Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
  • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems

Definitions

• Extracellular nucleotides released by tissue and organs during stress or injury activate a class of cell-surface receptors (P2Rs) to boost the innate and adaptive immune responses (1-3).
• P2Rs cell-surface receptors
• This mechanism acts as a time-dependent component of the signaling purinome, along with the anti-inflammatory adenosine receptors (ARs, also termed PI receptors), to protect the organism in various challenged circumstances.
• the P2Yi 4 receptor (P2Y M R) responds to endogenous agonists uridine-5'-diphosphoglucose and uridine-5'- diphosphate to mediate inflammatory activity, in part by activating neutrophil motility (4-6).
• the P2Y M R belongs to the d-branch of rhodoposin-like G protein-coupled receptors (GPCRs).
• GPCRs rhodoposin-like G protein-coupled receptors
• Three subtypes of the P2YRs are preferentially coupled to inhibition of adenylate cyclase through guanine nucleotide inhibitory (Gi) protein: P2Y ML P2Y 13R and P2Y M R.
• GPCRs rhodoposin-like G protein-coupled receptors
• P2Y M R guanine nucleotide inhibitory
• Selective P2Y M R antagonists are sought as potential agents for treating asthma, sterile inflammation of the kidney, diabetes and neurodegeneration (7-12). However, only a few classes of antagonists are known, so there is a clear need for more diverse competitive P2Y I 4 R antagonists.
• Antagonists of the P2Y 14R were first reported by Black and colleagues (19), and of the two classes reported, naphthoic acids and pyrido[4,3-c/]pyrimidines, only the former appeared to be competitive antagonists. Thus, there is an unmet need for diverse competitive P2Y I4 R antagonists.
• R 1 is halo or trifluoromethyl
• R 2 is COOH, CN, CONH 2 , or
• A is selected from the group consisting of
• R 3 is at each occurrence H, C1-C10 alkyl, C3-C10 alkynyl, benzyl, C1-C6
• alkoxycarbonyl -CO(CH 2 ) 2 0) 0 (CH2) P Q, or -(CH2)q(CH2)20) 0 (CH 2 ) P Q
• Q is H, Ci-C 6 alkyl, or NR 28 R 29 , wherein R 27 and R 28 are independently H, C1-C6 alkyl, Ci-C 6
• R 4 and R 5 are each H or F, or a pharmacologically acceptable salt thereof.
• the invention also provides a compound of formula (II), (III), (IV), or (V):
• R 6 is selected from the group consisting of
• R 8 is selected from the group consisting of C1-C10
• R i 0 is halo or CF 3 ,
• R ] 1 is halo, OH, or Ci-C 6 alkoxy
• R 12 and R 1 3 are independently H or Ci-C 6 alkyl
• R 14 and R 1 5 are independently H or Ci-C 6 alkyl
• R 16 is H, C1-C10 alkyl, or C3-C10 alkynyl
• R 17 and R 18 are both H or both F
• n 1 to about 10
• X’ and Y’ are CH or N
• Z’ is N or CR 9 wherein R 9 is H or Ci-Cf, alkyl,
• the invention further provides a method for antagonizing a P2Y 1 1R receptor in a mammal in need thereof comprising to the mammal a compound of the invention or a pharmaceutically acceptable salt thereof.
• the invention additionally provides a method of treating or preventing an inflammatory condition in a mammal in need thereof comprising to the mammal a compound of the invention or a pharmaceutically acceptable salt thereof.
• FIGS. 1A-1D show the structures of synthetic piperidine-containing intermediates for preparation of compounds in accordance with embodiments of the invention.
• the invention provides a compound of formula (I):
• R 1 is halo or trifluoromethyl
• R 2 is COOH, CN, CONH2, or V A is selected from the group consisting of
• R 3 is at each occurrence H, C 1 -C 10 alkyl, C 3 -C 10 alkynyl, benzyl, C 1 -C 6
• alkoxycarbonyl -CO(CH 2 ) 2 O) 0 (CH 2 ) P Q, or -(CH 2 )q(CH 2 )20) o (CH2)pQ
• Q is H, C 1 -C 6 alkyl, or NR 28 R 29 , wherein R 27 and R 28 are independently H, C1-C6 alkyl, C1-C6
• alkylcarbonyl or CV , alkoxycarbonyl, and wherein R 4 and R 5 are each H or F,
• X, Y, and N are all CH.
• R 1 is trifluoromethyl.
• the compound is selected from the group consisting of:
• the invention provides a compound of formula (II), (III),
• R 6 is selected from the group consisting of
• R 8 is selected from the group consisting of C 1 -C 10 14
• R 10 is halo or CF3,
• R 1 1 is halo, OH, or Ci-C 6 alkoxy
• R 12 and R 13 are independently H or Ci-C 6 alkyl
• R 14 and R 15 are independently H or Ci-C 6 alkyl
• R 16 is H, C 1 -C 10 alkyl, or C 3 -C 10 alkynyl, and
• R 17 and R 18 are both H or both F
• n 1 to about 10
• X’ and Y’ are CH or N
• Z’ is N or CR 9 wherein R 9 is H or Ci-C 6 alkyl
• R 7 is COOH
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (II), R 6 is
• the compound is of formula (III), R 6 is are all C, and R 8 is CONH(CH 2 ) 3 NH 2 .
• the compound is of formula (IV), R 6 is [0025] In certain particular embodiments, the compound is of formula (II), R 6 is
• the compound is of formula (V), R 6 is
• alkyl means a straight-chain or branched alkyl substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms.
• substituents include methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl, isobutyl, /e;7-butyl, pentyl, isoamyl, hexyl, and the like.
• cycloalkyl means a cyclic alkyl substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 4 to about 6 carbon atoms.
• substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
• the cyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.
• heterocyclyl refers to a monocyclic or bicyclic 5- or 6-membered ring system containing one or more heteroatoms selected from the group consisting of O, N, S, and combinations thereof.
• the heterocyclyl group can be any suitable heterocyclyl group and can be an aliphatic heterocyclyl group, an aromatic heterocyclyl group, or a combination thereof.
• the heterocyclyl group can be a monocyclic heterocyclyl group or a bicyclic heterocyclyl group. Suitable heterocyclyl groups include morpholine, piperidine, tetrahydrofuryl, oxetanyl, pyrrolidinyl, and the like.
• Suitable bicyclic heterocyclyl groups include monocylic heterocyclyl rings fused to a C6-C10 aryl ring.
• the heterocyclyl group is a bicyclic heterocyclyl group, both ring systems can be aliphatic or aromatic, or one ring system can be aromatic and the other ring system can be aliphatic as in, for example, dihydrobenzofuran.
• the term“heteroaryl” refers to a monocyclic or bicyclic
• heteroaryl group is unsaturated and satisfies Hiickel ' s rule.
• suitable heteroaryl groups include furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-2-yl, 5- methyl- 1, 3, 4-oxadiazole, 3-methyl-l,2,4-oxadiazole, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl,
• the heterocyclyl or heteroaryl group is optionally substituted with 1, 2, 3, 4, or 5 substituents as recited herein such as with alkyl groups such as methyl groups, ethyl groups, and the like, halo groups such as chloro, or hydroxyl groups, with aryl groups such as phenyl groups, naphthyl groups and the like, wherein the aryl groups can be further substituted with, for example halo, dihaloalkyl, trihaloalkyl, nitro, hydroxy, alkoxy, aryloxy, amino, substituted amino, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, thio, alkylthio, arylthio, and the like, wherein the optional substituent can be present at any open position on the heterocyclyl or heteroaryl group, or with benzo groups, to form a group of, for example, benzofuran.
• substituents as recited herein
• halo or“halogen,” as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.
• aryl refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art, and the term“C6-C10 aryl” includes phenyl and naphthyl. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 p electrons, according to HuckeTs Rule.
• metal center refers to a compound typically consisting of two cyclopentadienyl anions (Cp, which is C Hy) bound to a metal center (M) in the oxidation state II, with the resulting general formula (CsH . ⁇ M.
• the metal center can be Ti, V, Nb, Mo, or Fe. In a preferred embodiment, the metal center is Fe(II).
• a range of the number of atoms in a structure is indicated (e.g., a C1-C12, Ci-Cs, Ci-C 6 , C1-C4, or C2-C12, C2-C8, C2-C6, C2-C4 alkyl, alkenyl, alkynyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
• a range of 1- 8 carbon atoms e.g., Ci-C 8
• 1-6 carbon atoms e.g., C1-C6
• 1-4 carbon atoms e.g., C1-C4
• 1-3 carbon atoms e.g., C1-C3
• 2-8 carbon atoms e.g., Ci-C
• any chemical group e.g., alkyl, alkylamino, etc.
• any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms,
• 6-10 carbon atoms e.g., C6-C10
• any chemical group e.g., aryl
• 6-10 carbon atoms 6-9 carbon atoms, 6-8 carbon atoms, 6-7 carbon atoms, 7-10 carbon atoms, 7-9 carbon atoms, 7-8 carbon atoms, 8-10 carbon atoms, and/or 8-9 carbon atoms, etc., as appropriate).
• the compound or salt of formula (I), formula (II), formula (III), formula (IV), or formula (V) can have at least one asymmetric carbon atom.
• the compound or salt can exist in the racemic form, in the form of its pure optical isomers, or in the form of a mixture wherein one isomer is enriched relative to the other.
• the inventive compounds when the inventive compounds have a single asymmetric carbon atom, the inventive compounds may exist as racemates, i.e., as mixtures of equal amounts of optical isomers, i.e., equal amounts of two enantiomers, or in the form of a single enantiomer.
• single enantiomer is intended to include a compound that comprises more than 50% of a single enantiomer (i.e., enantiomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure enantiomer).
• the compound or salt can therefore exist as a mixture of diastereomers or in the form of a single diastereomer.
• “single diastereomer” is intended to mean a compound that comprises more than 50% of a single diastereomer (i.e., diastereomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure diastereomer).
• FIGS. 1A-1D show the structures of examples of synthetic chiral piperidine-containing intermediates useful for preparation of compounds of formulas (I)-(V).
• phrases“pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, 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, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
• Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like.
• suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
• Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like.
• Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts.
• Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety include hydrochloride and hydrobromide salts.
• the compounds of the present invention containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.
• solvates refers to a molecular complex wherein the solvent molecule, such as the crystallizing solvent, is incorporated into the crystal lattice.
• the solvent incorporated in the solvate is water, the molecular complex is called a hydrate.
• Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.
• the compound or salt of formula (I) can have at least one asymmetric carbon atom.
• the compound or salt can exist in the racemic form, in the form of its pure optical isomers, or in the form of a mixture wherein one isomer is enriched relative to the other.
• the inventive compounds when the inventive compounds have a single asymmetric carbon atom, the inventive compounds may exist as racemates, i.e., as mixtures of equal amounts of optical isomers, i.e., equal amounts of two enantiomers, or in the form of a single enantiomer.
• single enantiomer is intended to include a compound that comprises more than 50% of a single enantiomer (i.e., enantiomeric excess up to 100% pure enantiomer).
• the compound or salt can therefore exist as a mixture of diastereomers or in the form of a single diastereomer.
• “single diastereomer” is intended to mean a compound that comprises more than 50% of a single diastereomer (i.e., diastereomeric excess to 100% pure diastereomer).
• the present invention further provides a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.
• the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount, e.g., a therapeutically effective amount, including a prophylactically effective amount, of one or more of the aforesaid compounds, or salts thereof, of the present invention.
• the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical
• compositions comprising the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
• compositions of the present invention are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
• the choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
• suitable formulations of the pharmaceutical composition of the present invention are merely exemplary and are in no way limiting.
• Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
• Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
• Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid,
• microcrystalline cellulose acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
• Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
• a flavor usually sucrose and acacia or tragacanth
• pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
• the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
• aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
• Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
• the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2, 2-dimethyl- 1,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecy
• surfactant such as a soap or a detergent
• suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or
• carboxymethylcellulose or emulsifying agents and other pharmaceutical adjuvants.
• Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
• Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
• suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
• the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
• HLB hydrophile-lipophile balance
• parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
• sterile liquid carrier for example, water
• Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
• the compounds of the present invention may be made into injectable
• Topical formulations including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the invention for application to skin.
• Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels.
• Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa.
• the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant.
• the carrier can be a liquid, solid or semi-solid.
• the composition is an aqueous solution.
• the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components.
• the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral.
• the liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules.
• the solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site.
• the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.
• the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
• the dose administered to a mammal, particularly, a human, in accordance with the present invention should be sufficient to effect the desired response.
• Such responses include reversal or prevention of the adverse effects of the disease for which treatment is desired or to elicit the desired benefit.
• dosage will depend upon a variety of factors, including the age, condition, and body weight of the human, as well as the source, particular type of the disease, and extent of the disease in the human.
• the size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
• Suitable doses and dosage regimens can be determined by conventional range finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound.
• the present inventive method typically will involve the administration of about 0.1 to about 300 mg of one or more of the compounds described above per kg body weight of the animal or mammal.
• dosages will be between 0.01 mg/kg and 250 mg/kg of the subject’s body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subject’s body weight.
• unit dosage forms can be formulated based upon the suitable ranges recited above and the subject’s body weight.
• the term“unit dosage form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.
• dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
• administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m 2 to about 50 mg/m 2 , such as from about 10 mg/m 2 to about 40 mg/m 2 per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day.
• unit dosage forms also can be calculated using a subject’s body surface area based on the suitable ranges recited above and the desired dosing schedule.
• the invention further provides a method for antagonizing a P2Y M R receptor in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound or salt of formulas (I)-(VI).
• the invention further provides a method for treating or preventing an inflammatory condition in a mammal I need thereof, comprising administering to the mammal an effective amount of a compound or salt of formulas (I)-(VI).
• the inflammatory condition is selected from the group consisting of asthma, cystic fibrosis, and sterile inflammation of the kidney.
• the invention further provides a compound or salt of formulas (I)-(VI) for use in antagonizing a P2Y M R receptor in a mammal in need thereof.
• the invention further provides a compound or salt of formulas (I)-(VI) for use in treating or preventing an inflammatory condition in a mammal I need thereof.
• the compound is for use in treating or preventing inflammatory condition selected from the group consisting of asthma, cystic fibrosis, and sterile inflammation of the kidney.
• Schemes 1A-1D, 2, 3A-3D, 4A-4C, and 5 depict exemplary syntheses of compound embodiments of the invention.
• IC 50 values were determined from the gathered data with the program GraphPad Prism version7.0.
• Mobile phase linear gradient solvent system, 5 mM tetrabutylammonium dihydrogen phosphate-CH3CN from 100:0 to 0:100 in 15 min; the flow rate was 0.5 mL/min. Peaks were detected by UV absorption with a diode array detector at 230, 254, and 280 nm. All derivatives tested for biological activity showed >95% purity by HPLC analysis (detection at 254 nm).
• Method B A solution of compound in trifluoroacetic acid:tetrahydrofuran (1 : 1 or 2:1) was stirred at room temperature. The solvent was evaporated with toluene under reduced pressure. The residue was purified by silica gel column chromatography
• reaction mixture was partitioned diethyl ether (10 mL) and water (5 mL), and the aqueous layer was extracted with diethyl ether (10 mL x 2). The combined organic layer was washed brine (5 mL), dried over MgSO.i, filtered and evaporated under reduced pressure.
• reaction mixture was partitioned diethyl ether (10 mL) and water (5 mL), and the aqueous layer was extracted with diethyl ether (10 mL x 2). The combined organic layer was washed brine (5 mL), dried over MgS0 4 , filtered and evaporated under reduced pressure.
• the results for compounds of formula (I) are set forth in Table 1.
• the results for compounds of formulas (II), (III), (IV), (V), and (VI) are set forth in Table 2.
• P2Y I4 R antagonists were tested in vivo in a protease-mediated mouse model of asthma and found to be effective in reducing the presence of eosinophils in the
• bronchoalveolar lavage fluid The animals were first sensitized with ovalbumin/Aspergillus oryzae extract on days 0 and 7. Antagonists were injected i.p. at a dose of 10 mg/kg, 30 minutes prior to an ovalbumin challenge at day 14.
• MRS4458 Compound 23, 40.3 ⁇ 11.0%
• PPTN Compound 1, 43.9 ⁇ l2.8%)

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• 2019
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