CN101535299A - 5-lipoxygenase-activating protein (FLAP) inhibitors - Google Patents
5-lipoxygenase-activating protein (FLAP) inhibitors Download PDFInfo
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Abstract
Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of the following provisional applications: U.S. provisional application No.60/734,030, entitled "5-lipoxygenated PROTEIN (FLAP) INHIBITORS", filed on 4.11.2005; U.S. provisional application No.60/747,174 entitled "5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS" filed on 12.5.2006; and U.S. provisional application No.60/823,344, entitled "5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS", filed on 23.8.2006, all of which are incorporated herein by reference.
Technical Field
[0002] Described herein are compounds, methods of making the compounds, pharmaceutical compositions and medicaments comprising the compounds, and methods of using the compounds to treat or prevent diseases or disorders associated with 5-lipoxygenase-activating protein (FLAP) activity.
Background
[0003]Protein 5-lipoxygenase-activating protein (FLAP) is involved in the leukotriene synthesis pathway. In particular, 5-lipoxygenase-activating protein (FLAP) can cause arachidonic acid to bind and transfer to 5-lipoxygenase. See, e.g., Abramovitz, m. et al, eur.j. biochem.215: 105-111(1993). Then 5-lipoxygenase energyCapable of catalyzing the two-step oxidation and dehydration of arachidonic acid, converting it into the intermediate compound 5-HPETE (5-hydroperoxicosatetraenoic acid), and converting 5-HPETE into leukotriene A in the presence of FLAP4(LTA4)。
[0004] Leukotrienes are biological compounds formed from arachidonic acid in The leukotriene synthesis pathway (Samuelsson et al, Scienc 220, 568-575, 1983; Cooper, The Cell, A Molecular Approach, 2nd Ed. Sinauer Associates, Inc., Sunderland (MA), 2000). They are synthesized primarily by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes are involved in biological actions including, by way of example only, smooth muscle contraction, leukocyte activation, cytokine factor secretion, mucus secretion, and vascular function.
Summary of The Invention
[0005] Provided herein are methods, compounds, pharmaceutical compositions and medicaments for: (a) to diagnose, prevent or treat allergic and non-allergic inflammation, (b) to control conditions and symptoms associated with inflammation, and/or (c) to control proliferative or metabolic disorders. These disorders can be caused by genetic, iatrogenic, immunological, infectious, metabolic, neoplastic, toxic, and/or traumatic etiologies. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein include a 5-lipoxygenase-activating protein (FLAP) inhibitor described herein.
[0006] In one aspect, provided herein are compounds of formula (E), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, that antagonize or inhibit FLAP and may be used to treat patients suffering from leukotriene-dependent disorders or diseases, including but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory disorders.
[0007] The formula (E) is as follows:
wherein,
z is OC (R)1)2[C(R2)2]n、[C(R2)2]nOr [ C (R) ]2)2]nC(R1)2O, wherein each R1Independently is H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1May be linked to form a carbonyl (═ O); each R2Independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2May be linked to form a carbonyl (═ O); each n is independently 0, 1, 2 or 3;
y is-L1- (substituted or unsubstituted heteroalicyclic) provided that, when the heteroatom is directly bonded to Z, the heteroalicyclic is substituted;
wherein L is1Is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, or substituted or unsubstituted heteroalkynyl;
wherein each substituent is (L)sRs)jWherein each LsIndependently selected from the group consisting of a bond, -O-, -C (O) -, -S (O)2-、-NHC(O)-、-C(O)NH-、S(＝O)2NH-、-NHS(＝O)2、-OC(O)NH-、-NHC(O)O-、-OC(O)O-、-NHC(O)NH-、-C(O)O-、-OC(O)-、C1-C6Alkyl radical，C2-C6Alkenyl, -C1-C6Fluoroalkyl, heteroaryl, aryl, or heteroalicyclic groups; each RsIndependently selected from H, halogen, -N (R)4)2、-CN、-NO2，N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C 1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R4Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4The groups can together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
R6is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (═ O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl), or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroalicyclic group;
x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；
L4Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
G1Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G1Is W-G5Wherein W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl group, G5Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R9Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups can together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9Can form together a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Independently selected from: H. -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl, or heteroalkyl;
r5 is H, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted O-C1-C6An alkyl group;
R11is L7-L10-G6(ii) a Wherein L is7Is a bond, -O, -S (O)2-NH, -C (O) NH, -NHC (O), - (substituted or unsubstituted C 1-C6Alkyl) or (substituted or unsubstituted C2-C6Alkenyl);
L10is a bond, (substituted or not)Substituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group), and
G6is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -NHS (═ O)2R8、-S(＝O)2N(R9)2、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group), or (substituted or unsubstituted heteroaryl), and G7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L 5- (substituted or unsubstituted aryl) in which L5is-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
R12is H, (substituted or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C4Alkenyl); or an active metabolite, or a solvate, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
[0008]For any and all embodiments (e.g., formula (E), formula (E-I), and formula (E-II)), the substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Y is-L1- (substituted or unsubstituted heteroalicyclic). In a further or alternative embodiment, the heteroalicyclic group is selected from the group consisting of quinolizine, dioxine, piperidine, morpholine, thiazine, tetrahydropyridine, piperazine, oxazinone (oxazinone), dihydropyrrole, dihydroimidazole, tetrahydrofuran, dihydrooxazole, ethylene oxide, pyrrolidine, pyrazolidine, dihydrothiophenone (dihydrothiophenone), imidazolidinone, pyrrolidone, dihydrofuranone, dioxolanone, thiazolidine, piperidone, tetrahydronaphthyridine (tetrahydronaphthyridine), tetrahydroquinoline, tetrahydrothiophene, indoline, tetrahydroquinoline, and thiazepane (thiazepane). In a further or alternative embodiment, the heteroalicyclic group is selected from:
[0009]in a further or alternative embodiment, R6Is L2- (substituted or unsubstituted alkyl), or L2- (substituted or unsubstituted cycloalkyl), or L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O), -CH (OH), or substituted or unsubstituted alkyl.
[0010]In a further or alternative embodiment, R7Is L3-X-L4-G1(ii) a Wherein L is3Is a substituted or unsubstituted alkyl group; x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10) O-; and L4Is a bond or a substituted or unsubstituted alkyl group.
[0011]In a further or alternative embodiment, G1Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8Or G1Is W-G5Wherein W is a substituted or unsubstituted heteroalicyclic group or a substituted or unsubstituted heteroaryl group, G5Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8。
[0012]In a further or alternative embodiment, X is a bond, -O-, -CR9(OR9)、S、-S(O)、-S(O)2、-NR8-O-N ═ CH, -CH ═ N-O, -NHC (═ O), or-C (═ O) NH.
[0013]In a further or alternative embodiment, R12Is H, and R11Is L7-L10-G6Wherein: l is7Is a bond, (substituted or unsubstituted C1-C6Alkyl groups); l is10Is (substituted or unsubstituted aryl), (substituted or unsubstituted heteroAryl), or (substituted or unsubstituted heteroalicyclic). In a further or alternative embodiment, L 10Is (substituted or unsubstituted aryl).
[0014]In a further or alternative embodiment, G6Is W-G7Wherein W is (substituted or unsubstituted heteroalicyclic) or (substituted or unsubstituted heteroaryl), G7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)、OH、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R8、N(R9)2、-C(＝NR10)N(R8)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CON(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L5- (substituted or unsubstituted aryl), L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O).
[0015]In some embodiments, Z is [ C (R)2)2]nC(R1)2O。
[0016] Any combination of the above-described groups of the various variants is contemplated herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be synthesized by techniques known in the art as well as those methods set forth herein.
[0017]In a further or alternative embodiment, the compounds provided herein are inhibitors of 5-lipoxygenase-activating protein (FLAP). In advance ofIn a further or alternative embodiment, the compounds provided herein are inhibitors of 5-lipoxygenase-activating protein (FLAP), wherein the inhibitor is selective for FLAP. In a further or alternative embodiment, the inhibitor has an IC of less than 50microM in FLAP binding 50The value is obtained.
[0018] In one aspect, provided herein are compounds selected from the group consisting of:
(S) -2- [ 3-tert-butylsulfanyl (butylsul-fanyl) -2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (compound 1-1); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-2); (R) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 1-3); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -5-oxo-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-4); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -5-oxo-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-5); 3- [5- ((R) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-6); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -1-methanesulfonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-7); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-methanesulfonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-8); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -1-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-9); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (2, 2, 2-trifluoro-acetyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-10); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -4, 5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (compound 1-11); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (4, 5-dihydro-1H-imidazol-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-12); (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (compound 1-13); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2-morpholin-4-yl-2-oxo-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-14); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [ (S) -1- (2, 3-dihydro-1H-indol-2-yl) methoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-15); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-16); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (2-methyl-propane-2-sulfonyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-17); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-cyclopropanecarbonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-18); 3- [5- ((S) -1-benzoyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-19); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-isobutyryl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-20); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-propionyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-21); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (compound 1-22); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2, 3-dihydro-1H-indol-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-23); 3- [5- (1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-24); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (2-methyl-propane-2-sulfinyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-25); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-benzyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-26); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-27); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-28); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyryl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-29); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyryl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-30); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-ethyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-31); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-propyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-32); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-isobutyryl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-33); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclopropanecarbonyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-34); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-benzoyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-35); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclobutylcarbonyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-36); 3- [ 3-acetyl-5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-37); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-propionyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-38); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-isobutyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-39); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-40); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclobutylmethyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-41); 3- [5- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-42); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (1-phenylacetyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-43); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenyl-propionyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-44); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenoxy-benzoyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-45); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (4-phenoxy-benzoyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-46); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-3-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-47); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-48); 3- [5- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-49); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (1-phenylacetyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-50); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenyl-propionyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-51); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- ((S) -2-phenyl-cyclopropanecarbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-52); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-3-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-53); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-54); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- ((R) -2-phenyl-cyclopropanecarbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-55); 3- [ 3-tert-butylsulfanyl-5- [ (S) -1- (4-chloro-benzoyl) -pyrrolidin-2-ylmethoxy ] -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-56); 3- [5- {1- [2- (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-ylmethoxy } -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-57); 3- [5- {1- [2- (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-ylmethoxy } -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-58); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -piperidine-1-carboxylic acid tert-butyl ester (compound 1-59); 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -piperidine-1-carboxylic acid tert-butyl ester (compound 1-60); 2- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid 2-bromoethyl ester (compound 1-61); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-62); 3- {1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- [2- (2-methyl- [1, 3] dioxolan-2-yl) -ethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-63); (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-thiazol-2-yl-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 2-1); 3- [ 3-tert-butylsulfanyl-5- ((S) -1-pyrrolidin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-2); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-3); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-4); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-5); 3- {5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-6); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-7); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-8); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-9); 3- { 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- [2- (2-methyl- [1, 3] dioxolan-2-yl) -ethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-10); 3- { 3-tert-butylsulfanyl-5- [ (S) -1- (2-methoxy-acetyl) -2, 3-dihydro-1H-indol-2-ylmethoxy ] -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-11); 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy ] -1-morpholin-4-yl-ethanone (compound 3-1); (R) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-2); (R) -2- [ 3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-3); 1- { (R) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidin-1-yl } -ethanone (compound 3-4); 1- { (R) -2- [ 3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl ] -pyrrolidin-1-yl } -ethanone (Compound 3-5); and (S) -tert-butyl 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (3-hydroxy-2, 2-dimethyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylate (compound 3-6).
[0019] In one aspect, provided herein are pharmaceutical compositions comprising an effective amount of a compound provided herein and a pharmaceutically acceptable excipient.
[0020] In another aspect, provided herein is a method of treating inflammation in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein.
[0021]In yet another aspect, provided herein is a method of treating asthma in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein. In a further or alternative embodiment, provided herein is a method of treating asthma in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein, wherein Z is [ C (R)2)2]nC(R1)2O。
[0022]In another aspect, provided herein is a method of treating a respiratory disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein. In a further or alternative embodiment, provided herein is a method of treating a respiratory disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein, wherein Z is [ C (R)2)2]nC(R1)2O。
[0023] In another aspect, provided herein is a method of treating cardiovascular disease in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein.
[0024] Any combination of the above-described groups of the various variants is contemplated herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be synthesized by techniques known in the art as well as those methods set forth herein.
[0025] In another aspect, provided is a compound of any one of figures 8, 9, 10, or 11, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, and pharmaceutically acceptable solvate thereof, that antagonizes or inhibits FLAP and may be used to treat a patient suffering from a leukotriene-dependent disorder or disease, including but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory disorders.
[0026] In another aspect, provided is a compound of any one of tables 1, 2 or 3, a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, and a pharmaceutically acceptable solvate thereof, that antagonizes or inhibits FLAP and may be used to treat a patient suffering from a leukotriene-dependent disorder or disease, including but not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory disorders.
[0027]In a further or alternative embodiment, the compounds described herein may be inhibitors of 5-lipoxygenase-activating protein (FLAP), while in a still further or alternative embodiment, such inhibitors are selective for FLAP. In still a further or alternative embodiment, such an inhibitor has an IC of less than 50microM in the FLAP binding assay50The value is obtained.
[0028] In a further or alternative embodiment, the compounds described herein may be included in a pharmaceutical composition or medicament for treating a leukotriene-dependent or leukotriene mediated disorder or disease in a patient.
[0029] In another aspect, inflammatory disorders include, but are not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, aortic aneurysm, myocardial infarction, and stroke. In other aspects, proliferative disorders include, but are not limited to: conditions of cancer and non-cancerous lesions, including but not limited to those involving skin or lymphatic tissue. In other aspects, metabolic disorders include, but are not limited to, bone remodeling, loss or increase. In other aspects, such disorders are iatrogenic, and elevation or abnormal localization of leukotrienes can be caused by other treatments or medical or surgical methods.
[0030] In other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used to prevent cellular activation of 5-lipoxygenase, while in other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used to limit the formation of leukotrienes. In other aspects, the above methods, compounds, pharmaceutical compositions, and medicaments may include a FLAP inhibitor disclosed herein for use in treating asthma by: (a) reducing the concentration of leukotrienes in certain tissues of the patient's body or in the whole body, (b) modulating the activity of an enzyme or protein in the patient, wherein such enzyme or protein is involved in the leukotriene pathway, such as 5-lipoxygenase-activating protein or 5-lipoxygenase, or (c) combining the effects of (a) and (b). In other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used in combination with other therapeutic or surgical approaches.
[0031] In one aspect, is a method of reducing/inhibiting leukotriene synthesis activity of 5-lipoxygenase-activating protein (FLAP) in a mammal comprising administering to the mammal at least once an effective amount of a compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0032]In a further or alternative wayIn alternative embodiments, a "G" group (e.g., G) of any one of formula (E), formula (E-I), or formula (E-II)1、G5、G6、G7) Are all groups used to design the physical and biological properties of the (tailor) molecule. This design/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. Physical and biological properties modulated by the above-described modification of "G" include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. In addition, in vivo metabolism may include, by way of example only, controlling PK properties in vivo, off-target activities, potential toxicity associated with cypP450 interactions, drug-drug interactions, and the like. Further, the modification to "G" allows tailoring of the in vivo efficacy of the compound by, for example, modulating specific and non-specific proteins binding to plasma proteins and lipids and tissue distribution in vivo. In addition, such design/modification for "G" may design compounds that are selective for the 5-lipoxygenase-activating protein over other proteins. In a further or alternative embodiment, "G" is L 20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In a further or alternative embodiment, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, the affinity moiety allows site-specific binding, including but not limited to antibodies, antibody fragments, DNA, RNA, siRNA and ligands.
[0033] In another aspect, is a method of modulating comprising reducing and/or inhibiting the activity of a 5-lipoxygenase activating protein in a mammal, directly or indirectly, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0034] In another aspect, is a method of modulating comprising reducing and/or inhibiting the activity of a leukotriene in a mammal, directly or indirectly, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0035] In another aspect, is a method of treating a leukotriene-dependent or leukotriene mediated condition or disease comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0036] In another aspect, is a method of treating inflammation comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0037] In another aspect, is a method of treating a respiratory disorder comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). In a further embodiment of this aspect, the respiratory disease is asthma. In further embodiments of this aspect, respiratory diseases include, but are not limited to: adult respiratory distress syndrome and allergic (external) asthma, non-allergic (internal) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergy-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, equal carbon dioxide hyperventilation, childhood asthma (child-onset asthma), adult onset asthma (adult-onset asthma), cough variant asthma, occupational asthma, hormone resistant asthma, seasonal asthma.
[0038] In another aspect, is a method of treating chronic obstructive pulmonary disease comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). In further embodiments of this aspect, the chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis, and/or airway inflammation and cystic fibrosis.
[0039] In another aspect, is a method of preventing increased mucosal secretion and/or edema in a disease or condition comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0040] In another aspect, is a method of treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke comprising administering to a mammal an effective amount of a compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0041] In another aspect, is a method of treating organ reperfusion injury following organ ischemia and/or endotoxic shock comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0042] In another aspect, is a method of reducing vasoconstriction in a mammal comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0043] In another aspect, is a method of reducing or preventing elevated blood pressure in a mammal comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0044] In another aspect, is a method of preventing an increase in eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or monocytes comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0045] A further aspect is a method of preventing or treating abnormal bone remodeling, loss or increase, including diseases or disorders such as osteopenia, osteoporosis, Paget's disease, cancer and other diseases, comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I) or formula (E-II).
[0046] In another aspect, is a method of preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0047] In another aspect, is a method of treating a CNS disorder comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). CNS disorders include, but are not limited to: multiple sclerosis, parkinson's disease, alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema and craniocerebral injury.
[0048] In a further aspect, is a method of treating cancer comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). Cancer types may include, but are not limited to, pancreatic cancer and other solid or hematological tumors.
[0049] In another aspect, is a method of treating endotoxic shock and septic shock comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0050] In another aspect, is a method of treating rheumatoid arthritis and osteoarthritis comprising administering to a mammal at least once an effective amount of at least one compound having a structure of any one of formula (E), formula (E-I), or formula (E-II).
[0051] In another aspect, is a method of preventing an increase in GI disease comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). Such diseases include, by way of example only, chronic gastritis, eosinophilic gastroenteritis and gastric motor dysfunction.
[0052] In a further aspect, is a method of treating kidney disease comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II). Such diseases include, by way of example only, glomerulonephritis, cyclosporine nephrotoxic renal ischemia reperfusion.
[0053] In another aspect, is a method of preventing or treating acute or chronic renal insufficiency, comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0054] In another aspect, is a method of treating type II diabetes comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0055] In another aspect, is a method of reducing an inflammatory aspect of an acute infection of one or more solid organs or tissues, such as a kidney with acute pyelonephritis.
[0056] In another aspect, is a method of preventing or treating an acute or chronic condition involving eosinophil recruitment or activation comprising administering to a mammal at least once an effective amount of at least one compound described herein.
[0057] In another aspect, is a method of preventing or treating acute or chronic erosive disorders or motor dysfunction of the gastrointestinal tract caused by non-steroidal anti-inflammatory drugs (including selective or non-selective cyclooxygenase-1 or-2 inhibitors) comprising administering to a mammal at least once an effective amount of at least one compound described herein.
[0058] A further aspect is a method of preventing or treating rejection or dysfunction of a transplanted organ or tissue comprising administering to a mammal at least once an effective amount of at least one compound described herein.
[0059] In another aspect, is a method of treating an inflammatory response of the skin comprising administering to a mammal at least once an effective amount of at least one compound described herein. Such inflammatory reactions of the skin include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scars. In another aspect, is a method of reducing psoriatic lesions in the skin, joints or other tissues or organs comprising administering to a mammal an effective amount of a first compound having a structure of any one of formula (E), formula (E-I) or formula (E-II).
[0060] A further aspect is a method of treating cystitis, including, for example, interstitial cystitis, comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0061] In a further aspect, is a method of treating a metabolic syndrome, such as familial mediterranean fever, comprising administering to a mammal at least once an effective amount of at least one compound having the structure of any one of formula (E), formula (E-I), or formula (E-II).
[0062] In a further aspect, is a method of treating hepatorenal syndrome comprising administering to a mammal at least once an effective amount of at least one compound described herein.
[0063] In another aspect, is the use of a compound described herein for the manufacture of a medicament for treating an inflammatory disease or disorder in an animal, wherein the activity of at least one leukotriene protein causes the pathology and/or symptomology of the disease or disorder. In one embodiment of this aspect, the leukotriene pathway protein is a 5-lipoxygenase-activating protein (FLAP). In another or further embodiment of this aspect, the inflammatory disease or disorder is a respiratory, cardiovascular or proliferative disease.
[0064] In any of the above aspects is a further embodiment, wherein the administration is enteral, parenteral, or both, wherein (a) an effective amount of the compound is administered systemically to the mammal; and/or (b) orally administering to the mammal an effective amount of a compound; and/or (c) administering intravenously to the mammal an effective amount of the compound; and/or (d) administering an effective amount of the compound by inhalation; and/or (e) administering an effective amount of the compound intranasally; or/and/or (f) administering to the mammal an effective amount of a compound by injection; and/or (g) topically (dermally) administering to the mammal an effective amount of a compound; and/or (h) administering an effective amount of the compound for ocular administration; and/or (i) rectally administering to the mammal an effective amount of the compound.
[0065] In any of the above aspects, is a further embodiment, wherein the mammal is a human, including the following embodiments, wherein (a) the human has an asthmatic condition or one or more other conditions selected from: allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergy-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocarbon dioxide hyperventilation, childhood asthma, adult-induced asthma, cough-variant asthma, occupational asthma, hormone-resistant asthma, or seasonal asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension or interstitial pulmonary fibrosis. In any of the above aspects, is a further embodiment, wherein the mammal is an animal model for pulmonary inflammation, examples of which are provided herein.
[0066] In any of the above aspects, is a further embodiment comprising separately administering an effective amount of the compound, including further embodiments wherein (i) the compound is administered once; (ii) administering the compound to the mammal multiple times over a day; (iii) given frequently; or (iv) continuous administration.
[0067] In any of the above aspects, is a further embodiment comprising multiple administrations of an effective amount of the compound, including further embodiments wherein (i) a single dose of the compound is administered; (ii) the time between doses was every 6 hours; (iii) the compound is administered to the mammal every 8 hours. In further or alternative embodiments, the method comprises a drug holiday wherein administration of the compound is temporarily suspended, or the dose of the compound administered is temporarily reduced; at the end of the drug holiday, the dose of compound was restored. The length of the drug holiday can be 2 days to 1 year.
[0068]In any of the foregoing aspects directed to treating a leukotriene-dependent disease or disorder, is a further embodiment, comprising administering at least one additional agent, each agent being administered in any order, including, for example, an anti-inflammatory agent, a different compound having the structure of any one of formula (E), formula (E-I), or formula (E-II), CysLT1Receptor antagonists, or CysLT1/CysLT2A dual receptor antagonist. In a further or alternative embodiment, CysLT1The antagonist is selected from montelukast (Singulair)TM: [1- [ [1- [3- [2- [ (7-chloro-2-quinolinyl)]Vinyl radical]Phenyl radical]-3- [2- (1-hydroxy-1-methyl-ethyl) phenyl ]-propyl radical]Mercapto methyl group]Cyclopropyl group]Acetic acid), zafirlukast (Acclate)TM: 3- [ [ 2-methoxy-4- (o-tolylsulfonylcarbamoyl) phenyl ] amino]Methyl radical]-1-methyl-1H-indol-5-yl]Cyclopentyl carbamate) or pranlukast (Onon)TM: 4-oxo-8- [ p- (4-phenylbutoxy) benzoylamino group]-2-tetrazol-5-yl) -4H-1-benzopyran).
[0069]In further or alternative embodiments, anti-inflammatory agents include, but are not limited to: non-steroidal anti-inflammatory drugs such as cyclooxygenase inhibitors (COX-1 and/or COX-2), lipoxygenase inhibitors and steroids such as prednisone or dexamethasone. In a further or alternative embodiment, the anti-inflammatory agent is selected from: arthrotec
Mesalazine (Asacol), AuralganSulfasalazine, oxaprozin (Daypro), etodolac, mefenamic acid, mesalamine (Salofalk), sodium succinate methylprednisolone (Solu-Mekrol), aspirin, indomethacin (Indocin)TM) Rofecoxib (Vioxx)TM) Celecoxib (Celebrex)TM) Valdecoxib (Bextra)TM) Diclofenac, etodolac, ketoprofen, etodolac (Lodine), mobibac (mobil), nabumetone, naproxen, piroxicam, betamethasone (celesterone), prednisone, hydrocortisone (Deltasone), or any general equivalent thereof.
[0070]In any of the preceding aspects directed to treating proliferative disorders, including cancer, is a further embodiment comprising administering at least one additional agent selected from the group consisting of: alemtuzumab (Alemtuzumab), arsenic trioxide, asparaginase (pegylated or non-pegylated), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab (gemtuzumab), methotrexate, PaclitaxelTMTylosin (taxol), temozolomide, thioguanine, or classes of drugs including hormones (antiestrogens, antiandrogens, or gonadotropin releasing hormone analogues, interferons such as interferon alpha, nitrogen mustards such as busulfan or melphalan or nitrogen mustards, retinoids such as retinoic acid (tretinoin), topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefitinib (gefinitib) or imatinib (imatinib), or agents for treating signs or symptoms induced by such treatment, including allopurinol, filgrastim, granisetron/ondansetron/Palonosetron (Palonosetron), dronabinol.
[0071] In any of the preceding aspects directed to treating a transplanted organ or tissue or cell, is a further embodiment comprising administering at least one additional agent selected from the group consisting of: azathioprine, corticosteroids, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus or cinquelin (thymolobulin).
[0072] In any of the above aspects directed to treating interstitial cystitis, is a further embodiment comprising administering at least one additional agent selected from the group consisting of dimethylsulfoxide, omalizumab, and pentosan polysulfate.
[0073] In any of the above aspects directed to the treatment of a bone disorder, is a further embodiment comprising administering at least one additional agent selected from minerals (minorals), vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analog, and the cathepsin K inhibitor dronabinol.
[0074]In any of the preceding aspects directed to preventing or treating inflammation, is a further embodiment comprising: (a) detecting inflammation in the mammal; (b) measuring bronchoconstriction in the mammal; (c) determining the amount of supplementation of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or monocytes and/or lymphocytes of the mammal; (d) detecting mucosal secretion in a mammal; (e) measuring mucosal edema in a mammal; (e) determination of LTB of calcium ionophore-stimulated blood (calcium ionophores-challenge blood) in mammals 4Horizontal; (f) determination of LTE in urinary Excreta of mammals4Horizontal; or (g) identifying the patient by measuring leukotriene-induced inflammatory biomarkers, e.g., LTB4、LTC4、Il-6、CRP、SAA、MPO、EPO、MCP-1、MIP-、sICAMs、Il-4、Il-13。
[0075] In any of the preceding aspects directed to preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, is a further embodiment comprising identifying a patient by screening for leukotriene gene haplotypes. In a further or alternative embodiment, the leukotriene gene haplotype is a leukotriene pathway gene, while in a still further or alternative embodiment, the leukotriene gene haplotype is a 5-lipoxygenase-activating protein (FLAP) haplotype.
[0076] In any of the preceding aspects directed to preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, is a further embodiment, comprising identifying the patient by detecting any of:
i) at least one leukotriene-related inflammatory biomarker; or
ii) at least one functional marker response to a leukotriene modulator; or
iii) at least one leukotriene-related inflammatory biomarker and at least one functional marker response to leukotriene modulators.
In a further or alternative embodiment, the leukotriene-related inflammatory biomarker is selected from LTB4Cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, while in a still further or alternative embodiment, the functional marker response is significant lung capacity (FEV 1).
[0077] In any of the preceding aspects directed to preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, is a further embodiment comprising identifying the patient by any one of:
i) screening the patient for at least one leukotriene gene SNP and/or haplotype, including the internal (intron) or external (exonic) position of the SNP; or
ii) detecting at least one leukotriene-related inflammatory biomarker in the patient; or
ii) detecting at least one functional marker response of the patient to the leukotriene modulator.
In a further or alternative embodiment, the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In a still further or alternative embodiment, the leukotriene gene SNP or haplotype is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In a further or alternative embodiment, the leukotriene-related inflammatory biomarker is selected from LTB 4Cysteinyl leukotrienes, CRP, SAA, MPO,EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, and in a still further or alternative embodiment, the functional marker response is significant lung volume (FEV 1).
[0078] In any of the preceding aspects directed to preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, is a further embodiment comprising identifying the patient by at least two of:
i) screening the patient for at least one leukotriene gene SNP or haplotype;
ii) detecting at least one leukotriene-related inflammatory biomarker in the patient;
ii) detecting at least one functional marker response of the patient to the leukotriene modulator.
In a further or alternative embodiment, the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In a still further or alternative embodiment, the leukotriene gene SNP or haplotype is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In a further or alternative embodiment, the leukotriene-related inflammatory biomarker is selected from LTB4Cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4 and IL-13, while in a still further or alternative embodiment, the functional marker response is significant lung capacity (FEV 1).
[0079] In any of the preceding aspects directed to preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, is a further embodiment comprising identifying the patient by:
i) screening the patient for at least one leukotriene gene SNP or haplotype; and
ii) detecting at least one leukotriene-related inflammatory biomarker in the patient; and
ii) detecting at least one functional marker response of the patient to the leukotriene modulator.
In a further or alternative embodiment, the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In a still further or alternative embodiment, the leukotriene gene SNP or haplotype is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In a further or alternative embodiment, the leukotriene-related inflammatory biomarker is selected from LTB4, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4, and IL-13, while in a still further or alternative embodiment, the functional marker response is significant lung capacity (FEV 1).
[0080] In another aspect, is a method of preventing or treating a leukotriene-dependent or leukotriene mediated disease or condition, comprising administering to a patient an effective amount of a FLAP modulator, wherein the patient is identified using information obtained by:
i) Screening the patient for at least one leukotriene gene SNP or haplotype; and
ii) detecting at least one leukotriene-related inflammatory biomarker in the patient; and
ii) detecting at least one functional marker response of the patient to the leukotriene modulator.
In a further or alternative embodiment, the FLAP modulator is a FLAP inhibitor. In a further or alternative embodiment, the leukotriene gene SNP or haplotype is a leukotriene pathway gene. In a still further or alternative embodiment, the leukotriene gene SNP or haplotype is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In a further or alternative embodiment, the leukotriene-related inflammatory biomarker is selected from LTB4, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-, sICAM, IL-6, IL-4, and IL-13, while in a still further or alternative embodiment, the functional marker response is significant lung capacity (FEV 1). In further or alternative embodiments, the information obtained from the three diagnostic methods may be used in an algorithm where the information is analyzed to identify patients in need of treatment with a FLAP modulator, the treatment regimen, and the type of FLAP modulator used.
[0081] In any of the preceding aspects, leukotriene-dependent or leukotriene mediated diseases or conditions include, but are not limited to: asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, and endotoxic shock.
Certain chemical terms
[0082]Unless otherwise indicated, the following terms used in this application (including the specification and claims) have the following definitions. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Definitions for standardized chemical terms are available in the literature, including Carey and Sundberg "
"Vols.A (2000) and B (2001), Plenum Press, New York, 4 th edition. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used within the skill of the art. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms, such as "comprises", "comprising" and "including", is not limiting.
[0083] "alkoxy" refers to a (alkyl) O-group, wherein alkyl is as defined herein.
[0084] "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be "saturated alkyl," which means that it does not contain any alkene or alkyne moieties alkyl moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which is meant to contain at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight-chain or cyclic.
[0085]An "alkyl" moiety may have from 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the range given; e.g., "1 to 10 carbon atoms" refers to an alkyl group that may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is indicated). Alkyl groups may also be "lower alkyl" groups having 1 to 5 carbon atoms. The alkyl group of the compounds described herein may be referred to as "C 1-C4Alkyl "or similar names. By way of example only, "C1-C4Alkyl "indicates the presence of one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
[0086]The term "alkylamine" means-N (alkyl)xHyWherein x and y are selected from the group consisting of x-1, y-1 and x-2, y-0. When x is 2, the alkyl groups may together optionally form a cyclic ring system.
[0087]The term "alkenyl" refers to a hydrocarbon group in which the first two atoms of the hydrocarbon group form a double bond of a non-aromatic moiety. In short, an alkenyl group begins with the atom-C (R) ═ C-R, where R refers to the remainder of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl groups include: -CH ═ CH, -C (CH)3)＝CH、-CH＝CCH3and-C (CH)3)＝CCH3. The alkenyl moiety may be branched, straight-chain or cyclic (in which case it is also referred to as "cycloalkenyl").
[0088]The term "alkynyl" refers to a hydrocarbyl group in which the first two atoms of the hydrocarbyl group form a triple bond. In short, alkynyl groups start with the atom-C.ident.C-R, where R refers to the remainder of the alkynyl group, which may be the same or different. Non-limiting examples of alkynyl groups include: -C ≡ CH, -C ≡ CCH 3and-C ≡ CCH2CH3. The "R" moiety of the alkynyl moiety may be branched, straight chain or cyclic.
[0089] An "amide" is a chemical moiety with the formula C (O) NHR or NHC (O) R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heteroalicyclic (attached through a ring carbon). The amide may be an amino acid or peptide molecule attached to a compound of any of formula (E), formula (E-I) or formula (E-II), thereby forming a prodrug. Any amine or carboxyl side chain on the compounds described herein may be amidated. Methods and specific Groups for preparing such amides are known to those skilled in the art and are readily available in the literature, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
[0090] The term "aromatic" or "aryl" refers to an aromatic group having at least one ring possessing a conjugated pi-electron system, including carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "carbocycle" refers to a compound containing one or more covalently closed ring structures, and the atoms forming the ring backbone are all carbon atoms. Thus, the term can distinguish carbocycles from heterocycles (in which the ring backbone contains at least one atom other than carbon).
[0091] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered part of a larger substructure.
[0092] "cyano" refers to the group-CN.
[0093] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and can be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl includes groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties:
[0094] The term "ester" refers to a chemical moiety having the formula COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heteroalicyclic (attached through a ring carbon). Any of the hydroxyl or carboxyl side chains on the compounds described herein can be esterified. Methods and specific Groups for preparing such esters are known to those skilled in the art and are readily available in the literature, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety. The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
[0095] The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted with one or more halo groups or combinations thereof. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halogen is fluorine.
[0096] The terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" include optionally substituted alkyl, alkenyl, and alkynyl groups having one or more backbone chain atoms selected from non-carbon atoms, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
[0097] The term "heteroaryl" or "heteroaromatic ring" refers to an aryl group that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The "heteroaryl ring" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one ring backbone atom is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties:
[0098] The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, with the proviso that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl and an example of a 10-membered heterocyclic group is quinolyl. Examples of non-aromatic heterocyclic groups are: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholino, thiomorpholino, thiaxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepinyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiopentyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, piperidinyl, morpholino, dihydromorpholinyl, thiadiazolyl, and thiadiazolyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, and quinolizinyl. Examples of aromatized heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indenylyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl. The foregoing groups derived from the above list may be C-linked or N-linked, where such linking is possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, the groups derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxy moieties (═ O), for example pyrrolidin-2-one.
[0099] "heteroalicyclic" refers to a cycloalkyl group that contains at least one heteroatom selected from nitrogen, oxygen, and sulfur, i.e., a non-aromatic heterocyclic group. The free radical may be fused to an aryl or heteroaryl group. Illustrative examples of heterocycloalkyl groups (also referred to as heteroalicyclic groups) include:
[00100] The term "membered ring" may include any cyclic structure. The term "member" is intended to mean the number of backbone atoms constituting a ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.
[00101] An "isocyanato" group refers to an NCO group.
[00102] An "isothiocyanato" group refers to an NCS group.
[00103] "mercapto" group refers to an (alkyl) S-group.
[00104] The term "moiety" refers to a specific fragment or functional group of a molecule. Chemical moieties are often considered chemical entities that are embedded in or attached to a molecule.
[00105] "sulfinyl" refers to-S (═ O) -R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), and heteroalicyclic (attached through a ring carbon).
[00106]"Sulfonyl" means-S (═ O) 2-R, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heteroalicyclic (attached through a ring carbon).
[00107] A "thiocyanato" group refers to a-CNS group.
[00108]The term "optionally substituted" or "substituted" means that the reference group may be substituted with one or more other groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfinyl (alkylsulfoxide), arylsulfinyl (arylsulfoxide), alkylsulfonyl, arylsulfonyl, cyano, halogen, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothioyl, nitro, perhaloalkyl, perfluoroalkyl, silyl, and amino, including mono-and di-substituted amino, and protected derivatives thereof. For example, an optional substituent may be LsRsWherein each isL issIndependently selected from the group consisting of a bond, -O-, -C (O) -, -S (O)2-、-NH-、-NHC(O)-、-C(O)NH-、S(＝O)2NH-、-NHS(＝O)2-OC (O) NH-, -NHC (O) O-, - (substituted or unsubstituted C1-C6Alkyl), or- (substituted or unsubstituted C2-C6Alkenyl); each RsIndependently selected from H, (substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl, or heteroalkyl. Protecting groups that can form protected derivatives of the above substituents are known to those skilled in the art and are available in the above references such as Greene and Wuts.
[00109] The compounds provided herein may have one or more stereocenters, each of which may exist in either the R or S configuration. The compounds provided herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. If desired, the stereoisomers may be obtained by methods known in the art, for example by separation of the stereoisomers by chiral chromatography columns.
[00110] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some cases, the compounds may exist in tautomeric forms. All tautomers are included within the scope of the compounds provided herein. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered disclosed herein.
Certain pharmaceutical terms
[00111] The term "acceptable" as used herein with respect to a formulation, composition or component means that there is no lasting adverse effect on the overall health of the patient being treated.
[00112] The term "agonist" as used herein refers to a molecule that is capable of increasing the activity of other molecules or receptor sites, such as a compound, a drug, an enzyme activator, or a hormone modulator.
[00113] The term "antagonist" as used herein refers to a molecule, such as a compound, drug, enzyme inhibitor or hormone modulator, that is capable of impairing or preventing the action of other molecules or the activity of the receptor site.
[00114] The term "asthma" as used herein refers to a disease characterized by: any condition of the lungs in which pulmonary airflow is altered in association with airway constriction of any cause (internal, external, or both; allergic or non-allergic). The term "asthma" may be used in conjunction with one or more adjectives indicating the cause of the disease.
[00115] The term "Bone disease" as used herein refers to diseases or conditions of the Bone including, but not limited to, inappropriate Bone remodeling, loss or gain, osteopenia, osteomalacia, Bone fibrosis and Paget's disease [ Garcia, "leukotrine B4 muscle osseous Bone resorption Bone in endo and in vivo", J Bone Miner res.1996; 11: 1619-27].
[00116] The term "cardiovascular disease" as used herein refers to diseases affecting the heart or blood vessels or both, including but not limited to: cardiac arrhythmia; atherosclerosis and its sequelae; angina pectoris; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral obstructive arterial disease of limbs, organs or tissues; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; (ii) shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, insufficiency limited to a single organ or tissue. [ Lotzer K et al, "The 5-lipoxygenase pathway in intensive wall biology and theranosclerosis", Biochim Biophys Acta 2005; 1736: 30-7; helgadottir A et al, "The gene encoding 5-lipoxygenase activating protein conjugates of mycolic origin and Stroke", Nat Genet.2004 month 3; 36(3): 233-9.Epub 2004 Feb 8; [ Heise CE, Evans JF et al, "Characterisation of the human cysteinyl leukotrine 2 receiver", J Biol chem.2000 Sep 29; 275(39): 30531-6].
[00117] The term "cancer" as used herein refers to abnormal growth of cells that tend to proliferate in an uncontrolled manner, and sometimes metastasize (spread). Types of cancer include, but are not limited to: solid tumors (e.g., bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma), or hematological tumors (e.g., leukemia)) [ Ding XZ et al, "a noveltani-pancreatic cancer agent, LY293111," Anticancer drugs.2005 jun; 16(5): 467-73. Review; chen X et al, "Overexpression of5-lipoxygenase in rat and human esophageal carcinogens and inhibitoreffects of zileuton and celecoxib on cartigenesis", Clin Cancer Res.2004Oct 1; 10(19): 6703-9].
[00118] The term "carrier" as used herein refers to a relatively non-toxic compound or agent that can facilitate the uptake of the compound into a cell or tissue.
[00119] The terms "co-administration" and the like as used herein are meant to encompass the administration of a selected therapeutic agent to a single patient and are intended to encompass treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.
[00120] The term "skin disorder" as used herein refers to a skin disorder. Such dermatological conditions include, but are not limited to: proliferative or inflammatory disorders of the skin, for example, atopic dermatitis, bullous disorders (bullous disorders), collagenous diseases, eczema of contact dermatitis, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, urticaria [ Wedib et al, "dermatological role of leucostrines in dermatologics: potential thermal identities ", biodrugs.2001; 15(11): 729-43].
[00121] The term "diluent" refers to a compound used to dilute a useful compound prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which may also control or maintain pH) may be used in the art as diluents, including but not limited to phosphate buffered saline solutions.
[00122] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount required by a composition comprising a compound disclosed herein to provide a clinically significant reduction in disease. In any independent case, an appropriate "effective" amount may be determined using techniques, such as dose escalation studies.
[00123] The term "enhance" or "enhancement" as used herein refers to an increase or prolongation of the desired effect in terms of potency or duration. Thus, for enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the effect of other therapeutic agents on the system in terms of potency or duration. The term "enhancing-effective amount" as used herein refers to an amount sufficient to enhance the effect of other therapeutic agents in the target system.
[00124] The term "enzymatically cleavable linker" as used herein refers to a non-stable or degradable linker that can be degraded by one or more enzymes.
[00125] The term "fibrosis" or "fibrotic disorder" as used herein refers to a condition following acute or chronic inflammation and is associated with abnormal accumulation of cells and/or collagen, and includes, but is not limited to: fibrosis of an individual organ or tissue, such as heart, kidney, joint, lung or skin, including, for example, idiopathic pulmonary fibrosis and a condition of latent fibroalveolitis. [ Charbeneau RP et al, "Eicosanoids: mediators and therapeutic targets in fibrous longitudinally discrete ", Clin Sci (Lond).2005 Jun; 108(6): 479-91].
[00126] The term "iatrogenic" refers to leukotriene-dependent or leukotriene-mediated symptoms, disorders or diseases that result from or are exacerbated by medical or surgical treatment.
[00127] The term "inflammatory disorder" refers to those diseases or conditions characterized by one or more of the following symptoms: pain (pain due to production of toxic substances and nerve stimulation), fever (burning due to vasodilation), redness (redness of the skin due to vasodilation and increased blood flow), swelling (mass due to excessive inflow of fluid or restricted outflow), and loss of function (dysfunction, which may be partial or total, temporary or permanent). Inflammation has many forms, including but not limited to one or more of the following: acute, adhesive, atrophic, mucositic, chronic, sclerosing, diffuse, disseminated, exudative, cellulogenic, fibrotic, topical, granulomatous, proliferative, hypertrophic, interstitial, metastatic, gangrenous, occlusive, parenchymal, restorative (plastic), productive (productive), proliferative, pseudomembranous, purulent, sclerosing, serofibrinous, serous, simple, specific, subacute, purulent, toxic, traumatic, and/or ulcerative inflammation. Inflammatory disorders further include, but are not limited to, those affecting: blood vessels (polyarteritis, temporarl arteritis); joints (arthritis: crystalline, bone-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus) [ Harrison's Principles of internal Medicine, 16 th edition, Kasper DL, et al, eds.; McGraw-Hill, publisher ].
[00128] The term "interstitial cystitis" refers to a condition characterized by abdominal discomfort, urinary frequency, and sometimes pain from urination, which is not caused by anatomical abnormalities, infections, toxins, trauma, or tumors. [ Bouchelouche K et al, "The cysteine leukotrine D4 regenerative agglutinon montelukast for The treatment of The experimental plastics", J Urol 2001; 166: 1734].
[00129] The term "leukotriene-stimulated mediators"(s) as used herein refers to molecules that can be made in a patient that can be caused by stimulated overproduction of cells by leukotrienes, by way of example only, LTB4, LTC4, LTE4, cysteinyl leukotrienes (leuktorines), monocyte inflammatory protein (MIP-1 α), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemotactic protein (MCP-1), lytic intracellular adhesion molecule (sICAM; lytic ICAM), Myeloperoxidase (MPO), Eosinophil Peroxidase (EPO), and conventional inflammatory molecules, such as interleukin-6 (IL-6), C-reactive protein (CRP), and serum amyloid a protein (SAA).
[00130] The term "leukotriene-related mediator" as used herein refers to a molecule that can be made in a patient, which can be caused by stimulated overproduction of cells by leukotrienes, such as LTB4, LTC4, LTE4, cysteinyl leukotrienes (leuktorines), monocyte inflammatory protein (MIP-1a), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemotactic protein (MCP-1), lytic intracellular adhesion molecule (sICAM; lytic ICAM), Myeloperoxidase (MPO), Eosinophil Peroxidase (EPO), and conventional inflammatory molecules, such as interleukin-6 (Il-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).
[00131] The term "leukotriene-dependent" as used herein refers to a symptom or disorder that does not occur or does not occur to the same extent in the absence of one or more leukotrienes.
[00132] The term "leukotriene-mediated" as used herein refers to a symptom or disorder that may occur in the absence of leukotrienes, but is capable of occurring in the presence of one or more leukotrienes.
[00133]The term "leukotriene-responsive patient" as used herein refers to a patient that has been identified by: by the genotype of the leukotriene FLAP haplotype or by the genotype of one or more other genes in the leukotriene pathway, and/or by employing a new leukotriene modifier (including, for example, zileuton (Zyflo TM), montelukast (Singulair)TM) Pranlukast (Onon)TM) Zafirlukast (Acclate)TM) Patients that produce a positive clinical response, and/or are identified by their profile of leukotriene-stimulated mediators to their stimulation of excess leukotrienes by inflammatory cells, which may produce a favorable response to leukotriene modulator therapy.
[00134] The terms "kit" and "article of manufacture" are used synonymously.
[00135] A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolism" as used herein refers to the sum of the processes (including but not limited to hydrolysis and enzymatic reactions) by an organism to alter a particular substance. Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyl transferase catalyzes the conversion of an activated glucuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free thiols. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9 th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be determined by: or by administering the compound to the host and analyzing a tissue sample obtained from the host, or by culturing the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are well known in the art.
[00136] The term "modulate" as used herein refers to interacting, directly or indirectly, with a target in order to alter the activity of the target, including, by way of example only, increasing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
[00137] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonist and antagonist interactions.
[00138] The term "neurogenerative disease" or "neurological disorder" as used herein refers to a disorder that can alter the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to alzheimer's disease, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathy (neuropathies), parkinson's disease, those resulting from blunt or surgical trauma (including post-surgical cognitive dysfunction and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica. The abbreviation "CNS" refers to central nervous system disorders, i.e., disorders of the brain and spinal cord [ Sugaya K, et al, "Newhunti-inflimator treatment strategy in Alzheimer's disease", Jpn JPharmacol.2000 Feb; 82(2): 85-94 parts of; yu GL, et al, "Montelukast, acetyllactonyl leuktorsreceiver-1 antagnostist, dose-and time-dependent protectants against focal fiber in micro", Pharmacology.2005 Jan; 73(1): 31-40.Epub 2004 Sep 27; [ Zhang WP, et al, "neuroprotectant effect of ONO-1078, a leuktriene receptor agonist, on focal cellulose in rates', Acta Pharmacol sin.2002 Oct; 23(10): 871-7].
[00139] The term "ocular disease" or "ocular disease" as used herein refers to a disease that affects the eye and potentially surrounding tissues. Eye diseases or eye diseases include, but are not limited to, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis [ Toryama S., "Effects of leucotrine B4 receptor antagnostist oneexperimental autoimmunity in its rates", Nippon Ganka GakkaiZashi.2000 Jun; 104(6): 396-40 parts by weight; [ Chen F, et al, "Treatment of S antisense vector inhibition with lipoxygenase and cyclo-oxidase inhibitors", Ophthalmic Res.1991; 23(2): 84-91].
[00140] As used herein, "pharmaceutically acceptable" refers to a material that does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, e.g., a carrier or diluent. I.e., the substance can be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components contained in the composition.
[00141] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts may also be obtained by reacting a compound described herein with a base, for example, an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt with an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, lysine, and the like, or salts obtained by other methods known in the art.
[00142] The term "pharmaceutical combination" as used herein refers to a product resulting from the mixing or combination of more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound and a co-agent as described herein, are both administered to a patient simultaneously in a single entity or dosage form. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time period, wherein such administration provides effective levels of both compounds within the body of the patient. The latter is also applicable to cocktail therapy, e.g. the administration of three or more active ingredients.
[00143] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients. The pharmaceutical composition may facilitate administration of the compound to an organism. There are many techniques in the art for administering compounds, including but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
[00144] "prodrug" refers to an agent that can be converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they can be administered more easily than the parent drug. For example, they can be administered orally to increase bioavailability, whereas the parent cannot. Prodrugs may also have increased solubility over the parent drug in the pharmaceutical composition. Examples of prodrugs, but are not limited to, compounds of any of formula (E), formula (E-I) or formula (E-II) which are administered in the form of an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental to motility but which are metabolically hydrolyzed to the carboxylic acid (active entity) once inside the cell where water solubility is beneficial. Another example of a prodrug would be a short peptide (polyamino acid) linked to an acid group, where the peptide is metabolized to reveal the active moiety.
[00145] The term "respiratory disease" as used herein refers to a disease affecting organs involved in breathing, such as the nose, pharynx, larynx, trachea, bronchi and lungs. Respiratory diseases include, but are not limited to: asthma, adult respiratory distress syndrome and Allergic (extrinsic) asthma, non-Allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergy-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, carbon dioxide-iso hyperventilation, childhood asthma, adult-developed asthma, cough variant asthma, occupational asthma, hormone-resistant asthma, seasonal Allergic Rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation and cystic fibrosis and hypoxia [ Evans JF, [ TheCysteinyl Leucotriene (CysLT) Pathway in Allergic Rhinitis ], Allergologic International 2005; 54: 187-90); kemp JP., "Leukotriene receiver against the stream of the activity", IDrugs.2000 Apr; 3(4): 430-41; riccioni G, et al, "Effect of the two differential leukostrine receivers antagnostists, montelukast and zafirlukast, on quality of life: a 12-week randomizedstutdy ", Allergy Asthma proc.2004 Nov-Dec; 25(6): 445-8].
[00146] The term "subject" or "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian family: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
[00147] The terms "treat," "treating," or "treatment" as used herein include alleviating, attenuating, or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating or preventing an underlying metabolic cause of a symptom, inhibiting a disease or disorder, e.g., inhibiting the progression of a disease or symptom, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating a symptom caused by a disease or disorder, or prophylactically and/or therapeutically arresting a symptom of a disease or disorder.
[00148] Other objects, features and advantages of the methods and compositions described herein will become more apparent from the following detailed description. It should be understood, however: the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. All references, including patents, patent applications, and publications, cited herein are hereby incorporated by reference in their entirety.
Brief description of the drawings
[00149] Figure 1 provides an illustrative scheme for the synthesis of the compounds described herein.
[00150] Figure 2 provides an illustrative scheme for the synthesis of the compounds described herein.
[00151] Fig. 3 provides an illustrative scheme for synthesizing the compounds described herein.
[00152] Fig. 4 provides an illustrative scheme for synthesizing the compounds described herein.
[00153] Fig. 5 provides an illustrative scheme for synthesizing the compounds described herein.
[00154] Fig. 6 provides an illustrative scheme for synthesizing the compounds described herein.
[00155] Fig. 7 provides an illustrative scheme for synthesizing the compounds described herein.
[00156] Fig. 8 provides illustrative examples of compounds described herein.
[00157] Fig. 9 provides illustrative examples of compounds described herein.
[00158] Fig. 10 provides illustrative examples of compounds described herein.
[00159] Fig. 11 provides illustrative examples of compounds described herein.
[00160] Fig. 12 provides an illustrative schematic for treating a patient using the compounds and methods described herein.
[00161] Fig. 13 provides an illustrative schematic for treating a patient using the compounds and methods described herein.
[00162] Fig. 14 provides an illustrative schematic for treating a patient using the compounds and methods described herein.
Detailed description of the invention
Illustrative biological Activity
[00163]Leukotrienes (LTs) are potent mediators of contractile and inflammatory processes, produced by the release of arachidonic acid from cell membranes and produced in 5-lipoxygenase, 5-lipoxygenase-activating protein, LTA4Hydrolases and LTC4The enzyme is converted to leukotrienes by the action of the synthase. The leukotriene synthesis pathway or 5-lipoxygenase pathway involves a series of enzymatic reactions in which arachidonic acid is converted to leukotriene LTB4Or cysteinyl leukotrienes, LTC4、LTD4And LTE4. The pathway occurs primarily in the nuclear membrane and has been described. See, e.g., Wood, JW et al, j.exp.med., 178: 1935-1946, 1993; Peters-Golden, am.j.respir.crit.care med.157: S227-S232, 1998; drazen, et al, ed.five-Lipoxygenase Products in Ashma, Lung Biologyin Health and Disease Series, Vol.120, Chs.1, 2, and 7, Marcel Dekker, Inc.NY, 1998. The protein components specific for the synthesis pathway of leukotriene include 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein, LTA4Hydrolases and LTC4A synthase enzyme. The synthesis of leukotrienes has been described in the literature, for example, Samuelsson et al, Science, 220, 568-575, 1983; Peters-Golden, "Cell Biology of the 5-Lipoxygenase Pathway" Am J RespirCrit Care Med 157: S227-S232 (1998). Leukotrienes are synthesized directly from arachidonic acid by different cells, including eosinophils, neutrophils, basophils, lymphocytes, macrophages, monocytes, and mast cells. Excess LTA 4E.g. from activated neutrophils, may enter through a transcellular pathwayA cell. Most cells in the body have LTA4Hydrolases, thus LTB can be produced4. Platelets and endothelial cells have LTC4Synthase, thus providing LTA when provided by a transcellular pathway4When it is possible to prepare LTC4。
[00164]Arachidonic acid is a polyunsaturated fatty acid and is found primarily in the membranes of body cells. When inflammatory stimuli are present outside the cell, calcium is released and interacts with phospholipase A2(PLA2) and 5-LO. Cell activation leads to PLA2And 5-LO migrate from the cytoplasm into the endoplasmic reticulum and/or nuclear membrane, where, in the presence of FLAP, the released arachidonic acid is converted to the epoxide LTA via a 5-HPETE intermediate4. LTC by nuclear-binding, depending on cell type4Synthase, LTA4 can be immediately converted to LTC4Or LTA in the cytosol4Conversion to LTB by hydrolase4. LTB4 is excreted from the cells by an uncharacterized transmitter and can activate other cells, or cells producing LTB4, by high affinity binding to one of the two G protein-coupled receptors (GPCRs), namely BLT1R or BLT 2R. LTC4 is exported to the blood by MRP-1 anion pump and rapidly converted to LTD by gamma-glutamyltranspeptidase 4Then LTD by action of dipeptidase4Transition to LTE4。LTC4、LTD4And LTE4Together referred to as cysteinyl leukotrienes (or previously slow reacting substances of anaphylaxis, SRS-A). Cysteinyl leukotrienes pass through two GPCRs (i.e., CysLT)1R or CysLT2R) to perform high affinity binding, can activate other cells or produce their cells. CysLT1Receptors are found in human airway eosinophils, neutrophils, macrophages, mast cells, B-lymphocytes, and smooth muscle, and can induce bronchoconstriction. Zhu et al, Am J Respir Cell Mol Biol Epub Aug 25 (2005). CysLT2Receptors are located in human airway eosinophils, macrophages, mast cells and the pulmonary vasculature of humans, fig. aeoroa et al, Clin Exp Allergy 33: 1380-1388(2003).
Diseases or disorders in which leukotrienes are involved
[00165] Diseases in which leukotrienes are involved are described in detail in the literature. See, e.g., Busse, clin. exp. allergy 26: 868-79, 1996; o' Byrne, Chest111 (Supp.2): 27S-34S, 1977; sheftell, f.d., et al, Headache, 40: 158-163, 2000; klickstein et al, j.clin.invest, 66: 1166 1170, 1950; davidson et al, ann.rheum.dis, 42: 677-679, 1983. Leukotrienes produce a significant inflammatory response on human skin. Evidence of leukotriene involvement in human disease has been found in psoriasis, where leukotrienes are detected in psoriasis lesions (Kragballel et al, Arch. Dermatol., 119: 548-552, 1983).
[00166] For example, it has been proposed that inflammatory responses reflect three types of changes in local blood vessels. The initial change is an increase in vessel diameter, which results in increased local blood flow, and results in increased temperature, reddening, and a decrease in blood flow velocity, particularly along the surface of small vessels. The second change is activation of endothelial cells that coat blood vessels, expressing adhesion molecules that promote the binding of circulating leukocytes. The combination of slow blood flow and induced adhesion molecules allows leukocytes to attach to the endothelium and migrate into the tissue, a process known as extravasation. These changes originate from cytokines and leukotrienes produced by activated macrophages. Once inflammation has begun, the first cells attracted to the site of infection are usually neutrophils. They are followed by mononuclear leukocytes, which differentiate into more tissue phagocytic cells. In the later stages of inflammation, other leukocytes, such as eosinophils and lymphocytes, also enter the site of infection. The third major change in local vascular aspect is increased vascular permeability. Endothelial cells that cover the vessel wall separate rather than tightly bound together, resulting in the detachment of fluids and proteins from the blood and its local accumulation area in the tissue. (see Janeway, et al, immunology: the animal system in health and disease, 5 th edition, Garland Publishing, New York, 2001).
[00167]LTB4 caused relatively weak contractions of isolated tracheal and lung soft tissues and these contractions were partially blocked by inhibitors of cyclooxygenase, suggesting that the contractions were secondary to the release of prostaglandins. However, it has been demonstrated that LTB4LTB, an effective chemotactic agent for eosinophil and mast cell progenitors4Receptor BLT1Mice stunned can be protected against eosinophilic inflammation and T cell mediated allergic airway hyperreactivity. Miyahara et al JImmunol 174: 4979-4784; (Weller et al.J Exp Med 201: 1961-.
[00168]Leukotriene C4And D4Are potent smooth muscle contraction agents that promote bronchoconstriction in a number of species, including humans (Dahlen et al, Nature, 288: 484-486, 1980). These compounds have exquisite hemodynamic effects, constrict coronary vessels, and lead to reduced cardiac output efficiency (Marone et al, in Biology of Leukotrienes, ed.By R.Levi and R.D.Krell, Ann.New York Acad.Sci.524: 321-. However, leukotrienes also act as vasoconstrictors, with significant differences in different vascular beds. Leukotrienes have been reported to induce cardiac reperfusion injury following myocardial ischemia (Barst and Mullane, Eur. J. Pharmacol., 114: 383-387, 1985; Sasaki et al, Cardiovas. Res., 22: 142-148, 1988). By CysLT 2Activation of receptors and possibly other as yet undefined CysLT receptors to promote constriction of capillary endothelial cells, LTC4And LTD4Directly increase vascular permeability [ Lotzer et al Arterioscler Thromb Vasc Biol 23: e32-36 (2003)]. In two mouse models of atherosclerosis, namely the low density receptor lipoprotein receptor deficient (LDLr-/-) and apolipoprotein E-deficient (ApoE-/-) mice, LTB4Increased progression of atherosclerosis (Aiello et al, Arterioscler Thromb Vascbiol 22: 443-4Can increase human monocyte chemotaxisProtein (MCP-1), a known enhancer of atherosclerosis progression (Huang et al, Ateriosorter Thromb Vasc Biol 24: 1783-1788 (2004).
[00169] The role of FLAP in the leukotriene synthesis pathway is significant because FLAP performs the first step simultaneously with 5-lipoxygenase in the leukotriene synthesis pathway. Thus, leukotriene synthesis pathways provide many targets for compounds useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or disorders, including, for example, vascular and inflammatory disorders, proliferative diseases, and non-cancerous disorders.
[00170] Leukotriene-dependent or leukotriene mediated disorders treated using the methods, compounds, pharmaceutical compositions, and medicaments described herein include, but are not limited to: bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, skin diseases and disorders, eye diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorders, and non-cancerous disorders.
Treatment regimens
[00171]Leukotrienes are known to promote inflammation of the respiratory tract in patients with asthma. Has proven that CysLT1Receptor antagonists such as montelukast (Singulair)TM) Effective for asthma and allergic rhinitis [ Reiss et al Arch Intern Med 158: 1213-1220 (1998); phillip et al, Clin Exp Allergy 32: 1020-1028(2002)]. CysLT was also demonstrated1Pranlukast (Onon) R antagonistTM) And zafirlukast (Acclate)TM) Is effective in asthma.
[00172]A number of drugs have been designed to inhibit leukotriene formation, including the 5-lipoxygenase inhibitor zileuton (Zyflo)TM) Which shows efficacy in asthma, Israel et al ann lnjn Med 119: 1059-1066(1993). The 5-lipoxygenase inhibitor ZD2138 showed efficacy in inhibiting the decline of FEV1 (produced by aspirin induced asthma), Nasser et al, Thorax, 49; 749-756(1994). The following leukotriene synthesis inhibitors show effects on asthma: MK-0591, 5-lipids Specific inhibitors of oxidase-activating protein (FLAP), Brideau, et al, ca.j.physiol.pharmacol.70: 799-807(1992), specific inhibitors of MK-886, 5-lipoxygenase-activating protein (FLAP), Friedman et al Am Rev Respirdis, 147: 839-844(1993), and specific inhibitors of BAY X1005, 5-lipoxygenase-activating protein (FLAP), Fructmann et al, Agents Actions 38: 188-195(1993).
[00173]FLAP inhibition can reduce LTB derived from monocytes, neutrophils and other cells involved in vascular inflammation4And thereby reduce the progression of atherosclerosis. It has been shown that the FLAP inhibitor MK-886 can reduce the vasoconstrictive response after angioplasty in a porcine carotid injury model, Provost et al Brit J Pharmacol 123: 251-258(1998). MK-886 has also been shown to inhibit femoral intimal hyperplasia in the rat photochemical endothelial injury model, Kondo et al Thromb Haemost 79: 635-639(1998). In a mouse model, zileuton, a 5-lipoxygenase inhibitor, has been shown to reduce renal ischemia, Nimesh et al Mol Pharm 66: 220-227(2004).
[00174]FLAP modulators have been used to treat a number of diseases or conditions, including, for example, (i) inflammation (see, e.g., Leff AR et al, "Discovery of leukemia and the later of anti-leukemia agents," Ann Allergy Asherma Immunol 2001; 86(Suppl1) 4-8; Riccioni G, et al, "Advances in therapy with anti-leukemia drugs," Ann Clin Lab Sci.2004, 34 (4): 379-870; (ii) respiratory diseases, including Asthma, adult respiratory distress syndrome and allergic (in vitro) Asthma, non-allergic (intrinsic) Asthma, acute severe Asthma, chronic Asthma, clinical Asthma, nocturnal Asthma, Allergy-induced Asthma, aspirin-sensitive Asthma, exercise-induced Asthma, equal carbon dioxide over-ventilation Asthma, childhood Asthma, Asthma in person, Asthma in adult humans, cough variability, Asthma, hormone resistance, seasonal asthma (see, e.g., Riccioni et al, ann. clin. lab. sci., v34, 379-387 (2004)); (iii) chronic obstructive pulmonary diseases, including chronic bronchitis or emphysema, lung Arterial hypertension, interstitial pulmonary fibrosis and/or airway inflammation and cystic fibrosis (see, e.g., Kostikas K et al, "Leukotriene V4 in exotdbreath condensate and sputum supernates in tissues with COPD andasthma", Chest 2004; 127: 1553-9); (iv) increased mucosal secretion and/or edema in a disease or disorder (see, e.g., Shahab R et al, "Prostagladins, Leukotrienes, Andprenial rhinitis", J Larynggol Otol., 2004; 118; 500-7); (v) vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke (see, e.g., Jala et al, Trends in Immunol., v25, 315-; (vi) reducing organ reperfusion injury following organ ischemia and/or endotoxic shock (see, e.g., MatsuiN, et al, "Protective effect of the 5-lipoxygenase inhibiting tissue squirine A on pharmaceutical ischemia-perfusion in rats", planta Med.2005 Aug; 71 (8): 717-20); (vii) decreasing vasoconstriction (see, e.g., Stanke-LabesqueF et al, "Inhibition of leukemia synthesis with MK-886 preservation a ise in blood pressure and recovery a nordreadine-evke condensation in L-NAME-treated rates", Br J Pharmacol.2003 Sep; 140 (1): 186-94); (viii) reducing or preventing elevated blood pressure (see, e.g., Stanke-laboratory F et al, "Inhibition of leukemia synthesis with MK-886 preservation a disease in blood pressure and recovery of nordrenaline-expression in L-NAME-derived rates", Br J Pharmacol.2003 Sep; 140 (1): 186-94, and Walch L, et al, "Pharmacological evaluation for expression of cytokine secretion in human pulmony aryl muscle", Br J Pharmacol.2002 Dec; 137 (8): 1339-45); (ix) prevention of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or monocytes (see, e.g., Miyahara N, et al, "Leukotriene B4 receptor-1 isogenic for allergen-mediated diagnosis of CD8+ T cells and air wayPeresponsive), Immunol.2005 Apr 15; 174(8): 4979-84); (x) Abnormal bone remodeling, loss or augmentation, including osteopenia, osteoporosis, Paget's disease, cancer and other diseases (see, e.g., Anderson GI, et al, "Inhibition of leukemia therapy with modified tissues in bone cells differentiation and activity", Biomed Mater Res. 2001; 58 (4): 406. sup. 140; (xi) ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis and papillary conjunctivitis (see, e.g., Lambian et al, Arch. Optholmol., v121, 615. sup. 620(2003)), (xii) CNS disorders including, but not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine (see, e.g., dust Carval D, et al, "infection therapy with disease," 2002. sup. 10. diagnosis, 10. 12. sup. diagnosis, cancer therapy with disease, and cancer therapy with cancer, and other diseases, et al, "Montelukastin the prophyiaxis of migrine: a latent role for leukotrine modifiers ", Headache.2000 Feb; 40(2): 158-63); (xiii) Peripheral neuropathy/neuropathic pain, spinal cord injury (see, e.g., Akpek EA, et al, "A study of adenosine therapeutic amino acids in J. Effect on arachidonic acids, spine.1999 Jan 15; 24 (2): 128-32), cerebral edema, and craniocerebral injury; (xiv) Cancers, including but not limited to pancreatic Cancer and other solid or hematologic tumors (see, e.g., Poff and Balazy, curr. drug Targets Inflamm. Allergy, v3, 19-33(2004) and Steele et al, Cancer epidemic, Cancer &Prevention, v8, 467-483 (1999); (xv) Endotoxic and septic shock (see, e.g., Leite MS, et al, "mechanics of secreted and secreted porcine soluble-induced shock in microwave conditioned oligomeric oil-induced di et", shock.2005 Feb; 23 (2): 173-8); (xvi) Rheumatoid arthritis and osteoarthritis (see, e.g., Alten R, et al, "Inhibition of leukemia B4-induced CD11B/CD18(Mac-1)expression by BIIL 284，a new long acting LTB4receptor antagonist, in tissues with rhematoid arthritis ", Ann Rheum Dis.2004Feb; 63(2): 170-6); (xvii) Prevention of elevated GI disorders, including, for example, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction (see, e.g., Gyomber et al, J Gastroenterol hepatol., v11, 922 927 (1996); Quack I et al, BMC Gastroenterol v18, 24 (2005); Cuzzolorea S, et al, "5-Lipoxygenase models diagnosis of cancer through regulation of adhesion molecular expression and neutrophilic digestion", Lab invest.2005 Jun; 85 (6): 808-22); (xviii) Renal diseases, including, for example, glomerulonephritis, cyclosporine nephrotoxic renal ischemia reperfusion (see, for example, Guasch et al, Kidney Int., v56, 261-267; Butterly et al, v57, 2586-2593 (2000); Guasch A et al, "MK-591 acid reactors glucose size selection and reduce protein in human glucose modification", Kidney Int.1999; 261: 7; Buttery et al, "A roll for leukemia in cyclosporine reagent", Kidney Int.2000; 57: 2586-93); (xix) Preventing or treating acute or chronic renal insufficiency (see, e.g., Maccarron M, et al, "Activation of 5-lipoxygenase and dried cell membrane complications Patients", J Am SocNephrol.1999; 10: 1991-6); (xx) Type II diabetes (see, e.g., Valdivielso et al, v16, 85-94 (2003); (xxi) attenuating the inflammatory aspects of acute infections in one or more solid organs or tissues (e.g., kidneys with acute pyelonephritis) (see, e.g., Tardif M, et al, L-651, 392, "A potential leuktriene inhibitor, control inflators in Escherichia coli pyrothritis", antibiotic Agents Chemothermus 1994 Jul; 38 (7): 1555-60); (xxii) preventing or treating acute or chronic conditions involving increased or activated eosinophils (see, e.g., Quack I, et al, "eosinophicismuthentication in a yuung-localized lung disease", Gamma 2005 or non-selective treatment including acute or non-steroidal anti-inflammatory drugs; (xxii); BMC 24; selective treatment by BMC 24; acute or non-steroidal anti-inflammatory drugs; BMC.5: 24; (xxii) and Cyclooxygenase-1 or-2 inhibitors) or motor dysfunction (see, e.g., Marusova IB, et al, "functional gatroptective effect of a CysLT1 receptor sorbent in hose-induced losses of the rat stock mucosa", ekssklin Farmakol, 2002; 65: 16-8 and Gyomber E, et al, "effective of lipoxygenase inhibitors and leucotriene inhibitors on access and chronologic halberlogic mucosall derivatives in emulsion modules in the rat", J.gastroenterol.Hepatol., 1996, 11, 922-7) and Martin St, et al, "gastroentero dynamics: is eosinophilic mural organization a practical factor? ", Eur jgastroentol. hepatol., 2005, 17: 983-6; (xxiv) Treatment of type II diabetes (see, e.g., Valdiielso JM, et al, "Inhibition of 5-lipoxygenase activating proteins in diabetes rates", J Nephrol.2003 Jan-Feb; 16 (1)): 85-94, Parlapiano C, et al, "The related beta between circulating hemoglobin and hydrolytic nuclear leukemia B4 release in peptides with Diabetes mellitis", Diabetes Res Clin Practer 1999Oct 46 (1): 43-5, (xxv) treatment of metabolic syndromes, including, for example, familial Mediterranean fever (see, e.g., Bentancur AG, et al, "Urine leukotrine B4 in similar Mediterranean farm," Clin ExpRheumatol.2004 Jul-Aug; 22(4Suppl 34): s56-8, and (xxvi) treatment of hepatorenal syndrome (see, e.g., Capilla GL., "Anti-leuktriene drugs in the prevention and treatment of hepatic syndrome", Prostagladins Leukose FattyAcids, 2003 Apr; 68 (4)): 263-5. ]。
[00175] Some FLAP inhibitors have been described (Gillard et al, Can. J. Physiol. Pharmacol., 67, 456-464, 1989; Evans et al, molecular Pharmacol., 40, 22-27, 1991; Brideau et al, Can. J. Physiol. Pharmacol., Musser et al, J. Med. Chem., 35, 2501-2524, 1992; Steinhibler, curr. Med. chem.6 (1): 71-85, 1999; Riendeau, Bioorg Med. Chem. lett., 15 (14): 3352-5, 2005; Flabank et al, mol. Pharmacol.62 (2): 250-6, 2002; WO, et al, am. J. Respir. Crsit. 161, 2; Folcon, 293, Pt.32, 2000, 32; Fonama et al, 2246, 32).
Identification of leukotriene synthesis pathway inhibitors
[00176] The development and testing of novel FLAP inhibitors, which are effective alone or in combination with other drugs and which may produce minimal side effects, is beneficial for the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions. The inhibitors of the leukotriene synthesis pathway described herein may target any step of the pathway to prevent or reduce the formation of leukotrienes. Such leukotriene synthesis inhibitors may, for example, inhibit the level of FLAP or 5-LO, thereby minimizing the formation of various products in the leukotriene pathway, thereby reducing the amount of such compounds available in the cell. Leukotriene synthesis inhibitors can be identified based on their ability to bind to proteins in the leukotriene synthesis pathway. For example, a FLAP inhibitor can be identified based on its binding to FLAP.
Compound (I)
Compounds of formula (E), formula (E-I) and formula (E-II):
[00177] Compounds of formula (E), formula (E-I) and formula (E-II), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, may antagonize or inhibit FLAP and may be useful in treating a patient suffering from a leukotriene-dependent or leukotriene mediated condition or disease, including but not limited to asthma, myocardial infarction, cancer and inflammatory conditions.
[00178] The formula (E-I) is as follows:
wherein,
z is selected from N (R)1)、S(O)m、CR1＝CR1、-C≡C-、C(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2O、OC(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2S(O)m、S(O)mC(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2NR1、NR1C(R1)2[C(R2)2]n、[C(R2)2]nO[C(R1)2]n、[C(R1)2]nO[C(R2)2]n、-C(O)NR2-、-NR2C(O)-、-NR2C(O)O-、-OC(O)NR2-、-S(O)2NR2-、-CR1＝N-N-、NR2C(O)NR2-、-OC(O)O-、S(O)2NR2or-NR2S(O)2-, where each R is1Independently is H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1May be linked to form a carbonyl (═ O); each R2Independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2May be linked to form a carbonyl (═ O); m is 0, 1 or 2; each n is independently 0, 1, 2 or 3;
y is-C (O) NHS (═ O)2R3b、-S(＝O)2NHC(O)R4、-C(O)NR4C(＝NR3)N(R4)2、-C(O)NR4C(＝CR3)N(R4)2、-CON(R4)2、-L1- (substituted or unsubstituted heteroalicyclic group), -L1-C(＝NR4)N(R4)2、-L1-NR4C(＝NR3)N(R4)2、-L1-NR4C(＝CR3)N(R4)2Provided that when the heteroatom is directly bonded to Z, the heteroalicyclic group is substituted;
wherein L is1Is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroalkenyl group, or a substituted or unsubstituted heteroalkynyl group;
Wherein each substituent is (L)sRs)jWherein each LsIndependently selected from the group consisting of a bond, -O-, -C (O) -, -S (O)2-、-NHC(O)-、-C(O)NH-、S(＝O)2NH-、-NHS(＝O)2、-OC(O)NH-、-NHC(O)O-、-OC(O)O-、-NHC(O)NH-、-C(O)O-、-OC(O)-、C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, heteroaryl, aryl, or heteroalicyclic groups; each RsIndependently selected from H, halogen, -N (R)4)2、-CN、-NO2，N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R3Independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl, or heteroalkyl;
each R3bIndependently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R4Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4The radicals being able to form togetherTo form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R3bAnd R4Can together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
R6is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl) in which L 2Is a bond, O, S, -S (═ O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl), or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein, is,
L3is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroalicyclic group;
x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；
L4Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
G1is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G1Is W-G5Wherein W is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroalicyclic group or a substituted or unsubstituted heteroaryl group, G5Is H, tetrazolyl, -NHS (═ O) 2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R9Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups can together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9Can form together a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Independently selected from: H. -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl, or heteroalkyl;
R5is H, halogen, -N3、-CN、-ONO2、-L6- (substituted or unsubstituted C)1-C6Alkyl), -L6- (substituted or unsubstituted C)2-C6Alkenyl), -L6- (substituted or unsubstituted heteroaryl), or-L6- (substituted or unsubstituted aryl) in which L6Is a bond, O, S, -S (═ O), S (═ O)2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-, or-C (O) NH;
R11is L7-L10-G6(ii) a Wherein L is7Is a bond, -O, -S (O)2-NH, -C (O) NH, -NHC (O), - (substituted or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C6Alkenyl);
L10is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycloaliphatic), and
G6Is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -NHS (═ O)2R8、-S(＝O)2N(R9)2、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or (substituted or unsubstituted heteroaryl), G7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L5- (substituted or unsubstituted aryl) in which L5is-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O); and
R12is L8-L9-R13Wherein L is8Is a bond, (substituted or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C4Alkenyl); l is9Is a bond, O, S, -S (═ O), S (═ O) 2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-, -OC (O) O-, -NHC (O) -, -C (O) NH-, -C (O) O-, or-OC (O) -; r13Is H, (substituted or unsubstituted C1-C6Alkyl), (substituted or unsubstituted C3-C6Cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group);
or R7And R12May together form a 4 to 8-membered heterocyclic ring.
[00179] For any and all embodiments (e.g., formula (E), formula (E-I), and formula (E-II)), the substituent is selected from the listed alternatives. For example, in one embodiment, the heteroalicyclic group of Y is selected from the group consisting of quinolizines, dioxines, piperidines, morpholines, thiazines, tetrahydropyridines, piperazines, oxazinones, dihydropyrroles, dihydroimidazoles, tetrahydrofurans, dihydrooxazoles, oxiranes, pyrrolidines, pyrazolidines, dihydrothiophenones, imidazolidinones, pyrrolidones, dihydrofuranones, dioxolanones, thiazolidines, piperidones, tetrahydronaphthyridines, tetrahydroquinolines, tetrahydrothiophenes, and thiazepanyls (thiazepanes).
[00180] In a further embodiment, the heteroalicyclic group of Y is selected from the following structures:
by way of example only, the heteroalicyclic group of Y is selected from:
[00181]in a further or alternative embodiment, a "G" group (e.g., G)1、G5、G6、G7) Are all groups used to design the physical and biological properties of molecules. This design/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. Physical and biological properties modulated by this modification to "G" include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. In addition, in vivo metabolism may include, by way of example only, control of PK properties in vivo, off-target activity, potential toxicity associated with cypP450 interactions, drug-drug interactions, and the like. Further, modifications to "G" can be made to tailor the in vivo effects of the compounds by modulating specific and non-specific proteins that bind to, for example, plasma proteins and lipids and tissue distribution in vivo. In addition, such design/modification for "G" may design selectivity for 5-lipoxygenase-activating protein over for itA compound selective for other proteins.
[00182]In a further or alternative embodiment, "G" is L20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In a further or alternative embodiment, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, the affinity moiety allows for site-specific binding, including but not limited to antibodies, antibody fragments, DNA, RNA, siRNA and ligands.
[00183] The formula (E-II) is as follows:
wherein Z is selected from N (R)1)、S(O)m、CR1＝CR1、-C≡C-、C(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2O、OC(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2S(O)m、S(O)mC(R1)2[C(R2)2]n、[C(R2)2]nC(R1)2NR1、NR1C(R1)2[C(R2)2]n、[C(R2)2]nO[C(R1)2]n、[C(R1)2]nO[C(R2)2]n、-C(O)NR2-、-NR2C(O)-、-NR2C(O)O-、-OC(O)NR2-、-S(O)2NR2-、-CR1＝N-N-、NR2C(O)NR2-、-OC(O)O-、S(O)2NR2or-NR2S(O)2-, wherein each R1Independently is H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1May be linked to form a carbonyl (═ O); each R2Independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2May be linked to form a carbonyl (═ O); m is 0, 1 or 2; each n is independently 0, 1, 2 or 3;
y is-C (O) NHS (═ O)2R3b、-S(＝O)2NHC(O)R4、-C(O)NR4C(＝NR3)N(R4)2、-C(O)NR4C(＝CR3)N(R4)2、-CON(R4)2、-L1- (substituted or unsubstituted heteroalicyclic group), -L1-C(＝NR4)N(R4)2、-L1-NR4C(＝NR3)N(R4)2、-L1-NR4C(＝CR3)N(R4)2Provided that when the heteroatom is directly bonded to Z, the heteroalicyclic group is substituted;
wherein L is1Is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted heteroalkenyl group, or a substituted or unsubstituted heteroalkynyl group;
wherein each substituent is (L)sRs)jWherein each LsIndependently selected from the group consisting of a bond, -O-, -C (O) -, -S (O)2-、-NHC(O)-、-C(O)NH-、S(＝O)2NH-、-NHS(＝O)2、-OC(O)NH-、-NHC(O)O-、-OC(O)O-、-NHC(O)NH-、-C(O)O-、-OC(O)-、C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, heteroaryl, arylOr a heteroalicyclic group; each R sIndependently selected from H, halogen, -N (R)4)2、-CN、-NO2，N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R3Independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl, or heteroalkyl; each R3bIndependently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R4Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R3bAnd R4May together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
R6is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (═ O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl), or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein L is3Is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroalicyclic group; x is a bond, O, -C (═ O), -CR 9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；L4Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; g1Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O); or G1Is W-G5Wherein W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group, or substituted or unsubstituted heteroaryl; g5Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8(ii) a Each R8Independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, each R10Independently selected from H, -S (═ O) 2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl, or heteroalkyl;
R5is H, halogen, -N3、-CN、-ONO2、-L6- (substituted or unsubstituted C)1-C6Alkyl), -L6- (substituted or unsubstituted C)2-C6Alkenyl), -L6- (substituted or unsubstituted heteroaryl), or-L6- (substituted or unsubstituted aryl) in which L6Is a bond, O, S, -S (═ O), S (═ O)2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-, or-C (O) NH;
R11is L7-L10-G6(ii) a Wherein L is7Is a bond, -O, -S (O)2-NH, -C (O) NH, -NHC (O), - (substituted or unsubstituted C1-C6Alkyl radicals),Or (substituted or unsubstituted C2-C6Alkenyl); l is10Is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group); and G6Is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -NHS (═ O)2R8、-S(＝O)2N(R9)2、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O); or G6Is W-G 7Wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group), or (substituted or unsubstituted heteroaryl); g7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L5- (substituted or unsubstituted aryl) in which L5is-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
R12is L8-L9-R13Wherein L is8Is a bond, a (substituted or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C4Alkenyl); l is9Is a bond, O, S, -S (═ O), S (═ O)2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-, -OC (O) O-, -NHC (O) -, -C (O) NH-, -C (O) O-, or-OC (O) -; r13Is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group); or R7And R12May together form a 4 to 8-membered heterocyclic ring.
[00184]For any and all embodiments (such as, for example, formula (E), formula (E-I), and formula (E-II)), the substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Z is [ C (R)2)2]nC(R1)2And O. In a further or alternative embodiment, Y is-L1- (substituted or unsubstituted heteroalicyclic).
[00185]In a further or alternative embodiment, R6Is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl) or L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O), -CH (OH), or substituted or unsubstituted alkyl.
[00186]In a further or alternative embodiment, R7Is L3-X-L4-G1(ii) a Wherein L is3Is a substituted or unsubstituted alkyl group; x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；L4Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. In a further or alternative embodiment, G1Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8(ii) a Or G1Is W-G5Wherein W is a substituted or unsubstituted heteroalicyclic group or a substituted or unsubstituted heteroaryl group; andG5is tetrazolyl, -NHS (═ O) 2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8. In a further or alternative embodiment, X is a bond, -O-, -CR9(OR9)、S、-S(O)、-S(O)2、-NR8-O-N ═ CH, -CH ═ N-O, -NHC (═ O), or-C (═ O) NH.
[00187]In a further or alternative embodiment, R11Is L7-L10-G6Wherein L is7Is a bond, a (substituted or unsubstituted C1-C6Alkyl groups); l is10Is (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group). In a further or alternative embodiment, G6Is tetrazolyl, -NHS (═ O)2R8、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl); l is5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O). At the beginningIn step or alternative embodiments, L10Is (substituted or unsubstituted aryl). In a further or alternative embodiment, wherein G6Is W-G7(ii) a Wherein W is (substituted or unsubstituted heteroalicyclic group) or (substituted or unsubstituted heteroaryl); g7Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)、OH、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R8、N(R9)2、-C(＝NR10)N(R8)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CON(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L 5- (substituted or unsubstituted aryl); l is5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O).
[00188]In a further or alternative embodiment, L8Is a bond, a (substituted or unsubstituted C1-C6Alkyl groups); l is9Is a bond, -O-, -S (═ O)2、-NH-、-C(O)-、-(CH2) -, -NHC (O) O-, -NHC (O) or-C (O) NH; r13Is H, (substituted or unsubstituted C1-C6Alkyl) or (substituted or unsubstituted C3-C6Cycloalkyl groups).
[00189] In a further or alternative embodiment, the heteroalicyclic group of group Y may be selected from the group consisting of quinolizine, dioxine, piperidine, morpholine, thiazine, tetrahydropyridine, piperazine, oxazinone, dihydropyrrole, dihydroimidazole, tetrahydrofuran, dihydrooxazole, ethylene oxide, pyrrolidine, pyrazolidine, dihydrothiophenone, imidazolidinone, pyrrolidone, dihydrofuranone, dioxolanone, thiazolidine, piperidone, tetrahydronaphthyridine, tetrahydroquinoline, tetrahydrothiophene and thiazepane. In a further or alternative embodiment, the heteroalicyclic group of group Y may be selected from:
[00190]in a further or alternative embodiment, a "G" group (e.g., G)1、G5、G6、G7) Is L20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In a further or alternative embodiment, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, the affinity moiety allows for site-specific binding, including but not limited to antibodies, antibody fragments, DNA, RNA, siRNA and ligands.
[00191]In a further or alternative embodiment, a "G" group (e.g., G) having any one of formula (E), formula (E-I), or formula (E-II)1、G5、G6、G7) Are all groups used to design the physical and biological properties of molecules. This design/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. Physical and biological properties modulated by this modification of "G" include, by way of example only, solubility, absorption in vivo and metabolism in vivo. In addition, in vivo metabolism may include, by way of example only, and not by way of limitationIn particular, control of PK properties, off-target activity, potential toxicity associated with cypP450 interactions, drug-drug interactions, and the like in vivo. Further, improvements to "G" can be made by tailoring, by way of example only, the specific and non-specific proteins that bind to plasma proteins and lipids and tissue distribution in vivo to tailor the in vivo effects of the compounds. In addition, such design/modification for "G" may allow for the design of compounds that are selective for the 5-lipoxygenase-activating protein over other proteins. In a further or alternative embodiment, "G" is L 20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In further or alternative embodiments, the drug includes, for example, leukotriene receptor antagonists and anti-inflammatory agents. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, the affinity moiety allows for site-specific binding, including but not limited to antibodies, antibody fragments, DNA, RNA, siRNA and ligands.
[00192] All combinations of the above groups of the various variants are contemplated herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be synthesized by techniques known in the art as well as those methods set forth herein.
[00193] The formula (E) is as follows:
wherein,
z is OC (R)1)2[C(R2)2]n、[C(R2)2]nOr [ C (R) ]2)2]nC(R1)2O, wherein eachR is1Independently is H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1May be linked to form a carbonyl (═ O); each R2Independently H, OH, OMe, CF 3Or optionally substituted lower alkyl, and two R on the same carbon2May be linked to form a carbonyl (═ O); each n is independently 0, 1, 2 or 3;
y is-L1- (substituted or unsubstituted heteroalicyclic) provided that, when the heteroatom is directly bound to Z, the heteroalicyclic is substituted;
wherein L is1Is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, or substituted or unsubstituted heteroalkynyl;
wherein each substituent is (L)sRs)jWherein each LsIndependently selected from the group consisting of a bond, -O-, -C (O) -, -S (O)2-、-NHC(O)-、-C(O)NH-、S(＝O)2NH-、-NHS(＝O)2、-OC(O)NH-、-NHC(O)O-、-OC(O)O-、-NHC(O)NH-、-C(O)O-、-OC(O)-、C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6A fluoroalkyl, heteroaryl, aryl, or heteroalicyclic group; each RsIndependently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R4Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4The groups can together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
R6Is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl); wherein L is2Is a bond, O, S, -S (═ O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl), or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1(ii) a Wherein,
L3is a bond, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroalicyclic group;
x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；
L4Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;
G1is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L 5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G1Is W-G5(ii) a Wherein W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group, or substituted or unsubstituted heteroaryl; g5Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Independently selected from the group consisting ofOr unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R9Independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups can together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9Can form together a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Independently selected from: H. -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted O-C1-C6An alkyl group;
R11is L7-L10-G6(ii) a Wherein L is7Is a bond, -O, -S (O)2-NH, -C (O) NH, -NHC (O), - (substituted or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C6Alkenyl);
L10is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group); and
G6Is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -NHS (═ O)2R8、-S(＝O)2N(R9)2、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or-L5- (substituted or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G6Is W-G7(ii) a Wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group), or (substituted or unsubstituted heteroaryl); g7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L5- (substituted or unsubstituted aryl) in which L5is-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
R12is H, (substituted)Or unsubstituted C1-C6Alkyl), or (substituted or unsubstituted C2-C4Alkenyl); or an active metabolite, or a solvate, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
[00194]For any and all embodiments (e.g., formula (E), formula (E-I), and formula (E-II)), the substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Y is-L1- (substituted or unsubstituted heteroalicyclic). In a further or alternative embodiment, the heteroalicyclic group is selected from the group consisting of quinolizine, dioxin, piperidine, morpholine, thiazine, tetrahydropyridine, piperazine, oxazinone, dihydropyrrole, dihydroimidazole, tetrahydrofuran, dihydrooxazole, ethylene oxide, pyrrolidine, pyrazolidine, dihydrothiophenone, imidazolidinone, pyrrolidone, dihydrofuranone, dioxolanone, thiazolidine, piperidone, tetrahydronaphthyridine, tetrahydroquinoline, tetrahydrothiophene, indoline, tetrahydroquinoline, and thiazepane. In a further or alternative embodiment, the heteroalicyclic group is selected from:
[00195]in a further or alternative embodiment, R6Is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), or L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O), -CH (OH) or substituted or unsubstituted alkyl.
[00196]In a further or alternative embodiment, R 7Is L3-X-L4-G1(ii) a Wherein L is3Is a substituted or unsubstituted alkyl group; x is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9、-S(＝O)2NR9-、-NR9S(＝O)2、-OC(O)NR9-、-NR9C(O)O-、-CH＝NO-、-ON＝CH-、-NR9C(O)NR9-, heteroaryl, aryl, -NR9C(＝NR10)NR9-、-NR9C(＝NR10)-、-C(＝NR10)NR9-、-OC(＝NR10) -, or-C (═ NR)10)O-；L4Is a bond or a substituted or unsubstituted alkyl group.
[00197]In a further or alternative embodiment, G1Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、-OR9、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8、-S(＝O)2R8Or G1Is W-G5Wherein W is a substituted or unsubstituted heteroalicyclic group or a substituted or unsubstituted heteroaryl group; g5Is tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)2、OH、-OR8、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R9、CN、N(R9)2、-N(R9)C(O)R9、-C(＝NR10)N(R9)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8。
[00198]In a further or alternative embodiment, X is a bond, -O-, -CR9(OR9)、S、-S(O)、-S(O)2、-NR8-O-N ═ CH, -CH ═ N-O, -NHC (═ O), or-C (═ O) NH.
[00199]In a further or alternative embodiment, R12Is H, R11Is L7-L10-G6Wherein: l is7Is a bond, (substituted or unsubstituted C1-C6Alkyl groups); l is10Is (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group). In a further or alternative embodiment, L10Is (substituted or unsubstituted aryl).
[00200]In a further or alternative embodiment, G6Is W-G7Wherein W is (substituted or unsubstituted heteroalicyclic) or (substituted or unsubstituted heteroaryl), G7Is H, tetrazolyl, -NHS (═ O)2R8、S(＝O)2N(R9)、OH、-C(＝O)CF3、-C(O)NHS(＝O)2R8、-S(＝O)2NHC(O)R8、N(R9)2、-C(＝NR10)N(R8)2、-NR9C(＝NR10)N(R9)2、-NR9C(＝CR10)N(R9)2、-C(O)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CON(R9)2、-L5- (substituted or unsubstituted alkyl), -L 5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic), or-L5- (substituted or unsubstituted aryl); l is5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O).
[00201]In some embodiments, Z is [ C (R)2)2]nC(R1)2O。
[00202] All combinations of the above groups of the various variants are contemplated herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be synthesized by techniques known in the art as well as those methods set forth herein.
[00203] Further embodiments of formula (E), formula (E-I) and formula (E-II) include, but are not limited to, the compounds shown in FIGS. 8-11 and tables 1-3.
TABLE 1 non-aromatic R1Substituent and R2Chloro/bromo substituents
| Compound # | R1 | R2 | R3 | R4 | M+H |
| 1-1 | (S) -N-Boc-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 651 |
| 1-2 | (S) -N-acetyl-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 593 |
| 1-3 | (R) -N-Boc-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 651 |
| 1-4 | (S) -2-pyrrolidone-5-methyl group | Cl | 2-methyl-2-propylthio | H | 543 |
| 1-5 | (R) -2-pyrrolidone-5-methyl group | Cl | 2-methyl-2-propylthio | H | 543 |
| 1-6 | (R) -N-acetyl-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 571 |
| 1-7 | (R) -N-methylsulfonyl 2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 629(M+Na) |
| 1-8 | (S) -N-methylsulfonyl 2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 607,629(M+Na) |
| 1-9 | (R) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | See the examples |
| 1-10 | N-trifluoroacetyl 2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 625 |
| 1-11 | Boc-4, 5-dihydroimidazol-2-ylmethyl | Cl | 2-methyl-2-propylthio | H | 628 |
| 1-12 | 4, 5-dihydroimidazol-2-ylmethyl | Cl | 2-methyl-2-propylthio | H | 528 |
| 1-13 | (S) -N-Boc-indoline-2-methyl | Cl | 2-methyl-2-propylthio | H | 699(M+Na) |
| 1-14 | 2- (4-Morpholine) acetyl | Cl | 2-methyl-2-propylthio | H | 573 |
| 1-15 | (S) -indoline-2-methyl | Cl | 2-methyl-2-propylthio | H | 577 |
| 1-16 | (S) -N-acetylindoline-2-methyl | Cl | 2-methyl-2-propylthio | H | 619,641(M+Na) |
| 1-17 | (S) -N-acetylindoline-2-methyl | Cl | 2-methyl-2-propylthio-S, S-dioxide | H | 651 |
| 1-18 | (S) -N-Cyclopropylcarbonyl-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 597 |
| 1-19 | (S) -N-benzoyl-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 633 |
| 1-20 | (S) -N- (2-methylpropanoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 599 |
| 1-21 | (S) -N-propionyl-2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 585 |
| 1-22 | N-Boc-indoline-2-methyl | Cl | 2-methyl-2-propylthio | H | 699(M+Na) |
| 1-23 | Indolin-2-methyl | Cl | 2-methyl-2-propylthio | H | 577 |
| Compound # | R1 | R2 | R3 | R4 | M+H |
| 1-24 | N-acetylindoline-2-methyl | Cl | 2-methyl-2-propylthio | H | 619 |
| 1-25 | (S) -N-acetylindoline-2-methyl | Cl | 2-methyl-2-propylthio-S-oxide | H | 635 |
| 1-26 | (S) -N-acetylindoline-2-methyl | Cl | Benzyl radical | H | 621 |
| 1-27 | (S) -N-acetylindoline-2-methyl | Cl | H | H | 553(M+Na) |
| 1-28 | (S) -N-acetyl-2-pyrrolidinemethyl | Cl | H | H | See the examples |
| 1-29 | (S) -N-acetyl-2-pyrrolidinemethyl | Cl | 3, 3-dimethylbutyryl | H | 581 |
| 1-30 | (S) -N-acetylindoline-2-methyl | Cl | 3, 3-dimethylbutyryl | H | 629 |
| 1-31 | (S) -N-acetylindoline-2-methyl | Cl | Ethyl radical | H | 599 |
| 1-32 | (S) -N-acetylindoline-2-methyl | Cl | Propyl radical | H | 573 |
| 1-33 | (S) -N-acetylindoline-2-methyl | Cl | 2-methylpropionyl group | H | 601 |
| 1-34 | (S) -N-acetylindoline-2-methyl | Cl | Cyclopropyl carbonyl group | H | 599 |
| 1-35 | (S) -N-acetylindoline-2-methyl | Cl | Benzoyl radical | H | 635 |
| 1-36 | (S) -N-acetylindoline-2-methyl | Cl | Cyclobutyl carbonyl | H | 613 |
| 1-37 | (S) -N-acetylindoline-2-methyl | Cl | Acetyl group | H | 573 |
| 1-38 | (S) -N-acetylindoline-2-methyl | Cl | Propionyl group | H | 587 |
| 1-39 | (S) -N-acetylindoline-2-methyl | Cl | 2-methylpropyl radical | H | 609(M+Na) |
| 1-40 | (S) -N-acetylindoline-2-methyl | Cl | 3, 3-dimethylbut-1-yl | H | 615 |
| 1-41 | (S) -N-acetylindoline-2-methyl | Cl | Cyclobutylmethyl group | H | 621(M+Na) |
| 1-42 | (S) -N- (4-phenylbenzoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 709 |
| 1-43 | (S) -N- (phenylacetyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 647 |
| 1-44 | (S) -N- (3-phenylpropionyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 661 |
| 1-45 | (S) -N- (3-phenoxybenzoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 725 |
| 1-46 | (S) -N- (4-phenoxybenzoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 725 |
| 1-47 | (S)-N-(Nicotinoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 634 |
| Compound # | R1 | R2 | R3 | R4 | M+H |
| 1-48 | (S) -N- (pyridin-4-ylcarbonyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 634 |
| 1-49 | (S) -N- (4-phenylbenzoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 637 |
| 1-50 | (S) -N- (phenylacetyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 675 |
| 1-51 | (S) -N- (3-phenylpropionyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 689 |
| 1-52 | (S) -N- (phenylcyclopropylcarbonyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 701 |
| 1-53 | (S) -N- (nicotinoyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 662 |
| 1-54 | (S) -N- (pyridin-4-ylcarbonyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 662 |
| 1-55 | (S) -N- (phenylcyclopropylcarbonyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 673 |
| 1-56 | (S) -N- (4-Bhlorobenzoyl (Bhlorobenzonyl)) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 667 |
| 1-57 | (S) -N- (4-benzyloxyphenylacetyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | H | 754 |
| 1-58 | (S) -N- (4-benzyloxyphenylacetyl) -2-pyrrolidinemethyl | Cl | 2-methyl-2-propylthio | Et | 781 |
| 1-59 | N- (tert-Butoxycarbonyl) piperidin-2-ylmethyl | Cl | 2-methyl-2-propylthio | H | 644 |
| 1-60 | N- (tert-Butoxycarbonyl) piperidin-2-ylmethyl | Cl | 2-methyl-2-propylthio | Et | 572(M-BOC) |
| 1-61 | (S) -N- (2-bromoethoxycarbonyl) indoline-2-methyl | Cl | 2-methyl-2-propylthio | Et | 801 |
| 1-62 | (S) -pyrrolidin-2-ylmethyl | Cl | 2-methyl-2-propylthio | H | 529 |
| 1-63 | 2- (2-methyl-1, 3-dioxolan-2-yl) ethyl | Br | 2-methyl-2-propylthio | H | 604 |
TABLE 2.R2Aryl substituents
| Compound # | R1 | R2 | R3 | M+H |
| 2-1 | (S) -N-Boc-2-pyrrolidinemethyl | 2-thiazolyl group | 2-methyl-2-propylthio | 700(M+Na) |
| 2-2 | (S) -2-pyrrolidinemethyl | 2-thiazolyl group | 2-methyl-2-propylthio | 579 |
| 2-3 | (S) -N-acetyl-2-pyrrolidinemethyl | 2-thiazolyl group | 2-methyl-2-propylthio | 620 |
| 2-4 | (S) -N-acetyl-2-pyrrolidinemethyl | 2-thiazolyl group | H | 532 |
| 2-5 | (S) -N-acetyl-2-indolinylmethyl | 2-methoxy-4-pyridazinyl | 2-methyl-2-propylthio | 694 |
| 2-6 | (S) -N-acetyl-2-pyrrolidinemethyl | 2-methoxy-4-pyridazinyl | 2-methyl-2-propylthio | 645 |
| 2-7 | (S) -N-acetyl-2-indolinylmethyl | 2-methoxypyridin-5-yl | 2-methyl-2-propylthio | 692 |
| 2-8 | (S) -N-acetyl-2-indolinylmethyl | 2-Methoxythiazol-4-yl | 2-methyl-2-propylthio | 698 |
| 2-9 | (S) -N-acetyl-2-indolinylmethyl | 5-methoxypyridin-2-yl | 2-methyl-2-propylthio | 692 |
| 2-10 | 2- (2-methyl-1, 3-dioxolan-2-yl) ethyl | 2-methoxypyridin-5-yl | 2-methyl-2-propylthio | 633 |
| 2-11 | N- (methoxyacetyl) indolin-2-ylmethyl | 5-Trifluoromethylpyridin-2-yl | 2-methyl-2-propylthio | 760 |
TABLE 3 non-heteroaryl indole Tertiary alcohols
| Compound # | R1 | R2 | R4 | M+H |
| 3-1 | 2- (4-Morpholine) acetyl | 4-chlorobenzyl | 2-hydroxy-2-methylpropan-1-yl | 545 |
| 3-2 | Boc-2-pyrrolidinemethyl | 4-chlorobenzyl | 2-hydroxy-2-methylPhenylprop-1-yl radical | 543(M-BOC，+Na+H2O) |
| 3-3 | Boc-2-pyrrolidinemethyl | Pyridin-2-ylmethyl | 2-hydroxy-2-methylpropan-1-yl | 510(M-BOC，+Na+H2O) |
| 3-4 | N-acetyl-2-pyrrolidinemethyl | 4-chlorobenzyl | 2-hydroxy-2-methylpropan-1-yl | 543 |
| 3-5 | N-acetyl-2-pyrrolidinemethyl | Pyridin-2-ylmethyl | 2-hydroxy-2-methylpropan-1-yl | 511 |
| 3-6 | (S) -N-Boc-2-pyrrolidinemethyl | 4-chlorobenzyl | 1-hydroxy-2, 2-dimethylpropan-3-yl | 637(M+Na) |
[00204] In one aspect, provided herein are compounds selected from the group consisting of:
(S) -tert-butyl 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylate (Compound 1-1); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-2); (R) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 1-3); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -5-oxo-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-4); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -5-oxo-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-5); 3- [5- ((R) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-6); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -1-methanesulfonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-7); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-methanesulfonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-8); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((R) -1-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-9); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (2, 2, 2-trifluoro-acetyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-10); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -4, 5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (compound 1-11); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (4, 5-dihydro-1H-imidazol-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-12); (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (compound 1-13); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2-morpholin-4-yl-2-oxo-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-14); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [ (S) -1- (2, 3-dihydro-1H-indol-2-yl) methoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-15); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-16); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (2-methyl-propane-2-sulfonyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-17); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-cyclopropanecarbonyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-18); 3- [5- ((S) -1-benzoyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-19); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-isobutyryl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-20); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-propionyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-21); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (compound 1-22); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2, 3-dihydro-1H-indol-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-23); 3- [5- (1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-24); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (2-methyl-propane-2-sulfinyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-25); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-benzyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-26); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-27); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-28); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyryl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-29); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyryl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-30); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-ethyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-31); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-propyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-32); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-isobutyryl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-33); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclopropanecarbonyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-34); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-benzoyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-35); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclobutylcarbonyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-36); 3- [ 3-acetyl-5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-37); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-propionyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-38); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-isobutyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-39); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3- (3, 3-dimethyl-butyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-40); 3- [5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -1- (4-chloro-benzyl) -3-cyclobutylmethyl-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compounds 1-41); 3- [5- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-42); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (1-phenylacetyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-43); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenyl-propionyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-44); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenoxy-benzoyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-45); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (4-phenoxy-benzoyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-46); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-3-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-47); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-48); 3- [5- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-49); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (1-phenylacetyl-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-50); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (3-phenyl-propionyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-51); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- ((S) -2-phenyl-cyclopropanecarbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-52); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-3-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-53); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- (pyridine-4-carbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (compound 1-54); 3- { 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- [1- ((R) -2-phenyl-cyclopropanecarbonyl) -pyrrolidin-2-ylmethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-55); 3- [ 3-tert-butylsulfanyl-5- [ (S) -1- (4-chloro-benzoyl) -pyrrolidin-2-ylmethoxy ] -1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-56); 3- [5- {1- [2- (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-ylmethoxy } -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-57); 3- [5- {1- [2- (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-ylmethoxy } -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-58); 2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -piperidine-1-carboxylic acid tert-butyl ester (compound 1-59); 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -piperidine-1-carboxylic acid tert-butyl ester (compound 1-60); 2- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -2, 3-dihydro-indole-1-carboxylic acid 2-bromoethyl ester (compound 1-61); 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- ((S) -1-pyrrolidin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 1-62); 3- {1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- [2- (2-methyl- [1, 3] dioxolan-2-yl) -ethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 1-63); (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-thiazol-2-yl-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 2-1); 3- [ 3-tert-butylsulfanyl-5- ((S) -1-pyrrolidin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-2); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-3); 3- [5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-4); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-5); 3- {5- ((S) -1-acetyl-pyrrolidin-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-6); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-7); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-8); 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-9); 3- { 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- [2- (2-methyl- [1, 3] dioxolan-2-yl) -ethoxy ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-10); 3- { 3-tert-butylsulfanyl-5- [ (S) -1- (2-methoxy-acetyl) -2, 3-dihydro-1H-indol-2-ylmethoxy ] -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-11); 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy ] -1-morpholin-4-yl-ethanone (compound 3-1); (R) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-2); (R) -2- [ 3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-3); 1- { (R) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidin-1-yl } -ethanone (compound 3-4); 1- { (R) -2- [ 3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl ] -pyrrolidin-1-yl } -ethanone (Compound 3-5); and (S) -tert-butyl 2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (3-hydroxy-2, 2-dimethyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylate (compound 3-6).
Synthesis of Compounds
[00205] The compounds described in the previous section can be synthesized using standard synthetic techniques known to those skilled in the art, or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions provided herein may vary according to one of ordinary skill in the art.
[00206]The starting materials for the synthesis of the compounds described herein may be synthesized or may be obtained commercially, such as, but not limited to: aldrich Chemical co. (Milwaukee, Wis.), or Sigma Chemical co. (st. The compounds described herein, and other related compounds having different substituents, can be synthesized using techniques and materials known to those skilled in the art, such as described in: the mark is a mark of the mark, and the mark is a mark of the mark, 
4 th edition (Wiley 1992); the group consisting of Carey and Sundberg, 4 th edition, Vols.A and B (Plenum 2000, 2001), and Green and Wuts,
3 rd edition, (Wiley 1999) (the entire contents of which are incorporated herein by reference). General methods of preparing the compounds disclosed herein can be derived from reactions known in the art, and appropriate reagents and conditions, as will be recognized by the skilled artisan, can be utilized to modify the reactions in order to incorporate various moieties within the formulae provided herein. The following synthetic methods may be used for reference.
Reaction of electrophiles with nucleophiles to form covalent bonds
[00207] Various electrophiles or nucleophiles can be used to modify the compounds described herein to form new functional groups or substituents. Table 4, entitled "examples of covalent bonds and precursors thereof", lists examples of selected covalent bonds and precursor functional groups that are available and can be used as a guide for the various available combinations of electrophiles and nucleophiles. The precursor functional groups are shown as electrophilic and nucleophilic groups.
Table 4:examples of covalent linkers and precursors thereof
Use of protecting groups
[00208] In the described reactions, it is necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio or carboxyl groups, where these are required in the final product, from undesired participation in the reaction. Protecting groups serve to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. Preferably, each protecting group is removable by a different method. The protection groups which can be cleaved under completely different reaction conditions can meet the requirements of different removals. The protecting groups can be removed using acids, bases and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and can be used to protect carboxyl and hydroxyl reactive moieties in the case of amino protection with the Cbz group (which can be removed by hydrogenolysis) and the Fmoc group (which is labile to bases). In the presence of an amine blocked with an acid labile group such as tertiary butyl carbamate or with a carbamate (both acid and base stable, but hydrolytically removable), the carboxylic acid and hydroxyl reactive moieties can be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl groups.
[00209] The carboxylic acid and hydroxyl reactive moieties may also be blocked by a hydrolytically removable protecting group such as benzyl, while the amino group capable of hydrogen bonding to an acid may be blocked by a base labile group such as Fmoc. The carboxylic acid reactive moieties may be protected by conversion to the simple ester compounds exemplified herein, or they may be blocked with an oxidation-removable protecting group such as 2, 4-dimethoxybenzyl, while the co-existing amino groups may be blocked with a fluoride-labile silyl carbamate.
[00210]The allyl blocking group can then be used in the presence of acid and base protecting groups, since the former are stable and can subsequently be removed using metal or pi-acid catalysts. For example, allyl-interrupted carboxylic acids may be used in the presence of acid-labile tert-butyl carbamate or base-labile acetic acidWith Pd in the presence of an amine protecting group0-catalytic reaction for deprotection. Another form of protecting group is a resin to which a compound or intermediate may be attached. The functional groups can be blocked and not reacted as long as the residue is attached to the resin. Once released from the resin, the functional group can be used to react.
[00211] Typically, the blocking/protecting group may be selected from:
[00212] Further protecting groups plus detailed technical descriptions suitable for forming protecting groups and their removal are described in the following: greene and Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the entire contents of which are incorporated herein by reference.
[00213] Indole-containing compounds can be prepared using standard literature procedures, such as those obtained in: katritzky, "Handbook of Heterocyclic Chemistry" Pergamon Press, Oxford, 1986; pindur et al, J.Heterocyclic chem., vol25, 1, 1987, and Robinson "The Fisher index Synthesis", John Wiley & Sons, Chichester, New York, 1982, The entire contents of each of which are incorporated herein by reference.
[00214]According to scheme I shown in FIG. 1, a non-limiting example is shown for the synthesis of the indole compounds described herein, wherein a 4-substituted aniline (I-1) can be converted to the corresponding hydrazine (I-2) using standard procedures. Hydrazine (I-2) is reacted with the appropriately substituted ketone (I-3) under standard Fisher-indolisation conditions to give indole (I-4). Indole (I-6) is produced by N-alkylation of (I-4) with benzyl halide (I-5) (or tosylates (OTs) Or Mesylates (OMs)) in a solvent such as Tetrahydrofuran (THF) or Dimethylformamide (DMF) in the presence of a base such as NaH . In the case where the 5-substituent on the indole ring is methoxy (i.e. Z is MeO), the methyl group can be removed under standard conditions, for example using BBr3In a solvent such as CH2Cl2To obtain phenol (I-7). The phenol may be alkylated using an electrophile (YX) to provide an alkylated product (I-8). Alternatively, in the case when the 5-substituent on the indole ring is, for example, a halide or triflate (OTf; I-7), it can be coupled with a variety of reagents (using standard metal mediated coupling reactions well known to those skilled in the art of organic synthesis) to give alternative compounds having the structure (I-6). This chemistry is described below: comprehensive organometalic Chemistry II, vol12, Pergamon, edited by Abel, Stone and Wilkinson. The Z substituent of indole (I-6) may be further modified using standard chemical methods. In addition, when R is7Or R6Being bromine or iodine, standard cross-coupling reactions allow the introduction of a wide variety of functional groups using methods well known to those skilled in the art of organic synthesis. In addition, when R is7In the case of H, regioselective lithiation can be carried out using a strong base such as nBuLi under conditions such that the anion is then condensed with an electrophile to introduce a substituent at C-2 (see Hasan et al, J. org. chem., 46, 157-164, 1981).
[00215] According to scheme II in figure 2, another non-limiting example is shown regarding the synthesis of the compounds described herein. Starting from hydrazine I-2, N-alkylation with benzyl halide (or tosylate or mesylate; I-5) using the conditions described above provides the hydrazine derivative (II-1). Reaction with the appropriately substituted ketone (I-3) using standard Fisher-indolisation conditions affords indole (I-6).
[00216]According to scheme III in scheme 2, another non-limiting example is shown for the synthesis of the compounds described herein, where 3-H-indole (III-1) can be prepared directly using the methods described above, or by using in a solvent (e.g., CH)2Cl2) Wet AlCl in (1)3Treatment, prepared from 3-thioindole. The functionalization of the 3-position can be achieved using various reactions and methodsTo introduce a variety of substituents. By way of example only, in Lewis acids such as AlCl3In the presence of (A), an acyl group (I-6; R)6See Murakami et al, heterocyles, v14, 1939-. Starting from (III-1), by way of example only, compounds of the general structure (III-2) can be prepared using sulfenyl chloride in a suitable solvent, wherein R is 6Is SR "(Raban, j. org. chem., v45, 1688, 1980). A similar chemistry can be carried out using indole (III-3), or a diaryl disulfide (diaryldisulfide) can be used in DMF in the presence of a base such as NaH to yield (III-4) (Atkinson et al, Synthesis, 480-481, 1988). In Lewis acids (e.g. Yb (OTf)3.3H2O) with a 3-H indole (III-1) or (III-3) to give a 3-alkyl substituent of the general structure (III-2) or (III-4) (wherein R is6Is a substituted alkyl group; see Harrington and Kerr, Synlett, 1047-. Alternatively, in warm DMF, indole (III-3) may be reacted with benzyl derivative (I-5) to give (III-4), wherein R6Is a substituted benzyl group (Jacobs et al, J.Med.chem., v36, 394-409, 1993).
Alternative synthesis of indole and indole-type compounds
[00217] Other non-limiting examples of synthetic strategies for the indole or indole-like backbone of the compounds described herein include various modifications to the synthesis of the indole, including but not limited to: Batco-Leimgruber indole synthesis, Reissert indole synthesis, Hegedus indole synthesis, Fukuyama indole synthesis, Sugasawa indole synthesis, Bischler indole synthesis, Gassman indole synthesis, Fischer indole synthesis, Japp-Klingemann indole synthesis, Buchwald indole synthesis, Larock indole synthesis, Bartoli indole synthesis, Castro indole synthesis, Hemetsberger indole synthesis, Mori-Ban indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis, and other reactions not named. Non-limiting examples of such synthetic methods are shown in FIGS. 3-7.
Other forms of the Compounds
[00218] The compounds described herein may be prepared as pharmaceutically acceptable acid addition salts (which is one type of pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucic acid.
[00219] Alternatively, the compounds described herein may be prepared as pharmaceutically acceptable base addition salt forms (which is one type of pharmaceutically acceptable salt) by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including but not limited to: organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like, inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.
[00220] When an acidic proton, which may be replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or may be coordinated to an organic base, is present in the parent compound, the compounds described herein may be prepared in the form of a pharmaceutically acceptable salt. In addition, salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
[00221] It is to be understood that pharmaceutically acceptable salts include solvent addition forms or crystal forms thereof, in particular solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may conveniently be prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared by recrystallization from aqueous/organic solvent mixtures using organic solvents (including, but not limited to, dioxane, tetrahydrofuran, or methanol). In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
[00222] The compounds described herein may be in various forms including, but not limited to, amorphous, comminuted, and nanoparticle forms. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of compounds of the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, crystallization rate and storage temperature can produce a predominantly single crystal morphology.
[00223] The compounds of formula (E), formula (E-I) and formula (E-II) in their unoxidized form may be prepared from the N-oxides of compounds of formula (E), formula (E-I) and/or formula (E-II) by treatment with a reducing agent (such as, but not limited to, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromides, and the like) in a suitable inert organic solvent (such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, and the like) at from 0 to 80 ℃.
[00224] The compounds provided herein may be prepared as prodrugs. Prodrugs are generally prodrugs that, after administration to a subject and subsequent absorption, may be converted to an active or more active species by processes such as conversion through metabolic pathways. Some prodrugs have chemical groups present on the prodrug that may render the drug less active and/or impart solubility or other properties to the drug. Once the chemical group is cleaved from the prodrug and/or modified, the active drug is produced. Prodrugs are often useful because, in some cases, they can be administered more easily than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent is not. Prodrugs may also have increased solubility over the parent drug in the pharmaceutical composition.
[00225] Prodrugs can be designed as reversible drug derivatives that act as modulators to enhance drug transport to specific tissues at the site. To date, the design of prodrugs has been to increase the effective water solubility of the therapeutic compounds to target regions where water is the predominant solvent. See, e.g., Fedorak et al, am.j.physiol., 269: g210-218 (1995); McLoed et al, Gastroenterol, 106: 405-413 (1994); hochhaus et al, biomed.chrom, 6: 283-; larsen and h.bundgaard, int.j.pharmaceuticals, 37, 87 (1987); larsen et al, int.j.pharmaceuticals, 47, 103 (1988); sinkula et al, j.pharm.sci., 64: 181-210 (1975); volume 14 of t.higuchi and v.stella, Pro-drugs as Novel Delivery Systems, a.c.s.symposium Series; and Edward B.Roche, Bioreversible Carriers in Drug Design, American pharmaceutical Association and Pergamon Press, 1987, the entire contents of which are incorporated herein.
[00226] In addition, prodrug derivatives of the compounds provided herein can be prepared by methods known to those of ordinary skill in the art (see, e.g., Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985 for details). By way of example only, suitable prodrugs may be prepared by reacting a non-derivatized compound having any of formula (E), formula (E-I), or formula (E-II) with a suitable carbamylating agent such as, but not limited to, 1-acyloxyalkylcarbonyl chloride (acryloxyarylcarbanochloridate), p-nitrophenyl carbonate, and the like. Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the derivatives listed herein, are included within the claims. Indeed, some of the compounds described herein may be prodrugs of other derivatives or active compounds.
[00227] Sites on the aromatic ring portion of the compounds described herein can undergo various metabolic reactions, and thus, introduction of suitable substituents such as, by way of example only, halogens on the aromatic ring structure can reduce, reduce or eliminate such metabolic pathways.
[00228] The compounds described herein may be isotopically (e.g., with a radioisotope) or labeled by other means including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label or a chemiluminescent label. The compounds described herein may have one or more stereocenters, each of which may exist in either the R or S configuration. The compounds provided herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. The compounds described herein may be prepared as their single stereoisomeric forms by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Although enantiomeric resolution may be performed using covalent diastereomeric derivatives of the compounds described herein, separable complexes (e.g., crystalline diastereomeric salts) are preferred. Diastereomers have unique physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and can be readily separated by taking advantage of these dissimilarities. Diastereomers can be separated by chiral chromatography or, preferably, by separation/resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, and the reagents resolved, using any practical method that does not result in racemization. A more detailed description of a technique suitable for resolving stereoisomers of compounds from racemic mixtures of compounds can be found in: jean Jacques, AndreClet, Samuel H.Wilen, "Enantiomers, Racemates And solutions," John Wiley And Sons, Inc., 1981, which is incorporated herein by reference in its entirety.
[00229] In addition, the compounds and methods provided herein can exist in geometric isomeric forms. The compounds and methods provided herein include all cis (cis), trans (trans), syn, anti, entgegen (E), and zusammen (z) isomers, as well as suitable mixtures thereof. In some cases, the compounds may exist in tautomeric forms. All tautomers are encompassed within the general formulae described herein and are provided by the compounds and methods herein. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion can also be effective for the applications described herein.
Route of administration
[00230] Suitable routes of administration include, but are not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal (transmucosal), transdermal, vaginal, aural, nasal and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intravaginal, direct delivery intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
[00231] Alternatively, the compounds may be administered locally, rather than systemically, e.g., by direct injection of the compound into an organ, often with a depot or sustained release formulation. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In addition, administration can be with targeted drug delivery systems, such as with liposomes coated with organ-specific antibodies. The liposomes can be targeted to and selectively taken up by the organ. In addition, the drug may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
Pharmaceutical composition/formulation
[00232] Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen. Any of the well known techniques, carriers and excipients may be used in a manner suitable and understood in the art. An overview of the pharmaceutical compositions described herein can be found, for example, in the following: remington: the Science and Practice of Pharmacy, 19 th edition (Easton, Pa.: Mack Publishing Company, 1995); hoover, john e., Remington's pharmaceutical Sciences, Mack Publishing co, Easton, Pennsylvania 1975; liberman, h.a. and Lachman, L, editors, Pharmaceutical document Forms, Marcel Decker, New York, n.y., 1980; and Pharmaceutical Dosage Formsand Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), which are incorporated herein by reference in their entirety.
[00233] Provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable diluent, excipient, or carrier. Furthermore, as in combination therapy, the compounds described herein may be administered in the form of a pharmaceutical composition in which the compounds described herein are mixed with other active ingredients.
[00234] The term "pharmaceutical composition" as used herein refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition may facilitate administration of the compound to an organism. In practicing the methods of treatment or uses provided herein, a therapeutically effective amount of a compound provided herein is administered in the form of a pharmaceutical composition to a mammal having a disease or condition being treated. Preferably, the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and associated health status of the subject, the potency of the compound used and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of a mixture.
[00235] For intravenous injection, the compounds described herein can be formulated in water, preferably with a physiologically compatible buffer, such as Hanks's solution, ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
[00236] For oral administration, the compounds provided herein can be readily formulated by combining the active compound with excipients or pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, lozenges, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
[00237] Pharmaceutical preparations for oral use can be obtained in the following manner: mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations for example: corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose; or others, such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents can be added, for example cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof, for example sodium alginate.
[00238] The lozenge cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer (carbopol) gum, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound doses, dyes or pigments can be added to the tablet or lozenge coating.
[00239] Pharmaceutical formulations which can be used orally include push-fit capsules (push-fit capsules) made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
[00240] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges or gels formulated in conventional manner. Maternal injections may include bolus injections (bolus) or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules with an added preservative or in multi-dose containers. The pharmaceutical composition of any of formula (E), formula (E-I) or formula (E-II) may be in a form suitable for parenteral injection, such as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulatory agents, such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles (vehicles) include aliphatic oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds so that highly concentrated solutions can be prepared. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
[00241] The compounds described herein can be administered topically and can be formulated into a number of topically administered compositions, such as solutions, suspensions, lotions, gels, pastes, medicated strips, balms, creams or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00242] Formulations suitable for transdermal administration of the compounds described herein may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and/or dispersed in a polymer or binder. Such patches may be configured for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein may be achieved by means of iontophoretic patches and the like. In addition, transdermal patches may provide controlled delivery of the compounds described herein. The rate of absorption can be slowed by a rate controlling membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers may be used to increase absorption. The absorption enhancer or carrier may include a pharmaceutically acceptable solvent that is readily absorbed to aid passage through the skin. For example, the transdermal device is in the form of a band that includes a cushion component, a reservoir containing the compound optionally with a carrier, optionally a rate controlling spacer (to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time), and means to secure the device to the skin.
[00243] For administration by inhalation, the compounds described herein may be in the form of an aerosol, mist or powder. The pharmaceutical composition of any of formula (E), formula (E-I) or formula (E-II) may conveniently be delivered in the form of: aerosol sprays are provided from pressurized packs or nebulizers with the aid of suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a measured amount. Capsules and cartridges of, for example only, gelatin for inhalation or insufflation may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[00244] The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gelatinous suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG and the like. In suppository forms of the composition, a low melting paraffin such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
[00245] Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen. Any of the well known techniques, carriers and excipients may be used as appropriate and understood in the art. Pharmaceutical compositions comprising a compound described herein may be prepared in a conventional manner, such as, for example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, collecting or extruding processes.
[00246] The pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent or excipient and, as active ingredient, a compound described herein (in free acid or free base form, or in pharmaceutically acceptable salt form). In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds, which possess the same type of activity. In some cases, the compounds may exist in tautomeric forms. All tautomers are included within the scope of the compounds provided herein. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered disclosed herein. In addition, the pharmaceutical compositions may comprise further pharmaceutical or pharmaceutical agents, carriers, auxiliaries, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the pharmaceutical compositions may contain other therapeutically valuable substances.
[00247] A method of preparing a composition comprising a compound described herein, comprising formulating the compound with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions comprising the compounds, or solutions containing liposomes, micelles, or nanoparticles comprising the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The compositions may be in the form of liquid solutions or suspensions, solid forms suitable for forming solutions or suspensions in liquids prior to use, or in the form of emulsions. These compositions may also contain minor amounts of non-toxic, auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
[00248] Compositions comprising the compounds described herein may illustratively take the form of a liquid in which the agent is present as a solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the agent is present in solution and a second portion of the agent is present as particles suspended in a liquid matrix. In some embodiments, the liquid composition may comprise a gel formulation. In other embodiments, the liquid composition is aqueous.
[00249] Useful aqueous suspensions may also contain one or more polymers as suspending agents. Useful polymers include water soluble polymers, such as cellulosic polymers, e.g., hydroxypropyl methylcellulose; and water-insoluble polymers, for example, crosslinked carboxyl group-containing polymers. Useful compositions may also include mucoadhesive polymers, for example selected from carboxymethylcellulose, carbomers (acrylic acid polymers), poly (methyl methacrylate), polyacrylamide, polycarbophil (polycarbophil), acrylic acid/butyl acrylate copolymers, sodium alginate and dextran.
[00250] Useful compositions may also include solubilizing agents to aid in the dissolution of the compounds described herein. The term "solubilizing agent" generally includes agents that can result in the formation of a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizing agents, as may ophthalmically acceptable glycols, polyethylene glycols such as polyethylene glycol 400, and glycol ethers.
[00251] Useful compositions may also include one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate/glucose, sodium bicarbonate and ammonium chloride. The acid, base and buffer are included in amounts required to maintain the pH of the composition within an acceptable range.
[00252] Useful compositions may also contain an amount of one or more salts required to provide an osmotic pressure of the composition within an acceptable range. Such salts include those having a sodium, potassium or ammonium cation and a chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.
[00253] Other useful compositions may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing materials such as phenylmercuric nitrate (merfen) and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium bromide.
[00254] Other useful compositions may also include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60), hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxysan 10, octoxysan 40.
[00255] Other useful compositions may also include one or more antioxidants to enhance the desired chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
[00256] The aqueous suspension composition may be packaged in a single-dose non-resealable container. Alternatively, multi-dose resealable containers may be used, in which case a preservative is typically included in the composition.
[00257] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well known examples of excipients or carriers for the delivery of hydrophobic drugs. Certain organic solvents such as N-methylpyrrolidone may also be used, although usually at the expense of greater toxicity. In addition, sustained release systems may be used to deliver the compounds, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been identified and are well known to those skilled in the art. The sustained release capsule can release the compound for several weeks up to more than 100 days, depending on the chemical properties of the sustained release capsule. Other strategies for stabilizing proteins may be used depending on the chemical nature and biological stability of the therapeutic agent.
[00258] All of the formulations described herein may benefit from antioxidants, metal chelators, thiol containing compounds, and other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1mM to about 10mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) a combination thereof.
Methods of administration and treatment regimens
[00259] The compounds described herein may be used in the preparation of medicaments for the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions. Furthermore, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
[00260] Compositions containing the compounds described herein can be administered for prophylaxis and/or treatment. In therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The effective amount for such use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, response to the drug, and the judgment of the treating physician. Such therapeutically effective amounts are deemed suitable by those skilled in the art to be determined by routine experimentation, including but not limited to dose escalation clinical trials.
[00261] In prophylactic applications, compositions containing a compound described herein are administered to a patient susceptible to or at risk of contracting a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In such use, the exact amount will also depend on the health, weight, etc. of the patient. Such therapeutically effective amounts are deemed suitable by those skilled in the art to be determined by routine experimentation, including but not limited to dose escalation clinical trials.
. When used in a patient, an effective amount for such use will depend upon the severity and course of the disease, disorder or condition, previous treatment, the health and response of the patient to the drug, and the judgment of the treating physician.
[00262] In the event that the patient's symptoms do not improve, the compound may be administered for an extended period of time, i.e., for an extended period of time, including throughout the patient's life, at the discretion of the physician, in order to improve or control or limit the symptoms of the patient's disease or disorder.
[00263] In the case of an improved patient condition, the compound may be administered continuously, at the discretion of the physician; alternatively, the dose of drug administered may be temporarily reduced, or temporarily suspended for a period of time (i.e., a "drug holiday"). The length of the drug holiday can vary from 2 days to 1 year between: including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during a drug holiday can be 10% -100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
[00264] Once improvement occurs, maintenance doses are administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced to a level that maintains the disease, disorder, or improvement in the disorder, which is associated with the symptoms. However, in the event of any recurrence of symptoms, the patient may require intermittent treatment for extended periods of time.
[00265] The amount of agent administered corresponding to such an amount will vary depending upon a number of factors, such as the particular compound, the disease condition and its severity, the nature (e.g., weight) of the subject or host in need of treatment, and, although so, depending upon the particular circumstances surrounding the case (including, for example, the particular agent administered, the route of administration, the condition being treated, and the subject or host being treated), can generally be determined routinely in a manner known in the art. However, the dosages typically used for adult treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The required dose may conveniently be presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at suitable intervals (e.g. two, three, four or more sub-doses per day).
[00266] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosages. In unit dosage form, the preparation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dose can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packed tablets or capsules, and powders in vials or ampoules. The aqueous suspension composition may be packaged in a single dose non-resealable container. Alternatively, multi-dose resealable containers may be used, in which case a preservative is typically included in the composition. By way of example only, parenteral injection formulations may be presented in unit dosage forms including, but not limited to, ampoules, or in multi-dose containers with an added preservative.
[00267] A suitable daily dose of a compound described herein is from about 0.01 to 2.5 mg/kg body weight. In larger mammals, including but not limited to humans, the indicated daily dosage is in the range of about 0.5 mg to about 100 mg, and is conveniently administered in divided doses, including but not limited to up to four times a day, or in extended release form. Suitable unit dosage forms for oral administration include from about 1 to 50 milligrams of active ingredient. The foregoing ranges are merely suggestive, as the number of treatment regimens varies greatly for an individual, and it is not uncommon to have substantial deviations from these recommended values. Such dosages may vary depending upon a number of variables not limited to the activity of the compound employed, the disease or condition being treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
[00268]Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to: LD50(lethal dose for 50% of the population) and ED50(effective therapeutic dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as LD 50And ED50To each other. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dose of such a compound is preferably at circulating concentrations (including ED with minimal toxicity)50) Within the range. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
Use of FLAP modulators for the prevention and/or treatment of leukotriene-dependent or leukotriene mediated
Disease or disorder
[00269] Treatment of leukotriene-dependent or leukotriene mediated diseases or conditions is designed to modulate the activity of FLAP. Such modulation may include, by way of example only, inhibition or antagonism of FLAP activity. For example, a FLAP inhibitor may be administered to reduce leukotriene synthesis in an individual, or may down-regulate or reduce the expression or effectiveness of FLAP mRNA or a specific splice variant of FLAP mRNA. Downregulating or reducing the expression or effectiveness of intrinsic FLAP mRNA or a particular splice variant may minimize the expression or activity of, and thereby minimize the effect of, a defective nucleotide or particular splice variant.
[00270] According to one aspect, the compositions and methods described herein include compositions and methods for treating, preventing, reversing, halting or slowing the progression of, or treating symptoms associated with or associated with a leukotriene-dependent or leukotriene mediated disease or condition by administering to a subject a compound described herein, or a pharmaceutical composition or medicament comprising a compound described herein. At the time of administration, the subject may already have, or be at risk of developing, a leukotriene-dependent or leukotriene mediated disease or condition. The symptoms of leukotriene-dependent or leukotriene mediated diseases or disorders in a subject can be determined by those skilled in the art and are described in standard texts.
[00271] In a mammal, the activity of the 5-lipoxygenase activating protein may be modulated directly or indirectly by administering (at least once) an effective amount of at least one compound of formula (E), formula (E-I) or formula (E-II), or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I) or formula (E-II) to the mammal. Such adjustments include, but are not limited to: reducing and/or inhibiting the activity of a 5-lipoxygenase activating protein. Furthermore, the activity of leukotrienes can be directly or indirectly modulated, including reduced and/or inhibited, in a mammal by administering (at least once) to the mammal an effective amount of at least one compound of any of formula (E), formula (E-I), or formula (E-II), or a pharmaceutical composition or medicament comprising any of formula (E), formula (E-I), or formula (E-II). Such adjustments include, but are not limited to: reducing and/or inhibiting the activity of a 5-lipoxygenase activating protein.
[00272] Preventing and/or treating leukotriene-dependent or leukotriene mediated diseases or conditions may comprise administering at least once an effective amount of at least one compound of any of formula (E), formula (E-I) or formula (E-II) or a pharmaceutical composition or medicament comprising any of the compounds of formula (E), formula (E-I) or formula (E-II) to a mammal. For example, preventing and/or treating an inflammatory disease or disorder may comprise administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). Leukotriene-dependent or leukotriene mediated diseases or conditions that may be treated by a method comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (E), formula (E-I), or formula (E-II), or a pharmaceutical composition or medicament comprising any of formula (E), formula (E-I), or formula (E-II), include, but are not limited to: bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, skin diseases and disorders, eye diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorders, and non-cancerous disorders.
[00273] For example, included in the prophylactic/therapeutic methods described herein are methods of treating respiratory diseases comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). For example, the respiratory disease may be asthma; see Riccioni et al, Ann.Clin.Lab.Sci., v34, 379-387 (2004). In addition, respiratory diseases may include, but are not limited to: adult respiratory distress syndrome and allergic (external) asthma, non-allergic (internal) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergy-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, equal carbon dioxide hyperventilation, childhood asthma, adult-developed asthma, cough variant asthma, occupational asthma, hormone-resistant asthma, seasonal asthma, allergic rhinitis, vascular response, endotoxin shock, fibrosis, pulmonary fibrosis, allergic disease, chronic inflammation and adult respiratory distress syndrome.
[00274] For example, included in such treatment methods is a method of preventing chronic obstructive pulmonary disease comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). In addition, chronic obstructive pulmonary diseases include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation and cystic fibrosis.
[00275] For example, included in such treatment methods are methods of preventing increased mucosal secretion and/or edema in a disease or disorder, comprising administering to the mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II), or a pharmaceutical composition or medicament comprising any one of formula (E), formula (E-I), or formula (E-II).
[00276] For example, included in the prophylactic/therapeutic methods described herein are methods of preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II); see Jala et al, trends Immunol., Vol.25, 315-.
[00277] For example, included in the prophylactic/therapeutic methods described herein are methods of reducing cardiac reperfusion injury following myocardial ischemia and/or endotoxic shock comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00278] For example, included in the prophylactic/therapeutic methods described herein are methods of reducing vasoconstriction in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00279] For example, included in the prophylactic/therapeutic methods described herein are methods of reducing or preventing an increase in blood pressure in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00280] For example, included in the methods of prevention/treatment described herein are methods of preventing an increase in eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or monocytes comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I) or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I) or formula (E-II).
[00281] For example, included in the prophylactic/therapeutic methods described herein are methods of preventing or treating abnormal bone remodeling, loss or gain, including diseases or disorders such as osteopenia, osteoporosis, Paget's disease, cancer and other diseases. The method comprises administering to the mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00282] For example, included in the methods of prevention/treatment described herein are methods of preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II), or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II); see lamb et al, arch, volume 121, 615-.
[00283] For example, included in the methods of prevention/treatment described herein are methods of preventing a CNS disorder comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). CNS disorders include, but are not limited to: multiple sclerosis, parkinson's disease, alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema, and craniocerebral injury.
[00284] For example, included in the prophylactic/therapeutic methods described herein are methods of treating cancer comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). Cancer types may include, but are not limited to, pancreatic cancer and other solid or hematological tumors, see Poff and Balazy, Curr. drug TargetsInflamm. Allergy, Vol.3, 19-33(2004) and Steele et al, cancer epidemic & Prevention, Vol.8, 467-483 (1999).
[00285] For example, included in the prophylactic/therapeutic methods described herein are methods of preventing endotoxic shock and septic shock comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00286] For example, included in the prevention/treatment methods described herein are methods of preventing rheumatoid arthritis and osteoarthritis comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00287] For example, included in the methods of prevention/treatment described herein are methods of preventing an increase in GI disease comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). Such GI diseases include, for example, Inflammatory Bowel Disease (IBD), colitis, and Crohn's disease.
[00288] For example, included in the prophylactic/therapeutic methods described herein are methods of reducing inflammation while also preventing transplant rejection or preventing or treating tumors or promoting wound healing, comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00289] For example, included in the prophylactic/therapeutic methods described herein are methods of preventing or treating rejection or dysfunction of a transplanted organ or tissue comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00290] For example, included in the prophylactic/therapeutic methods described herein are methods of treating type II diabetes comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00291] For example, included in the prophylactic/therapeutic methods described herein are methods of treating an inflammatory response of the skin comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II). Such inflammatory reactions of the skin include, for example, psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing and scarring. In another aspect, is a method of reducing psoriatic lesions in the skin, joints or other tissues or organs comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I) or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I) or formula (E-II).
[00292] For example, included in the prophylactic/therapeutic methods described herein are methods of treating cystitis, including, for example, interstitial cystitis, comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II), or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
[00293] For example, included in the prophylactic/therapeutic methods described herein are methods of treating metabolic syndrome, such as familial mediterranean fever, comprising administering to a mammal at least once an effective amount of at least one compound of any one of formula (E), formula (E-I), or formula (E-II) or a pharmaceutical composition or medicament comprising a compound of any one of formula (E), formula (E-I), or formula (E-II).
Combination therapy
[00294] In certain instances, it is suitable to administer at least one compound of any of formula (E), formula (E-I), or formula (E-II) in combination with other therapeutic agents. For example, if one of the side effects experienced by a patient receiving one of the compounds herein is inflammation, then an anti-inflammatory agent may be administered in combination with the initial therapeutic agent. Or, for example, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant may itself have minimal therapeutic benefit, but in combination with other therapeutic agents, the overall therapeutic benefit to the patient is enhanced). Alternatively, the perceived benefit of the patient may be increased, for example, by administering a compound described herein with other therapeutic agents that also have therapeutic benefit (which also includes a treatment regimen). For example, in the treatment of asthma, including administration of one of the compounds described herein, the therapeutic benefit may be increased by also providing the patient with other therapeutic agents or asthma therapy. In any case, regardless of the disease, disorder, or symptom being treated, the overall benefit experienced by the patient may simply be the addition of two therapeutic agents, or the patient may experience a synergistic benefit.
[00295] It is known to those skilled in the art that when drugs are used in combination therapy, the therapeutically effective dose may vary. Methods for experimentally determining therapeutically effective doses of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses, in order to minimize toxic side effects, has been widely described in the literature. The combination treatment regimen may comprise: the treatment regimen with the FLAP or 5-LO inhibitor described herein is initiated before, during, or after treatment with the second agent as described above and continued for all times during or after termination of the treatment with the second agent. Also included are treatments in which the FLAP or 5-LO inhibitors described herein and the second agent used are administered in combination, which may be administered simultaneously or at different times and/or decreasing or increasing intervals during the treatment. Combination therapy further includes periodic therapy, which can be initiated and stopped at different times to help clinically manage the patient. For example, in combination therapy, the FLAP or 5-LO inhibitors described herein may be administered weekly at the initiation of treatment, reduced to biweekly administration, and further reduced, as appropriate.
[00296] Provided herein are compositions and methods for combination therapy. According to one aspect, the pharmaceutical compositions disclosed herein are used to treat leukotriene-dependent or leukotriene mediated disorders. According to another aspect, the pharmaceutical compositions disclosed herein are for use in the treatment of respiratory diseases in patients where treatment with FLAP inhibitors is indicated, in particular asthma, and for use in inducing bronchodilation. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat a subject having a disorder resulting from vascular inflammation. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat a subject having Myocardial Infarction (MI).
[00297] The combination therapies described herein may be used as part of a specific treatment regimen intended to provide beneficial effects from the co-action of the FLAP inhibitors described herein and concurrent therapy. It will be appreciated that the dosage regimen seeking palliative treatment, prevention or amelioration of a condition may be modified in accordance with a number of factors. These factors include the type of respiratory disorder and the type of bronchiectasis that the subject suffers from, as well as the age, weight, sex, diet and medical condition of the subject. Thus, the dosing regimen actually used may vary widely and thus may differ from the dosing regimens set forth herein.
[00298] For the combination therapies described herein, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, and the like. In addition, when one or more bioactive agents are co-administered, the compounds provided herein can be administered simultaneously or sequentially with the bioactive agents. If administered sequentially, the attending physician will determine the appropriate order in which to administer the protein in combination with the biologically active agent.
[00299] In any case, multiple therapeutic agents (one of which is a compound described herein) can be administered in any order or even simultaneously. If administered simultaneously, multiple therapeutic agents can be provided in a single, combined form, or in multiple forms (e.g., a single pill or two separate pills). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. The time between multiple doses may vary from above zero weeks to less than four weeks if not administered simultaneously. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; multiple therapeutic combinations may also be used.
[00300] In addition, the compounds described herein may also be used in combination with methods that may provide additive or synergistic benefits to a patient. For example, in the methods described herein, a patient is expected to receive therapeutic and/or prophylactic benefit, wherein a pharmaceutical composition of any of formula (E), formula (E-I), or formula (E-II), and/or a combination with other therapies, is combined with a genetic test to determine whether the individual is a vector for a mutated gene (which is known to be associated with certain diseases or conditions).
[00301] The compounds and combination therapies described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compound can vary. Thus, for example, the compounds can be used prophylactically and can be administered continuously to a subject having a predisposition to develop a condition or disease, such that the disease or condition is prevented. The compounds and compositions can be administered to a patient during or immediately after the onset of symptoms. Administration of the compound may begin within the first 48 hours of symptom onset, preferably within the first 48 hours of symptom onset, more preferably within the first 6 hours of symptom onset, and most preferably within 3 hours of symptom onset. Initial administration can be by any practical route, such as intravenous injection, bolus injection, infusion for 5 minutes to about 5 hours, pill, capsule, transdermal patch, oral delivery, and the like, or combinations thereof. Preferably, administration of the compound is feasible after the onset of the disease or condition is detected or suspected, and for the length of time necessary for treatment of the disease, for example, from about 1 month to about 3 months. The treatment time may vary for each subject, and the time may be determined using known criteria. For example, the compound or formulation containing the compound may be administered for at least 2 weeks, preferably from about 1 month to about 5 years, and more preferably from about 1 month to about 3 years.
[00302] For example, therapies that combine any of the compounds of formula (E), formula (E-I), or formula (E-II) with a leukotriene synthesis inhibitor or leukotriene receptor antagonist (acting at the same or other sites of the leukotriene synthesis pathway) may prove useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or disorders. Furthermore, for example, therapies combining any of the compounds of formula (E), formula (E-I), or formula (E-II) with an inhibitor of inflammation may prove particularly useful for treating leukotriene-dependent or leukotriene mediated diseases or disorders.
Anti-inflammatoryMedicine
[00303]In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease comprises: administering to a patient a compound, pharmaceutical composition, or combination of a drug described herein and an anti-inflammatory agent, including but not limited to: osbec (artrotec), asacol (asacol), auralglan, sulfasalazine, daypro, etodolac, mefenamic acid, salofur (Salofalk), and methylprednisolone sodium succinate (solumedrol); non-steroidal anti-inflammatory drugs, e.g. aspirin (Bayer)TM、BufferinTM) Indomethacin (Indocin)TM) Rofecoxib (Vioxx)TM) Celecoxib (Celebrex) TM) Valdecoxib (Bextra)TM) Diclofenac, etodolac, ketoprofen, etodolac (Lodine), mobicne (mobil), nabumetone, naproxen, piroxicam; and corticosteroids, such as betamethasone (celestetone), prednisone, and prednisone (Deltasone). Corticosteroids do not directly inhibit leukotriene production and thus co-administration with steroids may provide additional anti-inflammatory benefits.
[00304] For example, asthma is a chronic inflammatory disease characterized by eosinophilia and high responsiveness of the airways in the lungs. Zhao et al, Proteomics, 7/2005, 4 days. In patients with asthma, leukotrienes can release mast cells, eosinophils, and basophils. Leukotrienes are involved in the contraction of the smooth muscle of the respiratory tract, increased vascular permeability and mucus secretion, and have been reported to affect and activate inflammatory cells in the asthmatic respiratory tract (Siegel et al, editors, Basic Neurochemistry, Molecular, Cellular and medical accessories, 6 th edition, Lippincott Williams & Wilkins, 1999). Thus, in another embodiment described herein, a method of treating a respiratory disease comprises administering to a patient a compound, pharmaceutical composition, or medicament described herein in combination with an anti-inflammatory agent.
Leukotriene receptor antagonists
[00305]At another placeIn one embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease comprises: administering to the patient a compound, pharmaceutical composition, or medicament described herein in combination with a leukotriene receptor antagonist, including but not limited to: CysLT1/CysLT2Dual receptor antagonists and CysLT1A receptor antagonist. In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease comprises: administering to a patient a compound, pharmaceutical composition or medicament described herein with CysLT1/CysLT2A combination of dual receptor antagonists. CysLT1/CysLT2Dual receptor antagonists include, but are not limited to: BAY u9773, Cuthbert et al EP 00791576 (published 1997, 8/27), DUO-LT (Galczenski et al, D38, Poster F4, filed in American Thorac Society, 2002, 5/2002), and Tsuji et al, org.Biomol.Chem., 1, 3139-. The most suitable formulation or method for such combination therapy for a particular patient may depend on the type of leukotriene-dependent or leukotriene mediated disorder, the time period for which the FLAP inhibitor is used to treat the disorder, and CysLT 1/CysLT2Dual receptor antagonists are useful for inhibiting the time period of CysLT receptor activity. For example, such combination therapy may be used to treat patients suffering from respiratory disorders.
[00306]In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease comprises: administering to a patient a compound, pharmaceutical composition or medicament described herein with CysLT1A combination of receptor antagonists. CysLT1Receptor antagonists include, but are not limited to: zafirlukast (' Acclate)TM"), montelukast (" Singulair ")TM”)、Prankulast(“OnonTM"), and derivatives or analogs thereof. Such combinations may be used to treat leukotriene-dependent or leukotriene mediated disorders, including respiratory disorders.
[00307]FLAP or 5-LO inhibitors and CysLT as described herein1Receptor antagonismAnti-agents or dual CysLT1/CysLT2Co-administration of the receptor antagonist may have a higher profile than that achieved by administration of either FLAP or 5-LO inhibitor, or CysLT, alone1The therapeutic benefit of the benefit obtained by the R antagonist. By improving the activity of CysLT in the case where the substantial inhibition of leukotriene production has an undesirable effect1Receptor block and/or dual CysLT1/CysLT2Receptor block-bound pro-inflammatory LTB4And cysteinyl leukotrienes to partially inhibit this pathway, substantial therapeutic benefit can be obtained, particularly in respiratory diseases.
Other combination therapies
[00308]In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease, such as a proliferative disorder (including cancer), comprises: administering to the patient a compound, pharmaceutical composition, or medicament described herein in combination with at least one additional agent selected from the group consisting of: alemtuzumab (Alemtuzumab), arsenic trioxide, asparaginase (pegylated or non-pegylated), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemmtuzumab (gemtuzumab), methotrexate, PaclitaxelTMTylosin, temozolomide, thioguanine, or drugs including hormones (antiestrogens, antiandrogens, or gonadotropin releasing hormone analogs), interferons such as interferon alpha, nitrogen mustards such as busulfan or melphalan or methylene dichloride diethylamine, retinoids such as retinoic acid, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefitinib or imatinib, or agents for treating conditions or symptoms induced by such therapy, including allopurinol, filgrasetron, granisetron/ondansetron/Palonosetron (palosetron), dronabinol.
[00309] In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease, such as treatment of a transplanted organ or tissue or cell, comprises administering to the patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from azathioprine, corticosteroids, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, i.e., quinine.
[00310] In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease, such as atherosclerosis, comprises: administering to the patient a compound, pharmaceutical composition, or medicament described herein in combination with at least one additional agent selected from the group consisting of: HMG-CoA reductase inhibitors (e.g., statins in the lactonized or dihydroxy-opened acid form and their pharmaceutically acceptable salts and esters, including but not limited to lovastatin; simvastatin; dihydroxy-opened acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof; fluvastatin, particularly the sodium salt thereof; atorvastatin, particularly the calcium salt thereof; Nivastatin, also known as NK-104; rosuvastatin); agents that combine lipid-altering effects with other pharmaceutical activities; HMG-CoA synthase inhibitors; cholesterol absorption inhibitors such as ezetimibe; cholesteryl Ester Transfer Protein (CETP) inhibitors, such as JTT-705 and CP529, 414; a squalene epoxidase inhibitor; squalene synthetase inhibitors (also known as squalene synthetase inhibitors); acyl-coenzyme A: cholesterol Acyltransferase (ACAT) inhibitors, including selective inhibitors of ACAT-1 or ACAT-2 and dual inhibitors of ACAT-1 and-2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; nicotinic acid; a bile acid sequestrant; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, such as glycoprotein IIb/IIIa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator-activated receptor gamma (PPAR γ) agonists including compounds commonly referred to as glitazones, such as troglitazone, pioglitazone and rosiglitazone, and including those within the structural class known as thiazolinediones, as well as those PPAR γ agonists outside the structural class of thiazolinediones; PPAR α agonists such as clofibrate, fenofibrate, including micronized fenofibrate, and gemfibrozil (gemfibrozil); PPAR dual alpha/gamma agonists such as 5- [ (2, 4-dioxo-5-thiazolidinyl) methyl ] -2-methoxy-N- [ [4- (trifluoromethyl) phenyl ] methyl ] -benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin B12 (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester thereof, such as the sodium salt and the meglumine salt; antioxidant vitamins such as vitamin C and E and beta carotene; a beta-blocker; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazem; an endothelin antagonist; agents that enhance the expression of ABC1 gene; FXR and LXR ligands, including both inhibitors and agonists; bisphosphonates, such as sodium alendronate; and cyclooxygenase-2 inhibitors, such as rofecoxib and celecoxib.
[00311]In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, e.g., treating stroke, comprises administering to a patient a compound, pharmaceutical composition or drug described herein in combination with at least one other agent selected from: COX-2 inhibitors; nitric oxide synthase inhibitors, such as N- (3- (aminomethyl) benzyl) acetamidine; rho kinase inhibitors, such as fasudil; angiotensin type II-1 receptor antagonists including candesartan, losartan, irbesartan, eprosartan, telmisartan and valsartan; a glycogen synthase kinase 3 inhibitor; sodium or calcium channel blockers, including cronetin; p38MAP kinase inhibitors, including SKB 239063; thromboxane AX-synthetase inhibitors including ibogarel (Isbogrel), ozagrel sodium, ridogrel (ridogrel) and dazoloxybenzene; statins (HMG CoA reductase inhibitors) including lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, nivastatin, and rosuvastatin; neuroprotective agents including free radical scavengers, calcium channel blockers, excitatory amino acid antagonists, and neuroprotective agents Long-factor, antioxidants, e.g. edaravone, vitamin C, TROLOXTMCiticoline and miniccoline, and reactive astrocytic inhibitors, such as (2R) -2-propyloctanoic acid; beta-adrenergic blockers, such as propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol, and acebutolol; NMDA receptor antagonists including Memantine (Memantine); NR2B antagonists, such as troxoprodil; a 5-HT1A agonist; receptor platelet fibrinogen receptor antagonists including tirofiban (tirofiban) and lamifiban (lamifiban); a blood coagulation inhibitor; antithrombotic agents, such as argatroban; antihypertensive agents such as enalapril; vasodilators, such as cyclamate; nociceptin antagonists; a DPIV antagonist; GABA5 inverse agonist; and selective androgen receptor modulators.
[00312] In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease, such as treating pulmonary fibrosis, comprises administering to a patient a compound, pharmaceutical composition or drug described herein in combination with at least one other agent selected from: anti-inflammatory agents, such as corticosteroids, azathioprine or cyclophosphamide.
[00313] In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as treating interstitial cystitis, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from: dimethyl sulfoxide, omalizumab and pentosan polysulfate.
[00314] In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease, such as treating a bone disorder, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from: minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analog, and cathepsin K inhibitors.
Using CysLT
1
/CysLT
2
Receptor antagonists for treating leukotriene-based disorders or diseases
[00315]According to another aspect, the compositions and methods described herein are designed to deliver CysLT1/CysLT2Dual receptor antagonists to block CysLT receptor activity. The term "CysLT antagonist" or "CysLT receptor antagonist" or "leukotriene receptor antagonist" refers to a therapeutic agent that reduces signaling by CysLTs through the CysLT receptor. CysLT is typically LTC 4、LTD4Or LTE4. Cysteinyl leukotrienes are potent smooth muscle contraction agents, particularly in the respiratory and circulatory systems. These are via at least two cellular receptors, CysLT1And CysLT2(ii) mediated. CysLT1Receptor and CysLT2The receptor is a G protein-coupled receptor with 7 putative transmembrane and one intracellular domains that interact with G-proteins, Evans et al, Prostagladins and Other Lipid Mediators, 68-69, p587-597, (2002). CysLT1/CysLT2Examples of dual receptor antagonists are BAY u9773, Cuthbert et al, EP 00791576 (published 1997, 8, 27), DUO-LT (Galczenski et al, D38, shown on American Thorac Society's F4 poster, 2002, 5) and Tsuji et al, org.Biomol.Chem., 1, 3139-one 3141, 2003.
[00316]In certain embodiments, a method of treating a leukotriene-dependent or leukotriene mediated disorder or disease comprises: administering to a patient a composition comprising CysLT1/CysLT2A compound, pharmaceutical composition or medicament of a receptor antagonist. For example, such compounds, pharmaceutical compositions or medicaments may be used as medicaments for the treatment and/or prevention of respiratory diseases, including but not limited to chronic stable asthma.
Diagnosis of patient identityMethod
[00317] Screening of "leukotriene-responsive patients", optionally treated with a compound of any of formula (E), formula (E-I) or formula (E-II), or a pharmaceutical composition or medicament described herein comprising a compound of any of formula (E), formula (E-I) or formula (E-II), can be accomplished using the techniques and methods described herein. Such techniques and methods include, for example: assessing a genetic haplotype (genotyping), detection/determination of a biomarker (phenotyping), detection/determination of a functional marker (phenotyping), which may indicate that the patient responds to a known modulator of the leukotriene pathway, or any combination thereof.
Genotype analysis: FLAP polymorphism
[00318] Human FLAP has been purified and cloned and is an 18 kilodalton membrane-binding protein that is very highly expressed in human neutrophils. The FLAP gene is located at 13q12 and in some populations is associated with increased risk of myocardial infarction and stroke. Among the genes encoding FLAP, a number of polymorphisms and haplotypes have been identified in individuals (U.S. patent application 2005113408; Sayers, Clin. exp. allergy, 33 (8): 1103-10, 2003; Kedda et al, Clin. exp. allergy, 35 (3): 332-8, 2005). In some populations, specific FLAP haplotypes are associated with myocardial infarction and stroke (Helgadottir A et al Nature Genet.36: 233-; helgadottir A et al Am J Hum Genet 76: 505-; lohmussaar E et al Stroke 36: 731-736 (2005); kajimoto K et al, Circ J69: 1029-1034(2005), previously, it has been shown that polymorphisms in certain genes are associated with responsiveness to an administered treatment, for example, the responsiveness of cancer to specific chemotherapeutic agents (Erichsen et al, br.j. cancer, 90 (4)): 747-51, 2004, Sullivan et al, Oncogene, 23 (19): 3328-37, 2004), accordingly, for patients considered to be treated with the novel FLAP inhibitors described herein or a pharmaceutical combination comprising such a novel FLAP inhibitor, potential responsiveness to treatment can be screened based on its FLAP polymorphism or haplotype.
[00319]In addition, any polymorphisms in the synthesis or signaling genes that are devoted to the leukotriene pathway can result in patients that are more responsive or less responsive to leukotriene modulator therapy (FLAP or 5-LO inhibitors or leukotriene receptor antagonists). Genes involved in the leukotriene pathway are 5-lipoxygenase, 5-lipoxygenase-activating protein, LTA4Hydrolase, LTC4Synthase, LTB4Receptor 1 (BLT)1)、LTB4Receptor 2 (BLT)2) CysLT (cysteine acyl leukotriene receptor 1)1R), cysteinyl leukotriene receptor 2 (CysLT)2R). For example, the 5-LO gene has been implicated in aspirin-intolerant asthma and airway hyperresponsiveness (Choi JH et al Hum Genet 114: 337-344 (2004); Kim, SH et al Allergy 60: 760-765 (2005). it has been shown that genetic variants in the promoter region of 5-LO predict clinical responses to 5-LO inhibitors in asthma (Drazen et al Nature Genetics, 22, p168-170, (1999). LTC4The synthase gene is associated with atopy and asthma (Moissidi I et al Genet Med 7: 406-2The receptor is associated with asthma and atopy (Thompson MD et al Pharmacogenetics 13: 641-649 (2003); pilai SG et al Pharmacogenetics 14: 627-633 (2004); park JS et al Pharmacogenetgenomics 15: 483-492 (2005); fukai H et al Pharmacogenetics 14: 683-690(2004) any polymorphism or combination of polymorphisms or haplotypes of any leukotriene pathway gene, can result in altered sensitivity of the patient to treatment directed at reducing the pathological effects of leukotrienes, selection of patients who can best respond to the leukotriene modulator treatments described herein, the patient may be selected based on leukotriene pathway genotype alone, phenotype alone (biomarker or functional marker), or any combination of genotype and phenotype.
[00320] As used herein, "haplotype" refers to a combination of genetic markers ("alleles"). A haplotype can include one or more alleles (e.g., a haplotype containing a single SNP), two or more alleles, three or more alleles, four or more alleles, or five or more alleles. Genetic markers are specific "alleles" at "polymorphic sites" associated with FLAP. Nucleotide positions in the human population (where more than one sequence is permissible) are referred to herein as "polymorphic sites". If a polymorphic site is a single nucleotide in length, the site is referred to as a single nucleotide polymorphism ("SNP"). For example, if at a particular chromosomal location one member of a human has an adenine and another member of the human has a thymine at the same position, then that location is a polymorphic site, more specifically, a polymorphic site is a SNP. Polymorphic sites may allow for differences in sequence based on substitutions, insertions or deletions. For each form of the sequence of a polymorphic site, reference is made herein to an "allele" of the polymorphic site. Thus, in the previous example, the SNP allows for both an adenine allele and a thymine allele.
[00321] Typically, a reference sequence is referenced to a particular sequence. Alleles other than the reference are referred to as "variant" alleles. The term "variant FLAP" as used herein refers to a sequence that is different from, but substantially similar to, a reference FLAP sequence. The genetic markers that make up the haplotypes described herein are FLAP variants. In certain embodiments, the FLAP variants are at least about 90% similar to a reference sequence. In an alternative embodiment, the FLAP variant is at least about 91% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 92% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 93% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 94% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 95% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 96% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 97% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 98% similar to the reference sequence. In alternative embodiments, the FLAP variant is at least about 99% similar to the reference sequence.
[00322] In addition, in certain embodiments, FLAP variants differ from a reference sequence by at least one base, while in alternative embodiments FLAP variants differ from a reference sequence by at least two bases. In the alternative, the FLAP variant differs from the reference sequence by at least three bases, and in the alternative, the FLAP variant differs from the reference sequence by at least four bases.
[00323] Other variants may include changes that affect a polypeptide, such as a FLAP polypeptide. The polypeptide encoded by a reference nucleotide sequence is a "reference" polypeptide having a particular reference amino acid sequence, and the polypeptide encoded by a variant allele is referred to as a "variant" polypeptide having a variant amino acid sequence. FLAP nucleotide sequence differences may include when compared to a reference nucleotide sequence: the insertion or elimination of a single nucleotide, or more than one nucleotide, resulting in a structural change; altering at least one nucleotide resulting in an alteration of the encoded amino acid; altering at least one nucleotide resulting in the generation of an early stop codon; elimination of some nucleotides, resulting in the disappearance of the amino acid encoded by one or more nucleotides; the insertion of one or some nucleotides, for example by irregular recombination or gene conversion, results in the disruption of the coding sequence; copying all or a portion of the sequence; exchanging; or rearrangement of the nucleotide sequence, as detailed above. This sequence change alters the polypeptide encoded by the FLAP nucleotide. For example, if a change in the nucleotide sequence results in a structural change, the structural change may result in a change in the encoded amino acid, and/or may result in the production of an early stop codon, resulting in the production of a truncated polypeptide.
[00324] For example, polymorphisms associated with susceptibility to Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), stroke, or Peripheral Arterial Occlusive Disease (PAOD) can produce synonymous changes in nucleotide (i.e., changes that do not result in changes in amino acid sequence). Such polymorphisms can, for example, alter splice sites of the mRNA, decrease or increase expression levels of the mRNA, affect the stability or transport of the mRNA, or affect the transcription or translation of the polypeptide. Haplotypes, as described below, are found more frequently in individuals with MI, ACS, stroke, or PAOD than in individuals without MI, ACS, stroke, or PAOD. Thus, haplotypes may be of predictive value for detecting sensitivity to MI, ACS, stroke or PAOD in an individual.
[00325] Some variants of the FLAP gene have been reported to be associated with the onset of myocardial infarction in patients (Hakonasson, JAMA, 293 (18): 2245-56, 2005), and plus FLAP gene markers, which have been reported to be associated with the development of asthma risk, have been described in U.S. Pat. Nos. 6, 531, 279. Methods for identifying FLAP sequence variants are described, for example, in U.S. publication No.2005/0113408 and U.S. patent nos. 6, 531, 279, which are incorporated herein by reference in their entirety.
[00326] For example, the haplotypes associated with susceptibility to myocardial infarction or stroke include markers SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and SG13S35 at position 13q 12-13. Alternatively, the presence of alleles T, G, G, G, A and G (B6 haplotype) at SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and SG13S35, respectively, is a diagnostic for susceptibility to myocardial infarction or stroke. Alternatively, the haplotype associated with susceptibility to myocardial infarction or stroke includes markers SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42 at position 13q 12-13. Alternatively, the presence of alleles T, G, G, G and a (B5 haplotype) at SG13S99, SG13S25, SG13S106, SG13S30, and SG13S42, respectively, is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the haplotype associated with susceptibility to myocardial infarction or stroke includes markers SG13S25, SG13S106, SG13S30 and SG13S42 at position 13q 12-13. Alternatively, the presence of alleles G, G, G and a (B4 haplotype) at SG13S25, SG13S106, SG13S30, and SG13S42, respectively, is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the haplotype associated with susceptibility to myocardial infarction or stroke includes markers SG13S25, SG13S106, SG13S30 and SG13S32 at position 13q 12-13. Alternatively, the presence of alleles G, G, G and a (Bs4 haplotype) at SG13S25, SG13S106, SG13S30, and SG13S32, respectively, is diagnostic of susceptibility to myocardial infarction or stroke. In such embodiments, patients contemplated for treatment with a compound of any one of formula (E), formula (E-I) or formula (E-II), or a pharmaceutical combination described herein comprising a compound of any one of formula (E), formula (E-I) or formula (E-II), may be screened for potential responsiveness to treatment with a compound of any one of formula (E), formula (E-I) or formula (E-II) based on such haplotype.
[00327] For example, the haplotypes associated with susceptibility to myocardial infarction or stroke include markers SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32 at position 13q 12-13. Alternatively, the presence of alleles T, G, T, G and a (a5 haplotype) at SG13S99, SG13S25, SG13S114, SG13S89, and SG13S32, respectively, is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the haplotype associated with susceptibility to myocardial infarction or stroke includes markers SG13S25, SG13S114, SG13S89 and SG13S32 at position 13q 12-13. Alternatively, the presence of alleles G, T, G and a (a4 haplotype) at SG13S25, SG13S114, SG13S89, and SG13S32, respectively, is diagnostic of susceptibility to myocardial infarction or stroke. In such embodiments, patients contemplated for treatment with a compound of any one of formula (E), formula (E-I) or formula (E-II), or a pharmaceutical combination described herein comprising a compound of any one of formula (E), formula (E-I) or formula (E-II), may be screened for potential responsiveness to treatment with a compound of any one of formula (E), formula (E-I) or formula (E-II) based on such haplotype.
[00328] Detection of haplotypes can be accomplished using methods known in the art for detecting sequences at polymorphic sites, and thus patient selection can be made using genotype selection for FLAP, 5-LO or other leukotriene pathway gene polymorphisms. The presence or absence of a leukotriene pathway gene polymorphism or haplotype can be determined by various methods including, for example, using enzymatic amplification, restriction fragment length polymorphism analysis, electrophoretic analysis of nucleotide sequences, nucleotides derived from an individual, or any combination thereof. In certain embodiments, determining a SNP or haplotype can identify a patient that will respond to, or receive benefit from, treatment with a compound of any one of formula (E), formula (E-I), or formula (E-II). For example, a method of determining susceptibility to myocardial infarction or stroke in an individual includes: determining the presence or absence of certain Single Nucleotide Polymorphisms (SNPs), or the presence or absence of certain haplotypes, wherein the presence of an SNP or a haplotype is diagnostic of susceptibility to myocardial infarction or stroke.
And (3) phenotypic analysis: biomarkers
[00329] Patients contemplated to be treated with a compound described herein or a pharmaceutical combination described herein comprising a compound described herein may be screened for potential responsiveness to treatment based on the leukotriene-induced inflammatory biomarker phenotype.
[00330] Patients screened based on leukotriene-stimulated inflammatory biomarker phenotypes may replace or be complementary to patients screened by leukotriene pathway genotype testing. The term "biomarker" as used herein refers to a characteristic that can be measured and evaluated as an indicator of a normal biological process, a pathological process, or a pharmacological response to a therapeutic intervention. Thus, a biomarker may be any substance, structure or method that is detectable in vivo, or a product thereof, that may affect or predict the outcome or incidence of disease. Biomarkers can be classified as exposure, effect and sensitivity. Biomarkers can be physiological endpoints, such as blood pressure, or they can be analytical endpoints, such as blood glucose or cholesterol concentrations. Techniques for detecting and/or measuring biomarkers include, but are not limited to: NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS, FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequences, nucleic acid sequences, electrophoresis techniques, immunoassays, immunoblots, in situ hybridization, fluorescent in situ hybridization, PCR, radioimmunoassays, and enzyme immunoassays. Single Nucleotide Polymorphisms (SNPs) are also useful for identification of biomarkers of predisposition to certain diseases and sensitivity or responsiveness to drugs, such as chemotherapeutic and antiviral agents. These techniques, or any combination thereof, may be used to screen patients for leukotriene-dependent or leukotriene mediated diseases or conditions, where such patients may be advantageously treated with a compound described herein or a pharmaceutical combination described herein comprising a compound described herein.
[00331]For example, a patient may be selected by screening for an increase in an inflammatory blood biomarker, such as but not limited to stimulated LTB, for treatment with a compound described herein or a pharmaceutical combination described herein comprising a compound described herein4、LTC4、LTE4Myeloperoxidase (MPO), Eosinophil Peroxidase (EPO), C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), monocyte chemotactic protein (MCP-1), monocyte inflammatory protein (MIP-1), interleukin-6 (IL-6), TH2T cytokines interleukin 4(IL-4) and 13(IL-13) and other inflammatory cytokines. In certain embodiments, patients with inflammatory respiratory diseases including, but not limited to, asthma and COPD, or with cardiovascular disease may be selected as those who may be susceptible to inhibition of leukotriene synthesis using any of the compounds of formula (E), formula (E-I) or formula (E-II) by the use of leukotriene-stimulated inflammatory biomarkers.
And (3) phenotypic analysis: functional markers
[00332] Patients contemplated to be treated with a compound described herein or a pharmaceutical combination described herein comprising a compound described herein may be screened for a response to known modulators of the leukotriene pathway. Patients screened by assessing functional markers as indicators of their response to known modulators of the leukotriene pathway may be used as surrogate patients for patients screened by leukotriene pathway genotype detection (genotyping) and/or detecting/determining the biomarker phenotype of inflammation caused by leukotrienes, or may be complementary to the patients screened. Functional markers may include, but are not limited to: any physical property associated with a leukotriene-dependent disorder or disease, or knowledge of current or past drug treatment regimens.
[00333] For example, the assessment of lung volume and/or function can be used as a functional marker for leukotriene-dependent or leukotriene mediated diseases or conditions, such as respiratory diseases. For treatment with a compound described herein or a pharmaceutical composition or medicament comprising a compound described herein, a pulmonary function assay may be used to screen patients for such leukotriene-dependent or leukotriene mediated diseases or conditions. Such tests include, but are not limited to: lung volumes and volumes are evaluated, such as tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, inspiratory volume, effective residual volume, vital capacity, total lung volume, breaths per minute, alveolar ventilation, timed lung capacity, and ventilation. Methods of measuring lung volume and volume include, but are not limited to: maximum expiratory flow curve, maximum expiratory volume of 1 second (FEV1), maximum expiratory flow rate. In addition, other lung function tests useful as functional markers for the evaluation of patients described herein include, but are not limited to: respiratory muscle energy, maximum inspiratory pressure, maximum expiratory pressure, trans-phrenic pressure, distribution of ventilation, one-breath nitrogen testing, lung nitrogen clearance, and gas delivery.
[00334]In addition, for leukotriene-dependent disorders or diseases that are treated using the compounds described herein or pharmaceutical compositions or drugs comprising the compounds described herein, knowledge of the patient's past or current treatment regimen can be used as a functional marker to aid in screening patients. For example, such a treatment regimen may include past or current treatment with zileuton (Zyflo) TM) Montelukast (Singulair)TM) Pranlukast (Onon)TM) Zafirlukast (Acclate)TM)。
[00335] In addition, it is contemplated that patients treated with a compound described herein or a pharmaceutical combination described herein comprising a compound described herein may be screened for functional markers including, but not limited to: decreased increased numbers of eosinophils and/or basophils and/or neutrophils and/or monocytes and/or dendritic cells and/or lymphocytes, decreased mucosal secretion, decreased mucosal edema, and/or increased bronchiectasis.
[00336] Exemplary, non-limiting methods of treatment are shown in fig. 12, 13 and 14 for identification of patients in need of treatment for leukotriene-dependent or leukotriene mediated conditions or diseases, where patient samples are analyzed and the information obtained is used to determine the allowable methods of treatment. It is desirable for those skilled in the art to use this information in conjunction with other patient information, including but not limited to: age, body weight, sex, diet, and medical condition. Furthermore, it is desirable that each information unit can be given a specific weight in the decision process. In certain embodiments, the information obtained from the above-described regimens and any other patient information (including but not limited to age, weight, sex, diet, and medical condition) may be incorporated into an algorithm for interpreting the treatment regimen during the decision process, wherein each information unit may give specific weight.
[00337]In certain embodiments, patient samples are analyzed for leukotriene gene haplotypes, such as FLAP haplotypes, and the information obtained can identify patients in need of treatment using different treatment methods. Such treatments include, but are not limited to: administering a therapeutically effective amount of a compound described herein, or a pharmaceutical composition or medicament comprising a compound described herein, with a therapeutically effective amount of a leukotriene receptor antagonist (e.g., CysLT1/CysLT2Antagonists or CysLT1Antagonist) or a pharmaceutical composition or medicament comprising a compound described herein, or in combination with a therapeutically effective amount of another anti-inflammatory agent. In an alternative embodiment, patient samples are analyzed for leukotriene gene haplotypes, e.g., FLAP haplotypes, and/or phenotypic biomarkers, and/or phenotypic functional marker responses to leukotriene modulators. The patient may then be treated using a different treatment. Such treatments include, but are not limited to:administering a therapeutically effective amount of a compound described herein, or a pharmaceutical composition or medicament comprising a compound described herein, with a therapeutically effective amount of a leukotriene receptor antagonist (e.g., CysLT 1/CysLT2Antagonists or CysLT1Antagonist) or a pharmaceutical composition or medicament comprising a compound described herein, or in combination with a therapeutically effective amount of another anti-inflammatory agent. In an alternative embodiment, patient samples are analyzed for leukotriene gene haplotypes, e.g., FLAP haplotypes, and phenotypic biomarkers, and phenotypic functional marker responses to leukotriene modulators. The patient may then be treated using a different treatment. Such treatments include, but are not limited to: administering a therapeutically effective amount of a FLAP inhibitor or a pharmaceutical composition or medicament comprising a FLAP inhibitor, administering a therapeutically effective amount of a FLAP inhibitor or a pharmaceutical composition or medicament comprising a FLAP inhibitor in combination with a therapeutically effective amount of a leukotriene receptor antagonist (e.g. CysLT1/CysLT2 antagonist or CysLT1 antagonist), or administering a therapeutically effective amount of a FLAP inhibitor or a pharmaceutical composition or medicament comprising a FLAP inhibitor in combination with a therapeutically effective amount of another anti-inflammatory agent.
Kit/article of manufacture
[00338] In the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such a kit may comprise: a carrier, package, or partitioned receptacle that can hold one or more containers, such as vials, tubes, and the like, each container comprising a separate unit, for use in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be formed from a number of substances, such as glass or plastic.
[00339] For example, the container may include one or more compounds described herein, optionally in a composition or in combination with other agents disclosed herein. The container optionally has a sterile access port (e.g., the container may be an intravenous solution bag, or a vial having a pierceable stopper for a hypodermic injection needle). Such kits optionally include a compound (in connection with its use in the methods described herein) with an identification or label or instructions.
[00340] To use the compounds described herein, a kit typically can include one or more additional containers, each of which has one or more different materials (e.g., reagents, optionally in concentrated form, and/or devices) that are desirable from a commercial and user standpoint. Non-limiting examples of such materials include, but are not limited to: buffer, diluent, filter, needle, syringe; carriers, packages, containers, vial and/or tube labels (listing contents and/or instructions for use), and package instructions with instructions for use. A set of instructions is also typically included.
[00341] The label may be on or associated with the container. The label may be on the container when the text, numbers or other properties forming the label are affixed to, molded or etched into the container itself; when the label is provided within the container or within a carrier containing the container, for example in the form of a package insert, the label may be associated with the container. The label may be used to indicate the ingredients used for a particular therapeutic application. The label may also indicate instructions for use of the ingredient, for example, in the methods described herein.
Examples
[00342] These examples are for illustrative purposes only and are not intended to limit the scope of the claims provided herein.
Preparation of intermediates useful in the synthesis of compounds of formula (E), formula (E-I) and formula (E-II):
[00343] The starting materials and intermediates used in the synthesis of compounds of formula (E), formula (E-I) and formula (E-II) are commercially available or may be synthesized using synthetic methods known in the art or described herein. The preparation of intermediates such as those shown, for example, in table 5 (which are used herein and are not commercially available) is described below. Other intermediates used in the synthesis of compounds of formula (E), formula (E-I) and formula (E-II) are not specifically mentioned herein and may be prepared using the methods described herein or known in the art.
TABLE 5 intermediates used in the synthesis of Compounds of formula (E), formula (E-I) and formula (E-II)
Route 1:
step 1: BOC protection (intermediate-10)
[00344] 3-azetidinecarboxylic acid (Sigma Aldrich, 0.25 g, 2.5 mmol) was dissolved in tBuOH (5 mL) and 1N NaOH (2.7 mL, 2.7 mmol). Di-tert-butyl dicarbonate (0.59 g, 2.7 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with water, slowly acidified to pH 4 with 1N HCl, the mixture was extracted with EtOAc, stained by ninhydrin, until all the product was removed from the aqueous layer. The combined organic layers were dried, filtered, and concentrated to give the desired product.
Step 2: borane reduction (intermediate-10)
[00345]The acid from step 1 (0.7 g, 3.5 mmol) was dissolved in THF and under N2The atmosphere was cooled to 0 ℃. borane-THF complex was added to the solution and the reaction was stirred at room temperature overnight. The reaction was cooled to 0 ℃ and quenched with water. The mixture was extracted 3 times with EtOAc and the combined organic layers were MgSO4Dried, filtered and concentrated. The crude product was filtered through a plug of silica gel eluting with EtOAc to afford the desired compound.
Step 3 a: br2Bromide formation (intermediate-10)
[00346]Triphenylphosphine (1.7 g, 6.5 mmol) was dissolved in DMF and cooled to 0 ℃. Bromine (0.31 ml, 5.9 mmol) was added slowly and the solution was stirred for 30 min. The alcohol from step 2 (0.32 g, 2.0 mmol) in DMF was added and the reaction stirred at room temperature overnight. The mixture was diluted with water, extracted 3 times with EtOAc and over MgSO4The combined organic layers were dried, filtered and concentrated. The crude product was filtered through a plug of silica gel eluting with EtOAc to afford the desired compound.
And step 3 b: i is2Iodide formation (intermediate-73)
[00347](6-bromo-pyridin-3-yl) -methanol (0.5 g, 2.7 mmol) was dissolved in toluene (20 ml). Triphenylphosphine (0.9 g, 3.5 mmol) and imidazole (0.4 g, 6.0 mmol) were added, followed by dropwise addition of a solution of iodine (0.88 g, 3.5 mmol) in toluene. The reaction was stirred at room temperature for 15 minutes, and then saturated Na was poured2CO3In aqueous solution. The organic layer was washed with aqueous sodium thiosulfate, water, and then MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (EtOAc: hexane gradient) to afford the desired product.
And step 3 c: tosylation (intermediate-21)
[00348](S) - (-) -1- (tert-butyloxycarbonyl) -2-pyrrolidinemethanol (1.0 g, 5.0 mmol) was dissolved in pyridine (3 ml) and tosyl chloride (1.0 g, 5.5 mmol) was added. The reaction was stirred at room temperature overnight, diluted with water and extracted with EtOAc. The combined organic layers were washed with water and MgSO 4Dried, filtered and concentrated. The residue was purified on silica gel (0 to 10% EtOAc/hexanes) to give the desired product.
And step 3 d: methanesulfonic sulfide (intermediate-55)
[00349](R) - α -methyl-2-pyridinemethanol (1.0 g, 8.1 mmol) was dissolved in CH2Cl2(20 ml) and cooled to 0 ℃. Triethylamine (1.7 ml, 12.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (0.66 ml, 8.4 mmol). The reaction was stirred for 30 minutes and then treated with CH2Cl2Diluting, washing with water, and MgSO4Drying, filtering and concentrating to obtain the required product.
Route 2:
step 1: amide formation (intermediate-19)
[00350]Cyclopropylamine (0.35 mL, 5.0 mmol) and triethylamine (0.7 mL, 5.1 mmol) were dissolved in CH2Cl2(10 ml). The reaction was cooled to-10 ℃ and chloroacetyl chloride (0.4 ml, 5.0 mmol) was added dropwise. The reaction was stirred at-10 ℃ for 1 hour, then at room temperature for 2 hours, then quenched with water. The aqueous layer is replaced by CH2Cl2Extraction and drying of the organic layer, filtration and concentration gave the desired product.
Route 3:
step 1: imine formation (intermediate-20)
[00351]Chloroacetonitrile (0.5 g, 6.6 mmol) was dissolved in Et2O (10 ml) and cooled to 0 ℃. EtOH (0.43 mL, 7.3 mmol) was added followed by 4N HCl/1, 4-dioxane (15 mmol) L, 59.6 mmol). The reaction was stirred at 0 ℃ for 4 days and then concentrated to give the desired product as a white solid.
Step 2: cyclisation (intermediate-20)
[00352]The imine from step 1 (0.3 g, 2.0 mmol) was dissolved in EtOH (4 ml) and cooled to 0 ℃.1, 3-diaminopropane (0.17 ml, 2.0 mmol) was added followed by iPr2NEt (0.35 ml, 2.0 mmol). The reaction was stirred at 0 ℃ for 2 hours, then 4N HCl/1, 4-dioxane (0.5 ml, 2 mmol) was added. The mixture was filtered and the filtrate was concentrated to give the desired product.
Route 4:
step 1: mCPBA oxidation (intermediate-46)
[00353]2, 5-lutidine (5.0 g, 46.7 mmol) was dissolved in CHCl3(125 ml) and cooled to 0 ℃. M-chloroperoxybenzoic acid (70%; 13.9 g, 55.2 mmol) was added and the reaction stirred at room temperature overnight. With saturated Na2CO3The mixture was washed with aqueous solution and Na2SO4Drying, filtering and concentrating to obtain the required product.
Step 2: acetylation (intermediate-46)
[00354] The N-oxide from step 1 (46.7 mmol) was dissolved in acetic anhydride (25 ml) and heated at 100 ℃ under reflux for one hour. The mixture was cooled to room temperature and ethanol (46.7 mmol) was slowly added to quench the reaction. The solution was evaporated to dryness and purified on silica gel to give the desired product.
And step 3: hydrolysis (intermediate-46)
[00355] The acetate ester from step 2 (46.7 mmol) was dissolved in concentrated HCl (20 ml) and refluxed for 1 hour. The reaction was cooled and evaporated to dryness to give an orange solid which was used directly in the next reaction.
And 4, step 4: SOCl2Chloride formation (intermediate)Body-46)
[00356]The alcohol from step 3 (1.0 g, 8.1 mmol) was dissolved in thionyl chloride (3 ml) in N2The mixture was stirred at room temperature for 30 minutes under an atmosphere. The mixture was evaporated to dryness to afford the hydrochloride salt of the desired product, which was used directly in the subsequent reaction.
Route 5:
step 1: condensation (intermediate-60)
[00357]P-toluidine (10 g, 60.0 mmol) and triethylamine (8.4 ml, 60.3 mmol) were dissolved in CH at room temperature2Cl2(200 ml). Cinnamoyl chloride (6.5 g, 60.7 mmol) was added and the reaction stirred for 1 hour. The reaction was washed with water, dried, filtered, and concentrated. To the residue was added aluminum chloride (5 g, 37.5 mmol) which was heated neat. After 45 minutes, ice was added to form a precipitate. The mixture was stirred at room temperature overnight. Then filtering the precipitate, dissolving in CH2Cl2In (1), washed with 1N HCl, brine, MgSO4Drying, filtering and concentrating. The residue was recrystallized from ethanol to give the desired quinolinone product.
Step 2: POCl3Chloride formation (intermediate-60)
[00358]Quinolinone from step 1 (3.12 g, 19.6 mmol) in POCl3(10 ml) to 90 ℃. Once the starting material was not retained, the reaction was cooled and concentrated. The residue was taken up with EtOAc and saturated NaHCO3Dilute the aqueous and extract the aqueous layer with EtOAc. The combined organics were dried, filtered, and concentrated to give chloroquinoline product.
Step 3 a: NBS bromide formation of (alkyl) (intermediate-60)
[00359] Quinoline (19.6 mmol) from step 2 was heated to 80 ℃ in benzene (200 ml) with NBS (3.6 g, 20.2 mmol) and catalyzed benzoyl peroxide for 1 hour. The reaction mixture was concentrated and purified on silica gel to give the desired product.
And step 3 b: NBS bromide formation of (aryl) (intermediate-118)
[00360]2-aminopyrazine (4 g, 42 mmol) was dissolved in water (2 ml) and DMSO (70 ml) at 0 ℃ and NBS (7.5 g, 42 mmol) was added over a 1 hour period. The reaction was warmed to room temperature and stirred overnight. The mixture was poured onto ice and extracted 4 times with EtOAc. The combined organic layers were washed with 5% Na2CO3Water and brine, over MgSO4Drying, filtering and concentrating. The residue was purified on silica gel to give the desired product.
And step 3 c: NCS chloride formation (intermediate-50)
[00361]2-fluoro-6-methylpyridine (1.11 g, 10 mmol), NCS (2.0 g, 15 mmol) and catalytic benzoyl peroxide were dissolved in benzene and heated at reflux overnight. The reaction was concentrated and diluted with water and EtOAc. The organic layer was washed with saturated NaHCO3The aqueous solution was washed, dried, filtered and concentrated. The residue was purified on silica gel to give the desired product.
Route 6:
step 1: suzuki coupling (intermediate-71)
[00362]To a solution of (4-hydroxymethylphenyl) boronic acid (Combi-Blocks; 1.0 g, 6.6 mmol) in DME/water (16 mL, 2:1) was added 2-bromothiazole (1.2 g, 7.2 mmol) and K2CO3(2.7 g, 19.7 mmol). Will react with N2Degassing for 20 minutes. Adding Pd (PPh)3)4(0.76 g, 0.7 mmol) and the reaction was further degassed for 10 minutes. Then in N2The reaction was heated to 90 ℃ overnight under ambient. LCMS confirmed product formation. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were over MgSO4Drying, filtration, concentration and purification on silica gel (EtOAc: hexane gradient) afforded the desired product.
Step 2 a: f-alkylation (intermediate-71)
[00363]In N2The thiazole from step 1 (0.35 g, 1.8 mmol) was dissolved in THF (15 ml) under an atmosphere and cooled to-78 ℃. N-butyllithium (1.6M; 4.6 ml, 7.3 mmol) was added dropwise, followed by NFSi (1.2 g, 3.7 mmol). At-78 ℃ with saturated NH 4The reaction was quenched with aqueous Cl and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organics were extracted with MgSO4Dried, filtered and concentrated. The residue was purified on silica gel to give the desired compound.
And step 2 b: me-alkylation (intermediate-72)
[00364]In N2The thiazole from step 1 (0.33 g, 1.7 mmol) was dissolved in THF (15 ml) under an atmosphere and cooled to-78 ℃. N-butyllithium (1.6M; 4.3 ml, 6.7 mmol) was added dropwise followed by methyl iodide (0.16, 2.6 mmol). At-78 ℃ with saturated NH4The reaction was quenched with aqueous Cl and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organics were extracted with MgSO4Dried, filtered and concentrated. The residue was purified on silica gel to give the desired compound.
Route 7:
step 1: formation of acid chloride (intermediate 135)
[00365]3-phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH2Cl2In (1). Oxalyl chloride (0.32 g, 0.25 mmol) was added followed by 1-2 drops of DMF. The reaction was stirred at room temperature and then concentrated to give the desired acid chloride.
Route 8:
step 1: alkylation (intermediate-5)
[00366]To CH of imidazole (0.41 g, 6.0 mmol)2Cl2Bromoacetonitrile (0.21 g, 2.0 mmol) was added to the solution, and the reaction was refluxed for 30 minutes. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give the desired product.
Route 9:
step 1: methylation (intermediate-74)
[00367]To a solution of 4-m-tolyl-tetrahydro-pyran-4-ol (2.5 g, 13.0 mmol) in THF (50 ml) was added sodium hydride (60%; 0.8 g, 20.0 mmol) at room temperature. Methyl iodide (1.25 ml, 20 mmol) was added and the reaction stirred for 1 hour. The mixture was quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating. The residue was purified on silica gel to give the desired compound.
Route 10:
step 1: bromination of
[00368]To a solution of 4, 4-dimethyl-pentan-2-one (3.7 ml, 26.3 mmol) in MeOH (2.8 ml) was added bromine (1.34 ml, 26.3 mmol) as a single stream (single stream) at 0 ℃. The reaction was slowly warmed to 10 ℃ for 30 minutes to initiate the reaction, followed by stirring at room temperature for an additional 15 minutes. The reaction was diluted with water and ether and the aqueous layer was extracted three times with ether. With MgSO4The combined organic layers were dried, filtered, and concentrated to give the desired product as a colorless liquid.
Step 2: mercaptan addition
[00369]The bromide from step 1 (26.3 mmol) was dissolved in THF (50 ml) and the mixture was cooled to 0 ℃. 2-methyl-2-propanethiol (2.45 ml, 21.6 mmol) was added followed by triethylamine (7.9 ml, 56.8 mmol). The reaction was stirred at room temperature for 18 hours and then diluted with water. The aqueous layer was extracted with ether and the combined organic layers were over MgSO 4Dried, filtered and concentrated to give the desired product.
Scheme A:
example 1: 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid.
Step 1: n- [4- (pyridin-2-ylmethoxy) -phenyl ] -acetamide
[00370]A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6 g), 2-chloromethyl pyridine hydrochloride (80 g) and cesium carbonate (320 g) was stirred in DMF (1L) at 70 ℃ for 2 days. The mixture was cooled, poured into water (2 l) and extracted with EtOAC (× 6). The organic layer was washed with brine and dried (MgSO)4) Filtration gave a brown solid (A-1, 114 g), which was used as such in the next step.
Step 2: 4- (pyridin-2-ylmethoxy) -aniline hydrochloride
[00371]A-1(114 g) was dissolved in EtOH (1L) and KOH (50 g)/water (200 mL) was added. The solution was heated to 110 ℃ for 2 days, KOH (20 g in 100 ml water) was added, and heating was continued for an additional 2 days. The solution was cooled, EtOH removed in vacuo, and the residue partitioned between EtOAc and water. After extraction of water with EtOAc (× 3), the organic layer was washed with brine and dried (MgSO)4) And (4) filtering. To this solution was added saturated HCl/EtOAc and a precipitate formed immediately. The solid was collected by filtration and then dried in vacuo to afford the title compound (a-2, 95 g) as a pink solid.
And step 3: [4- (pyridin-2-ylmethoxy) -phenyl ] -hydrazine dihydrochloride
[00372]A-2(95 g) was dissolved in water (1L) at 0 ℃ and NaNO was added thereto2(26 g)/water (100 ml). The diazonium salt is allowed to form at 0 ℃ over a period of 45 minutes and then slowly poured over a period of 15 minutes into rapidly stirring Na2S2O4(350 g)/water (1l) and ether (1 l). Stirring was continued for 40 minutes, and then the mixture was made basic using concentrated KOH. After extraction with EtOAc (× 2), the organic layer was washed with water then brine and dried (MgSO)4) And (4) filtering.To this solution was added saturated HCl/EtOAc and a precipitate formed immediately. The solid was collected by filtration and then dried in vacuo to afford the title compound (a-3, 75 g) as a brown solid.
And 4, step 4: 3- [ 3-tert-Butylthio-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00373]A-3(75 g), 5- (tert-butylsulfanyl) -2, 2-dimethyl-4-oxo-pentanoic acid ethyl ester (prepared as described in US patent 5,288,743, 2.22.1994; 64 g), NaOAc (40 g) were stirred in toluene (800 ml) and HOAc (400 ml) for 3 days at room temperature. The mixture was poured into water and washed with solid Na2CO3Rendering it alkaline. The mixture was extracted with EtOAc (× 3), then washed with water (× 2), brine, dried (MgSO) and concentrated 4) Filtered and concentrated to give a dark red black oil. The mother liquor was chromatographed using column chromatography (silica gel packed in hexane; elution with hexane, then hexane-EtOAc 9:1 rising to 4: 1) to give 68 g of the title compound (a-4) as a yellow solid.
And 5: 3- [ 3-tert-Butylthio-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00374]Under the atmosphere of N2, 3- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl]Ethyl-2, 2-dimethyl-propionate (a-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 ml) and cooled to-10 ℃. Sodium hydride (60% dispersion in mineral oil; 2.0 g, 50.0 mmol) was added in portions and the reaction stirred at-10 ℃ for 45 minutes until the foam disappeared. To the dark reddish-brown solution was added dropwise 4- (6-methoxy-pyridin-3-yl) -benzyl methanesulfonate (intermediate-72; 16.0 g, 54.5 mmol) in DMF. The reaction was then stirred at-10 ℃ for 1 hour and slowly warmed to room temperature. After 16 h, LCMS confirmed the product formation. Reacting with saturated NH4The Cl was quenched and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. With MgSO 4Drying the combined organic layers, filtering, concentrating, and purifying the crude product by column chromatographyTo obtain the desired product (A-5).
Step 6: 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid
[00375]A-5(21.5 g, 33.7 mmol) was dissolved in THF (100 ml) and MeOH (100 ml) and stirred until a clear solution was obtained. 3N aqueous LiOH (56 ml, 168.5 mmol) was added and the reaction was refluxed at 80 ℃ for 2 hours. LCMS confirmed the product formation and the reaction was cooled to rt and partitioned between EtOAc and water. The pH of the aqueous solution was adjusted to 1 with 10% HCl and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating to obtain the required free acid (A-6).
Scheme B:
example 2: preparation of Compound 3-1, Compound 3-2 and Compound 3-3
[00376] Compound 3-1, compound 3-2 and compound 3-3 were prepared as outlined in scheme B. A detailed illustrative example of the reaction conditions shown in scheme B describes the synthesis of 1- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol.
Step 1: 4-tert-Butylthio-3-oxo-butyric acid ethyl ester
[00377] Ethyl 4-chloroacetoacetate (7.5 ml, 51.9 mmol), 2-methyl-2-propanethiol (5.6 ml, 49.7 mmol), triethylamine (10.8 ml, 77.4 mmol) and catalytic tetrabutylammonium bromide were dissolved in THF (250 ml) and stirred at room temperature overnight. Silica gel was added, the mixture was concentrated, and filtered through a silica gel plug to obtain the desired product (B-1), which was used without further purification.
Step 2: (3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl) -acetic acid ethyl ester
[00378]4-Methoxyphenylhydrazine hydrochloride (7.7 g, 44.1 mmol) and B-1(7.4 g, 33.9 mmol) were dissolved in 2-propanol (150 ml) and heated under reflux for 24 hours. The reaction mixture was concentrated and washed with EtOAc and saturated NaHCO3The aqueous solution was partitioned. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, MgSO4Dried, filtered and concentrated. The residue was purified on silica gel (0 to 30% EtOAc/hexanes) to provide the desired product (B-2).
And step 3: (3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl) -acetic acid ethyl ester
[00379]Aluminum chloride (7.5 g 56.0 mmol) was suspended in tert-butyl mercaptan (21 ml, 186.7 mmol) at 0 ℃. B-2(6.0 g, 18.7 mmol)/CH was added 2Cl2(21 ml) and the reaction was warmed to room temperature. After 2 hours, the reaction was complete as determined by TLC analysis, the solution was poured into ice and acidified with 10% aqueous HCl. The aqueous layer was extracted three times with EtOAc and the combined organics were extracted with MgSO4Drying, filtration and concentration gave the desired product (B-3).
And 4, step 4: 3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-ol
[00380]B-3(2.2 g, 7.0 mmol) was dissolved in THF (70 ml) and cooled to 0 ℃. Methyl magnesium chloride (3M; 14 ml, 42.0 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. To react with NH4Aqueous Cl was quenched and extracted with EtOAc. With MgSO4The combined organic layers were dried, filtered, concentrated, and purified on silica gel to give the desired product (B-4).
And 5: 1- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol
[00381]To a solution of B-4(0.18 g, 0.61 mmol) in DMF (6 mL) was added cesium carbonate (1.0 g, 3.1 mmol). In thatThe reaction was stirred at room temperature for 30 minutes, and then 2-chloromethyl pyridine hydrochloride (0.11 g, 0.67 mmol) and tetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, and the reaction was stirred at room temperature for an additional 16 hours. The reaction was partitioned between water and diethyl ether and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and MgSO 4Drying, filtering and concentrating. The residue was purified by silica gel to obtain the desired product (B-5).
Step 6: 1- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol
[00382]To a solution of B-5(0.05 g, 0.13 mmol) in DMF (3 mL) was added cesium carbonate (0.21 g, 0.65 mmol). The reaction was stirred at room temperature for 30 minutes, and then 1-chloro-4-chloromethylphenyl (0.03 g, 0.20 mmol) and tetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water and MgSO4Drying, filtration, concentration and purification on silica gel (EtOAc: hexane gradient) afforded the desired compound (B-6).
[00383] Mass spectrum data of compound 3-1, compound 3-2 and compound 3-3 are shown in tables 1-3.
Scheme C:
example 3: the following compounds were prepared: compound 1-1, compound 1-3, compound 1-4, compound 1-5, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-22, compound 1-59, compound 1-60, compound 1-63, and compound 3-6.
Compounds 1-1, compounds 1-3, compounds 1-4, compounds 1-5, compounds 1-11, compounds 1-12, compounds 1-13, compounds 1-14, compounds 1-22, compounds 1-59, compounds 1-60, compounds 1-63, and compounds 3-6 were prepared according to the forms set forth in scheme C. A detailed illustrative example of the reaction conditions shown in scheme C describes the synthesis of tert-butyl (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylate (compound 1-1).
Step 1: n- (4-chloro-benzyl) -N- (4-methoxy-phenyl) -hydrazine hydrochloride
[00384]4-Methoxyphenylhydrazine hydrochloride (10.0 g, 57.3 mmol), 4-chlorobenzyl chloride (9.2 g, 57.2 mmol), tetrabutylammonium bromide (3.7 g, 11.5 mmol) and diisopropylethylamine (20 ml, 115 mmol) in CH2Cl2The solution (250 ml) was stirred at room temperature for several days. The reaction mixture was diluted with water and the organic layer was MgSO4Dried, filtered and concentrated. The residue was taken up in toluene (200 ml) and diethyl ether (100 ml) at 0 ℃ and 1 equivalent of 4n hcl/dioxane was added. The mixture was stirred at room temperature for 2 hours and then evaporated to dryness to give the desired product (C-1; X ═ Cl) as a violet solid.
Step 2: 3- [1- (4-chloro-benzyl) -3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00385]C-1 (. about.16 g, 57.3 mmol), ethyl 5- (tert-butylsulfanyl) -2, 2-dimethyl-4-oxo-pentanoate (prepared as described in US patent 5,288,743, issued at 22.2.1994; 14.8 g, 57.3 mmol), NaOAc (5.2 g) were stirred in toluene (120 ml) and HOAc (66 ml) at room temperature in the dark for 5 days. The mixture was partitioned between EtOAc and water, the organic layer was then partitioned with solid NaHCO 3Stirred together, filtered and evaporated. The residue was purified on silica gel (0 to 55% CH)2Cl2Hexane), and the separated product was recrystallized from hexane to obtain the desired product (C-2; x ═ Cl).
And step 3: 3- [1- (4-chloro-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00386]Aluminum chloride (0.820 g,6.15 mmol) was suspended in tert-butylmercaptan (1.8 ml, 16 mmol) and cooled to 0 ℃. C-2(1.0 g, 2.0 mmol)/CH was added2Cl2(2.4 ml) and the reaction was warmed to room temperature. After 3 hours, the reaction was complete as determined by TLC analysis and the solution was taken up in CH2Cl2Diluted and washed with 10% ice-cooled aqueous HCl. The aqueous layer is replaced by CH2Cl2Extracting three times, and mixing the organic substances with MgSO4Dried, filtered and concentrated to give the desired product (C-3; X ═ Cl) as a colorless foam.
[00387] And 4, step 4: (S) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester
[00388]To 3- [1- (4-chloro-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]To a solution of ethyl (C-2, 2-dimethyl-propionate) (C-3; 0.5 g, 1.05 mmol) in DMF (2.5 mL) were added N-BOC- (S) -2- (toluene-4-sulfonyloxymethyl) pyrrolidine (0.39 g, 1.10 mmol) and Cs 2CO3(0.69 g, 2.1 mmol). The reaction was stirred at 45 ℃ for 2 hours, then catalyzed potassium iodide was added and the reaction was heated to 60 ℃ overnight. The reaction mixture was diluted with EtOAc, washed with water and Na2SO4Drying, filtering and concentrating. The residue was purified on silica gel (0 to 15% EtOAc/hexanes) to give the desired product (C-4; X ═ Cl).
And 5: (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester
[00389]The ester from step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 ml), THF (1 ml) and water (1 ml). Lithium hydroxide (0.6 g, 1.43 mmol) was added and the reaction was heated for 12 hours until no starting material was determined by TLC analysis. The reaction was diluted with water, acidified to pH5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating. Purification of the residue by silica gel(0 to 40% EtOAc/hexanes) to give the desired product (C-5; X ═ Cl).
[00390] Mass spectrum data of compound 1-1, compound 1-3, compound 1-4, compound 1-5, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-22, compound 1-59, compound 1-60, compound 1-63, and compound 3-6 are shown in tables 1-3.
[00391] Note that:
for compounds 1-11, after step 4, the dihydroimidazolyl group in the precursor was reacted with di-tert-butyl dicarbonate to give the BOC-dihydroimidazolyl group in the final product.
For compounds 3-6, i) after step 4, the ketone in the precursor was reduced with diisobutylaluminum hydride to give the alcohol in the final product, ii) without step 5.
Scheme D:
example 4: 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
Step 1: 3- { 3-tert-Butylthio-5-hydroxy-1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00392]Phenol (C-3, X ═ Br; 35.0 g, 67.5 mmol), bis (valeryl) diboron (Combi-Blocks; 25.0 g, 98.4 mmol) and KOAc (19.9 g, 209.1 mmol) from example 3, step 3 were dissolved in 1, 4-dioxane (350 ml) and treated with N2Degassing for 30 minutes. Adding PdCl2dppf (2.5 g, 3.1 mmol) with N2The reaction mixture was degassed for an additional 30 minutes. The reaction was heated at 85 ℃ overnight. The reaction mixture was partitioned between water and EtOAc and partitioned with EtOA c extracting the aqueous layer three times, washing the combined organic layers with water, brine, MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (15% EtOAc/hexanes) to provide the desired product (D-1, 33.5 g).
Step 2: 3- { 3-tert-Butylthio-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00393]D-1(25.34 g, 44.8 mmol), 5-bromo-2-methoxypyridine (Combi-blocks; 10.9 g, 70.3 mmol) and K are added2CO3(15.5 g, 112.1 mmol) was dissolved in DME (300 mL) and water (150 mL) and treated with N2Degassing for 30 minutes. Adding Pd (PPh)3)4(1.6 g, 1.4 mmol) with N2The reaction mixture was degassed for a further 15 minutes. The solution was heated to 80 ℃ overnight, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc 3 times and the combined organic layers were washed with water, brine, MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (0 to 8% EtOAc/hexanes) to provide the desired product (D-2, 23.7 g).
And step 3: 3- { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00394]To 3- { 3-tert-butylsulfanyl-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ]To a solution of (E) -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (D-2; 6.5 g, 11.9 mmol) in MeCN (75 mL) were added 2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol) and Cs2CO3(9.7 g, 29.8 mmol). The reaction was stirred at room temperature overnight, after which time LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc and the combined organic layers were MgSO4Drying, filtering and concentrating. The residue was purified on silica gel (0 to 25% EtOAc/hexanes) to provide the desired product (D-3, 7.6 g).
And 4, step 4: 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
[00395]D-3(6.58 g, 9.3 mmol) was dissolved in MeOH (36 ml), THF (75 ml) and water (36 ml). Lithium hydroxide (2.42 g, 57.7 mmol) was added and the reaction was heated at 60 ℃ for 6 hours until no starting material was determined by TLC analysis. The reaction was diluted with water, acidified to pH5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating. The residue was triturated with hexanes: EtOAc (9:1) overnight and filtered to give the desired product (D-4, 5.9 g).
Scheme E:
example 5: preparation of Compounds 2-10
[00396] Compounds 2-10 were prepared as shown in scheme E. A detailed illustrative example of the reaction conditions shown in scheme E describes the synthesis of 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid.
Step 1: 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00397]To 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]To a solution of ethyl (2, 2-dimethyl-propionate) (C-3; 0.25 g, 0.48 mmol) in DMF (2 ml) was added 2-chloromethyl-5-methyl-pyridine hydrochloride (0.13 g, 0.72 mmol), Cs2CO3(0.39 g, 1.21 mmol) and catalytic tetrabutylammonium iodide. The reaction was stirred at room temperature overnight, after which time LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc and the combined organic layers were MgSO4Drying, filtering and concentrating.The crude product was purified on silica gel (0 to 15% EtOAc/hexanes) to provide additional desired product (E-1, 0.30 g).
Step 2: 3- { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00398]E-1(0.06 g, 0.10 mmol), 2-methoxy-pyridine-5-boronic acid (0.02 g, 0.14 mmol) and K2CO3(0.03 g, 0.24 mmol) was dissolved in DME (1 mL) and water (0.5 mL) and treated with N2Degassing for 10 minutes. Adding Pd (PPh)3)4(0.01 g, 0.01 mmol) with N2The reaction mixture was degassed for a further 10 minutes. The solution was heated to 80 ℃ for 4 hours, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc 3 times and the combined organic layers were washed with water, brine, MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (0 to 50% EtOAc/hexanes) to provide the desired product (E-2).
And step 3: 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
[00399]E-2(0.22 g, 0.31 mmol) was dissolved in MeOH (0.1 ml), THF (0.1 ml) and water (0.1 ml). A1N aqueous solution of lithium hydroxide (0.1 mL) was added and the reaction heated at 60 ℃ for 4 hours until no starting material was observed by LCMS. The reaction was diluted with water and EtOAc, acidified to pH5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating to obtain the required product (F-4).
[00400] Mass spectral data for compounds 2-10 are shown in tables 1-3.
Scheme F:
example 6: preparation of Compound 2-1
[00401] Compound 2-1 was prepared as shown in scheme F. A detailed illustrative example of the reaction conditions shown in scheme F describes the synthesis of 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid.
Step 1: 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
[00402]To 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]To a solution of ethyl (C-3; 2.0 g, 3.9 mmol) 2, 2-dimethyl-propionate in MeCN (25 mL) was added 2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol) and Cs2CO3(2.5 g, 7.7 mmol). The reaction was stirred at room temperature overnight, after which time LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc and MgSO4The combined organic layers were dried, filtered, and concentrated. The residue was recrystallized from EtOAc: hexane to give the desired product (F-1, 1.9 g). The filtrate was concentrated and purified on silica gel (0 to 15% EtOAc in hexanes) to provide an additional 1 g of F-1.
Step 2: 3- { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl (dioxaborolan-2-yl)) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00403]In a sealed vessel, F-1(1.0 g, 1.5 mmol), bis (valeryl) diboron (Combi-Blocks; 1.1 g, 4.3 mmol) and KOAc (0.44 g, 4.5 mmol) were dissolved in 1, 4-dioxane (15 mL) and treated with N2Degassing for 10 minutes. Adding PdCl2dppf (0.13 g, 0.16 mmol) with N2The reaction mixture was degassed for a further 10 minutes. The vessel was sealed and the reaction was heated at 95 ℃ overnight. The reaction mixture was partitioned between water and EtOAc and partitioned with EtOAc extracting the aqueous layer three times, washing the combined organic layers with water, brine, MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (0 to 20% EtOAc/hexanes) to provide the desired product (F-2).
And step 3: 3- { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00404]F-2(0.25 g, 0.35 mmol), 2-bromo-6-methoxypyridine (0.09 g, 0.48 mmol) and K 2CO3(0.15 g, 1.05 mmol) was dissolved in DME (3.5 mL) and water (1.8 mL) and treated with N2Degassing for 10 minutes. Adding Pd (PPh)3)4(0.06 g, 0.05 mmol), with N2The reaction mixture was degassed for a further 10 minutes. The solution was heated to 85 ℃ for 4 hours, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc 3 times and the combined organic layers were washed with water, brine, MgSO4Drying, filtering and concentrating. The crude product was purified on silica gel (0 to 25% EtOAc/hexanes) to provide the desired product (F-3).
And 4, step 4: 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
[00405]F-3(0.22 g, 0.31 mmol) was dissolved in MeOH (1.5 ml), THF (3 ml) and water (1.5 ml). Lithium hydroxide (0.08 g, 1.9 mmol) was added and the reaction was heated at 60 ℃ for 3.5 hours until no starting material was determined by TLC analysis. The reaction was diluted with water, acidified to pH5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating to obtain the required product (F-4).
[00406] Mass spectrum data of compound 2-1 are shown in tables 1-3.
Scheme G:
example 6: the following compounds were prepared: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-43, compound 1-44, compound 1-45, compound, Compound 1-55, compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4, and compound 3-5.
[00407] As shown in scheme G, the following compounds were prepared: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-8, compound 1-9, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-43, compound 1-44, compound 1-45, compound, Compound 1-55, compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4, and compound 3-5. A detailed illustrative example of the reaction conditions shown in scheme G describes the synthesis of 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-5).
Step 1: 3- { 3-tert-Butylthio-5- [ (S) -1- (2, 3-dihydro-1H-indol-2-yl) methoxy ] -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00408]Reacting (S) -2- { 3-tert-butylsulfanyl-2- (2-ethoxycarbonyl-2-methyl-propyl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl]-1H-indol-5-yloxymethyl } -2, 3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.23 g, 0.30 mmol) in CH2Cl2(1.5 ml). TFA (1.5 ml) was added and the reaction was stirred at room temperature for 10 min until no starting material was determined by TLC analysis. The solution was concentrated in vacuo and the crude (G-1) was used without further purification.
Step 2: 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00409]Dissolving G-1(0.30 mmol) in CH2Cl2(1 ml). Diisopropylethylamine (0.5 ml) was added followed by acetic anhydride (33uL, 0.35 mmol) and the reaction stirred at room temperature until no starting material was observed by LCMS. By CH2Cl2Diluted with MeOH, concentrated, and redissolved in CH2Cl2In (1), washing with water and Na 2SO4Drying, filtering and concentrating. The residue was purified by silica gel to obtain the desired product (G-2).
And step 3: 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
[00410]G-2 (0.05G, 0.07 mmol) was dissolved in MeOH (0.5 ml), THF (0.5 ml) and water (0.5 ml). Lithium hydroxide (0.03 g, 0.7 mmol) was added and the reaction was heated at 60 ℃ for 6 hours until no starting material was determined by TLC analysis. The reaction was diluted with water, acidified to pH5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating. The residue was purified on silica gel to give the desired product (G-3).
[00411] Mass spectral data for the following compounds are shown in tables 1-3: compound 1-2, compound 1-6, compound 1-7, compound 1-8, compound 1-10, compound 1-15, compound 1-16, compound 1-17, compound 1-18, compound 1-19, compound 1-20, compound 1-21, compound 1-23, compound 1-24, compound 1-25, compound 1-42, compound 1-43, compound 1-44, compound 1-45, compound 1-46, compound 1-47, compound 1-48, compound 1-49, compound 1-50, compound 1-51, compound 1-52, compound 1-53, compound 1-54, compound 1-55, compound 1-23, compound 1-24, compound 1-17, compound 1-6, compound 1-8, compound 1-5, compound 1-15, compound 1-17, compound 1-18, compound 1-19, compound, Compound 1-56, compound 1-57, compound 1-58, compound 1-61, compound 1-62, compound 2-2, compound 2-3, compound 2-4, compound 2-5, compound 2-6, compound 2-7, compound 2-8, compound 2-9, compound 2-11, compound 3-4, and compound 3-5. NMR data of the compounds 1 to 9 are shown below.
[00412] Note that:
for compounds 1-9, i) only Steps 1 and 3, ii)1H NMR(CD3OD，400MHz)，d 7.13(d，1H)，7.09(m，3H)，6.81(m，3H)，5.49(s，2H)，4.35(m，1H)，4.05(dd，1H)，4.01(dd，1H)，3.36(m，1H)，2.76(app q，1H)，2.23(m，1H)，2.19-1.85(m’s，3H)，1.12(s，9H)，1.07(s，6H)。
For compounds 1-15, only steps 1 and 3 were performed.
For compounds 1-17, after step 2, the 3-tert-butylthio group in the precursor was oxidized with m-chloroperoxybenzoic acid to give 2-methylpropane-2-sulfonyl in the final product.
For compounds 1-23, only steps 1 and 3 were performed.
For compounds 1-25, after step 3, the 3-tert-butylthio group in the precursor was oxidized with m-chloroperoxybenzoic acid to give 2-methylpropane-2-sulfinyl group in the final product.
For compounds 1-62, only steps 1 and 3 were performed.
For compound 2-2, only steps 1 and 3 were performed.
For compounds 2-11, steps 2 and 3 were performed in reverse order.
For compounds 3-4, only steps 1 and 2 were performed.
For compounds 3-5, only steps 1 and 2 were performed.
Scheme H:
example 8: the following compounds were prepared: compound 1-26, compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1-31, compound 1-32, compound 1-33, compound 1-34, compound 1-35, compound 1-36, compound 1-37, compound 1-38, compound 1-39, compound 1-40, and compound 1-41.
[00413] As shown in scheme H, the following compounds were prepared: compound 1-26, compound 1-27, compound 1-28, compound 1-29, compound 1-30, compound 1-31, compound 1-32, compound 1-33, compound 1-34, compound 1-35, compound 1-36, compound 1-37, compound 1-38, compound 1-39, compound 1-40, and compound 1-41. A detailed illustrative example of the reaction conditions shown in scheme H describes the synthesis of 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid.
Step 1: 3- {5- (benzothiazol-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00414]Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH2Cl2(1 ml) and water (19) was added slowly at room temperatureuL, 1.0 mmol). The mixture was stirred for 5 minutes and then cooled to 0 ℃. Add 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl]-1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (0.12 g, 0.17 mmol) in CH2Cl2(1 ml) solution and the reaction stirred at room temperature for 2 hours. Once no starting material was observed by TLC, water was added and CH was used 2Cl2The mixture is extracted. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating. The residue was purified to give the desired product (H-1).
Step 2: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylcarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00415]To a solution of H-1(0.10 g, 0.17 mmol) in dichloroethane (5 mL) was added cyclobutanecarbonyl chloride (57uL, 0.50 mmol) and aluminum chloride (0.09 g, 0.66 mmol). Heating the reaction to N2The atmosphere was heated for 1.5 hours, then cooled to room temperature and quenched with saturated aqueous sodium potassium tartrate solution. The mixture was extracted with EtOAc and the combined organic layers were MgSO4The combined organic layers were dried, filtered, concentrated, and purified on silica gel to give the desired product (H-2).
And step 3: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
[00416]H-2(0.05 g, 0.08 mmol) was suspended in CH2Cl2In (1 ml) sodium borohydride (0.03 g, 0.8 mmol) in TFA and CH was added dropwise2Cl2(1 ml) solution. The mixture was stirred at room temperature for 4 hours, then quenched with water and basified with solid NaOH pellets. Subjecting the mixture to CH 2Cl2The combined organics were extracted and dried over MgSO4, filtered and concentrated. The residue was purified on silica gel to give the desired product (H-3).
And 4, step 4: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
[00417]H-3(0.03 g, 0.04 mmol) was dissolved in MeOH (0.5 ml) and THF (0.5 ml). Aqueous lithium hydroxide (1N, 0.5 ml) was added and the reaction was heated at 60 ℃ for 4 hours until no starting material was determined by LCMS. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water and MgSO4Drying, filtering and concentrating to obtain the required product (H-4).
[00418] Mass spectral data for the following compounds are shown in tables 1-3: compound 1-26, compound 1-27, compound 1-29, compound 1-30, compound 1-31, compound 1-32, compound 1-33, compound 1-34, compound 1-35, compound 1-36, compound 1-37, compound 1-38, compound 1-39, compound 1-40, and compound 1-41. NMR data of the compounds 1 to 28 are shown below.
[00419] Note that:
for compounds 1-27, only steps 1 and 4 were performed.
For compounds 1-28, i) only Steps 1 and 4, ii) were performed1H NMR (CDCl3, 300MHz, rotamers) d 7.18(m, 2H), 7.07(s, 1H), 7.07-6.94(m, 2H), 6.79-6.69(m, 3H), 6.34(m, 1H)5.29(m, 2H), 4.46-3.41 (m's, 7H), 2.93(m, 2H), 2.29-1.92(7H), 1.26(m, 6H).
For compounds 1-29, only steps 1, 2 and 4 were performed.
For compounds 1-30, only steps 1, 2 and 4 were performed.
For compounds 1-33, only steps 1, 2 and 4 were performed.
For compounds 1-34, only steps 1, 2 and 4 were performed.
For compounds 1-35, only steps 1, 2 and 4 were performed.
For compounds 1-36, only steps 1, 2 and 4 were performed.
For compounds 1-37, only steps 1, 2 and 4 were performed.
For compounds 1-38, only steps 1, 2 and 4 were performed.
Scheme I:
example 9: 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl ] -N- (2-hydroxy-ethyl) -2, 2-dimethyl-propionamide
Step 1: 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl ] -2, 2-dimethyl-propionyl chloride
[00420]To suspend in CH2Cl23- [ 3-tert-Butylthio-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl in (5 ml) ]-2, 2-dimethyl-propionic acid (prepared as described in US patent 5,081,138, published 14.1.1992; 0.25 g, 0.53 mmol) was added oxalyl chloride (48uL, 0.56 mmol) and a catalytic amount of DMF. The reaction was stirred at room temperature for 3 hours and then concentrated to give I-1, which was used without further purification.
Step 2: 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl ] -N- (2-hydroxy-ethyl) -2, 2-dimethyl-propionamide
[00421]To I-1(0.18 mmol) of CH2Cl2To the solution was added triethylamine (0.1 ml, 0.70 mmol) and aminoethanolamine (10uL, 0.19 mmol). The reaction was stirred at room temperature for 2 days, then concentrated and purified on silica gel (EtOAc: hexane gradient) to afford the desired product (I-2).
And step 3: 5- {4- [ 3-tert-butylsulfanyl-2- (2, 2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl ] -phenyl } - [1, 3, 4] oxadiazol-2-ylamine
[00422]To 4- [ 3-tert-butylsulfanyl-2- (2, 2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl]To a solution of benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 ml) was added C- (di-imidazol-1-yl) -methylidene amine (0.08 g, 0.50 mmol) and the reaction was heated at 85 ℃ for 3 hours. The mixture was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were MgSO 4Dried, filtered and concentrated. The residue was purified on silica gel (EtOAc: hexane gradient) to afford the desired product.
Example 10: FLAP binding assay
[00423]Non-limiting examples of such FLAP binding assays are as follows: packed (packed) human polymorphonuclear cell particles (1.8X 10)9Individual cells) (Biological speciality corporation) were resuspended, lysed, and 100,000g of membrane were prepared as described below (charles et al mol. pharmacol, 41, 873-. 100,000Xg of the particle membrane was resuspended in Tris-Tween assay buffer (100mM Tris HCl, pH 7.4, 140mM NaCl, 2mM EDTA, 0.5mM DTT, 5% glycerol, 0.05% Tween20) to give a protein concentration of 50-100 ug/mL. 10uL of the membrane suspension was added to a 96-well Millipore plate, 78L Tris-Tween buffer, 10L3HMK 886 or3H3- [5- (pyridin-2-ylmethoxy) -3-tert-butylsulfanyl-1-benzyl-indol-2-yl]-2, 2-dimethylpropionic acid (or125I MK591 derivative, Eggler et al, J. laboratory Compounds and radiopharmaceuticals, 1994, vXXXIV, 1147)) was added to 30,000cpm, 2L inhibitor and incubated at room temperature for 30 minutes. 100L of ice-cold wash buffer were added to the incubation mixture. The plates were then filtered and washed 3X with 200L ice-cold Tris-Tween buffer, the scintillation bottom sealed (scintillation dots), 100L of scintillant added, shaken for 15 minutes and then counted on a TopCount. Specific binding is defined as: in the presence of 10M MK886, total radioactive binding minus non-specific binding. Medicine for use Graphpad prism analysis of the titration curves (Graphpad prism and lysis) to determine IC 50.
Example 11: human blood LTB
4
Inhibition test
[00424]This human blood LTB4Non-limiting examples of inhibition assays are as follows:
blood was extracted from human volunteers into heparinized tubes and 125L aliquots were added to wells containing 2.5L 50% DMSO (excipient vehicle) or 2.5L drug/50% DMSO. The samples were incubated at 37 ℃ for 15 minutes. 2L of calcium ionophore A23817 (obtained from 50mM DMSO stock, diluted to 1.25mM in Hanks Balanced salt solution (Invitrogen) just before the assay) was added, the solutions mixed and incubated at 37 ℃ for 30 min. Samples were centrifuged at 1,000rpm (. about.200 Xg) for 10 minutes at 4 ℃, plasma removed, diluted 1:100, and analyzed for LTB using an ELISA (assay designs) assay4And (4) concentration. Achieving 50% inhibition of the excipient LTB was determined by logarithmic (log) nonlinear regression of% inhibition versus log drug concentration (Graphpad Prism)4The drug concentration (IC 50's).
Example 12: rat peritoneal inflammation and edema test
[00425] Non-limiting examples of such a rat peritoneal inflammation and edema test are as follows:
the in vivo efficacy of leukotriene biosynthesis inhibitors was evaluated using a rat model of peritoneal inflammation. Male Sprague-Dawley rats (weighing 200-. Compound (3 ml/kg in 0.5% methylcellulose excipient vehicle) was administered orally 2 to 4 hours prior to injection of zymosan. One to two hours after injection of zymosan, rats were euthanized with 10 ml phosphate buffered saline (P) BS) irrigation of the peritoneal cavity. The resulting liquid was centrifuged at 1,200rpm for 10 minutes. Vascular edema was evaluated by determining the amount of evans blue dye in the supernatant using a spectrophotometer (absorbance 610 nm). Determination of LTB in supernatants by ELISA4And the concentration of cysteinyl leukotrienes. By nonlinear regression (Graphpad Prism) of% inhibition versus log (log) of log drug concentration, it can be calculated that 50% inhibition of plasma leakage (evans blue dye) and inhibition of peritoneal LTB are achieved4And the drug concentration of cysteinyl leukotrienes.
Example 13: human leukocyte inhibition assay
[00426] Non-limiting examples of human leukocyte inhibition assays are as follows:
blood from human volunteers was drawn into heparinized tubes and equal volumes of 3% dextran, 0.9% normal saline were added. After sedimentation of the erythrocytes at 1000rpm, the remaining erythrocytes were subjected to hypotonic lysis (hypotonic lysis) and the leukocytes were sedimented. The particles were dosed at 1.25 x 105Cells/ml were resuspended and aliquoted into wells containing 2.5 μ L of 20% DMSO (excipient vehicle) or 2.5 μ L of drug/20% DMSO. The samples were incubated at 37 ℃ for 5 minutes. mu.L of calcium ionophore A23817 (from 50mM MSMSSO stock, diluted to 1.25mM in Hanks Balanced salt solution (Invitrogen) just before the assay) was added at 37 ℃ and the solutions were mixed and incubated for 30 min. Samples were centrifuged at 1,000rpm (. about.200 Xg) for 10 minutes at 4 ℃, plasma removed, diluted 1:4, and LTB determined using ELISA (assay designs) 4And (4) concentration. Achieving 50% inhibition of the excipient LTB was determined by nonlinear regression (Graphpad Prism) of% inhibition versus log (log) drug concentration4The drug concentration (IC 50's). The compounds provided in tables 1-4 have a measurement value of 1nM to 5. mu.M using this assay method.
Example 14: method for lavaging rat bronchoalveolar
[00427] Non-limiting examples of lavage assays for rat bronchoalveolar cells are as follows:
the efficacy of the leukotriene biosynthesis inhibitor in respiratory therapy target tissues was determined using a rat ionophore pore lung lavage model in respiratory therapy target tissues. Male Sprague-Dawley rats (weighing 200-300 g) were orally administered the compound (3 ml/kg in 0.5% methylcellulose excipient) 2 to 24 hours prior to lung lavage. At the appropriate time after compound administration, rats were placed in sealed plexiglass chambers and exposed to CO2For 1-2 minutes, or until respiration ceases. They are then removed and blood is obtained by cardiac puncture. Cervical dislocation was performed to ensure rats could not be deprived of CO2And (4) recovering. Next, the subject was placed in a supine position, the trachea was exposed by blunt dissection, and 7 ml of a bolus (bolus) in 7 ml of an ice-cold phosphate buffered saline solution (PBS containing 7% DMSO) (containing 20 μ g/ml a23187) was added dropwise using a 10 ml syringe equipped with a 20gauge blunt tip (20gauge blunt needle tip). After 3 minutes, the liquid was removed, mixed with an equal portion of ice-cold methanol and centrifuged at 10,000Xg for 10 minutes at 4 ℃. Determination of LTB in supernatants by EIA 4And the concentration of cysteinyl leukotrienes. Achieving 50% inhibition of lung LTB can be calculated by nonlinear regression (Graphpad Prism) of% inhibition versus log (log) drug concentration4And the drug concentration of cysteinyl leukotrienes.
Example 15: pharmaceutical composition
Example 15 a: parenteral compositions
[00428] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of any one of formula (E), formula (E-I) or formula (E-II) is dissolved in DMSO and then mixed with 10 ml of 0.9% sterile physiological saline. The mixture is incorporated into dosage unit forms suitable for administration by injection.
Example 15 b: oral composition
[00429] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of any one of formula (E), formula (E-I) or formula (E-II) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule suitable for oral administration.
Example 15 c: sublingual (hard lozenge) compositions
[00430] To prepare an orally delivered pharmaceutical composition, such as a hard candy lozenge, 100 mg of a compound of any one of formula (E), formula (E-I), or formula (E-II) is mixed with 420 mg of sugar powder, 1.6 ml of light corn syrup, 2.4 ml of distilled water, and 0.42 ml of peppermint extract. The mixture is gently mixed and poured into molds to form lozenges suitable for buccal administration.
Example 15 d: inhalation composition
[00431] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of any one of formula (E), formula (E-I) or formula (E-II) is mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% aqueous sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, suitable for administration by inhalation.
Example 15 e: rectal gel composition
[00432] To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of any one of formula (E), formula (E-I) or formula (E-II) is mixed with 2.5 g of methylcellulose (1500mPa), 100 mg of methyl paraben (methylparapen), 5 g of glycerol and 100 ml of purified water. The resulting gel mixture is then incorporated into a rectal delivery unit, such as a syringe suitable for rectal administration.
Example 15 f: topical gel compositions
[00433] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of any one of formula (E), formula (E-I), or formula (E-II) is mixed with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate, and 100 ml of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube suitable for topical administration.
Example 15 g: ophthalmic solution composition
[00434] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of any one of formula (E), formula (E-I), or formula (E-II) is mixed with 0.9 g NaCl in 100 ml purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye drop container suitable for ophthalmic administration.
[00435] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.
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| US73403005P | 2005-11-04 | 2005-11-04 | |
| US60/734,030 | 2005-11-04 | ||
| US74717406P | 2006-05-12 | 2006-05-12 | |
| US60/747,174 | 2006-05-12 | ||
| US82334406P | 2006-08-23 | 2006-08-23 | |
| US60/823,344 | 2006-08-23 | ||
| PCT/US2006/043095 WO2007056220A2 (en) | 2005-11-04 | 2006-11-03 | 5-lipoxygenase-activating protein (flap) inhibitors |
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| JPS60123485A (en) * | 1983-12-08 | 1985-07-02 | Yoshitomi Pharmaceut Ind Ltd | Indole-3-carboxamide derivative |
| US5081138A (en) * | 1986-12-17 | 1992-01-14 | Merck Frosst Canada, Inc. | 3-hetero-substituted-n-benzyl-indoles and prevention of leucotriene synthesis therewith |
| US5272145A (en) * | 1989-08-22 | 1993-12-21 | Merck Frosst Canada, Inc. | (Quinolin-2-ylmethoxy)indoles as inhibitors of the biosynthesis of leukotrienes |
| JP2661841B2 (en) * | 1992-07-23 | 1997-10-08 | ファイザー製薬株式会社 | Indoline derivatives |
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