WO1999042455A1 - Agents antiviraux - Google Patents

Agents antiviraux Download PDF

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Publication number
WO1999042455A1
WO1999042455A1 PCT/US1999/002947 US9902947W WO9942455A1 WO 1999042455 A1 WO1999042455 A1 WO 1999042455A1 US 9902947 W US9902947 W US 9902947W WO 9942455 A1 WO9942455 A1 WO 9942455A1
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group
hydrogen
compound
formula
heteroalkyl
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PCT/US1999/002947
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English (en)
Inventor
John A. Flygare
Juan C. Jaen
Patrick C. Kearney
Julio C. Medina
Mohanram Sivaraja
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Tularik Inc.
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Priority to AU32892/99A priority Critical patent/AU3289299A/en
Publication of WO1999042455A1 publication Critical patent/WO1999042455A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/84—Naphthothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to biaryl compounds and, more particularly, to novel heteroaryl-substituted benzenes and compositions, their preparation and their use as antiviral agents, particularly against herpes simplex virus.
  • HSV Herpes Simplex Virus
  • Both HSV type 1 and 2 show a predilection for infection of the ecodermal tissues wherein the infections by the virus cause lesions in the skin, oral cavity, vagina, conjunctiva, and the nervous system. Left untreated, HSV infections can lead to blindness, neonatal deaths and encephalitis.
  • Man serves as the natural host for HSV type 1 and 2 infections whereby the virus is transmitted during close personal contact.
  • Initial or primary infections by HSV types 1 and 2 are contracted through breaks in the mucus membrane.
  • the virus In the healthy carrier the virus can be isolated in the tears, saliva, vaginal and other secretions, even during the absence of overt disease. From the mucus membrane, they are able to replicate and spread to the regional lymph nodes. Occasionally these viruses can infect cells of the haemopoietic system and cause viremia.
  • HSV infections One difficulty in treating HSV infections is due to the ability of the viruses to persist in a latent or quiescent form. When the primary infection subsides or recedes, the virus generally resides in a latent form in the sensory nerve ganglia that innervate the site of primary infection.
  • the determinative period of latency of the HSV virus is unknown, but can be affected by heat, cold, sunlight, hormonal and emotional disturbances, or by immunosuppressive agents, resulting generally in recurrent infection.
  • Treatment of HSV infections has largely been ineffective.
  • a number of strategies to stop the virus have been developed. Generally, the methods involve inhibiting a specific viral function such as adsorption, uncoating, transcription, protein synthesis, nucleic acid acid replication, maturation and release.
  • Acyclovir is currently the preferred medication to treat HSVl or HSV2 infections, due to its antiviral effect and low toxicity.
  • drug-resistant viruses are now limiting the use of this drug.
  • the present invention provides compounds having the formula:
  • R 1 represents hydrogen or lower alkyl, or when Y is C or contains a carbon atom at the position adjacent to the bond connecting the two aromatic rings, R 1 can be a linking group between the benzene ring and Y.
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen or lower alkyl.
  • the symbols R 2 , R 3 and R 4 are independently selected from hydrogen, alkyl, heteroalkyl, arylalkyl, arylheteroalkyl, halogen, -CN, -NO 2 , alkoxy, arylalkoxy,
  • R 17 and R 18 are independently selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, and arylheteroalkyl, or, taken together with the nitrogen atom to which each is attached form a 5-, 6-, or 7-membered ring which is optionally fused with one or two additional aromatic rings.
  • the symbol R 19 represents hydrogen or lower alkyl
  • the symbols R 20 and R 22 independently represent hydrogen, lower alkyl, aryl, arylalkyl and arylheteroalkyl.
  • R 21 is a divalent radical selected from the group consisting of alkylene and heteroalkylene.
  • R 5 represents a hydrogen, lower alkyl, aryl, arylalkyl or -N(R 23 )(R 24 ), wherein R 23 and R 24 are independently hydrogen, alkyl, heteroalkyl and arylalkyl, or taken together with the nitrogen atom to which each is attached form a 5-, 6-, or 7-membered ring.
  • R 3 is further limited to halogen, -CN, -NO 2 , -OR 17 and -N(R 17 )(R 18 ), wherein -N(R I7 )(R 18 ) is other than -NH-C(O)-R 25 or -NH-C(O)-N(R 26 )(R 27 ) in which R 25 , R 26 and R 27 are independently selected from straight or branched chain alkyl, heteroalkyl, arylalkyl and arylheteroalkyl.
  • the compounds of the present invention are useful in therapeutic as well as prophylactic and diagnostic applications.
  • the present invention provides compositions containing the above compounds in admixture with pharmaceutically acceptable excipients or diagnostically acceptable excipients.
  • the invention further provides methods of inhibiting or suppressing certain viruses, and methods of treating individuals infected with such viruses, particularly HSV.
  • the present invention also provides methods for prophylactic treatments to prevent the onset of viral infection in patients.
  • Figures 1 and 2 provide structures for compounds of formula I in which R 2 and R 3 represent a variety of substituents, including arylalkyl and arylheteroalkyl groups.
  • Figure 3 provides structures for compounds of formula I in which -X-Y- is varied to provide different amino-substituted heteroaryl groups attached to the benzene ring.
  • Figure 4 provides structures for compounds of formula I in which R 2 and/or
  • R 3 are electronegative substituents, and -X-Y- is varied to provide different amino-substituted heteroaryl groups attached to the benzene ring.
  • Figure 5 provides structures for compounds of formula I in which R 3 represents various arylheteroalkyl groups which exhibit conformational restriction due to the presence of an additional ring.
  • Figure 6 provides structures for compounds of formula I in which R 1 is linked to Y to form fused tricyclic structures.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi- radicals, having the number of carbon atoms designated (i.e. C r C 10 means one to ten carbons).
  • saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as “cycloalkyl” and “alkylene.”
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CILCIl j CH j CH ⁇ .
  • an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include -CH,-CH,-O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 ,
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkyl those radicals described in more detail below as “heteroalkylene” and “heterocycloalkyl.”
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH ⁇ CH j -S-CILCH-- and -CH,-S- CH 2 -CH,-NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini.
  • alkylene and heteroalkylene linking groups as well as all other linking groups described herein, no specific orientation of the linking group is implied.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo or halogen
  • substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • fluoroalkyl are meant to include monofluoroalkyl and polyfluoroalkyl.
  • aryl employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • the rings may each contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • the aryl groups that contain heteroatoms may be referred to as "heteroaryl" and can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,
  • arylalkyl and arylheteroalkyl are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, l-naphthyloxy-3-propyl, and the like).
  • arylalkyl and arylheteroalkyl groups will typically contain from 1 to 3 aryl moieties attached to the alkyl or heteroalkyl portion by a covalent bond or by fusing the ring to, for example, a cycloalkyl or heterocycloalkyl group.
  • a heteroatom can occupy the position at which the group is attached to the remainder of the molecule.
  • arylheteroalkyl is meant to include benzyloxy, 2-phenylethoxy, phenethylamine, and the like.
  • R', R" and R'" each independently refer to hydrogen, unsubstituted(C [ -C 8 )alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C,-C 4 )alkyl groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH,-, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) r , where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (C r C 6 )alkyl.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds descnbed herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or m a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammo, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those de ⁇ ved from inorganic acids like hydrochlonc, hydrobromic, nit ⁇ c, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphonc, dihydrogenphosphonc, sulfunc, monohydrogensulfunc, hydnodic, or phosphorous acids and the like, as well as the salts denved from relatively nontoxic organic acids like acetic, propionic, isobutync, oxalic, maleic, malonic, benzoic, succinic, subenc, fumanc, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citnc, tartanc, methanesulfonic, and the like.
  • salts of amino acids such as argmate and the like, and salts of organic acids like glucuronic or galactunonc acids and the like (see, for example, Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1917, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the vanous salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention
  • the present invention provides compounds which are m a prodrug form.
  • Prodrugs of the compounds descnbed herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula I
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment
  • prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the present invention provides compounds, compositions and methods for the inhibition or treatment of viral infections, particularly those due to the herpes family of viruses. Without intending to be bound by a theory, it is believed that the compounds of the present invention exert their effect by interfering with a herpes helicase-primase enzyme, thereby interfering with the rate-limiting process in herpesvirus DNA replication. In view of the the conservation of herpesvirus helicase-primase across the human herpesviruses, the compounds, compositions and methods of the present invention will be useful in treating (suppressing or inhibiting viral replication) the full spectrum of herpesviruses, including HSV, varicella zoster virus, and cytomegalovirus.
  • the present invention provides compounds which are represented by the formula:
  • the letter X represents S, O or N-R 10 , wherein R 10 is hydrogen or lower alkyl, and the letter Y represents either N or C-R 11 , wherein R 11 is hydrogen or lower
  • Y can be linked to R 1 to form an additional ring fused to each of the heterocyclic and benzene ring systems shown in formula I.
  • X is S, O, NH or N(CH 3 ). More preferably, X is S.
  • Y is CH or represents a carbon atom linked to R 1 .
  • R 1 represents hydrogen or lower alkyl, or when Y is C or contains a carbori atom at the position adjacent to the bond connecting the two aromatic rings, R 1 can be a linking group between the benzene ring and Y.
  • R 1 is hydrogen or a linking group attached to Y.
  • Preferred linking groups are -C(R 13 )(R 14 )- or -C(R 13 )(R 14 )-C(R 15 )(R 16 )-. More preferably, R 1 is hydrogen or -CH 2 CH 2 - linked to Y. In the most preferred embodiments, R 1 is hydrogen.
  • R 2 , R 3 and R 4 independently represent hydrogen, alkyl, heteroalkyl, arylalkyl, arylheteroalkyl, halogen, -CN, -NO 2 , alkoxy, arylalkoxy, -SO,N(R 17 )(R 18 ), -N(R 17 )(R 18 ), -OR 17 , or radicals of the formula:
  • R 17 and R 18 independently represent hydrogen, alkyl, heteroalkyl, aryl, arylakyl or arylheteroalkyl, or, taken together with the nitrogen atom to which each is attached form a 5-, 6-, or 7-membered ring which is optionally fused with one or two additional aromatic rings.
  • the symbol R 19 represents hydrogen or lower alkyl
  • the symbols R 20 and R 22 independently represent hydrogen, lower alkyl, aryl, arylalkyl and arylheteroalkyl.
  • R 21 is a divalent radical selected from the group consisting of alkylene and heteroalkylene.
  • R 2 is hydrogen and R 3 and R 4 are independently selected from hydrogen, -CF 3 , aryl-heteroalkyl, halogen, -NO 2 , -N(R 17 )(R 18 ), -SO 2 N(R 17 )(R 18 ), and radicals of the formula:
  • R 5 represents a hydrogen, lower alkyl, aryl, arylalkyl or -N(R 23 )(R 24 ), wherein R 23 and R 24 are independently hydrogen, alkyl, heteroalkyl and arylalkyl, or taken together with the nitrogen atom to which each is attached form a 5-, 6-, or 7-membered ring.
  • R 5 is -N(R 23 )(R 24 ), more preferably -NH j , -NH(CH 3 ) or -N(CH 3 ) 2 .
  • R 5 is -NH 2 .
  • R 3 will be further limited to halogen, -CN, -NO 2 , -OR 17 and -N(R 17 )(R 18 ), wherein -N(R 17 )(R 18 ) is other than -NH-C(O)-R 25 or
  • R 25 , R 26 and R 27 are independently selected from straight or branched chain alkyl, heteroalkyl, arylalkyl and aryl-heteroalkyl.
  • Figures 1-6 provide illustrations of selected compounds of the present invention.
  • Figure 1 illustrates compounds in which the benzene ring has one or two substituents (other than a 4-(2-aminothiazolyl) group).
  • One of the substituents is a bulky arylalkyl or arylheteroalkyl-containing groups which is attached at either the R 2 or R 3 positions of formula I.
  • the bulky group is attached to the benzene ring via either a -NH-, -O- or -SO 2 NH- linkage.
  • Figure 2 A similar group of embodiments is illustrated in Figure 2.
  • the benzene ring has at least one
  • FIG. 10 electronegative substituent (e.g., -CF 3 , -NO 2 , -Cl and -Br) and an arylalkyl or arylheteroalkyl- containing substituent (as described for the embodiments illustrated in Figure 1).
  • Figure 6 provides structures for compounds of formula I in which R 1 is linked to Y to form fused tricyclic structures.
  • the compounds of the present invention are useful in therapeutic as well as prophylactic and diagnostic applications. Still further, the compounds are useful in the development of additional therapeutic agents as standards in a variety of assay formats. Accordingly, the present invention provides compositions containing the above compounds and pharmaceutically acceptable excipients or diagnostically acceptable excipients.
  • the invention further provides methods of inhibiting or suppressing certain viruses, and methods of treating individuals infected with such viruses, particularly HSV. In addition to treatments for existing conditions, the present invention also provides methods for prophylactic treatments to prevent the onset of viral infection in patient
  • Scheme 1 provides a general outline for the synthesis of compounds in which X is S, O or N(CH 3 ) and Y is CH.
  • a bromo- or chloro-substituted benzene derivative (i, having additional substitutents selected from R 1 , R 2 , R 3 and R 4 ) is metallated with either magnesium or n BuLi, and treated with CO 2 (or diethyl carbonate) to form benzoic acid derivative ii, or ethyl acetate (or acetonitrile) to form acetophenone derivative iii.
  • the benzoic acid derivative ii can also be converted to acetophenone iii, upon treatment with methylmagnesium bromide or methyllithium.
  • the acetophenone derivative iii serves as the key intermediate for the preparation of the targets iv, v and vi.
  • Schemes 2 and 3 illustrate synthesis outlines for the preparation of pyrimidine- substituted benzene derivatives vii and x.
  • Conversion of ii to benzonitrile viii can be accomplished via Curtius rearrangement, oxidation of the resultant amino group to a diazonium salt (with, for example, HNO 2 ) and displacement of the diazonium group using CuCN.
  • a number of substituted benzonitriles are commercially available from vendors such as Aldrich Chemical
  • Scheme 4 illustrates the preparation of compounds of formula I having carbamoyl groups at the R 3 position. Briefly, these compounds can be prepared beginning with 2-amino-4-(4-nitrophenyl)thiazole (xi). Conversion of xi to xii can be accomplished by first protecting the 2-amino group (the phthalimido protecting group is illustrated, but other protected groups are useful as well, see for example, Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, New York, NY (1991)), and then reducing the nitro group to a primary amine using conventional methods (e.g., Fe/HCl).
  • 2-amino-4-(4-nitrophenyl)thiazole xii
  • Conversion of xi to xii can be accomplished by first protecting the 2-amino group (the phthalimido protecting group is illustrated, but other protected groups are useful as well, see for example, Greene and Wuts, Protective Groups
  • a suitable acylating agent e.g., l,3-diphenyl-2-propyl chloroformate
  • the compounds of the present invention can be evaluated for efficacy against a variety of viruses.
  • the compounds can be evaluated in a HSV primase gel assay as described in Tenney, et al, J. Biol. Chem. 270(16):9129-9136 (1995) or in assays described in commonly owned and co-pending application USSN 08/882,606 (filed June 25, 1997).
  • compositions ' Formulation and Administration of the Compounds
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds described herein can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% or 10% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active compoinent with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from about 2 mg to about 2000 mg, preferably about 5 mg to about 150 mg according to the particular application and the potency of the active component.
  • composition can, if desired, also contain other compatible therapeutic agents (e.g., other antiviral agents such as acyclovir, ganciclovir, foscarnet, famciclovir, valaciclovir and cidofovir).
  • other antiviral agents such as acyclovir, ganciclovir, foscarnet, famciclovir, valaciclovir and cidofovir.
  • the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.05 mg/kg to about 20 mg/kg daily.
  • a daily dose range of about 0.05 mg/kg to about 2 mg/kg is preferred, with a daily dose range of about 0.05 mg/kg to about 0J mg/kg being most preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the
  • the total daily dosage may be divided and administered in portions during the day, if desired.
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA).
  • ⁇ -NMR spectra were recorded on a Varian Gemini 400 MHz NMR spectrometer. Significant peaks are tabulated in the order: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constant(s) in Hertz.
  • Electron lonization (El) mass spectra were recorded on a Hewlett Packard 5989A mass spectrometer.
  • Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard 1100 MSD electrospray mass spectrometer using the HP 1100 HPLC for sample delivery. Normally the analyte was dissolved in methanol at OJmg/mL and 1 microliter was infused with the delivery solvent into the mass spectromter which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using 1:1 acetonitrile/water with 1% acetic acid as the delivery solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2mM NH 4 OAC in acetonitrile/water as delivery solvent.
  • the title compound was synthesized from commercially available 5-chloro-l- indanone in two steps.
  • the title compound was prepared from 6-chloro-l-tetralone in a manner similar to that described for 6-chloro-8H-indino[lJ-d]thiazol-2-amine (Example 1).
  • the starting material, 6-chloro-l-tetralone was prepared according to literature methods (see, Owton and Brunavs, Synth. Commun., 1991, 21, 981-987).
  • the title compound was obtained as a solid in 99% yield.
  • This example illustrates the preparation of 2-amino-4-(4-chloro- 3-nitrophenyl)thiazole.
  • This example illustrates the preparation of 2-amino-4-(2-iodophenyl)thiazole.
  • This example illustrates the preparation of 2-amino-4-(4-chlorophenyl)thiazole.
  • This example illustrates the preparation of 2-amino-4-(4-bromophenyl)thiazole.
  • This example illustrates the preparation of 2-amino-4-phenylthiazole.
  • This example illustrates the preparation of 2-amino-4-(3,4- dichlorophenyl)thiazole.
  • This example illustrates the preparation of 2-amino-4-(4-nitrophenyl)thiazole.

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Abstract

L'invention porte sur des composés, des compositions et procédés supprimant et traitant les infections virales, en particulier celles dues aux virus de la famille de l'herpès.
PCT/US1999/002947 1998-02-19 1999-02-10 Agents antiviraux WO1999042455A1 (fr)

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029399A1 (fr) * 1998-11-12 2000-05-25 Boehringer Ingelheim (Canada) Ltd. Composes antiherpes
WO2000051995A1 (fr) * 1999-02-26 2000-09-08 Aventis Pharma Deutschland Gmbh Systemes 2-amino-thiazole polycycliques, leur procede de production et medicaments contenant ces composes
WO2002006269A1 (fr) * 2000-07-19 2002-01-24 Merck Patent Gmbh Derives d'aminoacide cycliques
US6348477B1 (en) * 1995-12-29 2002-02-19 Boehringer Ingelheim(Canada) Ltd. Anti-herpesvirus compounds and methods for identifying, making and using same
WO2002020014A1 (fr) * 2000-09-07 2002-03-14 Bayer Aktiengesellschaft Inhibiteurs non competitifs de l'helicase-primase
WO2002030358A2 (fr) * 2000-10-11 2002-04-18 Tularik Inc. Modulation de fonction de ccr4
WO2002038554A1 (fr) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Derives amides
US6500817B1 (en) 1999-03-08 2002-12-31 Bayer Aktiengesellschaft Thiazolyl urea derivatives and their utilization as antiviral agents
WO2003095435A1 (fr) * 2002-05-09 2003-11-20 Yamanouchi Pharmaceutical Co., Ltd. Derives d'amides
US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
US6689888B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
EP1583530A1 (fr) * 2002-01-16 2005-10-12 University Of Virginia Patent Foundation Activateurs allosteriques 2-aminothiazoles des recepteurs de l'adenosine a1
WO2006080406A1 (fr) * 2005-01-28 2006-08-03 Taisho Pharmaceutical Co., Ltd. Composes tricycliques
US7105553B2 (en) 1999-12-23 2006-09-12 Bayer Aktiengesellschaft Thiazolyl amide derivatives
US7144903B2 (en) 2001-05-23 2006-12-05 Amgen Inc. CCR4 antagonists
US7157470B2 (en) 2002-05-06 2007-01-02 Bristol-Myers Squibb Company Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US7446117B2 (en) 2002-09-16 2008-11-04 Glaxo Group Limited Cox-2 inhibiting pyridine derivatives
JP2009506979A (ja) * 2005-09-02 2009-02-19 アステラス製薬株式会社 新規化合物
WO2009127669A2 (fr) * 2008-04-15 2009-10-22 Ludwig Institute For Cancer Research Ltd Inhibiteurs de l'ido et ses utilisations thérapeutiques
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7618990B2 (en) 2006-08-15 2009-11-17 Wyeth Oxazolidone derivatives as PR modulators
US7883713B2 (en) 2001-06-22 2011-02-08 Aicuris Gmbh & Co. Kg Topical application of thiazolyl amides
KR101157074B1 (ko) * 2003-08-08 2012-06-22 아스텔라스세이야쿠 가부시키가이샤 아미드 유도체
US20120214767A1 (en) * 2009-10-29 2012-08-23 Dhar T G Murali Tricyclic heterocyclic compounds
WO2014036443A2 (fr) * 2012-08-31 2014-03-06 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales
US8784887B2 (en) 2005-03-30 2014-07-22 Aicuris Gmbh & Co. Kg Pharmaceutical preparation of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide
US9278962B2 (en) 2011-04-22 2016-03-08 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9975857B2 (en) * 2008-04-04 2018-05-22 North Carolina State University Inhibition of bacterial biofilms with imidazole-phenyl derivatives
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
US10590094B2 (en) 2016-04-06 2020-03-17 Innovative Molecules Gmbh Aminothiazole derivatives useful as antiviral agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DICKER I. B., BLASECKI J. W., SEETHARAM S.: "HERPES SIMPLEX TYPE 1: LACZ RECOMBINANT VIRUSES. II. MICROTITER PLATE-BASED COLORIMETRIC ASSAYS FOR THE DISCOVERY OF NEW ANTIHERPESAGENTS AND THE POINTS AT WHICH SUCH AGENTS DISRUPT THE VIRAL REPLICATION CYCLE.", ANTIVIRAL RESEARCH, ELSEVIER BV, NL, vol. 28., 1 January 1995 (1995-01-01), NL, pages 213 - 224., XP002919738, ISSN: 0166-3542, DOI: 10.1016/0166-3542(95)00049-R *

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6348477B1 (en) * 1995-12-29 2002-02-19 Boehringer Ingelheim(Canada) Ltd. Anti-herpesvirus compounds and methods for identifying, making and using same
US6458959B1 (en) * 1995-12-29 2002-10-01 Boehringer Ingelheim Pharmaceuticals, Inc. Anti-herpesvirus compounds and methods for identifying, making and using same
WO2000029399A1 (fr) * 1998-11-12 2000-05-25 Boehringer Ingelheim (Canada) Ltd. Composes antiherpes
WO2000051995A1 (fr) * 1999-02-26 2000-09-08 Aventis Pharma Deutschland Gmbh Systemes 2-amino-thiazole polycycliques, leur procede de production et medicaments contenant ces composes
US6251922B1 (en) * 1999-02-26 2001-06-26 Aventis Pharma Deutschland Gmbh Polycyclic 2- aminothiazole systems, processes for their preparation and pharmaceuticals comprising these compounds
US6500817B1 (en) 1999-03-08 2002-12-31 Bayer Aktiengesellschaft Thiazolyl urea derivatives and their utilization as antiviral agents
US7105553B2 (en) 1999-12-23 2006-09-12 Bayer Aktiengesellschaft Thiazolyl amide derivatives
WO2002006269A1 (fr) * 2000-07-19 2002-01-24 Merck Patent Gmbh Derives d'aminoacide cycliques
WO2002020014A1 (fr) * 2000-09-07 2002-03-14 Bayer Aktiengesellschaft Inhibiteurs non competitifs de l'helicase-primase
WO2002030358A3 (fr) * 2000-10-11 2009-06-11 Tularik Inc Modulation de fonction de ccr4
WO2002030358A2 (fr) * 2000-10-11 2002-04-18 Tularik Inc. Modulation de fonction de ccr4
US7262204B2 (en) 2000-10-11 2007-08-28 Amgen Inc. Modulation of CCR4 function
US6951872B2 (en) 2000-11-06 2005-10-04 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
WO2002038554A1 (fr) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Derives amides
US7144903B2 (en) 2001-05-23 2006-12-05 Amgen Inc. CCR4 antagonists
US7883713B2 (en) 2001-06-22 2011-02-08 Aicuris Gmbh & Co. Kg Topical application of thiazolyl amides
EP1583530A1 (fr) * 2002-01-16 2005-10-12 University Of Virginia Patent Foundation Activateurs allosteriques 2-aminothiazoles des recepteurs de l'adenosine a1
US7485655B2 (en) 2002-01-16 2009-02-03 University Of Virginia Patent Foundation 2-Aminothiazole allosteric enhancers of A1 adenosine receptors
EP1583530A4 (fr) * 2002-01-16 2008-07-23 Univ Virginia Activateurs allosteriques 2-aminothiazoles des recepteurs de l'adenosine a1
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
US6919460B2 (en) 2002-02-27 2005-07-19 Pfizer Inc, Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6689888B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
US7524863B2 (en) 2002-05-06 2009-04-28 Bristol-Myers Squibb Company Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US7157470B2 (en) 2002-05-06 2007-01-02 Bristol-Myers Squibb Company Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
WO2003095435A1 (fr) * 2002-05-09 2003-11-20 Yamanouchi Pharmaceutical Co., Ltd. Derives d'amides
US7446117B2 (en) 2002-09-16 2008-11-04 Glaxo Group Limited Cox-2 inhibiting pyridine derivatives
KR101157074B1 (ko) * 2003-08-08 2012-06-22 아스텔라스세이야쿠 가부시키가이샤 아미드 유도체
WO2006080406A1 (fr) * 2005-01-28 2006-08-03 Taisho Pharmaceutical Co., Ltd. Composes tricycliques
US8784887B2 (en) 2005-03-30 2014-07-22 Aicuris Gmbh & Co. Kg Pharmaceutical preparation of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide
JP2009506979A (ja) * 2005-09-02 2009-02-19 アステラス製薬株式会社 新規化合物
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
US7618990B2 (en) 2006-08-15 2009-11-17 Wyeth Oxazolidone derivatives as PR modulators
US9975857B2 (en) * 2008-04-04 2018-05-22 North Carolina State University Inhibition of bacterial biofilms with imidazole-phenyl derivatives
WO2009127669A2 (fr) * 2008-04-15 2009-10-22 Ludwig Institute For Cancer Research Ltd Inhibiteurs de l'ido et ses utilisations thérapeutiques
WO2009127669A3 (fr) * 2008-04-15 2010-04-08 Ludwig Institute For Cancer Research Ltd Inhibiteurs de l'ido et ses utilisations thérapeutiques
US9216972B2 (en) * 2009-10-29 2015-12-22 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds
US20120214767A1 (en) * 2009-10-29 2012-08-23 Dhar T G Murali Tricyclic heterocyclic compounds
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9278962B2 (en) 2011-04-22 2016-03-08 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9511070B2 (en) 2012-08-31 2016-12-06 Novadrug, Llc Heterocyclyl carboxamides for treating viral diseases
WO2014036443A2 (fr) * 2012-08-31 2014-03-06 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales
WO2014036443A3 (fr) * 2012-08-31 2014-04-24 Novadrug, Llc Carboxamides hétérocyclyle pour le traitement de maladies virales
US10590094B2 (en) 2016-04-06 2020-03-17 Innovative Molecules Gmbh Aminothiazole derivatives useful as antiviral agents
EP3440063B1 (fr) 2016-04-06 2020-08-05 Innovative Molecules GmbH Dérivés aminothiazoles en tant qu'agents antiviraux
US11278534B2 (en) 2017-10-05 2022-03-22 Innovative Molecules GmbG Enantiomers of substituted thiazoles as antiviral compounds
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
EP4209491A1 (fr) 2017-10-05 2023-07-12 Innovative Molecules GmbH Enantiometres d'une serie de composes antiviraux

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