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Definitions

• Prostaglandin D 2 (PGD 2 ) is the major proinflammatory mediator abundantly secreted by mast cells activated by allergen exposure of a previously sensitized host. PGD 2 is capable of illiciting a multitude of pathobiological responses relevant to inflammatory disorders including constriction of the airways, leukocyte influx, increase in vascular permeability, edema, and mucus secretion.
• the biological actions of PGD 2 are mediated by at least 3 distinct G-protein coupled receptors:
• the high affinity receptors DP-I (formerly known as DP) and DP-2 (formerly known as orphan receptor "G-protein receptor 44", GPR44 and "chemoattractant receptor homologue expressed in Th2 cells", CRTH2 (See Hirai, H., et al. J. Exp. Med. 2001, 193(2): 255-61; Nagata, K., J. Biol. Regul. Homeost. Agents 2003, 17(4): 334-7) and the thromboxane A2 receptor, TP, to which PGD 2 binds with low affinity.
• DP-2 receptor is a major contributor to the pathophysiological actions OfPGD 2 . Accordingly, pharmaceuticals that target this receptor are likely to be therapeutically beneficial for a host of disorders, specifically inflammatory conditions that have an allergic component, such as asthma (See Huang, J., J. Microbiol. Immunol. Infect 2005, 38(3): 158- 63). DP-2 is selectively expressed in Eosinophils, Basophils, and highly polarized Th2 cells in humans. These cell types are well known contributors to inflammatory disorders and other conditions.
• DP-2 a chemoattractant receptor
• Activation of DP-2 stimulates chemotaxis of human Th2 cells, eosinophils, and basophils both in vitro and in vivo and may mediate recruitment of relevant cell types to diseased sites and exacerbate end organ damage.
• DP-2 agonists are capable of directly activating inflammatory cells and DP-2-mediated activation and mediator release from Eosinophils and Basophils has been reported (see Gervais, F. G. et al.., J Allergy Clin Immunol (2004), 108 (6):982-8;
• Th2 effector T lymphocytes will elaborate inflammatory cytokines IL-4, IL-5 and IL- 13 in response to DP-2 stimulation (See Xue, L. et al, J. Immunol. 2005, 175(10): 6531-6). These cytokines in turn act as important regulators of inflammatory responses and support Th2 cell differentiation, mast cell growth, differentiation and IgE synthesis, and the differentiation, infiltration and survival of eosinophils.
• PGD 2 /DP-2 pathway acts as a positive feedback loop and augments pathologic responses in disorders associated with excessive or dysregulated PGD 2 production. Therefore, pharmaceutical agents that interfere with this pathway may have utility in the treatment of a broad array of allergic and inflammatory conditions and other disorders.
• DP-2 selective antagonists may be useful in the treatment of allergic rhinitis, other inflammatory conditions, other conditions where the PGD 2 pathway is deregulated, as well as other disorders where the utility of Ramatroban ® has been established.
• Minami et al. have demonstrated the effectiveness of Ramatroban ® on edema in experimental allergic conjunctivitis ⁇ See Minami, K., et al. Int. Immunopharmacol. 2004, 4(12): 1531-5). It has been demonstrated that DP-2 exerts an essential role in allergic disorders, specifically, IgE-mediated cutaneous responses that occur in chronic contact hypersensitivity ⁇ See Mitsumori, S., Curr. Pharm. Des., 2004, 10(28):3533-8); Moroi, R., et al. 30th Annu. Meet. Jpn. Soc. Invest. Dermatol. (Apr 20-Apr 22, Yokohama) 2005, Abst. 48).
• WO 2006021418 discloses a series of sulfamyl-benzoimidazole-1-yl-acetic acid compounds with DP-2 or PGD 2 antagonist activity.
• WO 2006021759 discloses a series of biphenyloxyacetic acid derivatives with PGD 2 and DP-2 modulating activity said to be useful for the treatment of respiratory disorders.
• WO 2005019171, WO 2004106302 and WO 2005054232 disclose a series of Acetic acid-indole, -indazole and -benzimidazole compounds said to be useful for the treatment of respiratory disorders.
• WO 2005105727 discloses phenoxy acetic acid compounds with DP-2 antagonistic activity.
• WO 2005018529 discloses phenoxy acetic acid compounds said to be useful for the treatment of asthma and rhinitis.
• WO 2005040114 and WO 2005040112 discloses a series of compounds with DP-2 or PGD 2 antagonist activity said to useful for the treatment of allergy, asthma and atopic dermatitis.
• WO 2004058164, U.S. Patent publication No. 2005038070 and WO 2005007094 disclose a series of compounds said to be useful for the treatment of allergy, asthma, cancer and inflammation.
• WO 2004096777 discloses a series of pyrimidine derivatives useful for the treatment of conditions mediated by DP-2, including asthma conjunctivitis, dermatitis, atopic rhinitis, allergic sinusitis.
• WO 2004078719 discloses a series of indole compounds said to be useful for the treatmeant of asthma and allergic rhinitis.
• U.S. Patent publication No. 2004132772 discloses a series of tetrahydroquinoline compounds as DP-2 antagonists said to be useful for the treatment of allergic asthma and allergic rhinitis.
• WO 2003066046, WO 2003066047, WO 2003101961, WO 2003101981, WO 2004007451 discloses a series of indole-acetic acids said to be useful in the treatment of asthma, chronic obstructive pulmonary disease (COPD), rhinitis and other conditions.
• WO 2003097598 discloses a series of compounds said to exhibit PGD 2 receptor antagonism.
• U.S. Patent No. 4,656,192 discloses a series of Tropolone compounds said to be useful a anti-tumor agents.
• EP 1170594 discloses methods for the identification of compounds useful for the treatment of conditions mediated by prostaglandin D2, a ligand for orphan receptor DP-2.
• GB 1356834 discloses a series of compounds said to possess anti-inflammatory, analgesic and antipyretic activity.
• phenyl acetic acids are potent DP-2 receptor antagonists.
• the phenyl acetic acids are selective DP-2 receptor antagonists over other PGD 2 receptors.
• the phenyl acetic acid compounds of the invention are expected to be potentially useful for the treatment or prevention of medical conditions or disorders responsive to DP-2 antagonism, or symptoms associated with such medical conditions or disorders, such as those having an allergic or inflammatory component. Examples conditions or disorders treatable or preventable with compounds and compositions of the invention are provided below.
• the invention provides compounds, pharmaceutical compositions and methods useful for treating or preventing conditions and disorders associated with inflammation and/or allergic processes.
• the invention provides compounds, pharmaceutical compositions and methods useful for treating or preventing asthma, allergic conditions, inflammatory conditions, cancer and viral infection.
• L is selected from the group consisting of a CR 6 R 7 , CO, CNR 6 and CS.
• A is a 5- 14-membered heterocyclic ring having 1 -4 ring heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being moncyclic or polycyclic, optionally substituted with 1-3 R 8 substituents.
• Q 1 is selected from the group consisting of: a bond, -C]-C 4 alkylene-, -C
• Each R 1 , R 2 , R 3 , R 6 and R 7 is independently selected from the group consisting of H, Ci- 6 alkyl, Co- 6 alkylaryl and Co- 6 alkylheteroaryl; wherein the aryl or heteroaryl portions are optionally substituted with Ci_ 6 alkyl, CN, OR, C i -6 haloalkyl, Ci_ 6 heteroalkyl, NR 2 , NO 2 , halo, C(O)R, CO 2 R, CONR 2 , SO q R, SO q NR 2 , OC(O)OR, OC(O)R, OC(O)NR 2 , NRC(O)NR 2 , NRC(O)R and NRC(O)OR.
• Each R 4 is independently selected from the group consisting of Ci -6 alkyl, Co- 4 alkylC 3- iocycloalkyl, Co -4 alkylaryl, Co ⁇ alkylheteroaryl, C 2-4 alkenylaryl, C 2 - 4 alkynylaryl, C 0 - 4 alkylheterocyclyl, CN, amino, NHCOR 1 , hydroxy, d_ 6 alkoxy, OC(O)R 1 , -OCo ⁇ alkylaryl, OCo- 4 alkylheteroaryl, -OC 0-4 alkylC 3 -i 0 cycloalkyl, OCo- 4 alkylC 3- ioheterocyclyl, OCo -4 alkylNR 8 , nitro, halo and haloCi_ 6 alkyl; or are combined together or with R 6 to form an aryl or heterocyclyl ring system having 1-2 heteroatoms selected from the
• R 5 is selected from the group consisting of Ci- 6 alkyl, C 0-4 alkylaryl, C 2-4 alkenylaryl, C 2-4 alkynylaryl and Co- 4 alkylheteroaryl, each of which is optionally substituted with 1-3 R 9 substitutents.
• Each R is independently selected from the group consisting of Ci -6 alkyl, Co- 6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, Co -6 alkylheteroaryl, oxo, Ci- 6 alkyl, CN, OR,
• Each R 9 is independently selected from the group consisting of Ci- 6 alkyl, CN, OR, oxo, Ci_ 6 haloalkyl, Ci_ 6 heteroalkyl, NR 2 , NO 2 , halo, C(O)R, CO 2 R, CONR 2 , SO q R, SO q NR 2 , OC(O)OR, OC(O)R, OC(O)NR 2 , NRC(O)NR 2 , NRC(O)R and NRC(O)OR.
• Each R is independently selected from the group consisting of H, Co- 4 alkylheteroaryl,Co-4heterocyclyl, C 3 _ 8 cycloalkyl and Co-4alkylaryl or when attached to the same nitrogen atom may be combined to form a 5-8 membered ring having 1-4 ring heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur.
• n is independently O, 1, 2, 3 or 4.
• Each subscript q is independently O, 1 or 2.
• the invention also provides pharmaceutically acceptable salts, hydrates, solvates and prodrugs of compounds of structure I.
• prodrugs are compounds wherein R 1 is Ci -6 alkyl, Co-6alkylaryl or Co- 6 alkylheteroaryl wherein the aryl or heteroaryl portions are optionally substituted as described herein.
• the invention also provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, excipient or diluent.
• the invention also provides methods for antagonizing a DP-2 receptor comprising contacting a DP-2 receptor with a compound of structure I as well as methods of selectively agonizing a DP-2 receptor over one or more PGD 2 receptors.
• the invention also provides methods for treating or preventing a disorder or condition responsive to the antagonizing a DP-2 receptor as wells as methods of treating or preventing a disorder or condition associated with elevated levels of PGD 2 or a metabolite thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure I.
• the invention further provides methods for treating or preventing an inflammatory disorder or condition with an inflammation or allergic component as provided herein.
• the invention also provides methods for treating or preventing a condition or disorder mediated by DP-2 and/or one or more other PGD 2 receptors, e.g., DP-I , comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.
• the invention also provides methods for selectively modulating DP-2 in the presence of one or more other PGD 2 receptors, e.g., DP-I, comprising contacting a cell with a compound of structure I.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e., C 1-8 means one to eight carbons).
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
• alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more double bonds.
• alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl) and higher homologs and isomers thereof.
• alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -Cs means two to eight carbons) and one or more triple bonds.
• alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
• alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
• an alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
• a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
• alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
• dialkylamino refers to an amino group having two attached alkyl groups that can be the same or different.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
• the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
• -CH 2 -CH N-OCH 3
• -CH CH-N(CH 3 )-CH 3
• up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3
• a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
• the number of carbons (2-8, in this example) is meant to include the heteroatoms as well.
• a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH 2 SH.
• heteroalkyl ene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 - - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyl eneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
• cycloalkyl by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively.
• cycloalkyl and heterocyclic ring are meant to be included in the terms “alkyl” and “heteroalkyl”, respectively.
• a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• cycloalkyl examples include cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
• a heterocyclic ring examples include pyrrolidinyl, pyrrolyl, piperadinyl, tetrahydropyridinyl, piperazinyl, piperazin-1 -oxide, morpholinyl, thiomorpholinyl, azepanyl, azepinyl, oxazepane, thiazepane, azocanyl, azocinyl, indolyl, azaindole, tetrahydroquinolinyl, decahydroquinoliny, tetrahydrobenzooxazepinyl dihydrodibenzooxepin, and the like.
• halo or halogen
• substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl” are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m'+l), where m' is the total number of carbon atoms in the alkyl group.
• haloCi_ 6 alkyl is meant to include trifiuoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
• haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+l) halogen atoms).
• perhalo alkyl means, unless otherwise stated, alkyl substituted with (2m'+l) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
• perhaloCi -6 alkyl is meant to include trifiuoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
• aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
• heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl,
• aryl refers to a phenyl or naphthyl group which is unsubstituted or substituted.
• heteroaryl refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group which is unsubstituted or substituted.
• aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
• arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
• alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
• an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naph
• R 1 , R" and R" 1 each independently refer to hydrogen, unsubstituted Ci- 6 alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-C
• R 1 and R" When R 1 and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
• -NR 1 R" is meant to include 1 -pyrrolidinyl and 4-morpholinyl.
• an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ).
• Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 )q-U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is O, 1 or 2.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ),-B-, wherein A and B are independently -CH 2 -, -0-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR 1 - or a single bond, and r is 1, 2 or 3.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) t - -, where s and t are independently integers of from O to 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
• the substituent R 1 in -NR'- and -S(O) 2 NR 1 - is selected from hydrogen or unsubstituted Ci_ 6 alkyl. Otherwise, R' is as defined above.
• heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
• pharmaceutically acceptable salts or “pharmaceutically acceptable carrier” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.
• the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
• the invention provides compounds which are in a prodrug form.
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of formula I which are antagonists of the DP-2 receptor.
• prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
• An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (e.g. wherein R 1 is substituted or unsubstituted Ci_ 6 alkyl, C 0 _ 6 alkylaryl or C 0-6 alkylheteroaryl, the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid (e.g. wherein R 1 is H, the "active entity").
• Additional examples include peptidyl derivatives of a compound of the invention.
• Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
• the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention.
• Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. These isomers can be resolved or asymmetrically synthesized using conventional methods to render the isomers "optically pure", i.e., substantially free of its other isomers.
• a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chrial auxilliary, where the resulting diastereomeric mixture is separated and the auxilliary group cleaved to provide the pure desired enantiomers.
• the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diasteromers thus formed by fractional crystallization or chromatagraphic means well known in the art, and subsequent recovery of the pure enantiomers.
• the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
• Radiolabled compounds are useful as therapeutic or prophylactic agents, e.g., cancer therapeutic agents, research reagents, e.g., DP-2 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
• an "antagonist” or “inhibitor” refers to an agent or molecule that inhibits or binds to, partially or totally blocks stimulation or activity, decreases, closes, prevents, delays activation or enzymatic activity, inactivates, desensitizes, or down regulates the activity of a receptor of the invention.
• antagonist also includes a reverse or inverse agonist.
• An "agonist” or “activator” refers to an agent or molecule that binds to a receptor of the invention, stimulates, increases, opens, activates, facilitates, enhances activation or enzymatic activity, sensitizes or up regulates the activity of a receptor of the invention.
• Modulators of activity are used to refer to "ligands", “antagonists” and “agonists” identified using in vitro and in vivo assays for activity and their homologs and mimetics. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, molecules and the like. Assays to identify antagonists and agonists include, e.g., applying putative modulator compounds to cells, in the presence or absence of a receptor of the invention and then determining the functional effects on a receptor of the invention activity. Samples or assays comprising a receptor of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect.
• Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a receptor of the invention relative to the control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a receptor of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher.
• treat includes partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition.
• Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
• prevent refers to a method of partially or completely delaying or precluding the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of acquiring or reaquiring a disorder or condition or one or more of its attendant symptoms.
• therapeutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
• the phrase "selectively" or “specifically” when referring to binding to a receptor refers to a binding reaction that is determinative of the presence of the receptor, often in a heterogeneous population of receptors and other biologies.
• the compounds bind to a particular receptor at least two times the background and more typically more than 10 to 100 times background.
• Specific binding of a compound under such conditions requires a compound that is selected for its specificity for a particular receptor.
• small organic molecules can be screened to obtain only those compounds that specifically or selectively bind to a selected receptor and not with other receptors or proteins.
• a variety of assay formats may be used to select compounds that are selective for a particular receptor. For example, High-throughput screening assays are routinely used to select compounds that are selective for a particular a receptor.
• the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
• the term "DP-2” refers to a DP-2 receptor protein (RefSeq Accession No. NP-007469) or a variant thereof that is capable of mediating a cellular response to PGD 2 in vitro or in vivo.
• DP-2 variants include proteins substantially homologous to native DP-2, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., DP-2 derivatives, homologs and fragments).
• the amino acid sequence of DP-2 variant preferably is at least about 80% identical to a native DP-2, more preferably at least about 90% identical, and most preferably at least about 95% identical.
• other PGD 2 receptor refers to a prostanoid receptor protein other than DP-2, or variant thereof, that is capable of mediating a cellular response to PGD 2 in vitro or in vivo.
• Another PGD 2 receptor may be selective for PGD 2 , e.g., DP-I (RefSeq Accession No. NP-000944), or may also interact with one or more other prostanoids (e.g., EPl, EP2, EP3 and EP4, FP, IP and TP).
• PGD 2 receptor variants include proteins substantially homologous to a corresponding native prostanoid receptor other than DP-2, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., derivatives, homologs and fragments of another PGD 2 receptor).
• the amino acid sequence of other PGD 2 receptor variants preferably is at least about 80% identical to the corresponding native other PGD 2 receptors, more preferably at least about 90% identical, and most preferably at least about 95% identical.
• another PGD 2 receptor is DP-I .
• DP-I refers to a DP-I receptor protein (RefSeq Accession No. NP-000944) or a variant thereof that is capable of mediating a cellular response to PGD 2 in vitro or in vivo.
• DP-I variants include proteins substantially homologous to native DP-I, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., DP-I derivatives, homologs and fragments).
• the amino acid sequence of DP-I variant preferably is at least about 80% identical to a native DP-I , more preferably at least about 90% identical, and most preferably at least about 95% identical.
• TP refers to a TP receptor protein (RefSeq Accession No. NP-963998) or a variant thereof that is capable of mediating a cellular response to PGD 2 in vitro or in vivo.
• TP variants include proteins substantially homologous to native TP, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., TP derivatives, homologs and fragments).
• the amino acid sequence of TP variant preferably is at least about 80% identical to a native TP, more preferably at least about 90% identical, and most preferably at least about 95% identical.
• modulate refers to the ability of a compound to increase or decrease the function and/or expression of DP-2 and/or one or more other
• PGD 2 receptors e.g., DP-I
• modululation may occur in vitro or in vivo. Modulation, as described herein, includes the inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with DP-2 and/or one or more other PGD 2 receptors, either directly or indirectly, and/or the upregulation or downregulation of the expression of DP-2 and/or one or more other PGD 2 receptors, either directly or indirectly.
• the modulation is direct.
• Inhibitors or antagonists are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signal transduction.
• Activators or agonists are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, activate, sensitize or upregulate signal transduction.
• the ability of a compound to inhibit the function of DP-2 and/or one or more other PGD 2 receptors can be demonstrated in a biochemical assay, e.g., binding assay, or a cell-based assay, e.g., a transient transfection assay.
• condition or disorder responsive to modulation of PGD 2 or a PGD 2 receptor refers to a condition or disorder associated with inappropriate, e.g., less than or greater than normal, activity of a PGD 2 receptor and at least partially responsive to or affected by modulation of a PGD 2 receptor (e.g., a PGD 2 receptor antagonist or agonist results in some improvement in patient well-being in at least some patients).
• a condition or disorder associated with a PGD 2 receptor may include a "DP-2-mediated condition or disorder".
• condition or disorder responsive to the antagonizing a DP-2 receptor refers to a condition or disorder characterized by inappropriate, e.g., greater than normal, DP-2 activity. Inappropriate DP-2 functional activity might arise as the result of DP-2 expression in cells which normally do not express DP-2 or increased DP-2 expression or degree of intracellular activation (leading to, e.g., inflammatory and immune-related disorders and conditions).
• a condition or disorder responsive to the antagonizing a DP-2 receptor may be completely or partially mediated by inappropriate DP-2 functional activity.
• a condition or disorder responsive to the antagonizing a DP-2 receptor is one in which modulation of DP-2 results in some effect on the underlying condition or disorder (e.g., an DP-2 antagonist results in some improvement in patient well-being in at least some patients).
• a class of compounds that antagonize DP-2 has been discovered. Depending on the biological environment (e.g., cell type, pathological condition of the host, etc.), these compounds can antagonize DP-2 and/or one or more other PGD 2 receptors (e.g., ligand binding). By antagonizing DP-2 and/or one or more other PGD 2 receptors, the compounds will find use as therapeutic agents capable of modulating disorders and conditions responsive to modulation of DP-2 and/or one or more other PGD 2 receptors and/or mediated by DP-2 and/or one or more other PGD 2 receptors. Examples of such conditions and disorders are provided below.
• the compounds of the invention are believed to exert their effects by selectively interacting with DP-2, the mechanism of action by which the compounds act is not a limiting embodiment of the invention.
• compounds of the invention may interact with PGD 2 receptor subtypes other than DP-2.
• the present invention specifically contemplates the activity of the disclosed compounds to selectively antagonize DP-2 receptor over e.g. DP-I receptor, and/or other prostanoid receptors, e.g., TP receptor.
• Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
• Compounds of the Invention include, but are not limited to, the exemplary compounds provided herein.
• the present invention provides compounds of the general structure (I):
• L is selected from the group consisting of CR 6 R 7 , CO, CNR 6 and CS.
• A is a 5-14-membered heterocyclic ring having 1-4 ring heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur, the heterocyclic ring being moncyclic or polycyclic, optionally substituted with 1-3 R substituents.
• Q 1 is selected from the group consisting of: a bond, -C
• Each R 1 , R 2 , R 3 , R 6 and R 7 is independently selected from the group consisting of H, C
• Each R 4 is independently selected from the group consisting of C
• R 5 is selected from the group consisting of Co -4 alkylaryl, C 2-4 alkenylaryl, C 2-4 alkynylaryl and Co- 4 alkylheteroaryl, each of which is optionally substituted with 1-3 R 9 substitutents.
• Each R 8 is independently selected from the group consisting of Ci_ 6 alkyl, C 0-6 alkylC 3-6 cycloalkyl, Co- 6 alkylaryl, Co- 6 alkylheteroaryl, oxo, Ci_ 6 alkyl, CN, OR, Ci- 6 -ialoalkyl, C ]-6 heteroalkyl, NR 2 , NO 2 , halo, C(O)R, CO 2 R, CONR 2 , SO q R, SO q NR 2 , OC(O)OR, OC(O)R, OC(O)NR 2 , NRC(O)NR 2 , NRC(O)R and NRC(O)OR.
• Each R 9 is independently selected from the group consisting of Ci -6 alkyl, CN, OR, oxo, Ci -6 haloalkyl, Ci -6 heteroalkyl, NR 2 , NO 2 , halo, C(O)R, CO 2 R, CONR 2 , SO q R, SO q NR 2 , OC(O)OR, OC(O)R, OC(O)NR 2 , NRC(O)NR 2 , NRC(O)R and NRC(O)OR.
• Each R is independently selected from the group consisting of H, Ci -6 alkyl, C 0-4 alkylheteroaryl,Co -4 heterocyclyl, C 3 _gcycloalkyl and C 0-4 alkylaryl or when attached to the same nitrogen atom may be combined to form a 5-8 membered ring having 1 -4 ring heteroatoms each independently selected from the group consisting of nitrogen, oxygen and sulfur.
• n is independently O, 1, 2, 3 or 4;
• Each subscript q is independently O, 1 or 2.
• the present invention provides pharmaceutically acceptable derivatives thereof.
• L is CR 6 R 7 .
• L is CO.
• L is CNR 6 .
• L is CS.
• R 1 , R 2 , R 3 , R 6 and R 7 are each independently selected from the group consisting of H, Ci_ 6 alkyl and Co- 6 alkylaryl. In one embodiment, R 1 , R 2 , R 3 , R 6 and R 7 are each independently selected from the group consisting of H, CH 3 and phenyl. In one embodiment, R 1 is H. In another embodiment, R 2 and R 3 are H.
• A has the structure (II):
• Y is selected from the group consisting of a bond, CH 2 , N, O, NO and SO q ;
• R 10 and R 1 ' are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;
• the subscript p is independently 0, 1 or 2;
• each dashed ring bond independently indicates the presence of a single, double or normalized bond
• the dotted line indicates the point of attachment to Q 1 and the wavy line indicates the point of attachment to L.
• A is selected from the group consisting of pyrrolidinyl, pyrrolyl, piperadinyl, tetrahydropyridinyl, piperazinyl, piperazin-1 -oxide, morpholinyl, thiomorpholinyl, azepanyl, azepinyl, oxazepane, thiazepane, azocanyl, azocinyl, indolyl, azaindole, tetrahydroquinolinyl and decahydroquinoliny.
• A has a formula selected from the group consisting of:
• n is and integer from O to 3;
• the dashed line indicates the point of attachment to Q 1 and the wavy line indicates the point of attachment to L.
• Q 1 is selected from a bond, -Ci ⁇ alkylene-,
• Q 1 is a bond.
• Q 1 is -C
• Q 1 is -Ci-C t heteroalkylene-.
• Q 1 is -CO-.
• Q 1 is a -NH-.
• Q 1 is a -0-.
• Q 1 is -SO q -. In another embodiment, Q 1 is -C(O)O-. In another embodiment, Q 1 is -OC(O)-. In another embodiment, Q 1 is -CONH-. In another embodiment, Q 1 is -NHCO-. In another embodiment, Q 1 is -NHCONH-. In another embodiment, Q 1 is -NHSO q -. In another embodiment, Q 1 is -SO q NH-. In another embodiment, Q 1 is -COCH 2 HNSOq
• the compound has a structure (III):
• Y is selected from the group consisting of a bond, CH 2 , N, O, NO and SO q ;
• R 1 and R ' are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;
• n 0, 1, 2 or 3;
• the subscript p is independently 0, 1 or 2;
• each dashed ring bond independently indicates the presence of a single, double or normalized bond.
• L is CR 6 R 7 . In another embodiment, L is CO. In another embodiment, L is CS.
• the compound has a structure (IV):
• Y is selected from the group consisting of a bond, CH 2 , N, O, NO and SO q ;
• R , i o and R are H or are combined together to form an aryl, heteroaryl or cycloalkyl ring;
• each dashed ring bond independently indicates the presence of a single, double or normalized bond.
• Y is CH 2 and p is 0.
• L is CR 6 R 7 .
• Q 1 is a bond
• Y is SOq and p is 0.
• the compound is selected from the group consisting of: [4-(4-Chloro-benzyloxy)-3-thiomorpholin-4-ylmethyl -phenyl] -acetic acid; [4-(4-Chloro-benzyloxy)-3-(l , 1 -dioxo-1 ⁇ 6 -thiomorpholin-4-ylmethyl)-phenyl] -acetic acid; and [4-(4-Fluoro-benzyloxy)-3 -( 1 , 1 -dioxo- 1 ⁇ 6 -thiomorpholin-4-ylmethyl)-phenyl] -acetic acid.
• Y is O and p is 0.
• the compound is [4-(4-Chloro-benzyloxy)-3-morpholin-4-ylmethyl-phenyl]-acetic acid.
• Y is N and p is 0.
• the compound is selected from the group consisting of: [4-(4-Chloro-benzyloxy)-3-(4-pyrimidin-2-yl-piperazin-l-ylmethyl)-phenyl]-acetic acid; ⁇ 4-(4-Chloro-benzyloxy)-3-[3-oxo-4-(4-trifluoromethyl-phenyl)-piperazin-l-ylmethyl]-phen yl ⁇ -acetic acid; and
• Q 1 is -CO-.
• the compound is selected from the group consisting of: (4-(4-Chloro-benzyloxy)-3- ⁇ 4-[2-(4-methoxy-phenyl)-acetyl]-piperazin-l-ylmethyl ⁇ -phenyl) -acetic acid;
• Q 1 is -C(O)O-.
• the compound is selected from the group consisting of: 4-[5-Carboxymethyl-2-(4-chloro-benzyloxy)-benzyl]-piperazine- 1 -carboxylic acid tert-buty ⁇ ester; 4-[5-Carboxymethyl-2-(4-chloro-benzyloxy)-benzyl]-piperazine-l -carboxylic acid methyl ester; 4-[5-Carboxymethyl-2-(4-chloro-benzyloxy)-benzyl]-piperazine-l -carboxylic acid isopropyl ester; 4-[5-Carboxymethyl-2-(4-chloro-benzyloxy)-benzyl]-piperazine-l -carboxylic acid ethyl ester.
• Q 1 is -SO q -.
• the compound is selected from the group consisting of:
• the compound is selected from the group consisting of: (4-Hydroxy-3- ⁇ phenyl-[4-(toluene-4-sulfonyl)-piperazin-l-yl]-methyl ⁇ -phenyl)-acetic acid; (3- ⁇ (2-Hydroxy-phenyl)-[4-(toluene-4-sulfonyl)-piperazin-l-yl]-methyl ⁇ -phenyl)-acetic acid; (3- ⁇ Phenyl-[4-(toluene-4-sulfonyl)-piperazin-l-yl]-methyl ⁇ -phenyl)-acetic acid; (3- ⁇ [4-(4-Fluoro-benzenesulfonyl)-piperazin-l-yl]-phenyl-methyl ⁇ -phenyl)-acetic acid; ⁇ 3-[(4-Benzenesulfonyl-piperazin-l-piperazin-l-
• R 4 and R 6 are combined together to form an aryl or heterocyclyl ring system.
• the compound has the structure IVa:
• Y 2 is selected from the group consisting of N, O and S; each R 12 is independently selected from the group consisting of C]_ 6 alkyl, CN, CONHR 1 , CO 2 R 1 , amino, Ci ⁇ alkoxy, halo, haloC
• the compound is selected from the group consisting of: 2- (1 l-(4-tosylpiperazin-l-yl)-6,l l-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid; 2-(l l-(4-(4- fluorophenylsulfonyl)piperazin-l-yl)-6,l l-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid; 2-(9- chloro-l l-(4-tosylpiperazin-l-yl)-6,l l-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid; 2-(9- chloro-1 1 -(4-(4-fluorophenylsulfonyl)piperazin-l -yl)-6,l 1 -dihydrodibenzo[b,e]
• the compound is l-(5-(carboxymefhyl)-2-(2,4- dichlorobenzyloxy)benzyl)-4-tosylpiperazine N-oxide.
• Q 1 is -C(O)O-.
• the compound is selected from the group consisting of: 4-[5-Carboxymethyl-2-(4-chloro-benzyloxy)-benzyl]-piperazine- 1 -carboxylic acid ter/-butyl ester.
• Q 1 is -CONH-.
• the compound is selected from the group consisting of:
• Y is CH 2 and p is 0.
• the compound is selected from the group consisting of: [4-(4-Chloro-benzyloxy)-3-piperidin-l-ylmethyl-phenyl]-acetic acid; and
• Q 1 is -NHSO q -.
• the compound is selected from the group consisting of
• L is CO
• the compound is selected from the group consisting of: ⁇ 4-(4-Chloro-benzyloxy)-3-[4-(toluene-4-sulfonyl)-piperazine-l-carbonyl]-phenyl ⁇ -acetic acid; and [4-(4-Chloro-benzyloxy)-3-(4-methanesulfonyl-piperazine-l-carbonyl)-phenyl] -acetic acid.
• the compound has a structure (V):
• Y is selected from the group consisting of a bond, CH 2 , N, O, NO and SO q ;
• R 10 and R 1 ' are H or are combined together to form an aryl, heteroaryl, or cycloalkyl ring;
• the subscript m is independently 0, 1 , 2 or 3 ;
• the subscript p is independently 0, 1 or 2;
• each dashed ring bond independently indicates the presence of a single, double or normalized bond.
• L is CR 6 R 7 .
• L is CO.
• L is CS.
• Q 1 is a bond. In another embodiment, Q 1 is -Ci-C 4 alkylene-. In another embodiment, Q 1 is -Ci-Qheteroalkylene-. In another embodiment, Q 1 is -CO-. In another embodiment, Q 1 is a -NH-. In another embodiment, Q 1 is a -O-. In another embodiment, Q 1 is -SO q -. In another embodiment, Q 1 is -C(O)O-. In another embodiment, Q 1 is -OC(O)-. In another embodiment, Q 1 is -CONH-. In another embodiment, Q 1 is -NHCO-. In another embodiment, Q 1 is -NHCONH-. In another embodiment, Q 1 is -NHSO q -. In another embodiment, Q 1 is -SO q NH-. In another embodiment, Q 1 is -COCT ⁇ HNSOq
• the invention encompasses novel compounds, novel pharmaceutical compositions and/or novel methods of use. While some compounds disclosed herein are available from commercial sources, the pharmaceutical compositions or methods of using these compounds are novel. Unless otherwise indicated, it is to be understood that the invention includes those compounds that are novel, as well as pharmaceutical compositions, various methods (e.g., methods of treating or preventing certain conditions and disorders mediated by DP-2 and/or one or more other PGD 2 receptors), and the like which include both the novel compounds of the invention and compounds that are commercially available.
• an alkyl phenyl acetate of formula A is mixed to a solution of para formaldehyde and a substituted heterocycle, such as a piperidine or a substituted piperazine, in a solvent system such as isopropyl alcohol for 1 to 12 hours at reflux to give B.
• a substituted heterocycle such as a piperidine or a substituted piperazine
• phenyl ring of the alkyl phenyl acetate A is substituted with a hydroxyl group (as shown)
• alkylation of the phenol using an appropriate alkyl or aryl halide in the presence of a base such as K 2 CO 3 , or CsCO 3 in a solvent such as DMF at temperatures ranging from 20 to 60 0 C, or acetone at temperatures ranging from 20 to 80 0 C, leads to further substituted compounds C.
• Saponification with a base such as potassium hydroxide (KOH) or sodium hydroxide (NaOH) in a solvent system such as methanol: water, for a period of 1-6 hours at temperatures between 35-65 0 C, leads to a carboxylic acid of formula D.
• KOH potassium hydroxide
• NaOH sodium hydroxide
• Benzaldehyde GGG was obtained by treatment a halotoluene with N- bromosuccinimide and AIBN in a solvent such as carbon tetrachloride, followed by addition of trimethylamine N-oxide in a solvent such as acetonitrile, at temperatures ranging from room temperature to 80 0 C, over 15 hours.
• Oxidation of F with Jone's reagent in a solvent such as acetone, followed by the Arndt-Eistert reaction leads to G.
• Aryl bromide G can be converted to the corresponding benzaldehyde via a palladium (0) mediated reaction in a solvent such as toluene in the presence of carbon monoxide.
• ketone I was treated with sodium borohydride in a solvent such as methanol at temperatures varying from -10 to 35 0 C, followed by treatment with thionyl chloride in DCM at room temperature over a period of 12 hours, to give J.
• substituted benzaldehyde L can be treated with an alkyl or aryl Grignard reagent in a solvent system such as THF at temperatures ranging from -20 to 20 0 C over a period of a few hours to give secondary alcohol M.
• a solvent system such as THF
• Aryl bromide N is then transformed into a boronate ester O using standard palladium (0) coupling conditions. Further palladium (0) coupling of O with ethyl-2-bromo acetate in the presence of a base such as K 2 CO 3 , in a solvent system such as dioxane or DME, at temperatures ranging from 15 to 85 0 C leads to phenyl acetate P. Saponification of P using conditions described in Scheme A leads to K.
• phenyl acetate A is treated with paraformaldehyde in AcCN at temperatures ranging from 25 to 100 0 C, and leads to Q.
• Oxidation of Q with potassium permanganate for example in a solvent system such as acetone/water for a few hours under reflux conditions leads to benzoic acid R.
• This acid S can then be coupled to a substituted heterocycle, such as a piperidine or piperazine using for example HATU and a base such as Et 3 N or DIEA in a solvent such as AcCN, at ambient temperatures for a period of 2 to 12 hours.
• benzaldehyde X is reacted with an amino acid such as Boc-Lysine or Boc-Ornithine,using sodium cyanoborohydride in the presence of zinc chloride in a solvent such as methanol for up to 30 min. to give amino acid Z.
• Cyclization of Z to AA takes place under standard coupling conditions such as hydroxybenzotriazole (HOBT) and l-[3-(dimethylamino)propoyl]-3-ethylcarbodiimide hydrochloride (EDCI) in a solvent system such as DCM or DMF, at temperatures ranging from -30 to 50 0 C, for up to 12 hours.
• HOBT hydroxybenzotriazole
• EDCI l-[3-(dimethylamino)propoyl]-3-ethylcarbodiimide hydrochloride
• benzyl bromide CC can be reacted with a heterocycle such as DD in the presence of a base such as Cs 2 CO 3 or K 2 CO 3 in a solvent system such as AcCN/DMF at temperatures ranging from 10 to 75 0 C over a few hours, followed by protecting group removal and alkylation as described in Schemes G and A. Saponification of EE leads to compound FF using standard reaction conditions as described in Scheme A.
• reductive amination of benzaldehyde GG with an alken-1 -amine under standard conditions described in Scheme G leads to HH.
• Coupling of amine HH to a protected amino acid such as 2-(tert-butoxycarbonylamino)pent- 4-enoic acid in the presence of HATU and a base such as tri ethyl amine or DIEA in a solvent such as AcCN or DMF for a few hours leads to II.
• Ring closure catalyzed by Grubb's first generation catalystin a solvent such as DCM for a few hours at temperatures ranging from 20 to 90 0 C leads to seven membered lactam JJ.
• the invention includes methods to evaluate putative specific agonists or antagonists of DP-2 and/or one or more other PGD 2 receptors. Accordingly, the invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the function of DP-2 and/or one or more other PGD 2 receptors.
• the compounds of this invention are useful for DP-2 mutants and/or one or more other PGD 2 receptor mutants, which are excellent screening tools for potent compounds.
• the compounds of this invention are useful in establishing or determining the binding site of other compounds to DP-2 and/or one or more other PGD 2 receptors, e.g., by competitive inhibition.
• the compounds of the instant invention are also useful for the evaluation of putative specific modulators of DP-2 over one or more other PGD 2 receptors.
• PGD 2 receptors One of skill in the art will appreciate that thorough evaluation of specific antagonists of PGD 2 receptors has been hampered by the lack of availability of specific, non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors.
• the compounds provided herein are particularly useful in this context.
• the above and other assays described herein are designed to be amenable to a high throughput format to detect or quantify the presence, absence, quantification, or other properties of particular compounds individually or as library containing a large number of potential therapeutic compounds (potential modulator compounds). Any of the assay steps may be automated and compounds from any convenient source may be provided to the assay. Assays are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays). Preferred assays detect enhancement or inhibition of DP-2, DP-2 and/or one or more other PGD 2 receptors function.
• High throughput screening systems are commercially available (see e.g., Zymark Corp., Hopkinton Mass.; Air Technical Industries, Mentor Ohio; Beckman Instruments, Inc., Fullerton Calif; Precision Systems, Inc., Natick Mass.; etc.). These systems typically automate entire procedures, including all sample and reagent pipetting, liquid dispensing, timed incubations, and final readings of the microplate in detector(s) appropriate for the assay.
• These configurable systems provide high throughput and rapid start-up as well as a high degree of flexibility and customization. The manufacturers of such systems provide detailed protocols for various high throughput systems.
• Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene transcription, ligand binding, and the like.
• the present invention relates to the identification of phenylacetic acid derivatives and their use as functional antagonists of the DP-2 receptor for the treatment of conditions or disorders mediated by PGD 2 , to pharmaceutical compositions containing these derivatives and to processes for their preparation.
• compounds and derivatives of the general formula I have activity as modulators of DP-2 receptor activity, and therefore may be used in the treatment of conditions or disorders which are caused by the excessive, unbalanced or deregulated expression of PGD 2 and its metabolites.
• Non-limiting example of such conditions and disorders include:
• Obstructive airway diseases such as: asthma, e.g., intermittent and persistent asthma, extrinsic (allergic) asthma, intrinsic (non-allergic) asthma, mixed extrinsic-intrinsic asthma, exercise induced asthma, nocturnal asthma, bronchial asthma, seasonal asthma, occupational asthma, cough variant asthma, chronic severe corticosteroid-dependent asthma, steroid-resistant asthma, allergic bronchopulmonary aspergillosis, asthma triad (including asthma nasal polyps, and aspirin sensitivity), and allergic airway syndrome; bronchitis, e.g., acute and chronic bronchitis, allergic rhinobronchitis, eosinophilic bronchitis, and chronic obstructive pulmonary disease (COPD)); rhinitis, including acute and chronic rhinitis, atrophic rhinitis, allergic and non- allergic rhinitis, seasonal (e.g., rhin
• dermatitis e.g., allergic contact dermatitis, atopic dermatitis (eczema), contact (and irritant contact) dermatitis, excematous dermatitis, neurodermatitis, perioral dermatitis, seborrheic dermatitis, statsis dermatitis, diaper dermatitis, dyshidrotic dermatitis (pompholyx), nummular dermatitis, autosenstitization dermatitis, lichen simplex chronicus, and urticaria; conjunctivitis, e.g., viral, allergic, bacterial, and chemical/toxic conjunctivitis; psoriasis; urticaria; erythemas; cutaneous eosinophilia; and chronic skin ulcers;
• dermatitis e.g., allergic contact dermatitis, atopic dermatitis (eczema), contact (and irritant contact) dermatitis, excematous dermatiti
• Gastrointestinal System conditions or disorders such as food-induced allergies (e.g., those that have effects remote form the gut such as migraine, rhinitis and eczema); eosinophilic gastroenteritis; mastocytosis; ulcerative colitis; Crohn's disease; irritable bowel syndrome; celiac disease;
• Conditions or disorders relating to other systems e.g., eosinophilis fascitis; hyper IgE syndrome; systemic mast cell disorder; Idopathic thrombocytopenia purpura; atherosclerosis; lupus erythematosus; systemic lupus erythematosus; sepsis; reperfusion injury; glomeruloephritis; allergic nephritis; nephritic syndrome; eosinophil related disorders such as Churg-Strauss syndrome; basophilic leukocytosis and basophilic leukemia and acquired immunodeficiency syndrome;
• Conditions or disorders relating to skeletal and joints systems e.g., arthritis and conditions associated therewith, e.g., osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive arthritis), tendonitis, bursitis, inflammation of joint lining, ankylosing spondylitis, Behcet's disease, childhood arthritis, diffuse idiopathic skeletal hyperostosis (DISH), Ehlers-Danlos syndrome, rheumatoid arthritis, Felty's syndrome, fibromyalgia, gout, pseudo gout, infectious arthritis, lupus, mixed connective tissue disease, osteoarthritis, Paget's disease, polymyalgia rheumatica, polyarteritis nodossa, Wegener's Granulomatosis, myositis (polymyositis dermatomyositis), psoriatic arthritis
• OA osteoarth
• the invention provides methods of treating or preventing a disorder or condition associated with DP-2 and/or one or more other PGD 2 receptors by administering to a subject having such a condition or disorder, a therapeutically effective amount of a compound or composition of the invention.
• disorders and conditions including chronic conditions and disorders of humans or other species, can be treated with modulators, or antagonists, of DP-2 and/or one or more other PGD 2 receptors.
• disorders and conditions include (1) inflammatory or allergic diseases such as systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergies, insect sting allergies, food allergies (including celiac disease and the like) and mastocytosis, (2) inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vasculitis, Behcet's syndrome, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies such as those derived from human papillomavirus, HIV or RLV infection, bacterial, fungal and other parasital cutaneous pathologies, and cutaneous lupus erythematosus, (5) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity lung diseases, chronic
• graft rejection including, e.g., allograft rejection and graft-v-host disease
• graft rejection including, e.g., allograft rejection and graft-v-host disease
• skin graft rejection e.g., skin graft rejection,, solid organ transplant rejection, bone marrow transplant rejection
• fever e.g., a fever
• cardiovascular disorders such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, thrombosis and vascular stenosis
• cerebrovascular disorders such as traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm
• cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract e.g., esophagus,
• the invention provides methods of treating or preventing a condition or disorder mediated, regulated or influenced by Th2 cells, eosinophils, basophils, platelets, Langerhans cells, dendritic cells or mast cells, comprising administering to a subject having such as condition or disorder a therapeutically effective amount of one or more of the subject compounds or compositions.
• the invention provides methods of treating or preventing a condition or disorder mediated, regulated or influenced by PGD 2 and metabolites thereof, such as 13,14-dihydro-15-keto-PGD 2 and 15-deoxy- ⁇ 12>14 PGJ 2 , comprising administering to a subject having such as condition or disorder a therapeutically effective amount of one or more of the subject compounds or compositions.
• the invention provides methods of treating or preventing a condition or disorder responsive to modulation of DP-2 and/or one or more other PGD 2 receptors comprising administering to a subject having such a condition or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
• the invention provides methods of treating or preventing a condition or disorder mediated by DP-2 and/or one or more other PGD 2 receptors comprising administering to a subject having such a condition or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
• the invention provides methods of modulating DP-2 and/or one or more other PGD 2 receptors comprising contacting a cell with one or more of the subject compounds or compositions.
• the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intraci sternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal, local) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
• the invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.
• an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
• the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
• a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
• compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent.
• composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically acceptable it is meant that the carrier or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• Formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailabilty, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
• pharmacokinetic properties e.g., oral bioavailabilty, membrane permeability
• compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
• the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the active object compound is included in an amount sufficient to produce the desired effect upon the process, condition or disorder.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil-medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• an oil-medium for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• sweetening agents such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example-beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.
• topical application is also meant to include the use of mouthwashes and gargles.
• the agents are administered directly to the lung by inhalation.
• the agents for use according to the invention may be formulated as inhalable powders in admixture with suitable physiologically acceptable excipients (see, U.S. Patent Publication No. 20060034776 which is incorporated herein by reference with respect to suitable methods of administering pharmaceutical agents by inhalation).
• the aerosol is generated by a medical nebulizer system that delivers the aerosol through a mouthpiece, facemask, etc. from which the mammalian host can draw the aerosol into the lungs.
• a medical nebulizer system that delivers the aerosol through a mouthpiece, facemask, etc. from which the mammalian host can draw the aerosol into the lungs.
• Various nebulizers are known in the art and can be used in the method of the present invention.
• the selection of a nebulizer system depends on whether alveolar or airway delivery (i.e., trachea, primary, secondary or tertiary bronchi, etc.), is desired.
• the composition is formulated as to not be too irritating at the required dosage.
• Nebulizers useful for airway delivery include those typically used in the treatment of asthma. Such nebulizers are also commercially available.
• a therapeutic amount of the agent is a sufficient amount to prevent, treat, or palliate asthma following administration of the composition to the host mammal's lung, particularly the alveoli or bronchopulmonary and bronchiolopulmonary smooth muscle and epithelial cells of the trachea, bronchi, bronchia, bronchioli, and alveoli.
• an effective amount of the aerosolized compound of the invention is a dose sufficient to effect treatment, that is, to cause alleviation or reduction of symptoms, to inhibit the worsening of symptoms, to prevent the onset of symptoms, and the like.
• the dosages of the preset compositions that constitute an effective amount can be determined in view of this disclosure by one of ordinary skill in the art by running routine trials with appropriate controls. Comparison of the appropriate treatment groups to the controls will indicate whether a particular dosage is effective in preventing or reducing particular symptoms.
• the total amount of compound delivered to a mammalian host will depend upon many factors, including the total amount aerosolized, the type of nebulizer, the particle size, breathing patterns of the mammalian host, severity of lung disease, concentration of the compound composition in the aerosolized solution, and length of inhalation therapy.
• an effective dose delivered usually lies in the range of about 1 mg/treatment to about 500 mg/treatment, although more or less may be found to be effective depending on the subject, agent, dosage regimen, and desired result. It is generally desirable to administer higher doses when treating more severe conditions. If the treatment is repeated, the mammalian host can be monitored to ensure that there is no adverse response to the treatment. The frequency of treatments depends upon a number of factors, such as the amount of the agent administered per dose, as well as the health and history of the subject.
• Inhalation aerosols containing propellant gas according to the invention may contain the agents for use according to the invention dissolved in the propellant gas or in dispersed form.
• the propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the propellant gases mentioned above may be used on their own or in mixtures thereof.
• propellant gases are halogenated alkane derivatives selected from TGl 34a, TG227, and mixtures thereof.
• the propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, preservatives and pH adjusters. All these ingredients are known in the art.
• the agents can, for instance, be formulated to have an average particle size of up to 10 microns or preferably from 0.1 to 5 microns, or from 1 to 5 microns.
• the propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art, such as metered dose inhalers. Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant gas-containing aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols.
• the solvent used may be an aqueous or alcoholic, preferably an ethanolic solution.
• the solvent may be water on its own or a mixture of water and ethanol.
• the relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water.
• compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of asthma, allergic diseases, inflammatory conditions and cancer and pathologies associated therewith (e.g., cardiovascular disease) or other adjuvant.
• compositions which include a compounds of the invention and an alternative agent have additive or synergistic effects when administered.
• the compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the disorder or conditions for which compounds of the invention are useful, including inflammatory conditions, immune disorders, asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, viral infection, thrombosis, fibrosis, flushing, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, inflammation, pain, conjunctivitis, nasal congestion, urticaria and those pathologies noted above.
• agents useful in the treatment, prevention, suppression or amelioration of the disorder or conditions for which compounds of the invention are useful including inflammatory conditions, immune disorders, asthma, allergic rhinitis, eczema, psoria
• Such other agents, or drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound of the invention.
• a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred.
• the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
• Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and corticosteroid analogs such as budesonide; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune ® , Neoral ® ), tacrolimus (FK-506, Prograi ), rapamycin (sirolimus, Rapamune ® ) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept ® ); (d) antihistamines
• the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the invention is combined with an NSAID, the weight ratio of the compound of the invention to the NSAID will generally range from about 1000:1 to about 1 : 1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
• spirometry can be used to assess lung function.
• the diagnosis of asthma in particular, may be made in part based upon family history or personal history of a severe and sudden episode or recurrent episodes of wheezing, coughing or shortness of breath which may be associated with exposure to an allergen or exacerbated or precipitated by moderate exercise.
• a physical exam is involved to detect the disorder or condition.
• the nose may be examined for signs of allergic disorder or condition such as increased nasal secretions, swelling or polyps which may be triggering asthma.
• a stethoscope may be used to listen to the sounds the lungs make during breathing. Wheezing sounds are one of the main indicators of the obstructed airways associated with asthma.
• allergic conditions such as eczema or hives, are often associated with asthma.
• Pulmonary function tests are particularly useful in confirming the diagnosis of respiratory disorders or conditions. These tests include spirometry to determine vital capacity, the maximum amount of air that you can inhale and exhale; the peak expiratory flow rate, also known as the peak flow rate, which is the maximum flow rate you can generate during a forced exhalation; and forced expiratory volume, which is the maximum amount of air you can exhale in one second.
• a bronchodilator drug used in asthma treatment can be administered to open obstructed air passages and the spirometry repeated. If the measurements improve significantly, asthma is likely.
• asthma may be diagnosed by challenging the individual with exercise, or by inhaling an airway-constricting chemical or taking several breaths of cold air. After the challenge with a symptom-producing substance or activity, the spirometry test is readministered. If the spirometry measurements fall significantly, asthma is indicated.
• the crude residue was purified via reverse phase HPLC (Column: Phenomenex, 250 X 10 mm, 10 micro, Luna 10 ⁇ ; Gradient: 90%:10%:0.05% H 2 O/CH 3 CN/TFA (or formic acid) to 10%/90%/0.05% H 2 O/CH 3 CN/TFA (or formic acid) over 20 min).
• Step B Methyl 2-(4-(isopentyloxy)-3-(piperazin-l-ylmethyl)phenyl)acetate (Compound 69B).
• Step C Methyl 2-(4-(isopentyloxy)-3-((4-tosylpiperazin-l-yl)methyl)phenyl)acetate (Compound 69C)
• Step D 2-(4-(isopentyloxy)-3-((4-tosylpiperazin-l-yl)methyl)phenyl)acetic acid (Compound 69D)
• Step B 2-(4-(isopentyloxy)-3-((4-(phenylcarbamoyl)piperazin-l-yl)methyl)phenyl)acetic acid (Compound 70B).
• Trifluoromethanesulfonic anhydride (0.691 mL, 4.12 mmol), DIEA (0.718 mL, 4.12 mmol), and DMAP (33 mg, 0.274 mmol) were added to a stirring solution of ?-butyl 4-(2-hydroxy-5-(2-methoxy-2-oxoethyl)benzyl)piperazine-l-carboxylate (Ig, 2.74 mmol) in CH 2 Cl 2 (20 mL) at 0 0 C. The resulting suspension was warm to rt and stirred over night followed by addition of satd. NaHCO 3 (30 niL).
• Step C 2-(2-((4-tosylpiperazin-l-yl)methyl)biphenyl-4-yl)acetic acid (Compound 85C).
• Example 88 Methyl 2-(4'-chloro-2-(thiomorpholindioxy-methyl)biphenyl-4-yl)acetate (Compound 88A) and 2-(4'-chloro-2-(thiomorpholindioxy-methyl)biphenyl-4-yl)acetic acid (Compound 88B).
• Step B 2-(4-(phenylethynyl)-3-((4-tosylpiperazin-l-yl)methyl)phenyl)acetic acid (Compound 89B).
• Step A Methyl 2-(4-hydroxy-3-((3-oxopiperazin-l-yl)methyl)phenyl)acetate (Compound 91A).
• Step B Methyl 2-(4-(4-chlorobenzyloxy)-3-((3-oxopiperazin-l-yl)methyl)phenyl)acetate (Compound 91B).
• Step A Methyl 2-(4-hydroxy-3-(phenyl(4-tosylpiperazm-l-yl)methyl)phenyl)acetate (Compound 94A).
• Step B 2-(4-hydroxy-3-(phenyl(4-tosylpiperazin-l-yl)methyl)phenyl)acetic acid (Compound 94B)
• Step A 2-((3-(hydroxymethyl)phenyl)(4-tosylpiperazin-l-yl)methyl)phenol .
• Step B 2-(3-((2-hydroxyphenyl)(4-tosylpiperazin-l-yl)methyl)phenyl)acetic acid
• Step B R-2-(3-((4-(4-fluorophenylsulfonyl)piperazin-l-yl)(phenyl)methyl)phenyl)acetic acid and S-2-(3-((4-(4-fluorophenylsulfonyl)piperazin- 1 -yl)(phenyl)methyl)phenyl)acetic acid (Compound 99B and C)
• Example 102 Methyl 2-(3-((4-(methylsulfonyl)piperazin- 1 -yl)(phenyl)methyl)phenyl)acetate (Compound 102A) and 2-(3-((4-(methylsulfonyl)piperazin-l-yl)(phenyl)methyl)phenyl)acetic acid (Compound 102B)
• Example 104 2-(3-chloro-5-(phenyl(4-(phenylsulfonyl)piperazin-l-yl)methyl)phenyl)acetic acid (Compound 104E).
• Step C tert-butyl 4-((3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(phenyl)methyl)piperazin e-1-carboxylate (Compound 104C)
• Step E 2-(3-chloro-5-(phenyl(4-(phenylsulfonyl)piperazin-l-yl)methyl)phenyl)acetic acid (Compound 104E)
• Step A 2-(4-chlorobenzyloxy)-5-(2-methoxy-2-oxoethyl)benzoic acid (Compound 106A)
• Step B 2-(4-(4-chlorobenzyloxy)-3-(4-tosylpiperazine-l-carbonyl)phenyl)acetic acid (Compound 106B)
• Step A methyl 2-(3-((but-3-enylamino)methyl)-4-(4-chlorobenzyloxy)phenyl)acetate (Compound 109A)
• Step D (S,Z)-2-(4-(4-chlorobenzyloxy)-3-((3-(4-methylphenylsulfonamido)-2-oxo-3,4,7,8-tetrahydro azocin-l(2H)-yl)methyl)phenyl)acetic acid (Compound 109D)

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