )-2- ⁇ [ferf-butyl(dimethyl)silyl]oxy ⁇ -2- [6-(2,5-dimethyl-1f -pyrrol-1-yl)-3-pyridinyl]ethyl ⁇ [(2f?)-6-iodo-3,4-dihydro-2/-/-chromen-2- yl]methyl ⁇ carbamate (Example 358) according to the method described for Example 81.
• Example 372 In similar fashion to that described above for Example 375, the title compound was prepared from Example 372 and used without further purification.
• reaction block was sealed with rubber gaskets and clamped, then heated at 80°C for 72 hours, with mixing by rotation. After allowing the reaction block to cool to room temperature, the block was disassembled, and the reaction well contents were filtered into a collection 96-well deep- well microtiter plate, washing with 2 portion of 200 ⁇ L of dioxane. The filtrate solutions were evaporated to dryness using a multiple sample centrifugal vacuum evaporator. Products were analyzed for purity and correct identity by LC/MS.
• An embodiment of the present invention is the administration of the compounds of this invention to a human or animal for the treatment of beta-3 adrenergic receptor mediated conditions such as diabetes, obesity, gastrointestinal disorders including irritable bowel syndrome and intestinal hypermotility disorders, peptic ulcerations, esophagitis, gastritis, and duodenitis, intestinal ulcerations including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis, and gastrointestinal ulcerations, as well as neurogenetic inflammation such as cough and asthma, and depression. It is also believed that the compounds of this invention are effective in the treatment of hyper-triglyceridemia, hypercholesterolemia and conditions of low or high density lipoprotein levels, artherosclerotic disease and cardiovascular disease and related conditions.
• the compounds of this invention are effective in the treatment of ocular hypertension and glaucoma, and in the treatment of urinary disorders including pollakiuria and incontinence, as well as in the treatment of prostate disease and as topical anti-inflammatory agents.

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