WO2011005871A1 - 8-[6-carbonylamino-3-pyridyle] xanthines substituées en tant qu’antagonistes de l’adénosine a2b - Google Patents

8-[6-carbonylamino-3-pyridyle] xanthines substituées en tant qu’antagonistes de l’adénosine a2b Download PDF

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Publication number
WO2011005871A1
WO2011005871A1 PCT/US2010/041228 US2010041228W WO2011005871A1 WO 2011005871 A1 WO2011005871 A1 WO 2011005871A1 US 2010041228 W US2010041228 W US 2010041228W WO 2011005871 A1 WO2011005871 A1 WO 2011005871A1
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alkyl
aryl
cycloalkyl
independently selected
occurrence
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PCT/US2010/041228
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Guoquan Wang
Jayson M. Rieger
Robert D. Thompson
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Pgxhealth, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Adenosine activates four subtypes of G protein-coupled adenosine receptors (ARs), A ⁇ IA 2A I ⁇ IB I ⁇ 3 - Enprofylline (below) is another example of a xanthine that has been reported to block A 2B adenosine receptors and is used
  • Enprofylline has a reported K 1 value of 7 ⁇ M and is somewhat selective in binding to human A 2B ARs. (See Robeva, A. S., et al., Drug Dev. Res . 1996, 39, 243-252 and Linden, J., et al, MoI. Pharmacol. 1999, 56, 705-713).
  • a 2B ARs are expressed in some mast cells, such as the BR line of canine mastocytoma cells, which appear to be responsible for triggering acute Ca 2+ mobilization and degranulation.
  • a 2B ARs also trigger Ca 2+ mobilization, and participate in a delayed IL8 release from human HMC-I mast cells.
  • Other functions associated with the A 2B AR are the control of cell growth and gene expression, (See Neary, J., et al., Trends Neurosci. 1996, 19, 13-18) endothelial-dependent vasodilation (See Martin, P.L., et al, J. Pharmacol. Exp. Ther.
  • A can be a bond
  • X can be a heteroaromatic ring
  • M is a carbonyl- substituted carbon-based linker. Baraldi et al. does not describe any substituted 8- [6- carbonylamino-3-pyridyl]xanthines.
  • X can be a heteroarylene
  • Y can be an alkylene
  • Z can be an aryl or heteroaryl ring.
  • Kalla et al. does not describe any substituted 8-[6-carbonylamino-3- pyridyl] xanthines .
  • X can be a pyridyl and Z can be an amino group.
  • Wang et al. does not describe any substituted 8-[6-carbonylamino-3-pyridyl]xanthines.
  • substituted 8-[6-carbonylamino-3- pyridyl] xanthines or stereoisomers or pharmaceutically acceptable salts that act as antagonists of A 2B adenosine receptors are provided herein.
  • compositions are also provided herein, which include any one of the compounds described herein and a
  • therapeutic methods are provided herein for treating a pathological condition or symptom in a mammal, such as a human, wherein the activity, e.g., over- activity, of adenosine A 2B receptors is implicated in one or more symptoms of the pathology and antagonism (i.e., blocking) is desired to ameliorate such symptoms.
  • antagonism i.e., blocking
  • provided herein is the use of the compounds as described herein for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, which is associated with deleterious A 2B receptor activation or activity.
  • the present teachings provide compounds which act as
  • a 2B receptor modulators e.g., A 2B receptor antagonists, such as substituted 8-[6- carbonylamino-3-pyridyl]xanthines.
  • a 2B antagonist refers to an agent that antagonizes the
  • Adenosine A 2B receptor with a Ki of ⁇ l ⁇ M may also be cross reactive with other adenosine receptor subtypes (e.g., A 1 , A 2A , and A 3 ).
  • An A 2B antagonist may be selective for A 2B (e.g., at least 10, 50, or 100/1 over another adenosine receptor subtype).
  • the A 2B antagonist may activate other receptors with a greater or lesser affinity than the A 2B receptor.
  • R is selected from: H, C 1 - O alkyl, C 1 - O haloalkyl, C 3 - 5 alkenyl, and C 3 - 5 alkynyl;
  • R 1 and R 2 are independently selected from: H, C 1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C 1 - S alkoxy, C 3 _io cycloalkyl, (C 3 _io cycloalkyl)Ci_ 8 alkyl-, C 4-1O heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-, wherein R 1 and R 2 are independently substituted with 0-2
  • R la at each occurrence, is independently selected from: F, Cl, Br, I, Cr 6 alkyl,
  • R a is independently selected from: H, Cr 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)Crs alkyl-, C 4-10 heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)Crs alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)Crs alkyl-, wherein alkyl is optionally interrupted with 1-2
  • heteroatoms selected from O, S(O) P , and NR b ;
  • R b is independently selected from: H, Cr 6 alkyl, and benzyl;
  • R 4 and R 5 are independently selected from: H, C 1-8 alkyl, -C 1-8 alkyl-(CO 2 R 6 ), -C 1-8 alkyl-(CONR 7 R 8 ), C 3-8 alkenyl, C 3-8 alkynyl, C 3-10 cycloalkyl,
  • R 4 and R 5 is selected from: -((CH 2 W YV(CH 2 WX 1 ,
  • X 1 is independently selected from: OR 6 , -COR 6 , -CO 2 R 6 ,
  • Y at each occurrence, is independently selected from: O, S, SO, S(O) 2 , and
  • NR i 4 ⁇ R5 forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(0) p , and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, 0R a , SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-Cr 8 alkyl-, R 13 R 0 N-Cr 8 alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 6 is independently is selected from: H, C 1-8 alkyl, R a O-Ci_ 8 alkyl, R b R c N-Ci- 8 alkyl-, C 1 -S haloalkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)Ci- 8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 4-10 heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, Cs -1 O heteroaryl, and (Cs -10 heteroaryl)Crs alkyl-, wherein R 6 is substituted with 0-3 R 6a groups;
  • R 6a at each occurrence, is independently selected from: halo, cyano, nitro, - 0R a , -SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-C 1 -S alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 7 and R 8 are independently selected from: H, C 1 - S alkyl, R a O-C 1-8 alkyl, R b R c N-C 1-8 alkyl-, C 1 - S haloalkyl, C 3-10 cycloalkyl,
  • R 7a and R 8a are independently selected from: H, C 1 - S alkyl, R a O-C 1-8 alkyl, R b R c N-C 1-8 alkyl-, C 1 - S haloalkyl, C 3-10 cycloalkyl,
  • R 9 at each occurrence, is independently selected from: halo, cyano, nitro, -0R a , -SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-C 1 -S alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R c at each occurrence, is independently selected from H, C 1 - O alkyl, and benzyl; alternatively, NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;
  • a at each occurrence, is independently selected from of 0, 1, and 2;
  • p at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4;
  • R 4 or R 5 is (a) phenyl-(alkyl)o-i-,
  • R 4 or R 5 is other than an unsubstituted alkyl, alkenyl, or alkynyl
  • the pyridyl of group (b) is at least substituted at the 3 position by R 4a. ;
  • the alkyl group of (a), (b), or (c) is substituted with at least one R 4a ;
  • R 1 is cycloalkyl or (C 3-1 O cycloalkyl)Ci-8 alkyl-; or
  • R is selected from: H, C 1 - O alkyl, C 1 - O haloalkyl, C 3 - 5 alkenyl, and C 3 - 5 alkynyl;
  • R 1 is C 3 _ 8 cycloalkyl substituted with 0-2 R la ;
  • R is selected from: H, C 1-8 alkyl, C 3 _g alkenyl, C 3 _g alkynyl, C 1 - S alkoxy, C 3 _g cycloalkyl, (C 3-8 cycloalkyl)Ci-8 alkyl-, C 4-1 O heterocyclyl, (C 4-1 O heterocyclyl)Ci-8 alkyl- , C 6 -Io aryl, (C 6-10 aryl)C 1-8 alkyl-, Cs -10 heteroaryl, and (Cs -10 heteroaryl)Ci- 8 alkyl-, and is substituted with 0-2 R la ;
  • R la is independently selected from: F, Cl, Br, I, Cr 6 alkyl, C 2 -6 alkenyl, C 2 - 6 alkynyl, -(CH 2 ) a OR a , -(CH 2 ) a NR a R a , -(CH 2 ) a NHOH, -(CH 2 ) a NR a NR a R a , -(CH 2 ) a NO 2 , -(CH 2 ) a CN, -(CH 2 ) a CO 2 R a , -(CH 2 ) a C(O)R a ,
  • R a is independently selected from: H, C 1 -O alkyl, C 2 _6 alkenyl, C 2 -6 alkynyl, C 3-1 O cycloalkyl, (C 3-1 O cycloalkyl)Ci-8 alkyl-, C 4-1 O heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 8TyI)Cr 8 alkyl-, C 5-10 heteroaryl, and (C 5 _ lo heteroa ⁇ yl)Cr 8 alkyl-, wherein alkyl is optionally interrupted with 1-2
  • heteroatoms selected from O, S(O) P , and NR b ;
  • R b is independently selected from: H, C 1 - O alkyl, and benzyl;
  • R 4 and R 5 are independently selected from: H, C 1-8 alkyl, -Ci -8 alkyl-(CO 2 R 6 ), -C 1 - S alkyl-(CONR 7 R 8 ), C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, C 3 _ lo cycloalkyl,
  • one of R 4 and R 5 is selected from: -((CH 2 W Y) 9 -(CH 2 ) ⁇ -X 1 , -NR 7 R 8 , -COR 6 , -CO 2 R 6 , -CONR 7 R 8 , and -S(O) 2 NR 7 R 8 ;
  • X 1 is independently selected from: OR 6 , -COR 6 , -CO 2 R 6 , and -NR 7a R 8a ;
  • Y at each occurrence, is independently selected from: O, S, SO, S(O) 2 , and
  • NR i 4 ⁇ R5 forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(0) p , and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, 0R a , SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-C 1 -S alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 6 at each occurrence, is independently is selected from: H, C 1-8 alkyl, R a O-C 1-8 alkyl, R b R c N-C 1-8 alkyl-, C 1 -S haloalkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)Crs alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 4-10 heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)Crs alkyl-, wherein R 6 is substituted with 0-3 R 6a groups; R 6a , at each occurrence, is independently selected from: halo, cyano, nitro, - OR a , -SR a , C 6 -I 0 aryl, C 6- Io aryl-O-, HO-Cr 8 alkyl-, R
  • R 7 and R 8 are independently selected from: H, C 1 - S alkyl, RO-Ci-8 alkyl, R b R c N-Ci_ 8 alkyl-, C 1 -S haloalkyl, C 3-10 cycloalkyl,
  • R 7a and R 8a are independently selected from: H, C 1 - S alkyl, R a O-C 1-8 alkyl, R b R c N-C 1-8 alkyl-, C 1 -S haloalkyl, C 3-10 cycloalkyl,
  • R 9 at each occurrence, is independently selected from: halo, cyano, nitro, -OR a , -SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-C 1 -S alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R c at each occurrence, is independently selected from H, Cr 6 alkyl, and benzyl; alternatively, NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;
  • a at each occurrence, is independently selected from of 0, 1, and 2;
  • p at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4.
  • R is selected from: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 alkenyl, and C 3-5 alkynyl;
  • R 1 is selected from: H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 4-10 heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl- , C 6-1O aryl, (C 6-1O aryl)Ci_ 8 alkyl-, Cs -1O heteroaryl, and (Cs -1O heteroaryl)C 1-8 alkyl-, and is substituted with 0-2 R la ;
  • R 2 is C 3-8 cycloalkyl substituted with 0-2 R la ;
  • R la at each occurrence, is independently selected from: F, Cl, Br, I, C 1 - O alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) a OR a , -(CH 2 ) a NR a R a , -(CH 2 ) a NHOH,
  • R a is independently selected from: H, C 1 -O alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, C 3-1 O cycloalkyl, (C 3-1 O cycloalkyl)Cr8 alkyl-, C 4-1 O heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)Cr 8 alkyl-, C 5-10 heteroaryl, and (Cs -1 O heteroaryl)Ci-8 alkyl-, wherein alkyl is optionally interrupted with 1-2
  • heteroatoms selected from O, S(O) P , and NR b ;
  • R b is independently selected from: H, Cr 6 alkyl, and benzyl;
  • R 4 and R 5 are independently selected from: H, C 1-S alkyl, -C 1-S alkyl-(CO 2 R 6 ), -C 1-8 alkyl-(CONR 7 R 8 ), C 3-8 alkenyl, C 3-8 alkynyl, C 3-10 cycloalkyl,
  • one of R 4 and R 5 is selected from: -((CH 2 ) 2 - 4 - Y) q -(CH 2 ) 2-4 -X 1 , -NR 7 R 8 , -COR 6 , -CO 2 R 6 , -CONR 7 R 8 , and -S(O) 2 NR 7 R 8 ;
  • X 1 is independently selected from: OR 6 , -COR 6 , -CO 2 R 6 ,
  • Y at each occurrence, is independently selected from: O, S, SO, S(O) 2 , and
  • NR 4 R forms a 4-10 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-4 heteroatoms selected from O, S(O) P , and N, wherein the ring is substituted with 0-4 substituents independently selected from: halo, cyano, nitro, OR a , SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-Cr 8 alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ; R 6 , at each occurrence, is independently is selected from: H, C 1 - S alkyl, R a O-Ci_ 8 alkyl, R 13 R 0 N-C 1-8 alkyl-, Cr 8 haloalkyl
  • R 6a at each occurrence, is independently selected from: halo, cyano, nitro, - OR a , -SR a , C 6 -I 0 aryl, C 6 -I 0 aryl-O-, HO-Cr 8 alkyl-, R b R c N-Crs alkyl-, C 1 -S haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 7 and R 8 are independently selected from: H, C 1 - S alkyl, R a O-Ci- 8 alkyl, R b R c N-Ci- 8 alkyl-, C 1 - S haloalkyl, C 3 . lo cycloalkyl,
  • R 7a and R 8a are independently selected from: H, C 1 - S alkyl, R a O-C 1-8 alkyl, R b R c N-C 1-8 alkyl-, C 1 -S haloalkyl, C 3-10 cycloalkyl,
  • R 9 at each occurrence, is independently selected from: halo, cyano, nitro, -OR a , -SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-Cr 8 alkyl-, R b R c N-d- 8 alkyl-, Cr 8 haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R c at each occurrence, is independently selected from H, Cr 6 alkyl, and benzyl; alternatively, NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring;
  • a at each occurrence, is independently selected from of 0, 1, and 2;
  • p at each occurrence, is independently selected from 0, 1, and 2; and, q, at each occurrence, is independently selected from 1, 2, 3, and 4.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • Alkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 - O alkyl for example, includes C 1 , C 2 , C 3 , C 4 , C 5 , and Ce alkyl groups.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
  • alkenyl includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur in any stable point along the chain, such as ethenyl and propenyl.
  • C 2 _ 6 alkenyl includes C 2 , C 3 , C 4 , C 5 , and Ce alkenyl groups.
  • Alkynyl includes the specified number of hydrocarbon atoms in either straight or branched configuration with one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl.
  • C 2 _ 6 Alkynyl includes C 2 , C 3 , C 4 , C 5 , and Ce alkynyl groups.
  • Cycloalkyl includes the specified number of hydrocarbon atoms in a saturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3 _g cycloalkyl includes C 3 , C 4 , C 5 , C 6 , C 7 , and Cg cycloalkyl groups.
  • Cycloalkyl also include bicycloalkyl and tricycloalkyl, both of which include fused and bridged rings (e.g., norbornane and adamantane).
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Aryl refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 membered monocyclic, bicyclic, or tricyclic ring, wherein at least one ring, if more than one is present, is aromatic.
  • aryl include fluorenyl, phenyl, naphthyl, indanyl, and
  • Heteroaryl refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered, (unless the number of members is otherwise recited), monocyclic, bicyclic, or tricyclic heterocyclic ring that is aromatic, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heteroaryl is defined by the number of carbons atoms, then 1, 2, 3, or 4 of the listed carbon atoms are replaced by a heteroatom. If the heteroaryl group is bicyclic or tricyclic, then at least one of the two or three rings must contain a heteroatom, though both or all three may each contain one or more heteroatoms.
  • heteroaryl group is bicyclic or tricyclic, then only one of the rings must be aromatic.
  • the N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (e.g., S, S(O), S(O) 2 , and N-O).
  • the heteroaryl ring may be attached to its pendant group at any nitrogen or carbon atom that results in a stable structure.
  • the heteroaryl rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • heteroaryl examples include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3 ⁇ - ind
  • heterocyclyl refers to any stable 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered, (unless the number of members is otherwise recited), monocyclic, bicyclic, or tricyclic heterocyclic ring that is saturated or partially unsaturated, and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. If the heterocyclyl is defined by the number of carbons atoms, then from 1, 2, 3, or 4 of the listed carbon atoms are replaced by a heteroatom. If the heterocyclyl is bicyclic or tricyclic, then at least one of the two or three rings must contain a
  • the N group may be N, NH, or N-substituent, depending on the chosen ring and if substituents are recited.
  • the nitrogen and sulfur heteroatoms optionally may be oxidized (e.g., S, S(O), S(O) 2 , and N-O).
  • the heterocyclyl may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclyls described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • heterocyclyls include, but are not limited to,
  • R 4 is selected from:
  • R 4 is selected from:
  • R 5 is selected from: H, C 1-8 alkyl, -C 1-8 alkyl-(CO 2 R 6 ), -C 1-8 alkyl-(CONR 7 R 8 ),
  • NR 4 R forms a 5-6 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-3 heteroatoms selected from O, S(O) P , and N, wherein the ring is substituted with 0-3 substituents independently selected from: halo, cyano, nitro, OR a , SR a , C 6-10 aryl, C 6-10 aryl-O-, HO-Cr 8 alkyl-, R b R c N-Ci- 8 alkyl-, Cr 8 haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 4 is pyrimid-2-yl substituted with 0-2 R 4a , or (pyrimid-2- yl)Ci-8 alkyl- substituted with 0-2 R 4a ; and the alkyl group optionally interrupted with 0- 1 CO 2 , C(O)NR 7 , or C(O)NR 8 , then:
  • R is other than an unsubstituted alkyl, alkenyl, or alkynyl
  • R 1 is cycloalkyl or (C 3-10 cycloalkyl)Ci_g alkyl-; or
  • R 4 is selected from:
  • R 4 is selected from:
  • R 5 is selected from: H, Ci -4 alkyl, C 3-6 cycloalkyl, and
  • NR 4 R 5 forms a 5-6 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(O) P , and N, wherein the ring is substituted with 0-3 substituents independently selected from: halo, cyano, nitro, OR a , SR a , phenyl, phenyl-O-, HO-Cr 4 alkyl-, R b R c N-d- 4 alkyl-, C r4 haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ; [0035]
  • R 4 is selected from:
  • R 4 is selected from:
  • R 5 is selected from: H and C 1-4 alkyl
  • NR 4 R 5 forms a 5-6 membered heterocyclic ring selected from: pyrrolidyl, piperidyl, piperazinyl, morpholinyl, and thiomorpholinyl, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, OR a , SR a , phenyl, phenyl-O-, HO-Cr 4 alkyl-, R b R c N-C r4 alkyl-, C r2 haloalkyl, -NR b R c , -COR a , -CO 2 R a , and -CONR b R c .
  • R 4 is selected from: C 1 -S alkyl-, C 6-8 aryl,
  • Rx is selected from: hydrogen, C 1 -S alkyl-, C 6-8 aryl, (C 6-8 OTyI)C 1 - 8 alkyl-, C5-7 heteroaryl, (Cs -7 heteroaryl)Ci-8 alkyl-, C5-7 heterocyclyl,
  • Ry is selected from -CO 2 R a , and -CONR b R d ;
  • R a at each occurrence, is independently selected from: H, C 1 - O alkyl, C 2 _ 6 alkenyl, C 2 _6 alkynyl, C 3-1 O cycloalkyl, (C 3-1 O cycloalkyl)Cr8 alkyl-, C 4-1 O heterocyclyl, (C 4-10 heterocyclyl)C 1-8 alkyl-, C 6-1 O aryl, (C 6-10 aryl)Cr 8 alkyl-, C 5-1 O heteroaryl, and (Cs -1 O heteroaryl)Cr 8 alkyl-;
  • R b and R c at each occurrence, are independently selected from: H, C 1 - O alkyl, and benzyl, or NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring
  • R d is selected from - (CH 2 CH 2 O) I -4 H and -(CH 2 CH 2 O)I -4 (Ci-S alkyl);
  • R 4 is selected from:
  • Ci- 8 alkyl substituted with 1-2 R 4a Ci- 8 alkyl substituted with 1-2 R 4a ,
  • R a is independently selected from: H, Ci -6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-1 O cycloalkyl, (C 3-1 O cycloalkyl)Ci- 8 alkyl-, C 4-1 O heterocyclyl, (C 4 -I 0 heterocyclyl)Ci_ 8 alkyl-, C 6-10 aryl, (C 6-10 aryl)Ci- 8 alkyl-, C 5-10 heteroaryl, and (C 5 _io heteroaryl)Ci- 8 alkyl-;
  • R b and R c are independently selected from: H, Cr 6 alkyl, and benzyl, or NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring.
  • R 4 is selected from:
  • R 4 is selected from: C 4-1O heterocyclyl and
  • R 4 is selected from:
  • R 4a is H or halo.
  • R 4 is C 1-8 alkyl substituted with - COO(C 1-6 alkyl), -CO(NH 2 ).
  • R 4 is pyridyl substituted with - COO(C 1-6 alkyl) or -CO(NH 2 ).
  • R 4 is (C 6-10 aryl)Ci- 8 alkyl- substituted on alkyl with -COO(C 1-6 alkyl), -CONH 2 , -CONH(CH 2 CH 2 O) 1-4 H or - CONH(CH 2 CH 2 O) 1-4 (C 1 - S alkyl).
  • R 4 is aryl substituted with - COO(C 1-6 alkyl), pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl .
  • R is selected from: H, C 1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl.
  • NR 4 R 5 forms a 5-7 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(0) p , and N, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, -OH, -O(C 1-8 alkyl), -COOH and -CO 2 (C 1-8 alkyl).
  • R is selected from: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 alkenyl, and C 3-5 alkynyl. In some embodiments, R is selected from: H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, and i-butyl. In some embodiments, R is hydrogen.
  • R 1 is selected from: C 1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl and (C 3-8 cycloalkyl)Ci-8 alkyl-.
  • R 2 is selected from: C 1 - S alkyl, C 3 _g alkenyl, C 3 _g alkynyl, C 3 _s cycloalkyl and (C 3 _g alkyl-.
  • R 1 and R 2 are independently selected from: H, Cr 4 alkyl, C 3 - 4 alkenyl, C 3 - 4 alkynyl, C3-6 cycloalkyl, (C 3 - 6 cycloalkyl)Ci- 4 alkyl-, phenyl, (phenyl)Cr 4 alkyl-, and (Cr 4 alkoxyphenyl)Ci- 4 alkyl-.
  • R 1 and R 2 are independently selected from: H, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, cyclopropyl, cyclopropylmethyl, phenyl, phenethyl, benzyl, and (methoxyphenyl)ethyl.
  • R 1 is selected from n-propyl and cyclopropyl; and, R 2 is n-propyl.
  • R 6 at each occurrence, is independently is selected from: H, C 1-4 alkyl, R a O-Ci- 4 alkyl, R b R c N-C 1-4 alkyl-, Cr 2 haloalkyl, C 3-6 cycloalkyl,
  • R 6 is substituted with 0-2 R 6a groups
  • R 6a is independently selected from: halo, cyano, nitro, -
  • R 6 at each occurrence, is independently is selected from: H, methyl, ethyl, CF 3 , cyclopropyl, cyclopropylmethyl, phenyl, and benzyl, wherein R 6 is substituted with 0-2 R 6a groups; and,
  • R 6a at each occurrence, is independently selected from: Cl, F, cyano, OH, OCH 3 , phenyl, phenyl-O-, and CF 3 .
  • R 7 and R 8 are independently selected from: H, Cr 4 alkyl, R a O-C 1-4 alkyl, R b R c N-C 1-4 alkyl-, Cr 2 haloalkyl, C 3-6 cycloalkyl, (C 3 - 6 cycloalky ⁇ C ⁇ alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-4 alkyl-,
  • R 9 at each occurrence, is independently selected from: F, Cl, -CN, -OH, OC 1-4 alkyl, phenyl, phenoxy, HO-C r4 alkyl-, CF 3 , -NR b R c , -COR a , -CO 2 R a , and -CONR b R c ;
  • R 7 at each occurrence, is independently selected from: H, C r4 alkyl, R a O-C 1-4 alkyl, and ((CH 2 ) 2 O) q -(CH 2 ) 2 -OH; and,
  • R 8 at each occurrence, is independently selected from: H and Cr 4 alkyl.
  • R a at each occurrence, is independently selected from: H, methyl, ethyl, n-propyl, cyclopropyl, cyclopropylmethyl, phenyl, and benzyl; and,
  • R b is independently selected from: H, methyl, ethyl, n-propyl, and benzyl.
  • X 1 at each occurrence, is independently OR 6 ;
  • Y at each occurrence, is independently O.
  • the present teachings provide compounds of formula I:
  • R is selected from: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3 _ 5 alkenyl, and C 3 _ 5 alkynyl;
  • R 1 is selected from: C 1-8 alkyl, C 3 _8 alkenyl, C 3 _8 alkynyl, C 3 _8 cycloalkyl and (C 3-8 cycloalkyl)Ci- 8 alkyl-;
  • R is selected from: C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl and (C 3-8 cycloalkyl)Ci- 8 alkyl-;
  • R 4 is selected from:
  • R a is independently selected from: H, Cr 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Io cycloalkyl, (C 3 _io cycloalkyl)Ci-8 alkyl-, C 4 _io heterocyclyl, (C 4-I0 heterocyclyl)Ci_ 8 alkyl-, C 6-I0 aryl, (C 6-I0 aryl)Cr 8 alkyl-, C 5-I0 heteroaryl, and (C 5 -I 0 heteroaryl)Ci-8 alkyl-;
  • R b and R c are independently selected from: H, Cr 6 alkyl, and benzyl, or NR b R c forms a ring selected from pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, and thiomorpholinyl ring; and
  • R 5 is selected from: H, Ci -8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl;
  • R 5 forms a 5-7 membered heterocyclic ring, consisting of: the shown N atom, carbon atoms, and 0-2 heteroatoms selected from O, S(0) p , and N, wherein the ring is substituted with 0-2 substituents independently selected from: halo, cyano, nitro, -OH, -O(Ci. 8 alkyl), -COOH and -CO 2 (d -8 alkyl).
  • At least one of R 1 or R 2 is a C 3-8 cycloalkyl or a (C 3-8 cycloalkyl)Ci_ 8 alkyl-.
  • the C(O)NR 4 R group of formula I is selected from:
  • the compounds provided herein do not include the compounds of U.S. Publication No. 20030207879.
  • the present teachings are intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • the compounds provided herein are stable.
  • stable means that the compound is suitable for pharmaceutical use.
  • the present invention covers stable compound and thus avoids, unless otherwise specified, the following bond types: heteroatom-halogen, N-S, O-S, O-O, and S-S.
  • the imidazole ring of the compounds described herein may exist in tautomeric forms or as tautomers, and thus are also included within the scope of the present teachings.
  • the tautomeric isomers are represented as the structures (Ia) and (Ib):
  • R, R 1 , R 2 , X, and Z are as defined herein.
  • R, R 1 , R 2 , X, and Z are as defined herein.
  • composition comprising: a therapeutically effective amount of any one of the compounds described hereinand a pharmaceutically acceptable excipient.
  • Examples of the molecular weight of compounds described herein can include (a) less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 grams per mole; (b) less than about 950 grams per mole; (c) less than about 850 grams per mole, and, (d) less than about 750 grams per mole.
  • the compounds described herein may have a chiral center and may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present teachings are intended to encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein; it being known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optic ally- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine therapeutic activity using the standard tests described herein or using other similar tests which are known in the art.
  • kits for treating a pathological condition or symptom in a mammal wherein the activity, e.g., overactivity, of adenosine A 2B receptors is implicated in one or more symptoms of the pathology and antagonism (i.e., blocking) of its action is desired.
  • the methods include administering to a mammal in need thereof a therapeutically effective amount of any one of the compounds described herein.
  • kits for treating a disease or condition include administering a therapeutically effective amount of at least one of the compounds described herein to a mammal in need thereof.
  • the disease or condition can be, for example, asthma, allergies, allergic diseases ⁇ e.g., allergic rhinitis and sinusitis), autoimmune diseases ⁇ e.g., lupus), diarrheal diseases, insulin resistance, diabetes ⁇ e.g., Type I and Type II), prevention of mast cell degranulation associated with ischemia/reperfusion injuries, heart attack, inhibition of angiogenesis in neoplastic tissues, and inhibition of angiogenesis in diabetic retinopathy or hyperbaric oxygen-induced retinopathy.
  • provided herein are compounds as described hereinfor the manufacture of a medicament useful for the treatment of a disease in a mammal.
  • mammals include warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, and bovine and (b) human.
  • treating or “treatment” of a mammal or subject includes the administration of a compound or composition to a mammal or subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder.
  • Treatment includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease- state, e.g., arresting its development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such
  • amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,
  • the "salt" of the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; salts with an organic acid such as acetic acid, fumalic acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl
  • the pharmaceutically acceptable salts of the present teachings can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p 1445, the disclosure of which is hereby incorporated by reference.
  • Therapeutically effective amount includes an amount of a compound of the present invention that is effective when administered alone or in combination to an indication listed herein.
  • “Therapeutically effective amount” also includes an amount of the combination of compounds claimed that is effective to treat the desired indication.
  • the combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased effect, or some other beneficial effect of the combination compared with the individual components.
  • the methods described herein include administration of an additional therapeutic agent. Administration can be simultaneously or in any order.
  • the two or more agents can be administered as a single pharmaceutical composition or as separate compositions.
  • the administration of the compound described herein can be prior to the other agent(s), within minutes thereof, or up to about hours (e.g., 24 or 48) after the administration of the other agent(s).
  • the compounds described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical, inhalation or subcutaneous routes.
  • a mammalian host such as a human patient
  • routes of administration e.g., orally or parenterally
  • intravenous, intramuscular, topical, inhalation or subcutaneous routes e.g., orally or parenterally
  • Exemplary pharmaceutical compositions are disclosed in "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable excipient such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable excipient such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, buffers or sodium chloride are included.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the methods of preparation included vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a
  • dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid
  • compositions can be applied from absorbent pads, used to impregnate bandages and other dressings or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of the present invention to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the
  • the concentration of the compound(s) of the present invention in a liquid composition will be from (a) about 0.1-25 wt% and (b) about 0.5-10 wt%.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be (a) about 0.1-5 wt% and (b) about 0.5-2.5 wt%.
  • the amount of the compound or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from (a) about 1.0-100 mg/kg of body weight per day, (b) about 10-75 mg/kg of body weight per day, and (c) about 5-20 mg per kilogram body weight per day.
  • the compound can be conveniently administered in unit dosage form; e.g., tablets, caplets, etc., containing (a) about 4-400 mg, (b) about 10-200 mg, and (c) about 20-100 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from (a) about 0.02-20 ⁇ M, (b) about 0.1-10 ⁇ M, and (c) about 0.5-5 ⁇ M. These concentrations may be achieved, for example, by the intravenous injection of a 0.005-0.5% solution of the active ingredient, or orally administered as a bolus containing about 4-400 mg of the active ingredient.
  • the compounds described herein can also be administered by inhalation from an inhaler, insufflator, atomizer or pressurized pack or other means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a value to deliver a metered amount.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the rat A 2B receptor cDNA was subcloned into the expression plasmid pDoubleTrouble using techniques described in Robeva, A. et al., Biochem. Pharmacol.,
  • the plasmid was amplified in competent JM 109 cells and plasmid
  • a 2B adenosine receptors were introduced into HEK-293 cells by means of Lipofectin as described in Feigner, P. L. et al, Proc. Natl. Acad. ScL USA, 84, 7413-7417 (1987).
  • Transfected HEK cells were grown under 5% CO 2 /95% O 2 humidified atmosphere at a temperature of 37 °C. Colonies were selected by growth of cells in 0.6 mg/mL G418. Transfected cells were maintained in DMEM supplemented with Hams
  • F12 nutrient mixture (1/1), 10% newborn calf serum, 2 mM glutamine and containing 50
  • AtA 2B receptors Confluent monolayers of HEK-A 2B cells were washed with PBS followed by ice cold Buffer A (10 niM HEPES, 10 mM EDTA, pH 7.4) with protease inhibitors (10 ⁇ g/mL benzamidine, 100 ⁇ M phenylmethanesulfonyl fluoride, and 2 ⁇ g/mL of each aprotinin, pepstatin and leupeptin).
  • Buffer A 10 niM HEPES, 10 mM EDTA, pH 7.4
  • protease inhibitors 10 ⁇ g/mL benzamidine, 100 ⁇ M phenylmethanesulfonyl fluoride, and 2 ⁇ g/mL of each aprotinin, pepstatin and leupeptin.
  • the cells were homogenized in a Polytron (Brinkmann) for 20 s, centrifuged at 30,000 x g, and the pellets washed twice with buffer HE (10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors). The final pellet was resuspended in buffer HE, supplemented with 10% sucrose and frozen in aliquots at -80 °C.
  • buffer HE 10 mM HEPES, 1 mM EDTA, pH 7.4 with protease inhibitors
  • the final pellet was resuspended in buffer HE, supplemented with 10% sucrose and frozen in aliquots at -80 °C.
  • membranes were thawed and diluted 5-10 fold with HE to a final protein concentration of approximately 1 mg/mL. To determine protein concentrations, membranes, and bovine serum albumin standards were dissolved in 0.2% NaOH/0.01% SDS and protein determined using fluorescamine fluorescence. Sto
  • Membranes were filtered on Whatman GF/C filters using a Brandel cell harvester (Gaithersburg, MD) and washed 3 times over 15-20 seconds with ice cold buffer (10 mM Tris, 1 mM MgCl 2 , pH 7.4).
  • B max and K D values were calculated by Marquardt's nonlinear least squares interpolation for single a site binding models. Marquardt, D. M., J. Soc. Indust. Appl. Math., U, 431-441.21 (1963). K 1 values for different compounds were derived from IC 50 values as described. Linden, J., J. Cycl. Nucl. Res., 8, 163-172 (1982). Data from replicate experiments are tabulated as means ⁇ SEM.
  • Pharmacol Exp. Therap. 251, 888-893 (1989). (Dupont NEN, Boston, MA) to A 2A receptors from rat striatal membranes was performed as described.
  • Adenosine deaminase (3 units/mL) was present during the preparation of the brain membranes, in a pre-incubation of 30 min at 30 °C, and during the incubation with the radioligands. All non-radioactive compounds were initially dissolved in DMSO, and diluted with buffer to the final concentration, where the amount of DMSO never exceeded 2%. Incubations were terminated by rapid filtration over Whatman GF/B filters, using a Brandell cell harvester (Brandell, Gaithersburg, MD). The tubes were rinsed three times with 3 mL buffer each.
  • HEK- A 2B cells from one confluent T75 flask were rinsed with Ca 2+ and Mg 2+ -free Dulbecco's phosphate buffered saline (PBS) and then incubated in Ca 2+ and Mg 2+ -free HBSS with 0.05% trypsin and 0.53 mM EDTA until the cells detached.
  • PBS Dulbecco's phosphate buffered saline
  • the cells were rinsed twice by centrifugation at 250 x g in PBS and resuspended in 10 niL of HBSS composed of 137 niM NaCl, 5 niM KCl, 0.9 niM MgSO 4 , 1.4 niM CaCl 2 , 3 niM NaHCO 3 , 0.6 niM Na 2 HPO 4 , 0.4 niM KH 3 PO 4 , 5.6 niM glucose, and 10 rnM HEPES, pH 7.4 and the Ca 2+ -sensitive fluorescent dye indo-1-AM (5 ⁇ M) 37 °C for 60 min.
  • the cells were rinsed once and resuspended in 25 rnL dye- free HBSS supplemented with 1 U/ml adenosine deaminase and held at room temperature.
  • Adenosine receptor antagonists prepared as IOOX stocks in DMSO or vehicle was added and the cells and transferred to a 37 °C bath for 2 minutes. Then the cells (1 million in 2 ml) were transferred to a stirred cuvette maintained at 37 °C within an Aminco SLM 8000 spectrofluorometer (SML instruments, Urbana IL). The ratios of indo-1 fluorescence obtained at 400 and 485 nm (excitation, 332 nm) was recorded using a slit width of 4 nm. NECA was added after a 100 s equilibration period.
  • Cyclic AMP generation was performed in DMEM/HEPES buffer (DMEM containing 50 mM HEPES, pH 7.4, 37 °C). Each well of cells was washed twice with DMEM/HEPES buffer, and then 100 ⁇ L adenosine deaminase (final concentration 10 IU/mL) and 100 ⁇ L of solutions of rolipram and cilostamide (each at a final
  • the filters were additionally rinsed with 4 times 2 mL 150 mM K 2 HPO 4 /10 mM EDTA (pH 7.5, 4 °C). Punched filters were counted in Packard Emulsifier Safe scintillation fluid after 2 hours of extraction.
  • Each antagonist was assayed at 3 concentrations (1OnM, 3OnM and 100 nM) and each concentration was tested in triplicate.
  • the EC50 for NECA in this assay was typically around 7OnM.
  • Endpoint fluorescence data were managed using Microsoft Excel software. Two readings were obtained prior to and 30 minutes after NECA stimulation. The ratios of the two readings (F30/F0) were plotted versus NECA concentration and a curve was fit with a four parameter logistic equation using PRISM 5TM (GraphPad Software, San Diego, CA). The best- fit values for the "bottom" and "top” of the NECA dose-response curve were used to normalize the raw data.
  • HEK cells human embryonic kidney cells
  • ZM 241385 4-(2-[7-amino-2- ⁇ furyl ⁇ l,2,4 ⁇ triazolo ⁇ 2,3- a ⁇ 1,3,5 ⁇ triazin-5-ylaminoethyl)phenol
  • Electro-spray-ionization (ESI) mass spectrometry was performed with a
  • ThermoFinnigan LCQ mass spectrometer ThermoFinnigan LCQ mass spectrometer.
  • 3A 5-(2,3,6,7-tetrahvdro-2,6-dioxo-l,3-dipropyl-lH-purin-8- yl)pyridine-2-carboxylic acid :
  • Selected compound 4 (compound 4 with a methyl ester group) (0.25 mmol) was suspended in IN LiOH (5 mL) and the mixture was stirred at room temperature until all of the solid disappeared (about 25 min). The mixture was neutralized with 1 N HCl and the solid was filtered, washed with cold water. The jelly- like solid was suspended in methanol and most of the methanol was evaporated. The solid was filtered and dried under vacuum to give product 5. The product was used in the next step without further purification.
  • 5A (R ⁇ -fS- ⁇ -cvclopropyl ⁇ . ⁇ J-tetrahvdro ⁇ . ⁇ -dioxo-S-propyl-lH- purin-8-yl)pyridine-2-carboxamido)-3-phenylpropanoic acid:

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Abstract

La présente invention a pour objet des 8-[6-carbonylamino-3-pyridyle] xanthines substituées de formule (I) et des compositions pharmaceutiques qui sont des antagonistes sélectifs des récepteurs de l’adénosine A2B (AR) et leurs stéréo-isomères et leurs sels pharmaceutiquement acceptables.
PCT/US2010/041228 2009-07-07 2010-07-07 8-[6-carbonylamino-3-pyridyle] xanthines substituées en tant qu’antagonistes de l’adénosine a2b WO2011005871A1 (fr)

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WO2016159745A1 (fr) * 2015-03-27 2016-10-06 Latvian Institute Of Organic Synthesis Ethynylxanthines, leurs préparations et leurs utilisations pour traiter le cancer
WO2017106352A1 (fr) 2015-12-14 2017-06-22 Raze Therapeutics, Inc. Inhibiteurs de caféine de mthfd2 et leurs utilisations
EP3280417A4 (fr) * 2015-04-08 2019-01-23 Lewis and Clark Pharmaceuticals, Inc. Carbamates d'alcynyle substitués par xanthine/carbamates inverses utilisés en tant qu'antagonistes d'a2b
WO2021018172A1 (fr) 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
WO2021018173A1 (fr) 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
WO2022246392A1 (fr) * 2021-05-18 2022-11-24 Purnovate, Inc. Pyridyl xanthines contenant un amide cyclique utilisées en tant qu'antagonistes d'a2b

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016159745A1 (fr) * 2015-03-27 2016-10-06 Latvian Institute Of Organic Synthesis Ethynylxanthines, leurs préparations et leurs utilisations pour traiter le cancer
GB2553684A (en) * 2015-03-27 2018-03-14 Latvian Inst Organic Synthesis Ethynylxanthines, preparation and use for cancer treatment
GB2553684B (en) * 2015-03-27 2020-06-03 Latvian Inst Organic Synthesis Ethynylxanthines, preparation and use for cancer treatment
EP3280417A4 (fr) * 2015-04-08 2019-01-23 Lewis and Clark Pharmaceuticals, Inc. Carbamates d'alcynyle substitués par xanthine/carbamates inverses utilisés en tant qu'antagonistes d'a2b
CN107530349B (zh) * 2015-04-08 2021-01-08 路易斯和克拉克制药公司 作为a2b拮抗剂的黄嘌呤取代的炔基氨基甲酸酯/反式氨基甲酸酯
WO2017106352A1 (fr) 2015-12-14 2017-06-22 Raze Therapeutics, Inc. Inhibiteurs de caféine de mthfd2 et leurs utilisations
EP3389664A4 (fr) * 2015-12-14 2020-01-08 Raze Therapeutics Inc. Inhibiteurs de caféine de mthfd2 et leurs utilisations
US11370792B2 (en) 2015-12-14 2022-06-28 Raze Therapeutics, Inc. Caffeine inhibitors of MTHFD2 and uses thereof
WO2021018172A1 (fr) 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
WO2021018173A1 (fr) 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
WO2022246392A1 (fr) * 2021-05-18 2022-11-24 Purnovate, Inc. Pyridyl xanthines contenant un amide cyclique utilisées en tant qu'antagonistes d'a2b
US11814387B2 (en) 2021-05-18 2023-11-14 Adovate, Llc Cyclic amide-containing pyridyl xanthines as A2B antagonists

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